Summer Edition August
Scottish Universities Medical Journal (Dundee)
Healthcare Student Journal for Scotland Volume 1 – Issue 2
Contact Information: L.D.Hughes@dundee.ac.uk
The Scottish University Medical Journal (Dundee) Team
Scottish Universities Medical Journal Editorial Board Editor in Chief ‐ Lloyd Hughes Deputy Editor – Katherine Walker Information & Technology Manager – Naomi McIlvenny Head Reviewer – Fiona Robertson Formatting Manager – Lauren Copeland Treasurer & PR Rep – James Millar
SUMJ Development and Reviewer Team Paul Connelly
Associate Editors and Consultant Reviewers for University of Dundee SUMJ Professor Sam Eljamel ‐ Consultant Neurosurgeon NHS Tayside, Honorary Professor in Neurosurgery University of Dundee Dr David Booth ‐ General Practitioner & Doctors Patients and Communities Facilitator, University of Dundee Professor Jeremy Hughes – Profesor of Experimental Nephrology and Honorary Consultant Nephrologist, University of Edinburgh and NHS Lothian
Editorial – Volume 1 Issue 2
Lloyd D Hughes, Editor‐in‐Chief 2011/12 Welcome to the second issue of the Scottish Universities Medical Journal. The significant increase in the number of submissions has made the selection process very challenging but we hope it will also provide many interesting and stimulating articles for our readership. Our feature article ‘Prisoner or Patient – The Challenges within Forensic Health Services’ by Catriona Neil (page 119) outlines the considerable challenges of managing patients in the prison setting including limited resources, small number of accessible hospital beds and the high healthcare need of prisoners. The authors discuss some recent high profile cases such as Anders Behring Brevik, stress the importance of managing people in prison with dignity and respect and outline how medical students should approach and think about prisoners who are in need of medical care. Returning to non‐forensic health services, there seems to have been endless discussion and debate about the implications of the 2012 Health and Social Care Act passed by the Conservative‐Liberal Democrat coalition government. However, many people may have a limited understanding of the proposed reforms. In their article ‘Your NHS‐ Myths Debunked and the Reforms Explained’ (page 123) Josh Coats and Ben Warner explain some of the key principles of the Act and argue that the Act might be unable to deliver on many of its promises. The second of our Clinical Anatomy series by John Kennedy focuses upon the lower respiratory tract and outlines the clinical relevance of key anatomical structures. I am pleased to announce that the newly commissioned ‘Clinical Research for Beginners’ series starts in this issue. Dr Lynda Cochrane and Shobitha Puvaneswaralingam discuss the importance of the planning process in undertaking good clinical research. Additional educational articles discuss important areas including age‐related macular degeneration, idiopathic pulmonary fibrosis and newly developed treatments of aortic stenosis. We are also delighted to publish two commissioned articles by leading experts in their respective fields: Professor Stewart Fleming discusses the importance of clinical pathology in modern multi‐disciplinary medicine and Professor Brian McKinstry outlines the therapeutic potential and challenges of the emerging discipline of telehealthcare. I am also pleased to announce that the SUMJ initiated an on‐line electronic publication program in April 2012 in a response to the increased level of interest in the journal and the increase in the number of submissions. The on‐line SUMJ E‐Pub section will enable the journal to publish more work by students than that currently allowed by our limited number of printed pages. It should be noted that these on‐line E‐Pub articles are subjected to the same academic peer‐review process as articles published in the printed SUMJ journal. All articles accepted for print or on‐line publication will be indexed in the Cumulative Index to Nursing and Allied Health Literature (CINAHL). I wish to extend my personal gratitude to the consultant staff for their advice and provision of excellent peer review of many submitted articles as well as the many student contributors. I would also like to thank the Medical Protection Society, the University of Dundee, Wesleyan Medical and PasTest for their generous sponsorship and support of the SUMJ. Finally, after my 12 months as Editor‐in‐Chief of the SUMJ I will be handing over the management of the journal to Katherine Walker, the current Deputy Editor, and I am sure that she will lead the journal from strength to strength.
Table of Contents Editorial .........................................................................................................p. 116 LD Hughes
Issue 2 ‐ Feature
Prisoner or Patient‐ The Challenges within Forensic Health Services ........ p. 119‐122 CE. Neil & Dr A. Morrison Healthcare Politics & Reform
Yours NHS‐ Myths Debunked and the Reforms Explained......................... p. 123‐127 J. Coats and B. Warner Original Research
Prediction of In‐Hospital Mortality in Acute Exacerbations of COPD......... p. 129‐139 R. Archibald, J Chalmers, T. Fardon et al. Clinical Practice
Pathogenesis and Management of Age‐Related Macular Degeneration.... p. 141‐153 C. Porte Medical Education
Clinical Research for Beginners Series (1) The Importance of Planning ..... p. 154‐164 Dr L. Cochrane & S. Puvaneswaralingam Clinical Practice
The Ethics of Acupuncture........................................................................ p. 165‐169 P. Connelly
Development of Minimally Invasive Surgical Treatment for Aortic Stenosis in Older Patients ................................................................................................... p. 170‐173 D. Manoharan & D. Manoharan Medical Education
Clinical Anatomy Series ‐ Part 2 Lower Respiratory Anatomy ................... p. 174‐179 JW. Kennedy
Telehealth – A Developing Medical Field .................................................. p. 180‐183 Prof B. McKinstry
Femoral Nerve Block – A Guide for Medical Students and Junior Doctors. p. 185‐191 Dr A. Bogacz & M. Jamison
Clinical Pathology – A Diagnostic Aid? ...................................................... p. 192‐198 Prof S. Fleming
Treatment of Idiopathic Pulmonary Fibrosis – An unmet clinical need...... p. 199‐203 Dr PM. Short & Dr N. Hirani
Submitting Articles to the SUMJ The SUMJ is an online and print journal open to all healthcare students studying in Scotland. If you wish to submit to the SUMJ the deadlines for each of our editions are noted below: •
Winter Edition February [Deadline for submissions is October 31st]
Summer Edition August [Deadline for submissions is April 30th]
Electronically Published Articles [Submissions open through the year]
Please attach copy of your submission to the new Editor Katherine Walker K.Z.Walker@dundee.ac.uk Please include the type of article (e.g. case report, research) you are submitting in the subject line and a cover letter. The guidelines for article submission can be found on the SUMJ Dundee website (http://sumj.dundee.ac.uk). The submitted article should be in Microsoft Word format and contain a declaration indicating that it is your own work. If you are submitting a case report you must submit a signed form by the patient in line with confidentiality considerations.
Prisoner or Patient The Challenges within Forensic Health Services
Issue 2 – Feature Article
Catriona E Neil (4th year MBChB; BMSc Hons) Correspondence to: Catriona E Neil : C.E.Neil@dundee.ac.uk
Offenders have very high rates of mental health problems with recent estimates suggesting that up to 90% of individuals serving custodial sentences have some form of diagnosable mental health condition. As a group, prisoners and forensic patients have specific healthcare needs that differ from the general population. The challenge for doctors is providing the best care to address complex psychiatric, medical and social needs within a challenging setting. Prisoners are vulnerable members of society and it is the doctor’s duty to make difficult decisions about treatment whilst keeping the patient’s best interests at heart. Key Words: psychiatry; forensic psychiatry/medicine; criminal justice; Breivik trial; insanity
Medicine is a career full of challenges and forensic psychiatry offers an interesting combination of legal, ethical and medical issues that all need to be considered for every patient. This, plus the additional responsibility of constantly assessing risk and the potential consequences when this is underestimated, sets forensic psychiatry apart from other specialities. As a group, prisoners and forensic patients have specific healthcare needs that differ from the general population.1 The challenge for doctors is providing the best care to address complex psychiatric, medical and social needs within a challenging setting. Although given the label of prisoners, this is a vulnerable group of patients who need help and must be treated with dignity and respect, regardless of their criminal conviction. The doctor must not judge or let their personal feelings compromise patient care. Prisoners are vulnerable members of society and it is the doctor’s duty to make difficult decisions about treatment whilst keeping the patient’s best interests at heart.
What is forensic psychiatry?
Forensic psychiatry is a diverse sub‐specialty of psychiatry where psychiatrists treat patients involved with the criminal justice system. There are a number of settings in which patients can be referred to forensic health services‐ at the time of arrest, during court proceedings, or if they become ill in prison. Forensic psychiatrists work in a number of settings that include low secure, medium secure, high secure units, prisons and within the community. Secure units are secure psychiatric wards that are usually located outwith a prison facility. The clear division between custodial and treatment services for prisoners makes forensic psychiatry unique to the United Kingdom.
The challenges of managing forensic patients
One of the challenges in a forensic setting is that prisoners present a high healthcare need. Offenders have very high rates of mental health problems with recent estimates suggesting that up to 90% of individuals serving custodial sentences have some form of diagnosable mental health condition.2‐3 Mental health problems range from severe psychosis to mild anxiety and rates of suicide and self‐harm are high. The number of self‐harm incidents in England and Wales in 2010 was 26,983, continuing an overall upward trend.4 The
management of these conditions is often complicated by alcohol and substance abuse problems, with half of all prisoners in 2009 saying that they were drunk at the time of their offence.5 Subsequently, dual diagnosis and treatment is key. Whilst some prisoners require to be transferred to a secure unit, the majority will be managed in a prison setting. The use of secure units and transfer of patients presents its own challenges. Secure units have the ability to forcibly treat patients, much like being sectioned in a hospital ward. However, there are a limited number of hospital beds and there is often strict exclusion criteria in place to protect service provision.2 For example the patient must have a treatable condition so it would be unusual for a patient with severe personality disorder to be placed in a secure unit. Therefore, assessments and transfers can take time, with delays affecting patient care. In the meantime, it is the difficult task of prison healthcare professionals to keep a patient safe, from themselves and others until a bed can be found. A large proportion of a professional’s time can be taken up by a small number of patients suffering with severe mental illness. However, low‐level mental health problems such as personality disorder, depression and anxiety can flourish in prison and often go undetected.1‐3 A number of factors including distance from home, frustration at the present situation and anxiety about the future all contribute to mental wellbeing. This is known to be a particular problem for female prisoners as female only prisons are few and far between meaning that prisoners are often hundreds of miles away from their family. In addition, poor physical health of patients with mental health conditions is well documented and the inextricable link between physical and mental health cannot be denied.6‐7 Patients have an increased mortality and morbidity associated with a range of physical conditions. For example, cardiovascular disease including type 2 diabetes is strongly associated with schizophrenia and depression.7 Lifestyle factors (smoking, poor diet, little exercise), medication side effects and inadequate physical healthcare all contribute to the poor physical health of a patient with mental illness.7 Smoking related illness continues to be the most likely cause of death for offenders.7 The rates of blood borne diseases (HIV & hepatitis) are high among prisoners with research in 1997 showing that HIV rate for men in prison is fifteen times higher than the general population and hepatitis C rate is twenty times higher than the general population.8 With the continuing practices of sharing injecting equipment, unprotected sex and tattooing in prison, it is important to recognise that blood borne viruses are an on‐going issue. Importantly, prison provides a safe environment to screen patients and provide them with counselling. Doctors play a vital role in helping psychiatric patients manage their physical conditions. It has been reported that GPs and psychiatrists are poor at treating physical conditions in all psychiatric patients.6 Proposed suggestions to combat this include increased education and awareness among doctors, standardization of assessment and incentives for detection and treatment of physical illness such as the Quality Outcomes Framework targets.6 Chronic medical conditions require patients to maintain a self‐care regime in order to manage symptoms and prevent disease progression that can be hindered by a mental health condition. Extra support, in prison and in the community, needs to be available so that these patients have a point of access to care when they are struggling to maintain their physical health due to mental health problems. One step is ensuring that on release all prisoners are registered with a GP. This would be a major improvement as 50% of prisoners are not registered with a GP prior to being sentenced and the same amount will not be registered on release.9 GP registration is essential for continuity of care and compliance with
treatment regimens started in prison. Detecting and treating physical and mental health problems within the prison population can be difficult. However, prison can provide an ideal environment for treating patients as there is time available to build a therapeutic relationship. This can prove especially important for patients with a dual diagnosis, who need concurrent treatment for more than one condition. This also provides an opportunity for the combination of pharmacological and psychological intervention.1 As a medical student it is important to carefully consider the mental health of a prisoner or former prisoner and any evidence to suggest that it is changing. The physical health of these patients must be even more carefully scrutinized as patients are more likely to experience physical problems which they may not readily communicate.7
Forensic Psychiatry in the Media
The challenges within forensic psychiatry has recently come under scrutiny after the publication of conflicting court reports in the trial of Norwegian Anders Behring Breivik who shot 77 people in two attacks in Norway 2011.10‐13 The first report published after observing and talking to the patient for weeks concluded that Breivik was suffering from paranoid schizophrenia when the car bomb and shootings took place.10 This report led to an outcry by the victims’ families who wanted Breivik held accountable for his actions.10 A second report concluded that Breivik suffered personality disorders but that he was not psychotic and subsequently should be held accountable for his actions.10 Due to the conflicting reports it was left to the court to decide whether Breivik should be sent to prison or a secure psychiatric unit.10
This highlights the apparent difficulty of assessing psychiatric patients. Diagnosis is subjective and based on observations and interaction with the patient at a specific time. Unfortunately, there are no physical tests that can confirm a diagnosis. Strict legal criteria are in place for a plea of insanity to be considered and these reports were challenging this legal definition in Norway.11 The debate surrounding Breivik’s mental state is whether he was psychotic at the time of committing the crime or suffers from a personality disorder and is thus accountable for his actions. Latterly, it seems that the debate is whether fanaticism, which Breivik presents through his extreme beliefs, is a form of madness comparable to being delusional.12
Norway and the United Kingdom (UK) have different legal systems and although Norwegian courts can disregard forensic psychiatry reports it is rare for them to do so.11 Due to Norwegian law the question of psychosis is crucial. Within the UK, for a plea of criminal insanity to be considered Breivik must have carried out the killings specifically because of his psychosis or he would have to serve a jail term.12 Breivik has stated he was aware what he was doing was illegal and so in the UK it would be unlikely that he could use this plea. The Norwegian legal system differs and if the accused was psychotic at the time of the incident that makes him exempt from punishment regardless of whether psychosis was the direct cause of his actions.12‐13 This area of Norwegian law has been debated in the past and Breivik’s case has once again brought this debate to the for‐front of criminal law. Fundamentally the problem come down to the definition of insanity. Editors Note:‐ On the 24th of August Brevik was sentenced to 21 years in jail after the court concluded that Brevik was sane at the time of his offence.13
As medical students and future doctors it is inevitable that we will be involved with the care of patients currently within or previously involved with the criminal justice system. Being
aware of the physical and mental health risks and the barriers to accessing care is key for this group of patients to effectively address their healthcare needs. Ill health, whether mental or physical, does not happen in isolation and social exclusion, unstable social relationships, unemployment and homelessness all contribute to a patient’s overall state of wellbeing. A holistic approach is especially important in these cases to promote recovery. Planning, continuity of care and integration between different service providers needs to be addressed to help tackle complex problems presented by service users and to allow the good work to continue when they leave prison. The prison environment presents its own set of specific challenges and is an interesting and stimulating environment to work in. Indeed, the recent case in Norway highlights some of the inherent challenges within this field. Lastly, I return to my original question: are these people a prisoner or patient? As doctors we have a duty of care to each person we meet. When working in the prison environment we must always remember that these people are patients first and prisoners second, our priority is their health and the fact that they are incarcerated at the present time should not affect the delivery of healthcare.
References 1. 2.
3. 4. 5.
6. 7. 8. 9. 10. 11. 12. 13.
Hughes LD (2012). Psychosocial treatments for depression in UK Criminal Justice – A Review of the Evidence. Scottish Universities Medical Journal. EPub 008 Department of Health (2005) Offender Mental Health Pathway, London: DH. Accessible from: www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/D H_4102231 Royal College of Nursing (2009). Health and nursing care in the criminal justice service: Guidance for Nursing Staff. RCN Publications London. Ministry of Justice (2011). Safety in Custody 2010 England and Wales. Accessible from: http://www.justice.gov.uk/downloads/statistics/prison‐probation/safety‐custody‐2010.pdf National Services Scotland (2011). Alcohol statistics Scotland 2011. Accessible from: http://www.alcoholinformation.isdscotland.org/alcohol_misuse/files/alcohol_stats_bulletin_ 2011.pdf Druss, B.G. and Walker, E.R., (2011). Mental disorders and medical co‐morbidity. Research Sythesis Report No. 21 Feb 2011 Osborn, D.P.J., (2001). The poor physical health of people with mental illness. Western Journal Medicine, (175) pp.329‐332. Department of Health (1998), Prevalence of HIV in England and Wales 1997. London: Department of Health. Social Exclusion Unit (2002) Reducing re‐offending by exprisoners. London: Social Exclusion Unit. Bevanger, L., (2012). Breivik trial: Psychiatric reports scrutinized. BBC. Accessible from: http://www.bbc.co.uk/news/world‐europe‐18440743 Anda, L.G., (2012). Breivik trial forces Norway to look again at insanity. BBC. Accessible from: http://www.bbc.co.uk/news/world‐europe‐17936894 Taylor, M. and Fahy, T., (2012). Do cases like that of Anders Breivik show that fanaticism is a form of madness? BMJ, (345) pp.24‐25. Bevanger, L. (2012). Anders Behring Breivik: Norway court finds him sane. BBC. Accessible from: http://www.bbc.co.uk/news/world‐europe‐19365616
The author wishes to thank Dr Audrey Morrison (Consultant Psychiatrist, NHS Tayside) for her support in an application to the Royal College of Forensic Psyhciatry for support to attend their annual conference earlier this year.
Your NHS‐ Myths Debunked and the Reforms Explained
Josh Coats (4th year MBChB; BMSc) Benedict Warner (4th year MBChB; BMSc) Correspondence to: Josh Coats: J.T.Coats@dundee.ac.uk
MEDSIN GLOBAL HEALTH SERIES
By the time the Health and Social Care Bill passed into law, becoming an Act, on 20th March 2012, it had garnered almost universal condemnation, with unprecedented agreement between the medical Royal Colleges, the British Medical Association, the Royal College of Nursing, the Royal College of Midwives, and many others – not forgetting nearly 180,000 signatures on the ‘Drop the Bill’ Government e‐petition (the second‐most signed petition on the site). The Bill, from a government that had promised ‘no top‐down reorganisations of the NHS’ at the last general election, represented a glaring democratic deficit. But how did such widespread opposition fall on deaf ears? Perhaps part of the failure of the opposition to the reforms was the difficulty in forming an adequate counter‐argument to the huge variety of issues raised by the Health and Social Care Bill. In this article, we will outline the key policies of the reforms and some of their potential consequences as well as indicating how students and citizens may become more involved in the future direction of the NHS.
Key Words: NHS; reforms; politics
Some myths debunked
“The NHS is too expensive!” Healthcare is expensive, but the NHS, when compared by percentage of gross domestic product spent on health with countries with similar outcomes, is very good value for money.1 Indeed, the head of health at the OECD, a think‐tank funded by wealthy governments, called the NHS one of the best performers in the world, and believes it would have even better outcomes were it not for the regular reforms brought on by successive governments.2 “An ageing population makes reform essential” Many politicians, when referring to the NHS, acknowledge that reform is inevitable due to the ageing population. However, the assumption that an ageing population makes the NHS unsustainable is not backed up by evidence. A UCL School of Pharmacy report suggested that an ageing population may even reduce the costs to the NHS, if such ageing is healthy. Indeed, increased life expectancy can increase the economic contribution of individuals, and need not be accompanied by increased morbidity – a concept known as ‘compression of morbidity’.3 “The NHS is failing!” Levels of public confidence and satisfaction in the NHS were higher than in any other country in a recent study by the Commonwealth Fund.4 The same study also found that accessibility of healthcare was highest in the UK. In another survey in Autumn 2010 by Ipsos MORI, more members of the public than ever believed the NHS was doing a good job.
However, the results of this latter survey were not published by the Government for over 6 months before they were eventually leaked; instead, the Department of Health showed results from 2007 on its website.5 The NHS has also been attacked for declining productivity that again warrants NHS reform. However, Nick Black, from the Department of Public Health and Policy at the London School of Hygiene and Tropical Medicine argued that productivity has probably increased over the past decade, and that the ONS analysis that had claimed decreased productivity had underestimated improvements in quality.6 “The reforms will cut bureaucracy” While the reforms carry out the Conservatives’ pre‐election promise to scrap two tiers of bureaucracy in the NHS (the Strategic Health Authorities and the Primary Care Trusts [PCTs]) they will be replaced by two new ones, in the form of the National Commissioning Board and hundreds of Clinical Commissioning Consortia. An arbitrary cut set at 45% in the amount spent on management costs is included in the Bill, but many of the commissioning tasks previously undertaken by PCTs will simply be outsourced by GPs too busy to take on the role, to the profit of private consultancy companies such as McKinsey and KPMG. However, it should be noted that charities (or the tertiary sector) are also competing for outsourced NHS services in addition to private companies. For example, the UK charity Whizz Kidz can provide a fitted wheelchair for a child more quickly than the NHS in parts of the UK for 80% of the cost.7 However, a recent Lancet article noted concern that the reform provides no economic protection to charities to enable them to make bids which are likely to be competitive with private healthcare companies.8 The authors suggest that without such financial protection from the state, charities will be almost always be out‐competed by private companies.8 “The reforms do not increase privatisation” The reforms abolish a cap on the proportion of beds available for private patients within NHS Foundation Trust hospitals. The previous limit was 2% and the Health and Social Care Act has raised this to 49%.9 Whether this will increase the number of private patients being treated within the NHS is still being debated but there can be no doubt that there is potential for this and the potential for this to be to the detriment of the care of NHS patients.
What do the reforms aim to do, and why?
In July 2010, the newly elected coalition Government published a White Paper entitled ‘Equity and Excellence: Liberating the NHS’, which set the agenda for the next 5 years. This was the first hint of the upheaval that was to come. Over the following months, the Bill had a stormy ride, with an unprecedented ‘listening pause’ in the face of mounting opposition. Despite this, the Act that passed into law contained many of the most worrying aspects of the Bill. The Health and Social Care Act is a vast piece of legislation, longer than the one that established the NHS in 1948. It was widely touted as giving power to GPs by handing over 80% of the £100 billion NHS budget to GP‐led Clinical Commissioning Groups (CCGs) and dismantling the PCTs that had previously been responsible for commissioning services. It was also intended to reduce the cost of NHS management and bureaucracy by scrapping the 10 Strategic Health Authorities that were responsible for enacting the Department of Health’s directives and implementing fiscal policy at a regional level.
These twin aims, empowering GPs and reducing bureaucracy, were broadly welcomed. But the Act went far further in its reach, and it was frequently these less publicised effects that were belatedly objected to by professional bodies and, eventually, by the public.
A significant change that the Bill introduced was a removal of the Secretary of State for Health’s overall responsibility for the NHS. Although he will still have a duty to ‘promote’ a comprehensive health service, the duty to ‘provide’ has been removed. As Pollock et al. argue in the BMJ, in transferring this duty to CCGs, who are not bound to provide the same statutory services that PCTs currently are, this provides the legal basis for a reduction in the health services provided for free on the NHS.10
What are the potential consequences of the reforms?
Part of the problem with assessing the potential consequences of the reforms is that we simply do not know what they might be. In preparing the legislation, the Department of Health drew up a register of anticipated risks, ranked according to likelihood and severity for each risk. However, despite repeated Freedom of Information requests, and a direct instruction by the Information Commissioner that they must release this risk register in the public interest, the Government has refused to do so. Many academics, however, have been analysing the Bill for its implications, and have drawn some disturbing conclusions. An academic analysis from the London School of Hygiene and Tropical Medicine describes how the reforms are best understood from the perspective of a narrative based upon the past track record of Conservative MPs such as Oliver Letwin and John Redwood. Both MPs laid out plans for increasing privatisation within the NHS as part of the Conservatives internal market scheme of the 1980s and 1990s.11 The previous history of the Conservative party politicians and political discussions to date, suggests that the ‘liberation’ of the NHS described by the original White Paper does not refer to the liberation of clinicians from red tape, but rather of the £100 billion budget from the public sector to the private.2,8 Another worrying development is the abolition of area‐based responsibilities, in favour of responsibility for registered patients who may be drawn from anywhere in the country. This represents a move towards insurance‐based provision, and patients who may not be registered with a GP (e.g. the homeless or undocumented migrants) may not be accounted for. As CCGs will receive capitation fees approximating to £2,000 per patient registered with them, it is not a huge step to consider individual patients with anticipated higher health costs being invited to ‘top up’ their insurance contributions.11 Healthcare will once more be provided according to ability to pay, rather than medical need.
What can you do?
The reforms represented a democratic failure – a ‘top‐down reorganisation’ for which the coalition government had no mandate, and which, in the face of widespread opposition, flatly contradicted Andrew Lansley’s much touted slogan, ‘no decision about me, without me’. Thanks in part to the influence of the Liberal Democrats on the Health and Social Care Act, however, certain institutions were introduced to allow greater democratic control over parts of the NHS – although still a far cry from the democratically accountable service Nye Bevan had envisaged. These include Health and Wellbeing Boards and HealthWatch. Many have argued that even these are toothless.10 For example, it is very hard to see how such channels could have been used to challenge Virgin’s contracts to deliver healthcare in Surrey, signed almost immediately after the Health Bill passed. However, despite these institutions being limited, engaging with these bodies can help challenge the disintegration of the NHS. This
process can work as the transfer of services out of the NHS in Gloucestershire were successfully challenged by a local pensioner who took the PCT to court.12 There are other ways citizens can get involved in shaping the future of the NHS. The passage of the Health and Social Care Bill was challenged throughout its journey through Parliament, and student activism played an important role in keeping it in the headlines. Medsin‐UK, a student network which campaigns on local and global health inequality issues, succeeded in collecting 2,000 medical students’ signatures representing every medical school in the country in under 36 hours, for a petition to drop the bill, and delivered it in person to Downing Street (Fig 1). The 38 Degrees movement, a large online campaigning community with close to one million members, raised funds to erect billboards and provide thousands of leaflets to raise greater awareness of the Bill. UK Uncut, an organisation which aims to promote alternatives to the government’s current deficit‐reduction plan through direct action, arranged a protest to “Block the Bridge, Block the Bill”, encouraging thousands of people to occupy Westminster bridge, which links the Houses of Parliament to St. Thomas’ Hospital across the Thames, in October 2011. Such public engagement needs to be carried forward, despite the passage of the Bill into law. Agenda setting on health remains the domain of the think‐tanks and sponsors who influence Government policy.11 The Peoples’ Health Movement, a movement of citizens and health care professionals from across the world, aims to return the initiative to the public. In India, they convened thousands of village meetings to build a Peoples’ Health Manifesto before elections, and succeeded in translating this into government policy when a coalition government was elected. It is time that such a manifesto emerged here in the UK, set apart from party politics and coming from the people, not the management consultant firms that stand to benefit from the increased outsourcing of commissioning within our NHS. The public know what they would like to see from the NHS. We all share and value the same principles of an equitable, tax‐funded system providing care according to need. But while we remain excluded from the process of policy‐making, we can only look on as the NHS continues in the opposite direction.
