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Volume 9, Issue 1 | 2019

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Medicine of our past and future... Guest

Dr Vitali Sintchenko: Unlocking the benefits of public health surveillance

Guest

Dr Mileham Hayes: A (constructive) criticism of medical curricula

Review

Benjamin Kalma: Overview of preoperative fasting for general anaesthesia www.amsj.org


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AM S J Australian Medical Student Journal Volume 9, Issue 1 | 2019


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Contents Page

Article

7 8 10 14 16 22

Affiliation Author/s

Editor’s welcome

A M Jae Lee S J

The development of professionalism and professional identity: the recognition and roles of intellectual humility, a growth mindset, and situational awareness

Guest

A/Prof Stuart Lane

A (constructive) criticism of medical curricula

Guest

Dr Mileham Hayes

Unlocking the benefits of public health surveillance

Guest

Dr Vitali Sintchenko

The association between pre-pregnancy body mass index and gestational weight gain (GWG) among women in rural NSW, Australia

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Dr Anna Power et al

Xanthomas seen on capsule endoscopy: What are they saying about your patient’s health?

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Dr Mian Li Ooi et al

Nanoparticle administration across the blood-brain barrier using MRI-guided focused ultrasound

26 30 36 41 45 50 54 58 64

Dr. Benjamin van Haeringen et al

Overview of preoperative fasting for general anaesthesia

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Benjamin Kalma

Management of burn wound pain in the hospital setting

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Tobias Richards et al

Paediatric simulation teaching for medical students: a review of current literature

8

Molecular Mechanism of Depression: A narrative review of the leading neurobiological theories of Depression

14

David Vu

A patient with right striatocapsular stroke complicated by relative adrenal insufficiency

13

Dr Anita M Smith et al

Book Review - Dermatology truly made easy

Ashani Mahawattege et al

Dr Nicholas van Rooij

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Susanna Sodini et al

A Review of Breath Metabolic Profiling for Non-invasive Testing in Inflammatory Bowel Disease Patients

6

Michaela Prove

TGA Reform and Why You Should Care About It

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Amy Vaux

Australian National University Bond University Deakin University Flinders University Griffith University James Cook University Monash University University of Adelaide University of Melbourne University of Newcastle University of New England University of New South Wales

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Dr Huy Duc Vu

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Australian Medical Schools 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.

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Prognostic and predictive clinical, pathological, and molecular biomarkers in metastatic colorectal carcinoma – a review

Efficacy and Safety of Allergen Immunotherapy to Treat House Dust Mite Allergic Asthma in Children

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13. University of Notre Dame (Fremantle) 14. University of Notre Dame (Sydney) 15. University of Queensland 16. University of Sydney 17. University of Tasmania 18. University of Western Australia 19. University of Western Sydney 20. University of Wollongong 21. Curtin University 22. Macquarie University

Australian Medical Student Journal


Become a GP

Volume 8, Issue 2 | 2018

Having recently graduated from medical school, Daniel is looking forward to a career that will give him both variety and flexibility. Which is why he wants to become a GP. As a GP, he’ll be the first port of call for an ever-changing variety of medical issues. So no two days will ever be the same. He’ll also become a part of his patients’ lives, building relationships and providing ongoing care. And he can do it just about anywhere he wants. As Daniel says, ‘I see general practice as a way that I’ll be able to develop a wide skill set, while living in a place that fits in with my passion for outdoor activities’. To learn more about Daniel’s story and to become a free student member of the RACGP, visit becomeaGP.org.au

becomeaGP

Daniel

Australian Medical Student Journal

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The AMSJ accepts submissions from all medical students in Australia. What makes the AMSJ unique is that it provides the opportunity to show-case your work within the academic rigours of a peerreviewed biomedical journal whilst sharing your ideas with thousands of students and professionals across the country. Whether your passions lie in advocacy, education or research, you can submit to the AMSJ today.


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Welcome Editor’s welcome Jae Lee Editor-in-Chief, AMSJ

W

elcome to Volume 9, Issue 1 of the Australian Medical Student Journal (AMSJ). AMSJ is a journal exclusively for all medical students in Australia. We pride ourselves as a platform to provide opportunities to publish and gain medical knowledge for Australian medical students. We are a peer-reviewed journal that aims to present high quality medical student’s research, perspectives and current issues in medicine. In this, we present past medicine and future medicine, where we review medical knowledge from the past and introduce exciting new approaches to medicine that may change the future of practice. In this issue, we have the honor and privilege to publish articles of distinguished medical professionals that dedicate their time both clinically and academically. Associate Prof. Stuart Lane dedicates his time to academia as an Associate Professor and coordinator of clinical studies at the University of Sydney. He is also the academic lead for education

and Senior Staff Specialist in Intensive Care Medicine at Nepean Hospital. Following his article from AMSJ V8|2 issue, Associate professor Lane discusses professionalism and professional identity. Dr. Mileham Hayes is a specialist physician and the director of MoleChex Skin Cancer and Melanoma Clinic in Brisbane, Australia. He provides us with constructive criticisms on current medical curriculum. Prof. Vitali Sintchenko is the Director at the Centre for Infectious Disease and Microbiology Public Health, Sydney West LHD and Pathology West. He is a faculty member of the Westmead Institute for Medical Research, Marie Bashir Institute and a professor of Sydney Medical School. He educates us on the benefits of public health surveillance.

executive members, the editorial team, the publicity team, university representatives and of course our sponsors. I would like to express my gratitude to all the medical students and authors that submitted their work regardless of the outcome. In addition, I would like to specially acknowledge the peer reviewers. The reviewers ensure that AMSJ circulates the highest quality publications. AMSJ continue to grow because of the support we get from the reviewers. And last but not the least, I would like to thank our medical student readers for their interest in fellow medical student’s work and reading the fruit of our labor. Please enjoy this issue.

Correspondence

J Lee: editorinchief@amsj.org

AMSJ is exclusively and organized by in Australia. I would like to recognize all the time and effort of all the medical students that were involved with this issue. This issue would not have been possible without the

Thank you to AMSJ Peer Reviewers (Volume 9, Issue 1) Hanna Anderson Parisa Aslani Anthony Brown Sharon Carey Sally Chan Peter Clifton Anne Darton Helen Douglas Matthew Fasnacht Peter Gibbs Michael Grimm

Davinder Hans Sarah Hayes Natalie Holowko Colleen Lau Gerhard Leinenga Thanh-Thao Adriana Le DM Levy Sultan Mahmood Dee Dee Murrell Ram Nataraja Kok Pin Ng

Kieren Po Aviv Pudipeddi Deshan Sebaratnam Tracy Schumacher Jenni Sokol Cyle Sprick Hang Ta Justin Vaughan Martin Veysey Gerald Watts Astrid Williams

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Guest Article

The development of professionalism and professional identity: the recognition and roles of intellectual humility, a growth mindset, and situational awareness A/Prof Stuart Lane MBBS FCICM MQHR Coordinator of Clinical Studies & Chair of the Personal and Professional Development (PPD) Theme, Sydney Medical Program; Senior Staff Specialist in Intensive Care Medicine, Nepean Hospital

A/Prof Stuart Lane is coordinator of Clinical Studies, and chair of the PPD theme for the Sydney Medical Program. He has a decorated record for teaching, and has developed a national and international reputation in researching human experience using qualitative methodologies. His PhD thesis explored the experiences of medical interns who had been involved in open disclosure. He is an examiner for the College of Intensive Care Medicine (CICM), Senior NSW CICM Supervisor of training, and Deputy Chair of the NSW CICM Regional Committee. He is a keen swimmer and successfully swam the English Channel in 2017.

Introduction In the most recent edition of AMSJ, I discussed the concepts of professionalism and professional identity, and encouraged medical students to consider what they understood by them, and how they might influence their future practice. In this edition of AMSJ, I will discuss some of the other concepts that were mentioned: intellectual humility, growth mindset, and situational awareness. These concepts are integral to how students and doctors develop their beliefs and attitudes towards professionalism and professional identity, and I will outline in this article how they relate to clinical decision making, lifelong learning, and working relationships. Intellectual humility Intellectual humility has been described as ‘Having a consciousness of the limits of one’s knowledge, including a sensitivity to circumstances in which one’s native egocentrism is likely to function selfdeceptively, sensitivity to bias, prejudice and limitations of one’s viewpoint. Intellectual humility depends on recognising that one should not claim more than one knows. It does not imply spinelessness or submissiveness. It implies the lack of intellectual pretentiousness, boastfulness, or conceit, combined with insight into the logical foundations, or lack of such foundations, of one’s beliefs. [1] Put simply it means that people have ‘knowledge of Ignorance’. When considering intellectual humility from a learning perspective, it could be described as a balance between the extremes of intellectual arrogance, and overconfidence in one’s own opinions and intellectual powers, and undue timidity in one’s intellectual life, or even intellectual cowardice. [2] This allows us as individuals to remedy headstrong decisions and reconsider incorrect interpretations, and ultimately allows interacting more constructively with one another. The concept of intellectual humility can be seen to be mirrored within the context of ethical decisionmaking, and therefore clinical practice. If we consider the ‘4 pillars of medical ethics’: autonomy, beneficence, non-maleficence, and social justice, non-maleficence or ‘first do no harm’ is often the most poorly understood. How can a doctor do harm, how can they act in a way that does not provide good? Many beneficial procedures that doctors perform and therapies that they provide inherently have associated risk, however the context of whether or not this risk is justified is whether the benefits outweigh the risks. The context where the risk outweighs the benefit is either when the procedure has no therapeutic benefit, or when the person providing the procedure is neither qualified nor skilled to perform it. This is where intellectual humility arises, in that a doctor must recognise that the task in front of them is beyond their level of expertise, and there is time and resources for it to be provided by another doctor. This is where a doctor recognises the limitations of their skills, and ultimately provides good by not doing harm.

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A/Prof Stuart Lane Growth mindset Experimentation is a vital part of learning, since when learners experiment they make mistakes, and making mistakes is vital to learning and for developing cognitive resilience. This idea resonates with the work of Dr Carol Dweck who outlines the connection between experimentation and the development of cognitive resilience. Dweck describes how individuals can be placed on a continuum according to their implicit views of where ability comes from. Some individuals believe their success is based on innate ability; these are said to have a ’fixed’ theory of intelligence. Other individuals believe their success is based on hard work, learning, training, and doggedness are said to have a ‘growth’ theory of intelligence. Individuals may not necessarily be aware of their own mindset, but their mindset can still be discerned based on their behaviour, especially in their reaction to failure. Fixedmindset individuals dread failure because it is a negative statement on their basic abilities, while growth mindset individuals do not mind or fear failure as much because they realise their performance can be improved and learning comes from failure. [4] These two mindsets play an important role in all aspects of a person’s life. Dweck argues that the growth mindset will allow a person to live a less stressful and more successful life. A pictorial explanation of the quotes and thoughts that accompany the fixed and growth mindset are seen in Figure 1. When considering Dweck’s theory, students who possess a fixed mindset believe their basic abilities are just fixed traits, and they only


Volume 9, Issue 1 | 2019 have a certain amount. Their goal becomes is to look intelligent all the time. With a growth mindset, students understand that their abilities can be developed through effort, good teaching, and persistence. This is important because Individuals with a ‘growth’ mindset are more likely to continue working hard despite setbacks, and an individual’s theory of intelligence can be affected by subtle environmental cues. For example, learners given praise such as ’good job, you’re very smart’ are much more likely to develop a fixed mindset, whereas if given compliments like ‘good job, you worked very hard’ they are likely to develop a growth mindset. [4] In other words, it is possible to encourage students, for example, to persist despite failure by encouraging them to think about learning in a certain way. Therefore, once again the role of the facilitator in this learning process is critical, since even with the correct environment of psychological safety, and the correct emotional arousal, the students still require the correct feedback to develop their growth mindset. A growth mindset aligns closely with educational learning theories, especially the circumplex theory of human emotion and learning. The circumplex model of human emotion [5] suggests that if something is learned in a greater state of arousal, irrespective of whether the state of arousal is in a negative or positive manner, then the information is better retained. This knowledge is referred to as activated rather than inert knowledge. Circumplex theory also suggests that learning in highly activated states; is recalled when similar states are invoked, that

Figure 1: A comparison of the thoughts associated with a growth mindset and a fixed mindset

intelligence allows clinicians to gain greater rapport with patients that enables them to extract more valuable data, to make more informed clinical decisions. Situational awareness is defined as ‘the perception of elements in the environment within a volume of time and space, the comprehension of their meaning, and the projection of their status in the near future. [7] People with good situational awareness have a good ‘feel’ for situations and people, and events that play out due to variables the subject can control. There are three levels of situational awareness: perception, comprehension, and projection. Perception is about achieving the status, attributes and dynamic elements in the environment. This involves the processes of monitoring, cue detection and simple recognition, which leads to an awareness of multiple situational elements and their current states. Comprehension involves a synthesis of the disjointed elements of perception through processes of pattern recognition, interpretation and evaluation. This requires integrating this information to understand how it will impact upon the individual’s goals and objectives. This includes developing a comprehensive picture of the world, or that portion of the world concerned to the individual. Projection is the highest level of situational awareness and involves the ability to project the future actions of these elements in the environment. This level is achieved through knowledge of the status and dynamics of the elements and comprehension of the situation and then extrapolating this information forward in time to determine how it will affect future states of the operational environment. Individuals vary in their ability to acquire situational awareness thus providing the same system and training will not ensure that there is similar situational awareness across these individuals. Situational awareness also involves a temporal and a spatial component since time is an important concept in situational awareness. The individual’s actions, task characteristics and the surrounding environment dictate the change in tempo of a situation. As new inputs enter the system, the individual incorporates them into this mental representation making changes as necessary in plans and actions in order to achieve desired goals. As mentioned earlier, a doctor with good situational awareness will extract more useful information form patients due to greater rapport, however this generation of rapport can be replicated across all relationships in the healthcare environment, making your working environment more pleasant, and fostering a better working culture. This is because the possession of good situational awareness usually translates to a perception of empathy.

positive emotion and mastery under stress can be anchored, is harder to erase. Figure 2 shows the graph of positive and negative human emotions with levels of activation and deactivation. According to circumplex theory, people learn better if they are situated at the upper portions of the graph during learning. However, this state of arousal can be either unpleasant or pleasant, as seen in the diagram by the terms nervous and tense versus alert and excited. From the perspective of a growth mindset, people are more likely to feel nervous and tense when they are out of their comfort zone, and this will be usually when they are challenging themselves often with something they have not experienced regularly, which will be an ongoing experience throughout medical school and your future medical career. Challenging one’s self implicitly carries the risk of failure, and therefore challenges can only be embarked upon when you possess the ability to accept the potential for failure: when you possess a growth mindset. Situational awareness and emotional intelligence Emotional Intelligence (EI), often measured as an Emotional Intelligence Quotient (EQ), describes a concept that involves the ability, capacity, skill, or a self-perceived ability, to identify, assess, and manage the emotions of one’s self, of others, and of groups. [6] Emotional

Figure 2. The circumplex model of human emotional learning

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Guest Article Empathy has been defined as ‘the feeling that you understand and share another person’s experiences and emotions: the ability to share someone else’s feelings’. [8] However there is disagreement about what true empathy is, and its role in healthcare, especially amongst physicians. Another definition is ‘A predominantly cognitive (as opposed to affective or emotional) attribute that involves an understanding (as opposed to feeling) of patients’ experiences, concerns, and perspectives combined with a capacity to communicate this understanding: an intention to help by preventing and alleviating pain and suffering is an additional feature of empathy in the context of patient care’. [9] The latter definition expands on the first definition by discussing the importance of cognition in empathy, rather than a purely emotional response. Halpern expands this further by suggesting that ‘empathy is an experiential way of grasping another’s emotional states, it is a perceptual activity that operates alongside logical inquiry. [10] Empathy can be practiced and can be improved, and the three ways in which you can achieve this are: improve your ability to see another person’s perspective – this requires listening and time, improve your ability to articulate how others are feeling – this requires listening and time, connect emotionally with other people – this requires listening and time. [11] The lesson is therefore very straightforward, if you wish

References

1. http://www.criticalthinking.org/pages/valuable-intellectual-traits/528. 2. https://www.templeton.org/what-we-fund/grants/the-philosophy-and-theology-ofintellectualhumility 3. Paige K. The four principles: Can they be measure and do they predict ethical decision-making. BMC Med Ethics. 2012. Vol. 13, (2012): 10 4. Dweck CS. Mindset: How You Can Fulfil Your Potential. Constable & Robinson Limited. 2012. 5. Barrett L. “The Structure of Current Affect: Controversies and Emerging Consensus.” Current Directions in Psychological Science. 1999. 8(1): 10-14. 6. Ioannidou F, Konstantikaki V. Empathy and emotional intelligence: What is it really about? International Journal of Caring Sciences. Sept - Dec 2008. Vol 1(3):118–123

to become more empathic, and improve your working relationships, give your colleagues time and listen to their stories. This will ultimately benefit you, since clinicians who possess greater empathy, suffer less from burnout. [10] Conclusion As mentioned in the previous manuscript in the recent AMSJ, as medical students you are being constantly instructed on how to be develop professionalism, and how to grow the correct professional identity. To achieve this you need to be aware of concepts that will allow you to develop and truly understand this, rather than just mirror the types of behaviour that are expected. There are of course more concepts to be aware of than intellectual humility, growth mindset, and situational awareness; however, these are some of the most pertinent and some of the most beneficial to harness into your developing professional identity. Having a greater understanding and a desire to want to understand and utilise them can only improve your practice, therefore the care you provide to patients, and ultimately the way you live your life.

7. Endsley M. Toward a theory of situation awareness in dynamic systems. Human Factors. 1995.37(1) 32-64. 8. Bellet PS, Maloney MJ. The importance of empathy as an interviewing skill in medicine. JAMA. 1991. 226 (13): 1831-1832. 9. Hojat M, Vergare M, Maxwell K, Brainard GC, Herrine SK, Isenberg JA. The Devil is in the Third Year: A Longitudinal Study of Erosion of Empathy in Medical School. Academic Medicine. September 2009. Volume 84(9). 1182-1191. 10. Halpern J. What is Clinical Empathy? Journal of General Internal Medicine. August 2003. 18(8): 670-674. 11. https://www.psychologytoday.com/au/blog/making-change/201411/want-betterrelationshipslearn- be-more-empathic

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Guest Article A (constructive) criticism of medical curricula Dr Mileham Hayes OAM, MBBS, FRCP (Lon. & Edin.) Medical Director, MoleChex Skin Cancer and Melanoma Clinic, Brisbane

Mileham Hayes is a specialist physician. He was appointed to the world’s first coronary care unit, and one of the earliest obesity and sports clinics. He is the author of two acclaimed medical textbooks and has now written the “Live Longest” series on prevention and nutrition. On a personal note, as an Air Force volunteer, one of his many adventures included flying with the Central Intelligence Agency, he ran own ABC radio and national (jazz) TV shows and was Australia’s Representative to the First Commonwealth Festival of Arts, appeared with many Jazz greats, and created the legendary “Cellar Club” restaurant “Sweet Patootie”, and has won the Tourism Award for his International Jazz and Blues Festivals. Hayes is a regular columnist for three leading newspapers, a medical journal and Australia’s then leading arts magazine (“The Bulletin”) for which he wrote a feature article on France’s greatest restaurants. He was awarded the Order of Australia in 1996. He is a passionate gardener, cook, lover of art, literature and classical and jazz music. In his spare time, Dr. Hayes moments he writes bad poetry and good limericks. He is currently the medical director of MoleChex Skin Cancer and Melanoma Clinic in Brisbane, Australia.

As I was informed by a very wise man, “there are two sorts of critics, the Destroyer and the Builder”. The “Destroyer” does just that, tears things down, leaves nothing, whereas the “Builder” replaces or rebuilds, constructively. I abhor the former “Negative Nellies” and intend this critique to be, not only constructive, but also achievable. The King of Hearts advised Alice (or was it the White Rabbit?) to “Start at the beginning”, but I have corrupted this to “begin at the end” viz: what do you want from your medical course and how well will you be equipped or trained when you graduate. I am not sure if my era’s “Toti-Potential Cell” is today’s “Stem Cell”, but I feel today’s analogous graduate would want what we all wanted back then – to be trained in all spheres to be competent and confident for the “most common things that occur most commonly”. Unfortunately, this is also the most commonly ignored axiom. And in this first few years, whether you recoil from the great unwashed and later flee to research, pathology or radiology and never have to see a live patient again, you will have to see them now, and the medical curricula should provide adequate training. I am sure the various medical schools attempt to do so, but the politics and funding gets in the way. The politics sees each professor or department fighting for kudos, while the funding limits employing the best teachers. When I did Anatomy, it was taught by a professor who was so incompetent he was never registered as a medical practitioner, despite graduating. He expanded his empire to 18 months and was the cause of the greatest number of failures in our six-year course. I remember in one practical exam, there was a horizontally transected heart across the atria with a dirty, faded piece of red cotton going up one of the arteries on the Aortic Arch. The specimen was swathed in formalindrenched rags making breathing difficult (let alone dangerous) and viewing almost impossible.

Dr Mileham Hayes And this brings me to my first constructive suggestion: as much as possible, all subjects should be taught by clinicians – even anatomy.

I straightened up and laughed such that the demonstrator, a good bloke with his FRACS asked “What’s up?” to which I replied, “This is bloody ridiculous. Only we and Michael De Bakey will ever see this”. De Bakey was then the world’s leading heart surgeon in Texas (and I doubt if even he ever saw this in any event).

My father used to say that anatomy, physiology and histo-pathology “were the fundamental tripod on which medicine was based” and, while I agree, these should be taught by clinicians to avoid spending incredible hours smoking drums and dissecting frogs to record a muscle’s “refractory period” and such. I am sure this is not done today, but I am equally sure it has been replaced by an equally not very useful substitute.

Yet, this “Prefesser” as I now call them, the incompetent ones that is, never knew or showed us where to inject the gluteus maximus, so as to avoid the sciatic nerve. He simply didn’t know. (The sad result of this was that I did see a permanent foot drop caused by such a mistake).

In my practice, I frequently examine exercise physiologists and it is stimulating to discuss their tests, which, without having done a great deal of post-degree cardiology, I could not. Surely a medical graduate should know as much as they?

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AM S J The “circus movement” hypothesis of the electrical conduction of the heart has now been replaced by “egg-beater” recordings from multiple sensors inserted into the atria. Atrial fibrillation is now an epidemic in those over 60 years of age, yet when I talk with medical students or most GPs, this is not known. But it is the most common preventable cause of strokes. I do not know how pharmacology is taught now, but I do know that drug companies hide any detrimental trials in their amoral pursuit of profits. I still have a pack of Vioxx, which caused some 140,000 deaths before Merck was forced to remove it. We were taught that, as doctors, we knew more than the drug reps, but series after series of studies show how doctors are ‘influenced’ by drug reps to prescribe their new wonder drug, such as Vioxx. Surely, there should be some pharmacology lectures to alert you to the chicanery of some drug companies, and where best to access the best information. Recently I examined the new Head of Emergency at one of our teaching hospitals and I asked her who had “taught her suturing” and, like me, she had to confess she “had learned it on the job”. I was appointed to a Sydney teaching hospital, which then had probably the busiest of casualty departments (now, of course as we Americanise, called “Emergency”) staffed by M.Ds, and while the alcoholics healed up beautifully, I was concerned about doing the best job possible on the faces of pretty young women who had gone through their windscreens. And so, I approached the plastic surgeons, who were wraith-like creatures we never saw, and asked them for a tute. Back came the answer “Why?” and it never happened. There are obviously different motives and drives for each of us to do medicine and for me, money was not one of them. That is not to say that as a great neurologist observed “a doctor’s income should be commensurate with his/her qualifications and responsibilities”. Judges are meant to be paid enough such that they are not tempted by bribes and what this eminent physician meant was, not that we should expect the latest German luxury vehicle, exotic holidays and a great wine cellar, but that like the judges, we should be paid adequately, which, I would define as an income that does provide for private school fees and a good, not exorbitant, lifestyle. Unfortunately, times have changed and what I didn’t realise, when I was shocked at the plastic surgeons’ rebuttal, was that I was witnessing the formal start of medicine as a highincome career. And this is a problem. These high-income doctors simply don’t, given their lifestyles, have the time to teach undergraduates for free. I am not “holier-than-thou”, here as I was asked to lecture and did so for a year at considerable inconvenience and financial loss – especially when the “Medical School”, all of whom were on salaries paid for out of my taxes, then pointed out how impoverished they were and what a noble gesture it would be if I donated my promised remittance to them, which I did, but I never went back. I simply couldn’t afford to. Now my income was pathetic compared to a high-rolling “Plastic” and that is why they don’t teach. I dare not tell you what a plastic surgeon earns in a morning, but they all have the latest German luxury cars, or two or three, at least those I know. Surely, there are enough skilled “Stitchers” to show every medical student how to best suture. I was so disgusted at the general standard I even wrote a book on surgery to pass on a few hints, but this does not replace actual practice. Now, GPs pay to be taught how to suture by

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the various skin cancer institutions. What then are the undergraduate courses taking your money for if you can’t even do subcuticular suturing or an A to T Flap? The skin is the body’s largest organ. Not a day goes past without a patient asking, “What is this?” whilst pointing to a rash or skin lesion. Yet, throughout the world, dermatology is not taught well. Again, I think this is the “Plastics Syndrome” – they can’t afford the time, but I also think they do like to keep skin as their own province. When I was asked to lecture, the dean was a great bloke, but I don’t think he had ever seen a live patient and he gave me a sheaf of lecture notes to deliver on “lead poisoning”. I actually knew a great deal about this having been taught by the acknowledged world expert (Brian Emmerson), and examined on it by the Royal College of Physicians of London, but for undergraduates, this was ridiculous. So, even before the movie, I taught the students how to make paper-planes from these turgid notes and we launched them from the upper story of the Medical School. I then taught them ‘How to dress,’ (one student was in a boiler suit and no shoes) and ‘How to write a prescription’. They did not even know that Rx was the Latin abbreviation for a ‘recipe’. The “Dressing” was not an affectation; studies, let alone common sense, have shown that patients feel more confident if the “doctor looks like a doctor” (and I offered to buy the barefoot boy a pair of shoes). Anyway, we progressed along these practical lines and I was rewarded by them telling my wife “they were the best series of lectures they had ever had.” This, I hasten to add is not chest-beating, but a tragic condemnation of the dross they had previously been served up. There was nothing new or world shattering in my lectures, just worldly-wise every day practical experience. And so we pass to my hobby horse(s)- Preventive Medicine and Nutrition. I had been appointed to the world’s first Coronary Care Unit, and as cardiovascular disease is our greatest killer, I figured I should learn something about it. Framingham had just started and since 1968 I have done my lipids almost yearly and watched as my very bright, or brighter than me, colleagues died, disabled or demented such that, at our 50th reunion I was the only one of this group left standing (the psychiatrist, of course, had committed suicide, but of the others, the Captain of Rugby no less had died from heart disease, the two GPs and the “Orthopod” were either in a foetal position incontinent of urine and faeces to just being vague as the amyloid and tau bodies obliterated their axons). In 1974, when I was in Edinburgh, one of the doyens of British cardiology (Michael Oliver) told me, he thought there were few, if any, tests that were any good for prevention. He was then right, but I thought and think otherwise. I realised it was early days, and by accumulating my lipid, MBA (Multiple Biochemistry Panel) and haematology profile, the next decades may shine some light as to whether any were actually of help. And it seems they were. Most illnesses can be prevented yet there seems to be little or no undergraduate training on this. Let me run this past you again in another way: the greatest good we can practically do as medical practitioners is not being taught by the dotards of academe. In a pang of conscience, I wrote to the Dean of my alma mater a few years ago, to point this out and he replied how a “Government Department,” that neither I, nor any of my colleagues, have ever heard about, “was doing a great job”. Pigs arse.


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Guest Article We are in the midst of the epidemic of the “Diseases of Affluence”: obesity, hyperlipidaemia, cardiovascular disease, type 2 diabetes and their sequelae of osteoarthritis, depression, cancer et al. with probably 40 to 90% being preventable! And at no or very little cost! I watch with horror as these lumbering, prematurely aged patients on about ten drugs try to get up on my examination couch, let alone roll over. “It’s no fun getting old, Doctor’” they admonish me, “wait till you’re my age” and so I look and see they are ten years younger than I. At medical conferences, I also watch with horror as my colleagues descend like locusts on the wedges and blobs of saturated fats and sugars presented as the most delicious and obviously irresistible morning- and afternoon-tea snacks, only to be supplemented at lunch and dinner by deep fried excess-on-excess. Even at a cardiology meeting the pudding was almost pure sugar! The only good nutrition I’ve had at a conference was at a business one. Why? What is going on? When I did medicine, and I can’t see that it’s changed, medical students were the acknowledged intellectual elite of the University, and yet we have surrendered nutrition to the dieticians. This is not only absurd, but bad medicine. No wonder we have an epidemic of these “Diseases of Affluence.” As medical practitioners we have abrogated our responsibility to inform our patients how and what to eat, because our universities have abrogated their responsibility to teach this essential medical subject. The other outstanding omission, as I see, from medical curricula, are those illnesses or medical events unique to the location of each particular medical school. Here in Queensland we have the highest incidence and prevalence in the world of melanoma, skin cancer and brown snake bites...yet these are not taught. Elsewhere, I would think chill-blains and ski-injuries and such should similarly be included if the medical school is located in such an area. Almost finally, I had great teachers. You must fight, as I did, to seek them out. You should also try for an appointment at the best teaching hospitals. When I “had” to write my books, it was the result of visiting a number of general practices, where it dawned on me that not only

were they chronically underfunded, but also that the GPs had also not been exposed to the best teaching units and standards. And finally, after your exposure to living patients, you then have to choose a career. Most, I assume, will be driven by their interests (and there was an hilarious algorithm in the BMJ to this effect), but it would be remiss of me not to alert you as to choices. World-wide general practice is being unmercifully screwed, as it is the only way governments can contain costs, so as the bureaucracy clones expands exponentially, along with its red tape, GP remuneration and prestige falls. The next problem is litigation. It is open season on doctors and any clinician is vulnerable to any zany making a complaint. Even for the stupidest and most unreasonable complaint the clinician has to “fully explain” such that, a patient from interstate who walked in and demanded an operation then complained when my colleague couldn’t do it there and then, caused my colleague to suffer a heart attack from the stress and retire prematurely. The great problem is that medicine has spawned an increasing retinue of camp-followers who “seek power without responsibility (the prerogative of the harlot for centuries)”. The lawyers, the insurance companies, the ombudsmen, the post-graduate training schemes, the colleges, “Uncle Tom Cobly and all”, all of whom keep shovelling it back to the doctor, while they dream up yet more paper-work and accept no responsibility. It all seems so “reasonable”, but rather than freeing up the doctor to spend more time with the patient, they impose more and more training demands, auditing and now we are even told we must “reflect” on how we may improve. I can only wonder at these bureaucrat doctors who justify their existence with such imposts. They are akin to “Kentucky Colonels”, who could buy their commission, but “never went to war”. Maybe it is they who should “reflect”. And finally, I pass on two aphorisms from my father and another from one of my teachers: 1.

Be very proud of medicine, there are only two real emergencies in the world – war and medicine.

2.

Gentility is the best anaesthetic.

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Guest Article Unlocking the benefits of public health surveillance Dr Vitali Sintchenko MBBS, PhD, FRCPA, FACHI Professor, Sydney Medical School Director, Centre for Infectious Diseases and Microbiology (CIDM) Public Health, Sydney West LHD and Pathology West Faculty Member, The Westmead Institute for Medical Research & Marie Bashir Institute

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Professor Vitali Sintchenko is a leading public health microbiologist and informatician who conducts research on biosurveillance of communicable diseases. He is a leader in public health and diagnostic microbiology team working toward improving laboratory and epidemiological investigations of communicable diseases by combining genomics and informatics in order to accurately predict the behaviour and modes of transmission of microbial pathogens and identify the source of disease outbreaks. This will enable early detection of outbreaks so that it can be controlled in a timely manner and revolutionize outbreak surveillance by providing new information on transmission chains including risk factors, modes of transmission, geography and timeline of spread, and identification of ‘superspreaders’ and transmission ‘hotspots’ ”. Professor Sintchenko has also authored seminal publications in the field and has published the world’s first book on infectious disease informatics. He is Chair of the Commonwealth Public Health Laboratory Network.

Ensuring security of international trade has become a major priority for global health [1], but the increasing role and capacity of public health surveillance in disease prevention has not been fully appreciated. Significant economic damages inflicted upon local economies in Asia, North America, and Europe by international outbreaks of SARS and Shiga-toxin producing Escherichia coli (STEC) call for better surveillance and preventive interventions. However, delays in outbreak recognition diminish the window of opportunity to mount an effective response and become increasingly costly to society. For example, it was estimated that, in Canada, a one-week delay in the implementation of control measures for SARS resulted in a 2.6-fold increase in the mean epidemic size and a four-week extension of the mean epidemic duration [2]. Outbreaks of foodborne diseases provide another example of global high-burden threats to public health and freedom of trade. The main argument for public health surveillance until now has been potential savings to health and households by reducing the size of outbreaks and preventing secondary cases [3]. The globalisation of food supplies and international outbreaks spread via large-scale sale channels have introduced another powerful argument. Foodborne diseases are responsible for significant morbidity and mortality worldwide. The globalisation of food markets and emerging food industries increases the risk of foodborne diseases. Recent World Health Organization estimates suggest that, in 2010, 22 bacterial, viral, and protozoal diseases resulted in two billion cases and over one million deaths, while around 582 million cases involved infection by contaminated food [4]. Up to 48 million illnesses, 128,000 hospital admissions, and 3,000 deaths are caused by contaminated food in the United States every year, with the estimated cost of illness reaching US$4.8 billion dollars [5]. High-resolution and timely surveillance has become essential for controlling bacterial foodborne diseases, defining their burden and attributing illnesses to specific foods and settings. Nevertheless, 1 value reimbursement remains a major barrier for translation of surveillance into public health, as it is sensitive to cutback during recession and austerity periods. Recent applications of whole genome sequencing for public health laboratory surveillance of salmonellosis, listeriosis, and STEC have radically improved jurisdictional and national capacity to determine the pathways of foodborne disease transmission and to track their global spread [6,7]. Furthermore, there is a shift in foodborne disease surveillance from reactive investigations of epidemiologically suspected outbreaks to proactive, prospective monitoring of laboratory confirmed cases by networks of reference centres. These centres are integrated into communicable disease control, and generate alerts and associated epidemiological hypotheses when clusters of pathogens

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Dr Vitali Sintchenko

with similar genomes are identified according to predefined rules for spatial and temporal variables. Such genomics-enhanced surveillance with enhanced resolution appeals to public health professionals by deciphering outbreaks involving complex food chains in circumstances where trace-back is complicated and labour-intensive. Evidence suggests that prospective genomics-guided surveillance can detect and solve more outbreaks and identify them earlier than contemporary systems [8,9]. The magnitude of averted food trade losses depends on three key variables: the number and size of markets accessible to food exporters, and the timeliness of surveillance signals. The detection of the outbreak in the food exporting country can reduce the size and duration of outbreaks associated with contaminated food exported to other markets. The sooner local outbreaks are recognised, the more cases of foodborne diseases in all markets that can be avoided. When public health surveillance in a food exporting state is efficient (for example,


Volume 9, Issue 1 | 2019 when outbreaks are recognised before the contaminated food reaches supermarket shelves in other markets), such local surveillance may have a truly global effect of minimising the chances of outbreaks in food importing countries. Our own experience in Australia has demonstrated that timely recognition of a salmonella outbreak in New South Wales and identification of its source allowed the local producer to stop the off-loading of containers with contaminated vegetables in overseas ports. In the global economic environment, the timeline of the public health alerts protects the exporter’s reputation, jobs, and market share in the global trade of fresh produce. However, the quantification of these trade benefits remains challenging. The currently used measures of health outcomes, such as qualityadjusted life years (QALY or quality and quantity of life lived), disability-

References

1. Harrison M. Contagion: How commerce has spread disease. Yale University Press, 2012. 2. Wallinga J, Teunis P. Different epidemic curves for Severe Acute Respiratory Syndrome reveal similar impacts of control measures. Am J Epidemiol 2004;160:509-16. 3. Scharff RL, Besser J, Sharp DJ, Jones TF, Gerner-Smidt P, Hedberg CW. An economic evaluation of PulseNet: a network for foodborne disease surveillance. Am J Prev Med 2016;50(5S1):S66-S73. 4. Kirk MD, Pires SM, Black RE, Caipo M, Crump JA, et al. World Health Organization estimates of the global and regional disease burden of 22 foodborne bacterial, protozoal, and viral diseases, 2010: a data analysis. PLoS Med 2015;12(12):e1001921. 5. Scallan E, Hoekstra RM, Mahon BE, Jones TF, Griffin PM. An assessment of the human health impact of seven leading foodborne pathogens in the United States using disability adjusted life years. Epidemiol Infect 2015;143:2795-804. 6. Aarestrup FM, Brown EW, Detter C, Gerner-Smidt P, et al. Integrating genome-based informatics to modernize global disease monitoring, information sharing, and response. Emerg Infect Dis 2012;18(11):e1.

adjusted life years (DALY or years of healthy l 1 ife lost), monetary cost-of2 illness, or willingness-to-pay measures do not capture the losses of trade potentially averted by preventive interventions. While acknowledging the challenges of data availability and sharing [10], we argue for the urgent need to develop and evaluate food systemsfocused models for capturing costs of trade in globalised markets. These models should reflect the monetary and non-monetary costs of disease outbreaks including the opportunity costs of preventive interventions at the point of emergence. In the era of global trade and health reforms, the added value of public health extends beyond national borders and strengthens the economic imperatives for public health surveillance. There is also a growing role for the medical profession in the advocacy for worldwide preventive high-resolution surveillance and response.

7. Expert Opinion on Whole Genome Sequencing for Public Health Surveillance: strategy to harness whole genome sequencing to strengthen EU outbreak investigations and public health surveillance. European Centre for Disease Prevention and Control, August 2016. 8. Sintchenko V, Holmes EC. The role of pathogen genomics in assessing disease transmission. Brit Med J 2015;359:h1314. 9. Jackson BR, Tarr C, Strain E, Jackson KA, Conrad A, et al. Implementation of nationwide real-time whole-genome sequencing to enhance listeriosis outbreak detection and investigation. Clin Infect Dis 2016;63:380-6. 10. Aarestrup FM, Koopmans MG. Sharing data for global infectious disease surveillance and outbreak detection. Trends Microbiol 2016;24:241-5.

Volunteer opportunities for medical students WHY VOLUNTEER • hear international and national speakers • networking opportunities • access workshop and program sessions Successful applicants will receive a complimentary ASM registration including a ticket to the Welcome Reception. Applications close Wednesday 31 July 2019.

the changing climate of emergency medicine GET INVOLVEd CONTaCT Us

www.acem2019.com/volunteer-program @acemonline #acem19 #acemvolunteers events@acem.org.au

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Original Research Article

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The association between pre-pregnancy body mass index and gestational weight gain (GWG) among women in rural NSW, Australia Dr Anna Power MD BPhEd Grad Dip University of Wollongong

Anna completed a Bachelor of Physical Education and Graduate Diploma in Marketing at Otago University (Dunedin, New Zealand) and worked for several years in New Zealand and the UK prior to starting medicine. Her interests include general practice and obstetrics.

Dr Teresa Treweek PhD M. Ed. (Higher Ed.) University of Wollongong

Teresa completed a Bachelor of Medicinal Chemistry (Hons) and worked in research at the University of Wollongong before teaching in Graduate Medicine. Her interests include reproductive physiology, biochemistry, and genetics.

Abstract Background: Pre-pregnancy body mass index (BMI) and excessive gestational weight gain (GWG) are associated with adverse outcomes of pregnancy. The Institute of Medicine (IOM) provides recommendations for weight gain during pregnancy based on prepregnancy BMI. Objectives: To evaluate the proportion of pregnant women in a rural medical practice not meeting the IOM guidelines and to assess a link between pre-pregnancy BMI or excessive GWG and delivery method in this population. Methods: A clinical audit of 168 patients in a rural NSW Medical Centre with a search criterion of ‘pregnancy’ was performed. Relevant patient details were collected and linked to patient files; pre-pregnancy weight, height, weights recorded during pregnancy, and delivery method. Results: Among the 87% of gestating women who did not meet the current GWG recommendations, 57% gained weight excessively and 30% inadequately. There was a statistically significant association between pre-pregnancy BMI and excessive GWG with overweight women more likely to gain excessively (Fisher’s exact test 29.04, p<0.001). Pre-pregnancy BMI was also associated with delivery method, with normal weight women more likely to have a normal vaginal delivery and obese women more likely to have an instrumental delivery or planned Caesarean-section (Fisher’s exact test 20.89; p<0.001). Gestational weight gain was not associated with delivery method, regardless of pre-pregnancy BMI. Conclusion: Given that the majority of women in this rural medical practice showed gestational weight gains outside the recommended limits and that pre-pregnancy BMI was associated with delivery method, there is a role for pre-conception and antenatal programs educating women regarding healthy prepregnancy weight and GWG. Introduction Pre-pregnancy obesity and excessive gestational weight gain (GWG) are associated with a wide range of adverse maternal, perinatal, puerperal, neonatal, childhood, and adulthood complications. Women with a higher pre-conception body mass index (BMI) have an increased risk of excessive GWG and of experiencing a miscarriage or stillbirth [16]. They also have increased risk of pre-eclampsia, gestational diabetes mellitus (GDM), dysfunctional labours, post-partum haemorrhage,

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wound infection, congenital abnormalities, prematurity, neonatal death, macrosomia and lower Apgar scores [1,5,7-15,17]. High prepregnancy BMI is also associated with increased risk of caesarean section (CS) [5,9,16,17], with odds ratios of 1.53, 2.26 and 3.38 for overweight, obese and morbidly obese categories, respectively [16]. High GWG imposes a further CS risk, regardless of pre-pregnancy BMI [18]. In addition to the immediate maternal and perinatal outcomes outlined above, maternal obesity is negatively associated with breastfeeding initiation and maintaining breastfeeding for the recommended six month period [14,19]. Breastfeeding is associated with decreased risk of maternal post-partum depression, childhood obesity, neonatal infections, Type 2 diabetes (T2DM) and obesity in the offspring [20,21,22,23]. The long-term health impacts of excessive GWG also extend beyond the immediate pregnancy, with an increased risk of post-partum weight retention, which further increases the risk of pre-eclampsia in subsequent pregnancies [9,24,25]. GDM and increased fat deposition may also precipitate impaired glucose tolerance and T2DM [26]. Furthermore, several studies show a positive association between high GWG and both childhood and adult obesity in offspring [27-30]. This is of increasing concern since a large proportion of women gain weight excessively during pregnancy. One U.S. multi-centre GWG study showed 73% of women exceeded the weight gain recommended for their BMI [7]. Accounting for a previous, more stringent set of recommendations, an earlier US cohort study showed only 43.7% of women exceeded the guidelines [31]. This suggests that even with a relaxation of weight-gain targets, there is an increased incidence of excessive GWG. Another Australian study found 38% of women gained in excess of the guidelines; however, several exclusions may account for some of the variation observed [32]. Given that some of the study’s exclusion criteria, including prematurity, neonatal death, language spoken and ethnicity have been linked with excessive GWG, the study may have underestimated the prevalence of women gaining above the guidelines [1,33,34].


