Inside: Whose life, whose death?: Pharmaceutical trials
in the developing world
RCSI
Serotonin – the missing
link between myocardial
infarction and suicide
Volume 7: Number 1. 2014
ISSN 2009-0838
smj
Royal College of Surgeons in Ireland
Student Medical Journal
RCSI DEVELOPING HEALTHCARE LEADERS WHO MAKE A DIFFERENCE WORLDWIDE
Acknowledgements
Thank you to RCSI Alumni for their continued support to us as students – providing career advice, acting as mentors, enabling electives,
enabling research, and supporting the publication of the RCSIsmj since its inception in 2008.
We, as today’s generation of students and tomorrow’s generation of Alumni, are very grateful for this on-going support.
We would also like to thank the Dean, Professor Hannah McGee, for her sponsorship, and Margaret McCarthy in the Dean's Office for her constant
endorsement and assistance.
A special thanks to Professor RonГЎn M. Conroy for the time and encouragement he has given to the RCSIsmj Journal Club.
The RCSIsmj was extremely privileged to have a number of professors and clinicians involved in this year's Journal Club. We would like to thank
the following for their support of, and participation in the Journal Club, and to express our appreciation of the time, knowledge, and expertise
they shared with us:
Doctor Emma Wallace
Professor Mary Cannon
Professor Arnold Hill
Professor Gerry McElvaney
Professor Ruairi Brugha
Doctor Eoghan De Barra
Professor Clive Lee
Professor Fergal O'Brien
Doctor Mary Aiken
RCSIsmjcontents
Royal College of Surgeons in Ireland
student medical journal
4
4
Editorial
Director’s welcome
RCSI Ethics Challenge
Executive Committee
Director
Editor-in-Chief
Vice Director
Senior Editor
Eoin Kelleher
Melissa Schorr
Ramia Jameel
Natalie Achamallah
5
6
Peer Review Director
Conor Cox
Assistant Peer
Review Director
Rachel Green
10 Evaluation of adverse events and patient satisfaction with day surgery before and
after the implementation of pre-assessment in an Irish teaching hospital
14 Regions of atrophy that correlate with cognitive impairment in subtypes of dementia
Senior Staff Writer
Elizabeth Ahern-Flynn
Staff writers
Nadine Straka
Amelia Reid
Moyser Mulla
Sean Ling
Peer review team
Matthew Wong
Sheau Wei Tan
Vincent Healy
Mark Abel
Daniel Cherfan
Valerie Curren
Sarah Pradhan
Anshuman Sood
Aine McCarthy
Kimberly Ng
Tara Rajiyah
Rebecca Horgan
Ian Elliott
Stephen Kenny
Executive Secretary
David Hakim
Education Officer
Adnan Abbas
Public Relations
Akshay Padki
Shivani Sritharan
Shari Ramsaran
Webmaster
Stephen Tsoukas
RCSIsmj Ethics Challenge 2014/2015
RCSIsmj Ethics Challenge winner 2013/2014
Original articles
Case reports
20 Malignant transformation of chronic ulcers (Marjolin’s ulcers): an emerging
at-risk population
23 Gliosarcoma: a rare variant of glioblastoma multiforme
26 MRSA of unknown aetiology causing prostate abscess in a patient with incidental
prostate adenocarcinoma
Review articles
28
33
36
41
46
49
Omalizumab in the treatment of severe persistent IgE-mediated asthma
Serotonin – the missing link between myocardial infarction and suicide
Rediscovering thalidomide: lessons learnt and evolving indications
Transvaginal cholecystectomy: a novel surgical technique
All in your head: is the use of placebos a form of benevolent deception?
Physiological mechanisms underlying exercise prescription non-compliance
in patients with type 2 diabetes mellitus
Staff reviews
54
58
62
65
69
The foetal origins of adult health
Sleep-deprived doctors and patient safety: an unresolved link
Unplugging platelet function tests: reassessing the gold standard
Sources of, and barriers to, healthcare in armed conflicts
Whose life, whose death?: Pharmaceutical trials in the developing world
Perspective
73 Ensuring safe surgery for our patients – do we do enough?
77 The white coat: does it have a future in Ireland?
81 Miraculous, malevolent or misunderstood: knowledge and attitudes
regarding electroconvulsive therapy
Elective report
84 Medicine and monsoons
Th!nk
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Volume 7: Number 1. 2014 | Page 3
RCSIsmjeditorial and director’s message
The imperfection and uncertainty of medicine
“We look for medicine to be an orderly field of knowledge and
procedure. But it is not. It is an imperfect science, an enterprise of
constantly changing knowledge, uncertain information, fallible
individuals, and at the same time lives on the line. There is science in
what we do, yes, but also habit, intuition, and sometimes plain old
guessing. The gap between what we know and what we aim for
persists. And this gap complicates everything we do.”
Atul Gawande, Complications: A Surgeon’s Notes on an Imperfect Science
With this year’s edition of the RCSIsmj, this gap narrows ever so slightly.
From psychiatry to surgery, from original work to reviews of age-old
practice, our pages are filled with evidence of medical progress.
Javeria Tabish explores brain atrophy as a new marker for cognitive
impairment in dementia, while Gurtej Singh discusses a new surgical
technique for cholecystectomy. Thorough reviews examine novel
theories: Nadine Straka looks at foetal origins of adult health; Michael
Bravo at a physiological barrier to exercise in patients with type 2
diabetes; and, Rachel Mattson at serotonin as a link between
myocardial infarction and suicide.
At the same time, articles by Amelia Reid, Elizabeth Ahern-Flynn and
David Hakim speak to the very human side of medicine, and the
failures – in research, practice and politics – we still face.
One of the reasons I love medicine is that it is forever evolving;
treatments we use regularly today were not yet developed when our
parents were in medical school, and many will be obsolete by the time
our children start their training. Limitations that once existed no longer
do, and yet, as we progress, we meet new obstacles, previously
unimagined.
It is an absolute privilege to be a medical student; the opportunities to
learn and develop are endless, the room for growth expansive, and our
peers are among the most innovative and compassionate. At the same
time, it is a humbling experience; despite our discipline and dedication
there is still so much unknown. The imperfection and uncertainty of
medicine remind us of the need for continued effort and further
development.
I hope that the articles in this issue spark your interest in, or help fuel a
growing passion for research, and encourage you to become more
involved in your education, your career, and the future of medicine. Let
us aim to continue to close the gap.
Melissa Schorr
Editor-in-Chief RCSIsmj 2013-2014
Director’s welcome
It is with great pleasure that I welcome you to the seventh issue of the
RCSI Student Medical Journal. Our team has put a huge amount of effort
and enthusiasm into producing another high quality publication. I have
every confidence that you will enjoy reading the work produced by
RCSI students.
This year marks a milestone for the RCSIsmj; it is the first time that it has
outlived the lifespan of a student in RCSI. Over the past seven years,
the RCSIsmj has gone from strength to strength. This year, our new
initiative, the student-run journal clubs, found their feet. There were
very interesting presentations from leading researchers in RCSI, which
sparked lively discussion among students. We were joined by another
influx of enthusiastic students to the team, and we received a huge
amount of excellent submissions for publication.
The RCSIsmj is an entirely student-run publication; the articles are all
written by students, reviewed by their peers, and edited by them as
well. The consistent high quality of the RCSIsmj is a testament to the
dedication and hard work of everyone involved. I want to thank
everyone who gave up their time from their busy schedules to be
involved. I also want to thank the Dean’s Office in RCSI for their
support and assistance, without whom this publication would not be
possible.
Page 4 | Volume 7: Number 1. 2014
As my four years of involvement with the RCSIsmj come to an end, I
pass stewardship on to the next generation of students. I have no
doubt that my colleagues will continue to grow the RCSIsmj in the
future. I hope that you find the RCSIsmj serves you well – as a learning
resource, a platform to publish your hard work, and a means to enter
into the fascinating and important world of medical research.
“The very first step towards success in any occupation is to become
interested in it.”
Sir William Osler (1849-1919), Canadian physician and founding
Professor of Medicine at Johns Hopkins Hospital.
Eoin Kelleher
Director, RCSIsmj 2013-2014
RCSIsmjprize
Ethics
Challenge
2014/2015
TO SELL AND BUY A KIDNEY
One
functioning
kidney to
save a life!
Potential donors
will be morally and
financially rewarded.
Donors will receive
$10,000
plus medical care.
The case
Ben is a 29-year-old man. He lives in the Philippines and is married with
three children. He works in a factory making sports equipment. The job
does not pay very well. His wife works in a shirt factory and is also poorly
paid. Both of them want to ensure that their children will not have to
work in factories or become migrant labourers to wealthy countries. They
are aware that this can only be achieved through education. But a good
education is expensive and they don’t have that kind of money. One day
Ben sees the following advertisement in a local newspaper:
WANTED!
One functioning kidney to save a life!
Potential donors will be morally and financially rewarded.
Donors will receive $10,000 plus medical care.
This is the sixth instalment of the RCSIsmj Ethics Challenge. The
editorial staff would like to congratulate Hailey Carroll on her
winning essay in the 2013/2014 Ethics Challenge. Please see
page 6 for her submission.
We invite students to submit an essay discussing the ethical
questions raised in the case presented. Medical ethics is an
essential aspect of the medical curriculum and we hope to
encourage RCSI students to think critically about ethical situations
that arise during their education and subsequent careers.
All essays will be reviewed by a faculty panel of experts and the
winning essay will be published in the 2015 print edition of the
RCSIsmj. The deadline for submission of entries will be the same as
the general submission deadline for the 2015 edition of the
RCSIsmj. Please visit our website at www.rcsismj.com for specific
dates. Please contact us at [email protected] with any questions or
concerns.
The advertisement makes Ben think. He has two kidneys and he is
healthy. He knows that donating one of his kidneys will not be
without risk, but he also knows that it could potentially save
someone’s life.
It would also give him enough money to pay for the education of
his children so that they would not have to work in factories. It
seems that everyone would benefit from the transaction.
Questions for consideration
1. Identify the ethical issues in this case.
2. What are the ethical implications of creating a market
for organ donation?
3. What other methods could be introduced to increase the
availability of organs for transplant?
Submission guidelines
Please construct a lucid, structured and well-presented discourse
for the issues raised by this case.
Please ensure that you have addressed all the questions highlighted
and discuss these ethical issues academically, making sure to
reference when necessary.
Your paper should not exceed 2,000 words.
Your essay will be evaluated on three major criteria:
1. Ability to identify the ethical issues raised by the case.
2. Fluency of your arguments.
3. Academic quality with regard to depth of research,
appropriateness of references and quality of sources.
The winning entry will be presented with a prize at the launch
of the eighth issue. Good luck!
Volume 7: Number 1. 2014 | Page 5
RCSIsmjethics challenge
ETHICS CHALLENGE WINNER 2013/2014
End of life care: explanations,
expectations and ethics
Hailey Carroll BSc BA
RCSI medical student
Introduction
The 2013/2014 RCSIsmj Ethics Challenge introduces the case of
92-year-old Joan, who, per her family, is receiving medical treatment
against her previously expressed wishes concerning her end-of-life
care (EOLC). Despite her desire to die at home, under direction of a
district nurse, Joan was removed from her home and admitted to
hospital. Although her family was told that the admission would be
for no longer than 48 hours, Joan is now in her fifth week as an
inpatient, despite constant protest on her behalf from her family
and GP.1 The aim of this article is to dissect the complex issue of
EOLC, the ethical dilemmas highlighted by this specific case, and
the need for an established practical and legal framework for EOLC
in Ireland.
Beneficence: a physician’s actions should always be for a patient’s
benefit and well-being.2
Non-maleficence: primum non nocere or �First, do no harm.’4
Justice: �the fair distribution of health resources’.5
Additional prima facie duties
Caring: a physician’s duty to protect, empathise with, and show
concern for a patient.
Veracity: honest exchange of information as needed for the
foundation of patient autonomy.6
Physicians as reflective-generative practitioners
Ethical dilemmas frequently arise “where power is concentrated
Core principles of medical ethics
Respect for autonomy: a patient’s right to make decisions regarding
care received. If a patient’s capacity is diminished, the physician is
expected to make decisions in the patient’s best interest.2,3
Page 6 | Volume 7: Number 1. 2014
and decisions are made by a single person”.7
With regard to EOLC, conflict arises when either this is the case,
or when one party desires it to be so; this situation should be
prevented.
RCSIsmjethics challenge
As reflective-generative professionals, physicians should use
synergic power in the doctor-patient relationship. Synergic
power, as opposed to coercive power, focuses on the recognition
of patients as people rather than objects.8
When used appropriately, this enables the doctor-patient
relationship to progress to a “partnership of shared responsibility
involving joint exploration” of the patient’s condition and
treatment.8
This should take place in the context of EOLC in the following
three steps:
1. As prognosis worsens, the physician’s willingness to take
on the burden of making a decision with the patient
should increase.
2. The preferred decision-making role of the patient and family
is assessed.
3. The approach is applied to the patient’s EOLC.9
Ideally, the core medical ethical principles, the additional prima
facie duties, and this three-stepped approach will converge,
yielding an agreed-upon EOLC plan that is ethical and optimal
for the patient, relevant family members, and physician. In this
case, Joan’s family and GP are not satisfied with her current
EOLC. They believe her wishes are not being honoured. It is
necessary to determine whether this is a breach of ethics, a result
of miscommunication between those involved, or
misunderstanding regarding Joan’s prognosis. Regardless, Joan’s
family feels that she is a victim of coercive power. Whether or not
this is true is only slightly relevant, as most importantly it
highlights the need to re-establish a synergic doctor-patient
relationship.
When is the �end of life’?
In order to aptly determine an EOLC treatment plan, �end of life’
as a concept must be defined. One of the most basic issues that
arises in EOLC is a disagreement on this definition when the
effectiveness of curative care comes into question. In order to
appropriately define �end of life’, two important perspectives
must be considered: firstly, “a disease-centred perspective based
on a period of irreversible decline before death”; and secondly,
“a time-based perspective”, which outlines how long this period
is.10 The majority of legislative bodies consulted for this paper
define �end of life’ as the three to six months preceding death,
during which time the patient’s condition is “unlikely to be
arrested by medical care”.10,11 Although the patient’s condition
in this case is not explained clearly from a medical perspective,
presuming that her described deteriorating state as a �skeleton of
a person’ who no longer eats or drinks is accurate, it can be
surmised that she is in the �end of life’ period from both
perspectives.1
Patient autonomy and capacity
The line where patient autonomy ends and physician
responsibility begins is often blurred. Autonomous rights of
elderly patients, especially those with dementia, can be extremely
difficult to assess.12 In such cases, “decisions of end-of-life care
often rely on statements made prior to loss of capacity; accounts
from family, healthcare practitioners or care staff; and,
retrospective analysis of patient records”.13 In the eyes of her
family and GP, Joan’s wishes with regard to EOLC were explicit,
and since they have been ignored, they consider her care
“hijacked”.1 It is unclear what justifications the district nurse had
for admitting Joan to hospital, but a proper assessment of her
capacity and ability to make autonomous decisions would have
been part of the admission process.
Curative versus palliative care
Curative care is characterised by the ability to achieve six
comprehensive goals:14
1. Be cured.
2. Live longer.
3. Improve or maintain function/quality of life
(QoL)/independence.
4. Be comfortable.
5. Achieve life goals.
6. Provide support for family/caregiver.
When the majority of these goals are no longer realistic,
Volume 7: Number 1. 2014 | Page 7
RCSIsmjethics challenge
treatment transitions to palliative care. Palliative care is defined as
care for patients with life-threatening conditions, but this case
management and directives on prolongation of dying, can be
expressed by the patient, allowing him/her to maintain a sense of
refers specifically to EOLC.15 The decision on how and when to
make this transition is difficult for physicians as they struggle with
“the dual responsibilities of saving lives and delivering end-of-life
choice and control in his/her own care.20 Some countries like
Norway do not give ADs or ACPs any legal standing, which puts
care”.9
It is at this crossroads that, in fairness to the patient, treatment
must be assessed in terms of both probability of survival as well
as the QoL associated with survival.9
The transition process itself then needs to address place of care,
level of care, and goals of care.16
In order to harmonise the wishes of the patient with the duties of
the physician, a conversation, driven by caring and veracity,
needs to take place. In this case, there has been an undeniable
breakdown in communication during this transitional process,
which will be difficult if not impossible to rectify as Joan’s health
declines and her family’s anger grows.
Developing a framework for discussion of EOLC
The most successful, synergic, and satisfying cases of EOLC are
characterised by “early communication”, and identification and
exploration of patients’ wishes.12
There is a lack of a structured protocol for physicians regarding
EOLC. This creates a burden on physicians regarding decisions
made during EOLC.16,17
The especially fragile nature of the elderly, compounded in this
case by the patient’s progressing dementia, results in an
end-of-life period that can be “protracted and unpredictable”.17
This highlights the dire need for an early discussion to construct
a plan for EOLC. Understandably, patients and their families may
be hesitant to discuss EOLC early on in a disease diagnosis.
Despite this, research shows that such a discussion “is not
associated with patient distress, and is associated with a
reduction in use of unsuccessful life-sustaining treatments, and
improved QoL”.9
This discussion should include:
1. A review of the medical facts and options for EOLC.
2. Discussion of the patient’s perspectives on death and dying.
3. Agreement on a care plan.
4. Discussion of the family’s role in EOLC and selection of a
surrogate.
5. An advanced care plan (ACP) or advanced directive (AD)
when applicable.18
ACPs and ADs
ACPs and ADs refer to documents that indicate a patient’s wishes
regarding specific aspects of their EOLC. ACPs and ADs are
supported in some healthcare systems and completely irrelevant
in others. Countries such as Germany, the United States,
Australia, and the United Kingdom have legislation to uphold
these documents.19-21 These systems recognise that, when
drafted by an autonomous patient of appropriate capacity,
factors key to “dying with dignity”, including symptom
Page 8 | Volume 7: Number 1. 2014
an undeniable strain on patient autonomy.19
Legal implications
When assessing legal implications in cases pertaining to EOLC,
one must consider:
1. The healthcare system in which the case takes place.
2. The patient’s capacity.
3. The patient’s autonomy.
4. The futility of treatment.
5. The legislative backing in the context of an ACP or AD.
6. The legislation regarding a patient’s right to refuse treatment.
7. Physicians’ decisions in the context of the principles of
medical ethics.2,3,19-23
Physicians must be confident and execute decisions regarding
EOLC with a “high level of certainty”, for if they do not, the
consequences they may face could be severe, whether handed
down from criminal courts, legal tribunals, or licensing
organisations.24
Many countries have court cases that have set precedents for
controversial aspects, with respect to the law, of EOLC. It is
suggested that if an issue does arise, a physician should seek
assistance from his/her respective ethical committees as well as
seeking legal counsel.22
Dying with dignity
Independently, �dying’ and �dignity’ are words that lack
definitional specificity. Thus, this phrase has been reassessed and
redefined constantly in the context of EOLC. The American Journal
of Hospice and Palliative Care defines �dying with dignity’ as:
“Having one’s human value and worth acknowledged; being
cared for with respect and empathy; having a voice regarding
one’s dying process; minimising physical and emotional suffering;
safeguarding one’s privacy; maintaining emotional connection
with others; resolving personal affairs; and, having access to
spiritual sources of support”.25
Conclusion of this case
EOLC is a complex issue that presents unique challenges towards
principles of medical ethics on a case-by-case basis. In looking at
this case in the context of the Irish health system, certain
questions need to be answered in order to assess the ethical
issues in this case:
■Is Joan in the �end of life’ period?
в– How, to whom, and when did Joan express her wishes
regarding her EOLC?
в– Did she have the capacity to express these wishes?
в– Did she have an ACP or AD?
в– Why did the district nurse see fit to move her to hospital?
RCSIsmjethics challenge
■Why was Joan’s family told the stay would be 48 hours
maximum?
в– What medical treatment is she receiving as an inpatient on the
ward that warrants her continued stay?
competent adult is not free to decline medical treatment”.3
However, if a competent Joan had drafted an AD, confusion
regarding her EOLC would still exist. The Irish Medical Council
itself claims that it is “difficult to state the legal position” of ADs
due to a lack of “relevant statuary provisions” in Irish
The answers to these questions will offer a better understanding
of the progression of this case. However, this ambiguous case is a
microcosm for EOLC in Ireland.
The lack of legislation regarding these issues only exacerbates the
complexity of this case. The Irish Constitution protects a patient’s
right to refuse treatment. In 2008, Judge Laffoy, when presiding
over Fitzpatrick vs K, ruled that “it could not be argued that a
legislation.26
This ambiguity is unacceptable and unfortunately allows Joan’s
experience with EOLC in the Irish system to be an example of
diminished dignity while dying simply due to a lack of protocol.
Perhaps it is not only the doctor-patient relationship that needs
to value synergic power, but also the relationship between the
Irish Medical Council and its constituents.
References
1. RCSI Ethics Challenge 2013/2014. Royal College of Surgeons in Ireland
Student Medical Journal. 2013;6(1):6.
2. Department of Health, Education, and Welfare. The Belmont Report:
Ethical principles and guidelines for the protection of human
subjects of research. 1979. [Internet] [cited 2011 October 28].
Available from:
http://www.recerca.uab.es/ceeah/docs/Belmont%20Report.pdf.
3. McCarthy J, Donnelly M, Dooley D, Campbell L, Smith D. End-of-Life
Care: Ethics and Law. Cork; Cork University Press, 2011.
4. Smith CM. Origin and uses of primum non nocere – above all, do no
harm! J Clin Pharmacol. 2005;45(4):371-7.
5. Lawson AD. What is medical ethics? Trends Anae Crit Care. 2011;1:3-6.
6. Capozzi JD, Rhodes R. Lying for the patient’s good. J Bone Joint Surg
Am. 2004;86-A(1):187-8.
7. Chambliss DF. Beyond Caring: Hospitals, Nurses, and the Social
Organisation of Ethics. Chicago; The University of Chicago Press, 1996.
8. Dokecki P. The Tragi-Comic Professional: Basic Considerations for Ethical
Reflective-Generative Practice. Duquesne University Press, 1996.
9. Curtis JR, Vincent JL. Ethics and end-of-life care for adults in the
intensive care unit. Lancet. 2010;376(9749):1347-53.
10. Lamont EB. A demographic and prognostic approach to defining the
end of life. J Palliat Med. 2005;8(Suppl. 1):12-21.
11. Lunney JR. Redefining our definition of end of life. J Hosp Palliat Nurs.
2001;3:5-6.
12. Goodman C, Amador S, Elmore N, Machen I, Mathie E. Preferences and
priorities for ongoing and end-of-life care: a qualitative study of older
people with dementia resident in care homes. Int J Nurs Stud.
2013;50(12):1639-47.
13. Goodman C, Baron NL, Machen I et al. Culture, consent, costs and care
homes: enabling older people with dementia to participate in research.
Aging Ment Health. 2011;15(4):475-81.
14. Kaldjian LC, Curtis AE, Shinkunas LA, Cannon KT. Review article: goals
of care toward the end of life: a structured literature review. Am J Hosp
Palliat Care. 2009;25(6):501-11.
15. Г–stlund U, Brown H, Johnston B. Dignity conserving care at end-of-life:
a narrative review. Eur J Oncol Nurs. 2012;16(4):353-67.
16. Hui D, Nooruddin Z, Didwaniya N et al. Concepts and definitions for
“actively dying”, “end of life”, “terminally ill”, “terminal care”, and
“transition of care”: a systematic review. J Pain Symptom Manage.
2014;47(1):77-89.
17. Pautex S, Curiale V et al. Palliative care in acute geriatric care units
across Europe: Some reflections about the experience of geriatricians.
Euro Geri Med. 2013;4:288-92.
18. Curtis JR, Engelberg RA et al. Studying communication about end-of-life
care during the ICU family conference: development of a framework. J
Crit Care. 2002;17(3):147-60.
19. Bahus MK, Steen PA, FГёrde R. Law, ethics and clinical judgment in
end-of-life decisions – how do Norwegian doctors think? Resuscitation.
2012;83(11):1369-73.
20. Detering KM, Hancock AD, Reade MC, Silvester W. The impact of
advance care planning on end of life care in elderly patients:
randomised controlled trial. BMJ. 2010;340:c1345.
21. Board of Citizens Information. Advance Care Directives. 2010. [Internet]
[cited 2013 October 27] Available from:
http://www.citizensinformation.ie/en/health/legal_matters_and_health/
advance_care_directives.html.
22. Emmanuel EJ, Arnold RM, Dizon D. Legal aspects of end of life care.
Literature Review current to September 2013. [Internet] [cited 2013
October 27]. Available from:
http://www.uptodate.com/contents/legal-aspects-of-end-of-life-care.
23. Bok S. Lying: moral choice in public and private life. New York; Vintage,
2002.
24. Hawryluck L, Sibbald R, Chidwick P. The standard of care and conflicts
at the end of life in critical care: lessons from medical-legal crossroads
and the role of a quasi-judicial tribunal in decision-making. J Crit Care.
2013;28(6):1055-61.
25. Proulx K, Jacelon C. Dying with dignity: the good patient versus the
good death. Am J Hosp Palliat Care. 2004;21(2):116-20.
26. Irish Medical Council. Advanced Directives. [Internet] [cited 2013
November 2] Available from:
http://www.medicalcouncil.ie/News-and-Publications/Publications/Discu
ssion-Documents/Advanced-Directives.html.
Volume 7: Number 1. 2014 | Page 9
RCSIsmjoriginal article
Evaluation of adverse events
and patient satisfaction with
day surgery before and after
the implementation of
pre-assessment in an Irish
teaching hospital
Abstract
YH Soon1
L McEvoy2
G Paul2
S Cowman2
1RCSI
medical student
2Faculty
of Nursing and
Midwifery, RCSI
Objectives: Advancements in surgical techniques have facilitated the rapid expansion of day
surgical services. In 2011, a study was carried out to evaluate patients’ satisfaction with the
day surgery process and their experience of adverse events. Based on the findings, a
nurse-led pre-assessment process was introduced as part of the development of best practice
for day surgery in Ireland.1 Subsequently, this study was carried out in 2013 for re-evaluation
of patient satisfaction and adverse events.
Methods: The study design was a telephone questionnaire. Patients who had undergone
nurse pre-assessment since November 2012 were given full information before being invited
to participate in the survey. Data collection was completed in July 2013.
Results: Of the 150 patients, 91 were eligible and completed the survey (60.67%). The data
was compared with 2011 data. Patients were satisfied overall with the implementation of the
pre-assessment process. Although adverse events increased over time, unplanned return visits
decreased in the 2013 cohort.
Conclusion: Clear communication before and after a procedure is vital to prevent
unnecessary return visits. The pre-assessment process helps in providing clarification and
reassurance to patients. Multidisciplinary collaboration is crucial to maintain a high level of
patient satisfaction.
Key words: Day surgery; pre-assessment; patient satisfaction; adverse event; return visit.
Royal College of Surgeons in Ireland Student Medical Journal 2014; 1: 10-13.
Page 10 | Volume 7: Number 1. 2014
RCSIsmjoriginal article
Table 1: Patient demographics of three survey studies.
Patient
satisfaction (2011)*
Adverse
events
(2011)*
Patient satisfaction and
adverse events in patients
that were nurse
pre-assessed (2013)
Eligible
patients
70
92
114
Completed
survey
60
83
91
Patient
response
rate
85.7%
90.2%
79.8%
Male:
female
ratio
24:36
29:54
43:48
Patient
mean
age
47 years
46 years
45 years
120%
100%
% of patients
80%
60%
40%
20%
0%
Information
leaflet
received
Patients who
read the
information
leaflets
received
Information
leaflet read by
patient and
family
Referred to
secondary
source
for more
information
n2011
87.95%
91.8%
29%
21.7%
n2013
93.4%
95.3%
44.71%
53.9%
FIGURE 1: Comparison of patient information prior to procedure, before
(2011) and after (2013) implementation of �Best Practice Statements
on Day Surgery in Ireland’.
Introduction
The Health Service Executive (HSE) defines a day case as a hospital
admission “on an elective basis for care and/or treatment, which does
not require the use of a hospital bed overnight and who is discharged as
scheduled”.2 Ongoing development of surgical techniques and
short-acting anaesthesia allows certain procedures to be performed as
day cases.3 Day surgery (DS) has several advantages, including
short-term hospital stay, faster recovery due to minimal invasiveness, and
cost reduction for the patients attending the hospital. This leads to a
more consumer-friendly treatment.4 According to a report by the World
Health Organisation (WHO), Canada and the US now expect 90% of
elective procedures to be carried out as DS.4 The UK and Scandinavian
countries are also dedicated to increasing DS levels.5 In Ireland, however,
DS uptake is still relatively low, although the HSE aims to increase the
current rate of 55% to 80%.6
The relatively low numbers of DS procedures in Irish hospitals have
resulted in a paucity of data on certain aspects of the process. Starting in
2011, a three-year project to improve the DS service in Ireland was
commenced. One of the aspects of the study was to measure patients’
satisfaction and adverse events associated with DS. Through this study,
high rates of unplanned return visits postoperatively were discovered.
These were due to various adverse events such as fatigue, drowsiness,
poor appetite, and sore throat. Stemming from this research, a set of
guidelines called the �Best Practice Statements on Day Surgery in Ireland’
were developed. These include patient information leaflets (PILs),
pre-assessment, documentation, management, discharge and
monitoring.1
The aim of this study was to verify patients’ satisfaction, and to quantify
and qualify adverse events following DS in an Irish teaching hospital, and
to compare these findings with those from the initiation of nurse-led
pre-assessment and of the �Best Practice Statements for Day Surgery’ in
2011.
Methods
The study design was a cross-sectional survey, using a telephone
questionnaire. All patients attending for DS between November 2012
and June 2013 inclusive, underwent pre-assessment with a nurse. All
*Data from the initial surveys carried out by the research team in 2011.
pre-assessed patients were invited to participate in the survey. Patients
were fully informed, assured of confidentiality, and made aware of their
right to opt out of the study at any time. Patients who agreed to
participate received a telephone call during a pre-arranged date and
time. The questionnaire was designed taking the 2011 study into
consideration. Construct validity was ensured through review of the
questionnaire by personnel involved in DS (chief nurse, research nurse,
consultant anaesthetist and consultant surgeon). Pilot testing was
completed and no further revisions were made. The completed
questionnaire contained 27 questions to evaluate five areas of the DS
process. The questions were generally closed, requiring a �yes’, �no’ or
�don’t know/don’t remember’ answer. Additional open questions were
asked to allow patients to give qualitative answers. All data was analysed
using Microsoft Excel. The study was approved by the hospital’s Research
Ethics Committee.
Results
A total of 150 patients were pre-assessed by the nurse prior to DS
between November 2012 and June 2013. Of these, 36 (24%) patients
were not eligible for the study as their surgery was not performed for
various reasons. The remaining 114 eligible patients were contacted by
phone in July 2013, and 102 (89.5%) responded. After contact had
unsuccessfully been attempted three times, 12 patients (10.5%) were
deemed unresponsive and not included in the study. Of the 102 patients
who did respond, 11 (10.8%) did not complete the survey. Reasons
included: patient declined participation; phone was not in service;
patient did not speak English; family bereavement; patient was deaf; and,
patient was transferred to another hospital. Therefore, 91 (79.8%)
patients out of 114 eligible patients completed the survey (Table 1).
Patient information leaflet
Of the 91 patients included in the study, 85 (93.4%) received a PIL
regarding their procedure, of which 81 (95.3%) reported actually having
read it. In 38 (44.71%) cases, both the patient and the patient’s carer
read the leaflet.
Forty-nine patients (53.9%) referred to a secondary source for more
information regarding the procedure (Figure 1).
Volume 7: Number 1. 2014 | Page 11
RCSIsmjoriginal article
80%
70%
25%
60%
20%
% of patients
% of patients
30%
15%
10%
5%
0%
Return to
hospital
Return
to GP
Return to
practice
nurse
50%
40%
30%
20%
10%
0%
Drowsy and
tired
Sore throat
Poor sleep and
appetite
Pain and
discomfort
n No pre-assessment
10.8%
26.5%
0%
n2011
33.7%
7%
8.4%
32.5%
n Pre-assessment
7.7%
16.5%
1.1%
n2013
55%
17.6%
30.8%
73.6%
FIGURE 2: Comparison of unplanned return after discharge, before
(2011) and after (2013) implementation of �Best Practice Statements
on Day Surgery in Ireland’.
Unplanned return to healthcare clinic post operatively
A total of 23 patients (25%) had an unplanned return to a healthcare
service provider following surgery (Figure 2). Overall, seven (7.7%)
patients had an unplanned return visit to the hospital following DS. The
reasons for their returns were: pain (n=3); symptoms of infection (n=2);
swelling (n=1); and, need for colonoscopy (n=1). The time period
between surgery and unplanned return ranged from four days to four
weeks. Three of the seven patients were reassured by staff and required
no additional management. In total, 15 (16.5%) patients had an
unplanned visit to their GP. One (1.1%) patient returned to the practice
nurse after DS. The reasons for their returns were: pain (n=4); weight
loss and fatigue (n=3); undissolved stitches (n=3); swelling (n=2);
symptoms of infection (n=2); leakage from the surgical site (n=1); and,
allergic reaction to bandages (n=1). The time between surgery and
return visits ranged from two days to 10 weeks, with a peak between
one and two weeks post operatively (n=6). Most patients were
managed by the GP or practice nurse; however, six (37.5%) were
referred to the hospital. Additionally, 10 (11%) patients phoned the Day
Surgery Unit (DSU), mainly with regard to wound healing.
Adverse events
Pain
Sixty-seven patients (73.6%) experienced some form of pain after being
discharged (Figure 3). Most patients’ pain was at the surgical site or
was wound specific (n=64; 95.5%). Pain severity on a scale of 1 to 10
(10 being the worst pain ever) was evenly distributed across the scale
with a mode of 6. Pain duration varied greatly from a few hours (n=6;
9%) to persisting (n=12; 17.9%). Of the 63 patients who took pain
relief tablets, 54 (85.7%) experienced full relief with no side effects. Six
patients had no pain relief and the other three experienced side effects.
Thirteen patients achieved pain relief by other conservative means. Of
the 67 patients who reported postoperative pain, 27 (40.3%) reported
that their lifestyle was affected due to the pain, with negative impacts
on sleeping, eating, mobility, and ability to go to work.
Nausea and vomiting
Eleven patients (12%) experienced nausea, vomiting or both after
discharge; eight patients reported disruption in sleep and eating as a result.
Page 12 | Volume 7: Number 1. 2014
FIGURE 3: Comparison of adverse events after surgery, before (2011)
and after (2013) implementation of �Best Practice Statements on Day
Surgery in Ireland’.
General adverse events
General adverse events included sore throat (17.6%), feeling drowsy
(55%), problems with sleeping (17.6%) and decreased appetite (13.2%).
Pre-assessment
Eighty-three patients recalled being pre-assessed by a nurse prior to day
surgery. Eighty-one (97.6%) of these found pre-assessment helpful, as it
provided explanation and information (n=45; 55.6%), saved time on
the day of the procedure as all the pre-operative requirements were
completed (n=7; 8.6%), and provided reassurance (n=29; 35.8%),
giving the patients the opportunity to ask questions. Two (2.4%)
patients did not find pre-assessment helpful. One stated that a patient
should already have been fully informed about their procedure even
without the pre-assessment, while the other was too eager to get the
surgery done and not interested in being informed. Forty-eight (52.7%)
patients reported having undergone a DS procedure before. When
asked to compare the experience with and without pre-assessment, 27
(56.3%) patients said pre-assessment was helpful to have, 10 (20.8%)
said that there was no difference, seven (14.6%) were not sure, and four
(8.3%) thought pre-assessment was not necessary in some cases,
especially if the patient had undergone the same procedure before, or
was going through a very simple procedure.
Post-op follow-up telephone call from a DS nurse
Patients were asked if a telephone call one week post discharge would
be helpful. Sixty-one (67%) patients said �yes’, 27 (29.6%) said �no’, and
three (3.3%) stated that it would depend on the complexity of the case.
The most common reasons for supporting the follow-up telephone call
was for a check-up on the patient’s progress (n=21; 34.4%), reassurance
(n=18; 29.5%), to ask questions (n=7; 11.5%), and to find out surgical
outcomes (n=7; 11.5%). Additionally, three patients suggested a
telephone call to be made later than one week post operatively to cover
long-term side effects, while one patient suggested a call within a few
days post operatively to cover immediate side effects.
