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Inside: Focus on Irish healthcare

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RCSI

Volume 4: Number 1. 2011 ISSN 2009-0838

smj Royal College of Surgeons in Ireland Student Medical Journal

Total artificial heart transplants: future or biding time?


RCSIsmjcontents Royal College of Surgeons in Ireland student medical journal

3 3

Editorial Director’s welcome

Executive Committee Director – Erik Vakil Vice Director – Alan Carew Chief Editor – Rowena Almeida Senior Editor – Anas Sarhan Junior Editor – Eoin Kelleher

RCSI prize

Peer review team Director – Neil Fennelly James Regan Emily Kuhlmann Ashley Freeman Paul Kinsella Rebecca Wolfe Jennifer Horgan Shane Crilly Shabbir Mewa Abir Zainal Munir Tarazi

Original articles

Staff writers Aideen Henry Aine Glennon Ankit Kapur Keith Pilson Rohini Boddu Geneva Weiglein Web designer Mary Ma RCSIsmj Bahrain Gurleen Bhatia Sameer Kassim

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RCSIsmj Ethics Challenge 2011/2012

RCSI Ethics Challenge 6

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16 21

RCSIsmj Ethics Challenge winner 2010

The influence of cytomegalovirus and Epstein-Barr virus serostatus on haemoglobin levels and erythropoietin-stimulating agent responsiveness in patients on the transplant list with stage 5 chronic kidney disease The prevalence of vitamin B12 deficiency in patients with type 2 diabetes mellitus on metformin The role of opioid receptors in mechanical and thermal pain

Case reports 28 31

Primary peritoneal carcinoma: an uncommon entity Ring-enhancing tumefactive multiple sclerosis

Review articles 35 39 46 53

Editors’ pick: Total artificial heart transplants: future or biding time? Subintimal angioplasty in critical limb ischaemia: a literature review Can magnesium sulphate provide neuroprotection in preterm infants? A literature review Cancer stem cell theory and emerging clinical application

Staff reviews Specialists team Education Officer – Eva Forman International Liaison – Naude du Plessis Public relations Director – Melisa Hamidon Lowla Al Obaid Shivraj Riar Neha Kapila Therese Boland Sponsors The Alumni Office and Louise Sherwin Professor Gerry McElvaney and the Department of Medicine

57 62 67 70 74 78

A practical approach to the physiotherapy assessment and treatment of conversion disorders Child’s play: an insight into paediatric physiotherapy in Ireland The surgical safety checklist eHealth: Ireland’s approach to medicine in the digital age Cultural competence: an overview of the health needs of the Irish Traveller community A review of abortion in Ireland

RCSI Bahrain 82

Visible and near-infrared absorption properties of blood from sickle cell patients and normal individuals

RCSI perspective 84 87

Physician-assisted suicide: the right to life or the right to death? The yin and yang of pharmaceutical companies

Th!nk Th nkMedia

Electives

The Malthouse, 537 NCR, Dublin 1. T: 01-856 1166 F: 01-856 1169 www.thinkmedia.ie Design: Tony Byrne, Tom Cullen and Ruth O’Sullivan Editorial: Ann-Marie Hardiman and Paul O’Grady

Abstracts

PROFESSIONAL PUBLISHING SERVICES

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96 97

A week in ‘Emergency’ The cost of living with and dying of AIDS in Tanzania

An investigation into the effects of anti-oxidants on platelet reactivity Hippocampal astrogliosis and neuronal cell loss in an experimental P10 neonatal model of mesial temporal lobe epilepsy

Please email comments to editorsmj@RCSI.ie or join our Facebook page and discuss journal articles. Submissions to submissionssmj@RCSI.ie Page 2 | Volume 4: Number 1. 2011


RCSIsmjeditorial Embracing change in Irish healthcare When written in Chinese, the word ‘crisis’ is composed of two characters. One represents danger and the other represents opportunity. John F. Kennedy (1917-1963) It has been an eventful year in Ireland, to say the least. The scale of the political and economic upheaval faced by the country has left the healthcare system facing new challenges. From politics to healthcare, now, more than ever before, we need to do things differently if we expect a change. With talk of existing systems collapsing, it would be productive for emerging doctors to instead recognise this time as an opportunity for complete participation and engagement with issues that influence the quality of healthcare that they will provide. One such opportunity for change is the willingness of the medical community to accept innovation. Undoubtedly medical innovation presents challenges, but why should that prevent us from pursuing it? Ankit Kapur addresses the eHealth infrastructure in Ireland and where it has placed itself in approaching medicine in the digital age (p. 70). Furthermore, William Johnson and Julian Davis acknowledge the latest advances in artificial hearts and cancer stem cells, respectively (pp. 35 and 53). On the physiotherapy front, Aideen Henry provides an in-depth look into the evolving role of the paediatric physiotherapist in Ireland (p. 62). This edition presents seemingly disparate articles that address a unifying message – we cannot let medicine in Ireland trail behind. Keith Pilson acknowledges the need for healthcare professionals in Ireland to assess their cultural competence and addresses this in the context of the Irish Traveller community (p. 74). Further, Rohini Boddu takes an impartial look at the long-standing abortion debate in Ireland, with recent events in the European Court of Human Rights that perhaps warrant a reflection on the existing legislation (p. 78).

Following the overwhelming response to our ethics challenge last year, we present the third instalment of the RCSIsmj Ethics Challenge to address the growing need for ethical reflection in medicine (p. 5). William Osler said that doctors should have a cool head and a kind heart and the same is true with medical ethics, says the ethicist Daniel Sokol. With this in mind, I would encourage students to attempt the Ethics Challenge in a bid to further their understanding of this minefield and to start thinking critically and logically. The RCSIsmj is a student-led initiative that was founded as a medium to promote student authorship and in turn foster the next generation of researchers and scientists. I would like to thank all our contributors and participants for giving us the opportunity to read and present their stellar work. This edition has witnessed unparalleled enthusiasm from students in medicine, physiotherapy and pharmacy. This reflects our fundamental need to inform and be informed. Finally, I hope that readers engage with the material presented in the following pages and form an educated opinion on the issues raised in this edition and those to follow. For better or for worse, our informed opinions and sharing of ideas have the capacity to influence the future of healthcare.

Rowena Almeida Chief Editor, RCSIsmj 2010/2011

Director’s welcome It is with great pleasure that I present Volume 4 of the RCSIsmj. The Irish perspective presented here perhaps could not have come at a better time. When the dust begins to settle from the current political turmoil, the future of Irish healthcare for the next generation of doctors and patients will begin to take shape. It is therefore never more relevant to think critically about the system in which we train today, so we can start building a better system for tomorrow. As I plan to pass the directorship of the RCSIsmj to my colleagues, I am aware of the exciting evolution that is starting to take place. Although we are still in our infancy, we are maturing at an inspiring pace. This year we have strengthened our relationship with RCSI Bahrain, redeveloped our website, created an

education arm to start training writers and editors, and have greatly increased our visibility and distribution. Even more exciting, however, is what the future holds, and I hope RCSI students will continue to engage with and be part of this evolution. In final I would like to extend the warmest thanks to all the RCSIsmj staff, authors and contributors. It has been a privilege to have worked with you and this production is a true testament to your dedication and commitment to excellence. Erik Vakil Director RCSIsmj 2010/2011

Volume 4: Number 1. 2011 | Page 3


RCSIsmjprize

Ethics Challenge 2011/2012 The case

Key issues to be addressed:

Two cousins raised in California’s rural Central Valley were both diagnosed with malignant melanoma after having spent most of their young adult lives working outdoors in the building trade. Both men were under 25 at the time of diagnosis and both had diseases with similar genetic profiles, specifically the mutant gene B-RAF. Together with stage IV disease, this mutation qualified them for enrolment in a Phase III trial comparing the efficacy of a new drug, PLX4032, with dacarbazine, the current standard of care. PLX4032 is produced by the Swiss pharmaceutical giant Roche and is a specific B-RAF inhibitor. Data from a recently completed Phase II trial demonstrated that PLX4032 halted tumour growth in 81% of patients for an average of eight months, compared to a dismal 15% of patients for an average of two months for dacarbazine. However, questions still remained as to whether PLX4032 actually increased survival since, when tumour growth did recommence, it was particularly aggressive in those having received PLX4032 compared with dacarbazine. Both men were ultimately enrolled in the trial but the younger of the two was randomised to the treatment arm and the other to the control arm. Both the older cousin and the oncologist looking after him were devastated at the news that he was not to receive the new drug. His oncologist was powerless except to prescribe dacarbazine, despite being convinced that this was not the best care for his patient, and after suffering nine agonising months as the cancer spread to his bones, the older cousin eventually passed away. Conversely, the younger cousin receiving PLX4032 had a dramatic improvement in quality of life as his tumour regressed rapidly within two months of starting PLX4032, and he remains alive today.

1. Identify the ethical issues involved in this case. Think about the trial itself, and the role of evidence-based medicine and of the physicians in implementing the trial protocol. 2. How would you address these ethical issues? 3. As the prescribing physician, discuss how you can or cannot justify enrolling these two cousins in this clinical trial. 4. Consider weaknesses in your position and address potential challenges to your arguments.

This is the third instalment of the RCSIsmj Ethics Challenge. The editorial staff would like to congratulate Alison DeMaio and Nathan Clendenen for their winning essay in the 2010 Challenge. Please see page 6 for their submission. Once again, we invite all students to submit an essay discussing the ethical questions raised in the case study presented here. Medical ethics is an essential aspect of the medical curriculum and we hope to encourage RCSI students to think critically about ethical situations that arise during their education and subsequent careers. All essays will be reviewed by a faculty panel of experts, and the winning essay will be published in the 2012 print edition of the RCSIsmj.

Submission guidelines Please construct a lucid, structured and well presented discourse for the issues raised by this case. Please ensure that you have addressed all the questions highlighted and discuss these ethical issues academically, making sure to reference when necessary. Your paper should not exceed 2,000 words. Your essay will be evaluated on three major criteria: 1. Ability to identify the ethical issues raised by the case. 2. Fluency of your arguments. 3. Academic quality with regard to depth of research, appropriateness of references and quality of sources. Good luck!

This is a perfect opportunity to be published and is the only officially guaranteed publication in the RCSIsmj. The deadline for submission of entries will be the same as the general submission deadline for the 2012 edition of the RCSIsmj. Please keep up to date by visiting our website at www.rcsismj.com. Any questions? Don’t hesitate to email us at editorsmj@rcsi.ie.

Volume 4: Number 1. 2011 | Page 5


RCSIsmjethics challenge RCSIsmj ETHICS CHALLENGE WINNER 2010

Can doctors say ‘enough’? Alison DeMaio,1 Nathan Clendenen1 1RCSI medical students

Introduction The RCSIsmj Ethics Challenge for 2010 presented a case of a woman with longstanding medical issues that ultimately resulted in her staying in the surgical ICU for four months, dependent on ventilator support, haemodialysis and total parenteral nutrition. Though her physicians felt that she had no hope of surviving outside of the hospital, the patient’s daughter continued to push for aggressive treatment.1 The aim of this article is to discuss the ethical issues highlighted by the case and to provide a course

of action for the patient that suitably addresses these issues. Where appropriate, counter-arguments are introduced to highlight the complexity of this case. Though the case occurs in New York, we have approached it largely from the perspective of healthcare in Ireland. However, the issues in the article are indeed universal and are worthy of discussion for medical professionals everywhere. When does life support begin to prolong death and suffering? How can a physician determine the limits of his duty of care? Should allocation of limited resources be considered by the physician when he is making his decision to withdraw life-sustaining treatment?

Definitions of core principles in medical ethics ■ Autonomy: the ability to deliberate and act upon personal goals, free from coercion. In relation to medical care, autonomy governs that a person may choose or refuse treatment; however, in cases of diminished mental capacity, patients are usually treated according to their best interests. ■ Beneficence: the duty of a physician to do that which promotes the well-being of the patient. ■ Non-maleficence: the obligation that a physician render no harm to his or her patient (primum non nocere). ■ Justice: equality in distribution of medical resources, including a physician’s time.2

Current guidelines for the transition to end-of-life care Although many attempts have been made, there are no formal guidelines regarding transition to palliative care that are accepted by the greater medical community. This is especially true in fields outside oncology, where patients are referred to palliative care once appropriate treatments are exhausted.3-5 In clinical practice, the decision is reached after careful consultation between the medical team, the patient (or their proxy) and the patient’s family. Page 6 | Volume 4: Number 1. 2011


RCSIsmjethics challenge The principles outlined by the American College of Surgeons for care at the end of life are as follows: ■ respect the dignity of both patient and caregivers; ■ be sensitive to and respectful of the patient and their family’s wishes; ■ use the most appropriate measures that are consistent with the choices of the patient or the patient’s legal surrogate; ■ ensure alleviation of pain and management of other physical symptoms; ■ provide access to therapies that may realistically be expected to improve the patient’s quality of life; ■ provide access to appropriate palliative care and hospice care; and, ■ recognise the physician’s responsibility to forego treatments that are futile.6

Ethical issues The key ethical issues illuminated by this case are as follows: ■ the patient’s autonomy and her right to refuse treatment; ■ the patient’s quality of life; ■ the physician’s dilemma of the balance of beneficence and non-maleficence; ■ the issue of medical futility; ■ the role of the daughter as surrogate medical decision maker; ■ the issue of justice and the allocation of limited resources; and, ■ physician duty of care and potential legal or ethical ramifications for refusing to continue treatment.

Patient autonomy Self-determination is a cornerstone of good medical care, and physicians have a duty to uphold patient autonomy. Their ability to do so is severely limited in cases where the patient’s ability to communicate is diminished. In this case, the patient is incapable of any sort of communication and left no directions for her care prior to falling ill, except for a vague statement to her daughter (“Don’t let anything happen to me”).1 This case underlines the importance of advanced directives and, more importantly, good communication between a physician and his patient. Discussing end-of-life care before the patient is too ill to do so has been shown to have positive results, including improved quality of life, less aggressive care, and families that are happier with their loved one’s care. Physicians may worry that discussing such topics may distress their patients, but this has not been shown to be the case.7,8 Preserving patient autonomy extends beyond explicit patient wishes, especially in cases where these cannot be known. This includes the duty of physicians to relieve pain and suffering, which is paramount to good care. If judged to be in the best interests of the patient, it is not considered unethical to withdraw life-sustaining treatments.9,10

Usual practice is that if a patient becomes incompetent, their family becomes their surrogate decision maker, if there is no advance directive instructing otherwise. A patient’s quality of life at the end of their life In order to adequately maintain a patient’s dignity and autonomy, their quality of life must be the primary concern of the physician. Quality of life is unique to each individual patient, and is defined by one’s interests and values.11 If these are not adequately known, the physician should make decisions on their medical care based on what they judge to be in the best interests of their patient.9,12 This becomes especially important in decisions about life-sustaining treatment, in which a physician must consider quality of life associated with survival, and also probability of survival.7 Maintaining quality of life is the aim of end-of-life (palliative) care. There comes a time when intensive care becomes a burden on the patient, and may even be seen as inhumane. Rather than preserving life, the extensive medical intervention may only prolong death. Thus, the interplay between beneficence and non-maleficence is disrupted; a physician can no longer claim that the benefit they are doing outweighs the harm endured by the patient.13 The patient in this case had no feasible possibility of recovering to a point where she could maintain life outside of the hospital, yet she continued to be subjected to treatments with their own complications. Not only was she continually septic, she had developed a deep sacral ulcer.1 Transitioning to end-of-life care would ensure the patient’s comfort and return her to a more acceptable quality of life, for however short a time. Furthermore, palliative care seeks to address issues the patient’s family members may have and aid in the bereavement process.14

Medical futility In the broadest meaning of the word, medical futility is the inappropriate use of medical intervention to treat patients who have no likelihood of benefit. In 1990, Schneiderman defined futility as treatment that has a less than 1% chance of benefiting the patient.15,16 Other definitions have been proposed since then in order to clarify the issue for physicians. Tan proposed that a futile intervention is one that cannot bring about an acceptable improvement to a patient’s quality of life.17 McConnell’s explanation of futility is more applicable to life-sustaining treatments, as one that maintains that a state of permanent unconsciousness or dependence on aggressive care may be declared futile.14,18 Gedge defines a specific type of futility – physiological futility – as those treatments that will not preserve a physiological function necessary to preserve life.19

Volume 4: Number 1. 2011 | Page 7


RCSIsmjethics challenge In this case, it is apparent that the patient’s treatment in the ICU may be deemed futile by any of the above definitions. Not only is it not benefiting her in any physiological way, the aggressive care has diminished her quality of life beyond an acceptable limit. Her physicians assert that there is no reasonable chance that she will recover to a point where she may live independent of hospital care. It can be argued that futility is a concept that is too difficult to define to be of clinical use and may be biased by the values of the physician. However, the American Medical Association has developed a fair unbiased process to determine futility and the subsequent withdrawal of futile interventions.20

Role of surrogate decision makers in end-of-life care While the decision to transition the patient to palliative care seems to be the obvious choice, this particular case is complicated by the demands of the patient’s daughter to continue with aggressive treatment. Usual practice is that if a patient becomes incompetent, their family becomes their surrogate decision maker, if there is no advance directive instructing otherwise. Communication between the surrogate and the physician is crucially important, and decisions should always be made based on what they believe the patient would have decided. The surrogate’s decisions are generally accepted as a rule, though there are exceptions that may require intervention: ■ no available family member is willing to become the surrogate decision maker; ■ there is disagreement among the family members; and, ■ a healthcare provider believes that the decision could not reasonably be judged to be in the patient’s best interests.9 Based on the principles of maintaining the patient’s autonomy and quality of life, in this case it is evident that the daughter is not acting in her mother’s best interests, despite honourable intentions.

End-of-life medical treatment poses especially difficult ethical questions for physicians. The burden of intervention is often high, benefits are insignificant, and patient quality of life often suffers. Justice and the allocation of limited resources A striking issue that presents itself in this case is the focus of enormous resources on one person, rather than many others who could benefit to an unknown extent. As of 2006, Ireland housed only 195 ICU beds and up to 30% of patients requiring admission to ICU are not granted access. Furthermore, the increased mortality on being denied ICU admission is astounding, such that for every

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five patients turned away, one patient died.13 Institutions have to carefully weigh issues of medical need when deciding which patients receive scarce medical resources. Criteria for making such a decision include likelihood of benefit, urgency of need, change in quality of life, and duration of benefit.21 In the case of this particular patient, continued aggressive treatment is highly unlikely to result in a positive outcome, and thus ICU resources would be better employed elsewhere. However, the unfair distribution of resources to one person in a seemingly futile case should not be a concern of the patient’s physician when making decisions about withdrawing life-sustaining treatments.7 The physician’s duty is the care of his patient, and thus decisions of allocation of resources should be out of his hands.21 Rather, the focus should be on the patient’s quality of life and what is in their best interest.11

Potential ethical and legal ramifications for withdrawing life-sustaining treatment Patient autonomy does have limits, and ends where the physician’s autonomy begins. Patients cannot compel their physician to act against their conscience, and they have a duty not to demand unrealistic treatment.22,23 Additionally, there is no ethical obligation that a physician deliver care that he believes has no possibility of benefiting his patient.24 Above all, the physician must concern himself with his patient’s best interests, even if that means discontinuing life-sustaining treatment and moving to end-of-life care. It can be difficult to know how far a physician’s duty of care extends, and it is important to assess each case on an individual basis. There is some precedence for these sorts of cases in the legal system in Ireland, which sheds light on the issue. For patients who are not wards of court, standard practice is that the physician consults with the patient’s family and from there makes decisions regarding their medical care. Though this practice has been questioned, the courts traditionally support physicians in their decision-making for incompetent patients.22,25

Conclusion End-of-life medical treatment poses especially difficult ethical questions for physicians. The burden of intervention is often high, benefits are insignificant, and patient quality of life often suffers.26,27 This case makes it evident that there is a need for clear guidelines to assist physicians when faced with dilemmas of life-sustaining treatment. In 2009, Bradley and Brasel proposed specific criteria that would refer patients in the surgical ICU on to a palliative care consult: ■ family request; ■ declaration of futility by the medical team; ■ family dispute with the medical team or the patient’s advanced directive, for more than seven days; ■ death expected during the same ICU stay; ■ ICU stay lasting more than one month; ■ a diagnosis with median survival for less than six months;


RCSIsmjethics challenge ■ more than three ICU admissions during the same hospitalisation; ■ Glasgow Coma Score of less than 8, for more than one week, in a patient over 75 years of age; and, ■ multiorgan failure in more than three systems.28 The patient in this case fits nearly all of these criteria, and it is abundantly clear that her medical care should be re-focused to

end-of-life comfort measures. Any medical intervention that the patient is receiving that does not directly alleviate pain and suffering should be discontinued. Before any transition takes place, there must be extensive communication with the patient’s daughter.29 Included in the palliative care umbrella is bereavement services for patients’ loved ones, and the daughter should be encouraged to avail of these services.

References 1.

RCSI. Ethics Challenge. Royal College of Surgeons in Ireland Student Medical Journal. 2010;3(1):5.

2.

The Belmont Report: Ethical principles and guidelines for the protection of human subjects of research. Cited October 13, 2010. Available from: ohsr.od.nih.gov/guidelines/belmont.html.

3.

Marsella A. Exploring the literature surrounding the transition into palliative care: a scoping review. Int J Palliat Nurs. 2009;15(4):186-9.

4.

Hauser JM. Lost in transition: the ethics of the palliative care handoff. J Pain Symptom Manage. 2009;37(5):930-3.

5.

Pattison N. Integration of critical care and palliative care at end of life. Br J Nurs. 2004;13(3):132-6,8-9.

6.

ST-28 Principles Guiding Care at the End of Life, 1998. Cited October 14, 2010. Available from: www.facs.org/fellows_info/statements/st-28.html.

7. 8.

to critiques. Ann Intern Med. 1996;125(8):669-74. 17. Tan SY. Medical decisions at the end of life: lessons from America. Hawaii Med J. 1995;54(4):514-20. 18. Layson RT, McConnell T. Must consent always be obtained for a do-not-resuscitate order? Arch Intern Med. 1996;156(22):2617-20. 19. Gedge E, Giacomini M, Cook D. Withholding and withdrawing life support in critical care settings: ethical issues concerning consent. J Med Ethics. 2007;33(4):215-8. 20. Council on Ethical and Judicial Affairs. Medical futility in end-of-life care: report of the Council on Ethical and Judicial Affairs. JAMA. 1999;281(10):937-41. 21. American Medical Association. E-2.03 Allocation of Limited

Curtis JR, Vincent JL. Ethics and end-of-life care for adults in the

Medical Resources, 1993. Cited October 19, 2010. Available

intensive care unit. Lancet. 2010; October 7 [epublished].

from:

Gries CJ, Curtis JR, Wall RJ, Engelberg RA. Family member

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satisfaction with end-of-life decision making in the ICU. Chest.

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2008;133(3):704-12. 9.

16. Schneiderman LJ, Jecker NS, Jonsen AR. Medical futility: response

American Medical Association. E-2.20 Withholding or Withdrawing Life-Sustaining Medical Treatment, 1996. Cited October 19, 2010. Available from: https://ssl3.ama-assn.org/apps/ecomm/PolicyFinderForm.pl?site=w ww.ama-assn.org&uri=/ama1/pub/upload/mm/PolicyFinder/policyfil es/HnE/E-2.20.HTM.

10. Cassell EJ. The principles of the Belmont report revisited. How have

cyfiles/HnE/E-2.03.HTM. 22. Gleeson D. Is it time for advance healthcare directives? Irish Council on Bioethics, 2007. 23. Torke AM, Alexander GC, Lantos J. Substituted judgment: the limitations of autonomy in surrogate decision making. J Gen Intern Med. 2008;23(9):1514-7. 24. American Medical Association. E-2.035 Futile Care. American Medical Association, 1994. Cited October 19, 2010. Available

respect for persons, beneficence, and justice been applied to

from:

clinical medicine? Hastings Cent Rep. 2000;30(4):12-21.

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11. American Medical Association. E-2.17 Quality of Life, 1994. Available from: https://ssl3.ama-assn.org/apps/ecomm/PolicyFinderForm.pl?site=w ww.ama-assn.org&uri=/ama1/pub/upload/mm/PolicyFinder/policyfil es/HnE/E-2.17.HTM. 12. Sims JM. A brief review of the Belmont report. Dimens Crit Care Nurs. 2010;29(4):173-4. 13. Intensive Care Society of Ireland. Adult intensive care capacity planning and development in Ireland. Dublin: Intensive Care Society of Ireland, October 2006. 14. Coustasse A, Quiroz T, Lurie SG. To the bitter end: disparities in end-of-life care. J Hosp Mark Public Relations. 2008;18(2):167-85. 15. Schneiderman LJ, Jecker NS, Jonsen AR. Medical futility: its meaning and ethical implications. Ann Intern Med. 1990;112(12):949-54.

www.ama-assn.org&uri=/ama1/pub/upload/mm/PolicyFinder/poli cyfiles/HnE/E-2.035.HTM. 25. Meisel A, Snyder L, Quill T. Seven legal barriers to end-of-life care: myths, realities, and grains of truth. JAMA. 2000;284(19):2495-501. 26. Walker RM. Ethical issues in end-of-life care. Cancer Control Journal. 1999;6:2. 27. Rousseau P. Ethical and legal issues in palliative care. Prim Care. 2001;28(2):391-400. 28. Bradley CT, Brasel KJ. Developing guidelines that identify patients who would benefit from palliative care services in the surgical intensive care unit. Crit Care Med. 2009;37(3):946-50. 29. Burt RA. The medical futility debate: patient choice, physician obligation, and end-of-life care. J Palliat Med. 2002;5(2):249-54.

Volume 4: Number 1. 2011 | Page 9


RCSIsmjoriginal article The influence of cytomegalovirus and Epstein-Barr virus serostatus on haemoglobin levels and erythropoietin-stimulating agent responsiveness in patients on the transplant list with stage 5 chronic kidney disease

Abstract

Cherisse Baldeo1, Professor Mark Denton2, Patrick O’Kelly3, Abdul Ali1 1RCSI medical students 2Consultant Nephrologist,

Beaumont Hospital, Dublin 3Statistician,

Beaumont Hospital, Dublin

Cytomegalovirus (CMV) seropositivity has been reported to be a major determinant of erythropoietin-stimulating agent (ESA) resistance in patients with chronic kidney disease (CKD). It is hypothesised that prior CMV infection induces significant changes in T-cell subtypes that promote bone marrow resistance to ESA. We examined whether CMV or Epstein-Barr virus (EBV) serostatus influenced haemoglobin (Hb) levels and/or ESA resistance in our population of CKD stage 5 patients. Data on CMV and EBV serology, age, sex and Hb was collected on 1,417 patients presenting for a renal transplant from 2000 to 2009 in Ireland. Patients were split into four groups (CMVneg/EBVneg, CMVpos/EBVneg, CMVneg/EBVpos, and CMVpos/EBVpos) and analysis of variance was performed to examine whether CMV and EBV serostatus influenced Hb levels pre transplantation. Data was then collected on 117 patients currently on the transplant pool from Beaumont and Tallaght Hospitals. CMV and EBV serostatus, Hb, ESA dose and other parameters associated with ESA responsiveness (iron studies, B12/folate, albumin, PTH, diabetes, vascular access, dialysis adequacy) were collected. Multivariate analysis was performed to determine factors associated with increased ESA dosage. CMV positivity was found to have no effect on Hb levels or ESA dosage. Likewise, EBV serostatus had no effect on these parameters. First, analysis of 1,417 patients showed no difference in mean Hb between the various CMV/EBV serostatus groups. Second, analysis of patients currently on the transplant pool also showed that there was no difference in mean Hb between CMV and EBV groups. Analysis of a subpopulation of haemodialysis patients alone showed that CMV positivity was associated with a higher mean Hb and a lower mean ESA dose. Our results contrast with those of a recent report by Betjes et al. linking ESA resistance to CMV seropositivity. No association was found between CMV or EBV serostatus and Hb levels or ESA dosage. CMV seropositivity is not associated with increased ESA requirements in our population. These conflicting results may be due to differences in patient demographics and a lower target Hb level in our study. Keywords: Haemoglobin, erythropoietin, CMV, EBV, renal disease. Royal College of Surgeons in Ireland Student Medical Journal. 2011;4(1):10-15.

Page 10 | Volume 4: Number 1. 2011


RCSIsmjoriginal article Introduction Anaemia associated with chronic kidney disease (CKD) is a common problem that is associated with reduced quality of life and increased morbidity and mortality.1 The main cause is erythropoietin (Epo) deficiency. Epo is secreted by the peritubular capillary cells of the kidney and its production decreases when glomerular filtration rate (GFR) falls below approximately 40ml/min. Other causes of anaemia in CKD are decreased red blood cell (RBC) survival, bone marrow dysfunction in the setting of uraemia, increased RBC loss from uraemic gastritis and blood loss associated with the dialysis procedure. The main treatment is administration of erythropoiesis-stimulating agents (ESAs) and ensuring adequate iron stores. ESAs are similar to the naturally occurring protein Epo, which stimulates RBC formation (erythropoiesis). Available ESAs include Epo, epoetin alfa (Procrit/Epogen), epoetin beta (NeoRecormon) and darbeopoetin (Aranesp).2,3 However, patients differ in their sensitivity to ESA treatment, and in those that are hyporesponsive, a larger dose is required to maintain the haemoglobin (Hb) at an adequate level.4 There is controversy over the optimal Hb target, but it is usually taken to be 11-12g/dL. Of note, complete correction of anaemia to Hb levels higher than these values may be associated with increased cardiovascular risk.5,6 There are a number of factors that cause Epo hyporesponsiveness, including iron deficiency, systemic inflammation, hyperparathyroidism, vitamin B12 or folate deficiency, and co-morbidities such as diabetes, ongoing blood loss and inadequate dialysis.7 There has been recent evidence that prior exposure to cytomegalovirus (CMV) infection resulting in seropositivity to CMV is associated with resistance to Epo treatment in CKD patients.8 CMV is a herpes DNA virus that causes infectious mononucleosis and is commonly acquired in the teenage years. Often, the infection is asymptomatic or associated with a mild flu syndrome. The prevalence of seropositivity increases with the age of the population, such that approximately 50% of 50 year olds are seropositive.9 It does not cause significant clinical problems unless a patient becomes immunosuppressed such as in renal transplant patients. CMV infection in immunocompromised individuals can be life threatening, such that reactivation of the virus can cause CMV retinitis and pneumonitis. Furthermore, it is associated with distinct changes in peripheral T-cell populations. Betjes et al. have shown that CKD patients with positive CMV serology required significantly more Epo to achieve target Hb values (median 12,000 vs. 6,300 units/week; p=0.02). They provide evidence that this Epo-resistant state is due to a CMV-mediated change in peripheral T-cell subsets. Prior CMV infection is associated with expanded CD4+ CD28 null T-cells that are pro-inflammatory and mediate bone marrow resistance to the effects of Epo.10 This study examined if there was an association between CMV serostatus and Epo responsiveness in our CKD population. A retrospective analysis of 1,417 CKD patients presenting for renal

Table 1: Erythropoietin dose conversion. Darbepoetin alfa (Aranesp) mg/week

Epoetin beta (NeoRecormon) iu/week

Methoxy polyethylene glycol-epoetin beta (Mircera) mg/month

<40 40-80 >80

<8000 8000-16000 >16000

120 200 360

transplantation was conducted to determine whether CMV serostatus correlated with Hb values prior to transplantation. Thereafter, a detailed analysis of 117 patients on the transplant waiting list in Beaumont and Tallaght Hospitals was performed to determine factors associated with Epo resistance in a multivariate analysis. In addition, we included serostatus for Epstein-Barr virus (EBV) infection in these patients as we hypothesise that infection with EBV may have a similar effect on Epo requirement. EBV is also a herpes virus like CMV and any findings in this area would be novel.

Methods Hospital data for the 1,417 patients who were transplanted in Ireland over the past 10 years (2000-2009) were collected. This information was obtained from hospitals across Ireland. No confidential patient details such as names were recorded and therefore ethics approval was not required before data collection. The data was then used in a retrospective analysis to determine whether CMV and EBV seropositivity affected Hb levels. The patients in our list were divided into four subgroups according to their serostatus, namely CMV+EBV+, CMV+EBV-, CMV-EBV+, and CMV-EBV-. Analysis of variance (ANOVA) was used to examine the mean Hb level for the various EBV and CMV status groups, and so a comparison was made to determine if the presence of CMV or EBV infection had an effect on Hb levels. The significance of other confounding factors such as age at transplantation, sex of patient and the year of transplant were also determined for these patients. Next, a sub-analysis of the 117 patients on the renal transplant list from Beaumont and Tallaght Hospitals was conducted. The criteria for selection were for the patient to have been on the transplant list from January 2010 and to be a patient at either of these hospitals. These patients in the transplant pool were selected for study, as a patientâ&#x20AC;&#x2122;s CMV and EBV serostatus are now routinely determined prior to being put on the transplant list. Patient information was collected using case notes, referral letters and hospital databases (Clinical Vision and PIPE for Beaumont Hospital renal patients). The data collected was then categorised and entered into an electronic database. First, the mean Hb levels for CMV+, CMV-, EBV+ and EBV- patient groups were calculated and differences among these values were compared. Second, the different types of Epo used by these

Volume 4: Number 1. 2011 | Page 11


RCSIsmjoriginal article Table 2: Standardised scoring system for erythropoietin dosage.

and EBV serostatus has on Epo dose and Hb concentration, while simultaneously looking at the effects of other key variables known to cause Epo hyporesponsiveness. The specific variables included were serum iron, vitamin B12 and folate levels, serum ferritin, transferrin saturation, serum albumin, diabetic status, parathyroid hormone (PTH) levels and the use of an angiotensin II receptor blocker (ARB) or ACE inhibitors (ACEIs).7 This enabled a comparison of the extent of influence each variable had on Epo dose and Hb levels.

Erythropoietin score

Aranesp

NeoRecormon

Mircera

0

0

0

0

1

10

2000

30

2

20

4000

60

3

30

6000

90

Results

4

40

8000

120

5

50

10000

180

6

60

12000

240

7

70

14000

-

8

80

16000

360

9

90

18000

-

10

100

20000

480

11

110

22000

-

12

120

24000

-

13

130

26000

-

14

140

28000

-

15

150

30000

-

The retrospective analysis showed that there were no significant differences in Hb levels among the various groups. Overall, the CMV-EBV- group reported high mean Hb levels, while the CMV+EBV- had the lowest mean Hb (Table 3). This difference in Hb levels between the seropositive and the seronegative patients was not significant when compared to the other confounders. However, the variables that were found to have significant effects on Hb levels were the gender of the patient and the year of the transplant (Table 4). The clinical and demographic data for the 117 patients on the transplant pool are outlined in Table 5. Of the 117 patients, 43 were female and 74 were male. Mean Hb was slightly higher in the CMV+ group (11.36g/dL) compared to the CMV- group (11.30g/dL). Aranesp proved to be the most popular Epo used by the patients. In the transplant pool, there were more people with diabetes in the CMV+ group (16.7% compared to 7.8%). In addition, the patients in this study were younger than those in Betjes’ study (mean age 47.3 years in the CMV+ group and 49.8 in the CMVgroup, compared to 57.4 years in Betjes’ haemodialysis patients). Albumin levels were roughly the same in both groups (CMV40.16g/dL; CMV+ 40.09g/dL). Serum iron was higher in the CMV- group (15µg/dL), and ferritin was higher in the CMV+ group (434ng/ml). The mean Epo score (Table 2) for the CMV+ group was 0.44 higher than the CMV- group. Of note, analysis of these patients also showed no difference in Hb levels among the various serostatus groups. The EBV patients had the highest mean Hb level of 11.57g/dL, but it was not statistically significant (Figure 1).

patients and the popularity of each were examined. Analysis of Epo dose required the use of the conversion system from either ESA (Table 1). Darbepoetin alfa (Aranesp) and epoetin beta (NeoRecormon) doses were quoted weekly, while Mircera was given monthly. A standardised scoring system was derived to allow comparison of differences in dosage of the various Epo types (Table 2). The validity of results derived from using this system was verified by standardising Aranesp dose from micrograms into units in the same manner as Betjes et al.7 This was done by multiplying the Aranesp dose by 200. Third, a multivariate analysis was performed using the patient data and these standardised doses to investigate the effect CMV

Table 3: Analysis of variance (ANOVA) examining equality of haemoglobin for EBV and CMV serostatus groups. EBV-CMV status

Mean haemoglobin (g/dl)

Standard deviation for haemoglobin (g/dl)

Minimum haemoglobin (g/dl)

Maximum haemoglobin (g/dl)

Neg-Neg Neg-Pos Pos-Neg Pos-Pos

12.3 11.8 12.3 12.3

1.8 1.4 1.6 1.6

7.1 8.8 7.2 7.6

17.8 14.1 17.8 16.3

Page 12 | Volume 4: Number 1. 2011


RCSIsmjoriginal article Table 4: Significance of confounders of age at transplantation, sex of patient and year of transplant. Variable

Partial sum of squares

Degrees of freedom

Mean sum of squares

F

P value

EBV-CMV

6.15697596

3

2.05232532

0.81

0.4888

Age at transplant

195.661828

69

2.83567866

1.12

0.2423

Sex

20.4179786

1

20.4179786

8.05

0.0046

Year

112.486054

10

11.248604

4.44

<0.0001

Table 5: The clinical and demographic characteristics of patients on the 2010 transplant waiting list. Variable

CMV positive (n=54)

CMV negative (n=63)

P value

% male gender

32

42

0.441

Age (mean)

47.3

49.8

0.263

Diabetes (%)

16.7

7.8

0.387

% Haemodialysis

0.54

0.52

0.623

% Peritoneal dialysis

0.32

0.43

% Pre-dialysis/not on dialysis

0.14

0.05

% Aranesp

0.57

0.49

% NeoRecormon

0.30

0.23

% Mircera

0.04

0.06

None

0.09

0.22

Erythropoieitin score (median [IQR])

3 [1.5-4]

3 [2-5]

0.505

Albumin (g/dL) (mean)

40.09

40.16

0.689

Hb (g/dL) (mean)

11.36

11.30

0.780

B12 (µg) (median [IQR])

353 [249-457]

327.5 [258.5-469]

0.965

Folate (µg) (median [IQR])

11.65 [8.4-15.1]

12.7 [8.7-16.5]

0.588

Serum Fe (µg/dL) (median [IQR])

12 [9.3-15]

13.6 [9.9-18.25]

0.089

Ferritin (ng/mL) (median [IQR])

405 [253-621.5]

400 [213-571.5]

0.507

Transferrin saturation (median [IQR])

30.12 [24.55-37.14]

31.03 [24-41.985]

0.432

PTH (pg/ml) (Median [IQR])

321 [215-545]

340.5 [171.5-598]

0.316

Weight (kg) (median [IQR])

75.75 [63-86.8]

72.4 [63.4-84.1]

0.649

Urea reduction ratio (%) (median [IQR])

73 [66-76.4]

69 [67-75]

0.333

% EBV-positive

0.96

0.87

0.172

% on ACEI/ARB

0.39

0.40

0.026

Dialysis type:

Erythropoietin type 0.557

Volume 4: Number 1. 2011 | Page 13


RCSIsmjoriginal article

CMV status

Neg. Pos.

Mean haemoglobin (g/dl)

Standard deviation for haemoglobin (g/dl)

10.55455 11.44483

1.025637 1.130609

Mean haemoglobin level (g/dl)

Table 6: The effect of CMV serostatus on haemoglobin levels for patients on haemodialysis. Median haemoglobin (g/dl)

10.9 10.9

11.6

11.45 11.4

CMV positive

CMV negative

Epo treatment No Epo

11.1462 12.5

10.7714 12.3786

11.35926

11.35 11.3

11.29841 11.30648

11.25 11.2 11.15 CMV+

Table 7: Comparison of mean haemoglobin levels (g/dL) for patients on erythropoietin therapy and those without therapy. Treatment status

11.56667

11.55 11.5

CMV-

EBV+

EBV-

Patient serostatus

FIGURE 1: Relationship between patient serostatus and mean haemoglobin levels showed no difference in haemoglobin levels among the various serostatus groups.

Table 8: The significance of the various factors on erythropoietin dose. Variable

Partial sum of squares

Degrees of freedom

Mean sum of squares

F

P value

CMV status

0.287095976

1

0.287095976

0.70

0.4065

High PTH

1.06657753

1

1.06657753

2.60

0.1128

High folate

0.02646765

1

0.02646765

0.06

0.8004

Low serum Fe

0.457643219

1

0.457643219

1.12

0.2956

High ferritin

1.77227242

1

1.77227242

4.32

0.0426

High transferrin saturation

0.152055625

1

0.152055625

0.37

0.5452

ACEI/ARB

0.338380885

1

0.338380885

0.83

0.3678

Diabetes

0.000193397

1

0.000193397

0.00

0.9828

Separate analysis conducted for patients on haemodialysis (excluding patients on peritoneal dialysis) showed that the mean Hb was higher in the CMV+ group (11.44g/dL) than in the CMV- group (10.55g/dL, p=0.016) (Table 6). Mean Hb for patients not on Epo was higher than for those not on treatment (CMV+ patients: 12.50g/dL vs. 11.15g/dL; CMV- patients: 12.38g/dL vs. 10.77). CMV+ patients in both categories had higher Hb levels than CMVpatients (Table 7). Patients not on Epo therapy and those receiving Mircera treatment were excluded, as they were few in number and would lower accuracy. The Epo doses of the remaining patients were then standardised by Betjesâ&#x20AC;&#x2122; method and this data was represented on a box plot (Figure 2).10 This showed that the CMV- patients required a higher median Epo dose than CMV+ patients, 8000U/wk and 6000U/wk, respectively. Univariate analysis showed that ferritin was the only variable that had a significant effect on Epo dose (p=0.0253), while the multivariate analysis showed that serum iron had a significant effect on erythropoietin dose (p=0.0441) (Table 8).