Volume 9, Issue 1 | 2019 While there is a paucity of literature focusing on GWG in rural Australia, studies elsewhere comparing urban and rural populations show mixed results. In comparison to women in urban areas, an Iranian study found rural women more likely to be underweight, while a U.S. study found rural women were more likely to be overweight or obese. Both studies found rural women had a lower GWG than their urban counterparts [35,36]. Differences in infrastructure and food availability may contribute to rural/urban differences in BMI and GWG. Across different BMI categories, the aforementioned study suggested that pre-pregnancy obesity might actually protect against excess GWG [36]. In contrast, another urban U.S. study reported that the single most predictive factor for ideal GWG was normal pre-pregnancy BMI [37] and an urban Australian study, which identified 56% 1 of overweight women compared to 30% of normal weight women gaining in excess of IOM recommendations (p<0.001) [32]. Postpregnancy weight retention is another issue facing rural populations. In Australia, between 42.5% and 58.1% of women of child-bearing age, and 63% of women living rurally and remotely are overweight or obese [38]. One rural U.S. study assessed the long-term effects of excess GWG and limited postpartum weight-loss [24]. The study, by Rooney and Schauberger, found no relationship between weight gain ten years postpartum and pre-pregnancy BMI, in contrast to other studies describing a positive correlation between these two factors [13,36]. More importantly, Rooney and Schauberger’s results revealed a positive correlation between excess GWG and weight retention at five years post-partum [24]. With higher rates of obesity and obesityrelated diseases, together with reduced access to medical care, these findings pertinent for the health of rural Australian women [38,39,40].

Software Pty Ltd, Bundaberg, Australia) file. Height, pre-pregnancy and pregnancy weight data and delivery details were extracted by the Practice Manager and patient information was de-identified. Patients with missing height information were excluded (n=136). A further 81 were excluded based on inadequate weight recordings, missing data or improbable values (Figure 1). This left 168 women in the study population. Pre-pregnancy BMI was calculated using the woman’s height and the record of either 1) their earliest pregnancy weight or 2) most recent pre-pregnancy weight (weight (kg)/height (m2)). Weight status was categorized according to the WHO BMI cut-off points (Table 1). Weight-gain during pregnancy was calculated via three methods (employed by other studies) allowing an assessment of whether method of calculation changed the outcome [7,15,32,36]. Calculations used were 1.

Total weight-gain: last weight minus first weight.

2.

Average weight-gain by week: total weight-gain divided by the number of gestational weeks.

Best Practice search: pregnancy active n = 385

The U.S. Institute of Medicine (IOM) has recommendations for GWG based on pre-pregnancy body BMI [41] and in the absence of Australian-specific guidelines, recommendations are generally based on this guidelines [1]. Overall, while increased risks associated with GWG and obesity in pregnancy are well documented, compliance in current Australian rural environments is less well known.

No height/BMI information n = 136

Other exclusions: n = 51 • Incomplete information/inadequate weights performed n = 29 • Weight not recorded within 6 weeks of delivery n = 7 • First weight measured beyond trimester 2 n = 6 • Patient transferred away n = 5

Total pregnancies less exclusions n = 198

This study addresses this gap in knowledge by evaluating the proportion of pregnant women in a rural medical practice not meeting the IOM guidelines using three different methods to calculate GWG. With the local hospital being low-risk, a secondary analysis assessed the link between pre-pregnancy BMI or GWG and delivery method. This study was conducted to quantify the number of women who may benefit from the newly implemented Expecting Changes program in the area, a program targeting weight control in women planning to conceive or newly pregnant.

• Twin pregnancy n = 2 • Pregnancy resulting in documented miscarriage n = 2

Expected due date beyond data collection period n = 37

Material and Methods Ethical approval was granted by the Human Research Ethics Committee (UOW, ethics number GSM16/015). An audit of quarterly snapshot data (2016) from a rural NSW medical centre (Modified Monash Model classification 4) was conducted using the PenCS Audit Tool™ (Pen CS Pty Ltd, Leichardt, Australia). Patients with an active search criterion of ‘pregnancy’ were isolated (n=385) and cross-referenced to their Best Practice (Best Practice

Total pregnancies included in maternal weight gain analysis n = 168

Expected due date beyond data collection period with expected delivery within 2 weeks of cut off & final weight within 6 weeks of delivery n=7

Figure 1. Participant inclusion and exclusion protocol.

Table 1. Institute of Medicine weight gain in pregnancy recommendation. Units, converted from pounds to kilograms [1].

Pre-pregnancy Weight Category

Body Mass Index

Recommended range of Recommended rate of weight in second and total weight (kg) third trimester (kg/week)

Underweight

Less than 18.5

12.7 - 18.1

0.45 (0.45 - 0.58)

Normal weight

18.5 - 24.9

11.3 - 15.8

0.45 (0.36 - 0.45)

Overweight

25 - 29.9

6.8 - 11.3

0.27 (0.22 - 0.31)

Obese (includes all classes

30 and greater

4.9 - 9.0

0.22 (0.18 - 0.27)

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Average weight-gain by week: weight-gains at each measurement divided by the number of weeks between weight measurements.

Based on these three calculation methods, GWG was classified as below, within, or above the IOM recommendations. A secondary analysis of delivery method was matched to each category prepregnancy BMI and GWG. Statistical analysis Cross-tabulations using chi-square and exact tests were used to determine the association between 1) pre-pregnancy BMI and GWG, based on the IOM recommendations, and 2) GWG and delivery method. Fisher’s exact test was used when the minimum expected cell frequency assumption was violated. Data were analysed using Excel (Microsoft® Corporation, Redmond, USA) and SPSS software (IBM, New York City, USA). Results Subjects Of the 168 women in the final study population, 4% were underweight, 32% were normal weight, 23% were overweight and 42% were obese. Indigenous status was collected, but not considered due to the small sample size (n=11). Age ranged from 18.9 to 46.2 years (mean: 30.6 years). GWG across all pregnancies The three methods used to evaluate GWG revealed slightly different proportions of women below, within and above the IOM

recommendations (Figure 2). Using total weight gained, 36% of participants gained above and 33% less than the guidelines. Almost a third of women (31%) gained weight within the recommendations. With regard to the methods of GWG classification, more women were found to have gained above the recommendations when total weightgain was broken down by week (57%, n=95), with only 13% (n=22) of women gaining within the recommendations. When assessing weightgain using the interval between weights, even fewer women had met the recommended guidelines (9%, n=15). GWG based on pre-pregnancy BMI On average, underweight, normal weight, overweight and obese women gained a total of 11.25 kg, 12.62 kg, 12.08 kg and 7.38 kg, respectively. Using the weight-gain by week calculation, underweight women gained an average of 0.354 kg per week; normal weight women, 0.478 kg; overweight women, 0.480 kg; and obese women, 0.311 kg (Table 2). A χ2 test of this weekly weight-gain calculation revealed a statistically significant association between pre-pregnancy BMI and weight-gain based on IOM recommendations (Fisher’s Exact test 29.01; p<0.001), with 76% (n=29) of overweight women (Table 3) gaining above the recommendations. Obese women were more likely gain less gestational weight than recommended by the IOM (Table 3). Women with normal pre-pregnancy BMIs were significantly more likely (p<0.001) to gain within the IOM recommendations. This significance was not observed when using the total weight-gain and interval weight-gain calculations; however, using each respective calculation, 50% (n=26) and 61% (n=23) of overweight, and 37% (n=26) and 55% (n=39) of obese women still gained above the recommendations. Using the interval calculation, 51% (n=27) of women within a normal pre-pregnancy weight range gained above the recommendation compared to 47% (n=25) using the average gain by week calculation. Despite the small sample size (n=6), the majority of women (67-83%) with an underweight pre-pregnancy BMI gained less than the IOM recommendations regardless of calculation method (Table 3). Pre-pregnancy BMI, excessive GWG and delivery method The association between pre-pregnancy BMI and delivery method was statistically significant, (Fisher’s Exact test 20.89; p<0.001), with obese women significantly more likely to have an instrumental delivery (n=8) or planned-CS (n=16) and less likely than expected to have normal vaginal delivery (NVD). Normal weight women were more likely to have a NVD and although the numbers were small, underweight women were significantly more likely to undergo emergency-CS (Table 4). There was no statistically significant association between GWG and delivery method (χ2=8.8; p=0.358) (Figure 3).

Figure 2. All pregnancy GWG relative to IOM recommendations showing proportion of women in each category across the three methods of calculation.

Table 2. Average total and weekly weight gain (with standard deviation) across BMI categories with IOM recommendations per BMI category.

Pre-pregnancy Weight Category

Participant average IOM Recommended Participant average total weight gain (kg) range of total weight weekly weight gain (±SD) (kg) (total weight/weeks pregnant) (±SD)

Participant average weekly weight gain (weight gain over interval between measurements) (±SD)

IOM Recommended rate of weight in second and third trimester (kg/week)

Underweight

11.25 (±4.27)

12.7 - 18.1

0.354 (±0.31)

0.381 (±0.11)

0.45 (0.45 - 0.58)

Normal weight

12.62 (±5.13)

11.3 - 15.8

0.478 (±0.28)

0.481 (±0.21)

0.45 (0.36 - 0.45)

Overweight

12.08 (±6.26)

6.8 - 11.3

0.480 (±0.29)

0.456 (±0.25)

0.27 (0.22 - 0.31)

Obese (includes all classes)

7.83 (±6.07)

4.9 - 9.0

0.311 (±0.36)

0.355 (±0.27)

0.22 (0.18 - 0.27)

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Table 3. Assessment of weight gain by pre-pregnancy BMI relative to IOM GWG recommendations using three methods of calculation, Fisher’s Exact statistic 29.04, p<0.001.

IOM Recommendation Above (n, %)

Within (n, %)

Below (n, %)

Total

Underweight

0 (0)

1 (5)

5 (10)

6 (4)

Normal weight

25 (26)

13 (59)

15 (29)

53 (35)

Overweight

29 (31)

5 (23)

4 (8)

38 (24)

Obses

41 (43)

3 (14)

27 (53)

71 (42)

Total

95

22

51

168

Discussion Regardless of pre-pregnancy BMI or calculation method, the majority of participants gained weight outside the IOM recommendations; only 9-31% of women gained within the recommended guidelines. Calculating GWG by week or interval rather than total weight-gain identified more women gaining outside the guidelines. Approximately one third of women gained less weight than recommended, regardless of calculation method. Whether this is related to the environment, inadequate antenatal education or overly strict guidelines, these results are consistent with, or lower than, those reported previously. Johnson, et al. found 73% of participants gained above the guidelines using a total weight and weekly weight gain calculation; however, a Taiwanese study, however, found significantly fewer to have gained above (27.7%) and many more to have gained within (45%) the guidelines [7,15]. Ethnic differences in body morphology are more likely to have played a role than in the current study and provide grounds for variation in the IOM recommendations to also consider ethnicity rather than just BMI. Additionally, in a Swedish study of 163,352 women, the proportion of women gaining in excess of the guidelines was linked to education status and parity, with 37.1% of women gaining in excess of the guidelines in the first pregnancy and 32.9% in the second [3]. Being retrospective in nature, the current study did not collect data regarding parity or education. Irrespectively, with such a high proportion of women experiencing excessive GWG there is a clear need for intervention. A common limitation for GWG studies is establishing pre-pregnancy weight. Various approaches have been used: many have used selfreported pre-pregnancy weight to determine BMI, while others have excluded women with incomplete BMI information [9,32,42,43]. In one study, where pre-pregnancy weight data were missing from participants’ records, it was estimated post-delivery [44]. It is not clear whether this estimation was objective or subjective. In a later study using IOM guidelines, subjective pre-pregnancy weight provided by participants was used to calculate GWG [7]. Given that many women

may neither be weighed prior to conceiving nor present within the first few weeks/months of pregnancy, it is difficult to assess true GWG based on pre-pregnancy weight. In an attempt to account for this limitation, Johnson, et al. assessed weekly weight-gain and provided an objective measure of weight upon study commencement [7]. This enabled a correlation between weekly weight-gain based on BMI and the IOM recommendations rather than a total weight-gain figure and formed the basis of the calculations used in this study. Another approach is using only the first prenatal visit weight to calculate GWG, with the justification that early pregnancy weight-gain should be relatively minor [24]. Using average weekly weight-gain, pre-pregnancy BMI was not associated with GWG outside the recommendations with more overweight and obese women gaining above the recommended weekly amounts. These findings are comparable with de Jersey et al., where their methods included only a total weight-gain calculated by weights performed at 16 and 36 weeks’ gestation [32]. The results do conflict with those of Gallagher et al. who found that rural overweight and obese women were less likely to have excessive GWG [36]. However, their finding that American rural women were more likely to have an overweight or obese pre-pregnancy BMI weight status is consistent with the demographic of the current study, with 64% of participants overweight or obese [36]. There was no statistically significant association between pre-pregnancy BMI and GWG when assessing total weight-gain and average weekly weight gained between measurements. A secondary analysis of delivery method was included 1 because the local hospital is classified as ‘low-risk’ (women with a BMI>40 must deliver at larger hospitals). An association between pre-pregnancy BMI and delivery method was observed with more obese women having instrumental deliveries or planned CS and more normal weight women having NVD. This finding is consistent with other large studies that found that compared to women with a normal pre-pregnancy BMI, overweight and obese women were more likely to undergo CS

Table 4. Delivery methods of women classified by pre-pregnancy BMI p<0.001 using Fisher’s exact test. Method of Delivery Total (n, %)

Unknown (n, %)

NVD (n, %)

Instrumental (n, %) Planned LSCS (n, %) E-LSCS (n, %)

Underweight

6 (4)

1 (25)

1 (25)

0 (0)

0 (0)

2 (50)

Normal weight

53 (35)

4 (8)

39 (74)

1 (2)

4 (8)

5 (9)

Overweight

38 (24)

6 (16)

24 (63)

1 (3)

4 (11)

3 (8)

Obese

71 (42)

7 (10)

34 (47)

8 (11)

16 (22)

8 (11)

Total

168

18 (11)

98 (58)

10 (6)

24 (14)

18 (11)

NVD: normal vaginal delivery, LSCS: lower segment Caesarean-section, E-LSCS: emergency lower segment Caesarean-section

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AM S J [5,7,16]. In a retrospective study (n=30,298), Scott- Pillai et al. further concluded the risk was greater for each increasing category of obesity; a breakdown of which was not included in the current study [5]. There was no statistically significant association between excessive GWG and delivery method which contrasts with previous studies; two in particular reported excessive GWG as an independent risk factor for CS delivery [16,4546,47]. The lack of association may have been related to the current study’s use of categorical data to classify GWG, as opposed to quantifying the impact of increasing kilograms of GWG on delivery method. While reasons for planned-CS may not be related to maternal weight-gain or BMI, in the current study, it may indicate the need for the inclusion of pre-conception weight control planning in the Expecting Changes program. Limitations As discussed above, establishing pre-pregnancy weight can be difficult [7,9,24,32]. To overcome this, the calculation of weight-gain by week based on total GWG and interval between weight measurements was used. This is similar to the method adopted by Johnson, et al. [7]. Although the result was not significant, calculation based on the interval between weights allowed for a more accurate assessment of weight-gain as it factored in a potential change in rate of weightgain occurring at different stages of pregnancy and allowed for consideration of lower weight gain targets in the first trimester. While this study reports a statistically significant difference in weightgain by women based on pre-pregnancy BMIs, there are limitations to the accuracy of such data and the representative nature of the sample size to the broader population of gestating rural women. Since the National Institute for Health and Care Excellence (NICE) guidelines advised against it, there has been a shift away from weighing women at every antenatal appointment [48]. This was reflected in the number of women excluded from the study due to lack of weight data. It may also be that weights were recorded on ‘yellow cards’ rather than in GP patient records, which this study did not have ethical approval to access. Midwives report anecdotal bias in that women who appear overweight tend to be weighed more than those who look normal or underweight. While this is associated with the local hospital’s low-risk status, it also potentially means that more normal or underweight women were excluded from the study. As such, the sample size of underweight women was too small to detect statistical significance. Other limitations leading to reduction in weight information include women opting-out of weighing and variation in doctor practice (including own biases and limitations in addressing the subject of weight with women).

Comorbidities were outside the scope of this research; however, the lack of consideration of possible confounding factors such as socioeconomic factors, education level, marital status, age, parity, smoking status, and indigenous status may have confounded our study results and reduced their generalisability. This information was not always available in the GP patient record and therefore would not have accurately reflected the participant characteristics. Additionally, inability to include information regarding hypertension or endocrine disorders would influence the results, although there does not seem to be a consistent approach regarding c 1 o-morbidities, with some studies excluding women based on comorbidities and others not [5,7,9,16,32,49]. Method of delivery was obtained from GP patient records, but given that in 11% of participants this parameter was unknown and many births in the area were excluded, the study sample was unlikely to have represented all delivery methods. Implications for the ‘Expecting Changes’ program Herein, we provide evidence of the need for pre- and/or postconception support for overweight and obese women in this rural area; however, given the total number of women with excessive GWG, more targeted antenatal counselling may be prudent for all expectant mothers. Data from this study may be applied to other rural populations in Australia and suggests that with limited access to services in rural areas, specific programs for weight control may be an important way to address this issue. Given increased rates of CS and instrumental deliveries related to high pre-pregnancy BMI the need for pre-conception planning is further emphasised [5,7,16]. Ongoing weight management in women of childbearing age is an important role for the GP, with recommendations of promoting moderate-intensity exercise and nutritional diets outlined in the current clinical guidelines [50]. Future research The findings of the current study will allow an accurate assessment of the effectiveness of the Expecting Changes program. Adverse outcomes of high pre-pregnancy BMI and excessive GWG extend beyond the immediate pregnancy to impact health outcomes for both mother and child. Regardless of pre-pregnancy BMI or method of GWG calculation, the majority of women in this small rural centre are gaining outside the recommended guidelines. Women with high pre-pregnancy BMIs are more likely to gain above the recommended amount and obese women are more likely to have a CS or instrumental delivery. Thus, there is a role for a program like the multi-disciplinary Expecting Changes program, targeting women with a pre-pregnancy BMI≥25 and further antenatal counselling on GWG is likely to benefit women both prior to and during pregnancy, regardless of BMI. Acknowledgements Thank you to the staff at the medical centre where this research was conducted. Conflicts of interest None declared.

Correspondence A Power: annacpower@gmail.com Figure 3. Delivery methods of women classified by GWG above, within and below the IOM recommendations (numbers within columns represent number of deliveries). NVD: normal vaginal delivery, LSCS: lower segment Caesareansection. Instrumental: forceps or ventouse (vacuum extraction).

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Volume 9, Issue 1 | 2019 References

[1] Ministry of Health. Guidance for Health Weight Gain in Pregnancy. Wellington, New Zealand: Ministry of Health; 2014. [2] Holowko N, Mishra G, Koupil I. Social inequality in excessive gestational weight gain. Int J Obes. 2014;38(1):91-6. [3] Bider-Canfield Z, Martinez MP, Wang X, Yu W, Bautista MP, Brookey J, et. al. Maternal obesity, gestational diabetes, breastfeeding and childhood overweight at age 2 years. Pediatr Obes. 2017;12(2):171-8 [4] Boots C, Stephenson MD. Does obesity increase the risk of miscarriage in spontaneous conception: a systematic review. Semin Reprod Med 2011;29(6):507-13. [5] Scott-Pillai RD, Spence CR, Cardwell, Hunter A, Holmes VA. The impact of body mass index on maternal and neonatal outcomes: a retrospective study in a UK obstetric population. Br J of Obstet Gynaecol. 2013;120(80):932-9. [6] Cnattingius S, Bergstrom R, Lipworth L, Kramer MS. Prepregnany weight and the risk of adverse pregnancy outcomes. N Engl J Med 1998;338(3):147-51. [7] Johnson J, Clifton RG, Roberts JM, Myatt L, Hauth JC, Spong CY, et al. Pregnancy outcomes with weight gain above or below the 2009 Institute of Medicine Guidelines. Obstet Gynecol. 2013;121(5)969-75. [8] Li N, Liu E, Guo J, Pan L, Li B, Wang P, et. al. Maternal prepregnancy body mass index and gestational weight gain on pregnancy outcomes. PLoS One. 2013;8(12); e82310. doi:10.1371/journal.pone.0082310 [9] Nohr E, Vaeth M, Baker J, Sorensen T, Olsen J, Rasmussen K. Combined associations of prepregnancy body mass index and gestational weight gain with the outcome of pregnancy. Am J Clin Nutr. 2008;88(6):1750-9. [10] Rahman MM, Abe SK, Kanda M, Narita S, Rahman MS; Bilano V, et. al. Maternal body mass index and risk of birth and maternal health outcomes in low- and middle-income countries: a systematic review and meta-analysis. Obes Rev. 2015;16(9):758-70. [11] Hung TH, Chen SF, Hsu JJ, Hsieh TT. Gestational weight gain and risks for adverse perinatal outcomes: a retrospective cohort study based on the 2009 Institute of Medicine guidelines. Taiwan J Obstet Gynaecol. 2015;54(4):421-5. [12] Sebire NJ, Jolly M, Harris JP, Wadsworth J, Joffe M, Beard RW, et al. Maternal obesity and pregnancy outcome: a study of 287,213 pregnancies in London. Int J Obes Relat Metab Disord. 2001;25(8):1175-82. [13] Blanco, R, Colombo A, Suazo J. Maternal obesity is a risk factor for orofacial clefts: a meta-analysis. Br J Oral Maxillofac Surg. 2015;53(8):699-704. [14] Korkmaz L, Bastug O, and Kurtoglu S. Maternal obesity and its short- and long-term maternal and infantile effects. J Clin Res Pediatr Endocrinol. 2016;8(2):114-24. [15] Hung TH, Hsieh TT. Pregestational body mass index, gestational weight gain, and risks for adverse pregnancy outcomes among Taiwanese women: a retrospective cohort study. Taiwan J Obstet Gynecol. 2016;55(4):575-81. [16] Poobalan AS, Aucott LS, Gurung T, Smith WC, Bhattacharya S. Obesity as an independent risk factor for elective emergency caesarean delivery in nulliparous women— systematic review and meta-analysis of cohort studies. Obes Rev. 2009;10(1):28-35. [17] Gaillard R, Durmus B, Hofman A, Mackenbach JP, Steegers E, Jaddoe AP, et al. Risk factors and outcomes of maternal obesity and excessive weight gain during pregnancy. Obesity (Silver Spring). 2013;21(5):1046-55. [18] Cedergren, M. Effects of gestational weight gain and body mass index on obstetric outcome in Sweden. Int J Gynaecol Obstet. 2006;93(3):269-74. [19] Babendure JB, Reifsnider E, Mendias E, Moramarco MW, Davila YR. Reduced breastfeeding rates among obese mothers: a review of contributing factors, clinical considerations and future directions. Int Breastfeed J. 2015;10:21. [20] Woolhouse H, James J, Gartland D, McDonald E, Brown SJ. Maternal depressive symptoms at three months postpartum and breastfeeding rates at six months postpartum: implications for primary care in a prospective cohort study of primiparous women in Australia. Women Birth. 2016;29(4):381-7. [21] Marseglia L, Manti S, D’Angelo G, Cuppari C, Salpietro V,; Filippelli M, et. al. Obesity and breastfeeding: the strength of association. Women Birth. 2015;28(2):81-6. [22] Stuebe A. The risks of not breastfeeding for mothers and infants. Rev Obstet Gynaecol. 2009;2(4):222-31. [23] Horta BL, deMola CL, Victoria CG. Long-term consequences of breastfeeding on cholesterol, obesity, systolic blood pressure and type 2 diabetes: a systematic review and meta-analysis. Acta Paediatr. 2015;104(467):30-7. [24] Rooney BL, Schauberger CW. Excess pregnancy weight gain and long-term obesity: one decade later. Obstet Gynecol. 2002;100(2):245-52. [25] Getahun D, Ananth CV, Oyelese Y, Chavez MR, Kirby RS, Smulian JC. Primary preeclampsia in the second pregnancy: effects of changes in prepregnancy body mass index between pregnancies. Obstet Gynaecol. 2007;110(6):1319-25.

[26] Gilmore LA, Klempel-Donchenko M, Redman LM. Pregnancy as a window to future health: Excessive gestational weight gain and obesity. Semin Perinatol. 2015;39(4):296-303. [27] Oken E, Gillman MW. Fetal origins of obesity. Obesity. 2003;11(4):496-506. [28] Nehring I, Lehmann S, and von Kries R. Gestational weight gain in accordance to the IOM/NRC criteria and the risk for childhood overweight: a meta-analysis. Pediatr Obes. 2013;8(3):218-24. [29] Ensenauer R, Chmitorz A, Riedel C, Fenske N, Hauner H, Nennstiel-Ratzel, et al. Effects of suboptimal or excessive gestational weight gain on childhood overweight and abdominal adiposity: results from a retrospective cohort study. Int J Obes. 2013;37:505-12. [30] Houghton LC, Ester WA, Lumey LH, Michels KB, Wei Y, Cohn BA, et al. Maternal weight gain in excess of pregnancy guidelines is related to daughters being overweight 40 years later. Am J Obstet Gynaecol. 2016;215(2):246.e1-8. [31] Schieve LA, Cogswell ME, Scanlon KS. Trends in pregnancy weight gain within and outside ranges recommended by the Institute of Medicine in a WIC population. Matern Child Health J. 1998;2(2)111-6. doi.org/10.1023/A:1022992823185 [32] deJersey SJ, Nicholson JM, Callaway LK, Danils LA. A prospective study of pregnancy weight gain in Australian women. Aust N Z J Obstet Gynaecol. 2012;52(6):545-51. [33] Hackney B, Fennie K, Applebaum J, Berry D, Melkus GD. The effect of language preference on prenatal weight gain and postpartum weight retention in urban hispanic women. Ethn Dis. 2010;20(2):162-8. [34] Pawlak MT, Alvarez BT, Jones DM, Lezotte DC. The effect of race/ethnicity on gestational weight gain. J Immigr Minor Health. 2015;17(2):325-32. [35] Maddah M, Nikooyeh B. Urban and ural differences in pregancy weight gain in Guilan, northern Iran. Matern Child Health J. 2008;12(6):783-6. [36] Gallagher A, Liu J, Probst JC, Martin AB, Hall JW. Maternal obesity and gestational weight gain in rural versus urban dwelling women in South Carolina. J Rural Health. 2013;29(1):1-11. [37] Asbee SM, Jenkins TR, Butler JR, White J, Elliot M, Rutledge A. Preventing excessive weight gain during pregnancy through dietary and lifestyle counseling: a randomized controlled trial. Obstet Gynaecol. 2009;113(2 Pt 1):305-12. [38] Australian Institute of Health and Welfare. Risk factors to health. [Internet]. 2017 Aug 07. Available from: https://www.aihw.gov.au/reports/risk-factors/risk-factors-to-health/ contents/risk-factors-and-disease-burden [39] Leung J, Funder J. Obesity: A national epidemic and its impact on Australia. Sydney, Australia: Obesity Australia; 2014. [40] Australian Institute of Health and Welfare. Australia’s health 2016. Australia’s health series no. 15. Cat. no. AUS 199. Canberra: AIHW; 2016. [41] Institute of Medicine and National Research Council. Weight gain during pregnancy: reexamining the guidelines. Washington, DC: The National Academies Press; 2009. [42] Polley BA, Wing RR, Sims CJ. Randomized control trial to prevent excessive weight gain in pregnant women. Int J Obes Relat Metab Disord. 2002;26(11):1494-1502. [43] Oken E, Kleinman KP, Belfort MB, Hammitt JK, Gillman MW. Associations of gestational weight gain with short- and longer-term maternal and child health outcomes. Am J Epidemiol. 2009;170(2):173-80. [44] DeVader SR, Neely HL, Myles TD, Leet TL. Evaluation of gestational weight gain guidelines for women with normal prepregnancy body mass index. Obstet Gynecol. 2007;10(4):745-51. [45] Chung J, Taylor RS, Thompson J, Anderson NH, Dekker GA, Kenny, LC, et. al. Gestational weight gain and adverse pregnancy outcomes in a nulliparous cohort. Eur J Obstet Gynaecol Reprod Biol. 2013;167(2):149-53. [46] Stotland NE, Hopkins LM, Caughey AB. Gestational weight gain, macrosomia, and risk of Caesarean birth in nondiabetic nulliparas. Obstet Gynaecol. 2004;104(4):671-7. [47] Johnson JWC, Longmate JA, Frentzen B. Excessive maternal weight gain and pregnancy outcome. Am J Obstet Gynaecol. 1992;167(2):353-72. [48] Brownfoot FC, Davey M-A, Kornman L. Women’s opinions on being weighed at routine antenatal visits. Br J Obstet Gynaecol. 2016;123(2):263-70. [49] Godoy AC, Lira do Nascimento S, Surita FG. A systematic review and meta-analysis of gestational weight gain recommendations and related outcomes in Brazil. Clinics (Sao Paulo). 2015;70(11):758-64. [50] Royal Australian College of General Practitioners. Preventive activities prior to pregnancy. In: Guidelines for preventive activities in general practice. Ninth Edition. East Melbourne, VIC: RACGP; 2016.

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Original Research Article Xanthomas seen on capsule endoscopy: What are they saying about your patient’s health?

AM S J

Dr Mian Li Ooi MBBS, DCH Service ENT Registrar, Modbury Hospital

Mian was a final year medical student when she conducted this research. She is now completing her PhD in ENT Surgery. Her PhD thesis looks into emerging treatment options for the management of recalcitrant chronic rhinosinusitis.

Dr Nivashini Ponnampalam MBBS Member of the Academy of Family Physicians of Malaysia (AFPM)

Nivashini was a final year medical student when she conducted this research. She later continued her work at the Malaysian Corneal Subspecialty Centre in Sungai Buloh and was involved in an audit involving operation cancellation rates of therapeutic penetrating keratoplasties. She is currently pursuing the postgraduate academic paper of Graduate Certificate of Family Medicine Malaysia.

Dr Penny Allen PhD, MPH, BA (Hons) Senior Research Fellow, Rural Clinical School, University of Tasmania

Penny’s background is in epidemiological research and evaluations of health services and health care interventions. Penny provides education and support for medical students undertaking research.

Dr Kathryn Ogden MBBS, MPH, FRACGP Senior Lecturer, Launceston Clinical School, School of Medicine, University of Tasmania

An academic GP and senior lecturer at University of Tasmania, Dr Ogden has a passion for supporting medical students to undertake research as part of their training, in addition to imparting skills relating to professionalism and compassionate patient-centred care.

Dr Iain K Robertson MMedSci, MBBCh, MPH Adjunct Senior Researcher, School of Health Sciences, University of Tasmania, and Biostatistician Clifford Craig Foundation.

Dr Robertson provides clinical epidemiology and biostatistical advice, support and analysis to University of Tasmania researchers and students, and Launceston General Hospital clinical staff, aiming to help them to understand the boundaries between certainty and uncertainty.

Dr John Wettenhall MBBS, FRACP

Consultant Gastroenterologist and Hepatologist at Launceston General Hospital, Tasmania and Senior Lecturer at University of Tasmania

Abstract Background: There is long-standing evidence of an association between cutaneous xanthomas and underlying lipid metabolism disorders, impaired glucose tolerance, secondary hyperlipoproteinemia and diabetes mellitus. Since the advent of capsule endoscopy (CE), substantial numbers of endoscopies have shown evidence of small bowel xanthomas. These have unknown significance to the patient and, consequently, are not routinely reported when identified. Our research is the first study to investigate the significance of small bowel xanthomas identified on CE with underlying lipid disorders or diabetes mellitus. Methods: 54 patients participated in this prospective cohort study. We recorded patients’ demographic details, medical history, medication list, height, weight, and waist circumference measurements. A blood sample for fasting lipids, fasting glucose and HbA1c was collected. A blinded gastroenterologist reported whether xanthomas were present and quantified the number of xanthomas.

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Results: 37% of participants had small bowel xanthomas visualised during CE. The presence of xanthomas was associated with a previous diagnosis of hyperlipidaemia currently treated with antilipid medication (IRR 4.43; 95%CI 1.32 to 14.9; p=0.048) and was also associated with increasing units of alcohol consumption (IRR 1.91; 95%CI 1.32 to 2.78; p=0.0007). Conclusion: This demonstrates an association between the presence of small bowel xanthomas with hyperlipidaemia, mainly in patients with hyperlipidaemia controlled by medication. We also detected an association between small bowel xanthomas and increased alcohol intake. The presence of small bowel xanthomas might trigger lipid evaluation, in future clinical practice.


Volume 9, Issue 1 | 2019 Introduction

Data collection

Xanthomas (also referred to as xantholesmas) are fatty deposits comprised of well-defined clusters of foamy lipid-laden histiocytes. They are characterised by a yellow-orange colour and are commonly observed dermally as subcutaneous plaques or tendinous nodules [1]. There is long-standing evidence of an association between cutaneous xanthomas and underlying lipid metabolism disorders, secondary hyperlipoproteinemia, impaired glucose tolerance and diabetes mellitus [1-5].

A member of the study team completed a data collection sheet for each participant and collected a blood sample for fasting lipids, fasting glucose and HbA1c tests. The data collection sheet included age, sex, body mass index, past medical history, co-morbidities and current medications. This information was entered onto the study database along with the CE results and pathology results.

In the gastrointestinal tract, xanthomas are more commonly reported in the gastric mucosa. They are often small (1-2mm), single or multiple, yellow, orange, or white well-demarcated sessile macules with irregular outlines [6]. They are believed to occur as a non-specific response to various insults, either iatrogenic or spontaneous [7,8]. However, small bowel xanthomas have rarely been described and are reported in only a handful of case reports, presenting either as a localised or diffuse pattern [9]. They are usually incidental findings [10]. As they are infrequently reported, the pathogenesis and significance of small bowel xanthomas has yet to be fully elucidated. Since 2001, capsule endoscopy (CE) has been used to visualise the small bowel [11]. CE is non-invasive, wireless, safe, does not require sedation and provides reliable visualisation of the small bowel mucosa. Commercially available capsule endoscopes are 24.5 mm to 27.9 mm in length and 10.8 mm to 13.0 mm in diameter [11]. The capsule contains a camera, battery, LED lights and a transmitter. They are capable of transmitting approximately 2 to 6 images per second to a receiver worn externally by the patient [11]. The images are subsequently uploaded into proprietary software for visualisation by a gastroenterologist. The European Society of Gastrointestinal Endoscopy and the British Society of Gastroenterology recommend CE as the first-line investigation of obscure gastrointestinal bleeding [12]. CE is also indicated for the diagnosis and management of NSAID side effects, Crohn’s disease, malabsorptive syndromes such as coeliac disease, inherited polyposis syndromes, small bowel transplant management and the detection of small bowel tumors [11-13]. Incidentally, CE has enabled easier detection of the presence of xanthomas in the small bowel. As there has been no evidence regarding the significance of these xanthomas, they are not routinely recorded on the formal endoscopy report when identified. Therefore this study is significant because it will provide the first evidence of an association between the presence of small bowel xanthomas and metabolic disorders, which could further implicate its pathogenesis. Our hypothesis is that small bowel xanthomas could be secondary to lipid disorders and diabetes mellitus. If this is the case, detection of xanthomas during CE may indicate a need to change reporting practices to ensure that general practitioners (GPs) are notified of these findings. Methods Participants and study design This prospective cohort study was conducted among patients attending the Day Procedure Unit of a single regional hospital (Launceston General Hospital). Ethics approval for the research was granted by the University of Tasmania Human Research Ethics Committee (reference number H11823). The study was therefore performed in accordance with the ethical standards laid down by the Declaration of Helsinki (2013). Patients aged 18 years or older who attended for CE between 23 September 2011 and 2 December 2013 were invited to participate in the study. All study participants provided written consent prior to recruitment.

During reporting of the CE, the gastroenterologist, who was blinded to the patient’s history and blood results, recorded whether xanthomas were present and quantified the number of xanthomas. Patients were excluded from the study if they had incomplete findings due to delay in the CE reaching the small bowel. Statistical analyses The clinical question being examined was whether xanthomas seen on CE occurred more frequently in the presence of either diabetes mellitus or hypercholesterolaemia. If an association was found, the presence of xanthomas in patients who had not been investigated might indicate the need for testing for diabetes mellitus or hypercholesterolaemia. Testing this association involved estimating the rate of occurrence of xanthomas in the different disease groups (incidence rates), and comparing the rates in patients without those diseases (incidence rate ratios). These estimations were performed using Poisson regression, which either estimate the mean number of xanthomas per patient (if the count of xanthomas for each patient was used as the outcome variable) or the proportion of patients with xanthomas (if the presence or absence of xanthomas was used). The relative risk (in this case the incidence rate ratios) of the different predictor conditions (e.g. the presence or absence of treated hyperlipidaemia) were examined simulataneously by multivariate Poisson regression, in order to remove the effects of confounding variables. In order to determine whether investigation of patients found to have small bowel xanthomas on capsule endoscopy would yield a higher diagnosis rate of uncontrolled hyperlipidaemia compared to random patient selection, the patients were classified into four groups according to their lipid status: 1) no current lipid abnormalities (total cholesterol (TC)<5.2mmol/L) and not on medications (n=17); 2) no past history of lipid abnormalities, but current raised lipids (TC≥5.2mmol/L) and not on medications (n=10); 3) past diagnosis of lipid abnormalities and current raised lipids (TC≥5.2mmol/L) and not on medications (n=3); and 4) past diagnosis of lipid abnormalities on lipid-lowering medication, whatever the current lipid levels (n=24). The assumption here is that doctors have decided that patients had sufficiently serious lipid abnormalities to justify commencing lipid-lowering medication, whilst other patients had lesser degrees of lipid abnormalities that were either not been detected in the past, or were 1 not sufficiently serious to justify lipidlowering medications. The association between the presence of small bowel xanthomas was estimated by calculating the incidence rate ratio using multivariable Poisson regression (IRR; 95% confidence intervals; p-values), with variables selected by backward stepwise regression from a list of variables included in the final model (hyperlipidaemia as classified above and diabetes mellitus status, presence of end-organ disease, and weekly alcohol intake) plus age, gender, body mass index, family history of hyperlipidaemia, family history of diabetes mellitus, cholesterol (total, LDL, HDL), log.triglycerides, log.fasting glucose and HbA1c percentage which were not included. All analyses were performed using Stata MP2 version14.1 (StataCorp, College Station, Tx USA).

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AM S J Results A total of 55 patients were invited to participate and 54 consented that were included in the study.

Table 1. Indication for capsule endoscopy

The most common indication for CE was recurrent iron deficiency anaemia (n=39) (Table 1). Mean age was 65.0 years (SD 16.0) and there were equal numbers of men (n=27) and women (n=27). 17 participants (31.5%) had a total cholesterol level of ≥5.2 mmol/L, 27 (50.0%) had a history of hyperlipidaemia and 12 (22.2%) had diabetes mellitus. 20 participants (37.0%) had small bowel xanthomas detected during CE.

Indications for capsule endoscopy

Small bowel xanthomas were detected in 12 of the 27 (44.4%) participants with hyperlipidaemia, 5 of the 12 (41.7%) participants with diabetes mellitus (either unmedicated or medicated) and in 3 of the 9 (33.3%) participants with end-organ disease.