Comparison to 2011
The results of this study compared to the results from the 2011 study
are outlined in Figures 1, 2 and 3. Overall distribution of PILs increased
RCSIsmjoriginal article
(from 87.95% to 93.4%), and they were read by more families (from
29% to 44.7%) from 2011 to 2013. However, there was also an
increase in referral to a secondary source for information, from 21.7%
in 2011 to 53.9% in 2013. Unplanned return visits decreased overall
from 2011 to 2013, with 7.7% returning to hospital in 2013 compared
to 10.8% in 2011, and 16.5% returning to the GP compared to the
previous 26.5%. Interestingly, adverse events increased from 2011 to
2013 over all four outcomes: drowsy/tired; sore throat; poor
sleep/appetite; and, pain/discomfort.
Discussion and conclusion
As the study is still in the initial stages of implementing �Best Practice
Statements on Day Surgery in Ireland’, and looks at only one aspect, it
is hard to draw conclusions about the guidelines as a whole. However,
it is interesting to compare differences between the surveys carried out
initially in 2011, and this current one. The number of patients provided
with an appropriate PIL remained high. However, the 2013 survey
showed an increased number of referrals to secondary sources for
further information. This may suggest that the leaflet does not provide
sufficient information. The research team is currently working to
improve the PILs for both hard copy and online versions. Overall, there
has been increased reporting of adverse events over time. This may be
explained by the different time frame in which the survey was carried
out. The 2011 survey was carried out three weeks post operatively,
whereas the 2013 survey was carried out from three weeks to six
months post operatively, covering both immediate and long-term
adverse events.
A study reports that the discomfort and other adverse events that
patients experience may last up to three months post sugery.7
However, this increase in adverse events must be evaluated taking into
account the number of patients who returned to a health service
provider as a result of these adverse events. Despite the higher rate of
adverse events, the 2013 report showed a lower rate of unplanned
return visits. This may be a result of pre-assessment. The nurse in
charge took approximately 20 minutes with each patient to go
through all the details involved in the procedure, thereby better
informing the patients and providing reassurance with regard to
possible side effects of the procedure. This may have prevented
patients from unnecessarily seeking advice from a healthcare
professional.
A national survey carried out in Ireland in 2010 reported return
admission rates ranging from 0.3% to 9.5%, with the majority less than
3%.8 Unanticipated hospital admission rate reported at the annual
scientific meeting in Glasgow in 2006 was also 1-2%.9 Although none
of the patients in this study who returned to hospital were admitted,
there is still room to improve on adverse events in patients that lead to
unplanned return visits.
Clear communication before and after a procedure is vital to provide
clarity to patients and to reassure them regarding the post-operative
course and management, and to prevent unnecessary return visits. This
current study adds to our knowledge of adverse events both short and
long term, and how pre-assessment may be an effective way of
preventing unnecessary healthcare facility visits, and therefore reducing
healthcare costs and waiting lists.
Acknowledgements
This study forms part of a larger Health Research Board (HRB) funded
study to develop best practice for the provision of day surgery in
Ireland (Professor S. Cowman, Principal Investigator). The student was
funded by the HRB grant, finance code 1319.
References
1. Cowman S. Day Surgery in Ireland. The development,
implementation and evaluation of a consensus derived, best
practice approach [unpublished lecture notes]. Health Service
Executive. Royal College of Surgeons in Ireland. ESRI Ireland. Health
Research Board. RCSI Day Surgery Conference [2013 October].
Page 18.
2. Cowman S. Maximizing Day Surgery in Ireland [unpublished
lecture notes]. Health Service Executive. Royal College of Surgeons
in Ireland. National Clinical Programme in Surgery. [2013 April].
Page 14.
3. Royal College of Anaesthetists. Guidelines for the Provision of
Anaesthetic Services for Day Surgery. Guidance on the provision of
anaesthetic services. [Internet] 2010; 17:1-6 [cited 2011 October
13]. Available from:
http://www.rcoa.ac.uk/docs/GPAS-daySurg.pdf.
4. Castoro C, Bertinato L, Baccaglini U, Drace CA, McKee M. Policy
Brief. Day Surgery: Making it Happen. European Observatory on
Health Systems and Policies. 2007; 1-32. [Internet] Available from:
http://www.euro.who.int/__data/assets/pdf_file/0011/108965/E90
295.pdf.
5. Hughes A. Day surgery: Trends in practice. Prospectus.
2007;1:1-24.
6. Brick A, Wiley MM. Day Surgery in Ireland: The Development,
Implementation and Evaluation of an Evidence Based and
Consensus Derived Best Practice Model. The Economic and Social
Research Institute. [Internet] 2007. [cited 2011 October 12].
Available from: http://www.esri.ie/research/current_research
_projects/search_results/index.xml?Area=5.
7. Rosen H, Bergh IHE, Lundman BM, Martensson LB. Patients’
experiences and perceived causes of persisting discomfort following
day surgery. BMC Nurs. 2010;9(16):1-8.
8. Cowman S, Gethin G, Mulligan E, Ryan K, Meshkat B. National
survey of the provision of day surgery across public and private
hospitals in Ireland. Ir J Med Sci. 2010;179:493-9.
9. Chung F. Adverse Events in Ambulatory Care. J. One-Day Surg.
2006;16(4):1-4.
Meshkat B. Day Surgery in Ireland: Current barriers and determining a
consensus driven best practice approach. [Unpublished thesis.] Royal
College of Surgeons in Ireland. 2011:1-192.
Volume 7: Number 1. 2014 | Page 13
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Regions of atrophy that
correlate with cognitive
impairment in subtypes
of dementia
Abstract
Javeria Tabish
RCSI medical student
Objectives: The objective of this study was to examine regions of volume loss in the different
subtypes of dementia to find novel biomarkers for diagnosis of the disease in vivo.
Methods: Sixty-three computed tomography (CT) scans of patients with diagnoses of mild
cognitive impairment (MCI, n=17), Alzheimer’s disease (AD, n=15), vascular cognitive
impairment (VCI, n=21) and vascular dementia (VaD, n=10) were obtained from the memory
disorders clinic at St Michael’s Hospital, Toronto. In addition to cognitive evaluation carried
out using the Behavioural Neurology Assessment (BNA), all patients underwent a CT scan.
Linear measurements were performed to assess degree and location of atrophy and then
correlated with the BNA.
Results: Patients with MCI showed significant loss of volume in the temporal horn (p<0.01),
suprasellar cistern (p<0.05) and frontal (p<0.05) regions which correlated with declining
memory. Patients with AD displayed significant loss of temporal horn volume (p<0.01) and
third ventricle regions (p<0.05), which correlated with memory loss. Patients with VCI
displayed decreased volume in the suprasellar cistern (p<0.01), bicaudate (p< 0.05) and third
ventricle (p<0.05) regions, which correlated with memory loss. Similar correlations in the
suprasellar cistern (p<0.01) and bicaudate (p<0.05) regions were found in VaD, in addition to
volume loss in frontal (p<0.05) regions, which correlated with declining executive function.
Conclusion: Although the pattern of atrophy seen with MCI and AD patients was as
expected, new regions of volume loss were found in patients with VCI. The existence of
atrophy in the bicaudate region is a novel finding for this diagnosis, as atrophy was previously
suspected in more frontal regions. This implies that volume loss in the bicaudate region can
be used as a biomarker when correlated with memory to predict conversion from VCI to VaD.
Royal College of Surgeons in Ireland Student Medical Journal 2014; 1: 14-19.
Page 14 | Volume 7: Number 1. 2014
RCSIsmjoriginal article
Introduction
Alzheimer’s disease (AD) and vascular dementia (VaD) are the two
most prevalent forms of dementia worldwide. Although these two
diseases have different aetiologies, both result in devastating health
implications for the individual, socio-economic impositions on the
caregiver, and a staggering worldwide annual cost of US$604 billion.1
The clinical hallmark of AD is amnestic deficit prior to cognitive
decline that affects all other cognitive domains. Clinical manifestation
of VaD, by contrast, is dependent on the anatomical location of the
insults.2,3
Interestingly, both of these forms of dementia may
vascular
be the end result of a progressive syndrome of impairment in one or
more cognitive domains that does not cause functional impairment.
Mild cognitive impairment (MCI) is a recognised prodromal stage of
AD,4 and though vascular cognitive impairment (VCI) serves as an
�umbrella term’ for multiple other cerebrovascular dementias, a VCI
diagnosis can also precede one of VaD.5 AD is a neurodegenerative
disease, involving beta amyloid plaque formation and tau-containing
neurofibrillary tangles.2 VaD reflects a more dynamic disease. It can
result from a variety of cerebrovascular disorders including
haemorrhagic or ischaemic brain damage.6 The subsequent clinical
features and therapeutic interventions vary for each disease;2-4,6 thus,
it is essential to distinguish between the subsets of dementia in the
early stages of diagnosis. Although the course of functional decline in
both diseases – gradual in Alzheimer’s compared to a stepwise decline
typically seen in VaD4 – helps clinicians to make a diagnosis, an earlier
marker that appears before significant impairment is key.
Neuroimaging studies at present focus on identifying in vivo
biomarkers to enable earlier diagnosis, and monitor disease
progression and therapeutic effect.4 Numerous structural magnetic
resonance imaging (MRI) studies on AD have reported significant
atrophy of structures in the medial temporal lobes and in the
temporo-parietal association areas.7-12 Imaging studies of patients with
VaD, however, seldom focus on atrophic change, and more commonly
show multiple or significant single infarcts, haemorrhages, multiple
lacunes and white matter lesions.6 Memory is initially and most
severely affected in AD,13,14 compared to frontal dysfunction in VaD.
Insult to the frontal or pre-frontal areas of the brain can impair
executive functioning and have detrimental effects on ability to make
plans, verbal reasoning, inhibition, and mental flexibility.3,15 A review
of the scientific literature indicates that substantial research has been
carried out using MRI measures of disease progression. However,
studies using computed tomography (CT) are limited16,17 even
though CT is the most prevalent form of neuroimaging for patients
referred to memory clinics.18 The ability to identify patients who are
likely to progress from MCI to AD and VCI to VaD using simpler
methods than MRI analysis is invaluable. The present study uses linear
measurements as described by Zhang et al.19 to measure regional
cerebral atrophy and correlate this data with the different cognitive
domains outlined by the Behavioral Neurology Assessment (BNA).20
The BNA is a neuropsychiatric assessment tool used most commonly
in hospitals and clinics in the Greater Toronto Area. It is a quick
measure (<20 minutes) of the degree of cognitive impairment
(sensitivity of 93%, specificity of 93%) in patients with suspected
dementia.13,20 The aim of this study is to use those diagnostic
methods routinely used in memory clinics to find novel biomarkers for
the diagnosis of dementia and establish methods to differentiate AD
from VaD earlier in the course of the disease.
Methods
Participants
Scans of 63 patients with diagnoses of MCI, AD, VCI and VaD were
obtained from the memory disorders clinic at St Michael’s Hospital in
Toronto, Canada. Prior to a CT scan, all patients were evaluated via
history, physical examination and cognitive function evaluations,
including the Mini Mental State Exam (MMSE) (total score out of 30)
and BNA (total score out of 114). The BNA includes measures of
memory, language, attention, visuospatial function, naming and
executive function; a higher score indicates more cognitive
impairment, whereas a lower score on the MMSE signifies a greater
decline. AD and VaD patients were matched by age, BNA and MMSE
scores (see Table 1). The same was done for MCI and VCI patients. All
patients spoke English as a first language. This study received approval
from the hospital’s Research Ethics Board.
CT acquisition
All participants underwent non-contrast axial cranial CT. The following
parameters were used: 120Kv at 2.5mm and 5mm slice thickness with
a range of 170-340mA at 2.5mm slice thickness and 140-280mA at
5mm slice thickness.
CT measurements
Linear measurements were taken using the digital calipers in Analyze
9.0. The rater was blinded to the participants’ clinical data. The
following seven linear measurements deemed statistically significant by
Zhang et al. were used: maximal transverse intracranial width (A);
maximal width of the frontal skull (B); maximal width of the third
ventricle (C); minimal intercaudate difference (D); maximal frontal
horn width (E); suprasellar cistern (F); and, temporal horn diameter
(derived from averaging the left and right temporal horn diameters)
(G). Using these measurements, the following indices and ratios were
calculated: third ventricle ratio (C/A); bicaudate ratio (D/A); Evans
Table 1: Demographic and cognitive values of AD and VaD patients.
AD (n=15)
Mean
SD
VaD (n=10)
Mean
SD
p-value
Age at CT scan
77.7
6.2
76.2
8.6
Overall BNA (/114)
66.5
14.4
63
14.4
0.56
MMSE (/30)
22.2
3.7
24.3
4
0.20
0.64
Volume 7: Number 1. 2014 | Page 15
RCSIsmjoriginal article
ratio (E/B); Huckman’s number (D+E); suprasellar cistern ratio (F/A);
and, temporal horn ratio (G/A) (Figure
1).19
Statistics
A one-tailed bivariate correlation (where r=Pearson’s coefficient) was
used when a decreasing BNA domain was hypothesised to increase
the CT ratios. A two-tailed correlation was used when the nature of
the relationship could not be predicted.
Results
Demographic data of the four diagnostic groups is outlined in Tables 1
and 2. When compared to their cognitive counterpart, there were no
statistically significant differences between groups in age at CT, total BNA
or total MMSE score, as all p-values were >0.10. Tables 3 and 4 compare
the means of the BNA subsets within groups that share the same
aetiology, i.e., MCI with AD and VCI with VaD. P-values were <0.05, with
the exception of attention and concentration, across VCI and VaD.
B
E
D
G
F
C
A
FIGURE 1: Linear measurements obtained from axial CT slices: maximal
transverse intracranial width (A); maximal width of the frontal skull (B);
maximal width of the third ventricle (C); minimal intercaudate
difference (D); maximal frontal horn width (E); suprasellar cistern (F);
and, temporal horn diameter (G). Using these measurements, the
following indices were calculated: third ventricle ratio (C/A); bicaudate
ratio (D/A); Evans ratio (E/B); Huckman’s number (D+E); suprasellar
cistern ratio (F/A); and, temporal horn ratio (G/A).
Table 2: Demographic and cognitive values of MCI and VCI patients.
MCI (n=17)
VCI (n=21)
Mean
p-value
Mean
SD
SD
Age at CT scan
69.1
10.9
70.9
9.9
0.60
Overall BNA (/114)
89.1
10
89.3
7.8
0.94
MMSE (/30)
27.8
1.3
27.4
2.7
0.56
Table 3: Measures of the BNA subsets of AD and MCI patients.
AD (n=15)
MCI (n=17)
p-value
Mean
SD
Mean
SD
1.87
1.41
4.24
1.52
p<0.001
Memory
16.53
3.96
21.41
4.03
0.00086
Naming
17.33
5.29
22.76
4.49
0.0022
Visuospatial function
11.27
2.58
13.12
2.18
0.019
Executive function
19.53
7.66
27.59
4.00
0.00076
Attention
and concentration
Table 4: Measures of the BNA subsets of VaD and VCI patients.
VaD (n=10)
VCI (n=21)
p-value
Mean
SD
Mean
SD
2.9
1.91
3.67
1.71
0.15
Memory
16.6
4.14
22.86
2.29
0.00041
Naming
16.4
3.95
22.29
4.22
0.00062
Visuospatial function
11.4
2.67
13.71
1.49
0.013
Executive function
15.5
8.00
26.81
5.11
0.00068
Attention
and concentration
Page 16 | Volume 7: Number 1. 2014
RCSIsmjoriginal article
Table 5: Bivariate correlation of CT measures and the cognitive domains of the BNA in 17 MCI patients.
MCI
Suprasellar
cistern ratio
Temporal
horn ratio
Bicaudate ratio
Huckman’s
number
Third
ventricle ratio
Evans ratio
0.093
0.724
0.065
0.806
0.116
0.658
0.118
0.652
-0.054
0.838
Attention and
concentration
Pearson correlation
Sig. (2-tailed)
0.024
0.928
Memory
Pearson correlation
-0.421*
-0.606**
-0.23
-0.514*
-0.110
-0.358
Sig. (1-tailed)
0.046
0.01
0.19
0.017
0.337
0.079
-0.241
Naming
Pearson correlation
-0.216
-0.457
-0.386
-0.386
-0.223
Sig. (2-tailed)
0.406
0.066
0.126
0.126
0.39
0.352
Pearson correlation
-0.234
-0.103
-0.089
-0.088
-0.178
-0.249
function
Sig. (2-tailed)
0.366
0.694
0.734
0.736
0.494
0.336
Executive
Pearson correlation
-0.066
-0.062
-0.398
-0.359
-0.156
-0.274
function
Sig. (1-tailed)
0.400
0.407
0.057
0.079
0.275
0.144
Huckman’s
number
Third
ventricle ratio
Evans ratio
Visuospatial
Table 6: Bivariate correlation of CT measures and the cognitive domains of the BNA in 15 AD patients.
AD
Suprasellar
cistern ratio
Temporal
horn ratio
Bicaudate ratio
Attention and
concentration
Pearson correlation
Sig. (2-tailed)
-0.319
0.268
-0.226
0.416
-0.400
0.140
-0.247
0.374
-0.425
0.114
0.190
0.498
Memory
Pearson correlation
Sig. (1-tailed)
-0.044
0.438
-0.655**
0.004
-0.318
0.124
-0.299
0.139
-0.468*
0.039
0.022
0.469
Naming
Pearson correlation
Sig. (2-tailed)
-0.275
0.320
-0.207
0.458
-0.234
0.408
-0.232
0.406
-0.288
0.298
0.105
0.71
Visuospatial
function
Pearson correlation
Sig. (2-tailed)
-0.064
0.822
0.147
0.602
0.286
0.302
0.297
0.282
0.486*
0.066
0.096
0.734
Executive
function
Pearson correlation
Sig. (1-tailed)
0.381
0.081
-0.022
0.469
-0.177
0.264
-0.108
0.351
-0.205
0.232
0.144
0.304
Table 7: Bivariate correlation of CT measures and the cognitive domains of the BNA in 21 VCI patients.
VCI
Suprasellar
cistern ratio
Temporal
horn ratio
Bicaudate ratio
Huckman’s
number
Third
ventricle ratio
Evans ratio
Attention and
concentration
Pearson correlation
Sig. (2-tailed)
-0.056
0.808
0.362
0.106
0.091
0.696
0.266
0.244
0.307
0.176
0.311
0.170
Memory
Pearson correlation
Sig. (1-tailed)
-0.484**
0.01
-0.32
0.08
-0.479*
0.049
-0.214
0.176
-0.414*
0.031
-0.020
0.466
Naming
Pearson correlation
Sig. (2-tailed)
-0.220
0.338
0.121
0.602
0.078
0.738
0.083
0.720
-0.111
0.634
-0.068
0.770
Visuospatial
function
Pearson correlation
Sig. (2-tailed)
0.188
0.414
-0.051
0.828
-0.004
0.986
-0.071
0.760
-0.036
0.878
0.012
0.960
Executive
function
Pearson correlation
Sig. (1-tailed)
-0.227
0.161
0.052
0.411
-0.095
0.341
-0.114
0.311
0.009
0.484
0.019
0.468
Huckman’s
number
Third
ventricle ratio
Evans ratio
Table 8: Bivariate correlation of CT measures and the cognitive domains of the BNA in 10 VaD patients.
VascularI
dementia
Suprasellar
cistern ratio
Temporal
horn ratio
Bicaudate ratio
Attention and
concentration
Pearson correlation
Sig. (2-tailed)
0.042
0.908
0.285
0.424
0.005
0.988
-0.582
0.078
0.338
0.340
-0.515
0.128
Memory
Pearson correlation
Sig. (1-tailed)
-0.806**
0.002
0.238
0.254
-0.652*
0.021
-0.153
0.337
-0.267
0.228
0.230
0.261
Naming
Pearson correlation
Sig. (2-tailed)
-0.315
0.376
0.446
0.196
-0.495
0.146
-0.144
0.692
0.338
0.34
0.011
0.976
Visuospatial
function
Pearson correlation
Sig. (2-tailed)
-0.387
0.27
0.297
0.406
-0.136
0.708
-0.584
0.076
0.320
0.366
-0.459
0.182
Executive
function
Pearson correlation
Sig. (1-tailed)
0.097
0.395
0.166
0.323
-0.254
0.240
-0.604*
0.032
0.066
0.428
-0.676*
0.05
**Correlation is significant at the 0.01 level.
*Correlation is significant at the 0.05 level.
Volume 7: Number 1. 2014 | Page 17
RCSIsmjoriginal article
The results obtained from the CT measurements and their BNA
correlates are shown in Tables 5 to 8 for each diagnostic group.
The strongest correlation for patients with MCI was seen when
correlating memory with the temporal horn ratio (p<0.01),
suprasellar cistern ratio (p<0.05) and Huckman’s number (p<0.05).
Memory in patients with AD correlated with the temporal horn
ratio (p<0.01) and third ventricle ratio (p<0.05).
Patients with VCI displayed strong correlations between memory
and the suprasellar cistern ratio (p<0.01), the bicaudate ratio (p<
0.05) and the third ventricle ratio (p<0.05). Similar correlations
with memory and the suprasellar cistern ratio (p<0.01) and
bicaudate ratio (p<0.05) were found in VaD, in addition to
correlations of executive function with Huckman’s number
(p<0.05) and Evans ratio (p<0.05).
Discussion
In this study, simple CT measures were used to compare regions of
atrophy and the areas of cognition they affected in four diagnostic
groups. AD was matched with VaD and MCI with VCI on the basis
of demographic and cognitive data to allow accurate comparisons
between the two pathologies. Additionally, to demonstrate that
MCI and VCI patients had less cognitive impairment than AD and
VaD patients across all cognitive domains, the means of the BNA
subsets were calculated and compared. These two comparative
measures were done to further validate the subsequent correlation
analysis.
They hypothesised that cerebrovascular disease contributes to
caudate nucleus atrophy, which in turn disrupts fronto-subcortical
circuits. Although atrophy of this structure increased from the
control group to stroke and VaD patients, the study did not
compare VaD patients with any other subtypes of dementia,
making this measure sensitive but not specific. Looi and colleagues
do, however, provide some insight to our findings. If the caudate
nucleus is affected in the early stages of vascular cognitive
impairment, then perhaps progressive atrophy of this structure
may lead to the pathognomonic frontal dysfunction in VaD via
association areas and circuits.
Further studies should be conducted on caudate nucleus volume
in relation to the different dementia subtypes, especially as all
forms of dementia have such different aetiologies. Comprehensive
MRI measures – both structural and functional – should be
conducted to examine precise anatomical subregions of atrophy
within the bicaudate region. Additionally, future studies should use
more extensive neuropsychiatric batteries, as the BNA is a
relatively quick measure used in the interest of time in memory
clinics.19 Currently, CT is used more as a screening measure to
exclude causes of secondary dementias such as haematomas,
hydrocephalus and neoplasms.6 However, in light of these new
findings, it is worthwhile to analyse linear measurements for
patients referred to the memory clinic with cardiovascular risk
factors. Once those patients at risk of developing VaD have been
identified, aggressive management of cardiovascular risk factors as
well as cholinergic treatments – which show great promise when
Regions of atrophy
A pattern of atrophic change is clearly visible when looking at CT
ratios of MCI and AD patients. Memory is the only cognitive
domain affected in both diagnostic groups, though the correlation
with the temporal horn ratio is much stronger in AD than in MCI.
This finding is consistent with previous studies, as the temporal
horn ratio is the most indicative of AD pathology when compared
implemented early – can commence.6
to the other ratios.21,22 Furthermore, this suggests an acceptable
sensitivity of using CT linear measurements in conjunction with
the BNA, as similar results of regions of atrophy in MCI and AD are
widely accepted. Interestingly, memory is the only domain that
correlated with the CT ratios, specifically the bicaudate ratio, in
VCI patients. This pattern is also seen in VaD (though the
correlations are stronger), in addition to the expected correlation
of executive function with the ratios that indicate frontal atrophy.
This finding suggests that memory change associated with the
bicaudate ratio is most predictive of disease progression from VCI
to VaD, and that frontal dysfunction occurs later on in the disease.
This study is the first to establish this new marker to predict
the onset of dementia.26-30 In addition, further investigation on
the location of the vascular insults in VCI and VaD to look for
whether the infarcts are clustered or evenly distributed is needed.
Once the anatomical locations are documented, hypotheses on
why the atrophic change occurred within the particular regions
can be formed.
conversion to VaD and distinguish it from AD.17,21-25
The caudate nucleus and the future
Although the suprasellar cistern is associated with memory loss,
not,19,22
the bicaudate ratio is
this warrants the question of what
specific anatomical structures, which contribute to the bicaudate
ratio, are affected. An MRI volumetric study by Looi et al. explores
caudate nucleus volumes in control, stroke and VaD patients.26
Page 18 | Volume 7: Number 1. 2014
Limitations
Limitations of this study include an absence of an education and
occupation measure. The four diagnostic groups are not
comparable on the basis of education – for many, higher
education increases baseline function, which can appear to delay
Conclusion
This study affirms and expands upon findings of atrophic change
in the conversion of MCI to AD, and provides a novel marker of
atrophic change in the conversion of VCI to VaD. Linear
measurements performed on CT, together with the BNA, have
established that atrophy of the bicaudate region is a novel
diagnostic method and a discriminant between the early forms of
the two most common forms of dementia. As both CT scans and
cognitive tests are frequently used in memory clinics,19 the simple
measures used here can be easily reproduced in a memory clinic
setting and act as a new diagnostic marker. Early identification of
at-risk individuals will allow treatment to begin before significant
functional impairment occurs.
RCSIsmjoriginal article
References
1. Alzheimer’s Disease International. Statistics [homepage on the internet].
c2012 [cited 2012 Apr 10]. Available from:
http://www.alz.co.uk/research/statistics.
2. Denihan A, Wilson G, Cunningham C, Coakley D, Lawlor BA. CT
measurement of medial temporal lobe atrophy in Alzheimer’s disease,
vascular dementia, depression and paraphrenia. Int J Geriatr Psychiatry.
2000;15(4):306-12.
3. Kandiah N, Narasimhalu K, Lee J, Chen CLPH. Differences exist in the
cognitive profile of mild Alzheimer’s disease and subcortical ischemic
vascular dementia. Dement Geriatr Cogn Disord. 2009;27(5):399-403.
4. Fennema-Notestine C, McEvoy LK, Hagler DJ Jr, Jacobson MW, Dale AM,
The Alzheimer’s Disease Neuroimaging Initiative. Structural neuroimaging
in the detection and prognosis of pre-clinical and early AD. Behav Neurol.
2009;21(1):3-12.
5. Moorhouse P, Rockwood K. Vascular cognitive impairment: current
concepts and clinical developments. Lancet Neurol. 2008;7:246-55.
subcortical ischemic vascular dementia in comparison to Alzheimer’s
disease. Dement Geriatr Cogn Disord. 2002;13(2):101-11.
16. Heinik J, Reider-Groswasser II, Solomesh I, Segev Y, Bleich A. Clock
drawing test: correlation with linear measurements of CT studies in
demented patients. Int J Geriatr Psychiatry. 2000;15(12):1130-7.
17. Voss SE, Bullock RA. Executive function: The core feature of dementia?
Dement Geriatr Cogn Disord. 2004;18:207-16.
18. Rose M, Scharf S. Is there any role for computed tomography
measurements of medial temporal lobe atrophy in dementia? A review of
the literature and case series from a memory clinic. Intern Med J.
2008;38(2):136-9.
19. Zhang Y, Londos E, Minthon L, Wattmo C, Liu H, Aspelin P et al.
Usefulness of computed tomography linear measurements in diagnosing
Alzheimer’s disease. Acta Radiol. 2008;49(1):91-7.
20. Darvesh S, Leach L, Black SE, Kaplan E, Freedman M. The Behavioural
Neurology Assessment. Can J Neurol Sci. 2005;32(2):167-77.
21. Zhang Y, Londos E, Minthon L, Wattmo C, Blennow K, Liu HJ et al. Medial
6. Black SE. Vascular dementia. Postgrad Med 2005;117(1):15-6, 19-25.
temporal lobe atrophy increases the specificity of cerebrospinal fluid
7. Atiya M, Hyman BT, Albert MS, Killiany R. Structural magnetic resonance
biomarkers in Alzheimer disease with minor cerebrovascular changes.
imaging in established and prodromal Alzheimer disease: a review.
Alzheimer Dis Assoc Disord. 2003;17(3):177-95.
8. Braak H, Alafuzoff I, Arzberger T, Kretzschmar H, Del Tredici K. Staging of
Alzheimer disease-associated neurofibrillary pathology using paraffin
sections and immunocytochemistry. Acta Neuropathol.
2006;112(4):389-404.
9. Braak H, Braak E. Neuropathological staging of Alzheimer-related
changes. Acta Neuropathol (Berl). 1991;82:239-59.
10. Ramani A, Jensen JH, Helpern JA. Quantitative MR imaging in Alzheimer
disease. Radiology 2006;241:26-44.
11. Apostolova LG, Thompson PM. Mapping progressive brain structural
changes in early Alzheimer’s disease and mild cognitive impairment.
Neuropsychologia. 2008;46(6):1597-612.
12. McEvoy LK, Brewer JB. Quantitative structural MRI for early detection of
Alzheimer’s disease. Expert Rev Neurother. 2010;10(11):1675-88.
13. Jacova C, Kertesz A, Blair M, Fisk JD, Feldman HH. Neuropsychological
testing and assessment for dementia. Alzheimers Dement.
2007;3(4):299-317.
14. Schmand B, Eikelenboom P, van Gool WA, The Alzheimer’s Disease
Neuroimaging Initiative. Value of neuropsychological tests, neuroimaging,
Acta Radiol. 2009;50(6):674-81.
22. Schweizer TA, Ware J, Fischer CE, Fergus IMC, Bialystok E. Bilingualism as
a contributor to cognitive reserve: evidence from brain atrophy in
Alzheimer’s disease. Cortex. 2012;48(8):991-6.
23. Sachdev PS, Valenzuela M. Brain and cognitive reserve. Am J Geriatr
Psychiatry. 2009;17(3):175-8.
24. Pantel J, Schroder J, Essig M, Jauss M, Schneider G, Eysenbach K et al. In
vivo quantification of brain volumes in subcortical vascular dementia and
Alzheimer’s disease. Dement Geriatr Cogn Disord. 1998;9(6):309-16.
25. Sung YH, Park KH, Lee YB, Park HM, Shin DJ, Park JS et al. Midbrain
atrophy in subcortical ischemic vascular dementia. J Neurol.
2009;256(12):1997-2002.
26. Looi JC, Tatham V, Kumar R, Maller JJ, Millard E, Wen W et al. Caudate
nucleus volumes in stroke and vascular dementia. Psychiatry Res.
2009;174(1):67-75.
27. Pasi M, Poggesi A, Pantoni L. The use of CT in dementia. International
Psychogeriatrics. 2011;23(2):6-12.
28. Fratiglioni L, Paillard-Borg S, Winblad B. An active and socially integrated
lifestyle in late life might protect against dementia. Lancet Neurol.
2004;3(6):343-53.
and biomarkers for diagnosing Alzheimer’s disease in younger and older
29. Stern Y. Cognitive reserve. Neuropsychologia. 2009;47(10):2015-28.
age cohorts. J Alzheimers Dis. 2012;29(3):641-8.
30. Valenzuela MJ, Sachdev P. Brain reserve and dementia: A systematic
15. Cannata AP, Alberoni M, Franceschi M, Mariani C. Frontal impairment in
review. Psychol Med. 2006;36(4):441-54.
Volume 7: Number 1. 2014 | Page 19
RCSIsmjcase report
Malignant transformation
of chronic ulcers (Marjolin’s
ulcers): an emerging
at-risk population
FIGURE 1: The patient has
been in the surgical ward
for weeks waiting for the
surgery fees.
Abstract
Adnan Abbas
RCSI medical student
Children born with neural tube defects (NTDs) have significant high morbidity and mortality
rates. Myelomeningocele is a form of NTD that causes severe neurological deficits. Other
serious complications can arise from poor adaptation to these resulting deficits. Preventive
measures and proper management are essential to improve healthcare outcomes, and to
reduce health and financial burdens on both individuals and society.
A 30-year-old Kenyan gentleman presented to the hospital with chronic, painful, non-healing
gluteal ulcers. He had a background history of congenital myelomeningocele, with resulting
paraplegia and incontinence. A biopsy of the lesion showed areas of squamous cell carcinoma
(Marjolin’s ulcers). This was believed to have resulted from life-long abnormal mobility
techniques, leading to chronic ulceration and inflammation of the gluteal region; the patient
used his arms to slide his bottom across the floor, as he could not afford a wheelchair. His
management plan included a wide excision of the tumour followed by skin grafting. A loop
colostomy had to be performed prior to surgery to allow for proper wound healing,
counselling and follow-up were also required.
Chronic inflammation, chronic wounds and scars are all predisposing factors in the
development of Marjolin’s ulcers. Marjolin’s ulcers are an aggressive form of squamous cell
carcinoma that requires immediate surgical intervention. The incidence of Marjolin’s ulcers is
increasing in Africa due to an increase in the survival rate of babies born with NTDs; thus,
health education for patients with regard to ulcer prevention and treatment should be
advocated by healthcare professionals.
Royal College of Surgeons in Ireland Student Medical Journal 2014; 1: 20-22.
Page 20 | Volume 7: Number 1. 2014
RCSIsmjcase report
FIGURE 2: The lesion on the patient’s right buttock after debridement.
This lesion represents a Marjolin’s ulcer.
FIGURE 3: The lesion on the patient’s left buttock. Note right foot
talipes resulting from myelomeningocele.
Introduction
The initial diagnosis was chronic deep pressure sores (grade
four) based on the patient’s history of longstanding
compromised mobility, and he was managed accordingly. After
two weeks of antibiotics and daily wound cleaning and
dressing, the ulcerations had not improved, so he was admitted
again, and skin debridement and biopsy under general
anaesthesia were performed.
The histopathology report showed the following:
Macroscopic findings included multiple hard, isolated and
fungating skin nodules on the sacrum (10cm), left gluteal
region (15cm) and right gluteal region (10cm). The skin
showed desquamation and �watery appearance’. There were no
features of infection. Microscopic findings included some areas
of moderate to poorly differentiated SCC arising from surface
dysplasia. Other areas showed extensive parakeratosis and
pseudoepitheliomatous hyperplasia. No lymphovascular invasion
was seen.These findings are consistent with moderate to poorly
differentiated keratinising SCC.
Detailed personal and collateral histories revealed a long history
of abnormal mobility pattern adopted by the patient since
childhood, as his parents could not afford to buy a wheelchair.
The patient learned to move around using his arms to drag his
buttocks across the floor. The repetitive trauma to the sacral
and gluteal epithelium led to chronic ulcerations that had
undergone malignant transformation into SCC over 30 years.
He required a wide excision of the malignant lesion, followed
Malignant transformation of chronic wounds is rare and often
misdiagnosed. Sites of chronic inflammation, chronic wounds
and scars are all susceptible to malignant transformation into
squamous cell carcinoma (SCC); this form of SCC may present
as chronic skin ulceration that fails to heal spontaneously or
with appropriate therapy. The term Marjolin’s ulcer is used to
refer to SCC arising from chronically inflamed skin lesions.1
Delay in diagnosis of Marjolin’s ulcers may result in a poor
prognosis. Marjolin’s ulcers are uncommon but aggressive
tumours. They have a high rate of local recurrence and lymph
node metastases, and often require immediate surgical
intervention with wide margin excision and lymph node
dissection.
There is a wide variation in the interval between the initial skin
damage and the appearance of the tumour; SCC can appear
any time between six weeks and 60 years after the initial
traumatic event.2,3
Case report
This is the case of a 30-year-old Kenyan gentleman who
presented to the Rift Valley Provincial General Hospital in
Nakuru, Kenya, complaining of longstanding, painful, multiple
gluteal ulcerations. He had a background history of congenital
myelomeningocele, which led to arrested hydrocephalus,
paraplegia, incontinence and mild learning difficulties.