Page 14 | Volume 4: Number 1. 2011

Discussion This study examined 1,417 CKD patients transplanted in Ireland over the past ten years and found that neither their CMV nor EBV serostatus affected their mean Hb levels at the time of transplantation. The sex of the patient and the year of transplantation had an effect on Hb levels. It is well known that women have lower Hb levels, and any effect the year of transplantation might have may in fact represent changes in clinical practice, such as different target Hb in current practice. The lack of an effect of CMV serostatus on Hb is similar to the findings by Betjes et al.10 However, any potential effect of CMV serostatus on Hb values may be masked by the fact that most CKD patients are receiving ESA agents and clinical management involves increasing the dose of ESA to achieve Hb levels within the target range. Betjes et al. concluded that CMV seropositivity affects anaemia management in CKD by significantly decreasing the bone marrow responsiveness to ESA, and showed that patients who are CMV+ require significantly higher doses of ESA agents.10 Moreover, Betjes et al. examined a subpopulation of patients not on ESA therapy and found that CMV+ patients were on average


CMVNEG

CMVPOS

0

10,000

20,000

30,000

RCSIsmjoriginal article

FIGURE 2: Box-plot of erythropoietin doses standardised by Betjes’ method. CMV- patients required a higher median erythropoietin dose of 8000U/wk in comparison to the CMV+ patients, who required 6000U/wk. more anaemic. In this study, CMV serostatus did not affect responsiveness to ESA agents in the CKD population and these results were not in agreement with Betjes et al.’s findings. Analysis of patients on haemodialysis shows that the mean Hb is higher in CMV seropositive patients (11.44g/dl) than in the CMV seronegative group (10.55g/dl). However, CMV+ patients received a lower mean dose of ESA. This is a novel finding, as previous studies found that CMV seropositivity leads to higher ESA requirements.10 In the multivariate analysis, the only factor positively associated with ESA dose was serum iron, and it is well known that iron deficiency causes ESA hyporesponsiveness.The marked difference in the results here may possibly be due to differences in patient demographics between study populations. Moreover, the mean Hb in our patient population was lower than that in Betjes et al.’s study. Overall, our patient population received a lower mean dose of ESA (mean

6871.9U/wk for haemodialysis patients) compared to those in Betjes et al.’s study (10,399U/wk). This may be because the target Hb level at our institutions is lower, or perhaps the effect of CMV serostatus on ESA responsiveness only manifests when attempting to achieve a higher Hb level in these patients. The mean age of our population was younger than those studied by Betjes et al. (47.3 years vs. 57.4 years). This may be an important factor because the effect of CMV on T-cell subpopulations (enhanced CD4+, CD28- population) is age dependent. We also had a lower percentage of patients with diabetes in our study, and there was a difference in the percentage of patients with diabetes between groups. This may be important because of the influence of diabetes on anaemia. Of note, renal impairment due to microvascular complications of diabetes could lead to impaired Epo production and, ultimately, anaemia.11 Additionally, the patients on the transplant list were perhaps in better health by virtue of being younger than those with end-stage renal disease included in Betjes et al.’s study. The inconsistency between the results presented by Betjes et al. and those in this study demonstrates that the relationship between CMV serostatus and Epo dose is still unclear. Further large-scale studies should be conducted to definitively determine the association between patient CMV serostatus and required Epo dose, if any. Currently, patients with renal disease may pay thousands annually for Epo treatment, and costs can be as much as double that paid for the alternative treatment of RBC transfusions.12 Careful control and surveillance of influencing factors, such as glucose control in patients with diabetes and prevention of iron deficiency, may help to lower Epo requirements, and thereby decrease the cost for patients.

Acknowledgements I would like to thank Dr Mark Denton for all his guidance, as well as Mr Patrick O’Kelly, Abdul Ali, Susan Spencer and the dialysis nurses at Beaumont and Tallaght Hospitals for all their help during this research project.

References 1. Weiss G, Goodnough LT. Anaemia of chronic disease. N Engl J Med. 2005;352(10):1011-23. 2. Ashley C, Morlidge C (eds.). Introduction to Renal Therapeutics. London: The Pharmaceutical Press, 2008:45-54. 3. Eschbach JW, Kelly MR, Haley NR, Abels RI, Adamson JW. Treatment of the anaemia of progressive renal failure with recombinant human erythropoietin. N Engl J Med. 1989;321(3):158-63. 4. Eschbach JW, Egrie JC, Downing MR, Browne JK, Adamson JW. Correction of the anaemia of end-stage renal disease with recombinant human erythropoietin. Results of a combined phase I and II clinical trial. N Engl J Med. 1987;316(2):73-8. 5. Drueke T. Hyporesponsiveness to recombinant human erythropoietin. Nephrol Dial Transplant. 2001;16(Suppl. 7):25-8. 6. Courtney AE, Maxwell AP. Critiques of clinical guidelines in nephrology: anaemia. Nephron Clin Pract. 2008;110(2):c115-25. 7. Singh AK, Szczech L, Tang KL, Barnhart H, Sapp S, Wolfson M et al.;

CHOIR Investigators. Correction of anaemia with epoetin alfa in chronic kidney disease. N Engl J Med. 2006;355(20):2085-98. 8. Kanbay M, Perazella M, Kasapoglu B, Koroglu M, Covic A. Erythropoiesis stimulatory agent-resistant anaemia in dialysis patients: review of causes and management. Blood Purif. 2010;29(1):1-12. 9. Kumar P, Clark M (eds.). Clinical Medicine (6th ed.). London: Elsevier Saunders, 2005:680. 10. Betjes MGH, Weimar W, Litjens NHR. CMV seropositivity determines epoetin dose and haemoglobin levels in patients with CKD. J Am Soc Nephrol. 2009;20(12):2661-6. 11. Dikow R, Schwenger V, Shömig M, Ritz E. How should we manage anaemia in patients with diabetes? Nephrol Dial Transplant. 2002;17(Suppl. 1):67-72. 12. Fain J, Hilsenrath P, Widness JA, Strauss RG, Mutnick AH. A cost analysis comparing erythropoietin and red cell transfusions in the treatment of anaemia of prematurity. Transfusion. 1995;35(11):936-43.

Volume 4: Number 1. 2011 | Page 15


RCSIsmjoriginal article The prevalence of vitamin B12 deficiency in patients with type 2 diabetes mellitus on metformin Abstract The aim of this study is to determine the prevalence of vitamin B12 deficiency among Irish patients with type 2 diabetes mellitus on metformin therapy. We also seek to determine if the dose and duration of metformin use is associated with vitamin B12 deficiency and if the vitamin B12 deficiency is associated with clinical complications. The incidence of type 2 diabetes mellitus in the Irish population is increasing, and it is therefore important to minimise morbidity. Vitamin B12 deficiency is an easily preventable side effect of metformin therapy. It is essential to determine the prevalence of this condition in order to prevent the occurrence of complications, such as peripheral neuropathy and megaloblastic anaemia. Data was collected through the examination of participantsâ&#x20AC;&#x2122; hospital charts and the use of the electronic database (Patient Information Profile Expander) in Beaumont Hospital, Dublin. This study finds a high prevalence of vitamin B12 deficiency in patients with type 2 diabetes mellitus on metformin therapy. An inverse relationship exists between vitamin B12 levels and the dose and duration of metformin use. Therefore, we suggest that the measurement of vitamin B12 should become an essential part of the annual review in all patients with type 2 diabetes mellitus on metformin therapy. Keywords: Vitamin B12 deficiency, metformin, type 2 diabetes mellitus. Royal College of Surgeons in Ireland Student Medical Journal. 2011;4(1):16-20.

Introduction

Omar Marar1, Sera Senturk1, Amar Agha2, Chris Thompson2, Diarmuid Smith2 1RCSI medical students 2Department of

Endocrinology/RCSI Medical School, Beaumont Hospital, Dublin

Page 16 | Volume 4: Number 1. 2011

Type 2 diabetes mellitus (T2DM) affects 4.8% of the Irish population, and this figure is expected to increase by 37% over the next decade.1 The epidemic of T2DM is driven primarily by a sedentary lifestyle, increasing obesity, lack of physical exercise, increased life expectancy, and earlier diagnosis to a certain extent. Metformin, a biguanide, is the first-line oral hypoglycaemic agent used in the treatment of the overweight or obese patient with T2DM. Metformin acts on several tissues via activation of the adenosine monophosphate-activated protein kinase (AMPK) system to reduce serum glucose. The primary effect of metformin is to suppress hepatic gluconeogenesis.2 Side effects of metformin therapy are gastrointestinal upset and, rarely, lactic acidosis. Another clinically relevant side effect of metformin therapy is vitamin B12 deficiency. This side effect is well described, frequently forgotten and not routinely screened for. In 2009, Pflipsen et al. showed that 22% of patients with T2DM had a vitamin B12 deficiency, and those on metformin had reduced serum vitamin B12 levels with an increased risk of vitamin B12 deficiency.3 Moreover, Ting et al. showed that the dose and duration of metformin use is directly correlated to a decreased

serum level of vitamin B12.4 The mechanism by which metformin therapy causes vitamin B12 deficiency is not clear, but it is thought to be due to either alterations in small bowel motility, which stimulate small bowel bacterial overgrowth and subsequent vitamin B12 deficiency, or by directly decreasing vitamin B12 absorption.2,5 The absorption of the vitamin B12-intrinsic factor complex by cells of the terminal ileum is calcium dependent, and metformin alters intracellular handling of calcium, thereby reducing absorption.2,5 The latter theory is supported by the fact that the administration of calcium reverses metformin-induced vitamin B12 deficiency.5 It is important to recognise the clinical consequences of vitamin B12 deficiency. Vitamin B12 is required for DNA synthesis, cellular repair and the normal production of red blood cells. Thus, vitamin B12 deficiency is a known cause of megaloblastic anaemia, characterised by enlarged red blood cells and distinctive changes in neutrophils.6 Prolonged vitamin B12 deficiency may also result in neuropathy, ranging from paraesthesia and decreased peripheral sensation to altered mental status, subacute combined degeneration of the spinal cord and dementia.6 A proposed mechanism


RCSIsmjoriginal article for these neurological effects is the disturbance of myelin synthesis due to impaired production of methionine.7 Therefore, it is worthwhile to consider the prevalence of vitamin B12 deficiency among the growing T2DM population. The prevalence of vitamin B12 deficiency in patients with T2DM on metformin therapy in Ireland is unknown and the measurement of serum vitamin B12 in T2DM patients on metformin is not part of the standard annual review examination. The objective of this study is to determine the prevalence of vitamin B12 deficiency among Irish patients with T2DM on metformin therapy. This would inform the need for routine annual vitamin B12 measurements in T2DM patients on metformin. We also want to determine whether dose and duration of metformin therapy is associated with vitamin B12 deficiency, and whether vitamin B12 deficiency in patients on metformin is associated with clinical complications such as anaemia or peripheral neuropathy.

Methods This is a cross-sectional study to examine the prevalence of vitamin B12 deficiency in patients with T2DM on metformin attending the Beaumont Hospital diabetes service.

the use of metformin. The dose of metformin was based on the most recent medical record documenting the dose. Patients with a vitamin B12 measurement in the three months preceding study initiation were included in the study. Serum vitamin B12 was measured using an immunoassay (Beckman Coulter – Unicel DxI 800 Access Immunoassay System) with a co-efficient of variation of approximately 10% or less. Low vitamin B12 measurements have low reproducibility. As such, all vitamin B12 readings below 140ng/L are repeated, and the average of the two readings is reported. The severity of vitamin B12 deficiency was split into three groups: mild vitamin B12 deficiency, defined as a vitamin B12 level of 160-180ng/L; moderate deficiency (120-160ng/L); and, severe deficiency (<120ng/L). Anaemia is defined by the World Health Organisation (WHO) guidelines as a Hb value of <12g/dl for females and <13g/dl for males.8 A macrocytic anaemia was defined as the presence of a low Hb in conjunction with an MCV of >96fl. Patients with T2DM attending the diabetes service are reviewed annually to assess their metabolic control and to screen for diabetes-related complications. We are interested in determining whether low vitamin B12 levels are associated with complications such as peripheral neuropathy, and thus refer to data from annual reviews.

I. Participant selection Inclusion criteria for study group: a diagnosis of T2DM and a prescription history of metformin for ≥18 months. Inclusion criteria for control group: a diagnosis of T2DM and no history of metformin use in the past five years. Exclusion criteria: a diagnosis of pernicious anaemia, vitamin B12 supplementation, malabsorption (coeliac disease, inflammatory bowel disease, gastrointestinal surgery), malnutrition (pure vegans, anorexia nervosa), iron deficiency anaemia, history of thyroid disease and thyroxine treament and/or a history of other organ-specific autoimmune conditions (vitiligo, Addison’s, primary ovarian failure, hypoparathyroidism).

III. Aims The aims of the study were as follows: 1. Determine the background prevalence of vitamin B12 deficiency in patients with T2DM not on metformin and with no history of or treatment for autoimmune disease(s). 2. Determine the prevalence of vitamin B12 deficiency in patients with T2DM on metformin and if the presence of vitamin B12 deficiency correlates with dose or duration of metformin therapy. 3. Determine if metformin-induced vitamin B12 deficiency is associated with anaemia as measured by Hb and MCV, or peripheral neuropathy as measured by the absence of sensation to 10g monofilament.

II. Demographic data The following data was recorded for each patient: age, sex, weight, height, body mass index (BMI), years with diabetes, total daily dose of and years on metformin, haemoglobin (Hb), mean corpuscular volume (MCV), glycated haemoglobin (HbA1c), vitamin B12, folate, thyroid-stimulating hormone (TSH), free thyroxine (T4), urine albumin-creatinine ratio (ACR), serum creatinine, and the presence or absence of peripheral neuropathy measured using a 10g monofilament. All data collected was acquired by the examination of participants’ hospital charts and their diabetes folders stored in the Diabetes Day Centre, and identification of patients at the weekly diabetes outpatient clinics and through the use of the hospital’s electronic database, Patient Information Profile Expander (PIPE). Number of years with diabetes was calculated based on the date of diagnosis as indicated in the medical chart. For those charts that did not mention a particular date of diagnosis, the date of the earliest documentation of a diagnosis of diabetes was used. If the date that metformin was commenced was not available in the medical records, the number of years on metformin was calculated based on the date of the earliest medical record documenting

IV. Statistics Data was analysed using student’s t-test (Microsoft Excel 2007) and Fisher’s test (GraphPad 2007).

Results Two hundred and sixteen patients with T2DM on metformin therapy (137 males, 79 females) were identified, and a control group of 70 patients with T2DM not on metformin therapy (40 males, 30 females) was included in the study. Groups were similar with respect to age, sex, duration of diabetes, weight, BMI and HbA1c (Table 1). Seventy-one (33%) patients on metformin had a vitamin B12 deficiency compared to only five (7.5%) in the control group (p<0.00001) (Table 2). Among patients with vitamin B12 deficiency on metformin therapy, there was no difference in relation to age, sex, duration of diabetes, BMI or diabetes control as measured by HbA1c (Table 3). The dose of metformin inversely affected serum vitamin B12 levels (Table 3). We compared the vitamin B12 levels among patients taking less than 1,000mg of metformin per day to patients taking doses over

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RCSIsmjoriginal article Dose vs. vitamin B12 vitamin B12 (ng/l)

1,000mg per day, and the difference was found to be statistically significant (p<0.008). This correlation also existed when comparing the average dose of metformin among B12-deficient patients (~2,024mg/day ± 597.43) to the average dose among the normal patients (~1,793mg/day ± 578.68) (Figure 1). Duration of metformin therapy was also found to influence vitamin B12 levels. The metformin group and the vitamin B12-deficient group was divided into those who were on metformin therapy for over five years and those who had taken it for less than five years. In the metformin group, those who were on it for less than five years had an average vitamin B12 of 261.5ng/L ± 132.6, compared to an average vitamin B12 of 227.5ng/L ± 110.8 in those patients taking metformin for more than five years (p<0.043). With the vitamin B12-deficient patients in the metformin group, no statistical significance was found when comparing those on metformin for less than five years to those on it for over five years (p<0.13) (Figure 2). In the metformin group, 17 patients had a mild vitamin B12 deficiency, 33 had a moderate deficiency and 21 had a severe deficiency. Out of the five deficient patients in the control group, two patients were found to be mildly vitamin B12-deficient, two were moderately deficient and one was severely deficient (Figure 3). Among all patients on metformin therapy, 27% (58/216) were found to be anaemic. In the vitamin B12-deficient metformin group, 31% (22/71) were anaemic. None of the patients had a macrocytic anaemia and only two patients had a macrocytosis. Some 29% (5/17) of the mildly, 18% (6/33) of the moderately and 52% (11/21) of the severely vitamin B12-deficient patients were found to be anaemic. In the group with normal vitamin B12 levels, 24% (35/145) of the patients were anaemic, and none were found to have macrocytic anaemia or macrocytosis. Within the control group,

1000 900 800 700 600 500 400 300 200 100 0 0

500

1000

1500

2000

2500

3000

3500

Dose (mg/day)

FIGURE 1: The inverse relationship (r-value = -0.12) between the dose of metformin (mg/day) and vitamin B12 levels (ng/L). Table 2: Metformin group vs. control group. Demographics

Metformin group

Control group

P-value

Weight (kg) Average Range

90.99 ± 17.60 50-141.8

87.10 ± 17.66 50.90-140

0.15

B12 (ng/L) Average Range

247.98 ± 125.23 60-961

323.23 ± 112.21 0.00001 81-658

Hb (g/dL) Average Range

13.30 ± 1.51 9.8-16.7

13.38 ± 1.47 9.1-16.8

0.7

MCV (fl) Average Range

86.13 ± 4.99 70.9-103.5

86.76 ± 4.59 69.4-95.7

0.34

HbA1c (%) Average Range

7.27 ± 1.29 5-13.3

7.13 ± 1.32 5.2-11.1

0.44

Creatinine (umol/L) Average Range

79.76 ± 21.41 45-159

88.89 ± 38.08 13-245

0.07

TSH (mIU/L) Average Range

2.01 ± 1.21 0.27-9.37

1.84 ± 0.95 0.19-4.92

0.22

Neuropathy Absent Present

151 (94%) 10 (6%)

43 (96%) 2 (4%)

Table 1: Demographics. Demographics

Metformin group

Control group

Sex Males (%) Females (%)

137 (63%) 79 (37%)

39 (56%) 31 (44%)

Age (years) Average

64 ± 10.6

66 ± 10

Years with diabetes Average

8.45 ± 6.07

8 ± 6.59

P-value

0.09

0.83

Weight (kg) Average

90.99 ± 17.60

87.10 ± 17.66

0.15

BMI (kg/m2) Average

33.37 ± 6.17

32.10 ± 6.51

0.42

HbA1c (%) Average

7.27 ± 1.29

7.13 ± 1.32

0.44

BMI: body mass index; HbA1c: haemoglobin A1c.

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Hb: haemoglobin; MCV: mean corpuscular volume; HbA1c: haemoglobin A1c; TSH: thyroid-stimulating hormone.


RCSIsmjoriginal article Length of metformin vs. B12

Table 3: Metformin group – vitamin B12-deficient vs. normal. 300

P value = 0.043

Metformin group

P value = 17.3

Deficient (≤180ng/L)

Normal (>180ng/L)

Number of patients Number of males Number of females

71 (33% of total) 49 (69%) 22 (31%)

145 (67% of total) 88 (61%) 57 (39%)

Age (years) Average Range

64 ± 9.85 41-90

63 ± 10.96 36-91

0.46

Weight (kg) Average Range

94.47 ± 17.66 61.2-141.8

89.35 ± 17.40 50-133.4

0.067

BMI (kg/m2) Average Range

33.61 ± 6.61 27.5-48.6

33.26 ± 6.05 22.3-51.4

0.84

B12 (ng/L) Average

136.51 ± 29.56

302.57 ± 117.74 <0.00001

Range

60-179

180-961

Hb (g/dL) Average Range

13.05 ± 1.50 9.8-16.3

13.43 ± 1.50 9.9-16.7

0.085

MCV (fl) Average Range

85.47 ± 5.08 72.1-98.5

86.46 ± 4.94 70.9-103.5

0.18

HbA1c (%) Average Range

7.25 ± 1.13 5.3-11.8

7.28 ± 1.36 5-13.3

0.87

P-value

200

< 5 Years > 5 Years

150 100 50

Creatinine (umol/L) Average 79.39 ± 23.62 Range 45-159

79.94 ± 20.38 48-158

TSH (mIU/L) Average Range

2.02 ± 1.42 0.46-9.37

Dose (mg/day) Average Range

2023.94 ± 597.43 1793.45 ± 578.68 500-3000 500-2550

2.01 ± 1.10 0.27-5.76

261.5 + 132.6 227.5 + 110.8

141.7 + 26.0

130.9 + 32.4

0 Entire metformin group

Deficient metformin group

FIGURE 2: This relationship suggests that the duration of metformin therapy may influence vitamin B12 levels in the entire metformin group and the vitamin B12-deficient metformin subgroup. Metformin group deficiencies 190 170 Vitamin B12 (ng/L)

Demographics

Average B12 (ng/L)

250

Average = 169.8ng/L 17 patients (24%)

150

Average = 143.8ng/L 33 patients (16%)

130 110

Average = 98.2ng/L 21 patients (30%)

90 70 50 Mild deficiency (>160ng/L)

0.88

0.98

0.008

Years on metformin Average 5.59 ± 2.72 Range 2-14

5.40 ± 3.39 2-24

0.66

Years with diabetes Average Range

9.45 ± 6.98 2-42

8.12 ± 5.66 2-34

0.28

Neuropathy Absent Present

49 (92.5%) 4 (7.5%)

102 (96%) 6 (4%)

0.73

BMI: body mass index; Hb: haemoglobin; MCV: mean corpuscular volume; HbA1c: haemoglobin A1c; TSH: thyroid-stimulating hormone.

Moderate deficiency (120-160ng/L)

Severe deficiency (<120ng/L)

FIGURE 3: The number of patients in the vitamin B12-deficient metformin sub-divisions with mild (>160ng/L), moderate (120-160ng/L) and severe (<120ng/L) vitamin B12 deficiency. 14% (10/70) were anaemic. No patients in the control group had a macrocytosis. Peripheral neuropathy was not recorded in all patients. In the vitamin B12-deficient patients on metformin, four out of 53 (7.5%) recorded values indicating neuropathy compared to six out of 108 (4%) recorded values for the patients on metformin with normal vitamin B12 levels. Among the vitamin B12-deficient controls (five patients), three neuropathy values were recorded, one of which was positive (33%). Within the normal controls, 42 neuropathy values were recorded, one of which was positive (2%).

Discussion In this cross-sectional study, 27% (76/286) of patients with T2DM in the study group had a vitamin B12 deficiency. In those patients on metformin therapy, it was found that vitamin B12 deficiency existed in one out of three patients, compared to one out of 14 patients in the

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RCSIsmjoriginal article control group. Both of these figures are higher than in previously reported studies.3,4 Pflipsen et al. found that 22% (44/203) of their patients with T2DM had a vitamin B12 deficiency.3 The researchers obtained informed consent from patients that met the inclusion criteria and collected data by having the participants complete a survey with questions about demographics, medication and supplement use, and exclusion criteria.3 Although the demographics and exclusion criteria used by Pflipsen et al. are very similar to those used in this study, the method of data collection differs; Pflipsen et al. only examined participant medical records through charts and the hospital’s database, and identified patients at the weekly diabetes outpatient clinics. Pflipsen et al. had an advantage by using surveys, which allowed for the immediate and up-to-date delivery of information. Another part of the survey required the patient to indicate their use of metformin, insulin (any form), other hypoglycaemic medications, acid blockers (H2 blockers and/or proton pump inhibitors), herbal supplements, multivitamins, and B-complex vitamins;3 this study only documented patients taking metformin and excluded those on vitamin B12 supplements. Additionally, Pflipsen et al. defined vitamin B12 deficiency as serum vitamin B12 levels <100pg/mL or serum vitamin B12 levels of 100-350pg/mL with elevation of serum methylmalonic acid >243nmol/L or homocysteine >11.9nmol/L.3 In this study, deficiency parameters consisted of three subdivisions of vitamin B12 levels into mild (160-180ng/L), moderate (120-160ng/L) and severe (<120ng/L). Therefore, it is evident that the methods and parameters used by Pflipsen et al. produced a more refined and representative T2DM study population in comparison to this study with regard to the level of vitamin B12 deficiency overall. Likewise, Ting et al. showed an increased risk of vitamin B12 deficiency associated with duration of metformin and dose, and found these parameters to be high risk factors for developing B12 deficiency.4 In this study, the data showed a statistically significant inverse relationship between length of metformin use and vitamin B12 levels when comparing patients on metformin for five years or less to those taking it for more than five years. Thus, there is an increased risk of developing vitamin B12 deficiency in patients with T2DM on metformin therapy for over five years. There was a statistically significant correlation between the dose of metformin and vitamin B12 deficiency – the higher the dose, the lower the average vitamin B12 level. This is similar to the

finding by Ting et al., in which there was a two-fold increase in risk of developing vitamin B12 deficiency with each 1g/day dose increment.4 Despite the significantly increased prevalence of vitamin B12 deficiency among the metformin group when compared to the controls, it was not associated with neuropathy or macrocytic anaemia. The majority of patients, both in the metformin and control groups, did not have neuropathy. However, the recorded values for neuropathy were too few to draw any solid conclusions regarding the risk of neuropathy among those with vitamin B12 deficiency. Possible explanations for the lack of association with neuropathy or macrocytic anaemia in our study may be the small study population, or that these side effects require longer periods of deficiency in order to manifest. Anaemia was found to be prevalent in all groups of patients: 31% in the vitamin B12-deficient metformin group, 24% in the metformin group with normal serum vitamin B12 levels and 14% in the control group. The high incidence of anaemia in patients with T2DM is a concern and may reflect the association of T2DM with shortened red cell lifespan or possibly mild renal impairment. However, since there was no statistically significant correlation between the average Hb or MCV and vitamin B12 levels in the groups, we cannot conclude that vitamin B12 is responsible. The weaknesses of the study are a lack of sufficient data, as illustrated by the incomplete peripheral neuropathy data, and dependency on diabetic charts without full examination of each patient’s medical records, since many of the diabetic files had incomplete data. However, the data on serum vitamin B12 levels and metformin therapy, including dose and duration of therapy, were available for all patients. All of the serum vitamin B12 levels were performed within three months of the start of the study and so reflect the current risk of vitamin B12 deficiency in patients with T2DM on metformin attending Beaumont Hospital’s diabetes service. We have thus demonstrated a high prevalence of vitamin B12 deficiency in patients with T2DM treated with metformin. As such, we suggest that the measurement of vitamin B12 should become an essential part of the annual review in all patients with T2DM on metformin therapy.

Acknowledgements We would like to thank the staff of the Diabetes Day Centre in Beaumont Hospital for their tremendous help during this study.

References 1. Diabetes Federation of Ireland [homepage on the internet]. Tablets for type 2 diabetes. Updated 2009. Cited February 14, 2010. Available from: http://www.diabetes.ie/WebSite/Content/educational_articles/2009_Type2medic ation.aspx. 2. Diamanti-Kandarakis E, Christakou CD, Kandaraki E, Economou FN. Metformin: an old medication of new fashion: evolving new molecular mechanisms and clinical implications in polycystic ovary syndrome. Eur J Endocrinol. 2009;162(2):193-212. 3. Pflipsen MC, Oh RC, Saguil A, Seehusen DA, Topolski R. The prevelance of vitamin B12 deficiency in patients with type 2 diabetes: a cross sectional study. J Am Board Fam Med. 2009;22(5):528-34. 4. Ting RZ, Szeto CC, Chan MH, Ma KK, Chow KM. Risk factors of vitamin B12 deficiency in patients receiving metformin. Arch Internal Med. 2006;166:1975-9.

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5. Liu KW, Dai LK, Jean W. Metformin-related vitamin B12 deficiency. Age and Ageing. 2006;35(2):200-1. 6. American Association for Clinical Chemistry [homepage on the internet]. Vitamin B12 and folate deficiency. Updated 2010. Cited February 21, 2010. Available from: http://www.labtestsonline.org/ understanding/conditions/vitaminb12-4.html. 7. Toosi TD, Shahi F, Afshari A, Roushan N, Kermanshahi M. Neuropathy caused by B12 deficiency in a patient with ileal tuberculosis: A case report. J Med Case Reports. 2008;2:90. 8. World Health Organisation. Indicators and Strategies for Iron Deficiency and Anemia Programmes. Report of the WHO/UNICEF/UNU Consultation. Geneva, Switzerland, December 6-10, 1993. WHO, 1994.


RCSIsmjoriginal article The role of opioid receptors in mechanical and thermal pain Abstract Some analgesics, including opioids, mediate their action through inhibitory G-protein-coupled receptors (GPCRs). Most opioid agonists act on either the δ-opioid receptor (DOR) or the µ-opioid receptor (MOR) at the spinal level to provide anti-nociception in tests of acute pain. Here, we examine the anti-nociceptive effects of subtype-selective agonists, namely deltorphin II, [D-ALA2,N-Me-Phe4,Gly-ol5]-Enkephalin (DAMGO); (+)- 4-[(α R)-α((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)- 3 –methoxybenzyl]-N, N-diethylbenzamide (SNC80) and morphine, on heat or mechanical pain in wild-type (wt) mice to determine the role of MOR and DOR in mediating pain modalities. Our results show no characteristic trend that links analgesia to a pain modality of DOR or MOR subtypes in assays for analgesic efficacy against heat (paw withdrawal and tail flick) and mechanical (von Frey) stimuli. Keywords: Opioid, δ-opioid receptor, μ-opioid receptor, pain modality.

Royal College of Surgeons in Ireland Student Medical Journal. 2011;4(1):21-27.

Introduction

Sarah Amrani RCSI medical student

It has been established that opioid receptors can produce anti-nociception, thus inhibiting perception and reaction to painful stimuli.1,2 Three opioid receptors, mu (µ), delta (δ) and kappa (κ), have been characterised, each displaying distinctive distribution patterns and pharmacological profiles.3,4 The µ and δ opioid receptors (MORs and DORs) are G-protein-coupled receptors (GPCRs) that act through inhibitory transduction systems to inhibit pain transmission upon binding of endogenous opioids (endorphins and enkephalins).5 MOR is an attractive drug target, as most opiate analgesics used clinically activate it; however, the various central nervous system (CNS) side effects resulting from MOR activation have directed research in favour of the more selective, safe and efficacious DOR.5 A binding specificity exists between particular agonists and receptor subtypes. For example, DOR mediates anti-nociception that can be blocked by δ-selective antagonists but not by µ-selective antagonists.6,7 Also, studies using MOR knock-out (MOR-KO) mice have revealed that analgesia mediated by the preferential MOR agonist morphine is attenuated as expected.1,2 However, in anti-nociceptive assays, MOR-KO mice also showed decreased anti-nociceptive potency and efficacy in response to the spinally-administered DOR agonists, deltorphin II

and DPDPE.1,2,8,9,10 This well-documented phenomenon suggests that either these DOR agonists have a direct action on MORs or that DOR activity is enhanced by the presence of MORs, and that both MORs and DORs are needed to achieve full anti-nociceptive potency by these agonists. This further supports the existence of a functional and/or physical interaction between MORs and DORs, which would require these receptors to be co-expressed.11,12 There is a lack of consensus concerning the anatomical distribution of these receptors, and thus, the mechanism of action of opioid analgesia at the spinal cord level is uncertain. To address this issue, Scherrer et al. visualised DOR in vivo using a green fluorescent protein reporter (GFP)-tagged DOR knock-in mouse strain, and found DOR to be expressed in a neuronal subpopulation that they suggest does not transduce painful heat signals.13 Further supported by a set of behaviour studies, Scherrer et al. proposed that MORs and DORs mediate analgesia differentially according to thermal and mechanical modalities, respectively. The results of these experiments, however, are controversial because of inconsistencies with previous literature and concerns about experimental design. Specifically, the design has been criticised because the investigators measured pain in two

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RCSIsmjoriginal article different anatomical locations – thermal pain in the tail and mechanical pain in the paw. Thus, the modality-specific analgesic differences observed may be due to selection of different anatomical locations on the mouse. The aim of this study is to determine if analgesia mediated by the activation of spinal MORs and DORs is specific for either a thermal or mechanical pain modality. We hypothesise that MOR and DOR agonists do not exclusively inhibit heat or mechanical pain, respectively; rather, we expect them to have different efficacies in each modality. To do so, we will evaluate the anti-nociceptive effects of four intrathecally administered agonists: a non-selective opioid agonist, morphine; a DOR-selective peptide agonist, deltorphin; a more selective, non-peptidergic DOR agonist, SNC80; and, a full MOR-selective and potent peptide agonist, DAMGO. Anti-nociception from these drugs will be measured by responses to thermal and mechanical pain using tail flick, von Frey and paw withdrawal assays.

Materials and methods Animals The experimental subjects were 120 male, cluster of differentiation-1 (CD-1) mice (Charles River) that weighed 20-25g. Subjects were housed in age-matched groups of two to five in a temperature- and humidity-controlled environment. They were placed on a 12-hour light/dark cycle to accommodate their nocturnal nature, and had free access to food and water except during testing. Each animal was used up to three times and an interval of about one week was allowed between uses. All experiments were approved by the McGill University Animal Care Committee.

Drugs Morphine sulphate (Medisca Pharmaceutical), deltorphin II (DELT) (Tocris) and [D-ALA2,N-Me-Phe4,Gly-ol5]-Enkephalin (DAMGO) (Tocris) were prepared into serial dilutions in sterile saline and frozen until the day of experiment. (+)- 4-[(α R)-α((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)- 3 –methoxybenzyl]-N, N-diethylbenzamide (SNC80) (Tocris) was dissolved in saline with 0.3% tartaric acid. Drug concentrations ranged from 0.003-20nmol in the paw withdrawal and from 0.3-20nmol in the tail flick and von Frey tests. We obtained full dose-response (D-R) curves for each drug and starting doses were determined from unpublished data from Dr Laura Stone’s pain laboratory (McGill University, Montreal, Canada).

Drug delivery The drugs were injected intrathecally (i.t.) by direct lumbar puncture in awake mice, and were administered by Dr Stone according to the method developed by Hylden and Wilcox.14 The insertion was considered to be successful when it was followed by a reflexive straightening and lifting of the tail. After proper insertion, the drug was injected in volumes of 5µl. The experimenter conducting the tests was blinded to all drugs and doses used.

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Anti-nociceptive assay Tail flick test Thermal nociception was measured in the tail using the tail flick test.15 The tail flick test was performed by placing the tail of the mouse in a 52.5°C water bath, a temperature deemed to be safe yet uncomfortable. Animals were gently wrapped in a cloth so that only their tails were exposed. The bottom two-thirds of the tail was immersed in the water bath, and the latency to withdraw or to flick the tail rapidly was measured. A 12-second cut-off was employed to avoid tissue damage, which corresponds to the maximum possible anti-nociception. Latencies were measured at 10 and 30 minutes post drug administration and the results were conveyed as a percent of the maximum possible effect (% MPE) according to the equation:

% MPE =

Experimental latency – Baseline latency x 100 12 sec – Baseline latency

Radiant heat paw withdrawal assay Thermal nociception was measured by applying radiant heat to the right hind paw using the paw withdrawal apparatus.16 Baseline measurements were taken prior to drug administration and were compared to post-drug treatment values. The mice were first allowed to habituate in enclosed plastic cubicles on an elevated glass grid for one hour. The stimulus was achieved by a moveable radiant heat (infrared, IR=30) source that was directed to the plantar surface of the hind paw, and the latency to withdraw the hind paw was measured. To avoid tissue damage, the cut-off time was set to 14 seconds. Latencies were measured at 10 and 30 minutes post drug administration and the results were conveyed as % MPE according to the equation:

% MPE =

Experimental latency – Baseline latency x100 14 sec – Baseline latency

Von Frey test Mechanical nociception was measured in the right hind paw using the von Frey test.17 The sensitivity to mechanical stimuli was evaluated with calibrated monofilaments (von Frey filaments). The animals were placed on a wire mesh platform and allowed to habituate for approximately one hour. The filaments were then applied, in ascending order, to the plantar surface of the right hind paw to the point of bending, and this was held for three seconds. The results were converted to 50% withdrawal threshold using the GraphPad Prism statistical analysis software. The maximum cut-off force applied was 2g. The 50% withdrawal threshold was measured at 10 and 30 minutes post drug administration.

% MPE =

Experimental threshold – Baseline threshold x100 2g – Baseline threshold


RCSIsmjoriginal article Data analysis The data from each experiment were averaged and converted to % MPE on Microsoft™ Excel, and were fit to a linear slope using GraphPad Prism. Individual dose and/or time points are expressed as means with standard error of mean. All D-R analyses were performed with the FlashCalc 4.5.3 pharmacological statistics software package. The 50% effective dose (ED50) values were calculated using the linear portion of each curve.

Results Thermal and mechanical anti-nociception mediated by the MOR-selective agonists DAMGO and morphine, and the DOR-selective agonists SNC80 and DELT were examined using tail flick, paw withdrawal and von Frey tests in wt CD-1 mice.

Time course To examine the nature of each agonist’s action and the time to the peak of its action, we performed time course analyses of DAMGO, DELT, morphine and SNC80. The time course of morphine is shown (Figure: 1 A-C) in all three tests compared to saline controls. The doses varied from 0.003-20nmol (i.t.) in paw withdrawal and 0.3-20nmol (i.t.), in the von Frey and tail flick assays. The latencies to withdraw increased in a dose-dependent manner (with a few exceptions, tail flick and von Frey), with the 10nmol dose appearing to be more efficacious than the 20nmol one. Higher doses were an exception. In all tests, measurements at 10 minutes were generally more effective than or equally effective as those taken at 30 minutes. In contrast, the tail flick test was the only test where morphine showed a greater anti-nociceptive effect at 30 minutes. Deltorphin and DAMGO’s time courses (Figure 1: D-I) showed similar patterns. In general, animals had increased latencies after 10 minutes compared to saline controls, and the higher dose was the most effective in all three tests. The mice tended to lose anti-nociception after 30 minutes. Deltorphin was almost as effective as DAMGO in paw withdrawal, but its efficacy decreased significantly in the tail flick and von Frey assays. These data suggest that DAMGO can create a higher peak analgesic response than deltorphin, and that the response is reversible, as indicated by a return to baseline after 30 minutes. SNC80 (Figure 1: J-L) did not exhibit analgesic effects in the tail flick test, but it offered a significant latency in paw withdrawal and an above-baseline threshold in the von Frey assay. It had an anti-nociceptive effect at both 10 and 30 minutes and only returned to baseline at 60 minutes. These data suggest that most of the drugs tested have an analgesic response that increases with time, and that most anti-nociceptive responses are reversible, as indicated by a return to baseline after 30 minutes.

Potency and efficacy Dose-response curves To examine the potency and maximal efficacy of each agonist, we generated (D-R) curves for all tests at 10 and at 30 minutes. In the paw withdrawal assay, all drugs produced anti-nociception, with

FIGURE 1: Anti-nociceptive time course of morphine (A-C), deltorphin (D-F), DAMGO (G-I) and SNC80 (J-L) in the paw withdrawal, tail flick and von Frey assays. morphine and DELT as the most potent at 10 minutes. The effect returned to baseline for all drugs except morphine, which was still effective at 30 minutes (Figures 2A and 3A). The tail flick assay was more sensitive to analgesics at both time points than the other tests; anti-nociception increased with dose in all drugs except SNC80, which was comparable to controls (Figures 2B and 3B). The effect was less pronounced at 30 minutes than at 10 minutes with all drugs, with the exception of SNC80 (no change). Significant anti-nociception was seen with all drugs in the von Frey assay, but DAMGO was more potent than the other analgesics at 10 and 30 minutes (Figures 2C and 3C).

Maximum possible effect and 50% effective dose The dose and % MPE reflects the nature of each agonist’s anti-nociceptive effect and its most effective dose. The ED50 was calculated for each drug and test at the 10-minute time point. In general, the % MPE curves mirrored the responses seen in the D-R curves (Figures 4 and 5: A-C). With the exception of SNC80 in the tail flick test, all drug-treated measurements differed from baseline. Morphine and deltorphin achieved anti-nociceptive efficacy of 80-100% of baseline in the paw withdrawal and tail flick tests. DAMGO was highly efficacious and had reached anti-nociceptive levels of about 170% in the von Frey test.

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RCSIsmjoriginal article

FIGURE 2: The dose-response curves of intrathecally administered drugs DAMGO, deltorphin, morphine and SNC80 in all tests at 10 minutes. (A) Modest anti-nociceptive effect in paw withdrawal in all drugs. (B) All drugs produced anti-nociception in the tail flick assay, except SNC80. (C) In the von Frey assay, some anti-nociception was seen with all drugs. DAMGO was much more efficacious than the others. (D) A magnified image of the von Frey assay that excludes DAMGO shows anti-nociception in the other drugs.

FIGURE 3: The dose-response curves of intrathecally administered drugs DAMGO, deltorphin, morphine and SNC80 in all tests at 30 minutes. (A) A general lack of anti-nociception in paw withdrawal in all drugs except high morphine and DAMGO doses (20 and 1nmol, respectively), which were anti-nociceptive. (B) Anti-nociception in tail flick persisted only in higher doses of morphine and DAMGO. (C) In the von Frey assay, anti-nociception was still present in all drugs except deltorphin.

The ED50 values are good indicators of potency, such that a low value that is within the dose range is more potent than a higher value. For morphine, the ED50 values for paw withdrawal and tail flick were 0.0255nmol (CI 0.0023-0.2859) and 0.741nmol (CI 0.0641-8.88), respectively (Table 1). The von Frey test could not be used to generate ED50 values due to the absence of a linear % MPE curve. Thus, morphine was potent in both thermal tests, but values were not calculable in the mechanical test. The ED50 values for deltorphin in the paw withdrawal, tail flick and von Frey tests were 5.05nmol (CI 0.905-28.2), 16.5nmol (CI 6.48-42.1) and 0.997nmol (CI 0.0773-12.9), respectively (Table 1). The ED50 values for DAMGO in the paw withdrawal, tail flick and von Frey tests were 0.0142nmol (CI 0.0018-0.112), 0.0229nmol (CI 0.0121-0.0434) and 0.0079nmol (CI 0.0032-0.0195), respectively (Table 1). In particular, the effect of DAMGO in the von Frey test was the most potent analgesic effect, as reflected by the low ED50. The ED50 value for SNC80 in the von Frey test was 5.78nmol (CI 0.0867-385), while the paw withdrawal and tail flick test data did not show a linear % MPE curve (Table 1).

Efficacy across the three tests

Page 24 | Volume 4: Number 1. 2011

To determine the efficacy of each agonist across the three tests, we plotted % MPE curves at 10 minutes for all drugs in each test (Figure 6: A-D). This allowed us to compare drug-induced anti-nociception in the different pain modalities. While DAMGO and deltorphin produced anti-nociception in all tests, they were both most efficacious in the von Frey test (Figures 6A and 6B). Morphine also produced anti-nociception, but was most effective at low doses in the paw withdrawal test and at high doses in the von Frey test. SNC80 was not efficacious in the tail flick assay and showed limited dose-dependent efficacy in assays applied to the paw. The poor solubility of SNC80 in a physiologically compatible vehicle prevented us from testing higher doses.

Discussion Modality-specific anti-nociception was measured following intrathecal injections of: the non-selective opioid agonist, morphine; the MOR-selective agonist, DAMGO; the DOR agonist, deltorphin;


RCSIsmjoriginal article

FIGURE 5: The % MPE of intrathecally administered drugs DAMGO, deltorphin, morphine and SNC80 in all tests at 30 minutes. (A) A general lack of anti-nociception in paw withdrawal in all drugs except high morphine doses (10 and 20nmol i.t.), which were anti-nociceptive. (B) Anti-nociception in tail flick persisted in only morphine and DAMGO. (C) In the von Frey assay, some anti-nociception was seen with all drugs, except deltorphin.

FIGURE 4: The % MPE of intrathecally administered drugs DAMGO, deltorphin, morphine and SNC80 in all tests at 10 minutes showed: (A) A modest dose-dependent anti-nociceptive effect in paw withdrawal in all drugs. (B) Anti-nociception in the tail flick assay was observed in all drugs except SNC80. (C) In the von Frey assay, some anti-nociception was seen with all drugs, except DAMGO, which showed a very effective anti-nociception. (D) A magnified image of the von Frey assay that excludes DAMGO shows anti-nociception in the other drugs.