Further investigation following suspicious findings on 2 another GI investigation

Preliminary analyses found that the presence of small bowel xanthomas was associated with a prior diagnosis of hyperlipidaemia (IRR 2.86; 95% CI 1.14 to 7.18; p=0.025), but not to current poor control of blood lipids (IRR 1.04; 95% CI 0.50 to 2.17; p>0.90). The final multivariable regression model (Table 2) demonstrated that the risk of the presence of xanthomas is raised (IRR 4.43; 95%CI 1.32 to 14.9; p=0.048) in patients with prior diagnosis of hyperlipidaemia treated with lipid-lowering medication compared to no past or current diagnosis of lipid abnormalities, after adjustment for diabetes status, presence of end organ disease and current alcohol intake. Alcohol intake as a continuous measure is associated with increasing risk of xanthomas (IRR 1.91; 95%CI 1.32 to 2.78; p=0.0007). Diabetes status does not appear to be related to the risk of presence of xanthomas.

n = 54

Blood loss Recurrent iron deficiency anaemia

39

Recurrent GI bleeding

13

Possible neoplasm

Further investigation following removal of GI neoplasms

2

Investigation of possible small bowel obstruction

1

Others Crohn’s disease assessment

2

Chronic diarrhoea

2

Unspecified abdominal symptoms

2

Recurrent GI pain

1

Peutz-Jeghers syndrome review

1

Note: several participants had more than one indication for capsul endoscopy

Table 2. Association between hyperlipidaemia and diabetes status and other predictors and presence of small bowel xanthomas on capsule endoscopy Predictor status

Xanthomas of Total (%)

IRR1

95% CI

P-value2

No prior hyperlipidaemia and current TC<5.2mmol/L (comparator category)

5 of 17 (29.4%)

1.00

No prior hyperlipidaemia and current TC≥5.2mmol/L

3 of 10 (30.0%)

Prior hyperlipidaemia not on anti-lipid medication

1 of 3 (33.3%)

1.40

(0.42 to 4.63)

0.59

2.29

(0.47 to 11.1)

0.30

Prior hyperlipidaemia on anti-lipid medication

11 of 24 (45.8%)

4.43

(1.32 to 14.9)

0.048

No prior DM diagnosis (comparator category)

15 of 42 (35.7%)

1.00

Prior DM diagnosis not on DM medication

3 of 5 (60.0%)

1.48

(0.55 to 3.95)

0.44

Prior DM diagnosis on DM medication

2 of 7 (28.6%)

0.52

(0.20 to 1.37)

0.37

No end-organ disease (comparator category)

17 of 45 (37.8%)

1.00

End-organ disease present

3 of 9 (33.3%)

0.35

(0.14 to 0.86)

0.022

Mean 2.88 (SD 6.08)

1.91

(1.32 to 2.78)

0.0007

Hyperlipidaemia

3

Diabetes mellitus

Evidence of End-Organ Disease

Alcohol Intake Alcohol units per week4

Incidence rate ratio for the presence of xanthomas, estimated using multivariate Poisson regression (IRR; 95% confidence intervals; P-values); each predictor variable estimate is adjusted for the presence of the other three predictor variables. 2 P-values were corrected for multiple comparisons where appropriate using the Holm method. 3 Patients were classified according to their lipid status into four groups: 1) no current lipid abnormalities (TC<5.2mmol/L) and not on medications (N=17); 2) no past history of lipid abnormalities and not on medications, but current raised lipids (TC≥5.2mmol/L) (N=10); 3) past diagnosis of lipid abnormalities and not on medications, and current raised lipids (TC≥5.2mmol/L) (N=3); 4) past diagnosis of lipid abnormalities on lipid-lowering medication, whatever the current lipid levels (N=24). 4 Alcohol intake (showing mean (SD)) is analysed as a continuous standardised normal transformed variable [(variable value – mean)/standard deviation], with the IRR representing the linear slope of the association between likelihood of presence of xantholesmas and the alcohol intake; the IRR can be thought of as the slope of the relationship. 1

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Discussion Our research provides the first evidence of an association between the presence of small bowel xanthomas and hyperlipidaemia, even among patients with hyperlipidaemia controlled by medication. We also detected an association between small bowel xanthomas and increased alcohol intake. No association with diabetes mellitus was seen. In patients with small bowel xanthomas, 70% had a prior diagnosis of hyperlipidaemia or had a total cholesterol â&#x2030;Ľ5.2 mmol/L on the day of the capsule endoscopy. Interestingly, 44% of these patients were already on lipid-lowering medications. The persistence of small bowel xanthomas in patients with hyperlipidaemia on medication may suggest a slow rate of xanthoma clearance even when lipid-lowering is adequate. Alternatively, it could indicate that patients might have had even higher lipid levels prior to commencement of lipid lowering medications resulting in the deposition and persistence of small bowel xanthomas. The association between small bowel xanthomas and increased alcohol intake is consistent with our understanding of the effects of alcohol in dysregulating lipid metabolism and elevating triglycerides [14]. It has been shown that chronic alcohol intake delays the clearance of triglycerol-rich lipoproteins and these abnormal chylomicron remnants then affects the feedback regulation of cholesterol synthesis in hepatocytes, resulting in increased secretion of triglycerol-rich lipoproteins by the liver [15]. This may result in deposition and the formation of small bowel xanthomas. When one or more xanthomas are seen during a CE examination, it may be appropriate to report the occurrence of the observation to the GP. In this study, it appears that the GPs looking after this group of patients had investigated them for hyperlipidaemias and managed them appropriately. Nevertheless, in a less well-investigated population, an alert to the GP may be appropriate. The main limitation of the study was the small number of study participants due to the relatively small catchment population in the area. A power calculation indicated that a sample size of around

250 would be required to detect a 20% absolute difference between comparator groups (30% vs 50%), with larger numbers required if smaller differences were needed to be detected. The study period would have had to be extended considerably to recruit this number of participants as the hospital, in which the study was conducted performs only 30-40 CEs per year. Strengths of the study include a single blinded gastroenterologist visualising the CE images, thereby reducing the possibility of reporting bias and the collection of a blood sample at recruitment for fasting lipids, fasting glucose and HbA1c tests, rather than relying on patient records. Nevertheless, the lipid status of the patients was not fully characterised and subgroups of lipid disorders may have been present that increased or decreased the likelihood of presence of small bowel xanthomas in some patients. Conclusion In conclusion, our research provides the first evidence of an association between the presence of small bowel xanthomas and hyperlipidaemia and increasing alcohol intake, even among patients with hyperlipidaemia controlled by medication. This suggests that gastroenterologists should notify GPs when xanthomas are detected during capsule endoscopies. Acknowledgements This research was partly funded by a grant from the Clifford Craig Foundation, Launceston. The authors wish to thank the patients who participated in the research. Conflicts of interests None of the authors have conflicts of interest to declare. Correspondence Dr Mian Li Ooi: mianli.ooi@gmail.com

References

[1] Cruz PD, Jr., East C, Bergstresser PR. Dermal, subcutaneous, and tendon xanthomas: diagnostic markers for specific lipoprotein disorders. J Am Acad Dermatol. 1988;19(1 Pt 1):95-111. [2] McGavack T, Shepardson H. Xanthoma accompanied by hypercholesterolemia, occurring in an otherwise normal individual, and in an individual with acromegaly and diabetes. Ann Intern Med. 1933;7(5):582-604. [3] Stawiski MA, Voorhees JJ. Cutaneous signs of diabetes mellitus. Cutis. 1976;18(3):415- 21. [4] Feingold KR. The outer frontier: the importance of lipid metabolism in the skin. J Lipid Res. 2009;50 Suppl:S417-22. [5] Doyle JR. Tendon xanthoma: a physical manifestation of hyperlipidemia. J Hand Surg. 1988;13(2):238-41. [6] Vimala R, Ananthalakshmi V, Murthy M, Shankar TR, Jayanthi V. Xanthelasma of esophagus and stomach. Indian J Gastroenterol. 2000;19(3):135. [7] Delacruz V, Takahashi H, Nishida S, Tzakis A, Ruiz P. Segmental xanthomatosis of the small intestine. A case report and review of the literature. Hum Pathol. 2009;40(1):139-42. [8] Nielsen SL, Ingeholm P, Holck S, Talbot I. Xanthomatosis of the gastrointestinal tract with focus on small bowel involvement. J Clin Pathol. 2007;60(10):1164-6. [9] Diaz Del Arco C, Alvarez Sanchez A, Fernandez Acenero MJ. Non-gastric Gastrointestinal Xanthomas: Case Series and Literature Review. J Gastrointestin Liver 2016;25(3):389-94. [10] Becheanu G, Dumbrava M, Arbanas T, Diculescu M, Hoyeau-Idrissi N, Flejou JF. Esophageal xanthoma--report of two new cases and review of the literature. J Gastrointestin Liver Dis. 2011;20(4):431-3. [11] Van de Bruaene C, De Looze D, Hindryckx P. Small bowel capsule endoscopy: Where are we after almost 15 years of use? World J Gastrointest Endosc. 2015;7(1):13-36.

[12] Pennazio M, Spada C, Eliakim R, Keuchel M, May A, Mulder CJ, et al. Small-bowel capsule endoscopy and device-assisted enteroscopy for diagnosis and treatment of small31 bowel disorders: European Society of Gastrointestinal Endoscopy (ESGE) Clinical Guideline. Endoscopy. 2015;47(04):352-86. [13] Liao Z, Gao R, Xu C, Li ZS. Indications and detection, completion, and retention rates of small-bowel capsule endoscopy: a systematic review. Gastrointest Endosc. 2010;71(2):280-6. [14] Capurso NA, Petrakis I. Dyslipidemia associated with heavy alcohol use. Am J Addict. 2016;25(3):188-90. [15] Lakshmanan MR, Ezekiel M. Relationship of alcoholic hyperlipidemia to the feed-back regulation of hepatic cholesterol synthesis by chylomicron remnants. Alcohol Clin Exp Res. 1982;6(4):482-6.

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Feature Article Nanoparticle administration across the blood-brain barrier using MRI-guided focused ultrasound Dr Huy Duc Vu Bachelor of Medicine, Bachelor of Surgery (Honours) James Cook University, Alumnus Princess Alexandra Hospital, Intern

Huy is an intern at Princess Alexandra Hospital who graduated from James Cook University. Originally from Melbourne, he moved to Townsville in 2012 to pursue his childhood goal of studying Medicine. Outside of his interest in research, involvement in medical education, and aspirations for a career in surgery, Huy enjoys reading, playing sports, and practicing music.

Abstract A vast array of medical conditions affects the central nervous system (CNS), implying a tremendous scope of therapeutic interventions that must target the brain. However, all medical therapy to the brain faces the inherent physiological obstacle of the blood-brain barrier (BBB). Furthermore, after the BBB, drugs must navigate the additional barrier of the brain extracellular space (ECS), which presents its own unique biochemical obstacles. Both the BBB and brain ECS present considerable difficulties for drug therapy to treat diseases affecting the brain. With advancing technology, there has been significant progress towards the goal of overcoming these barriers. An exciting development is the use of MRI-guided focused ultrasound (MRIgFUS) to deliver drug-loaded nanoparticles (NP). This article describes and explores the use of MRIgFUS and NPs, together as a novel method in CNS drug therapy. First, the basic scientific principles underlying the approach are described. Then, studies that demonstrate key concepts, advancements, strengths, and limitations are discussed to outline directions that have been pursued towards the goal of implementing MRIgFUS NP delivery in practice.

Introduction The gamut of conditions affecting the central nervous system is vast. Whether they are infectious, inflammatory, neoplastic, degenerative, or psychiatric, the diversity of these diseases’ aetiologies implies a tremendous scope of therapeutic interventions targeting the brain, but all drug therapy to the brain faces the inherent structural obstacle of the blood-brain barrier (BBB) [1]. A healthy BBB is important to brain homeostasis as it prevents circulating toxins and pathogens reaching the brain while also controlling the transport of important nutrients and solutes. However, in the pharmacological sense, it hampers the efficacy of drug treatment because most medications administered systemically are often unable to penetrate the BBB in therapeutically relevant doses [2]. Doses must, therefore, be increased to achieve adequate effects, raising the potential for side effects and limiting therapeutic potential. Once a drug passes the BBB, it must then navigate the extracellular space (ECS) of the brain; this presents its own obstacles, such as the tiny intercellular spaces, ionic composition of extracellular fluid and the meshwork of molecules comprising the extracellular matrix [3]. Both BBB and brain ECS present considerable difficulties in using drug therapy to treat the brain. With advancing technology and scientific effort, there have been significant strides towards the goal of overcoming these barriers, such as the use of MRI-guided focused ultrasound (MRIgFUS) to deliver drug-loaded nanoparticles (NP).

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Circumventing the barriers In developing methods to overcome the BBB, multiple approaches have been previously attempted. For example, drugs were developed with more lipophilic properties to better pass through the BBB, or they were bound to carrier molecules to exploit endogenous transport mechanisms [4,5]. A less conservative method involved intra-arterial catheterisation and administration of a hypertonic solution that caused widespread disruption of the BBB to allow molecules through [6]. A more invasive approach was the direct injection of the brain following a craniotomy and visualisation of the brain [7]. A less invasive and promising development is the use of focused ultrasound (FUS) to induce localised BBB disruption (Figure 1) [8,9]. The molecular basis of this can be explained by two main pathways: 1) the absorption of acoustic energy by tissue and 2) the propagation of the acoustic wave through fluid [10]. Firstly, when acoustic waves interact with tissue, there is absorption of the acoustic energy leading to a temperature increase, resulting in local injury. Secondly, when the wave propagates through a fluid medium, “cavitation” occurs; this is the formation of one or many bubbles. These “microbubbles” (MBs) pulsate and collapse or “pop”, resulting in mechanical stresses and temperature changes to the surrounding tissue. Significant improvements to this technique have included using agents containing preformed MBs and establishing safe ultrasound delivery parameters so as to avoid in vivo cavitation that can inadvertently damage brain tissue or non-target BBB sites [8,9]. A recent addition has been the introduction of MRI into the process. This presents multiple advantages, such as providing a guide for FUS exposure, visualising the BBB opening and monitoring MB distribution [11,12]. In terms of overcoming the brain ECS, the research focus was initially to characterise the size of the spaces a therapeutic agent would have to pass in order to reach the parenchyma. Studies have been done in both animal and human brains to better understand the interstitial dimensions and, unsurprisingly, the spaces are exceedingly small [13]. Therapeutics must, therefore, be small enough and have compatible


Volume 9, Issue 1 | 2019 chemical properties to pass through the brain ECS. In the pursuit of this, nanoparticles have become relevant. Nanoparticles are structures which can range in size between 1 to 100 nm, though the term is often used to describe particles up to several hundred nanometres in size [14]. One 1 of the significant ways NPs have become relevant in medicine is in the ability to load them with a therapeutic agent and thereby allow them to serve as a “nanocarrier” for medication delivery [15]. Advancements in this area have included synthesizing NPs that are able to pass the BBB and traverse the ECS improving their

characteristics to make delivery and distribution more effective, and successfully attaching various therapeutic agents. Key studies demonstrating the concept The techniques involved in BBB disruption and NP drug delivery must encapsulate multiple key elements: 1) the NP must penetrate and move through the brain ECS, 2) the NP must avoid rapid clearance, and 3) there must be a non-invasive approach to circumvent the BBB [16]. Many studies, which explore various aspects of the topic while

Table 1. Studies examining various aspects of focused ultrasound and nanoparticle administration.

Author

Aim

Key Findings

Hynynen et al. [9]

To determine if focused ultrasound could be used in targeted blood-brain barrier opening by monitoring with MRI

To examine pore size in the brain extracellular space and analyse the diffusion of nanoparticles with varying size and coatings

Perlstein et al. [20]

To demonstrate the use of CED for nanoparticles in a rat brain

CED was successful in the infusion of nanoparticles into the rat brain, and this was confirmed with MRI.

Yao et al. [21]

To use ultrasound and microbubbles in the delivery of PEG-coated nanoparticles across the blood-brain barrier

Nanoparticles were significantly more distributed (> 250% more as quantified by electron microscopy analysis of tissue) in brains treated with ultrasound compared to untreated controls. Ultrasound induced the cavitation of microbubbles, and this was a key determinant allowing nanoparticles across the blood-brain barrier.

To examine focused ultrasound mediated bloodbrain barrier disruption in an animal model of Alzheimer’s disease

To use focused ultrasound mediated blood-brain barrier opening in the delivery of DNAcontaining nanoparticles and monitor for gene expression

Nance et al. [17]

Burgess et al. [29]

Mead et al. [36]

• •

• •

Blood-brain barrier opening was confirmed with MRI contrast at targeted sites. Blood-brain barrier opening was achieved with the lowest ultrasound power, avoiding damage to surrounding tissue. Nanoparticles up to 114 nm in diameter coated with PEG could diffuse through the brain extracellular space. PEG coating avoided the premature elimination of nanoparticles.

Blood-brain barrier permeability was lower in the disease group compared to the control group. Presence of amyloid plaque reduced blood-brain barrier opening. Ultrasound delivery parameters may require an adjustment in Alzheimer’s disease models. Gene expression occurred in the ultrasound treated region and lasted for 28 days. In the ultrasound treated region, 42% of cells were transfected compared to 6% in the untreated region. No toxicities were observed.

CED, Convection-enhanced drug delivery; PEG, Polyethylene glycol.

outlining the applicability of FUS and NP delivery systems to medical treatment, have been conducted (Table 1). Hynynen et al. were the first to describe the use of MRI to guide the FUS procedure, now known as MRI-guided FUS [9]. Ultrasound contrast agent containing MBs was injected into rabbits, then FUS was administered while MRI scans were done to monitor temperature and tissue changes. Afterwards, relaxation time shortening MRI contrast was administered and further MRIs were performed. The contrast was visualised through signal intensity changes at target sites, and this confirmed BBB disruption. This study was pivotal in improving FUS23 mediated BBB disruption by making it more targeted. Furthermore, it contributed to increasing the safety of the procedure. By detecting tissue changes during sonication, ultrasound power may be monitored to prevent brain tissue damage.

effectively move through the brain ECS [13]. By coating NPs with low molecular weight polyethylene glycol (PEG), Nance et al. showed that NPs with a hydrodynamic diameter up to 114 nm could diffuse through the experimental tissue. This observation was partly explained by the presence of the PEG coating, which inhibited the processes that endogenously eliminate the NPs. This way, the PEGylated NPs had more time to distribute and accumulate. In a follow-up study, the use of PEGylated NPs was combined with MRIgFUS and MBs in a rat model to achieve the safe delivery of 60 and 75 nm NPs [16]. A recent paper by Hersh et al. demonstrated that ultrasound could be used to enlarge the interstitial spaces in living rat brains, opening up the possibility of using larger NPs and improving NP dispersion throughout the brain [18]. Finding an accord between NP size characteristics and FUS delivery is challenging but important, as the value of larger NPs lies in reducing the restrictions on the possible drug and payload sizes.

In terms of modifying the structure of the NP to improve brain delivery, a study by Nance et al. provides evidence for this [17]. Both fresh human and mice brain tissues were used to determine whether NP diffusion could occur through the pores of the experimental brain ECS, thereby characterising the NP sizes that could move through. Thorne and Nicholson gave the pivotal first direct estimates of ECS width in living brains, suggesting that nanoparticles up to 64 nm could

In terms of improving the delivery of NPs from circulation to the brain, a technique called localised convection enhanced delivery (CED) has been demonstrated as a promising approach [19]. This involves a therapeutic agent being continuously injected in a fluid medium under positive pressure (convection) by a pump via a catheter directly inserted into the brain. This creates a significant continuous pressure gradient in vivo across which drugs can move into tissue. Drug delivery

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AM S J via CED has been tested with multiple different NPs. In a study by Perlstein, CED was used to administer NPs into the striatum 1 of a rat model [20]. The authors employed an MRI-guided technique and also used coated NPs. The NPs were coated in dextran, rather than PEG and worked by similar clearance-evading mechanisms to improve distribution. The value of CED is that it augments the simple diffusion of NPs into the brain, achieving larger volumes of distribution and reaching drug concentrations markedly greater compared to regular means of systemic administration. Challenges remain before CED could be considered in clinical practice. Key limitations include the invasiveness and heterogeneity in the formation of convection which is influenced by many factors such as the NP structure, nature of the infusate, size of delivery catheters and rate of infusion [19]. Advancing the concept There are many aspects of the research of MRIgFUS and NP drug delivery that deal with the advancement of the technique. While it possesses great breadth, the technique also has significant depth that has been experimentally explored, such as better NP design, improvements to MRI or FUS delivery and loading NPs with active therapeutics for delivery to the brain. Pivotal to the success of MRIgFUS is the design of an NP that can effectively reach the brain parenchyma. As mentioned previously, molecular coatings have proven to be effective in avoiding premature elimination of NPs [17,20,21]. From examinations of NP surface charge, it has been shown that cationic properties allowed NPs to deposit in the brain [22]. Self23 assembling NPs that have the hybrid role of acting as both the MB that disrupts the BBB and the carrier that moves drugs across it have also been developed [23,24]. With the introduction of MRI to guide FUS, there have been strides in molecular design that make NPs more visible on imaging [25].

Considering the risks These novel techniques and procedures are not without risks. The FUS used to mediate NP delivery may cause a sterile inflammatory response comparable to those elicited during ischemia or mild traumatic brain injury, with unknown downstream effects on neurological function [18]. There may be irreversible damage to the BBB, potentially allowing entry to the brain parenchyma for unintended molecules or microorganisms [16]. While MRI guidance has its advantages, recent evidence suggests that the gadolinium present in many contrast agents can accumulate in the brain [38-40]. The consequences of the latter are unclear, but may yet prove important when considering use of repeated MRIgFUS in patients who would require long-term therapy for chronic conditions. Nevertheless, the safety profile of this approach continues to be established and supported with pre-clinical and animal studies [18,41]. Researchers are optimistic that current and future approaches will remain safe, ensuring that tissue damage is reversible or negligible when balanced against the benefits of treatment. Conclusion The BBB and brain ECS are significant obstacles preventing medications moving from the vascular compartment to the brain parenchyma. Using MRIgFUS and NP drug delivery is a way to potentially provide therapeutics noninvasively while also improving treatment efficacy. Recent research demonstrates that this approach is a multifaceted entity with many aspects that must be improved and progressed before implementation into clinical practice. It is a promising and generic technique, and a cause for much excitement because the possibilities for its application are only as limited as the number of conditions treatable with drug therapy. Appendix

Improving the MRIgFUS technique beyond NP design is also important [26]. The route by which drugs are administered has been explored, with one novel method using an intranasal approach rather than the conventional intravascular method [27]. A better understanding of FUS and MBs in terms of their optimum parameters has also been gained through the quantification of BBB permeability at different FUS doses, MB sizes, and MB concentrations [28]. The pursuit of perfect parameters is complicated by disease states. For example, a mice model of Alzheimer’s disease demonstrate that the pathological changes in cerebral vasculature due to amyloid plaques may reduce BBB permeability and thereby require an alteration of FUS parameters [29]. This highlights the importance of progressing to studies that are more clinically relevant and applicable.

For the “Key studies demonstrating the concept” and “Advancing the concept” sections, a literature search was performed to identify studies for discussion in this article. The search was performed on the Medline database using the search terms: exp Nanoparticles/ OR *Nanostructures/ OR exp Drug Delivery Systems/ AND exp Brain/ AND exp Ultrasonography/ OR exp Ultrasonics/ OR exp Ultrasonic Waves/ OR exp Ultrasonic Therapy/ OR *Sonication/ OR exp Microbubbles/ OR focused ultrasound.mp. This returned 147 articles. Following limitation to English language and publications within the last five years, 94 articles remained. After screening the literature by the author title, abstract and full text assessments, 19 articles were included for discussion.

The ultimate goal for using NPs with MRIgFUS is to deliver therapeutic agents to the brain, and the approach to this has been varied. A majority of studies in the literature have focused on anti-cancer agents with the intention of targeting tumours in animal models [30-34]. Outside of chemotherapy, docosahexaenoic acid has also been trialled because of its known neuroprotective effects [35]. There is also interest in loading NPs with non-drug molecules. In particular, DNA and other genetic material have been delivered to the brain in a promising approach to gene therapy [36], while nanoparticles containing gold have also demonstrated therapeutic potential when coupled with FUS [37]. With the breadth of CNS diseases requiring medical therapy, there is great scope for further research into other drugs and their potential for delivery via NPs and MRIgFUS.

Correspondence

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H Vu: huy.vul@my.jcu.edu.au


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References [1] Patel M, McCully C, Godwin K, Balis FM. Plasma and cerebrospinal fluid pharmacokinetics of intravenous temozolomide in non-human primates. J Neurooncol. 2003;61:203-7. [2] Rosso L, Brock CS, Gallo JM, Saleem A, Price PM, Turkheimer FE, et al. A new model for prediction of drug distribution in tumor and normal tissues: pharmacokinetics of temozolomide in glioma patients. Cancer Res. 2009;69:120-7. [3] Sykova E, Nicholson C. Diffusion in brain extracellular space. Physiol Rev. 2008;88:1277340. [4] Pardridge WM. Drug and gene targeting to the brain with molecular Trojan horses. Nat Rev Drug Discov. 2002;1:131-9. [5] Pardridge WM. Blood-brain barrier genomics and the use of endogenous transporters to cause drug penetration into the brain. Curr Opin Drug Discov Devel. 2003;6:683-91. [6] Doolittle ND, Miner ME, Hall WA, Siegal T, Jerome E, Osztie E, et al. Safety and efficacy of a multicenter study using intraarterial chemotherapy in conjunction with osmotic opening of the blood-brain barrier for the treatment of patients with malignant brain tumors. Cancer. 2000;88:637-47. [7] Kroll RA, Neuwelt EA. Outwitting the blood-brain barrier for therapeutic purposes: osmotic opening and other means. Neurosurgery. 1998;42:1083-99; discussion 99-100. [8] Hynynen K, McDannold N, Sheikov NA, Jolesz FA, Vykhodtseva N. Local and reversible blood-brain barrier disruption by noninvasive focused ultrasound at frequencies suitable for trans-skull sonications. Neuroimage. 2005;24:12-20. [9] Hynynen K, McDannold N, Vykhodtseva N, Jolesz FA. Noninvasive MR imaging-guided focal opening of the blood-brain barrier in rabbits. Radiology. 2001;220:640-6. [10] Vykhodtseva NI, Hynynen K, Damianou C. Histologic effects of high intensity pulsed ultrasound exposure with subharmonic emission in rabbit brain in vivo. Ultrasound Med Biol. 1995;21:969-79. [11] Martin E, Jeanmonod D, Morel A, Zadicario E, Werner B. High-intensity focused ultrasound for noninvasive functional neurosurgery. Ann Neurol. 2009;66:858-61. [12] McDannold N, Clement GT, Black P, Jolesz F, Hynynen K. Transcranial magnetic resonance imaging- guided focused ultrasound surgery of brain tumors: initial findings in 3 patients. Neurosurgery. 2010;66:323-32. [13] Thorne RG, Nicholson C. In vivo diffusion analysis with quantum dots and dextrans predicts the width of brain extracellular space. Proc Natl Acad Sci U S A. 2006;103:5567-72. [14] Wilczewska AZ, Niemirowicz K, Markiewicz KH, Car H. Nanoparticles as drug delivery systems. Pharmacol Rep. 2012;64:1020-37. [15] Cho K, Wang X, Nie S, Chen ZG, Shin DM. Therapeutic nanoparticles for drug delivery in cancer. Clin Cancer Res. 2008;14:1310-6. 16] Nance E, Timbie K, Miller GW, Song J, Louttit C, Klibanov AL, et al. Non-invasive delivery of stealth, brain-penetrating nanoparticles across the blood-brain barrier using MRI42 guided focused ultrasound. J Control Release. 2014;189:123-32. [17] Nance EA, Woodworth GF, Sailor KA, Shih T-Y, Xu Q, Swaminathan G, et al. A Dense Poly(ethylene glycol) Coating Improves Penetration of Large Polymeric Nanoparticles within Brain Tissue. Sci Transl Med. 2012;4:149ra19. [18] Hersh DS, Anastasiadis P, Mohammadabadi A, Nguyen BA, Guo S, Winkles JA, et al. MR-guided transcranial focused ultrasound safely enhances interstitial dispersion of large polymeric nanoparticles in the living brain. PLoS One. 2018;13:e0192240. [19] Allard E, Passirani C, Benoit JP. Convection-enhanced delivery of nanocarriers for the treatment of brain tumors. Biomaterials. 2009;30:2302-18. [20] Perlstein B, Ram Z, Daniels D, Ocherashvilli 1 A, Roth Y, Margel S, et al. Convection enhanced delivery of maghemite nanoparticles: Increased efficacy and MRI monitoring. Neuro Oncol. 2008;10:153-61. [21] Yao L, Song Q, Bai W, Zhang J, Miao D, Jiang M, et al. Facilitated brain delivery of poly (ethylene glycol)–poly (lactic acid) nanoparticles by microbubble-enhanced unfocused ultrasound. Biomaterials. 2014;35:3384-95. [22] Joshi S, Singh-Moon R, Wang M, Chaudhuri DB, Ellis JA, Bruce JN, et al. Cationic surface charge enhances early regional deposition of liposomes after intracarotid injection. J Neurooncol. 2014;120:489-97. [23] Aslund AK, Berg S, Hak S, Morch Y, Torp SH, Sandvig A, et al. Nanoparticle delivery to the brain--By focused ultrasound and self-assembled nanoparticle-stabilized microbubbles. J Control Release. 2015;220:287-94.

[24] Huang HY, Liu HL, Hsu PH, Chiang CS, Tsai CH, Chi HS, et al. A multitheragnostic nanobubble system to induce blood-brain barrier disruption with magnetically guided focused ultrasound. Adv Mater. 2015;27:655-61. [25] Diaz RJ, McVeigh PZ, O’Reilly MA, Burrell K, Bebenek M, Smith C, et al. Focused ultrasound delivery of Raman nanoparticles across the blood-brain barrier: Potential for targeting experimental brain tumors. Nanomedicine. 2014;10:e1075-e87. [26] Chai WY, Chu PC, Tsai MY, Lin YC, Wang JJ, Wei KC, et al. Magnetic-resonance imaging for kinetic analysis of permeability changes during focused ultrasound-induced blood-brain barrier opening and brain drug delivery. J Control Release. 2014;192:1-9. [27] Chen H, Chen CC, Acosta C, Wu SY, Sun T, Konofagou EE. A new brain drug delivery strategy: focused ultrasound-enhanced intranasal drug delivery. PLoS One. 2014;9:e108880. [28] Shi L, Palacio-Mancheno P, Badami J, Shin DW, Zeng M, Cardoso L, et al. Quantification of transient increase of the blood-brain barrier permeability to macromolecules by optimized focused ultrasound combined with microbubbles. Int J Nanomedicine. 2014;9:4437-48. [29] Burgess A, Nhan T, Moffatt C, Klibanov AL, Hynynen K. Analysis of focused ultrasoundinduced blood-brain barrier permeability in a mouse model of Alzheimer’s disease using two-photon microscopy. J Control Release. 2014;192:243-8. [30] Chen YC, Chiang CF, Wu SK, Chen LF, Hsieh WY, Lin WL. Targeting microbubbles32 carrying TGFbeta1 inhibitor combined with ultrasound sonication induce BBB/BTB disruption to enhance nanomedicine treatment for brain tumors. J Control Release. 2015;211:53-62. [31] Fan CH, Ting CY, Chang YC, Wei KC, Liu HL, Yeh CK. Drug-loaded bubbles with matched focused ultrasound excitation for concurrent blood-brain barrier opening and brain tumor drug delivery. Acta Biomater. 2015;15:89-101. [32] Lin Q, Mao KL, Tian FR, Yang JJ, Chen PP, Xu J, et al. Brain tumor-targeted delivery and therapy by focused ultrasound introduced doxorubicin-loaded cationic liposomes. Cancer Chemother Pharmacol. 2016;77:269-80. [33] Wu SK, Chiang CF, Hsu YH, Lin TH, Liou HC, Fu WM, et al. Short-time focused ultrasound hyperthermia enhances liposomal doxorubicin delivery and antitumor efficacy for brain metastasis of breast cancer. Int J Nanomedicine. 2014;9:4485-94. [34] Zhao YZ, Lin Q, Wong HL, Shen XT, Yang W, Xu HL, et al. Glioma-targeted therapy using Cilengitide nanoparticles combined with UTMD enhanced delivery. J Control Release. 2016;224:112-25. [35] Mulik RS, Bing C, Ladouceur-Wodzak M, Munaweera I, Chopra R, Corbin IR. Localized delivery of low-density lipoprotein docosahexaenoic acid nanoparticles to the rat brain using focused ultrasound. Biomaterials. 2016;83:257-68. [36] Mead BP, Mastorakos P, Suk JS, Klibanov AL, Hanes J, P 1 rice RJ. Targeted gene transfer to the brain via the delivery of brain-penetrating DNA nanoparticles with focused ultrasound. J Control Release. 2016;223:109-17. [37] Etame AB, Diaz RJ, O’Reilly MA, Smith CA, Mainprize TG, Hynynen K, et al. Enhanced delivery of gold nanoparticles with therapeutic potential into the brain using MRI6 guided focused ultrasound. Nanomedicine. 2012;8:1133-42. [38] Cao Y, Huang DQ, Shih G, Prince MR. Signal Change in the Dentate Nucleus on T1Weighted MR Images After Multiple Administrations of Gadopentetate Dimeglumine Versus Gadobutrol. AJR American journal of roentgenology. 2016;206:414-9. [39] Eisele P, Alonso A, Szabo K, Ebert A, Ong M, Schoenberg SO, et al. Lack of increased signal intensity in the dentate nucleus after repeated administration of a macrocyclic contrast agent in multiple sclerosis: An observational study. Medicine (Baltimore). 2016;95:e4624. [40] Jost G, Lenhard DC, Sieber MA, Lohrke J, Frenzel T, Pietsch H. Signal Increase on Unenhanced T1-Weighted Images in the Rat Brain After Repeated, Extended Doses of Gadolinium-Based Contrast Agents: Comparison of Linear and Macrocyclic Agents. Invest Radiol. 2016;51:83-9. [41] Mullick Chowdhury S, Lee T, Willmann JK. Ultrasound-guided drug delivery in cancer. Ultrasonography. 2017;36:171-84.

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Review Article

Prognostic and predictive clinical, pathological, and molecular biomarkers in metastatic colorectal carcinoma – a review Dr. Benjamin van Haeringen BSc/MBBS (Hons) University of Queensland

Benjamin recently completed his medical studies with Class I Honours at UQ and has commenced work as an intern at Princess Alexandra Hospital in 2018. He is interested in pursuing physician or pathology specialty training at this stage in his career.

A/Prof. David Wyld MBBS (Hons), FRACP Director of Medical Oncology, Royal Brisbane and Women’s Hospital.

David has been the Director of Medical Oncology at the Royal Brisbane and Women’s Hospital for almost twenty years, and also consults privately in Rockhampton. He has an interest in gastrointestinal and neuroendocrine cancers.

Dr. Matthew Burge MBChB, FRACP Medical Oncologist, Royal Brisbane and Women’s Hospital.

Matthew is a staff specialist medical oncologist with a strong interest in gastrointestinal malignancies. He is highly involved in oncology research, and has established a prospective database of Queensland metastatic colorectal cancer patients.

Abstract Ongoing research increasingly reveals that metastatic colorectal carcinoma (mCRC) is a highly heterogeneous entity. Despite extension of the median survival of mCRC patients due to advances in therapeutic options available, further improvement and better rationalisation of resources could be achieved by more accurately predicting individual patient prognoses and responses to specific treatments. It is hence important to further our understanding of prognostic and predictive biomarkers in mCRC to enable accurate estimation of treatment benefit for individual patients and therefore guide patient selection. This information can also be used for improving patient stratification in future studies. The aim of this literature review is to highlight potential prognostic and predictive clinical, pathological and molecular biomarkers in mCRC. Broad categories include patient and tumour markers, protein markers and cell-free DNA, inflammatory markers and genetic markers. The potential prognostic and predictive values of factors such as performance status, BRAF mutational status and neutrophil:lymphocyte ratio (NLR) >5 are supported by consistently strong evidence, but interpretation of the roles of other factors is difficult due to inconsistent findings between studies; however, many studies examine only small cohorts of patients, thereby limiting statistical power and variability in cut-off points may have contributed to different findings between trials. Although existing evidence may be used to select patient treatments and guide stratification in trials, future research with larger patient cohorts and clarification of appropriate cut-off values may prove helpful in elucidating the value of these biomarkers. Introduction In Australia, colorectal carcinoma (CRC) has the second highest incidence and mortality rate of all cancers (excluding non-melanoma skin cancers), with approximately 16,680 diagnoses and 4,110 deaths, annually [1]. Long-term prognosis is largely determined by the presence of distant metastases as part of stage IV metastatic CRC (mCRC), which most commonly involve the liver [2,3]. Up to 20-25% of patients have liver metastases at the time of diagnosis and as many as 50- 75% will develop liver metastases over the course of their disease [2-6]. The past two decades have seen the development of multiple novel

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chemotherapeutic and targeted biologic agents, as well as improved surgical techniques and supportive care. These advancements have substantially improved the prognosis of mCRC; however, individual prognoses and responses to chemotherapy remain highly variable and are not adequately explained or predicted by markers used in clinical practice [2,7-9]. Therefore, in the era of individualised therapy, identification of biomarkers (molecules, genes, or characteristics which can denote prognostic or predictive information) is an important and ongoing area of research and may help to guide and optimise patient treatment decisions and outcomes, and inform future therapeutic targets. Materials and Methods This review aims to summarise current understanding of potential prognostic (relating to survival) and predictive (relating to response) biomarkers in mCRC and highlight relative strengths and deficiencies in this knowledge. It will be limited in scope to patients with metastatic disease. Potential biomarkers will be broadly considered in the categories of patient and tumour characteristics, protein markers and cell-free DNA, inflammatory markers and genetic markers. Literature searches were conducted from March 2016 to September 2017. The biomarkers to be discussed in this report were selected based on the quantity and quality of evidence available regarding their role in prognosis and prediction of treatment benefit.


Volume 9, Issue 1 | 2019 Patient and tumour characteristics Patient characteristics Age has generally been found not to bear prognostic significance in mCRC [4,10-17], although more advanced (≥75 years) and younger (≤40 years) age categories have been independently linked with poorer survival in a small number of studies [5,18-20]. No consistent relationship has been demonstrated between sex and prognosis [4,1012,14,16-18]. In contrast, the independent prognostic significance of Eastern Cooperative Oncology Group (ECOG) performance status has been well validated in mCRC, with values of ≥1 [8,21-23] or ≥2 [5,16,17,22-24] predicting poorer outcomes in most series. Tumour grade The influence of primary tumour grade on outcome is unclear. Although some studies report that high tumour grade is an independent negative prognostic factor for survival [10,25], others report that it is not [16,2628]. The degree of differentiation of colorectal liver metastases has also been investigated, but does not appear to have an independent effect on prognosis [6,27]. Mucinous vs. non-mucinous histology Mucinous adenocarcinoma represents 5-15% of primary CRC, and is associated with younger patients, proximal tumour location, more advanced disease at presentation, lower p53 expression, microsatellite instability (MSI), specific KRAS mutations, BRAF mutation, and a higher index of diploidy [24,29]. It has been independently associated with poor overall survival and resistance to first-line chemotherapy [23,24,29]. Contrasting reports exist [11,30], although one of these projects, Hill et al., [30] studied a paediatric population, which may represent a distinct subgroup of patients with unique tumour biology and behaviour. Tumour size The size of the primary tumour, Dukes stage, and T stage (of the TNM staging system) do not appear to independently correlate with survival in mCRC [10,11,16,27,28,31]. In assessing the impact of the diameter of the largest liver metastasis, varying cut-off values have been used. Neither ≥3 cm [27,32,33] nor ≥5 cm [6,10,13,14,18] diameter cutoffs significantly impacted on survival rates on multivariate analysis in any previous study. However, Rees et al. [25] yielded a significant independent negative association with survival using a cut-off of ≥10 cm diameter. No studies reviewed examined metastasis size as a continuous variable. It is therefore possible that using a larger cut-off for metastasis diameter may be valuable. Primary tumour location Right-sided colon cancers appear to be a distinct subgroup of CRC, with a different pattern of metastasis and molecular characteristics to left-sided tumours. Right-sided cancers are more likely to be poorly differentiated, be mucinous and harbour KRAS and BRAF mutations [16,34,35]. Clinically, the pattern of metastatic spread differs, with fewer liver and lung metastases [16]. Recent data suggest that rightsided tumours might be more resistant to epidermal growth factor receptor (EGFR) inhibitors [16]. Right-sided tumours also appear to have an association with synchronous metastatic disease at diagnosis [34], but this may be subject to lead time bias given that right-sided tumours tend to cause fewer symptoms and therefore are commonly diagnosed later. Overall, right-sided cancers seem to be associated with poorer survival on multivariate analysis [5,11,34-36]. However, Brule et al. found that right sided cancer did not confer inferior prognosis in patients who received only supportive care, although it

did predict inferior progression-free survival for wild-type (unmutated) KRAS patients treated with cetuximab [16]. In light of the above, it is evident that right-sided tumours are clinically different to left-sided tumours and that primary tumour location should be considered in the prognosis and treatment of all patients. F 1 urther research is necessary to understand what drives these differences, particularly at the molecular level. Nodal status of the primary tumour Involvement of locoregional lymph nodes by metastatic tumour has been variably reported to impact survival. Some studies suggest that the presence [5,11,25] and number ≥4 [28] of nodal metastases both independently impact survival, but the majority of reports suggest that these are not useful markers in mCRC [4,6,10,13,14,16,27]. Minagawa et al. [28] specifically identified the presence of hepatic lymph node metastases as an independent prognostic marker, which may offer one promising avenue of future research. Synchronous vs. metachronous metastases Although synchronous metastases (those diagnosed within six months of the primary tumour) may bear worse prognosis than metachronous metastases on univariable analysis [2,37], an independent prognostic effect has not been consistently demonstrated [2,10,13,14,18]. Number and location of metastases The number of distant metastatic sites (e.g. liver, lungs) is inconsistently reported to impact survival. Although two studies did find an independent prognostic impact of ≥2 sites of metastasis [24,38] and another found that ≥3 had independent impact [16], other studies have stated that the number of sites does not significantly affect prognosis [5,12,15]. Currently, no strong evidence links metastases in any particular location with poorer prognosis. Liver involvement is generally found not to exert an independent influence on survival [22,35,39], although extrahepatic dissemination, in general, may predict poorer survival in patients with known hepatic metastases [2,11,25]. Peritoneal dissemination has been associated with poorer survival [24,31], although this association is inconsistent [5,35] and this relationship may be due to an association with BRAF mutations [35]. Protein markers and cell-free DNA (cfDNA) Carcinoembryonic antigen (CEA) CEA is a tumour marker commonly elevated in mCRC. Its prognostic value is historically inconsistent, with cut-off values that vary greatly and studies arriving at opposite conclusions [5,6,10,1315,25,27,28,32,33,39,40]. This may be because elevated CEA is not specific to CRC, and therefore CEA levels are influenced by other factors such as systemic inflammation and cigarette smoking. Adjusting for these confounding factors may increase the value of CEA in patient stratification [41]. Alkaline phosphatase (ALP) ALP is commonly elevated in CRC. Only a small number of studies have yet assessed the prognostic significance of ALP on multivariate analysis, but those that have suggest an independent association with overall survival [16,22,42]. Lactate dehydrogenase (LDH) LDH is important in cancer metabolism and is also a marker of cell lysis, so is commonly raised in malignant disease. Only a limited number of studies investigated serum LDH levels, but all report a significant independent association with survival [16,23,38]. However, despite

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AM S J being prognostic, it is unlikely that ALP or LDH will have a major impact on clinical decision-making given their non-specific nature, similar to CEA. C-reactive protein (CRP) CRP is a non-specific marker elevated in systemic inflammatory conditions, and is frequently found to be elevated in CRC. Elevated CRP â&#x2030;Ľ10 mg/L has consistently been reported to be significantly associated with poorer survival on multivariate analysis [14,32,39,43,44]. Read et al. [22] did not find a significant association with outcome when analysing CRP as a categorical variable, but an independent prognostic role was discovered when re-analysing as a continuous variable. Only Sharma et al. [15] did not define a prognostic role for CRP, and this study was limited in statistical power by a small cohort size. Therefore, current consensus suggests that CRP is a potentially valuable marker in mCRC.

survival [42,53,54]. Adams et al. [54]specifically identified that a high platelet count predicts worse outcomes in patients receiving intermittent (as opposed to continuous) chemotherapy, suggesting that it may be preferable to avoid this strategy in these patients. Genetic markers KRAS

cfDNA refers to small circulating DNA fragments. Recently, cfDNA has been demonstrated to be useful not only as an alternative means of obtaining information about the genetic composition of the tumour in mCRC, but also as a prognostic marker [45-49]. Higher quantitative levels of cfDNA have been linked with poorer survival in a number of small studies [45-48], and qualitative characteristics such as cfDNA methylation and fragmentation have additionally been associated with prognostic roles [48,49]. Further investigation of cfDNA in larger patient cohorts may help to consolidate its role in mainstream clinical use.