Volume 7: Number 1. 2014 | Page 21
RCSIsmjcase report
by skin grafting. A loop colostomy needs to be performed prior
to the main surgery to allow for proper wound healing, as the
patient has suffered from urine and bowel incontinence since
birth. These procedures have not yet been carried out however,
because the patient cannot afford the surgical fees. He has been
kept in the hospital for several months while attempting to raise
money to pay the fees.
Hospital policy requires that surgical fees be paid before the
procedure; this further complicates his financial struggle, as he
continues to accumulate additional fees during his unnecessarily
long hospital stay. This also complicates his health condition as
his disease continues to progress. Throughout his stay in the
hospital, the patient is being nursed daily; his wounds are being
cleaned and dressed once a day. His list of medications includes
oral penicillin and diclofenac.
Discussion
Neural tube defects (NTDs) are the second most common
congenital anomalies worldwide (following congenital cardiac
abnormalities) and are a common cause for chronic disabilities.
Myelomeningocele is the most common form of NTD with an
incidence ranging from one to seven per 1,000 live births,
depending on ethnic, geographic, and nutritional factors.4
Myelomeningocele is the most severe birth defect that is
compatible with survival. Maternal screening programmes,
along with folic acid supplementation, have a significant role in
the assessment and prevention on NTDs.
In some developing countries, resources for prenatal screening
programmes and patients’ education levels are not sufficient to
prevent and properly manage congenital NTDs; this ultimately
leads to unfavourable health outcomes.
A recent study showed that myelomeningocele had the highest
disease burden out of all the congenital anomalies in children
born in Kenya.5 This burden is two-fold: there are deficits that
occur as a result of the defect (paralysis, incontinence, etc.);
and, a spectrum of additional sequelae, which may seem
unrelated but are actually consequences of these deficits. In the
case of our patient, the presentation of SCC is the end result of
chronic inflammation, which indirectly resulted from the
congenital defect.
Conclusion
Improved healthcare awareness has helped children born with
NTDs to survive into adulthood in Africa. This has resulted in an
emerging at-risk population for Marjolin’s ulcers, cancers that
are at present rare but virulent.
Chronic non-healing ulcers, especially in this population, should
carry a high index of suspicion and should be biopsied and
treated urgently. Delay in diagnosis may result in poorer
prognosis; early detection and close follow-up of Marjolin’s
ulcers improves health outcomes significantly.6
In addition to direct action against Marjolin’s ulcers, aggressive
public campaigns should encourage periconceptional folate
supplementation and prenatal screening to help reduce the
disease burden of NTDs, especially in resourced-limited regions.
Life-long follow-up and health education should be provided to
patients with NTDs and their caregivers, focusing on pressure
ulcer prevention by using proper mobility, and early treatment
of ulcers. These measures will help to reduce the incidence of
Marjolin’s ulcers in this high-risk population and hence reduce
mortality.7
NTDs include:
в– anencephaly;
в– encephalocele;
в– spina bifida occulta;
в– meningocele; and,
в– myelomeningocele.
Myelomeningocele might be associated with:
в– paraplegia;
в– hip dislocation and talipes;
в– sensory loss;
в– neuropathic bladder and bowel;
в– scoliosis; and,
в– hydrocephalus.
References
1. Esther RJ et al. Marjolin ulcers: secondary carcinomas in chronic
wounds. J South Orthop Assoc. 1999;8(3):181-7.
2. Love RL, Breidahl AF. Acute squamous cell carcinoma arising
within a recent burn scar in a 14-year-old boy. Plast Reconstr
Surg. 2000;106(5):1069-71.
3. Friedman R et al. Squamous cell carcinoma arising in a
Leishmania scar. Dermatol Surg. 2003;29(11):1148-9.
4. Frey L, Hauser WA. Epidemiology of neural tube defects.
Epilepsia. 2003;44(Suppl. 3):4-13.
Page 22 | Volume 7: Number 1. 2014
5. Wu VK et al. Burden of surgical congenital anomalies in Kenya: a
population-based study. J Trop Pediatr. 2013;59(3):195-202.
6. Chalya PL et al. Marjolin’s ulcers at a university teaching hospital
in Northwestern Tanzania: a retrospective review of 56 cases.
World J Surg Oncol. 2012;10:38.
7. Nthumba PM. Marjolin’s ulcers: theories, prognostic factors and
their peculiarities in spina bifida patients. World J Surg Oncol.
2010;8:108.
RCSIsmjcase report
Gliosarcoma: a rare variant of
glioblastoma multiforme
Abstract
Gliosarcoma (GS) is a rare malignant neoplasm of the central nervous system. It is a variant of
glioblastoma multiforme (GBM) consisting of both glial and sarcomatous components. This is
a case of a 51-year-old, right-handed male with a history of recurrent GS, despite multiple
resections, radiation therapy, and multiple rounds of chemotherapy.
The patient first presented with sudden loss of comprehension, hallucinations, and aphasia.
Magnetic resonance imaging (MRI) showed a left posterior parietal lobe lesion. He underwent
a craniotomy with resection, postoperative radiation and chemotherapy. GBM has a high rate
of recurrence, and in the two years following diagnosis, the tumour increased in size on six
occasions. Over this time period, the patient underwent multiple rounds of surgery,
chemotherapy, and radiation treatments. The patient survived for approximately three years
after his first presentation.
Currently, the treatment of newly diagnosed GBM patients includes temozolomide
chemotherapy in combination with radiation therapy. Ongoing clinical trials have also shown
bevacizumab to be a useful agent in patients with recurrent GBM.
The prognosis following a diagnosis of GBM has recently improved due to the introduction of
drugs such as temozolomide and bevacizumab. However, the outlook is still poor. Mean
survival for GBM patients with standard-of-care surgery, radiation therapy, and chemotherapy
is 15 months. The rate of recurrence is high, and the treatment required is aggressive.
Royal College of Surgeons in Ireland Student Medical Journal 2014; 1: 23-25.
Introduction
Gliosarcoma (GS) is considered an exceptionally
rare neoplasm, representing 1-8% of all malignant
gliomas. The 2007 World Health Organisation
(WHO) report on the classification of central
nervous system tumours described GS as a grade
four neoplasm and a variant of glioblastoma
multiforme (GBM), which consists of both glial and
sarcomatous components. GS has similar natural
history and presentation to GBM, with a slightly
higher propensity for temporal lobe involvement.
GBM itself is considered the most common and
aggressive form of primary malignant brain
cancer.1,2
Mean survival for patients with GBM is 15 months
with standard-of-care surgery, radiotherapy and
Yousif Alshuaib
RCSI medical student
chemotherapy.3 Even with aggressive management,
there is a high rate of recurrence. Patient and
treatment factors associated with outcome in the
GS variant are ill defined because of the small
number of patients reported in the literature. One
study, however, used the Surveillance,
Epidemiology, and End Results (SEER) database to
analyse more than 300 adult patients with GS. The
most important factors influencing overall survival
were identified as: age; extent of resection; and, use
of adjuvant radiation therapy.1 One promising
chemotherapy agent is temozolomide, an alkylating
agent that methylates DNA causing apoptotic death
of tumour cells, which was approved by the US
Food and Drug Administration (FDA) in 2005. It has
been shown to increase overall survival (OS). In one
study, the combined use of temozolomide and
radiation therapy showed 24-month OS of 24.2%
in treated patients between 2006 and 2008,
compared with 12.1% between 2000 and 2003.
This may be correlated with the widespread use of
temozolomide and adjuvant radiation therapy after
2005.4 Ongoing clinical trials have also
demonstrated the benefit of anti-angiogenesis
therapy in patients with recurrent GBM in the form
of bevacizumab (a humanised monoclonal
antibody), which binds vascular endothelial growth
factor (VEGF) and inhibits formation of tumour
blood vessels.3
Volume 7: Number 1. 2014 | Page 23
RCSIsmjcase report
FIGURE 1: Magnetic resonance imaging (MRI) showing a left
temporo-parietal mass.
FIGURE 2: Haematoxylin and eosin stain (20x) showing sarcomatous
component with nuclear pleomorphism arranged in intersecting fascicles
and increased mitotic activity.
Case report
We report a case of a 51-year-old, right-handed male with a history of
recurrent GS post multiple resections, radiation therapy, and multiple
rounds of chemotherapy. The patient first presented in November 2006
with sudden loss of comprehension, hallucinations, and aphasia.
Magnetic resonance imaging (MRI) showed a left posterior parietal lobe
lesion. The following month he underwent a craniotomy with gross total
resection. Biopsy of the lesion at this time revealed GBM. Postoperative
radiation and temozolomide adjuvant chemotherapy were administered,
and a follow-up MRI showed that the tumour had regressed.
A year later, in November 2007, a repeat MRI showed tumour
recurrence; a repeat craniotomy with tumour resection was performed.
For a brief time the patient was able to return to work and resumed
playing golf. In October 2008, he once again returned presenting with
worsening symptoms of delayed word finding, expressive aphasia, and
decrease in fine motor co-ordination in the right hand. An MRI (Figure
1) revealed a 4cm enhancing mass in the left temporo-parietal area
suggestive of recurrent disease. The heterogeneous mass signal intensity
identified was consistent with the central necrosis with cell debris found
in high-grade gliomas. There was no mass effect visible on the left lateral
ventricle, but it did appear to be secondarily enlarged due to local
volume loss after previous resections. Basal cisterns were open and there
was no evidence of hydrocephalus. MR spectroscopy showed elevated
lactate and choline associated with inflammation and necrosis, also
consistent with tumour recurrence. A functional MRI (fMRI) scan revealed
that the recurrent tumour was very close to Wernicke’s area. A left
temporo-parietal craniotomy with tumour resection and biopsy was
performed with awake, intra-operative language mapping, motor evoked
potential, and somatosensory evoked potential monitoring to avoid
iatrogenic functional loss. Post-operatively, the patient was started on
irinotecan chemotherapy and bevacizumab. Tissue biopsy was sent for
haematoxylin and eosin (H&E) staining to mark for features of
malignancy, and immunohistochemistry (IHC) staining to mark for glial
and sarcomatous components. Sarcomatous components were present;
nuclear pleomorphism and increased mitotic activity were noted (Figure
2). H&E staining also showed vascular proliferation with myxoid and
Page 24 | Volume 7: Number 1. 2014
chondromatous areas (Figure 3). IHC staining showed positive glial
fibrillary acidic protein (GFAP) antibody staining for the glial component
and positive reticulin staining for the sarcomatous component.
Beginning approximately three years after diagnosis, the tumour began
to grow more aggressively and the chemotherapy regime was changed
accordingly. The patient was initially on carboplatin and bevacizumab for
one month; however, the tumour continued to grow and the patient
was then put on etoposide and bevacizumab. When this failed to halt
tumour progression, the chemotherapy regimen was changed to
procarbazine accompanied by bevacizumab. During his last visit, the
patient presented with nephrotic syndrome, likely secondary to
bevacizumab. His neurological exam at this stage showed impaired
comprehension; the patient was able to follow one-step but not two-step
commands, most likely as a result of the lesion in Wernicke’s area. He also
had a right homonymous hemianopia and decreased pinprick sensation
on the right side of his face, consistent with previous post-contrast
coronal MRIs that showed abnormal leptomeningeal enhancement
involving the optic nerves, anterior chiasm, and seventh and eight cranial
nerves within the internal auditory canal.
Because the patient became thrombocytopaenic, procarbazine was
discontinued. He was treated with dexamethasone, an oral
corticosteroid, for his thrombocytopaenia and bowel incontinence.
Dexamethasone also prevents brain oedema and raised intracranial
pressure, and could potentially help to alleviate the patient’s confusion.
The patient was discharged home with a prescription for a hospital bed
and received palliative care. Unfortunately, the patient survived only 35
months from first presentation.
Mean survival in gliosarcoma is 15 months with standard-of-care
treatment.2 Variations of prognosis in individuals may be due to
individual clinicians and their management, namely the extent of
resected margins and whether gross total resection is possible. With
regard to the poor prognosis associated with GBM, clinical trials are
ongoing in search of the optimal treatment. Current treatment strategies
include temozolomide for newly diagnosed GBM, and bevacizumab in
combination with temozolomide for recurrent GBM.3,4
RCSIsmjcase report
patients with GBM following maximal safe surgical resection.4 In 2009,
the FDA approved bevacizumab, a promising treatment approach that
targets the tumour’s blood supply. GBMs are highly vascularised
tumours and express high levels of vascular endothelial growth factor
(VEGF). Bevacizumab, a humanised monoclonal antibody that targets
VEGF, has shown promise as an angiogenic inhibitor. When used in
combination with temozolomide chemotherapy, bevacizumab has
shown positive results in two prospective phase two studies and was
granted accelerated approval by the FDA as a therapeutic agent for
recurrent GBM.3 A recent retrospective study demonstrated that
bevacizumab was more effective in older patients ( 55 years); the
authors hypothesised that this may be due to differences in levels of
FIGURE 3: Haematoxylin and eosin stain (20x) showing vascular
proliferation with myxoid and chondromatous areas.
Discussion
The low incidence of GS means that there are a small number of cases,
which has made it difficult to characterise the disease. However, the
epidemiology, clinical and radiological features, and neurological
sequelae of GS are very similar to those of GBM and thus treatment is
usually the same.1,5 While the first line of treatment for newly
diagnosed GBM patients is radiation therapy in combination with
temozolomide, there is still no standard of care for recurrent GBM.
GBM has a high rate of recurrence, and response to treatment is seen
in less than 10% of patients.3 This may prove to be an area of
importance when exploring strategies to improve prognosis. In 2005, a
phase III randomised clinical trial showed that postoperative radiation
and concurrent temozolomide, followed by maintenance
temozolomide for six months, improved median survival in newly
diagnosed GBM patients from 12.1 months to 14.6 months, as
compared with radiation therapy alone.3,6 This regimen is now the
standard of care for newly diagnosed GBM. There is currently no
prospective evidence to justify the use of temozolomide in GS patients
specifically; however, a small retrospective series showed similar clinical
outcomes in patients with GS compared to GBM.4 The current
guidelines set by the National Comprehensive Cancer Network (NCCN)
recommend that patients with GS undergo the same treatment as
VEGF expression in different age groups.3
Patients who relapse after initial response to bevacizumab are a
particularly challenging group to treat, since there is no consensus on
their optimal treatment. Current strategies include: discontinuing
bevacizumab and treating with either alternative cytotoxic
chemotherapy or an investigational agent; or, more commonly,
continuing with bevacizumab and adding another chemotherapy agent
such as carboplatin.3
Conclusion
Ongoing clinical trials have shown the benefit of anti-angiogenesis
therapy in the treatment of recurrent GBM. However, there are still
unknown aspects of the use of bevacizumab, such as optimal dosage
and treatment duration, which chemotherapeutic partner should be
used, and what the best criteria are for measuring radiographic
response. Ongoing clinical trials will be key in addressing these issues.
Outcomes may depend on factors such as individual clinicians and their
management, in particular whether gross total resection of the tumour
is performed.
Finally, differences in survival may be correlated with patient factors,
namely response to treatment. The patient presented surpassed the
mean survival while being treated with bevacizumab among other
agents. Further studies may help us to understand why certain cohorts
of patients respond more favourably than others. Until then, GBM,
including GS, remains particularly challenging to treat due to the high
rate of recurrence. The key to improving survival may lie in studies
exploring individual clinician’s management, patient response to
treatment, and the optimal use of bevacizumab.
References
1. Kozak KR, Mahadevan A, Moody JS. Adult gliosarcoma:
epidemiology, natural history, and factors associated with outcome.
Neuro Oncol. 2009;11(2):183-91.
2. Louis DN, Ohgaki H, Wiestler OD et al. The 2007 WHO classification
of tumours of the central nervous system. Acta Neuropathol.
2007;114(2):97-109.
3. Chemberlain MC. Bevacizumab for the treatment of recurrent
glioblastoma. Clin Med Insights Oncol. 2011;5:117-29.
4. Walker GV, Gilbert MR, Prabhu SS et al. Temozolomide use in adult
patients with gliosarcoma: an evolving clinical practice. J
Neurooncol. 2013;112(1):83-9.
5. Ayadi L, Charfi S, Khabir A, Kalle R, Sellami A, Makni S et al.
Cerebral gliosarcoma: clinico-pathologic study of eight cases. Tunis
Med. 2010;88(3):142-6.
6. Linhares P, Carvalho B, Figueiredo R, Reis RM, Vaz R. Early
pseudoprogression following chemoradiotherapy in glioblastoma
patients: the value of RANO evaluation. J Oncol. 2013;690585.
[Epub 2013 Aug 13.]
Volume 7: Number 1. 2014 | Page 25
RCSIsmjcase report
MRSA of unknown aetiology
causing prostate abscess in
a patient with incidental
prostate adenocarcinoma
Abstract
Community-acquired methicillin resistant Stahphylococcus aureus (CA-MRSA) infection is a relatively
under-recognised cause of bacterial prostatitis. This report presents a case of bacterial prostatitis due
to CA-MRSA in a patient with an additional incidental finding of prostate adenocarcinoma. Our
patient presented with urinary symptoms and worsening suprapubic pain. A magnetic resonance
imaging (MRI) scan revealed an abscess in the prostate, which was drained. A decision was made to
treat him with antibiotics delivered via a peripherally inserted central catheter (PICC) line for six
weeks. Unfortunately, due to lack of insurance, he was unable to complete treatment. An incidental
prostatic mass was biopsied and identified as adenocarcinoma with unusual cytology. Though
studies have not confirmed a correlation between chronic inflammation and prostate
adenocarcinoma, the relationship between persistent inflammatory states and neoplasia is known in
other cancers. The unusual presentation of this patient may suggest that CA-MRSA prostatitis may
have contributed to the development of a prostatic adenoma.
Royal College of Surgeons in Ireland Student Medical Journal 2014; 1: 26-27.
Introduction
Acute bacterial prostatitis is relatively common in
patients with risk factors such as diabetes mellitus,
cirrhosis and suppressed immune system. The
bacteria can be introduced via an ascending
infection, or through iatrogenic procedures such as
prostate biopsy.1 The most common causative
organisms are Escherichia coli and Enterococcus.1 The
incidence of community-acquired methicillin
resistant Staphylococcus aureus (CA-MRSA) infection
as a cause of prostate abscess is quite low. There are
only nine published case reports in PubMed where a
prostate abscess is noted to be caused by
CA-MRSA.2-5 In this article we discuss a case of
bacterial prostatitis with CA-MRSA abscess in a
patient with no significant risk factors, who was also
incidentally found to have prostate adenocarcinoma.
Tisa Saha
RCSI medical student
Page 26 | Volume 7: Number 1. 2014
Case report
This is a case of a 44-year-old African-American
gentleman, Mr WS, who presented to the
Emergency Department (ED) on July 13, 2013,
complaining of a one-day history of localised
suprapubic abdominal pain, dysuria and urinary
retention. He also had a history of back pain around
the lower lumbar region, which had worsened over
the last three days, and during which he also
reported subjective fever and chills. He denied any
night sweats. He reported neither haematuria nor
difficulties with passing stool. At presentation, his
suprapubic pain was a 7 out of 10. He denied
urgency, frequency or incomplete voiding. His past
medical history did not reveal any history of urinary
retention or any other genitourinary symptoms. Mr
WS’s past medical history was significant for a
gunshot wound on his left lower leg in 2000, and a
neck abscess, which was incised and drained in
1996. He did not take any medications at home. His
family history was non-contributory. He had a
25-pack year history of smoking, but did not drink
alcohol. He also admitted to engaging in illegal
substance use (such as cocaine) but did not disclose
his method of intake. On examination, Mr WS was
alert and oriented. His vitals were: temperature
98ВєF, blood pressure 155/89mmHg, respiratory rate
16, and O2 saturation of 99% on room air. On
palpation, his abdomen was tender and full around
the suprapubic region. There was perianal
anaesthesia; however, a digital rectal examination
(DRE) was refused. There was mild lumbosacral
tenderness bilaterally but no step off and no
costovertebral angle tenderness. His cardiovascular,
respiratory and neurological exams were
non-contributory. In the ED, the patient was given a
litre of IV fluids and a Foley catheter was inserted,
which drained more than a litre of fluid. The
catheter was taken out once the bladder was
drained. He was given another litre of IV fluids, but
only managed to excrete 10-20mL on his own. His
bladder scan revealed more than 250cc of fluid; a
Foley catheter was reinserted. His urine cultures
were negative for Chlamydia trachomatis, Neisseria
gonorrhoea and Trichomonas vaginalis. His urinalysis
revealed yellow hazy urine with red blood cells of
6-10 units per high power field (HPF), white blood
cells of 0-2 units per HPF and presence of mucus.
RCSIsmjcase report
Urinalysis was negative for glucose and protein level was 25mg/dL. He
had a non-contrast magnetic resonance imaging (MRI) that revealed
small herniated discs at L2-3, L3-4, L4-5 and L5-S1, with no visible
acute changes or compression of the cauda equina. No epidural
abscess collections were noted. He was discharged home with a Foley
catheter in situ and told to follow up with his urologist in two days or
return to the ED if he could not follow up due to lack of insurance. Two
days post discharge, Mr WS returned to the ED requesting the removal
of his catheter. He was in severe pain, which he rated 10 out of 10, and
reported haematuria. His vitals were: blood pressure of 112/77mmHg,
temperature 98.2ВєF, respiratory rate 16, and O2 saturation of 99% on
room air. His urinalysis was significant for red blood cell count of 3-5
per HPF, white blood cell count of 11-20 per HPF, grossly positive for
blood, leukocyte esterase level of 500/uL and protein level of 25mg/dL.
He was given a litre of IV fluid, paracetamol and IV ceftriaxone. He soon
became afebrile and was able to urinate on his own. His bladder scan
revealed 54ml of fluid after voiding 100ml of urine. He was discharged
the same day and told to follow up with his urologist in a week’s time.
The following day, the urine culture obtained on his first visit returned
positive for methicillin-resistant Staphylococcus aureus (MRSA). One out
of the four vials of blood taken for culture on his initial admission and
four out of four taken on his second admission returned positive for
MRSA. Mr WS was called to return to the ED for further evaluation. He
denied any skin infections, abscesses, history of IV drug use, cough or
shortness of breath. He still had significant dysuria and reported new
increased frequency. He denied any haematuria. His last cocaine use
was six days previously. New findings on his examination included
bilateral inguinal lymphadenopathy and suprapubic tenderness of
increased severity. His inguinal region and penile shaft appeared
normal. His DRE was not completed due to severe pain; however, a
severely tender and enlarged prostate was evident.
The rest of the examination was non-contributory. His vitals were stable
and he was afebrile. His toxicology reports were negative. He was
started on IV vancomycin 1.25g every 12 hours. Other tests performed
included a transoesophageal echocardiography and a chest x-ray,
which did not reveal any significant findings. Due to severe pain, an
ultrasound of the prostate was not performed and instead a computed
tomography (CT) with contrast was performed, which revealed
multiloculated fluid collection with peripheral enhancement that
measured approximately 5x6.4x5.1cm. The mural lining was thickened
in the anterior superior portion of the distended bladder, suggestive of
cystitis. There was no evidence of pyelonephritis or renal abscess. The
patient was taken in for incision of the abscess via a transurethral
approach. He recovered well from the procedure. Unfortunately, the
cytology report confirmed adenocarcinoma of the prostate with a
Gleason score of 6. A peripherally inserted central catheter was placed
for the intended six weeks of IV antibiotics regimen. However, he was
discharged soon after on oral medications due to lack of insurance and
scheduled to return to the clinic for further follow-up or if there was
deterioration in his health.
Discussion
Among the few published cases of MRSA prostatitis, most of the
patients have some associated comorbidity or risk factor such as IV
drug abuse (IVDA) or diabetes mellitus.2,5 It is highly likely that with a
past medical history of a neck abscess, our patient could have been
engaging in IV drug abuse. Due to the lack of insurance, follow-up
from this patient is highly unlikely. However, this case is also unique
due to the incidental finding of a prostate cancer. It has been noted in
prior case reports that prompt treatment with IV antibiotics such as IV
vancomycin, trimethoprim-sulfonamide and rifampin, as well as
transurethral resection of prostate, can reduce hospital admission days
and speed recovery from prostate abscess.2 However, the challenge is
identifying the disease itself, which requires a high index of suspicion.
In our case, the diagnosis was not confirmed until a contrast CT of the
abdomen was performed on the third admission and blood cultures
came back positive. The presenting symptoms in most cases include
those of urethral obstruction such as retention, urgency and suprapubic
pressure. This opens the door for a vast list of differentials including
benign prostate hypertrophy and urosepsis. Due to the delay of blood
culture positivity, it is also futile to treat a patient with CA-MRSA with
empiric IV antibiotics due to the high likelihood of resistance. This case
also highlights the role of DRE findings in guiding the diagnosis of
bacterial prostatitis. Our patient initially refused a DRE; however, had it
been done earlier, he could have also had a CT with contrast
performed earlier, which would have allowed for earlier diagnosis. The
aetiology of this infection still remains unknown. A few possibilities
include an ascending infection leading to bacteraemia, or an initial
bacteraemia, possibly from IVDA, with seeding of the prostate. It is also
likely that if this is an ascending infection, it has been there for an
extended period, since an abscess was discovered around the infected
site, which raises the question of whether there is any relation between
the chronic inflammatory state of the prostate and the incidental
adenocarcinoma finding in such a young patient. Delongchamps et al.’s
study reveals that chronic inflammation has some influence on benign
prostate hypertrophy (BPH) but none on the risk of cancer.6 However,
Abdel-Meguid et al.’s study of Saudi Arabian men demonstrated a
connection between chronic inflammation and both BPH and cancer,
with higher incidence in the BPH subcategory.7 Further studies are
required to establish the magnitude of this correlation.
References
1. Brede CM, Shoskes DA. The etiology and management of acute prostatitis. Nat
Rev Urol. 2011;8(4):207-12. [Epub 2011 Mar 15.]
2. Naboush A, Abou Yassine A, Yasmin M, Mobarakai N. Community-acquired
methicillin-resistant Staphylococcus aureus prostatic abscess presenting as acute
urinary retention: a case report and review of the literature. Case Rep infect Dis.
2013;2013:761793. [Epub 2013 May 12.]
3. Park SC, Lee JW, Rim JS. Prostatic abscess caused by community-acquired methicillin
-resistant Staphylococcus aureus. Int J Urol. 2011;18(7):536-8. [Epub 2011 May 26.]
4. Pierce JR Jr, Saeed Q, Davis WR. Prostatic abscess due to community-acquired
methicillin-resistant Staphylococcus aureus. Am J Med Sci. 2008;335(2):154-6.
5. Baker SD, Horger DC, Keane TE. Community-acquired
methicillin-resistant Staphylococcus aureus prostatic abscess. Urology.
2004;64(4):808-10.
6. Delongchamps NB, de la Roza G, Chandan V, Jones R, Sunheimer R,
Threatte G et al. Evaluation of prostatitis in autopsied prostates – is chronic
inflammation more associated with benign prostatic hyperplasia or cancer?
J Urol. 2008;179(5):1736-40. [Epub 2008 Mar 17]
7. Abdel-Meguid TA, Mosli HA, Al-Maghrabi JA. Prostate inflammation.
Association with benign prostatic hyperplasia and prostate cancer. Saudi
Med J. 2009;30(12):1563-7
Volume 7: Number 1. 2014 | Page 27
RCSIsmjreview
Omalizumab in the treatment
of severe persistent
IgE-mediated asthma
Abstract
Zain Hasnain
RCSI medical student
Over 300 million people worldwide suffer from asthma, a chronic respiratory condition
characterised by airway obstruction, inflammation and bronchial hyperresponsiveness.
This figure is set to rise to 400 million by 2025.
Despite a wide variety of treatment protocols and guidelines available for alleviation of
symptoms, 5-10% of patients with asthma are non-responsive and are said to have
severe, persistent (or refractory) asthma.
These patients account for the majority of disease burden on the healthcare system in
terms of mortality, morbidity and treatment costs. In approximately 50-80% of these
patients, asthma is mediated by immunoglobulin E (IgE), which is critical in the
inflammatory cascade.
Omalizumab is a humanised monoclonal anti-IgE antibody used in the treatment of
severe allergic asthma. It works by inhibiting cellular IgE binding and reducing the
number of IgE receptors on pro-inflammatory cells. It has been shown to improve
symptoms and quality of life, and reduce asthma exacerbations and the need for
systemic corticosteroids.
This review will look at the socioeconomic impact of severe allergic asthma on the Irish
population and give a cost–benefit analysis of omalizumab and guidelines for its use in
patients. Furthermore, it will discuss how to best optimise its use in the management of
people with severe asthma, and illustrate the importance of critically reviewing trial
data that is used to formulate and re-appraise guidelines in clinical practice.
Royal College of Surgeons in Ireland Student Medical Journal 2014; 1: 28-32.
Page 28 | Volume 7: Number 1. 2014
RCSIsmjreview
Introduction
Asthma is a chronic respiratory disease of heterogenous aetiology
with varied pathological and clinical phenotypes. It is
characterised by differing patterns of airway inflammation
associated with a plethora of pro-inflammatory cell types, which
lead to bronchial hyperresponsiveness and airway obstruction.1
Over 300 million people globally are affected by asthma, a figure
that epidemiologists expect will continue to increase.2 This is due
to a complex and incompletely elucidated interaction between a
genetic predisposition to atopy and environmental factors.
Certain stimuli trigger a pathologically exacerbated
bronchoconstriction in affected patients; these include certain
weather conditions (cold, damp climate), perennial aeroallergens
(e.g., dust mites, airborne pollutants), and respiratory viruses.
Exposure to these allergens leads to a pro-inflammatory cascade,
which can persistently cause debilitating and even fatal
symptoms such as dyspnoea, wheezing, chest tightness and
coughing.1
The majority of patients manage their symptoms with a
combination of environmental control and pharmacological
agents, which include 2-adrenergic receptor agonists and
corticosteroids as per the Global Initiative for the management of
guidelines.3
The small percentage of patients with
Asthma (GINA)
asthma (5-10%) who, despite this treatment, still have recurrent
symptoms, are said to have severe or refractory asthma. The
inadequate control of symptoms, in conjunction with confounding
comorbidities such as rhinitis, sinusitis and obstructive sleep
в– at least one urgent care visit for asthma per year;
■three or more oral steroid �bursts’ needed for treatment
per year;
в– rapid deterioration with 25% reduction in oral or inhaled
glucocorticoid dose; or,
в– at least one near-fatal asthmatic event in the past.
The European Network For Understanding Mechanisms Of Severe
Asthma (ENFUMOSA), a multi-centred, cross-sectional study, was
the first comprehensive assessment of severe asthma in Europe.
The data gathered by ENFUMOSA suggested that severe asthma
was a distinct clinical entity compared to mild to moderate
asthma, with structural changes in airway remodelling being a
key feature of severe asthma.8
According to the Asthma Insights and Realities in Ireland (AIRI)
study in 2005, there were approximately 470,000 asthma
sufferers in Ireland, the fourth highest prevalence globally. It is
estimated that one in ten adults and one in five children under
the age of 14 in Ireland suffer from asthma. Furthermore, 90,000
people are said to have inadequate symptom control and Irish
adults with asthma lose on average 12 days from work yearly,
while children lose ten school days yearly.9 The Asthma Society of
Ireland estimates that 6,300 Irish people with asthma meet the
criteria for severe asthma, with up to 100 deaths annually in
Ireland. The total cost to Ireland in 2003 due to asthma was
reported to be 463 million, with 227 million accounting for
emergency care and hospitalisation.10
life.4
apnoea, results in a poor quality of
These patients account for
the most significant burden on healthcare services, as they
frequently access emergency services and often require long-term
hospital admissions and expensive chronic therapeutic
intervention. There are also heavy socioeconomic costs related to
loss of work or school days in this group.5,6
The classification of “severe persistent” or “refractory” asthma
proposed by the American Thoracic Society (ATS)7 requires that
patients are compliant with medication, that other conditions are
excluded, and that other environmental factors are treated. It also
requires the patient to be on glucocorticoid treatment, fulfilling
one of the following two major criteria for maintenance of control:
в– continuous or near continuous ( 50% of the year) treatment
with oral glucocorticoids; or,
в– treatment with high-dose inhaled glucocorticoids.
Furthermore, the patient is required to fulfill two of the following
seven minor criteria:
в– short-acting -agonist for near-daily control of asthma
symptoms;
■daily treatment with �controller’ medication (e.g., long acting
-agonist, theophylline or leukotriene antagonist);
в– persistent airflow limitation (with a forced expiratory volume
in the first second or FEV1 <80% predicted with >20% diurnal
variability in peak expiratory flow);
Omalizumab
Omalizumab (Xolair) is a recombinant humanised monoclonal
anti-Immunoglobulin E (IgE) antibody that is used in the
treatment of severe atopic asthma. IgE is a critical mediator in
allergic diseases such as asthma.11 Following exposure to a
stimulant, allergic individuals produce allergen-specific IgE.
Circulating IgE attaches to pro-inflammatory cells such as mast
cells, basophils and macrophages via the Fc portion linked to
Fc-epsilon-RI receptors. Upon further allergen exposure,
cross-bridging of IgE and allergen on the surface of effector cells
leads to the release of inflammatory mediators such as histamine,
prostaglandins and leukotrienes.12
In people with asthma, chronically high serum IgE levels
potentiate this system, leading to airway inflammation and
bronchial hyperresponsiveness. It is estimated that 50-80% of
treatment-resistant patients have an allergic component, with IgE
playing a key role in the triggering and maintenance of airway
inflammation and an exaggerated bronchoconstrictive
response.13 Anti-IgE therapy was included in 2006 within step 5
of the GINA guidelines as an add-on to corticosteroids,
long-acting 2-agonists and/or other controller medications.14
Omalizumab works by binding free serum IgE at Fc-epsilon-RI,
the site that normally binds receptors on mast cells and
basophils. This prevents cross-linking of receptors and subsequent
degranulation and release of pro-inflammatory mediators.
Perhaps as a result of decreased circulating free IgE, the drug
Volume 7: Number 1. 2014 | Page 29
RCSIsmjreview
and oral corticosteroids, along with smoking cessation (if clinically
appropriate). The costs per annum for standard therapy are
estimated to be ВЈ1,197 for adults and adolescents, and ВЈ810 for
children.22
A multi-centred, observational, retrospective cohort study of 63 Irish
patients was conducted, which compared clinical outcomes six
months before and after treatment with omalizumab.23 Their
findings (all p<0.0001) showed:
в– в– в– в– в– FIGURE 1: Mechanism of action of omalizumab.
causes a decrease in the number of cell-surface IgE receptors of
mast cells and basophils over time. The mechanism of action for
omalizumab is illustrated in Figure 1.15
In 2005, the European Medicines Agency (EMA) issued a marketing
licence for the use of omalizumab as an add-on therapy for patients
with severe persistent allergic asthma aged 12 and above; this
license was extended in 2009 to include children over the age of
a 61% decrease in asthma exacerbations;
a 67% decrease in hospital admissions;
a 68% decrease in bed days (a saving of 12 bed days per patient);
a 62% decrease in courses of oral corticosteroids required; and,
a 90% decrease in work days lost.
Cost saving for the patients who responded to omalizumab was
834 per patient over six months, mainly due to a drastic reduction
in hospital admissions and bed stays.