Table 1: ED50 values, in nmol, of morphine, deltorphin, DAMGO and SNC80 in paw withdrawal, tail flick and von Frey. Drug agonist (nmol)

Paw withdrawal (CI)

Tail flick (CI)

Von Frey (CI)

Morphine

0.0255 (0.0023-0.2859)

0.741 (0.0641-8.88)

-

Deltorphin

5.05 (0.905-28.2)

16.5 (6.48-42.1)

0.997 (0.0773-12.9)

DAMGO

0.0142 (0.0018-0.112)

0.0229 (0.0121-0.0434)

0.0079 (0.0032-0.0195)

SNC80

-

-

5.78 (0.0867-385)

Volume 4: Number 1. 2011 | Page 25


RCSIsmjoriginal article

FIGURE 6: Intrathecally administered DAMGO, deltorphin, morphine and SNC80 produce anti-nociception. % MPE curves made to compare the effect of each drug in paw withdrawal, tail flick and von Frey in (A) DAMGO (B) Deltorphin (C) Morphine (D) SNC80. Each data point represents the mean S.E.M. and, the highly selective DOR agonist, SNC80. Mechanical pain was assessed by the von Frey test and thermal pain was assessed by the tail flick and paw withdrawal tests. The present study demonstrates that MOR and DOR agonists do not exclusively inhibit heat or mechanical pain. In fact, we show that MOR and DOR agonists have anti-nociceptive effects in both pain modalities. Our results are consistent with previous findings of three lines of MOR-KO mice that retained DOR-mediated anti-nociceptive efficacy from DPDPE and/or deltorphin.1,2,8 In fact, Hosohata et al. demonstrated that deltorphin, the DOR-selective agonist, produced anti-nociception in the tail flick assay in MOR-KO mice.2 Time course and D-R experiments showed no characteristic trend that linked pain modality to opioid receptor subtype. For instance, as shown in Figure 4, the MOR agonist DAMGO is the most potent and most effective drug in both thermal and mechanical assays. The less selective DOR agonist, deltorphin, shows moderate anti-nociception in all assays. Additionally, the partial efficacy of the DOR selective agonist SNC80 in both paw withdrawal and von Frey tests does not concur with the subtype-specific analgesic modality theory.13 In fact, SNC80 has performed similarly in mechanical and thermal assays; it has equal anti-nociceptive effects in both paw withdrawal and von Frey assays. When the % MPE of the same drug is compared across the three tests, the von Frey assay is almost

Page 26 | Volume 4: Number 1. 2011

always the most responsive to either MOR or DOR agonists at low doses. This challenges the subtype-specific and independent regulation of different pain modalities and instead favours literature that supports the presence of a functional and/or physical interaction between MOR and DOR. Thus, DOR agonists may have a direct action on MORs or enhance anti-nociception at these receptors.11,12 Our results support the findings of Guo et al. that both MORs and DORs are needed to achieve full anti-nociceptive potency.1 Although anti-nociception was maintained in MOR-KO mice, there was a decrease in the efficacy and potency of DPDPE and/or deltorphin. This suggests that deltorphin and DPDPE could have off-site targeting on MORs.1,2,8 Antagonist studies of MORs with CTOP, a MOR-selective antagonist, showed that CTOP antagonised both DAMGO- and DPDPE-induced antinociception.18 To overcome uncertainties regarding drug action, mainly receptor specificity, we propose antagonist and MOR/DOR-KO studies that would characterise drug action, since we cannot exclude the possibility that the agonists are acting on the other receptor subtype. In addition, there are limitations in translating these results from the mouse model to human clinical therapies, such as production of more effective drugs that target specific types of pain. Our findings regarding agonist efficacy in both the thermal and


RCSIsmjoriginal article mechanical assays, along with previous MOR-KO studies, do not support Scherrer et al. regarding the segregation of pain modalities into opioid subtypes.13 However, these results are consistent with their findings that SNC80 does not produce an efficacious anti-nociceptive response in the tail flick assay. We find it to be effective in the paw withdrawal test. This does not conflict with modality used in Scherrer et al.’s study; rather, they need to extend the design to include anti-nociception in the paw as well, possibly since the low solubility of SNC80 may prevent it from diffusing to the tail. Clearly, MOR and DOR agonists have differential efficacies in thermal and mechanical anti-nociception and further research is warranted to elucidate their mode of action within each modality.

Acknowledgements This research project was made possible with the help of everyone in the Stone Pain Lab. I would like to thank Dr Stone for administering i.t. injections, and Ms Chabot-Dore, Dr Millecamps, Ms Tajerian and Ms Naso for instructing me in experimental techniques.

References 1.

Guo XH, Fairbanks CA, Stone LS, Loh HH. DPDPE-UK14,304 synergy is retained in mu opioid receptor knockout mice. Pain. 2003;104(1-2):209-17.

2.

Hosohata Y, Vanderah TW, Burkey TH, Ossipov MH, Kovelowski CJ, Sora I et al. delta-opioid receptor agonists produce antinociception and [S-35]GTP

3.

F. Antinociceptive interactions of opioid delta-receptor agonists with morphine in mice – supraadditivity and subadditivity. Life Sciences.

Qiu CY, Sora I, Ren K, Uhl G, Dubner R. Enhanced delta-opioid European Journal of Pharmacology. 2000;387(2):163-9.

BP et al. Cross-linking of human [I-125] beta-endorphin to opioid receptors in rat striatal membranes – biochemical evidence for the

Differential antinociceptive effects of endomorphin-1 and endomorphin-2 in

existence of a mu-delta-opioid receptor complex. Journal of

Kieffer BL, Gaveriaux-Ruff C. Exploring the opioid system by gene knockout. Progress in Neurobiology. 2002;66(5):285-306. Porreca F, Heyman JS, Mosberg HI, Omnaas JR, Vaught JL. Role of mu and delta receptors in the supraspinal and spinal analgesic effects of [D-Pen2, D-Pen5]Enkephalin in the mouse. Journal of Pharmacology and

7.

O’Donnell D et al. Dissociation of the opioid receptor mechanisms that control mechanical and heat pain. Cell. 2009;137(6):1148-59. 14. Hylden JLK, Wilcox GL. Intrathecal morphine in mice – a new technique. European Journal of Pharmacology. 1980;67(2-3):313-6. 15. Janssen PA, Niemegeers CJE, Dony JGH. The inhibitory effect of

Experimental Therapeutics. 1987;241(2):393-400.

fentanyl and other morphine-like analgesics on the warm water-induced tail withdrawal reflex in rats. Arzneimittelforschung.

Research. 1987;420(1):100-8. Sora I, Takahashi N, Funada M, Ujike H, Revay RS, Donovan DM et al. Opiate receptor knockout mice define mu receptor roles in endogenous nociceptive responses and morphine-induced analgesia. Proceedings of the National Academy of Sciences of the United States of America. 1997;94(4):1544-9. 9.

Pharmacology and Experimental Therapeutics. 1990;253(1):419-26. 13. Scherrer G, Imamachi N, Cao YQ, Contet C, Mennicken F,

Heyman JS, Mulvaney SA, Mosberg HI, Porreca F. Opioid sigma-receptor involvement in supraspinal and spinal antinociception in mice. Brain

8.

1992;50(20):1535-41. 12. Schoffelmeer ANM, Yao YH, Gioannini TL, Hiller JM, Ofri D, Roques

Tseng LF, Narita M, Suganuma C, Mizoguchi H, Ohsawa M, Nagase H et al.

2000;292(2):576-83.

6.

and morphine lethality. Molecular Brain Research. 1998;54(2):321-6. 11. Horan P, Tallarida RJ, Haaseth RC, Matsunaga TO, Hruby VJ, Porreca

Pharmacology. 2000;388(3):241-8.

the mouse. Journal of Pharmacology and Experimental Therapeutics. 5.

receptor knockout in mice: effects on ligand-induced analgesia

gamma S binding in mu receptor knockout mice. European Journal of

receptor-mediated antinociception in mu-opioid receptor-deficient mice. 4.

10. Loh HH, Liu HC, Cavalli A, Yang WL, Chen YF, Wei LN. mu opioid

Slowe SJ, Clarke S, Lena I, Goody RJ, Lattanzi R, Negri L et al.

1963;13:502-7. 16. Hargreaves K, Dubner R, Brown F, Flores C and Joris J. A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain. 1988;32:141-67. 17. Chaplan SR, Bach FW, Pogrel JW, Chung JM and Yaksh TL. Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Method. 1994;53:55-63. 18. He L, Lee NM. Delta opioid receptor enhancement of mu opioid

Autoradiographic mapping of the opioid receptor-like 1 (ORL1) receptor in

receptor-induced antinociception in spinal cord. Journal of

the brains of mu-, delta- or kappa-opioid receptor knockout mice.

Pharmacology and Experimental Therapeutics. 1998;285(3):1181-6.

Neuroscience. 2001;106(3):469-80.

Volume 4: Number 1. 2011 | Page 27


RCSIsmjcase report Primary peritoneal carcinoma: an uncommon entity

Royal College of Surgeons in Ireland Student Medical Journal. 2011;4(1):28-30.

Background

Kah Poh Loh1, Hatem Ghorab1, Dr Jane Thorne2, Mr Athar Sheikh3, Professor Arnold Hill4 1RCSI medical students 2Pathology Registrar,

Histopathology Department,

Primary peritoneal carcinoma (PPCa) is a rare neoplasm originating from the cells of the peritoneal cavity, first described in 1959 by Swerdlow.1 It is less common than peritoneal carcinomatosis, an advanced stage of abdominal malignancy with extensive metastasis of tumours to the peritoneum. PPCa was also previously known as extra-ovarian primary peritoneal carcinoma or primary serous papillary carcinoma of the peritoneum. Histologically, PPCa cannot be differentiated from primary epithelial ovarian carcinoma, as the ovary and the peritoneal epithelium share a common embryological origin. As such, the diagnosis of PPCa is based on minimal or non-involvement of the ovaries.2 Overall, PPCa is thought to account for 10% of ovarian malignancies. Previous reports have identified women with primary peritoneal cancer as being older and with late menarche.4 PPCa has been reported most frequently in postmenopausal women with a mean age of 64.4 years.4

Beaumont Hospital, Dublin 3Senior Registrar in Surgery,

Department of Surgery, Beaumont Hospital, Dublin, and RCSI 4Professor of Surgery,

Department of Surgery, Beaumont Hospital, Dublin, and RCSI

Page 28 | Volume 4: Number 1. 2011

The case We report the case of a 58-year-old woman who presented with a three-day history of progressive generalised abdominal pain slowly localising to the left iliac fossa and the back. The pain was associated with constipation and abdominal distension. The patient had a background history of hypothyroidism and hypercholesterolaemia. Her social and family history was non-contributory. On physical

examination, she was in tachycardia but was otherwise haemodynamically stable. There was generalised abdominal guarding and focal tenderness over the left iliac fossa. Bowel sounds were present and there was no evidence of ascites or bleeding per rectum. Clinical suspicion at that time was of a perforated diverticulum with diverticulitis causing an acute abdomen. Further investigations showed significant raised C-reactive protein (248mg/L). Chest and abdominal x-ray did not suggest any abnormality. An abdominal CT scan demonstrated a large inflammatory mass in the lower abdomen and left iliac fossa. The mass was thought to represent multiple loops of markedly thickened small bowel with adjacent inflammatory change (Figure 1). There was no evidence of obstruction. A diagnosis of probable intra-abdominal malignancy was made. The patient underwent laparotomy. During the operation, a large mass was identified adjacent to the mesentery of the small bowel and transverse colon (Figure 2). The mass was well circumscribed with a smooth outline. Thickened loops of small bowel were also seen. The mesenteric mass was excised along with a short segment of adherent small bowel. Both ovaries had a normal gross appearance. Since abdominal lymphoma is a common small bowel malignancy, it was deemed the most likely diagnosis. The patientâ&#x20AC;&#x2122;s post-operative course was uneventful. The resected mass and small


RCSIsmjcase report

FIGURE 1: Computed tomography (CT) scan showing a left abdominal mass (arrow).

FIGURE 2: Macroscopic appearance of the resected mass during laparotomy.

bowel were sent for histological evaluation. The mass measured 155 x 120 x 80mm with attached mesenteric fat, and in aggregate weighed 570g. The external aspect of the mass was smooth, and the cut surface was heterogeneous with lobules of creamy material and areas of haemorrhage. No cystic areas were seen. The resected length of small bowel measured 280mm and appeared to be dusky and haemorrhagic with areas of exudate on the surface. The mucosa was friable in areas. The appearance was consistent with the clinical suspicion of a lymphoma. Microscopically, the tumour was well circumscribed and composed of solid sheets of malignant cells lining micro-papillary structures (Figure 3a). Abundant psammomatous calcification and necrosis was identified (Figure 3a). Vascular invasion was evident. The serosal surface of the small bowel was infiltrated with tumour but none of the 11 mesenteric lymph nodes retrieved

were involved (Figure 3b). Following discussion at a multidisciplinary conference involving the pathology, surgical and oncology teams, the consensus was that because of the absence of ovarian pathology, the tumour should be considered as a primary peritoneal micro-papillary serous carcinoma. Following the diagnosis, an abdominal and pelvic ultrasound showed endometrial fundus thickening greater than 10mm, but no cystic or solid lesions were noted in the ovaries. A repeat CT abdomen identified a few small lymph nodes in the retroperitoneal space with no mesenteric deposits. In addition, there were no suspicious metastatic lesions or lymph nodes involved. The tumour marker cancer antigen 12-5 (CA12-5) was shown to be elevated at 207kU/L (0-35kU/L). Serologies for tumour markers CA19-9 and carcinoembryogenic antigen (CEA) were negative. The patient was subsequently referred to a medical oncologist for six courses of chemotherapy, specifically carboplatin 770mg/m2 and paclitaxel 276mg/m2.

FIGURE 3a: Microscopic findings of tumour cells showing micro-papillary structures (black arrow) and psammoma bodies (white arrow) (H&E staining, magnification x400).

FIGURE 3b: Microscopic image showing tumour infiltration of the small bowel serosal surface (arrow) (H&E staining, magnification x100).

Volume 4: Number 1. 2011 | Page 29


RCSIsmjcase report Discussion About 1.9% of acute abdomen cases are associated with intra-abdominal malignancy, and this figure increases to 10% in patients over 50 years.5 PPCa is best considered as a diagnosis of exclusion; the more evident diagnosis of metastatic carcinoma or primary lymphoma must be considered first. Presenting complaints of patients with PPCa are similar to that of primary ovarian cancer, which include abdominal pain and distension, back pain, irregular period and dyspareunia.6 Ascites is the most frequent presenting clinical sign.6 In this case, there was no clinical, radiological or operative suspicion of a PPCa. The patient presented with abdominal and back pain associated with abdominal distension and constipation, but ascites was not present during physical examination and laparotomy. The patient’s presenting symptoms are often associated with benign conditions and warrant thorough investigation. The differential diagnosis for left iliac fossa pain includes diverticulitis, ischaemic bowel, inflammatory bowel disease, bowel obstruction, colorectal carcinoma and ovarian carcinoma. In this case, an abdominal aortic aneurysm was also suspected given the patient’s complaint of back pain. However, relevant negative symptoms, including blood in the stool, absent bowel sounds, ascites, consistent family or social history, chest pain, bruits or an abdominal pulsating mass, helped to rule out these differential diagnoses. Imaging techniques aided in the diagnosis and management of the patient. In fact, the abdominal CT scan revealed a large inflammatory mass in the left iliac fossa that was not detected on chest and abdominal x-ray. Such a mass suggests intra-abdominal malignancy; however, a definitive diagnosis cannot be reached without histological confirmation. A laparotomy was performed with curative intent. However, the resected mass was

subsequently evaluated, which established the diagnosis of PPCa. PPCa and ovarian cancer have similar responses to chemotherapy and are treated with the same chemotherapeutic agents.7 The standard first-line chemotherapeutic agents in ovarian carcinoma or PPCa are carboplatin and paclitaxel.8 Intraperitoneal chemotherapy was reported to improve overall survival in patients with ovarian carcinoma or PPCa by 5.5 months when compared to intravenous administration. This was attributed to a greater bioavailability of chemotherapeutic agents when delivered directly into the peritoneal cavity.9 The patient underwent a primary cytoreductive surgery and six cycles of chemotherapy. Recurrence of the malignancy has yet to be detected. The prognosis of PPCa is generally poor. A recent systematic review reported a median survival for PPCa of two to six months less than survival rates for ovarian cancer.10 However, the largest published UK series of patients with PPCa suggested similar prognosis and survival in both groups – 21 months and 19 months for PPCa and ovarian carcinoma, respectively.4 In summary, tissue diagnosis must first be established to diagnose a PPCa. Since the presenting complaints and initial clinical investigations from patients with PPCa are similar to those with primary ovarian cancer, intra-operative assessment of the ovaries with corresponding ovarian imaging is essential to exclude a primary ovarian epithelial tumour. PPCa should be considered in patients who present with abdominal pain, particularly in the presence of a mass on imaging and absence of ovarian pathology.

Acknowledgements We would like to thank the Department of Radiology at Beaumont Hospital for providing the radiological image.

References 1.

Swerdlow M. Mesothelioma of the pelvic peritoneum reassembly

form of extraovarian peritoneal serous papillary carcinoma with

papillary cystadenocarcinoma of the ovary. Am J Obstet Gynecol.

solitary tumor in the abdominal wall: A case report and literature review. J Obstet Gynaecol Res. 2009;35(6):1142-7.

1959;77:197-200. 2.

Moccia F, Cimmino M, Santabarbara G, De Vita F, Trapani V, Romano

7.

Eltabbakh GH, Piver MS. Extraovarian primary peritoneal carcinoma.

8.

Metzger-Filho O, Moulin C, Dhondt V. First-line systemic treatment of

Oncology. 1998;12:813-9.

G et al. A rare case of extraovarian primary peritoneal carcinoma in a 72-year-old woman. BMC Geriatrics. 2010;10(Suppl. 1):A16. 3.

Rothacker D, Mobius G. Varieties of serous surface papillary

ovarian cancer: a critical review of available evidence and

carcinoma of the peritoneum in Northern Germany: A thirty-year

expectations for future directions. Curr Opin Oncol. 2010;22(5):513-20.

autopsy study. Int J Gynecol Pathol. 1995;14:310-8. 4.

Jaaback KS, Ludeman L, Clayton NL, Hirschowitz L. Primary peritoneal carcinoma in a UK cancer center: comparison with advanced ovarian carcinoma over a 5-year period. Int J Gynecol Cancer. 2006;16(Suppl. 1):123-8.

5.

6.

9.

Armstrong DK, Bundy B, Wenzel L, Huang HQ, Baergen R, Lele S et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med. 2006;354:34-43.

10. Pentheroudakis G, Pavlidis N. Serous papillary peritoneal carcinoma:

De Dombal FT, Matharu SS, Staniland JR, Wilson DH, MacADam WA,

unknown primary tumour: ovarian cancer counterpart or a distinct

Gunn AA et al. Presentation of cancer to hospital as ‘acute abdominal

entity? A systematic review. Crit Rev Oncol Hematol.

pain’. Br J Surg. 2005:67(6):413-6.

2010;75(1):27-42.

Matsuura T, Sugihara K, Kohmura Y, Sugimura H, Kanayama N. Rare

Page 30 | Volume 4: Number 1. 2011


RCSIsmjcase report Ring-enhancing tumefactive multiple sclerosis

Royal College of Surgeons in Ireland Student Medical Journal. 2011;4(1):31-34.

Yoshihiro Katsuura RCSI medical student

Multiple sclerosis (MS) is an inflammatory disorder characterised by the demyelination of axons producing plaques in the brain and spinal cord.1 The pattern of inflammation follows a relapsing course punctuated by periods of remyelination, with symptoms of neurodegeneration that correspond to the site and onset of inflammatory lesions.1 MS lesions are disseminated in time and space, in that new lesions occur over time in different areas of the central nervous system (CNS). The disease is triggered in genetically predisposed individuals by poorly understood environmental factors.1 While the aetiology of the disease remains elusive, there is growing evidence that viruses trigger the disease.1,2 Of note, the regional prevalence of MS is proportional to the distance from the equator.1 MS is diagnosed using a combination of clinical evidence, and laboratory and radiographic findings.1,3 Typical MS plaques appear on MRI as well demarcated, homogenous, ovoid lesions with no mass effect.4 However, atypical features

on MRI, such as solitary lesions larger than 2cm with mass effect and/or ring enhancement, have been described.5,6 Such lesions fall under the category of CNS inflammatory demyelinating disease or tumefactive MS.5 Because of its relative rarity (one to two cases per 1,000 MS cases), tumefactive MS is often mistaken for other conditions, such as brain tumour or cerebral abscess.6,7 The clinical presentation of tumefactive MS varies based on the site of the lesion, but can include cognitive abnormalities, mental confusion, aphasia, apraxia and/or seizures.5

Case A 27-year-old woman with no pre-existing medical conditions initially reported to her GP that she was feeling ‘slow’ and was having difficulty typing messages at work. Specifically, she reported difficulty with spelling, and could no longer remember how to spell correctly. She compared the feeling to ‘being drunk’, and reported that her 32-year-old sister had been

Volume 4: Number 1. 2011 | Page 31


RCSIsmjcase report Table 1: Microbiology and toxicology screen. Basic metabolic panel Sodium Potassium Chloride CO2 Glucose Urea nitrogen Creatinine Calcium GFR calculation Phosphorus Albumin Total protein Bilirubin total Bilirubin direct Alkaline phos. SGOT (AST) SGPT (ALT)

138 (ref: 135-147mEq/L) 4 (ref: 3.5-5mEq/L) 102 (95-105mEq/L) 24 (ref: 33-44mmHg) 145 (ref: 70-110mg/dL) 10 (7-18mg/dL) 0.7 (0.6-1.2mg/dL) 9.7 (ref: 8.4-10.2mg/dL) >60ml/min 4.4 (ref: 3-4.5mg/dL) 4.5 (ref: 3.5-5.5g/dL) 7.4 (ref: 6-7.8g/dL) 0.7 (ref: 0.1-1mg/dL) 0.2 (ref: 0-0.3mg/dL) 55 (ref: 30-120IU/L) 14 (ref: 10-40IU/L) 24 (ref: 9-60IU/L)

Urine drug screen Amphetamines Barbiturates Benzodiazepines Cannabinoids Cocaine Opiates Methadone Phencyclidine Oxycodone

Negative Negative Negative Negative Negative Negative Negative Negative Negative

CSF viral panel Fungal CSF culture Cryptococc AG CSF CMV by PCRCMV by PCR HSV by PCRHSV by PCR

Negative Negative Negative Negative Negative Negative

Bacteriology Blood culture CSF culture Urine culture

Negative Negative Negative

Bacterial Ag-CSF E. coli K1 H. influenzae T S. pneumoniae Group B strep. N. meningitidis GR.B N. meningitidis A/Y N. meningitidis C/W135

Negative Negative Negative Negative Negative Negative Negative

Miscellaneous microbiology Syphilis screen

Negative

Page 32 | Volume 4: Number 1. 2011

FIGURE 1: Axial CT head showing right frontal periventricular hypointensity. diagnosed with MS. Her GP referred her to the emergency room at Montefiore Medical Center, New York, where she was subsequently referred to the neurological inpatient service. At Montefiore, a neurological physical examination was conducted, and it was found that the patient had a slight right-sided facial droop with forehead sparing and partial right ptosis. The patient had difficulty performing the clock drawing test (a tool to assess cognitive function) and was visibly confused.8 Differential diagnoses for encephalopathy, including bacterial and viral meningitis, metabolism-associated encephalopathy (hepatic encephalopathy, hypoglycaemia), and drug and alcohol abuse, were ruled out based on normal metabolic parameters, toxicology reports and negative cerebrospinal fluid (CSF), blood and urine cultures (Table 1). The patient underwent a CT brain, which did not reveal any pathology. However, under close scrutiny, a right-sided frontal hypodensity in the periventricular area could be vaguely discerned, but the nature of the lesion, if any, was unclear (Figure 1). Further investigations were ordered, including a lumbar puncture and an MRI of the brain. What was unclear in the CT scan became strikingly obvious in the MRI. It showed a large, arresting periventricular white matter lesion with concentric ring


RCSIsmjcase report

FIGURE 2: Axial T2-weighted fluid-suppressed MRI at the level of the anterior cingulate gyrus showing a large (>2cm) hyperintense ovoid lesion with ring enhancement and mass effect. enhancement and mass effect, consistent with a number of cerebral pathologies, including tumefactive MS (Figure 2). Another smaller lesion was noted in the inferior sections (Figure 3). The lumbar puncture results supported the clinical suspicion of MS by demonstrating an elevated white cell count, a high protein level and a positive oligoclonal IgG band reading (Table 2). The patient was started on a course of intravenous methylprednisolone, which is useful in alleviating acute episodes of MS.1 This treatment resolved the patientâ&#x20AC;&#x2122;s cognitive symptoms and she was subsequently discharged. The patient was re-admitted to the hospital one week later with a similar attack of greater severity. She reported symptoms of worsening confusion, slurred speech and left hand weakness, which were consistent with a right-sided cerebral lesion. Another course of methylprednisolone was administered and the patient was discharged on oral steroids. A diagnosis of tumefactive MS was made based on a combination of clinical, laboratory and radiological criteria.

Discussion The patient presented in an acute state of confusion and encephalopathy, both of which are common in tumefactive MS.5 Positive CSF for oligoclonal bands and a large ovoid lesion with ring enhancement on MRI are also suggestive of tumefactive MS. Establishing a diagnosis of MS is challenging, as there are no pathognomonic clinical findings or tests.2 In addition, imaging results and clinical signs can be confused with other conditions, specifically neoplasms and cerebral abscesses.5,6 The diagnosis of MS is facilitated by the McDonald diagnostic criteria.3 The McDonald criteria use a combination of clinical, laboratory and radiological findings to standardise the diagnostic process and provide clinicians with a means to detect MS in its early stages with high specificity (Table 3).3 These criteria reaffirm the need to demonstrate dissemination of clinical events and lesions in time and space.5

FIGURE 3: Axial T2-weighted fluid-suppressed MRI roughly at the level of dorsal caudate, splenium and genu of the corpus callosum, showing the inferior aspect of the large lesion and a small, hyperintense ovoid lesion in the splenium of the corpus callosum. In this case, the patient met the McDonald criteria: firstly by demonstrating a clinical presentation of one acute event of cognitive decline; secondly, there was evidence for two or more clinical lesions disseminated in space; and, thirdly, dissemination in time was demonstrated by a second clinical episode one week after discharge. Typically, radiological findings of MS include multiple, well demarcated, homogenous, small ovoid lesions with no mass effect, often oriented perpendicular to the long axis of the lateral ventricles.5 This patient was diagnosed with tumefactive MS based on the following MRI criteria: a solitary large lesion greater than 2cm in diameter; associated mass effect (mild sulcal effacement or moderate subfalcine or uncal herniation); and, perilesional oedema and/or the presence of ring enhancement.5,6 As tumefactive MS mimics other pathologies, it is sometimes necessary to confirm the diagnosis with a brain biopsy, although awareness of the clinical spectrum may obviate this need.5 Based on this patientâ&#x20AC;&#x2122;s clinical symptoms and findings, as well as her family history of MS, an invasive biopsy was deemed unnecessary. Close follow-up, including Table 2: CSF parameters. Cerebrospinal fluid (CSF) Colour WBC count RBC count Glucose Total protein Oligoclonal IgG bands IgG/pro IgG CSF

colourless/clear 25 cells/mm3 (ref: 0-5 cells/mm3) 51 cells/mm3 (ref: 0 cells/mm3) 70mg/dL (ref: 40-70mg/dL) 42mg/dL (ref: <40mg/dL) Positive 0.15 (ref: high nl is 0.14) 6.2 (ref: 0.5-6mg/dL)

Volume 4: Number 1. 2011 | Page 33


RCSIsmjcase report Table 3: The McDonald criteria: diagnostic criteria for multiple sclerosis.5,7 Clinical presentation

Additional data needed

Two or more attacks; objective clinical evidence of two or more lesions

None

Two or more attacks; objective clinical evidence of one lesion

Dissemination in space demonstrated by – MRI; – two or more MRI-detected lesions consistent with MS plus positive CSF; or, – await further attack implicating a different site

One attack; objective clinical evidence of two or more lesions

Dissemination in time demonstrated by: – MRI; or, – second clinical attack

One attack; objective clinical evidence of one lesion

Dissemination in space demonstrated by: – MRI; or, – two or more MRI-detected lesions consistent with MS plus positive CSF And, Dissemination in time demonstrated by: – MRI; or, – second clinical attack

Insidious neurological progression suggestive of MS

One year of disease progression (retrospectively or prospectively determined) and two of the following: – positive brain MRI (nine T2 lesions or four or more T2 lesions with positive VEP); – positive spinal cord MRI (two focal T2 lesions); or, – positive CSF

Attack: an episode of neurological disturbance caused by lesions that are inflammatory and demyelinating in nature. MRI abnormality: three of the following: 1. At least one gadolinium-enhancing lesion or nine T2 hyperintense lesions if there is no gadolinium-enhancing lesion. 2. At least one infratentorial lesion. 3. At least one juxtacortical lesion. 4. At least three periventricular lesions. MRI evidence of dissemination in time: either of the following: 1. Detection of gadolinium enhancement three months after onset of initial clinical event at a different site. 2. Detection of a new T2 lesion if it appears at any time compared with a reference scan done at least 30 days after the onset of the initial clinical event. CSF: oligoclonal IgG bands in the CSF (and not serum) or increased IgG index.

Page 34 | Volume 4: Number 1. 2011

repeat MRI scans to monitor lesion development and medical management in an outpatient setting, was determined to be the most appropriate coarse of action. Typical therapy for MS consists of three approaches, namely immune-modifying agents targeting the pathogenesis of MS, palliative treatments directed at individual symptoms, and disability/psychological management.2 Immune-modifying agents include high-dose methylprednisolone, interferon and monoclonal antibodies. Intravenous methylprednisone is used to treat acute episodes and should not be administered more than twice a year since it has no impact on prognosis. Interferon decreases relapses and lesion accumulation by 30% and has little impact on degree of disability. Monoclonal antibodies (natalizumab) decrease relapse rate in relapsing-remitting MS and reduce MRI lesions. A multi-disciplinary approach towards the management of MS is necessary, and therefore physical and occupational therapists, neuropsychologists and social workers must be involved.

Conclusion This report showcases an extremely rare variant of MS known as tumefactive MS and describes the clinical facets involved in its diagnosis. Tumefactive MS is estimated to account for one to two cases per 1,000 cases of MS, and can often confound the diagnostic process by presenting with atypical radiographic features mimicking other CNS pathology, such as tumours or cerebral abscesses.5,6 Use of the McDonald criteria can assist the physician in making a diagnosis of MS, reducing unnecessary surgical and medical intervention.

References 1. Compston A, Coles A. Multiple sclerosis. Lancet. 2008;372:1502-17. 2. Longmore M, Wilkinson IB, Rajagopalan SR. Oxford Handbook of Clinical Medicine (8th ed.). Oxford: Oxford University Press, 2010:500-1. 3. Polman CH, Reingold SC, Edan G, Filippi M, Hartung HP, Kappos L et al. Diagnostic Criteria for Multiple Sclerosis: 2005 Revisions to the ‘McDonald Criteria’. Ann Neurol. 2005;58:840-6. 4. Barkhof F, Filippi M, Miller DH, Scheltens P, Campi A, Polman CH et al. Comparison of MRI criteria at first presentation to predict conversion to clinically definite multiple sclerosis. Brain. 1997;120:2059-69. 5. Lucchinetti CF, Gavrilova RH, Metz I. Clinical and radiographic spectrum of pathologically confirmed tumefactive multiple sclerosis. Brain. 2003;131:1759-75. 6. Schwartz K, Erickson BJ, Lucchinetti CF. Pattern of T2 hypointensity associated with ring-enhancing brain lesions can help differentiate pathology. Neuroradiology. 2006;48:143-9. 7. Annesley-Williams D, Farrell MA, Staunton H, Brett FM. Acute demyelination, neuropathological diagnosis, and clinical evolution. J Neuropathol Exp Neurol. 2000;59(6):477-89. 8. Forti P, Olivelli V, Rietti E, Maltoni B, Ravaglia G. Diagnostic performance of an Executive Clock Drawing Task (CLOX) as a screening test for mild cognitive impairment in elderly persons with cognitive complaints. Dement Geriatr Cogn Disord. 2010;30(1):20-7.


RCSIsmjreview Editors’ pick Total artificial heart transplants: future or biding time? Abstract Artificial heart transplant machines now provide viable treatment options for heart failure. The shortage of donor organs has created a need for artificial transplant machines. These machines exhibit increasing success in providing a ‘bridge to transplant’ period during which a donor organ can be found. Now artificial hearts have improved survival rates to approximately 80%. It is possible that these machines may have a greater role to play as their costs decrease and technological improvements increase reliability. This article outlines the latest advances in both artificial hearts and the role of these devices in the treatment of heart conditions in the future. In addition, there is a brief discussion on competing technologies and their limitations. Keywords: Artificial, bridge to transplant, heart, SynCardia (CardioWest), transplant. Royal College of Surgeons in Ireland Student Medical Journal. 2011;4(1):35-38.

Introduction

William MG Johnson RCSI medical student

Heart failure is a syndrome defined by the inability of the heart to eject enough blood to meet the demands of the body. It affects approximately 20 million people worldwide.1,2 Treatment options, both pharmaceutical and non-pharmaceutical, have evolved over the years, showing promise of a cure. The current gold standard of treatment with regard to end-stage heart failure is a total heart transplant (HTx).3 With only 10% of the total transplant requirement worldwide met in 2008, the consequence of mortality is a reality for many patients who are awaiting a HTx.4 From the first heart–lung perfusion machines to the more modern left ventricular assist devices (LVADs), and now total artificial heart transplants (TAHs), this period, known as ‘bridge to transplant’ (BTT), has become dramatically less associated with

mortality.5 Since the implementation of the SynCardia TAH, bridge to transplant survival rates have increased from 46% to 79%.6 In the immediate future, these devices can be extended beyond their use only as BTT devices for more long-term therapy, much as LVADs have already done. There will soon be an FDA-approved total permanent artificial heart transplant as a destination therapy.7 Clinical trials are underway on the AbioCor implantable replacement heart (IRH), which, in a recent study, was implanted in seven patients.7 However, this may not become first-line therapy, as smaller LVADs, in vitro organ growth, and in situ cell replacement therapy could show substantial advancements in the prevention and treatment of heart failure.

Volume 4: Number 1. 2011 | Page 35


RCSIsmjreview

FIGURE 1: Chest x-ray of a patient with an implanted SynCardia device highlighting the replacement of the native valves and the deviceâ&#x20AC;&#x2122;s pneumatic diaphragm. Note the four prosthetic valves (A), two diaphragms (B) and the two coil-reinforced polyurethane tubes (C). (Courtesy: Syncardia.com.5)

Left ventricular assist devices The first of the modern treatments for heart failure lay in the development of assist devices. These paved the way for the development of more complicated mechanisms such as the TAH. These apparatus do not act to take over the action of the heart; rather, they reduce the stress exerted on the heart, allowing it to rest and recover. Development of these devices accelerated in the 1960s and â&#x20AC;&#x2DC;70s due to complications and mortality associated with early total HTxs.8 The evolution of pump technology brought about two main types of devices: pulsatile LVADs, where blood is pumped through the internal device via an external pump mimicking the action of the heart; and, continuous flow pumps (axial and centrifugal), in which a magnetically controlled rotor forces blood

FIGURE 2: The portable pneumatic driver seen here attached to a SynCardia TAH offers the patient mobility and enables the patient to return home until the heart transplant. (Courtesy: syncardia.com.5)

through the device. It should be noted that when a continuous flow pump is implanted the patient will employ an abnormal non-pulsatile state, posing difficulties in clinical measurement of pulse and blood pressure. Both types of devices are implanted in the thorax and attached via a cannula to the left and/or right ventricle (RVAD), finally inserting into the aorta.8 Mechanical failure is a challenge with these devices and primarily affects the moving parts of the device. A new approach is being implemented in continuous flow pumps where traditional ball bearings are being replaced by hydrodynamic and magnetic suspensions.8 This allows for only one moving part, the rotor, ultimately decreasing the incidence of mechanical failure. This trend in reducing the number of moving parts can be seen in many heart

FIGURE 3a-d: The sequence in which the native heart is removed and the SynCardia total artificial heart transplant is placed. (Courtesy: syncardia.com.5)

Page 36 | Volume 4: Number 1. 2011


RCSIsmjreview Table 1: Occurrence of adverse events in a group of 95 patients who received a SynCardia implant.9

Adverse event

Percentage experienced

Infection Bleeding Hepatic dysfunction Respiratory dysfunction Renal dysfunction Neurologic event Operation complications Reduced blood pressure Device malfunction Peripheral thromboembolism Reduced cardiac index Fitting complication Haemolysis Technical or procedural problem Other problem

77% 62% 37% 36% 31% 27% 24% 19% 17% 14% 9% 5% 4% 3% 9%

devices.8 Another complication that plagues similar cardiac apparatus is the risk of thromboembolism.6,8 In the future, these devices are predicted to flourish, not only as a cheaper alternative to TAHs but also because improvements in design, making these devices smaller, will make them less invasive.8 It can be foreseen that future devices will be implemented in the earlier stages of heart failure, acting in a prophylactic manner to prevent the advancement of heart disease.8

SynCardia total artificial heart transplant The SynCardia TAH (also known as the CardioWest TAH) is the only FDA-approved TAH on the market today and has been implanted in approximately 850 patients to date.5 The device is composed of two symmetrical chambers in which a pneumatically driven diaphragm is depressed and then elevated, causing the injection and ejection of blood at a rate of up to 9.5L/min.5 This system uses the patientâ&#x20AC;&#x2122;s own muscle tone and body movement to alter its ejection fraction in response to exercise by up to 30%.5 This allows for increased patient activity in contrast to similar systems. Like the pulsatile LVADs, the device is attached to an external pneumatic driver. This driver is initially non-mobile and upon patient recovery can be switched to a mobile model that can be carried5 (Figure 2). The implantation of the SynCardia TAH involves bilateral removal of the ventricles along with all four native valves at the ventricular valvular junctions between the atria, pulmonary artery and aorta (Figure 3a). The atria, pulmonary artery and aorta are then preserved for attachment to the TAH (Figure 3b). Quick connect devices then attach the TAH to the residual portions of the heart via sutures, creating a contact for the TAH (Figure 3c). Finally, the TAH is attached and the commencement of artificial perfusion follows (Figure 3d).5

FIGURE 4: Anatomical position of the SynCardia TAH and its pneumatic drivelines. The drivelines enter the patient along the left midclavicular line, approximately 5cm below the costal margin. The TAH lies in the mediastinum attached to the atria, pulmonary artery and the aorta. (Courtesy: syncardia.com.5) What sets the SynCardia TAH apart from other devices is its ability to eliminate ventricular, valvular and electrical complications, such as ventricular tachycardia, sinus tachycardia and atrial fibrillation, which are experienced with pacemakers.9,10 In addition, the apparatus exhibits certain advantages over the use of LVADs, such as its application in patients with recurrent intracardiac thrombi, shunts, structural damage and congenital defects.11 As with all prostheses, inherent complications can occur, as outlined in Table 1. An overwhelming number of patients acquire post-procedural infections, contributing to a mortality rate as high as 9% in infected patients.9 Platis et al. recorded respiratory infections in up to 40%, genito-urinary infections in up to 22%, and pneumatic insertion line-associated infections in up to 14% of post-procedural patients.6 Other studies have recorded infection rates as low as 20%.12 Aggressive antibiotic treatment is the current treatment for these infections, but increasing microbial resistance is a potential challenge.12 The compounded results of these complications are exhibited in patients experiencing multiple organ failure, which has ultimately resulted in increased mortality rates.12 Additionally, formation of intra-prosthesis thromboemboli poses a serious threat to the individual.6 With the current treatment involving the use of anti-coagulative therapy, postoperative bleeding is a significant risk to the patient.12 The future looks forward to the development of less thrombogenic materials and hence devices that can avoid these complications. The use of diaphragms in future devices is promising, as fewer moving parts may increase durability. Upcoming developments in perfusion-correcting technologies are heralded to reduce many complications, such as those associated with hepatic, renal and mesenteric ischaemia.12

Volume 4: Number 1. 2011 | Page 37


RCSIsmjreview Valuation of cost to health systems funded.13

Currently, the majority of TAH transplants are privately The current price of a SynCardia TAH transplant is approximately $150,000US, compared to the cost of an LVAD in the range of $100,000US, depending on country.13 Increasing pressure on public health centres for the best available treatment conflicts with budgetary constraints in many countries. It seems pragmatic to adopt more feasible approaches to heart failure, such as the use of widespread, less effective drug treatments. Such treatments include diuretic regimes that offer only a modest resolution of patient symptoms.2 With the growing interest by many prosthetic development companies and an increasing demand for artificial heart transplant technology, it seems plausible that devices will become more affordable.8 Nevertheless, it is unrealistic to say that this technology will be available for all patients with heart failure in the future.

Future advancements Currently, TAH is implemented as a BTT treatment rather than a destination therapy. The AbioCor IRH is in the process of obtaining FDA approval, but complications associated with thromboembolic events and thrombus formation on its atrial attachments must be resolved before it receives market and professional approval.6,7 This new device offers a transcutaneous energy transfer (TET) system and a radio communication system, avoiding the use of vents and intra-abdominal ports. Other features include automated monitoring and control of motor speeds, pump rate and flow balance by means

of an intra-abdominal sensor system.7 Future models of LVADs and TAHs will employ these features of transcutaneous current transduction as a means to power devices, thus eliminating the need for intra-abdominal line placement and reducing line infection.7,14 Other technologies under development rely on increasing the afterload of the heart by constricting the aorta. The C-Pulse (Sunshine Heart Inc, Tustin, CA) device relies on an inflatable cuff that intermittently expands around the circumference of the ascending aorta, thereby increasing cardiac output.15 However, the use of intra-abdominal lines may result in line sepsis that can have devastating consequences, contributing to fatality of approximately 1%.9 This was demonstrated in the case study by Mitnovetski et al.15 With the current technology, it is plausible that the use of TAHs will increase, as will the development of devices with lower mechanical faults, more systemic control, increased patient freedom and fewer overall complications. Artificial heart transplant machines provide viable treatment options for heart failure, so this medical field warrants further research and development to keep pace with the emerging technology.

Acknowledgements I would like to thank all of my colleagues at St Vincentâ&#x20AC;&#x2122;s Private Hospital, Sydney, Australia, and a special thank-you to Dr Frank Junius for his help and mentoring.

References 1. Joseph SM, Cedars AM, Ewald GA, Geltman EM, Mann DL. Acute decompensated heart failure. Tex Heart Inst J. 2009;36(6):510-20. 2. Dynamed. Heart Failure [homepage on the internet], c2010. Updated November 3, 2010. Cited November 25, 2010. Available from: http://dynaweb.ebscohost.com. 3. Boilson BA, Raichlin E, Park SJ, Kushwaha SS. Device therapy and cardiac transplantation for end-stage heart failure. Curr Probl Cardiol. 2010;35(1):8-64. 4. transplant-observatory.org [homepage on the Internet]. Global Observatory on Donation and Transplantation, c2006. Updated 2008. Cited October 8, 2010. Available from: http://www.transplant-observatory.org/Pages/DataReports.aspx. 5. Syncardia.com [homepage on the Internet]. SynCardia Systems, Inc., c2010. Updated October 7, 2010. Cited October 8, 2010. Available from: http://www.syncardia.com/. 6. Platis A, Larson DF. CardioWest temporary total artificial heart. Perfusion. 2009;24(5):341-8. 7. Dowling RD, Gray LA, Etoch SW et al. The AbioCor implantable replacement heart. Ann Thorac Surg. 2003;75:S93-S99. 8. Frazier OH. Current status of cardiac transplantation and left ventricular assist devices. Tex Heart Inst J. 2010;37(3):319-21.