Figure 1 – Committee Members of Medsin handing over the petition to ‘Drop the Bill’ to Downing Street
2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.
OECD Health Data 2011 ‐ Frequently Requested Data [Internet]. Organization for Economic Cooperation and Development. [cited 2012 Jun. 11]. Available from: http://www.oecd.org/document/16/0,3746,en_2649_37407_2085200_1_1_1_37407,00.html Ramesh R. Coalition health bill will undermine NHS, says OECD thinktank | Society | The Guardian [Internet]. The Guardian. [cited 2012 Jun. 11]. Available from: http://www.guardian.co.uk/politics/2011/nov/23/health‐bill‐nhs‐oecd‐report Kmietowicz Z. Ageing population is not a drain on economy or NHS, says report. BMJ. 2012 Apr. 24;344(apr24 4):e2934–4. Ingleby D, McKee M, Mladovsky P, Rechel B. How the NHS measures up to other health systems. BMJ. British Medical Association; 2012;344. Helm T. Andrew Lansley accused of burying poll showing record satisfaction with NHS | Society | The Observer [Internet]. The Guardian. [cited 2012 Jun. 10]. Available from: http://www.guardian.co.uk/society/2011/mar/19/nhs‐andrew‐lansley‐healthcare‐reform Black N. Declining health‐care productivity in England: the making of a myth. Lancet. 2012 Mar. 24;379(9821):1167–9. Frontier Economics (2011). Impact of Whizz‐Kidz support to Primary Care Trusts ‐ An Evaluation (Oct 2011). Reynolds L & McKee M (2012). "Any qualified provider" in NHS reforms: but who will qualify?. The Lancet. Mar. 379;9821. p.1083‐1084. Briggs H. BBC News ‐ “Planned 49% limit” for NHS private patients in England [Internet]. BBC. [cited 2012 Jun. 11]. Available from: http://www.bbc.co.uk/news/health‐16337904 Pollock A, Price D. Health and Social Care Bill 2011: a legal basis for charging and providing fewer health services to people in England. BMJ. 2012. Reynolds L, Lister J, Scott‐Samuel A, McKee M. Liberating the NHS: source and destination of the Lansley reform. 2011. BBC News ‐ NHS Gloucestershire settles legal battle out of court [Internet]. BBC. [cited 2012 Jun. 11]. Available from: http://www.bbc.co.uk/news/uk‐england‐gloucestershire‐16966274
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Prediction of In‐Hospital Mortality in Acute Exacerbations of COPD Ross Archibald (4th year MBChB, BSc (Hons)), James Chalmers (Clinical Lecturer), Tom Fardon (Consultant Respiratory Physician), Philip Short (Clinical Research Fellow), Pete Williamson (Consultant Respiratory Physician), Joanne Taylor (5th year MBChB), Aran Singanayagam (SpR Respiratory Medicine), Louise Peet (4th year MBChB, BMSc), Muhder Al‐Khairalla (Consultant Respiratory Physician) & Stuart Schembri (Consultant Respiratory Physician). : Correspondence to: Ross Archibald firstname.lastname@example.org
Background: Physicians lack a robust and validated method of measuring severity or predicting poor outcome in patients with acute exacerbation of COPD (AECOPD). Such a predictive tool would allow optimisation of treatment plans for these patients, as well as best use of health care resources. Objective: To determine predictors of in‐hospital mortality in AECOPD, and develop a predictive scoring system to identify patients at higher risk of in‐hospital mortality. Methods: Analysis of clinical patient data from the exacerbations of obstructive lung disease managed in UK Secondary care [EXODUS] study database, collected from 11 UK hospitals. Results: A total of 1031 patients were included in the validation cohort. The in‐hospital mortality rate was 5.2%. Independent predictors of mortality were identified and a new scoring system (“CAUDA70”), for prediction of in‐hospital mortality in AECOPD was derived. The score incorporated 6 easily obtained clinical variables: acidosis, albumin, urea, the presence of confusion, MRC dyspnoea score and age. The score displayed strong discrimination, with an area under the receiver operating characteristic (ROC) curve of 0.84. This performance was reproduced in a further validation dataset of 312 patients. The discrimination of the new score exceeds that of existing scores validated for use in AECOPD (CURB65, CRB65 and BAP‐ 65). Conclusion: A new scoring system composed of six readily available clinical variables can accurately predict in‐hospital mortality in AECOPD.
Key Words: Respiratory Medicine; Acute Medicine; Predictive Tools; Chronic Obstructive Pulmonary Disease
Chronic Obstructive Pulmonary Disease (COPD) represents a significant burden in terms of morbidity and mortality, accounting for nearly 6% of deaths globally in 20081. In the UK, COPD is a leading cause of mortality, accounting for over 29,000 deaths in 20082 and ranked as the 5th leading cause of mortality in England and Wales in 20053. At present, there is no established method of predicting mortality risk amongst patients admitted to hospital with acute exacerbation of COPD (AECOPD), and current national guidelines do not recommend the use of a severity tool for this purpose4. Forced expiratory volume in one second (FEV1) is often used to gauge disease severity in COPD, but is not a reliable predictor of mortality5. Variables which have been commonly linked to an increased risk of in‐hospital mortality in AECOPD have included age6,7, heart rate7,8 and serum creatinine8,9, sodium8,9 and urea7,8. However, one review paper notes that there is a wide variation in prognostic variables between studies10, which may be related to differences in the characteristics of patient cohorts, clinical variables recorded and the geographical setting of different studies. In addition, although some overlap exists, prediction of post‐ discharge and in‐hospital mortality in AECOPD appears to involve distinct clinical variables10. In addition to identifying prognostic predictors in AECOPD, a number of groups have formulated clinical prediction tools, although as yet, none have been validated in independent cohorts or accepted into clinical practice. One such study of a large cohort of patients with AECOPD developed and validated a risk score for prediction of in‐hospital mortality or the need for invasive mechanical ventilation (BAP‐65) involving age, heart rate, serum urea and acute onset confusion7. A further study identified predictors of risk of in‐ hospital mortality and the need for post‐hospital support in initially non‐life threatening AECOPD admissions6. These factors were patient age, cyanosis, impaired neurological status, lower limb oedema, asterixis (flapping tremor), use of accessory inspiratory or expiratory muscles, and dyspnoea grade in the stable state. Whilst this study led to derivation of a prediction score with good discrimination, this was done without certain important clinical data (e.g. arterial blood gases), as well as specifically targeting patients admitted to emergency departments within a fairly short time frame6. Another study derived a simple equation to predict death and the need for mechanical ventilation in AECOPD9. However, the cohort studied was relatively small and drawn from a tertiary referral centre, with a relatively high number of patients with severe disease9. Further studies producing outcome prediction models for hospital mortality in AECOPD have only included high‐risk patients admitted to ICU/HDU8,11 or have only predicted survival for an extended period following admission8,11,12. Clinical prediction tools have proven useful in other acute respiratory diseases, such as community acquired pneumonia (CAP). The CURB65 score was derived and validated for use in CAP13 and is a severity score that has been widely adopted in clinical practice14. A similar bed‐side prognostic tool to CURB65 may be equally useful in AECOPD in order to stratify patients by risk and target their management more effectively, a view recognised by at least two other research groups15,16. A retrospective study found that this score also predicted short‐term mortality in AECOPD15. The simplified version of this score, CRB65, has also been validated for use in AECOPD, showing modest performance as a predictor of short‐term mortality16. Both studies suggest that these scores have similar efficacy in predicting short‐ term mortality in AECOPD patient cohorts to CAP cohorts15,16. Despite extensive research into important clinical parameters in AECOPD, we still do not have the ability to accurately predict outcomes such as mortality in a hospitalised patient. None of the models developed thus far for this purpose have been recommended by
guidelines, and none having undergone extensive external evaulation6,7,9, thus making conclusions on whether rules may be clinically useful across different patient populations impossible. It is proposed that the development of a clinically useful prediction tool for in‐hospital mortality in AECOPD may allow more effective disease classification on admission, as well as optimisation of subsequent management and resource allocation decisions.
Study database and data collection This study uses data collected in EXODUS (Exacerbations of Obstructive Lung Disease managed in UK Secondary care), a prospective observational study of patients with a diagnosis of COPD exacerbation, hospitalised for more than 12 hours in a UK hospital. Patients were enrolled for inclusion in EXODUS using a standard proforma, and anonymous data held on a secure NHS server. Enrolment took place at the following hospitals: Royal Infirmary of Edinburgh, Western General Hospital (Edinburgh), St John’s Hospital (Livingston), Borders General Hospital (Melrose), Perth Royal Infirmary, Ninewells Hospital (Dundee), Victoria Hospital (Kirkcaldy), St Mary’s Hospital (London), Doncaster Royal Infirmary, Milton Keynes General Hospital and John Radcliffe Hospital (Oxford). The EXODUS study has been approved by the Lothian Research Ethics Committee (LREC), and local Caldicott Guardian approval was obtained for each participating centre. Patient case selection This study uses data obtained from patients enrolled in the EXODUS study between November 2009 and January 2012. Selection bias was minimised by ensuring that enrolment occurred in a consecutive manner. Inclusion criteria for the EXODUS database are: • • • •
Age >40 years. Presentation to hospital from the community with a primary diagnosis of AECOPD. Symptom(s) of exacerbation (e.g. increasing breathlessness) in a patient with known (confirmed by spirometry) COPD, OR: Symptom(s) of exacerbation (e.g. increasing breathlessness) in a patient aged >40 years with a history of cigarette smoking in which the diagnosis of COPD can be confirmed by spirometry during or subsequent to the hospitalisation.
Exclusion criteria for the EXODUS database are: • • • • • •
Age <40 years. Hospitalisation primarily for a reason other than COPD, e.g. pulmonary embolism, congestive cardiac failure, acute myocardial infarction. Elective hospitalisations, such as for CT‐guided lung biopsy, or intravenous antibiotic eradication of Pseudomonas aeruginosa. Airways disease primarily due to a cause other than COPD (severe asthma, bronchiectasis, allergic broncho‐pulmonary aspergillosis). Interstitial lung disease. Patients in whom active treatment is not considered appropriate (palliative care). This includes patients not treated with steroids, antibiotics or other active measures. (Patients with DNAR orders, or “not for ICU orders” but who are otherwise actively treated ARE included.)
Selection and measurement of variables EXODUS collects routinely available demographic, clinical, laboratory, management and outcome data for patients with AECOPD, shown in Table 1. Most of this data was available from standard hospital clerk‐in proformas used for new patient admissions. Where possible, all measurements in the EXODUS database were those first recorded on presentation to hospital, and all clinical variables (e.g. blood pressure, pulse rate) were recorded within 6 hours of admission to hospital. The outcome of interest in this study was in‐hospital mortality. Statistical methods All data were analysed using SPSS version 13 for Windows. The derivation cohort was made up of consecutive patients from all enrolling hospitals from November 2009 to November 2011. The validation cohort was made up of consecutive patients from Edinburgh and Tayside collected between January 2011 and January 2012. Table 1
Variables recorded in EXODUS study
Age & Gender
Current medication use
COPD background data
Long term O2 therapy (LTOT)
Medical Research Council (MRC) dyspnoea grade when well Asthma and bronchiectasis
Exacerbations in last year
Clinical & Lab Data
Blood tests/Chest x‐ray abnormalities Treatment prior to admission
Treatment on admission
Duration of admission
Respiratory treatments (e.g. mechanical ventilation) Microbiology results
Complications (e.g. MI, stroke, GI bleed, MRSA/C.difficile infection)
Descriptive statistics for demographic and clinical variables are presented as median (interquartile range) unless otherwise stated. Demographic, clinical, laboratory and radiographic variables were converted to binary variables, as in previous studies, based on cut‐offs identified in the published literature. The following cut‐offs were applied: age >70 years, pulse >100 beats per minute, respiratory rate >30 breaths per minute, systolic blood pressure <90mmHg, temperature >38oC, Hb <11.5g/dL, WCC >12x109/L, Na <135mmol/L, urea >7mmol/L, pH <7.35, glucose >7mmol/L, albumin <35g/L. Odds ratios were calculated for each variable, presented with 95% confidence intervals in brackets. The univariate tests used to analyse the categorical and numerical data were the chi‐square (χ2) test and Mann‐Whitney U test respectively. For multivariate analysis, statistically significant candidate variables were entered into a multivariate logistic regression model using a backward stepwise approach. The methodology used to develop the regression model is similar to those used to develop other severity scores6,11. In clinical practice, simple and easy to use scoring systems are more likely to be used than those based on multiple factors. Therefore, a prediction score was constructed by beginning with several simple scores involving four of the strongest predictors of mortality derived from multivariate analysis. Further mortality predictors were added in sequence to the scores with the best combination of sensitivity and specificity, allowing identification of the simplest scores with the greatest overall predictive accuracy. The area under the receiver operating characteristic curve* (AUC) was then assessed for the best performing scoring systems in order to test discriminatory power. The approach described by Hanley and MacNeil17 was used to compare the ROC curves. A 2‐tailed p‐value of <0.05 was considered statistically significant for each analysis.
A total of 1343 patients were included in the study. 1031 patients (77%) were assigned to the derivation cohort with 312 patients (23%) assigned to the validation cohort. The in‐ hospital mortality rate was 5.2% (54 deaths). 10.4% of the derivation cohort received ** assisted ventilation with all but 7 of these patients receiving bi‐level ventilation . Patient characteristics Selected patient characteristics and clinical variables are displayed in Table 2. The median age in the derivation cohort was 74 years old. 33% of patients were current smokers, 7% had long‐term oxygen therapy, and 4.1% were resident in a nursing home. In terms of respiratory disability, 63.6% of patients were classified as having a MRC Dyspnoea score of 4 or 5. Significant co‐morbidities included ischaemic heart disease (30.7%) and congestive cardiac failure (21.8%).
ROC curves graphically represent how well a diagnostic test discriminates, or separates individuals into two classes; in this case, survivors and non‐survivors. The maximum value for the AUC is 1.0, indicating a perfect test (i.e. 100% sensitive and 100% specific). ** Also known as bi‐level positive airway pressure (BiPAP, this form of mechanical ventilation aids the inspiratory phase of the respiratory cycle by delivering high pressures during inspiration, and lower pressure during expiration. This allows retained carbon dioxide to be expired as a result of the positive end‐expiratory pressure ‘stenting’ the airways open.
Clinical and laboratory variables On initial presentation, confusion was recorded for 12.9% of patients. 14.4% of patients had a heart rate of >125 beats per minute, and 33% had a respiratory rate of >30 breaths per minute. A systolic blood pressure of <90mmHg was seen in 7.3% of the cohort. The median temperature on presentation was 37.1oC. Characteristics of patients in the derivation cohort
COPD background information # FEV1 predicted Mean 46% (SD 19%)
74 (IQR* 63‐75)
529 males (51.3%) 502 females (48.7%)
33.0% current smokers 7.0%
MRC dyspnoea grade when well I
13.9% # *IQR – interquartile range SD – standard deviation
Nursing home resident
In terms of laboratory findings, 8.6% of patients had a haemoglobin concentration of <10.5g/dL, and 60.3% had a white blood cell count of >12x109/L. Sodium levels were found to be <135mmol/L in 26.4% of the cohort, with 52.9% having a blood urea level of >7mmol/L. In 10.5% of patients, blood albumin was recorded as <35g/L, and in 36.3%, blood glucose was >7mmol/L. Factors associated with in‐hospital mortality Table 3 shows the factors associated with in‐hospital mortality on univariate analysis, and the number of surviving and non‐surviving patients for whom each variable is positive. Table 4 presents the results of multivariate logistic regression analysis where all statistically significant univariate predictive variables were entered into the model. Table 3
Factors associated with mortality in the derivation cohort
Univariate odds ratio
Univariate odds ratio
2.44 (95% CI from 1.3 to 5.2)
MRC dyspnoea ‐ score MRC dyspnoea ‐ score
Systolic blood pressure
37.3 (36.9‐ 38.1)
37.1 (37.0‐ 38.0)
Smoking status 15 (27.8%)
White cell count
14.5 (9.2‐17.8) 13.5 (9.9‐17.6) 0.81 (0.47‐1.41)
Nursing home resident
11.0 (7.5‐15.1) 7.2 (4.9‐10.2)
45.7 (38.0‐ 60.2)
31.5 (27.3‐36. 0)
Development of prediction score Figure 1 describes the predictive score developed using six of the independent predictors of mortality in Table 4. One point was assigned to each variable present, giving a six point scoring system. Table 5 compares the prediction characteristics of the new score against those of existing prediction scores validated for use in prediction of in‐hospital mortality in AECOPD. Table 6 presents the mortality and survival for each scoring level of the new prediction score. Mortality strongly increased with increasing prediction score in the derivation cohort. The prediction score showed strong discrimination for in‐hospital mortality, with an AUC of 0.84 (Figure 2). Table 4
Independent predictors of mortality in the derivation cohort
Multivariate odds ratio
5.09 (2.69 – 9.61)
3.06 (1.24 – 7.55)
2.41 (1.19 – 4.89)
MRC dyspnoea >4
2.61 (1.08 – 7.16)
2.43 (1.17 – 5.05)
2.15 (1.01 – 4.57)
2.77 (1.45 – 5.32)
2.04 (1.11 – 3.99)
2.11 (1.11 – 3.99)
Heart rate >125/min
2.11 (1.10 – 4.03)
2.25 (1.02 – 4.96)
Breakdown of new prediction score “CAUDA70”
Acidosis (pH <7.35)
1 point score
MRC Dyspnoea score >4 1 point out of 6
Age >70 years
Validation of prediction score When tested in the validation cohort of 312 patients, the new scoring system reproduced a similar performance as in the derivation cohort, with a sensitivity of 89.3%, a specificity of 59.7% (using a predictive score of 3 or greater for a positive result), and an AUC of 0.84 (95% C.I. 0.80 – 0.89). Table 5
Performance of CAUDA70 score in derivation cohort versus existing prediction scores
Sensitivity* % Specificity* % Positive predictive value %* Negative predictive value %* Area under the ROC curve (AUC)
Prediction score New score CURB‐65
87.04 64.38 12.57 98.83
55.56 81.15 14.78 96.88
53.70 83.66 16.20 96.85
*using score >= 3 for positive result, and score <= 2 for negative result
Table 6 Score
Mortality and survival at each scoring level of CAUDA70 score Number of in‐ hospital deaths (% mortality)
Number alive at Score discharge (% surviving)
Number of in‐ hospital deaths (% mortality)
Number alive at discharge (% surviving)
ROC curve for CAUDA70 score
True positive rate (sensitivity)
False positive rate (1‐specificity)
The principal result of the present study is the identification of strong predictors of in‐ hospital mortality in patients admitted with AECOPD. In addition, the study allowed derivation of a predictive scoring system based on these factors. To our knowledge, this prediction tool has the highest level of discrimination of any scoring system yet produced for prediction of in‐hospital mortality in AECOPD. These findings should help in determining which patients are at high risk of in‐hospital death, and whether they should be managed as an in‐patient or at home with early supported discharge. Predictors of in‐hospital mortality Only a small number of studies have previously derived predictive scoring systems for in‐ hospital mortality in AECOPD6‐9,11. The number of subjects used in these ranges from 1518 – 88,0747. The predictive ability of the scoring systems derived also varies with AUC values of 0.7188, 0.727, 0.739 and 0.796 respectively. Of these studies, one did not perform multivariate analysis7 and one was carried out with ICU/HDU patients alone8. None of these studies have been independently validated, subject to an impact analysis or implemented into clinical practice6‐9,11. It is useful to consider possible reasons why the six variables in the new prediction score correlate with in‐hospital mortality in AECOPD. It is likely that the majority of these variables represent significant organ dysfunction. For example, confusion, (which is also an important marker of poor outcome in community acquired pneumonia13), can arise in AECOPD due to hypercapnia, and may act as an indicator of the body’s response to underlying pathophysiological processes. Similarly, urea has also previously appeared as an important predictor of poor outcome in respiratory disease7,8,13. This may reflect acute kidney injury resulting from volume depletion due to hyperventilation or poor oral fluid intake prior to admission. It should also be noted that it was the pathophysiological markers of disease, rather than underlying co‐morbid conditions themselves, which were the strongest predictors of in‐hospital mortality in AECOPD. Development of prediction score During development of the predictive score, the cut‐off value separating a positive and negative result (i.e. high or low risk of in‐hospital mortality) was varied. As expected, when a score of greater than or equal to 2 was taken as a positive result, this resulted in a slightly higher sensitivity (96.3%) and much lower specificity (36.6%) than for a cut‐off of greater
than or equal to 3 (Table 5). As a result, the latter was deemed to have better clinical utility, owing to a better balance between sensitivity and specificity. In the single‐point scoring system described in Figure 1, patients with a score of 0‐1 are at low risk of death and are likely to be safely managed at home. Patients with a score of 2 are also at low risk but will need to be hospitalised if they are confused or acidotic. Scores of 3 or more indicate that a patient is at high risk of in‐hospital mortality, as the mortality at this level climbs to 14%. Scoring systems were tested which allocated two points each for confusion and acidosis, and one point for all other clinical variables. This was done as these factors, when present, are absolute indications for hospital admission. It was noted that mortality was very low in the group of patients scoring 0 or 1 point with the new predictive scoring system in Figure 1. It was supposed that if confusion or acidosis were instead scored with 2 points each, this might allow a further degree of certainty that any patient who scored 0 or 1 point (i.e. confusion or acidosis not present), was low risk and could be managed at home with early supported discharge. This more complex scoring system performed slightly better than the chosen scoring system, with an AUC of 0.85 (as opposed to 0.84). However, despite its slightly increased level of discrimination and a slightly lower mortality rate at low prediction scores, these were not deemed to be significant enough to outweigh the ease of use of the chosen single‐point scoring system. Limitations of present study Lung function tests results are commonly used to quantify the severity of COPD, and these could potentially be of interest in the assessment of mortality risk. However, the lung function test data collected in the EXODUS study were not used in the development of this predictive scoring system as this information is often unavailable to clinicians when a patient is admitted with AECOPD. As previously described, the conditions for measurement of arterial blood gases were kept consistent by using the first results available after admission to hospital. However, some degree of heterogeneity may have been introduced by variable use of supplemental oxygen across the patient group. This may in turn have influenced the predictive potential of variables dependent on this, such as acidosis. Although data from the EXODUS study is available for 90 day and 6‐month mortality, the present study does not assess the performance of the new scoring system in prediction of post‐hospital mortality. This would be required to more fully assess the ability of the new predictive score to quantify mortality risk, as well as the validity of subsequent management decisions such as the use early supported discharge. In addition, a large prospective study is required to externally validate the new scoring system.
This study presents a new scoring system (CAUDA70), predictive of in‐hospital mortality in patients presenting with acute exacerbation of COPD. The six variables included in the score are all easily obtainable clinically, and are very simple to translate to an overall severity score. Following external validation, this new scoring system may be useful in decisions on patient admission, discharge management and health care resource allocation.
1. World Health Organisation (WHO) World Health Statistics, Summary of Deaths by Cause in WHO Regions, 2008. 2. WHO World Health Statistics, Disease and Injury Country Estimates, 2008.
3. National Statistics, Health Statistics Quarterly No. 30, 2006, p53. 4. National Institute for Health and Clinical Excellence (NICE) Clinical Guideline 101 – Chronic Obstructive Pulmonary Disease: Management of chronic obstructive pulmonary disease in adults in primary and secondary care (partial update). Issue date: June 2010. 5. Celli B, Cote C, Marin J, Casanova C, Montes de Oca M, Mendez R, Plata V, Cabral H (2004). The Body‐Mass Index, Airflow Obstruction, Dyspnea, and Exercise Capacity Index in Chronic Obstructive Pulmonary Disease. N Engl J Med. 350(10): 1005‐1012. 6. Roche N, Zureik M, Soussan D, Neukirch F, Perrotin D (2008). Predictors of outcomes in COPD exacerbation cases presenting to the emergency department. Eur Respir J. 32: 953‐961. 7. Tabak Y, Sun X, Johannes R, Gupta V, Shorr A (2009). Mortality and Need for Mechanical Ventilation in Acute Exacerbations of Chronic Obstructive Pulmonary Disease. Arch Int Med. 169(17): 1595‐1602. 8. Wildman M, Harrison D, Welch C, Sanderson C (2007). A new measure of acute physiological derangement for patients with acute exacerbations of obstructive airways disease: The COPD and Asthma Physiology Score. Respiratory Medicine. 101: 1994‐2002. 9. Mohan A, Bhatt S, Mohan C, S. Arora S, Luqman‐Arafath T, Guleria R (2008). Derivation of a Prognostic Equation to Predict In‐Hospital Mortality and Requirement of Invasive Mechanical Ventilation in Patients with Acute Exacerbation of Chronic Obstructive Pulmonary Disease. Indian J Chest Dis Allied Sci. 50: 335‐342. 10. Steer J, Gibson G, Bourke S (2010). Predicting outcomes following hospitalization for acute exacerbations of COPD. Q J Med. 103: 817‐829. 11. Wildman M, Sanderson C, J. Groves J, Reeves B, Ayres J, Harrison D, Young D, Rowan K (2009). Predicting mortality for patients with exacerbations of COPD and Asthma in the COPD and Asthma Outcome Study (CAOS). Q J Med. 102: 389‐399. 12. Antonelli Incalzi R, Fuso L, De Rosa M, Forastiere F, Rapiti E, Nardecchia B, Pistelli R (1997). Co‐ morbidity contributes to predict mortality of patients with chronic obstructive pulmonary disease. Eur Respir J. 10: 2794‐2800. 13. Lim WS, van der Eerden M, Laing R, Boersma W, Karalus N, Town G, Lewis S, Macfarlane J (2003). Defining community acquired pneumonia severity on presentation to hospital: an international derivation and validation study. Thorax. 58: 377‐382. 14. Lim W, Baudouin S, George R, Hill A, Jamieson C, Le Jeune I, Macfarlane J, Read R, Roberts H, Levy M, Wani M, Woodhead M (2009). BTS Guidelines for the management of community acquired pneumonia in adults: update 2009. Thorax. 64 (supplement III): iii1‐55. 15. Chang C, Sullivan G, Karalus N, Mills G, McLachlan J, Hancox R (2011). Predicting early mortality in acute exacerbation of chronic obstructive pulmonary disease using the CURB65 score. Respirology. 16: 146‐151. 16. Edwards L, Perrin K, Wijesinghe Mm Weatherall M, Beasley R, Travers J (2011). The value of the CRB65 score to predict mortality in exacerbations of COPD requiring hospital admission. Respirology. 16: 625‐629. 17. Hanley JA, McNeil BJ (1983). A Method of Comparing the Areas under Receiver Operating Characteristic Curves Derived from the Same Cases. Radiology. 148(3): 839‐843.