KRAS encodes a protein involved in signal transduction downstream from the epidermal growth factor receptor (EGFR), and is a key player in colorectal cancer initiation and progression. KRAS mutation has been associated with prognostic and predictive roles in mCRC, being linked with reduced survival [16,21,55-57] and resistance to the antiEGFR monoclonal antibodies cetuximab and panitumumab [55,56,5864]. It does not confer resistance to conventional chemotherapeutic agents [57]. The role of KRAS mutation in predicting complete lack of benefit from anti-EGFR antibodies is very well established. However, its prognostic impact on overall survival has been disputed [12,58]. Furthermore, not all studies reporting a negative association performed multivariate analysis of factors influencing survival [56]. Regardless of the impact of KRAS mutation on survival, these findings have changed clinical practice so that all mCRC patients are tested for KRAS mutations prior to initiating treatment with anti-EGFR-based therapies [65]. Kodaz et al. [66] also suggested that primary tumour resection may offer a survival advantage for KRAS mutant patients, but not for patients with KRAS wild-type tumours. The underlying mechanism accounting for this observation is unclear and there are many factors impacting a decision to remove the primary tumour in mCRC, which must also be considered.

Inflammatory markers

NRAS

Neutrophil:lymphocyte ratio (NLR)

NRAS encodes a signalling protein closely related to KRAS. De Roock et al. [55] identified that in KRAS wild-type patients, carriers of NRAS mutations have a significantly lower response rate to cetuximab-based therapy when compared to NRAS wild-type patients. A subsequent analysis of the PRIME study by Douillard et al. [67] confirmed that mutations in exons 2, 3, and 4 of KRAS or NRAS all predicted a lack of benefit from anti-EGFR antibodies. Further, Schirripa et al. [68] concluded that NRAS mutations also confer poorer overall survival in addition to resistance to anti-EGFR-based chemotherapy. Therefore, it is now routine to test for all these mutations in an extended RAS panel prior to initiating anti-EGFR therapy [65].

Cell-free DNA (cfDNA)

NLR serves as an indicator of the interaction between the tumour and the patientâ&#x20AC;&#x2122;s immune system, and is associated with a distinct expression profile of cytokines [38]. In particular, elevated NLR values represent a high degree of non-specific systemic inflammation, which can lead to cachexia and may also represent poor lymphocytic cellmediated immunity against the cancer. Genomic instability and DNA damage induced by chronic inflammation also help to promote carcinogenesis [38]. NLR can be cheaply measured via peripheral blood samples, and although optimum cut-off limits are yet to be defined or standardised [50], NLR >5 has consistently been associated with an independent negative impact on survival [4,8,13,14,38,40]. Its normalisation during treatment has also been shown to predict improved outcomes [8,13]. Therefore, NLR represents an inexpensive, readily available, and reliable biomarker for the prediction of survival in patients with mCRC. Similarly, Okano et al. [51] found that a dense lymphocytic infiltrate alone in the tumour independently predicted superior overall survival compared to patients with weak lymphocytic infiltration. This reinforces the benefit of a strong lymphocytic immune response to malignancy. Platelet:lymphocyte ratio (PLR) and thrombocytosis PLR has been investigated as an alternative to NLR in the assessment of the patientâ&#x20AC;&#x2122;s immune response to the tumour, and as a prognostic marker, but it is considered to be inferior to NLR, because despite correlation with survival on univariate analysis [4,40,52,53], only Neofytou et al. [52] found it to be independently predictive. Neofytou et al. [52] also unconventionally defined elevated NLR as NLR >2.4 rather than >5.0, possibly confounding this conclusion. Therefore, it is suggested that NLR should be used over PLR for prognostication in mCRC. Absolute thrombocytosis has been more consistently demonstrated to have an independent negative association with

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BRAF BRAF encodes a protein kinase directly downstream from KRAS in the EGFR signalling pathway. BRAF mutations have been found to have a substantial and clinically significant prognostic impact on overall survival [21,23,35,55,57,59,63,64,69]. It appears BRAF may also have a negative predictive effect for anti-EGFR efficacy [55,59], although not as conclusively as KRAS and NRAS mutations. Tran et al. [35] suggest that differences in survival with BRAF mutation may be due to a higher rate of metastases to sites not typically amenable to resection, such as the peritoneum and distant lymph nodes. EGFR Counterintuitively, evidence supports that detected expression of EGFR by immunohistochemistry may not be a prerequisite for response to anti-EGFR therapy [60-62,64]. Only Chen et al. [26] reported a correlation between increased protein expression and improved survival in response to cetuximab treatment. However, while some studies claim that high EGFR gene copy number or amplification is associated with response to cetuximab [58,60,69], others claim that the gene status of EGFR is also not relevant to response or survival


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[62,64]. It has been suggested that methodological issues such as choice of fixative and storage time may be responsible for these findings [60], and therefore further investigation into the potential role of EGFR is warranted. Microsatellite instability (MSI) MSI represents approximately 15% of sporadic CRC cases and is an alternate pathway of tumourigenesis characterised by loss of function of DNA mismatch re 1 pair genes [70]. MSI has been found to impart a variable impact on survival in mCRC [71-74] and no apparent impact on benefit from any particular therapeutic agent [70,75]. Tran et al. [35]found a negative prognostic effect of MSI on univariate, but not multivariate analysis, and propose this relationship is explained by the association of MSI with BRAF mutation demonstrated in this study. This suggests a potentially confounding effect from BRAF status that was not accounted for in the other studies above. In contrast, Liang et al. [73] suggested an independent positive prognostic role of MSI status, postulating that the superior chemosensitivity of MSI tumours is responsible for their improved survival. Overall, MSI status does not appear to have a major impact on prognosis in mCRC. Of increasing interest is that MSI tumours have a high mutational burden and immune cell infiltrate, and therefore these patients may benefit from treatment with checkpoint inhibitors such as pembrolizumab and nivolumab [76]. Conclusion Within this review, a number of patient and tumour characteristics, protein markers and cfDNA, inflammatory markers, and genetic markers have been assessed regarding their potential roles as prognostic and predictive biomarkers in mCRC (Table 1). A recurring theme across each of these three broad categories has been a lack of clear consensus on the significance of various factors, driven by issues such

as small sample sizes, methodological issues and inadequate statistical analysis. Additionally, the picture may be confounded by associations between multiple poor prognostic factors such as right-sided primary tumour, BRAF mutation, and mucinous carcinoma, leading to difficulty assessing the individual impact of each factor. Although the significance of some markers is relatively clear, such as for ECOG performance status, NLR >5, and KRAS and BRAF mutational statuses, the value of other biomarkers requires clarification by multivariate analysis of data from larger patient cohorts. Further, although some markers appear to carry independent prognostic significance (such as LDH and ALP), their use in clinical practice for guiding treatment decisions may be limited, with a greater importance placed on markers which reflect molecular drivers of the disease process and hence potential targets for cytotoxic or biological agents. The findings from this study contribute to arguments for and against the use of each of the mentioned biomarkers in prognostication and treatment prediction in mCRC, which will in turn help to guide clinical decision-making and the provision of information to patients. Accurate estimation of prognosis is important to patients as well as clinicians, and better knowledge of relevant prognostic factors in an individual patient may facilitate this discussion. Additionally, predictive factors indicating resistance to particular treatments should be used to guide selection of chemotherapeutic agents, underscoring the need for adequate genetic screening of patients presenting with mCRC early in their disease course. Identification of those factors that confer poorer prognosis or resistance to chemotherapy might also elucidate possible drivers of cancer aggressiveness or resistance, and thereby highlight potential targets for the development of future treatments. Correspondence B van Haeringen: benjamin.vanhaeringen@uqconnect.edu.au

Table 1: Summary of markers and their effect on prognosis or prediction of response in mCRC. Markers

Effect

Patient characteristic

Age and sex are unlikely to have significant role [4,10-18]

Higher ECOG scores appear to correlate with poorer prognosis [5,8,16,17,21-24]

Tumour grade

Unlikely to have significant role [6,16,26-28]

Mucinous histology

Likely associated with poor prognosis and resistance to chemotherapy [23,24,29]

Tumour size

Primary tumour or metastasis size unlikely to have significant role [6,10,11,13,14,16,18,27,28,31-33]

Diameter of largest liver metastasis may have role in very large sizes (>10cm) [25]

Primary tumour location

Right-sided tumours may be more resistant to anti-EGFR therapies and are associated with poorer prognosis [5,11,16,34- 36]

Nodal status

Unlikely to have significant role [4,6,10,13,14,16,27]

Synchronous vs. metachronous

No significant independent role [2,10,13,14,18]

Number and location of metastases

Number of sites of metastases inconsistently reported to impact survival [5,12,15,16,24,38]

Location of metastases unlikely to have significant role [5,22,35,39]

CEA

CEA is unlikely to have a significant predictive or prognostic role, but remains a useful marker for monitoring response to treatment [5,6,10,13-15,25,27,28,32,33,39,40]

ALP

High ALP is associated with poorer prognosis [16,22,42]

LDH

High LDH is associated with poorer prognosis [16,23,38]

CRP

High CRP is associated with poorer prognosis [14,32,39,43,44]

cfDNA

Quantitative levels are a marker of poorer prognosis [45-48]

Qualitative features such as methylation and fragmentation also may have prognostic roles [48,49]

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NLR >5 is associated with poorer prognosis [4,8,13,14,38,40]

Normalisation of NLR predicts better prognosis [8,13]

PLR is unlikely to have a significant role [4,40,52,53]

Thrombocytosis is associated with poorer prognosis [42,53,54]

Currently both assessed using extended RAS screening [65]

Most widely utilised currently for very strong prediction of lack of response to anti-EGFR therapies (e.g. cetuximab) [55,56,58-64,67]

Also probable markers for poorer prognosis [16,21,55-57,68]

Strong marker of poor prognosis [21,23,35,55,57,59,63,64,69]

Possible role in further predicting poor response to anti-EGFR therapies and conventional chemotherapy [55,59]

EGFR mutation and copy number

Unlikely to have major role in predicting response, even to anti-EGFR therapies, or prognosis [60-62,64]

Microsatellite instability

Unlikely to have major role in predicting response or prognosis [70-75]

PLR and thrombocytosis KRAS and NRAS mutations

BRAF mutation

References [1] Australian Institute of Health and Welfare. Cancer in Australia: an overview 2014. Cancer series No 90, Cat. no. CAN 88. Canberra: AIHW; 2014. [2] Lemke J, Cammerer G, Ganser J, Scheele J, Xu P, Sander S, et al. Survival and prognostic factors of colorectal liver metastases after surgical and nonsurgical treatment. Clin Colorectal Cancer. 2016;15(4):e183-92. [3] Amano R, Yamada N, Nakata B, Kimura K, Yashiro M, Ohira M, et al. A prognostic indicator for the resection of liver metastasis of colorectal cancer. Surg Today. 2014;44(7):1287-92. [4] Neal CP, Cairns V, Jones MJ, Masood MM, Nana GR, Mann CD, et al. Prognostic performance of inflammation-based prognostic indices in patients with resectable colorectal liver metastases. Med Oncol. 2015;32(5):144. [5] Stillwell AP, Ho YH, Veitch C. Systematic review of prognostic factors related to overall survival in patients with stage IV colorectal cancer and unresectable metastases. World J Surg. 2011;35(3):684-92. [6] John SK, Robinson SM, Rehman S, Harrison B, Vallance A, French JJ, et al. Prognostic factors and survival after resection of colorectal liver metastasis in the era of preoperative chemotherapy: an 11-year single-centre study. Dig Surg. 2013;30(4-6):293-301. [7] Boisen MK, Johansen JS, Dehlendorff C, Larsen JS, Østerlind K, Hansen J, et al. Primary tumor location and bevacizumab effectiveness in patients with metastatic colorectal cancer. Ann Oncol. 2013;24(10):2554-9. [8] Chua W, Charles KA, Baracos VE, Clarke SJ. Neutrophil/lymphocyte ratio predicts chemotherapy outcomes in patients with advanced colorectal cancer. Br J Cancer. 2011;104(8):1288-95. [9] Grimminger PP, Shi M, Barrett C, Lebwohl D, Danenberg KD, Brabender J, et al. TS and ERCC-1 mRNA expressions and clinical outcome in patients with metastatic colon cancer in CONFIRM-1 and -2 clinical trials. Pharmacogenomics J. 2012;12(5):404-11. [10] Arru M, Aldrighetti L, Castoldi R, Di Palo S, Orsenigo E, Stella M, et al. Analysis of prognostic factors influencing long-term survival after hepatic resection for metastatic colorectal cancer. World J Surg. 2008;32(1):93-103. [11] Chafai N, Chan CL, Bokey EL, Dent OF, Sinclair G, Chapuis PH. What factors influence survival in patients with unresected synchronous liver metastases after resection of colorectal cancer? Colorectal Dis. 2005;7(2):176-81. [12] Choi YJ, Chang WJ, Shin SW, Park KH, Kim ST, Kim YH. The prognostic role of serum C-X-C chemokine receptor type 4 in patients with metastatic or recurrent colorectal cancer. Onco Targets Ther. 2016;9:3307-12. [13] Kishi Y, Kopetz S, Chun YS, Palavecino M, Abdalla EK, Vauthey JN. Blood neutrophil-tolymphocyte ratio predicts survival in patients with colorectal liver metastases treated with systemic chemotherapy. Ann Surg Oncol. 2009;16(3):614-22. [14] Malik HZ, Prasad KR, Halazun KJ, Aldoori A, Al-Mukhtar A, Gomez D, et al. Preoperative prognostic score for predicting survival after hepatic resection for colorectal liver metastases. Ann Surg. 2007;246(5):806-14. [15] Sharma R, Zucknick M, London R, Kacevska M, Liddle C, Clarke SJ. Systemic inflammatory response predicts prognosis in patients with advanced-stage colorectal cancer. Clin Colorectal Cancer. 2008;7(5):331-7. [16] Brule SY, Jonker DJ, Karapetis CS, O'Callaghan CJ, Moore MJ, Wong R, et al. Location of colon cancer (right-sided versus left-sided) as a prognostic factor and a predictor of benefit from cetuximab in NCIC CO.17. Eur J Cancer. 2015;51(11):1405-14. [17] Davidov D. Prognostic factors for survival in patients with metastatic colorectal cancer treated with first-line chemotherapy. J of IMAB. 2017;23(2):1532-5. [18] Halazun KJ, Aldoori A, Malik HZ, Al-Mukhtar A, Prasad KR, Toogood GJ, et al. Elevated preoperative neutrophil to lymphocyte ratio predicts survival following hepatic resection for colorectal liver metastases. Eur J Surg Oncol. 2008;34(1):55-60. [19] Deng Y, Cai Y, Lin J, Jiang L, Hu H. Survival of patients with KRAS wild-type metastatic colorectal cancer is identical after sequential treatment with cetuximab and bevacizumab regardless of the sequence – a retrospective single-center study. Gastroenterol Rep. 2015;3(4):339-43.

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[20] Li ZM, Peng YF, Du CZ, Gu J. Colon cancer with unresectable synchronous metastases: the AAAP scoring system for predicting the outcome after primary tumour resection. Colorectal Dis. 2016;18(3):255-63. [21] Schirripa M, Bergamo F, Cremolini C, Casagrande M, Lonardi S, Aprile G, et al. BRAF and RAS mutations as prognostic factors in metastatic colorectal cancer patients undergoing liver resection. Br J Cancer. 2015;112(12):1921-8. [22] Read JA, Choy ST, Beale PJ, Clarke SJ. Evaluation of nutritional and inflammatory status of advanced colorectal cancer patients and its correlation with survival. Nutr Cancer. 2006;55(1):78-85. [23] Mekenkamp LJ, Heesterbeek KJ, Koopman M, Tol J, Teerenstra S, Venderbosch S, et al. Mucinous adenocarcinomas: poor prognosis in metastatic colorectal cancer. Eur J Cancer. 2012;48(4):501-9. [24] Catalano V, Loupakis F, Graziano F, Torresi U, Bisonni R, Mari D, et al. Mucinous histology predicts for poor response rate and overall survival of patients with colorectal cancer and treated with first-line oxaliplatin- and/or irinotecan-based chemotherapy. Br J Cancer. 2009;100(6):881-7. [25] Rees M, Tekkis PP, Welsh FK, O'Rourke T, John TG. Evaluation of long-term survival after hepatic resection for metastatic colorectal cancer: a multifactorial model of 929 patients. Ann Surg. 2008;247(1):125-35. [26] Chen Y, Shi Y, Lin J, Ye YB, Wang XJ, Chen G, et al. Combined analysis of EGFR and PTEN status in patients with KRAS wild-type metastatic colorectal cancer. Medicine. 2015;94(40):e1698. [27] Kobayashi T, Teruya M, Kishiki T, Endo D, Takenaka Y, Miki K, et al. Elevated C-reactive protein and hypoalbuminemia measured before resection of colorectal liver metastases predict postoperative survival. Dig Surg. 2010;27(4):285-90. [28] Minagawa M, Yamamoto J, Kosuge T, Matsuyama Y, Miyagawa S, Makuuchi M. Simplified staging system for predicting the prognosis of patients with resectable liver metastasis: development and validation. Arch Surg. 2007;142(3):269-76. [29] Negri FV, Wotherspoon A, Cunningham D, Norman AR, Chong G, Ross PJ. Mucinous histology predicts for reduced fluorouracil responsiveness and survival in advanced colorectal cancer. Ann Oncol. 2005;16(8):1305-10. [30] Hill DA, Furman WL, Billups CA, Riedley SE, Cain AM, Rao BN, et al. Colorectal carcinoma in childhood and adolescence: a clinicopathologic review. J Clin Oncol. 2007;25(36):580814. [31] Katoh H, Yamashita K, Kokuba Y, Satoh T, Ozawa H, Hatate K, et al. Surgical resection of stage IV colorectal cancer and prognosis. World J Surg. 2008;32(6):1130-7. [32] Ishizuka M, Kita J, Shimoda M, Rokkaku K, Kato M, Sawada T, et al. Systemic inflammatory response predicts postoperative outcome in patients with liver metastases from colorectal cancer. J Surg Oncol. 2009;100(1):38-42. [33] Nakagawa K, Tanaka K, Nojiri K, Kumamoto T, Takeda K, Ueda M, et al. The modified Glasgow prognostic score as a predictor of survival after hepatectomy for colorectal liver metastases. Ann Surg Oncol. 2014;21(5):1711-8. [34] Loupakis F, Yang D, Yau L, Feng S, Cremolini C, Zhang W, et al. Primary tumor location as a prognostic factor in metastatic colorectal cancer. J Natl Cancer Inst. 2015;107(3). [35] Tran B, Kopetz S, Tie J, Gibbs P, Jiang ZQ, Lieu CH, et al. Impact of BRAF mutation and microsatellite instability on the pattern of metastatic spread and prognosis in metastatic colorectal cancer. Cancer. 2011;117(20):4623-32. [36] Schrag D, Weng S, Brooks G, Meyerhardt JA, Venook AP. The relationship between primary tumor sidedness and prognosis in colorectal cancer. J Clin Oncol. 2016;34(15 suppl):3505. [37] Muller CI, Schulmann K, Reinacher-Schick A, Andre N, Arnold D, Tannapfel A, et al. Predictive and prognostic value of microsatellite instability in patients with advanced colorectal cancer treated with a fluoropyrimidine and oxaliplatin containing firstline chemotherapy. A report of the AIO Colorectal Study Group. Int J Colorectal Dis. 2008;23(11):1033-9.


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[38] Chen ZY, Raghav K, Lieu CH, Jiang ZQ, Eng C, Vauthey JN, et al. Cytokine profile and prognostic significance of high neutrophil-lymphocyte ratio in colorectal cancer. Br J Cancer. 2015;112(6):1088-97. [39] Lee S, Song A, Eo W. Serum ferritin as a prognostic biomarker for survival in relapsed or refractory metastatic colorectal cancer. J Cancer. 2016;7(8):957-64. [40] He W, Yin C, Guo G, Jiang C, Wang F, Qiu H, et al. Initial neutrophil lymphocyte ratio is superior to platelet lymphocyte ratio as an adverse prognostic and predictive factor in metastatic colorectal cancer. Med Oncol. 2013;30(1):439. [41] Kang HY, Choe EK, Park KJ, Lee Y. Factors requiring adjustment in the interpretation of serum carcinoembryonic antigen: a cross-sectional study of 18,131 healthy nonsmokers. Gastroenterol Rep Pract. 2017;2017:9858931. [42] Köhne C-H, Cunningham D, Di Costanzo F, Glimelius B, Blijham G, Aranda E, et al. Clinical determinants of survival in patients with 5-fluorouracil- based treatment for metastatic colorectal cancer: results of a multivariate analysis of 3825 patients. Ann Oncol. 2002;13(2):308-17. [43] Hamilton TD, Leugner D, Kopciuk K, Dixon E, Sutherland FR, Bathe OF. Identification of prognostic inflammatory factors in colorectal liver metastases. BMC Cancer. 2014;14(1):17. [44] Wong VKH, Malik HZ, Hamady ZZR, Al-Mukhtar A, Gomez D, Prasad KR, et al. C-reactive protein as a predictor of prognosis following curative resection for colorectal liver metastases. Br J Cancer. 2007;96(2):222-5. [45] Matikas A, Voutsina A, Trypaki M, Georgoulias V. Role of circulating free DNA in colorectal cancer. World J Gastrointest Oncol. 2016;8(12):810-8. [46] Spindler KL, Appelt AL, Pallisgaard N, Andersen RF, Brandslund I, Jakobsen A. Cell-free DNA in healthy individuals, noncancerous disease and strong prognostic value in colorectal cancer. Int J Cancer. 2014;135(12):2984-91. [47] Spindler KL, Pallisgaard N, Vogelius I, Jakobsen A. Quantitative cell-free DNA, KRAS, and BRAF mutations in plasma from patients with metastatic colorectal cancer during treatment with cetuximab and irinotecan. Clin Cancer Res. 2012;18(4):1177-85. [48] El Messaoudi S, Mouliere F, Du Manoir S, Bascoul-Mollevi C, Gillet B, Nouaille M, et al. Circulating DNA as a strong multimarker prognostic tool for metastatic colorectal cancer patient management care. Clin Cancer Res. 2016;22(12):3067-77. [49] Philipp AB, Stieber P, Nagel D, Neumann J, Spelsberg F, Jung A, et al. Prognostic role of methylated free circulating DNA in colorectal cancer. Int J Cancer. 2012;131(10):2308-19. [50] Forget P, Khalifa C, Defour J-P, Latinne D, Van Pel M-C, De Kock M. What is the normal value of the neutrophil-to-lymphocyte ratio? BMC Res Notes. 2017;10:12. [51] Okano K, Maeba T, Moroguchi A, Ishimura K, Karasawa Y, Izuishi K, et al. Lymphocytic infiltration surrounding liver metastases from colorectal cancer. J Surg Oncol. 2003;82(1):2833. [52] Neofytou K, Smyth EC, Giakoustidis A, Khan AZ, Cunningham D, Mudan S. Elevated platelet to lymphocyte ratio predicts poor prognosis after hepatectomy for liver-only colorectal metastases, and it is superior to neutrophil to lymphocyte ratio as an adverse prognostic factor. Med Oncol. 2014;31(10):239. [53] Baranyai Z, Krzystanek M, Josa V, Dede K, Agoston E, Szasz AM, et al. The comparison of thrombocytosis and platelet-lymphocyte ratio as potential prognostic markers in colorectal cancer. Thromb Haemost. 2014;111(3):483-90. [54] Adams RA, Meade AM, Seymour MT, Wilson RH, Madi A, Fisher D, et al. Intermittent versus continuous oxaliplatin and fluoropyrimidine combination chemotherapy for firstline treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet Oncol. 2011;12(7):642-53. [55] De Roock W, Claes B, Bernasconi D, De Schutter J, Biesmans B, Fountzilas G, et al. Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. Lancet Oncol. 2010;11(8):753-62. [56] Prenen H, De Schutter J, Jacobs B, De Roock W, Biesmans B, Claes B, et al. PIK3CA mutations are not a major determinant of resistance to the epidermal growth factor receptor inhibitor cetuximab in metastatic colorectal cancer. Clin Cancer Res. 2009;15(9):3184-8. [57] Richman SD, Seymour MT, Chambers P, Elliott F, Daly CL, Meade AM, et al. KRAS and BRAF mutations in advanced colorectal cancer are associated with poor prognosis but do not preclude benefit from oxaliplatin or irinotecan: results from the MRC FOCUS trial. J Clin Oncol. 2009;27(35):5931-7. [58] Bengala C, Betelli S, Fontana A, Bertolini F, Sartori G, Malavasi N, et al. EGFR gene copy number, KRAS and BRAF status, PTEN and AKT expression analysis in patients with metastatic colon cancer treated with anti-EGFR monoclonal antibodies ± chemotherapy.

J Clin Oncol. 2009;27. [59] Di Nicolantonio F, Martini M, Molinari F, Sartore-Bianchi A, Arena S, Saletti P, et al. Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol. 2008;26(35):5705-12. [60] Frattini M, Saletti P, Romagnani E, Martin V, Molinari F, Ghisletta M, et al. PTEN loss of expression predicts cetuximab efficacy in metastatic colorectal cancer patients. Br J Cancer. 2007;97(8):1139-45. [61] Loupakis F, Pollina L, Stasi I, Ruzzo A, Scartozzi M, Santini D, et al. PTEN expression and KRAS mutations on primary tumors and metastases in the prediction of benefit from cetuximab plus irinotecan for patients with metastatic colorectal cancer. J Clin Oncol. 2009;27(16):2622-9. [62] Perrone F, Lampis A, Orsenigo M, Di Bartolomeo M, Gevorgyan A, Losa M, et al. PI3KCA/PTEN deregulation contributes to impaired responses to cetuximab in metastatic colorectal cancer patients. Ann Oncol. 2009;20(1):84-90. [63] Souglakos J, Philips J, Wang R, Marwah S, Silver M, Tzardi M, et al. Prognostic and predictive value of common mutations for treatment response and survival in patients with metastatic colorectal cancer. Br J Cancer. 2009;101(3):465-72. [64] Tol J, Dijkstra JR, Klomp M, Teerenstra S, Dommerholt M, Vink-Borger ME, et al. Markers for EGFR pathway activation as predictor of outcome in metastatic colorectal cancer patients treated with or without cetuximab. Eur J Cancer. 2010;46(11):1997-2009. [65] Cancer Council Australia Colorectal Cancer Guidelines Working Party. Molecular pathology and biomarkers – implications for systemic therapy. [Internet]. 2017 Feb 24 [updated 2017 Nov 7; cited 2018 Apr 22]. Available from: https://wiki.cancer.org. au/australiawiki/index.php?title=Guidelines:Colorectal_cancer/Systemic_therapy_ molecular_pathology. [66] Kodaz H, Erdogan B, Hacibekiroglu I, Turkmen E, Tozkir H, Albayrak D, et al. Primary tumor resection offers higher survival advantage in KRAS mutant metastatic colorectal cancer patients. Hepatogastroenterology. 2015;62(140):876-9. [67] Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, et al. Final results from PRIME: randomized phase III study of panitumumab with FOLFOX4 for first-line treatment of metastatic colorectal cancer. Ann Oncol. 2014;25(7):1346-55. [68] Schirripa M, Cremolini C, Loupakis F, Morvillo M, Bergamo F, Zoratto F, et al. Role of NRAS mutations as prognostic and predictive markers in metastatic colorectal cancer. Int J Cancer. 2015;136(1):83-90. [69] Laurent-Puig P, Cayre A, Manceau G, Buc E, Bachet JB, Lecomte T, et al. Analysis of PTEN, BRAF, and EGFR status in determining benefit from cetuximab therapy in wild-type KRAS metastatic colon cancer. J Clin Oncol. 2009;27(35):5924-30. [70] Des Guetz G, Uzzan B, Nicolas P, Schischmanoff O, Morere JF. Microsatellite instability: a predictive marker in metastatic colorectal cancer? Target Oncol. 2009;4(1):57-62. [71] Brueckl WM, Moesch C, Brabletz T, Koebnick C, Riedel C, Jung A, et al. Relationship between microsatellite instability, response and survival in palliative patients with colorectal cancer undergoing first-line chemotherapy. Anticancer Res. 2003;23(2c):1773-7. [72] Calvo B, Fuente N, Aresti U, Jangi M, Carrera S, Buque A, et al. Mutations of the p53 gene and microsatellite instability (MSI) as prognostic factors in metastatic colorectal cancer (CRC). J Clin Oncol. 2008;26(15S). [73] Liang JT, Huang KC, Lai HS, Lee PH, Cheng YM, Hsu HC, et al. High-frequency microsatellite instability predicts better chemosensitivity to high-dose 5-fluorouracil plus leucovorin chemotherapy for stage IV sporadic colorectal cancer after palliative bowel resection. Int J Cancer. 2002;101(6):519-25. [74] Haddad R, Ogilvie RT, Croitoru M, Muniz V, Gryfe R, Pollet A, et al. Microsatellite instability as a prognostic factor in resected colorectal cancer liver metastases. Ann Surg Oncol. 2004;11(11):977-82. [75] Braun MS, Richman SD, Quirke P, Daly C, Adlard JW, Elliott F, et al. Predictive biomarkers of chemotherapy efficacy in colorectal cancer: results from the UK MRC FOCUS Trial. J Clin Oncol. 2008;26(16):2690-8. [76] Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372(26):2509-20.

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Review Article Overview of preoperative fasting for general anaesthesia Benjamin Kalma Doctor of Medicine University of Queensland Student

Ben is a first year medical student, with an interest in preoperative fasting protocols and their effect on perioperative acute kidney injury.

Abstract The primary goal of fasting prior to general anaesthesia is to reduce the risk of pulmonary aspiration, displacement of gastric contents into the lungs. As gastric volume, alongside patient age, current medications and type of surgery are associated with increased incidence of pulmonary aspiration. The preoperative fasting guidelines have been developed to reduce total fasting duration. Most recommend clear fluids up to two hours prior to surgery and solid food up to six hours prior to surgery. Reducing fasting time aims to minimize the negative metabolic effects of prolonged fasting, such as insulin resistance, catabolism, increased gastric acidity, discomfort, hypotension and dehydration. When combined with the negative effects associated with surgical trauma, many of these, particularly insulin resistance, have been associated with poor postoperative outcomes. Preoperative carbohydrate loading through the use of a glucose beverage has been examined as a method of reducing insulin resistance. There is a large amount of evidence suggesting it is a safe and effective preoperative tool. Patient compliance has been identified as a limitation of preoperative fasting guidelines, associated with a lack of understanding regarding their risk of pulmonary aspiration. Altering guidelines to include a default treatment program, consisting of carbohydrate treatment, minimum hydration requirements and enhancements in preoperative assessments to improve patient understanding, would likely improve patient outcomes.

Introduction Although there are enormous benefits of general anaesthesia in surgical procedures, the use of general anaesthesia nonetheless poses innate risks to patient safety. To minimise these risks, evidencebased guidelines are implemented into clinical practice. These guidelines consolidate the best up-to-date evidence to provide health practitioners with easily accessible and accurate information. Often, these are region-specific and adapted at multiple levels of health service provision. Australian anaesthetic guidelines are developed by the Australian and New Zealand College of Anaesthetists (ANZCA), with similar organisations existing for different regions worldwide [1]. While management decisions are ultimately up to the treating team, these standardised guidelines provide a useful reference tool to assist in the decision-making process. The objective of standardised guidelines is to minimise the risk of events, which may lead to iatrogenic morbidity or mortality of patients undergoing general anaesthesia. One of the most well-known preoperative recommendations outlined in guidelines is on preoperative fasting. In all forms of its existence, the goal of preoperative fasting has been to diminish the risk of perioperative pulmonary aspiration, by reducing gastric volume and acidity [2]. When developing fasting protocols, the risk of pulmonary aspiration must be balanced against other negative metabolic effects associated with fasting.

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This review will compare previous and current international preoperative fasting guidelines and integrate information regarding the event of pulmonary aspiration, discuss the development and future advancement of current fasting guidelines. Historical 1 Perspective on Fasting Knowledge regarding gastric emptying time has progressed significantly since being first identified in 1833 by Beaumont [3], who observed that it took up to five hours for solid food to be cleared from the stomach and significantly less time for clear fluids. In 1883, Lister [4] suggested that a fast from solid foods was required approximately five to six hours prior to surgery. He also suggested that two hours was adequate time for removal of clear fluids, such as water. Although it is not clear when the transition occurred, it was reported that American anaesthetics textbooks in the 1960s published â&#x20AC;&#x153;nil-by-mouthâ&#x20AC;? (NPO) guidelines [5]. These guidelines advised against the consumption of solid food and clear and non-clear liquid after midnight the night before surgery. In some cases, patients had fasting times of 15 hours or more. NPO technique was commonplace during the decades following, and in a 1995 survey of American anaesthetists, 50% still used the nil-bymouth fasting guideline indiscriminately [6]. However, the prevalence of NPO was declining and in a 1999 review, the American Society of Anaesthesiologists (ASA) published new guidelines for preoperative fasting [7]. These permitted clear fluids two or more hours, breast milk four or more hours and solid food and non-human milk six or more hours prior to surgery. Pulmonary Aspiration Pulmonary aspiration is defined as the displacement of gastric contents into the tracheobronchial tree [8]. Although outcomes can be severe, the risk of pulmonary aspiration may appear falsely low due to its infrequent occurrence. Since 1970, three large population studies have investigated the incidence of fatal and non-fatal pulmonary aspiration events in patients undergoing general anaesthesia during elective and emergency surgery. These took place at major centres in Sweden, America, and Norway (n=185,358, n=215,488, and n=85,594 patients, respectively) [9-11]. Of the total 486,440 patients, there was an average pulmonary aspiration event rate of 1 in 2,717 surgeries. When examined


Volume 9, Issue 1 | 2019 exclusively, it can be seen that fatal primary aspiration events were less common; however, large variation exists between reported incidences. From two of the studies above (n=185,358 and n=215,488 patients), the average incidence of fatal aspiration event was calculated to be 1 in 57,274 surgeries, but the Royal College of Anaesthetists 4th National Audit Project (NAP4) estimated a much lower incidence in the United Kingdom of 1 in 360,000 [12].

anaesthetist experience levels. The NAP4 project found that of the 29 aspiration cases reviewed 15 were performed by a trainee [12]. The type of surgery may also play a role, as aspiration occurred three times more often in thoracic surgeries compared to any other region [10]. The position chosen for intubation and extubation also altered the likelihood of aspiration, with a sideways orientation being associated with lower risk [16].

Whilst death is a consequence of the most severe adverse events, non-fatal cases also have detrimental long-term effects on health. For example, Olsson et al. reported that 47% of non fatal cases of perioperative pulmonary aspiration went on to develop severe postoperative lung damage secondary to aspiration pneumonitis [9].

Other identified risk factors directly relate to an increase in the gastric volume of the stomach. Gastric volume is implicated in the occurrence of pulmonary aspiration events, with greater gastric volume associated with a high risk of aspiration [19]. The decreased rate of gastric emptying, for example, in the cases of gastrointestinal obstruction or diabetes mellitus, results in an increase of gastric volume [20]. Conditions, such as these, which decrease gastrointestinal motility, worsen the risk of an aspiration event. Similarly, opioid use also reduces motility and gastric emptying and significantly increases the patient’s risk of aspiration [18]. Pregnancy has also been documented to increase gastric volume [21].