Current guidelines
The United Kingdom’s National Institute for Health and Clinical
Excellence (NICE) recommended the use of omalizumab first in 2007
for patients aged 12 years or above as an add-on treatment for
six.16 In 2006, a Cochrane review of 14 trials looked at the response
of 3,143 patients with mild to severe IgE-mediated asthma and
found omalizumab to be generally well tolerated, with positive
physician and patient assessments. There was a clinically significant
number of patients who were able to reduce or withdraw their
inhaled corticosteroid (ICS) use compared to placebo. There was
also a reduction in the frequency of asthma exacerbations when
omalizumab was used as an add-on with ICS. However, “impressive”
placebo effects were noted in the control groups, bringing into
question the “true” effects of omalizumab and suggesting that the
clinical value of steroid reduction has to be weighed against the
severe, persistent allergic asthma.24 NICE also specified that
omalizumab should be limited to patients who, within the past year,
had more than two hospital admissions, or one admission plus two
emergency department admissions, for asthma exacerbations. The
evidence reviewed in their appraisal found that the number needed
to treat (NNT) in one year to prevent one clinically significant asthma
exacerbation (defined as peak flow or FEV1 <60% of personal best)
costs of the drug.17
Cost–benefit analysis of omalizumab
higher than what NICE considered cost-effective.26 Furthermore, a
study of 510 UK patients with severe asthma found that only 27 (or
5.3%) were eligible for treatment, with NICE’s prescribing guidelines
The dosage of omalizumab is dependent on the patient’s body
weight and the total serum baseline IgE level. It is currently approved
in the European Union for patients with allergic asthma with total
plasma IgE levels ranging from 30-1500IU/mL with a dosing formula
of 0.016mg/kg per IU/mL. Following subcutaneous administration,
omalizumab has a bioavailability of 62% and induces a reversible
reduction of unbound serum IgE by at least 84%, which can last up
requiring hospital admissions for patients within the past year.27
In response to NICE’s re-appraisal in 2010, some of the UK’s leading
paediatric pulmonologists contested the way the QALYs were
calculated, saying they lacked an appreciation of the importance of
asthmatic exacerbations and disrupted schooling when measuring
paediatric QALY. In the same editorial, NICE was also criticised for
having only one paediatrician on the 34-member committee that
to six weeks.18,19 Currently, a physician’s evaluation is recommended
16 weeks after commencing therapy. The cost of omalizumab is
ВЈ256.16 for a 150mg vial and ВЈ128.07 for a 75mg vial. The drug is
administered every two to four weeks, with a fortnightly maximal
formulated the new guidelines.28
In November 2012, NICE’s assessment panel withdrew their
recommendation of omalizumab as a cost-effective therapy
altogether for both adolescents and adults, citing a lack of
quantifiable data to justify omalizumab as a cost-effective use of NHS
dosage of 600mg.20 The cost per patient can be up to ВЈ26,640 per
annum, with the average yearly cost for adults and adolescents being
11.21
ВЈ8,056, and ВЈ8,455 for children aged six to
In contrast, the standard treatment regimen for those with severe
asthma consists of inhaled high-dose corticosteroids, long-acting
beta agonists (LABAs), leukotriene receptor antagonists, theophyllines
Page 30 | Volume 7: Number 1. 2014
was 2.2.25
In 2010, despite the EMA’s recommendation of the treatment for
children six to 11 years old one year earlier, NICE stated that the cost
per quality adjusted life year (QALY) gained for that age group was
resources.29
However, in March 2013, NICE reversed its position and expanded
the recommendation to include adults, adolescents and children
aged six and over. The requirement for hospital admissions was also
removed. The panel acknowledged the conclusions of clinical experts
RCSIsmjreview
who pointed out that in clinical practice, patients receiving
omalizumab had much more severe asthma than those enrolled in
studies, and trial evidence therefore underestimated the benefits
gained. Novartis also agreed to make omalizumab available to the
NHS under a patient access scheme at a discounted price. This
lowered the cost-effectiveness ratio to ВЈ23,200 per QALY gained,
which was within the range of £20,000-£30,000 – the range that
NICE considers cost-effective. The guidelines will be reviewed again
control. Nurse-led home visits to 71 children in the UK diagnosed
with severe asthma showed that more than half had potentially
reversible factors, including inadequate adherence to medication,
in March 2016.30
with efficacy of therapy.36
Studies of omalizumab’s effect on pulmonary function tests such as
Future perspectives
FEV1 have shown inconsistent results.37 However, in certain patients,
omalizumab decreases biomarkers of TH2 inflammation such as
The latest decision by NICE was welcomed by asthma charities and
groups in the United Kingdom and in Ireland.31,32 In 2011, Novartis
Ireland said they would introduce the Xolair Patient Outcomes
Reimbursement Programme – a programme that would refund stock
used by patients who were not benefitting at the 16-week evaluation
point that is used to evaluate efficacy and to determine whether to
treatment.33
continue with
The Asthma Society of Ireland has stated,
however, that omalizumab is not reimbursable under any
Government schemes, and access depends on hospitals’ pharmacy
budgets; this means that the drug is unavailable to 50% of patients
who need it.34
While omalizumab is a significant advancement as an add-on
treatment for severe persistent atopic asthma, it is imperative that it
is targeted at those most likely to benefit. This can be achieved by
ensuring that only patients who are genuinely treatment resistant are
referred to specialists for consideration of anti-IgE therapy. Isolation
of these patients may be facilitated by better education with regard
to medication (e.g., correct use of inhalers) and environmental
along with tobacco and allergen exposure at home.35
Furthermore, the 16-week guideline for assessing its efficacy may be
flawed, as it presupposes that omalizumab is responsible for the
improvement in clinical parameters as opposed to other factors.
There are also doubts as to whether IgE levels are directly correlated
fractional exhaled nitric oxide, peripheral blood eosinophil count,
serum periostin38 and endothelin-1 in exhaled breath condensate.
This has been shown to correlate with improved spirometry
parameters and reductions in protocol-defined asthma
exacerbations.39 The feasibility of their use as prognostic indicators
of omalizumab efficacy in treatment for asthma and accurately
identifying responders may be worth exploring in clinical practice.
For many patients, asthma remains a severely debilitating condition.
Omalizumab has provided a better quality of life for patients with
severe asthma for whom treatment options are otherwise limited.
However, it is imperative, given the costs associated with the drug,
that it is used judiciously and targeted at those most likely to
benefit.
Furthermore, there needs to be a scrupulous methodology used
when calculating QALY, which takes into account various
socioeconomic factors along with the input of clinicians,
epidemiologists and patient groups.
References
1. Anderson GP. Endotyping asthma: new insights into key pathogenetic
7. American Thoracic Society. Proceedings of the ATS workshop on refractory
mechanisms in a complex, heterogeneous disease. Lancet.
asthma: current understanding, recommendations, and unanswered
2008;372(9643):1107-19.
questions. Am J Respir Crit Care Med. 2000;1626:2341-51. Available from:
2. Masoli M, Fabian D, Holt S, Beasley R. The global burden of asthma:
executive summary of the GINA dissemination committee report. Allergy.
2004;59(5):469-78.
3. Bateman ED, Hurd SS, Barnes PJ, Bousquet J, Drazen JM, FitzGerald M et al.
Global strategy for asthma management and prevention: GINA executive
summary. Eur Respir J. 2008;31:143-78.
4. Boulet LP. Influence of comorbid conditions on asthma. Eur Respir J.
2009;33(4):897-906.
5. Dolan CM, Fraher KE, Bleecker ER et al. Design of baseline characteristics of
the epidemiology and natural history of asthma: outcomes and treatment
http://www.thoracic.org/statements/resources/allergy-asthma/refracasthma
.pdf.
8. ENFUMOSA (European Network For Understanding Mechanisms Of Severe
Asthma) Study Group. The ENFUMOSA cross-sectional European
multicentre study of the clinical phenotype of chronic severe asthma. Eur
Respir J. 2003;22(3):470-7.
9. Health Service Executive (HSE). Incidence of Asthma in Ireland. HSE.ie
[Internet] 2013 [cited 2013 Nov]. Available from:
http://www.hse.ie/eng/health/hl/living/asthma/aboutasthma/.
10. Asthma Society of Ireland. Expert says nearly two people die of asthma
regimens (TENOR) study: a large cohort of patients with severe or
each week in Ireland. Asthma.ie [Internet 2007 Jun 19] [cited 2013 Nov].
difficult-to-treat asthma. Ann Allergy Asthma Immunol. 2004;92(1):32-9.
Available from:
6. Chung KF, Godard P, Adelroth E et al. Difficult/therapy-resistant asthma:
the need for an integrated approach to define clinical phenotypes,
evaluate risk factors, understand pathophysiology and find novel therapies.
Eur Respir J. 1999;13:1198-208.
http://www.asthma.ie/news/expert-says-nearly-two-people-die-asthma-eac
h-week-ireland.
11. Presta LG, Lahir SJ, Sheilds RL et al. Humanization of an antibody directed
against IgE. J Immunol. 1993;151:2623-32.
Volume 7: Number 1. 2014 | Page 31
RCSIsmjreview
12. Galli SJ, Tsai M, Piliponsky AM. The development of allergic
inflammation. Nature. 2008;454(7203):445-54.
13. Haselkorn T, Borish L, Miller DP, Weiss ST, Wong DA. High prevalence
of skin test positivity in severe or difficult-to-treat asthma. J Asthma.
2006;43(10):745-52.
14. Global Initiative for Asthma (GINA). Global strategy for asthma
management and prevention 2006 [Internet] 2007 July 20 [cited
2013 Nov]. Available from:
http://ginasthma.org/local/uploads/files/GINA_Report_072007_1.pdf.
15. Pelaia G, Gallelli L, Renda T et al. Update on optimal use of
26. National Institute for Health and Care Excellence. Omalizumab for
the treatment of severe persistent allergic asthma in children aged
6-11 – NICE technology appraisal guidance 201 [Internet] 2010 Oct
[cited 2013 Nov]. Available from: http://guidance.nice.org.uk/TA201.
27. Burton AJ, Hargadon B, Murphy AC et al. P20 The eligibility of
patients with difficult asthma for omalizumab since the change to
the treatment criteria. Thorax. 2010;65:84-5.
28. Bush AW, Lenney W et al. Not NICE: a better way forward? Arch Dis
Child. 2011;96:907-8.
29. National Institute for Health and Care Excellence. Asthma (severe,
omalizumab in management of asthma. J Asthma Allergy.
persistent, patients aged 6+, adults) – Omalizumab (rev TA133,
2011;(4):49-59.
TA201): appraisal consultation document [Internet] 2012 Nov [cited
16. European Medicines Agency. European public assessment report
(EPAR) for Xolair [Internet] 2010 July [cited 2013 Nov]. Available
from:
2013 Nov]. Available from:
http://guidance.nice.org.uk/TAG/287/Consultation/DraftGuidance.
30. National Institute for Health and Care Excellence. Omalizumab for the
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Su
treatment of severe persistent allergic asthma (review of technology
mmary_for_the_public/human/000606/WC500057293.pdf.
appraisal guidance 133 and 201) – NICE technology appraisal guidance
17. Walker S, Monteil M, Phelan K et al. Anti-IgE for chronic asthma
in adults and children. Cochrane Database Syst Rev.
2008;(4):CD003559. [cited 2013 Nov]. Available from:
278 [Internet] 2013 Apr [cited 2013 Nov]. Available from:
http://www.nice.org.uk/nicemedia/live/14157/63689/63689.pdf.
31. Reuters. UK health cost body backs Novartis asthma drug in fresh
http://www.thecochranelibrary.com/userfiles/ccoch/file/CD00355
U-turn. [Internet] 2013 Mar 6 [cited 2013 Nov]. Available from:
9.pdf.
http://www.reuters.com/article/2013/03/07/us-novartis-britain-xolair
18. Hendeles L, Sorkness CA. Anti-immunoglobulin E therapy with
omalizumab for asthma. Ann Pharmacother. 2007;41(9):1397-410.
19. Miller CWT, Krishnaswamy N, Johnston C, Krishnaswamy G. Severe
asthma and the omalizumab option. Clin Mol Allergy. 2008;6:4.
20. Medicines Information Online. Xolair 150mg solution for injection
[Internet] 2012 Jun 8 [cited 2013 Nov]. Available: from:
http://www.medicines.ie/medicine/14874/SPC/Xolair+150mg+solutio
n+for+injection/.
21. National Institute for Health and Care Excellence. Costing statement:
Omalizumab for severe persistent allergic asthma (Review of
technology appraisal guidance 133 and 201) [Internet] 2013 April
[cited 2013 Nov]. Available from:
http://www.nice.org.uk/nicemedia/live/14157/63691/63691.pdf.
22. Norman G, Faria R, Paton F, Llewellyn A, Fox D, Palmer S et al.
Omalizumab for the treatment of severe persistent allergic asthma: a
systematic review and economic evaluation. Health Technol Assess.
2013;17(52):1-342.
23. Costello RW, Long DA, Gaine S et al. Therapy with omalizumab for
patients with severe allergic asthma improves asthma control and
reduces overall healthcare costs. Ir J Med Sci. 2011;180:637-41.
24. National Institute for Health and Care Excellence. Omalizumab for
severe persistent allergic asthma – NICE technology appraisal
guidance 133 [Internet] 2007 Nov [cited 2013 Nov]. Available from:
http://www.nice.org.uk/nicemedia/pdf/TA133Guidance.pdf.
25. Humbert M, Beasley R, Ayres J et al. Benefits of omalizumab as
-idUSBRE92600L20130307.
32. Asthma Society of Ireland. Asthma Society welcomes UK’s NICE
decision recommending innovative life changing treatment.
[Internet] 2013 Apr 16 [cited 2013 Nov]. Available from:
https://www.asthma.ie/news/asthma-society-welcomes-uks-nice-decis
ion-recommending-innovative-life-changing-treatment.
33. Irish Medical Times. New Irish study on Xolair and asthma.
[Internet] 2011 Jul 1 [cited 2013 Nov]. Available from:
http://www.imt.ie/mims/
2011/07/new-irish-study-on-xolair-and-asthma.html.
34. Irish Medical Times. Clinical update on asthma. [Internet] 2013 Oct
13 [cited 2013 Nov]. Available from: http://www.imt.ie/clinical
/2013/10/clinical-update-on-asthma-2.html.
35. Bracken M, Fleming L, Hall P et al. The importance of nurse-led
home visits in the assessment of children with problematic asthma.
Arch Dis Child. 2009;94:780-4.
36. Garcia G, Magnan A, Girodet PO et al. A proof-of-concept
randomized-controlled trial of omalizumab in patients with severe
difficult to control nonatopic asthma. Chest. 2013;144(2):411-9.
37. Ledford DK. Omalizumab: overview of pharmacology and efficacy in
asthma. Expert Opin Biol Ther. 2009;9(7):933-43.
38. Hanania NA, Wenzel S, Rosen K et al. Exploring the effects of
omalizumab in allergic asthma: an analysis of biomarkers in the
EXTRA study. Am J Respir Crit Care Med. 2013;187:804-11.
39. Zietkowski Z, Skiepko R et al. Anti-IgE therapy with omalizumab
add-on therapy in patients with severe persistent asthma who are
decreases endothelin-1 in exhaled breath condensate of patients
inadequately controlled despite best available therapy (GINA 2002
with severe persistent allergic asthma. Respiration.
step 4 treatment): INNOVATE. Allergy 2005;60:309-16.
2010;80(6):534-42.
Page 32 | Volume 7: Number 1. 2014
RCSIsmjreview
Serotonin – the missing
link between myocardial
infarction and suicide
Abstract
The prevalence of myocardial infarction (MI) and suicide has risen over the past 40 years in
Ireland, causing considerable societal burdens. Interestingly, these conditions share common
underlying pathologies, including abnormalities in both serotonin levels and platelet cell
signalling function. Serotonin levels are decreased in the brains of depressed patients and in the
cerebral spinal fluid of suicidal patients. A single serotonin transporter (SERT) regulates the
release of serotonin stored within platelets and promotes platelet aggregation. Limitations of
antiplatelet therapies necessitate novel therapeutic approaches for treating patients who have
suffered an MI. The hypothesised underlying biochemical abnormality shared by suicide and MI
suggests a role for the use of antidepressants in treating and preventing both of these diseases.
Royal College of Surgeons in Ireland Student Medical Journal 2014; 1: 33-35.
Rachel Mattson
RCSI student
Introduction – two problems worth solving
and ninth leading causes of death in Ireland,
Suicide rates have risen exponentially in Ireland
since the 1970s and are currently regarded as
being at an epidemic level. The rates for males
are particularly alarming, having doubled from
18.3 per 100,000 in 1989 to 39.9 per 100,000 of
respectively.2 These overwhelming societal
burdens appear to be rising in conjunction with
one another and exploration is required to
determine if they are arising from a common
aetiology, and thus may be treated by targeting
the same biochemical process.
the population.1,2 Similarly, mortality rates in
Ireland from ischaemic heart disease rose steadily
until they plateaued at an alarmingly high rate in
the 1970s and onward.3 Between 1970 and
1999, 46-53% of deaths in Ireland were
attributed to ischaemic heart disease. Currently,
ischaemic heart disease and suicide are the first
Epidemiology – myocardial infarction
and suicide
In a 2013 Danish study, Larsen et al. explored
depression following MI and found that
depression itself was an independent risk factor
Volume 7: Number 1. 2014 | Page 33
RCSIsmjreview
for recurrent MIs. All patients over the age of 18 who were
discharged following an MI (ICD-10 code I21) in 2009 in the
Central Denmark Region were invited to participate. One in five (of
the 589 who enrolled) was diagnosed with depression in the three
months post MI. Furthermore, MIs were associated with a 1.53
times higher risk of suicide than in the general population.
Fortunately, moderate to severe depressive symptoms in post-MI
patients may be successfully reduced through the use of
antidepressants (effect size, 0.66; 95% CI, 0.38-0.94).4 Selective
serotonin reuptake inhibitors (SSRIs) are used preferentially over
tricyclic antidepressants in this population because of the adverse
cardiovascular events, such as prolonged QT interval, associated
with tricyclic antidepressants. The study by Larsen et al. illustrates
the close association between ischaemic heart disease and
depression. It also highlights adverse prognostic outcomes post MI
imparted by comorbid depression, including new cardiovascular
events or death, in addition to patients’ increased predisposition to
suicide.
Exploration of biochemical imbalances
In an attempt to identify the biological markers for suicidality,
Pandey et al. obtained platelets, lymphocytes, and cerebrospinal
fluid from the peripheral tissue of suicidal patients or from brains of
suicide victims obtained post mortem. They reported variations in
cytokine levels and lymphocyte gene expression in depressed
patients. The maximum number of binding sites of serotonin
receptors on platelets was significantly higher in suicidal patients, to
an effect size of 1.12 when compared to normal control subjects.5
Abnormalities of serotonin levels (such as decreased CSF 5-HIAA)
and in platelet signalling (such as increased 5HT2A receptors in
platelets) point to physiological changes that may aid in the
identification of patients predisposed to suicidal behaviours, as well
as the elucidation of novel targets for treatments aimed at suicide
prevention.5 Current biological therapy for depression is based upon
correcting the hypothesised underlying biochemical abnormality of
decreased serotonin levels in the brain. Likewise, SSRIs may be
efficacious when added to a biopsychosocial regimen for patients
without a clear history of depression, but who are at risk of suicide.
Given the finding of abnormal plasma serotonin in suicidal patients,
the rationale for the use of these drugs for suicide prevention is
similar to that for its use in depression.6 This observed relationship
has been confirmed by studies such as that conducted by Ruljancic
et al., which demonstrated a positive correlation between serotonin
concentrations and healthy controls as compared to a negative
correlation between serotonin levels in suicidal and non-suicidal
patients.7
depressed
Serotonin dysregulation also has a role in the pathophysiology of
coronary artery disease. Increased plasma levels of serotonin were
seen by Breener et al. in serum samples of patients with
hypertension. Normally, a serotonin transporter (SERT) regulates
plasma levels by transporting free serotonin into platelets to be
stored; this occurs through a negative feedback mechanism. By
regulating serotonin plasma levels, SERT counters the pathological
vasoconstriction that contributes to hypertension.8 Serotonin
Page 34 | Volume 7: Number 1. 2014
contributes to systemic vascular vasodilation by relaxing smooth
muscle, inhibiting sympathetic tone, and increasing
endothelium-derived relaxing factor.9 SERT also plays a part in
promoting platelet aggregation, a key pathophysiologic process
contributing to ischaemic heart disease.10 Patients expressing high
levels of SERT – thus having low levels of serotonin in the circulation
– are not only likely to have hypertension as a result, but are also at
even greater risk of MI because of a greater propensity for platelet
aggregation.
In light of these biochemical mechanisms, SERT is a promising
biochemical marker; it has the potential to explain a common
underlying pathophysiologic abnormality that predisposes to both
suicide and coronary artery disease.
Novel therapeutic approaches for post-MI therapy
Currently, antiplatelet drugs are a central component of post-MI
therapy.11 Aspirin and dipyridamole inhibit platelet aggregation
through thromboxane synthesis inhibition at the level of
cyclooxygenase and thromboxane synthase, respectively.11
Compliant patients respond positively to aspirin therapy; however,
patients do not respond in the same manner to other antiplatelet
drugs such as clopidogrel.12 In an abstract from the 2012
International Congress on Thrombosis, Cattaneo et al. stated that
one-third of patients are poor responders to clopidogrel,
highlighting the highly variable pharmacological response to
antiplatelet agents.12 These findings demonstrate a role for
personalised medicine in the treatment of patients at risk for or
following MI, and suggest the possibility of varying underlying
processes contributing to thrombus formation causing
cardiovascular disease.
The inverse relationship between plasma serotonin levels and MI,
along with the demonstrated comorbidities of depression and
suicidal ideation, suggest that SERT and serotonin may be
interesting new targets for potential exploitation in the post-MI
medical discharge plan. Serotonin and the catecholamines
(dopamine, epinephrine and norepinephrine) are all monoamine
neurotransmitters whose receptors have been implicated in von
Willebrand factor-mediated platelet thrombus formation.13 By
increasing plasma serotonin levels, negative feedback mechanisms
mediated by SERT would decrease platelet serotonin receptors,
subsequently reducing platelet thrombus formation.8 The use of
medications that manipulate serotonin may confer the additional
benefit of mitigating depression and suicidal ideation. Both are
independent risk factors for recurrent MIs and have been shown to
be associated with low levels of serotonin in the brain.4,14
Developing an effective protocol for the prevention and treatment
of MI and suicide is feasible given the evidence of a shared
biochemical target. Patient accessibility factors are a concern when
attempting to prevent consequences of mental health problems.
However, a study conducted in the United States found that 81% of
individuals who died by suicide attended healthcare services within
one year prior to their death.15 This suggests a potential role for
active screening to detect patients at risk of suicide. Early
interventions and preventive measures targeted at these high-risk
RCSIsmjreview
individuals could be employed to reduce the incidence of suicide
and self-harm. Such preventive measures may include interventions
aimed at increasing plasma serotonin levels. Dietary
supplementation with tryptophan rich egg protein hydrolysate, for
example, has been shown to increase tryptophan availability for
serotonin production. This effectively reduced depressed mood in all
test subjects and improved their perceptual and motor responses,
be an aetiological link between these two leading causes of death in
Ireland. The costs to families and society of premature death due to
these conditions is enormous. Heart disease remains the leading
cause of mortality in Ireland and this is further compounded by the
both of which are decreased in patients with depression.16
Additionally, those patients who suffer from, and survive MIs may
benefit from treatments that increase their serotonin levels, such as
SSRIs. Hypothesised benefits include reduction of platelet-induced
thrombus formation as well as treatment for post-MI depression,
both of which increase the risk of MI recurrence. SSRIs may also
prove effective in modulating platelet function in patients who are
refractory to treatment using traditional anti-platelet medications
such as clopidogrel, thus contributing to an arsenal of therapeutic
options to personalise medical treatment post MI.
2001 due to workforce absence and health service utilisation.15 The
poor financial climate in Ireland will be further burdened by the
continually increasing suicide rates, especially prevalent in young
high prevalence of depression in this patient population.2,4 The
Department of Economics at the National University of Ireland in
Galway estimated the total cost of suicide at over 906 million in
Given the relationship between low brain serotonin levels and
suicide, as well as the role of serotonin in thrombus formation
central to the pathophysiology of MI, it appears that serotonin may
men who are so crucial to the workforce and societal function.16,17
The emotional consequences of suicide for family, friends, and
society are massive, highlighting the importance of combatting this
issue.
The finding of low plasma serotonin levels contributing to
depression and consequently suicide, as well as platelet plug
formation and resultant MI, is promising in providing an explanation
for the pathophysiology behind and treatment of MI recurrence and
the aggravating comorbidity depression. The targeted utilisation of
SSRIs in patients post MI may prove beneficial by addressing a
common underlying biochemical abnormality contributing to MI
recurrence, as well as to depression and suicide.
References
9. Mylecharane EJ. Mechanisms involved in serotonin-induced vasodilatation.
Conclusion
1. Ireland. Houses of the Oireachtas. Joint Committee on Health & Children.
The High Level of Suicide in Irish Society; July 2006. P19. Report No.: 7.
Available from: http://www.nosp.ie/oireachtas_report.pdf.
2. World Life Expectancy. Ireland: life expectancy [Internet]. 2011 [updated
2011; cited 2013 Nov 2]. Available from:
http://www.worldlifeexpectancy.com/ireland-life-expectancy.
3. Irish Heart Foundation. 50 Years of Heart Disease in Ireland. Mortality,
morbidity and health services implications. [Internet] February 2011.
Available from:
http://www.irishheart.ie/iopen24/pub/positionstatements/heart_for_pdf.p
df.
4. Larsen KK. Depression following myocardial infarction – an overseen
complication with prognostic importance. Dan Med J. 2013;60(8):B4689.
5. Pandey GN. Biological basis of suicide and suicidal behaviour. Bipolar
Disord. 2013;15(5):524-41.
6. Thase M, Connolly RK. Unipolar depression in adults: Treatment of
resistant depression. UpToDate [Internet] 2013 [cited 2013 Nov 2].
Available from:
http://www.uptodate.com.proxy.library.rcsi.ie/contents/unipolar-depressio
n-in-adults-treatment-of-resistant-depression?source=preview&anchor=H4
456801&selectedTitle=4~150#H4456801.
7. Ruljancic N, Mihanovic M et al. Platelet serotonin and magnesium
concentrations in suicidal and non-suicidal depressed patients. Magnes
Res. 2013;26(1):9-17.
8. Brenner B, Harney JT et al. Plasma serotonin levels and the platelet
serotonin transporter. J Neurochem. 2007;102(1):206-15.
Blood Vessels. 1990;27(2-5):116-26.
10. Carneiro AMD, Cook EH, Murphy DL, Blakely RD. Interactions between
integrin IIb 3 and the serotonin transporter regulate serotonin transport
and platelet aggregation in mice and humans. J Clin Invest.
2008;118(4):1544-52.
11. Lincoff M. Antiplatelet agents in acute ST elevation myocardial infarction.
UpToDate [Internet] 2013 [cited 2013 Nov 2]. Available from:
http://www.uptodate.com.proxy.library.rcsi.ie/contents/antiplatelet-agents
-in-acute-st-elevation-myocardial-infarction?source=related_link.
12. Cattaneo M. Mechanisms of variability in antiplatelet agent response.
Thromb Res. 2012;130(Suppl. 1):S27-8.
13. Goto S. Understanding the mechanism of platelet thrombus formation
under blood flow conditions and the effect of new antiplatelet agents.
Curr Vasc Pharmacol. 2004;2(1):23-32.
14. Young SN. Elevated incidence of suicide in people living at altitude,
smokers and patients with chronic obstructive pulmonary disease and
asthma: possible role of hypoxia causing decreased serotonin synthesis. J
Psychiatry Neurosci. 2013;38(6):423-6.
15. Ahmedani B, Simon G, Stewart C et al. PS1-30: Examining Health Service
Utilization in the Year Prior to Suicide Death. Clin Med Res.
2013;11(3):168.
16. Kennelly B. The economic cost of suicide in Ireland. Crisis.
2007;28(2):89-94.
17. TheJournal.ie. Suicide rate amongst young people in Ireland fourth
highest in EU. [Internet] 2013 [updated 2013 May 9; cited 2013 Nov 2].
Available from: http://www.thejournal.ie/suicide-rates-1070842-Sep2013/.
Volume 7: Number 1. 2014 | Page 35
RCSIsmjreview
Rediscovering thalidomide:
lessons learnt and evolving
indications
Abstract
Thalidomide ( -phthalimido-glutarimide), a hypnotic sedative and anxiolytic with anti-emetic
properties, was withdrawn in 1961 after four short years on the drug market. Prescribed to
pregnant women to reduce morning sickness, it was found to cause limb and other
malformations in newborns. The huge scale of the catastrophe was attributed to the
presumption of thalidomide’s safety, combined with relaxed drug safety regulations and
irresponsible actions on the part of the drug company. Since then, thalidomide has driven a
revolution both in drug safety legislation and in the way pharmaceutical compounds are
researched – for example, through its demonstration of species specificity. Several potential
mechanisms by which thalidomide induces teratogenesis have been proposed, of which three
widely supported hypotheses will be discussed.
Thalidomide has not disappeared from clinical use, however. It was first tried in erythema
nodosum leprosum (ENL) three years after its withdrawal with impressive success. Two classes
of analogues – immunomodulatory drugs (IMiDs) and selective-cytokine-inhibitory drugs
(SelCIDs) have been developed to enhance efficacy and reduce toxicities. Today, thalidomide
and IMiDs are the approved treatments for ENL, multiple myeloma and myelodysplastic
syndrome. Despite knowledge about the activities of these drugs, their exact mechanisms of
action are only known for a few diseases, including multiple myeloma. Thalidomide and
IMiDs are currently being studied in solid tumours, HIV-associated diseases and refractory
dermatological conditions. The future of thalidomide and its derivatives in the mentioned
fields are summarised in this review.
Royal College of Surgeons in Ireland Student Medical Journal 2014; 1: 36-40.
Introduction
Thalidomide was developed by the German
pharmaceutical company Chemie GrГјnenthal as part
of a search for an easier and cheaper method to
synthesise antibiotics.1 It had neither the antibiotic
nor any of the other pharmacological properties
being tested for in animals; however, thalidomide
was believed to be a human sedative due to its
structural similarity to barbiturates.1 The low lethal
dose of barbiturates gave thalidomide huge market
potential as a non-toxic tranquiliser.1 Upon finding
that a lethal dose was indeterminable in rats,
GrГјnenthal proceeded with human trials of
effectiveness.1
Following its approval in 1957,
thalidomide was sold over the counter to treat
ailments from colds to insomnia.1,2 Though no
specific studies had been done, thalidomide was
women.1
Sheau Wei Tan
RCSI medical student
Page 36 | Volume 7: Number 1. 2014
claimed to be safe for pregnant
Mild to
severe side effects such as dizziness, �hangover’,
allergy and peripheral neuropathy were reported.1
Although healthcare providers pressured the US Food
and Drug Administration (FDA) to put thalidomide
under prescription, no action was taken to control its
usage.1 In 1961, Lenz and McBride independently
published a link between maternal consumption of
thalidomide and limb malformations among
neonates, mainly phocomelia (short limbs with hands
and feet located much nearer to the trunk).3,4 Other
less common thalidomide-associated defects include
external ear, eye, kidney, spinal cord, heart and
gastrointestinal abnormalities.2,5,6 Although
thalidomide was immediately withdrawn from the
market, 10,000 malformed babies had been born
worldwide and an incalculable number of
spontaneous abortions had occurred.5,6
A single dose of thalidomide taken between 20 and
36 days after fertilisation – the period of limb
development – is sufficient to cause malformations in
20-30% of newborns.5,7 Today, 5,000 survivors still
live with its impacts.1 Nevertheless, new discoveries
made over the last five decades have returned
thalidomide to the market, albeit for different
indications. This review will discuss lessons learnt
from this medical tragedy, as well as the current and
potential clinical applications of thalidomide.
RCSIsmjreview
Lessons learnt
Revolution in drug safety
Cereblon
The damage caused by thalidomide could have been minimised if
GrГјnenthal had undertaken more vigorous trials and post-marketing
monitoring. When doctors suspected thalidomide as the culprit for
peripheral neuropathy and birth defects, GrГјnenthal denied all claims
and repeatedly distributed letters re-affirming thalidomide’s safety
its teratogenic effect.14 Thalidomide-CRBN binding inhibits
ubiquitination, a process that marks substrates for degradation,
causing them to build up and downregulate fibroblast growth
proof.1
The generally lenient atmosphere
without further scientific
surrounding approval of new pharmaceutical agents during the 1960s
allowed potentially dangerous drugs like thalidomide to remain on the
market unchecked. For example, new drugs submitted for approval in
the United States were cleared automatically if the FDA was unable to
disprove their safety within 60 days of application.1 Clinical trials
required no pre-approval and were subject to minimal guidelines.1 In
response to thalidomide, however, the FDA’s Dr Frances Kelsey
demanded solid evidence of the drug’s safety – not a common practice
50 years ago.1 Even so, thalidomide was distributed to 20,000 patients
in the US alone.1 The ensuing catastrophe was a catalyst for FDA
reformation and legislation to safeguard patient interests.1 Today, drugs
must undergo intense preclinical studies before entering three-phased
clinical trials, and require post-market monitoring to evaluate long-term
benefits and risks.8
The recent discovery of cereblon (CRBN), the binding target of
thalidomide, marked a major breakthrough in the understanding of
factors.14,15 Introducing mutant CRBNYW/AA with low affinity for
thalidomide into zebrafish and chicks reduced
thalidomide-associated defects in these species.14
Problem with animal models
Grünenthal’s trials of thalidomide demonstrated a major downfall of
drug testing in animals: the same drug can have different effects on
different species. Thalidomide is teratogenic in rabbits, chicks and
zebrafish, but not in mice, pigs or rats.16 Unfortunately, rats were
the only species tested by GrГјnenthal.1 Thalidomide needs to be
metabolically activated to become anti-angiogenic; this seems to
occur to a greater extent in humans and rabbits compared to rats.17
Rats also have more glutathione stores in their limb buds than
rabbits, and so are better able to counteract oxidative stresses.14
Modern toxicological studies routinely assess drug effects in several
species, including rodents and non-rodents. Still, human responses
can never be fully predicted.
Mechanisms of teratogenesis
Due to its complex biochemistry, the exact pathway by which
thalidomide induces embryopathy has not been established, although
over 30 hypotheses have been proposed.5 The actual mechanism may
be a combination of present models. Recent research has focused
mainly on three of these models: anti-angiogenesis; oxidative stress;
and, cereblon.
Anti-angiogenesis
Angiogenesis, the outgrowth of new blood vessels from pre-existing
ones,9
is essential to the growth of developing limb buds. The DNA
intercalation model suggests that thalidomide prevents the
transcription of pro-angiogenesis genes by directly binding to their
DNA promoter regions.10 CPS49, a thalidomide analogue, has been
shown to reduce vessel density in chick limb buds via alterations of
expression.11
These include the suppression of fibroblast growth
gene
factors required for cell proliferation and limb patterning.5,11
Interestingly, earlier exposure to CPS49 resulted in worse outcomes.11
This could explain the spectrum of limb defects observed in humans,
i.e., amelia (total absence of limb/s), phocomelia (defective proximal
limbs) and digit
loss.11
Oxidative stress
Thalidomide is bioactivated by embryonic enzymes to form a free
Evolving indications
Thalidomide’s titanic history did not sentence it to death. In 1964,
Dr Sheskin, a dermatologist in Jerusalem, administered thalidomide
to a man suffering from weeks of insomnia due to pain from
erythema nodosum leprosum (ENL) – a complication of leprosy –
after several other sedatives failed to put him to sleep.1,18 Dramatic
resolution of his insomnia – as well as (astonishingly) his pain, fever
and cutaneous sores – prompted further study of thalidomide for
the treatment of ENL; it received approval in 1998.18 Although
better drugs have since been developed,6 this discovery kickstarted
the new fate of thalidomide, and several new indications have since
been discovered.