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Pathogenesis and Management of Age‐Related Macular Degeneration
Clare Porte (1st year MBChB) Correspondence to: Clare Porte : C.I.Porte@dundee.ac.uk
Age related macular degeneration (AMD) was responsible for 8.7% of all blindness worldwide in 2007, and this figure is expected to double by 2020 as a result of population ageing. Macular degeneration is defined by the NHS as a painless disease that leads to loss of central vision and is an umbrella term that denotes many eye‐disorders which lead to loss of detailed vision, the most common being AMD. AMD is the most common cause of severe vision loss in industrialised countries, with more adult Americans being affected by AMD than cataracts and glaucoma combined. This article will outline the pathogenesis and discuss the clinical management of this common and serious ophthalmology condition. Key Words: macular degeneration; ophthalmology; education article
Age related macular degeneration (AMD) was responsible for 8.7% of all cases of blindness worldwide in 2007, and this figure is expected to double by 2020 as a result of population ageing.1 Macular degeneration is defined by the NHS as a painless disease that leads to loss of central vision and is an umbrella term that denotes many ocular disorders which lead to loss of detailed vision, the most common being AMD.2 Indeed, AMD is the most common cause of severe vision loss in industrialised countries with more adult Americans being affected by AMD than cataracts and glaucoma combined.3 The risk of developing AMD is in excess of 35% by the age of 75, and is increased by a family history of the disease or environmental factors such as cigarette smoking, nutritional deficiency, excessive sunlight exposure and hypertension.4 It could also present as the late‐onset of genetic disease, but age is the most significant of all risk factors.5 This article is a study of current research into the relevant anatomy and predisposing factors for the onset of AMD and the current management algorithm for AMD specific to Tayside. Possible alternative treatment methods that could improve prognosis and retard the pathogenesis of this disease will also be discussed. In addition, the article will discuss two hypothetical patients highlighting the differences between the two forms of AMD.
Anatomy of the Eye
A more detailed understanding of the anatomy of the eye is required to fully appreciate the pathogenesis of AMD (Fig 1). The eye consists of 3 main layers. The outer coat is known as the Fibrous Layer and comprises of the tough, fibrous sclera and the transparent, avascular cornea for focusing light.6,7
Figure 1: Diagram showing the anatomical structures of the eye
The layer internal to this is the Vascular Layer and consists of 3 structures; the choroid layer which contains dark pigment to prevent internal reflection of light,8 the ciliary muscle which contracts under parasympathetic control making the lens more convex and focusing light onto the retina7and finally the iris which is the coloured part of the eye and contains sphincter papillae and dilator papillae smooth muscles which alter the diameter of the pupil to regulate the amount of light entering the eye to prevent damage to the sensitive cells of the retina.6 The innermost layer is the Inner Layer, otherwise known as the retina (Fig 2). The retina is a thin sheet of receptor cells that is located between the choroid layer and vitreous body.9 It lines the posterior three‐quarters of the eyeball and is the beginning of the visual pathway.10 The retina is made up of two layers known as the optic‐part and the non‐visual retina. The optic part is further subdivided into a pigmented layer and a neural layer.6 The pigmented layer is found between the choroid and neural layer and consists of a sheet of melanin‐containing cuboidal epithelial cells called the Retinal Pigment Epithelium (RPE). Due to the melanin component these cells aid the action of the choroid layer in ensuring visual acuity by preventing light scattering.6 The melanin granules also act to absorb free radicals and protect the light sensitive structures of the retina. Thus the decrease in melanin associated with aging impairs protection against short wave radiation and the toxic effects of free radicals.11 The RPE is adherent to the neural layer but, due to the varying embryological origins of the two layers, they are not firmly attached via junction complexes and are thus easily separated in cases of trauma or disease. The tips of rod outer segments are deeply inserted into invaginations in the RPE and numerous microvilli on the cell surfaces project between the outer segments of the rods or cones. The RPE also plays a major role in removal of waste products from rod and cone degradation. Once shed, the aged outer rod and cone segment discs are absorbed into the cell cytoplasm which carries out lysosomal destruction to form lipofuscin granules.9 The RPE then acts as a selectively permeable barrier by releasing the resulting metabolic waste at the basal side to be taken up by the blood vessels in the choroid into the blood stream. In contrast to melanin, lipofuscin granule levels increase and accumulate in the lipofuscin compartments of RPE cells with age. This lipofuscinogenesis is thought to be due to antioxidant deficiency or pro‐oxidant conditions, as it is caused by the decreasing melanin levels leading to free radical build up.11 Many blood components are harmful to the retina and are kept away from it by this filter function of the RPE. The choroidal vascular supply to the RPE cells also means they help to nourish and support the rods and cones by transferring nutrients from the blood. Other roles of the RPE include regeneration of bleached visual pigment, production of immunosuppressive factors and antioxidant action. Failure of any of the numerous functions of the RPE would result in diminished retinal function and eventually blindness.9
Retinal Pigment Epithelium Bruch’s Membrane
Figure 2: Illustration to show the layers that constitute the retina
The Neural layer is a multi‐layered outgrowth of the brain that processes visual data to convert the optical image into neural activity by sending impulses into axons that form the optic nerve. There are 3 distinct layers of retinal neurones; the photoreceptor cell layer, the bipolar cell layer and the ganglion cell layer. Light passes through the ganglion and bipolar cell layers before contacting the photoreceptor layer.10 The second layer of the retina, or the non‐visual retina, is a continuation of the pigmented layer and is a layer of supporting cells extending over the ciliary body and posterior surface of the iris.6 The macula lutea is a small oval area of the retina rich in photoreceptor cells, or Cones, which are specialised for acute vision, specifically colour perception and for daylight vision. It is temporal and inferior to the optic disc (the ‘blind spot’ at which the optic nerve exits the eye), and is seen fundoscopically as an avascular area with a yellow tinge [Fig 3]. The central area of the macula is a small depression called the fovea centralis which contains only cones and is not covered by the layers of pigmented cells which scatter light such that it is the point of highest visual acuity or resolution. As the macular region is rich in cones it grants central vision, whilst rods are much more plentiful in the surrounding retina so the peripheral retina accommodates peripheral and lower light intensities.10
Macula Fovea Figure 3: Fundoscopic image of a normal retina using a hand‐held ophthalmoscope to show the anatomical positioning of the macula and fovea
Pathogenesis of Macular Degeneration
Age‐related macular degeneration is characterised by the build‐up of cellular debris between the retina and choroid. This process is also associated with both hyperpigmentation and hypopigmentation of the retina due to morphological changes. These early conditions alone are not associated with loss of central vision, but visiual loss may occur if the disorder is allowed to progress causing retinal atrophy and eventually wet macular degeneration.12 There are two forms of this illness, wet and dry macular
degeneration. Early macular degeneration can progress pathologically to either of these forms that have completely different clinical outcomes and management methods. Dry AMD Dry or atrophic macular degeneration accounts for 85% of AMD cases and is equally common in males and females.3 Dry macular degeneration is characterised by the accumulation of deposits of waste products or drusen beneath the RPE within Bruch’s Membrane. Bruch’s membrane is an acellular membrane beneath the RPE formed of 5 layers that acts as the barrier between the retina and the choroid. Nutrients and oxygen diffuse from the underlying choriocappillaris through Bruch’s membrane to the RPE and retina, whilst waste products of metabolism are voided in the opposite direction into the choroid. Bruch’s membrane undergoes many morphological changes with increasing age, including thickening, calcification, degeneration of collagen and elastin fibres and splitting. Transport between the retinal RPE and choroid can also be impaired by incomplete clearance of waste with age leading to the accumulation of lipid‐rich metabolic products.13 This drusen can be seen as pale yellow dots upon fundoscopic examination [Fig 4].
Figure 4: Fundoscopic image to show drusen accumulation deep to the macular region
There are two types of drusen ‐ soft drusen and hard drusen. As the disease progresses, small discrete drusen coalesce into larger deposits to form soft drusen. Soft drusen is considered to be an early indicator of macular degeneration and is the form most associated with loss of vision and separation between the retinal layers. This soft form presents as large pale yellow deposits with ill‐defined borders [Fig 5]. If an individual has a strong family history of macular degeneration, regular fundoscopy should be carried out to monitor these soft drusen deposits.14
Figure 5 : Optical Coherence Tomography (OCT) and fundoscopy showing a large area of soft drusen deep to the RPE
Hard drusen appears as a well‐defined, small, round deposits in the RPE. They are very common with age and can develop into the soft kind. Hard drusen is not indicative of exudative changes in the RPE and so the patient will generally have minimal change in visual acuity.15 Optical Coherence Tomography (OCT) can show other characteristic morphological changes associated with AMD, such as geographical atrophy. Geographical atrophy is the end stage of dry macular degeneration where pigmentation is disrupted across large areas of the macula and areas of the RPE atrophy and breakdown, leading to cell death. As a
result, irregular areas of thinner retina can be observed by OCT [Fig 6] and the patient will begin to notice attendant loss of central vision.16
Figure 6: OCT showing areas of geographical atrophy of the RPE
Wet AMD Wet or neovascular AMD is an alternative pathway of early AMD progression where separation of the RPE and choroid layer alongside an increase in vascular endothelial growth factor (VEGF) stimulates angiogenesis of choroidal blood vessels into the retina beneath the macula.3 Angiogenesis begins with vasodilatation and increases in vascular permeability, followed by activation and proliferation of vascular endothelial cells. Accompanying degradation of the surrounding extracellular matrix facilitates endothelial cell migration, which assemble to form cords and develop lumens. Further differentiation and remodelling to accommodate local requirements eventually forms a complex vasculature.17 Choroidal neovascularisation breaches the normal anatomical barrier of Bruch’s membrane and invades the subpigment epithelial and or subretinal spaces.18 These newly formed blood vessels are fenestrated and frequently bleed causing the macula to bulge or form a mound, often surrounded by small haemorrhages and tissue scarring.5 This ultimately leads to the separation of Bruch’s membrane, the RPE and the retina from each other and so the accumulation of intraretinal fluid and generalised thickening of the retina or the formation of cystic spaces. These pathological manifestations cause the photoreceptors to become misaligned and eventually degenerative changes occur with cell loss and eventual fibrosis.19 These processes will present clinically as distortion of central vision and the appearance of dark spots. Neovascularisation can also arise de novo in the macular retina and is referred to as retinal angiomatous proliferation.20 The progression of dry AMD may take place over years, whilst wet AMD can progress in mere months or even weeks.
Causes of AMD
A number of factors have been discovered to predispose to the development and progression of AMD (Fig 7). They include age, smoking, obesity, positive family history, hypertension, cardiac disease, heavy alcohol consumption, Alzheimer’s disease, hearing loss and low circulating levels of endogenous antioxidants.21 Smoking is the most consistent risk factor for the development of late AMD with current smokers more than doubling their risk of developing AMD. Individuals with a genetic susceptibility are also more likely to develop the disease if they smoke. These factors in themselves do not directly cause macular degeneration, but rather the chemical and pathological reactions they induce.22 The progression and severity of macular degeneration, as with all age‐related diseases, are exacerbated by factors such as oxidative stress, inflammation, hyperglycaemia and poor vascular health.5 It is thought that the retina may be particularly vulnerable to oxidative stress because of a combination of exposure to visible light and high oxygen concentrations.3 Normal structural changes in the retina that occur with aging, such as the thickening of Bruch’s membrane, could elevate oxidative stress by producing poorer perfusion of RPE cells by the choroidal circulation. Oxidative damage could also occur through the accumulation of reactive waste products such as A2E, a component of lipofuscin that is formed during the catabolism of photoreceptor outer segments by RPE cells.22 As a result, particular interest
has focused on the possibility of prophylactic treatment of individuals who have been identified as high risk for developing AMD with antioxidant micronutrients. Macular pigment is composed of two carotenoids, lutein and zeaxanthin, which are solely of dietary origin and are found in a wide variety of green leafy plants such as spinach and kale, and in some animal products such as egg yolks. It is thought that they protect the retina from the harmful effects of free radicals released by visible light.18 Studies such as the Beaver Dam Eye Study, the Blue Mountains Eye Study, and the Carotenoids and Age‐related Eye Disease Study (CAREDS), show that diets higher in carotenoids, zinc, vitamin C and vitamin E are associated with a lower risk of AMD. These observational studies form the basis for further research into the relationship between dietary intake or serum levels of antioxidant nutrients and risk of AMD.23 Indeed, clinical trials carried out in the USA have established a link to the carotenoid lutein further implicating a role of nutritional supplements and vitamins in delaying the progression of AMD and vision loss.5 Unfortunately, antioxidant trials have many limitations as researchers are unable to manage the composition of control groups, so they often suggest correlations where there are none. Furthermore, the trials do not last long enough as it may not be possible to show the benefits of antioxidant treatment over several years if the therapy is trying to reverse the effects of decades of oxidative stress. As a result, there have been no major changes in AMD treatment algorithms towards the use of carotenoid supplements in clinical practice. It has also been suggested the complement system may have a key role in AMD pathogenesis, as several genes which code for proteins involved in the complement cascade have been identified to significantly increase the risk of AMD including factor H (CFH) and complement component 3 (C3). The Wilkinson study in 2005 showed for the first time that the mutation of CFH is strongly associated with AMD,24 and variation in C3 was shown to increase the risk of developing AMD up to 2.6 fold.
Social Factors ‐ Smoking ‐ Age ‐ Obesity ‐ Increased alcohol consump}on
Concomitant Illnesses ‐ Vascular disease ‐ Alzheimer's disease ‐ Hypertension ‐ Cardiac disease
Genehc Factors ‐ Family history ‐ Complement factor gene H polymorphism
Environmental Factors ‐ Oxida}ve stress ‐ Decreased dietary lutein ‐ Low circula}ng an}oxidant levels
Figure 7: Summary of factors that predispose to and accelerate AMD progression
This article will discuss two hypothetical patients, Ms Watson and Mr Jones in order to outline the key differences between the diagnosis, clinical management and long‐term outcomes of the dry and wet AMD.
Patient 1: Ms Watson 59 year‐old female who works as an accountant in West Scotland. She has a BMI of 29 and has a very limited diet of high fat convenience foods, saying she has little time to shop for fresh vegetables and meat as her job is very time consuming and stressful. She has no medical history of diabetes, epilepsy, but was diagnosed with hypertension aged 39 and angina at 48 years old. Her father died of myocardial infarction at 74 years old, and her mother was diagnosed with AMD aged 62. Her current medications are Bisoprolol (10mg orally once daily), Lisinopril (20mg orally once daily) and GTN PRN. She does not drink any alcohol and has never smoked cigarettes. Patient 2: Mr Jones 77 year‐old male from South England. He previously worked as a building merchant but retired 10 years ago by choice, and currently lives with his wife in their own home. He has no medical family history, and no previous complaints himself other than he was prescribed glasses 6 years ago that he only uses for reading. He does not suffer from diabetes, epilepsy or cardiovascular problems, but was diagnosed with hypertension 15 years ago. His current medications consist of Bendroflumethiazide (2.5mg orally once daily) and Simvastatin (40mg orally once daily). He does not consume any alcohol and he does not smoke, having given up at 45 years of age when he had smoked 30 cigarettes daily.
Diagnosis of AMD The eye has very few mechanisms to convey a diseased state and so a careful and detailed history gives the key information needed to make a working diagnosis. Patients with dry macular degeneration where atrophy of the retina is bilateral and involves the fovea of both eyes generally present with deterioration of central vision, commonly noticing increasing difficulty with reading initially with the smallest sizes of print and then later with larger print or words.25 Diagnosis of dry macular degeneration is normally confirmed by stereo biomicroscopy using a high definition fundus lens. This will reveal characteristic areas of pallor with sharply defined and scalloped edges, large choroidal vessels within the area and usually areas of drusen and focal hyperpigmentation adjacent to the patch. OCT can also be used for diagnosis to identify areas of geographical atrophy that cannot be seen clinically by biomicroscopy.26 Monitoring the progression of dry AMD is necessary as the early identification of progression to wet AMD can significantly improve prognosis and reduce vision loss. The system used was created by AREDS (Age‐Related Eye Disease Study) and consists of 4 stages (Table 1).26
Table 1: AREDS classification to monitor progression of wet AMD
Category 1 No AMD: none or a few small drusen
Patients are essentially free of age‐related macular abnormalities, with a total drusen area less than five small drusen and minimal deterioration of visual acuity in 23 either eye
2 Early AMD: Patient will present with any of multiple small drusen, few intermediate drusen (63 to 124 μm in diameter), or RPE abnormalities
Cases have these mild or borderline, age‐ related macular features, still with little 22 change in visual acuity
3 Intermediate AMD: Individual
will have extensive intermediate drusen, and at least one large drusen (125 μm) or geographic atrophy, not affecting the fovea 4 Advanced AMD: Geographical atrophy affecting the fovea and/or or any of the features of neovascular AMD
The patient must not have advanced AMD in both eyes, or at least have one eye with 23 visual acuity of 20/32 or better
These patients have visual acuity of 20/32 or better and no advanced AMD in one eye, whilst the other has lesions of advanced AMD, or visual acuity less than 20/32 with AMD abnormalities sufficient to 24 explain reduced visual acuity
This classification system allows easy monitoring of disease progression so people at high risk of developing late AMD are identified and made aware of certain lifestyle changes they could make to reduce their risk.25 Wet macular degeneration presents differently with the appearance of central visual blurring and distortion. As AMD causes the impairment of central vision, patients generally have complaints such as difficulty with close‐work activities, straight lines appearing wavy or distorted and dark patches in the central field of vision.5 An Amsler grid test should be carried out to quantify the degree of visual distortion and locate early visual problems related to macular disease. It simply involves holding the grid 30cm from the patients eye and asking if they can see all four corners of the grid and if any of the lines appear blurry, wavy, bent or are missing, whilst looking at the central dot.26 GPs, nurses and optometrists need to be aware of the urgent nature of referral for patients with recent onset of distortion and visual loss, as these patients may still have treatable disease and so must be referred to an ophthalmologist.5 For confirmation of wet macular degeneration diagnosis, examination of the macula will usually show an exudative macular lesion along with other features of early AMD, for example drusen and pigmentary irregularities. These features are often only seen soon after development of wet AMD, and begin to disappear as the disease progresses. As a result, both eyes must always be examined, even if the patient has not experienced concomitant symptoms in both eyes, as the other eye usually exhibits some of these early clinical signs and can help confirm that the neovascular lesion is due to AMD. It is essential to monitor the progression of wet macular degeneration using OCT imaging as the morphological changes seen will determine whether treatment is efficacious, or if the dosage of medication should be increased or decreased to improve prognosis. The areas of fluid, appearing as a dark black area within the retinal layers [Fig 9], can only be estimated in size and need comparative values to quantify the severity. Thus, these areas of leaking and swelling are observed over time to determine if the condition is improving, worsening or is stable.
Figure 9: OCT scan of Wet AMD showing leakage and swelling
An accurate Snellen visual acuity must also be recorded in all patients with an eye problem as this categorises the level of visual acuity and allows monitoring of deterioration or improvements in future.18 Patient 1: Ms Watson Diagnosed by her optician with dry AMD following a routine appointment. She reported that she had noticed increasing problems whilst doing numerical work and had to concentrate much harder to ensure she did not get the numbers mixed up. Patient 2: Mr Jones Presented to his GP after noticing that the edges of door frames and walls appeared wavy. He noticed himself that his right eye was much worse and that any straight objects appeared out of focus and distorted. Mr Jones GP referred him to the ophthalmologist for more specialised testing. Over the next two months required for these tests to be undertaken, Mr Jones noticed a mistiness forming ‘over’ his right eye that became progressively darker until he could only see what he described as a ‘black blob’ in his central vision.
Intervention or Chemical and Surgical Management Dry AMD The management of dry AMD aims to minimise visual loss and disability in order to maintain independence, rather than actually treating the pathology of the disease. Dry AMD itself cannot be reversed, so management is to prevent progression of the disease to late macular degeneration. Current strategies include careful monitoring by examining fundus photographs and using the AREDS model to observe large drusen formation and the development of hypopigmentation followed by geographical atrophy.23 This ensures that the progression of the disease is quantified such that suitable prophylactic treatment can be administered to minimise disease development. Laser treatment is currently being studied as a prophylactic treatment option. Focal laser treatment has been shown in multiple studies to be able to disintegrate drusen, but in most cases has also increased the risk of choroidal neovascularisation. As a result, research is ongoing into the alternative use of large spot size lower power laser treatment.26 As the full benefits of antioxidants on the pathology of AMD has not yet been proven, some ophthalmologists may advise patients to take vitamin, zinc or lutein supplements, but again there is no definitive proof at present that this is an efficacious prophylactic treatment.18 Treatment for non‐neovascular AMD is limited and consists mainly of counselling and rehabilitation. Patients should be encouraged to maintain their independence by using low visual aids, such as magnifying glasses, when reading or whenever necessary. Patients should also be encouraged to attempt to utilise their peripheral vision more, and they will develop a preferential retinal locus with time.17 Patient 1: Ms Watson As dry AMD has no definitive cure Ms Watson has simply had to learn to live with the effects of her illness. For the first 3 years following her diagnosis only her right eye was affected so it did not pose much of a problem. Unfortunately at age 62 her vision began to deteriorate in her left eye and she was forced to give up driving and her job, as she was increasingly misquoting figures when preparing financial statements. Throughout the following 10 years Ms Watson’s central vision deteriorated rapidly meaning she is no longer able to identify the faces of her friends when passing them in the street, and is no longer able to partake in many of her favourite hobbies such as tapestry and calligraphy. At age 75 her central vision has declined to such an extent that she now requires a white stick when walking somewhere unfamiliar or busy and can only read very large texts using a magnifying glass given to her by an AMD support group.
Wet AMD Angiogenesis has a role in many vascular disorders, including wet AMD. Since the rapid angiogenesis into the choroid layer causes the leakage of immature vessels between the RPE and choroid in wet AMD patients, the management of this underlying pathological
angiogenic process is vital. The main regulators of angiogenesis are vascular endothelial growth factor (VEGF), fibroblast growth factor 2, pigment epithelium‐derived growth factor, angiopoietins and extracellular matrix molecules. Identification of these has facilitated the development of novel therapeutic agents, most importantly Bevacizumab that blocks VEGF‐ A.27 Although these multiple growth factors have been attributed to angiogenic processes, VEGF appears critical for a number of reasons: it is triggered by hypoxia, is involved in multiple aspects of the angiogenic process, and causes vascular dilatation and promotes vasopermeability which facilitate the growth of new vessels. Its discovery triggered a new therapeutic era, with the utilisation of VEGF blockade for the management of chorioretinal diseases with vascular hyperpermeability or neovascularisation.17 All of the anti‐VEGF medications work in a similar fashion by binding to VEGF and inhibiting its biologic activity, so reducing the formation of abnormal blood vessels. They also reduce the amount of leakage and therefore reduce swelling in the macula. These actions lead to preservation of vision in patients with wet macular degeneration.3 Currently two drugs, pegaptanib sodium and ranibizumab, have successfully qualified all the necessary phases of drug development to obtain licensing approval by regulatory bodies and form the mainstay of treatment for neovascular AMD.28 Lucentis, or Ranibizumab, is an antibody fragment able to target all VEGF‐A isoforms when administered monthly via intravitreal (IVT) injection. Ranibizumab was licensed for use in the USA following the MARINA and ANCHOR studies. In the MARINA (Minimally Classic/Occult Trial of the Anti‐VEGF Antibody Ranibizumab in the Treatment of Neovascular AMD) trial, patients were randomised to receive monthly injections of IVT Ranibizumab or monthly placebo injections. 12 months into the study, visual acuity was found to have improved by 15 or more letters in 33.8% of the 0.5 mg group, with only 5% similar improvement in the placebo group. In addition, the 94.6% of patients receiving IVT Ranibizumab in the trial reported no visual loss and only 62.2% of the control group managed to do so. In the ANCHOR (Anti‐VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularisation in AMD) trial, individuals with leaking choroidal neovascularisation received either 24 monthly Ranibizumab IVT injections of Ranibizumab or photodynamic therapy with verteporfin. Visual acuity improved by 15 letters or more in only 5.6% of individuals treated with verteporfin. As in the MARINA trial, those receiving Ranibizumab also demonstrated a mean increase in visual acuity whilst the control group experienced a mean decrease. Similarly, 96.4% reported no visual loss compared with 64.3% of individuals in the verteporfin group.17 Current NICE guidelines recommend Ranibizumab as treatment for wet AMD if the patient has all of the following criteria: 1. The best possible visual acuity after correction with glasses or contact lenses is between 6/12 and 6/96. 2. There is no permanent damage to the fovea 3. The area affected by AMD is no larger than 12 times the size of the optic disc29 The second approved drug, Pegaptanib sodium, is an RNA aptamer that only targets the VEGF isoform responsible for pathological ocular neovascularisation, VEGF 165. Despite the apparent efficacy of this drug, it does not provide the extent of VEGF blockade necessary for optimal clinical outcomes, and as a result recent NICE guidelines do not recommend Pegaptanib as a management option for patients presenting with wet AMD.17 Although Ranibizumab and pegaptanib are the only two drugs with licensing approval, Bevacizumab, a recombinant humanised monoclonal antibody against all VEGF‐A isoforms, has shown considerable promise as an off label treatment method. It was originally
developed to treat metastatic carcinoma of the colon and rectum and is derived from the same monoclonal antibody as Ranibizumab, therefore it recognises the same epitope on VEGF as Ranibizumab but binds with a different affinity.29 Trials have shown that Bevacizumab can penetrate through all layers of the retina, and it has been used off licence as AMD treatment to positive effect. A case series by Michels et al on the systemic administration of Bevacizumab in the management of choroidal neovascularisation demonstrated this treatment’s benefits, with recordings showing reduced retinal thickening and improved visual acuity. These findings encouraged further studies, such as the Cleveland Clinic trials, reporting similar outcomes when administered by IVT injection.21 In 2011, the results of the CATT (Comparison of Age‐Related Macular Degeneration Treatments Trials) study provided further evidence for the efficacy of Bevacizumab in neovascular AMD. In this trial, 31.3% of patients treated with Bevacizumab monthly gained 15 or more letters from baseline visual acuity and 94% of patients lost fewer than 15 letters of visual acuity from baseline. Furthermore, mean visual acuity increased by 8 letters over the study period in those receiving Bevacizumab monthly. This study also allowed comparison of outcomes with Bevacizumab or Ranibizumab management; 34.2% of patients treated with Ranibizumab monthly gained 15 or more letters from baseline visual acuity, with 31.3% of patients treated with monthly Bevacizumab IVT injections. 94.4% of patients receiving Ranibizumab monthly lost fewer than 15 letters of visual acuity from baseline, whilst 94% of patients reported similar results with monthly Bevacizumab injections. This trial concluded that there was little clinical evidence to determine if Bevacizumab or Ranibizumab would be the most efficacious treatment for wet AMD as the difference between percentage of visual acuity regained was inconsequential.17 Considering the outcome of these trials alongside the fact that the drug cost to the NHS will be considerably less, Bevacizumab would appear as the logical primary treatment for wet AMD. Despite this, the drug companies who produce Bevacizumab have yet to apply to the European Medicines Evaluation Agency to license Bevacizumab as a treatment option for wet AMD. Instead, continued use of the costly but licensed Ranibizumab injections is advised. The decision to register Ranibizumab as a primary treatment for wet AMD can only be made by the drug production company and to do so would greatly reduce their financial income. Many practitioners chose to administer Bevacizumab regardless, but its continued unlicensed use raises both ethical and legal questions. Over the past decade, there have been extensive developments in AMD treatments necessitating new guidelines to ensure the best therapeutic options are available to all patients in the NHS, whilst ensuring efficient use of NHS resources. The Tayside treatment algorithm does this by managing neovascular AMD with IVT Ranibizumab injections. In the first year following diagnosis with wet AMD the patient is administered 3 loading doses of IVT Ranibizumab 1 month apart with follow up and/or booster injections every 6 weeks for the rest of that year. In the second year following diagnosis the patient should only receive the IVT injections if necessary so treatment efficacy is monitored with 2 monthly reviews [Appendix 1]. The frequency of injections and reviews is progressively decreased as the patient responds to the treatment. If the patient has no signs of disease or does no longer require the Ranibizumab injections after these 2 years of treatment, they are discharged. Patient 2: Mr Jones Mr Jones was diagnosed with wet AMD and immediately treated with IVT Ranibizumab injections. Gradually after 2‐4 injections he noticed definite improvements as the blackness began to disappear and the ‘mist began to clear’ and after 5 months of injections he reported that only a light mist remained, slightly obscuring his central vision. He still has problems focusing and identifying fine detail, but he has regained the ability to read and drive. His main concern was that the wet AMD would also affect his left eye but he has had no symptoms in that eye.