Risk Factors Contributing to Occurrence of Pulmonary Aspiration There are a number of factors that increase a patient’s risk of suffering a pulmonary aspiration event. Accurate preoperative assessment of these factors is a crucial component of identifying a patient’s level of risk. Guidelines have been published by ANZCA as to the goals, expected outcomes, and methodology of a proper preoperative assessment [1]. Initial assessment segregates patients in accordance with the ASA physical status classification system (Table 1). Physical status is assessed on a scale, ranging from 1 (normal and healthy) to 6 (braindead) [13]. Higher grades of preoperative 1 ASA physical status have been shown to be a predictor for increased incidence of pulmonary aspiration [14,15]. Following assessment, further precautions may then be taken with high-risk patients to reduce patient harm and improve surgical outcomes. Robinson and Davidson summarise a lis of available strategies for high-risk patients [16]. In the context of anaesthesia, where laryngeal protective reflexes, such as cough and gag reflexes are obtunded, risk factors that alter the integrity of the upper and/or lower oesophageal sphincter are particularly relevant. As increased age is associated with decreased oesophageal sphincter muscle tone [17], elderly patients fall into this risk category. Similarly, certain medications, including opioids, muscarinic receptor antagonists, and both β- adrenoreceptor agonists and antagonists, have been found to decrease sphincter tone [18]. Inadequate depth of anaesthesia also poses a risk, where accidental stimulation of previously attenuated gastrointestinal motor response could contribute to an aspiration event [16]. Risks for pulmonary aspiration are also present at a health service level, for example, it has been found that risk varies based on Table 1: American Society of Anaesthesiologists Physical Status classification levels and associated definitions. ASA Physcial Status Definition Classification 1

Normal healthy patient

2

Patient with mild systemic disease

3

Patient with severe systemic disease

4

Patient with severe systemic disease that is a constant threat to life

5

Moribund patient who is not expected to survive without the operation

6

Declared brain-dead patient whose organs are being removed for donor purposes

Preoperative fasting guidelines have been established and developed over time to reduce perioperative gastric volume. In cases of emergency surgery, where a strict preoperative fasting protocol is not possible, the risk of an aspiration event is significantly increased. Previous studies found that the incidence of such an event increased three to fourfold when comparing emergency surgery to elective procedures [14,22,23]. Metabolic Consequences of Preoperative Fasting and Surgical Trauma Whilst preoperative fasting is necessary to reduce the incidence of pulmonary aspiration, prolonged lack of solids or fluid has been demonstrated to have a number of negative metabolic effects, which can in fact worsen postoperative patient outcomes. The primary result of any period of fasting is a decrease in the body’s physiological response to insulin, insulin resistance [24]. Insulin resistance is a protective metabolic mechanism and is also seen following surgical trauma. The gold-standard method of measuring insulin resistance is the hyperinsulinaemic/euglycaemic glucose clamp technique [25]. To achieve the greatest postoperative outcome, a balance must be sought between fasting enough to reduce perioperative gastric volume and not fasting for longer t 1 han necessary, in order to reduce the degree of insulin resistance and other negative metabolic effects. Prolonged fasting results in a hypometabolic state with generalised catabolism to maintain energy requirements. This is hormonally mediated and adrenaline release results in adrenergic activation, with subsequent lipolysis, free fatty acid release and ketogenesis [26]. The rate of insulin release is also reduced, resulting in a decrease in the endogenous insulin/glucagon ratio, initiating gluconeogenesis in the liver and peripheral tissues in conjunction with the above mentioned insulin resistance [26]. The body’s response to surgical trauma is a state of catabolism, similar to a starvation response. In contrast to the starvation response, surgical trauma increases the overall metabolic rate, increasing the required energy of tissues. This is a consequence of the release of stress hormones, including adrenaline, catecholamines, cortisol, and glucagon [26]. These facilitate the breakdown of glycogen, protein and fat. Insulin release is also a major event that occurs following the physiological stress of surgery; however, due to decreased insulin sensitivity, blood glucose concentrations remain constant and, in most cases, increase perioperatively [27]. The resultant degree of insulin resistance is dependent on the type (for example, gastrointestinal or thoracic) and the length of surgery,

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AM S J with positive association between surgery time and degree of insulin resistance [28]. Onset is almost immediately after initial tissue trauma occurs and significant metabolic effects are present for approximately five days postoperatively. Normalisation of the insulin response occurs, on average, after 20 postoperative days [27]. Insulin resistance is associated with prolonged recovery times whereas postoperative normalisation of insulin sensitivity significantly correlates with reduced length of postoperative stay [29]. Enhanced recovery after surgery (ERAS) is a multinational initiative to prevent postoperative complications, including insulin resistance, across a range of systems. ERAS protocols involve modifications to care practices in order to decrease surgical stress response and maintain preoperative organ function across many surgical specialties [30]. ERAS protocols for reducing perioperative insulin resistance during surgery involve preoperative carbohydrate loading, using thoracic epidural anaesthesia and early enteral feeding [31]. Managing the effects of insulin resistance through an insulin infusion may also be an effective strategy for reducing insulin resistance and mortality associated with physiological trauma and stress in a surgical setting. This has been demonstrated in an intensive care setting, where stress-related hyperglycaemic conditions were prevented via insulin infusion. This significantly reduced mortality and complication rates when compared to cases where hyperglycaemia was not treated with infusion [32]. The management of insulin resistance in surgical cases may, therefore, play an important role in reducing mortality during surgical procedures. Along with the hormonal changes seen, prolonged fasting has a number of other negative effects. Fasting has been shown to lower the pH of the gastric and duodenal contents, with longer periods of fasting associated with higher acidity [40]. Whilst the event of pulmonary aspiration has a decreased incidence in the fasted state, there is still potential for an aspiration event to occur. In this case, increased gastric acidity would cause a greater degree of damage to the lungs in comparison to chemical pneumonitis from stomach contents in a fed state. The process of fasting is uncomfortable and has many short-1 term side effects. These can include discomfort, nausea, headaches, dizziness, and hypotension [41]. While none of these conditions are life threatening, they are important to consider when implementing strict fasting guidelines. In the event of excessive fasting, patients suffer these symptoms for no benefit, and may be exposed to potential risks such as insulin resistance, which leads to increased postoperative recovery time, and lowered pH of the gastric contents. Hydration status is also important to consider in fasting patients.

Adequate preoperative hydration is associated with decreased perception of pain, decreased postoperative nausea and improved postoperative recovery [42,43,44]. Dehydration may also increase the risk of postoperative acute kidney injury in some patients [45,46]. Prevention of Insulin Resistance in a Clinical Setting To investigate whether the addition of glucose pre-, peri-, and/ or postoperatively can prevent insulin resistance and large-scale catabolism, applications of glucose solution have been examined. Ljungqvist et al. saw that a constant intravenous infusion of 300 g glucose solution between three hours preoperatively and three hours postoperatively reduced the length of hospital stay by an average of 20% (one day) [30]. Using a similar methodology (continuous glucose and insulin infusion of 5 mg/kg/min and 0.8 mU/kg/min, respectively, from three hours prior to surgery), Nygren et al. saw similar effects, with a difference in insulin sensitivity of approximately 50% between treatment and control groups [33]. Preoperative oral carbohydrate solution administration has also been examined. Four studies have examined the effect of oral carbohydrate solution on gastric emptying in order to identify if there was an increased risk of pulmonary aspiration risk [34-37]. No significant difference between gastric emptying times of water and carbohydrate solution was found in any of the studies [34-37]. Subsequent studies thus treated carbohydrate solution as a ‘clear fluid’, enabling it to be safely consumed closer to the time of surgery than a solid meal, without the increased risk of aspiration. In a 2014 systematic review, Bilku et al. described seven studies examining the effect of preoperative carbohydrate solution on insulin resistance, six of which reported a significant decrease in insulin resistance and one study reported nonsignificance [38]. Soop et al. also reported a significant effect, with glucose beverage consumed two hours preoperatively decreasing the reduction of insulin sensitivity by 25% compared to the control group [39]. Recent Guidelines Current guidelines take the risks of prolonged fasting and residual gastric volume into consideration. The current guidelines from the American Society of Anaesthesiologists (ASA), European Society of Anaesthesiology (ESA), and the Australian and New Zealand College of Anaesthetists (ANZCA) are summarised in Table 2 [1,47,48]. It can be seen that the recommendations of all three associations are very similar, with the only variation being with regard to high fat foods. Most current guidelines have a shorter minimum duration of fasting than previous nil-by mouth after midnight guidelines. This has been due to evidence supporting the safety of shorter fasting periods (gastric

Table 2: Comparison of international preoperative fasting guidelines for various substances Association

Clear Liquid

EL

Non-fatty solid food EL and nonhuman milk

High fat food or Meat

EL

ASA (2017)

> 2hrs

1++

>6

1

>8

*

ESA (2011)

> 2hrs

1++

>6

1+

No differentiation between high-fat and low-fat solids

*

ANZCA (2016)

> 2hrs

*

> 6 (“Light meal only”) *

No differentiation between high-fat and low-fat solids

*

All values represented as number of hours prior to surgery. Evidence level (EL) measures the strength of the supplied evidence; represented as a grade from 1 to 4. 1=high-quality metaanalyses, systematic reviews of RCT’s or RCT’s with very low risk of bias. 2= well-conducted case-control or cohort study with low risk of bias. 3= non-analytical study. 4= expert opinion. *Level of evidence not provided. “+” represents evidence of greater strength.

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Volume 9, Issue 1 | 2019 volume studies previously mentioned) and the detrimental metabolic effects of prolonged fasting, including insulin resistance, decreased blood glucose concentration, discomfort, and worsened postoperative recovery. This evidence has a prompted a reduction in fasting to the minimum amount 1 of time that has been shown to provide a safe gastric volume whilst not increasing the risk of pulmonary aspiration. A point of interest is that Table 2 does not include preoperative oral carbohydrate beverages. Whilst not listed, all three guidelines allow these to be consumed up to two hours prior to surgery. The ASA guideline review discusses their safety, citing studies that have examined gastric emptying times and conclude that they are safe for preoperative consumption, but does not mention any metabolic advantages. European Society of Anaesthesiology guidelines similarly mention gastric emptying and safety, but also cite research concluding an improved metabolic response and increased patient well-being using carbohydrate beverages. However, whilst these are permitted, they are not a requirement and their use is up to the anaesthetist’s discretion. Similarly, there is no required level of fluid consumption outlined in for any of the guidelines. All three organisations “encourage clear fluid consumption up to two hours prior to surgery,” yet level of consumption is not measured or controlled. Even though clear fluid consumption is permitted, dehydration may occur if consumption is not monitored, along with the previously discussed negative outcomes that are associated with preoperative dehydration. Challenges and Advancements While institutions develop these guidelines to improve patient safety, noncompliance is a detrimental limitation to their effectiveness. Current noncompliance with preoperative fasting guidelines has been reported to range between 1.5 and 3.9% [49-51]. Due to the significant risks associated with noncompliance, improvement in this area is required. One of the reasons for noncompliance has been identified as a lack of patient understanding regarding the risks of anaesthesia, the severity of noncompliance and the fundamental reasons for fasting preoperatively [51,52]. Lim et al. saw that only 44.6% of surveyed patients understood the reason for fasting. Those who could identify the correct reason were more likely to perceive it as important [51]. Walker et al. produced similar conclusions, with patients who did not understand the reason for fasting being five times more likely to underrate the importance of compliance [52]. This identifies a problematic lack in communication between medical professionals and patients, which can be addressed through education during the preoperative assessment of the patient.

References [1] Australian and New Zealand College of Anaesthetists [Internet]. Melbourne Vic: ANZCA; 2016. ANZCA Professional documents: PS15 Guidelines on pre-anaesthesia consultation and patient preparation; 2016 April [cited 2018 July 23]; [2 screens]. Available from: http:// www.anzca.edu.au/resources/professional-documents [2] Mellin-Olsen J, Fasting S, Gisvold SE. Routine preoperative gastric emptying is seldom indicated. A study of 85 594 anaesthetics with special focus on aspiration pneumonia. Acta Anaesthesiol Scand. 1996;40(10):1184-8. [3] Beaumont W. Gastric juice and the physiology of digestion. Plattsburgh: Allen, 1833; 277:159-60. [4] Lister J. On anaesthetics, Part III. In: Holmes' system of surgery, Vol Ill, 3rd ed. London, 1883. (Reprinted in: The Collected Papers of Joseph Lister, Birmingham: The Classics of Medicine Library 1979:171-2). [5] JR. M. Preoperative fasting guidelines. Can J Surg. 2006;49(2):138-9. [6] McKinley AC, James RL, GR. M. NPO after midnight before elective surgery is no longer common practice for the majority of anesthesiologists. Am J Anesthesiol. 1995;22(2):88-92. [7] Apfelbaum JL, Caplan RA, Connis RT, Epstein BS, Nickinovich DG, Warner MA. Practice guidelines for preoperative fasting and the use of pharmacologic agents to reduce the risk of pulmonary aspiration application to healthy patients undergoing elective procedures. Anesthesiology. 1999;90(3):896-905.

Gastric sonography is one method of assessing a patient’s aspiration risk without having to consider other comorbidities or compliance with preoperative fasting protocols [53]. Gastric sonography involves a bedside assessment of a patient’s gastric contents, analysing the nature of the contents (solid or clear fluid) and the gastric volume. A systematic review conducted by Van de Putte and Perlas analysed seventeen individual studies that addressed the identification of gastric contents and/or volume [54]. It reported two mathematical models of gastric volume prediction that are currently thought of as accurate and clinically applicable. Gastric sonography is thought to be a useful clinical tool to assess aspiration risks in cases of emergency surgery, patient non-compliance and the presence of multiple significant comorbidities that delay gastric emptying. Conclusion Preoperative fasting is a critical protocol put in place to reduce the risk of perioperative pulmonary aspiration. Originally implemented with long fasting periods of up to fifteen hours, protocols have been improved to reduce unnecessary fasting times and he subsequent negative metabolic effects. This review describes both historical and current guidelines and explains the reasons for their development. Understanding the risks associated with anaesthesia and the most up-to-date protocols to reduce aspiration risk is important to medical students interested in anaesthetics and surgical specialties. Whilst AMA, ESA, and ANZCA literature lists fasting as compulsory, there is limited regulation of minimum consumption levels of clear fluid, disposing patients to dehydration, or compulsory preoperative carbohydrate uptake, which has been associated with decreased postoperative insulin resistance. Future incorporation of these factors into current guidelines may improve patient outcomes. Increasing patient compliance may also improve outcomes. The preoperative assessment should be altered to increase patient understanding regarding the risk factors involved with anaesthesia, and underlying reason and clinical significance of the preoperative fasting protocols. The results of previous studies suggest that lack of education in this area is responsible for noncompliance. Finally, gastric sonography is an accurate and reliable bedside test that may improve clinicians’ abilities to accurately assess gastric volume and thus a patient’s risk of pulmonary aspiration. Correspondence B Kalma: Benjamin.kalma@uq.net.au

[8] Nason KS. Acute intraoperative pulmonary aspiration. Thorac Surg Clin. 2015;25(3):3017. [9] Olsson GL, Hallen B, Hambraeus-Jonzon K. Aspiration during anaesthesia: a computer26 aided study of 185 358 anaesthetics. Acta Anaesthesiol Scand. 1986;30(1):84-92. [10] Sakai T, Planinsic RM, Quinlan JJ, Handley LJ, Kim TY, Hilmi IA. The incidence and outcome of perioperative pulmonary aspiration in a university hospital: a 4-year retrospective analysis. Anesth Analg. 2006;103(4):941-7. [11] Warner MA, Warner ME, Weber JG. Clinical significance of pulmonary aspiration during the perioperative period. Anesthesiology. 1993;78(1):56-62. [12] Cook T, Frerk C. 4th National Audit Project (NAP 4): Major complications of airway management in the United Kingdom report and findings, 2011 March The Royal College of Anaesthetists and The Difficult Airway Society [13] American Society of Anesthesiologists [Internet]. Schaumburg IL: ASA House of Delegates; 2018. ASA Physical status classification system; 2014 Oct 15 [cited 2018 July 23]; [1 screen]. Available from: https://www.asahq.org/resources/clinical-information/asa physical-status-classification-system [14] Borland LM, Sereika SM, Woelfel SK, Saitz EW, Carrillo PA, Lupin JL, et al. Pulmonary aspiration in pediatric patients during general anesthesia: incidence and outcome. J Clin Anesth. 1998;10(2):95-102.

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Review Article [15] Meals C, Roy S, Medvedev G, Wallace M, Neviaser RJ, O'Brien J. Identifying the risk of swallowing-related pulmonary complications in older patients with hip fracture. Orthopedics. 2016;39(1):e93-7. [16] Robinson M, Davidson A. Aspiration under anaesthesia: risk assessment and decision making. Continuing Education in Anaesthesia, Critical Care & Pain. 2014;14(4):171-5. [17] Asai T. Editorial II: Who is at increased risk of pulmonary aspiration? Br J Anaesth. 2004;93(4):497-500. [18] Benington S, Severn A. Preventing aspiration and regurgitation. Anaesth Intensive Care. 2007;8(9):368-72. [19] Strunin L. How long should patients fast before surgery? 1 Time for New Guidelines. Br J Anaesth. 1993;70(1):1-4. [20] Nimmo WS. Gastric emptying and anaesthesia. Can J Anaesth. 1989;36(S1):S45-S7. [21] Pinder A. Complications of obstetric anaesthesia. Curr Anaesth Crit Care. 2006;17(34):151-62. [22] Jenkins K, Baker AB. Consent and anaesthetic risk. Anaesthesia. 2003;58(10):962-84. [23] Mellin-Olsen J, Fasting S, Gisvold SE. Routine preoperative gastric emptying is seldom indicated. A study of 85 594 anaesthetics with special focus on aspiration pneumonia. Acta Anaesthesiol Scand. 1996;40(10):1184-8. [24] Black PR, Brooks DC, Bessey PQ, Wolfe RR, Wilmore DW. Mechanisms of insulin resistance following injury. Ann Surg. 1982;196(4):420-35. [25] DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol. 1979;237(3):E214-23. [26] Nygren J. The metabolic effects of fasting and surgery. Best Pract Res Clin Anaesthesiol. 2006;20(3):429-38. [27] Thorell A, Efendic S, Gutniak M, Haggmark T, Ljungqvist O. Insulin resistance after abdominal surgery. Br J Surg. 1994;81(1):59-63. [28] Thorell A, Nygren J, Ljungqvist O. Insulin resistance: a marker of surgical stress. Curr Opin Clin Nutr Metab Care. 1999;2(1):69-78. [29] Ljungqvist O, Nygren J, Thorell A. O.10 Preoperative carbohydrates instead of overnight fasting reduces hospital stay following elective surgery. Clin Nutr. 1998;17:3. [30] ERAS Society. Enhanced Recovery After Surgery [Internet]. Gustavsberg Sweden: Gula Hunden Web Agency; 2016 [updated 2018 July 13; cited 2018 July 22]. Available from: http://erassociety.org/ [31] Ljungqvist O. Insulin resistance and outcomes in surgery. J Clin Endocrinol Metab. 2010;95(9):4217-9. [32] Van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, et al. Intensive insulin therapy in critically ill patients. N Engl J Med. 2001;345(19):1359-67 [33] Nygren JO, Thorell A, Soop M, Efendic S, Brismar K, Karpe F, et al. Perioperative insulin and glucose infusion maintains normal insulin sensitivity after surgery. Am J Physiol. 1998;275(1):E140. [34] Hausel J, Nygren J, Lagerkranser M, Hellstrom PM, Hammarqvist F, Almstrom C, et al. A carbohydrate-rich drink reduces preoperative discomfort in elective surgery patients. Anesth Analg. 2001;93(5):1344-50. [35] Henriksen MG, Hessov I, Dela F, Hansen HV, Haraldsted V, Rodt SA. Effects of preoperative oral carbohydrates and peptides on postoperative endocrine response, mobilization, nutrition and muscle function in abdominal surgery. Acta Anaesthesiol Scand. 2003;47(2):191-9. [36] Nygren J, Thorell A, Jacobsson H, Larsson S, Schnell PO, Hylen L, et al. Preoperative gastric emptying. Effects of anxiety and oral carbohydrate administration. Ann Surg. 1995;222(6):728-34.

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AM S J [37] Yagci G, Can MF, Ozturk E, Dag B, Ozgurtas T, Cosar A, et al. Effects of preoperative carbohydrate loading on glucose metabolism and gastric contents in patients undergoing moderate surgery: a randomized, controlled trial. Nutrition (Burbank, Los Angeles County, Calif). 2008;24(3):212-6. [38] Bilku DK, Dennison AR, Hall TC, Metcalfe MS, Garcea G. Role of preoperative carbohydrate loading: a systematic review. Ann R Coll Surg Engl. 2014;96(1):15-22. [39] Soop M, Nygren J, Myrenfors P, Thorell A, Ljungqvist O. Preoperative oral carbohydrate treatment attenuates immediate postoperative insulin resistance. Am J Physiol. 2001;280(4):E576-83. [40] Dressman JB, Berardi RR, Dermentzoglou LC, Russell 1 TL, Schmaltz SP, Barnett JL, et al. Upper gastrointestinal (GI) pH in young, healthy men and women. Pharm Res. 1990;7(7):756-61. [41] Gibson RS. Principles of nutritional assessment / Rosalind S. Gibson. 2nd ed.. ed. New York: New York : Oxford University Press; 2005. [42] Hayhurst C, Durieux ME. Enteral hydration prior to surgery: the benefits are clear. Anesth Analg. 2014;118(6):1163-4. [43] Yavuz MS, Kazancı D, Turan S, Aydınlı B, Selçuk G, Özgök A, et al. Investigation of the effects of preoperative hydration on the postoperative nausea and vomiting. Biomed Res Int. 2014;2014:302747. [44] Mythen MG, Swart M, Acheson N, Crawford R, Jones K, Kuper M, et al. Perioperative fluid management: Consensus statement from the enhanced recovery partnership. Perioper Med (Lond). 2012;1(1):2. [45] Moghadamyeghaneh Z, Phelan MJ, Carmichael JC, Mills SD, Pigazzi A, Nguyen NT, et al. Preoperative dehydration increases risk of postoperative acute renal failure in colon and rectal surgery. J Gastrointest Surg. 2014;18(12):2178-85. [46] Ellis RJ, Del Vecchio S, Kalma B, Ng K, Morais C, Francis R et al. Association between preoperative hydration status and acute kidney injury in patients managed surgically for kidney tumours. Int Urol Nephr. 2018 Jun 5; 50(7):1211-17. [47] Practice guidelines for preoperative fasting and the use of pharmacologic agents to reduce the risk of pulmonary aspiration: application to healthy patients undergoing elective procedures: an updated report by the American Society of Anesthesiologists Committee on Standards and Practice Parameters. Anesthesiology. 2011;114(3):495-511. [48] Smith I, Kranke P, Murat I, Smith A, O'Sullivan G, Soreide E, et al. Perioperative fasting in adults and children: guidelines from the European Society of Anaesthesiology. Eur J Anaesthesiol. 2011;28(8):556-69 [49] Adudu OP, Egwakhide EO, Adudu OG. Parents and patients' compliance to revised preoperative fasting guidelines in Benin, Nigeria. Paediatr Anaesth. 2008;18(10):1013-4. [50] Laffey JG, Carroll M, Donnelly N, Boylan JF. Instructions for ambulatory surgery-patient comprehension and compliance. Ir J Med Sci. 1998;167(3):160-3. [51] Lim HJ, Lee H, Ti LK. An audit of preoperative fasting compliance at a major tertiary referral hospital in Singapore. Singapore Med J. 2014;55(1):18-23. [52] Walker H, Thorn C, Omundsen M. Patients' understanding of pre-operative fasting. Anaesthesia and intensive care. 2006;34(3):358-61. [53] Perlas A, Davis L, Khan M, Mitsakakis N, Chan V. Gastric sonography in the fasted surgical patient: a prospective descriptive study. Anesth Analg. 113(1):93-97 [54] Van de Putte P, Perlas A. Ultrasound assessment of gastric content and volume. Br J


AM S J

Review Article Management of burn wound pain in the hospital setting Tobias Richards Doctor of Medicine 4-year degree, 4th year (final year) University of Western Australia

Tobias is a final year medical student at the University of Western Australia. He has a keen interest in medical research and its implications in improving the quality of care delivered to patients.

Lauren Corso Doctor of Medicine 4-year degree, 4th year (final year) University of Western Australia

Lauren is a final year medical student studying at the University of Western Australia. She has broad research interests in paediatrics, infectious diseases, and general practice.

Abstract In Australia, burns are common, accounting for around 5500 hospital injuries each year. The proper management of burn pain is crucial to the rehabilitation process and in reducing the chance of long term psychological sequelae, such as depression and posttraumatic stress disorder. A wide array of therapeutic options is available to the clinician in managing burn pain in a hospital setting. These evidence-based options include opioids, non-opioid medications, anxiolytics, anaesthetics, as well as relaxation techniques and cognitive behavioural therapy. In managing chronic pain, therapeutic options vary between pharmacological and non-pharmacological approaches used for acute pain. Consideration of these pain relief options can optimise the management of patients with burns and maximise their rehabilitation, leading to earlier hospital discharge.

Introduction Thermal injury to the skin can be one of the most painful forms of trauma [1]. In Australia, burns accounted for around 5500 hospital admissions and constituted 1.2% of all injury causes in 2014 [2]. The most common cause of burn injuries is contact with hot substances and materials, such as fluids and cooking equipment, with the most commonly injured body parts being the wrists and hands [2]. Burn pain poses a unique challenge to clinicians because its intensity varies greatly between patients and the perception of pain fluctuates over the course of a patient’s admission [3]. Furthermore, there is currently limited evidence on management of burns injury. Current treatment is based on data extrapolated from several randomised clinical trials, case series and reports, and relevant areas of pain medicine [4]. This type of pain can also be unpredictable and depends on anatomical, physiological, psychological, and premorbid behavioural factors [2]. Distinctive to burn injury is the notable link to psychological harm. Burn wounds are associated with disorders such as acute stress disorder, depression, suicidal ideation, and post-traumatic stress disorder for as long as two years after the initial injury [5]. Moreover, insufficient management of burn pain itself has been associated with a range of diseases and loss of patient confidence, which can complicate treatment and slow rehabilitation. Inadequately managed pain can also limit patient mobilisation and thereby limit physiotherapy that can cause prolonged hospital stays and hospital acquired infections [6,7]. This relationship has been documented in the literature with burn

pain being a stronger predictor, rather than the size of the burn or the length of hospitalisation, of psychological adjustment [8]. It is because of this that the management of pain in patients suffering from burn injuries should be carefully considered in order to maximise recovery. A number of Australian guidelines exist for burn injuries, including those by the New South Wales (NSW) State-wide Burn Injury Service, Australian Pain Management Association, Australian and New Zealand Burn Association, The Royal Children’s Hospital and The Royal Australian College of General Practitioners. The aim of this review is to assess the available literature in order to provide a comprehensive review of evidence-based approaches to managing burn pain in a hospital setting. Methods In November 2017, a systematic search of the PubMed, Cochrane, and UpToDate databases was conducted using combinations of keywords such as “burn”, “thermal injury”, “pain”, “hospital”, “analgesia”, and “management” to identify available data sources. Only studies in English were included in the review. Selection criteria for the review included academic articles from peer-reviewed journals and evidencebased clinical resources, such as UpToDate and BMJ Best Practice. Managing initial acute pain The instant pain that follows a burn injury is due to the stimulation and damage of skin thermoreceptors, mechanoreceptors, and a selection of exogenous and endogenous mediators [7]. Nerve endings that are entirely destroyed will not transmit pain, but those that remain undamaged and exposed will generate pain throughout the time and course of treatment, a response termed primary hyperalgesia [7].

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AM S J Furthermore, damaged and regenerating nerve tissues can give rise to complex neuropathic pain syndromes, whereby the sensation of the painful stimulus outlives its expected duration [1]. Other symptoms characteristic of neuropathic pain include tingling, stiffness, cold or hot pain, as well as itching [1]. Pain assessment is an important component of pain care and should be assessed regularly. Evidence-based scores include the Verbal Numerical Rating Score, a score from 0 to 10 ranked from no pain to the worst pain possible [9]. Also useful is the Wong-Baker FACESÂŽ Pain Rating Scale, which uses visual faces to represent pain and is useful if patients have difficulty quantifying their pain numerically [9]. First-aid management of burns include cooling the area with tepid or cold water for 20 minutes, which may terminate the burning process and reduce the pain of the injury [3,4,6]. Elevation of the injured part and the application of a compressive dressing, or oedema gloves in the case of hand burns, can help reduce oedema and can minimise the development of pain associated with swelling and stiffness [4,6,10]. Immediate and effective analgesia medication should be provided. Rapid options include intranasal fentanyl or intravenous (IV) morphine [3]. Non-steroidal anti-inflammatory (NSAID) medications may be useful as adjuncts to opioids or used alone to manage small burn injuries [7]. Managing burn pain in the hospital There are different types of pain experienced by burn patients in the hospital, for which adequate analgesia strategies should be considered. These range from background pain, which is continuous and present at rest, procedural pain evoked during dressing removal and cleaning, as well as emotional and psychological pain experienced by the individual [11,12]. While pharmacological and non-pharmacological methods exist for managing burn pain, a multimodal approach to pain management has provided good results in controlling pain while minimising the patientsâ&#x20AC;&#x2122; risk of experiencing side effects [1]. Strategies that utilise pre-emptive regular dosing with supplemental prescriptions for breakthrough pain are most effective in practice [1]. During the transition from acute burn injury to burn healing, burns can contract and be a source of pain to patients [13]. It is important, therefore, that pre-emptive pain control is utilised to ensure adequate allied health support can be provided, ideally from the day of patient admission into hospital [10]. For example, stretching injured tissue during physiotherapy or occupational therapy in the hospital setting is vital to optimise burn recovery and support return of function [10,18]. Inadequate pre-emptive pain control jeopardises the crucial role these Table 1. Pain management options for burn pain in the hospital setting.

Pain management options for Level of evidence available burn pain in the hospital setting Pharmacological Opioids

I [27-28]

Non-opioids (paracetamol, non- Paracetamol - III-2 [29] steroidal anti-inflammatory drugs) Anxiolytics (midazolam)

I [30]

Anaesthetics (ketamine, nitrous Ketamine â&#x20AC;&#x201C; II [31] oxide, propofol, sevoflurane) Non-pharmacological Relaxation techniques

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allied health service have in the rehabilitation process, increasing the risk of scarring and contractures [10,14]. Pharmacological pain management options include opioid analgesics, non-opioid analgesics, anxiolytics, and anaesthetics (Table 1). The type of medication used is determined by the severity of the pain, anticipated duration of the pain and availability of intravenous access. These medications have variable durations of action and should be 1 titrated to meet the needs of the patient in each clinical setting [3]. In order to control background pain associated with burns, it is recommended to aim for near constant plasma levels of regularly scheduled analgesics, such as long-acting analgesics, non-opioid analgesics, or long-acting IV opioid infusions in patients unable to take oral medications [3]. Guidance from a pain specialist should be sought early and can guide the implementation of a multimodal pain strategy. Pharmacological Pain Management Opioid analgesics Opioids are a mainstay option for the treatment of burn pain, especially in the acute phase [17]. They are also the most efficacious medication in perioperative moderate and severe pain management [17]. Opioids can be delivered via a variety of routes, including oral, intravenous, transdermal, sublingual and rectal routes. It is available in short or long-acting formulations [17]. In the initial presentation of severe burns, analgesia is best achieved by titration of IV opioids, as other routes may be less reliable in the presence of hypovolaemia and vasoconstriction associated with burns [4]. For acute burn injuries, patient-controlled analgesia (PCA) with IV morphine can be considered. It offers the burn patient a safe and effective method of achieving flexible analgesia, provided the patient is alert and competent enough to use the device [4]. For breakthrough pain during the acute phase or healing phase, short-acting potent opioids should be used and can be titrated to effect by increasing the dose while maintaining the dosing interval [15]. For example, short-acting opioids such as fentanyl can provide good analgesia during dressing changes when administered via target-controlled IV infusions of PCA [4]. During the acute phase, controlled release or long half-life opioids, such as methadone, can be effective for background pain when administered by clinicians trained in its use [13,16]. Side effects are common with opioids, with some studies finding that up to 92% of patients experience at least one side effect, such as constipation, nausea, respiratory depression, or sedation [17]. Prophylactic antiemetics and aperients should be considered when opioids are given [8]. Non-opioid analgesics Paracetamol and NSAIDs provide mild analgesia and can supplement opioids. Paracetamol and NSAIDs exhibit a ceiling effect in their doseresponse relationship, rendering them unsuitable as single agents for the treatment of severe burn pain, but they can be effective as adjuvants to opioid medications for background pain [18]. Care should be taken when using NSAIDs in older patients and in patients with renal impairment or gastric injury. While NSAIDs are effective against inflammatory pain, their use should not be recommended in patients with significant burns who are at an increased risk of renal failure [19]. Other non-opioid medications which have been shown to be useful in controlling acute pain are neuropathic agents, such as antidepressants and anticonvulsant agents [20]. Antidepressant medications, such as tricyclic antidepressants, can enhance opioid analgesia, especially in patients with chronic pain [20]. Also, there is evidence that anticonvulsant agents, such as pregabalin and gabapentin, can be used


Volume 9, Issue 1 | 2019 to reduce pain following acute burn injury, with gabapentin use being associated with reduced opioid usage [4,21]. The use of pregabalin or gabapentin should be considered by clinicians as a part of multimodal analgesia for patients suffering from neuropathic pain after acute burns injury [4,21].

procedural pain [19,25]. While its use for the hospitalised burn patient has not been explored in the literature, evidence does highlight its utility in reducing anticipatory pain and distress, reducing catastrophic thinking during procedures and assisting to distract from pain by diverting attention [26].

Anxiolytics

Chronic burn pain

Anxiolytic medications are commonly used in burn uni 1 ts to reduce patient anxiety before or during procedures, such as debridement and to reduce the exacerbation of pain [2]. Studies have shown that benzodiazepine therapy can improve post-procedural pain scores in burn patients, although one recent study investigating this found the effect to only be significant in those with high baseline pain [22]. The benzodiazepine midazolam may be useful for its dissociative, anxiolytic, and sedative qualities and may help reduce pain in patients undergoing dressing changes or wound cleaning [11].

Damage inflicted by burns can cause a range of chronic pain syndromes in patients. Studies have found that chronic burn pain is a significant problem, with one study in the United States finding 52% of burn patients had ongoing pain around 12 years after injury [15]. This can significantly affect the patientâ&#x20AC;&#x2122;s rehabilitation by affecting sleep, impairing performance and resulting in depressive symptoms [1]. General advice for the management of chronic pain involves consideration of the principles of multimodal analgesia with support from interdisciplinary team members [23]. In the 1 management of chronic burn pain, conventional analgesics, such as opioids, have a lesser role and should be monitored diligently for ongoing benefit and adverse outcomes [1,22]. Treatment with antidepressants, such as amitriptyline, and anticonvulsants, such as pregabalin and gabapentin, also have a role in controlling neuropathic pain and reducing opioid requirements [1,15].

Anaesthetics A range of anaesthetics have a role in the management of burn pain if used under the guidance of a trained clinician such as an anaesthetist [3,4]. General anaesthesia or deep sedation with anaesthetic agents, such as propofol, may be considered for patients undergoing intensely painful procedures, such as large dressing changes [3,4]. Also, the inhaled agent nitrous oxide can be useful during short, moderately painful procedures, typically as a 50% mixture in 50% oxygen [3,10]. This can be self-administered by an awake, cooperative and spontaneously breathing patient via a mouthpiece or mask [3]. The anaesthetic agent ketamine can have potent analgesic effects when administered at subanaesthetic doses and can be used to facilitate procedures such as dressing changes [4]. Ketamine induces a dissociative state with a fast onset of action and distressing psychomimetic symptoms [1,10]. Non-pharmacological pain management Relaxation techniques Relaxation techniques are used to lower arousal, including unnecessary muscle tension that can increase pain, particularly during dressing changes and debridement [1]. Techniques that have been shown to be useful include deep breathing, progressive muscle relaxation and music interventions [1,22]. One quasi-experimental study of 64 burn patients investigating abdominal breathing exercises found a significant reduction in pain scores compared to the control group [22]. This effect may be dependent on the technique of relaxation; however, a separate study investigating jaw relaxation techniques did not detect a significant difference in pain intensity [23].

When considering non-pharmacological treatment options, there is some evidence to suggest CBT and hypnosis therapy can assist in management of pain [1,3,4]. Hypnosis has been well described in conjunction with conventional analgesic medication, with case reports suggesting synergistic and stand-alone effects in patients undergoing burn dressing changes [1,3]. In cases of resistant chronic pain, patients should be referred to a pain specialist for ongoing management. Conclusion The effective management of pain after a burn injury is essential in the acute hospital setting, as well as in the subsequent program of rehabilitation. Burn injury pain is a common medical problem, for which many therapeutic management options exist. This review has highlighted a range of currently used evidence-based therapeutic options. A multimodal analgesic plan should consider options such as opioid and non-opioid analgesics, anaesthetics, anxiolytics, as well as relaxation techniques and CBT as required. Input from a pain specialist should be sought early in cases of both acute and chronic burn pain. Acknowledgements Thank you to Dr Helen Douglas and the Fiona Stanley Hospital Burns Unit for your kind support.

Cognitive behavioural therapy (CBT)

Correspondence

These techniques include diversion, information provision, coping skills, and relaxation techniques that modify the patientâ&#x20AC;&#x2122;s thought process about painful experiences [24]. Catastrophising pain can increase levels of perceived pain and CBT aims to reduce these perceptions and provide control to the patient in their pain management [25]. CBT has been shown to be an effective pain control technique in treating

T Richards: tobias.richards@health.wa.gov.au

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AM S J References [1] Norman A, Judkins K. Pain in the patient with burns. BJA Education. 2004;4(2):57-61. doi:10.1093/bjaceaccp/mkh016 [2] Pointer S, Tovell A. Hospitalised burn injuries, Australia, 2013-2014. Injury research and statistics series no. 102. Cat. no. INJCAT 278. Canberra: Australian Institute of Health and Welfare; 2016. [3] Wiechman S, Shararar S. Management of burn wound pain and itching. 2017 [Internet]. Uptodate. Available from: https://www.uptodate.com/contents/management-of-burnwound-pain-and-itching [4] Schug SA, Palmer GM, Scott DA, Halliwell R, Trinca J, editors. Acute Pain Management: Scientific Evidence. Fourth Edition. Australian and New Zealand College of Anaesthetists: Melbourne; 2015. [5] Dalal P, Rahul S, Agarwal M. Psychiatric aspects of burn. 20. Indian J Plast Surg. 2010; 43(Suppl):S136-42. doi:10.4103/0970-0358.70731 [6] Cleland H. Thermal burns—assessment and acute management in the general practice setting. Aust Fam Physician. 2012;41(6):372-5. [7] Latarjet J, Choinere M. Pain in burn patients. Burns. 1995;21(5):344-8. [8] Australian Pain Management Association. Burns Pain. 2017. Available from: https:// www.painmanagement.org.au/using-joomla/extensions/components/contentcomponent/article-category-list/217-burns-pain.html [9] Victorian Adults Burns Service: Alfred Hospital. Burns Management Guidelines. 2017. Available from: http://www.vicburns.org.au/minor-burns/minimise-infection/painmanagement-1/ [10] Castro R, Leal P, Sakata R. Pain management in burn patients. Rev. Bras. Anestesiol. 2013;63(1). doi:10.1590/S0034-70942013000100013 [11] Edgar D, Brereton M. Rehabilitation after burn injury. BMJ. 2004;329(7461):343-5. [12] Browne A, Andrew R, Schug S, Wood F. Persistent pain outcomes and patient satisfaction with pain management after burn injury. Clin J Pain. 2011;27(2):136-45. [13] Summer G, Puntillo K, Miaskowski C, Green P, Levine J. Burn injury pain: the continuing challenge. J Pain. 2007;8(7):553-48. [14] James D, Jowza M. Principles of burn pain management. Clin Plast Surg. 2017; 44(4):737-47. doi:10.1016/j.cps.2017.05.005 [15] Dauber A, Osgood P, Breslau A, Vernon H, Carr D. Chronic persistent pain after severe burns: a survey of 358 burn survivors. Pain Med. 2002;3(1):6-17. doi:10.1046/j.15264637.2002.02004.x [16] Rowan M, Cancio L, Elster E, Burmeister D, Rose L, Natesan S, et al. Burn wound healing and treatment: review and advancements. Crit Care. 2015;19:243. doi:10.1186/s13054015-0961-2 [17] Richardson P, Mustard L. The management of pain in the burns unit. Burns. 2009;35(7):921-36. doi:10.1016/j.burns.2009.03.003

[18] Bittner E, Shank E, Woodson L, Martyn J. Acute and perioperative care of the burninjured patient. Anesthesiology. 2015;122(2):448-64. doi:10.1097/ALN.0000000000000559 [19] Gray P, Kirby J, Smith M, Cabot P, Williams B, Doecke J, et al. Pregabalin in severe burn injury pain: a double-blind randomised placebo-controlled trial. Pain. 2011;152(6);127988. doi:10.1016/j.pain.2011.01.055 [20] Patterson D, Ptacek J, Carrougher G, Sharar S. Lorazepam as an adjunct to opioid analgesics in the treatment of burn pain. Pain. 1997;72(3):367-74. [21] Morgan M, Deuis J, Frosig-Jorgensen M, Lewis R, Cabot P, Gray P, Vetter I. Burn pain: a systematic and critical review of epidemiology, pathophysiology, and treatment. Pain Med. 2018;19(4):708-34. doi:10.1093/pm/pnx228 [22] Park E, Oh H, Kim T. The effects of relaxation breathing on procedural pain and anxiety during burn care. Burns. 2013;39(6):1101-6. doi:10.1016/j.burns.2013.01.006 [23] Forough R, Fahimeh M, Roohangiz O. Effectiveness of jaw relaxation for burn dressing pain: randomized clinical trial. Pain Manag Nurs. 2014;15(4):845-53. doi:10.1016/j. pmn.2013.11.001 [24] Wiechman S. Psychosocial aspects of burn injuries. BMJ. 2004;329(7462):391-93. doi:10.1136/bmj.329.7462.391 [25] Thurber C, Martin-Herz, Paterson D. Psychological principles of burn wound pain in children. I: theoretical framework. J Burn Care Rehabil. 2000;21(4):376-87. [26] Li J, Zhou L, Wang Y. The effects of music intervention on burn patients during treatment procedures: a systematic review and meta-analysis of randomized controlled trials. BMC Complement Altern Med. 2017;17:158. doi: 10.1186/s12906-017-1669-4 [27] Yang Cm Xiao-min X, Guang-Zhao H. Efficacy and feasibility of opioids for burn analgesia: An evidence-based qualitative review of randomized controlled trials. Burns. 2017;44(2):241-8. doi: 10.1016/j.burns.2017.10.012 [28] Rovers J, Knighton J, Neligan P, Peters W. Patient-controlled analgesia in burn patients: a critical review of the literature and case report. Hosp Pharm. 1994;29(2):106, 108-11. [29] Meyer W, Nichols R, Cortiella J, Villarreal C, Marvin J, Blakeney P, Herndon D. Acetaminophen in the management of background pain in children post-burn. J Pain Symptom Manage 1997;13(1):50-5. [30] Patterson D, Ptacek J, Carrougher G, Sharar S. Lorazepam as an adjunct to opioid analgesics in the treatment of burn pain. Pain. 1997;72(3):267-74. [31] McGuinness S, Wasiak J, Cleland H, Symonds J, Hogan L, Hucker T, Mahar P. A systematic review of ketamine as an analgesic agent in adult burn injuries. Pain Med. 2011;12(10): 1551-8. doi:10.1111/j.1526-4637.2011.01220.x [32] Forough R, Fahimeh M, Roohangiz O. Effectiveness of jaw relaxation for burn dressing pain: randomized clinical trial. Pain Manag Nurs. 2014;15(4):845-53. doi:10.1016/j. pmn.2013.11.001

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Review Article Paediatric simulation teaching for medical students: a review of current literature Ashani Mahawattege MBBS University of Adelaide

The authors are sixth year undergraduate medical students studying at the University of Adelaide, who share a special interest in paediatrics and child health. This review was inspired by a Simulation Education Selective undertaken together at the Adelaide Health Simulation and Skills Centre.