Major factors that initiated thalidomide’s re-emergence include the
ineffectiveness of standard treatments, mainly in relapse settings.19
Additionally, certain disease characteristics can be targeted by its
anti-angiogenic, immunomodulatory and anti-inflammatory
properties.5 Thalidomide decreases tumour necrosis factor-alpha
(TNF- ) and interleukin-12 production in monocytes and
macrophages.20 This may explain its efficacy in diseases hallmarked
by elevated TNF- levels, including ENL.18 Thalidomide also inhibits
the production of pro-inflammatory cytokines, co-stimulates CD8+
T-cells, promotes T-cell expansion and IFN- release, and induces a
radical
This substance produces reactive oxygen species
(ROS) that damage embryonic DNA and proteins.12 Pre-treatment of
rabbits with a free radical spin trapping agent before exposure to
shift from Th-1 to Th-2 immune response.20 Two classes of
thalidomide derivatives – immunomodulatory drugs (IMiDs)21 and
selective-cytokine-inhibitory drugs (SelCIDs)22 – were developed in
recent years to enhance potency and avoid thalidomide-associated
thalidomide reduces defects at birth.12 Furthermore, Knobloch and
colleagues demonstrated how ROS alters the Bmp/Dkk1/Wnt signalling
pathway, which eventually promotes the apoptosis of progenitor cells
toxicities.23 Clinically important IMiDs include
lenalidomide/CC-5013 and pomalidomide/CC-4047.21 SelCIDs have
not yet been widely studied clinically, but CC-7034 and CC-9088
that are critical for limb and eye developments.13
have shown anti-tumour effects in murine cancers.22
intermediate.12
Volume 7: Number 1. 2014 | Page 37
RCSIsmjreview
Thalidomide
and IMIDВ®s
Thalidomide
and IMIDВ®s
inhibition of proliferation
induction of cell cycle
arrest and/or apoptosis
Thalidomide
and IMIDВ®s
inhibition of adhesion
Levels of VCAM and
selectins decrease
MM cells
Bone marrow
stromal cells
Cellular
interaction
Inhibition of
expression
Thalidomide
and IMIDВ®s
Bone marrow
blood vessels
Levels of VEGF1
IL-6 and TNFincrease
Activation
Inhibition of
angiogenesis
Lysis of MM cells
Release of
cytotoxic
mediators
Levels of
INF- and
IL-2
increase
T-cell activation
and proliferation
Stimulation of
production
Th1
cells
Thalidomide
and IMIDВ®s
NK cells
FIGURE 1: Thalidomide and IMiDs inhibit the growth and encourage the death of multiple myeloma cells.
Haematological malignancies
Multiple myeloma (MM) is characterised by aberrant proliferation of
bone marrow plasma cells,24 which leads to skeletal lesions, anaemia,
hypercalcaemia, increased infection risk and kidney failure.25,26
Though MM is incurable, the survival rate has increased from 35.6%
in 1998-2001 to 44% in 2006-2009 (in the US) partly due to the
introduction of thalidomide and lenalidomide.26,27 Addition of
thalidomide to a standard dexamethasone regimen shows
significantly higher response rates (63%) than the dexamethasone
only regimen (41%).20 Lenalidomide-dexamethasone is approved for
relapsing and refractory MM,20 and plays a role in maintenance
therapy.28 Thalidomide and IMiDs inhibit the growth and encourage
the death of MM cells.18
The adhesion of normal bone marrow cells to MM cells via cell
adhesion molecules (CAMs) elevates the local levels of vascular
endothelial growth factor (pro-angiogenesis factor) and interleukin-6
signal).18
Thalidomide and its derivatives reduce
(MM cell survival
the expression of CAMs,18 partly by downregulating TNF- .29 They
also reduce the proliferation of MM cells by inhibiting DNA
synthesis.18
Cell death is promoted via two pathways – apoptosis by activation of
caspase 8 via FasL and lysis by stimulation of natural killer cells
(Figure 1).18,29 IMiDs are also useful in the treatment of
myelodysplastic syndromes, a group of haematological conditions
arising from bone marrow failure with a tendency to progress into
leukaemia.30,31
acute myeloid
Lenalidomide is the approved first-line treatment for low-risk patients
with the del(5q) karyotype with anaemia, who are non-eligible for
Page 38 | Volume 7: Number 1. 2014
haematopoietic stem cell transplantation.32 In a Phase III study of
patients fulfilling these criteria, 56% became RBC transfusionindependent (main treatment goal to prevent organ damage and
iron overload) for 26 weeks following lenalidomide therapy.32
Recently, lenalidomide was approved for a new indication – mantle
cell lymphoma, specifically in patients who are refractory to
bortezomib or bortezomib-containing regimen and patients in
relapse.33
Non-haematological malignancies
Thalidomide and lenalidomide have limited roles in solid tumours.
Phase I/II studies using these agents in castration-resistant prostate
cancer showed exciting results with 50% serum reduction of
prostate-specific antigen, the disease biomarker.34,35
Nevertheless, negative results from the Phase III MAINSAIL study of
lenalidomide indicated the need for further analysis.34 In renal cell
carcinoma, disease stabilisation was achieved with thalidomide
alone, but with severe toxicities including lethargy, peripheral
neuropathy, deep vein thrombosis and pulmonary embolism.36
Several combination immunotherapy and chemotherapy regimens
have been studied; combination thalidomide/interleukin-2 treatment
is potentially entering Phase III study for metastatic renal cell
carcinoma.37
Thalidomide/temozolomide has demonstrated some efficacy in
malignant melanoma38 and glioblastoma multiforme.39
Disappointingly, little or no benefit was found for breast, ovarian,
colorectal, hepatocellular, small-cell and non-small-cell lung
carcinomas.40,41,42,43
RCSIsmjreview
HIV-associated conditions
Oral aphthous ulcers, though normally self-limiting in healthy
people, are progressive in patients with AIDS. Many groups have
disease;44
one group has
reported thalidomide’s activity in this
achieved complete healing in 55% of the subjects.45 A Phase II
study of Kaposi’s sarcoma showed a 40% response rate but did
not replicate the peripheral blood reduction of Kaposi’s sarcoma
virus (HHV8) seen in previous smaller studies.46 In AIDS-related
wasting and diarrhoea, both associated with elevated TNFlevel, thalidomide induced weight gain and reduced bowel
movements in affected patients.47
Dermatological conditions
Thalidomide’s success in the treatment of ENL inspired studies of
its efficacy in diverse refractory dermatological problems. Case
reports and small studies bloomed in the 1980s and showed
exciting results for various conditions.48
Thalidomide has been effective in refractory actinic prurigo,
prurigo nodularis, paraneoplastic pruritus and chronic discoid
lupus erythematosus.49 Prolonged thalidomide treatment for
sarcoidosis shows impressive rates of resolved cutaneous
lesions.50 Accumulating data is suggesting that thalidomide
should be the primary treatment for vulvar Langerhans’ cell
histiocytosis, but further studies are required.51 The
anti-inflammatory and immunomodulatory properties of
thalidomide are most probably responsible for its dermatological
activities.18 However, not all initially promising results have led to
clinical use. Despite confirmed efficacy in Behcet’s syndrome, a
systemic vasculitis characterised by recurrent uveitis, and oral and
genital ulcers,52 significant side effects, especially a high
incidence of deep vein thrombosis, prohibit thalidomide’s use in
most patients.53 Recent studies of its use in chronic
graft-versus-host-disease have disproved clinical benefits
suggested by earlier research.54
Conclusion
Thalidomide has fallen and risen in favour over the past five
decades. Since its disastrous introduction to the market as a
sedative, and subsequent withdrawal, we have learned much
about thalidomide, and appreciate some of the plausible
mechanisms behind its teratogenicity.
We have learnt how to manipulate the drug for new applications;
thalidomide and lenalidomide have improved the prognoses of
MM and myelodysplastic syndrome and are widely studied in
other areas such as dermatology and HIV-associated conditions.
Nevertheless, teratogenicity and adverse effects still limit their
clinical applications. We have also learned important lessons
about the pharmaceutical industry generally, including the
limitations of animal models in drug testing and the importance
of stringent drug safety regulations.
With these lessons in mind, research on thalidomide’s therapeutic
potential should continue. An exciting prospect is the
development of analogues that preserve thalidomide’s beneficial
activities without its toxicities. Meanwhile, new and existing
combination therapies await further exploration. With these
lessons in mind and bright prospects for the future, the
resurrection of thalidomide can continue to benefit mankind
without repeating its dark history.
References
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revival as a vital medicine. Massachusetts; Perseus Publishing, 2001.
2. Rajkumar SV. Thalidomide: tragic past and promising future. Mayo Clin
Proc. 2004;79(7):899-903.
3. Moos R, Stolz R, Cerny T, Gillessen S. Thalidomide: from tragedy to
promise. Swiss Med Wkly. 2003;133:77-87.
4. Definition of phocomelia in English. [Internet]. Oxford: Oxford University
Press; [Date unknown, cited 2013 Dec 28]. Available from:
http://www.oxforddictionaries.com/definition/english/phocomelia.
5. Vargesson N. Thalidomide-induced limb defects: resolving a 50-year-old
puzzle. Bioassays. 2009;31:1327-36.
6. Pannikar V. The return of thalidomide: new uses and renewed concerns.
Lepr Rev. 2003;74(3):286-8.
7. Annas GJ, Elias S. Thalidomide and the Titanic: reconstructing the technology
tragedies of the twentieth century. Am J Public Health. 1999;89(1):98-101.
8. Cox D. Drug evaluation. [Lecture notes]. Royal College of Surgeons,
Ireland; notes provided at a lecture given 2011 December 13.
9. Stallings R. Cancer cell biology (angiogenesis and metastasis). [Lecture
10. Stephens TD, Bunde CJW, Fillmore BJ. Mechanism of action in thalidomide
teratogenesis. Biochem Pharmacol. 2000;59:1489-99.
11. Therapontos C, Erskine L, Gardner ER, Figg WD, Vargesson N. Thalidomide
induces limb defects by preventing angiogenic outgrowth during early limb
formation. Proc Natl Acad Sci. 2009;106(21):8573-8.
12. Parman T, Wiley MJ, Wells PG. Free-radical mediated oxidative DNA damage in
the mechanism of thalidomide teratogenicity. Nat Med. 1999;5(5):582-5.
13. Knobloch J, Shaughnessy JD, RГјther U. Thalidomide induces limb deformities
by perturbing the Bmp/Dkk1/Wnt signalling pathway. FASEB J.
2007;21:1410-21.
14. Ito T, Handa H. Deciphering the mystery of thalidomide teratogenicity.
Congenit Anom (Kyoto). 2012;52:1-7.
15. Jefferies C. Regulation of protein levels and post-translational modification of
proteins. [Lecture notes]. Royal College of Surgeons, Ireland; notes provided at
a lecture given 2012 March 9.
16. Stephens TD. The impact of thalidomide and its revival as a vital medicine –
lessons learnt from history. [Conference presentation]. Danish Society for
Pharmacology 2010: 16th World Congress on Basic and Clinical
notes]. Royal College of Surgeons, Ireland; notes provided at a lecture
Pharmacology; 2010 Jul 17-23; Copenhagen, Denmark. Available from:
given 2012 April 18.
http://www.worldpharma2010.org/powerpoints.php.
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17. Bauer KS, Dixon SC, Figg WD. Inhibition of angiogenesis by thalidomide
requires metabolic activation, which is species-dependent. Biochem
Pharmacol. 1998;55:1827-34.
18. Teo SK, Stirling DI, Zeldis JB. Thalidomide as a novel therapeutic agent: new
uses for an old product. Drug Discov Today. 2005;10(2):107-14.
19. Matthews SJ, McCoy C. Thalidomide: a review of approved and
investigational uses. Clin Ther. 2003;25(2):342-95.
20. Melchert M, List A. The thalidomide saga. Int J Biochem Cell Biol.
2007;39:1489-1499.
21. Zimmerman T. Immunomodulatory agents in oncology. Update Cancer Ther.
2009;3:170-81.
22. Gee MS, Makonnen S, al-Kofahi K et al. Selective cytokine inhibitory drugs
with enhanced antiangiogenic activity control tumor growth through
vascular inhibition. Cancer Res. 2003;63:8073-8.
23. Huang YT, Hsu CW, Chiu TH. Thalidomide and its analogs as anticancer
agents. Tzu Chi Med J. 2008;20(3):188-95.
24. Mahindra A, Hideshima T, Anderson KC. Multiple myeloma: biology of the
disease. Blood Rev. 2010;24(1):S5-11.
25. Kumar S. Multiple myeloma – current issues and controversies. Cancer Treat
Rev. 2010;36(2):S3-11.
26. Mariz JM, Esteves GV. Review of therapy for relapsed/refractory multiple
myeloma: focus on lenalidomide. Curr Opin Oncol. 2012;24(2):S3-12.
27. Pulte D, Redaniel MT, Brenner H, Jansen L, Jeffreys M. Recent improvement
in survival of patients with multiple myeloma: variation by ethnicity. Leuk
Lymphoma. 2013:1-7.
28. Kagoya Y, Nannya Y, Kurokawa M. Thalidomide maintenance therapy for
patients with multiple myeloma: Meta-analysis. Leukemia Res.
2012;36:1016-21.
29. Quach H, Ritchie D, Stewart AK et al. Mechanism of action of
immunomodulatory drugs (IMiDs) in multiple myeloma. Leukemia.
2010;24:22-32.
30. Komrokji RS, List AF. Role of lenalidomide in the treatment of myelodysplastic
syndromes. Semin Oncol. 2011;38(5):648-57.
31. Al-Ameri A, Cherry M, Garcia-Manero G, QuintГЎs-Cardama A. Standard
therapy for patients with myelodysplastic syndromes. Clin Lymphoma
Myeloma Leuk. 2011;11(4):303-13.
32. Lyons RM. Myelodysplastic syndromes: therapy and outlook. Am J Med.
2012;125(7A):S18-23.
33. FDA approval for lenalidomide [Internet]. Maryland: National Cancer
Institute [Date unknown, cited 2014 January 8]. Available from:
http://www.cancer.gov/cancertopics/druginfo/fda-lenalidomide.
34. Nabhan C, Petrylak DP. The role of IMiDs alone or in combination in prostate
cancer. Clin Genitourin Cancer. 2012;10(3):141-6.
35. Macpherson GR, Franks M, Tomoaia-Cotisel A, Ando Y, Price DK, Figg WD.
Current status of thalidomide and its role in the treatment of metastatic
prostate cancer. Crit Rev Oncol Hematol. 2003;46:S49-57.
36. Amato RJ. Thalidomide therapy for renal cell carcinoma. Crit Rev Oncol
Hematol. 2003;46:S59-65.
Page 40 | Volume 7: Number 1. 2014
37. Amato RJ, Morgan M, Rawat A. Phase I/II study of thalidomide in
combination with interleukin-2 in patients with metastatic renal cell
carcinoma. Cancer. 2006;106(7):1498-506.
38. Kasper B, D’Hondt V, Vereecken P, Awada A. Novel treatment strategies for
malignant melanoma: a new beginning? Crit Rev Oncol Hematol.
2007;62:16-22.
39. Tuettenberg J, Friedel C, Vajkoczy P. Angiogenesis in malignant glioma: a
target for antitumor therapy? Crit Rev Oncol Hematol. 2006;59:181-93.
40. Morabito A, Sarmiento R, Bonginelli P, Gasparini G. Antiangiogenic
strategies, compounds and early clinical results in breast cancer. Crit Rev
Oncol Hematol. 2004;49:91-107.
41. Rossi A, Maione P, Palazzolo G et al. New targeted therapies and small-cell
lung cancer. Clin Lung Cancer. 2008;9(5):271-9.
42. Horn L, Sandler AB. Emerging data with antiangiogenic therapies in early
and advanced non-small-cell lung cancer. Clin Lung Cancer.
2009;10(1):S7-16.
43. Sleijfer S, Kruit WHJ, Stoter G. Thalidomide in solid tumours: the resurrection
of an old drug. Eur J Cancer. 2004;40:2377-82.
44. Tseng S, Pak G, Washenik K, Pomeranz MK, Shupack JL. Rediscovering
thalidomide: a review of its mechanism of action, side effects and potential
uses. J Am Acad Dermatol. 1996;35(6):969-79.
45. Jacobson JM, Greenspan JS, Spritzler J et al. Thalidomide for the treatment of
oral aphthous ulcers in patients with human immunodeficiency virus
infection. N Engl J Med. 1997;336(21):1487-93.
46. Little RF, Wyvill K, Pluda JM et al. Activity of thalidomide in AIDS-related
Kaposi’s sarcoma. J Clin Oncol. 2000;18(13):2593-602.
47. Calabrese L, Fleischer AB. Thalidomide: current and potential clinical
applications. Am J Med 2000;108:487-95.
48. Stirling DI. Thalidomide and its impact in dermatology. Semin Cutan Med
Surg. 1998;17(4):231-42.
49. Steinhoff M, Cevikbas F, Ikoma A, Berger TG. Pruritus: management
algorithms and experimental therapies. Semin Cutan Med Surg.
2011;30:127-37.
50. Fazzi P, Manni E, Cristofani R et al. Thalidomide for improving cutaneous and
pulmonary sarcoidosis in patients resistant or with contraindications to
corticosteroids. Biomed Pharmacother. 2012;66:300-7.
51. El-Safadi S, Dreyer T, Oehmke F, Muenstedt K. Management of adult primary
vulvar Langerhans cell histiocytosis: review of the literature and a case history.
Eur J Obstet Gynecol Reprod Biol. 2012;163:123-8.
52. Behcet disease [Internet]. New York: WebMD LLC; [Date unknown, cited
2014 January 8]. Available from:
http://emedicine.medscape.com/article/329099-overview.
53. Evereklioglu C. Current concepts in the etiology and treatment of Bechet
disease. Surv Ophthalmol 2005;50(4):297-349.
54. Horwitz ME, Sullivan KM. Chronic graft-versus-host disease. Blood Rev.
2006;20:15-27.
RCSIsmjreview
Transvaginal cholecystectomy:
a novel surgical technique
Abstract
Over the past 25 years, there has been a swift evolution of techniques for the performance of
a cholecystectomy. In an effort to reduce pain, scar size and recovery time, laparoscopy has
largely replaced the traditional open technique. Endeavours to eliminate surface scar
formation and reduce postoperative pain have led to the development of natural orifice
transluminal endoscopic surgery (NOTES). In NOTES a flexible endoscope is passed through
an existing bodily orifice to reach the abdominal cavity. Transvaginal cholecystectomy (TVC)
is the most commonly performed NOTES procedure. It involves accessing the abdominal
cavity through a posterior colpotomy and using the vaginal incision as an operative port. TVC
is a feasible operation when performed by senior surgeons highly trained in endoscopy. Issues
such as surgical platform, spatial orientation, and technical challenge must be addressed
before TVC is routinely practised. Patient preference, postoperative sexual function, and
dyspareunia need to be thoroughly investigated. This review aimed to explore TVC in detail,
as well as barriers to its widespread clinical use, and future implications.
Keywords: scarless surgery; transvaginal cholecystectomy; natural orifice transluminal
endoscopic surgery.
Royal College of Surgeons in Ireland Student Medical Journal 2014; 1: 41-45.
Introduction
Gurtej Singh
RCSI medical student
Cholelithiasis is one of the most common medical
problems needing surgical intervention, affecting
approximately 10% of the adult population in the
US. Approximately 500,000 cholecystectomies are
performed for symptomatic cholelithiasis every year.
Known risk factors include female gender, obesity,
increased age, multiple pregnancies, and certain
an attractive surgical approach to both doctors and
patients. Complications of laparoscopy are few but
include surgical wound infection, wound adhesions,
ethnic groups.1
Since the late 1980s, laparoscopic cholecystectomy
has largely replaced laparotomy as the treatment of
postoperative pain and scar formation.4 Surgeons
have reduced the size and number of abdominal
operating ports, the size of instruments and, most
excitingly, have introduced the use of flexible
choice for symptomatic cholelithiasis.2 Shorter
recovery times and lower levels of trauma make it
postoperative pain, and scar formation.3
In recent years, attempts have been made to
minimise the invasiveness of laparoscopic
cholecystectomy with the goal of reducing
endoscopy.2-6
Volume 7: Number 1. 2014 | Page 41
RCSIsmjreview
FIGURE 1: (a) Illustrates the passage of the endoscope through the vaginal canal and (b) as seen through the
monitor.42
FIGURE 2: Transvaginal
cholecystectomy. Note the long
and curved path of the flexible
endoscope.6
Table 1: Contraindications to vaginal NOTES15
Prior pelvic or abdominal surgery
History of endometriosis
Pelvic inflammatory disease
Retroflexed uterus
NOTES can be performed by introducing an endoscope into any
external natural orifice such as the anus, mouth, vagina or umbilicus
to gain entry into various cavities (Figure 1). The transvaginal
approach is currently preferred as there is a decreased risk of
intestinal leakage and infection through the access site.12
Furthermore, gynaecologists and general surgeons have used
Pregnancy
American Society of Anaesthesiology grades 3/4
Performing a cholecystectomy using flexible endoscopy
eliminates surface incision, which can theoretically reduce
postoperative pain and wound infection while improving
cosmesis and recovery times. This technique takes advantage of
natural orifices to allow for endoscopic therapy. This procedure,
called natural orifice transluminal endoscopic surgery (NOTES),
has garnered a great deal of attention in the surgical community
and is purported to be the next leap forward in minimally
invasive surgery.7-10
NOTES provides the potential for incisionless surgery, which has
major implications for all surgical procedures, not just
cholecystectomy. The first NOTES procedure was performed by
al.11
at Johns Hopkins Hospital, Maryland, in 2005. This
Kaloo et
initial procedure sparked great interest and subsequent
publications involving successful transluminal endoscopic
surgeries.
Transvaginal cholecystectomy (TVC) is an exciting novel
procedure that represents a philosophical shift in the way surgery
is performed. The feasibility of this procedure in everyday clinical
practice is debated, and its superiority over the conventional
questionable.12-16
laparoscopic cholecystectomy is
This article will
describe a TVC procedure in detail, examine barriers to its
widespread clinical use, and discuss future implications.
Page 42 | Volume 7: Number 1. 2014
Discussion
The procedure
transvaginal access for years with very good results.13 Compared to
other access points, the vagina is easily closed and has low risk of
gastric or colonic fistula.14 Contraindications to vaginal access are
listed in Table 1.
Bessler et al. performed the first TVC using no abdominal entry
points (Figure 2).15 The patient was placed in the lithotomy
position and strapped in. The table was then elevated and the
patient put in steep Trendelenburg position to minimise risk of small
bowel damage during surgery.
A 1cm colpotomy was performed in the posterior fornix of the
vagina. A 15mm port was passed through the colpotomy incision.
The port allowed for insertion of endoscopic devices (Figure 3) and
was left in the posterior fornix for the remainder of the surgery.
Through the 15mm port, pneumoperitoneum was achieved.15
A 12mm double-channel therapeutic gastroscope was placed
directly into the 15mm port. This gastroscope was then retroflexed
to visualise the entry site and make sure no structures were
damaged upon entry. A second colpotomy was made just lateral to
the initial site and a 5mm trocar introduced. The 5mm trocar
allowed for insertion of an extra long curved retractor. The
retroflexed gastroscope was used to guide the entry of the curved
retractor into the abdomen.15
The curved retractor was used to grasp Hartmann’s pouch and the
gallbladder was retracted upwards and laterally to expose the
structures of the triangle of Calot. An endoscopic knife and grasper
RCSIsmjreview
FIGURE 3: Placement of 15mm transvaginal trocar.44
FIGURE 4: (a) The ANUBISCOPEВ® with its tulip-shaped deployable
instrument channels (Karl Storz).32(b) The DDES (Boston Scientific).33
(c) Prototype flexible endoscope in live porcine model improving
triangulation and visualisation with single-site laparoscopic access
system (Ethicon Endo-SurgeryВ®).39
forceps were passed through the two channels of the gastroscope and
used to dissect these structures. The cystic duct and artery were each
clipped three times using modified endoscopic clips. The gallbladder
was resected and removed through the 15mm trocar. The
pneumoperitoneum was aspirated via the endoscope. The two trocars
were removed and the colpotomies closed with a running stitch.15
Patient concerns
Researchers26,27 have attempted to address these issues by developing
a novel magnetic guidance system that uses external magnets to steer
and operate instruments. These instruments are inserted through the
vaginal orifice and controlled externally by a large hand-held magnet.
When the magnet is moved along the abdominal surface the
instruments move to a different location in the abdominal cavity.
This novel technique has challenges of its own. There are many
For TVC to become an approved treatment the patient population
must consider it a viable option. A recent survey of 300 women
indicated that 96% expressed concerns before the procedure about
reports28-30 of magnetic technology use in human cases. A large
human study performed by Dominguez et al.29 reported no
magnetic-related complications in 40 patients undergoing
NOTES-assisted cholecystectomy. However, there are very few studies
sexual function and fertility.16,17
Bucher et al.17 suggest that this trepidation occurs because physicians
are unable to answer questions regarding postoperative fertility and
of actual tissue effects in humans. Best et al.30 reported mild
blanching and petechiae of the porcine peritoneum after four hours of
constant compression with the internal and external magnets.
sexuality. A 2013 study18 conducted at Yale investigated quality of life
and sexual function after TVC. The study suggests that sexual function
remains unchanged and quality of life either is unchanged or
improved one month after the procedure; however, the cohort was
relatively small. There is limited published data regarding
postoperative effects after TVC; however, there are many studies19-22
investigating sexual function after transvaginal hysterectomy. These
studies found no negative effects and actually noted improvements in
sexual function post procedure. It is questionable whether these
results can be applied to TVC, a non-gynaecological procedure.
Spatial orientation
Unique issues with depth perception and anatomy recognition make
learning and performing NOTES very difficult. In traditional
laparoscopy, three or more abdominal ports are usually used, which
preserves triangulation. In pure NOTES, where no abdominal ports are
used, triangulation is substantially decreased. The problem of
orientation and guidance in the abdominal cavity has been discussed
in several review articles.23-25
Surgical platform
The current endoscopes are difficult to operate intra-abdominally, as
they are designed for movement inside a lumen.31 These endoscopes
are often modified gastroscopes with only a small number of working
instrument channels, and are highly flexible. This flexibility is
advantageous when passing through the lumen of the vagina and
into the peritoneal cavity, but becomes problematic as it is too flexible
intra-abdominally.31 When the target organ is reached, adequate
retraction and dissection are extremely difficult as the working
channels are small and few. A larger, stronger surgical platform with
numerous working channels is crucial for a successful NOTES
procedure.32
There are several new instruments under investigation (Figure 4). A
prototype called the ANUBISCOPE (Karl StorzEndoskope; Tuttlingen,
Germany) uses a four-way articulating flexible endoscope with a
16mm articulating vertebrae section and an 18mm unique distal head
(Figure 4a). The distal head has two movable arms with 4.2mm
working channels. External to these arms are a pair of jaws that create
Volume 7: Number 1. 2014 | Page 43
RCSIsmjreview
triangulation of the working channels. Perretta et al.32 have reported a
successful TVC in 60 minutes using the ANUBISCOPE.
The direct drive endoscopic system (DDES; Boston Scientific, Natick,
MA, USA) is a multitasking platform that overcomes some of the
limitations of current endoscopes (Figure 4b).
The system consists of three working ports and a distal guide sheath
that can accept a 6mm endoscope and two 4mm articulating
instruments. It is unique because it allows the surgeon to operate
instruments bimanually at the distal sheath and simulates a
laparoscopic procedure. Thompson et al.33 used this novel
multitasking platform to demonstrate triangulation, grasping, suturing
and cutting.
They concluded that complex endosurgical techniques that would
normally be difficult, if not impossible, with standard endoscopes can
successfully be performed using the DDES.
An area of further research is robotised endoscopes in NOTES. This
technology is still in the initial stages of development with few studies
conducted.34,35 Robotic endoscopy aims to complement NOTES
procedures by improving abdominal and peritoneal exploration while
reducing postoperative pain and discomfort.35
Bridging the gap: laparoscopic-assisted TVC
TVC is rarely performed, even in academic centres.36 The largest trial
to date included only 551 patients.37 Many researchers36-38 believe
that more prospective, randomised clinical trials are needed
comparing natural orifice surgery with standard laparoscopy before
TVC can be routinely practised.
There are several �hybrid’ approaches that aim to ease the transition
between laparoscopic surgery and pure NOTES procedures. These
techniques combine transvaginal access with conventional abdominal
ports. Hybrid procedures have been shown to reduce adhesion
development, decrease postoperative pain, and lead to faster recovery
times.36-38
Geng et al.39 recently published a meta-analysis of hybrid NOTES
versus conventional laparoscopic cholecystectomy. Continuous
variables were compared using the weighted mean difference (WMD).
The study found that hybrid procedures were superior to conventional
laparoscopy in cosmetic score (WMD=1.15, p<0.001), had a shorter
length of incision (WMD=-3.285, p=0.029), and decreased
postoperative pain within 12 hours (WMD=-0.704, p=0.026).
A recent study conducted in the Netherlands showed promising
results in 50 women undergoing hybrid NOTES procedures. The
average operative time was 61 minutes and there were no major
complications. None of the sexually active women experienced
dyspareunia after the procedure and all had excellent cosmetic
results.40 Many researchers41-43 believe that until there is a dedicated
NOTES surgical platform, a hybrid procedure is the best minimally
invasive technique. The single abdominal port in hybrid NOTES allows
for surgeons to use established techniques and operate at a
comfortable level while still largely maintaining cosmetic results.
Conclusion
Transvaginal cholecystectomy represents the next step in minimally
invasive surgery, combining surgical principles with advanced
endoscopy. This novel procedure avoids surface incision, improves
ease of access, and reduces postoperative pain; however, it has several
limitations. Until issues such as surgical platform, spatial orientation,
and technical challenge have been resolved, it is unlikely to be
routinely practised. Some 90% of cholecystectomies in women are
still being performed laparoscopically.45 Concerns about sexual
function and dyspareunia need to be thoroughly investigated. The
hybrid NOTES aids in the transition from a laparoscopic to pure
NOTES procedure by utilising a single abdominal port. As surgeons
become more experienced and endoscopes become more
technologically advanced, it is likely that pure NOTES procedures will
become a viable surgical technique.
References
1. Schirmer BD, Winters KL, Edlich RF. Cholelithiasis and cholecystitis. J
Long Term Eff Med Implants. 2005;15(3):329-38.
2. Brescia A et al. Laparoscopic assisted transvaginal cholecystectomy:
single centre preliminary experience. Surgeon. 2013;11(Suppl. 1):S1-5.
3. Zornig C, Emmerman A, von Waldenfels HA et al. Laparoscopic
cholecystectomy without visible scar: combined transvaginal and
transumbilical approach. Endoscopy. 2007;39(10):913-5.
4. Marescaux J, Dallemagne B, Perretta S et al. Report of transluminal
cholecystectomy in a human being. Arch Surg. 2007;142:823-6.
5. Branco Filho AJ, Noda RW, Kondo W et al. Initial experience with hybrid
transvaginal cholecystectomy. Gastrointest Endosc. 2007;66(6):1245-8.
6. Bessler M, Stevens PD, Milone L et al. Transvaginal
laparoscopically-assisted endoscopic cholecystectomy: a hybrid
7. Zorron R, Filgueiras M, Maggioni LC et al. NOTES transvaginal
cholecystectomy: report of the first case. Surg Innov. 2007;14(4):279-83.
8. ASGE, SAGES. ASGE/SAGES Working Group on Natural Orifice Translumenal
Endoscopic Surgery White Paper October 2005. Gastrointest Endosc.
2006;63:199-203.
9. Tsin DA, Colombero LT, Lambeck J, Manolas P. Minilaparoscopy-assisted
natural orifice surgery. JSLS 2007;11(1):24-9.
10. Mintz Y, Horgan S, Cullen J et al. NOTES: the hybrid technique. J
Laparoendosc Adv Surg Tech A. 2007;17(4):402-6.
11. Kalloo AN, Singh VK, Jagannath SB et al. Flexible transgastric peritoneoscopy:
a novel approach to diagnostic and therapeutic interventions. Gastrointest
Endosc. 2004;60:114-7.
12. Lehmann KS, Ritz JP, Wibmer A et al. The German registry for natural orifice
approach to natural orifice surgery. Gastrointest Endosc.
translumenal endoscopic surgery: report of the first 551 patients. Ann Surg.
2007;66(6):1243-5.
2010;252:263-70.
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13. Tarantino I, Linke GR, Lange J et al. Transvaginal rigid-hybrid natural
30. Best SL, Kabbani W, Scott DJ et al. Magnetic anchoring and guidance
orifice transluminal endoscopic surgery technique for anterior resection
system instrumentation for laparo-endoscopic single-site surgery/natural
treatment of diverticulitis: a feasibility study. Surg Endosc.
orifice transluminal endoscopic surgery: lack of histologic damage after
2011;25:3034-42.
prolonged magnetic coupling across the abdominal wall. Urology.
14. Linke GR, Tarantino I, Hoetzel R et al. Transvaginal rigid-hybrid NOTES
cholecystectomy: evaluation in routine clinical practice. Endoscopy
2010;42:571-5.
15. Gumbs AA, Fowler D, Milone L et al. Transvaginal natural orifice
translumenal endoscopic surgery cholecystectomy: early evolution of the
technique. Ann Surg. 2009;249(6):908-12.
16. Nijhawan S, Barajas-Gamboa JS, Majid S et al. NOTES transvaginal hybrid
2011;77(1):243-7.
31. Dallemagne B, Marescaux J. NOTES: past, present and future. Asian
Journal of Endoscopic Surgery. 2010;3(3):115-21.
32. Perretta S, Dallemagne B, Barry B, Marescaux J. The ANUBISCOPEВ®
flexible platform ready for prime time: description of the first clinical
case. Surg Endosc. 2013;27(7):2630.
33. Thompson CC, Ryou M, Soper NJ, Hungess ES, Rothstein RI,
cholecystectomy: the United States human experience. Surg Endosc.
Swanstrom LL. Evaluation of a manually driven, multitasking platform
2013;27(2):514-7.
for complex endoluminal and natural orifice transluminal endoscopic
17. Bucher P, Ostermann S, Pugin F et al. Female population perception of
conventional laparoscopy, transumbilical LESS, and transvaginal NOTES
for cholecystectomy. Surg Endosc. 2011;25(7):2308-15.
18. Wood SG, Solomon D, Panait L et al. Transvaginal cholecystectomy:
effect on quality of life and female sexual function. JAMA Surg.
2013;148(5):435-8.
19. Rhodes JC, Kjerulff KH, Langenberg PW et al. Hysterectomy and sexual
functioning. JAMA. 1999; 282:1934-41.
20. Roovers JP, van der Bom JG, van der Vaart CH et al. Hysterectomy and
sexual wellbeing: prospective observational study of vaginal
hysterectomy, subtotal abdominal hysterectomy, and total abdominal
hysterectomy. BMJ. 2003;327:774-8.
21. Dragisic KG, Milad MP. Sexual functioning and patient expectations of
sexual functioning after hysterectomy. Am J Obstet Gynecol.
2004;190:1416-8.
22. Lee JH, Choi JS, Hong JH et al. Does conventional or single port
laparoscopically assisted vaginal hysterectomy affect female sexual
function? Acta Obstet Gynecol Scand. 2011;90:1410-5.
23. Bergman S, Melvin WS. Natural orifice translumenal endoscopic surgery.
Surg Clin North Am. 2008;88:1131-48.
24. Rassweiler J, Baumhauer M, Weickert U et al. The role of imaging and
navigation for natural orifice translumenal endoscopic surgery. J Endourol.
2009;23:793-802.
25. Swanstrom L, Zheng B. Spatial orientation and off-axis challenges for
NOTES. Gastrointest Endosc Clin N Am. 2008;18:315-24.
26. Cadeddu J, Fernandez R, Desai M et al. Novel magnetically guided
intra-abdominal camera to facilitate laparoendoscopic single-site surgery:
initial human experience. Surg Endosc. 2009;23(8):1894-9.
27. Raman JD, Bergs RA, Fernandez R et al. Complete transvaginal NOTES
nephrectomy using magnetically anchored instrumentation. J Endourol.
2009;23(3):367-71.
28. Cadeddu J, Eberhart R, Fernandez R et al. Transabdominal magnetic
anchoring system for trocar-less laparoscopic surgery. J Urol.
2002;167:16.
29. Dominguez G, Durand L, De Rosa J et al. Retraction and triangulation
surgery applications (with video). Gastrointest Endosc.
2009;70(1):121-5.
34. Rentschler ME, Dumpert J, Platt SR, Farritor SM, Oleynikov D. Natural
orifice surgery with an endoluminal mobile robot. Surg Endosc.
2007;21(7):1212-5.
35. Tiwari MM, Reynoso JF, Lehman AC, Tsang AW, Farritor SM, Oleynikov
D. In vivo miniature robots for natural orifice surgery: State of the art
and future perspectives. World J Gastrointest Surg. 2010;2(6):217-23.
36. Lehmann KS, Zornig C, Butters M et al. 512 The Learning Curve for
Transvaginal Hybrid Notes Cholecystectomy. Gastrointest Endosc.
2012;75(4):AB150.
37. Swain P. A justification for NOTES – natural orifice translumenal
endosurgery. Gastrointest Endosc. 2007;65(3):514-6.