AMD is the leading cause of vision loss in industrialised countries, and so clearly is an extensive health problem. Whilst research is on‐going as to new treatment options and prophylactic management for this disease, further trials are required to provide definitive treatment options for either wet or dry macular degeneration. At present causative factors have been researched considerably more and guidelines have been defined, so patients should be advised on the modifiable predisposing factors discussed earlier to aim to prevent the disease, rather than treating it retrospectively. Changing lifestyle factors such as these can improve the patient’s prognosis and delay disease progression significantly. Drug treatments are still developing rapidly, with seemingly effective drugs such as pegaptanib sodium being discarded for an even more efficacious drug, Ranibizumab. Recent trials identifying Bevacizumab as an alternative to Ranibizumab further show that drug advances for AMD treatment are still very much ongoing. Under the current economic pressures and cost/benefit criteria practised in the medical environment, Bevacizumab is a cheaper alternative to the more refined Ranibizumab and has the potential to become a standard treatment for wet AMD treatment. Considering it would cost the NHS up to 100 times less to administer this drug, it would be the best option to optimise NHS resources and ensure that society as a whole benefits from other possible uses of these funds.32 As to whether drug companies will choose to apply to licence Bevacizumab, or to not and so majorly increase their net profit by continuing to advise the considerably more expensive Ranibizumab, is yet to be seen.
 Global initiative for the elimination of avoidable blindness: Action plan 2006–2011. Geneva: WHO Press; 2007. Pages 32–3.  NHS Choices [homepage on the internet]. Epub: Cited February 2012 http://www.nhs.uk/conditions/macular‐degeneration/Pages/Introduction.aspx  Life Extension. Age‐Related Macular Degeneration. Epub: Cited January 2012. http://www.lef.org/protocols/eye_ear/macular_degeneration_01.htm  VRMNY. Dry (Atrophic) Macular Degeneration. Epub: Cited January 2012. http://www.vrmny.com/pe/amd/dmd.html th  Redfern SJ, Ross FM. Nursing older people. 4 ed. London: Elsevier; 2006. Pages 203‐205. th  Moore KL, Dalley AF, Agur AMR. Clinically orientated anatomy. 6 ed. USA: Lipincott Williams and Wilkins; 2010. th  Hiatt JL, Gartner LP. Textbook of head and neck anatomy. 4 ed. Maryland: Lipincott Williams and Wilkins; 2010.  McMinn RMH, Gaddum‐Rosse P, Hutchings RT, Logan BM. McMinn’s functional and clinical anatomy. London: Mosby; 1995. Pages 164‐166 th  Standring S. Gray’s anatomy. 40 ed. USA: Elsevier; 2008. Pages 688‐695 th  Tortora GJ, Nielson MT. Principles of human anatomy. 12 ed. London: John Wiley & Sons, Inc.; 2012. Pages726‐728.  Alberti WE, Richard G, Sagerman RH. Age‐related macular degeneration; Current treatment concepts. New York: Springer; 2001.  The Royal College of Ophthalmologists. Age‐related macular degeneration guidelines for management. London: The Royal College of Opthalmologists; 2009.  Alberti WE, Richard G, Sagerman RH. Age‐related macular degeneration; Current treatment concepts. New York: Springer; 2001.  Degner L. Drusen ‐ Know the Difference Between Hard and Soft Drusen. Epub: May 2012. http://ezinearticles.com/?Drusen‐‐‐Know‐the‐Difference‐Between‐Hard‐and‐Soft‐ Drusen&id=1905548  Kinshuck D, Hope M. ARMD pathology and treatment. Epub: Cited January 2012. http://www.goodhope.nhs.uk/departments/eyedept/images/geographiccnvl.jpg  Thompson W. Classification of age‐related macular degeneration. Lippincott, Williams and Wilkins: Philadelphia; 2006.
 Pearse A, Keane S, Srinivas R. Development of Anti‐VEGF therapies for intraocular use: A guide for clinicians. London: Journal of Opthalmology; 2011.  Bird AC, Bressler NM, Bressler SB, et al. An international classification and grading system for age‐related maculopathy and age‐related macular degeneration. Surv Opthalmol: USA; 1995.  Age‐Related Eye Disease Study Research Group. The Age‐Related Eye Disease Study system for classifying age‐related macular degeneration from stereoscopic color fundus photographs: the Age‐Related Eye Disease Study Report Number 6. Am J Opthalmol: New York; 2001.  Wang JJ, Foran S, Smith W, et al. Risk of age‐related macular degeneration in eyes with macular drusen or hyperpigmentation: the Blue Mountains Eye Study cohort. Arch Ophthalmol: New York; 2003.  Spaide R. Etiology of late‐age‐related macular disease ‐ Age related macular degeneration: a comprehensive textbook, Lippincott, Williams and Wilkins: Philadelphia; 2006.  Sparrow JR, Fishkin N, Zhou J et al. A2E, a byproduct of the visual cycle. Vis Res: New York; 2003.  Hyman L, Schachat AP, He Q, et al. Hypertension, Cardiovascular Disease and Age‐Related Macular Degeneration. Arch Ophthalmol: New York; 2000.  AREDS. Risk factors associated with age‐related macular degeneration ; A case‐control study in the age‐related eye disease study: age‐related eye disease study report number 3. Ophthalmology: Texas; 2000. th  Kumar P, Clark M. Kumar and Clark’s; Clinical medicine. 7 ed. London: Elsevier; 2009.  Edwards AO, Ritter R, Abel KJ. Complement factor H polymorphism and age‐ related macular degeneration. Cited February 2012. Epub: Texas; 2005.  Martinez‐Barricante R, Recalde S, Fernandez‐Robredo P, et al. Relevance of Complement Factor H‐Related 1 (CFHR1) Genotypes in Age‐Related Macular Degeneration. Department of Cellular and Molecular Medicine: Madrid; 2012.  Eugene WM, Anthony P, Adamis, M. Targeting angiogenesis, the underlying disorder in neovascular age‐related macular degeneration. Can J Ophthalmol: New York; 2005.  NICE Guidelines. Pegaptanib and ranibizumab for the treatment of age‐related macular degeneration. Cited February 2012. http://www.nice.org.uk/TA155  Rosenfeld PJ, Brown DM, Heier JS et al. Ranibizumab for Neovascular Age‐Related Macular Degeneration. N Engl J Med: USA; 2006  Stevenson W, Cheng SF, Dastjerdi MH et al. Corneal Neovascularization and the Utility of Topical VEGF Inhibition: Ranibizumab (Lucentis) Vs Bevacizumab (Avastin). Schepens Eye Research Institute: Masacheusettes, USA; 2012.
Available on online edition – http://sumj.dundee.ac.uk
Clinical Research for Beginners ‐ The Importance of Planning
Dr. Lynda A Cochrane (Dundee Epidemiology and Biostatistics Unit) & Shobitha Puvaneswaralingam (4th MBChB; BMSc) Correspondence to: Lynda Cochrane : email@example.com
While the identification of the individual who said “Failing to plan is planning to fail!” is in doubt, the wisdom of the words is not especially in the context of undertaking clinical research. There appears to be a view in some quarters that collecting a set of data, for example on people with a particular condition, and carrying out a series of analyses to try to find something of statistical significance constitutes a scientific investigation ‐ it does not! A clinical research study must have a clearly defined aim with a comprehensive plan including a statement of the population of interest, which data are to be collected, how they will be measured, by whom, when and with what, as well as details of how subjects are to be allocated to interventions (if any). The purpose of this article is to give an introduction to some of the issues involved in constructing such a plan. It is by no means a definitive guide and further details can be found in the reference list.
Key Words: clinical study; design; outcomes; sample
Planning a study Most statisticians will have encountered the following situation: a researcher, having collected a set of data, consults the statistician for the first time and asks “Which test do I use?”. What, you might enquire, is the problem? Isn’t that what statisticians do ‐ advise on and carry out data analysis? Well, yes, that’s true. But it is only part of the service they provide. One of the most important roles of a statistician is to ensure that a research study is designed so that its aims can be achieved. Without such planning, there is a possibility that the study will be inadequate and thus fail to meet the proposed aims. Would anyone construct a bridge by gathering some materials and then asking a construction engineer which tools to use in order to put them together? Of course not: we all understand the need to plan the project and use scientific principles to determine which type of design will best meet the requirements of the structure, such as the load it is to carry, the environment in which it is situated and the funds available. The same principles apply to a clinical research study. We must identify a clear aim, indicate the population of interest and the inclusion and exclusion criteria for potential study participants, define the measurements we need to make and when we will make them, establish the methods of data analysis and so on. The importance of involving a statistician in the initial design, as well the analysis, of a research study is highlighted by Professor Douglas Altman1. The main steps involved in planning a study are listed in Figure 1 and discussed individually below.
Figure 1: Components of a Study Plan • • • • • • • • • • • • •
Aim(s) Population Interventions Outcomes Data collection: measuring outcomes (when, by whom, how, to what level of accuracy) Confounding factors Inclusion and exclusion criteria Sampling strategy Study design Sample size Compliance Data storage and management Analysis
The first step in planning a study is to identify a clear, achievable and ethical aim. All studies need to have a purpose and aim to develop knowledge or understanding in a particular area. Examples include: A1) Compare changes in the blood pressure of hypertensive patients achieved with drug therapy alone with those with drug therapy and exercise A2) Compare the outcomes of conservative and surgical treatment of scaphoid lunate fracture A3) Describe the natural history of Duchenne muscular dystrophy (DMD) A4) Identify the risk factors for liver cirrhosis A5) Investigate factors linked to lower limb amputations in patients with diabetes mellitus (DM) Examples of inappropriate, vague or unethical aims include: A6) Monitor changes to the brain prior to the onset of Alzheimer’s disease A7) Identify the outcomes of regularly exceeding the recommended dose of paracetamol A8) Assess prescribing patterns in Dundee
Identifying the population
This is the set of patients about which we wish to make an inference. For example, in A2) above, the population is patients who have suffered a scaphoid lunate fracture and in A3) it is patients with a diagnosis of DMD. Identifying the population is not always so straightforward. For example, will patients with DM (A5) include Type 1, Type 2, gestational, MODY, LADA, Type 3, Type 1.5 etc? These different groups are likely to differ in, for example, age, drug treatment and co‐morbidities and this heterogeneity would complicate the investigation.
Define the interventions
An intervention is any action that is done to the subject, or to his or her environment. This can include, for example, a drug treatment (including placebo), surgery, wearing a support device, counselling or a combination of two or more treatments. The interventions for the hypertension study could be a six‐month programme of bendroflumethiazide, 2.5mg early in
the morning (the drug therapy) and 30 minutes of walking at a steady pace (3mph) five days each week (the exercise programme).
Identifying the outcome
Outcomes are endpoints or measures of the response to an intervention. The outcomes for aims A1), A4) and A5) above are clear: systolic & diastolic blood pressure, liver cirrhosis and the occurrence of a lower limb amputation, respectively. For A2), it would be useful to have a score constructed from several aspects of wrist function, including subjective (e.g. pain) and objective (e.g. flexion) measures such as the Modified Gartland and Werley Score2. The natural history of a disease such as DMD could be described by the different aids required (such as limb supports and a wheelchair), drug therapies and the time to these events. The occurrence, severity and time of onset of complications such as chest infection and osteoporosis would also be of interest.
Data collection: measuring outcomes
There are several issues to consider when measuring the outcome. How will it be measured? When will it be measured and by whom? What is the level of accuracy and how valid and reliable is the measurement of the outcome? How will it be recorded and the data stored? Who will take responsibility for data management? These are particularly important matters when data are collected by more than one person and/or at more than one site. Wherever possible, data should be measured and recorded as accurately as possible. It is tempting to group observations but this can be misleading and limiting. Suppose, for example, a researcher wishes to test his hypothesis that high heel height leads to back pain. Should he classify heels simply as ‘high’ and ‘not high”, as ‘high’, ‘medium’ and ‘low’ or something else? Ideally, shoe heel height should be measured with a tape measure, at the back of the heel and recorded in millimetres. Judgements such as high and low are subjective: someone who regularly wears flat shoes might regard 30mm to be a high heel, whereas a stiletto‐heel wearer might regard this as low. The measuring device itself must be accurate. For example, a set of scales that give a reading that is higher than the true weight should not be used. Also of interest are the validity of the measuring instrument (does it measure what it claims to measure) and its reliability (how consistent is it when measurements are repeated).
Variables that are related to both the outcome of a study and the intervention can distort the effect of the intervention. These are known as confounding factors. There is some evidence, for example, that ethnicity can affect the response to enalapril, with black patients responding least well3. Therefore, the effectiveness of this anti‐hypertensive drug would be reduced if there were a preponderance of black patients in the population studied. It is important to identify any such confounding factors during the planning phase and include them as independent variables.
Inclusion and exclusion criteria
As the names suggest, inclusion and exclusion criteria identify who will be included or excluded from the sample. Patients who could benefit from the intervention are described by the inclusion criteria. Those for whom the intervention is inappropriate or could be dangerous, or who have co‐morbidities that could mask its effect, are identified by the exclusion criteria. Inclusion criteria for the investigation of hypertensive patients (A1) would be patients with hypertension defined by the NICE Clinical Healthcare Guideline 344. It would be reasonable to exclude those with isolated systolic hypertension and those with secondary causes of hypertension such as renovascular disease, genetic causes and pregnancy. Also
excluded would be patients with any of the contraindications to taking the intervention drug as specified in the British National Formulary (BNF)5.
Sampling the population
Usually it is impossible to study all of the members of a population and a subset or sample of the population is therefore chosen6. The simplest technique is random sampling. First, we define the population (e.g. patients in Tayside with cerebral palsy) then give every member of the population a number (from 1 to N inclusive, where N is the size of the population). For a sample size n, we select n random numbers. The corresponding members of the population are selected. Sampling is a vital step in any research and governs any inferences that can be made. For example, if we investigate factors linked to lower limb amputations in patients with Type 2 DM, then we can make conclusions only about this group. The findings cannot be extrapolated to patients with other types of DM. If the population is to include other DM patients then the sample should be chosen to reflect the prevalence of the respective types in the general population. This is known as stratified sampling. Often it is either not possible or not practical to select a random sample (e.g. if the population cannot be enumerated). In such cases, a clinician might choose to study a sample of patients in his/her clinic. Even if this sample itself is selected randomly, this does not constitute a truly random sample of the population: it is a random sample of a subset of the population that has not itself been chosen randomly. Such selections are referred to as convenience samples.
Types of study design
There are many different types of study and each has merits in particular situations7. In a prospective study, subjects are selected from a population and analysed for a defined future outcome. In contrast, a retrospective study is an analysis of existing data. A study is said to be experimental if the effect of an intervention (e.g. a drug treatment or exercise program) otherwise it is an observational study. A study is described as cross‐sectional if measurements are made at only one time point whilst a longitudinal study analyses multiple time points. An analytical study is one in which the aim is to analyse the data gathered in order to make an inference about the effect of an intervention on an outcome variable. In a descriptive study, the data are summarised using descriptive statistics (e.g. measures of centre and spread, frequencies) without consideration of the effects of one or more of the variables on the others. One of the most widely known designs is the randomised controlled trial (RCT). A sample of subjects is selected from the population and allocated randomly to one of two or more groups (or arms) of the trial. One of the treatments is a control, which could be an existing treatment, a placebo or no treatment. Wherever possible, trials should be double blinded such that both the subjects and the researchers are unaware of the treatment allocations. However, although ideal, this may be impossible, for example when one of the treatments is counselling and the other is a drug therapy. A parallel group design is a RCT in which subjects are allocated randomly to either the treatment or the control group. By allocating subjects completely randomly, the expectation is that any known or unknown factors that could affect the outcome – other than the treatment(s) – would be equally distributed between each arm of the trial. This is not necessarily the case and one way of dealing with this is to use a matched design8 in which the subjects in each arm are matched for the factors known to affect the response to the treatment (e.g. age, BMI). This design requires fewer subjects than a random design because
some of the variability of the response has been controlled for. Further efficiency can be achieved by using a within‐subjects design, in which individuals are allocated to both arms of the trial (simultaneously or consecutively). As a result, the inter‐subject variability is eliminated because each subject acts as his/her own control. Interventions that can be applied simultaneously include topical treatments applied to each leg. If treatments are consecutive (e.g. the comparison of two drugs to relieve chronic pain), care should be taken to avoid a carry‐over effect between treatments by allowing a washout period. In addition, the order in which treatments are applied should be randomised to avoid any order effects. Cross sectional studies provide information about a population of interest at a particular moment in time. Examples include surveys to estimate the prevalence of a disease and studies to investigate the reliability of a measuring instrument.
Identifying risk factors
Some of the most commonly reported studies involve identifying risk factors for disease. It would be unethical to deliberately subject individuals to something that could be harmful, although instances have been known (e.g. in the 1960s, French soldiers were deliberately exposed to radiation during nuclear tests in order to investigate their physiological and psychological responses)9. There are thus two primary ways of assessing risk factors for various diseases: prospective cohort and retrospective case‐control studies. In a prospective cohort study, a group of healthy individuals are monitored until they develop the disease under investigation. These tend to be long, large and therefore expensive but provide the most reliable results. Case‐control studies involve comparing subjects with the disease (cases) with individuals who do not have the disease (controls) but otherwise are similar (e.g. same gender, age, co‐morbidities etc.). These are shorter studies and less expensive but less reliable than prospective cohort studies. Despite its shortcomings, this type of design has generated some important findings, most notably the association between tobacco smoking and lung cancer found by Professor Richard Doll and his team10.
Another question frequently asked is how many subjects are needed in a study. There is no simple answer to this and the sample size depends on several factors11. First, how variable is the outcome? The required sample size required for the study increases according to the variability of the data. Estimates of likely variability of the data can be obtained either from existing literature or by carrying out a pilot study, which tests the feasibility of the main experiment and provides useful information about measures of centre and spread. Second, there is the effect size. This is a measure of the size and direction of the effect of a treatment (intervention). For continuous outcomes, usually this is expressed as a proportion of the standard deviation of the response (SD): that is to say, it is calculated as (change in outcome with treatment ‐ change in outcome with control) ÷ SD. This removes the effect of scale and allows comparisons to be made between different studies. When the outcome is binary (e.g. did the patient develop a hospital acquired infection: Yes / No), one measure of effect size is the number of subjects that would need to be treated to prevent one outcome (NNT, e.g. the occurrence of one infection) and this is known as the ‘number needed to treat’. Another measure of effect size in studies with binary outcomes is the odds ratio (OR). This is the ratio of the odds of the outcome observed with one treatment divided by the odds observed with another e.g. the odds of survival to 1 year with two regimes of chemotherapy in patients with pancreatic cancer. Provision should also be made for patients who drop out of the study.
Compliance, or lack of it, is one of the hazards of clinical studies: patients do not always follow the instructions they are given. This is especially likely if the intervention is inconvenient or unpleasant. There are two approaches to the subsequent analysis of the data: per intention to treat (ITT) or per protocol (PP, sometimes referred to as modified intention to treat). In the former, data are analysed according to what the intention (plan) stated and in the latter patients who do not adhere to the protocol are omitted from the analysis. For example, suppose there are two arms of a trial in which Group 1 follow a low‐ fat diet and walk for 20 minutes each day and Group 2 follow a low‐fat diet plan. If a patient in Group 1 follows the diet but does not exercise then in the ITT analysis the patient would be included in Group 1 whereas the per protocol analysis would exclude him/her from the analysis. There are some repercussions that can arise with PP analyses12 and many statisticians prefer the ITT option13.
Data storage and collection
Unless data are accurate, valid and reliable, the results of a medical research study will be unreliable. Security, including the protection of patient identifiable data, is of critical importance when dealing with clinical information. Many institutions have a specialised unit which co‐ordinates the collection, storage and management of research data and this is the preferred option.
Details of the analyses to be undertaken and the statistical tools to be used should be specified in the study plan. This will be the subject of a subsequent article.
Two sets of guidelines are available for reporting observational studies (STROBE14) and RCTs (CONSORT15). You might find they help you to think through your study design.
It is important to become familiar with the above clinical research terms/concepts when planning any research project. Indeed, one of the best ways to achieve this is by reading and looking at examples of real clinical research program. Outlined in Figure 2 is a suggested design for a study to investigate the relationship between exercise and blood pressure in patients with hypertension. For her BMSc project, SP carried out a study entitled “Does weight loss improve cardiovascular morbidity in patients with type 2 diabetes mellitus?” (Figure 3). This was a retrospective cohort study of linked data extracted from databases held by the University of Dundee’s Health Informatics Centre (HIC). It became clear during the course of the analysis that there were a number of problems with the design (Figure 4). Suggested ways of overcoming these are shown in Figure 5.
Figure 2: Design of Exercise and Hypertension Study Aim(s) To investigate the relationship between exercise and blood pressure in Tayside patients with hypertension Population Patients with hypertension, defined as in the NICE clinical guideline 343 Interventions Counselling relating to the benefits of exercise and the provision of a pedometer to measure the number of steps taken per day Outcomes Systolic and diastolic blood pressure Total number of steps taken Data collection 1) Measurements to be made by Researcher A, a trained HCP, at the start of the intervention and 6 months later: a) Systolic and diastolic blood pressure (according to NICE clinical guideline 343) b) Weight: kg to 1 dp c) Height: m to 1 dp 2) Number of steps to be recorded daily by the patient, on forms produced by Researcher A. Total taken over 6 months to be calculated by Researcher A 3) BMI: calculated by Researcher A according to the formula mass (kg)÷(height (m))2 4) High and low density lipids: mmol/L to 2 dp obtained from hospital laboratory assay, at the start of the intervention and 6 months later (blood to be collected by Researcher A). 5) Gender, date of birth, date of diagnosis as noted in the patients’ records Confounding factors Secondary causes of hypertension (e.g. renal failure, hyperthyroidism ) Inclusion and exclusion criteria Exclude: Cases of secondary hypertension Include: Patients with hypertension (defined as in the NICE clinical guideline 343) aged 20‐65 years. Sampling strategy A simple random sample of eligible cases will be selected from the database of all Tayside patients with hypertension. Study design Prospective experimental Sample size Assuming SDs of systolic and diastolic blood pressure to be 20 and 10mmHg respectively16, the sample size required to detect reductions of 5 and 2.5mmHg, respectively, at the 5% significance level with 80% power, is 128. Assuming a drop‐out rate of 30%, the number of cases required is 192. Data storage and management
Data storage, extraction, anonymisation and record linkage to be performed by XYZ Data Solutions. All data will be stored in a data safe haven and accessed via a password‐protected system.
These would be determined from research and identified by WHO ICD10 codes in the patient record
Figure 3: Design of Weight Loss and CVD Study Aim(s): To investigate the relationship between weight loss and cardiovascular morbidity in Tayside patients with type 2 DM.