Samantha Burns MBBS University of Adelaide

Abstract The objective of this review article is to determine whether simulation-based education could enhance the teaching of paediatrics to Australian medical students. A literature search of PubMed and Embase was performed and from 595 identified articles, 34 papers were included in this review. There are several benefits of simulation teaching in paediatrics, including skill acquisition, improvement, maintenance, enhanced confidence, better understanding of human factors, improved teamwork skills and an opportunity to debrief as well as the potential for downstream improvements in patient outcomes. However, several challenges of simulation teaching for paediatrics were acknowledged, such as resource availability. Approaches to overcoming these challenges were proposed by the use of low-fidelity manikins, alternatives to standardised patients, the judicious use of simulation education, optimisation of student preparation for simulation sessions, the use of registrars as simulation facilitators and the utilisation of remote facilitation. With further research regarding the impact of simulation teaching on real-life clinical performance as well as methods to optimise its delivery, efficiency and cost-effectiveness, paediatric simulation teaching has considerable potential to enhance education for medical students in Australia.

and learning in medicine, but has, to date, been predominantly used in postgraduate training programs in Australia [7]. There are no published data documenting the amount of simulation-based education used in paediatric teaching in Australia. Surveys of paediatric institutions in America and Switzerland reported paediatric simulation being used in 89% (n=71) and 66.6% (n=30) of the centres, respectively [5,7]. The purpose of this paper is to answer the question: could simulation teaching enhance the teaching of paediatrics to Australian medical students? In answering this question, the need for and benefits of simulation training in teaching paediatrics to medical students will be examined, the potential barriers to its implementation will be described and the recommendations for its use will be made. Materials and Methods

Introduction Simulation describes “an artificial representation of a real-world process to achieve educational goals through experiential learning” [1]. Simulation-based education was originally used in the 1970s by the National Aeronautics and Space Administration (NASA) in the United States to build teamwork skills and to reduce error to prevent airline crashes [2]. Simulation has since been used in other industries, such as the military, oil industry and healthcare [3]. Simulation-based teaching in healthcare places learners in lifelike environments where they experience scenarios that mimic real clinical encounters [4]. Simulation uses modalities such as low-fidelity and high-fidelity manikins and standardised patients. Fidelity describes the degree to which simulation replicates reality [5]. The term fidelity can be applied to manikins; lowfidelity manikins are basic unchanging models, whereas high-fidelity manikins are computer-based and can be programmed to demonstrate physiologic responses to the user, for example, breath sounds, pulses, and eye signs [6]. Standardised patients are individuals who are trained to portray an actual patient or illness [6]. Simulation allows learners to acquire and practice new skills without posing a risk to real patients. It is a well-established tool for teaching

A literature search of PubMed and Embase was performed on July 2nd 2017. Search terms were grouped under the broad themes of “simulation”, “paediatrics” and “medical students”. A full list of search terms is provided in Appendix 1. The reference lists of identified papers were reviewed to identify additional articles. The initial literature search identified 595 articles. The search was limited to English language publications. The articles were examined by two reviewers and the papers focusing on teaching in specialty paediatric training, nursing and allied health professions, or the use of simulation as an assessment tool were excluded. Studies from overseas were included, as few Australian studies have been conducted. A PRISMA diagram is included below to demonstrate the search strategy used (Figure 1). Subsequently, 34 papers were included for the literature review. Results Benefits of simulation education Simulation education is an evolving teaching modality with potential benefits to both medical students and their future patients. Undergraduate medical education has previously been primarily delivered in the form of lectures and practical lessons. Simulation

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AM S J teaching provides an opportunity to apply knowledge to clinical scenarios in a safe and controlled environment [6,8-11]. Given that clinical environments are often busy, the provision of a facilitated debriefing following each scenario is not always afforded. Simulation enables identification and correction of errors as well as adaptation of behaviours to enable better care and clinical outcomes for patients [12]. Furthermore, a fundamental component of simulation education is the delivery of â&#x20AC;&#x2DC;human factor trainingâ&#x20AC;&#x2122; in non-technical skills such as leadership, communication and prioritisation [8,9]. Simulation-based teaching also allows exposure to a broad range of clinical scenarios to address specific educational objectives [6,8,10,11]. Hence, simulation education has great potential for integration into medical curriculum worldwide. Benefits of paediatric simulation teaching There is now a growing body of evidence supporting the efficacy of simulation education as a teaching tool in the undergraduate paediatric curriculum. Paediatric simulation teaching demonstrates many benefits when compared with traditional forms of medical education. Traditional teaching is centred around a combination of time spent on a paediatric ward in a hospital setting, lectures, and tutorials. However, recent increases in medical student numbers in Australia have raised concerns about the systemâ&#x20AC;&#x2122;s ability to provide quality clinical placements [13]. In addition to this, opportunities to learn and practice skills on sick children are limited by ever more stringent restrictions [7]. At the completion of a medical program, the paediatric experience of two undergraduate students from the same university can vary greatly; for example, one student may have completed their paediatric rotation in a rural general hospital, while another completed theirs in a tertiary paediatric hospital. Thus, not all medical students will encounter patients with the same range of clinical conditions or experiences. Simulation education can be used to standardise undergraduate paediatric experience, ensuring all medical students are exposed to both common and rare presentations [6,10]. Thus, simulation education has a particular role to play in the teaching of paediatrics to medical students. Increased student confidence A small observational study by Hayes et al. [14] reported a 75% increase in medical student confidence in the management of paediatric emergencies following the introduction of simulation training. Similarly, in a study at John Hopkins University School of Medicine, the inclusion of simulation-based teaching in a paediatric rotation resulted in more than 95% of students feeling confident to see paediatric patients [10]. A further study by Whitt et al. [15] demonstrated statistically significant increases (p<0.05; Bonferroni correction, p<0.006) in student confidence and self-perceived ability in paediatric settings following three simulated patient encounters. Improvements in knowledge and understanding Paediatric simulation teaching facilitates improved understanding and identification of knowledge gaps through facilitated debriefs that address behaviours, skills and clinical decision making during the simulation [11,7,16]. In an observational study of the integration of a high-fidelity simulator in a third-year paediatrics clerkship, 1 98% of students agreed this form of learning experience produced better understanding of clinical issues [8]. In the United States, students exposed to simulation also scored substantially higher on the National Board of Medical Examiners paediatric examination [10]. In an observational study undertaken with 56 final year medical students at Monash University, Malaysia, a significant knowledge gain was reported immediately following a simulation workshop [17]. Furthermore, knowledge retention has been shown to be greater following simulation compared traditional teaching methods [18]. A

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prospective cohort study undertaken by Drummond et al. [19] showed at six to twelve months following a paediatric cardiopulmonary arrest course, knowledge of 411 students attending simulation teaching was significantly higher (p< 0.001) than those attending traditional lectures. Development of clinical skills A prospective mixed methods study by Dudas et al. [10] showed a simulation-based curriculum improved medical student clinical performance with greater rates of history taking, performing examinations and procedural skills during their paediatric clerkship. Following simulation teaching, Objective Structured Clinical Examination (OSCE) scores are higher in students who receive this form of teaching compared to traditional methods [8,20,21]. A prospective cohort study of 385 students reported that students who undertook simulation training were more compliant with guidelines for paediatric resuscitation and ventilation skills were more effective [19]. Clinical skills acquired through simulation education transfer into better resident performance and improved patient care [4,19]. Thus, paediatric simulation training can be used as a powerful tool to improve patient outcomes. Promotion of communication and teamwork Current data indicates that preventable human factor errors, such as those brought about by communication problems within a team during an emergency, still occur in medical diagnosis and treatment [2]. Paediatric simulation teaching could potentially reduce these types of errors by allowing students the opportunity to practice working in inter-professional teams [2,22]. Student satisfaction Paediatric simulation teaching is superior to traditional teaching methods with regards to student satisfaction and motivation [23-25]. Instructor enthusiasm and knowledge in paediatric simulation teaching is also rated highly by medical students [23]. An American prospective mixed-methods study evaluating a five-day long simulation-based clinical skills curriculum for 200 students reported that the time taken out of real clinical skills experiences, which was used for simulationbased teaching was considered, by students, as a worthwhile trade-off [10]. Challenges of paediatric simulation teaching Despite its proven benefits, widespread implementation of simulation education in paediatric teaching of medical students has been impeded by several factors. A 2012 survey of 71 Pediatric Clerkship Directors in North America found the most commonly reported barriers to simulation-based education to be: available faculty time (66%, N=71), available time in clerkship (55%, n=71), funding considerations (54%, n=71) and lack of technical staff for simulation (32%, n=71) [6]. Resources Health systems worldwide are facing funding s 1 hortages, including funding for medical education [26]. Simulation is resource intensive, involving costs of equipment, physical space, standardised patients and simulation education staff [3]. A simulation-based curriculum for medical students trialed by Dudas et al. [10] in the United States in 2014 cost $3600 per five-day session. This included the cost of space, staff support and disposable supplies. In a 2012 French study, comparing simulation with a traditional lecture, the cost of the simulation course was 24-times more expensive, but there is suggestion that the high cost of simulation may be offset by a reduction in adverse safety events and prevention of deaths [3,19].


Volume 9, Issue 1 | 2019 Simulation teaching is time-consuming [8]. Competing and increasing demands of patient care, administration, research and professional development mean clinical staff, who often play the role of simulation facilitators, are often left with little time to support such teaching activities [8]. A potential solution to this problem is having a sustainable training program for simulation facilitators. Time constraints and competing priorities within the medical student paediatric curriculum itself have proved further barriers to the use of simulation education. Shortages of non-clinical simulation technicians further limit the utilisation of simulation in paediatric teaching of medical students and erode the quality of the educational experience delivered [27]. Poor student attitudes The interactive nature of simulation education necessitates a willingness of students to participate in the process. Students with reluctance to participate were reported in two of the papers reviewed [7,21]. This is in contrast with the majority of studies where students valued and were satisfied with the simulation experience [11,18,19,23,24,28,29]. Where students were reluctant to participate, group dynamics were listed as a limiting factor in student engagement. Thus, attention by simulation facilitators to student interactions and areas for improvement in these relationships may have a favorable effect on student attitudes. Retention of skills and knowledge Another important consideration in simulation education is a decline in skills or knowledge learned over time. More than half of the knowledge acquired after a three-hour simulation based neonatal resuscitation workshop in Malaysia was lost after one year [17]. A similar decline in knowledge was observed following a short course in simulation-based life-saving clinical skills delivered to third-year medical students in the United States [30]. Neither of these two studies compared the loss of knowledge following simulation teaching with traditional teaching methods. Repeat simulation sessions soon after initial exposure are therefore necessary to maintain students’ competence in new skills [17]. It should be noted that a decline in skills or knowledge learned is also a concern for education provided through more traditional teaching methods. Recommendations for the use of paediatric simulation education in the future

Alternatives to standardised patients The use of standardised patients is also resource intensive and includes recruitment, training, and paid employment [26]. Several studies have proposed and tested alternatives to standardised patients. An Austrian pilot program using trained medical students to deliver paediatric simulation training to their peers concluded that this was a feasible and low-cost option [28]. Another study comparing student satisfaction and learning efficacy in simulation training with standardised patients versus peer role play found superior results with peer role play, a lowcost tool which is relatively easy to put into practice [26]. Another alternative to standardised patients are child and adolescent actors, shown in one study to be effective in training medical students in complex interviewing skills, such as in the discussion of challenging mental health issues [31]. Since 2003, the University of Melbourne has used high-school students to provide simulation experiences to medical students and enhance teaching of adolescent medicine through its popular ‘Learning Partnerships’ program [32]. Judicious use of simulation education Given the potential cost of simulation education, it must be used judiciously and efficiently alongside other teaching methods. As simulation teaching has been shown to be effective in developing skills and behaviours, it should be used when these are the focus of teaching, while traditional methods should be prioritised when knowledge is the focus [23]. While the opportunities afforded by simulation in paediatrics are endless, simulation fits particularly well with the teaching of paediatric emergencies. This is because critical events are uncommon and correct management leads to optimal outcomes [23]. “Just six conditions make up 83% of acute paediatric attendances: difficulty breathing, febrile illness, diarrhoea, abdominal pain, rash and seizure” [20]. It is therefore feasible to consider, for example, that a sixstation simulation training package could be developed and included in the paediatric curriculum for medical students. Optimising student preparation Effective student preparation for simulation sessions, such as mandatory pre-reading, reduces simulation education staff workload and makes better use of time available for teaching [33]. Use of registrars as simulation facilitators

Given its demonstrated educational value, the incorporation of simulation teaching into medical student paediatric curricula should be a high priority for medical educators [4]. Use of low-fidelity manikins, alternatives to standardised patients and a focus on using simulation education judiciously may help to overcome challenges in the implementation of simulation. Shortages of simulation education staff may be overcome by optimising student preparation, using paediatric registrars as simulation tutors and delivering simulation teaching remotely.

A 2012 study at the Indiana University School of Medicine found medical residents (a position roughly equivalent to an Australian registrar) to be as effective as experienced faculty in facilitating simulation debriefings [34]. Using registrars to oversee simulation experiences may ease pressure on more senior clinical staff, thereby allowing additional simulation sessions to be incorporated into medical student paediatric curricula [34]. However, the availability of registrars to assist in simulation facilitation will be influenced by time constraints and competing priorities as previously discussed.

Use of low-fidelity manikins

Utilisation of remote facilitation

High-fidelity simulation scenarios require significant resources including expensive high fidelity manikins, supporting software and instructors trained in the use of that particular software. Cost-effective delivery of simulation may be achieved by using low-fidelity manikins and alternatives to standardised patients. A Canadian study by Curran et al. [11] comparing low-fidelity and high-fidelity manikin simulators in the teaching of neonatal resuscitation concluded that there was no significant difference between the two groups in resuscitation program performance and teamwork competencies. Thus, low-fidelity manikins may present a cost-effective alternative to high-fidelity manikins in some situations.

Most simulation facilities are based in major population centres. Although not all rural centres lack access to simulation facilities and educators, some do. There is, therefore, a risk that incorporating simulation education into a paediatric curriculum may disadvantage students studying remotely. Remote facilitation uses a system that enables bidirectional live video communication between students at a remote site and an educator at a simulation centre [27]. Using this system, simulation educators can observe students’ performances and communicate with on-site staff and students [27]. A Japanese study in 2016 compared the effectiveness of remote versus on-site facilitation and found that improvement in teamwork performance was not significantly different between the two groups [27]. Remote simulation

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AM S J is feasible to conduct technically and financially and could be used to overcome geographical limitations in the delivery of paediatric teaching to medical students, such as for students undertaking rural rotations [27]. Areas for further research We recommend simulation education to be promoted as a modern and powerful tool to teach paediatric medicine to medical students. Research is needed into the impact of simulation training on real-life clinical performance and confidence over time [20]. Further research is also required to clarify when and how to use simulation most effectively and efficiently [35]. Conclusion This review of the current literature on paediatric simulation teaching is highly relevant to Australian medical students. The literature highlights a deficiency in volume and variety of clinical experience, as well as a lack of opportunities to debrief in traditional paediatric teaching, resulting in low student confidence in management of paediatric patients. Thus, there is a need for enhanced paediatric teaching in the form of simulation education. Paediatric simulation teaching is beneficial for medical students through promotion of clinical understanding and knowledge, identification of knowledge gaps and effective skill acquisition, improvement and maintenance. It also facilitates the development of teamwork, communication skills and repetitive practice in a safe environment. Furthermore, there is high student satisfaction regarding the use of this evolving method of teaching in medical education.

References [1] Sharma J, Myers D, Dinakar C. Simulation in pediatrics. Mo Med. 2013;110(2):147-9. [2] Gordon M, Darbyshire D, Baker P. Non-technical skills training to enhance patient safety: a systematic review. Med Educ. 2012;46:1042-54. doi:10.1111/j.1365-2923.2012.04343.x [3] Clerihew L, Rowney D, Ker J. Simulation in paediatric training. Arch Dis Child Edu Pract Ed. 2016;101(1):8-14. doi:10.1136/archdischild-2015-309143 [4] McGaghie WC, Issenberg SB, Cohen ER, Barsuk JH, Wayne DB. Does simulationbased medical education with deliberate practice yield better results than traditional clinical education? A meta-analytic comparative review of the evidence. Acad Med. 2011;86(6):706-11. doi:10.1097/ACM.0b013e318217e119 [5] Stocker M, Laine K, Ulmer F. Use of simulation-based medical training in Swiss pediatric hospitals: a national survey. BMC Med Educ. 2017;17(1):104. [6] Vukin E, Greenberg R, Auerbach M, Chang L, Scotten M, Tenney-Soeiro R, et al. Use of simulation-based education: a national survey of paediatric clerkship directors. Acad Pediatr. 2014;14(4):369-74. doi:10.1016/j.acap.2014.04.001 [7] Stewart M, Kennedy N, Cuene-Grandidier H. Undergraduate interprofessional education using high-fidelity paediatric simulation. Clin Teach. 2010;7(2):90-6. doi:10.1111/j.1743498X.2010.00351.x [8] Ortiz N, Pedrogo Y, Bonet N. Integration of high-fidelity simulator in third-year paediatrics clerkship. Clin Teach. 2011;8(2):105-8. doi:10.1111/j.1743-498X.2011.00438.x [9] Morrissey B, Jacob H, Harnik E, Mackay K, Moreiras J. Simulation in undergraduate paediatrics: a cluster-randomised trial. Clin Teach. 2016;13(5):337-42. doi:10.1111/ tct.12442 [10] Dudas RA, Colbert-Getz JM, Balighian E, Cooke D, Golden WC, Khan S, et al. Evaluation of a simulation-based pediatric clinical skills curriculum for medical students. Simul Healthc. 2014;9(1):21-32. doi:10.1097/SIH.0b013e3182a89154 [11] Curran V, Fleet L, White S, Bessell C, Deshpandey A, Drover A, et al. A randomised controlled study of manikin simulator fidelity on neonatal resuscitation program learning outcomes. Adv Health Sci Educ Theory Pract. 2015;20:205-18. doi:10.1007/s10459-0149522-8 [12] Fielder EK, Lemke DS, Doughty CB, Hsu DC, Middleman AB. Development and assessment of a pediatric emergency medicine simulation and skills rotation: meeting the demands of a large pediatric clerkship. Med Educ Online. 2015;20:29618. [13] Jolly R. Medical practitioners: education and training in Australia [Internet]. Canberra, ACT: Parliament of Australia; 2009 15 July [cited 2017 July 6]. Available from: https://www. aph.gov.au/About_Parliament/Parliamentary_Departments/Parliamentary_Library/pubs/ BN/~/link.aspx?_id=4FB58821DB2B49F58743E7802D1C4ED3&_z=z [14] Hayes A, Grimbley J, Williams JD. Is simulation an effective method for teaching paediatric emergencies to final year medical students? Arch Dis Child. 2017;102:A99. doi:10.1136/archdischild-2017-313087.246 [15] Whitt R, Toussaint G, Bruce Binder S, Borges NJ. Strengthening student communication through pediatric simulation patient encounters. J Educ Eval Health Prof. 2014;11:21.

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Nevertheless, the implementation of paediatric simulation into medical curricula has been impeded by time constraints, funding limitations and a lack of technical staff. These challenges can be overcome by the judicious use of paediatric simulation for targeted learning objectives, use of common and rare, but life-threatening scenarios, as well as teaching with low-fidelity manikins. Further avenues for overcoming challenges include utilisation of peers and high school students as standardised patients, provision of debriefing by registrars and remote teaching. There is scope for further research regarding the influence of paediatric simulation teaching on real-life clinical performance, including the long-term retention of skills and confidence following graduation from medical school. With optimisation of efficiency and effectiveness, as well as further research and refinement of delivery, paediatric simulation teaching has great potential to enhance paediatric education for medical students throughout Australia. Acknowledgements The authors thank Dr. Gillian Laven for supervising the writing of this review article and for assistance with technical editing. We also thank the Adelaide Health Simulation and Skills Centre for introducing us to simulation education. Correspondence PO Box 4194, Norwood South, South Australia 5067

[16] Coolen EHA, Draaisma JMT, Hogeveen M, Antonius TAJ, Lommen CML, Loeffen JL. Effectiveness of high fidelity video-assisted real-time simulation: a comparison of three training methods for acute pediatric emergencies. Int J Paediatr. 2012;2012:709569. [17] Lai NM, Ngim CF, Fullerton PD. Teaching medical students neonatal resuscitation: knowledge gained and retained from a brief simulation-based training workshop. Educ Health. 2012;25(2):105-10. doi:10.4103/1357-628.103457 [18] Curran VR, Aziz K, O’Young S, Bessell C. Evaluation of the effect of a computerised training simulator on the retention of neonatal resuscitation skills. Teach Learn Med. 2004;16(2):157-64. doi:10.1207/s15328015tlm1602_7 [19] Drummond D, Arnaud C, Thouvenin G, Guedj R, Grimprel E, Duguet A, et al. An innovative pedagogic course combining video and simulation to teach medical students about pediatric cardiopulmonary arrest: a prospective cohort study. Eur J Pediatr. 2016;175:767-74. doi:10.1007/s00431-016-2702-1 [20] Mathai SS, Joshi D, Choubey M. Bedside infant manikins for teaching newborn examinations to medical students. Indian Pediatr. 2017;54:208-10. doi:10.1007/s13312017-1032-3 [21] Zundel S, Blumenstock G, Herrmann-Werner A, Trueck M, Schmidt A, Wiechers S. Undescended testis? How to best teach the physical examination. J Pediatr Urol. 2016;12:406.e1-406.e6. doi:10.1016/j.jpurol.2016.07.003 [22] Michael M, Abboudi H, Ker J, Khan MS, Dasgupta P, Ahmed K. Performance of technology-driven simulators for medical students – a systematic review. J Surg Res. 2014;192:531-43. doi:10.1016/j.jss.2014.06.043 [23] Bittencourt Couto T, Farhat SCL, Geis GL, Olsen O, Schvartsman C. High-fidelity simulation versus case-based discussion for teaching medical students in Brazil about pediatric emergencies. Clinics (Sao Paulo). 2015;70(6):393-9. doi:10.6061/clinics/2015(06)02 [24] Halaas GW, Zink T, Brooks KD, Miller J. Clinical skills day preparing third year medical students for their rural rotation. Rural Remote Health. 2007;7(4):788. [25] Cavalerio AP, Guimaraes H, Calherios FL. Training neonatal skills with simulators. Acta Paediatr. 2009;98(4):636-9. doi:10.1111/j.1651-2227.2008.01176.x [26] Bosse HM, Nickel M, Huwendiek S, Schultz JH, Nikendei C. Cost-effectiveness of peer role play and standardised patients in undergraduate communication training. BMC Med Educ. 2015;15:183. [27] Ohta K, Kurosawa H, Shiima Y, Ikeyama T, Scott J, Hayes S, et al. The effectiveness of remote facilitation in simulation-based pediatric resuscitation training for medical students. Pediatr Emerg Care. 2017;33(8):564-9. [28] Wagner M, Mileder LP, Goeral K, Klebermass-Schrehof K, Cardona FS, Berger A, et al. Student peer teaching in paediatric simulation training is a feasible low-cost alternative for education. Acta Paediatr. 2017;106:995-1000. doi:10.1111/apa.13792 [29] O’Keefe M, Sawyer M, Roberton D. Medical students taking the role of the mother in paediatric interview evaluation. Med Educ. 2004;38:294-301. doi:10.1046/j.13652923.2004.01768.x


Volume 9, Issue 1 | 2019 [30] Ander DS, Heilpern K, Goertz F, Click L, Kahn S. Effectiveness of a simulation-based medical student course on managing life-threatening medical conditions. Simul Healthc. 2009;4(4):207-11. doi:10.1097/SIH.0b013e3181a9dd84. [31] Brown R, Doonan S, Shellenberger S. Using children as simulated patients in communication training for residents and medical students: a pilot program. Acad Med. 2005;80(12):1114-20 [32] Cahill H, Coffey J, Sanci L. ‘I wouldn’t get that feedback from anywhere else’: learning partnerships and the use of high school students as simulated patients to enhance medical students. BMC Med Educ. 2015;15:35. [33] Lehmann R, Bosse HM, Huwendiek S. Blended learning using virtual patients and skills laboratory training. Med Educ. 2010;44:521-2. doi:10.1111/j.1365-2923.2010.03653.x [34] Cooper DD, Wilson AB, Huffman GN, Humbert AJ. Medical students’ perception of residents as teachers: comparing effectiveness of residents and faculty during simulation debriefings. J Grad Med Educ. 2012;486-9. doi:10.4300/JGME-D-11-00269.1 [35] Cook DA, Hatala R, Brydges R, Zendejas B, Szostek JH, Wang AT, et al. Technologyenhanced simulation for health professions education: a systematic review and metaanalysis. JAMA. 2011;306(9):978-88. doi:10.1001/jama.2011.1234

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Review Article Molecular Mechanism of Depression: A narrative review of the leading neurobiological theories of Depression David Vu MBBS BBNSc (Hons) University of Notre Dame Australia

Abstract Affective disorders, notably major depression and anxiety, are a significant cause of mortality and morbidity in society today, with the prevalence of depression estimated to be 10-16% in the general population and it is important to have effective treatments available for potentially life-threatening affective disorders. Yet, our understanding of the pathophysiology of depression and anxiety disorders has traditionally been limited due to the difficulty in investigating the brain in vivo. Thus, the molecular bases of these medication targets remain unclear. Recent advances in neuroscience have allowed us to gain a better understanding of the pharmacological basis of medical treatments for affective disorders. This new knowledge may pave the way for improved management of depression and anxiety. This review summarises some of the leading theories surrounding the neurobiology of depression and link them with both current and potential pharmacological treatments for depression Introduction Mood disorders, including chronic anxiety states and major depressive disorder (MDD) are colloquially referred to as depression. MDD is primarily defined by such features as significantly low mood throughout most of the day and/or the loss of interest or pleasure in previously enjoyable activities, persisting for a period of at least two weeks [1]. It is a psychiatric condition with a serious risk of suicide. Worldwide, depression is becoming a significant burden with respect to global health. The World Mental Health Survey Initiative conducted by the World Health Organization found lifetime prevalence of anxiety disorders to be between 9.9% and 16.7% and that of depression to be between 9.8% and 15.8% [2]. Locally, the results of the 2012 Australian Health Survey indicated that 2.1 million Australians, or 9.7% of the population, currently experience a mood disorder and that over 800,000 Australians, or 3.8% of the population, report having an anxiety disorder [3]. Together, anxiety and depression have the highest reported prevalence of any mental illness in the Australian population [3]. Since the efficacy of existing treatments for MDD have been called into question, there is a pressing global need for safe and effective treatments [4,5]. This article intends to review major theories about the biological basis of MDD in relation to the mechanism of action of therapeutic substances. Beyond biomedical models, there are also psychological models that may play a part in the development of MDD such as cognitive and psychodynamic theories, which will not be covered in this review. Monoamine Hypothesis The first generation of antidepressants include monoamine oxidase inhibitors (MAO-I) and tricyclic antidepressants (TCA). MAO-Is block the breakdown of neurotransmitters such as dopamine (DA), noradrenaline (NA), serotonin (5HT), while TCAs block the reuptake

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of these substances back into the cells. These mechanistic insights in the 1960s led to the proposition of the monoamine hypothesis of depression, which posited that a functional deficiency in at least one of the three biogenic monoamine neurotransmitters may be implicated in depression [6]. Clusters of neurons producing these neurotransmitters have been localised in various regions of the midbrain, hypothalamus and pons, with projections to the thalamus and higher cortical areas [7]. While 5HT was the first substance implicated as a ‘depression’ neurotransmitter, the other monoamines may be involved in modulating the symptomatology of depression, perhaps giving rise to different biological ‘subtypes’ of depression [7–9]. Quite likely, these key neurotransmitters work in an integrated fashion, despite having distinct biochemical and neuroanatomical pathways. For example, in experimental animals studies, the combination of a NA reuptake inhibitor with a 5HT and NA receptor antagonist enhanced release of DA within the prefrontal cortex, whereas the individual drugs had a lesser effect [10]. This suggests a considerable degree of interaction between NA, DA and 5HT. Clinical Applications The monoamine hypothesis of depression remains one of most enduring explanations for the development of depression. Indeed, it is the explanation provided to patients beginning antidepressant agents such as selective serotonin reuptake inhibitors (SSRI), although the uncritical manner, in which this is described to the general public has been criticised [11]. Nonetheless, most anti-depressive medications, currently in the market, implicitly lend credence to the monoamine hypothesis, in that their net effect is to increase intrasynaptic concentrations of DA, NA or 5HT with the assumption that at least one of these substrates is deficient. Evidence of the endurance of the monoamine hypothesis can also be inferred from more recent studies which overall intend to extend its validity 1 and will be evaluated in this article. While several alternative models are described below, the putative role of neurotrophins in MDD is in particular linked directly to the monoamine hypothesis, since these substances must act upon monoamine neurotransmitters to exert their beneficial effects [12].


Volume 9, Issue 1 | 2019 Critical Analysis of the Theory

Brain-Derived Neurotrophic Factor

As noted above, the efficacy of mainstream antidepressants has been repeatedly criticised during the past two decades. Some authors have argued that the antidepressant effects of SSRIs (i.e. Prozac), can be attributed solely to placebo effects [13–15]. However, other research has shown the opposite, that SSRIs indeed impart some clinical benefit [16]. The conflict revolves around the interpretation of effect sizes using arbitrary interpretations of effect size [15–18]. Effect size interpretations need to be considered in a particular clinical context [18]. Regarding SSRIs and other antidepressants, effect sizes must be interpreted in the context of other available psychiatric treatments. Psychotherapeutic approaches to the treatment of depression are an example of a non-pharmacological alternative; however, the effect size for such approaches may be considerably smaller than medication-based approaches, with Cohen’s d of just 0.22 [19]. Like psychopharmacological research, psychotherapeutic research is subject to significant publication bias, resulting in distortion of the reported data [19,20]. In addition, the effect sizes of psychoactive medication are comparable to other pharmacological treatments for a number different medical conditions [21].

Current neurobiological explanations of depression consider the intracellular response of neurons to monoamines, in an extension of the existing monoamine hypothesis of depression. When neurotransmitters such as NA, DA, or 5HT bind to their receptors, they activate a variety of second messengers within the postsynaptic neuron. An important target protein in this process is cAMP response element-binding protein (CREB), which begins the gene transcription process and regulates the production of mRNA. One of the genes that is regulated through the CREB pathway encodes a brain-derived neurotrophic factor (BDNF) – a protein responsible for the development of new neurons as well as the growth, differentiation and interconnections formed between existing neurons [12] Chronic stress reduces the expression of BDNF in the hippocampus [12,22,24]. This reduced expression may be mediated in part through epigenetic means, providing a potential explanation of how environmental factors can induce depressive symptoms that persist past the period of actual stress [24]. Serum taken from patients with depression show lower BDNF levels compared with non-depressed subjects and the chronicity of the depression was linked with an increase in BDNF levels [25]. In both human and animal studies, antidepressant treatment with SSRIs and serotonin/noradrenaline reuptake inhibitors appears to increase BDNF levels and reduce depressive symptoms [22,26,27]. This exciting development means that BDNF, as well as its target receptor TrkB, are targets for potential new treatments for depression, but, no clinical trials have been performed on new medications of this class at the time of writing [28].

Taken together, these studies suggest that whilst medication is not a definitive treatment for MDD, it is effective in alleviating symptoms across a broad section of the clinically depressed population. The effect size of 0.32 in studies comparing the effectiveness of antidepressants to psychotherapy provides support for antidepressants being the best current treatment for depression [16]. The effect sizes correspondingly suggest the monoamine hypothesis does not account entirely for the phenomenon of MDD. The known 2 to 3 weeks delay from the initial administration of current antidepressant medications to observed efficacy also supports this proposition, in that some additional factors must come into play [22]. These may include downstream gene expression changes caused by chronic treatment with antidepressants. Thus, targeting monoamines may not directly target the core mechanisms underlying MDD, or indeed anxiety disorders. It is now speculated that SSRIs and other contemporary antidepressants must be acting upon additional pathways to bring about the observed treatment efficacy [22]. In clinical practice, there are other issues related to the efficacy of antidepressants. They must often be taken over long periods of time, possibly for years, to protect patients from relapse. In addition, the major side effects associated with antidepressants, such as weight gain, insomnia and sexual dysfunction, can be disruptive to daily living. This contributes to poor compliance rates in patients, which in turn increases the likelihood of relapse [22]. The monoamine hypothesis of depression has resulted in a search for evidence of the presumed monoamine substrate deficiency in patients diagnosed with MDD. This research has been facilitated in recent years by molecular imaging with positron emission tomography (PET) and other methods employing tracers for the 5HT transporters. A meta-analysis of 20 such publications demonstrated a reduction in 5HT transporter levels in untreated MDD patients with an effect size of approximately 0.5 [23]. However, the meta-analysis showed that there was only a 10% difference in the number of 5HT transporters between patients with depression and normal controls. This suggests that 1 serotonin on its own may not fully account for this disorder. These substantive issues have led researchers to explore other potential avenues to explain the neurobiology of depression. To date, newer theories of depression have not supplanted the monoamine hypothesis, but rather complement the monoamine hypothesis in exploring the fundamental causes of depression.

Clinical Applications Electroconvulsive therapy (ECT) is the application of electrical current to patients with the aim of inducing an epileptic event. Controlled seizures can bring rapid remission of depressive symptoms [29]. First used in the late 1930s, ECT’s mechanism of action has long been a mystery, but recent research suggests that an epileptic event increases BDNF levels within the hippocampus [30]. This is supported by animal studies showing that increases in BDNF levels and reduction of depressive-type symptoms occur following electrical stimulus of pre-limbic areas of the brain [26]. Indeed, BDNF serum levels at pretreatment baseline can predict whether or not a patient will respond to ECT [31]. Emerging treatments for depression, such as transcranial magnetic stimulation (TMS) and deep brain stimulation (DBS) may also operate through increasing BDNF levels [32,33]. Neuropeptides Investigation into the potential involvement of hypothalamic neuropeptides in a monoamine hypothesis of depression represents a more recent approach to investigating MDD. The potential therapeutic use of oxytocin analogues and vasopressin antagonists has received increasing attention in the past few years. The theoretical justification for this new focus involves the interactions between oxytocin and 5HT systems, as well as vasopressin and the classical hypothalamicpituitary-adrenal (HPA) axis, long implicated in depression, anxiety, and stress-related disorders. Oxytocin Oxytocin is a neurohormone produced primarily in the paraventricular (PVN) and supraoptic nuclei (SON) of the hypothalamus and is then secreted from the posterior pituitary gland [34]. Its traditional physiological role involves the promotion of uterine contractions during parturition as well as triggering lactation soon after birth to allow the release of breast milk [35,36]. Recently, oxytocin has been found to be involved in signalling other behavioural and physiological processes, including maternal bonding, social behaviour, self-perception, sexual behaviour and pair bonding [37–39].

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AM S J More recent studies investigate oxytocinâ&#x20AC;&#x2122;s potential involvement in mood disorders, a line of research that has been substantiated by the growing evidence of the links between oxytocinergic and 5HT systems [40]. Anatomical evidence suggests that serotonergic projections from the DRN and MRN have substantial connections with the anterior magnocellular region of the PVN and anterodorsal parts of the SON, where there are large numbers of oxytocinergic cells [41,42]. In addition, some effects of the SSRIs are known to be mediated in part through oxytocinergic neurons and the hypothalamus has a very dense serotonin innervation [43]. Further support for the role of oxytocin in depression arises from the observation that plasma oxytocin levels appear to be affected by early childhood stress, a risk factor for depression in later life [44]. A reduction of plasma oxytocin in people with low-high levels of depressive symptoms, has been seen in humans [45,46]. Caution must be taken in interpreting these studies, as plasma oxytocin is unlikely to be representative of central oxytocin release; oxytocin does not readily cross the blood-brain barrier [47]. Nonetheless, these findings compliment earlier studies, which have shown that oxytocin inhibits the HPA axis activity in animal models of stress [38]. Indeed, the first investigations of the antidepressant effects of oxytocin were carried out in Sprague Dawley rats [48]. In this study, administration of the oxytocin analogue carbetocin reduced immobility of the rats in the Forced Swim test. Immobility, a sign of behavioural despair, is often used as a proxy to measure depressive-type behaviour in animals [49]. This result suggests that oxytocin has a role in alleviating depressivetype disorders in humans. A similar finding was found using the elevated plus maze, which is a test for anxiety-type behaviours in animals [50]. However, generalisation of those studies is limited since they did not use a validated model of acquired depression. Many of the proposed mechanisms for the effects described above involve interactions between oxytocin and other neuronal systems. One recent explanation proposes that the connections between 5HT neurons of the raphe nuclei to the PVN of the hypothalamus via the medial forebrain bundle can trigger oxytocin release in the hypothalamus. This may in turn reduce release of corticotrophin releasing factor (CRF), a key hypothalamic hormone of the HPA axis, which is involved in both depression and anxiety aetiology [38,51]. Another model focuses on the role of second messengers triggered when oxytocin binds with its receptors, causing changes to expression of CREB and downstream effects on BDNF [34]. It is possible that the combination of CRF and second messengers together bring about the mood and behavioural changes associated with depression and anxiety, but further work is required to understand the precise molecular mechanisms involved as well as the interaction of these systems with the environmental and psychological stressors that can give rise to depression and anxiety. Overall, this line of evidence demonstrates the integral nature of oxytocin in relation to its involvement in both depression and anxiety. Oxytocin in many ways serves as a bridge, linking previously known functions of other monoamine 1 neurotransmitters in relation to existing neurobiological theories of depression and thus potentially extending our understanding of the mechanisms underlying depression and anxiety. Certainly there is a need for further research to resolve the many limitations that still prevent the conclusive demonstration of a link between oxytocin and depression. Critical Analysis of the Theory A meta-analysis has suggested that intranasal oxytocin may be effective in the management of depression [52]. This effect may also be additive with current antidepressant medications, but these studies have been criticised for their methodology, with critics suggesting that it is physiologically impossible for therapeutic levels of oxytocin to enter

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the brain via the intranasal route [53]. Further, many of the outcome measures used in these studies, such as serum oxytocin, have been shown to not correlate with levels of central oxytocin [47,54]. Given that oxytocin has physiological functions in uterine contractions as well as central actions, there has been significant research connecting post-partum depression (PPD) and oxytocin levels. Patients in thirdtrimester pregnancy that had lower expression of oxytocin receptor (OXTR) genes in cortical tissue, and lower plasma levels of oxytocin were more likely to develop PPD [55,56]. Interestingly, childhood abuse appears to have a potentiating effect on OXTR gene expression, which supports other studies that found epigenetic changes between maternal stress and OXTR expression [55,57]. Of note, many of these studies have utilised genome-wide associations with small sample sizes, which may be underpowered [17,58,59]. As implied by the low effect size in many antidepressant trials, many patients are unresponsive to conventional treatments, which is termed treatment-resistant depression. Patients with treatmentresistant depression in one study were shown to have high serum levels of oxytocin compared to non-depressed controls [60]. Patients with treatment responsive depression had lower plasma levels of oxytocin compared to the treatment resistant patients, suggesting that oxytocin may discriminate between these types of depression, but the small sample size again calls for caution in interpretation of these results. Of treatment-resistant group, four out of ten patients had serum oxytocin levels different from the rest of the group, whilst the other six patients had similar serum levels to both the treatmentresistant depression group and control group. This raises the possibility that the differences found was due to outliers in the data, rather than representing significant differences. Similar to the criticisms levelled at studies looking at intranasal oxytocin, it is questionable whether serum oxytocin levels correlate with levels of oxytocin in the CNS, particularly before treatment with oxytocin [47,54]. Since other human studies have suggested that low levels of oxytocin may be associated with depressive symptoms, this issue can only be resolved in sufficiently powered clinical studies [56]. Conclusions Decades after the emergence of the monoamine model of depression, defining the pathophysiology of mood disorders remain an elusive goal. Existing antidepressants are moderately effective at treating depression, but they have significant side effects limiting their use. In addition, some patients are non-responders to these medications. This has spurred further research into other mechanisms involved in the pathophysiology of mood disorders that extend beyond the classical monoamine-based theories, but these new theories do not supplant previous ideas, rather compliment them. To date, these recent developments have not yet been translated into new pharmacological treatments for mood disorders. Nonetheless, the inclusion of factors such as BDNF and neuropeptides in our understanding of the pathophysiology of depression allow a greater understanding of how existing treatments may work at a molecular level. Future research should aim to further elucidate these new theories and provide further stimulation for medication and/or procedural development. Acknowledgements I would like to acknowledge my Honours Supervisor, Jillian H Broadbear for her assistance in editing a previous version of this review, which was used as part of the requirements for my Honours degree. Correspondence D Vu: contact@davidvu.me


Volume 9, Issue 1 | 2019

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[32] Do-Monte FH, Rodriguez-Romaguera J, Rosas-Vidal LE, Quirk GJ. Deep brain stimulation of the ventral striatum increases BDNF in the fear extinction circuit. Front Behav Neurosci. 2013;7:102. [33] Niimi M, Hashimoto K, Kakuda W, Miyano S, Momosaki R, Ishima T, et al. Role of brain-derived neurotrophic factor in beneficial effects of repetitive transcranial magnetic stimulation for upper limb hemiparesis after stroke. PLoS One. 2016;11(3):e0152241. [34] Matsuzaki M, Matsushita H, Tomizawa K, Matsui H. Oxytocin: a therapeutic target for mental disorders. J Physiol Sci. 2012;62(6):441-4. [35] Sala NL, Luther EC, Arballo JC, Cordero Funes JC. Oxytocin reproducing reflex milk ejection in lactating women. J Appl Physiol. 1974;36(2):154-8. [36] Wilson JL, Parsons MT, Flouret G. Inhibition of oxytocin-induced uterine contractions by an oxytocin antagonist in the pregnant baboon. Am J Obstet Gynecol. 1991;165(2):45660. [37] Cardoso C, Ellenbogen MA, Linnen A-M. Acute intranasal oxytocin improves positive self-perceptions of personality. Psychopharmacology. 2012;220(4):741-9. [38] Neumann ID, Krömer SA, Toschi N, Ebner K. Brain oxytocin inhibits the (re)activity of the hypothalamo–pituitary–adrenal axis in male rats: involvement of hypothalamic and limbic brain regions. Regul Pept. 2000;96(1-2):31-38. [39] Viero C, Shibuya I, Kitamura N, Verkhratsky A, Fujihara H, Katoh A, et al. REVIEW: Oxytocin: Crossing the bridge between basic science and pharmacotherapy. CNS Neurosci Ther. 2010;16(5):e138. [40] Marazziti D, Baroni S, Giannaccini G, Betti L, Massimetti G, Carmassi C, et al. A link between oxytocin and serotonin in humans: Supporting evidence from peripheral markers. Eur Neuropsychopharmacol. 2012;22(8):578-83. [41] Larsen PJ, Hay-Schmidt A, Vrang N, Mikkelsen JD. Origin of projections from the midbrain raphe nuclei to the hypothalamic paraventricular nucleus in the rat: a combined retrograde and anterograde tracing study. Neuroscience. 1996;70(4):963-88. [42] Sawchenko PE, Swanson LW, Steinbusch HWM, Verhofstad AAJ. The distribution and cells of origin of serotonergic inputs to the paraventricular and supraoptic nuclei of the rat. Brain Res. 1983;277(2):355-60. [43] Neumann ID, Landgraf R. Balance of brain oxytocin and vasopressin: implications for anxiety, depression, and social behaviors. Trends Neurosci. 2012;35(11):649-59. [44] Heim C, Owens MJ, Plotsky PM, Nemeroff CB. The role of early adverse life events in the etiology of depression and posttraumatic stress disorder. Focus on corticotropinreleasing factor. Ann N Y Acad Sci. 1997;821:194-207. [45] Holt-Lunstad J, Birmingham W, Light KC. The influence of depressive symptomatology and perceived stress on plasma and salivary oxytocin before, during and after a support enhancement intervention. Psychoneuroendocrinology. 2011;36(8):1249-56. [46] Opacka-Juffry J, Mohiyeddini C. Experience of stress in childhood negatively correlates with plasma oxytocin concentration in adult men. Stress. 2012;15(1):1-10. [47] Leng G, Ludwig M. Intranasal oxytocin: myths and delusions. Biol Psychiatry. 2016;79(3):243-50. [48] Arletti R, Bertolini A. Influence of protease inhibitors on the antidepressant activity of oxytocin. Neuropeptides. 1987;10(3):241-8. [49] Chaviaras S, Mak P, Ralph D, Krishnan L, Broadbear JH. Assessing the antidepressantlike effects of carbetocin, an oxytocin agonist, using a modification of the forced swimming test. Psychopharmacology. 2010;210(1):35-43. [50] Mak P, Broussard C, Vacy K, Broadbear JH. Modulation of anxiety behavior in the elevated plus maze using peptidic oxytocin and vasopressin receptor ligands in the rat. J Psychopharmacol. 2012;26(4):532-42. [51] Mairesse J, Gatta E, Reynaert ML, Marrocco J, Morley-Fletcher S, Soichot M, et al. Activation of presynaptic oxytocin receptors enhances glutamate release in the ventral hippocampus of prenatally restraint stressed rats. Psychoneuroendocrinology. 2015;62:3646. [52] Hofmann SG, Fang A, Brager DN. Effect of intranasal oxytocin administration on psychiatric symptoms: A meta-analysis of placebo-controlled studies. Psychiatry Res. 2015;228(3):708-14. [53] Scantamburlo G, Hansenne M, Geenen V, Legros JJ, Ansseau M. Additional intranasal oxytocin to escitalopram improves depressive symptoms in resistant depression: an open trial. Eur Psychiatry. 2015;30(1):65-8. [54] Valstad M, Alvares GA, Egknud M, Matziorinis AM, Andreassen OA, Westlye LT, et al. The correlation between central and peripheral oxytocin concentrations: a systematic review and meta-analysis. Neurosci Biobehav Rev. 2017;78:117-24. [55] Kimmel M, Clive M, Gispen F, Guintivano J, Brown T, Cox O, et al. Oxytocin receptor DNA methylation in postpartum depression. Psychoneuroendocrinology. 2017;69:150-60. [56] Massey SH, Backes KA, Schuette SA. Plasma oxytocin concentration and depressive symptoms: A review of current evidence and directions for future research. Depress Anxiety. 2016;33(4):316-22. [57] Unternaehrer E, Bolten M, Nast I, Staehli S, Meyer AH, Dempster E, et al. Maternal adversities during pregnancy and cord blood oxytocin receptor (OXTR) DNA methylation. Soc Cogn Affect Neurosci. 2016;11(9):1460-70. [58] Ioannidis JPA. Why most published research findings are false. PLoS Med. 2005;2(8):e124. [59] Mayo DG, Spanos A. Severe testing as a basic concept in a Neyman-Pearson philosophy of induction. Br J Philos Sci. 2006;57(2):323-57. [60] Sasaki T, Hashimoto K, Oda Y, Ishima T, Yakita M, Kurata T, et al. Increased serum levels of oxytocin in ‘Treatment Resistant Depression in Adolescents (TRDIA)’ Group. PLoS One. 2016;11(8):e0160767.