Page 38 | Volume 4: Number 1. 2011

9. Copeland JG, Smith RG, Arabia FA et al. Cardiac replacement with a total artificial heart as a bridge to transplantation. N Engl J Med. 2004;351(9):859-67. 10. Dietrich PF, Werner J, Wolfgang F. Complications of pacemaker-defibrillator devices: diagnosis and management. Am Heart J. 1994;127:1073-80. 11. El-Banayosy A, Arusoglu L, Morshuis M. CardioWest total artificial heart: bad Oeynhausen experience. Ann Thorac Surg. 2005;80(2):548-52. 12. Frazier OH, Shah NA, Myers TJ. Total artificial heart [monograph on the internet]. New York: McGraw-Hill, 2003:1507-1514. Cited October 8, 2010. Available from: http://cardiacsurgery.ctsnetbooks.org/. 13. Benson K. How to mend a broken heart. The Sydney Morning Herald, August 19, 2010. Available from: www.smh.com.au. 14. Bank AJ, Mir SH, Nguyen DQ et al. Effects of left ventricular assist devices on outcomes in patients undergoing heart transplantation. Ann Thorac Surg. 2000;69:1369-74. 15. Mitnovetski S, Almeida AA, Barr A. Extra-aortic implantable counterpulsation pump in chronic heart failure. Ann Thorac Surg. 2008;85:2122-5.


RCSIsmjreview Subintimal angioplasty in critical limb ischaemia: a literature review

Abstract The aim of this review was to determine accurate estimates of the success rate of subintimal angioplasty and to compare those estimates with surgery in terms of ability to recanalise occluded vessels, patency over time and limb salvage rates. Each study included was analysed for the three primary outcome measures of technical success, 12-month primary patency, and 12-month limb salvage rates. The results of each outcome are presented as a percentage. Pooled estimates for technical success, primary patency at 12 months and limb salvage at 12 months were 87.7% (95% confidence interval: 86.8%-88.6%, 1,484 limbs), 55.8% (95% confidence interval: 51.9%-60%, 584 limbs), and 91.1% (95% confidence interval: 89.1%-93.1%, 762 limbs), respectively. This study demonstrates that the outcomes for subintimal angioplasty are good and that it should be considered as an alternative to surgical bypass in the treatment of critical limb ischaemia. Keywords: Subintimal, angioplasty, percutaneous intentional extraluminal revascularisation, critical limb ischaemia, peripheral arterial disease. Royal College of Surgeons in Ireland Student Medical Journal. 2011;4(1):39-45.

Introduction

Robert P Brennan RCSI medical student

Critical limb ischaemia (CLI) is defined as â&#x20AC;&#x2DC;ischaemic rest painâ&#x20AC;&#x2122; or Grade II Category IV on the Rutherford-Baker classification of peripheral arterial disease.1 Rest pain is defined as a severe unremitting pain in the foot, which is aggravated by lying supine. It is partially relieved by dangling the foot over the edge of the bed or standing on a cold floor. Patients may also have gangrene or ulceration of the tissue.2 The definition of CLI is summarised in Table 1. Studies have shown that CLI is associated with significant coronary artery disease in 75% of cases and 20% mortality in the first year post diagnosis. If their affected limb cannot be revascularised, 25% of these patients require a major amputation within one year.3 In addition to aggressive risk factor modification, most require surgical bypass to ensure

limb vascular patency. Infra-inguinal bypass surgery for occlusive peripheral vascular disease is associated with high hospital costs, significant morbidity and mortality rates, and poor long-term outcomes in terms of both limb salvage and mortality.4 Table 1: Definition of CLI. Rest pain

Ankle blood pressure

Limb salvage without revascularisation

Subcritical limb ischaemia

Yes

>40mmHg 27%

Critical limb ischaemia

Yes

<40mmHg 5%

Volume 4: Number 1. 2011 | Page 39


RCSIsmjreview Technique of subintimal angioplasty Following arterial puncture, an angled-tip catheter (e.g., Kumpe) is introduced proximally to the occlusion. 5,000IU of heparin is then administered. An angled guide wire (e.g., Terumo-0.035in) is then introduced, and it is encouraged to form a loop when the tip abuts the occlusion. During dissection, the loop will also appear to be slightly wider than the native vessel lumen diameter. If the wire is endoluminal the loop will appear narrow. Without the loop, the guide wire would not create a sufficiently wide subintimal channel and would also tend to go down collateral vessels or cause perforation. The loop also allows the stiffer part of the guide wire to be used to continue the dissection. While maintaining the loop in the guide wire, the catheter is then advanced behind it. The guide wire will naturally tend to re-enter the true lumen when it again encounters normal patent vessel. Successful re-entry into the lumen is usually heralded by a loss of resistance to the wire. This can be confirmed with injection of a small volume of contrast. There are now devices available to aid re-entry in difficult cases such as the Outback catheter and intravascular ultrasound (IVUS) guided Pioneer catheter. The whole length of the subintimal channel then undergoes angioplasty with rapid inflations of a long balloon (approximately 12-15cm) (Figure 2).

FIGURE 1 (from left): The wire beginning the dissection with the catheter; the dissection being continued with the looped wire; and, the wire breaking back into the lumen prior to angioplasty. (Courtesy: GE Healthcare.)

a

b

c

d

e

f

Unfortunately, there are few alternatives other than major lower limb amputation in those patients with long arterial occlusions who are unsuitable for transluminal angioplasty. Subintimal angioplasty (SIA) or percutaneous intentional extraluminal revascularisation involves intentional subintimal dissection with neolumen generation in occluded lower-limb arteries.11 Initially applied to the femoro-popliteal segments, this technique has been extended to the crural and iliac vessels.5,6 It was first reported by Bolia et al. in 1989, who inadvertently created a subintimal channel during the endovascular treatment of a long popliteal occlusion.7 This was recognised and a balloon angioplasty was performed, with a subsequent patency duration greater than nine years8 (Figure 1). According to the authors of this first report, vascular interventional radiology has been polarised into those who can reproduce these results and are proponents of SIA, and those who cannot.9 The published literature reflects these polarised viewpoints, with some authors supporting the technique and others dismissing it. The majority of these reports feature small series of patients and, to date, there remains little long-term follow-up data. For SIA to be a viable alternative to surgical bypass, long-term patency and limb salvage rates need to be evaluated and compared with those associated with surgery. Such is the aim of this literature review.

Page 40 | Volume 4: Number 1. 2011

FIGURE 2: (a,b) Images from a 79-year-old man who presented with ulceration and rest pain of his right foot demonstrate a long right superficial femoral arterial occlusion (arrow) with a prominent collateral vessel (arrowhead) at the origin of the occlusion. (c) The lesion was crossed subintimally; note the wide diameter of the guide wire loop (arrow) as it travels within the subintimal space. (d) The diameter of the guide wire loop (arrow) reduces as it re-enters the patent lumen below the level of the occlusion. (e) Luminal re-entry is confirmed with contrast agent injection (arrow). (f) After successful balloon dilation, patency is restored (arrow), with preservation of the collateral vessel (arrowhead).11

Methods Literature search A systematic search of the literature was performed with the assistance of a clinical librarian in the medical databases Embase and Pubmed. The timeframe for the searches was January 1980 to March 2010; the period prior to the first description of SIA was included to ensure that no earlier references existed. The keywords “subintimal angioplasty”, “percutaneous intentional extraluminal revascularisation”, and “peripheral arterial disease” were used, along with synonyms of them.

Study selection Studies were included in the analysis if they provided details of patients with CLI undergoing treatment for a femoral, popliteal or crural occlusion by SIA and their outcomes (immediate technical success, primary patency and limb salvage). Technical success was defined as good antegrade flow at completion of the procedure. Articles were rejected if they contained no primary data, contained data previously or subsequently reported in other articles, and were reports of small case series (fewer than 10 patients) or highly selected subgroups of patients.


RCSIsmjreview Table 2: Summary data for all 11 studies. First author Mid-date of study

R/P

Study type

Selection criteria

Disease severity

Lesion location

No. Technical SIA success

n

Akesson12

%

12-month follow-up data provided or extractable

Maximum length of follow-up data provided (months)

Primary Limb patency salvage

Primary Limb patency salvage

Stents used?

01/07/2000 R

Case note review

Unless very fit for surgery

CLI

Infrainguinal

193 148 77

No

No

36

36

Yes

Desgrange13 19/01/2001 R

Case note review

Not stated

Claudication and CLI

Infrainguinal

100 88

No

No

24

24

No

Hynes14

01/08/2002 R

Case Not note/ stated database review

CLI

Infrainguinal

158 158 100

No

Yes

12

No

Laxdal, 200315

01/04/2001 P

Registry Not review stated

Claudication and CLI

Femoro -popliteal

104 88

85

No

No

12

No

Laxdal, 200416

03/07/1999 R

Case note review

Not stated

Claudication and CLI

Femoro -popliteal

124 112 90

No

Yes

12

No

Lazaris17

31/08/2001 R

Case note review

Diabetics with CLI

CLI

Infrainguinal

112 100 89

No

Yes

36

No

London18

16/08/1989 R

Case note review

All patients

Claudication and CLI

Infrainguinal

200 159 80

Yes

No

Scott19

01/06/2003 R

Case note review

Not stated

Claudication and CLI

Femoro -popliteal

105 91

87

Yes

No

Tartari20

15/04/2004 R

Case note review

All patients

CLI

Infrainguinal

109 92

84

No

Tisi21

02/07/1999 R

Case note review

All patients

Claudication and CLI

Popliteotibial

158 135 85

Trocciola22

02/03/2003 P

Registry All review patients

Claudication and CLI

Femoro -popliteal

121 121 100

88

18

No

36

6

Yes

Yes

9

Yes

Yes

Yes

24

No

Yes

Yes

12

Yes

12

R = Retrospective; P = Prospective All blank fields indicate that the required information was unavailable. Volume 4: Number 1. 2011 | Page 41


RCSIsmjreview Data extraction The three principle outcome measures assessed in this study were immediate technical success rate of SIA, 12-month primary patency rate, and 12-month limb salvage rate. For each study, the total number of limbs treated and outcomes were recorded on a per-limb basis. The location of the lesions treated in each study was also recorded. For both primary patency and limb salvage rates, data were recorded on an intention-to-treat basis with the numerator being the number of limbs saved or patent at each time point and the denominator being the number of limbs that underwent attempted SIA at the outset of the study. As a temporal reference point for each study the mid-date of the study was calculated (the date mid-way from the reported start of the study to the end of the study). Three variables that were of interest were extracted from each study, for the purposes of determining whether these had any effect on patient outcome: the degree of limb ischaemia in patients undergoing SIA; the use of adjunctive stents; and, lesion location/patient selection criteria for SIA. Data pertaining to study design (retrospective or prospective, randomisation, size) were also determined.

Statistical methods Each study included was analysed for the three primary outcome measures of technical success, 12-month primary patency and 12-month limb salvage rates. Results of each outcome are presented as a percentage. Tables were constructed to demonstrate these results. The confidence intervals around a mean result were calculated using online statistical testing.10

extending from the femoral into the iliac artery). In view of the general aim of this literature review, the 11 largest studies were included.12-22 A larger sample size ensures a more accurate estimated confidence interval. No randomised controlled trials were found. All of the studies were retrospective (n=9) or prospective (n=2) patient series.

Study characteristics The 11 studies included in the analysis gave details of 1,484 limbs treated by SIA over a period of 14.67 years (study mid-dates August 1989 to May 2004) and the characteristics of these studies are shown in Table 2.

Analysis Technical success rates are shown in Tables 3 and 4. In patients with critical limb ischaemia, technical success rates show a large variation. The mean estimate for technical success rates in these studies was 87.7% (95% confidence interval: 86.8%-88.6%). The definition of patency varied considerably between studies. Primary patency was defined differently among studies as either patency of segment without intervention or absence of occlusion and absence of >50% or <30% stenosis in the treated segment. The mean estimate for the 12-month primary patency rate (four studies, 584 limbs) was 55.8% (95% confidence interval: 51.9%-60%).18,19,21,22 The mean 12-month limb salvage for the

Results Literature search

Table 4: Percentage technical success accompanied by 95% confidence interval of all studies reporting patients with mixed claudication and CLI, subdivided according to location of lesion; (a) femoropopliteal, (b) popliteotibial and (c) infrainguinal vessels.

A total of 190 articles were identified by the literature search, of which 155 were excluded after screening of title and abstract. The most frequent reasons for exclusion were study design, technique (other than SIA), and location of lesion (iliac artery or

a. Laxdal 200315

Table 3: Percentage technical success accompanied by 95% confidence interval of all studies reporting patients with CLI. The location of lesions in all these studies is infrainguinal.

Laxdal 200416 Scott19 Trocciola22

Akesson12

b. Tisi21

Hynes14 c.

0%

Lazaris17

Desgranges13

Tartari20

London18 50%

Page 42 | Volume 4: Number 1. 2011

100%

0%

50%

100%


RCSIsmjreview Table 5: Outcomes of studies reporting about patients with CLI (+/- claudication), subdivided according to location of lesion (femoropopliteal, popliteotibial or infrainguinal). Study

Technical success (95% CI)

12-month primary patency (95% CI)

12-month limb salvage (95% CI)

Lesion (mostly) in femoropopliteal artery Laxdal 200315

Laxdal 200416

84.6%

90%

(76.4%-90.4%)

(83.4%-94.2%)

90.3% (83.7%-94.4%)

Scott19

Trocciola22

86.7%

62%

(78.7%-91.9%)

(52.4%-70.8%)

99.2%

79.0%

95%

(94.4%-99.9%)

(70.8%-85.4%)

(89.4%-97.7%)

85.4%

27%

89%

(79%-90.1%)

(20.6%-34.6%)

(83.1%-93%)

Lesion (mostly) in popliteotibial artery Tisi21

Infrainguinal lesions Akesson12

76.7% (70.2%-82.1%)

Desgranges13

88% (80.0%-91.3%)

Hynes14

Lazaris17

London18

Tartari20

99.5%

97.8%

(95.0%-99.9%)

(93.9%-99.2%)

89.3%

88%

(82.1%-93.8%)

(80.6%-92.8%)

79.5%

55.9%

(73.3%-84.5%)

(49.0%-62.7%)

84.4%

87%

(76.4%-90.1%)

(79.3%-92.1%)

All blank fields indicate that the required information was unavailable

Volume 4: Number 1. 2011 | Page 43


RCSIsmjreview six studies that reported this outcome (762 limbs) was 91.1% (95% confidence interval: 89.1%-93.1%).14,15,17,20-22 The results of all outcomes are highlighted in Table 5.

Discussion This review demonstrates that the overall technical success rate for SIA in the published literature is acceptable (approximately 88%). While actual primary patency over time is approximately 56% and does not match this high initial success rate, long-term limb salvage is excellent at approximately 91%. This figure remains constant irrespective of the degree of ischaemia in patient groups undergoing SIA, the use of adjunctive stenting or the selection criteria used to identify patients for SIA. There appears to have been no change in technical success, limb salvage or primary patency rates in the time period described, suggesting that the perceived learning curve for the technique is relatively steep in those centres that choose to pursue this method of angioplasty and have published their results. The limitations of this review principally lie in the quality of the studies included in the analysis. In the vast majority, the criteria used to select patients for SIA were not given. In addition, there was a lack of conformity to reporting data according to set standards, such as the Rutherford-Baker classification. This is probably because many of these criteria, such as degree of ischaemia, are difficult to define accurately. As already indicated, information on additional variables was sought, namely the degree of limb ischaemia, the use of adjunctive stents and lesion location/patient selection criteria. No major influence on outcomes was seen. However, few of the studies used rigid definitions for any of these sub-classifications, except for lesion location, and in this case many authors reported on â&#x20AC;&#x153;infrainguinalâ&#x20AC;? groups of lesions. This lack of structured classification may have led to the fact that little difference is seen in the outcomes for each subgroup. In this study, only primary patency data was extracted from the studies in the analysis. While data on primary-assisted and, indeed, secondary patency would also have been useful to study, unfortunately few studies reported these outcomes. Specifically, two studies quoted primary-assisted patency and no studies quoted secondary patency.13,15 Four studies quoted primary patency of the vessel, and all four studies did so at 12 months post procedure. Therefore, primary patency was deemed the most useful data to extract. The BASIL trial is the only multicentre randomised controlled trial to have compared the clinical and cost-effectiveness of bypass surgery-first and conventional balloon angioplasty-first revascularisation strategies for infrainguinal severe limb ischaemia.23 Despite being associated with costs equivalent to about one-third higher than those with an angioplasty-first strategy, surgical bypass has been promoted as superior in some interpretations of the BASIL trial. A review by Beard et al.

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concluded that the long-term results of the trial favoured surgery over angioplasty if there was a good vein and the patient was fit.28 However, the results for SIA demonstrated in this study are encouraging. In published series detailing outcomes following lower limb bypass surgery, primary patency rates are greater than those observed in this analysis. Particularly, the primary patency rates were 83% for an above-knee femoropopliteal bypass with a saphenous vein graft, 78% for a polytetrafluoroethylene (PTFE) graft and 82% even for a popliteal-to-distal vein bypass after one year.24,25 The comparatively lower patency rates for SIA must be balanced against the fact that this technique is minimally invasive and requires only local anaesthesia, which are advantages with respect to surgical revascularisation procedures. In addition, failed SIA does not preclude the opportunity for such procedures.26 The source publications used in this study were, in the majority, retrospective case reviews. Only two were prospective studies, no randomised controlled studies have been published, and it is unlikely that any large datasets will be available in the near future. The clearest inference that can be made from this work is that further research is required in this area if the place of SIA in modern interventional radiology is to be better defined. As mentioned above, there are no randomised controlled trials of SIA. The reasons for this, although complex, principally lie in what technique to randomise patients against and which patients to randomise among these procedures. It is important to use standardised methods, such as the Rutherford-Baker classification, for reporting results of treatment for peripheral arterial disease and, especially, for lower-limb arterial endovascular procedures, in order to facilitate future meta-analyses.1,27 In conclusion, this literature review shows that, despite the moderate long-term patency rates of the revascularised segments, SIA can play an important role in the treatment of critical limb ischaemia. Further studies of higher methodological quality are required and should include entire cohorts of patients admitted for CLI, instead of selected series, to better appreciate this technique in relation to bypass surgery.

Acknowledgements I would like to thank the staff of the Department of Academic Radiology in Beaumont Hospital, particularly Dr Michael Slattery and Professor MJ Lee, whose contributions to the research and proofreading of this article are sincerely appreciated.


RCSIsmjreview References 1. Rutherford RB, Baker JD, Ernst C, Johnston KW, Porter JM, Ahn S et al. Recommended standards for reports dealing with lower extremity ischaemia: revised version. J Vasc Surg. 1997;26(3):517-38. 2. Hiatt WR. Medical management of peripheral arterial disease and claudication. N Engl J Med. 2001;344:1608-21. 3. Lee MJ. Subintimal angioplasty in critical limb ischaemia. Presented at Beaumont Hospital. Dublin, 2010. 4. Adam DJ, Beard JD, Cleveland T, Bell J, Bradbury AW, Forbes JF et al. Bypass versus angioplasty in severe ischaemia of the leg (BASIL): multicentre, randomised controlled trial. Lancet. 2005;366(9501):1925-34. 5. Bolia A, Sayers RD, Thompson MM, Bell PR. Subintimal and intraluminal recanalisation of occluded crural arteries by percutaneous balloon angioplasty. Eur J Vasc Surg. 1994;8:214-9. 6. Bolia A, Fishwick G. Recanalisation of iliac artery occlusion by subintimal dissection using the ipsilateral and the contralateral approach. Clin Radiol. 1997;52:684-7. 7. Bolia A, Brennan J, Bell PR. Recanalisation of femoro-popliteal occlusions. Improving success rates by subintimal recanalisation. Clin Radiol. 1989;40:325. 8. Bolia A, Bell PRF. Subintimal angioplasty. In: Dyet JF, Ettles DF, Nicholson AA, Wilson SE (eds.). Textbook of Endovascular Procedures (1st ed.). Philadelphia: Churchill Livingstone, 2000:126-38. 9. Bown MJ, Bolia A, Sutton AJ. Subintimal angioplasty: meta-analytical evidence of clinical utility. Eur J Vasc Endovasc. Surg 2009;38(3):323-37. 10. SISA. T-test. Including odds-ratios, risk-ratios, and NNT [online]. Accessed April 14, 2010. Available from: http://www.quantitativeskills.com/sisa/statistics/t-test.htm. 11. Keeling AN, Khalidi K, Leong S, Given MF, McGrath FP, Athanasiou T et al. Subintimal angioplasty: predictors of long-term success. J Vasc Interv Radiol. 2009;20(8):1013-22. 12. Akesson M, Riva L, Ivancev K, Uher P, Lundell A, Malina M. Subintimal angioplasty of infrainguinal arterial occlusions for critical limb ischaemia: long-term patency and clinical efficacy. J Endovasc Ther. 2007;14(4):444-51. 13. Desgranges P, Boufi M, Lapeyre M, Tarquini G, Van Laere O, Losy F et al. Subintimal angioplasty: feasible and durable. Eur J Vasc Endovasc Surg. 2004;28(2):138-41. 14. Hynes N, Mahendran B, Manning B, Andrews E, Courtney D, Sultan S. The influence of subintimal angioplasty on level of amputation and limb salvage rates in lower limb critical ischaemia: a 15-year experience. Eur J Vasc Endovasc Surg. 2005;30(3):291-9. 15. Laxdal E, Jenssen GL, Pedersen G, Aune S. Subintimal angioplasty as a treatment of femoropopliteal artery occlusions. Eur J Vasc Endovasc Surg. 2003;25(6):578-82.

16. Laxdal E, Eide GE, Wirsching J, Jenssen GL, Jonung T, Pedersen G et al. Homocysteine levels, haemostatic risk factors and patency rates after endovascular treatment of the above-knee femoro-popliteal artery. Eur J Vasc Endovasc Surg. 2004;28(4):410-7. 17. Lazaris AM, Salas C, Tsiamis AC, Vlachou PA, Bolia A, Fishwick G et al. Factors affecting patency of subintimal infrainguinal angioplasty in patients with critical lower limb ischaemia. Eur J Vasc Endovasc Surg. 2006;32(6):668-74. 18. London NJM, Srinivasan R, Naylor AR, Hartshorne T, Ratliff DA, Bell PRF et al. Subintimal angioplasty of femoropopliteal artery occlusions: the long-term results. Eur J Vasc Surg. 1994;8(2):148-55. 19. Scott EC, Biuckians A, Light RE, Scibelli CD, Milner TP, Meier 3rd GH et al. Subintimal angioplasty for the treatment of claudication and critical limb ischemia: 3-year results. J Vasc Surg. 2007;46(5):959-64. 20. Tartari S, Zattoni L, Rolma G, Sacco A. Subintimal angioplasty of infrapopliteal artery occlusions in the treatment of critical limb ischaemia. Short-term results. Radiologia Medica. 2004;108(3):265-74. 21. Tisi PV, Mirnezami A, Baker S, Tawn J, Parvin SD, Darke SG. Role of subintimal angioplasty in the treatment of chronic lower limb ischaemia. Eur J Vasc Endovasc Surg. 2002;24(5):417-22. 22. Trocciola SM, Chaer R, Dayal R, Lin SC, Kumar N, Rhee J et al. Comparison of results in endovascular interventions for infrainguinal lesions: claudication versus critical limb ischaemia. Am Surg. 2005;71(6):474-80. 23. Bradbury AW. Bypass versus angioplasty in severe ischaemia of the leg (BASIL) trial: what are its implications? Semin Vasc Surg. 2009;22(4):267-74. 24. Klinkert P, Post PN, Breslau PJ, van Bockel JH. Saphenous vein versus PTFE for above-knee femoropopliteal bypass. A review of literature. Eur J Vasc Endovasc Surg. 2004;27(4):357-62. 25. Albers M, Romiti M, Brochado-Neto FC, De Luccia N, Pereira CA. Meta-analysis of popliteal-to-distal vein bypass grafts for critical ischaemia. J Vasc Surg. 2006;43(3):498-503. 26. Sandford RM, Bown MJ, Sayers RD, London JN, Naylor AR, McCarthy MJ. Is infrainguinal bypass grafting successful following failed angioplasty? Eur J Vasc Endovasc Surg. 2007;34(1):29-34. 27. Ahn SS, Rutherford RB, Becker GJ, Comerota AJ, Johnston KW, McClean GK et al. Reporting standards for lower extremity arterial endovascular standards. J Vasc Surg. 1993;17(6):1103-7. 28. Beard JD. Which is the best revascularisation for critical limb ischaemia: endovascular or open surgery? J Vasc Surg. 2008;48(6 Suppl.):11S-16S.

Volume 4: Number 1. 2011 | Page 45


RCSIsmjreview Can magnesium sulphate provide neuroprotection in preterm infants? A literature review

Abstract

Carmen Goojha RCSI medical student

The aim of this literature review is to determine if prenatal administration of magnesium sulphate (MgSO4) provides neuroprotection in preterm infants. Data was analysed from five randomised controlled trials (MagNET, ACTOMgSO4, MAGPIE, PREMAG and BEAM). The data from each trial supported a correlation between MgSO4 and neuroprotection; however, only one trial was statistically significant â&#x20AC;&#x201C; BEAM. Previously conducted systematic reviews and meta-analyses combined data from the trials and produced statistically significant results in favour of MgSO4 for neuroprotection. Studies suggest that MgSO4 acts as an NMDA (N-Methyl-D-Aspartate) receptor antagonist, reducing the neuronal damage secondary to increased intracellular calcium. Other studies suggest that it prevents neuronal insult by decreasing intrauterine inflammation. The challenges of using MgSO4 are with determining the therapeutic window, appropriate timing of administration, re-treatment possibilities, bias in tocolytic choices, serious maternal side effects (hypotension, tachycardia), and neonatal side effects. Further research is needed to determine the neuroprotective mechanisms, specific indications for MgSO4, optimum gestational age, timing of administration, dosing, and need for re-treatment. Follow-up trials should assess the long-term effects of MgSO4 on preterm infants. In conclusion, MgSO4 provides neuroprotection in preterm infants and likely improves their quality of life. Key words: Magnesium sulphate, neuroprotection, preterm infants, randomised controlled trials, systematic review, meta-analysis. Royal College of Surgeons in Ireland Student Medical Journal. 2011;4(1):46-52.

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RCSIsmjreview Introduction Preterm birth and extremely low birth weight (less than 1,000g) are major risk factors for detrimental neurologic outcomes such as cerebral palsy.1-4 Cerebral palsy is a group of disorders of varying severity that results in abnormal movement and posture, which ultimately leads to limited activity.5,6 It is due to non-progressive brain damage that occurs in utero or in infancy, with a multitude of consequences including chronic disability along with medical, emotional and economic burdens.7,8 Lifetime costs include direct costs such as physician visits, hospital stays, medications, and home/vehicle alterations, while indirect costs include productivity costs.9 The lifetime cost for an individual with cerebral palsy is approximately €860,000 for men and about €800,000 for women.10 It is proven that the risk of neurological abnormalities increases with decreasing gestational age, and 25% of new cases of cerebral palsy occur in infants born at less than 34 weeks’ gestation.11-13 There has been an increase in survival rates among these preterm and low birth weight infants that can be attributed to improvements in perinatal and neonatal intensive care.4 Since these children have a much higher risk of neurological deficits like cerebral palsy, while also having a much higher rate of survival, it is of the utmost importance to explore preventive measures, such as magnesium sulphate (MgSO4), treatment that may improve their quality of life. MgSO4 has two principal uses in obstetrics. First, it can be used as seizure prophylaxis in pre-eclampsia and treatment of eclampsia. Second, it is an agent of tocolysis, whereby it delays preterm labour to facilitate administration of corticosteroids to be given for foetal maturation, patient transport, or successful treatment of reversible aetiologies of preterm labour.23,24 It is believed that MgSO4 also provides neuroprotection in preterm infants when given to mothers when labour is imminent. Observational studies by Nelson, Grether, and Schendel et al. reported such findings, which were later supported by several randomised controlled trials.15,16 This report will discuss the findings of five randomised controlled trials pertaining to the correlation between antenatally administered MgSO4 and subsequent neuroprotection in preterm infants, possible mechanisms that allow MgSO4 to act as a neuroprotective agent, clinical challenges faced when using MgSO4 for neuroprotection, and important research that needs to be done in the future.

Methods A literature search was performed using Ovid/Medline (1950 to February 2010) to identify randomised controlled trials and other published data associated with using MgSO4 for neuroprotection in the foetus. A variety of key words were used including “magnesium sulphate”, “neuroprotection”, and “preterm”. The “AND” function was often used to combine these terms with each other or with the names of known authors. Bibliographies of significant studies, meta-analyses, and systematic reviews were

assessed for additional relevant data. Google Scholar was used to obtain full text articles when only abstracts could be found in Medline. The Cochrane database was also searched. Further information and published data was retrieved from clinicians who had been to conferences where oral presentations relating to the subject were given and from those who had been involved in the development of hospital protocols to administer MgSO4 to patients for the purpose of neuroprotection in preterm infants. The following principal outcome measures were extracted from the systematic reviews/meta-analyses: relative risk (cerebral palsy, gross motor dysfunction and paediatric mortality); absolute risk of cerebral palsy with MgSO4; and, number needed to treat. The relative risk is the ratio of the probability of developing cerebral palsy, gross motor dysfunction or paediatric death in the MgSO4-treated group versus a control group. When this ratio is less than 1, developing any of the previously listed adversities is less likely to occur in the treated group than in the control group. The opposite is true if the ratio is more than 1. The absolute risk is the probability of developing cerebral palsy with MgSO4 or with a control, and is calculated without comparing the two groups. The number needed to treat is the number of patients who need to be treated with MgSO4 in order for just one patient to benefit. As the number needed to treat increases, the effectiveness of the MgSO4 decreases.

Selection criteria Systematic reviews/meta-analyses were included if they evaluated the following five randomised controlled trials: BEAM, MagNET, ACTOMgS04, MAGPIE and PREMAG.5,17-21 The studies had to investigate any differences in relative or absolute risk of cerebral palsy compared with control groups and they also had to calculate number needed to treat with MgSO4 in order to prevent one case of cerebral palsy. Only published studies were used to explain the possible neuroprotective mechanism of MgSO4, while published and non-published information was used to assess best practice measures. One reviewer evaluated and selected the literature reviews, meta-analyses and studies that would be included in this paper.

Statistical methods The results from the reviews/meta-analyses calculated relative risk (cerebral palsy, gross motor dysfunction, paediatric mortality) and number needed to treat with confidence intervals, while the absolute risk was calculated in percentages. The reviews used a mixture of the following analytical tools to examine and combine the data from the various trials: Mantel-Haenszel chi-squared model, Wilcoxon rank-sum test, chi-square test, Fisher’s exact test, examining the symmetry of funnel plots, and statistically by using the Egger test, Review Manager software (RevMan 2008), MIX software version 1.7, and SAS software, version 8.2. In this literature review, these values were analysed and tabulated, allowing simple comparison of results.

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RCSIsmjreview Table 1: Characteristics of five randomised controlled trials analysed in the systematic reviews and meta-analyses. Name of trial, authors

Year

Number of centres

Number of participants

Control

Gestational age

Aim of study

MgSO4 dose

Neuroprotective conclusions

BEAM, Rouse et al.

2008

20 (United States)

2,241 mothers

Placebo

24-31 weeks

Determine if foetal exposure to MgSO4 before preterm birth might reduce the risk of cerebral palsy

Loading dose of 6g, maintenance dose of 2g/hr

Significant decrease in the risk of moderate or severe cerebral palsy among surviving children in the MgSO4 group

MagNET, Mittendorf et al.

2002

1 (United States)

149 mothers

Placebo or, â&#x20AC;&#x2DC;Otherâ&#x20AC;&#x2122; tocolytic

25-33 weeks

Determine if using antenatal MgSO4 prevents neonatal intraventricular haemorrhage, periventricular leucomalacia, death and cerebral palsy

Tocolytic arm: loading dose of 4g, maintenance dose of 2-3g/hr

Antenatal MgSO4 was associated with worse, not better, perinatal outcome in a dose-response fashion

Neuroprotective arm: loading dose of 4g

ACTOMgSO4, 2003 Crowther et al.

16 (Australia and New Zealand)

1,062 mothers

Placebo

<30 weeks

Determine the effectiveness of magnesium sulphate given for neuroprotection to women at risk of preterm birth

Loading dose of 4g (8ml of 60ml bag), maintenance dose of 2ml/hour (of 60ml bag)

Total mortality, cerebral palsy and the combined outcome of mortality or cerebral palsy were all lower in the magnesium sulphate group, but differences were not statistically significant

Magpie Trial (follow-up), Magpie Trial Follow-Up Study Collaborative Group

125 (19 countries, five continents)

3,375 mothers

Placebo

Not considered in the inclusion criteria

Assess the long-term effects of in utero exposure to MgSO4 for children whose mothers had pre-eclampsia

Loading dose of 4g, maintenance dose of 1g/hr IV

17 surviving children were identified as having cerebral palsy, 10 were among those whose mothers were allocated placebo, two arose during embryogenesis. This imbalance could have arisen by chance, but the trend shows a tendency to a lower risk of cerebral palsy

Determine if MgSO4 given to women at risk of very preterm birth would be neuroprotective in preterm newborns and prevent neonatal mortality and severe white matter injury

Loading dose of 4g

2007

PreMAG Trial + 2007 Follow-up and Trial, 2008 Marret et al.

18 (all in France)

Page 48 | Volume 4: Number 1. 2011

573 (mothers in the original trial) 472 (children followed up at two years)

Placebo

<33 weeks

or, Loading dose of 4g IV + 10g IM, maintenance dose of 5g/4hrs IM

Original trial: non-significant decrease in risks of short-term, severe white matter injury, mortality before hospital discharge Follow-up trial: prenatal low-dose MgSO4 has beneficial neuroprotection effects, which approached significance and achieved significance when considering combined death and gross motor or cognitive dysfunction


RCSIsmjreview Table 2: Results from systematic reviews/meta-analyses. Author

Gestational age

Number of trials analysed and infants included

Reduced relative risk of CP

Absolute risk of CP with MgSO4 versus placebo

Number needed to treat

Reduced relative risk of gross motor dysfunction

Relative risk of total paediatric mortality

Other neurological outcomes in newborn or first years of life

Doyle et al.22 <37 weeks

5 trials× 6,145 infants

0.69 (95% CI 0.54-0.87)

3.7% vs. 5.4%

63 (95% CI 43-155)

0.61 (95% CI 0.44-0.85; 5,980 infants considered)

1.01 (95% CI 0.82-1.23)

None

CondeAgudelo and Romero13

<34 weeks

5 trials× 5,357 infants

0.69 (95% CI 0.55-0.88)

3.9% vs. 5.6%

52 (95% CI 31-154)

0.60 (95% CI 0.43-0.83; 4,387 infants considered)

1.01 (95% CI 0.89-1.14)

None

*Costantine et al.23

<3234 weeks

5 trials× 5,235 infants

0.70 (95% CI 0.55-0.89)

—-

56 (95% CI 34-164)

—-

1.01 (95% CI 0.89-1.14)

—-

*Costantine et al.23

<30 weeks

3 trials×× 3,107 infants

0.69 (95% CI 0.52-0.92)

—-

46 (95% CI 26-287)

—-

1.00 (95% CI 0.87-1.15)

—-

Abbreviations: CP: cerebral palsy; MgSO4: magnesium sulphate; CI: confidence interval; —-: not evaluated; None: no other neurological outcomes found. ×5 trials (all randomised controlled trials): BEAM,5 MagNET,17 ACTOMgSO ,18 MAGPIE19 and PREMAG20,21 (two-year follow-up) 4 ××3 trials (all randomised controlled trials): BEAM, ACTOMgSO and MAGPIE 4

*Costantine et al. separated the results of their meta-analysis based on two separate groups of gestational ages (<32-34 weeks and <30 weeks)

Results Literature search

Analysis

Three systematic reviews/meta-analyses met the inclusion criteria. These reviews analysed data from the following randomised controlled trials: BEAM, MagNET, ACTOMgS04, MAGPIE, and PREMAG.5,17-21 The characteristics of these trials are outlined in Table 1 and the findings are summarised in Table 2. All of the randomised controlled trials compared MgSO4 with placebo/other treatment in patients at risk for preterm delivery (gestational age <37 weeks), were all performed in the last 10 years, had a large number of participants, and drew conclusions on MgSO4 and subsequent neuroprotection.

There are five significant randomised controlled trials that could have a major impact on the use of MgSO4 for neuroprotection: the Magnesium and Neurologic Endpoints Trial [MagNET]; the Australasian Collaborative Trial of Magnesium Sulphate [ACTOMgSO4]; the Magnesium Sulphate for Prevention of Eclampsia [MAGPIE]; PREMAG; and, the Beneficial Effects of Antenatal Magnesium Sulphate [BEAM].5,17-21 Four of the trials revealed a trend of reduced rates in cerebral palsy in MgSO4-treated groups with no effect on total paediatric mortality.5,18-21 However, the results regarding decreased cerebral

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RCSIsmjreview palsy were only statistically significant in the BEAM trial.5 The MagNET trial resulted in reduced rates of cerebral palsy in the magnesium-exposed group compared to the placebo group in its tocolytic arm, but its neuroprotective arm showed more cases of cerebral palsy in the magnesium group compared to the placebo group.17 However, according to Mittendorf et al.: â&#x20AC;&#x153;this study was too small and the complication of cerebral palsy was too uncommon for meaningful statistical analysisâ&#x20AC;?.17 This trial also suggested a trend towards increased foetal/childhood death in MgSO4 groups; however, this was refuted in subsequent systematic reviews and meta-analyses.14,22,23,30 Another statistically significant result found in the individual trials was decreased substantial gross motor function in the BEAM and ACTOMgSO4 studies.5,18 When the data from these trials was combined through well conducted systematic reviews and meta-analyses, statistically significant results were attained that confirmed the neuroprotective role of MgSO4 therapy administered to women at risk of preterm delivery.14,22,23 The following conclusions were made in the reviews/meta-analyses regarding MgSO4 administered to mothers at risk for preterm birth: it reduced the risk of cerebral palsy in their children;14,22,23 it decreased the absolute risk of cerebral palsy compared to placebo;22,14 on average, the number of people needed to treat to prevent one case of cerebral palsy was 54;14,22,23 and MgSO4 reduced the rate of substantial gross motor dysfunction in their children.14,22 MgSO4 administration also had no statistically significant effect on paediatric mortality,14,22,23 or other poor outcomes in the newborn period or in the first few years of life (e.g., blindness, deafness, developmental delay).14,22 The outcomes investigated in the newborn period were Apgar scores less than 7 at five minutes, ongoing respiratory support, intraventricular haemorrhage, periventricular leukomalacia, convulsions,14,22 respiratory distress syndrome, bronchopulmonary dysplasia, mechanical ventilation, and necrotising entercolitis (NEC), even though a drift toward increased NEC was found.14 All of the reviews also found that the studies giving MgSO4 exclusively for neuroproection provided the most compelling evidence for reduced risk of cerebral palsy. While the major randomised controlled trials did not independently exhibit significant results, collectively they produced strong evidence that may persuade clinicians to use MgSO4 as a neuroprotective agent.