Population: Patients in Tayside diagnosed with type 2 DM
Interventions: None Outcomes: CVD Data collection NICE guidelines11 recommend annual risk factor assessment for CVD; therefore, values for each of the following should be available on a yearly basis from diabetic clinic appointments:
Weight: kg to 1 dp as measured by a trained HCP at outpatient appointments Height: m to 1 dp as measured by a trained HCP at outpatient appointments 2 BMI: calculated by researcher according to the formula mass (kg)÷(height (m))
Systolic and diastolic blood pressure: mmHg to 1 dp as measured by a trained HCP according to NICE guidelines1
Cholesterol: mmol/L to 2 dp (measured lipid biochemistry results)
Drugs: extracted from electronic records of prescriptions dispensed in the community
CVD: As recorded in inpatient records. Identified through ICD‐10 codes of CVD
Confounding factors: Unintentional weight loss
Inclusion and exclusion criteria Include: Patients aged 35‐65 years. Those younger than 35 are at risk of having type 1 DM rather than type 2 DM. Patients over the age of 65 are at higher risk of cardiovascular disease due to natural ageing, which would obstruct the effect of any weight loss, and are also at higher risk of unintentional weight loss due to ill health. Exclude: Patients with unintentional weight loss, patients prescribed insulin within 1 year of diagnosis because this may suggest possible type 1 DM.
Sampling strategy: All eligible Tayside patients with type 2 DM diagnosed in 2005 to be selected. This would allow observation of both short‐ and long‐term outcomes over the most recent five‐year period.
Study design: Retrospective cohort study
Sample size: All who meet the criteria
Data storage and management
Electronic data including hospital admissions, dispensed medication and laboratory results from immunology, virology and biochemistry will be extracted and anonymised by HIC according to HIC Standard Operating Procedures. Ethical approval will be obtained from the Tayside research ethics committee and databases will be used in accordance with procedures approved under the Data Protection Act and Caldicott Guardian.
Figure 4: Problems with Weight Loss and CVD Study
Measuring outcomes Outcomes found in electronic patients records rely upon the completeness and accuracy of the record keeping of others. Since we were working with anonymised patient data, the source documents could not be traced to clarify outcomes and data, and records with dubious data were thus deleted. Confounding factors In addition to intentional weight loss, drugs used to treat hypertension and hypercholesterolaemia should have been included: weight gain can make it difficult to control blood pressure and cholesterol and therefore these patients might be prescribed drugs to manage their condition. This could lead to an observed reduction in blood pressure and cholesterol with weight gain. Inclusion and exclusion criteria Excluding conditions that do not necessarily cause weight loss (such as benign neoplasms) and failing to exclude conditions that can cause weight loss (such as inflammatory bowel disease and cirrhosis) resulted in a specifically selected healthier sample of younger age in which cardiovascular outcomes were unlikely to develop. Sample size No sample size calculation was performed. All eligible cases were included and complete data were available for 570 patients.
Scottish Universities Medical Journal [Dundee] Healthcare Student Journal of Scotland
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Figure 5: Revised Design for Weight Loss and CVD Study Aim To investigate the relationship between weight loss and cardiovascular morbidity in Tayside patients with type 2 DM. Population Patients in Tayside diagnosed with type 2 DM. Interventions None Outcomes CVD as recorded in outpatient and inpatient records of primary and secondary care. Data collection NICE guidelines17 recommend annual risk factor assessment for CVD; therefore, values for each of the following should be available on a yearly basis from diabetic clinic appointments: Weight: kg to 1 dp as measured by a trained HCP at outpatient appointments Height: m to 1 dp as measured by a trained HCP at outpatient appointments BMI: calculated by researcher according to the formula mass (kg)÷(height (m))2 Systolic and diastolic blood pressure: mmHg to 1 dp as measured by a trained HCP according to NICE guidelines1 Cholesterol: mmol/L to 2 dp (measured lipid biochemistry results) Drugs: extracted from electronic records of prescriptions dispensed in the community CVD: As recorded in inpatient records. Identified through ICD‐10 codes of CVD Confounding factors Drug therapy for CVD risk factors (blood pressure and cholesterol). Inclusion and exclusion criteria Include: Patients diagnosed with type 2 DM from 1/1/2002 to 31/12/2012 Exclude: Patients prescribed insulin within 1 year of diagnosis as it may suggest possible type 1 DM, and those with co‐morbidities causing unintentional weight loss such as inflammatory bowel disease and cirrhosis. A full list of exclusion conditions to be established in discussion with a senior clinician. Sampling strategy All patients with type 2 DM in the Tayside area, who meet the inclusion and exclusion criteria, will be included in the sample. Study design Retrospective cohort
References 1. 2. 3.
4. 5. 6. 7. 8. 9.
10. 11. 12. 13. 14. 15.
Altman DG. The scandal of poor medical research. BMJ 1994;308(6924): 283‐284. Gartland JJ Jr, Werley CW. Evaluation of healed Colles’ fracture. J Bone Joint Surg Am 1951;33:895–907. Exner DV, Dries DL, Domanski MJ, Cohn JN. Lesser response to angiotensin‐converting‐enzyme inhibitor therapy in black as compared with white patients with left ventricular dysfunction. N Engl J Med 2001;344:1351‐1357. National Institute for Health and Clinical Excellence. Hypertension: management of hypertension in adults in primary care (partial update). NICE Clinical Guideline 34. London: NICE; 2006. British National Formulary. London: Joint Formulary Committee; March 2012. Altman DG. Practical Statistics for Medical research. London: Chapman and Hall; 1991. Fleiss JL. The design and analysis of clinical experiments. New York: John Wiley & Sons; 1986. Bland JM, Altman DG. Matching. BMJ 1994;309: 1128. FRANCE 24 International News 24/7[homepage on the Internet]. France [updated 2010 Feb 16; cited 2012 May 13]. Available from: http://www.france24.com/en/20100216‐soldiers‐ deliberately‐exposed‐nuclear‐tests‐says‐report. Doll R, Hill AB. "Smoking and Carcinoma of the Lung". BMJ 1950;2 (4682): 739–748. Chow S‐C, Shao J, Wang H. Sample size calculations in clinical research. New York: Marcel Dekker Inc; 2003. Abraha I, Montedori A, Romagnoli C. Modified intention to treat: frequency, definition and implication for clinical trials [abstract]. Sao Paulo, Brazil: XV Cochrane Colloquium, 2007;86‐7. Hollis S, Campbell F. What is meant by intention to treat analysis? Survey of published randomised controlled trials. BMJ 1999;319:670‐4. Begg C, Cho M, Eastwood S, Horton R, Moher D, Olkin I, Pitkin R, Rennie D, Schulz KF, Simel D, Stroup DF. Improving the quality of reporting of randomized controlled trials: the CONSORT statement. JAMA 1996; 276(8):637‐639. von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP, for the STROBE Initiative: Strengthening the reporting of observational studies in epidemiology (STROBE) statement: guidelines for reporting observational studies. BMJ 2007;335:806‐8. Haider A, Larson M, Franklin S, Levy D. Systolic blood pressure, diastolic blood pressure, and pulse pressure as predictors of risk for congestive heart failure in the Framingham Heart Study. Ann Intern Med 2003;138:10‐16. National Institute for Health and Clinical Excellence. Lipid modification: cardiovascular risk assessment and the modification of blood lipids for the primary and secondary prevention of cardiovascular disease. Clinical Guideline 67. London: NICE; 2008.
The Ethics of Acupuncture
Paul Connelly (5th year MBChB) Correspondence to: Paul Connelly : firstname.lastname@example.org
Complementary and alternative medicine (CAM) incorporates a broad range of healthcare systems and therapeutic practices that are not traditionally associated with conventional medicine. The use of CAM has increased substantially in the last 20 years and it is believed as much as a fifth of the UK population utilize this form of healthcare in some form. This article discusses some of the principles that clinicians should think about when managing patients who use CAM practices themselves or when referring patients to NHS supported CAM therapy providers using a case study. Key Words: Complementary Medicine; Acupuncture; Medical Ethics
A 49‐year old female with multiple sclerosis presented to general practice with a 9‐week history of a progressively worsening, persistent, aching, left shoulder pain. At its most severe this pain measured 8/10 on a pain scale. Previous treatments had included the use of paracetamol, diclofenac and co‐codamol. Such agents were found to be ineffective and resulted in the patient experiencing side effects such as nausea, drowsiness and indigestion. In response to the expression of dissatisfaction with conventional analgesia, the patient’s neighbour, a practice nurse, suggested the use of acupuncture to alleviate this discomfort. The patient’s local surgery incorporated 3 general practitioners that provided this therapy on the NHS. After 4 sessions the patient indicated that there had been a significant reduction in her pain. This patient also has a history of multiple miscarriages and it was suggested that she would not be able to carry a pregnancy to term. She attributes the subsequent birth of her daughter to the use of reflexology. As a consequence, this patient is very open towards the use of complementary and alternative treatments. However, when such treatments are not available on the NHS she limits their use due to the cost implications.
Complementary and Alternative Medicine
Complementary and alternative medicine (CAM) incorporates a broad range of healthcare systems and therapeutic practices and includes acupuncture, osteopathy and homeopathy that are not traditionally associated with the conventional medical profession1. The use of CAM has increased substantially in the last 20 years and it is believed as much as 20% of the UK population utilize this form of healthcare2. Although the majority of these services are offered by private practitioners, many treatments are now offered by the NHS. The integration of these treatments occurs predominantly within primary care, whereby therapies such as acupuncture may be performed by physicians3. In the treatment of disease clinicians must uphold moral, ethical and legal obligations towards their patients and therefore such principles must be addressed with regards to CAM if they are to be considered as a viable treatment option (Table 1).
Table 1. Glossary of ethical principles Principle
Respect for the patient’s wishes and right to self‐determination
The physician’s obligation to act in the best interest of the patient
The physicians obligation to do no harm
Consideration of risks and benefits to society as a whole
CAM is becoming more popular and acceptable in the UK2. In Western society the most frequent users of CAM are educated, middle class Caucasians between the ages of 25 and 494. It has been posited that patients gravitate towards CAM for numerous sociocultural and personal factors including a sense of dissatisfaction with conventional medicine, a desire for personal control in their healthcare, and philosophical congruence, whereby CAM appear more compatible with patient’s values, worldview, spiritual philosophy and meaning of health and illness5. Accordingly, this patient demonstrated frustration in the ineffectiveness of conventional analgesia, the desire to manage her condition and an active spiritual orientation, and therefore conforms to this cohort. Furthermore, this patient’s previous experience with reflexology will undoubtedly shape her views regarding her healthcare beliefs and the potential efficacy of acupuncture6. Acupuncture is defined as the practice of inserting one or more needles into specific points on the body surface for therapeutic purposes 7. This therapy is endorsed by approximately 25% of general practitioners (GPs) in the UK and is most frequently utilized for the treatment of chronic pain8. Despite originating in China 3,000 years ago the use of acupuncture remains highly controversial within the medical profession primarily due to its limited advances towards evidence based practice and in particular the paucity of randomised control trials (RCTs)9‐11. Meta‐analyses and systematic reviews investigating the potential analgesic effect of acupuncture have yet to unequivocally demonstrate an effect greater than that produced by placebo12, 13. An ethical dilemma therefore arises as a physician must question whether it is right to perform a therapeutic intervention in the absence of quantifiable efficacy in order to respect a patient’s health beliefs10.
Is the use of acupuncture in the NHS ethical?
The principle of autonomy requires the physician to respect the wishes of the patient. Adopting paternalism and disregarding a patient’s health beliefs would be detrimental to the doctor‐patient relationship by diminishing the physician’s capacity to address the physical, emotional, and spiritual manifestations of illness14. Furthermore, this would only encourage the patient to seek this therapy from private practitioners10. It is argued that the patient centred approach employed in CAM guarantees a respect for patient autonomy15, 16. However, to uphold this principle, physicians have the responsibility to ensure that patients are appropriately informed11. This obligation to obtain informed consent would therefore require the physician to discuss evidence of acupuncture and the limitations of this intervention. Some authors argue that informed consent cannot truly be obtained with regards to CAMs due its inadequate investigation, while an awareness of treatment
limitations may in turn negate any potential placebo effect and therefore violate beneficence1, 16. The ‘nihil nocere’ principle requires physicians to base treatment decisions on risk benefit analysis. Application of beneficence and non‐maleficence to acupuncture is however difficult due to the insufficient evidence supporting the substantial claims of efficacy and safety reported by some practitioners9. With only 0.0085% of the UK medical research budget spent on CAM, it is unsurprising that the potential advantages of acupuncture have yet to be elucidated17. Uncertainty is not uncommon in orthodox medicine with only an estimated 13% of treatments demonstrating robust evidence of their beneficial effects18. However, the level of ambiguity concerning the effectiveness of acupuncture, and CAM in general, is considerably greater. This patient stated that she felt more comfortable receiving this treatment from her GP who was performing this treatment in her best interests rather than to make a profit. Therefore in addition to putative analgesic effects, providing acupuncture in primary care may also improve continuity of care and strengthen patients’ trust in doctors as a consequence of addressing their health needs. This is undoubtedly advantageous with regards to patient enablement, compliance and the therapeutic effect of the doctor‐patient interaction19. Evidence regarding the risks of acupuncture such as pain, bleeding and bruising are better understood and believed to occur in 7‐11% of patients7. Despite the majority of adverse events being minor in nature, rarer complications such as a pneumothorax, cardiac tamponade, or the transmission of hepatitis C or HIV have also been documented10, 20. Nevertheless, if this treatment alleviates the suffering of patients and anecdotally exceeds the total therapeutic effect of conventional analgesia without exposing the patient to any great harm, it could be argued that such actions do serve the patient’s best interest and should be utilized. In the UK acupuncture is predominately accessed through either private practitioners or individual GPs offering this service. This therapy is time consuming, due to the requirement of frequent appointments, and largely unfunded, whereby GPs as independent contractors are not remunerated for performing such treatments. Acupuncture is therefore not available across all socioeconomic classes or geographical regions2. Assuming CAMs provide more good than harm, the unequal distribution of these therapies in the population violates the fundamental ethical principle of justice21. In order to adhere to this principle and permit patient autonomy, general access would have to be provided throughout the health service. The uniform integration of this service into the NHS will undoubtedly redistribute funds from services with stronger evidence of efficacy and therefore would be both unethical and inefficient16. Accordingly patients will experience limitation in healthcare choices until the utility of this treatment has been fully validated6.
Acupuncture regulation in Scotland
Practitioners require the competence to ensure the maximum benefit of any given treatment is delivered while imposing the least amount of acceptable risk. However, there is great disparity among the standards of practice exhibited by those providing CAM as a consequence of the diversity and informality of qualifications available and the proliferation of unregulated training bodies10. Professional self regulation aims to ensure high, uniform standards of practice22. Several professional acupuncture organizations exist, such as the British Medical Acupuncture Society; however, there is no statutory regulation of this profession and therefore no assured level of proficiency23. In Scotland, acupuncturists, who are not members of a regulated health profession, are required to be licensed with the local authority under The Civic Government (Scotland) Act 1982 in the same manner in which a
tattoo artist is required to be licensed24. The absence of a regulatory body therefore poses risks to the public through the inability to identify practitioners with adequate levels of knowledge and experience, and to hold them accountable for actions deemed to be hazardous. Nevertheless, the position relating to the regulation of health professionals, such as doctors, who wish to incorporate CAM into their reperoire of therapies is different from the position of CAM practitioners. The code of ethics and disciplinary procedures of the General Medical Council (GMC) extend to the use of all therapies utilized in treating patients. It is acknowledged that under the Medical Act 1983, a registered medical practioner is free to practice any form of unconventional therapy, including CAM, if they believe it will benefit their patients25. Consequently, additional training undertaken by this physician in this complementary discipline and subsequent reasonable practice renders his or her actions legally defensible26. However, ambiguity exists regarding whether the training of conventional healthcare professionals by professional organizations is adequate to negate risk27. Controversy regarding this regulatory arrangement also exist as a consequence of the GMC Good Medical Practice guidelines, which state that doctors ‘must provide effective treatments based on the best currently available evidence27. This would not encourage the use of acupuncture. Nevertheless, this guidance also stipulates the importance of treating pain and therefore to withold a treatment, which is providing relief, would be equally unacceptable.
Philosophical, epistemological and practical differences exist between mainstream and alternate medicine26, 28 Nevertheless, these disciplines share the goals of promoting health and relieving the suffering of patients. The integration of CAM into general practice therefore permits the utilization of a holistic approach of promoting wellness and treating disease. Despite the inadequacies of the acupuncture evidence base, to disregard this treatment and ignore cultural health beliefs would inevitably drive patients towards a largely unregulated profession and erode the doctor‐patient relationship. From the standpoint of a consequentialist, I would suggest that the utilization of acupuncture is therefore justified.
1. Sugarman J, Burk L. Physicians ethical obligations regarding alternative medicine. JAMA. 1998;280(18):1623‐5. 2. Ernst E. The BBC survey of complementary medicine use in the UK. Complement Ther Med 2000;8(32‐36). 3. Rajput M. Attitudes about acupuncture and homeopathy among doctors in research positions: a survey. J Altern Complement Med. 2005;11:229‐31. 4. Astin JA. Why Patients Use Alternative Medicine. JAMA: The Journal of the American Medical Association. 1998;279(19):1548‐53. 5. Vincent C, Furnham A. Whydo patients turn to complementary medicine? An empirical study. Br J Clin Psychol. 1996;35:37‐48. 6. Ernst E. Patient choice and complementary medicine. Journal of the Royal Society of Medicine. 2004;97:41. 7. Ernst E. Acupuncture – a critical analysis. Journal of Internal Medicine. 2006;259(2):125‐37. 8. White A, Resch K, Earnst E. Complementary medicine: use and attitudes among GPs. Fam Pract. 1997;14:302‐6. 9. Ramey D, Buell P. A true history of acupuncture. Focus Altern Complement Ther. 2004;9(269‐273). 10. Stone J. Ethical issues in complemtary and alternative medicine. Complementary Therapies in Medicine. 2000;8:207‐13. 11. Schneiderman L. Alternative Medicine or Alternatives to Medicine? A Physician's Perspective. Cambridge Quarterly of Healthcare Ethics. 2000;9(01):83‐97.
12. Masden M, Gotzsche P, Hrobjartsson A. Acupuncture treatment for pain: systematic review of randomised clinical trials with acupuncture, placebo acupuncture, and no acupuncture groups. BMJ. 2009;338(330‐3). 13. Green S, Buchbinder R, Hetrick S. Acupuncture for shoulder pain. Cochrane database of systematic reviews. 2005(2):CD005319. 14. Barrett B. Alternative, complementary, and conventional medicine: is integration upon us? . J Alt Comp Med. 2003;9:417‐27. 15. Mertz M. Complementary and alternative medicine: The challenges of ethical justification. Medicine, Health Care and Philosophy. 2007;10(3):329‐45. 16. Ernst E. The ethics of complementary medicine. Journal of Medical Ethics. 1996;22:197‐8. 17. Colquhoun D. What to do about CAM? BMJ. 2007;335:736. 18. Garrow JS. How much of orthodox medicine is evidence based? BMJ. 2007;335(7627):951‐. 19. Kearley K, Freeman G, Heath A. An exploration of the value of the personal doctor–patient relationship in general practice. British Journal of General Practice. 2001;51(470):712–8. 20. Ernst E, White A. Life‐threatening adverse reactions after acupuncture? A systematic review. Pain. 1997;71:123‐6. 21. Ernst E, Cohen M, Stone J. Ethical problems arising in evidence based complemntary and alternative medicine. J Med Ethics. 2004;30:156‐9. 22. Stone J, Matthews J. Complementary medicine and the law. Oxford: Oxford University Press; 1996. 23. Analysis report on the 2009 consultation on the statutory regulation of practitioners of acupuncture, herbal medicine, traditional Chinese medicine and other traditional medicine systems practised in the UK. In: Health Do, editor. 2011. 24. The Scottish Government. The Civic Government (Scotland) Act 1982 (Liscensing of skin piercing and tattooing) Order 2006. Edinburgh2006. 25. Great Britain. Medical Act 1983. London: HMSO; 1983. 26. Zollman C, Vickers A. Complementary medicine in conventional practice. BMJ. 1999;319(7214):901‐4. 27. Department of Health. Report to ministers from the Department of Health steering group on the statutory regulation of practitioners of acupuncture, herbal medicine, traditional Chinese medicine and other traditional medicine systems practised in the UK. London: Department of Health, 2008. 28. Kaptchuk TJ, Miller FG. Viewpoint:: What is the Best and Most Ethical Model for the Relationship Between Mainstream and Alternative Medicine: Opposition, Integration, or Pluralism? Academic Medicine. 2005;80(3):286‐90.
Declaration of Interest
Paul Connelly is a member of the SUMJ Dundee committee. This article, as with all SUMJ articles, was subject to rigorous double‐blind peer review to prevent bias.
The SUMJ Website :‐ http://sumj.dundee.ac.uk
Development of Minimally Invasive Surgical Treatment for Aortic Stenosis in Older Patients
Deepika Manoharan (4th year MBChB, BSc (Hons)) & Divya Manoharan (4th year MBChB, BSc (Hons)) : Correspondence to: Deepika Manoharan email@example.com
Aortic stenosis (AS) is the term used to describe the narrowing of the valve within the aorta (aortic valve). The restricted opening of the valve results in the obstruction of the left ventricular outflow leading to a reduced volume of blood entering the systemic circulation. Once patients develop symptoms, particularly of chest pain, breathlessness, syncope and heart failure, the prognosis becomes poor with drug treatments providing only symptomatic relief. Increasingly older patients with multi‐morbidities are developing AS and as such the traditional open‐heart surgical methods of treatment are less well tolerated or contraindicated. This article discusses some recent developments in less invasive surgical techniques for older patients with comorbid health problems which is hoped to improve outcomes for older patients with AS. Key Words: Cardiology; Aortic Stenosis; Geriatrics; Interventional Cardiology
Aortic stenosis (AS) is the term used to describe the narrowing of the valve within the aorta (aortic valve).1 This is typically noted on examination by a mid‐systolic ejection murmur. The restricted opening of the valve results to the obstruction of the left ventricular outflow leading to a limited volume of blood entering the systemic circulation.1‐2 Following the onset of symptoms especially chest pain, breathlessness, syncope and heart failure, the prognosis becomes poor with medical treatments providing only symptomatic relief (Figure 1).3‐4 Mortality rates rise rapidly to 3% within a few months and progresses to 50% in 2 years, with three quarters of patients dying within 3 years from the onset of symptoms.4‐6 In industrialised countries, AS is the most prevalent valvular heart disease due to the rise in life expectancy and the resultant effect of an expanding ageing population.3‐4,7 Degenerative/senile calcific AS is the commonest type and the disease process, recently thought to be analogous to artherosclerosis, mainly happens in the sixth, seventh and eighth decades of life.4,8 Treatment is vital and a medication‐only regime proves to be ineffective and eventually fatal in patients with significant AS. Indeed, medication regimes only treat the symptoms and complications of AS including heart failure, hypertension, increased risk of bacterial endocarditis and arrythmias. Commonly used medications include digoxin, angiotensin converting enzyme inhibitors, and loop diuretics . The most valued and recommended treatment involves the mechanical correction of the valve in selected patients as this alleviates the debilitating and life‐threatening symptoms previously mentioned.4
Signs associated with Reduced Systema}c Circulatory Volume
Bacterial Endocardi}s (pa}ents with AS at higher risk)
Figure 1 – Summary of some Key Clinical Associations with Aortic Stenosis (AS)
Aortic Stenosis & Surgery
Surgical aortic valve replacement (SAVR) is the gold standard method of treatment for those with AS and is the most widely performed valve treatment.3,9 SAVR is commonly advised in symptomatic patients and in asymptomatic patients with <50% ejection fraction in order to improve survival rates.6,9 However, the procedure is invasive and involves sternotomy, aortotomy and cardiopulmonary bypass.10‐11 Therefore, SAVR is not recommended in high‐ risk patients, particularly in the elderly, due to the invasive and complicated nature of the surgery.3 Even though old age plays an influential role in contraindicating SAVR, it is also necessary to formulate a risk/benefit ratio and use multivariate scores such as the logistic EuroSCORE score or the Society of Thoracic Surgeons risk calculator.7,9,12 Studies show that over 30%‐40% of elderly patients with severe aortic stenosis are excluded from surgical treatment owing to their advanced age, general fraility and the presence of co‐morbidities such as COPD, cerebrovascular disease, chronic kidney disease and wide‐spread artherosclerosis. In addition, some older patients do not wish to undergo cardiothoracic surgery. Hence, the unsuitability and subsequent denial of SAVR in a large proportion of elderly patients has a definite impact upon their quality of life and longevity.7 However, advancements in the last decade have led to the development of an alternative minimally invasive aortic valve replacement (AVR) method ideal for use in high‐risk elderly patients. A transcatheter aortic valve implantation (TAVI) procedure can be done either by a percutaneous or a transapical approach.13 A percutaneous method is performed by inserting the prosthesis in a delivery catheter through the femoral artery (the most common route), axillary artery or subclavian artery (all retrograde techniques). The transapical method is carried out by gaining access to the left ventricular apex through an anterolateral minithoractomy. In both methods, fluoroscopy (continuous X‐Ray monitoring showing moving structures) and echocardiography are used throughout the procedure to aid the clinician position and direct the delivery catheter with the compressed prosthetic valve to the aortic annulus where it is later expanded.12,14 Figure 2 shows the difference in size when the valve replacement is expanded. The first successful percutaneous AVR was performed by Cribier et al in 2002 and since 2008 the methodology has been quickly adapted for use throughout the globe.8 In contrast, the transapical AVR is a fairly new cardiology intervention and has been developed as an alternative method for elderly patients whom both the SAVR and the percutaneous AVR approach is contraindicated because of the presence of small, torturous or severe peripheral
vascular disease affecting the femoral, iliac or aortic vessels.9,12,14 Transapical AVR also proves to be less technically challenging than the percutaneous AVR and is performed by cardiac surgeons instead of interventional cardiologists. However, limitations to the transapical approach also exist and the procedure is not suitable in patients with left ventricular apical thrombus, aneurysm or scarring. Despite these limitations, both approaches of TAVI are still being constantly revised and developed as they are very useful procedures in high‐risk elderly candidates.9
Figure 2 – TAVI being inflated16 (Image used with permission from Papworth Foundation Trust) Recent reviews have indicated TAVI success with 30‐day survival rates being 93% and 90%, respectively, for the percutaneous transfemoral approach and 94% and 88%, respectively, for the transapical approach.11‐15 The main complications related to TAVI include arrhythmias, vascular site problems, cerebrovascular events (less common in transapical AVR), myocardial infarction and hemodynamic collapse. The higher 30‐day mortality rate of 11% in TAVI compared to the 3‐4% in SAVR is also slightly discouraging, although patients’ undergoing TAVI are typically older with more comorbidities. Indeed, one study showed that TAVI mortality proved to be lower than the operative mortality rate predicted by the EuroSCORE for high‐risk elderly patients.15 Most importantly, 1‐year mortality rate, including death from any cause, is 20% lower with TAVI than with standard medical therapy.6
The availability of less invasive treatments to AS and the opportunity of lengthening lifespan is the perfect option for elderly patients deemed unsuitable for SAVR. The invention of TAVI increases the number of elderly patients who can benefit from treatment for AS when compared to the rapid rise in morbidity and mortality that occurs with medical treatment alone.6‐7 TAVI holds the key to future change in the treatment of AS, but since the development of this technique is fairly new, it is necessary to conduct long‐term studies in patients who have undergone the procedure. Further follow‐up of large numbers of patients is necessary to draw clearer conclusions and to determine the surgical risk, complications, long‐term outcomes and cost‐effectiveness of TAVI in comparison with SAVR.9 Whether TAVI has the potential to become a therapeutic option in normal risk patients and perhaps be the next gold‐standard procedure for the treatment of AS still remains unclear. Further modifications and rigorous evaluations of the outcome of patients undergoing TAVI is necessary to answer this question and hence, younger patients who are more likely to benefit with the conventional open heart SAVR (first‐line of treatment), should not yet be considered for TAVI.12
(1) National Institute for Health and Clinical Excellence. Transcatheter aortic valve implantation for aortic stenosis. London: National Institute for Health and Clinical Excellence 2008 IPG266. (2) Faggiano P, Antonini‐Canterin F, Baldessin F, Lorusso R, D'Aloia A, Cas LD. Epidemiology and cardiovascular risk factors of aortic stenosis. Cardiovasc Ultrasound 2006 Jul 1;4:27. (3) Chiam PT, Ruiz CE. Percutaneous transcatheter aortic valve implantation: assessing results, judging outcomes, and planning trials: the interventionalist perspective. JACC Cardiovasc Interv 2008 Aug;1(4):341‐350. (4) Carabello BA, Paulus WJ. Aortic stenosis. Lancet 2009 Mar 14;373(9667):956‐966. (5) Das P, Pocock C, Chambers J. The patient with a systolic murmur: severe aortic stenosis may be missed during cardiovascular examination. QJM 2000 Oct;93(10):685‐688. (6) Leon MB, Smith CR, Mack M, Miller DC, Moses JW, Svensson LG, et al. Transcatheter aortic‐valve implantation for aortic stenosis in patients who cannot undergo surgery. N Engl J Med 2010 Oct 21;363(17):1597‐1607. (7) Lung B. Management of the elderly patient with aortic stenosis. Heart 2008 Apr;94(4):519‐524. (8) Cribier A, Eltchaninoff H, Tron C, Bauer F, Agatiello C, Sebagh L, et al. Early experience with percutaneous transcatheter implantation of heart valve prosthesis for the treatment of end‐stage inoperable patients with calcific aortic stenosis. J Am Coll Cardiol 2004 Feb 18;43(4):698‐703. (9) McRae ME, Rodger M, Bailey BA. Transcatheter and transapical aortic valve replacement. Crit Care Nurse 2009 Feb;29(1):22‐37; quiz 38. (10) Webb JG, Pasupati S, Humphries K, Thompson C, Altwegg L, Moss R, et al. Percutaneous transarterial aortic valve replacement in selected high‐risk patients with aortic stenosis. Circulation 2007 Aug 14;116(7):755‐763. (11) Descoutures F, Himbert D, Lepage L, Iung B, Detaint D, Tchetche D, et al. Contemporary surgical or percutaneous management of severe aortic stenosis in the elderly. Eur Heart J 2008 Jun;29(11):1410‐1417. (12) Walther T, Simon P, Dewey T, Wimmer‐Greinecker G, Falk V, Kasimir MT, et al. Transapical minimally invasive aortic valve implantation: multicenter experience. Circulation 2007 Sep 11;116(11 Suppl):I240‐5. (13) Bleiziffer S, Ruge H, Mazzitelli D, Schreiber C, Hutter A, Laborde JC, et al. Results of percutaneous and transapical transcatheter aortic valve implantation performed by a surgical team. Eur J Cardiothorac Surg 2009 Apr;35(4):615‐20; discussion 620‐1. (14) Lichtenstein SV, Cheung A, Ye J, Thompson CR, Carere RG, Pasupati S, et al. Transapical transcatheter aortic valve implantation in humans: initial clinical experience. Circulation 2006 Aug 8;114(6):591‐596. (15) Coeytaux RR, Williams JW,Jr, Gray RN, Wang A. Percutaneous heart valve replacement for aortic stenosis: state of the evidence. Ann Intern Med 2010 Sep 7;153(5):314‐324. Image (16) Image of TAVI being expanded in clinical practice. Image used with permission from NHS Papworth Hospital Foundation Trust. [Accessed 21/06/2012] Available from:‐ http://www.papworthhospital.nhs.uk/content.php?/our_services/cardiac_services_heart/transcathet er_aortic_valve_implantation
Clinical Anatomy Series‐ Lower Respiratory Tract Anatomy
John W. Kennedy [5th year MBChB, BMSc] Correspondence to: John Kennedy: J.Y.Kennedy@dundee.ac.uk
ABSTRACT As discussed in the previous article of this series,1 the necessity for a greater understanding of anatomy has never been more pertinent.2,3 This paper continues on from the cardiac anatomy covered in the last issue by staying in the thorax as the lower respiratory tract is reviewed and placed in a clinical context relevant to undergraduates and junior doctors.