38. Rossi P, Bugiantella W, Graziosi L et al. Transvaginal laparoscopically
assisted endoscopic cholecystectomy: report of 3 cases. Gastrointest
Endosc. 2008;68(6):1226-8.
39. Geng L, Sun C, Bai J. Single incision versus conventional laparoscopic
cholecystectomy outcomes: a meta-analysis of randomised controlled
trials. PLoS ONE. 2013;8(10):e76530.
40. Van den boezem PB, Velthuis S, Lourens HJ, Samlal RA, Cuesta MA,
Sietses C. Hybrid transvaginal cholecystectomy, clinical results and
patient-reported outcomes of 50 consecutive cases. J Gastrointest Surg.
2013;17(5):907-12.
41. Galvao Neto M, Ramos A, Campos J. Single port laparoscopic access
surgery. Techniques in Gastrointestinal Endoscopy. 2009;11(2):84-93.
42. Zornig C, Mofid H, Emmermann A, Alm M, V waldenfels HA, FelixmГјller
C. Combined transvaginal and transumbilical approach for
cholecystectomy with no visible scarring. Chirurg. 2009;80(4):364-9.
43. Navarra G, Rando L, La malfa G, Bartolotta G, Pracanica G. Hybrid
transvaginal cholecystectomy: a novel approach. Am J Surg.
2009;197(6):e69-72.
44. Zorron R, Palanivelu C, GalvГЈo Neto MP et al. International multicenter
trial on clinical natural orifice surgery – NOTES IMTN study: preliminary
results of 362 patients. Surg Innov. 2010;17(2):142-58.
45. Csikesz NG, Singla A, Murphy MM, Tseng JF, Shah SA. Surgeon volume
with neodymium magnetic forceps for single-port laparoscopic
metrics in laparoscopic cholecystectomy. Dig Dis Sci.
cholecystectomy. Surg Endosc. 2009;23:1660-6.
2010;55(8):2398-405.
Volume 7: Number 1. 2014 | Page 45
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All in your head: is the use
of placebos a form of
benevolent deception?
Abstract
The study aimed to explore the view that the use of placebos is a form of benevolent
deception, based on the evidence available.
A literature search was carried out using mainly electronic databases such as Ovid Medline,
PubMed and The Cochrane Library. Scirus and Google Scholar were also used.
Placebo is Latin for �I will please’, and this is what it aims to do. For the purpose of this paper,
placebo is defined as a pharmacologically inert medication, but the broader term �placebo
effect’ and all that it encompasses is also explored.
A Cochrane Review found placebos to have a significant statistical effect on pain and nausea,
using only quality-controlled studies. Although many placebo trials claim to significantly
improve both patient- and observer-reported outcomes, a 2010 Cochrane review shows that
most of these reports are founded on studies that have failed to randomise patients to
placebo or no treatment groups, thereby reducing their reliability.
Although the placebo should not be considered a wonder drug, it can alleviate symptoms
when applied to specific conditions such as pain. Significant ethical issues are yet to be
resolved before the use of the placebo in clinical practice could be considered.
Royal College of Surgeons in Ireland Student Medical Journal 2013; 14: 46-48.
Iolanda Tiedt
RCSI medical student
Page 46 | Volume 7: Number 1. 2014
RCSIsmjreview
Introduction
The bright side
The term �placebo’ is Latin for �I will please’, a translation which
aptly describes the actual purpose of a placebo. The goal of the
placebo is to elicit a positive response without the use of
pharmacologically active medication. For the purpose of this
article, placebo is defined as a pharmacologically inert
medication, and �the placebo effect’ as an effect brought about
without necessarily using medication, inert or otherwise.
The history of the placebo is long and eccentric. The term
originated in the 14th century, where it referred to hired
Placebos have been shown to alleviate many symptoms such as pain
funerals;1
even then it was used to describe
mourners at
pretence. In 1811, the revised Quincy’s Lexicon-Medicum defined
placebo as “an epithet given to any medicine adapted more to
please than to benefit the patient”.2
Until the 1950s, the perception of the placebo was that “it
cannot harm and may comfort the patient”.3 The idea of the
placebo is presented as a sort of panacea, but physicians are
aware that it is only efficacious in limited circumstances.
However, in the same way a cancer therapy would not be
discredited for failing to cure migraines, all illnesses should not
be grouped together when measuring the effectiveness of
placebos.
All in your head: neurobiology of the placebo effect
In order to understand placebos and the placebo effect, we must
consider their mode of action, or the neurobiological reactions
they elicit. Results suggest that placebo-induced analgesia is
mediated by the endogenous opioid system.4
In an experiment carried out using functional magnetic
resonance imaging (fMRI), placebo-controlled analgesia was
associated with decreased activity in pain-sensitive regions of the
brain. It was also linked to an increase in activity in the prefrontal
cortex, which modulated the experience of pain. MRI images
clearly demonstrate the physiological effect of the placebo on
response.5
pain
Many studies link placebo analgesia with
activation and heightened functioning within various areas of the
brain and spinal cord.
Conditioning and expectancy both play a role in this. The
placebo effect can be achieved through classical conditioning,
whereby both an actual stimulus and a placebo are used
concurrently, until the placebo is associated with the effect from
the actual stimulus.6 In our society, we are conditioned to
associate tablets or injections with the alleviation of unpleasant
sensations. Therefore, just the experience of taking a tablet or
receiving an injection may allow us to believe that we have
gained some symptomatic relief, even if this is not the case. An
�expectancy’ effect is displayed whereby a placebo, believed to
be an active medication, has an effect comparable to that of the
active medication.
Enhancement of the expectancy effect can be achieved through
variables such as enthusiasm of the physician, use of particular
sizes and colours of tablets, or alternative methods of delivery
such as injections over tablets.7
and nausea.8 In patients with depression, antidepressants and
placebos have a similar effect on both the physiological mechanisms
within the brain and on the patient-reported outcomes. A recent
Cochrane review reported a small statistical difference between the
efficacy of active antidepressants and of placebos. This difference
was in favour of the active drug, but leads us to question whether
the effect of the placebo is underestimated in the treatment of this
condition.9 It was feared that using placebos in trials to test
antidepressant medication might increase the risk of suicide. This
proved to be untrue.10 It is worth noting that many of these studies
were carried out before the widespread use of standardised
diagnostic criteria and rating scales, so the severity of the depression
in the studies is unknown. During clinical trials, new drugs
frequently fail to pass efficacy tests because of the placebo eliciting
almost as positive a result as the drug itself. This has led some
medical professionals to argue that many compounds used as active
medications may be only slightly more sophisticated than the
placebo.
How reliable are the results?
Although many placebo trials claim to significantly improve both
patient- and observer-reported outcomes, a 2010 Cochrane review
showed that a lot of these reports on the effect of the placebo are
based on studies that failed to randomise patients.8 Variations in the
effect of the placebo were partly explained by differences in how
trials were conducted and what information patients received.
Patient-reported outcomes can be positively influenced by treatment
with a placebo, but differentiating between valid patient-reported
outcomes and biased reporting is complex. Although pain is one of
the symptoms that placebos have been shown to alleviate, there is
still considerable heterogeneity between results of studies reporting
on this effect, even among trials with low risk of bias.8
Pharmacologically inert substances may also cause harmful effects
when taken by patients; this is termed the �nocebo’ effect. Like the
placebo effect, the nocebo effect is thought to be influenced by
subconscious conditioning and by the expectancy effect.11 If the
expectation of a positive outcome increases its likelihood, it is only
fitting that negative expectations function in the same way. A
history of adverse reactions to drugs can be correlated with an
increased rate of future nocebo effects. In a study of 600 patients
whose medical history included adverse drug reactions, 27%
developed side effects when given the pharmacologically inert
placebo.12
Ethical dilemma
Treating patients using a placebo presents a huge ethical dilemma.
There is a long-running debate about whether placebos should be
used in clinical practice, as well as in treatment trials. Many articles
have been published supporting both sides of the argument.13
Patients have the right to know what medication they are taking.
When prescribing a placebo, if the nature of the treatment is not
Volume 7: Number 1. 2014 | Page 47
RCSIsmjreview
revealed, we remove this right. Medical health practitioners cannot
ask the general public to place their trust in physicians if they do not
know that they are being treated in a truthful manner. Though the
phrase �the end justifies the means’ comes to mind, damage done
to the doctor-patient relationship would outweigh the benefits in
this case. In addition to this, if a patient displays a hypersensitive
immune response to an allergen in the placebo, it can be entirely
disadvantageous. As there is no substance known to be completely
inert, there is always a small risk associated with taking a placebo.
This is illustrated by an AIDS medication trial, which was halted
because of a high dropout rate in the placebo group. The placebo
used in the trial contained lactose; incidentally, HIV/AIDS is
associated with high rates of lactose intolerance.14
Placebos are a necessary part of medical research. In studies
involving a disorder for which there is an available, effective
treatment, a placebo arm of the trial would be unethical. For many
studies, however, comparison with a placebo is integral to drawing
a conclusion on the validity of the results and the efficacy of the
treatment.15
The axiological deviation between placebo use in clinical trials and
in clinical practice is that, in clinical trials, patients are fully briefed
on the possibility of receiving a placebo, thereby making it far more
ethical.
Conversely, there is the argument that it is not ethical to abstain
from the use of placebos when we know that they have a marked
impact on some conditions, such as anxiety. If a placebo can aid in
a patient’s treatment, when paired with an empathetic physician, it
may be unethical to withhold this treatment.
Conclusion
Care should be taken not to resort to using placebos as a
replacement for what could be achieved by a positive doctor-patient
relationship.16 Although the placebo has proven to alleviate some
symptoms, most of the placebo effect can be achieved without the
use of a physical placebo pill. Treatment isn’t as linear as prescribing
the patient medication and sending them home. As Hippocrates
advised, physicians should “heal occasionally, relieve often, and
comfort always”.
The placebo has potential as a clinical intervention, but there are
important ethical issues that must be appropriately addressed. One
way of overcoming the mistrust surrounding placebos would be to
rename them. The term in itself is reactionary, intrinsically associated
with dupery and deceit. Patients could be prescribed an inert
treatment, with full disclosure that, although pharmacologically
inactive, may alleviate their symptoms. The negativity associated
with the word placebo could be avoided, while still making use of
its effect.
Placebos can be considered a form of benevolent deception, but the
repercussions of prescribing them have the potential to be far from
benign.
References
1. De Craen AJM, Kaptchuk TJ, Tijssen JGP, Kleijnen J. Placebos and
placebo effects in medicine: historical overview. J R Soc Med.
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2. Quincy J. Quincy’s Lexicon-Medicum: A New Medical
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3. Pepper OH. A note on the placebo. Am J Pharm.
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4. Petrovic P, Kalso E, Petersson KM, Ingvar M. Placebo and opioid
analgesia – imaging a shared neuronal network. Science.
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5. Wager TD, Rilling JK, Smith EE, Sokolik A, Casey KL, Davidson RJ
et al. Placebo-induced changes in fMRI in the anticipation and
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6. Voudouris NJ, Peck CL, Coleman G. Conditioned response
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EE et al. Components of placebo effect: randomised controlled
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8. HrГіbjartsson A, GГёtzsche PC. Placebo interventions for all
clinical conditions. Cochrane Database Syst Rev.
2010;(1):CD003974.
Page 48 | Volume 7: Number 1. 2014
9. Moncrieff J, Wessely S, Hardy R. Active placebos versus
antidepressants for depression. Cochrane Database Syst Rev.
2004;(1):CD003012.
10. Khan A, Warner HA, Brown WA. Symptom reduction and
suicide risk in patients treated with placebo in antidepressant
clinical trials. Arch Gen Psychiatry. 2000;57:311-7.
11. Rajagopal S.The nocebo effect. [Internet]. [updated 2007 Sept;
cited 2010 Nov 24]. Available from:
http://priory.com/medicine/Nocebo.htm.
12. Liccardi G, Senna, G, Russo M, Bonadonna P, Crivellaro M,
Dama AJ et al. Evaluation of the nocebo effect during oral
challenge in patients with adverse drug reactions. J Investig
Allergol Clin Immunol. 2004;14(2):104-7.
13. Raz A, Harris CS, de Jong V, Braude H. Is there a place for
(deceptive) placebos within clinical practice? The American
Journal of Bioethics. 2009;9(12): 52-54.
14. Golomb BA. Doctoring the evidence: The case against lying to
patients about placebos. Am J Bioeth. 2009;9(12):34-6.
15. Nunn R. It’s time to put the placebo out of our misery. BMJ.
2009;338:b1568
16. Bostick NA, Sade R, Levine MA, Steward DM Jr. Placebo use in
clinical practice: Report of the American Medical Association Council
on Ethics and Judicial Affairs. J Clin Ethics. 2008;19(1):59-61.
RCSIsmjreview
Physiological mechanisms
underlying exercise prescription
non-compliance in patients
with type 2 diabetes mellitus
Abstract
Michael Bravo
RCSI medical student
Type 2 diabetes mellitus (T2D) is a growing epidemic worldwide. One of the key treatments
for T2D is exercise. Exercise has been shown to have positive effects on many aspects of the
disease including improving serum glucose levels and insulin sensitivity. Unfortunately,
patients with T2D tend to have poor compliance with exercise regimes. A number of reasons
for the failure of exercise programmes have been suggested. This article aims to explore some
of the possible explanations, and to outline future directions in this area of research.
Royal College of Surgeons in Ireland Student Medical Journal 2014; 1: 49-53.
Volume 7: Number 1. 2014 | Page 49
RCSIsmjreview
Introduction
Type 2 diabetes mellitus (T2D) is one of the fastest developing
worldwide epidemics. There are currently nearly 300 million
people suffering from this disease.1 It has long been known that
physical activity is one of the cornerstones of the management of
T2D.2 However, it is also recognised that persons with T2D have
low adherence to exercise programmes, even when prescribed by
doctors.3 This has been attributed to poor exercise tolerance by
people with T2D.4 It has been suggested that a number of
physiological mechanisms could contribute to this exercise
intolerance, such as an impaired cardiac response to exercise, a
deficit in the skeletal muscle diffusion, or impairments in oxygen
delivery (Figure 1).5 The current primary focus of investigation is
the possibility that impaired oxygen delivery may underlie this
poor exercise tolerance. This review will attempt to explain the
mechanism of non-compliance in patients with T2D and
potential future areas of research and treatment.
FIGURE 2: Schematic of vasodilator and vasoconstrictor influence. 1.
Vasodilator influence from various dilator substances in the blood. 2 +
3. Vasoconstrictor influence – MMR-induced increases in MSNA results
in a vasoconstrictor influence at the level of the muscle vasculature. 4.
Vasoconstrictor influence – the baroreflex exerts a vasoconstrictor
influence by attempting constricting vasculature to return MAP to
homeostatic levels. 5. Vasodilator influence – sympatholytic agents
blunt the effects of the MSNA by preventing the activation of
alpha-adrenergic receptors.
their doctors. In one study by Thomas et al., only 34% of
patients with T2D performed any kind of exercise, and of those
only 9% performed sufficient exercise to cause a “large” change
in heart rate or breathing.9 The authors found that the most
significant barrier to performing physical activity was a lack of
confidence in being able to perform the exercise and feelings of
“tiredness”.9 Interestingly, it has been demonstrated that higher
levels of glycosylated haemoglobin (HbA1C) correlated with a
lower exercise capacity in patients with diabetes.10 Thus, there
may be a physiological mechanism underlying the exercise
prescription compliance issue in people with T2D.
FIGURE 1: Potential contributors to decreased exercise tolerance. 1. A
reduced diffusive conductance. 2. A reduction in metabolic oxygen
consumption. 3. A reduction in convective oxygen delivery.
Exercise as treatment for T2D
While there are a number of pharmacological interventions that
can be prescribed for patients with T2D, it is recognised that one
of the ideal treatment methods is physical activity.2 Physical
activity has been shown to target many of the major symptoms
of T2D. For example, exercise has been shown to reduce blood
glucose levels,6 elevate insulin sensitivity and insulin-independent
muscle glucose uptake,7 and mitigate the insulin resistance that
exists in patients with T2D. It has been demonstrated by a
number of research groups that patients with T2D who exercise
also have lower resting and submaximal exercise heart rates,
increased stroke volume and cardiac output, enhanced oxygen
extraction, and lower resting and exercise blood pressure.2,5,8
While it is generally recognised that physical activity is highly
effective for the management of T2D, many patients have
difficulty adhering to the exercise prescription given to them by
Page 50 | Volume 7: Number 1. 2014
Exercise intolerance in patients with T2D
A number of physiological mechanisms could be responsible for
this exercise intolerance, such as an impaired cardiac response to
exercise, a deficit in the skeletal muscle diffusion, or impairments
to oxygen delivery.5 Current research is focused on the impaired
convective oxygen delivery theory. Of these studies, there are
two main categories of investigation: those addressing muscle
blood flow during the transition to exercise; and, those
addressing steady-state exercising muscle blood flow.
Blood flow during transition to exercise
When exercise is initiated, an oxygen deficit becomes established,
which forces the body to compensate by increasing flow either
through increased pressure or increased vasodilation. However, if
there is a defect in these responses, as has been established in
people with T2D, the body cannot compensate, resulting in
early-onset fatigue. One study has established a decreased kinetic
response in people with T2D compared to obese controls,4 while
other studies have shown that there is a greater reliance on
oxygen extraction in an attempt to compensate for this initial
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FIGURE 3: Schematic of the muscle metaboreflex. 1: Metabolites
accumulate in the exercising muscle and increase the firing of muscle
afferents to the NTS. 2: The NTS receives muscle afferent input and
responds by increasing sympathetic output. 3: Sympathetic output causes
an increase in cardiac output and muscle sympathetic nervous activity.
FIGURE 4: Net drive hypothesis. The net drive hypothesis describes the
attempt to maintain ATP production for use in force production. The
oxygen content of the cell, the phosphate potential, and the redox
potential all contribute to the production of ATP and any decrease in
one of these factors necessitates an increase in the others to maintain
force production.
oxygen deficit.11 Although there are few studies looking into the
responses to decreased muscle blood flow at the onset of
exercise in patients with T2D, their conclusions are clear: there is
a reduced kinetic oxygen uptake response in patients with T2D
during the transition to exercise.
Steady-state exercise blood flow
In addition to failed recovery of initial oxygen deficit, T2D causes
significant reduction in steady-state exercising muscle blood flow.
Of particular note is a 2003 study by Kingwell et al.,12 which
demonstrated an impaired blood flow response in the legs during
cycling exercise in subjects with T2D when compared to ageand weight-matched controls. This was due to increased vascular
resistance, which persisted despite raised blood pressure.13
Another study14 demonstrated a 25% reduction in blood flow
that was independent of cardiac output, suggesting that the
major complication in subjects with T2D was related to a
reduction in vascular function. Taken together, these two studies
point to an impaired ability to dilate the peripheral vasculature in
response to exercise, that is, a reduction in the capacity to
increase vascular conductance in response to increased metabolic
demand. This could be due to impaired vasodilation, increased
vasoconstriction from the sympathetic nervous system, or a
combination of both.
Impairments to vasodilation
Normally, there are several receptor types lining the endothelial
wall. These respond to circulating mediators such as adenosine
triphosphate (ATP), nitric oxide (NO) and prostaglandins, to
cause both local and upstream (towards the originating artery)
vasodilation. This increases vascular conductance and improves
overall blood flow (Figure 2). However, this process may not
function normally in patients with T2D. Several studies have
focused on the function of endothelial-dependent vasodilatory
capabilities of patients with T2D. For example, Sprague and
colleagues have demonstrated a reduced erythrocyte release of
ATP, thus reducing ATP-mediated vasodilation.15 Normally ATP
released from red blood cells binds to purinergic receptors on the
Volume 7: Number 1. 2014 | Page 51
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luminal surface of the endothelium and catalyses the production
of NO, a major upstream vasodilator.16 Erythrocyte release of ATP
is reduced in patients with T2D, which impairs the NO cascade.
Similar results have been demonstrated for other vasodilatory
mechanisms. However, this might not be the only contributor to
vascular conductance – there may also be an increase in
sympathetic activity, which increases systemic vascular resistance.
In normal muscle, there are two factors governing oxygen
delivery to muscle – arterial pressure and vascular resistance. In
order to facilitate the increase in blood flow at the onset of
exercise, arterial pressure must increase, vascular resistance must
decrease, or a combination of the two must occur. Generally, an
immediate increase in local vasodilatory factors increases vascular
conductance, which increases the overall blood flow to the
muscle.17 However, when the vascular conductance has reached
its peak, the heart must play a greater role in maintenance of
flow.18
blood
By increasing cardiac output, the heart increases
the mean arterial pressure, which has the effect of conducting
more blood through the dilated artery in the muscle. There must
be a balance between systemic vascular conductance and cardiac
output in order to maintain arterial pressure. A problem arises
when blood pressure is not sufficient to maintain the perfusion of
exercising muscle. If this occurs, a secondary response termed
the �muscle metaboreflex’ (MMR) acts to increase perfusion
pressure and blood flow to the exercising muscle by reducing the
conductance to other muscles.5
Muscle metaboreflex
The MMR is an exercise-induced pressor response that is
activated during moderate- or high-intensity exercise (Figure 3).
It involves a gradual increase in muscle sympathetic nervous
activity (MSNA) during exercise, which differs from the almost
immediate increase of heart rate and arterial pressure described
above. It is thought to be a chemically stimulated feedback
pathway that increases vasoconstriction and elevates mean
exercise.18
arterial pressure during
This increase in sympathetic
vasoconstriction seems counter-intuitive, as it causes
vasoconstriction in muscle that requires increased blood flow;
however, complex mechanisms actually allow for increase in
mean arterial pressure and therefore flow.
Contracting muscle produces a number of metabolic by-products
that accumulate in the blood, such as lactate, inorganic
phosphate (Pi) and potassium.19 Some of these metabolites,
including H+, activate the free-endings of group IV muscle
afferents, which have central nervous projections.20 The
activation of these group IV muscle afferents results in an
increase in their firing rate. This information is processed at the
level of the nucleus tractus solitarii in the medulla, the site of the
cardiovascular control centre, which responds with an increase in
sympathetic efferent activity in the form of systemic MSNA.21,22
This leads to vasoconstriction in, and therefore reduced flow to,
all major tissues, including the exercising muscle. By reducing the
overall conductance to tissues in the body, there is a subsequent
increase in mean arterial pressure.21,22 An advantage is only
Page 52 | Volume 7: Number 1. 2014
gained if vasoconstriction is caused in all other tissues except the
exercising muscle – vasoconstriction at the exercising muscle
would be counter-productive. To take advantage, there are two
pathways that reduce the effect of vasoconstriction at the level of
the exercising muscle: vasodilation and sympatholysis (the
exercise-induced blunting of the MSNA).18 At higher intensities
of exercise, the release of vasodilators counteracts the
vasoconstricting effects of elevated MSNA from the MMR.18
Some of these vasodilator substances, including ATP, also blunt
the effects of the MSNA at the level of the free-nerve ending.18
ATP activates vascular smooth muscle cell potassium channels
that modulate the activity of the alpha-adrenergic
vasoconstriction.23 The combined effect of vasodilation and
blunted constriction protects vascular conductance to the
exercising muscle at a level sufficient to benefit from the increase
in mean arterial pressure.24 Thus, the maintenance of
vasodilation in the exercising muscle coupled with the
metaboreflex-induced increase in arterial pressure, leads to an
increase in flow to the exercising muscle and thus an increase in
oxygen delivery. However, if there are defects in either
vasodilation or sympatholysis, as occurs in people with T2D,
exercising muscle blood flow may be reduced.
MMR overactivity in T2D
There is a significant reduction in mitochondrial volume and
electron transport chain function in diabetic muscle when
compared to obese or lean controls.25 This altered morphology
exaggerates the MMR. This means that these individuals rely
more heavily on glycolytic and aerobic enzyme pathways.
Because the onset of the MMR is governed by the production of
metabolites such as H+, it is important to identify the methods by
which these substrates are produced. The �net drive hypothesis’
describes the ability of the muscle to produce ATP through the
collective contributions of oxygen (PcellO2), the phosphate
energy state of the cell and the redox energy state (Figure 4).26
If any of these factors is decreased, there is a compensatory
increase in the others in an effort to maintain ATP production
sufficient to meet the demand of the muscle.26 If we consider
that there is an oxygen deficit at the onset of exercise in T2D,
then there must be a subsequent increase in both redox state
and phosphate energy state in the myocyte. Thus, the onset of
the MMR occurs at lower exercise intensities in an individual with
T2D compared to a healthy individual. This would cause an
increase in vasoconstriction and could result in the impairment to
blood flow, contributing to the exercise intolerance that has been
demonstrated in patients with T2D.
In addition to decreased ability to appropriately dilate the
peripheral vessels, patients with T2D may have higher baseline
MSNA, which, when coupled with MMR-induced MSNA, creates
an overly vasoconstricted state in response to exercise. As a
result, the MMR, which generally acts as a flow-restorative
mechanism in healthy individuals, might in fact be self-defeating
in patients with T2D and lead to the exercise intolerance that
makes management of this disease so difficult.
RCSIsmjreview
Conclusion
Exercise is a vital prescription for the treatment of patients with
T2D – it can lower blood glucose,6 improve insulin sensitivity7
and target many of the complications of T2D. However, the
difficulty for this population is that there is a solid physiological
basis for early-onset fatigue in people with T2D. This has clinical
implications for the prescription of exercise as a method of
treatment; physicians must be mindful of potential additional
References
1.
Lipscombe LL, Hux JE. Trends in diabetes prevalence, incidence, and
mortality in Ontario, Canada 1995-2005: a population-based study.
Lancet. 2007;369:750-6.
2.
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Albright A, Franz M, Hornsby G, Kriska A, Marrero D, Ullrich I et al.
diabetes is associated with impairment of both cAMP generation
Morrato EH, Hill JO, Wyatt HR, Ghushchyan V, Sullivan PW. Physical
Regensteiner JG, Bauer TA, Reusch JE, Brandenburg SL, Sippel JM,
women with type II diabetes mellitus. J Appl Physiol. 1998;85:310-7.
Regensteiner JG, Sippel J, McFarling ET, Wolfel EE, Hiatt WR. Effects of
non-insulin-dependent diabetes on oxygen consumption during
treadmill exercise. Med Sci Sports Exerc. 1995;27:661-7.
HГјbinger A, Franzen A, Gries FA. Hormonal and metabolic response to
physical exercise in hyperinsulinemic and non-hyperinsulinemic type 2
diabetics. Diabetes Res. 1987;4:57-61.
7.
Bruce CR, Hawley JA. Improvements in insulin resistance with aerobic
exercise training: a lipocentric approach. Med Sci Sports Exerc.
2004;36:1196-201.
8.
Baldi JC, Aoina JL, Oxenham HC, Bagg W, Doughty RN. Reduced exercise
arteriovenous O2 difference in Type 2 diabetes. J Appl Physiol.
2003;94:1033-8.
9.
Exerc. 2008;40:612-7.
15. Sprague RS, Stephenson AH, Bowles EA, Stumpf MS, Lonigro AJ.
Reduced expression of G(i) in erythrocytes of humans with type 2
Vogelsong AM et al. Abnormal oxygen uptake kinetic responses in
6.
during submaximal exercise in type 2 diabetes. Med Sci Sports
diabetes. Med Sci Sports Exerc. 2000;32:1345-60.
2003. Diabetes Care. 2007;30:203-9.
5.
14. Lalande S, Gusso S, Hofman PL, Baldi JC. Reduced leg blood flow
American College of Sports Medicine position stand. Exercise and type 2
activity in U.S. adults with diabetes and at risk for developing diabetes,
4.
requirements such as exercise aids, more manageable exercise
regimes, or alternative therapies that might ameliorate this
deficit.
Further research into the significance of the MMR and its
potential contributions to exercise fatigue in this population will
elucidate ways to combat this oxygen deficit, and make the
exercise prescription more tolerable and thus feasible for the T2D
patient population.
Thomas N, Alder E, Leese GP. Barriers to physical activity in patients with
diabetes. Postgrad Med J. 2004;80:287-91.
10. Demir I, Ermi C, Altunba H, Balci MK. Serum HbA1c levels and exercise
capacity in diabetic patients. Jpn Heart J. 2001;42:607-16.
11. Bauer T, Reusch J, Levi M, Regensteiner JG. Skeletal muscle
deoxygenation after the onset of moderate exercise suggests slowed
microvascular blood flow kinetics in type 2 diabetes. Diabetes Care.
2007;30(1):2880-5.
12. Kingwell BA, Formosa M, Muhlmann M, Bradley SJ, McConell GK. Type 2
diabetic individuals have impaired leg blood flow responses to exercise:
role of endothelium-dependent vasodilation. Diabetes Care.
2003;26:899-904.
13. Kingwell BA, Formosa M, Muhlmann M, Bradley SJ, McConell GK. Nitric
oxide synthase inhibition reduces glucose uptake during exercise in
individuals with type 2 diabetes more than in control subjects. Diabetes.
and ATP release. Diabetes. 2006;55:3588-93.
16. McCullough WT, Collins DM, Ellsworth ML. Arteriolar responses to
extracellular ATP in striated muscle. Am J Physiol.
1997;272:H1886-91.
17. Tschakovsky ME, Sheriff DD. Immediate exercise hyperemia:
contributions of the muscle pump vs. rapid vasodilation. J Appl
Physiol. 2004;97:739-47.
18. Saunders NR, Pyke KE, Tschakovsky ME. Dynamic response
characteristics of local muscle blood flow regulatory mechanisms in
human forearm exercise. J Appl Physiol (1985). 2005;98:1286-96.
19. Kniffki KD, Mense S, Schmidt RF. Responses of group IV afferent
units from skeletal muscle to stretch, contraction and chemical
stimulation. Exp Brain Res. 1978;31:511-22.
20. Mense S, Stahnke M. Responses in muscle afferent fibres of slow
conduction velocity to contractions and ischaemia in the cat. J
Physiol. 1983;342:383-97.
21. Piepoli M, Clark AL, Coats AJ. Muscle metaboreceptors in
hemodynamic, autonomic, and ventilatory responses to exercise in
men. Am J Physiol. 1995;269:H1428-36.
22. Rowell LB, O’Leary DS. Reflex control of the circulation during
exercise: chemoreflexes and mechanoreflexes. J Appl Physiol (1985).
1990;69:407-18.
23. Rosenmeier JB, Hansen J, GonzГЎlez-Alonso J. Circulating ATP-induced
vasodilatation overrides sympathetic vasoconstrictor activity in
human skeletal muscle. J Physiol. 1994;558:351-65.
24. Cornett JA, Herr MD, Gray KS, Smith MB, Yang QX, Sinoway LI.
Ischemic exercise and the muscle metaboreflex. J Appl Physiol
(1985). 2000;89:1432-6.
25. Kelley DE, He J, Menshikova EV, Ritov VB. Dysfunction of
mitochondria in human skeletal muscle in type 2 diabetes. Diabetes.
2002;51:2944-50.
26. Tschakovsky M, Pyke K. Physiological Bases of Human Performance
During Work and Exercise. (1st ed.). Churchhill-livingstone, 2008.
2002;51:2572-80.
Volume 7: Number 1. 2014 | Page 53
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The foetal origins
of adult health
Abstract
Life course epidemiology examines the biological,
behavioural and psychosocial processes that
operate throughout an individual’s life and
influence the risk of disease. This approach is
based on the foetal origins hypothesis, which
examines how early life exposures can have
long-term effects on adult health. This theory
emerged from research that demonstrated the
association between low birth weight and
cardiovascular disease in adults. However, many
criticisms were raised, as these initial studies did
not provide a biological explanation for this
association. More recently, animal and human
nutritional studies have provided putative
mechanisms linking the irreversible changes that
occur during the perinatal period to adult health.
Further, epigenetic studies have also provided
support for the foetal origins hypothesis, as it has
been demonstrated that permanent structural
DNA modifications can occur early in life.
Importantly, there are several methodological
issues at play that challenge the life course study
design, and the interpretation and relevance of
results must be discussed. This article will explore
the development of the foetal origins hypothesis
and examine its supporting evidence, as well as
discussing the methodological constraints and
applications of this approach.
Royal College of Surgeons in Ireland Student Medical Journal 2014; 1: 54-57.
Introduction
What if birth weight could predict disease risk in
adulthood? Research suggests that environmental
conditions during the perinatal period may result
in biological changes that predispose individuals
to develop chronic disease as adults. This theory,
known as the foetal origins hypothesis, is gaining
momentum in the scientific community and
reflects our growing knowledge of the complex
aetiology of chronic disease. An emerging
approach known as life course epidemiology aims
to test this hypothesis.
Nadine Straka
RCSI medical student
puberty, can be modified over time.1 In order to
determine the particular environmental factors that
affect these developmental periods, life course
epidemiology integrates psychological, cognitive
and biological research.2
A life course approach
Central to the life course approach is the idea that
early social and physical environments alter
biological development and result in long-term
Page 54 | Volume 7: Number 1. 2014
health implications. From conception through to
adulthood, individuals will undergo phases of
development known as critical and sensitive
periods. Insults occurring during critical periods
have irreversible consequences, such as those
occurring during conception and organogenesis;
however, insults occurring during sensitive periods,
such as during the perinatal period, childhood and
Evolution of the foetal origins hypothesis
The notion that conditions in early life contribute
to adult health has prevailed since the 1930s. A
RCSIsmjstaff review
study conducted in England, Scotland and Wales from 1855 until
1930 investigated mortality rates by year of birth.3 Predictably, the
authors found that all cause mortality rates improved with time,
which likely reflected improvements in living conditions and
healthcare. However, the authors also noted that despite these
improvements, mortality rates for a given birth cohort remained the
same throughout the lifetime of that cohort. In other words,
regardless of exposure to improved living conditions, the mortality
of a given cohort was not altered. While further investigation would
be needed to draw any conclusions about the impact of the
perinatal environment associated with the year of birth and
subsequent adult mortality, the authors brought attention to their
finding, known as a cohort effect, and offered broad explanations
for it. They suggested that the perinatal environment is an
important determinant of future mortality and that conditions later
in life may only minimally impact adult health.3
By the 1950s, the potential for early life exposures to impact lifelong
health was gaining momentum as a theory, but little had been done
to explore the effect of these influences during development. Dubos
et al. were among the first to use animal models to investigate the
importance of maternal nutrition during the perinatal period.4 In
identical environmental conditions, two groups of pregnant mice
were fed either optimal or suboptimal diets until delivery, at which
point both groups received the optimal diet. The mothers and their
young were then examined over time. Offspring whose mothers
were fed the suboptimal diet prenatally, weighed less at the time of
weaning than the offspring of mothers fed the optimal diet. This
weight difference was maintained over time, despite switching to
the optimal diet post partum and maintaining identical
environmental conditions. Exposure to a sub-optimal diet had a
significant impact on morbidity and mortality, as the offspring
demonstrated decreased efficiency of food utilisation, resistance to
infection and lifespan, compared to those fed the optimal diet.4
Additionally, a later study used the setting of the Dutch famine of
1944-1945 to retrospectively investigate the effects of maternal
starvation during pregnancy on the mental status of offspring in
adult life.5 Near the end of World War II, the Nazis imposed a
transport embargo on German-occupied Western Holland in
response to Dutch refusal to co-operate. The severe winter that year
froze the canals and no food reached the area. Food rations were
distributed and, at the lowest point of the famine, intake was
restricted to 450 calories per day.5 The authors reconstructed birth
cohorts in this setting to determine how foetal age at famine
exposure affected mental status 19 years later. Measures of mental
status included intellectual quotient (IQ) and degree of intellectual
disability. The findings from this study did not support the authors’
hypothesis that mental status is associated with famine exposure
during the perinatal period. However, the authors did note a strong
positive association between IQ and social class. The authors
suggested that despite the lack of support for perinatal famine
exposure and mental status, other environmental factors in
childhood related to low social class, such as poor education and
living conditions, might have long-lasting effects on mental
development. Overall, the authors concluded that, while the
perinatal period is a crucial developmental time, the environment in
which a child is raised is also of great importance in determining
mental development.5
The foetal origins hypothesis
While not the first to recognise the importance of the prenatal
environment on long-term health outcomes, English physician David
J. Barker famously brought attention to the foetal origins hypothesis.
In the late 1980s, Barker observed that the poorest regions of
England and Wales had the highest rates of coronary artery disease
(CAD), and that areas of high perinatal mortality were also those of
predominantly low socio-economic status and poor living
conditions. He hypothesised that physical and psychosocial stressors
in this environment may affect developmental periods of growth
and manifest as low birth weight. If exposure to stressors during
critical and sensitive periods is associated with increased risk of
disease later in life, then babies born with low birth weight may
have increased risk of CAD. To test this theory, Barker and colleagues
obtained birth records from these areas and located these
individuals as adults. They found that men with the lowest birth
weights had the highest mortality from CAD; additionally, weight at
one year of age and CAD were inversely related.6
Barker’s work faced criticism for several reasons. To begin with, his
study lacked biological plausibility because he could not describe a
mechanism linking early life conditions to cardiovascular disease.