Discussion The exact mechanism by which MgSO4 provides neuroprotection is still unknown. Currently, there are two theories that describe how magnesium may inhibit neuronal damage, namely hypoxic-ischaemic damage and inflammatory damage. Cerebral palsy is thought to be a result of periventricular white matter damage that predominates in premature infants, especially those born before 32 weeks gestational age.24,25 Periventricular damage is illustrated by loss of oligodendrocytes (brain cells that myelinate or insulate nerves) and gain of astrocytes (cells involved in scarring).25 Hypoxic-ischaemic damage is a result of low oxygen and glucose supply, which ultimately leads to excessive glutamate

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release.24 Glutamate stimulates the N-methyl-D-aspartate (NMDA) receptor, allowing a large influx of sodium and calcium into the neuron.24 Intracellular calcium induces several enzymes that cause neuronal death, while reperfusion causes oxidative damage through free radicals.24 MgSO4 is an NMDA receptor antagonist24,31 and NMDA antagonists have proven to be strong neuroprotectants in various animal models.26 However, NMDA receptors are vital in certain aspects of brain development, which raises the issue that MgSO4 could have the potential to disrupt normal foetal brain development if given at specific stages in neurodevelopment.24 It is important to remember that there is a strong correlation between spontaneous preterm birth and intrauterine inflammation.27 The fact that preterm birth due to inflammation and cytokine production leads to neuronal insult has been shown in animal models.28,29 Burd et al. investigated the explicit mechanisms responsible for the injury and found that injured foetal neurons in mice are capable of damaging other normal neurons.25 They also found that foetal brains of mice exposed to lipopolysaccharide, a bacterial antigen that causes intrauterine inflammation, exhibited abnormal neuronal morphology with decreased dendritic processes, which can ultimately disrupt neuronal synaptic communication.25 A subsequent animal study demonstrated that foetal brains subjected to inflammation that were later treated with MgSO4 did not display neuronal injury associated with fewer dendritic processes.27 The medical community continues to face difficulties regarding best practice and antenatal use of MgSO4 despite years of its clinical use and significant findings from combined data.30 Concerns arise in the context of appropriate dosing and timing of administration, tocolytic choice, maternal side effects, and infant side effects. Several studies and reviews suggest that high tocolytic doses of 50g or more30 increase paediatric mortality.31-34 Although the major randomised controlled trials used differing dosing regimens, total dose remained low. The median total exposure to MgSO4 in the ACTOMgSO4 trial was less than 10.5g (4g bolus infusion with 2g/hour maintenance up to 24 hours) with a maximum allowable total dose of 28g;30 total exposure in the PREMAG trial was 4g (single bolus infusion);20 and, median total dose in the BEAM trial was 31.5g (6g bolus infusion with 2g/hour maintenance).31 The low doses used in all of these trials showed a decrease in a subsequent diagnosis of cerebral palsy. There may have been even more improvement in cerebral palsy outcome in the lower dose trials versus the higher dose BEAM trial.30 Determining the therapeutic window above which MgSO4 could be toxic to the foetus has proven difficult, since detecting magnesium levels in the infant can be unreliable. Babies delivered soon after magnesium infusions may have falsely high magnesium levels, whereas babies born after prolonged magnesium exposure may have falsely low magnesium levels. Another clinical challenge arises when considering the optimum time to administer MgSO4 to mothers in preterm labour. The MagNET and BEAM trials used active preterm labour and cervical dilatation (>4cm and 4-8cm) as indications for treatment.5,17 Women were eligible for treatment in the BEAM, ACTOMgSO4 and


RCSIsmjreview PREMAG trials if delivery was expected within 24 hours.5,18,20 The Brigham and Womenâ&#x20AC;&#x2122;s Hospital (BWH) in Boston, Massachusetts, has developed a new protocol regarding MgSO4 for neuroprotection, and their goal for initiating infusion is set for four hours prior to delivery.35 However, there are difficulties in predicting when a woman will deliver, and the question of whether or not to re-treat (give another loading dose and maintenance infusions) emerges if the patient has not delivered within 24 hours of the original dose. Although the largest randomised controlled trial, the BEAM trial,5 would continue MgSO4 infusion if six hours had passed since treatment stopped, there is not enough evidence to strongly support re-treatment.35 There is controversy over the number of times a patient can be re-treated and the amount of magnesium to which a patient can safely be exposed. Concern over biased use of MgSO4 for tocolysis also arises given its neuroprotective quality. Clinicians are faced with the dilemma of administering magnesium as the primary tocolytic instead of what is currently used, or to use MgSO4 simultaneously with the hospitalâ&#x20AC;&#x2122;s preferred tocolytic, such as indomethacin or nifedipine.36 Combining MgSO4 and calcium channel blockers is especially challenging, as it may lead to serious maternal side effects such as hypotension.36 The BWH has dealt with this issue in their protocol by discontinuing nifedipine and beginning infusion with magnesium when delivery is believed to occur within four hours.35 However, tocolysis and neuroprotection should be thought of separately, and all of the relevant data surrounding various tocolytics, along with individual patient traits, must be considered in order to choose the most suitable tocolytic.31 Maternal side effects are another important issue in antenatal MgSO4 use. Both reviews and independent studies reported a greater number of adverse side effects in MgSO4-treated groups compared to placebo-treated groups. Minor adverse effects included flushing, nausea, vomiting, sweating, problems at injection site, lethargy and blurred vision,5,14,18,31 and seemed to subside once treatment was finished.37 More serious side effects such as hypotension and tachycardia were also seen,14,18,37 and were increased by as much as 50% in the MgSO4 group compared to the placebo group.14 MgSO4 therapy was rarely associated with severe side effects such as death,5,14,18,20,31,37 cardiac and respiratory arrest,5,14,18,20,31,37 pulmonary oedema,5,14 postpartum haemorrhage,14,18,20 and caesarean section.5,14,18,20 Clinicians must also be cautious of fluid overload, which can lead to severe cardiovascular complications.35 Infants exposed to MgSO4 may also have side effects. Although these were not statistically significant in trials and reviews, they are a clinical reality. It has been noted by several clinicians at BWH that these infants often emerge less vigorous than those who have not been exposed to magnesium, but this is short-lived. However, if this is a known, transient effect, clinicians may be less concerned when it occurs and this could subsequently cause neglect of serious medical problems that warrant aggressive treatment. There is no evidence to support this finding, but it could be an interesting

focus of research in the future. The issues associated with using MgSO4 for neuroprotection are crucial in terms of best practice and should be carefully considered. Supplementary studies must be performed to provide imperative information about antenatal use of MgSO4 for neuroprotection in preterm birth. More randomised controlled trials are needed to determine the optimum gestational age, timing of administration, dosing, need for re-treatment,14,22,23 increased risk of NEC,14 and the immediate effects on the newborn infant. There is need for follow-up of the infants included in both new and previously performed trials into later childhood,14,22 since neurological outcomes such as cerebral palsy are sometimes not fully recognised until children are older.22 Indications for MgSO4 therapy must be further investigated,23,31 since there was a lack of consistency in patient characteristics among the five major trials.23 Various indications for treatment ranged from pre-eclampsia to preterm labour and preterm premature rupture of membranes, and MgSO4 may affect these indications differently.23 The mechanism by which MgSO4 provides neuroprotection24,31 to the human foetal brain must also be determined; however, this poses ethical, technical and financial difficulties.24 If the mechanisms at work in individual infants could be determined, this would provide the potential to develop treatments that matched specific patient needs.24 Finally, substantial information regarding serious maternal side effects should be obtained. For instance, only the BEAM trial looked into maternal pulmonary oedema, while the ACTOMgSO4 was the only trial to explore maternal tachycardia.5,18 Neuroprotection in preterm infants should be considered as a healthcare priority, since there has been an increase in the survival of preterm infants who have an increased risk of neurological injury leading to debilitating outcomes. Neurological problems such as cerebral palsy result in serious burdens faced by the diagnosed individual, their carers, and the healthcare system. Antenatal use of MgSO4 is a simple and economical way to relieve such burdens. Randomised controlled trials demonstrated a trend towards neuroprotection without subsequent neurological impairment or paediatric mortality when MgSO4 was administered to mothers in preterm labour. These findings were verified by large-scale systematic reviews and meta-analyses. The neuroprotective mechanisms employed by magnesium have yet to be determined and clinical trials are warranted to resolve the challenges posed by antenatal use of MgSO4. Although some centres have begun using MgSO4 for neuroprotection, future research is key to determine its optimal clinical use.

Acknowledgements I would like to thank my supervisor, Dr Steven Ringer MD PhD, Director of Newborn Medicine at Brigham and Womenâ&#x20AC;&#x2122;s Hospital in Boston, Massachusetts, and Dr Nicole Smith MD MPH, who explained the MgSO4 protocol used at BWH and provided further information from conferences she attended.

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RCSIsmjreview References 1.

Anderson P, Doyle LW. Neurobehavioural outcomes of school-age children born extremely low birth weight or very preterm in the 1990s. JAMA. 2003;289:3264-72.

2.

Bhutta AT, Cleves MA, Casey PH et al. Cognitive and behavioural outcomes of school-aged children who were born preterm: a meta-analysis. JAMA. 2002;288:728-37.

3.

Hack M, Taylor HG, Drotar D et al. Chronic conditions, function limitations and special health care needs of school-aged children born with extremely low birth weight in the 1990s. JAMA. 2005;294:318-25.

4.

5.

and neurologic outcome in preterm infants: a systematic review. Obstet Gynecol. 2009;113:1327-33. 23. Constantine MM, Weiner SJ. Eunice Kennedy Shriver National Institute of Child Network (MFMU). Effect of antenatal exposure to magnesium sulphate on

decades: II. Efficiency. Pediatrics. 2004;113:510-4.

neuroprotection and mortality in preterm infants: a meta-analysis. Am J Obstet

Rouse DJ, Hirtz DG, Thom E et al. A randomised, controlled trial of magnesium Rosenbaum P, Paneth N, Leviton A et al. A report: the definition and

Executive Committee for the Definition of Cerebral Palsy. Proposed definition and classification of cerebral palsy, April 2005. Dev Med Child Neurol. 2005;47:571-6.

9.

very preterm birth to protect infant brain. Pediatrics. 2008;121:225-6. 22. Doyle LW, Crowther CA, Middleton P, Marret S. Antenatal magnesium sulphate

Health and Human Development (NICHD) Maternal-Foetal Medicine Units

2007;109(Suppl.):8-14.

8.

trial. BJOG. 2007; 121: 310-8. 21. Marret S, Marpeau L, Benichou J. Benefit of magnesium sulphate given before

Doyle LW; Victorian Infant Collaborative Study Group. Evaluation of neonatal

classification of cerebral palsy April 2006. Dev Med Child Neurol. 7.

very preterm birth to protect infant brain: the randomised controlled PREMAG

intensive care for extremely low birth weight infants in Victoria over two

sulphate for the prevention of cerebral palsy. N Engl J Med. 2008;359:895-905. 6.

20. Marret S, Marpeau L, Zupan-Simunek V et al. Magnesium sulphate given before

Kuban KCK, Leviton A. Cerebral palsy. N Engl J Med. 1994;330:188-95. Honeycutt A, Dunlap L, Chen H, al Homsi G, Gross S, Schendel D. Economic costs associated with mental retardation, cerebral palsy, hearing loss, and vision impairment â&#x20AC;&#x201C; United States 2003. MMWR. 2004;53:57-9.

10. Kruse M, Michelsen SI, Flachs EM et al. Lifetime costs of cerebral palsy. Developmental Medicine & Child Neurology. 2009;51(8):622-8. 11. Himpens E, Van den Broeck C, Oostra A et al. Prevalence, type, distribution, and severity of cerebral palsy in relation to gestational age: a meta-analytic review. Dev Med Child Neurol. 2008;50:334-40. 12. Moster D, Lie RT, Markestad T. Long-term medical and social consequences of preterm birth. N Engl J Med. 2008:359:262-73. 13. Himmelmann K, Hagberg G, Beckung E, Hagberg B, Uvebrant P. The changing panorama of cerebral palsy in Sweden: IX, prevalence and origin in the birth-year period 1995-1998. Acta Paediatr. 2005;94:287-94. 14. Conde-Agudelo A, Romero R. Antenatal magnesium sulphate for the prevention of cerebral palsy in preterm infants less than 34 weeksâ&#x20AC;&#x2122; gestation: a systematic review and meta-analysis. Am J Obstet Gynecol. 2009;200(6):596-609. 15. Nelson KB, Grether JK. Can magnesium sulphate reduce the risk of cerebral palsy in very low birth weight infants? Pediatrics. 1995;95:263-9.

Gynecol. 2009;114:354-64. 24. Degos V, Gauthier L, Mantz J, Gressens P. Neuroprotective strategies for the neonatal brain. Anesth Analg. 2008;106:1670-80. 25. Burd I, Chai J, Gonzalez J et al. Beyond white matter damage; foetal neuronal injury in a mouse model of preterm birth. Am J Obstet Gynecol. 2009;201:279.e1-8. 26. Johnston MV, Nakajima W, Hagberg H. Mechanisms of hypoxic neurodegeneration in the developing brain. Neuroscientist. 2002;8:212-20. 27. Burd I, Breen K, Friedman A et al. Magnesium sulphate to prevent adverse neurological injury: providing biological evidence. Am J Obstet Gynecol. 2009;201(6):S3. 28. Elovitz MA, Gonzalez J, Chai J et al. Preterm labour is insufficient to evoke foetal brain injury: activation of inflammatory pathways is an essential mechanism. Reprod Sci. 2008;15:181. 29. Elovitz MA, Mrinalini C, Sammel MD. Elucidating the early signal transduction pathways leading to foetal brain injury in preterm birth. Pediatr Res. 2006;59:50-5. 30. Pryde PG, Mittendorf R. Contemporary usage of obstetric magnesium sulphate. Obstet Gynecol. 2009;114:669-73. 31. Mercer BM, Merlino AA. Society for Maternal-Foetal Medicine. Magnesium sulphate for preterm labour and preterm birth. Obstet Gynecol. 2009;114:650-68. 32. Cox SM, Sherman ML, Leveno KJ. Randomised investigation of magnesium sulphate for prevention of preterm birth. Am J Obstet Gynecol. 1990;163:767-72. 33. Mittendorf R, Covert R, Boman J et al. Is tocolytic magnesium sulphate associated with increased total paediatric mortality? Lancet. 1997;350:1517-8. 34. Crowther CA, Hiller JE, Doyle LW. Magnesium sulphate for preventing preterm

16. Schendel DE, Berg CJ, Yeargin-Allsopp M et al. JAMA. 1996;276:1805-10.

birth in threatened preterm labour. The Cochrane Database of Systematic

17. Mittendorf R, Dambrosia J, Pryde PG et al. Association between the use of

Reviews 2002, Issue 4. Art. No.:CD001060. DOI:

antenatal magnesium sulphate in preterm labour and adverse health outcomes in infants; Am J Obstet Gynecol. 2002;186:1111-8. 18. Crowther CA, Hiller JE, Doyle LW et al. Australasian Collaborative Trial of Magnesium Sulfate (ACTOMgSO4) Collaborative Group. Effect of magnesium sulphate given for neuroprotection before preterm birth: a randomised controlled trial. JAMA. 2003;290:2669-76. 19. Magpie Trial Follow-Up Study Collaborative Group. The Magpie Trial: a

10.1002/14651858.CD001060. 35. Smith N, Acker D, Ringer S et al. Use of magnesium sulphate for neuroprotection. Staff Memo 2010;1-2. 36. Rouse DJ. Magnesium sulfate for the prevention of cerebral palsy. Am J Obstet Gynecol. 2009;200(6):610-2. 37. Doyle LW, Crowther CA, Middleton P et al. Magnesium sulphate for women at risk of preterm birth for neuroprotection of the foetus. The Cochrane Database

randomised trial comparing magnesium sulphate with placebo for

of Systematic Reviews 2009, Issue 1. Art. No.: CD004661. DOI:

pre-eclampsia. Outcome for children at 18 months. BJOG. 2007;114:289-99.

10.1002/14651858.CD004661.pub3.

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RCSIsmjreview Cancer stem cell theory and emerging clinical application

Abstract New understanding of the basic nature of malignancy is emerging due to novel studies drawing from stem cell biology. Cancer stem cell (CSC) theory proposes that a small subset of cells within a heterogeneous tumour have the capacity to form tumours, and that these cells demonstrate the abilities of stem cells, namely self-renewal and production of a varied repertoire of daughter cells. Evidence points to dysregulated tissue stem cells as the origin of CSCs. This stem cell nature may confer an inherent resistance to conventional cancer treatment, and be responsible for disease recurrence even after a dramatic clinical response. CSCs have been predominantly demonstrated in mouse xenotransplantation studies, where isolated putative CSC cell populations are able to form and recapitulate parent tumours in the host. Several genes related to stem cells and early embryonic development have been found to be active in CSCs and are thought to give CSCs their tumourigenic abilities. These genes also represent potential therapeutic targets, along with the microenvironment that supports the stem cell. Therapies against these targets are in development and include monoclonal antibodies, RNA interference and small molecules. A small number of CSC-specific therapeutics are in early clinical trials. If CSC theory is clinically validated, it stands to dramatically change the way we think of and treat cancer. Keywords: Cancer, stem cells, tumour-initiating cells, tumourigenesis, translational medicine, oncology. Royal College of Surgeons in Ireland Student Medical Journal. 20011;4(1):53-56.

Julian R Davis MA RCSI medical student

Introduction

Stem cells

Cancer remains the second leading cause of mortality in Ireland and other developed nations despite decades of intensive preventive and novel treatment efforts.1 However, new understanding of the fundamental mechanisms of tumour initiation and propagation may lead to a dramatic paradigm shift in cancer treatment. It may also explain the existing difficulty in treating cancer with conventional means. This new understanding is at the intersection of cancer biology and stem cell biology, and is positioned to have profound clinical significance in the coming years.

Stem cells have two important abilities. First, they are able to produce a varying range of progenitors or differentiated cells, and second, they are also able to self-renew.2 Pluripotent stem cells can produce cells of all three germ layers, i.e., endoderm, mesoderm and ectoderm. Unipotent stem cells in tissue produce one type of downstream progenitor in addition to renewing themselves in asymmetric division. Stem cells between these two are termed multipotent, meaning that they can produce several distinct types of daughter cells but not every cell type in the body.3

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RCSIsmjreview Understanding of basic stem cell biology, including the replicative repertoire of different stem cells, is crucial to the development of cancer stem cell (CSC) theory. This emerging and controversial theory states that both solid tumours and leukaemias are composed of a heterogeneous population of cells, of which a certain fraction are cells that have stem cell-like properties and are able to initiate and recapitulate a new heterogeneous tumour.4 This theory also implicates CSCs as the cause of metastasis because of their tumourigenic capability.5 Evidence of CSCs, also called tumour-initiating cells, was first reported in leukaemia in 1997, and has since been shown in many solid tumours including brain, breast, pancreatic, lung, colon, ovarian, and endometrial.6-14 The primary assay used in demonstrating CSCs is serial xenotransplantation of a putative CSC-enriched population in immunodeficient mice. Specifically, a definition of what CSCs are in the given solid tumour is established by an expression pattern of cell-surface markers, which is then used to isolate cells via fluorescence-activated cell sorting (FACS). This cell population is transplanted into immunodeficient mice, most often NOD/SCID (non-obese diabetic/severe combined immunodeficiency) and a tumour containing many different cells, including those expressing the CSC definition markers, is found. CSCs of the same definition can then be enriched from the secondary tumour and again transplanted into another mouse. This serial transplantation can be repeated for several generations, the number of which is associated with the aggressiveness of the tumour.14 Tumourigenic cells with stem cell abilities can also be characterised based on expression of intracellular enzymes. An example of such is aldehyde dehydrogenase (ALDH), which has been found to confer resistance to taxane and platinum-based chemotherapies in ovarian cancer, and is associated with poor prognosis in pancreatic adenocarcinoma.15,16 There is controversy regarding the origin of CSCs and whether they actually are as rare as previous reports have demonstrated.17 It is important to understand if CSCs are normal stem cells that have become dysregulated, or if they are cancerous progenitors that have acquired stem cell abilities. Studies have shown evidence for both but neoplastic transformation of tissue stem cells is often more efficient and phenotypic similarities between normal stem cells and CSCs are very strong.5,18

Research Recent research has elucidated the mechanisms that CSCs use to exert their effects. Many of them are related to signalling pathways and gene expression profiles seen in early embryonic development. For example, Notch, Wnt/β-catenin, Hedgehog, and Epithelial-to-mesenchymal transition (EMT) are key developmental processes that have been implicated in CSCs.19-23 In addition, Oct4, one of the primary genes responsible for maintenance of pluripotency in embryonic stem cells (ESCs) and induced pluripotent stem cells (iPS) is also involved in CSCs.18,24 Fitting emerging CSC findings into models of cancer recurrence

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after treatment offers some hypotheses. The CSC population within a given tumour may be small, far less than 1%, but if this population has intrinsic resistance to the applied therapy, an apparently dramatic clinical response could still leave behind those cells responsible for repopulating a tumour. This hypothesis is supported by studies showing that the expression of CSC markers is associated with poor prognosis in colorectal carcinoma and other cancers.16,25,26 CSCs are thought to be resistant to conventional cancer therapies in a number of ways. First, they can be quiescent, much like normal stem cells, with a very low mitotic rate, making them insensitive to agents that preferentially affect rapidly dividing cells. Downstream progenitor cells are much more mitotically active than CSCs and are responsible for populating the bulk of a solid tumour.27 Second, CSCs may express a higher level of multidrug resistance ATP-binding cassette pumps, which allow these cells to pump out chemotherapeutic compounds, greatly reducing their effectiveness.28 CSCs have also been found to upregulate DNA damage response checkpoint genes, making them more resistant to radiation therapy.29

Implications for treatment The first step in the treatment of malignancies from a CSC perspective is to target them. One targeting strategy is based on their definition of extracellular surface markers. A unique cell surface epitope separating CSCs from normal tissue stem cells would make an ideal target. Initial investigations have nominated CD133 and EpCAM as potential candidates for monoclonal antibodies.30 In reality, true CSCs may have a subtle pattern of extracellular marker expression that is a combination of surface proteins expressed by a variety of normal cells. This probably makes them poor targets, and even the ‘selective’ markers like CD133 have been found on normal stem cells.31,32 Another strategy is to disrupt the supportive microenvironment that maintains the CSC.33 It is established that factors in the extracellular milieu of each tissue are crucial to the function of normal tissue stem cells.34 This knowledge can be translated to CSCs, especially as the link between normal tissue stem cells and CSCs grows stronger. The importance of microenvironment is dampened by the use of non-HLA-matched immunodeficent mice for xenotransplantation studies that have become the standard for demonstrating CSCs. In a clinical situation, the malignant cells are the patient’s own, so an inherent immunocompatibility allows tumourigenic cells to more easily engraft within a tissue and form a new tumour. Because HLA compatibility is not part of the criteria of the xenotransplantation model, human cancer cells might have a more difficult time adapting to the foreign mouse microenvironment, lowering the tumourigenic cell frequency. When Kelly and colleagues transplanted leukaemic cells into histocompatible mice, the percentage of cells able to initiate new tumours increased to at least 10%. This was far above the figure reported in the prototype CSC report of 1997, as well as most of the solid tumour CSC reports, which found tumourigenic


RCSIsmjreview populations as low as 0.1%.17 Unfortunately, the incredible diversity of tumour architecture, phenotype, and the definition of CSCs themselves, will make it difficult to target the stem cell microenvironment.35 Success hinges on finding common extracellular factors crucial for the maintenance of pluripotency and self-renewal. However, some progress has been made in specific tissues. In breast cancer, Wicha and colleagues discovered that after administration of chemotherapy, dying tumour cells release inflammatory interleukin-8 (IL-8), which selectively stimulates the CSC population to expand. Therefore, blocking the IL-8 receptor CXCR1 with an antibody or a small molecule inhibits this effect in vivo.36 Understanding the active molecular pathways that give CSCs their abilities opens the door to targeted molecular therapy. Turning off or inhibiting genes responsible for driving tumourigenic cells depends on delivery of therapeutic agents, and thus RNA interference (RNAi) delivery technology is a burgeoning field that will impact on all of medicine, not just oncology. RNAi utilises small double-stranded RNA elements targeted to a specific RNA desired to be knocked down. The cellâ&#x20AC;&#x2122;s own machinery recognises the dsRNA, processes it, and allows the antisense portion to hybridise to the target RNA, causing degradation or translational repression of the target. In this way, the expression of specific genes can be significantly inhibited.37 In the context of CSCs, genes related to the maintenance of stemness and early embryonic development are ideal targets for RNAi knockdown. By knocking down these genes, it may be possible to differentiate CSCs to a state of reduced aggressiveness, and/or increased sensitivity to traditional chemotherapeutics. Additionally, anti-apoptotic, signal transduction pathway, and growth factor or cytokine elements are all plausible targets. Currently, there are three RNAi-based therapies in early clinical trials for cancer.38 RNAi is also powerfully used for discovery, where high-throughput assays can knock down thousands of different genes in independent experiments, with different measures of output depending on the investigation. Previous cancer studies in

this regard have looked at the viability and proliferation of tumour cells as outputs. However, in the case of CSCs, some measure of stemness and tumourigenicity will need to be used in the in vitro setting of these screening assays.39,40 Small molecule inhibitors that can block crucial molecular pathways may radically change cancer treatment in the future. Even though the mechanisms by which these pathways affect CSCs are not completely understood, clinical trials aimed at inhibiting them are underway. Currently, five small molecule Hedgehog antagonists are in phase I and II trials.22 In addition, a Notch pathway inhibitor developed by Merck is being evaluated in four different cancer trials.41 Preliminary results are not yet available, as this field is in its clinical infancy. Assuming that CSC theory is correct, measurement of residual tumour bulk is not a good indicator of treatment success, since intrinsically resistant CSCs may still be present in very small numbers. Creation of assays that measure the presence and activity of CSCs is crucial for drug development, treatment response and prognostic index.16

Conclusion In summary, CSC theory is poised to have a significant impact on cancer treatment because it changes our basic understanding of what cancer is and where it comes from. This perhaps provides an intriguing explanation for current difficulty in treating malignancy. The rapid progression of the basic science and emerging translational studies regarding tumourigenesis, coupled with the increasing relevance of this disease in our ageing population, makes this field an exciting and important focus for researchers, clinicians and patients. It warrants much more investigation, and stretches across many disciplines in biology and medicine. Creation of improved experimental and diagnostic assays for early identification and patient-specific characterisation of CSCs, followed by targeted blockade or elimination of their molecular drivers, are the keys to a potentially dramatic increase in therapeutic efficacy in our treatment of cancer.

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recruitment of the DNA damage response machinery. J Neurosci.

14. Hubbard SA, Friel AM, Kumar B, Zhang L, Rueda BR, Gargett CE. Evidence for cancer stem cells in human endometrial carcinoma. Cancer Res. 2009;69(21):8241-8. 15. Landen CN, Goodman BW, Katre AA, Steg AD, Nick AM, Stone R et al. Targeting aldehyde dehydrogenase cancer stem cells in ovarian cancer. Molecular Cancer Therapeutics. 2010;9:3103. 16. Rasheed ZA, Yang J, Wang Q, Kowalski J, Freed I, Murter C et al. Prognostic significance of tumorigenic cells with mesenchymal features in pancreatic adenocarcinoma. J Natl Cancer Inst. 2010;102(5):340-51. 17. Kelly PN, Dakic A, Adams JM, Nutt SL, Strasser A. Tumor growth need not be driven by rare cancer stem cells. Science. 2007;317(5836):337. 18. Tai MH, Chang CC, Kiupel M, Webster JD, Olson LK, Trosko JE. Oct4 expression in adult human stem cells: evidence in support of the stem cell theory of carcinogenesis. Carcinogenesis. 2005;26(2):495-502. 19. Pannuti A, Foreman K, Rizzo P, Osipo C, Golde T, Osborne B et al. Targeting Notch to target cancer stem cells. Clin Cancer Res. 2010;16(12):3141-52.

2010;30(30):10096-111. 30. Deonarain MP, Kousparou CA, Epenetos AA. Antibodies targeting cancer stem cells: a new paradigm in immunotherapy? MAbs. 2009;1(1):12-25. 31. Hill RP. Identifying cancer stem cells in solid tumors: case not proven. Cancer Res. 2006;66(4):1891-5, discussion 90. 32. Eramo A, Lotti F, Sette G, Pilozzi E, Biffoni M, Di Virgilio A et al. Identification and expansion of the tumorigenic lung cancer stem cell population. Cell Death Differ. 2008;15(3):504-14. 33. Albini A, Cesana E, Noonan DM. Cancer stem cells and the tumor microenvironment: soloists or choral singers? Curr Pharm Biotechnol. 2011;12(2):171-81. 34. Keung AJ, Kumar S, Schaffer DV. Presentation counts: microenvironmental regulation of stem cells by biophysical and material cues. Annu Rev Cell Dev Biol. 2010;26:533-56. 35. LaBarge MA. The difficulty of targeting cancer stem cell niches. Clin Cancer Res. 2010;16(12):3121-9. 36. Ginestier C, Liu S, Diebel ME, Korkaya H, Luo M, Brown M et al. CXCR1 blockade selectively targets human breast cancer stem cells in vitro and in xenografts. J Clin Invest. 2010;120(2):485-97.

20. Takahashi-Yanaga F, Kahn M. Targeting Wnt signalling:

37. Pecot CV, Calin GA, Coleman RL, Lopez-Berestein G, Sood AK. RNA

can we safely eradicate cancer stem cells? Clin Cancer.

interference in the clinic: challenges and future directions. Nat Rev

Res 2010;16(12):3153-62. 21. Kanwar SS, Yu Y, Nautiyal J, Patel BB, Majumdar AP. The Wnt/beta-catenin pathway regulates growth and maintenance of colonospheres. Mol Cancer. 2010;9:212. 22. Merchant AA, Matsui W. Targeting Hedgehog – a cancer stem cell pathway. Clin Cancer Res. 2010;16(12):3130-40. 23. Martin A, Cano A. Tumorigenesis: Twist1 links EMT to self-renewal. Nat Cell Biol. 2010;12(10):924-5. 24. Karoubi G, Cortes-Dericks L, Gugger M, Galetta D, Spaggiari L, Schmid RA. Atypical expression and distribution of embryonic stem cell marker, OCT4, in human lung adenocarcinoma. Journal of Surgical Oncology. 2010;102(6):689-98.

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Cancer. 2011;11(1):59-67. 38. Clinical Trials.gov [homepage on the internet], 2010. Cited January 4, 2011. Available from: http://clinicaltrials.gov. 39. Arora S, Gonzales IM, Hagelstrom RT, Beaudry C, Choudhary A, Sima C et al. RNAi phenotype profiling of kinases identifies potential therapeutic targets in Ewing’s sarcoma. Mol Cancer. 2010;9:218. 40. Scholl C, Frohling S, Dunn IF, Schinzel AC, Barbie DA, Kim SY et al. Synthetic lethal interaction between oncogenic KRAS dependency and STK33 suppression in human cancer cells. Cell. 2009;137(5):821-34. 41. US National Cancer Institute. MK0752 – Active Clinical Trials. US National Cancer Institute, 2010.


RCSIsmjstaff review A practical approach to the physiotherapy assessment and treatment of conversion disorders

Royal College of Surgeons in Ireland Student Medical Journal. 2011;4(1):57-61.

Áine Glennon RCSI medical student

Conversion disorder is a mechanism of illness by which psychological distress is expressed as a form of physical illness.1 Conversion disorders are part of a wider group of conditions called somatoform disorders.1 Somatoform disorders are dominated by somatic symptoms that resemble physical illness; however, the symptoms cannot be fully explained by organic causes.2 It typically presents with deficits of sensory or voluntary motor function, which may represent a general medical or neurological condition.2 Psychological factors play an important role in the diagnosis of a conversion disorder; exacerbation of symptoms is often preceded by a stress or inner turmoil. It is important to realise that the symptoms of a conversion disorder are not deliberately produced or simulated by the patient as would be the case in a factitious (assumption of the

sick role, which is motivated by obtaining medical assessment and treatment), or malingering (obvious gain to be achieved from sick role such as financial reward, avoidance of duty, etc.) disorder.2,3 Originally termed ‘hysteria’, conversion disorders are classified by the DSM-IV into four subtypes:1,2 1. Motor symptom/deficit Patients present with impaired balance or co-ordination, or with paralysis or localised weakness, which does not follow any particular pattern.2,4 Problems associated with gait are termed astasia-basia: impaired balance without the falls or a dramatically unbalanced gait that cannot be explained by decreased muscle strength (Figure 1).1,5 This subtype is the one most often encountered by physiotherapists.

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RCSIsmjstaff review

FIGURE 1: Astasia-basia.20

FIGURE 2: Hoover’s sign.20

2. Sensory symptom/deficit Patients present with altered sensation – most often loss of touch or pain sensation.4 Blindness, deafness and hallucinations can also be common symptoms.2 3. Seizures/convulsions Seizures with voluntary motor or sensory components – often termed psychogenic seizures.2,6 4. Mixed presentation Symptoms of more than one category are present.2

Hoover’s sign, which involves an assessment of hip extension strength on the paralysed limb5 (Figure 2). The therapist asks the patient to flex the unaffected limb against resistance while supporting the affected limb at the heel. During resisted flexion, the paralysed limb will extend at the hip in the patient, confirming muscle activation in the affected limb.5 In addition, symptoms are associated with suggestion, so physiotherapy assessment can exacerbate or decrease the presenting complaint.4 For example, one physiotherapist may suggest a trial of walking without a mobility aid, which can assist in increasing independent function, while another physiotherapist who provides a gait aid to this patient can exacerbate symptoms. However, in chronic cases it may be difficult to positively influence symptoms, as patient beliefs are fixed.7 It is difficult to estimate the incidence of conversion disorders, but estimates range from five to 50 per 100,000 per annum.4,8 The challenge in accounting for these patients is that they are rarely referred to psychiatry and plague the acute medical system as chronic ‘problematic’ patients.4 Nevertheless, evidence strongly suggests that this disorder is not disappearing.8

The symptoms of conversion disorders do not follow any physiological or pathological pathways that are typically associated with neurological disease.1,4 The symptoms, however, are ideogenic and tend to follow the patient’s perception of how a neurological disorder presents.7 For instance, in a patient complaining of paralysis, the deficit typically involves an entire body part or inability to perform a specific movement instead of loss of function along a particular myotome.1 As conversion symptoms are often inconsistent, the paralysed limb can be inadvertently moved when attention is diverted during assessment. This can be elicited during a physiotherapy assessment by

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RCSIsmjstaff review Table 1: Overview of the management of conversion disorders.20 Treatment overview

■ Understand underlying conflict

Table 2: Elements of physiotherapy treatment.15 Develop rapport

■ Initial assessment goal setting with staff, patient and family

before curing symptom ■ Indicate belief in presenting symptoms

■ Explanation of therapy programme

■ Do not accuse patient

■ Patient involvement in selection of rewards/privileges ■ Consistent MDT staffing

Counselling

■ Foster therapeutic

■ Insight-oriented therapy – learn to

physiotherapist–patient relationship

accept sexual/aggressive impulses ■ Behavioural therapy – induce relaxation, thus decreasing need for symptom reduction

Pre-gait activities

■ Stretching, general strengthening, bed mobility skills

Medication

■ Static balance activities (sitting/standing)

■ Benzodiazepine for anxiety and

■ Co-ordination activities (throwing/

muscular tension, antidepressants

catching a ball)

or serotonergic drugs for

■ Transfer training

obsessive ruminations

Other management

■ Weight-shifting activities

■ Hypnosis and re-education, narcoanalysis

Supported gait activities

■ Standing and beginning gait training in parallel bars, use of gait aids (frame, crutches) ■ Gait broken down into stepping

Aetiology

and weight shifting

The aetiology of conversion disorders is still relatively unknown. In recent years, some theories have been offered, but these have been largely unsubstantiated. A few of these theories are listed below. It is important to appreciate that many patients with a neurological impairment may also present with symptoms of a conversion disorder, which is sometimes termed functional overlay.

■ Progression to step to and then step over step gait pattern ■ Sidestepping, backward walking

General mobility

■ Negotiating obstacles (cones/steps)

Psychodynamic theories According to these theories, there is an initial emotional stressor, which has been converted to physical symptoms. Depression has been observed in 54-88% of patients with a conversion disorder.7 Freud believed that conversion symptoms were a result of repression: the repression being deliberate, while the conversion symptoms were unconscious.9 Janet Pierre suggested that conversion resulted from a mind–body disconnection, in that the symptoms were demonstrated in the body in order to protect the mind.10

■ Increasing endurance, add bike or treadmill ■ Privilege of walking in room and to therapy sessions ■ Multi-tasking activities such as walking and talking

Community Social factors The onset and development of conversion symptoms has shown an inverse correlation with socioeconomic status.7 Neurophysiological mechanisms Recent discussion has evolved from the results of functional

■ Progression to gait outside of parallel bars

re-integration

■ Walking outside of therapy and hospital setting ■ Architectural barriers ■ Incorporate job/school/domestic tasks (liaise with occupational therapy) ■ Discharge planning with family

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RCSIsmjstaff review neuroimaging. These scans are compatible with the hypothesis that there is malfunctioning of normal connections between areas of the brain that control the intention of movement and those concerned with initiation of movement.11 Vuillemier et al. have shown that conversion deficits are maintained by functional disorder of the striato-thalamo-cortical circuits. In particular, the caudate nucleus of the basal ganglia plays a vital role in the motor process based on emotional information gained from the limbic system.12 It has recently been demonstrated that when a patient with a conversion disorder attempted to move the paralysed leg, the primary motor cortex failed to activate. Instead, the right orbitofrontal and right anterior cingulate cortex, which have a known role in moderation of reward and benefit, were activated, thereby acting as an inhibition mechanism.13 4. Cognitive explanations It has been suggested that the symptoms of conversion disorder are directly related to activation of the portrayal of symptoms in an individual’s memory. Thus, conversion disorder is heightened by attention directed at these memories.14 5. Cultural explanations Symptoms diagnosed as conversion disorder in Western societies are classified as possession or trance-like states in other cultures.4

Physiotherapy and conversion disorders A brief overview of the management of conversion disorders is addressed in Table 1. However, physiotherapy plays a vital role in the rehabilitation of individuals with conversion disorders.7 Treatment entails using a plan of care for the presenting symptoms and the use of common physiotherapy strategies to achieve normal movement patterns, strengthening, balance rehabilitation, gait re-education and safe transfer training15 (Table 2). A key feature of treatment is to incorporate behaviour modification through the Skinnerian model of learning theory.15,16 Skinner’s model states that if a particular behaviour produces favourable reinforcement, then there is an increased likelihood of this behaviour occurring again.17 Thus, the therapist disregards unwanted movement patterns and only rewards desired behaviours such as smooth movement and normal gait.15 An important concept to integrate into the physiotherapy programme is motor learning. This is the process by which an individual acquires or modifies movement.18 As the patient progresses through the programme, the therapist should provide less cueing, less physical support and more intrinsic feedback.15 Programmes that include strengthening, general flexibility, gait retraining in parallel bars and weight-bearing activities can influence the patient’s confidence in their ability to succeed, and thereby reintegrate into community activities.

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Current physiotherapy treatment and management of conversion disorders in Ireland At present in Ireland, conversion disorders are managed in the acute general hospital setting as patients frequently present to the Accident & Emergency (A&E) Department with symptoms or are referred by their general practitioner (GP) for further investigation. Thereafter, physiotherapy treatment is individualised to the patient and comprises many of the elements outlined in Table 2. The following case presents a patient with the motor symptom/deficit subtype of conversion disorder and illustrates the physiotherapy management of conversion disorders in Ireland. I had the opportunity to observe the treatment of this patient with Roisin Moloney, Senior Physiotherapist in Neurology at Beaumont Hospital, Dublin.

Case study A 27-year-old teacher presented to A&E following review by her GP. She had a four-week history of abdominal pain, headache, fatigue and progressive tremor. She had previously been treated by her GP for a viral infection, which presented as generalised fatigue. On presentation to A&E, she had a whole-body tremor. Her past medical history was unremarkable and she was not on any medication at the time. Laboratory and radiological investigations, namely liver function tests, lumbar puncture, electrocardiogram and magnetic resonance imaging, were normal. The patient was admitted to the neurology ward in Beaumont Hospital and was referred by her medical team to physiotherapy. On initial assessment, we ascertained the patient’s hobbies and found her to be very well prior to admission; she had been training for a triathlon and her training schedule included running 10km, swimming and cycling for two hours, three times a week. She was also a competitive camogie player, training three times a week, and enjoyed physically challenging herself by increasing her training. This schedule had been halted due to a one-week history of decreased balance, progressive tremor and decreased endurance such that she was tired after 100m of mobility. Objectively, muscle strength of the upper and lower limbs was 4/5 on the Oxford Scale with give-way weakness described as a sudden collapse of muscle resistance throughout the examination. Grip strength was 4kg on her right upper limb and 18kg on her left upper limb. During gait assessment, the patient walked 10m in 35 seconds using 30 steps with the assistance of one physiotherapist. Whole-body tremor was present throughout the balance assessment, making it difficult to ascertain a score on the Berg balance test. The patient was able to complete a tandem stand (one foot placed in front of the other foot with heel-to-toe alignment), but not without uneconomical posture adaptations, including constant knee and hip flexion, in an attempt to maintain the tandem stand. A key aspect to successful treatment of this patient was to incorporate a goal-oriented programme. These goals have to be


RCSIsmjstaff review patient-specific, related to function and have a definite timeline. Regular multi-disciplinary meetings were conducted with the physiotherapy, neuropsychiatry and psychology teams to discuss goal achievement, adherence to the rehabilitation programme and treatment progression. Physiotherapy treatment of this patient consisted of several treatment techniques. Proprioceptive neuromuscular facilitation (PNF) promotes functional movement through the excitation and inhibition of appropriate muscle groups. This technique aims to stimulate the proprioceptive system as a basis for muscle re-education and to stretch muscles to stimulate activity of the muscle spindle. Relaxation techniques, such as Pilates and yoga, were recommended for relaxation, along with deep breathing exercises to help with stress management. Roisin Moloney emphasised the importance of rest from exercise for the body to recover prior to the next session. Gait re-education was the focal point of treatment, whereby the patient was provided with verbal cues to adopt economical postures and educated on safe mobility. Praise was a means of rewarding the patient when normal patterns of movement were adopted. A gradual return to exercise was set as goal, encouraging the patient to continue to exercise at lower intensity and for a shorter duration, which was steadily increased throughout treatment. Treatment enabled the patient to progress from walking 10m with the assistance of one person at the time of admission to

being able to jog 20m independently on the treadmill at the time of discharge. She scored 48/56 on her Berg balance test and her tremor was present only on slow movement and was gradually decreasing at each assessment. Her physiotherapy home exercise programme included jogging (not exceeding 80% maximum heart rate) for 10 minutes, with continued emphasis on the importance of rest and gradual return to work and exercise. She continued to visit neuropsychology and physiotherapy for treatment sessions. Patient symptoms should be continuously re-evaluated to avoid overlooking emerging neurological disease. For instance, multiple sclerosis, post-encephalitis syndrome and brain or spinal tumours can go undetected or be obscured by a diagnosis of conversion disorder.15-19 Thus, conversion disorders are complex conditions that require careful management. Recovery is ultimately facilitated through an individualised programme devised through precise communication and planning by various members of the multidisciplinary team. Physiotherapy plays a vital role in this recovery, providing patients with the environment to regain independent function through goal-driven therapy.

Acknowledgements With thanks to Roisin Moloney, Senior Physiotherapist in Neurology at Beaumont Hospital, for her advice and assistance with this article.

References 1.

Marcangelo M. Somatoform disorders. In: Roberts L, Hoop J, Heinrich T,

10. Janet P. The Major Symptoms of Hysteria (2nd ed.). London: Macmillan, 1907.

(eds.). Clinical Psychiatry Essentials. Philadelphia: Lippincott Williams &

11. Marshall J. Contemporary Approaches to the Study of Hysteria: Clinical

Wilkins, 2009:228-37. 2.

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (4th ed.). Washington, DC: American Psychiatric Association, 2000.

3.

Shapiro A, Teasell R. Behavioural interventions in the rehabilitation of acute v. chronic non-organic (conversion/factitious) motor disorders. Br J Psychiatry. 2004;185:140-6.

4.

Gelder M, Harrison P, Cowen P. Shorter Oxford Textbook of Psychiatry

5.

Stone J, Carson A, Sharpe M. Functional signs and symptoms in

(5th ed.). Oxford: Oxford University Press, 2006. neurology: assessment and diagnosis. J Neurol Neurosurg Psychiatry. 2005;76(Suppl. 1):i2-i12. 6.

Irwin K, Edwards M, Robinson R. Psychogenic non-epileptic seizures: management and prognosis. Arch Dis Child. 2000;82:474-8.

7.

Hurwitz T. Somatisation and conversion disorder. Can J Psychiatry. 2003;49:172-8.

8.

Singh SP, Lee AS. Conversion disorders in Nottingham: alive, but not kicking. J Psychosom Res. 1997;43:425-30.

9.

Freud S, Breuer J. Studies in Hysteria. London: Penguin, 2004.

and Theoretical Perspectives. Oxford: Oxford University Press, 2001. 12. Vuillemier P, Chicherio C, Assal F. Functional neuroanatomical correlates of hysterical sensorimotor loss. Brain. 2001;123:1077-90. 13. Marshall J, Halligan P, Gereon R, Wade D, Fraekowiack R. The functional anatomy of a hysterical paralysis. Cognition. 1997;64:B1-B8. 14. Brown R. The cognitive psychology of dissociative states. Cogn Neuropsychiatry. 2002;7(3):221-35. 15. Ness D. Physical therapy management for conversion disorder: case series. J Neurol Phys Ther. 2007;31(1):30-9. 16. Speed J. Behavioural management of conversion disorder: a retrospective study. Arch Phys Med Rehabil. 1996;78:264-8. 17. Weiten W. Psychology: Themes and Variations Briefer Version (7th ed.). USA: Thosmson Wadsworth, 2008. 18. Carr J, Shepherd R. Neurological Rehabilitation: Optimising Motor Performance. London: Butterworth-Heinemann, 1998. 19. Stonnington C, Barry J, Fisher R. Conversion disorder. Am J Psychiatry. 2006;163(9):1510-7. 20. Stone J, Zeman A, Sharpe M. Functional weakness and sensory disturbance. J Neurol Neurosurg Psychiatry. 2002;73(3):241-5.

Volume 4: Number 1. 2011 | Page 61


RCSIsmjstaff review Child’s play: an insight into paediatric physiotherapy in Ireland

An image from 1953 showing the physical therapist assisting two children with polio holding on to a rail while they exercise their lower limbs. (Courtesy: CDC/Charles Farmer.) Royal College of Surgeons in Ireland Student Medical Journal. 2011;4(1):62-66.