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Case Report A patient with right striatocapsular stroke complicated by relative adrenal insufficiency Dr Anita M Smith Doctor of Medicine University of Notre Dame, Fremantle Intern, Sir Charles Gairdner Hospital

Anita is an intern at Sir Charles Gairdner Hospital and recently graduated in 2017 with a Doctor of Medicine. She also holds a Bachelor’s degree in Pharmacy, and previously worked as a clinical pharmacist at The Alfred Hospital and The Royal Childrens’ Hospital in Melbourne.

Adj Clin Prof J A Millar Director, General Medicine and Consultant Physician and Clinical Pharmacologist, WACHS-Great Southern, 2012-2017

Prof. Millar’s adjunct clinical appointment is with the Department of Medical Education, Curtin University. He retired from clinical work at Albany Regional Hospital in 2017. Prof. Millar has an interest in stroke medicine and cardiovascular medicine, and was Clinical Lead in a Stroke Project to upgrade stroke services at Albany Hospital in 2012.

Abstract Introduction: Relative adrenal insufficiency can occur throughout the progression of critical illness and is generally transient. Case: This case report describes a 74 year-old male with right hemispheric stroke syndrome on a background of multiple cardiovascular risk factors. A CT scan showed no acute change. An MRI scan revealed an acute right striatocapsular infarction. No acute therapies (thrombolysis or endovascular clot retrieval) were performed, as the time of symptom onset was unknown (patient awoke with symptoms). One week later, hyponatraemia was noted with a concurrent decline in function. A repeat MRI showed no interval change or haemorrhagic transformation to account for the functional decline. Complications included relative adrenal insufficiency, diagnosed presumptively and managed with cortisone, and gait instability managed with rehabilitation and allied health input. Discussion: We review the literature concerning the association between acute ischaemic stroke and adrenal insufficiency and the clinical and biochemical overlap in our patient. This case report aims to increase awareness of relative adrenal insufficiency following a stroke and provide a discussion of possible mechanisms.

Introduction Abnormal changes in the hypothalamic pituitary adrenal (HPA) axis have been reported in patients during the initial post-stroke phase [1]. Adrenal insufficiency has been shown to affect between 10 – 77 % of medical patients who are critically ill [2-4]. The term “relative adrenal insufficiency” is used to define inadequate production of corticosteroids in periods of severe illness in the absence of structural abnormalities in the HPA axis [5]. Here, we report the case of relative adrenal insufficiency detected in a patient with an ischaemic stroke following an otherwise unexplained clinical deterioration. The Case A 74 year-old male retired agricultural worker presented to the emergency department of a small rural hospital (< 10 beds) with leftsided weakness and difficulty speaking, with symptoms first noted upon waking at 7am that morning. On examination, he was unable to raise his left arm, had weakness in the left leg compared to the right, dysarthria, dysphagia, left-sided facial droop, and left-sided tongue

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deviation. He had difficulty with upward gaze; however, visual fields were intact. No acute therapies (thrombolysis or endovascular clot retrieval) were performed, as time of symptom onset was unknown. He was transferred to a regional health campus, where a CT Brain showed no acute intracranial pathology. His National Institutes of Health Stroke Scale (NIHSS) score was 10. On admission, his blood pressure was 148/61 mmHg, blood glucose level was 6 mmol/L, serum creatinine 76 micromol/L, sodium 139 mmol/L, and potassium 3.6 mmol/L. An MRI of the brain conducted the following day showed restricted diffusion in the right striatocapsular region consistent with an acute ischaemic stroke (Figures 1-3), classified as a partial anterior circulation infarct (PACI) on the Oxfordshire Community Stroke Project Classification. Carotid Doppler showed all velocities and waveforms within normal limits and minimal intimal thickening in both common carotid arteries. An ECG showed sinus bradycardia. Past medical history included type II diabetes mellitus (diet controlled, previously treated with metformin), colorectal cancer (surgical resection with anastomosis 10 years previously), and chronic obstructive pulmonary disease (ex-smoker, 50 pack-year history). Family history was significant for a fatal myocardial infarction in his father, at age 56. Regular medications before admission included tiotropium 18 microgram inhaled daily, fluticasone/salmeterol 250/25 microgram twice daily, dutasteride 0.5 mg /tamsulosin 0.4 mg mane, paracetamol 1 gram three times daily as required and magnesium supplementation 500 mg twice daily. Physiotherapy and nursing staff reported a decline in function from one week post-stroke. The patient reported fatigue, insomnia, nausea, and restless legs. On examination, he was hypotensive, bradycardic, with an unstable gait, body drift and collapse to the left. Blood biochemistry revealed a sodium level of 127 mmol/L and a potassium level of 4.7 mmol/L. Clinically he was euvolaemic. Sodium chloride 600 mg tablets were commenced, as initially a fluid restriction was not deemed clinically appropriate due to a deficient baseline fluid intake. A repeat MRI brain showed a slight increase in the size of the infarct (Figures 4-6) but no haemorrhagic transformation (Figure 7) to account for the functional decline. Plasma osmolality was 261 mmol/kg and a spot urine osmolality was 722 mmol/kg. A 1.5 L fluid restriction was commenced ten days post stroke. Urinary sodium was not investigated. Early morning serum cortisol was reduced at 35 nmol/L with an adrenocorticotrophic hormone (ACTH) level of 1.4 ρmol/L. Serum sodium continued to decrease to 118 mmol/L despite sodium


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Figure 1: Axial fluid-attenuated inversion recovery (FLAIR) MRI image of the brain showing acute right striatocapsular infarction affecting the lateral aspects of the basal ganglia and extending slightly into the periventricular white matter. The FLAIR sequence on MRI adjusts to remove the signal from the cerebrospinal fluid (CSF). This allows for detection of changes close to the CSF (periventricular areas).

Figure 2: Diffusion weighted imaging (DWI) through a stereotypic sequence of apparent diffusion coefficient (ADC) reduction MRI image of the brain showing an acute right striatocapsular infarction affecting the lateral aspects of the basal ganglia and extending slightly into the periventricular white matter.

Figure 3: MRI image (T2) of the brain showing acute right striatocapsular infarction demonstrated in the coronal plane. Striatocapsular infarcts involve a proximal middle cerebral artery occlusion, affecting areas such as the anterior limb of the internal capsule, caudate nucleus, and putamen.

Figure 4: Six days post-stroke, axial fluid-attenuated inversion recovery (FLAIR) MRI image of the brain showing a slight increase in size of the known right striatocapsular infarct.

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Figure 5: Six days post-stroke, MRI image (T2) of the brain showing a slight increase in size of the known right striatocapsular infarct demonstrated in the coronal plane.

Figure 6: Six days post-stroke, diffusion weighted imaging (DWI) through a stereotypic sequence of apparent diffusion coefficient (ADC) MRI image of the brain showing a slight increase in size of the known right striatocapsular infarct.

replacement tablets. Oral cortisone acetate 25 mg BD was commenced as a treatment for hypocortisolism An ACTH stimulation test (250 microgram) showed a serum cortisol level of 660 nmol/L at 30 minutes, indicating an adequate response. However, interpretation of the test was complicated by the prior commencement of exogenous cortisone therapy. Fluid restriction was ceased. Further investigation found other pituitary hormones to be within normal limits (prolactin 81 mU/L, luteinizing hormone 6.4 U/L, thyroid-stimulating hormone 0.9 mU/L). Aldosterone serum/renin plasma ratio (supine) was 334 Ď mol/L:26 mU/L. After 25 days of rehabilitation (including physiotherapy, oc 1 cupational therapy and speech therapy), there was a significant improvement in left-sided power from Medical Research Council (MRC) grade of muscle strength 2/5 to 4+/5 with functional independence. The modified Rankin Scale (mRS) on discharge was 2+. Prior to discharge, there was ongoing difficulty with fine motor movements in his left hand, for which occupational therapy was to continue following discharge. Prior to discharge, serum sodium had returned to 137 mmol/L and potassium to 4 mmol/L. Following a good response to cortisone acetate, the patient was discharged on a 25 mg/day until review at two months at which sodium levels had normalised. Discussion

Figure 7: Six days post-stroke, susceptibility weighted imaging (SWI) showing no haemorrhagic transformation. SWI is useful for detecting small amounts of haemorrhage and blood products that may not be apparent on other MRI sequences.

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Relative adrenal insufficiency can occur throughout the progression of a severe illness and is generally transient [1]. A study of 58 acute ischaemic stroke patients found the prevalence of relative adrenal insufficiency in such patients is 65.5 % based on a low dose synacthen test (1 microgram), or 31 % based on a standard dose synacthen test (250 microgram) [1]. In our patient, it was difficult to interpret the ACTH stimulation test as exogenous cortisone had been commenced; however, secondary adrenal insufficiency was mechanistically possible


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from a CNS insult in a patient who was otherwise systemically well. Other anterior pituitary hormones were within normal range. For patients recently started on steroid replacement, steroid therapy should be withheld on the evening prior to, and morning of, the ACTH stimulation test. In certain clinical scenarios, such as critical illness, changes in cortisol-binding globulin levels can influence postdose total serum cortisol levels during the ACTH stimulation test. In such situations, other pathology tests (plasma free cortisol, salivary cortisol or free cortisol index) can be ordered to investigate underlying abnormalities in the HPA axis [6]. These tests were unfortunately not utilised in this case. The underlying mechanism behind relative adrenal insufficiency in stroke has previously been suggested to involve vasospasm resulting in a reduction in the blood supply to the pituitary gland and/or hypothalamus [1]. Another proposed mechanism includes increases in inflammatory cytokines, which inhibit the synthesis of cortisol from the adrenal gland and in turn facilitate resistance to corticosteroids at a tissue-specific level [5]. In regards to rehabilitation, one study investigating stroke patients with upper limb impairment found that 95 % of patients achieved their maximal functional recovery by nine weeks post-stroke, and 80 % by three weeks post-stroke [7]. Improvements in neurological deficits post-stroke in our case were comparable to this timeframe. Stroke medicine has rapidly advanced in the past decade. For large vessel occlusion causing acute ischaemic strokes, endovascular thrombectomy is considered best practice in selected patients [8]. Further research is ongoing into tissue plasminogen activator time limits, alternatives for thrombolytics and patient selection for endovascular thrombectomy [9]. In this particular case, thrombolysis was not applicable as this patient awoke with symptoms (wake-up stroke) and therefore time of symptom onset is taken from when the patient was last seen well (over six hours). The current time limit for intravenous thrombolysis is four and a half hours and six hours for endovascular clot retrieval; however, recent trials (DEFUSE-3 [10] and DAWN [11]) have shown that selected patients may benefit from thrombectomy up to 16 to 24 hours after symptom onset. For regional and outer metropolitan hospitals offering thrombolysis only, there could be a shift towards the “drip and ship” model with an initiation

References

1] Wahab NA, Razak NZ, Sukor N, Zaimudin S, Razali AM, Mustafa N, et al. Relative adrenal insufficiency amongst hospitalized mild to moderate acute ischaemic stroke patients. Arch Iran Med. 2015;18(2):89-93. [2] Redington AE, Meng QH, Springall DR, Evans TJ, Cremion C, Maclouf J, et al. Increased expression of inducible nitric oxide synthase and cyclo-oxygenase-2 in the airway epithelium of asthmatic subjects and regulation by corticosteroid treatment. Thorax. 2001;56:351-7. [3] Marik PE, Pastores SM, Annane D, Meduri GU, Sprung CL, Arit W, et al. Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: consensus statements from an international task force by the American College of Critical Care Medicine. Crit Care Med. 2008;36:1937-49. [4] Michalaki M, Margeli T, Tsekouras A, Gogos CH, Vagenakis AG, Kyriazopoulou V. Hypothalamic-pituitary-adrenal axis response to the severity of illness in non-critically ill patients: does relative corticosteroid insufficiency exist? Eur J Endocrinol. 2010;162(2):341- 7. [5] Knapp PE, Arum SE, Melby JC. Relative adrenal insufficiency in critical illness: a review of the evidence. Curr Opin Endocrinol Diabetes Obes. 2004;11(3):147-52. [6] Therapeutic Goods Administration. Synacthen® (tetracosactin) 250 micrograms/mL product information. [Internet]. 2015 [updated 2015 Jul; cited 2018 Feb 28]. Available from: https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP2015-PI- 02056-1&d=2018022816114622483

of thrombolysis and urgent transfer to comprehensive stroke centres [12]. This is already in place in some states, such as Victoria, which offer a statewide service for endovascular clot retrieval in acute ischaemic stroke [13]. Conclusion Our patient made a progressive recovery over 25 days, showing significant improvement in left-sided power with a mRS score of 2+ at discharge, improving to 4+ at one year follow-up. Cortisone therapy was ceased after two months, in keeping with the literature stating that if relative adrenal insufficiency occurs throughout the progression of an illness it is generally transient [1]. This case serves as a reminder to clinicians and medical students of the importance of monitoring for functional decline and electrolyte imbalances in patients undergoing rehabilitation post-stroke. The learning points from this case are: to be vigilant in monitoring expected and unexpected complications post-stroke and to encourage participation in rehabilitation, especially in patients who do not receive acute therapy. This increases the likeliness of a return to near baseline function. Consent Declaration Informed consent was obtained from the patient for publication of this case report and accompanying figures. Acknowledgments The author would like to acknowledge Adj. Clin. Prof. J A Millar from Albany Regional Hospital for his mentorship, and his dedication and enthusiasm for teaching medical students. Also, a special mention to Dr. Paul Salmon (Radiologist, Great Southern Radiology) for his assistance with the MRI images. Conflicts of interest None declared. Correspondence A Smith: anita.smith2@health.wa.gov.au

[7] Nakayama H, Jorgensen HS, Raaschou HO, Olsen TS. Recovery of upper extremity function in stroke patients: the Copenhagen Stroke Study. Arch Phys Med Rehabil.1994;75:394. [8] Motyer R, Asadi H, Thornton J, Nicholson P, Kok, H. Current evidence for endovascular therapy in stroke and remaining uncertainties. J Intern Med. 2018;283(1):2-15. [9] Asadi H, Williams D, Thornton J. Changing management of acute ischaemic stroke: the new treatments and emerging role of endovascular therapy. Curr Treat Options Neurol. 2016; 18:20. [10] Albers G, Marks M, Kemp S, Chistensen S, Tsai S, Ortega-Gutierrez R. et al. Thrombectomy for stroke at 6 to 16 hours with selection by perfusion imaging. N Engl J Med. 2018;378(8):708-18. [11] Nogueria R, Jadhav A, Haussen D, Bonafe A. Thrombectomy 6 to 24 hours after stroke with a mismatch between deficit and infarct. N Engl J Med. 2018;378(1):11-21. [12] Linley R, Levi C. The spectacular recent trials of urgent neurointervention for acute stroke: fuel for a revolution. Med J Aust. 2015 Jul 20;203:58-60. [13] Department of Health and Human Services. Victoria State Government. Endovascular clot retrieval for acute stroke – statewise service protocol [Internet]. 2016 [published 2016 Feb 10, cited 2018 Jun 3]. Available from: https://www2.health.vic.gov.au/about/ publications/policiesandguidelines/endovascular-clot42retrieval-for-acute-stroke-statewideservice-protocol.

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Book Review Book Review - Dermatology truly made easy Dr. Nicholas van Rooij BBiomedSc, MD The Prince Charles Hospital

Nicholas is an intern with a keen interest in how dermatological conditions represent the manifestation of systemic disease.

Despite its unique complexities and significant prevalence of its subject, dermatology is often regarded as one of the great forgotten specialties within medical education. Many would argue that this is counterintuitive, considering the proud position of the integumentary system as the largest human organ. The skin often gives the first impression of a patient and provides a multitude of information regarding their overall health to the dermatologically-trained eye. For the untrained eye; however, most students would be the first to admit that they glaze over at the mention of a macule, lichenification or the Koebner phenomenon. The perplexing world of all things skin can be a little less daunting with Dermatology Made Easy. This accomplished resource combines Dr. Amanda Oakley’s experience with over three decades in clinical practice, authorship of the world’s most successful online dermatology resource, DermNet New Zealand, and current work as an adjunct A/Prof. of Dermatology at the University of Auckland. Oakley has ingeniously compiled sufficient detail to fulfil the appetite of both novices and professionals alike in this user-friendly guide. The first chapter appropriately introduces readers to a systematic diagnostic approach and is most useful for patients presenting with specific skin complaints. It provides a differential diagnostic tool categorised by symptoms, morphology and body site. This is a great way to learn some of the more common causes within each category (for example, morphologic conditions such as purpura or scaly rashes) and may assist in the retention of some of the more challenging descriptive terminology. This section also highlights particular pattern of a disease and how predilections for certain body sites can assist in diagnosis. While rare within comparable references, this introductory section is an extremely useful addition to the text, particularly for students. Subsequent chapters cover common day-to-day skin complaints, including infections, inflammatory rashes, non-inflammatory conditions and skin lesions. These are covered under subheadings in sufficient detail for the understanding of the salient points of each condition, including its aetiology, complications, management and prognosis. Each condition is summarised on a couple of pages and complemented with multiple high-quality clinical images. The author should also be commended for providing links to the free DermNet NZ resource for further details on topics mentioned, but not fully covered in the text. For example, if you are chasing even more extensive detail about a certain condition, such as on which arm of the chromosome genetic aberrations are located.

References [1] Oakley, A. Dermatology made easy. United Kingdom: Scion Publishing Ltd; 2017.

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In the concluding chapter, the author covers relevant investigations and treatments available for the plethora of dermatological conditions in the earlier chapters. This is a useful addition to provide a stepwise approach to the many management options available in the field. However, such an addition does seem slightly redundant because most topics already cover basic relevant pharmacological and procedural approaches to management. Although Oakley does cover important dermatological emergencies and focuses the text at an appropriate level for the target audience, some students may be disappointed with the lack of rare and intriguing integumentary conditions. Medical students will benefit from this text as it offers high-yield concepts, with prominent examples being skin cancer, infective dermatosis and dermatitis, all of which are frequently examined in both written and clinical settings. Furthermore, the text provides a useful template for conducting a dermatological history and describes the important visual signifiers to look for during an examination. These steps help develop important skills, such as providing an approach for identifying the sometimes challenging aetiology of a drug eruption and its subsequent management. Benchmarked against similar resources, such as Fitzpatrick’s Color Atlas and Synopsis of Clinical Dermatology, Oakley’s text is better value, wellstructured, concise and provides high-quality imagery and portability. Despite the availability of free online resources such as DermNet NZ, this text provides a comprehensive overview of high-yield topics for medical students seeking a low-cost, high-quality resource that is readily available. This book is the perfect companion for any student presented with a head-scratching rash in the clinical environment. With most texts originating from overseas markets, this ‘pocket sized’ dermatology dynamite is a unique and valuable high-quality resource with local regional relevance. If you were considering purchasing your own copy of a dermatology textbook, look no further than Oakley as you will not be disappointed. This resource will be a valuable reference throughout your studies and years as a junior doctor, enabling the retention of challenging descriptive terminology and training the keen dermatological eyes of the future.

Correspondence N van Rooij: nicholas.vanrooij@griffithuni.edu.au


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Literature Review

Efficacy and Safety of Allergen Immunotherapy to Treat House Dust Mite Allergic Asthma in Children Susanna Sodini Bachelor of Medicine, Bachelor of Surgery University of Queensland

Susanna has recently finished her medical studies at the University of Queensland, after developing an interest in immunotherapy during her undergraduate studies.

Associate Professor Jane Peake Queensland Paediatric Immunologist and Allergist Lady Cilento Children’s Hospital, South Brisbane, Queensland

Abstract Allergic asthma is a significant disease of childhood, of which, house dust mite is the most common trigger. There have been many investigations into the role of allergen immunotherapy in preventing the development of allergic asthma, and potentially its treatment following formal diagnosis, as evidenced by studies demonstrating significant improvements in medication use, asthma symptoms, and respiratory function. However, there is a paucity of research into specific populations – significantly, paediatric populations. This article reviews the recent literature regarding the efficacy and safety of allergen immunotherapy in the treatment of house dust mite-allergic asthma, with a focus on paediatric populations. This review suggests that immunotherapy effectively improves asthma symptoms and severity in paediatric populations. While adverse reactions may occur, serious or life-threatening reactions are rare. More research is required to investigate immunotherapy in populations who are polysensitised or who have severe or uncontrolled asthma – preliminary evidence suggests immunotherapy may have a role in the treatment of these patients.

Introduction Asthma is a condition affecting people of all ages that is increasing in prevalence. Approximately 50% of asthmatics have a significant allergic basis to their disease development, with up to 95% exhibiting a positive skin prick test to one or more allergens [1]. Allergic asthma (AA) is most commonly identified in people allergic to house dust mite (HDM), specifically Dermatophagoides farinae and Dermatophagoides pteronyssinus [2]. Asthmatics sensitised to HDM have lower FEV1 and FEV1/FVC ratios on lung function testing than non-sensitised asthmatics [3]. AA often develops as part of the atopic march in children, along with allergic rhinitis, allergic conjunctivitis and atopic dermatitis [1-3]. Current first-line management of asthma involves medications that reduce smooth muscle constriction and airway inflammation, alongside allergen avoidance [1]. However, unlike allergen immunotherapy (AIT), these treatments do not alter the natural history of the disease [4]. The appeal of AIT lies in its potential to induce tolerance through repeated exposure to increasing doses of an allergen, with a “buildup phase” and a “maintenance phase [1]”. AIT produces significant immunological changes, including increased specific IgG and, to a

lesser extent, decreased specific IgE [5-9]. Originally, allergens were administered via subcutaneous immunotherapy (SCIT) injections, with subsequent development of sublingual immunotherapy (SLIT) liquids and tablets. SCIT is delivered in a controlled clinical setting, while SLIT can be delivered in the patient’s home without clinical supervision and offers appealing ease of administration in paediatric populations. Current evidence suggests that SLIT is safer than SCIT, although they appear to be equally effective [4,10,11], but most literature examines adult populations. This review aims to evaluate the current efficacy and safety evidence of SCIT and SLIT in the treatment of paediatric HDM-AA. Efficacy of house dust mite immunotherapy to treat asthma The efficacy of HDM immunotherapy, both SCIT and SLIT, in treating AA has been validated. Three years of immunotherapy is effective in improving asthma symptoms, asthma-free rates, validated questionnaire scores, and medication use [6,11-15], with the literature demonstrating that the efficacy of SCIT and SLIT are comparable. SCIT has additionally been shown to significantly decrease the likelihood of developing additional sensitisations [16]. Longer duration of immunotherapy is not associated with improved outcomes [12,17] and shorter duration of immunotherapy tends to observe fewer or non-significant improvements [5,7,18-21]. Unless stated otherwise, all papers referenced studied monoallergenic HDM-AIT in HDM-allergic populations not controlled for polysensitivity. The efficacy of SCIT and SLIT is compared in Table 1.

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Paramter Significantly decreased asthma symptom score, compared to baseline

Subcutaneous immunotherapy (SCIT)

Sublingual immunotherapy (SLIT)

70-100% of participants [12]

64-83% of participants [14]

63-86% improvement [11,13,17]

44-86% improvement [11,13]

−1.4 to 2.1 points (four-point scale) [6] Significantly improved medication scores (undefined), compared to baseline Significantly decreased inhaled corticosteroid use, compared to baseline

100% of participants [12]

Trends of improvement [14]

82% improvement (undefined scale) [11,13]

64% improvement (undefined scale) [11,13]

− 125.4 μg [6]

Decreased requirement from 12 to 7 months per year [15] − 120 μg [15]

Significantly higher inhaled corticosteroid cessation rate compared to control

28.9% [6]

52% [15]

Significantly increased peak expiratory flow, compared to baseline

+ 28 L/min [6]

No significant results

Asthma-free rates compared to baseline

62.7-74.6% [12,17]

No significant results

Other

Significantly decreased likelihood of developing additional sensitisations [16]

Papers that studied fewer than three years of immunotherapy

Observed fewer, or non-significant, improvements in clinical and medication outcomes [5,18]

Observed fewer, or non-significant, improvements in clinical and medication outcomes [7,19-21]

Paediatric investigations into SCIT

Adult investigations into SCIT and SLIT

Arroabarren et al. [12] investigated 71 children and reported that three years of SCIT significantly decreased asthma symptom score, medication score, and global symptom and medication score compared to baseline. Sixty nine percent of asthmatic participants were reported as asthma-free with normal lung function testing and pharmacologyfree for three months [12]. These findings are supported by a study of 90 children [6], which demonstrated that, compared to placebo, three years of SCIT resulted in a significantly decreased inhaled corticosteroids (ICS) dose, significantly higher ICS cessation rate, significantly lower asthma symptom scores and significantly increased peak expiratory flow (PEF). Another study of 31 children [11,13] confirmed that three years of SCIT significantly improved their visual analogue scale score by 63%, significantly decreased their total asthma symptom score by 86% and significantly decreased their total medication score by 82%.

Studies in both adult and limited paediatric populations have found that three years of AIT is efficacious and that a shorter duration of therapy tends to have fewer significant outcomes [8,17,19-21,23]. Tabar et al. [17] reported on a mixed paediatric/adult population, randomised to three or five years of SCIT, and reported that three years of SCIT significantly improved asthma symptoms and asthma-free rates. Blumberga et al. [8,23] reported on 42 adults and show that, compared to control, three years of SCIT significantly improved HDM tolerance and decreased inflammatory responses. Potter et al. [21] reported on two years of SLIT in 48 adults and found no significant differences compared to placebo for ICS use and clinical outcomes. A study of one year of SLIT in 604 adults [19,20] demonstrated improvements in daily ICS use and ICS cessation rate compared to placebo. There were no statistical differences for any asthma parameters. Virchow et al. [7] reported on six months of SLIT in 834 adults, finding a significantly reduced risk of moderate or severe asthma exacerbation compared to placebo, but no significant difference in questionnaire scores.

Paediatric investigations into SLIT Ozdemir et al. [15] demonstrated that in 90 children, three years of SLIT significantly decreased the number of months per year requiring ICS, the mean daily dose of ICS and the ICS cessation rate, but longer than three years of SLIT show no significant difference in respiratory outcomes. Trebuchon et al. [14] retrospectively analysed 736 children, in whom the median duration of SLIT treatment was 3.1 years. Although there was no control group, physicians perceived SLIT to be efficacious in 83% of participants, and asthma symptoms to have improved in 64%. Compared to baseline, there were trends of reductions in medication use, including oral antihistamines, ICS, long-acting beta-agonists and short-acting beta-agonists. Eifan et al. [13] and Karakoc-Aydiner et al. [11] demonstrated three years of SLIT significantly improved asthma and medication scores compared to control; however, there were no differences in lung function. De Bot et al. [22] found two years of SLIT in children lowered dyspnoea/wheeze score compared to placebo, but there was no difference for dry cough score.

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Efficacy of SCIT and SLIT Although three years of immunotherapy, whether SCIT or SLIT, has proven efficacious in reducing medication use and improving asthma symptoms, there is still marked variability in outcomes even within the same duration of treatment. Studies clarifying optimal dosing and administration, particularly in paediatric populations, may reinforce whether or not there is a role for SCIT and/or SLIT in treating HDM-AA in children.


Volume 9, Issue 1 | 2019 Table 2: Comparison of safety of subcutaneous immunotherapy 1 and sublingual immunotherapy. Referenced papers studied three years of monoallergenic house dust mite (HDM) immunotherapy in HDM-allergic populations not controlled for polysensitivity.

Adverse reaction

Subcutaneous immunotherapy (SCIT)

Sublingual immunotherapy (SLIT)

Occurred, not quantified [11,13,16,18]

3.3-15.9% of participants [14,15]

0.38-11.6% of doses [6,17,27,29]

“Common”, not quantified [19,21]

Local Reactions Local skin / oral reaction

11.9% of participants [29] Other oral reaction

One case – moderate laryngeal oedema, did not compromise airway [7]

Systemic Reactions Unspecified

0.06-4.7% of doses [6,8,23,27,29]

3.1% of participants [14]

3.7-24% of participants [8,23,29] Fatigue

“Common”, not quantified [16]

Dizziness / migraine

1.9% of participants [19]

Arthralgia

0.1% of participants [7]

Rhinorrhoea / sneezing

1.1% of participants [15]

Asthma / shortness of breath

0.035-0.067% of doses [12,17,27]

0.1% of participants [7]

2.4-6.5% of participants [11,13,16,27] Anaphylactoid / anaphylaxis (not fatal)

0.8% of participants [16]

One case (see text) [34]

Death

One per 2.5 million doses [9]

Nil reported to date

Safety of house dust mite immunotherapy to treat asthma Inherent in AIT is the potential to induce local or systemic adverse reactions [1,24,25]. The World Allergy Organisation (WAO) has standardised reporting of SCIT- and SLIT-related adverse reactions [25]. Local SCIT reactions include erythema, pruritus and injection site swelling, while local SLIT reactions include mouth/ear, upper gastrointestinal, and lower gastrointestinal reactions. The spectrum of systemic reactions ranges from mild rhinitis to cardiac arrest and anaphylaxis. SLIT is widely considered to be safer than SCIT, with fewer adverse reactions and no deaths reported to date [1,10,26]. The safety of SCIT and SLIT is compared in Table 2. Local reactions to immunotherapy Local reactions to SCIT are not uncommon, though the size of a local reaction is not standardised in the literature [6,12,18,27]. Nacaroglu et al. [27] found that HDM-SCIT was significantly more likely to precipitate a wide local reaction (>5cm) compared to grass, olive, or weed pollen SCIT. The reported rates of injections producing local reactions range from one per nine doses [6] to one per 260 doses [27]. Local reactions generally resolve spontaneously, though oral antihistamines can be used to good effect [12]. It is generally accepted that SLIT produces more local than systemic reactions [1,14,15,26] and that these predominantly consist of oral itching or taste sensation. Systemic reactions to immunotherapy The most common systemic reaction reported in SCIT and SLIT are asthma symptoms [11-13,16,26]. Other reported systemic effects include fatigue [16], dizziness [19], migraine [19], arthralgia [7], rhinorrhoea [15] and sneezing [15]. The reported rates of SCIT-related systemic reactions vary from one reaction per 300 doses [28] to one per 3,300 doses [12]. The rate of near-death reactions has been reported at one in a million and the rate of death due to SCIT has previously been reported at one per 2.5 million doses [9] – no deaths due to SCIT have been reported

since 2009, when a 43 year old male developed airway obstruction and cardiopulmonary arrest [29,30]. Uncontrolled asthma has been identified as an important risk factor for fatal and near-fatal reactions in HDM-SCIT [30]. Severe reactions are rare in SLIT, with a reported rate of one severe reaction per 384 treatment years, and no life-threatening reactions reported to date [1,27,31]. Two recent paediatric case reports detail two cases of severe reactions to HDM-SLIT. Galip and Bahceciler [32] reported on a five year old boy with HDM-allergic rhinitis who, during the up-dosing phase of SLIT, began vomiting intractably after five minutes of administration. The boy remained nauseated for 40 minutes. This occurred whenever the particular dose was administered. Blazowski [33] reported on a sixteen year old girl with HDM-AR and HDM-AA who, in her third year of maintenance SLIT, self-ceased her usual dose of 10 drops daily for three weeks, then self-administered 60 drops. This induced a severe systemic anaphylactic reaction, which required ICU support. These two reports demonstrate that severe systemic reactions to SLIT are possible, but that much of the risk of harm can be mitigated by observing the patient following SLIT administration. Further high-quality studies in both paediatric and adult populations have already been called for [1,10,24], and would help to define the safety of SLIT in the treatment of HDM-AA in children. SCIT vs. SLIT in the paediatric patient Due to the scarcity of studies specifically investigating paediatric patients, it is difficult to draw strong conclusions. Using what data is available (Table 1), it can be seen that SLIT, whilst significantly effective in its own right, may be less efficacious than SCIT. Further statistical testing to assess this question in this review is not possible as the raw data from these investigations are not available. Separate from the question of whether SCIT or SLIT is more effective in a head to head comparison is the question of practicality and ease of administration for patients. Following the first observed dose of SLIT, all subsequent doses can be self-administered at home [34] – this

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AM S J option is not available for SCIT. The increased safety profile of SLIT may also be more attractive to the parents of these patients. As reviewed earlier in two case studies [32,33]; however, SLIT does inherently have a risk of adverse reaction and should these complications arise in the home rather than the hospital, appropriate staff and treatment may not be close to hand. For these reasons, it is imperative to discuss with patients and their parents the risks and benefits to each of SLIT and SCIT and ensure they are well informed prior to starting any treatment. HDM-AIT in polysensitised patients Up to 30-80% of allergic patients worldwide are polysensitised [35]. There is concern regarding the safety and efficacy of single- or multiple-allergen immunotherapy in polysensitised patients, with a small number of recent studies addressing this. Nacaroglu et al. [27] retrospectively evaluated adverse reactions to single-allergen or multiple-allergen SCIT in children, 48.9% of whom were sensitised to HDM. They found that adverse reactions were significantly more common in patients undergoing polyallergenic SCIT compared to monoallergenic SCIT, and in HDM-SCIT compared to SCIT with grass, olive, or weed pollens; animal dander; or Alternaria fungi. There was no statistically significant difference in adverse reactions between monosensitised or polysensitised participants. Nelson [36] reviewed 13 studies utilising polyallergenic AIT and identified that simultaneous administration of multiple allergens is clinically effective, but called for more studies to draw stronger conclusions – a position recognised by a 2014 international consensus paper [37], which noted that virtually all published RCTs are of single-allergen AIT, but acknowledged that the evidence so far indicates that AIT is equally effective in monosensitised and polysensitised patients. Of note, while many RCTs of AIT do not exclude polysensitised participants, it is difficult to draw conclusions from these papers as results are typically not analysed or reported separately. Interestingly, it has been demonstrated that immunotherapy in monosensitised children can reduce the rate of development of subsequent polysensitivity [16]. House dust mite immunotherapy in poorly-controlled or moderatesevere asthma The use of AIT in varying severity of disease has been heavily debated, guided by the risk of adverse reactions. The risk of allergic reaction suggests AIT may be better suited for mild AA, with a lower risk of anaphylaxis [38], while the risk of anaphylaxis implies AIT should be a final-line therapy in uncontrolled severe AA – the position of many governing bodies [37]. A number of studies have investigated the safety and efficacy of AIT in moderate to severe asthma [7,19,23,39]. Gonzalez et al. [39] investigated SCIT in eight adults with severe persistent HDM-AA and observed few minor local reactions, no significant reactions and no late reactions. Blumberga et al. [23] reported on SCIT in 42 adults with moderate to severe HDM-AA, finding mixed efficacy, but generally safe outcomes: 38% of SCIT participants developed mild systemic or non-life-threatening reactions, one severe local reaction was treated with oral ICS and nebulised β2-agonists and there were no life-threatening reactions. De Blay et al. [19] analysed SLIT in 604 adults. They found that medication and symptom scores were significantly more improved in patients with partly-controlled asthma compared to patients with non-severe asthma. While there was a dose-dependent increase in adverse reactions, the majority were mild or moderate. Virchow et al. [7] reported comprehensive safety data of SLIT in 834 adults with partly-controlled asthma. Of participants, 30.6% experienced adverse reactions compared to 3.4% of non-SLIT participants: 74.1% of these were local reactions and while 3% were considered severe, none compromised the airway. There were no severe or life-threatening systemic reactions. Uncontrolled asthma is an important risk factor in the development of adverse reactions to AIT [30]. The literature demonstrates that AIT in