Chest Wall and Diaphragm
It is difficult to discuss the anatomy of the respiratory system without first considering the chest wall and diaphragm, given the crucial role of these structures in respiration. The thoracic wall consists of skeletal and muscular components, extending between rib 1 superiorly and rib 12, the costal margin and the xiphoid process inferiorly. There are 12 ribs; seven ‘true’ ribs that articulate with the sternum via costal cartilage and five ‘false’ which do no not connect anteriorly. On the inferior aspect of each rib is a subcostal grove which contains a nerve, artery and vein – i.e. a neurovascular bundle.4 Between the ribs are the intercostal muscles that and allowing for alterations in thoracic volumes. These consist of three layers – the external, internal and innermost intercostal muscles. The external layer aids inspiration, whilst the internal and innermost contributes to expiration.4 The diaphragm is a thin muscular sheet that defines the lower limit of the thorax. It gains attachment at the xiphisternum, costal margin and upper lumbar vertebrae. Multiple structures pass through it, including (from anterior to posterior) the inferior vena cava, oesophagus, aorta, azygous vein and thoracic duct. It is innervated by the phrenic nerve (anterior rami of cervical spinal nerves 3, 4 and 5). Arising in the neck, the left and right phrenic nerves pass over anterior scalene muscles deep to the carotid sheath, enter the thorax posterior to the brachiocephalic veins and descend over the heart within the fibrous pericardium before piercing the diaphragm. Upon contraction, the diaphragm flattens to increase the volume within the thorax and allow for inspiration. In addition, sternocleidomastoid and the scalene muscles of the neck act as accessory muscles of respiration, which are utilised typically during respiratory distress.4 Clinical relevance Chest drain insertion is a commonly performed procedure in the management of pleural effusion, pneumothorax and empyema. To do so, a chest tube is inserted typically at the 4th or 5th intercostal space in the mid‐axillary line and passes through the intercostal muscles and parietal pleura into the pleural space. During this procedure it is important to direct the incision and drain to the superior aspect of the rib (e.g. incise over superior border of 6th rib when passing through 5th intercostal space) otherwise damage can occur to the neurovascular bundle lying in the inferiorly located subcostal groove.5 Importantly, this can produce a haemothorax due to vessel injury.6 As mentioned, both the intercostal muscles and diaphragm are vital for respiration. Therefore, any impairment of their function can be life threatening. The intercostal muscles are innervated by intercostal nerves T1 – T114 and as such, a cervical spinal cord lesion
would be required to affect all nerve roots. However, in conditions such as Guillian‐Barré syndrome, myasthenia gravis and motor neurone disease, where weakness and paralysis can occur in multiple areas, there can be a significant reduction in respiratory function, potentially leading to type 2 respiratory failure (i.e. low pO2 and high pCO2).7 Given the long route of the phrenic nerve from C3‐5 in the neck, it can be damaged at many points along its course to the diaphragm. Common causes of injury include cervical trauma (such as vertebral fracture8 and during forceps delivery of the newborn9), and malignancy in the neck and thorax,10 particularly where the nerve lies anterior to the lung hilum.4
The lungs lie within the pleural cavities. Each cavity, found lateral to the mediastinum, is lined by pleura – a layer composed of mesothelial cells and connective tissue. The pleura are subdivided into parietal and visceral components; the parietal adheres to the chest wall while the visceral covers the lungs, with a relative vacuum between the 2 layers known as the pleural cavity or space. A small volume of pleural fluid is present in this potential space between the two layers that acts to lubricate movement between the pleura during respiration. Inferiorly, below the lung bases, spaces exist between the parietal pleura adherent to the chest wall and diaphragm, known as the costodiaphragmatic recesses. These recesses expand during expiration as the lung bases move superiorly.4
In the pleural space, there is the potential for excess air (pneumothorax) or fluid (pleural effusion) to accumulate. The causes for a pleural effusion to develop are multiple, and the composition of the effusion can be split into transudates and exudates, reflecting different aetiologies (Table 1). Transudates have a low protein level (<25g/L) and generally arise due to increased venous pressure or hypoproteinaemia. For example, an increase in left ventricular diastolic pressure occurs in left sided heart failure, producing a rise in pressure within the pulmonary veins and capillaries.7 In contrast, exudates exhibit a high protein level (>35g/L) and occur as a result of increased capillary permeability, typically secondary to infection, inflammation or malignancy.11 Table 1: examples of causes for transudates and exudates
Transudates Heart failure Liver cirrhosis Nephrotic syndrome Myxoedema
Exudates Malignancy Pulmonary embolism Pancreatitis Rheumatoid arthritis
Each lung originates from the central hilum that contains a number of key structures including the pulmonary artery, two pulmonary veins, a main bronchus, bronchial vessels, nerves and lymphatics.4 The right lung is composed of three lobes that are diveded by an oblique and horizontal fissure. The oblique fissure runs between the lower and middle lobe, and the horizontal fissure runs between the middle and upper lobe. A number of structures are adjacent to the right lung, and indeed leave impressions upon its medial surface. These include the heart, inferior and superior venae cavae, azygos vein and oesophagus.4 The left lung is slightly smaller than the right due to the predominantly left sided position of the mediastinum, and is split into an upper and lower lobe by the oblique fissure. Additionally, a tongue‐like projection, called the lingula, extends from the upper lobe over
the heart anteriorly. Key structures which lie in close approximation to the medial aspect of the left lung are the heart, aortic arch, thoracic aorta and the oesophagus.4
When auscultating the chest, it is important to appreciate the surface landmarks of each lobe. This aids determining which lobe is affected by disease. On the right, the fissures are demarcated as follows: * Horizontal fissure follows the 4th intercostal space * Oblique fissure follows a curved line from the T2 spinous process posteriorly to rib 6 anteriorly4 The upper lobe is therefore auscultated superior to the 4th intercostal space, the middle lobe between the 4th intercostal space and 6th rib anteriorly, and the lower lobe inferior to the T2 spinous process posteriorly.
For the left lung the oblique fissure follows a curved line from the T2 spinous process posteriorly to the costal cartilage of rib 6 anteriorly4 The left upper lobe is therefore auscultated superior to T2 spinous process posteriorly and rib 6 anteriorly, and the lower lobe inferior to these points. In addition, the lung apices should be auscultated bilaterally above the clavicles.12 As noted, several important structures lie in close proximity to the medial aspects of the lungs. Therefore, any mass arising in this area can quickly involve a number of surrounding structures, and this will clearly affect the clinical picture. Examples of structures that may be affected and resulting symptoms are presented in Table 2. Table 2: structures in close proximity to the lungs, and symptoms arising from their dysfunction7 Anatomical structure affected Symptom Left recurrent laryngeal nerve Hoarseness Phrenic nerve Dyspnoea Sympathetic plexus Horner’s Syndrome (miosis, ptosis, anhidrosis) Oesophagus Dysphagia, postprandial coughing Pericardium Palpitations Pleura Chest pain, cough Superior vena cava Dilated neck veins, plethora, dyspnoea
The bronchial tree begins superiorly with the trachea, which is composed of ‘C’ shaped cartilage rings with an open posterior wall composed of smooth muscle. This bifurcates into the left and main bronchi at vertebral level T4/5. This is also the level of the sternomanubrial joint (i.e. the sternal angle), the pulmonary trunk, the beginning and end of the aortic arch, and the entry point of the superior vena cava into the right atrium. The right bronchus is both more vertical and wider than the left. These two main bronchi then split into lobar or secondary bronchi that supply a lobe each, and then further divide into segmental or tertiary bronchi to supply one of 10 bronchopulmonary segments in each lung. These bronchopulmonary segments are discrete functionally independent sections of lung that can be removed surgically without affecting adjacent segments. Further subdivisions occur before reaching the level of the bronchioles, the luminae of which are no longer maintained by cartilage.4
Given the more vertical course of the right bronchus and its wider lumen, aspiration more commonly affects the right lung.13 Furthermore, the right bronchus first divides into an upper lobe bronchus and the bronchus intermedius. The bronchus intermedius continues for around 5cm before dividing into the middle and lower lobe bronchi, and therefore foreign material or masses which block this bronchus will collapse both the lower and middle lobes.14 As mentioned, the bronchioles are not maintained by cartilage. They do contain smooth muscle, however, and as such can constrict (i.e. bronchoconstriction) when stimulated to do so. This mechanism of small airway constriction forms the basis of asthma.7
Pulmonary Vasculature Arteries
The pulmonary arteries arise from the pulmonary trunk and transport deoxygenated blood from the right ventricle to the lungs. The right artery is longer than the left, however both pass through the hilum of their respective lung and branch into lobar, segmental and subsegmental arteries before terminating as capillaries which line the walls of the alveoli.14 The bronchial arteries branch from the thoracic aorta and posterior intercostal arteries to supply the lung tissue and pleura. The vessels, carrying oxygenated blood, create an anastomotic network with the pulmonary arteries and veins.4
The pulmonary veins originate at the lung hilum as a superior and inferior vein. These carry oxygenated blood from the lungs to the left atrium. Some bronchial veins also join with these pulmonary vessels.4
The principle route of lymphatic drainage for the body is through the thoracic duct. This extends from vertebral level L2 to the root of the neck. It begins superior to the confluence of several lymph ducts, known as the cisterna chyli, which drains the abdomen, pelvis and lower limbs. The thoracic duct enters the thorax posterior to the aorta through the diaphragm, and traverses superiorly through the posterior mediastinum to the right of the midline. It then moves to the left in the superior mediastinum, lying posterior to the oesophagus, before entering the neck where it is joined by the left jugular and subclavian trunks that drain the left head, neck and upper limb. The thoracic duct then empties into the venous circulation at the junction between the left subclavian and internal jugular veins.4 A large palpable node in the supraclavicular area where the thoracic duct empties into the venous circulation is known as Virchow’s node, and classically indicates abdominal malignancy.7 Lymphatic drainage from the right side of the head, neck and upper limb enters circulation via the right jugular and subclavian trunks at the junction between the right subclavian and internal jugular veins.4
Pulmonary embolus (PE) is a common and potentially fatal condition. However, the diagnosis is often delayed due to non‐specific symptoms and signs which naturally worsens prognosis.15 As represented in Virchow’s triad, predisposing factors to PE include endothelial injury, stasis or turbulent blood flow, and hypercoagulable states.10
Examples of aetiological factors include16: Venous stasis: immobilisation, polycythaemia, dehydration Hypercoagulability: surgery, antithrombin III deficiency, protein S & C deficiency Surgery and trauma: particularly orthopaedic and spinal surgery Pregnancy Malignancy: particularly pancreatic and bronchopulmonary tumours Acute medical illness: e.g. inflammatory bowel disease, MI, heart failure16 Emboli often arise from the deep veins of the lower limb (i.e. DVT), such as the popliteal and femoral veins, but not exclusively as the upper limbs and right side of the heart represent other potential sites of thrombus formation. The diameter of the pulmonary artery lumen that is occluded will determine the clinical picture, hence the variability of presentation, and this is in part related to emboli size. The embolism can be characterised as central or peripheral depending on the site of occlusion; central refers to the pulmonary trunk, pulmonary arteries and lobar arteries, whereas peripheral indicates segmental and subsegmental arteries.17 Occlusion of a pulmonary arterial vessel results in increased alveolar dead space with subsequent hypoxaemia, and an elevated pulmonary arterial pressure that reduces cardiac output due to increased right ventricular afterload. Common symptoms and signs which patients’ may present with are described in Table 3. Note that ‘small/medium’ embolism refers to peripheral vessel occlusion whilst a ‘massive’ embolism involves occlusion of central arteries. A further subdivision is chronic PE, where patients experience dyspnoea, syncope on exertion, and weakness over weeks and months. Again, it is important to note the variability with which patients present, and not all symptoms and signs are likely to be evident.10 The modified Wells score can be used to calculate the likelihood of PE.18 The diagnosis of PE is primarily made with radiological investigations, however attention should be paid to the arterial blood gas (type I respiratory failure if significant embolism), D‐ dimer (excludes PE if undetectable) and the ECG (may show evidence of right heart strain: e.g. right axis deviation, right bundle branch block and T wave inversion, however the classical pattern of “S1, Q3, T3” is relatively rare).10 If a PE is suspected, a chest X‐ray (CXR) should first be performed. This may show linear atelectasis or a small pleural effusion, however these are not diagnostic. However, the importance of performing the CXR is to determine which investigation to request next: if the CXR is normal, a V/Q scan should be performed but if any abnormalities are identified on the CXR, a CT pulmonary angiogram should be carried out instead.19 However, it should be noted that less and less centres are performing V/Q perfusion scans as the availability of CT pulmonary angiograms is improving. Table 3: common symptoms and signs found in small/medium and massive PE 10 Small/medium PE Massive PE Pleuritic chest pain Severe central chest pain Dyspnoea Pale and sweaty Haemoptysis Syncope Tachypnoea Tachypnoea Localiased pleural rub Tachycardia Normal CVS examination Hypotension Elevated JVP Death
Treatment of PE involves low molecular weight heparin (weight dependent dose) for at least five days, in addition to high flow O2 and analgesia. Treatment with heparin should not be delayed until after diagnostic imaging in patients with a high suspicion of PE. In pregnancy, different treatment regimes exist, which should be consulted. If there is significant cardiovascular compromise thrombolysis with a recombinant tissue plasminogen activator, such as alteplase, should be considered (in the absence of contraindications) and urgent senior advice sought.19 It is important to review local guidelines relating to the diagnosis and management of PE, however, to optimise the delivery of care.
1‐ Parkin I, Logan B M, McCarthy M. Core Anatomy Illustrated. London: Hodder Arnold, 2007 2‐ Ellis H. Clinical Anatomy: Applied Anatomy for Students and Junior Doctors. London: Wiley‐ Blackwell, London, 2010
1. Kennedy JW. Clinical anatomy series: Cardiac anatomy. Scottish Universities Medical Journal 2012;1:1. pp.76‐80. 2. Waterston SW, Stewart IJ. Survey of clinicians' attitudes to the anatomical teaching and knowledge of medical students. Clin Anat 2005;18‐5:380‐84. 3. Turney BW. Anatomy in a Modern Medical Curriculum. Ann R Coll Surg Engl 2007;89‐2:104‐7. 4. Drake RL, Vogl W, Mitchell AWM. Gray's Anatomy for Students. Churchill Livingstone, 2005. 5. D Laws, E Neville, J Duffy. BTS guidelines for the insertion of a chest drain. Thorax 2003;58:53‐9. 6. Bailey RC. Complications of tube thoracostomy in trauma. J Accid Emerg Med 2000;17:111‐4. 7. Colledge NR, Walker BR, Ralston SH. Davidson's Principles and Practice of Medicine. 21st ed.: Elsevier, 2010. 8. Bell D, Siriwardena A. Phrenic nerve injury following blunt trauma. J Acc Emerg Med 2000;17:419‐ 20. 9. Smith BT. Isolated phrenic nerve palsy in the newborn. Paediatrics 1972;49:449‐51. 10. Kumar P, Clark M. Clinical Medicine. 6th ed.: Elsevier Limited, 2005. 11. Maskell NA, Butland RJA. BTS guidelines for the investigation of a unilateral pleural effusion in adults. Thorax 2003;58:8‐17. 12. Douglas G. Macleod's Clinical Examination. 11th ed.: Churchill Livingstone, 2005. 13. Longmore M, Wilkinson IB, Rajagopalan S. Oxford Handbook of Clinical Medicine. 6 ed.: Oxford University Press, 2004. 14. Standring S, Healy J, Johnson D, Williams A. Gray's Anatomy: The Anatomical Basis of Clinical Practice. 39 ed.: Churchill Livingstone, 2004. 15. Ozsu S, Oztuna F, Bulbul Y, et al. The role of risk factors in delayed diagnosis of pulmonary embolism. Am J Emerg Med 2011;29:26‐32. 16. Heit JA, O'Fallon WM, Petterson TM, Lohse CM, et al. Relative impact of risk factors for deep vein thrombosis and pulmonary embolism: a population‐based study. Arch Intern Med 2002;162:1245‐8. 17. Ouellette DR. Pulmonary embolism eMedicine, 2011. 18. Writing Group for the Christopher Study Investigators. Effectiveness of managing suspected pulmonary embolism using an algorithm combining clinical probability, D‐Dimer testing, and computed tomography. JAMA 2006;295:172‐9. 19. British Thoracic Society Standards of Care Committee Pulmonary Embolism Guideline Development Group. British Thoracic Society guidelines for the management of suspected acute pulmonary embolism. Thorax 2003;58:470‐83.
Telehealth‐ A Developing Medical Field
Professor Brian McKinstry (Professor Primary Care E‐Health) University of Edinburgh Correspondence to: Professor Brian McKinstry : bmckinst@firstname.lastname@example.org
Telehealth makes use of information technology and telecommunication to help to provide clinical care over distances. This article outlines the potential for improving clinical care using these interventions, the current evidence base for tele‐health programmes and the challenges to their efficacy.
Telehealth makes use of information technology and telecommunication to help to provide clinical care over distances. While initially indicated for rural communities, the technology is more widely used now for people who have difficulty physically accessing healthcare regardless of their location. In recent years increasing attention has been paid to the role of telehealth in reducing the costs of care, the premise being that patients themselves will take over routine measurements with oversight from professionals, who can advise with a brief phone‐call rather than a more time‐consuming clinic or domiciliary visit. There are an increasing number of elderly people throughout the Western world and the number with long‐term conditions is set to double in the next twenty year. This is compounded by a relative diminishing of the pool of clinically trained people throughout the world over the same time period. For many governments around the world telehealthcare is seen as a solution to this growing challenge. Telehealth has been applied in a variety of long‐term conditions. In this article I will focus on its use in the areas in which it is most frequently applied namely, congestive cardiac failure (CCF), chronic obstructive pulmonary disease (COPD), asthma, diabetes mellitus and high blood pressure (HBP). In COPD, CCF and asthma the aim of telehealth is to alert the patient and the clinician of a deteriorating clinical condition in time to allow intervention to prevent serious deterioration and hospital admission (with for example antibiotics in COPD or increased diuretic in CCF). In diabetes and hypertension it can be used to titrate medication more quickly and accurately to achieve optimal glycaemic and blood pressure control. There are several variations on how telehealth may be applied from simple open access for example by phone to a clinician,1 through video‐consulting or automatic feedback based on symptoms or physiological monitoring combined with daily monitoring from a call‐centre2 or specialist nurse or physiotherapist. Systems may be based on simple telephone landlines, mobile SMS or internet, or wired internet. Most current systems make use of a mixture of symptom checklists and physiological measures, for example oxygen saturation, pulse‐rate, spirometry/peak‐flow‐rate, temperature, weight, blood pressure and blood glucose. In COPD and CCF symptom checklists are sometimes linked to algorithms to determine the likelihood of exacerbation.
What is the evidence base? There is increasing evidence that telehealth can be effective in improving outcomes, however, there are few rigorous economic evaluations. This section will outline the current evidence base for telehealth programmes.
CCF: The current evidence base on the effectiveness of telemonitoring in the management of CHF is inconclusive.3 While the most recent meta‐analyses indicate that telemonitoring may improve clinical outcomes on patients with CHF,4‐5 these conclusions have been challenged by the findings of more recent large randomised controlled trials.6‐7 The result of a large UK RCT is expected soon.8 COPD: There have been a large number of descriptive and uncontrolled studies and some small good quality randomised controlled trials which are promising,9‐12 suggesting reduction in re‐admission rates, emergency room attendance, reduced hospital bed stays and improved quality of life. However systematic reviews in the area have been more circumspect,13‐15 drawing attention to the fact that that the telemonitoring intervention is often provided alongside enhanced care in the form of specialist nurses or other clinicians which is not available to the normal care group. It has therefore been difficult to determine if telemonitoring per se has added any value. Given the large investment required to roll‐out telehealthcare services it is essential that it is based on the best possible evidence. The results of two large RCTs9‐16 are expected soon one of which has attempted to determine the separate effects of telemonitoring. Asthma: The evidence for the use of telemonitoring in asthma is less clear when compared with routine self‐monitoring. One meta‐analysis suggests some impact in terms of preventing hospital admissions,17 but a recent large randomised trial of mobile phone use in asthma has shown no effect.18 Once again, it can be difficult to unpick the effects of telehealth from other services provided alongside it. The authors conclude that the technology might be best reserved for those with the most serious unstable disease. Diabetes Mellitus: In a systematic review of the management of diabetes using telemonitoring Paré and colleagues19 concluded that, while there was evidence that the technology may achieve a reduction of HBA1c, the scale of that reduction was small. Many of the studies considered were small and methodologically weak. They concluded that further research was required to confirm benefit and also to explore the cost‐effectiveness of the technology. Such trials have been completed and the results awaitedor are ongoing.20 Hypertension: Systematic reviews in the use of telemonitoring,21‐22 in hypertension suggest that telemonitoring in high blood pressure is effective in lowering blood pressure in people whose blood pressure has been difficult to control. Once more, many of the studies considered were methodologically weak or involved additional interventions. Qualitative work exploring telehealth from the patient and carer perspective is generally very positive in COPD and CCF.23‐24 Patients perceive improved access to care and are reassured that someone is monitoring them. Concerns that the technology might lead to increased dependence on the healthcare team and reduced self‐care is not apparent for the majority of people. On the contrary patients say that daily recording of symptoms and physiological measures has improved their knowledge of their condition and their self‐ confidence in managing their condition. Negative views are largely down to technology problems and occasionally due to concerns that clinicians may not always be watching or responding in time to symptoms. Clinical staff and service planners are less enthusiastic about the introduction of telehealthcare. While generally seeing that it will be an important part of future strategies, to some it is seen as a ‘disruptive technology,25 with little evidence base, particularly a health economic base which leads to a necessary reorganisation of care pathways. They are
worried about increased workloads as a result of improved access, time wasted by ‘false alerts’ and the creation of a group of patients obsessed with their health status. Such fears are not groundless. In a pilot study in Lothian, Scotland the introduction of telehealth in COPD led to a doubling in prescribing of antibiotics and steroids and a five‐fold increase in telephone calls. Multiple alerts were also a problem with eighty per cent of patients raising red alerts on some days.