Introduction

Aideen Henry RCSI medical student

Page 62 | Volume 4: Number 1. 2011

The role of the paediatric physiotherapist has evolved considerably over the past 20 years because of improved understanding of paediatric illness and an increase in research devoted to this area. This branch of physiotherapy aims to enable the child to reach his/her full potential through developmental play, therapeutic exercise and functional training activities, with a focus on the role and involvement of the parent and extended family.1 The evolution of interventions that concentrate on function instead of impairment, as well as improved understanding of development – such as the neuromaturational theory, the dynamic systems theory and the neuronal groups selection theory – has facilitated rapid improvement in paediatric

rehabilitation over the past two decades.2 Modern paediatric physiotherapy has expanded to become more than just intervention, such as airway clearance or exercise prescription. Instead, the individual physiotherapy regime is now considered in conjunction with the active participation of the family or carer, and with the acknowledgment of influencing factors such as age, motor ability, learning development, personality, culture and personal ambition.3 The paediatric physiotherapist has “historically been involved with every aspect of childcare, giving valued support and advice to families and carers and undertaking at times very structured therapy programmes and exercise regimens”.4 In Ireland, paediatric physiotherapists work with children in a variety of settings, including


RCSIsmjstaff review special schools, hospitals, primary care teams and at home.1 These physiotherapists deal with a diverse group of diseases, such as cystic fibrosis, cerebral palsy, spina bifida, congenital syndromes and postural problems. Their goal is to facilitate development, growth and achievement of full potential as an adult.2 Chartered paediatric physiotherapists are closely involved in nationwide health initiatives, such as the recent ‘Move4health’, which aims to combat rising obesity levels in children.5 Irish physiotherapists also work with charities such as Enable Ireland to provide assistance, advice and treatment to children with disabilities and their families.6 A number of physiotherapy teams have also flown to Haiti from Ireland to assist in the rehabilitation of children injured in the earthquake, providing vital care and support to these children and their families. This article will examine the role of the paediatric physiotherapist in the country’s largest paediatric hospital, Our Lady’s Children’s Hospital in Crumlin (OLCHC). A brief overview of physiotherapy treatments and practice for cystic fibrosis (CF) in OLCHC will be provided, along with the incidence, prevalence and clinical features of the disease, and current research regarding physical management.

Our Lady’s Children’s Hospital, Crumlin OLCHC was opened in 1956 and is Ireland’s largest paediatric hospital, providing the majority of the country’s tertiary care services for children. The hospital is the national centre for many services, including cardiac surgery, haematology, oncology, major burns, medical genetics, and medical research for childhood illnesses. Annually, the hospital treats over 24,500 inpatients, 76,000 outpatients and 30,100 emergency department attendances, and more than 13,500 operations are performed.7 The Extracorporeal Life Centre (ELC) was established in 2005, and supports post-operative cardiac patients who have come off bypass and the recovery of patients with cardiomyopathy. OLCHC was recently made a Centre of Excellence for services provided by the ELC. The physiotherapy department in OLCHC employs 18 physiotherapists, who work in a variety of highly specialised areas, such as respiratory medicine, cardiology, neurology, the transitional care unit, burns and plastics, and rheumatology. They liaise closely with the rest of the multidisciplinary team (MDT) in both of the intensive care units in the hospital – one with eight beds and the other with 12. Specialised physiotherapists work with patients with CF, both as inpatients and outpatients. The medical tower, which was opened in 2005 and contains two dedicated physiotherapy rooms, caters for many outpatient clinics, including the CF clinic. In OLCHC, two CF clinics are held weekly that can accommodate approximately 12 patients at a time. Each week, four annual patient reviews are also held to assess physical function and management, and to implement any new changes in therapy or treatment. A drop-in outpatient service is also available for CF patients on weekdays. These services play an essential role in the care and management of CF.

Cystic fibrosis CF is a genetic, chronic inflammatory disease that commonly presents with recurrent respiratory infection and malnutrition.8 A mutation in the gene of the cystic fibrosis transmembrane conductance regulator (CFTR) protein causes this disease, a protein that is necessary for the regulation of the production of mucus, digestive juices and sweat. A multisystem disease, CF typically affects the gastrointestinal, endocrine and respiratory systems, but a number of other systems in the body can be included in the presentation (Figure 1). Impaired water and ion transfer across the epithelial surfaces of the body causes malabsorption in the GI tract and insufficiency of the pancreas. Mucus in the lungs becomes viscous, and neutrophils may further thicken the secretions. CF occurs in almost all ethnic groups, but is the most common autosomal recessive disease in Caucasians. With a carrier frequency of one in 25.9,10 Ireland has the highest incidence of CF worldwide, with one in 1,461 of the population affected.9 Each year in Ireland, 30 to 40 children are diagnosed with this lethal condition. Despite the vast improvements made in the prognosis and management of CF, the current median age of survival is approximately 40 years.11,12 Chronic respiratory disease results from prolonged bronchial obstruction, infection, inflammation and bronchiectasis, all of which lead to permanent lung damage. In younger patients, considerable damage may be present before airflow resistance is increased and a decreased flow can be measured.3 Most patients die from chronic respiratory failure and, as there is currently no cure, their management incorporates medical treatment and respiratory physiotherapy techniques that aim to improve quality of life and extend survival.8 Therefore, a comprehensive healthcare service is essential to provide these patients with the care and management they require throughout their lives. Ireland has not yet instituted newborn screening for CF, but this service is expected to commence in the first half of 2011. As a result, the majority of patients are diagnosed on presentation of their symptoms. Since the cornerstone of CF treatment is symptomatic management, physiotherapy plays an essential role. The presentation of CF is highly variable and individual to each patient, so it is accepted that no predetermined physiotherapy regime is applicable to all patients.3 The implementation of a successful physiotherapy programme depends on comprehensive knowledge of respiratory anatomy and physiology, the goals of modern-day CF management, and a thorough overview and understanding of evidence-based practice regarding physiotherapy techniques.3 “Good physiotherapy is the mainstay of clinical wellbeing in CF,” since physiotherapy aims to slow progression of lung disease and optimise physical function and quality of life.3,13

Physiotherapy management of cystic fibrosis Daily physiotherapy management is implemented in the treatment of CF to ensure adequate ventilation of the lungs and

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FIGURE 1: Diagram depicting the manifestations of cystic fibrosis. (Courtesy: Kliegman R; Source: Kliegman RM. Nelson Essentials of Pediatrics. St. Louis, Elsevier Saunders, 2006.) to minimise lung damage secondary to impaired mucociliary clearance. The focus of treatment is prevention of lung deterioration and the incorporation of the physiotherapy principles of airway clearance and exercise into everyday life. A number of methods are utilised by Irish physiotherapists in the treatment of CF.

The active cycle of breathing technique The active cycle of breathing technique (ACBT) is comprised of three techniques, which mobilise and clear excess bronchial secretions.14 The cycle begins with a period of breathing control, which reduces bronchoconstriction and aims to relax the patient. Thoracic expansion exercises then follow, which reduce resistance to airflow through the collateral channels of ventilation. An inspiratory hold at the end of thoracic expansion allows for air to flow slowly into the diseased and healthy areas of the lung for equal ventilation.14,15 The final stage of ACBT is the forced expiration technique (FET), which involves huffing at both low and high volumes to mobilise secretions from small peripheral airways into large, central airways.14,16 The technique should be performed while seated, and cycle repetitions can be adjusted to suit the needs and requirements of the patient.15 This effective method of secretion mobilisation should be performed independently when appropriate and utilised by the patient when necessary.14,15,16,17

Positive expiratory pressure Positive expiratory pressure (PEP) utilises end-expiratory resistance to mobilise secretions from closed or blocked

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peripheral airways.14,18 A face mask that incorporates a one-way valve, resistor and manometer is held tightly to the face, with the patient sitting down and leaning forward, elbows resting on a table. A cycle of 12-15 breaths is performed, using active tidal volume breaths that give a pressure reading of 10-20cmH20 mid-expiration.14 A cycle of FET is then performed to clear mobilised secretions, and the cycle may be repeated depending on patient requirements. Accurate instruction as to the correct performance of the technique is essential to ensure optimal effect.14,18,19

Postural drainage Postural drainage and percussion techniques were initially introduced in CF management in the 1950s.14 Despite having been replaced by less time-consuming and more lifestyle-friendly methods of secretion clearance, they still play an important role in CF management. Postural drainage is achieved by placing the patients in between six and 12 positions, depending on the lobe or lung segment affected, to enable gravity to influence secretion clearance.14 Chest percussion is then performed for three to ten minutes while the patient maintains this position. Deep breathing exercises can also be incorporated into the treatment, along with the vibration method of manual clearance and FET.14 Adherence to postural drainage is generally poor, and the risk of aspiration following head-down positioning has led to a modification of drainage positions.20,21 The implementation of postural drainage in a CF management programme is generally only advised for very young children when other modern methods of secretion clearance are unsuitable.21


RCSIsmjstaff review Autogenic drainage

Exercise

Autogenic drainage involves the modulation of inspiratory and expiratory flow to create shearing forces that clear secretions from the bronchi.14 A low-velocity inspiration is followed by exhalation, in which optimal shearing forces are localised to the site of secretion and accumulation within the lungs. Upper airways are cleared first, followed by the peripheral airways.14 Assisted autogenic drainage is utilised in very young or non-compliant patients.14 The functional breathing level of the patient is modulated manually or by elastic straps in order to obtain optimal airflow velocity, which can be targeted at specific secretions. The childâ&#x20AC;&#x2122;s abdominal wall must be stabilised to prevent paradoxical movements. Assisted autogenic drainage can be combined with gentle bouncing on a physiotherapy ball, which may aid in relaxation and optimisation of expiratory air flow.14,22

Exercise is also encouraged in the physiotherapy management of CF, with approximately 36% of patients incorporating it regularly into their treatment regimes.23 Exercise tolerance may be severely limited in CF, since dyspnoea and an abnormal ventilatory response to physical activity are a consequence of the progressive nature of the respiratory disease.27 However, participation in a tailored exercise programme can result in improved appetite, body image, pulmonary function, feelings of wellbeing, and work and sport performance. Exercise can also have beneficial effects on anxiety, depression and the development of osteoporosis.27,28,29,30 Future research is required to focus on the duration and type of exercise programmes that will deliver the most benefit, especially for paediatric patients. At OLCHC, patients are encouraged to participate in a wide variety of exercises, both at home and in school, a suggestion based on studies that have indicated that children prefer exercise to other forms of treatment.31 Irish paediatric physiotherapists also focus on the management and maintenance of posture in CF patients. Evidence suggests that compromise of the respiratory system can have a detrimental effect on the control of postural trunk muscles, which can thereafter impede growth, development and normal movement.32,33 Pain is a commonly reported symptom in CF, resulting from poor bone mineral density, postural adaptations, coughing and osteoporotic fractures.33 Pain is detrimental to core muscle control and can lead to the development of trunk deformities, such as thoracic kyphosis.33 The subsequent development of poor posture, musculoskeletal deformity and tissue contractures can have an adverse effect on respiratory function and hastens the progression of chronic respiratory deterioration.33 Therefore, advice and musculoskeletal techniques provided by the physiotherapist in the management of posture is essential for the growth and development of the CF patient.

Oscillatory positive expiratory pressure Oscillatory positive expiratory pressure (PEP) is utilised in devices such as the Flutter or the Acapella. The Flutter device facilitates mucociliary clearance by inhibiting premature closure of the bronchi.14 FET is used post treatment to facilitate expectoration. On exhalation through the Flutter, the bronchi undergo a series of vibrations that are combined with PEP (18-35cmH20) and variations in endobronchial pressure.14 The spatial position of the device relative to gravity determines the oscillation frequency. The Acapella, on the other hand, is not gravity-dependent and may prove easier for certain patients to use at low-velocity expiration.14 With the patient sitting comfortably, the mouth must form a tight seal around the device. The patient inhales through the nose and, following a brief inspiratory hold, exhales maximally. A cycle of 10-15 breaths is performed through the device, followed once again by FET.14 Although further research is required to determine the efficacy of the Flutter as a method of secretion clearance compared to other interventions, current best practice dictates its incorporation into a varied physiotherapy regime rather than its standalone use.14 Based on information gathered by the Cystic Fibrosis Registry of Ireland in 2007, the most popular physiotherapy modalities used by Irish CF patients are PEP, the Acapella device, percussion techniques and regular exercise.23 Mucociliary clearance and defence against infection are limited in CF due to abnormal airway surface liquid. This results in a continuous cycle of chronic inflammation, infection, excess mucus and airway obstruction, which culminates in irreversible bronchiectasis. As a result, airway clearance techniques have historically formed the foundation for the physiotherapy treatment of CF. A systematic review conducted by Van der Schans et al. concluded that chest physiotherapy is effective in the short-term treatment and management of CF.24 However, definitive research comparing the efficacy of the different clearance modalities is missing from the literature because of a lack of appropriate outcome measures, control groups and subjects. Meta-analyses have concluded that there is little difference between the various methods, but that patient preference points towards the self-administered methods of airway clearance.19,25 Patient preference is an important element to consider since adherence rates to physiotherapy treatment in CF are estimated at less than 50%.27

Conclusion The role of the paediatric physiotherapist in Ireland is both diverse and demanding. A variety of skills is required to meet the needs of this patient group and assist in their development and growth. The encouragement, education and inclusion of parents and carers are vital to ensure optimal management of the child. The physiotherapists working at OLCHC display all these attributes and capabilities. Despite the demanding environments in which they work, these physiotherapists promote positive and nurturing atmospheres, combining their specialised skills with a dedication to meeting the needs of their patients. The role of the paediatric physiotherapist in Ireland will continue to evolve, especially as further comprehensive research is required to consolidate evidence-based practice and determine optimal treatment approaches. The future for paediatric

Volume 4: Number 1. 2011 | Page 65


RCSIsmjstaff review physiotherapy is exciting and opportunities for research, learning and development are numerous, with Irish physiotherapists leading the way in providing comprehensive and innovative care for their patients.

Acknowledgements I would like to thank Karen Ingoldsby, Senior Physiotherapist, OLCHC, and Gillian Nugent, Clinical Specialist, OLCHC, for their assistance and encouragement in the writing of this article.

References 1. Irish Society of Chartered Physiotherapists [homepage on the internet], 2010. Cited October 22, 2010. Available from: http://www.iscp.ie/. 2. Helders P, Engelbert Rh, Custers JW, Gorter JW, Takken T, van der Net J. Creating and being created: the changing panorama of paediatric rehabilitation. Pediatr Rehabil. 2003;6(1):5-12. 3. Lannefors L, Button B, Mcllwaine M. Physiotherapy in infants and young children with cystic fibrosis: current practice and future developments. J R Soc Med. 2004;97(44):8-25. 4. Carter A. Principles of paediatric physiotherapy. In: Porter S. Tidy’s Physiotherapy. London: Churchill Livingstone Elsevier, 2003. 5. Irish Society of Chartered Physiotherapists. Move4Health Campaign [homepage on the internet], 2010. Cited October 22, 2010. Available from: http://www.iscp.ie/content/view/793/520/. 6. Enable Ireland [homepage on the internet], 2010. Cited October 22, 2010. Available from: http://www.enableireland.ie/. 7. Our Lady’s Children’s Hospital in Crumlin [homepage on the internet]. History and Information, 2010. Cited October 22, 2010. Available from: http://www.olhsc.ie/AboutUs/. 8. Wagener J, Headley A. Cystic fibrosis: current trends in respiratory care. Respir Care. 2003;48(3):234-45. 9. Devaney J, Glennon M, Farrell G, Ruttledge M, Smith T, Houghton JA et al. Cystic fibrosis mutation frequencies in an Irish population. Clin Genet. 2003;63:121-5. 10. Doring G, Conway SP, Hejerman HG. Antibiotic therapy against Pseudomonas aeruginosa in cystic fibrosis: a European consensus. Eur Respir J. 2000;16(4):749-67. 11. Dodge JA, Lewis PA. Cystic fibrosis is no longer an important cause of childhood death in the UK. Arch Dis Child. 2005;90(5):547. 12. Elborn JS, Shale DJ, Britton JR. Cystic fibrois: current survival and population estimates to the year 2000. Thorax. 1991;46(12):881-5. 13. Jaffé A, Bush A. Cystic fibrosis: a review of the decade. Monaldi Arch Chest Dis. 2001;56(3):240-7. 14. International Physiotherapy Group for Cystic Fibrosis. Physiotherapy for people with cystic fibrosis: from infant to adult [homepage on the internet], 2009. Cited October 22, 2010. Available from: http://www.cfww.org /docs/ipg-cf/bluebook/bluebooklet2009websiteversion.pdf. 15. Pryor J, Prasad S. Physiotherapy for Respiratory and Cardiac Problems (4th ed.). Edinburgh: Churchill Livingstone, 2008. 16. Lapin, CD. Airway physiology, autogenic drainage, and active cycle of breathing. Respir Care. 2002;47(7):778-85. 17. Wilson GE, Baldwin AL, Walshaw MJ. A comparison of traditional chest physiotherapy with the active cycle of breathing in patients with chronic suppurative lung disease. Eur Respir J. 1995;8(Suppl. 19):171S.

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18. Darbee JC, Ohtake PJ, Grant BJB, Cerny FJ. Physiological evidence for the efficacy of PEP as an airway clearance technique in patients with CF. Phys Ther. 2004;84(6):524-37. 19. Bradley JM, Moran FM, Elborn JS. Evidence for physical therapies (airway clearance and physical training) in cystic fibrosis: an overview of five Cochrane reviews. Respir Med. 2006;100(2):191-201. 20. Button BM, Heine RG, Catto-Smith AG, Phelan PD, Olinsky A. Postural drainage and gastro-oesophageal reflux in infants with cystic fibrosis. Arch Dis Child. 1997;76(2):148-50. 21. Button BM, Heine RG, Catto-Smith AG, Olinsky A, Phelan PD, Dichfield MR et al. Chest physiotherapy in infants with CF: to tip or not? A five-year study. Pediatr Pulmonol. 2003;35(3):208-13. 22. Chevaillier J. Autogenic drainage: an airway clearance technique, in unpublished abstracts 2000. 21st European Cystic Fibrosis Conference: Switzerland, 2000. 23. Cystic Fibrosis Registry of Ireland. Cystic Fibrosis Registry of Ireland Annual Report, 2007:25. 24. Van der Schans C, Prasad A, Main E. Chest physiotherapy compared to no chest physiotherapy for cystic fibrosis. Cochrane Database Syst Rev. 2000;(2):CD001401. 25. Main E, Prasad A, Schans C. Conventional chest physiotherapy compared to other airway clearance techniques for cystic fibrosis. Cochrane Database Syst Rev. 2005;(1):CD002011. 26. Myers LB, Horn SA. Adherence to chest physiotherapy in adults with cystic fibrosis. J Health Psychol. 2006;11(6):915-26. 27. O’Neill PA, Dodds M, Phillips B, Poole J, Webb AK. Regular exercise and reduction of breathlessness in patients with cystic fibrosis. Br J Dis Chest. 1987;81(1):62-9. 28. Peebles AD. Physiotherapy. In: Hill CM (ed.). Practical Guidelines for Cystic Fibrosis Care. London: Churchill Livingstone, 1998. 29. Wolman RL. Osteoporosis and exercise. In: McLatchie G et al. ABC of Sports Medicine. BMJ publishing, 1999. 30. American College of Sports Medicine. Guidelines for Exercise Testing and Presecription. (6th ed.). W.L. Kenny: Lippincott Williams and Wilkins, 2000. 31. Moorcroft AJ, Dodd ME, Webb AK. Exercise limitations and training for patients with cystic fibrosis. Disabil Rehabil. 1998;20:247-53. 32. Massery M. Musculoskeletal and neuromuscular interventions: a physical approach to cystic fibrosis. J R Soc Med. 2005;98(Suppl. 45):55-66. 33. Tattersal R, Walshaw MJ. Posture and cystic fibrosis. J R Soc Med. 2003;96(43):18-22.


RCSIsmjstaff review The surgical safety checklist

Royal College of Surgeons in Ireland Student Medical Journal. 2011;4(1):67-69.

In March 2008, an eight-year-old boy in Our Lady’s Hospital for Sick Children in Crumlin had his healthy left kidney surgically removed. A series of mistakes resulted in the removal of the healthy kidney from the boy, and he left the operating theatre with only his diseased right kidney, functioning at 9% of normal. Prior to the surgery, his parents sensed that there was some confusion as to which kidney would be removed and voiced their concerns to several staff members.1 Despite this, the boy became another surgical error statistic, one that could have been avoided with the correct use of a surgical safety checklist.

Medical errors – causes and solutions

Geneva Weiglein RCSI medical student

An integral part of human nature is that despite our greatest efforts, we all make mistakes. However, mistakes happen for different reasons, including forgetfulness, haste, disorganisation, intimidation and ‘groupthink’.2 Psychologist Irving Janis’ theory of groupthink explains how groups can prioritise cohesion among group members over individual critical thinking. As a result, groups can agree on subpar ideas that are potentially detrimental.3 Similarly, the Swiss Cheese Model of Error exemplifies how a series of mistakes at different logistical levels can combine to create a serious yet avoidable situation.4 In January 2007, in an effort to address the safety of surgical care, the World Alliance for Patient Safety initiated work on the World Health Organisation’s (WHO) Safe Surgery Checklist.5 The surgical safety checklist was created to safeguard against specific errors during all stages of surgery. When

implemented correctly, it can significantly reduce cumulative oversights that lead to surgical error and considerably increase patient safety.6 Medical errors are estimated to seriously harm approximately one in ten hospitalised patients in the United States.7 A study done by the UK National Patient Safety Agency estimated that approximately 35,000 medical errors occur annually in Irish hospitals.7 In addition to mortality and morbidity, the financial cost of medical errors can also be devastating. Ireland spent approximately €74 million settling claims against health agencies between 2003 and 2008.8 While it is not feasible to eliminate human error entirely, Haynes et al. conducted a study that found that surgical deaths were reduced by approximately one-half and surgical complications were reduced by more than one-third when the surgical safety checklist was implemented.6,9 Thus, it seems worthwhile to implement simple yet effective strategies such as the surgical safety checklist to reduce error and undue surgical sequelae.6,9 Dr Atul Gawande, Director of the WHO’s Global Challenge for Safer Surgical Care, spearheaded the development of the surgical safety checklist that is being implemented globally to reduce surgical errors and standardise surgical safety.10 The checklist is a concise, single-page list divided into three phases: before anaesthesia; before the first incision; and before the patient is transferred to the surgical recovery room. Only once each task has been completed can the next item on the list be addressed (Figure 1).

Volume 4: Number 1. 2011 | Page 67


RCSIsmjstaff review

FIGURE 1: The World Health Organisation Surgical Safety Checklist.19

The surgical safety checklist in Ireland In operating theatres in Ireland, the head theatre sister is in charge of the checklist. The term â&#x20AC;&#x2DC;surgical time-outâ&#x20AC;&#x2122; is used, referring to the time designated to completing the checklist in theatre. During the first phase of the checklist, the patient participates in the confirmation of their surgical site and has it marked before any anaesthesia is administered. During the second phase, the surgeon and surgical staff confirm the correct patient, procedure and surgical site. During the third phase, when the surgery is complete and the patient is about to leave the theatre, there is a recapitulation of the procedure, a count of surgical instruments and a record of any errors made. The checklist consists of basic tasks arranged in a logical sequence and involves the patient and all members of the surgical multidisciplinary team. As a result, no single person is responsible for the verification procedure. Rather, several medical staff members have specific tasks allocated to them at different times, and they must confirm that their task was completed in front of other team members so that it may be ticked off the checklist. Intuitively, distributing responsibility and increasing transparency reduces the possibility for error. By having more people involved in the safety protocol, there are more people designated to catch

Page 68 | Volume 4: Number 1. 2011

mistakes. Also, by structuring and standardising procedures, the potential for groupthink and errors attributable to hierarchical intimidation are decreased. The checklist is a basic outline and is intended to be tailored to each specific procedure for optimal efficacy. The correct use of the surgical safety checklist has demonstrably decreased patient morbidity and mortality dramatically, and is in the process of being implemented globally. Moreover, Gawande et al. have estimated that between $15 and $25 billion USD per year would be saved if the WHO surgical safety checklist were implemented in operating theatres across the United States.11 The UK, Canada, Ireland, Jordan and the Philippines have already integrated the surgical safety checklist into their nationwide operating theatres protocol.12,13 Currently, Ireland is reforming healthcare policies to increase accountability and public trust in the hope of changing societal attitudes towards healthcare. One goal is to increase public interest in the healthcare system, with an emphasis on public feedback and responsibility. Increasing the collection and availability of information about mortality rates, healthcare-related adverse events, hospital ratings, complaints and consequent actions would help to increase transparency and has been proposed as a future improvement.7,14 The Health Service Executive (HSE) has endorsed this movement by


RCSIsmjstaff review implementing the Transformation Programme between 2007 and 2010, the main goal of which is to advance services and to maintain new standards within the healthcare field so as to enable the Irish population to live healthier lives. “Success depends on all of us being open and willing to change, not just those directly or immediately involved”.15 The surgical safety checklist is being implemented across Ireland with varying adherence and criticism. To investigate the use of surgical checklists at Beaumont Hospital, Professor Arnold Hill, Chairman of Surgery at the Royal College of Surgeons in Ireland and Beaumont Hospital, and Mr Patrick J Broe, Vice President of the RCSI Council and Consultant Surgeon at Beaumont Hospital, were contacted by personal correspondence.16,17 Professor Hill and Mr Broe are both proponents of the surgical safety checklist, and agree that it is effective and valuable as long as there is strong leadership behind it and willingness from all team members to participate. From their experience, they note that the checklist engages the entire surgical team and allocates a specific time point to ensure that all team members introduce

themselves. This seemingly insignificant component is particularly relevant in larger hospitals, where the staff members often do not know one another at the time of surgery. Even in smaller hospitals, such introductions help to reaffirm each member’s role and responsibility. This small step can encourage junior team members to speak up if they have cause for concern and can potentially be the difference between a successful surgery and a harmful procedure. Each person is also reminded that they have a clear responsibility to the patient’s safety, thereby diminishing the incidence of groupthink. So long as the checklist is continually reassessed and updated, Professor Hill and Mr Broe both predict that it will continue to be an integral part of surgical safety and significantly contribute to better patient outcomes. The eight-year-old boy from Our Lady’s Hospital for Sick Children survived the operation but serves as a reminder of the impact of cumulative errors and the life-saving efficacy of a surgical safety checklist. The checklist has enormous potential for improving surgical morbidity and mortality well into the future.18

References 1.

Donnellan E. Mother asked for check before child’s wrong kidney removed. [homepage on the internet]. The Irish Times, May 28, 2010. Cited September 1, 2010. Available from: http://www.irishtimes.com/newspaper/frontpage/2010/0528/12242713

2.

Adopting a surgical safety checklist could save money and improve the quality of care in US hospitals. Health Aff (Millwood).

Mccauley C. Group dynamics in Janis’s theory of groupthink: backward

4.

Reason J. Human error: models and management. BMJ. 2000;320:768.

5.

World Alliance for Patient Safety. WHO surgical safety checklist and

and forward. Organ Behav Hum Decis Process. 1998;73(2/3):142-62.

implementation manual [homepage on the internet], 2008. Cited September 1, 2010. Available from:

Safe Surgery Saves Lives. In: World Alliance for Patient Safety, 2010. 13. World Health Organisation. Surgical Safety Web Map [homepage on the internet], 2006. Cited December 23, 2010. Available from: http://maps.cga.harvard.edu:8080/Hospital/. 14. O’Malley R. Complete transparency is only way to rebuild trust

http://www.who.int/patientsafety/safesurgery/ss_checklist/en/index.html.

[homepage on the Internet], March 11, 2010. Cited November 1, 2010. Available from:http://www.independent.ie/opinion/analysis/

findings: a surgical safety checklist could save hundreds of thousands of

rebecca-omalley-complete-transparency-is-only-way-to-rebuild

Available from: http://www.who.int/patientsafety/safesurgery/checklist_saves_lives/en/.

-trust-2095042.html. 15. Health Service Executive. Transformation Programme 2007-2010. In: Health Service Executive, 2008.

Hunter N. Getting serious about medical error [homepage on the

16. Hill A. Interviewed by Weiglein G, October 26, 2010.

internet], April 23, 2008. Cited October 20, 2010. Available from:

17. Broe P. Interviewed by Weiglein G, October 30, 2010.

http://www.irishhealth.com/article.html?id=13454&ss=surgical%20error.

18. Donnellan E. Doctors cleared of misconduct in kidney mix-up case

Hunter N. State’s €74m health errors pay-out [homepage on the

[homepage on the internet]. The Irish Times, September 4, 2010. Cited

internet], October 5, 2009. Cited October 20, 2010. Available from:

November 6, 2010. Available from: http://www.irishtimes

University of California website: http://www.irishhealth.com/article.html?id=16216&ss=surgical%20error. 9.

2010;29(9):1593-9. 12. World Health Organisation. The Second Global Patient Safety Challenge:

World Health Organisation. New scientific evidence supports WHO lives [homepage on the internet], 2010. Cited September 1, 2010.

8.

http://www.who.int/patientsafety/about/atul_gawande/en/. 11. Semel ME, Resch S, Haynes AB, Funk LM, Bader A, Berry WR et al.

00512.html.

3.

7.

2010. Cited October 20, 2010. Available from:

Raven BH. Groupthink, Bay of Pigs, and Watergate reconsidered. Organ Behav Hum Decis Process. 1998;73(2/3):352-61.

6.

10. World Health Organisation. Atul Gawande [homepage on the internet],

.com/newspaper/ ireland/2010/0904/1224278203643.html. 19. World Health Organisation. Safe Surgery Saves Lives: The Second Global

Haynes AB, Weiser TG, Berry WR. A surgical safety checklist to reduce

Patient Safety Challenge [homepage on the internet], 2009. Cited

morbidity and mortality in a global population. New Engl J Med.

December 23, 2010. Available from:

2009;360:491-9.

http://www.who.int/patientsafety/safesurgery/en/index.html.

Volume 4: Number 1. 2011 | Page 69


RCSIsmjstaff review eHealth: Ireland’s approach to medicine in the digital age

Royal College of Surgeons in Ireland Student Medical Journal. 2011;4(1):70-73.

Ankit Kapur RCSI medical student

Page 70 | Volume 4: Number 1. 2011

Over the last decade, Ireland has experienced tremendous growth. Its gross domestic product (GDP) has more than doubled, the population has grown by a startling 20%, and spending on public healthcare has tripled.1,2 Such enormous progress was largely attributed to Ireland’s burgeoning information and communications technology (ICT) sector.3 This nascent technological engine spurred massive advances in almost all aspects of Irish life. However, the traditionally conservative field of medicine was not so readily swept forward. While 70% of all Irish households had a computer by 2008, only 58.5% of all single GP practices were equipped with a computer, the second lowest percentage of any EU country.4,5 Such aversion to change is characteristic of medicine’s inherent conservatism, which tries to protect patients from the potential harm of untested and unproven theories. However, this conservatism can, and has, come at a cost to patients, with pioneering advances being unnecessarily resisted or ignored. In the 1700s, Dr Lind’s treatment for scurvy was discounted, in the 1800s Dr Semmelweis’ passionate arguments for hand washing were resisted, and in the 1900s Dr Fleming’s discovery of penicillin was initially dismissed. Now in the 21st century we face our own test with accepting innovation, as technology entwines itself further with the domain of healthcare, creating a new hybrid entity known as ‘eHealth’.

eHealth The goal of this hybrid entity is to improve the health of patients and populations by utilising advances in ICT across the whole spectrum of healthcare-related functions.6 Although the definition of eHealth is continually evolving, there is consensus that eHealth incorporates not only the discipline of medical informatics, but that it also includes the use of more generalised communications through networked digital technologies such as the internet. In its broadest sense, eHealth is the application of emerging ICT in order to improve or enable health and healthcare.6 However, the pervasive nature of technology makes such a broad definition of eHealth a real challenge when trying to clearly understand its scope. Indeed, there are many growing fields that can stand to benefit from ICT, and can thus all be considered elements of ‘eHealth’ (Table 1). Instead of trying to create an overarching definition of eHealth, it is perhaps more useful to explore the limits and potentials of this field by closely examining one technology that has become synonymous with the field – electronic medical records (EMR). The issues and arguments surrounding the wide-scale adoption of EMR systems are indicative of the greater debate around eHealth, and a closer look at the promises and challenges faced by EMR provides a useful snapshot of the present and future of eHealth as a whole.


RCSIsmjstaff review Electronic medical records: promises and challenges At a practical level, EMRs are simply a database solution whereby patients’ medical information is encoded in a digital format allowing for ease of searchability, information transfer, improved legibility and automation. Proponents of EMRs argue that they reduce administrative costs (e.g., automatic billing and scheduling), improve treatments (e.g., reduced prescription errors), allow for quick and easy sharing of patient records (e.g., eReferrals, electronic lab results), increase the use of evidence-based medicine (e.g., online decision support tools such as UptoDate), and provide an unparalleled amount of data for research purposes.7 Opponents, however, are quick to point out substantial barriers that have prevented the full realisation of EMRs’ potential benefits. Notably, EMR systems require a significant dedication of time during transitioning, can be expensive, necessitate additional training and do not have the same assurances of reliability and quality expected of other medical products.7 These concerns are not merely conjecture, but are rather real hindrances, as proven in a 2003 survey by the Irish College of General Practitioners. They found that lack of time, cost and poor training were the top three reasons preventing respondents from computerising their practices.8 In addition, a unique barrier that Irish practitioners identified was the problems surrounding system crashes due to power outages, computer viruses or hardware failures.9 These major barriers are largely related to the initial effort of digitising paper records, the cost and time associated with training staff, and the purchasing expense of database systems. The expense can vary widely depending on the database functionalities, the size of the practice and the extent of integration and customisation.10 However, in return for these initial outlays, EMRs hold the promise of greatly increasing efficiency and reducing wastage of medical resources (e.g., duplicated laboratory tests), thereby freeing up time and increasing profits in the long term. Another significant issue that has limited the uptake of EMRs is the lack of legislation governing the vast number of products currently on the market, thus limiting trust in the quality and reliability of EMR systems. Currently, no centralised mechanism is in place for reporting problems with EMR systems, as exists for drugs and medical devices. Rather, contracts regularly stop clients from reporting systemic problems.7 There have been calls for regulatory agencies such as the United States Food and Drug Administration (FDA) and Irish Medicines Board to evaluate and approve EMRs using a process similar to that which governs medical devices and pharmaceuticals. Until Irish public policy catches up with technology, EMR systems will not be perceived to have the standards that are expected of medical products. The most detrimental criticism of EMRs is the lack of conclusive evidence demonstrating their efficacy in improving the quality of healthcare or in yielding significant savings.7,11,12 A 2007 study by Linder et al. found no relationship between EMRs and the

quality of patient care. However, the authors pointed out that even though their National Ambulatory Medical Care Survey (NAMCS) data set was the best available in terms of size and accuracy, it was outdated from a technological perspective. In addition, their analysis was limited to asking physicians whether they had an EMR and did not take into account the actual extent of EMR implementation.11,12 This study was pivotal in concluding that it is simply not enough to install EMR systems; rather, the usage of EMR systems is instrumental to quality improvements in healthcare. Thus far, evidence-based studies that support EMRs only report modest benefits. Parente and McCullough analysed four years of Medicare data and found just marginal improvements in patient outcomes because of EMRs: specifically, two fewer infections a year at the average US hospital.13 Another study by the Veterans Administration in the United States showed similar small gains from EMRs in reducing costs and improving care through enhanced patient safety, in particular automatic detection of drug interactions.7 In an attempt to reconcile these two divergent arguments, Greenhalgh et al. from University College London undertook a meta-analysis of EMRs in order to identify “fundamental and often overlooked tensions in the design and implementation of [EMRs]”.14 Interestingly, the study’s results found an unexplored middle ground. It identified that certain administrative functions are made more efficient by EMRs, while clinical work can actually be made less efficient. Significantly, the rigid nature of EMR templates do not always allow for clinicians to arrange information in a manner most suitable for the patient history, and the technical challenges of digital drawings eliminated the ability to include diagrams and sketches. This study acknowledged that paper-based systems offer superior flexibility in clinical work when compared to the EMR systems, and it found that smaller localised EMR systems have greater efficacy than larger ones. If we regard EMRs and their parent field of eHealth as merely another set of medical tools, then any measure of their effectiveness will depend not just on their intrinsic properties, but also on our appropriate use of them in correct situations. This elucidates that the technology alone is not enough; we must also know how to use it. It is only through a clear understanding of the possibilities, limits, costs and benefits of eHealth that we will be able to realise the full potential of this emerging entity.

Ireland’s approach to digital medicine Ireland has been relatively progressive in its strategic policies regarding the integration of eHealth into its larger ongoing healthcare reforms. Following the creation of the Health Services Executive (HSE) in 2004, a National ICT Directorate was formed. For the first time, this agency examined eHealth in an Irish context in their report ‘Embedding the e in health’. The HSE followed up on this by implementing Ireland’s current eHealth strategy, titled ‘National Health Information Strategy’ (NHIS), which sets targets and strategies for modernising the Irish health

Volume 4: Number 1. 2011 | Page 71


RCSIsmjstaff review Table 1: The scope of eHealth. Areas of eHealth

Definitions

Aspects

Electronic patient/health/medical records

A database solution whereby patientsâ&#x20AC;&#x2122;

Immediate access in emergencies to medical

medical information is encoded in a digital

alerts, multi-professional access to patientsâ&#x20AC;&#x2122;

format allowing for ease of searchability,

medical records, record linkage for family

information transfer and automation.

members, clinical coding for easy searchability.

Professional clinical informatics

Consumer health informatics

Electronic resources used by healthcare

Decision aids for practitioners (e.g., prompts,

professionals in order to make medical

guidelines), educational aids, overview of

decisions or to inform themselves about

latest medical journals and best practice,

medical topics.

clinical management tools.

Electronic resources used by patients or

Decision aids for patients, shared

a population in order to make medical

decision-making tools, informed consent

decisions or inform themselves about

aids, clinicianâ&#x20AC;&#x201C;patient communication tools,

medical topics.

online screening, TV or web-based medical information.

Healthcare administrative management

Electronic solutions catering to the

Appointment scheduling, work schedule

administrative duties surrounding healthcare.

management, billing and tracking systems, audit and quality assessment systems.

Telemedicine

The provision of medical consultations

Medical services to remote/rural

and treatments at a distance.

communities, on board ships/planes, space-based medicine, clinical email and web-based messaging systems.

New technologies

Advances in science making previously

Robotics, nanotechnologies, virtual reality

unrealised medical potentials possible

environments (e.g., remote surgery), mobile

or improving on current functions.

telephone-based monitoring, paperless palmtop technologies (e.g., iPad charts).

Research outcomes

Utilisation of electronic databases and informatics for larger population-based studies.

Page 72 | Volume 4: Number 1. 2011

Epidemiological research, bioinformatics.


RCSIsmjstaff review sector’s ICT infrastructure by 2011.5,15 The Oireachtas is considering a Health Information Bill, which will address issues relating to the collection, use, storage and disclosure of personal health information.16 In contrast to these progressive policy initiatives, the state of eHealth infrastructure in Ireland is below the European average. Compared to a European average of 80%, only 65% of GP practices in Ireland store administrative patient data and use local EMRs.5 The transfer of EMRs is even less common, with only 40% and 17% of practices exchanging medical data and administrative data, respectively. In light of this mixed performance, it is no surprise that in 2008, the European Commission found Ireland to be performing at an average level in the eHealth sector when compared to other EU27 members.5

To improve its performance, Ireland must overcome the massive challenges of a shrinking economy, an ageing population and unprecedented cuts in Government budgets, to the amount of €600 million for 2011.17 These issues are likely to converge, such that the Irish healthcare sector will be faced with the challenge to provide for a greater number of patients with fewer resources. This perhaps presents an opportunity for growth and, given the current need for increased efficiency, cost saving and enhanced productivity, it is an ideal time to implement appropriate eHealth solutions. The future of eHealth in Ireland will largely depend on the willingness of the medical community to accept these latest innovations and capitalise on these changes, which will be beneficial for both patients and healthcare professionals.

References 1.

2.

World Bank [homepage on the internet]. World Development Indicators;

island of Ireland [document on the internet]. Dublin: Irish College of General Practitioners, General Practice Information Technology Group,

http://data.worldbank.org/data-catalog/world-development-indicators.

2005. Available from:

Department of Health and Children (Ireland). Health in Ireland: Key

http://www.icgp.ie/go/in_the_practice/information_technology/publicati

Health and Children, December 1, 2009. Cited October 10, 2010. Available from: http://www.dohc.ie/press/releases/2009/20091201.html. 3.

O’Riain S. The flexible developmental state: globalisation, information

4.

Central Statistics Office (Ireland). Information Society Statistics, First

technology and the ‘Celtic Tiger’. Polit Soc. 2000;28(2):158. Results 2008, Household Statistics [document on the internet]. Dublin: Central Statistics Office, December 10, 2008. Available from: http://www.cso.ie/releasespublications/documents/industry/current/issh. pdf. Dobrev A, Haesner M, Hüsing T, Korte W, Meyer I. Benchmarking ICT use

7.

2008;18(13):4. 11. Linder JA, Ma J, Bates DW, Middleton B, Stafford RS. Electronic health record use and the quality of ambulatory care in the United States. Arch Intern Med. 2007;167(13):1400-5. 12. Gabriel B. Technology: do EMRs make you a better doctor? Physicians Practice. 2008;18(11):1. 13. Parente ST, McCullough JS. Health information technology and patient safety: evidence from panel data. Health Aff (Millwood). 2009;28(2):357-60. 14. Greenhalgh T, Potts H, Wong G, Bark P, Swinglehurst D. Tensions and

internet]. Bonn: European Commission, Information Society and Media

paradoxes in electronic patient record research: a systematic literature

Directorate General, April 2008. Available from:

review using the meta-narrative method. The Milbank Quarterly.

http://ec.europa.eu/information_society/eeurope/i2010/docs/benchmarki

2009;87(4). Available from:

Pagliari C, Sloan D, Gregor P, Sullivan F, Detmer D, Kahan J et al. What is

http://www.milbank.org/quarterly/8704feat.html. 15. European Commission. eHealth priorities and strategies in European

eHealth (4): a scoping exercise to map the field. J Med Internet Res.

Countries [document on the internet]. European Commission, April 10,

2005;7(1):e9.

2007. Available from: http://ec.europa.eu/information_

Terhune C, Epstein K, Arnst C. The dubious promise of digital medicine. Business Week, April 23, 2009. Available from:

8.

ons_reports. 10. Moore P. Tech survey: navigating the tech maze. Physicians Practice.

among general practitioners in Europe – final report [Document on the

ng/gp_survey_final_report.pdf. 6.

Lordan G, Normand C. Attitudes of GPs towards computerisation on the

October 10, 2010. Available from:

Trends in 2009 [document on the internet]. Dublin: Department of

5.

9.