Additionally, interpreting birth weight as a marker of foetal growth
is flawed, even when adjusting for gestational age. Several pathways
could result in low birth weight, but without detailed information
about prenatal growth, it is impossible to know exactly when the
growth restriction occurred. For example, growth restriction during
the first trimester may have more devastating effects than during
the third trimester, but both could result in low birth weight.
Furthermore, because of the time elapsed between the perinatal
period and adulthood, it is almost impossible to account for the
many anthropometric, biological, behavioural, or psychosocial
variables that could confound the results over time. Finally, Barker’s
work was thought to undermine public health interventions that
had traditionally focused on minimising disease by targeting adult
risk factors.
Despite initial criticism, Barker’s observations have been replicated in
several studies. The Helsinki Birth Cohort Study included 4,630 men
born in Helsinki University Hospital between 1934 and 1944, and
has been used to investigate foetal growth parameters on health
and disease.7 The study found that low birth weight was associated
with CAD; men with the lowest birth weights (<2,500g) had the
highest hazard ratios of CAD. A slow rate of growth, which was
determined by low BMI at one year of age, was also associated with
an increased risk of CAD – an effect that was independent of birth
weight. However, compensatory growth (low BMI at two years and
high BMI at 11 years) was also associated with increased risk of
CAD. All three variables – low birth weight, low BMI at one year,
and increased compensatory growth – were associated with type 2
diabetes in adult life. These findings have been replicated in the
United States,8 Sweden9 and India.10
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Mechanisms
Much of our knowledge about the association between low birth
weight and CAD arises from studies exploring perinatal nutritional
status and infant development. Two biological explanations
propose mechanisms for this association: phenotypic plasticity and
compensatory growth.11 Phenotypic plasticity occurs when a
single genotype gives rise to various phenotypes. This
phenomenon is evidenced by several animal studies, which
demonstrate that minor changes in the nutrition of pregnant
animals can produce permanent changes such as altered blood
pressure, and changes in glucose regulation and lipid
metabolism.12,13 Compensatory growth, where a period of
suboptimal nutrition is restored and followed by a period of
growth acceleration, is also suspected to link birth weight to CAD
in adulthood. It is thought that low birth weight infants lack
muscle due to growth restriction during a critical period of muscle
development. If infants gain weight rapidly to compensate for
their low birth weight, they are more likely to accumulate fat
rather than muscle. This may lead to excess fat mass later on in life
and predispose these individuals to CAD.14 Kidney growth is also
thought to contribute to this phenomenon where low birth weight
infants have smaller kidneys and reduced numbers of nephrons,
which may predispose these individuals to hypoperfusion and
eventually to glomerular sclerosis and hypertension.15,16 Finally,
liver function has also been implicated. The liver remains plastic
until around five years of age; growth during this time may affect
liver function permanently, resulting in lipid
dysregulation.17
Epigenetics
In addition to the biological mechanisms outlined, the foetal
programming hypothesis has led to an interest in epigenetics.
Epigenetics refers to heritable genetic changes that are not coded
in the genome, but are regulated by structural DNA modifications.
DNA methylation, acetylation of histone proteins and synthesis of
non-coding RNAs inhibit gene expression and are examples of
epigenetic mechanisms.18
The insulin-like growth factor II (IGF2) gene plays an important
role in human growth and development. This gene has received
attention as a possible explanation for the link between abnormal
foetal growth and metabolic disorders in adulthood. IGF2 is known
to be maternally imprinted where only the paternal allele is
expressed19 and hypomethylation of the differentially methylated
region (DMR) leads to bi-allelic expression of IGF2.20 A 2008 study
by Hejimans et al. investigated whether prenatal exposure to
DMR.21
famine was associated with persistent changes in the IGF2
Once again, in the setting of the Dutch Famine of 1944-1945, the
authors looked at periconceptional and late gestational exposure
to famine in same-sex siblings, as well as unexposed births during
this time. The authors hypothesised that imprinting of IGF2 DMR
may be impacted by nutritional status in early gestation, which
may result in hypomethylation and subsequent bi-allelic expression
of IGF2 DMR. Furthermore, they suspected that, because this
epigenetic change is permanent, this effect would be detectable
during the time their study was conducted, six decades later.
Page 56 | Volume 7: Number 1. 2014
Indeed, the study found that individuals who were exposed to
famine prenatally demonstrated a significant reduction in DNA
methylation, compared to their unexposed, same-sex siblings. This
finding provides strong evidence that prenatal environmental
influences can impact critical periods in development and that
these changes can have long-lasting effects.
Life course study design
There are several methodological issues inherent in the life course
approach. First of all, cohorts must be followed from birth into
adulthood. This can only be facilitated through the use of
extensive resources that minimise loss to follow-up during the long
period between exposure and disease. Furthermore, when such an
extensive time period has elapsed between exposure and
outcome, it is difficult to rule out confounding factors that may
lead to erroneous conclusions about the relationship between the
exposure and the outcome of interest. Another complicating issue
is that our ability to observe the prenatal period is extremely
limited and more reliable markers of perinatal growth, other than
birth weight, must be established. Overall, the life course approach
necessitates data that includes maternal information and repeated
observations of exposures of interest over time, which can be
extremely costly. Two study designs are commonly used in life
course epidemiology. First, the natural experiment looks at events
such as earthquakes or famines, where people are naturally
selected into exposed and unexposed groups.22 A historical cohort
can be reconstructed retrospectively from such events, as was
done in the Dutch Famine Study,23 and health outcomes can be
assessed. This method may rely on medical records, but may also
use self-reported information, which may introduce recall bias,
especially if the study is conducted retrospectively. In a historical
cohort, temporality may also be an issue, because it is difficult to
prove that a given exposure occurred prior to, and actually
resulted in, a negative health outcome. Another relevant life course
study design is a prenatal cohort with archived biological
specimens. Women in this type of study are enrolled during early
pregnancy, biological samples are archived for later analysis and
the children of the mothers are followed into adulthood. This
approach achieves temporality (exposure occurred before the
outcome), collects detailed behavioural and health information,
and allows for the assessment of multiple exposures. However, this
type of study is extremely expensive to conduct and must allocate
sufficient resources to prevent attrition of the enrolled population
over the long study period.1 Studies using these types of cohorts
can be conducted retrospectively to increase efficiency and cost
effectiveness, but rely on the availability of sufficient data.
Public health implications
The importance of the perinatal environment has been
demonstrated in relation to CAD,6,7 body size24,25 and
diabetes,25,26 and has even been implicated in the development of
psychiatric conditions, such as schizophrenia.27-29 Life course has
also brought attention to the accumulation of stressors over the
lifetime, or allostatic load, which can contribute to poor adult
RCSIsmjstaff review
health. Notably, these effects are disproportionately seen among
groups of low socioeconomic status, as this population is more
likely to live in resource-scarce environments, be less educated,
and have limited access to healthcare.30,31 The wide-scale public
health implications of these findings must be determined and
employed to shape health policy. If the perinatal environment is an
important risk factor in chronic disease risk, perhaps such
recommendations should focus on improving access to perinatal
care, especially among vulnerable groups. Until the research
becomes conclusive, the life course approach should be used to
further gain insight into the complexity of chronic disease and its
foetal origins.
References
1. Lynch J, Smith GD. A life course approach to chronic disease
epidemiology. Annu Rev Public Health. 2005;26:1-35.
2. Kuh D, Ben-Shlomo Y, Lynch J, Hallqvist J, Power C. Life course
epidemiology. J Epidemiol Community Health. 2003;57(10):778-83.
3. Kermack WO, McKendrick AG, McKinlay PL. Death-rates in Great Britain
and Sweden. Some general regularities and their significance. Int J
Epidemiol. 2001;30(4):678-83.
4. Dubos R, Savage D, Schaedler R. Biological Freudianism. Lasting effects of
early environmental influences. Pediatrics. 1966;38(5):789-800.
5. Stein Z, Susser M, Saenger G, Marolla F. Nutrition and mental
performance. Science. 1972;178(4062):708-13.
6. Barker DJ, Winter PD, Osmond C, Margetts B, Simmonds SJ. Weight in
infancy and death from ischaemic heart disease. Lancet.
1989;2(8663):577-80.
7. Eriksson JG. Early growth and coronary heart disease and type 2 diabetes:
findings from the Helsinki Birth Cohort Study (HBCS). Am J Clin Nutr.
2011;94(Suppl. 6):1799S-802S.
8. Rich-Edwards JW, Stampfer MJ et al. Birth weight and risk of
cardiovascular disease in a cohort of women followed up since 1976.
BMJ. 1997;315(7105):396-400.
9. Leon DA, Lithell HO, Vagero D et al. Reduced fetal growth rate and
increased risk of death from ischaemic heart disease: cohort study of
15,000 Swedish men and women born 1915-29. BMJ.
1998;317(7153):241-5.
10. Stein CE, Fall CH, Kumaran K, Osmond C, Cox V, Barker DJ. Fetal growth
and coronary heart disease in south India. Lancet.
1996;348(9037):1269-73.
11. Barker DJ. Foetal programming of coronary heart disease. Trends
Endocrinol Metab. 2002;13(9):364-8.
12. Desai M, Hales CN. Role of foetal and infant growth in programming
metabolism in later life. Biol Rev Camb Philos Soc. 1997;72(2):329-48.
13. Kwong WY, Wild AE, Roberts P, Willis AC, Fleming TP. Maternal
undernutrition during the preimplantation period of rat development
causes blastocyst abnormalities and programming of postnatal
hypertension. Development. 2000;127(19):4195-202.
14. Metcalfe NB, Monaghan P. Compensation for a bad start: grow now, pay
later? Trends Ecol Evol. 2001;16(5):254-60.
15. Brenner BM, Chertow GM. Congenital oligonephropathy and the
etiology of adult hypertension and progressive renal injury. Am J Kidney
Dis. 1994;23(2):171-5.
16. Luyckx VA, Brenner BM. Low birth weight, nephron number, and kidney
disease. Kidney Int Suppl. 2005;(97):S68-77.
17. Desai M, Crowther NJ, Ozanne SE, Lucas A, Hales CN. Adult glucose
and lipid metabolism may be programmed during foetal life. Biochem
Soc Trans. 1995;23(2):331-5.
18. Egger G, Liang G, Aparicio A, Jones PA. Epigenetics in human disease
and prospects for epigenetic therapy. Nature.
2004;429(6990):457-63.
19. Smith FM, Garfield AS, Ward A. Regulation of growth and metabolism
by imprinted genes. Cytogenet Genome Res. 2006;113(1-4):279-91.
20. Cui H, Cruz-Correa M et al. Loss of IGF2 imprinting: a potential
marker of colorectal cancer risk. Science. 2003;299(5613):1753-5.
21. Heijmans BT, Tobi EW, Stein AD et al. Persistent epigenetic differences
associated with prenatal exposure to famine in humans. Proc Natl
Acad Sci USA. 2008;105(44):17046-9.
22. Opler MGA, Bresnahan MA, G DS, Susser E. Linking fetal experience
to adult health. In: Eaton W (ed.). Medical and Psychiatric
Comorbidity over the Course of Life. Arlington; American Psychiatric
Publishing, Inc, 2006:39-60.
23. Stein Z, Susser M, Saenger G, Marolla F. Nutrition and mental
performance. Science. 1972;178(4062):708-13.
24. Huang C, Li Z, Wang M, Martorell R. Early life exposure to the
1959-1961 Chinese famine has long-term health consequences. J
Nutr. 2010;140(10):1874-8.
25. Ravelli AC, van Der Meulen JH, Osmond C, Barker DJ, Bleker OP.
Obesity at the age of 50 y in men and women exposed to famine
prenatally. Am J Clin Nutr. 1999;70(5):811-6.
26. Li Y, He Y, Qi L, Jaddoe VW, Feskens EJ, Yang X et al. Exposure to the
Chinese famine in early life and the risk of hyperglycemia and type 2
diabetes in adulthood. Diabetes. 2010;59(10):2400-6.
27. Hoek HW, Susser E, Buck KA, Lumey LH, Lin SP, Gorman JM. Schizoid
personality disorder after prenatal exposure to famine. Am J Psychiatry.
1996;153(12):1637-9.
28. St Clair D, Xu M, Wang P, Yu Y, Fang Y, Zhang F et al. Rates of adult
schizophrenia following prenatal exposure to the Chinese famine of
1959-1961. JAMA. 2005;294(5):557-62.
29. Xu MQ, Sun WS, Liu BX, Feng GY, Yu L, Yang L et al. Prenatal
malnutrition and adult schizophrenia: further evidence from the
1959-1961 Chinese famine. Schizophr Bull. 2009;35(3):568-76.
30. Geronimus AT. Deep integration: letting the epigenome out of the
bottle without losing sight of the structural origins of population
health. Am J Public Health. 2013;103(Suppl. 1):S56-63.
31. Loi M, Del Savio L, Stupka E. Social epigenetics and equality of
opportunity. Public Health Ethics. 2013;6(2):142-53.
Volume 7: Number 1. 2014 | Page 57
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Sleep-deprived doctors
and patient safety:
an unresolved link
Abstract
Sean Ling
RCSI medical student
In autumn 2013, Ireland’s non-consultant hospital doctors went on a 24-hour strike to protest
at the Health Service Executive’s lack of compliance with the European Working Time
Directive. This paper reviews the literature regarding the relationship between sleep
deprivation, doctor performance and patient safety. Detrimental effects on doctor
performance, including cognitive ability and in real and simulated surgery, have not been
clearly demonstrated. However, the long-term effects of sleep deprivation on doctor health
and burnout remain unclear. Relatively few strategies, ranging from changes to scheduling
programmes to pharmacological interventions, have been investigated to manage sleep
deprivation more effectively. Ultimately, more long-term research is required to elucidate the
link between sleep deprivation and patient safety.
Royal College of Surgeons in Ireland Student Medical Journal 2014; 1: 58-61.
Page 58 | Volume 7: Number 1. 2014
RCSIsmjstaff review
Introduction
Sleep deprivation and performance
A serious prescription error and subsequent fatal drug interaction led to
the death of 18-year-old Libby Zion in New York Hospital in 1984. This
incident brought sleep deprivation and the long hours worked by
medical interns to the forefront of public attention. It was Libby’s father,
Many tasks, including driving a car and flying a plane, are significantly
Sidney Zion, a lawyer and journalist, who took the hospital to court.1 As
a result, a panel of experts known as the Bell Commission convened to
review medical training and education in New York. One of the most
important proposals to come out of this panel was the working hours
limitation in 1989, which restricted residents to 80 hours per week and
no more than 24 consecutive hours. However, the Accreditation Council
on Graduate Medical Education (ACGME) only made this mandatory for
resident training programmes in the USA in 2003. More recently, in July
2011, the ACGME limited postgraduate year one trainees to 16 hours of
Medicine.2
call, based on recommendations from the Institute of
Sleep
deprivation is not an issue restricted to American medical residents; in
autumn 2013 in Ireland, non-consultant hospital doctors (NCHDs) went
on a 24-hour strike to protest at the lack of compliance with the
European Working Time Directive (EWTD) by the Health Service
Executive. In a letter to the Annals of Surgery, executive director of The
American Board of Surgery Frank R. Lewis suggests that Libby Zion’s
death did not result from sleep-deprived doctors, but rather from
residents with too much responsibility and not enough senior
supervision.3 Despite this evidence, he states that on the one hand,
80-110 hours per week is an extremely heavy workload and that if
doctors are sleep deprived and have impaired judgement, patient safety
may be endangered. On the other hand, he said that decreasing hours
can reduce the clinical experience of residents and disrupt the continuity
care.3
of patient
In the balance is patient health and safety, both of
which are paramount to the medical profession. Perhaps, then, the
relationship between sleep deprivation, performance, and patient safety
in medical professionals and students is not as unambiguous as we would
immediately believe. This paper examines the literature to date.
affected by disruption of sleep schedules.4 However, studies
examining the effects of sleep disruption on medical management
and surgical task performance have turned up mixed results. In a
prospective study by Halbach et al., there was significant decline in
the cognitive function of medical students and residents pre and post
call.5 In Ireland, working consecutive, long hour shifts negatively
affected cognitive functioning, attention, information processing, and
motor skills among junior doctors.6 Conversely, in a similar study
looking at the effects of different styles of call (call every fourth night
or a week of 12-hour �night float’ shifts) on third-year American
medical students, there was no change in cognitive function pre and
post call.7 The authors of this study point out, however, that cognitive
function does not necessarily assess judgment and decision-making –
both very important to any physician. In addition, the study
participants were all medical students who may not experience the
same amount of fatigue as on-call doctors making decisions
throughout the night.
Simulated surgery
Using verified outcome measures such as the Epworth Sleepiness Scale
(ESS) and the National Aeronautic and Space Administration – Task
Load Index (NASA-TLX), which determines subjective workload,
Tomasko et al. determined that a 24-hour call period preceding a
simulated laparoscopic surgical task had no effect on learning a new
technique or applying a previously learned technique in medical
students.4 However, call was associated with a higher subjective
workload, which could detrimentally affect the ability of doctors to
deal with unexpected events, i.e., bleeding vessel during surgery, and
emotional stress. In a randomised controlled trial by Uchal et al.,
voluntary surgeons and nurses were assessed on a laparoscopic
physical simulator (suturing a perforated ulcer) after a 24-hour duty
Volume 7: Number 1. 2014 | Page 59
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(call) versus an eight-hour work day, and again no difference in
Sleep deprivation and doctor safety, health and education
performance was evident.8 As the author readily suggests, however,
the results may not be representative of what chronic fatigue might
eventually lead to with regard to effects on surgical performance. In
another study using an Eyesi surgical simulator, nine residents were
assessed at three different times – pre call, post work and post call – in
a simulated ophthalmic anterior segment surgery, and evaluated on
number of performance errors. There were no differences in the
Sleep deprivation can also have a significant effect on doctor
safety. Residents are more likely to fall asleep at the wheel of a car
number of performance errors.9
Sleep deprivation and patient safety
Although the association between sleep deprivation and performance
remains controversial, an important aspect of sleep deprivation is its
effect on patient safety and outcomes. In a study by Landrigan et al.,
medical interns made 36% more medical errors (including serious
medication and diagnostic errors) if they worked consistent 24-hour
shifts when compared to shorter shifts.10 Emergency doctors on night
shifts tended to make more mistakes as the night continued, were
slower at intubating a mannequin, and were more likely to place
patients incorrectly in a triage test at the end of the shift when
when driving home after a call shift.15 Post-call residents are at
significantly increased risk of needlestick injury.16 Mental health
may also be negatively affected by sleep deprivation; according to
Babson and colleagues, sleep deprivation increased the reporting
of symptoms of anxiety, depression, and general distress in adults
recruited from the general population.17 Sleep is important for
maintenance of general health; doctors who do not get the
appropriate amount of sleep can go on to develop chronic
conditions, putting significant strain on the healthcare system in
the future.18 Interestingly, although burnout, which is defined as
the feeling of long-term, emotional exhaustion and reduced
interest in work, is a common problem among medical trainees at
the beginning of training, one study showed that excessive
sleepiness based on the ESS was not correlated to burnout, but
rather to personality type.19
Strategies to reduce sleep deprivation
compared to doctors working day shifts.11 Conversely, Mitchell and
colleagues looked at the root cause analysis of sentinel events (major
medical errors) in a health system in Dallas and found no association
The difficulty in addressing sleep deprivation lies in balancing
three parameters: patient care; resident education; and, resident
satisfaction/stress. No resident training programme or call
with resident fatigue.12
schedule has successfully done so, thus far.20 One of the main
strategies proposed to reduce sleep deprivation is simply to
reduce working hours. However, to date the evidence behind the
reduction of work hours and improving patient outcomes has
been inconclusive. A study looking at the 2011 work hour
restrictions by the ACGME (16 hours for first-year residents) found
that although residents were more well rested, they found they
suffered increased work compression (doing the same amount of
Surgical outcomes
A retrospective study at the University of Virginia, which looked at over
6,000 cardiac procedures performed by attending cardiac surgeons
over nine years, found no association between surgeon fatigue and
patient morbidity and mortality.13 In an analysis of appendectomies
and cholecystectomies performed at night (after a 16-hour shift) versus
during the day by residents at Harbor-UCLA Medical Center, there
were no differences in complication rates, length of operation or
conversion in these common surgical procedures.14
Page 60 | Volume 7: Number 1. 2014
work in a shorter amount of time).21 The authors concluded that
programmes should adapt their schedules to decrease work
compression. Night float is a type of call schedule where doctors
RCSIsmjstaff review
are assigned to work a shift, but not necessarily to a specific ward,
and instead �float’ to whichever team requires them. In a study by
Matthews et al., students subjectively felt more alert for clinical
duties while on night float.7 In another study, Ray et al. looked at
the use of modafinil, a wakefulness-promoting drug used in
narcolepsy or shift work disorder, as an effective pharmacological
countermeasure to one night of sleep deprivation and reduction
in cognitive decline.22 The authors, however, do not state that
this should be considered as a strategy for chronically
sleep-deprived residents, as long-term effects of using these
countermeasures are unknown.
Conclusion
The recent action by NCHDs in Ireland demonstrates the
widespread importance of limiting the work hours of trainee
doctors. The evidence for an association between sleep
deprivation and doctor performance is not as plain as logic
suggests, although many authors point out that there are
limitations to their studies. For instance, measurement of
performance is often based on completion of a single task done
after a call shift. These studies fail to take into account the effects
of chronic fatigue on overall patient safety. Future studies that
follow patient outcomes over extended periods of time and
include a range of procedures may be beneficial.
Even if there is no clear case for a detrimental effect on patient
health, sleep deprivation certainly affects the physical and mental
well being of doctors. Most studies lack insight into a lifetime of
sleep deprivation and stress. Current strategies to mitigate this
issue have focused on reducing work hours. However, this may
only serve to decrease the amount of time allotted to do the same
amount of work. Future research should focus on developing
more strategies, such as night float, which reduce work
compression, and on ways to better utilise and train doctors in a
shorter period of time. Based on the evidence to date, a great
deal more work is required in this field to better serve patients
and doctors alike.
References
1. Lerner BH. A case that shook medicine. Washington Post. [Internet] 2006
November 28. Available from:
http://www.washingtonpost.com/wp-dyn/content/article/2006/11/24/A
R2006112400985.html.
2. Hegar MV, Truitt MS, Mangram AJ, Dunn EL. Resident fatigue in 2010:
where is the beef? Am J Surg. 2011;202(6):727-31.
3. Lewis FR Jr. Should we limit resident work hours? Ann Surg.
2003;237(4):458-9.
4. Tomasko J, Pauli EM, Kunselman AR, Haluck RS. Sleep deprivation
increases cognitive workload during simulated surgical tasks. Am J Surg.
2012;203(1):37-43.
5. Halbach MM, Spann CO, Egan G. Effect of sleep deprivation on medical
resident and student cognitive function: A prospective study. Am J
Obstet Gynecol. 2003;188(5):1198-201.
6. Flinn F, Armstrong C. Junior doctors’ extended work hours and the
effects on their performance: the Irish case. Int J Qual Health Care.
23(2):210-7.
7. Matthews ML, Gross P, Herbert WN. Post-call cognitive function and
satisfaction in medical students on different call schedules: a prospective
observational pilot study. Am J Obstet Gynecol. 2006;195(5):1484-8.
8. Uchal M, Tjugum J, Martinsen E, Qiu X, Bergamaschi R. The impact of
sleep deprivation on product quality and procedure effectiveness in a
laparoscopic physical simulator: a randomised controlled trial. Am J Surg.
2005;189(6):753-7.
9. Erie EA, Mahr MA, Hodge DO, Erie JC. Effect of sleep deprivation on the
performance of simulated anterior segment surgical skill. Can J
Ophthalmol. 2011;46:61-5.
10. Landrigan C, Rothschild J, Cronin J, Kaushal R, Burdick E, Katz J et al.
Effect of reducing interns’ work hours on serious medical errors in
intensive care units. N Engl J Med. 2004;351(18):1838-48.
11. Smith-Coggins R, Rosekind MR et al. Relationship of day versus night
12. Mitchell CD, Mooty CR, Dunn EL, Ramberger KC, Mangram AJ. Resident
fatigue: is there a patient safety issue? Am J Surg. 2009;198(6):811-6.
13. Ellman P, Law M, Tache-Leon C, Reece T, Maxey T, Peeler B et al. Sleep
deprivation does not affect operative results in cardiac surgery. Ann
Thorac Surg. 2005;78(3):906-11.
14. Yaghoubian A, Kaji AH, Ishaque B et al. Acute care surgery performed by
sleep-deprived residents: are outcomes affected? J Surg Res.
2010;163:192-6.
15. Barger LK, Cade BE, Ayas NT et al. Extended work shifts and the risk of
motor vehicle crashes among interns. N Engl J Med. 2005;352:125-34.
16. Ayas NT, Barger LK, Cade BE et al. Extended work duration and the risk
of self-reported percutaneous injuries to interns. JAMA.
2006;296(9):1055-62.
17. Babson KA, Trainor CD, Feldner MT, Blumenthal H. A test of the effects of
acute sleep deprivation on general and specific self-reported anxiety and
depressive symptoms: an experimental extension. J Behav Ther Exp
Psychiatry. 2010;41(3):297-303.
18. Schiöth HB, Brooks SJ, Benedict C. Healthcare systems never sleep: are
medical residents today the patients of tomorrow? Sleep Med.
2012;13(7):965.
19. Ripp J, Fallar R, Babyatsky M, David R, Reich L, Korenstein D. Prevalence
of resident burnout at the start of training. Teach Learn Med.
2010;22(3):172-5.
20. Sawyer RG, Tribble CG, Newberg DS, Pruett TL et al. Intern call schedules
and their relationship to sleep, operating room participation, stress, and
satisfaction. Surgery. 1999;126(2):337-42.
21. Auger KA, Landrigan CP, Gonzalez del Rey JA, Sieplinga KR, Sucharew HJ,
Simmons JM. Better rested, but more stressed? Evidence of the effects of
resident work hour restrictions. Acad Pediatr. 2012;12(4):335-43.
22. Ray K, Chatterjee A, Panjwani U, Kumar S, Sahu S, Ghosh S et al.
Modafinil improves event related potentials P300 and contingent
sleep to physician performance and mood. Ann Emerg Med.
negative variation after 24 h sleep deprivation. Life Sci.
1994;24(5):928-34.
2012;91(3-4):94-9.
Volume 7: Number 1. 2014 | Page 61
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Unplugging platelet function
tests: reassessing the
gold standard
Abstract
As students of medicine and the allied healthcare fields, we are taught to assess research
methodology with a critical eye and not to take conclusions at face value. How often,
however, are we encouraged to question established practice? This article describes the
re-evaluation of current best practice in diagnosing platelet function abnormalities. The gold
standard test among platelet function tests (PFTs) is light transmission aggregometry (LTA).
This test has been used for more than two decades, and it has only recently been proposed
that LTA is due for re-evaluation; critics suggest that it never wholly fulfilled its function to
begin with.
Royal College of Surgeons in Ireland Student Medical Journal 2014; 1: 62-64.
Introduction
The concept of platelets existing in blood was
discovered more than 120 years ago. The use
of tests to assess their function began in 1910
at Duke University, when researchers postulated
that bleeding time provided an indirect
measure of platelet function. The Duke
bleeding time test is simple: the skin is
punctured using a needle and the length of
Moyser Mulla
RCSI medical student
time taken for bleeding to stop is measured.1
Since then other tests have been developed
which use newer technology to measure
platelet function. Light transmission
aggregometry (LTA) was developed in the
1960s and has since been considered the gold
standard method for measuring platelet
function.2 No new tests have been introduced
since LTA, and only recently have critics begun
Page 62 | Volume 7: Number 1. 2014
to suggest that it may never have wholly
fulfilled its function.
Biomedical research is continually reshaping
the way medicine and the allied healthcare
fields are understood and practised. The way
we do research has evolved dramatically over
the last century; from individually conducted
investigations subjected to no regulatory
bodies, what we understand as �research’ is a
field integral to scientific progress, requiring
teamwork, accuracy, and reproducible
methods, with strict adherence to an ethical
code. The volume of research we produce has
also escalated to numbers that could not have
seemed possible even decades ago. MEDLINE,
an online database of published biomedical
research, has added anywhere from 500,000
to nearly 900,000 new citations every year
RCSIsmjstaff review
since 2001.3 The internet has globalised the world and with it
medicine, making it easier and faster to transfer research ideas
from one setting to another. This has led to the ability to build on
previously made conclusions rather than trying to �re-invent the
wheel’. Whether the large body of scientific findings we obtain
from research is always beneficial may be questionable. There is
no way to know for certain how credible published studies
actually are. This problem is addressed as part of our medical
education; as students, we are constantly encouraged to critique
the ethics and methodologies used in individual research studies
and come to our own conclusions about the validity of the
results. What we are not often asked to do, however, is critique
and question established practices, especially simple and
longstanding ones. For example, platelet function tests (PFTs)
have been in use since the early 19th century and LTA, the
current gold standard, since the 1960s. This paper provides
background about platelet function testing and presents some
evidence that LTA may not actually be achieving its objectives.
This example illustrates that tools that are seen as best practice
need to be analysed and critiqued on an ongoing basis.
Why measuring platelets is important
Cardiovascular disease (CVD), which predisposes individuals to
events such as myocardial infarction (MI) and stroke, is the
world’s second leading cause of death.4 Atherosclerosis heavily
contributes to this disease burden. It is well recognised that
rupture of atherosclerotic plaques and resulting thrombus
formation cause MI and stroke; some studies suggest that platelet
thrombosis may also be an initial cause of atherosclerotic plaque
formation.5
Thus, understanding platelet biology, and being able
to measure platelet activity and function, is crucial for the
assessment and management of patients with CVD.
Platelets play a major role in the tight regulation of homeostasis
in our blood. Normally our blood vessels are lined with a
protective layer of endothelial cells, which guards the underlying
connective tissue from exposure to blood.6,7 However, if there is
a break or intravascular injury to the endothelial lining, collagen
(a potent activator of platelets) is exposed to the intravascular
blood and initiation of coagulation commences. Resting platelets
circulate as discoid cells, however, when they encounter
extravascular material such as collagen, their morphology
changes and they become activated, assisting in the formation of
a �homeostatic plug’.8,9 This plug, which consists mostly of
platelets, walls off the area of injury until a fully formed thrombus
can seal it off. If this thrombus occludes a vessel that supplies
heart muscle, or breaks off and travels into the brain, serious
damage may occur to the tissue.
Measurement of platelets is crucial for assessing thrombotic risk.
It also provides important information for determining
post-intervention risk of thrombosis. For example, PFTs may give
an indication of the risk of developing a major adverse cardiac
event (MACE) after a percutaneous coronary intervention (PCI).10
They also help in assessing preoperative bleeding status and
bleeding risk during surgical procedures.11
Platelet function tests
The value of being able to accurately assess platelet function is
unquestionable. Still, there has been little interest in developing
new and better methods for doing so. Though the newest test is at
least 20 years old and the others even older, only recently has their
primary function been questioned.
Bleeding time
Researchers at Duke University first introduced the concept of
measuring platelet function by the length of time it took for
bleeding to stop following a pinprick. Bleeding time testing was
easy, cheap, and could be done at the bedside.11 Though newer
tests were later developed, bleeding time continued to be used
until the early 1990s. After this time clinicians began to abandon
bleeding time in favour of less invasive and time-consuming tests.
Even so, it was and still is one of very few tests that measures
platelet function in vivo.11,12
Light transmission aggregometry
In LTA, a sample of blood is taken and an agonist introduced, then
the sample is stirred to initiate coagulation. This process mimics
the intravascular stress that platelets are subjected to in the event
of an endothelial injury. Platelets in the blood sample are activated
and clump together, and the clumps fall to the bottom of the test
tube causing the sample to clear. Light is then passed through the
tube by an aggregometer.
The more active the platelets are, the clearer the sample is after
introducing the agonist and therefore more light transmits and is
measured.2
Though LTA is more sensitive and less invasive than the bleeding
test, it requires large volumes of blood, time and expertise. LTA
also lacks the accurate measurement of in vivo conditions offered
by bleeding time as platelets only clump together after adding an
artificial agonist. The physiological shear stress on platelets is not
accounted for, as the stress of mixing them does not mimic the
extent of the stress forces that occur in the body. In our blood
vessels, platelets are subjected to shear stress up to 100,100-1/s,
which causes platelets to become activated and bond to one
another. However, this stress cannot be replicated in vitro, meaning
that LTA likely measures platelet adhesion rather than actual
activation.8,11
Regardless, it is considered the best diagnostic research tool and
the gold standard in clinical practice for diagnosing acquired and
congenital platelet defects.13
In the 1990s a more bedside-friendly version of the LTA was
developed. The platelet function analyser (PFA-100), unlike LTA,
could assess platelet aggregation under shear stress and use less
volumes of blood. It is a point of care (POC) device, meaning that
it works rapidly without need of a lab.7,10 Another POC device, the
Verify Now rapid platelet function analyser (Verify Now), is used to
measure the effects of anti-platelet medications such as aspirin or
clopidogrel on certain platelet receptors. The uses of Verify Now
are limited as it assesses three specific platelet receptors only:
aspirin; P2Y12; and, glycoprotein (GP) IIb-IIIa.
Volume 7: Number 1. 2014 | Page 63
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Do PFTs tell us what we really want to know?
The need to re-evaluate established practice
The ideal characteristics of a PFT for screening and diagnosis can
In light of this evidence, maybe it is time to assess the value of
current PFTs on a larger scale. Although most of these tests
have been in use for decades, only recently has the observation
be summarised in four points.10 A PFT should be able to:
1. Detect platelet hyper-reactivity at baseline.
2. Detect inter-patient variation in platelet reactivity to allow
individualised antiplatelet medication.
3. Predict risk of future thrombosis.
4. Predict bleeding risk.
To date there is no test that fits the above criteria, including LTA.
Current PFTs do not give a clear definition of a normal and a
hyper-reactive range.10 They are also not ideal for individualising
antiplatelet therapy. Petricevic et al. point out that even when giving
antiplatelet therapy, the expected platelet inhibition does not always
happen – in fact up to 45% of patients have a low response to
aspirin or clopidogrel.13 PFTs do not reliably measure response to
antiplatelet therapy, nor do they detect resistance to therapy. They
cannot differentiate between patients who are on or off clopidogrel,
making it very difficult to diagnose compliance with antiplatelet
medication regimens.10 Current PFTs also do not definitively
measure the risk of future thrombosis or bleeding. In one study, the
PFA-100 did not predict the risk of MACE after PCI or stent
thrombosis following a drug-eluting stent (DES) implantation.10,13
PFTs also do not always reflect bleeding risk. Assessing bleeding risk
is crucial prior to surgical procedures; this affects the time at which
preoperative antiplatelet management is stopped and postoperative
bleeding risk assessed.11 If PFTs cannot accurately predict these risks,
clinical decisions cannot be made based on their results.
been made that they are not fulfilling their purpose.10
Until this is done, current PFTs will continue to be used in
clinical practice and remain the gold standard.
We take for granted that the evidence-based practices in use are
built on the best evidence available, however, this is not always
the case.
Despite the great quantity of scientific research that is
generated every year, it is important to be mindful of the
quality of this research and whether it is appropriately
integrated into day-to-day practice.
Published results take time to be implemented, and only
research that makes it to publication can inform whether we
change our practice; negative and unpublished results are much
more difficult to incorporate.
These considerations are important for us as students in the
healthcare field. Our attitudes towards accepting current best
practice as students will form the attitudes we have as
professionals.