Challenges for telehealth Large‐scale implementation One of the biggest challenges facing telehealth is in large‐scale implementation. What is possible for a small group of enthusiastic people to achieve is harder to replicate on a larger scale. Imagine the eighty per cent alert rate mentioned above if that were multiplied a hundred fold. While reliable inexpensive technology is important, what is most important is integrating telehealth within the existing or creating new clinical pathways. To achieve this clinicians have to believe that it will make their jobs easier or at the very least no harder. The evidence for this remains patchy. While patients undoubtedly like the improved care and attention that telehealth brings them, it may not be affordable as it currently stands. Improved physiological measures and algorithms It is not yet entirely clear how helpful some physiological measures are. There is a wide day‐ to‐day variation in parameters such as spirometry, pulse rate, oxygen saturation and blood pressure which can make interpretation difficult and it is not clear how in a home setting how these interact with symptoms. Newer potentially more predictive physiological measures have the potential to improve the management of patients. There is increasing interest in measuring respiratory rate and activity as early predictors of decline in COPD and CCF but it is not known if adding in such parameters will merely increase the complexity of telehealthcare without increasing its positive predictive value with respect to warning of impending clinical deterioration. One way to reduce the clinical monitoring workload is by creating new algorithms which may filter out unnecessary alerts. This must be a priority for the future of telehealth and smarter machines, using routines tailored to individuals, based on their existing risk profile and learning from their previous clinical presentations may be able to provide basic advice for example to repeat an unusual reading only contacting a professional if initial management fails or symptoms are worrying. In addition, some of the lower level monitoring could be taken over, using a social media approaches, by friends and family or even possibly by communities of patients themselves. Varying telehealth input according to need In the early phase of telehealth a single solution was applied to all patients. What has become apparent is that patients vary over time in their requirement for telehealth monitoring with more intensive input being required for example at the time of a hospital discharge and gradually, with coaching from monitoring staff, the patient taking on self‐ monitoring and no longer requiring oversight, but with a ‘hot‐line’ for advice if necessary. Newer models of telehealth will incorporate people being monitored or self‐managed at different levels.
Telehealthcare is and will become an important means of managing long term conditions. It is popular with patients. For some conditions it improves quality of care and for others the evidence is less certain, although information from large trials will be available soon. The
current evidence suggests that it may not save resources in the short term, but this may change in the longer term. However, for it to be economically viable new automated methods of monitoring and management must be found for it to realise its full potential.
1. Roberts MM, Leeder SR Robinson TD (2008). Nurse‐led 24‐h hotline for patients with chronic obstructive pulmonary disease reduces hospital use and is safe. Internal Medicine J. 38(5): 334‐40 2. The Telescot trials: COPD. www.telescot.org 3. Anker SD, Koehler F, Abraham WT (2012). Telemedicine and remote management of patients with heart failure. Lancet. 378: 731–39. 4. Maric B, Kaan A, Ignaszewski A, Lear SA (2009). A systematic review of telemonitoring technologies in heart failure. Eur J Heart Fail. 11:506–17. 5. Clark R, Inglis, S., McAlister, F (2007). Telemonitoring or structured telephone support programmes for patients with chronic heart failure: systematic review and meta‐analysis. BMJ. 334:942–51. 6. Koehler F, Winkler S, Schieber, M et al (2011). Impact of remote telemedical management on mortality and hospitalizations in ambulatory patients with chronic heart failure: the telemedical interventional monitoring in heart failure study. Circulation. 23(17):1873‐80. 7. Chaudhry SI, Mattera JA, Curtis JP, et al (2010). Telemonitoring in Patients with Heart Failure. N Engl J Med. 363:2301‐2309. 8. The Whole System Demonstrator. Kings Fund Online. 9. Casas A, Troosters T, Garcia‐Aymerich J, et al (2006). Integrated care prevents hospitalisations for exacerbations in COPD patients. Eur Respir J 28:123–30 18 10. de Toledo P, Jimenez S, del Pozo F et al (2006).Telemedicine experience for chronic care in COPD. IEEE Trans Inf Technol Biomed. 10:567–73 11. Bourbeau J, Julien M, Maltais F et al (2003). Reduction of hospital utilization in patients with chronic obstructive pulmonary disease: a disease‐specific self‐management intervention. Arch Intern Med. 163(5):585‐91. 12. Vitacca M, Bianchi L, Guerra A et al (2009). Tele‐assistance in chronic respiratory failure patients: a randomised clinical trial. Eur Respir J. 33(2):411‐8. 13. Polisena J, Tran K, Cimon K et al (2010). Home telehealth for chronic obstructive pulmonary disease: a systematic review and meta‐analysis. J Telemed Telecare. 16(3): 120‐27 14. Bolton CE, Waters CS, Peirce S et al (2011). Insufficient evidence of benefit: a systematic review of home telemonitoring for COPD. Journal of Evaluation in Clinical Practice 17: 1216‐22 15. McLean S, Nurmatov U, Liu JLY et al (2011). Telehealthcare for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. CD007718 16. Pinnock H, Hanley J, Lewis S. et al (2009).The impact of a telemetric chronic obstructive pulmonary disease monitoring service: randomised controlled trial with economica evaluation and nested qualitative study. Prim Care Respir J 18(3): 233‐235 17. McLean S, Chandler D, Nurmatov U et al (2011). Telehealth for asthma: a systematic review and meta‐analysis. CMAJ. 183 (11) 733‐742. 18. Ryan D, Pinnock H, Lee AJ et al (2012). Clinical and cost‐effectiveness of mobile phone supported self‐monitoring of asthma: multicentre randomised controlled trial. BMJ 344:e1756 19 Pare G, Jaana M, Sicotte C. Systematic Review of Home Telemonitoring for Chronic Diseases: The Evidence Base. J Am Med Inform Assoc. 2007; 14(3): 269–277 20 The Telescot diabetes trial. http://www.telescot.org/diabetes.html 21 Verberk WJ, Kessels AG, Thien T. Telecare is a valuable tool for hypertension management, a systematic review and meta‐analysis. Blood Press Monit . 2011;16(3):149‐55. 22 Omboni S, Guarda A. Impact of home blood pressure telemonitoring and blood pressure control: a meta‐analysis of randomized controlled studies. American Journal of Hypertension 2011; 24: 989‐998 23 Ure J, Pinnock H, Hanley J, et al (2012). Piloting tele‐monitoring in COPD: a mixed methods exploration of issues in design and implementation. Prim Care Respir J. 21(1):57‐64 24 Mortara A, Pinna GD, Johnson P, et al (2009). Home telemonitoring in heart failure patients: the HHH study (Home or Hospital in Heart Failure). Eur J Heart Fail. 11:312–18. 25 Bower, Joseph L. & Christensen, Clayton M. (1995). Disruptive Technologies: Catching the Wave. Harvard Business Review, January–February 1995
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Femoral Nerve Block – A Guide for Medical Students and Junior Doctors
Andrew R. Bogacz (Specialty Registrar, Department of Emergency Medicine, Ninewells Hospital) & Michael Jamison (5th year MBChB) Correspondence to: Andrew R Bogacz : email@example.com
ABSTRACT A femoral fracture is a painful and distressing traumatic injury that is commonly encountered when working in an emergency department. The incidence of femoral shaft fracture has been estimated at 1.0‐1.3 per 10,000 of population. The acute treatment of such an injury involves placement of the injured limb into a Thomas traction splint, which requires the provision of pain relief, commonly through use of a femoral nerve block. A femoral nerve block is a specific regional anaesthetic technique used by doctors in emergency medicine to provide anaesthesia and analgesia of the affected leg, to allow relief of pain from the fracture and facilitate movement of the injured limb into a splint. This article provides an educational overview of this practical procedure for junior doctors and medical students alike. We describe the technique as traditionally performed, as well as highlighting an increasingly favoured method using ultrasound as an adjunct to improve the accuracy and safety of the procedure. Key Words: Femoral Fracture, Femoral Nerve Block, Emergency medicine; Clinical Procedures
A femoral fracture is a painful and distressing traumatic injury that is commonly encountered when working in an emergency department (fig.1). The incidence of femoral shaft fracture has been estimated at 1.0‐1.3 per 10,000 of population.1 Acute treatment of such an injury involves placement of the injured limb into a Thomas traction splint for distraction. Movement of the limb exacerbates the discomfort from the fracture site, which is often compounded by spasm of the quadriceps muscles that are inadequately supported by the fractured femoral bone. Figure 1. Radiograph image of a midshaft right femoral fracture and Thomas splint. [Image: Emergency Department, Ninewells Hospital, Dundee]
A femoral nerve block is a specific regional anaesthetic technique used by doctors in emergency medicine to provide anaesthesia and analgesia of the affected leg, to allow relief of pain from the fracture and facilitate movement of the injured limb into a splint.2 Femoral nerve blocks are also used in pre‐hospital care, as well as in theatre anaesthetic practice for operations involving the femoral bone, knee and anteriomedial thigh. The superficial position of the femoral nerve in the proximal thigh and its proximity to easily identified anatomical landmarks makes the femoral nerve block a relatively straightforward technique that is easy to learn and provides a useful introduction to regional anaesthesia; a knowledge of which will be of interest to medical students and junior doctors considering careers in emergency medicine, anaesthetics or orthopaedics. Ultrasound imaging is increasingly seen as compulsory for elective central venous line placement and has become commonplace for regional anaesthesia in operating theatres. In this article we describe the technique for femoral nerve block as traditionally performed, as well as an increasingly favoured method using ultrasound as an adjunct to improve the accuracy of anaesthetic infiltration and aid the safety of the procedure.
The Femoral Nerve
The femoral nerve is derived from the lumbar plexus, arising from the ventral rami of the L2‐ L4 nerve roots. The femoral nerve descends through the pelvis, deep to the midpoint of the inguinal ligament and is found 1‐2cm lateral to the femoral artery and vein (fig.2), before dividing into terminal branches that innervate the anterior thigh muscles, hip and knee joints as well as the skin of the anteriomedial thigh. The nerve lies deep to two fascial membranes, the fascia lata and the fascia iliaca. The relative orientation of the femoral neurovascular structures, from lateral to medial, can remembered by the acronym NAVY; Nerve, Artery, Vein, Y‐fronts!
Figure 2. Right groin and thigh with surface anatomy representations of the inguinal ligament (grey) between the anterior superior iliac spine and the pubic tubercle, the femoral nerve (yellow), femoral artery (red) and femoral vein (blue). [Image: A.Bogacz]
There are many anaesthetic agents available for regional anaesthesia. Lignocaine and levo‐ bupivicaine (Chirocaine) are two of the most commonly used agents for femoral nerve block, either used alone or as a combined mixture. Lignocaine has a slightly shorter onset time and levo‐bupivicaine has a longer duration of effect. The recommended maximum safe dose of lignocaine is 3mg/kg and for levo‐bupivicaine is 2mg/kg. 3 A volume of 10‐20ml of 1% lignocaine or 0.25‐0.5% levo‐bupivicaine is usually sufficient for femoral nerve anaesthesia.
Traditional Femoral Block Technique
The patient should be lying supine, ideally with their leg extended. The pulsation of the femoral artery can be felt immediately distal to the mid‐point of the inguinal ligament, between the anterior superior iliac spine of the pelvic ilium and the pubic tubercle at the pubic symphysis. The skin should be cleaned and an aseptic technique employed.
Figure 3. Injection of local anaesthetic lateral to the palpable femoral pulse. [Image: A.Bogacz]
The injecting needle should be inserted through the skin approximately 1cm lateral to the femoral artery pulsation (fig.3), to a depth of around 2‐3cm. Aspiration should be attempted with the syringe, to check for blood from accidental vascular puncture; if blood is aspirated the needle should be withdrawn and pressure applied over the injection site for a few minutes to prevent haematoma formation, then injection can be reattempted. Local anaesthetic can be slowly infiltrated as the needle position is adjusted laterally in a fanning motion to spread the distribution of local anaesthetic. Success of the block can be assessed by checking for loss of sensation over the anteriomedial thigh and most importantly by the patient reporting a reduction of pain. The patient should be observed for signs of local anaesthetic toxicity.
Complications of Femoral Nerve Block
The proximity of the femoral artery and vein to the femoral nerve makes vascular puncture a complication associated with femoral nerve block. As with all local anaesthetic infiltration procedures it is important that the operator attempts to aspirate with the syringe to check for blood, which would highlight vascular puncture and should prevent inadvertent intravascular injection and subsequent local anaesthetic toxicity. Systemic local anaesthetic toxicity from intravascular injection or overdose can affect the cardiovascular and
neurological systems resulting in bradycardia, tachyarrythmia or asystole, hypotension, seizures, agitation or decreased conscious level and may be preceded by symptoms of dizziness, perioral paraesthesia or dysarthria.4 Inadequate or ineffective block is another complication of the technique. The fascia lata and iliaca can act as barriers to local anaesthetic infiltration; should the injecting needle not penetrate these fascias then the local anaesthetic solution will be prevented from reaching the nerve and result in ineffective block. Specific needles for regional anaesthetic use that are used in theatre anaesthetic practice will often transmit a popping sensation as each fascia is crossed. This is less easy to detect with the standard, sharp injection needles used in emergency departments or hospital wards.
Ultrasound Guided Femoral Nerve Block A simple ultrasound scanner can be used for a femoral nerve block. A mobile ultrasound scanner is often used, which is primarily designed to visualise blood vessels beneath the skin, amongst muscle, fat and connective tissue to facilitate needle guidance for vascular access procedures. Using the same visual image information, ultrasound scanners can be used to direct a needle away from vascular structures and towards a nerve for infiltration of local anaesthetic for peripheral nerve blockade. Use of an ultrasound scanner can improve the precision of the femoral nerve block technique and reduce the likelihood of the aforementioned complications by improving the accuracy of local anaesthetic infiltration around the nerve, reducing the volume of local anaesthetic agent necessary for effective block as well as providing visual confirmation of infiltration away from adjacent vascular structures.5
Figure 4. Confirming correct orientation of the ultrasound probe. There are corresponding orientation markers on the probe and monitor screen (green arrows) as well as mid‐point marker dots on the monitor image to represent the middle of the scanning surface of the probe (red arrows). [Image: A.Bogacz]
The location of the femoral nerve is identified by a method similar to the traditional technique. The patient should be lying supine with their leg extended. The femoral artery can be palpated to ensure accurate positioning of the ultrasound probe. Before attempting to visualise the nerve, the skin should be cleaned using an aseptic technique. The ultrasound probe should be covered with a protective sheath to prevent contamination of the probe and aid the sterility of the procedure. The correct orientation of the probe can be checked by tapping the end of the scanning surface of the probe beside the orientation marker and
observing a movement artefact next to the corresponding dot on the image on the monitor (fig. 4).
Figure 5. Placement of ultrasound probe over the palpable femoral pulse. [Image: A.Bogacz]
The ultrasound probe is placed over the femoral artery pulsation (fig. 5) and moved medially or laterally to visualise and identify the femoral vessels by their individual characteristics. Blood vessels appear as dark, circular areas in cross section on an ultrasound image. An artery is pulsatile and non‐compressible on an ultrasound image, whereas a vein is non‐ pulsatile and compresses/collapses when the ultrasound probe is used to apply downward pressure to the skin overlying the vessel. The compartment containing the femoral nerve appears as a speckled triangular structure lateral to the femoral artery6 (fig 6.).
Figure 6. Ultrasound image of femoral artery (red), femoral vein (blue), femoral nerve compartment (yellow), fascia lata (green) and fascia iliaca (orange). [Image: A.Bogacz]
The midpoint marker of the ultrasound probe/monitor can be positioned directly above the femoral nerve compartment and the injection needle inserted through the skin directly under the probe (fig.7).
Figure 7. Insertion of the injection needle under the mid‐point of the ultrasound probe, which is overlying the femoral nerve. [Image: A.Bogacz]
The needle can often be visualised on the ultrasound monitor, particularly with angles of insertion greater than 45 degrees. Advancement of the needle causes visible movement of the subcutaneous tissues on screen and correlates with the position of the tip of the needle. When the needle tip has crossed the fascia lata and fascia iliaca and into the femoral nerve compartment, aspiration should be attempted with the syringe to check for blood to ensure against accidental vascular puncture.
Figure 8. A small 1ml injection and small spread of local anaesthetic (left image) confirms the needle tip position within the nerve compartment. The widened spread of soft tissue with continued local anaesthetic infiltration (right image). [Image: A.Bogacz]
A 1ml ‘test dose’ of local anaesthetic can be slowly infiltrated and a corresponding small spread of local anaesthetic should be seen on the monitor to further confirm correct needle position (fig 8). Continued infiltration of local anaesthetic can proceed with visualised widening of the soft tissue space within the femoral nerve compartment and around the nerve as observed on the monitor7 (fig 8). Downward compression/movement of the nerve compartment and/or blood vessels, usually combined with spread of tissue and local anaesthetic above the nerve compartment, is suggestive of infiltration of anaesthetic above the fascial membranes and will likely result in ineffective block. Effectiveness of the block
should be assessed. Although ultrasound‐guidance should reduce the risk of complication, intravascular injection and local anaesthetic toxicity are still possible and patients should still be observed afterwards as a matter of good medical practice.
The femoral nerve block is likely to be the most widely performed lower limb regional anaesthetic procedure6 and its common use and the relative simplicity of the procedure makes the femoral nerve block a useful means to inform medical students and junior doctors of the principles, practice and complications of regional anaesthetic techniques. We hope this article has been an interesting and educational overview of a commonly used procedure for the treatment of an emergency injury, as well as an informative insight into the increasing use of ultrasound beyond the radiology department and as an adjunct for regional anaesthesia outside of theatre anaesthetic practice. The use of ultrasound is a skill that requires practice, and experience is vital to achieve competence. Interpreting ultrasound images can be bewildering at first; however, this improves with experience and becomes clearer with increasing familiarity. An experienced clinician should always supervise inexperienced operators when performing a procedure with local anaesthetic, with the availability of resuscitations facilities a prerequisite.
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Stannard, JP. Schmidt, AH. Kregor, PJ. Surgical Treatment of Orthopaedic Trauma. New York: Thieme Medical Publishers, 2007. Wyatt J, Illingworth R, Graham C, Clancy M. Oxford Handbook of Emergency Medicine. Third Edition. Oxford Medical Handbooks. Oxford: Oxford University Press. 2006. Allman KG, Wilson IH. Oxford Handbook of Anaesthesia. Second Edition. Oxford Medical Handbooks. Oxford: Oxford University Press. 2007. Di Gregorio G, Neal JM, Rosenquist RW, Weinberg GL. Clinical Presentation of Local Anesthetic Systemic Toxicity: A Review of Published Cases, 1979 to 2009. Regional Anesthesia and Pain Medicine. 2010; 35(2): 181‐187. Fingerman M, Benonis JG, Martin G. A Practical Guide to Commonly Performed Ultrasound‐ Guided Peripheral Nerve Blocks. Current Opinion in Anaesthesiology. 2009; 22: 600‐607. Szucs S, Morau D, Iohom G. Femoral Nerve Blockade. Medical Ultrasonography. 2010; 12(2): 139‐144. Popovic J, Morimoto M, Wambold D, Blanck TJJ, Rosenberg AD. Current practice of Ultrasound‐Assisted Regional Anesthesia. Pain Practice. 2006; 6(2):127‐134.
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Clinical Pathology‐ A Diagnostic Aid?
Professor Stuart Fleming (Professor of Cellular and Molecular Pathology, University of Dundee) Correspondence to: Prof Stuart Fleming: firstname.lastname@example.org
ABSTRACT Clinical pathology is now an essential component of high quality clinical care. Pathology tests are important to reaching a diagnosis in 85% of hospital patients. Indeed in some areas including oncology, infection and transplantation medicine diagnosis and optimum treatment cannot be delivered without histopathological investigation. Pathology testing is a core component of early cancer detection through screening for breast, bowel, cervix and prostate cancers. In the last twenty years pathology has moved from a useful diagnostic aid to a clinical essential.
In this article I will argue that Pathology is no longer a useful diagnostic aid but an essential component of high quality clinical care and the practice of evidence based medicine. Indeed through research and clinical trials pathology has often provided the evidence upon which modern patient management is based. The word Pathology was first used in English by Sir Phillip Sidney in his pastoral epic Arcadia (1585). Sidney, like so many Elizabethan courtiers was well educated in the classics, and in his use of ‘pathology’ he meant the study of suffering and pain (From Greek pathos; suffering and logos; study). In modern medicine it has tended to have two overlapping meanings; one academic the other clinical. Pathology, as the academic study of disease mechanisms seeking to progress our understanding of disease, is central to evidence based medical practice and the development of new treatments (1). Indeed this continuum from understanding disease to developing new drugs and testing their efficacy has been recognised by the award to Scotland by the MRC of a unique clinical research fellowship programme, the Scottish Clinical Pharmacology and Pathology programme, designed to bring together young pharmacologists and pathologists in joint research efforts. The second sense of pathology is in the use of laboratory methods for diagnosis and patient management. Clinical pathology of this type covers all the main lab disciplines including histopathology, morbid anatomy, haematology, microbiology, clinical biochemistry, immunology and genetics. The importance of these disciplines to modern medicine is emphasised by national healthcare statistics that show that 85% of hospital patients have a diagnosis made on the basis of pathology testing. In the field of histopathology, my own specialty, our major contributions are in the fields of cancer, where virtually every diagnosis depends on pathology, specific infections, inflammatory disease, transplantation and health promotion through screening. The major skills in histopathology are visual; examining and dissecting abnormal tissue, viewing slides prepared from the tissue on a microscope and adding molecular investigations which allow us to see the expression of protein and RNA in cells. Although the sophistication of microscopy and the addition of molecular methods have greatly improved the accuracy of diagnosis in recent years the principles of histopathology have remained. A skilled histopathologist examining a biopsy under a microscope is simultaneously assessing a large number of phenotypic variables that can account for the disordered physiology giving rise to the signs and symptoms experienced by patients. These visual skills then are to the histopathologist what clinical examination skills are to the GP or physician.
How do these visual assessments contribute to patient management?
Cancer screening programmes are a huge health promotion and disease prevention effort in this country. Pathology practice is an essential component of bowel, breast, cervical and prostate cancer screening (Figure 1). Bowel cancer screening is offered every two years from 50 years of age, the first invitation arrives on the week of your fiftieth birthday! The test is based on the detection of faecal occult blood (Chemical pathology), a positive test leading to an invitation to attend for the second stage of investigation by large bowel endoscopy (2). Lesions seen by the endoscopist are usually biopsied and submitted for pathological examination. These will most often be polyps, often in a pre‐malignant phase, which when removed will no longer progress to cancer. However, some of these polyps may show dysplasia and even early malignancy. The UK programme was piloted in Fife, Tayside and Grampian and it became clear during the pilot that pathologists were seeing much earlier colo‐rectal cancers than were seen previously from symptomatic patients (3). This was, of course, what was hoped, since these earlier cancers are more likely to be cured, but it has generated challenges to pathologists in their ability confidently to recognise small early cancers reliably. Scottish pathologists have therefore been at the forefront of rolling out the programme across the UK, training other pathology consultants elsewhere in the UK in the diagnosis of early bowel cancer. It is early days but the results of the screening programme are encouraging with many bowel cancers being recognised and treated earlier than previously with the potential to fulfil the aim of reducing bowel cancer mortality.
The anatomy of cancer spread ‐ staging
When a polyp has undergone malignant change the best option for cure is surgical resection. Following surgery, the resected bowel is sent to pathology for investigation. The tissue usually arrives in the pathology department fresh and this enables samples to be taken for genetics and for research. Careful examination, description and dissection of a resected tumour by an experienced pathologist are crucial to many of the treatment decisions for the patient in the post‐operative phase of their care. During the 1990s work by a pathologist, Professor Phil Quirke, and his surgical colleagues in Leeds showed that the main factor determining local recurrence and subsequent metastasis of rectal cancer was incomplete resection on the radial meso‐rectal margin (4). This work has led to changes in both surgical and pathology practice which has dramatically reduced the frequency of locally recurrent disease (5). The pathologist in his assessment of the resected tumour will make important observations such as the depth of invasion, the presence of lymph node metastases in the mesentery or vascular invasion. These data contribute to tumour staging, measured in all types of cancers, which is a way of assessing the extent of tumour spread and indirectly predicting the likelihood of metastases becoming apparent later. Different staging systems exist for different cancer types however the basic principle is the same for all, staging is an assessment of how far the tumour has spread. The staging systems use measurements of local extent of the tumour (T), the presence of lymph node deposits (N) and distant metastases (M), hence the TNM classification. Perhaps the best‐known staging system is that of Dukes staging for colorectal cancer. Whilst this was developed more than 50 years ago and cancer treatment has changed so much it is remarkable that the principles of this classification are still used as a sound guide to prognosis and treatment. The stage of any tumour therefore has a major influence on clinical decision‐making about the need for further radiation or medical oncology treatment and is soundly based on good anatomical pathology.
The diagnosis of malignancy
During the dissection the pathologist will also take samples from tumour, adjacent mucosa, other polyps and the excision margins to be processed to slides for microscopic examination by the laboratory scientific staff. The pathologist will then examine the slides to formulate a
diagnosis of the tumour type based on morphological criteria. The pathologist examines the tissue for changes in both the architecture of the tissue and in the cytology, the shape and size of cells and their nuclei. They will also look for evidence of increased proliferation rate, most usually by seeing mitotic figures, evidence of haemorrhage and necrosis and of invasion of the underlying lamina propria. All of these are the cardinal features that identify malignancy in an organ.