[about 2 screens]. Washington, DC: The World Bank Group; c2010. Cited

society/newsroom/cf/itemlongdetail.cfm?item_id=3346. 16. Irish Medical Times. Health Information Bill to be published in June

http://www.businessweek.com/magazine/content/09_18/b41290306062

[document on the internet]. Irish Medical Times, May 20, 2010. Available

14.htm.

from:

Irish College of General Practitioners, General Practice Information

http://www.imt.ie/news/regulation/2010/05/health-information-bill-to-b

Technology Group. National GPIT Group Results of Survey on Computerisation in General Practice [document on the internet]. Dublin:

e-published-in-june.html. 17. Staines A. HSE needs a programme of rapid, focused cost savings

ICPG & GPIT, 2003. Available from:

[document on the internet]. The Irish Times, October 2, 2010. Available

http://www.google.ie/search?sourceid=chrome&ie=UTF-8&q=National+G

from: http://www.irishtimes.com/newspaper/opinion/

PIT+Group+Results+of+Survey+on+Computerisation+in+General+Practice.

2010/1002/1224280187472.html.

Volume 4: Number 1. 2011 | Page 73


RCSIsmjstaff review Cultural competence: an overview of the health needs of the Irish Traveller community

Royal College of Surgeons in Ireland Student Medical Journal. 2011;4(1):74-77.

Introduction

Keith Pilson RCSI medical student

Page 74 | Volume 4: Number 1. 2011

Economic, political and cultural reform in 20th century Ireland brought a change from a state of emigration to one of immigration, with an associated change from monoculturalism to multiculturalism. Ireland was hesitant to join the multicultural arena, being the last western European country to do so.1 Today, despite the taming of the Celtic Tiger and the decline of vulnerable sectors in which many immigrants were employed, the country is still home to approximately half a million people who do not fall under the ethnic or cultural category of â&#x20AC;&#x2DC;white Irishâ&#x20AC;&#x2122;.2 It appears that multicultural Ireland has a more than transient nature. When we consider ideas from social identity theory about the tendency for even highly educated individuals to show inter-group prejudice,3,4 combined with strong competition for employment and cuts in public expenditure, it can be argued that the doors of cultural prejudice in Irish society are still wide open. In healthcare systems, barriers to equality of care include poor cultural competence, accessibility and prejudice. Culture affects how and where individuals approach and use health services. It

also affects what people expect from service providers. Equality legislation, EU directives and health sector policies and strategies guide the Irish system towards a culturally competent, equal and accessible service. Equal access to healthcare does not mean treating everyone the same. Rather, it means offering everyone the same opportunity to achieve comparable health outcomes, which in turn requires cultural competence.5 While cultural competence and awareness slowly grows in the different layers of the Irish healthcare system, individual healthcare providers can work on improving their own cultural awareness. The purpose of this review is to highlight the need for cultural awareness, to introduce the Irish Traveller community, along with its specific healthcare needs, and to provide suggestions for further reading. There are at least 25 minority groups in Ireland.6 The Irish Traveller community was chosen based on population size and its contrast to the background population. In September 2010, Mary Harney, the then


RCSIsmjstaff review

FIGURE 1: Life expectancy in the Traveller vs. settled populations. Minister for Health and Children, published a report on a massive health study undertaken on the Irish Traveller community over the preceding three years. The study, called the All-Ireland Traveller Health Study (AITHS), which was largely based on self-report, included a survey of every identifiable Traveller family in the Republic of Ireland. It had a response rate of 80%, making it the most significant study of its kind. An important caveat for even the most useful generalisations is that they should not be used as a basis for stereotyping. Individual patients may not fit into any one category, and it is unwise to presume patient characteristics.

The Irish Traveller community The Irish Traveller community has a strong tradition and culture based on a nomadic existence. The vast majority are Roman Catholic, and religion has a strong, albeit waning, impact on the Traveller value system and beliefs.7 The most recent Irish census data suggest that the population of the Irish Traveller community is approximately 22,000 members. A 2010 survey revised that figure to more than 36,000.7 Irish Travellers have official recognition as a minority ethnic group in the United Kingdom. While the Irish Government recognises the distinct grounds for protection held by Travellers, the specific status of minority ethnic group has not yet been assigned. The implications of this lack of an ethnic identifier include a lack of robust data required for effective planning, provision and assessment of services. Travellers have a long history of suffering social exclusion and disadvantage in Ireland, which continues into the present day, and which has been recently addressed in Government policy and strategy formation.8 The Traveller community, with its traditional skills and culture, struggles to thrive in modern-day Ireland. Lack of employment and a dependency on social welfare payments heighten feelings of frustration and exclusion.7

Travellers and health Levels of health in the Traveller community are significantly lower than those in the settled population, with current Traveller health comparable with the levels found in the settled population of the

1940s.8 Poor living conditions, social exclusion and low levels of education are some of the many factors that contribute to substandard health in the Traveller community. Compared with the settled population, Traveller men live approximately 15 years less, while life expectancy for Traveller women is approximately 12 years less. As shown in Table 1, life expectancy for Traveller males has not improved over the past 20 years, while males from the general population have widened the original gap of 10 years by a further five years. This is in contrast with Traveller females, who have had a five-year increase in life expectancy compared with 20 years ago, marginally closing the original gap between them and settled women. The infant mortality rate (IMR) is a useful indicator of a populationâ&#x20AC;&#x2122;s development and health. The Traveller IMR improved from 18.1 in 1987 to 14.1 in 2008 compared with figures of 7.4 in 1987 and 3.9 in 2008 for the general population. Traveller infants in 1987 were 2.4 times more likely to die than infants in the general population, and this gap had widened in 2008 to make Traveller infants 3.6 times more likely to die. It is clear that Traveller infants are not benefiting from advances in health compared to those in the non-Traveller population. There are several important gender-specific issues in Traveller health. Relevant contrasting practices among Traveller women include a low usage of the oral contraceptive pill and low levels of breastfeeding.7 Irish Traveller women face hardship on many fronts â&#x20AC;&#x201C; as women, as Travellers, and as Traveller women. Traveller women are almost four times more likely to be affected by depression than settled women, with one survey suggesting that up to one in three Traveller women are affected by long-term depression.9 Another stark reality highlighted in the recent study is the high level of non-accidental injuries occurring to Traveller women.7 The study found that compared with women of the settled population, injuries to Traveller women were three times more likely to be non-accidental. The exact nature of this violence was not revealed; however, domestic violence in the Traveller community is a known problem, which has yet to be successfully tackled.7 It appears that a traditional patriarchal culture persists in the Traveller community at the expense of female autonomy. This may have some bearing on the female-specific issues mentioned above. This may also become evident in the healthcare setting, when a male attempts to represent a female or family on health matters, requiring a culturally sensitive response from the healthcare worker. One aspect of poor health outcomes in the Traveller community is the availability of healthcare services to Travellers. Interestingly, recent data suggest that Irish Travellers have the same options in availing of healthcare services as the settled population.7 In addition, utilisation of general practitioner and emergency services is higher in the Traveller than in the settled population. Irish Traveller womenâ&#x20AC;&#x2122;s health screening rates are higher than the general population.7 Again, this does not necessarily imply equal access, since Travellers are not denied specific services. Instead, this demonstrates that the challenges facing healthcare workers

Volume 4: Number 1. 2011 | Page 75


RCSIsmjstaff review Table 1: Life expectancy in the Traveller community compared to the general population. Year

2008

Gender

Males

Females

1987

Males

Females

Age

Traveller

Travellers

General population

deficit (years)

0

61.7

76.8

15.1

15

48.1

62.3

14.2

45

23.7

33.8

10.1

65

10.6

16.6

6

0

70.1

81.6

11.5

15

55.9

67

11.1

45

28

37.7

9.7

65

12.3

19.8

7.5

0

61.7

71.6

9.9

15

48.9

57.4

8.5

45

21.3

28.8

7.5

65

10.1

13.1

3

0

65.3

77.2

11.9

15

52.1

62.9

10.8

45

25.1

33.6

8.5

65

10.4

16.4

6

in providing equal care to Irish Travellers are more complex than just availability of services. Attitudes to health among the Traveller community include a predilection for avoidance, except in emergencies. Men present late for healthcare, while preventive care and outpatient services are under-utilised when compared to the background Irish population.7 Yet another factor that is a significant barrier to health is poor education. Census data from 2006 show that participation in higher education was less than 1% in the Traveller community compared with more than 30% of the settled population. The AITHS reported that Irish Travellers have great difficulty with articulation in the healthcare setting. Both Traveller men and women tend to internalise breakdown in communication as a personal failure associated with their inability to read or write, or to comprehend the healthcare worker. Feelings of embarrassment and shame can result, which may discourage them from seeking clarifications. Another plausible factor in communication breakdown can be the number of foreign medical staff working in Ireland, such that it may be difficult for non-Irish workers to understand the Irish Traveller accent and vice versa, leading to suboptimal consultations. The main language used in the travelling community is English, in spite of the existence of a traditional language called â&#x20AC;&#x2DC;Cantâ&#x20AC;&#x2122;.

Page 76 | Volume 4: Number 1. 2011

Life-expectancy (years)

Literacy is typically poor, with up to 80% of the adult community believed to be unable to read.6,8 A recent survey shows that approximately 50% of Travellers requiring prescription medications have reported difficulty reading the instructions, creating yet another barrier to health and health promotion.7 Special care must be taken to ensure that instructions and documents are understood, particularly those surrounding issues where consent is required. Irish Travellers report lower satisfaction with Irish health services compared to the settled population. There is significantly less trust placed in healthcare professionals, along with increased perceptions of being treated with less respect and dignity.7 Out of the 1,324 Travellers surveyed, only 46% agreed that they had enough time to discuss their health problems with the health professionals, compared with 78% of the settled population. Traditional clinical training can lead to a tendency for the doctor to be neutral to race and culture, which in such circumstances may contribute to poor satisfaction due to a perceived lack of empathy and understanding. With regard to other traditional practices in the Irish Traveller community, consanguinity resulting from endogamy often causes an increased prevalence of genetic disorders.10,11 Sensitive counselling in this regard may be required. It is also worthwhile


RCSIsmjstaff review to enquire about any traditional healing sought, since it is known that members of the Traveller community may seek traditional healing practices where direct hands-on contact with a wound site may be made by the healer.6 The AITHS shows that despite subjectively rating their health in a positive light, Irish Travellers have a significantly raised burden of chronic disease, along with higher rates of smoking, hypertension, hypercholesterolaemia and poor diet, compared to the general population. In addition, key areas to address to improve Traveller health include mother and child health, and respiratory and cardiovascular disease aetiology. Health attitudes, engagement in preventive practices and gender-specific issues, including mental health, are other areas that warrant improvement.

Conclusions Culture affects many aspects of patient interaction with health services. Healthcare workers in multicultural societies often face additional challenges when caring for patients, be it a Muslim patient fasting during Ramadan,12,13 a Jehovah’s Witness who will not accept blood,14 or an Irish Traveller with a fatalistic attitude towards health. To provide equal access, a health service must offer all patients the same opportunity to achieve comparable

health outcomes, which requires a culturally competent service. Ireland is home to people of 188 nationalities,15 practising at least 21 different religions, so it is a challenge for healthcare providers to become culturally competent. However, there are resources available to assist us in this challenge, including cultural mediation and a wealth of knowledge on the specific health service needs of different cultural and religious groups.

Cultural awareness resources available for healthcare professionals: ■ National Health Services Intercultural Guide: Responding to the needs of diverse religious communities and cultures in healthcare settings.6 ■ Intercultural Health Strategy, 2007-2012.1

References 1. Banks M. Modern Ireland: multinationals and multiculturalism. Information, Society and Justice. 2008;2(1):63-93. 2. Central Statistics Office. Census 2006, Volume 5 – Ethnic or Cultural Background. Cited September 2010. Available from: http://www.cso.ie/census/Census2006_Volume5.htm. 3. David CC. Intergroup attitudes and policy support: How prejudice against minority groups affects support for public policies. International Journal of Public Opinion Research. 2009;21(1):85-97. 4. Brewer MB. The psychology of prejudice: ingroup love or outgroup hate? Journal of Social Issues. 1999;55(3):429-44. 5. Minervino S, Martin MC. Cultural competence and cultural mediation: diversity strategies and practices in health care. Translocations. 2007;2(1):190-8. 6. Health Service Executive. Health Services Intercultural Guide: Responding to the needs of diverse religious communities and cultures in healthcare settings. Cited September 2010. Available from: http://www.hse.ie/eng/services/Publications/services/ SocialInclusion/InterculturalGuide/interculturalguide.pdf. 7. Department of Health and Children. All Ireland Traveller Health Study. Cited September 2010. Available from: http://www.dohc.ie/publications/aiths2010/ExecutiveSummary/ AITHS2010_SUMMARY_LR_All.pdf. 8. Department of Health and Children. Traveller Health: A National Strategy 2002-2005. Cited September 2010. Available from: http://www.dohc.ie/publications/pdf/traveller_health.pdf.

9. Pavee Point Travellers Centre. Traveller health press release 2005. Cited September 2010. Available from: http://www.paveepoint.ie/press_dec_05_3.html. 10. Irish Health Independent Medical Reviewers. Health and the Travelling Community. Cited September 2010. Available from: http://www.irishhealth.com/article.html?id=1079. 11. Pavee Point Travellers Centre. Travellers and consanguinity. Cited September 2010. Available from: http://www.paveepoint.ie/pav_consang.html. 12. Felias-Christensen G, Corl D. Muslim religious observances and diabetes. Cited September 2010. Available from: http://ethnomed.org /clinical/diabetes/muslim-religious-observances-and-diabetes. 13. Al-Arouj M et al. Recommendations for management of diabetes during Ramadan. Diabetes Care. 2005;28(9):2305-11. 14. Royal College of Physicians of Ireland. An issue of patient informed consent: Jehovah’s Witnesses and blood transfusions. Cited September 2010. Available from: http://www.rcpi.ie/News/Pages/AnIssueofPatientInformedConsentJe hovahsWitnessesandBloodTransfusions.aspx. 15. Central Statistics Office. Census 2006, Non-Irish Nationals Living in Ireland. Cited September 2010. Available from: http://www.cso.ie/census/Non-Irish%20Nationals.htm. 16. Health Service Executive. National Intercultural Health Strategy, 2007-2012. Cited September 2010. Available from: http://www.hse.ie/eng/services/Publications/services/SocialInclusion/ National_Intercultural_Health_Strategy_2007_-_2012.pdf.

Volume 4: Number 1. 2011 | Page 77


RCSIsmjstaff review A review of abortion in Ireland

Royal College of Surgeons in Ireland Student Medical Journal. 2011;4(1):78-81.

Introduction Induced abortion is an international issue that encompasses medical, legal, emotional, personal and psychological domains. In 2003, the total number of induced abortions worldwide was 41.6 million, compared to 46 million in 1995.1 Most abortions occur in developing countries (35 million) rather than in developed countries (seven million), which is reflective of the relative population distribution. The average annual rate at which women chose to end unwanted pregnancies in 2003 was similar in developed and developing regions, i.e., 26 per 1,000 women aged 15-44 years in the developing world and 29 per 1,000 women aged 15-44 years in developed countries.1,2 Despite significant differences in legislation on abortion across the globe, the stringency of laws does not seem to affect incidence. The estimated abortion rate in Europe, where abortion is legal in the majority of countries, is 28 per 1,000 women, whereas the rate in Africa, where abortion is illegal in most countries, is roughly 29 per 1,000 women. Western and northern Europe boast the lowest rates of abortion in the world (12 and 17 per 1,000 women, respectively), even though access to induced abortion is unrestricted in most cases.3

abortifacient herbs, vigorous exercise, energetic jumping and the use of sharpened instruments.5 Currently, the most effective medical regimen for inducing abortion is the combination of an antiprogesterone, such as mifepristone, and a prostaglandin, such as misoprostol.6 Due to limited access to mifepristone worldwide, various combinations of medical abortion protocols have been developed using either prostaglandins alone or in combination with methotrexate, a dihydrofolate reductase inhibitor.6 The most effective and safe surgical abortion method includes electric or manual vacuum aspiration.7 The legality, safety and availability of induced abortions are closely tied to one another. Roughly 48% of all induced abortions are unsafe, with the majority of unsafe procedures occurring in developing countries.1,3 The World Health Organisation defines unsafe abortion as a procedure to terminate unintended pregnancy that is performed by individuals without the necessary skills, or in an environment that does not conform to medical standards, or both.1 Globally, complications due to unsafe abortion procedures account for approximately 70,000 maternal deaths per year.

The legal situation worldwide Abortion

Rohini Boddu RCSI medical student

Page 78 | Volume 4: Number 1. 2011

Abortion is defined as the termination of a pregnancy resulting in or closely followed by the death of the embryo or foetus.4 Abortion can be spontaneous or induced by either medical or surgical methods. Historically, induced abortion techniques have included

Laws governing abortion vary widely from one country to another1,2 (Figure 1). Abortion of any kind is illegal in 32 countries, even in cases where the motherâ&#x20AC;&#x2122;s life is threatened. In 36 countries, one of which is Ireland, abortion is permitted to save the life of the pregnant mother, and in particular cases, such as when


RCSIsmjstaff review

THE WORLD’S ABORTION LAWS FIGURE 1: The worldwide abortion laws as summarised in a map (2007). Source: The World’s Abortion Laws 2007 Map. Cited November 20, 2010. Available from: http://reproductiverights.org/en/document/the-worlds-abortion-laws-map-2007. the mother is a victim of rape. Fifty-nine countries have less stringent abortion laws, allowing abortion in order to preserve the physical and/or mental health of the mother. Fourteen of these countries also consider the socioeconomic situation of the mother to be a valid reason for terminating the pregnancy. The remaining 56 countries have liberal abortion laws, which are limited only by the stage of gestation (commonly before 12 weeks) and consent requirements, such as parental consent if the mother is legally a minor or spousal consent if she is married.1,2

Abortion in Ireland Abortion laws in Ireland have evolved in response to legal proceedings, prominent events, public response and medical ethos. Legislation dates back to 1861, when The Offences Against the Person Act criminalised abortion in the United Kingdom of Great Britain and Ireland.8 In the United Kingdom, the Abortion Act of 1967 legalised the abortion of foetuses prior to 28 weeks’ gestation by registered medical practitioners, and regulated the free provision of such medical practices in the UK through the National Health Service.9 No such liberalisation of the legislation occurred in Ireland, which led many women from Ireland to travel abroad to seek abortion services, a trend that was dubbed

“abortion tourism” by the local press.10 Records indicate that in 1968 fewer than 100 Irish women travelled to Britain to obtain an abortion. This number increased over 30 years, and in 1999 over 6,000 women travelled abroad to obtain an abortion.10,11 However, this may be an underestimation, since many women choose not to disclose their address.11 The most recent statistics from 2008, published by the UK’s Department of Health, indicate that on average about 12 Irish women (4,600 women aged between 15 and 44 per year) travel each day to Britain to access abortion services.12 In 1983 an anti-abortion campaign, the Pro-Life Amendment Campaign, argued that the Constitution could be interpreted by the Irish Supreme Court as granting the right to abortion on the grounds of privacy. The campaign cited a precedent in the United States, namely the 1973 case of Roe vs. Wade.13 Following a referendum, the Eighth Amendment, known as the ‘Pro-Life Amendment’, came into existence to deter the legalisation of abortion in the future. The amendment contained three assertions: the unborn’s right to life must be protected; the unborn’s right to life was equal to that of the mother; and, this right to life would be defended to the greatest degree practicable. From 1986 to 1988, the Irish Society for the Protection of Unborn Children (SPUC)

Volume 4: Number 1. 2011 | Page 79


RCSIsmjstaff review campaigned against pregnancy counselling centres and student union officers where it felt that these were in violation of foetal rights by providing information and assistance to Irish women seeking to travel abroad for an abortion. The courts ruled in favour of the SPUC and declared the distribution of information regarding abortion to be illegal.13 In 1992, a landmark Supreme Court case had a profound influence on abortion legislation in Ireland and brought the Irish abortion debate to international attention. In the ‘X case’, a 14-year-old rape victim (‘Miss X’) was prevented by a High Court injunction from travelling to the UK to obtain an abortion. The girl’s family claimed that she was at risk of suicide if she was not allowed to obtain an abortion. This decision was appealed to the Supreme Court, which overturned the High Court order, stating that if there was a real and substantial risk to the life of the mother, and this risk could only be averted by termination of the pregnancy, this would be lawful.13,14 The Court accepted risk of suicide as a real and substantial risk to life, effectively making abortion legal in Ireland under these circumstances. As a result of the X case, the Government put forward three amendments to the Constitution in a referendum. The first sought to overturn the Supreme Court ruling and was defeated. The other two amendments addressed the issues of freedom to travel outside the country for an abortion, and freedom to obtain or make available information on abortion services outside the State. These two amendments were passed, and established the ‘right to travel’ and the ‘right to information’.13,15 To date, no legislation has been enacted on foot of the Supreme Court ruling. In 1995, The Regulation of Information (Services Outside the State for the Termination of Pregnancies) Act was passed by the Government to regulate the manner in which information about abortion is available to women in Ireland. For example, it is unlawful for the “person or the employer or principal of the person to advocate or promote the termination of pregnancy to the woman or to any person on her behalf”.16 In 1998, the guide to ethical conduct and behaviour from the Irish Medical Council was published, stating (section 26.5: The Child In Utero) that “the deliberate and intentional destruction of the unborn child is professional misconduct. Should a child in utero suffer or lose its life as a side-effect of standard medical treatment of the mother, then this is not unethical”.17 This was changed in 2001 when the Irish Medical Council voted to shift its stance on abortion. Moving away from an outright ban on abortion, the new guidelines stated that the termination of pregnancy was permissible where there is “a real and substantial risk to the life of the mother”. The guidelines for assessing the risk were formulated by the Institute of Obstetricians and Gynaecologists.18 In 2001, a floating Dutch reproductive health clinic, ‘Women on Waves’, led by Dr Rebecca Gomperts, came to Ireland aboard the ship Aurora.19 The initiative set out to empower Irish women and to encourage them to exercise their right to legal abortion and other reproductive health services. With the invitation of the Dublin Abortion Rights and Cork Women’s Right to Choose

Page 80 | Volume 4: Number 1. 2011

Groups, the Aurora anchored approximately 12 miles from the Dublin coast outside territorial waters. Although ‘Women on Waves’ lasted for only five days, they were contacted by more than 300 Irish women, and provided reproductive health information, contraception workshops and information on legal abortions in Europe.20,21 The legal issues surrounding abortion came into the public eye once again in 2007 when Miss D, a 17-year-old, decided to seek termination of her pregnancy after an ultrasound scan indicated an anencephalic foetus.22 The Irish Health Service Executive stated that they would only allow Miss D to travel with a court order. The District Court refused the order, the reason cited being the protection of the life of the unborn child by the Constitution of Ireland and the lack of substantial risk to the life of the mother. However, the High Court Judge, Mr Justice Liam McKechnie, decided that the case was about the right to travel, not the right to an abortion. It was ruled that there were no constitutional grounds to prevent Miss D from travelling abroad to terminate her pregnancy.22 In addition to the legal and social aspects of induced abortion in Ireland, one must consider the professional attitudes towards abortion of healthcare professionals.23 A recent study compared the attitudes of medical students from a university in Belfast, to those from Oslo, Norway. In contrast to Northern Ireland, the 1975 abortion law of Norway is more liberal and allows abortion on request during the first 12 weeks’ gestation.24,25 The main finding of the study indicated a significant difference in opinion between the two groups, with 78% of students from Oslo and only 14.3% of students from Belfast being in favour of abortion. It was concluded that the difference in attitudes between the student bodies reflects the difference in religious, legal and educational experiences of each subject population.23 Lipp et al. also noted that the attitudes of healthcare professionals towards termination of pregnancy were dependent on nationality, experience in termination care, personal experiences, religious beliefs and the reason for termination.26

Present day For the first time in 15 years, Ireland’s law on abortion was challenged recently, this time in the European Court of Human Rights (ECHR) in Strasbourg by three women living in Ireland, known as A, B and C.27 The three women challenged the ban on the grounds that it forces women to travel abroad to procure abortions, jeopardising their health and well-being in violation of the European Convention on Human Rights. Specifically, it violated the provisions of the right to life; the prohibition of torture; the right to respect for family and private life; and the prohibition of discrimination. The Grand Chamber of the European Court of Human Rights heard ABC vs. Ireland in December 2009. This Strasbourg-based court is separate from the European Union and adjudicates on human rights issues among all 47 Member States of the Council of Europe. On December 16, 2010, the ECHR unanimously ruled that Ireland had breached


RCSIsmjstaff review applicant C’s “right to respect for her private life given the failure to implement the existing constitutional right to lawful abortion in Ireland”. The court also ruled that there had been no violation of the rights of the other two women in the case, ‘A’ and ‘B’.28 Ireland is a signatory to the ECHR and therefore the Irish Government is obliged to remedy any breaches of the convention. Although Irish abortion laws have had incremental changes over the last three decades, Ireland still stands as an outlier among neighbouring countries. The ruling of ABC vs. Ireland may force Ireland to join the global trend to liberalise abortion laws.27

Conclusion The abortion debate, with its wide disparities worldwide, remains a prominent issue for women’s reproductive rights in the 21st century. The history of abortion law in Ireland clearly denotes the political, legal and social importance of this issue and its impact on medical practice and professional attitudes. While it is debatable that the Irish Government has not pushed aside the issue of abortion, Ireland’s evolving laws on abortion reflect the complexity of this issue. Appropriate legislation on the lawful termination of pregnancy will have to be moulded to respect and serve the people of Ireland.

References 1.

Guttmacher Institute, 2009. Abortion worldwide: a decade of uneven progress. Cited September 11, 2010. Available from: http://www.guttmacher.org/pubs/Abortion-Worldwide.pdf.

2.

Myers JE, Self MW. Global perspective of legal abortion – trends analysis

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and accessibility. Best Pract Res Clin Obstet Gynecol. 2010;24(4):457-66. induced abortion worldwide. Cited September 11, 2010. Available from: http://www.guttmacher.org/pubs/fb_IAW.html. 4.

Merriam-Webster Dictionary. Cited September 11, 2010. Available from:

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Fox P. Abortion in the ancient and premodern world. A history of

http://www.merriam-webster.com/. traditional methods. Cited September 11, 2010. Available from: http://womenshistory.about.com/od/abortion/a/ancientabortion.htm. 6.

Bartz D, Goldberg A. Medication abortion. Clin Obstet Gynecol. 2009;52(2):140-50.

7.

Tristan SB, Gilliam M. First trimester surgical abortion. Clin Obstet Gynecol. 2009;52(2):151-9.

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Offences Against the Person Act. Legislation.Gov.UK. Cited November 20, 2010. Available from: http://www.legislation.gov.uk/ukpga/Vict/24-25/100.

9.

16. Irish Statute Book. Cited November 20, 2010. Available from: (http:// www.irishstatutebook.ie/1995/en/act/pub/0005/sec0003. html#zza5y1995s3). 17. Medical Council, The. A Guide to Ethical Conduct and Behaviour (5th ed.). Medical Council, 1998. Cited November 20, 2010. Available from: http://hdl.handle.net/10147/45840. 18. Payne D. Irish Medical Council softens its line on abortion. BMJ. 2001;323(7314):654. 19. Gomperts R. Women on waves: where next for the abortion boat? Reprod Health Matters. 2002;10(19):180-3. 20. Payne D. Dutch ship fails to offer Irish women abortions. BMJ. 2001;322(7301):1507. 21. Birchard K. Abortion boat faces legal complications. Lancet. 2001;357(9273):2035. 22. Dyer C. Girl carrying anencephalic fetus is granted right to travel. BMJ. 2007;334(7602):1026. 23. Steele R. Medical students’ attitudes to abortion: a comparison between Queen’s University Belfast and University of Oslo. J Medical Ethics. 2009;35(6):390-4. 24. Ministry of Health and Care Services. The Abortion Act. Cited November

Tietze C. Abortion in Europe. Am J Public Health Nations Health.

20, 2010. Available from:

1967;57(11):1923-32.

http://www.regjeringen.no/en/dep/hod/documents/veiledninger_og_bro

10. Oaks L. Antiabortion positions and young women’s life plans in contemporary Ireland. Soc Sci Med. 2003;56(9):1973-86. 11. Payne D. More British abortions for Irish women. BMJ. 1999;318(7176):77. 12. Abortion Statistics, England and Wales: 2008. Statistical Bulletin. May

sjyrer/2000/about-the-abortion-act.html?id=419252. 25. Department of Health, Social Services and Public Safety. Guidance on the termination of pregnancy: The law and clinical practice in Northern Ireland. July 2008. Cited November 20, 2010). Available from: http://www.dhsspsni.gov.uk/guidance_on_the_termination

2009 Bulletin 2009/01. Cited November 20, 2010. Available from:

_of_pregnancy__the_law_and_clinical_practice_in_northern_

http://www.dh.gov.uk/en/Publicationsandstatistics/Publications/Publicati

ireland.pdf.

onsStatistics/DH_099285. 13. Fletcher R. National crisis, supranational opportunity: the Irish construction of abortion as a European service. Reprod Health Matters. 2000;8(16):35-44. 14. Birchard K. New ethical guidelines on abortion released in Ireland. Lancet. 1998;352(9143):1840. 15. Constitution of Ireland. Thirteenth and Fourteenth Amendments of the Constitution Act, 1992.

26. Lipp A. A review of termination of pregnancy: prevalent healthcare professional attitudes and ways of influencing them. J Clin Nurs. 2008;17:1683-8. 27. Dyer C. Women challenge Irish law on abortion in Europe on human rights grounds. BMJ. 2009;339:b5457. 28. The Irish Times. Irish abortion laws breach human rights, court rules. Cited December 23, 2010. Available from: http://www.irishtimes.com/ newspaper/breaking/2010/1216/breaking11.html.

Volume 4: Number 1. 2011 | Page 81


RCSIsmjBahrain VISIBLE AND NEAR-INFRARED ABSORPTION

properties of blood from sickle cell patients and normal individuals Maysa F AlMulla A1, Aysha W Agab1, Lulwa S Almannai1, Fryad Z. Henari2 1RCSI-Bahrain medical students 2Department of Basic Medical Science, Royal College of Surgeons in Ireland, Medical University of Bahrain, Kingdom of Bahrain

Background Sickle cell disease (SCD) is a genetic blood disorder characterised by red blood cells that assume an abnormal and rigid shape.1 A point mutation in the beta globin chain of haemoglobin results in glutamic acid to be replaced with valine at the sixth position. The abnormal haemoglobin (HbS) leads to the distortion of red blood cells in certain conditions, such as low oxygen tension, and leads to sickling.1,2 Sickling decreases the flexibility of red blood cells and causes microvascular occlusion, which may manifest as stroke, acute chest syndrome, pulmonary hypertension or organ damage.1 SCD occurs primarily among people of sub-Saharan African, Mediterranean, Middle Eastern and Indian descent.3 Of note, sickle cell anaemia refers to people who are homozygous for the mutation causing HbS, while sickle cell trait refers to heterozygotes who have one normal haemoglobin gene and one sickle cell gene. Approximately 250,000 children worldwide are born each year with sickle cell anaemia. According to the Gulf Genetic Center (GGC), abnormal haemoglobin was detected in 44.35% of neonatal samples in Bahrain. Of those, 18.1% had sickle cell trait and 2.1% had SCD. Additionally, the GGC reported that in the non-neonatal cases, the overall frequency of SCD was found to be 10.44%.4 Several techniques are used to screen for sickle cell trait or SCD, such as high-performance liquid chromatography (HPLC), haemoglobin electrophoresis and DNA sequencing. HPLC uses ultraviolet rays to detect the difference in shape and surface area between the normal blood cells and the sickle cells.5 Haemoglobin electrophoresis differentiates between the haemoglobin forms based on charge, while DNA sequencing of the haemoglobin gene can detect the presence of the single amino acid substitution implicated in SCD. First reported in 1942, five different formsof haemoglobin (oxyhaemoglobin, Page 82 | Volume 4: Number 1. 2011

carbomyl haemoglobin, methaemoglobin, reduced haemoglobin and metcyanhaemoglobin) were detected based on marked differences in the absorption spectra in the visible (380nm-760nm) and near-infrared (760nm-2,500nm) region of the electromagnetic spectrum.6 No such investigation comparing the absorption spectra of normal adult haemoglobin (HbA) and sickle cell haemoglobin (HbS) has been conducted in the visible and near-infrared region. Such is the aim of this brief study.

Methods Four whole blood samples were obtained from the haematology laboratory in the Bahrain Defense Force (BDF) Hospital. 400ml each of two normal samples and two sickle cell samples were identified and collected in EDTA anticoagulant tubes. The samples were diluted with 2ml of normal saline solution and 0.4ml of diluted blood from each sample was inserted into a 1mm-thick tube. A light source of halogen broadband spectrum, with a wavelength between 250nm and 2,500nm, was focused on the sample using an arrangement of lenses. Lens L1 was used to collimate the light, lens L2 was used to focus the light on the sample and lens L3 was used for collecting the light from the sample, which was then focused onto the charge-coupled-device (CCD) spectrometer through the fibre. The spectrometer measured the absorbance at various wavelengths and the collected data was plotted by the computer software Origin 6.1 (Figure 1).

Results The absorption spectra of HbA and HbS in the visible near-infrared region are demonstrated in Figure 2. This difference in absorption spectra of the HbS versus normal HbA was not evident at a


RCSIsmjBahrain L1

L2

L3 0.40

Light source

Absorbance (AU)

0.35

Sample

0.30 0.25 0.20 0.15

Fibre optic lens 0.10 0.05

CCD spectrometer

0.00 200

400

600

800

1000

1200

Wavelength (nm) Normal blood

Sickle cell blood

FIGURE 1: A schematic of the experimental set-up. A light source, L1, is a collimation lens, while L2 and L3 are focusing lenses.

FIGURE 2: Absorption spectra of normal HbA and HbS blood samples in the visible near-infrared region show a significant difference in the absorption properties beyond 500nm. Note the peak absorption for HbA at 500 ± 10nm compared with 600nm ± 10nm for HbS.

wavelength range between 400 and 500nm but is clearly detected in their absorption pattern beyond 500nm. Specifically, HbS shows a higher absorption pattern than normal HbA, especially at the range between 700nm and 900nm, which lies in the near-infrared region. In addition, the two forms of haemoglobin differed with respect to their absorption peak. The absorption peak of HbS was found to be in the region of 600nm ± 10nm whereas the peak for HbA was approximately 500 ± 10nm.

could provide a quick and affordable assay of blood products for SCD. Currently, SCD can be diagnosed by methods of comparable accuracy such as HPLC, electrophoresis and DNA sequencing. However, further research is required with other variants of haemoglobin such as haemoglobin C (lysine group attached to the haem group), foetal haemoglobin (HbF), and oxygenated and non-oxygenated haemoglobin S. Furthermore, research is required to determine whether visible and near-infrared spectroscopy would be a reliable method for diagnosing SCD in comparison with the gold standard diagnostic methods.

Discussion The variation in optical properties shown between the two forms of haemoglobin could be due to the difference in size, shape, or three-dimensional structure.7-9 Based on these results, the estimation of the absorption spectra of HbA and HbS blood samples

Acknowledgements We would like to thank Dr Wahid Ali Agab and Dr Khalil Jassim for the provision of blood samples and equipment used in this study.

References 1. Stuart MJ, Nagel RL. Sickle-cell disease. Lancet. 2004;364(9442):1343-60. 2. Medline Plus [homepage on the internet]. Bethesda: US National Library of Medicine; c2010. Updated January 31, 2010. Cited December 29, 2010. Available from: http://www.nlm.nih.gov/medlineplus/ency/article/000527.htm. 3. Sickle Cell Society. Information for Health Professionals [website]. Cited April 26, 2009. Available from: http://www.sicklecellsociety.org/healthpr.html. 4. Al Arrayed SS, Haites N. Features of sickle-cell disease in Bahrain. East

www.chemguide.co.uk/analysis/chromatography/hplc.html. 6. Horecker B. The absorption spectra of hemoglobin and its derivatives in the visible and near infra-red regions. J Biol Chem. 1943:148:173-83. 7. Optical Absorption of Hemoglobin. Cited March 21, 2009. Available from: http://omlc.ogi.edu/spectra/hemoglobin/index.html. 8. Kids Health. Sickle Cell Disease. Cited April 24, 2009. Available from: http://kidshealth.org/parent/medical/heart/sicklecell_anemia.html#a_Diagnoi. 9. AAFP. Sickle Cell Disease in Childhood [website]. Cited April 25, 2009. Available from: http://www.aafp.org/afp/20000901/1013.html.

Mediterr Health J. 1995;1(1):112-9. 5. High Performance Liquid Chromatography – HPLC. Cited December 29, 2010. Available from:

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RCSIsmjperspective PHYSICIAN-ASSISTED SUICIDE:

the right to life or the right to death? MARIA ALISHA GABRIEL offers a view on the issues surrounding this most contentious subject.

End-of-life issues are at the forefront of moral and political debate as medical technology advances and our population ages. Recently, Kathleen Gilderdale was acquitted of charges of assisting the suicide of her 31-year-old daughter, who had suffered from myalgic encephalomyelitis.1 On January 20, 2010, Frances Inglis was given a life sentence for injecting her brain-damaged son with lethal amounts of heroin in order to perform “an act of mercy”.2 Arguments surrounding physician-assisted suicide (PAS) are morally complex and have caused great controversy in the United Kingdom (UK).

Clarification of terminology Tom Beauchamp, a leading bioethicist, defines PAS as a patient’s voluntary choice of death with the assistance of a physician.3 The World Medical Association (WMA) identifies PAS as “knowingly and intentionally providing a person with the knowledge or means or both required to commit suicide, including counselling about lethal doses of drugs, prescribing such lethal doses or supplying the drugs”.4 In other words, the physician provides the means for death but the patient administers the lethal medication, thus committing suicide. Beauchamp makes a distinction between PAS and euthanasia on the basis that PAS patients do not need to be acutely suffering or terminally ill to request to die.3 The bioethicist Gregory Pence describes euthanasia as “the killing of one person by another

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for allegedly merciful reasons”.5 The term euthanasia has also been defined as knowingly and intentionally performing an act or practice that ends a person’s life in order to release the person from an incurable disease, intolerable suffering or undignified death.4 Euthanasia can be further distinguished from PAS by the fact that the physician directly causes the death of the patient by administering a lethal injection or by withholding treatments in order to bring about the death of the patient. Euthanasia can be further classified into non-voluntary, involuntary, voluntary, active and passive. Non-voluntary euthanasia occurs when “the person killed is not capable of making or refusing to make such a request”, whereas involuntary euthanasia occurs “when the person killed is capable of making such a request but has not done so”.6 Voluntary euthanasia occurs when the patient is fully competent and requests that the physician end his/her life. Active euthanasia entails an act in relation to end of life that has as its organised objective the termination of life.3 An omission can be defined as neglecting to do something that is vital to the survival of the patient. Therefore, by omitting treatment, life support or resuscitation, the physician is theoretically letting the patient die naturally. In end-of-life cases, this is termed ‘passive euthanasia’, and an important distinction is made between overseeing a refusal of treatment and assisting in a suicide.7


RCSIsmjperspective The principle of double effect

The competent adult’s case for physician-assisted suicide

Although the active–passive distinction is used as a moral guideline to separate acceptable practices from condemnable practices, one must ask if there is a conceptual distinction between the two. It can be argued that there is fundamentally no distinction between active and passive euthanasia since the aim and end result of both are the same. Therefore, one may argue that the distinction between the two is only a moral fiction – are not killing and letting die of the same substance? Alternatively, there is an argument that actions and omissions are distinct entities. This draws on the principle of the double effect, whereby each action can be seen to have two outcomes – one ‘good’ and the other ‘bad’. According to this principle, the action is permissible if the ‘bad’ outcome is only foreseen, and not intended. Therefore, giving a high dose of pain medication with no intention to kill but with an awareness of the possibility of the medication hastening death is morally justified under the double effect.8 Nevertheless, common opinion seems to be that passive death at a patient’s or family’s request, that is, with intention, is acceptable, but the active hastening of death is not.3,7

A core argument for PAS draws on the fact that the right to die should be a fundamental freedom of each person.3 This liberty derives from a series of landmark cases from In re Quinlan (1976), whereby the New Jersey Supreme Court stated that a patient’s rights and autonomy should prevail over the physician’s judgment regarding end-of-life decisions.3 The UK group Dignity in Dying argue that “mentally competent, terminally ill adults should have the choice of an assisted death, within strict legal safeguards, if they feel their suffering has become unbearable”.10 Supporters of assisted suicide believe that one should die with dignity and not have to endure a drawn out, painful death. Derek Humphrey of the Hemlock Society USA, a national right-to-die organisation, writes: “It isn’t just a question of pain. It is a question of dignity, self-control and distress. If you can’t eat, sleep or read, and there is certainty that you are dying, it is a matter of dignity to be able to end your life”.5 An argument for the legalisation of PAS also draws on the principle of the patient’s autonomy. Autonomy can be defined as a “self rule or freedom of the will that is free from both controlling interference by others and from limitations, such as inadequate understanding, that prevent meaningful choice”.7 The WMA ethics manual states that physicians are obligated to respect the decision-making capacities of autonomous persons.4 Decisions about death are personal, and because of this, advocates of PAS believe that any competent person has the right to make decisions about when to end his or her own life.7 It has been argued that complete prohibition on assisted death infringes upon the patient’s personal liberty. This argument centres on the belief that the State should not impose a view of when or how its citizens should die.

The slippery slope argument As pointed out by Beauchamp, a practice or policy that allows physicians to intervene to cause death runs the risk of abuse and may cause more harm than benefit. This argument is not based on the fear that serious abuses will occur immediately, but that they will grow incrementally over time.7 A system that does not have clear-cut boundaries may be open to abuse. Additionally, legalising PAS would effectively cause a decline in the quality of palliative care, and vulnerable patients may be manipulated into ending their lives against their original wishes. Although there is no extensive evidence to support this argument, Beauchamp alludes to the precautionary principle that counsels us that it is better to be safe than sorry. He cautions against taking the chance of eroding the general attitude of respect for life in our society, and alerts us to the risk of inadvertently causing unwarranted deaths, reducing the quality of palliative care or causing mistrust of physicians.7 Yet, the likelihood of projected moral erosion is not something we can assess by good evidence. Beauchamp elucidates: “Judging from the past track record of our society, we should seriously take into account that the slope of the trail toward the unjustified taking of life will be so slippery and precipitous that we ought to never embark on it”.7 Those in favour of PAS dismiss the slippery slope argument because of lack of evidence and because of its so-called “heavily metaphoric character”.7 Instead, supporters of PAS use empirical evidence from Belgium, Luxemburg, the Netherlands, Switzerland and certain states in the United States (Montana, Oregon and Washington), where PAS is legalised. Timothy Quill’s ‘Latest Report Card of Legal Regulation of PAS’ provides evidence that none of the abuses predicted have materialised in Oregon. Quill also concedes that the restrictions set out in the state of Oregon’s Death With Dignity Act have been neither loosened nor broadened.9

Physician-assisted suicide and the autonomous disabled Respecting the autonomy of patients is a professional obligation that extends to those who are disabled but competent. Such is the case of Paul Longmore, a ventilator-dependant quadriplegic.4 Longmore argues that our society is hostile and prejudiced against those who look differently and function differently because they require and increasingly demand alternative physical and social arrangements to live ‘normally’.11 In our society, disability incurs a loss of self-control and self-determination, loss of one’s humanity and separation from the human community or, in other words, social death. This impression stigmatises and segregates those who are disabled, leaving them in a position where their so-called autonomous decisions to die are actually bogus.12 By creating intolerable conditions for disabled people, society paints them into a corner whereby the right to die inevitably becomes a duty to die. Such patients are so socially oppressed that they feel pressured into ‘choosing’ to end their lives. The message to disabled people is that rather than upholding your right to live productively and meaningfully, this society chooses to engineer your death.5,12 Essentially, the argument is made that advocates of assisted suicide assume a non-existent autonomy and therefore offer an illusory self-determination.11 It must be kept in mind that life can continue to be fulfilling even with severe disability. Pence states that: “[al]though wanting to die after being horribly burned or after being diagnosed

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RCSIsmjperspective with a terminal disease is understandable, people who are in the throes of depression frequently don’t understand how they can come to feel much better”.5 By this logic, their request to die is irrational since it can be argued that such patients are not competent and therefore are not autonomous.