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poorly-controlled or severe asthma enacts similar or greater efficacy than in mild asthma, without a significantly higher risk of severe adverse reactions – a position that is at odds with current guidelines. Current guidelines for immunotherapy to treat allergic asthma Many guidelines exist to direct AIT in the management of AA, with most recommending a cautious approach. The 2016 Australasian Society of Clinical Immunology and Allergy recommends that AIT can be considered based on clinical judgement when symptoms are severe, the allergen is difficult to avoid and medications are ineffective or intolerable. Future directions for allergen immunotherapy In addition to ongoing trials to clarify the efficacy and safety of SCIT and SLIT, there is ongoing research into adjuvants to increase tolerability and into alternative immunotherapy methods [34]. Adjuvants such as tolllike receptor 4 and 9 agonists increase Th1 and Treg responses, though clinical trials have shown inconsistent efficacy. Depots of allergens with a second immunogenic material such as alum or calcium phosphate have been used in Europe, though further assessment is needed before more widespread use. Alternative delivery methods, including epicutaneous and intralymphatic methods are also being investigated, though to date no studies for HDM-AR or AA have been performed. Further investigations into alternate hypoallergenic allergens and the co-administration of monoclonal antibodies with the allergen are also underway. As these studies progress, more information about the various options, efficacy, and safety of immunotherapy will become apparent. Conclusion Allergen immunotherapy has the potential to change the natural history of allergic asthma [4] and as such, should be considered in the management of patients with AA. The literature suggests that AIT is superior to placebo in improving asthma symptoms, asthmafree rates, and medication use [6,11-15]. Adverse reaction rates vary between SCIT and SLIT, but serious or life-threatening reactions are rare [1,12,27,28,31], with no SLIT-related death reported [10] and no SCITrelated death since 2009 [29,30]. Ongoing concerns regarding safety remain, and the superiority of SCIT or SLIT has not been ascertained. More research is required to investigate AIT in the polysensitised and severe or uncontrolled asthma populations, with current evidence suggestive of a role for both SLIT and SCIT in these patients. The current lack of high-powered well-designed studies in specific populations such as paediatric, HDM-AA, or severe asthma, renders analysis by systematic review or meta-analysis problematic. Further studies into the efficacy and safety of HDM-AIT in these specific populations will make the role of treatment clearer. AIT can facilitate a significantly improved quality of life in the appropriate patient: our role as clinicians will be to identify these patients. Conflicts of Interest There are no conflicts of interest to declare. Correspondence S Sodini: susanna.sodini@uqconnect.edu.au


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References [1] Normansell R, Kew KM, Bridgman AL. Sublingual immunotherapy for asthma. Cochrane Database Syst Rev. 2015;(8):CD011293. [2] Di Rienzo V, Cadario G, Grieco T, Galluccio AG, Caffarelli C, Liotta G, et al. Sublingual immunotherapy in mite-sensitized children with atopic dermatitis: a randomized, open, parallel-group study. Ann Allergy Asthma Immunol. 2014;113(6):671-3.e1. [3] Biagtan M, Viswanathan R, Bush RK. Immunotherapy for house dust mite sensitivity: where are the knowledge gaps? Curr Allergy Asthma Rep. 2014;14(12):482. [4] Calderón MA, Casale TB, Togias A, Bousquet J, Durham SR, Demoly P. Allergen-specific immunotherapy for respiratory allergies: From meta-analysis to registration and beyond. J Allergy Clin Immunol. 2011;127(1):30-8. [5] Zielen S, Kardos P, Madonini E. Steroid-sparing effects with allergen-specific immunotherapy in children with asthma: A randomized controlled trial. J Allergy Clin Immunol. 2010;126(5):942-9. [6] Hui Y, Li L, Qian J, Guo Y, Zhang X, Zhang X. Efficacy analysis of three-year subcutaneous SQ-standardized specific immunotherapy in house dust mite-allergic children with asthma. Exp Ther Med. 2014;7(3):630-4. [7] Virchow JC, Backer V, Kuna P, Prieto L, Nolte H, Villesen HH, et al. Efficacy of a house dust mite sublingual allergen immunotherapy tablet in adults with allergic asthma. JAMA. 2016;315(16):1715-25. [8] Blumberga G, Groes L, Dahl R. SQ-standardized house dust mite immunotherapy as an immunomodulatory treatment in patients with asthma. Allergy. 2011;66(2):178-85. [9] Cox LS, Linnemann DL, Nolte H, Weldon D, Finegold I, Nelson HS. Sublingual immunotherapy: A comprehensive review. J Allergy Clin Immunol. 2006;117(5):1021-35. [10] Canonica GW, Bagnasco D, Ferrantino G, Ferrando M, Passalacqua G. Update on immunotherapy for the treatment of asthma. Curr Opin Pulmonary Med. 2016;22(1):18-24. [11] Karakoc-Aydiner E, Eifan AO, Baris S, Gunay E, Akturk E, Akkoc T, et al. Long-term effect of sublingual and subcutaneous immunotherapy in dust mite-allergic children with asthma/rhinitis: A 3-year prospective randomized controlled trial. J Investig Allergol Clin Immunol. 2015;25(5):334-42. [12] Arroabarren E, Tabar AI, Echechipía S, Cambra K, García BE, Alvarez-Puebla MJ. Optimal duration of allergen immunotherapy in children with dust mite respiratory allergy. Pediatric Allergy and Immunology. 2015 2015/01/05;26(1):34-41. [13] Eifan AO, Akkoc T, Yildiz A, Keles S, Ozdemir C, Bahceciler NN, et al. Clinical efficacy and immunological mechanisms of sublingual and subcutaneous immunotherapy in asthmatic/ rhinitis children sensitized to house dust mite: an open randomized controlled trial. Clin Exp Allergy. 2010;40(6):922-32. [14] Trebuchon F, Lhéritier-Barrand M, David M, Demoly P. Characteristics and management of sublingual allergen immunotherapy in children with allergic rhinitis and asthma induced by house dust mite allergens. Clin Transl Allergy. 2014;4:15. [15] Ozdemir C, Yazi D, Gocmen I, Yesil O, Aydogan M, Semic-Jusufagic A, et al. Efficacy of long-term sublingual immunotherapy as an adjunct to pharmacotherapy in house dust mite-allergic children with asthma. Pediatr Allergy Immunol. 2007;18(6):508-15. [16] Pajno GB, Barberio G, De Luca FR, Morabito L, Parmiani S. Prevention of new sensitizations in asthmatic children monosensitized to house dust mite by specific immunotherapy. A six-year follow-up study. Clin Exp Allergy. 2001;31(9):1392-7. [17] Tabar AI, Arroabarren E, Echechipía S, García BE, Martin S, Alvarez-Puebla MJ. Three years of specific immunotherapy may be sufficient in house dust mite respiratory allergy. J Allergy Clin Immunol. 2011;127(1):57-63.e3. [18] Tsai TC, Lu JH, Chen SJ, Tang RB. Clinical efficacy of house dust mite-specific immunotherapy in asthmatic children. Pediatr Neonatol. 2010;51(1):14-8. [19] de Blay F, Kuna P, Prieto L, Ginko T, Seitzberg D, Riis B, et al. SQ HDM SLIT-tablet (ALK) in treatment of asthma—post hoc results from a randomised trial. Resp Med. 2014;108(10):1430-7.

[20] Mosbech H, Deckelmann R, de Blay F, Pastorello EA, Trebas-Pietras E, Andres LP, et al. Standardized quality (SQ) house dust mite sublingual immunotherapy tablet (ALK) reduces inhaled corticosteroid use while maintaining asthma control: a randomized, double-blind, placebo-controlled trial. J Allergy Clin Immunol. 2014;134(3):568-75.e7. [21] Potter PC, Baker S, Fenemore B, Nurse B. Clinical and cytokine responses to house dust mite sublingual immunotherapy. Ann Allergy Asthma Immunol. 2015;114(4):327-34. [22] de Bot CMA, Moed H, Berger MY, Röder E, Hop WCJ, de Groot H, et al. Sublingual immunotherapy not effective in house dust mite-allergic children in primary care. Pediatr Allergy Immunol. 2012;23(2):150-8. [23] Blumberga G, Groes L, Haugaard L, Dahl R. Steroid-sparing effect of subcutaneous SQ-standardised specific immunotherapy in moderate and severe house dust mite allergic asthmatics. Allergy. 2006;61(7):843-8. [24] Campbell DE. Sublingual immunotherapy for children: are we there yet? Paediatr Respir Rev. 2009;10(2):69-74. [25] Cox L, Larenas-Linnemann D, Lockey RF, Passalacqua G. Speaking the same language: The world allergy organization subcutaneous immunotherapy systemic reaction grading system. J Allergy Clim Immunol. 2010;125(3):569-74.e7. [26] Passalacqua G, Baena-Cagnani CE, Bousquet J, Canonica GW, Casale TB, Cox L, et al. Grading local side effects of sublingual immunotherapy for respiratory allergy: speaking the same language. J Allergy Clin Immunol. 2013;132(1):93-8. [27] Nacaroglu HT, Erdem SB, Sumer O, Karaman S, Unsal Karkıner CS, Asilsoy S, et al. Local and systemic reactions to subcutaneous allergen immunotherapy: ten years’ experience in a pediatric clinic. Ann Allergy Asthma Immunol. 2016;116(4):349-53. [28] Moreno C, Cuesta-Herranz J, Fernandez-Tavora L, Alvarez-Cuesta E. Immunotherapy safety: a prospective multi-centric monitoring study of biologically standardized therapeutic vaccines for allergic diseases. Clin Exp Allergy. 2004;34(4):527-31. [29] Epstein TG, Liss GM, Murphy-Berendts K, Bernstein DI. AAAAI/ACAAI surveillance study of subcutaneous immunotherapy, years 2008-2012: an update on fatal and nonfatal systemic allergic reactions. J Allergy Clin Immunol Pract. 2014;2(2):161-7.e3. [30] Epstein TG, Liss GM, Murphy-Berendts K, Bernstein DI. AAAAI and ACAAI surveillance study of subcutaneous immunotherapy, Year 3: what practices modify the risk of systemic reactions? Ann Allergy Asthma Immunol. 2013;110(4):274-8.e1. [31] Makatsori M, Calderon MA. Anaphylaxis. Curr Opin Allergy Clin Immunol. 2014;14(4):316-22. [32] Galip N, Bahceciler N. Rare adverse events due to house dust mite sublingual immunotherapy in pediatric practice: two case reports. Immunotherapy. 2015;7(12):1235-9. [33] Blazowski L. Anaphylactic shock because of sublingual immunotherapy overdose during third year of maintenance dose. Allergy. 2007;63(3):374. [34] Gunawardana NC, Durham SR. New approaches to allergen immunotherapy. Ann Allergy Asthma Immunol. 2018;121(3):293-305. [35] Calderón MA, Cox L, Casale TB, Moingeon P, Demoly P. Multiple-allergen and singleallergen immunotherapy strategies in polysensitized patients: Looking at the published evidence. J Allergy Clin Immunol. 2012;129(4):929-34. [38] Nelson HS. Multiallergen immunotherapy for allergic rhinitis and asthma. J Allergy Clin Immunol. 2009;123(4):763-9. [37] Jutel M, Agache I, Bonini S, Burks AW, Calderon M, Canonica W, et al. International consensus on allergy immunotherapy. J Allergy Clin Immunol. 2015;136(3):556-68. [38] Custovic A. Immunotherapy for asthma – con. Paediatr Respir Rev. 2011;12(Suppl 1):S13. [39] González R, Poza P, Matheu V, Sánchez-Machín I. Safety of modified dust mite subcutaneous immunotherapy in severe allergic asthma. J Allergy Clin Immunol. 2013;131(2):AB205.

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Literature Review

A Review of Breath Metabolic Profiling for Non-invasive Testing in Inflammatory Bowel Disease Patients Michaela Prove MBBS James Cook University

Michaela Prove is currently a fourth-year undergraduate medical student at James Cook University, Cairns, Queensland. Following a diagnosis of Crohnâ&#x20AC;&#x2122;s disease in her third year, she currently has interests in paediatric gastroenterology and is dedicated to providing holistic, patient-centred care to patients.

Abstract This review aims to summarise the current literature on employing exhaled breath volatile organic molecules (VOMs) as novel biomarkers for non-invasive testing in inflammatory bowel disease (IBD) patients. Inflammatory bowel disease is a multifactorial disease that significantly diminishes the quality of life of affected individuals. Currently, the tools employed in IBD diagnosis and monitoring are numerous, imprecise and invasive for patients. This has necessitated the need to develop new biomarkers that are accurate. The use of VOM breath testing is one such potential modality. This review discusses the efficacy of current IBD testing modalities and the principles of metabolic profiling. It evaluates the use of breath VOM profiling in IBD testing and postulates its implications for future practice. The VOM profiles of IBD patients are different to those of healthy individuals. VOM profiles also differ between IBD subcategories and correlate to disease severity. VOM profiling via the breath headspace is accurate, non-invasive and has the potential for point-of-care testing. VOM profiling offers an exciting avenue as a frontline diagnostic and monitoring tool for IBD patients and thus merits further research. Introduction Inflammatory bowel disease (IBD) is a chronic, relapsing inflammatory condition of the gastrointestinal tract, comprising of two subcategories: Crohnâ&#x20AC;&#x2122;s disease (CD) and ulcerative colitis (UC) [1,2]. While both forms have commonalities in their clinical presentation, mainly abdominal pain, diarrhoea and weight loss, CD and UC can be differentiated by their histological features and extent of colonic involvement. CD can affect the entirety of the gastrointestinal tract and is characterised by discontinuous transmural lesions. In UC, inflammation is continuous, affecting only the superficial mucosal layer of the large intestine [3,4]. The pathophysiology of IBD is largely elusive. It is thought to arise from an inappropriately heightened mucosal immunological response to environmental stimuli in individuals who are genetically predisposed to the condition [5,6]. Currently, there are no gold standards for IBD diagnostic and monitoring tools [7]. Traditional approaches to diagnosis involve eliciting a detailed patient history along with physical examination, serology, faecal biomarker investigations, imaging studies, endoscopic investigations and histology [8]. This regime is substandard for patients due to its invasive nature. Furthermore, there are often high rates of misdiagnosis, delayed diagnosis and incorrect sub-categorization [8,9]. The highly debilitating nature of IBD, increasing incidence and subsequent healthcare expenditure inflation necessitates the development of new

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diagnostic and monitoring modalities [2,3]. One such modality is the use of metabolic profiling. This involves the analysis of volatile organic molecules (VOMs) using urine, stool and exhaled breath samples [6]. There is surmounting evidence that metabolic profiling can be used to successfully diagnose conditions, in which there is increased oxidative stress. The emerging technology has currently been employed in the diagnosis of breast cancer, lung cancer, diabetes, and tuberculosis, so it offers great potential as a diagnostic modality for gastrointestinal diseases [9]. This review will first focus on current clinical practice before evaluating the use of exhaled VOMs as novel biomarkers for IBD diagnosis and management. Current efficacy of IBD diagnostics Physicians often face difficulty in diagnosing IBD based on clinical presentation alone, given that symptoms of IBD can overlap with those for irritable bowel syndrome (IBS) [1]. Consequently, few patients being referred for endoscopic evaluation have IBD [10], with up to 50% of patients with IBS being referred for unnecessary endoscopic evaluation [11]. To complicate things further, IBD diagnosis is often missed or delayed. Since timely treatment is critical to halt disease progression, a mean diagnostic delay of nine months places IBD patients at a greater risk of surgical intervention [12]. Once a diagnosis of IBD has been made, sub-categorisation into CD or UC can pose another challenge for physicians, with subcategory reclassification rates of 10% [7]. In 1015% of patients, sub-categorisation is indiscernible, which results in an undifferentiated diagnosis of indeterminate colitis [7,13]. Accurate sub-categorisation is essential in establishing a prognosis, evaluating a patientâ&#x20AC;&#x2122;s risk of complications and implementing optimal management strategies [6,7]. Incorrect diagnosis can lead to diminished quality of life and places a heavy burden on the healthcare system [14]. This underpins the need for a non-invasive and accessible tool to prioritise patients for colonoscopy and reduce unnecessary investigations in those with IBS.


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Current diagnostic and monitoring tools in clinical practice Endoscopic investigations and subsequent histological findings are most often used in clinical practice to diagnose and monitor disease activity in patients with IBD. Colonoscopies are favourable for diagnosis as physicians are able to simultaneously diagnose IBD via biopsy, investigate its complications and remove colonic polyps. For the patient, these investigations are invasive due to bowel purgation and the need for anaesthetic. As such, frequent endoscopic evaluations are not suitable for monitoring disease activity [15]. Furthermore, endoscopic procedures do not come without risk [7]. Gastrointestinal perforation occurs in 4.5-9.7 cases per 10,000 patients during such investigations [16]. Radiological assessment is often used in IBD diagnosis and monitoring [7]. While CT scanning is accessible and minimally invasive, it exposes a typically young cohort of patients to ionizing radiation. As such, repeated scanning to monitor disease activity should be avoided. The quality of imaging can be limited by the intraluminal localisation of contrast. Likewise, ultrasound is dependent upon sonographer experience as it is difficult to follow the entirety of the intestines [5]. MR enterography is often used to monitor disease activity and response to treatment for IBD patients. It is favourable in that it gives physicians a full transmural view of the bowel wall, as well as extra-intestinal complications, and does not expose patients to radiation; however, it is problematic for patients who are claustrophobic and risky in those with renal insufficiency due to the need for large volumes of contrast [17]. Active periods of IBD are accompanied by an immune response that is detectable by blood based biomarkers, including C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). These serological tests can be used to confirm diagnosis and for monitoring response to treatment. They are cheap, rapid and easily accessible [2]. CRP is produced by hepatocytes in response to pro-inflammatory cytokines and its short half-life makes it a responsive indicator of acute inflammation [18]. Being a systemic marker of inflammation, CRP is non-specific and can rise in response to a range of inflammatory conditions [1,9]. Conversely, up to 50% of patients with endoscopically active IBD do not have an elevated CRP level [19]. Since CRP only rises during active inflammation, diagnosis can be missed in those with quiescent IBD [11]. ESR, another systemic inflammatory indicator, rises due to an increase in plasma viscosity as a result of acute phase protein generation. ESR peaks later than CRP and is more indicative of chronic inflammation. It is, unfortunately, equally non-specific and can be affected by haematocrit, reducing its accuracy [18]. Stool samples can be analysed for white cell proteins [9]. They are costeffective investigations and highly specific for inflammatory conditions localised to the bowel [19]. Classified as a danger-associated molecular pattern, faecal calprotectin is a protein derived from neutrophils, monocytes and macrophages during inflammation [18]. It is raised in IBD and sensitive for differentiating IBD from healthy controls, but it can be raised in gastrointestinal infections and as a result of non-steroidal anti-inflammatory drug use [1]. Notably, 8% of patients receive false negative results and not all IBD patients have raised faecal calprotectin [11]. Another stool-based biomarker, faecal lactoferrin, an iron-binding protein released upon neutrophil degranulation, is also increased in IBD. Reluctance of patients to provide samples, storage of faeces outside of optimal temperature, high intra-individual variability and false positive results reduce its effectiveness as a diagnostic and monitoring tool [1]. The principles of metabolic profiling Volatile organic molecules are disease-specific gas phase biomarkers that characterise the interactions of colonocytes with intestinal microbiota and pathogens [8]. While VOM profiling is in its early stages

of development, it is clear that the VOM profiles of IBD patients are different from those of healthy individuals. This is thought to result from the associated alterations in metabolic processes, inflammatory changes and microbial dysbiosis of IBD [14,16]. Profiles also differ between IBD subcategories, with many VOMs being upregulated in CD, allowing for subcategory classification. This most likely reflects the transmural nature and potentially greater extent of inflammation associated with CD [14]. There is also evidence that these biomarkers differ during periods of active disease and remission in patients with previously diagnosed IBD. Intestinal VOMs can be excreted in faeces and urine or transported via the bloodstream into the lungs and exhaled in breath [3]. VOMs are identified by gas chromatography or via a selective ion flow tube and measured by mass spectrometry or flame ionisation [7]. While VOMs can be measured from all three samples, patients are often reluctant to provide urine or stool samples and collection may not be feasible in patients experiencing diarrhoeal symptoms [6]. Testing is also highly dependent upon sample storage, since temperature and contamination can compromise sample quality [1,2]. Metabolic profiling via breath samples is advantageous due to many factors (Table 1). Breath samples can be obtained spontaneously via a non-invasive process that is comfortable and convenient for patients and where storage issues are non-existent. Other advantages of using breath samples is that patients are not exposed to ionising radiation and bowel preparation or contrast is not required [6]. As such, breath testing offers a more patient-centred Table 1. Advantages and disadvantages of VOM profiling via breath samples [6].

Advantages

Disadvantages

Non-invasive (no bowel preparation, anaesthetic, or contrast is required)

The effects of antibiotics and co-morbidities on VOM profiles are not known

Does not expose patient to radiation

Not widely studied in paediatric cohorts

Minimal risks Potential for point-of-care bedside testing

approach to IBD diagnosis and monitoring. It is more likely to be accepted by patients, improving compliance and satisfaction, as well as generating more accurate results than other VOM profiling headspaces. For these reasons, breath samples offer the most promising avenue of metabolic profiling for IBD diagnosis and will be the focus of this review. Distinguishing IBD patients from healthy controls The most widely studied exhaled VOMs are alkanes. These 1 include pentane, butane, ethane, and propane. Like many VOMs, alkanes are produced as a result of excessive reactive oxygen species-induced lipid peroxidation during an inflammatory response [1,14]. A study led by Pelli et al. [20] revealed significantly increased ethane, propane and pentane concentrations in the exhaled breath of IBD patients compared to healthy controls. Another breath analysis of 487 VOMs showed that increased exhaled alkanes were unique to IBD patients. In this study CD active individuals and healthy controls were differentiated with a sensitivity of 96% and a specificity of 97%. Heptadecane was upregulated in CD groups compared to healthy controls, 2,2,4-trimethylpentane was higher in CD active groups compared to CD remission and healthy controls and 2,2,4,4-tetramethyloctane and 2,4,4- trimethylhexane were higher in active CD than remission. This study also implicated aldehydes as a potential VOM biomarker for IBD diagnosis. It found that breath samples of IBD patients contained higher aldehyde concentrations than

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AM S J healthy controls [1]. This is consistent with results from Hicks where exhaled butanal and nonanal were increased in both CD and UC, with CD patients having the highest concentrations across all cohorts [6]. Patel et al.â&#x20AC;&#x2122;s [2] study did find, however, that hydrogen sulphide concentrations were reduced in IBD patient breath samples compared to healthy controls, with significance in a paediatric population. These results were consistent with studies on adult IBD populations by Hicks et al. and Reider et al. [6,12]. However, since hydrogen sulphide is produced by the intestinal microbiota, it may not be suitable to differentiate between IBD and IBS, limiting its use [6]. Distinguishing IBD patients from IBS patients Condensed cytokines, namely interleukins, such as IL-1B, IL-6, IL-8, and tumour necrosis factor alpha (TNF-a) were in greater abundance in the exhaled breath of IBD patients compared to healthy controls [21]. Since immune cells release these pro-inflammatory cytokines during intestinal inflammation, cytokine profiling is a potential avenue for IBD diagnosis, particularly when distinguishing IBD from non-inflammatory conditions such as IBS. A 2017 study showed that an IL-1B and a TNF-like cytokine were increased in IBD patients compared to IBS patients, distinguishing them with a sensitivity of 50% and specificity of 80%. [22] Distinguishing CD patients from UC patients Dryahina et al. [3] showed significant differences between the exhaled pentane concentrations of CD and UC patients, with CD patients having much higher readings, although sensitivity and specificity were low. Patel et al. [2] showed that the more widespread the intestinal inflammation of IBD patients, the higher exhaled pentane concentration. They found that exhaled pentane levels were higher in CD patients with known ileocolonic disease, and thus more extensive inflammation, compared to UC. As such, it can be said that exhaled pentane has the potential to offer greater clinical value as a biomarker to diagnose IBD, differentiate between CD and UC, and determine disease location in patients with known CD. However, the only known study on paediatric breath testing shows that these correlations are not significant in children [2]. Further studies are needed to establish the efficacy of pentane as a biomarker in paediatric IBD diagnosis. Use in IBD management The use of metabolic profiling is not limited to IBD diagnosis. Pentane has been found to correlate with the severity of inflammation seen in IBD. IBD patients with severe intestinal inflammation was confirmed by imaging studies showed much greater exhaled pentane concentrations (4.3 nmol/L) than those with moderate 1 inflammation (3.1 nmol/L) and than those with absent inflammation (2.1 nmol/L) [23]. It has also been demonstrated that VOM levels normalise following treatment and where remission is achieved. Waltonâ&#x20AC;&#x2122;s [24] multivariate analysis on faecal VOMs of bacterial origin found that, following therapy, IBD VOM profiles normalised to levels found in healthy controls. As such, metabolic profiling is a promising individualised and non-invasive approach of mapping disease activity and monitoring responsiveness to treatment. Future studies should be pursued in this context, as metabolic profiling of breath samples would provide great clinical value in facilitating the management of IBD patients, leading to better health outcomes for these individuals. Implications for future practice The use of VOMs as an investigative modality for IBD has the potential to relieve the burdens associated with current diagnostic and monitoring regimes. While metabolic profiling should not replace current diagnostic modalities, it may have a role in distinguishing IBS from IBD, thus prioritising patients for endoscopic evaluation, speeding up the diagnostic

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process and reducing the number of unnecessary colonoscopies currently seen in clinical practice. It may also offer an alternative to current monitoring tools in patients with established IBD. However, despite surmounting evidence that metabolic profiling can be used to distinguish healthy adults and IBS patients from those with IBD, its use is limited by minimal studies (Table 1). It is unclear whether metabolic profiling can be applied to a paediatric cohort. Furthermore, it has not been fully established whether it can provide sufficient discrimination between CD and UC. It has not been fully established if VOM profiles can accurately follow disease progress. Limited studies report the effects of antibiotics and/or other drugs or having other inflammatory conditions on VOM profiles. Currently, traditional VOM testing modalities cannot be employed at the bedside. Further research of VOMs is needed and may lead to the development of timely and non-invasive point-of-care testing for all patients. A 2015 preliminary study utilised a field asymmetric ion mobility spectroscopy (FAIMS) portable device to detect VOMs in the exhaled breath of 76 patients. Patients with IBD were distinguished from healthy controls with a sensitivity and specificity of 74% and 75%, respectively, while differentiating between CD and UC with a specificity and sensitivity of 67%. Since FAIMS technology is 10-20% of the cost of traditional VOM testing devices, the study manifests the potential of this technology to provide much needed non-invasive point-of-care bedside testing for IBD patients [8]. Conclusion Inflammatory bowel disease is a multifactorial, debilitating disease of the gastrointestinal tract. Current tools employed in IBD diagnostics and monitoring are substandard with notable limitations, placing a heavy physiological and psychological burden on patients. Analysing the VOM composition in the exhaled breath of IBD patients is a highly promising approach that has the potential to be used in clinical practice. While complementing existing diagnostic tools, VOMs may be employed in the future as a means of delivering non-invasive point of care testing for IBD diagnosis, monitoring disease activity and responsiveness to treatment. VOMs such as alkanes, aldehydes, hydrogen sulphide, and cytokines have been implicated as potential biomarkers, with concentrations correlating to disease activity in adult IBD patients. While it is known that VOM concentrations differ with IBD severity, it is unclear if a single VOM biomarker that is subcategory-specific exists in the breath headspace of patients. In the future, further understanding of VOMs may lead to the identification of such CD-specific or UC-specific biomarkers, which would be revolutionary to clinical practice. This may help prioritise patients and reduce the current diagnostic delay experienced by some patients, leading to a restoration of their quality of life, which is of paramount importance. Moreover, the VOM profiles of paediatric patients differ to those of adults and more studies are needed to ascertain the efficacy of profiling in these patients. The preliminary evidence implicates breath metabolic profiling as an encouraging diagnostic and monitoring modality for IBD. The challenge remains to develop disease activity indices for VOM breath testing that are subcategory-specific in both adult and paediatric populations, with the ability to provide point of care testing. If achieved, VOM profiling has the potential to offer patients with IBD much needed optimism regarding the management of their condition and maximise their quality of life. Acknowledgements None. Correspondence M Prove: michaela.prove@my.jcu.edu.au


Volume 9, Issue 1 | 2019

References [1] Bodelier AG, Smolinska A, Baranska A, Dallinga JW, Mujagic Z, Vanhees K, et al. Volatile Organic Compounds in Exhaled Air as Novel Marker for Disease Activity in Crohn’s Disease: A Metabolomic Approach. Inflammatory Bowel Dis. 2015;21(8):1776-85. [2] Patel N, Alkhouri N, Eng K, Cikach F, Mahajan L, Yan C, et al. Metabolomic analysis of breath volatile organic compounds reveals unique breathprints in children with inflammatory bowel disease: a pilot study. Alimentary Pharmacol Ther. 2014;40(5):498-507. [3] Dryahina K, Španěl P, Pospíšilová V, Sovová K, Hrdlička L, Machková N, et al. Quantification of pentane in exhaled breath, a potential biomarker of bowel disease, using selected ion flow tube mass spectrometry. Rapid Commun Mass Spectrom. 2013;27(17):1983-92. [4] Nanau RM, Neuman MG. Metabolome and inflammasome in inflammatory bowel disease. Trans Res. 2012;160(1):1-28. [5] Kilcoyne A, Kaplan JL, Gee MS. Inflammatory bowel disease imaging: Current practice and future directions. World J Gastroenterology. 2016;22(3):917-32. [6] Hicks LC, Huang J, Kumar S, Powles ST, Orchard TR, Hanna GB, et al. Analysis of Exhaled Breath Volatile Organic Compounds in Inflammatory Bowel Disease: A Pilot Study. J Crohns Colitis. 2015;9(9):731-7. [7] Kurada S, Alkhouri N, Fiocchi C, Dweik R, Rieder F. Review article: breath analysis in inflammatory bowel diseases. Aliment Pharmacol Ther. 2015;41(4):329-41. [8] Arasaradnam RP, McFarlane M, Daulton E, et al. Non-invasive exhaled volatile organic biomarker analysis to detect inflammatory bowel disease (IBD). Dig Liver Dis. 2016;48(2):148-53. [9] Aggio R, Probert C. Future methods for the diagnosis of inflammatory bowel disease. Dig Dis (Basel, Switzerland). 2014;32(4):463-7. [10] Shepherd SF, McGuire ND, de Lacy Costello BP, Ewen RJ, Jayasena DH, Vaughan K, et al. The use of a gas chromatograph coupled to a metal oxide sensor for rapid assessment of stool samples from irritable bowel syndrome and inflammatory bowel disease patients. J Breath Res. 2014;8(2):026001. [11] Soubieres AA, Poullis A. Emerging role of novel biomarkers in the diagnosis of inflammatory bowel disease. World J Gastrointest Pharmacol Ther. 2016;7(1):41-50. [12] Rieder F, Kurada S, Grove D, Cikach F, Lopez R, Patel N, et al. A Distinct ColonDerived Breath Metabolome is Associated with Inflammatory Bowel Disease, but not its Complications. Clin Trans Gastroenterol. 2016;7(11):e201.

[13] Shergill AK, Lightdale JR, Bruining DH, Acosta RD, Chandrasekhara V, Chathadi KV, et al. The role of endoscopy in inflammatory bowel disease. Gastrointest endosc. 2015;81(5):1101-1121.e1101-1113. [14] Ahmed I, Greenwood R, Costello B, Ratcliffe N, Probert CS. Investigation of faecal volatile organic metabolites as novel diagnostic biomarkers in inflammatory bowel disease. Aliment Pharmacol Ther. 2016;43(5):596-611. [15] Cauchi M, Fowler DP, Walton C, Turner C, Jia W, Whitehead RN, et al. Application of gas chromatography mass spectrometry (GC–MS) in conjunction with multivariate classification for the diagnosis of gastrointestinal diseases. Metabolomics. 2014;10(6):1113-20. [16] Blotiere PO, Weill A, Ricordeau P, Alla F, Allemand H. Perforations and haemorrhages after colonoscopy in 2010: a study based on comprehensive French health insurance data (SNIIRAM). Clin Res 1 Hepatol Gastroenterol. 2014;38(1):112-7. [17] Kaushal P, Somwaru AS, Charabaty A, Levy AD. MR enterography of inflammatory bowel disease with endoscopic correlation. RadioGraphics. 2017;37(1):116-31. [18] Sands BE. Biomarkers of Inflammation in Inflammatory Bowel Disease. Gastroenterology. 2015;149(5):1275-1285.e1272. [19] Smith LA, Gaya DR. Utility of faecal calprotectin analysis in adult inflammatory bowel disease. World J Gastrolenterology. 2012;18(46):6782-9. [20] Pelli MA, Trovarelli G, Capodicasa E, De Medio GE, Bassotti G. Breath alkanes determination in ulcerative colitis and Crohn’s disease. Diseases of the colon and rectum. 1999;42(1):71-6. [21] Krenke K, Peradzynska J, Lange J, Banaszkiewicz A, Lazowska-Przeorek I, Grzela K, et al. Inflammatory cytokines in exhaled breath condensate in children with inflammatory bowel diseases. Pediatr pulmonol. 2014;49(12):1190-5. [22] Kim JH, Lin E, Pimenterl M. Biomarkers of irritable bowel syndrome. J Neurogastroenterol Motil. 2017;23(1):20-6. [23] Kokoszka J, Nelson RL, Swedler WI, Skosey J, Abcarian H. Determination of inflammatory bowel disease activity by breath pentane analysis. Dis Col Rectum. 1993;36(6):597-601. [24] Walton C, Fowler DP, Turner C, Jia W, Whiteheard RN, Griffiths L, et al. Analysis of volatile organic compounds of bacterial origin in chronic gastrointestinal diseases. Inflammatory Bowel Dis. 2013;19(10):2069-78.

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Letter TGA Reform and Why You Should Care About It Amy Vaux MBBS Honours Monash University.

Amy Vaux is a fourth-year medical student from Monash University. Following an interest in health advocacy and public health she participated in a Summer Research Scholarship with the Monash School of Public and Preventative Health under the supervision of Associate Professor Ken Harvey.

TGA reform and why you should care about it How potentially dodgy products end up on your pharmacy shelf and how to tell which ones to trust. Whilst consumer law hardly seems like a topic to engage doctors and medical students, the changes to the Therapeutic Goods Act have great significance for all healthcare professionals. The Therapeutic Goods Act contains the rules and regulations that determine, which pharmaceutical products are sold in Australia, and what health claims they can make. When shopping in a pharmacy, most consumers and patients assume that the products available to them have been assessed for their safety and efficacy, which is not always the case [1,2].

Compare the 2 products above: Same store, same price, same therapeutic claims. Yet only one product has ever had to demonstrate any evidence that it works to end up on your pharmacy shelf with the letter ”R”, the other end up with a letter “L”. One little letter, a lifetime of difference. When a product is registered with the Therapeutic Goods Administration (TGA), the sponsor must provide high quality evidence to support any claims it makes; however, when a product is listed with the TGA, sponsors are only required to say that they do hold evidence to support their claims. At no point are they required to produce this evidence; and no part of the process checks that this evidence actually exists [2].

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How do consumers tell the difference between registered and listed products? A tiny “AUST R” label for registered products and an “AUST L” for listed products is the only indicator on the packet. 1 A survey conducted by CHOICE in 2016 found that 80% of consumers were unaware that products had these codes on the label [4]. Even when the labels were pointed out to consumers, most were unsure of what “AUST R” and “AUST L” meant [4]. Both registered and listed products represent a substantial component of Australian patients’ healthcare. Consumers spent roughly $10.8 billion on vitamins, supplements and over-the-counter medications between 2015-2016; more than that spent on dental care and public hospitals combined [5].

Consumers rely on the TGA to guide their treatment choices, which involves both controlling product availability and package labelling, but as consumers are unaware that these package codes exist, or what the codes mean, they are misled by product claims they believe have been substantiated. Consumers need to be adequately educated and informed about the difference between listed and registered products. This sentiment was reflected in the 2015 Medicines and Medical Devices Review recommendation that prominent disclaimers should be applied to all advertising material relating to listed complementary medicines and state that the efficacy of the claims made for these products has not been independently assessed [6].


Volume 9, Issue 1 | 2019 Additionally, it is also crucial to strengthen the pre-approval system that examines the claims of listed products before they are placed on the market. Doing this will limit the exposure of consumers and patients to products with unsubstantiated claims in the first place.

After hearing a range of submissions from consumer advocates to industry representatives, the government reached a compromised amendment, extending the pre-approval system for another two years with re 1 view after 18 months; however, the calls to add disclaimers have not been addressed [7,11].

A bill to amend the Therapeutic Goods Act, the legislation that guides the TGA, was put forward in Parliament in 2017. The bill proposed to scrap the pre-approval system altogether in favour of shifting towards more “self-regulatory models by industry” and rejected calls to require disclaimers on products that have not been critically appraised [7].

So the flawed system of regulation is to here to stay, but the proposed changes, that would potentially make this system even worse, have been stopped for now. It is important for healthcare students and professionals to take notice of these changes to the TGA and understand how the system works. The right of patients to informed choice and consent in their medical treatment is a key ethical pillar that extends outside of the consultation room. This right exists also in pharmacy, where patients are even more vulnerable as they largely rely on the regulators alone to protect their interests and to ensure they are informed.

The concern is that this will remove the only, albeit weak, regulatory barrier to publishing erroneous packaging claims. Instead, the system would rely on a post market surveillance system to discourage bad behaviour. In this system, companies would only be prosecuted after unverifiable claims have been published and purchased, consumers mislead and well after the horse has truly bolted. With these changes, even greater reliance would be placed on the AUST R/L coding system to inform consumers of the potential merit of product claims; a system which, as discussed, consumers do not understand [5].

The debate now moves to the Code Council who is drafting a new Therapeutic Goods Advertising Code. Submissions closed on 27th April 2018 [12]. Let’s hope that consumer groups continue to advocate on behalf of the public and our patients and that healthcare groups do more to take notice.

Fortunately, after staunch campaigns from consumer advocate groups such as Choice and The Greens, the bill failed to pass the senate, and was sent to a senate committee for review [8-10].

Correspondence A Vaux: aevau1@student.monash.edu

References [8] Han E. Public health groups slam removal of pre-approval of complementary medicine advertisements. The Sydney Morning Herald. [Internet]. 2018 Jan 23. [cited 2018 July 1]. Available from: https://www.smh.com.au/healthcare/public-health-groups-slam-removalof-preapproval-of-complementary-medicine-advertisements-20180123-h0mw7i.html [9] Harvey K. Therapeutic Goods Amendment Bill 2017 passed by Senate [Internet] Australia: Medreach Pty Ltd. 2018 February 15 [cited 2018 July 1]. Available from: http://www. medreach.com.au/?p=2490. [10] Han E. ‘Softens hardness’: TGA under fire for health claim list that critics say endorses pseudoscience. The Syndey Morning Herald [Internet]. 2018 February 8. [cited 2018 July 1]. Available from: https://www.smh.com.au/healthcare/softens-hardness-tga-under-fire-forhealth-claim-list-that-endorses-pseudoscience-20180207-h0vfst.html [11] Therapeutic Goods Amendment (2017 Measures No.1) Bill 2017 Supplementary Explanatory Memorandum. [cited 2018 July 1]. Available from: https://www.aph.gov.au/Parliamentary_Business/Bills_Legislation/Bills_Search_Results/Result?bId=r5977 [12] Consultation: Draft therapeutic goods advertising code 2018 and associated guidelines. Therapeutic Goods Administration (TGA). [Internet]. 2018 [updated 2018 April 27; cited 2018 July 1]. Available from: https://www.tga.gov.au/consultation/consultation-drafttherapeutic-goods-advertising-code-2018-and-associated-guidelines

[1] Swallowing it [television broadcast]. Four Corners. Australia: Australian Broadcasting Corporation; 2018. Available from https://iview.abc.net.au/show/four-corners/series/2017/video/NC1704H002S00 [2] Therapeutic Goods Act 1989 (Cth). [3] Dent G. How much Australians spend on health. The Sydney Morning Herald [Internet]. 2017 Feb 23. Available from: https://www.smh.com.au/money/saving/how-much-australians-spend-on-health-20170223-gujalb.html [4] Bray K. Check the Label. Choice Health and Body. [Internet]. 2018 Feb 21 [cited 2018 July 1]. Available from: https://www.choice.com.au/health-and-body/medicines-and-supplements/vitamins-and-supplements/articles/listed-vs-registered-medicines [5] Australian Institute of Health and Welfare. Australia’s health 2018. Australia’s health series no. 16. AUS 221. Canberra: AIHW; 2018. [6] Sansom L, Delaat W, Horvath J. Review of Medicines and Medical Devices Regulation [Internet]. Canberra: Australian Government, Department of Health; 2015 July [cited 2018 July 1]. Available from: http://www.health.gov.au/internet/main/publishing.nsf/content/ 8ADFA9CC3204463DCA257D74000EF5A0/$File/Review%20of%20Medicines%20and%20 Medical%20Devices%20-%20Recommendations_Accessible.pdf [7] Therapeutic Goods Amendment (2017 Measures No. 1) Bill 2017 (Cth).

All staff at the AMSJ would like to sincerely thank Deakin University for their support in funding this edition of the journal. Their generosity allows us to continue to share student research in an accessible and high-quality manner.

Zakary Doherty Director (External)

Rose Brazilek Director (Internal)

All staff at the AMSJ would like to sincerely thank DPM for their support in funding this edition of the journal. Their generosity allows us to continue to share student research in an accessible and high-quality manner.

Zakary Doherty Director (External)

Rose Brazilek Director (Internal)

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AMSJ Volume 9, Issue 1 2019  

Australia Medical Student Journal, Volume 9, Issue 1. Published on June 18, 2019

AMSJ Volume 9, Issue 1 2019  

Australia Medical Student Journal, Volume 9, Issue 1. Published on June 18, 2019

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