The classification of tumours
Within many organs there may be several different types of malignancy. In the lung we have small cell carcinoma, squamous carcinoma, adenocarcinoma, large cell undifferentiated carcinoma and other rarer types. In my own field although we know much about the genetic basis of kidney cancer the classification is based on morphology, albeit with an extremely strong correlation with known genetic changes (6, 7). These diagnoses, based on histology, are crucially important in patient management since the treatment of small cell carcinoma is different from the other types. So the dual diagnostic process of identifying malignancy and then classifying it is an important part of the pathologists work.
The assessment of cancer aggressiveness ‐ grading
In addition to using microscopy to make a diagnosis the pathologist will grade tumours by their histological appearances. Grading systems broadly examine the degree of similarity of a tumour to the tissue from which it has arisen. There are many different grading systems for different tumour types with specific histological criteria used to describe the different grades. For some the cellular differentiation is most important whereas others concentrate on nuclear changes. However, the important thing is that these are all indirect measures of the biological aggressiveness of the tumour.
Molecular changes and therapeutic decisions
Pathologists are key to the identification of important molecular changes that influence management decisions. The best established of these is seen in the pathology of breast cancer. Two types of change are particularly important ‐ hormone receptor expression and Her2 amplification. Nowadays the most reliable way to identify the expression of oestrogen and progesterone receptors is by using immunocytochemistry. In this technique antibodies to the two different hormone receptors are used to stain slides of tumour with the antibody binding then visualised by colour based staining. The intensity of the stain reflects the level of antibody binding and hence the level of receptor expression. Immunocytochemistry allows the pathologist to confirm that it is indeed the tumour cells expressing the receptor and not adjacent normal tissue, a problem which confounded earlier biochemistry testing(8). The pathologist can then score each breast cancer for oestrogen or progesterone receptor expression which will determine the likelihood of response to Tamoxifen treatment. One of the other important alterations in breast cancer is amplification of the Her2 gene leading to overexpression of the Her2 member of the epidermal growth factor receptor family and receptor driven cancer cell survival and proliferation. With the development of a humanised monoclonal antibody targeting Her2, trastuzamab or Herceptin, testing for Her 2 amplification became important. Although initially done using fluorescent in situ hybridisation (FISH) directly to visualise the amplified portion of the genome this is now performed using either immunocytochemistry alone or in combination with FISH (9, 10). These tests performed on pathology slides from the tumour are now used to identify those women likely to respond to Herceptin. Furthermore some tumours fail to express any of these markers, so called triple negative breast cancer, and these are managed differently again.
In some tumours molecular testing for oncogenic mutations is used to guide therapy. Lung cancers are frequently driven by overexpression of the epidermal growth factor receptor and are now treated by a humanised monoclonal antibody directed to the receptor. However, the EGFR signalling pathway includes the KiRas oncogene so when mutation of KiRas is also present tumour cell growth is driven preferentially by Ras rather than EGFR. In patients with mutant KiRas bearing tumours EGFR directed treatment is ineffective. Pathologists now routinely test for KiRas mutations in these lung cancers and anti‐EGFR treatment is only used for those cases with EGFR overexpression and lacking KiRas mutation (11). Therefore pathology and pathology based molecular analysis beyond traditional histology are now used in critical therapeutic decision making.
Pathology and infection
Although Medical Microbiology emerged as a separate discipline decades ago histopathology contributes significantly to the diagnosis of some infections. When I was a medical student gastritis, peptic ulcer disease and gastric cancer were huge health care problems leading to gastrectomies, vagotomies and patients being treated for years with various drug treatments. That was changed dramatically by one of the most important medical discoveries during my professional life made by a pathologist, a gastroenterologist and a medical student doing a summer vacation project. Helicobacter pylori, a difficult to detect gram negative organism, was found by Barry Marshall and Robin Warren in the stomachs of patients with gastritis and peptic ulcers. They went on to show that it was pathogenic in these situations but also in gastric cancer and lymphoma. Diseases which previously required major surgery with a high morbidity and mortality could now be controlled in most patients by a course of appropriate antimicrobial therapy. For this remarkable work they deservedly won the Nobel Prize for Medicine in 2005 (12). Identification of Helicobacter in gastric biopsies, usually by Giemsa staining, is now an important component of the treatment of patients with upper gastrointestinal symptoms (Figure 2). In my own field of renal and transplant pathology the histopathological identification of opportunistic infection, particularly by viruses such as CMV and BK virus, in renal transplant biopsy is a frequent problem (13). Since the clinical differential diagnosis is often between rejection or infection this is an important diagnosis to make. The transplant patient experiencing rejection needs to increase his or her immunosuppression but that could be potentially life threatening in the patient with CMV infection. So the demonstration of viral nephropathy by a combination of morphology and immunocytochemistry and its distinction from rejection is an important part of the renal transplant team’s care of the kidney recipient.
Histopathology has played a key role in identifying new diseases and in dissecting the pathogenesis. The most high profile of these in recent times has been the discovery of a new form of Creutzfeldt Jacob disease (CJD) caused by dietary exposure to the prion responsible for bovine spongiform encephalopathy (BSE). BSE, or as the tabloid press would have it ‘mad cow disease’, emerged as a significant veterinary health care problem amongst dairy herds in England in the late 1980s. Initially government played down the relevance to human health, but the discovery of variant CJD by James Ironside a neuropathologist, based on unusual histopathological features changed that perception. Ironside showed that this was a new disease, the clinical features were unusual in that it affected younger patients and eventually he, with others, proved the link with the BSE prion (14, 15). Histopathology remains the only robust diagnostic criterion for variant CJD(16, 17). A major public health response was put in place aiming to reduce exposure of the population to potentially
contaminated bovine tissues by exclusion from the food chain. These public health measures have eventually been successful and after a peak incidence early this century variant CJD is now declining in frequency. Hundreds of lives have been saved by the histopathological discovery of new variant CJD and the resulting public health response. Histopathology is no longer regarded as a diagnostic aid but in many fields, cancer, renal medicine, hepatology, dermatology, neurosurgery and transplantation to name but a few, it is an essential component of patient management. It is incorporated into clinical decision making through multidisciplinary team meetings which are now a standard of care throughout hospital practice. In all health care economic analysis pathology services emerge as one of the most cost effective branches of medicine. Pathology training in Scotland remains at the forefront with four training schools centred on the four clinical medical schools of Aberdeen, Dundee, Edinburgh and Glasgow. Figure 1. Pathology involvement (*) in bowel cancer screening
Bowel cancer screening invitation Faecal occult blood testing* If positive invitation for endoscopy Lesional (polyp) biopsy Histopathological diagnosis* Diagnosis of malignancy* Bowel cancer resection surgery Pathology diagnosis, staging and grading* Post operative management plan and implementation This figure highlights that pathology is a fundamental aspect of good clinical management of tumours. It helps guide treatment and aids clinicians discuss prognosis with the patient.
Figure 2. Histopathological examination of a gastric biopsy from a middle aged man with upper abdominal discomfort and pain shows an active chronic gastritis (LEFT) H&E X200. The causative Helicobacter organisms are readily seen in a Giemsa stained section of the biopsy ‐ Giemsa X1000 (RIGHT).
References 1. Muir RS, Levison DA. Muir's textbook of pathology. 14th ed. / edited by David A. Levison ... [et al.]. ed. London: Hodder Arnold; 2008. 2. Thompson MR, Steele RJ, Atkin WS. Effective screening for bowel cancer: a United kingdom perspective. Dis Colon Rectum. 2006 Jun;49(6):895‐908. 3. Steele RJ, McClements PL, Libby G, Black R, Morton C, Birrell J, et al. Results from the first three rounds of the Scottish demonstration pilot of FOBT screening for colorectal cancer. Gut. 2009 Apr;58(4):530‐5. 4. Adam IJ, Mohamdee MO, Martin IG, Scott N, Finan PJ, Johnston D, et al. Role of circumferential margin involvement in the local recurrence of rectal cancer. Lancet. 1994 Sep 10;344(8924):707‐11. 5. Scott N, Jackson P, al‐Jaberi T, Dixon MF, Quirke P, Finan PJ. Total mesorectal excision and local recurrence: a study of tumour spread in the mesorectum distal to rectal cancer. Br J Surg. 1995 Aug;82(8):1031‐3. 6. Fleming S. The impact of genetics on the classification of renal carcinoma. Histopathology. 1993 Jan;22(1):89‐92. 7. Kovacs G, Akhtar M, Beckwith BJ, Bugert P, Cooper CS, Delahunt B, et al. The Heidelberg classification of renal cell tumours. J Pathol. 1997 Oct;183(2):131‐3. 8. Paterson DA, Reid CP, Anderson TJ, Hawkins RA. Assessment of oestrogen receptor content of breast carcinoma by immunohistochemical techniques on fixed and frozen tissue and by biochemical ligand binding assay. J Clin Pathol. 1990 Jan;43(1):46‐51. 9. Kay E, O'Grady A, Morgan JM, Wozniak S, Jasani B. Use of tissue microarray for interlaboratory validation of HER2 immunocytochemical and FISH testing. J Clin Pathol. 2004 Nov;57(11):1140‐4. 10. Ellis IO, Bartlett J, Dowsett M, Humphreys S, Jasani B, Miller K, et al. Best Practice No 176: Updated recommendations for HER2 testing in the UK. J Clin Pathol. 2004 Mar;57(3):233‐7. 11. Langer CJ. Roles of EGFR and KRAS Mutations in the Treatment Of Patients With Non‐Small‐ Cell Lung Cancer. P T. May;36(5):263‐79. 12. Pincock S. Nobel Prize winners Robin Warren and Barry Marshall. Lancet. 2005 Oct 22‐ 28;366(9495):1429. 13. Johnston O, Jaswal D, Gill JS, Doucette S, Fergusson DA, Knoll GA. Treatment of polyomavirus infection in kidney transplant recipients: a systematic review. Transplantation. May 15;89(9):1057‐70.
14. Will RG, Ironside JW, Zeidler M, Cousens SN, Estibeiro K, Alperovitch A, et al. A new variant of Creutzfeldt‐Jakob disease in the UK. Lancet. 1996 Apr 6;347(9006):921‐5. 15. Ironside JW. Neuropathological findings in new variant CJD and experimental transmission of BSE. FEMS Immunol Med Microbiol. 1998 Jun;21(2):91‐5. 16. Ironside JW, Head MW, Bell JE, McCardle L, Will RG. Laboratory diagnosis of variant Creutzfeldt‐Jakob disease. Histopathology. 2000 Jul;37(1):1‐9. 17. Will RG, Zeidler M, Stewart GE, Macleod MA, Ironside JW, Cousens SN, et al. Diagnosis of new variant Creutzfeldt‐Jakob disease. Ann Neurol. 2000 May;47(5):575‐82.
Submitting Articles to the SUMJ The SUMJ is an online and print journal open to all healthcare students studying in Scotland. If you wish to submit to the SUMJ the deadlines for each of our editions are noted below: •
Winter Edition February [Deadline for submissions is October 31st]
Summer Edition August [Deadline for submissions is April 30th]
Electronically Published Articles [Submissions open through the year]
Please attach copy of your submission to the new Editor Katherine Walker K.Z.Walker@dundee.ac.uk Please include the type of article (e.g. case report, research) you are submitting in the subject line and a cover letter. The guidelines for article submission can be found on the SUMJ Dundee website (http://sumj.dundee.ac.uk). The submitted article should be in Microsoft Word format and contain a declaration indicating that it is your own work. If you are submitting a case report you must submit a signed form by the patient in line with confidentiality considerations.
The Treatment of Idiopathic Pulmonary Fibrosis: an unmet clinical need
Dr Philip M Short (Registrar in Respiratory Medicine, Royal Infirmary of Edinburgh) & Dr Nik Hirani (Consultant Respiratory Physician, University of Edinburgh) : Correspondence to: Philip Short email@example.com
ABSTRACT Idiopathic Pulmonary Fibrosis (IPF) is a progressive lung condition with no clear underlying definitive cause. This article will discuss previous landmark studies in IPF and review current and potential future treatment options. Key Words: Idiopathic pulmonary fibrosis; respiratory medicine; restrictive lung disease
Whilst many causes of pulmonary fibrosis can be identified and treated, including sarcoidosis, hypersensitivity pneumonitis such as bird‐fanciers’ lung and drug induced causes including methotrexate, bleomycin and nitrofurantoin, the management of idiopathic pulmonary fibrosis (IPF) is largely palliative, with no proven effective therapy. IPF describes a progressive condition of characteristic clinical symptoms and signs including breathlessness and fine basal inspiratory crackles (90% of cases) and the presence of finger clubbing (49‐66% of cases).1,2 In addition to these findings, in IPF patients, upon lung biopsy pathological evidence of usual interstitial pneumonia (UIP) can be found in addition to the characteristic HRCT appearance of bibasal sub pleural reticular opacities with honeycombing.3 Other interstitial lung diseases can present with clinical and radiological features very similar to IPF, notably non‐specific interstitial pneumonia (NSIP). However distinguishing IPF from other similar conditions is important given that the 5 year‐survival in IPF is usually <20%, compared to >50% for NSIP3 Accurate diagnose of IPF requires integration of clinical radiological and where available histological data in a multi‐disciplinary setting. This article will review the previous and current management strategies of IPF and discuss potential future treatment options.
Mr HS is a 60 year‐old‐man and presented to the respiratory outpatient clinic with a 14 months history of worsening shortness of breath. Mr HS described how his breathlessness was worse on exertion and was associated with a dry cough. Mr HS has never smoked and works as a school‐teacher. He has a history of hypertension and hypercholesterolaemia and has a family history of ischaemic heart disease. He has no history of asbestos exposure and does not have any pets. He lives at home with his wife, who is in good health. He takes ramipril and simvastatin. On examination Mr HS has evidence of finger clubbing. Bibasal crackles were heard on chest auscultation. Chest radiography was abnormal with bi‐basal fine reticular shadowing and HRCT showed established pulmonary fibrosis with honeycombing (see figure 1). Spirometry showed a restrictive pattern with a reduced carbon monoxide transfer factor (TLCO).
Fig 1. HRCT showing peripheral honeycomb appearance consistent with IPF.
Mr HS underwent a surgical lung biopsy that showed a usual interstitial pneumonia pattern of disease. In view of the clinical history and radiological and pathological investigations a diagnosis idiopathic pulmonary fibrosis was made. Mr HS has asked about possible treatment options and the evidence for each. The most relevant drugs that may be applicable in this setting are discussed below.
N‐acetylcysteine, Azathioprine and Prednisolone Therapy Historically corticosteroids, often at high dose (e.g. prednisolone 60mg/day or higher) were given alone for the treatment of IPF due to largely observational studies reporting subjective improvements in patient outcome. However there are no randomised controlled studies which directly support the use of corticosteroid monotherapy in IPF and as a result a Cochrane Review concluded that there was no evidence for this approach.4 Several randomised controlled trials have however focussed upon the use of corticosteroids as an adjunct to immunosuppressive therapy in IPF patients. Raghu et al performed a clinical trial, where 27 patients with IPF were randomised to either prednisolone with azathioprine versus prednisolone alone. 5 In this small study, a survival benefit was seen with the prednisolone with azathioprine group in comparison with prednisolone alone. However there was no significant difference between survival until after 9 years follow up. As we know that the median survival of IPF is approximately 3 years,6 it is unclear whether the patients in the study had typical IPF by current diagnostic criteria. In addition, there was no placebo group in this study, and indeed there are no randomised controlled trials that compare corticosteroids and immunosuppressive therapy versus placebo. Despite these shortcomings, for the subsequent 15 years at least, prednisolone and azathioprine was advocated as a reasonable, but unproven treatment strategy for IPF. N‐actetylcysteine (NAC) is the derivative of the amino acid L‐cysteine and is the precursor in the formation of the anti‐oxidant glutathione. Glutathione deficiency has been found in patients with IPF.7 With these observations studies began to focus upon the use of N‐ acetylcysteine in the treatment of IPF,8 and culminated in a large phase 3 trial in IPF patients. The INFIGENIA study was a double‐blind controlled trial where each patient received prednisolone and azathioprine and were then randomised to receive NAC or matched
placebo9. In 155 patients, with radiological imaging consistent with IPF, the use of NAC was associated with a preservation of lung function. Whilst neither treatment regimes halted a decline in lung function, forced vital capacity (FVC) and transfer factor (DLCO) were 9% and 24% greater in the NAC group after 1 year follow up. Although this study did not compare NAC versus placebo alone, these findings resulted in a treatment regime of prednisolone, azathioprine and NAC being considered by some clinicians as “standard treatment” for patients with IPF, effectively replacing the previously considered ‘standard’ of prednisolone and azathioprine. Since there was no true placebo group (i.e. patients that did not receive any active drug) it cannot be determined whether there were actually any beneficial effects with NAC in IPF or whether NAC simply reduced the potential side effects attributable to prednisolone and azathioprine.10 In order to partially address the unanswered questions raised by the INFIGENIA study, the PANTHER study, was designed to assess whether there were any benefits with NAC, prednisolone and azathioprine treatment versus no therapeutic treatment.11 As of October 2011, PANTHER had enrolled 238 out of the 390 expected participants. The three treatment limbs within the study were NAC, prednisolone and azathioprine versus NAC alone versus placebo. Interim data released by the National Heart Lung and Blood Institute, found that participants treated with NAC, prednisolone and azathioprine had increased mortality (11% versus 1% in placebo limb), serious adverse events (31% versus 9% in placebo limb) without any evidence of therapeutic benefit.12 Due to these findings the treatment limb including NAC, prednisolone and azathioprine was stopped. No safety issues identified with participants with the NAC treatment limb and as a result the study has been continued comparing NAC alone versus placebo. This will help us to determine whether or not NAC monotherapy has any benefit in IPF for the treatment of IPF. These interim findings of the PANTHER study highlight the fundamental importance of performing placebo‐controlled trials in IPF. Understandably when “standard” therapies have been established with or without an evidence base, it can be ethically challenging to perform clinical trials including placebo limbs as these are seen to be denying participants putatively beneficial treatments. Pending the final outcome of the PANTHER study, international guidelines do not recommend the use of NAC, prednisolone or azathioprine, as monotherapy or combined therapy, for the majority of patients with IPF.13 Pirfenidone Pirfenidone is a pyridone compound that has been investigated as a therapy for IPF. Pirfenidone has been shown to inhibit fibroblast proliferation and collagen synthesis in vitro, 14,15 and has also been shown to ameliorate bleomycin induced pulmonary fibrosis in murine models. 16,17 Whilst both open‐labelled and placebo controlled studies have been performed looking at the potential benefits of pirfenidone, the impact of these studies was limited due to issues including small sample size, premature trial termination and change of primary endpoint.18‐20 The CAPACITY programme, included 2 concurrent phase 3 multi‐centre randomised controlled trials investigating the role of pirfenidone in patients with mild‐to‐ moderate IPF.21 Patients were randomised to either pirfenidone or matched placebo for 72 weeks. In study 004, 174 patients were assigned to high dose pirfenidone, 87 to low dose pirfenidone and 174 to placebo. In study 006, 171 patients were assigned to the same high dose of pirfenidone used in study 004 and 173 to placebo. The primary endpoint for the CAPACITY programme, in common with most recent studies in IPF, was based upon measures of lung function with the change in FVC % predicted at 72 weeks being used in each case. Despite the same endpoint being used for both studies the results were conflicting. In study 004, high‐dose pirfenidone significantly reduced the
decline in percentage predicted FVC with an effect size of 4∙4% at week 72; but in study 006, there was no difference between the groups in the primary endpoint at week 72. However, in study 006 a consistent pirfenidone treatment effect was found up to week 48. When the results of both studies were pooled together, significant improvements were found with pirfenidone treatment in both lung function and exercise tolerance. These findings led the authors to conclude that pirfenidone was an appropriate treatment option for patients with IPF. At present the potential use of pirfenidone for the treatment of IPF in the United Kingdom is being reviewed and evaluated by the National Institute of Clinical Excellence (NICE).22
Alternatives to Drug Therapy Lung Transplantation and Best Supportive Care Lung transplantation has the potential to significantly improve survival in selected patients with IPF However, the risks of transplantation rise considerably in patients over the age of 60 yrs. Since the median age of presentation in IPF is around 70 yrs, only a small fraction of patients will be eligible for transplantation. Younger patients with IPF who are deemed suitable for lung transplantation should be referred to a transplant centre if the disease is advanced or progressive based upon changes in lung function following serial monitoring.3 The estimated 5‐year survival post‐transplant is encouraging at 50‐56%.23,24 For the vast majority of patients in whom lung transplantation is not an option, best supportive care remains the cornerstone of IPF management. Best supportive care involves managing patients’ symptoms and includes the use of oxygen therapy, pulmonary rehabilitation, prescription of analgesics/anxiolytics and close monitoring thereby achieving early recognition of terminal decline and liaison with palliative care specialists when appropriate.3
There is no doubt that an effective treatment for idiopathic pulmonary fibrosis is urgently needed. Whilst previous treatments have in part been based upon small studies and observational work, the importance of placebo‐controlled trials is clearly seen within the evolution of potential treatments for IPF. Whilst some medical therapies offer promise to the management of IPF at present the management of patients with idiopathic pulmonary fibrosis is extremely challenging. When dealing with patients who are aware they have a progressive disease, the lack of curative treatment, results in patient care being focused upon symptom control and maintaining quality of life. Whilst lung transplantation can be considered for the minority, for the majority, enabling best supportive care and recruitment to high quality clinical trials, ideally coordinated through specialist IPF clinics, remains the best treatment option.
References 1. Turner‐Warwick M, Burrows B, Johnson A. Cryptogenic fibrosing alveolitis: clinical features and their influence on survival. Thorax 1980;35:171‐80. 2. Johnston ID, Prescott RJ, Chalmers JC, Rudd RM. British Thoracic Society study of cryptogenic fibrosing alveolitis: current presentation and initial management. Fibrosing Alveolitis Subcommittee of the Research Committee of the British Thoracic Society. Thorax 1997;52:38‐44. 3. Bradley B, Branley HM, Egan JJ, et al. Interstitial lung disease guideline: the British Thoracic Society in collaboration with the Thoracic Society of Australia and New Zealand and the Irish Thoracic Society. Thorax 2008;63 Suppl 5:v1‐58. 4. Richeldi L, Davies HR, Ferrara G, Franco F. Corticosteroids for idiopathic pulmonary fibrosis. Cochrane Database Syst Rev 2003:CD002880.
5. Raghu G, Depaso WJ, Cain K, et al. Azathioprine combined with prednisone in the treatment of idiopathic pulmonary fibrosis: a prospective double‐blind, randomized, placebo‐controlled clinical trial. Am Rev Respir Dis 1991;144:291‐6. 6. Hubbard R, Johnston I, Britton J. Survival in patients with cryptogenic fibrosing alveolitis: a population‐based cohort study. Chest 1998;113:396‐400. 7. Cantin AM, Hubbard RC, Crystal RG. Glutathione deficiency in the epithelial lining fluid of the lower respiratory tract in idiopathic pulmonary fibrosis. Am Rev Respir Dis 1989;139:370‐2. 8. Behr J, Maier K, Degenkolb B, Krombach F, Vogelmeier C. Antioxidative and clinical effects of high‐dose N‐acetylcysteine in fibrosing alveolitis. Adjunctive therapy to maintenance immunosuppression. Am J Respir Crit Care Med 1997;156:1897‐901. 9. Demedts M, Behr J, Buhl R, et al. High‐dose acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med 2005;353:2229‐42. 10. Hunninghake GW. Antioxidant therapy for idiopathic pulmonary fibrosis. N Engl J Med 2005;353:2285‐7. 11. McGrath EE, Millar AB. Hot off the breath: triple therapy for idiopathic pulmonary fibrosis‐‐ hear the PANTHER roar. Thorax 2012;67:97‐8. 12. http://www.nhlbi.nih.gov/new/pantherQA.htm (Accessed 02/05/2012) 13. Raghu G, Collard HR, Egan JJ, et al. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence‐based guidelines for diagnosis and management. Am J Respir Crit Care Med 2011;183:788‐824. 14. Hirano A, Kanehiro A, Ono K, et al. Pirfenidone modulates airway responsiveness, inflammation, and remodeling after repeated challenge. Am J Respir Cell Mol Biol 2006;35:366‐77. 15. Nakazato H, Oku H, Yamane S, Tsuruta Y, Suzuki R. A novel anti‐fibrotic agent pirfenidone suppresses tumor necrosis factor‐alpha at the translational level. Eur J Pharmacol 2002;446:177‐85. 16. Oku H, Nakazato H, Horikawa T, Tsuruta Y, Suzuki R. Pirfenidone suppresses tumor necrosis factor‐alpha, enhances interleukin‐10 and protects mice from endotoxic shock. Eur J Pharmacol 2002;446:167‐76. 17. Iyer SN, Wild JS, Schiedt MJ, Hyde DM, Margolin SB, Giri SN. Dietary intake of pirfenidone ameliorates bleomycin‐induced lung fibrosis in hamsters. J Lab Clin Med 1995;125:779‐85. 18. Raghu G, Johnson WC, Lockhart D, Mageto Y. Treatment of idiopathic pulmonary fibrosis with a new antifibrotic agent, pirfenidone: results of a prospective, open‐label Phase II study. Am J Respir Crit Care Med 1999;159:1061‐9. 19. Taniguchi H, Ebina M, Kondoh Y, et al. Pirfenidone in idiopathic pulmonary fibrosis. Eur Respir J 2010;35:821‐9. 20. Collard HR. Idiopathic pulmonary fibrosis and pirfenidone. Eur Respir J 2010;35:728‐9. 21. Noble PW, Albera C, Bradford WZ, et al. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet 2011;377:1760‐9. 22. http://guidance.nice.org.uk/index.jsp?action=byID&o=13039 (Accessed 02/05/2012) 23. Mason DP, Brizzio ME, Alster JM, et al. Lung transplantation for idiopathic pulmonary fibrosis. Ann Thorac Surg 2007;84:1121‐8. 24. Keating D, Levvey B, Kotsimbos T, et al. Lung transplantation in pulmonary fibrosis: challenging early outcomes counterbalanced by surprisingly good outcomes beyond 15 years. Transplant Proc 2009;41:289‐91.