Distributive justice Distributive justice refers to the fair, equitable and appropriate distribution of all rights, responsibilities and goods in society.7 At a time when medical funding is restricted and progressively decreasing, is it ethical to engage in expensive treatment of terminally ill people in order to extend their lives by a few weeks? This argument is called ‘the rule of rescue’ and is continually put forth by PAS advocates. For example, Elizabeth Bouvia, a woman almost paralysed by cerebral palsy, fought to refuse sustenance in order to end her life. The courts denied her request in 1986 and, as of 2008, she is still alive and receiving 24-hour care.5 As a result, the money used for her care was not available for other medical services. Distributive justice warrants us to consider if it is ethical to spend money on those who wish to die when there are others who want to live but do not have the resources. From 1933 to 1945, during the Third Reich in Germany, Nazi doctors justified medical killing with the crude concept of Lebensunweretes Leben, which translates to “life unworthy of life”.5 This idea, purporting that those who are weak and dying are not worthy of life, completely diminishes the sanctity and value of human life. This argument is easy to refute on the basis that treating those who are dying as a numerical value or a burden on society contradicts the duty of the physician to preserve every life, especially those who are weak and suffering. Moreover, prognosis is an imperfect science, and it is not uncommon for terminal cases to survive for years despite having been given a prognosis on the order of months.

Concluding remarks I believe that conditional or unconditional legislation permitting PAS would drastically lower the respect for and value of human life. PAS may seem like a quick fix for the pain and suffering that our society is so eager to resolve; however, I believe we must be cautious of the consequences of ‘the slippery slope’. Although it has been argued that PAS allows for the dignified death of a patient, I would not consider suicide to be a dignified death. By condoning the death of those who are terminally ill, PAS may in turn lead to discrimination against those who are mentally and physically weakest in society. Furthermore, this promotes the idea that life is only worth living if you have a certain level of health. In my opinion, it would be better to promote ideals that are centred on the value of life and to inform patients and their families of alternatives to PAS. If these patients were made to feel that they were not a burden to society and were provided with better care and resources, I believe they would learn to value their life, regardless of age, disease or disability. The Hippocratic Oath, which we as physicians take, promotes the preservation and sanctity of life, and thus cannot condone PAS. “Our present social context is marked by a dramatic struggle between the culture of life and the culture of death; therefore, we must develop a deep critical sense capable of discerning true values and authentic needs.”13 Pope John Paul II

Acknowledgements I would like to sincerely thank Dr David Smith and Dr Noreen Carroll for inspiring my interest in bioethics, for their help with editing and their continuous support. I would like to acknowledge the help of my sister, Maryssa Gabriel LLB, for her technical support in examining the legal arguments surrounding PAS. Maria Alisha Gabriel is a medical student at the RCSI.

References 1. BBC News. Mother cleared of ME daughter’s attempted murder [homepage on the internet]. Updated January 10, 2010. Cited February 27, 2010. Available from: http://news.bbc.co.uk/2/hi/uk_news/england/sussex/8479211.stm. 2. Ryan M, White S. Francis Inglis killed son “with love in her heart” [homepage on the internet]. Updated January 20, 2010. Cited Feb 27, 2010. Available from: http://news.bbc.co.uk/2/hi/uk_news/8466140.stm. 3. Beauchamp TL, Walters L, Khan JP, Mastroianni AC. Contemporary Issues in Bioethics (7th ed.). USA: Thomas Wadsworth, 2008. 4. World Medical Association. Medical Ethics Manual [homepage on the internet], 2009. Cited February 3, 2010. Available from: http://www.wma.net/en/30publications/30ethicsmanual/pdf/ethics_manu al_en.pdf. 5. Pence G. Classic Cases in Medical Ethics (4th ed.). New York: McGraw-Hill, 2004. 6. Keown J. Euthanasia Examined (1st ed.). Cambridge: Cambridge University Press, 2004.

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7. Beauchamp TL, Childress J. Principles of Biomedical Ethics (6th ed.). New York: Oxford University Press, 2009. 8. Nuffield Council on Bioethics. Relieving Pain and Causing Death: The Doctrine of the Double Effect [homepage on the internet], 2010. Cited February 15, 2010. Available from: http://www.nuffieldbioethics.org/go/screen/browseablepublications/critica lCareDecisionFetalNeonatalMedicine/report_498.html. 9. Quill T. Legal regulation of physician-assisted deaths – the latest report card. New Engl J Med. 2007;356:1911-3. 10. Dignity In Dying [homepage on the internet], 2010. Cited February 3, 2010. Available from: http://www.dignityindying.org.uk/sitemap.html. 11. Longmore P, Bouvia E. Assisted suicide and social prejudice. J Law Med. 1987;3(2):141-68. 12. Beauchamp TL. Methods and principles in biomedical ethics. J Med Ethics. 2003;29:269-74. 13. Furton E, Cataldo P, Moraczewski OP. Catholic Health Care Ethics (2nd ed.). Philadelphia: The National Catholic Bioethics Center, 2009.


RCSIsmjperspective THE YIN AND YANG OF

pharmaceutical companies DARREN CHEW and ERIC M YOSHIDA look at the pros and cons of this powerful industry.

Some 50% of Ireland’s exports are linked to pharmaceutical production, and Ireland is the second largest net exporter of medicines in the world.1 According to the Industrial Development Agency (IDA) Ireland, the estimated replacement value of the Irish pharmaceutical sector is more than €40 billion. Furthermore, 20% of research and development in Ireland goes towards research and development of chemicals and chemical products.2 However, the industry’s research integrity and overall benefit to the public has constantly been questioned. Some argue that although newer drugs may be superior to existing ones, the exponential increase in prices imposes an unnecessary burden of expense. Others counter that the long-term benefits outweigh increasing costs, since even small improvements in current drugs can lead to scientific breakthroughs down the road. Compounding the controversial role of pharmaceutical companies are those of researchers and prescribing physicians – are they co-operative conspirators or consumer crusaders?

Pharmaceutical companies in the media In the popular 1993 movie The Fugitive, Dr Richard Kimble (played by Harrison Ford) is framed for murder by employees of a pharmaceutical company because his research would eliminate any possibility of their drug acquiring FDA approval. While not as corrupt as Hollywood portrays them to be, pharmaceutical companies have had their fair share of scandals exposed in the public domain. One widely reported example was the market withdrawal of the then-popular cyclooxygenase-2 (COX-2) inhibitor agent, rofecoxib, under the brand name Vioxx (Merck & Co Inc, Whitehouse Station, NJ). With a budget of $100 million allocated towards advertising per year, at one point the United States saw 10 million prescriptions of Vioxx written per month.3 After having been consumed by 80 million patients with a sales profit of $2.5 billion in five years, the drug was withdrawn by Merck because the APPROVe study on colorectal adenoma prophylaxis demonstrated a 1.92-fold

increase in the relative risk of myocardial infarctions and strokes.4 Despite concerns by some physicians regarding the adverse effects of Vioxx, Merck-sponsored studies claimed the drug’s cardiovascular safety. Last year, it was reported that Pfizer, a large pharmaceutical company, paid $2.3 billion to the United States federal and state governments in settlement of civil and criminal allegations that it had illegally marketed several drugs. In addition, another COX-2 inhibitor, Bextra (valdecoxib), encountered the same fate as Vioxx and was withdrawn by Pfizer in 2005.5 While Bextra could still provide relief for indications such as post-surgical pain, its lack of FDA approval for this particular use relegated its prescription for acute pain to off-label. Although off-label use is not illegal, Pfizer’s sales representatives were allegedly directed by the company to promote the drug for treatment of acute and surgical pain at doses well above those approved by the FDA. John Kopchinski, a former Pfizer sales representative who was an initial complainant regarding the allegation, was quoted by the New York Times as saying: “The whole culture of Pfizer is driven by sales, and if you didn’t sell drugs illegally, you were not seen as a team player”.5 However, it was also revealed that the half dozen ‘whistle-blowers’ would share a Government bounty in excess of $102 million.

Benefits of the pharmaceutical industry Despite legitimate public concerns about pharmaceutical companies, it is clear that the industry, along with the manufacturers of medical devices and equipment, is necessary for medical progress. Without pharmaceutical-funded research and development, finding alternative financial resources to further clinical knowledge would be difficult.6 Relying solely on government funds to research, develop, manufacture and provide a means of distributing drugs to those in need has proven to be inadequate. In fact, this year the Irish Minister for Health and Children requested financial assistance from the pharmaceutical industry because of the recession.1

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RCSIsmjperspective Recently, regulations have been developed to maintain medical integrity and to address perceived deficiencies within the private sector. Unfortunately, well-publicised pharmaceutical scandals have diverted attention away from significant advances made by these companies, which produced revolutionary drugs and improved medical care.7 For instance, Pfizer also developed Lipitor (atorvastatin), which is currently the most prescribed drug worldwide.8 Atorvastatin, a HMG CoA reductase inhibitor, plays a critical role in treating patients with hyperlipidaemia by lowering cholesterol and preventing fatal cardiac events such as cerebrovascular accidents or myocardial infarctions.9,10 Furthermore, pharmaceutical companies have developed and manufactured antiviral agents to treat hepatitis B, hepatitis C and HIV – all of which, until recently, had no efficacious therapy.11 Another example of the pharmaceutical industry’s contribution to healthcare was Hoffman-La Roche’s response to the call by politicians and scientists for a greater and faster production of oseltamivir (Tamiflu) to fight the H1N1 swine flu last year.12 There are several protocols in place to ensure that marketing practice provides accurate and unbiased information on drugs so that rational, evidence-based decisions can be made. These codes of behaviour are determined both by European law (legislation SI541 – Control of Advertising on Medicinal Products)13 and self-regulating Irish bodies (IPHA – the Irish Pharmaceutical Healthcare Association),14 of which all big pharmaceutical companies are members. These provide specific codes of conduct to guarantee ethical behaviour and eliminate fringe benefits. For example, sales representatives may not give gifts for the personal benefit of healthcare professionals (clause 14.3 of the IPHA guidelines), and meetings cannot take place at venues that are known for entertainment or extravagance (clause 16.3).14 As part of marketing authorisation requirements for all pharmaceutical companies, all employees must obtain annual training on SI541 and the IPHA code of practice before they are certified to promote products to medical professionals.14 Furthermore, all commercial products and every word or design on them must have legal, medical and regulatory sign-off from the pharmaceutical company’s internal committees, who in turn answer to the IPHA and SI541. The Irish Medicines Board is the competent authority in Ireland and has the power to audit pharmaceutical companies to ensure that they are compliant with SI541 and other legislation to maintain their marketing authorisation licence.15 Written requests by doctors for drug samples are required, and only a maximum of six samples can be given to a doctor per year.14 The IPHA guidelines are becoming more stringent, in that starting next year, only four samples can be given to a doctor per year.16 Drug safety is also intensely regulated, and all potential pharmaceutical agents must successfully complete a series of registered clinical trials from phase I (demonstrating safety and determining dose ranges) to phase III (demonstrating both safety and efficacy) before obtaining licensure that allows marketing for a specific indication.17 During clinical trials, the pharmaceutical company follows strict protocols developed by the sponsor’s medical officers and leading academic specialists in the field to determine patient eligibility requirements, schedule of tests, procedures, medications, dosages and length of

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study. Numerous safety measures are taken to ensure the participants’ protection. All registered clinical trials have an interim analysis conducted by an independent drug safety and monitoring board (DSMB) consisting of medical specialists in the particular area that are not directly involved in the clinical trial at hand.18 On the authority of the DSMB, a study can be terminated prematurely if the therapeutic arm of the study performs far superiorly or inferiorly than the control arm, or due to safety concerns. Participating centres must have the new protocols and any amendments that occur during the trial approved by an independent institutional review board (IRB), sometimes called a clinical research ethics board, before the study commences.19 The IRB consists of appointed medical specialists, nurses, social workers, statisticians and medical ethicists who act in the interest of the study participants. Every subject must give informed consent after being provided with a document written in lay language explaining the study protocol, rationale for the protocol, possible benefits of the study medications, possible adverse effects and, most importantly, that participation is entirely voluntary such that the patient may choose to withdraw from the study at any point. Patients are also protected by the Clinical Centre Patients’ Bill of Rights, which ensures privacy, confidentiality and access to their medical records.20 In addition, the United States public law and the FDA mandates that the sponsors or designated principal investigators register and report the results of clinical trials.14 Monitors are sent to verify that all protocol requirements are met; otherwise, the centre’s data are disqualified, and the internal validity of the study suffers. In addition to drug contributions, pharmaceutical companies take the concept of corporate citizenship very seriously. For example, Pfizer is involved in several programmes that promote health without advertising their products. These include partnership in: ‘pain proposal’ – an EU document raising issues around the treatment and awareness of chronic pain; ‘healthy heart campaigns’ – a movement that raises awareness and provides nursing support for doctors involved in cardiac care; and, the ‘quit with help’ campaign – a drive that encourages smoking cessation in conjunction with organisations such as the Irish Cancer Society.16

The role of healthcare professionals Government assistance and support from non-governmental organisations and philanthropic foundations is available for many aspects of basic science research, where a potential financial payout is not readily perceived. On the other hand, the progress of modern clinical medicine requires the entrepreneurial spirit of rival pharmaceutical companies as a driving force. The incentive of market share and profit creates a willingness to invest in innovation, while a competitive environment ensures that only the best products make it to the market. Physician involvement in the pharmaceutical process is integral, whether success is defined by better patient outcomes or, from the perspective of the industry and its shareholders, enhanced market share and profitability. Development of pharmaceutical-sponsored clinical trials requires


RCSIsmjperspective medical specialists to define the endpoints of clinical trials, to develop the study protocols, to serve on a clinical trial’s DSMB and to conduct the trials. Once licensure is achieved and the drug is ready for sale, pharmaceutical companies often create medical advisory boards to provide clinical advice on the product and its market.16 As such, physicians are in a position to ensure that the pharmaceutical process works in the best interests of patients and the medical profession. Since the consumer of pharmaceutical products is often perceived to be the prescribing physician rather than the patient, physicians can exert substantial leverage in an industry that blurs the distinction between medical education and product marketing. Many major medical conferences use pharmaceutical sponsorship to fund the event, but physicians and medical students can reduce industry bias by insisting that sponsorship and funding of events be made through unrestricted educational grants.

However, this is difficult in reality, since funds are scarce. Furthermore, physicians and medical students can be ‘watchdogs’ to alert appropriate government agencies, the media and the public if serious ethical or clinical breaches occur. Overall, one may argue that the benefits provided by the pharmaceutical industry outweigh deficiencies within the system, especially when the appropriate checks and balances, such as SI541 and the IPHA code of practice, are in place to protect the public interest. Whether in the form of education, programme implementation, economic stimulation or breakthrough drugs that improve life expectancy, it is evident that pharmaceutical companies contribute towards healthcare innovation and progress. Darren Chew is a medical student at the RCSI. Professor Eric M Yoshida MD MHSc FRCP(C) FACP FACG is Professor of Medicine and Head, Division of Gastroenterology, University of British Columbia, Vancouver, BC, Canada.

References 1. Irish Pharmaceutical Healthcare Association. Pharmaceutical Healthcare Facts

12. Centers for Disease Control and Prevention [document on the internet].

and Figures, 2010. Cited August 17, 2010. Available from:

Updated Interim Recommendations for the Use of Antiviral Medications in

http://www.ipha.ie/alist/healthcare-facts-and-figures.aspx?article=0e253271-e6f

the Treatment and Prevention of Influenza for the 2009-2010 Season.

b-4ce3-af3f-4a4c28f2e3e7#SelectedArticle.

Updated December 07, 2009. Cited August 17, 2010. Available from:

2. Forfas. Research and Development Statistics in Ireland – 2009 at a glance. Cited August 17, 2010. Available from: http://www.forfas.ie/media/forfas090908_research_development_statistics.pdf. 3. Topol EJ. Failing the public health – rofecoxib, Merck, and the FDA. N Engl J Med. 2004;351(17):1707-9. 4. Bresalier R, Sandler RS, Quan H, Bolognese JA, Oxenius B, Horgan K et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med. 2005;352(11):1092-102. 5. Harris, G. Pfizer pays $2.3 billion to settle marketing case. The New York Times, September 2, 2009. Cited August 17, 2010. Available from: http://www.nytimes.com/2009/09/03/business/03health.html?_r=2&hp. 6. Campbell EG, Gruen RL, Mountford J, Miller LG, Cleary PD, Blumenthal D. A national survey of physician-industry relationships. N Engl J Med. 2007:356(17):1742–50. 7. Stossel TP. Has the hunt for conflicts of interest gone too far? Yes. BMJ. 2008;336(7642):476. 8. IMS Health Midas. Top 15 Global Products, 2009, Total Audited Markets. Cited August 17, 2010. Available from:

http://www.cdc.gov/h1n1flu/recommendations.htm. 13. Statutory Instrument No. 541 of 2007 [document on the internet]. Medicinal Products (Control of Advertising) Regulations 2007. Cited December 26, 2010. Available from: http://www.dohc.ie/legislation/statutory_instruments/pdf/si20070541.pdf?di rect=1. 14. Irish Pharmaceutical Healthcare Association. Code of Marketing Practice for the Pharmaceutical Industry. Cited December 11, 2010. Available from: http://www.ipha.ie/alist/codes-of-practice.aspx?article=7fb4ec4f-7ccd-4da6a11c-722f543316e1. 15. Irish Medicines Board [homepage on the internet]. About us. Cited December 26, 2010. Available from: http://www.imb.ie/EN/About-Us.aspx. 16. Head of Sales Primary Care, Pfizer Healthcare Ireland. Interviewed by Chew D. December 10, 2010. 17. Clinicaltrials.gov. Protocol Registration System [document on the internet]. General Requirements. Cited August 17, 2010. Available from: http://prsinfo.clinicaltrials.gov/fdaaa.html. 18. Chen M [document on the internet]. The Fundamentals of International

http://www.imshealth.com/deployedfiles/imshealth/Global/Content/StaticFile/T

Clinical Research Workshop: Data and Safety Monitoring Board (DSMB).

op_Line_Data/Top%2015%20Global%20Products_2009.pdf.

Cited December 26, 2010. Available from:

9. Arca M, Gaspardone A. Atorvastatin efficacy in the primary and secondary prevention of cardiovascular events. Drugs. 2007;67(Suppl. 1):29-42. 10. Gaspardone A, Arca M. Atorvastatin: its clinical role in cerebral vascular protection. Drugs. 2007;67(Suppl. 1):55-62. 11. Centre for Disease Control. IDU HIV Prevention [document on the internet]. Medical Management of Chronic Hepatitis B and Chronic Hepatitis C. Cited

http://www.icssc.org/PRESENTATIONS%20USED%20AT%20WORKSHOP/25 %20DSMB.pdf. 19. National Institute of Environmental Health Sciences – National Institutes of Health. Institutional Review Board. Cited December 26, 2010. Available from: http://www.niehs.nih.gov/about/orgstructure/boards/irb/index.cfm. 20. NIH Clinical Center [document on the internet]. FAQs About Clinical

August 17, 2010. Available from:

Studies. Cited August 17, 2010. Available from:

http://www.cdc.gov/idu/hepatitis/manage_chronich_hep_b-c.pdf.

http://www.cc.nih.gov/participate/faqaboutcs.shtml.

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RCSIsmjelective PAUL DHILLON and HARITH ALI describe surgical care in a war zone.

The Emergency hospital, Kabul, Afghanistan.

A WEEK IN

â&#x20AC;&#x2DC;Emergencyâ&#x20AC;&#x2122; Many medical students aspire to work with non-governmental organisations at some stage in their medical careers. We were not immune to this desire and this led us to Kabul, Afghanistan, to participate in the activities of the Italian NGO Emergency in the summer of 2010. When thinking of Afghanistan, news headlines and images of war come most readily to mind. For the past few years, and in some parts of the country for decades, this has been an accurate picture of the turmoil that occurs daily across the country. However, this has not always been the case. Afghanistan was a nexus for the meeting of people from the Middle East, South Asia, East Asia and Central Asia. The Khyber Pass, Silk Road and Alexander the Great are iconic historical places and people intimately tied to Afghanistan and its narrative. However, years of occupation and war, coupled with the lack of a stable central government and enforcement of the rule of law, have led to a nation that is unstable and unsafe through wide swathes of its territory. Currently, there is limited access to emergency surgery throughout the provincial and district hospitals; this is where Emergency fills a vital need.1

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Emergency Emergency is an independent NGO, founded in 1994, that provides free healthcare to civilian victims of war and poverty, and works to promote a culture of solidarity, peace and respect for human rights.2 The medical activities operated by Emergency are designed, built and run by international personnel, who provide training for local staff. This organisation has worked in 15 countries to date. First, it aims to guarantee treatment to anyone in need of assistance, without any discrimination as to race, colour, sex, religion, social origin or political opinion. Second, it provides high quality assistance, employing standardised therapeutic and work protocols already tested in emergency situations. Third, it aims to train national staff thoroughly, with the intent of transferring all the health facilities to the local health authorities as soon as self-sustainability can be achieved. Emergency has been active in Afghanistan since 1999 and the Surgical Centre in Kabul opened in 2001 in an abandoned and bombed out nursery school near the city centre. The centre was temporarily closed after a raid by armed Taliban but reopened with


RCSIsmjelective

Clockwise from left: Nine children were brought to the hospital after a rocket attack while they were playing in their backyard; Child undergoing respiratory physiotherapy; Shattered fragments of bone following a bullet injury. the coalition invasion in November 2001. Since Emergency started operations, they have treated over 2,659,223 people across the country.1 Emergency is staffed in the majority by national staff, with nurses and surgeons from Italy and across the world serving the organisation in their working language of English.

Emergency is an independent NGO, founded in 1994, that provides free healthcare to civilian victims of war and poverty, and works to promote a culture of solidarity, peace and respect for human rights.

with bullet, mine, shell, knife, and rocket injuries were admitted, skewing what was seen of the total burden of surgical cases in the country. After discussion of the cases among the surgeons, anaesthetists and international nursing staff, the team would split. One half commenced a ward round of the entire hospital including both adult and paediatric wards. The hospital consisted of 100 beds divided among five wards, one of which was dedicated to paediatrics. The other half of the team would proceed to one of the two surgical theatres and commence the dayâ&#x20AC;&#x2122;s theatre list and any emergency cases that presented to the hospital. Wards were simple but immaculately kept by the cleaning staff, which illustrated that quality medicine and surgery can be provided in an austere and limited resource environment.

A day in the life So what is a day like in the Emergency hospital in Kabul? Each day begins similarly to what one would expect in any surgical team that was admitting from the previous day: a morning round of patients that were admitted during the previous 24 hours along with plain film radiology or CT scan summaries. In the absence of mass casualty events in the city, there would be approximately 10-12 admissions per day. We had to keep in mind that most of Afghanistan is essentially an active war zone, and the admission criteria were such that only patients

An eye-opening experience Our first ward rounds were eye opening in terms of learning about the relative simplicity with which basic war trauma is managed in surgical terms. War trauma is assumed to be dirty, and therefore uncomplicated wounds are simply debrided and left open for a period of five days, before undergoing delayed primary closure. Seeing many of these large and extensive wounds for the first time impressed on us the ability of the body to withstand large amounts of physical trauma. Radiology that

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RCSIsmjelective

From left: Thoracotomy closure post stab wounds to the anterior chest wall and abdomen. was reviewed during the ward round was impressive and unlike any we had ever seen in Ireland. The destruction and shattering of bone by bullet is difficult to imagine without having seen it in person. In the theatre it was intriguing to see the wide variety of cases that were operated on by the general surgeons. Whereas in Ireland, and most of the developed world, surgeons tend to sub-specialise, here there was one international general surgeon supported by eight national surgical staff who operated on orthopaedic, vascular, neurological and general cases. Brooks et al. found that there was a paucity of technical hands-on experience with specialist registrars in England, such that they are involved with a median of only two blunt and one penetrating trauma laparotomy per annum. The majority will neither observe nor be involved in an emergency thoracotomy throughout the five years of their training.3 This situation was reversed in Kabul, where in one 24-hour period we witnessed three emergency thoracotomies. Interesting cases aside, the sheer volume of trauma patients was something we had never witnessed before. Having nine children arrive to the hospital after a rocket attack while they had been simply playing in their backyard is not a pleasant experience. It was admirable to see the Italian and Afghani national staff working together to manage the multiple casualties in this particular case. All of the children survived; however, a different outcome was noted when patients arrived and the message that was transmitted to the staff included the words â&#x20AC;&#x2DC;brain outâ&#x20AC;&#x2122;.

Although this experience was an extreme one, it gave us a clear idea of what it entails to work with a medical NGO in a war environment. On paper it seems to be an interesting and exciting environment to work in. However, a difficult aspect of this endeavour is the fact that international staff will spend three to six or more months away from family and friends, with limited rest, and in a dangerous environment. In the current situation there were severe limitations on the staffâ&#x20AC;&#x2122;s movement, with activities in both work and social spheres limited to the hospital compound and a quick walk across the street with a guard to the staff housing facility.

A difficult aspect of this endeavour is the fact that international staff will spend three to six or more months away from family and friends, with limited rest, and in a dangerous environment. Nevertheless, the exposure to trauma and the ability to provide care of a high standard to populations that would not otherwise have access to such care, is not only fulfilling in an emotional and educational sense, but also provides a beneficial service to the children and adults we serve.

References 1. EMERGENCY. Cited October 7, 2010. Available from: http://www.emergency.it/en-index.html. 2. Contini S, Taqdeer A, Cherian M et al. Emergency and essential surgical services in Afghanistan: still a missing challenge. World J Surg. 2010;34:473-9.

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3. Brooks AJ, Ramasamy A, Hinsley D, Midwinter M. Military general surgical training opportunities on operations in Afghanistan. Ann R Coll Surg Engl. 2009;91:417-9.


RCSIsmjelective PAUL TSOUKAS describes the challenges faced by patients with HIV/AIDS in west Africa.

THE COST OF LIVING WITH AND DYING OF

AIDS in Tanzania “The rich are very different from you and me...yes, they have more money.” Ernest Hemingway, ‘The Snows of Kilimanjaro’1

This quotation from Hemingway’s short story rings true near the base of Kilimanjaro. From Kilemma Hospital, Tanzania, near the Kenyan border, you can see what the local Masai call ‘the house of God’. The Hospital is supported by the church and the Canada Africa Community Health Alliance, a humanitarian foundation and non-governmental organisation that helps to fight HIV/AIDS and provide healthcare to destitute African communities. On the slopes of Kilimanjaro, the foundation established a HIV/AIDS clinic that treats patients from the surrounding communities. For my first elective in medical school, I had the privilege of witnessing a collage of melancholic yet interesting medicine.

Kaposi’s sarcoma During my second week in Kilemma Hospital, a woman with HIV presented to the clinic for her quarterly check-up complaining of dysphagia and limb pain. She appeared older than her actual age. It was not clear if the signs of premature ageing were due to her disease or were a result of treatment with nucleoside reverse transcriptase inhibitors (NRTIs). NRTIs can cause mitochondrial toxicity and an increase in reactive oxygen species that affect adipocyte differentiation, leading to some of the physical changes noted in premature ageing.2 These changes include lipoatrophy – the loss of subcutaneous fat of the face – and an increase in abdominal fat. These HIV drugs are used less commonly in the developed world because of this associated lipodystrophy. After the local medical officer obtained a brief updated history, a visiting North American physician and HIV expert examined the patient. Upon opening her mouth, a Kaposi’s sarcoma was seen on the patient’s hard palate, the likely source of her complaints. Kaposi’s sarcoma frequently presents as purple papules on the

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RCSIsmjelective Previous page: Kilemma Hospital with Mount Kilimanjaro obscured by clouds in the background; the pathway to the HIV clinic is called ‘the walk of shame’ by the villagers. Staff outside the hospital (from left): Julius, medical officer; Sister Daria, staff physician; and, Sister Clarissa, staff surgeon.

Even with an abundance of natural resources, Tanzania remains poor. Money is needed to properly train healthcare workers, improve infrastructure, and provide free or cheap diagnostic investigations and treatments. skin or mucosa, but can affect any organ in the body. Commonly, it is found in the gastrointestinal tract and can present with massive oesophageal or intestinal haemorrhage.3 The physician explained that the mass was large and likely extended down the oesophagus. Such tumours are now rarely seen in the western world because of the early commencement of anti-retroviral treatment. Since the introduction of highly active anti-retroviral treatment (HAART) in 1996 in Europe, North America and Australia, the incidence of AIDS-associated Kaposi’s sarcoma has drastically been reduced.4 In Africa, however, HAART is only commenced at very late stages of HIV infection. As such, a greater number of cases of opportunistic infections and Kaposi’s sarcoma are seen, and those with AIDS have a poor prognosis. In such resource-limited areas, not only do patients present late and receive treatment late, but there are also limited long-term treatment options for sarcoma because of financial constraints. In addition to dysphagia, the woman complained of left leg pain. On examination, the leg had a peau d’orange appearance and was warm, features that are consistent with severe oedema. A

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mass was present in the pelvis and the inguinal nodes were swollen and tender. The physician suggested that the mass may have also been due to a second malignancy – a non-Hodgkin’s lymphoma, commonly associated with HIV/AIDS. HIV-associated immune suppression, and in particular the low CD4+ lymphocyte status, may facilitate carcinogenesis. HIV-associated lymphomas are a consequence of an inability to regulate B lymphocytes, leading to uncontrolled B lymphocyte proliferation.2 Unfortunately, the required biopsy could not be performed due to the patient’s financial status. Despite her young age, there was no other option but to discharge her from the hospital and let her condition progress at home. Although treatment of malignancies is free in Tanzania, the histopathologic tests required to make a diagnosis are not. Cancer therapy is also only provided in large cities and the patients’ families are expected to provide the daily care and support needed during treatments. The major limiting factor in receiving cancer treatment appears to be the cost of travel and housing for the patient and their relatives. This financial burden was beyond the capacity of most of the poor farmers I met at the hospital. In the short story ‘The Snows of Kilimanjaro’, Hemingway portrays a man who faces death from infection and regrets many of the choices he has made in his life. His resentment of money and of those trying to make him comfortable is in sharp contrast to the attitudes of patients currently admitted to Kilemma Hospital. Despite their hardships and financial constraints, the people and community of Kilemma show a remarkable ability to adapt in the face of adversity.


RCSIsmjelective AIDS in Tanzania Despite all the hardships I witnessed, I was struck by the ability of most of the impoverished patients to maintain an optimistic outlook. They would often smile and converse happily despite their suffering. I was also surprised to see a profound stigma surrounding HIV/AIDS. HIV patients were clearly identified when they visited the AIDS centre. Not only did they travel along the solitary pathway to the clinic, dubbed by the villagers ‘the walk of shame’, but they were easily recognisable because of their distorted physical features as a result of lipodystrophy. Many of the patients attending the clinic also presented with other visible comorbidities such as lymphoma, Kaposi’s sarcoma, oral hairy leukoplakia, oral thrush and herpes zoster.

The major limiting factor in receiving cancer treatment appears to be the cost of travel and housing for the patient and their relatives. This financial burden was beyond the capacity of most of the poor farmers at the hospital. Even with an abundance of natural resources, Tanzania remains poor. Money is needed to properly train healthcare workers, improve infrastructure, and provide free or cheap diagnostic investigations and treatments. I witnessed a number of patients who were denied standard therapies, not because the staff were oblivious to their existence, but because of the sobering fact that they could not pay for the treatment. In 2006, the WHO identified Tanzania as among the

top 20 countries in highest need of antiretroviral treatments.6 Funds are required to educate the population about HIV/AIDS and to reduce the stigma associated with this disease. Astonishingly, only one in five HIV/AIDS cases is reported. This was reflected in the clinic’s predominately female cohort, with many ailing men not willing to be tested. Many countries, Ireland among them, have contributed to the fight against AIDS in sub-Saharan Africa. In 2006, the White Paper on Irish Aid allocated at least €100 million per year to combat HIV/AIDS and other communicable diseases in developing countries.7 Despite these efforts, a greater international effort is imperative; Tanzania ranks 148th out of 169 countries based on calculations of the Human Development Index and life expectancies.8 The Tanzania Commission for AIDS (TACAIDS) was first established in 2000 by an act of parliament with a mandate to prevent and control the HIV/AIDS epidemic, to provide healthcare and counselling for HIV/AIDS patients and to help HIV/AIDS orphans.9 In 2003, the WHO estimated that 260,000 people in Tanzania required treatment and set a treatment target of 130,000 people by 2005. The Government initially declared a national target of 220,000 HIV-infected people on antiretroviral therapy by the end of 2005, but estimates from the Ministry of Health indicated that only 8,300 people were receiving antiretroviral therapy in June 2005. In 2005, Tanzania succeeded in obtaining approximately $500 million USD from the Global Fund to Fight AIDS, Tuberculosis and Malaria for the care and treatment of HIV/AIDS patients.10 It remains to be seen if these funds will translate into the achievement of future HIV/AIDS treatment targets and a concomitant decrease in the number of HIV-associated comorbidities seen.

References 1. Hemingway E. The Snows of Kilimanjaro. Esquire, August 1936. 2. Caron-Debarle M, Lagathu C, Boccara F, Vigouroux C, Capeau J. HIV-associated lipodystrophy: from fat injury to premature aging. Trends Mol Med. 2010;16(5):218-29. 3. Engels EA. Human immunodeficiency virus infection, aging, and cancer. J Clin Epidemiol. 2001;54(Suppl. 1):S29-S34. 4. Casper C. The increasing burden of HIV-associated malignancies in resource-limited regions. Annu Rev Med. 2010. [Epub ahead of print.] 5. Lopez G, Graza Y. Extensive Kaposi’s sarcoma in a HIV positive patient: A case report. The Internet Journal of Infectious Diseases [serial on the internet], 2009; 7 (1). Cited October 11, 2010; Available from:

7. Irish Aid. White Paper on Irish Aid, 2006. Cited December 29, 2010. Available from: http://www.irishaid.gov.ie/whitepaper/. 8. United Nations Developmental Program. Human Development Report 2010 – 20th Anniversary Edition; The Real Wealth of Nations: Pathways to Human Development. November 2010. Cited December 26, 2010. Available from: http://hdr.undp.org/en/reports/global/hdr2010/. 9. Tanzania Commission for AIDS [homepage on the internet]. Dar es Salaam: TACAIDS c2008. Cited October 11, 2010. Available from: http://www.tacaids.go.tz/home.html. 10. World Health Organisation. The United Republic of Tanzania: Summary

http://www.ispub.com/journal/the_internet_journal_of_infectious_dise

Country Profile for HIV/AIDS Treatment Scale-Up. December 2005.

ases/volume_7_number_1_20/article/extensive_kaposi_s_sarcoma_in_a

Cited October 11, 2010. Available from:

_hiv_positive_patient_a_case_report.html.

http://www.who.int/hiv/pub/en/.

6. World Health Organisation. Progress on Global Access to HIV Antiretroviral Therapy: a report on 3 by 5 and beyond. March 2006.

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RCSIsmjabstract RCSI Alumni funded

An investigation into the effects of anti-oxidants on platelet reactivity Boland T1, Murphy D2, Reddy E2, O’Neill S2 1RCSI medical student 2Department of Molecular and Cellular Therapeutics, RCSI

Platelet thrombosis.

Background

Results

Oxidative stress is associated with disturbances in the redox environment of plasma, which potentially affects platelet reactivity, in turn leading to thrombus formation. Although oxidative stress has been shown to play an integral role in the pathogenesis of diseases such as atherosclerosis and diabetes, the role of anti-oxidants in vascular disease prevention is still unclear.1,2 Although ascorbic acid (vitamin C) is a known anti-oxidant, there is limited information available regarding the impact of ascorbic acid on platelet function in vitro. This investigation is crucial in order to establish mechanisms of action and target sites of anti-oxidants. The focus of this study is to investigate the effects of ascorbic acid on platelet reactivity as indicated by platelet aggregation.

The data showed that the anti-oxidants ascorbic acid (45µm), NAC (45µm) and cysteine (45µm) inhibited platelet aggregation when platelets were activated with collagen, but not with TRAP or ADP. The reducing NAC/CySS and Cys/CySS redox potentials significantly inhibited platelet aggregation to collagen (p<0.0001), but not to convulxin.

Methods Platelets were activated using various platelet agonists known to cause platelet aggregation – collagen, thrombin receptor-activating peptide (TRAP), adenosine diphosphate (ADP) and convulxin. Both ‘pro-oxidant’ and ‘anti-oxidant’ concentrations of ascorbic acid were used. N-acetyl cysteine (NAC), a known dietary anti-oxidant supplement and pharmaceutical drug, was also tested. The external redox environment of the platelets was altered by combining ratios of both NAC and cysteine (Cys) with cystine (CySS) to form a spectrum of redox couples (NAC/CySS and Cys/CySS) from reducing to oxidising potentials. A platelet aggregometer was used to measure the degree of aggregation.

Conclusion Platelet aggregation is only inhibited when platelets are activated with collagen. Therefore, it appears that the anti-oxidants and redox couples with reducing redox potentials exert a direct effect on the collagen pathway, leading to inhibition of platelet aggregation. We suggest that this is occurring through a modification of integrin α2β1, a collagen-only receptor on the platelet surface. Collagen is a naturally occurring protein in the body, which acts as a potent platelet activator. Further understanding of the mechanism by which collagen-mediated activation is modulated could aid in the development of novel anti-thrombotic drugs.

Acknowledgements This work was kindly supported by a grant from the RCSI Alumni Fund.

References 1.

Freedman JE. Oxidative stress and platelets. Arterioscler Thromb Vasc Biol. 2008;28(3):s11-6.

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2.

Madamanchi NR, Vendrov A, Runge MS. Oxidative stress and vascular disease. Arterioscler Thromb Vasc Biol. 2005;25(1):29-38.


RCSIsmjabstract Hippocampal astrogliosis and neuronal cell loss in an experimental P10 neonatal model of mesial temporal lobe epilepsy Crilly S1, Dunleavy M2, Henshall DC3 medical student 2Postdoctoral fellow, Department of Physiology and Medical Physics, RCSI 3Associate Professor, Department of Physiology and Medical Physics, RCSI

1RCSI

Background Mesial temporal lobe epilepsy (MTLE) is the most common form of intractable seizure disorder in adults. It is associated with an asymmetrical pattern of neuron loss within the hilus and CA1 hippocampal subfields, with relative sparing of the dentate granule neurons and the CA2 subfields. The amygdalar nuclei and the cortical neurons are other areas that are rarely involved in MTLE.1 The neuropathological changes that bring about focally evoked seizures in the adult are thought to begin in the early stages of neonatal life. A wide range of factors have been implicated in the causation of MTLE, such as febrile seizures and traumatic brain injury.2 Some studies indicate that up to 74% of those who experience early life status epilepticus develop epilepsy at a later stage.2 The objective of this study is to investigate the neuropathological changes induced by intra-amygdalar kainic acid (KA) microinjection in a postnatal day 10 (P10) rat model of MTLE.3

Methods Seizure induction by intra-amygdalar microinjection of KA was modified from experimental models developed by Henshall et al.4 Pups received either 2µl of vehicle (phosphate buffer, pH 7.4; n=4) or 2µl KA (n=4). EEG was recorded for up to 90 minutes, during which behaviour associated with inter-ictal events were monitored. Immunofluorescence microscopy was performed on fresh frozen

rat brains for glial fibrillary acidic protein (GFAP) (1:400), a marker of astrogliosis, and neuronal nuclei (NeuN) (1:400), a marker of neuronal nuclei. Flurojade B staining (FjB) was also performed to assay for neuronal cell death. Statistical analysis was carried out using non-paired student t-tests.

Results Following injection of 2µg of KA, initial low amplitude, high frequency EEG developed to high amplitude, high frequency epileptiform EEG seizures consistent with status epilepticus. All KA-treated pups (n=4) displayed seizure-like behaviour, including initial masticatory movements and salivation, developing periods of forelimb myoclonus and progressing to wild swimming behaviours. Histological analysis of the rat brains treated with KA showed a reduction of the overall size of the ipsilateral hippocampus as well as atrophy of the pyramidal cell layers. Hydrocephalus ex vacuo of the ipsilateral lateral ventricle was also noted in one of four rat brains. Ipsilateral P10 CA3 NeuN counts in KA-treated rats were approximately 75% of that in the control group (n=4, p<0.01), demonstrating preferential CA3 subfield-specific neuronal cell death in KA-treated pups. Ipsilateral FjB-positive cell counts in treated animals were approximately 20 times greater than in the control animals (n=4, p<0.05). In addition, there was diffuse astrogliosis in the ipsilateral hippocampus of treated animals.

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RCSIsmjabstract

Conclusion In summary, intra-amygdalar KA microinjection in neonatal rats causes status epilepticus and extensive acute unilateral hippocampal neurodegeneration. The ipsilateral hippocampus displayed neuropathological changes similar to the pattern reported previously by Dunleavy et al.3 The neurometabolic role

of extensive astrogliosis after cell death within the hippocampus requires further study. It is hoped that understanding of the mechanisms of neonatal status epilepticus and its role in the aetiology of MTLE will aid in the development of novel anti-epileptogenic treatments.

(a) (i) Ipsilateral hippocampus: 2µg KA. FIGURE 1: (a) Hippocampal cell death at P10 following neonatal status epilepticus; representative inverted pictomicrographs of the hippocampus of rats treated with intra-amygdalar microinjection of either 2µg (i) KA (n=4), or (ii) vehicle (n=4). Cell death occurs preferentially in the CA3/hilus of the hippocampus. The decrease in neuronal cell layer depth in the CA1 region in the KA-treated animal relative to control is indicative of cell death/apoptosis. (b) Diffuse astrogliosis (GFAP) and pyramidal cell layer narrowing (NeuN) within the ipsilateral CA3 region of a KA-treated animal.

(b) Ipsilateral CA3 NeuN/GFAP 2µg KA.

References 1.

Mouri G, Jimenez-Mateos E, Engel T, Dunleavy M, Hatazaki S, Paucard A et

Dunleavy M, Shinoda S, Schindler C, Ewart C, Dolan R, Gobbo OL et al. Experimental neonatal status epilepticus and the development of temporal lobe

epileptogenesis after intra-amygdala microinjection of kainic acid in mice.

epilepsy with unilateral hippocampal sclerosis. Am J Path. 2010;176(1):330-42.

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