PFTs are only one example of the kind of practices that we
should be questioning as we move forward in our careers. With
this example in mind, we must continue our studies as future
healthcare practitioners who are not only receptive but also
thoughtful and analytical.
References
1. De Caterina R, Lanza M, Manca G, Strata GB, Maffei S, Salvatore L.
Bleeding time and bleeding: an analysis of the relationship of the
bleeding time test with parameters of surgical bleeding. Blood Journal.
1994;84:3363-70.
2. Alan DM. Methods for the measurement of platelet function. Am J
Cardiol. 2009;103(Suppl. 3):20A–26A.
3. NIH National Library of Medicine (US). MEDLINE citation counts by year
of publication [Internet]. 2014 [updated 2013 March 22] [cited 2014
January 20]. Available from:
http://www.nlm.nih.gov/bsd/medline_cit_counts_yr_pub.html.
4. American Stroke Association. Atherosclerosis and Stroke. [Internet]
Updated 2013, [cited 2013 April] Available from:
http://www.strokeassociation.org/STROKEORG/LifeAfterStroke/HealthyLiv
ingAfterStroke/UnderstandingRiskyConditions/Atherosclerosis-and-Stroke
_UCM_310426_Article.jsp.
5. Salvador CF, Helmi LL. Ischemic Stroke. Medscape [Internet] Updated
7. Pakala R, Waksman R. Currently available methods for platelet function
analysis: advantages and disadvantages. Cardiovasc Revasc Med.
2011;12(5):312-22.
8. Hawiger J. Formation and regulation of platelet and fibrin haemostatic
plug. Human Pathology. 1987;18(2):111-22.
9. Maree AO, Fitzgerald DJ. Variable platelet response to aspirin and
clopidogrel in atherothrombotic disease. Circulation.
2007;115:2196-207.
10. Gorog DA, Fuster V. Platelet function tests in clinical cardiology:
unfulfilled expectations. J Am Coll Cardiol. 2013;61(21):2115-29.
11. Sun B, Tandon NN, Yamamoto N, Yoshitake M et al. Luminometric assay
of platelet activation in 96-well microplate. Biotechniques.
2001;31:1174,1176,1178.
12. Grove EL, Hossain R, Storey RF. Platelet function testing and prediction of
procedural bleeding risk. Thromb Haemost. 2013;109:817-24.
13. Pualu P, Osmancik P et al. Lack of association between clopidogrel
2013 April. [cited 2013 April]. Available from:
responsiveness tests using point-of-care assay and prognosis of patients
http://emedicine.medscape.com/article/1916852-overview.
with coronary artery disease. J Thromb Thrombolysis. 2013;36(1):1-6
6. Patni R, Nawaz MA, Macys A et al. Assessment of platelet function in
patients on antiplatelet therapy undergoing cardiac surgery: a review.
Heart Lung Circ. 2012;21(8):455-62.
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Sources of, and barriers to,
healthcare in armed conflicts
Abstract
Armed conflict challenges healthcare providers by creating new threats to health and limiting
healthcare resources. This article looks at some of the major armed conflicts of the 20th and
21st centuries, and examines the specific threats posed to the health of populations affected,
using the conflicts in Rwanda, the Western Balkans and Syria as specific case examples.
Sources of healthcare resources are critiqued, and the relative advantages and disadvantages
of humanitarian intervention versus humanitarian assistance are explored. The vulnerabilities
and limitations of humanitarian assistance are identified, with special attention to examples
from recent armed conflicts. Finally, this article discusses the challenges facing the
international community in making collaborative decisions about the best providers of
healthcare in armed conflict. These challenges include many competing interests and
limitations of the United Nations as a primary body for making decisions regarding the
legitimacy of humanitarian intervention.
Royal College of Surgeons in Ireland Student Medical Journal 2014; 1: 65-68.
Introduction
“The only thing necessary for the
triumph of evil is that good men
should do nothing.”
Elizabeth Ahern-Flynn
RCSI medical student
This is a quote often attributed, rightly or
wrongly, to Irish political philosopher and
statesman Edmund Burke. Whatever the true
source of this quote, it is an aphorism that
often appears whenever the issue of
humanitarian intervention during times of
armed conflict is raised. At the end of the 20th
century, the Rwandan genocide and Balkans
war challenged global notions of responsibility
to intervene. Both involved international
intervention, which was widely considered to
have been mishandled. The 21st century has
given us its own challenges, with the United
States-led invasion of Iraq garnering much
international criticism for its lack of a United
Nations (UN) mandate, and accusations of the
US using the pretence of humanitarian
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Table 1: Medical issues encountered in armed conflict zones. (Note: this is a list of examples and is not exhaustive.)
Medical issue
Situation
Sequelae of sarin gas attacks, including loss of consciousness,
convulsions, paralysis, respiratory failure, death.4
Syrian Civil War, 20135
Infectious diseases (most common: diarrhoeal diseases, measles,
acute respiratory infections, malaria).
Zaire, 1994;2,6 Tanzania, 19952
Displaced peoples: malnutrition and dehydration from living in
refugee camps; decreased access to chronic disease care;
inability of medical teams to access remote locations.
Tanzania 1995;2 Syrian Civil War, 2012-present;7 NATO War in
Afghanistan 2003-present8
Gender-based violence, including rape, leading to HIV and other
STIs, unwanted pregnancy, fistula and traumatic genital
injury and its psychological sequelae.
Yugoslavia 1990s;9 Rwanda 1994;
Eastern Congo 2003-2006
War-related injuries: penetrating injuries; burns.
Western Balkans, 1990s6
Increased mental health needs.
Syrian Civil War, 2013-present10
intervention to further its own geopolitical interests. In recent
times the intervention debate du jour is whether Western nations
should intervene in Syria on humanitarian grounds in response
to the use of chemical weapons on civilians by the Assad
regime. This article examines humanitarian assistance and
intervention from a health perspective in the context of armed
conflict. The types of humanitarian assistance – both military
and non-military – are discussed, and the benefits and pitfalls of
each for the health of populations are explored.
Humanitarian assistance versus humanitarian intervention
Whereas humanitarian assistance refers to non-military
organisations providing aid to people affected by humanitarian
crises and is protected by international humanitarian law, there
is much debate among academics as to what constitutes
humanitarian intervention, with no international consensus.
One definition is: “humanitarian coercive action by states
involving the use of armed force in another state without the
consent of its government, with or without authorisation from
the United Nations Security Council, for the purpose of
preventing or putting to a halt gross and massive violations of
human rights or international humanitarian law”.1 This lack of
consensus is not merely academic, but extends to multilateral
organisations such as the UN and the North Atlantic Treaty
Organisation (NATO). As there is no international consensus on
what humanitarian intervention entails, problems arise when an
intervention purported by a state to be undertaken on
humanitarian grounds is opposed by the international
community, as was the experience when the US declared war
on Iraq in 2003, in the absence of a UN mandate.
The need for humanitarian assistance
Armed conflicts have a profound effect on the general health of
nations. Not only do particular healthcare needs increase as a
direct result of armed conflicts (Table 1), but when states are
Page 66 | Volume 7: Number 1. 2014
engaged in armed conflict, spending may be diverted from
healthcare to fund the conflict. This mismatch between
healthcare supply and demand creates a long-lasting
dependency on external aid.2
In addition, in times of armed conflict these increased
healthcare needs may be provided for by local political or
paramilitary organisations that use the provision of
badly-needed healthcare and education to garner political
capital.
They then redeem this for positions of political authority, as is
the case with Hezbollah in Lebanon and Palestine.3 In addition
to the relief of suffering during armed conflict, public health
activities promote peace, prevent violence and allow enemies to
reconcile.2
Humanitarian organisations
Apolitical humanitarian organisations such as MГ©decins Sans
FrontiГЁres (MSF), the UN and the International Red
Cross/Crescent represent an alternative to political organisations
in areas of armed conflict.
These organisations allocate health resources to the people
affected by armed conflict on the basis of need and not political
affiliation, allowing them to operate in conflict zones tolerated
by the conflicting parties.2 A further advantage of these groups
is that their intervention is based on humanitarian grounds and
not the promise of gaining a geopolitical advantage, as may be
seen when states or blocks of states intervene in armed conflicts
under ostensibly �humanitarian’ grounds.
The International Committee of the Red Cross/Crescent (ICRC)
is particularly well placed to serve the needs of people affected
by complex humanitarian emergencies, as it has local branches
in almost every zone of conflict and can ultimately allow local
healthcare workers to assume responsibility for primary
healthcare, thus decreasing dependence on external
intervention.2
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Vulnerability
Humanitarian workers, including both military and non-military
medical personnel, are protected from attack under the Geneva
Convention and its additional protocols.8 The convention
declares that medical personnel should be afforded specific
protection from attacks and that they should not be prevented
or prohibited from providing medical care to those who need it.
However, in reality the disadvantage of humanitarian
organisations is that their apolitical, non-military stance makes
their workers vulnerable, as they have little means to protect
themselves in the face of aggression.
While the concept of international law protecting medical
personnel may seem noble, those engaged in armed conflict
tend to care little for compliance with such laws; the mere
existence of the International Criminal Court (ICC) is testament
to this fact.
Attack on medical vehicles branded with Red Cross and Red
Crescent signage in Afghanistan, coupled with the 2009
kidnapping of Irish aid worker Sharon Commins and her
Ugandan colleague Hilda Kawuki in Darfur in Sudan, serve as
sober reminders of the vulnerability of humanitarian workers in
apolitical, non-military organisations.8,11
The vulnerability of humanitarian organisations can interfere
with their ability to provide care to victims of war. In 1994, MSF
was forced to close maternal health clinics at night in a Zaire
(present day Democratic Republic of the Congo) refugee camp
as midwives reported being raped at night by the centre’s
guards.9
Military intervention
A third provider of healthcare in regions of armed conflict is
individual states or blocks of states, such as NATO or the UN.
They have the advantage of being militarily equipped and thus
able to defend themselves and their equipment, as well as their
medical corps having the protection of international law under
the Geneva Convention.8 However, the invasion of one nation
state by another directly contravenes the sovereignty of the
invaded state, regardless of the grounds for invasion. Thus,
medical and military personnel from the invading state are at
increased risk of violence and aggression as the invaded state
attempts to defend itself. The individual medical corps of NATO
forces were only able to provide limited healthcare to Kosovan
refugees in Stenkovec One refugee camp in Macedonia during
the war in the Western Balkans in 1999; as they were active
combatants in a war, their presence endangered the lives of the
refugees.2
A further hazard of military humanitarian intervention is that,
while apolitical humanitarian organisations direct their aid
towards those regions that require it most, military intervention
is strongly influenced by strategic regional interests and
international relations. UN peacekeeping troops have the
advantage of being non-aggressors and favouring no particular
side during a conflict; their stated role is purely to preserve
peace. But even their presence did not prevent the genocide of
Rwandan Tutsis by Hutu gangs in 1994.2
Conclusion
Humanitarian aid and intervention is fraught with difficult
ethical decisions – to close the medical centre and put patients
at risk, or to force staff to work in an environment with a high
probability of rape? To provide healthcare by an army corps in
the knowledge that its presence may draw fire on a refugee
camp? To violate the sovereignty of another country to �save’ its
people from its leader?
The �right’ answers to these questions often only become
apparent retrospectively after much discussion and analysis, but
may still be a subject of debate for generations. When
considering the superiority of one form of health service
delivery over another, it is important to examine the evidence
at hand. NGOs offering humanitarian assistance must be
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accountable to numerous donors, often from different
countries; value for money and evidence-based interventions
are a priority, but are difficult to achieve.12 The medical
resources and experience of decades of humanitarian assistance
during complex humanitarian emergencies has made this
branch of medicine almost a specialty in itself, with medical
journals such as Disasters and Prehospital Disaster Medicine
providing a medium to communicate research in this growing
area of specialisation. Difficulties arise, however, when
humanitarian workers are unable to defend themselves from
violence, and their safety and ability to provide care becomes
compromised. Peaceful humanitarian intervention should
therefore be maximised in complex humanitarian emergencies
in order to minimise the effect of armed conflict on the health
of populations.
In cases where there is a tangible threat to the provision of
humanitarian assistance by conflicting armed forces, it is then
legitimate for an external military party to intervene, provided
that the intention of the intervention is to preserve the integrity
of such relief efforts and not to further strategic regional
interests.
In these cases, where military intervention is needed to
augment the work of non-military organisations, the decision to
intervene should be taken multilaterally – in so far as it is
possible – to avoid a dominant military force exerting undue
influence over the area for geopolitical advantage. The largest
multilateral organisation in the world is the UN, which
undertakes health initiatives around the world through the
World Health Organisation (WHO). The UN subscribes to the
idea of �responsibility to protect’, believing that: “The
international community has a responsibility to use appropriate
diplomatic, humanitarian and other means to protect
populations... If a state is manifestly failing to protect its
populations, the international community must be prepared to
take collective action to protect populations, in accordance with
the UN Charter”.13 However, when it comes to issues of
humanitarian intervention, the vetoing power of the United
States, China, Russia, the United Kingdom and France within
the United Nations’ Security Council can act as a barrier to
intervention.
This barrier may not necessarily be a disadvantage, as it may act
to prevent one dominant power exerting undue influence, but
equally it can prevent timely humanitarian assistance from
reaching vulnerable populations.
There is no easy answer as to when humanitarian intervention
may be used; indeed, the UN itself does not have a set of
criteria for when it will intervene, preferring instead to judge
each conflict on its individual situation.
As armed conflict increases in the Middle East and Africa, it is
likely that humanitarian organisations will become increasingly
limited in what they can provide, as is already the case in Syria,
with five staff members of MSF having been detained in January
of this year.14 This will increase the need for humanitarian
intervention to bring stability to conflict zones so that NGOs
can continue to provide healthcare to populations affected
by violence.
References
1. Ryniker A. The ICRC’s position on “humanitarian intervention”.
International Committee of the Red Cross. June 2001.
2. Gardemann J. Primary health care in complex humanitarian emergencies:
Rwanda and Kosovo experiences and their implications for public health
training. Croat Med J. 2002;43(2):148-55.
3. Irin News. Lebanon: The many hands and faces of Hezbollah. [Internet].
8. Goniewicz M, Goniewicz K. Protection of medical personnel in armed
conflicts – case study: Afghanistan. Eur J Trauma Emerg Surg.
2013;39(2):107-12. [Epub 2013 Feb 9].
9. Shanks L, Schull MJ. Rape in war: the humanitarian response. CMAJ.
2000;163(9):1152-6.
10. Doctors Without Borders. “An emergency in itself”: mental health needs
Beirut. 2006 Mar [cited 2013 October]. Available from:
among Syrians in Iraq [Internet]. New York 2013 October [cited 2014
http://www.irinnews.org/report/26242/lebanon-the-many-hands-and-face
January]. Available from: http://www.doctorswithoutborders.org/
s-of-hezbollah.
4. Centres for Disease Control and Prevention. Facts about Sarin [Internet]
Atlanta. 2013 May [cited 2014 January]. Available from:
http://www.bt.cdc.gov/agent/sarin/basics/facts.asp.
5. Reuters. UN has testimony that Syrian rebels used sarin gas: investigator.
[Internet]. Geneva. 2013 May 5. [cited 2014 January]. Available from:
news/article.cfm?id=7095#sthash.k9F4wVbR.dpu.
11. The Irish Times. Sharon Commins reunited with family. 2009 October 10.
12. Banatvala N, Zwi AB. Conflict and health. Public health and humanitarian
interventions: developing the evidence base. BMJ.
2000;321(7253):101-5.
13. United Nations. Background information on the responsibility to
http://www.reuters.
protect [Internet] [cited 2014 January]. Available from:
com/article/2013/05/05/us-syria-crisis-un-idUSBRE94409Z20130505.
http://www.un.org /en/preventgenocide/rwanda/about/
6. Toole MJ, Waldman RJ. The public health aspects of complex emergencies
and refugee situations. Annu Rev Public Health. 1997;18:283-312.
7. United Nations News Centre. Syrian refugees straining health services in
bgresponsibility.shtml.
14. Reuters. MГ©decins Sans FrontiГ©res says five staff detained in Syria.
[Internet]. Beirut. 2014 January 3. [cited 2014 January] Available from:
region, UN warns in new report [Internet] 2013 April 26 [cited 2014
http://www.reuters.com/article/2014/01/03/us-syria-crisis-msf-idUSBREA
January]. Available from: http://goo.gl/LU42xR.
020JE20140103.
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Whose life, whose death?:
Pharmaceutical trials in the
developing world
Abstract
The number of clinical trials being undertaken in developing countries has increased
significantly in the last three decades. For pharmaceutical companies, the move to undertake
trials in developing economies presents a convenient cost- and time-saving measure.
However, this trend raises some pertinent ethical questions. This article examines whether the
use of a trial drug or treatment, where no other choice exists, is a form of coercion; if it is
ethical to run a trial of expensive new drugs in an impoverished country where that particular
medication will, in all likelihood, never be affordable for most people; and, finally, whether it
is acceptable to conduct a trial on subjects without their explicit and informed consent, even
if the researchers are reasonably certain the drug is better than the current �gold standard’.
The regulatory regimes in most developing countries are less stringent than in the developed
world, and the risks are more difficult to explain as a result of cultural barriers, poverty and
educational disadvantage. The locations and regulation of clinical trials should be the concern
of all who benefit from treatment with new and emerging drugs.
Royal College of Surgeons in Ireland Student Medical Journal 2014; 1: 69-72.
Amelia Reid
RCSI medical student
Introduction
In Kano, a small Nigerian town on the southern
edge of the Sahara desert, approximately 5,000
children will die of bacterial meningitis during
the dry season in any given year. The entrenched
poverty and arid, unsanitary conditions are ideal
for the spread of infectious diseases such as
measles, cholera and bacterial meningitis. During
the worst dry season on record – 1996 – an
epidemic swept through Kano and killed more
than 11,000 children. MГ©decins Sans FrontiГ©res
health personnel were providing treatment to
those families who could not otherwise afford it,
or were unable to be seen at the already
overflowing government hospital.1 At the time,
the World Health Organisation (WHO)
recommended that the first line of treatment for
children who presented with suspected bacterial
meningitis should be chloramphenicol – a cheap,
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prototypical, broad-spectrum antibiotic.2 Midway through this
epidemic, a team from Pfizer flew to Kano from the United States
to recruit subjects for a trial of trovafloxacin (Trovan), its new
orally delivered antibiotic.3 Trovan, a quinolone antibiotic, was yet
to be proven effective against bacterial meningitis. The safety of
Trovan had not been established and initial animal studies had not
yielded promising results. In fact, Pfizer would later be advised by
the Food and Drug Administration (FDA) to remove Trovan from
toxicity.4
the market because of concerns about liver
In the United
States, where Pfizer has its headquarters, approximately 4,000
year.5
people contract bacterial meningitis every
In Nigeria,
however, Pfizer could recruit hundreds, if not thousands of
paediatric patients with the illness in a matter of weeks.6 If they
were able to establish that Trovan was effective for the treatment
of meningitis in children, Pfizer would break into the lucrative
worldwide paediatric market, including countries where there is
either a high incidence of the disease or periodic epidemics.
The Trovan study presents a myriad of ethical quandaries. Is the use
of a trial drug or treatment, where no other choice exists, a form of
coercion? Is it ethical to run a trial of expensive new drugs in a
country where that particular medication will, in all likelihood,
never be affordable for most people? Is it acceptable to conduct a
trial on subjects without their explicit and informed consent, even if
the researchers are reasonably certain the drug is better than the
current �gold standard’?
Coercion
The conduct of clinical trials in developing countries by researchers
from the developed world has become more commonplace over
the last three decades.4
Apart from the relative ease of recruiting subjects, companies can
make significant savings on human labour, which accounts for
around half of the costs incurred.7 In India, an academic institution
or affiliated hospital is said to charge approximately 10 times less
for recruiting participants and conducting a preliminary trial than
Page 70 | Volume 7: Number 1. 2014
centres in the United States.7 Furthermore, there are fewer
regulatory obstacles for researchers to overcome in developing
countries, and this presents another significant incentive. Some
might argue that the high front-end costs of developing a new
drug justify the most cost-efficient methods of testing its efficacy.
The incentives to lower costs are patent: it is estimated that the
cost of manufacturing one new drug can be in excess of US$5
billion.8 A pharmaceutical executive wrote that, between 2000 and
2008, the price of shares in the top 15 pharmaceutical companies
dropped by more than half – from 32 to 13 times earnings.7
Pharmaceutical companies are, in a perverse sense, aided and
abetted in their efforts by the very people they seek to recruit. For
the very poor who cannot afford healthcare, or are living in areas
where access to health infrastructure or personnel is limited, a
clinical trial is a way of obtaining free treatment or care. Most trials
involve clinical testing, medication, and follow-up free of charge –
all of which would be otherwise inaccessible. Moreover, the
apparent authority and status of the providers gives those without
the knowledge or means to judge the reassurance that their
treatment is effective and safe. Coercion is not synonymous with an
explicit threat; the threat is inherent in the transaction. If the
subjects do not accept what they are offered, they may well be
offered nothing – an unpalatable choice when one’s child is ill or
near death.
Access
Until 2008, the FDA required that all trials conducted in foreign
countries comply with the Declaration of Helsinki. However, this is
no longer the case. Foreign trials are now only required to comply
with “good clinical practice guidelines” (GCP).9 These guidelines,
outlined by the International Conference on Harmonisation – a
group aimed at bringing together authorities from the regulatory
bodies in Japan, the USA and Europe – are worthy, but do not
encompass all of the principles outlined in the Declaration of
Helsinki. For instance, one of the tenets of the Declaration is that
RCSIsmjstaff review
drug testing can only be conducted on a population that will, in
all probability, be afforded access to and benefit from those
drugs in the long term. The GCP guidelines do not require
this.1,10
In impoverished countries, as in the case of the disenfranchised
poor in the West, access to even basic healthcare is marginal at
best. Variables such as income, education, employment,
geography, and culture influence life’s chances across a spectrum
of health conditions and have well-demonstrated impacts on
longevity. In this context, one of the weighty dilemmas facing
researchers is whether to conduct a trial for a new therapy
against the best available treatment anywhere in the world or the
best available treatment in that country.10,11 Some have
defended the use of placebo-controlled studies on the grounds
that the controls are receiving no more and no less than they
would normally receive (little or nothing), and those receiving
the experimental drug may benefit.11 In a developed country,
�standard of care’ is taken to mean the best evidence-based
practice, not a standard determined by the relative wealth or
poverty of the study population.9,10 The �better than nothing’
defence has a certain seductive logic, but it scarcely meets the
criterion of moral defensibility.
For instance, the AIDS Clinical Trial Group (ACTG) Study 076,
which compared vertical transmission rates of HIV in pregnant
women receiving the antiretroviral drug zidovudine versus
placebo, was prematurely stopped when it became clear that
1964, holds that subjects in a trial must fully understand the
anticipated benefits and risks and be aware of any conflicts of
those receiving zidovudine had much lower transmission rates.12
Zidovudine soon became the standard of care in the United
States. However, the regime is unaffordable for most people in
countries where the maternal-foetal transmission of HIV is at
they enroll in a trial.21
The problem in Kano was this: the ethical regulations that guide
research and trials in any developed country are not applied with
the same rigour and oversight in the developing world. Pfizer did
not have to gain the approval of the FDA prior to leaving for
epidemic proportions.13,14 In Uganda, to administer the
ziduvodine regimen to HIV-infected pregnant women would cost
healthcare.15
400 times the country’s yearly expenditure on
A
less costly alternative was therefore urgently needed. WHO
officials concluded that placebo-controlled trials would �offer the
best option for obtaining rapid results’.16 Subsequently, 18
placebo-controlled trials, involving more than 17,000 women,
were undertaken in several developing countries, which aimed to
assess a number of interventions to reduce mother-to-child HIV
transmission rates. These included the use of vitamin A and
intrapartum vaginal washing.14 The �better than nothing’
principle was thus brought to bear on a crisis by those whose
only interest was in arresting the epidemic. For �big pharma’, the
conflicts of interest are acute and the risk of exploitation real,
most especially if the drugs being tested will never be accessible
to those whose bodies were used to establish their efficacy.
Informed consent
The first clause of the Nuremberg Code – developed after the
Second World War and to which researchers must conform when
undertaking studies on humans – holds that subjects of research
should give informed and voluntary consent, and be able to
exercise the �free power of choice’, including the right to opt out
of a trial at any stage.17,18 The Declaration of Helsinki, adopted in
interest the researchers involved might have.19,20 These
documents established the principle of informed consent for
participants in research. Unfortunately, many study participants
from the developing world are unaware of their rights or the
obligations of researchers, and do not understand the risks when
Kano.22 They argued that there was no international protocol or
accepted norm requiring them to obtain informed consent when
undertaking research with experimental drugs in Africa.4 The
participants in the trial were not asked to sign consent forms
prior to being assigned to an arm of the trial. Pfizer alleged that
the children were too young to sign and the parents did not
speak enough English to understand the purposes and risks of
the trial, and therefore, to give informed consent. The parents
later claimed that they did not even know their children were
part of a clinical trial.4
Obtaining truly informed consent from a vulnerable individual or
population in a culturally appropriate way and with research
integrity may be difficult, but this does not release researchers
from the obligation.23
The standard consent procedures utilised in developed countries
are not necessarily appropriate in settings where there are
language and social barriers, a lack of individual autonomy (for
instance, in conservative patriarchal societies) or hesitation by the
participants to challenge authority. In Kenya, researchers who
wanted to conduct a trial on orphaned children were required to
adhere to the sociocultural norms of the �Mabaraza’ – a
traditional hierarchical community assembly. The benefits were
twofold; the researchers were better able to understand the
Volume 7: Number 1. 2014 | Page 71
RCSIsmjstaff review
community perspectives and beliefs on health and healthcare
delivery; and, the local community were more amenable to the
researchers and their work as they felt their values and traditions
had been considered and
respected.24,25
Conclusion
In 2007, the Nigerian government sought to sue Pfizer for US$7
billion. The final outcome of the case – a reported US$75 million
settlement – is subject to a confidentiality agreement.26 However,
some of the more embarrassing and damning details were leaked
through the Wikileaks cables, prompting Pfizer to issue several
justificatory press releases.26 The Nigerian Health Ministry has
References
1. Goldacre B. Bad Pharma: How Drug Companies Mislead Doctors and
Harm Patients. Harper Collins Publishers; London, 2012.
2. World Health Organisation. Standardized Treatment of Bacterial
Meningitis in Africa in Epidemic and Non Epidemic Situations, Epidemic
and Pandemic Alert and Response, 2007.
3. Shah S. Globalization of clinical research by the pharmaceutical industry.
Int J Health Serv. 2003;33(1):29-36.
4. Wise J. Pfizer accused of testing new drug without ethical approval. BMJ.
2001;322(7280):194.
since released a report on the trial saying that Pfizer violated
Nigerian law, the UN Declaration on the Rights of the Child and
the Declaration of Helsinki.27
While unregulated clinical trials are conducted in poor countries,
we in the West are conflicted, knowing that our medical care
may come at the cost of others’ well-being and of the moral
integrity of our corporations. The question, then, is whether we
in the developed nations insist on the same enforceable
standards for others, who do not have the same voice or means,
even if that means foregoing, or slowing, the availability of new
and more effective drugs. It is not just a matter of life and death,
but whose life, and whose death.
15. Lurie P, Wolfe SM. Unethical trials of interventions to reduce perinatal
transmission of the human immunodeficiency virus in developing
countries. N Engl J Med. 1997;337(12):853-6.
16. World Health Organisation. Recommendations from the meeting on
mother to infant transmission of HIV. Geneva, Switzerland, June 23-25,
1994.
17. Shuster E. Fifty years later: The significance of the Nuremberg Code. N
Engl J Med.1997;337:1436-40.
18. The Nuremberg Code (1947). BMJ. 1996;313:1448.1.
5. Centre for Disease Control and Prevention. 2012. Bacterial Meningitis
19. World Medical Association. 2013. WMA Declaration of Helsinki – Ethical
Fact Sheet [Internet] Accessed 2012 September 11. Available from:
Principles for Medical Research Involving Human Subjects. [Internet]
http://www.cdc.gov/meningitis/bacterial.html.
[Accessed 2013 September 11]. Available from:
6. Boseley S, Smith D. The Guardian. As doctors fought to save lives, Pfizer
flew in drug trial team. [Internet] 2010 December 9. Available from:
http://www.theguardian.com/business/2010/dec/09/doctors-fought-save
-lives-pfizer-drug.
7. Garnier J. Rebuilding the R&D engine in big pharma. Harv Bus Rev.
2008;86(5):68-70.
8. Herper M. Forbes Magazine. The cost of creating a new drug now five
billion, pushing big pharma to change. [Internet] [Accessed 2013
November]. Available from:
http://www.forbes.com/sites/matthewherper/2013/08/11/how-the-stagg
ering-cost-of-inventing-new-drugs-is-shaping-the-future-of-medicine/.
9. Glickman SW et al. Ethical and scientific implications of the globalisation
of clinical research. N Engl J Med. 2009;360(8):816-23.
10. Emanuel EJ, Wendler D, Killen J, Grady C. What makes clinical research in
developing countries ethical? The benchmarks of ethical research. J Infect
Dis. 2004;189(5):930-7.
11. Angell M. The ethics of clinical research in the Third World. N Engl J
Med. 1997;337(12):847-9.
12. Annas GJ, Grodin MA. Human rights and maternal-fetal HIV transmission
prevention trials in Africa. Am J Public Health. 1998;88(4):560-3.
13. Susser M. The prevention of perinatal HIV transmission in the
less-developed world. Am J Public Health. 1998;88(4):560-3.
14. Bayer R. The debate over maternal-fetal HIV transmission prevention
trials in Africa, Asia and the Caribbean: Racist Exploitation or Exploitation
of Racism? Am J Public Health. 1998;88(4):567-70.
Page 72 | Volume 7: Number 1. 2014
http://www.wma.net/en/30publications/10policies/b3/.
20. Kimmelman J, Weijer C, Meslin E. Helsinki discords: FDA, ethics and
international drug trials. Lancet. 2009;373(9657):13-4.
21. Hill Z, Tawiah-Agyemang C, Odei-Danso S, Kirkwood B. Informed
consent in Ghana: what do participants really understand? J Med Ethics.
2008;34(1):48-53.
22. Willyard C. Pfizer lawsuit spotlights ethics of developing world clinical
trials. Nat Med. 2007;13(7):763.
23. Benatar S. Reflections and recommendations on research ethics in
developing countries. Soc Sci Med. 2002;54(7):1131-41.
24. Onvomaha Tindana P, Kass N, Akweongo P. The informed consent
process in a rural African setting: a case study of the Kassena-Nankana
district of Northern Ghana. IRB. 2006;28(3)1-6.
25. Vreeman R, Kamaara E, Kamanda A. Community perspectives on
research consent involving vulnerable children in Western Kenya. J Empiri
Res Hum Res Ethics. 2012;7(4):44-55.
26. MГ©dicins Sans FrontiГ©res. Pfizer retracts allegations against MSF. Press
Release, January 4, 2011. Available from:
http://www.doctorswithoutborders.org/press/release_print.cfm?id=4941.
27. Stephens J. Washington Post. Panel faults Pfizer in ’96 clinical trial in
Nigeria. [Internet] 2006 May 7. Available from:
http://www.washingtonpost.com/wp-dyn/content/article/2006/05/06/A
R2006050601338.html.
RCSIsmjperspective
Ensuring safe surgery
for our patients –
DO WE DO ENOUGH?
DAVID HAKIM
looks at
attitudes to
surgical safety,
particularly in
the UK health
service.
Last year in the UK, 223 people died while undergoing surgical
procedures. Statistics produced by the UK’s National Health
Service (NHS) show that 28.3% of all operations carried out last
year were associated with some form of complication – defined
as any undesirable or unexpected result.1,2 Although only 0.1%
of these were fatal, complications still carry a high potential for
morbidity.2 Post-surgical infections, for example, range from mild
cellulitis to uncontrollable sepsis with variable morbidity.3 When
standard preoperative, intraoperative, and postoperative safety
measures are taken, infections still sometimes occur.4
In 2001, the US National Quality Forum (NQF) introduced the
concept of the �never event’ and defined 27 surgical events,
including wrong site, wrong patient and wrong procedure, which
should never occur.5 Medical and surgical advances over the last
decade have undeniably made today’s healthcare system safer
and much more efficient than it was when the initial list was
released. Despite this, the �never event’ tally is still worryingly
high, which forces us to ask: are we doing enough?
The checklist manifesto
One successful strategy, endorsed by the World Health
Organisation (WHO), is the �time out’ surgical safety checklist,
which was developed in partnership with Harvard-based general
surgeon, author, and pioneer in error reduction, Atul Gawande.
Since its 2007 introduction, the checklist has been applied by
more than 4,000 hospitals in 122 countries. The UK Department
of Health successfully implemented this checklist across all
hospitals by February 2010. Publications from several medical
centres – such as the 2009 Gawande et al. pilot study of eight
hospitals worldwide6 – continue to confirm that use of the WHO
checklist improves communication and increases the reliability of
“routine interventions such as antibiotic prophylaxis and
thromboembolic prophylaxis”.7
Gawande was inspired to create surgical checklists after watching
pilots perform pre-flight checks before every take-off.8 He
continues to lead the Safe Surgery Saves Lives (SSSL) initiative of
the patient safety division at the WHO.9 Studies done by SSSL
Volume 7: Number 1. 2014 | Page 73
RCSIsmjperspective
One successful strategy,
endorsed by the WHO, is the
�time out’ surgical safety
checklist, which was developed
in partnership with
Harvard-based general surgeon,
author, and pioneer in error
reduction, Atul Gawande
in 2007.
found that there were improvements in safety attitudes, which
positively correlated with the reduction of postoperative
complication rates. In total, 93.4% of clinicians questioned by
the SSSL stated that before having an operation, they would
used.10
want the checklist to be
There are, however, those who remain critical of this safety
precaution. According to the President of the Royal College of
Anaesthetists, 37% of medics are against the scheme; they find
that there is insufficient time to use the checklist in operating
theatres.11
Use of the WHO checklist improves
communication and increases the
reliability of “routine interventions such
as antibiotic prophylaxis and
thromboembolic prophylaxis”.7
Communication
Another important contributor to safe surgery is the level of
communication in the operating theatre. Communication failures
are a well-known cause of inadvertent patient harm across
specialties.12
Over the last decade or so, team
medical
performance has been identified as an essential foundation of
good surgical care; open channels of communication within a
functions.13
team are a key determinant of how well the team
This presents a special challenge in the field of surgery, which is
traditionally rigidly hierarchical.14
Promotion of an open atmosphere, wherein less senior team
members are comfortable bringing potential problems to the
attention of their superiors, is especially important, as teamwork
Page 74 | Volume 7: Number 1. 2014
and communication have been shown to be correlated with
better surgical outcomes.15,16
In medical centres with internationally trained staff, language
presents another potential barrier to communication.17 The UK’s
Medical Act of 1983 prevents the General Medical Council
(GMC) from doing any language testing of doctors from the
European Economic Area (EEA). However, the GMC and the
Nursing and Midwifery Council argue that failing to test foreign
medics’ English exposes patients to serious risks.18 Asking that
operating theatre staff be expected to speak English to a certain
standard, therefore, is not an unreasonable request. The
30-year-old Medical Act needs re-evaluation to address this issue.
Technology
Surgery has evolved dramatically in the past two decades.19 The
first minimally invasive procedure – a laparoscopic
cholecystectomy – was performed in 1987.20 Since then the field
has burgeoned; minimally invasive options for complex
procedures such as cardiac valve replacement and donor
nephrectomies exist.21,22 Minimally invasive surgery (MIS) offers
benefits such as: shorter operation times; smaller incisions;
reduced postoperative trauma; and, smaller amounts of blood
loss.23 For example, the �finger-assisted nephrectomy’ technique
allows significantly smaller incision lengths than the traditional
open procedure, without risking patient safety and with fewer
postoperative complications.24 This is not only beneficial to the
patient but to the hospital and doctors too; quicker operations
and shorter hospitalisation times allow more patients to be
treated. MIS procedures use video-assisted equipment, allowing
the surgeon better visualisation and magnification of internal
organs and structure. This translates into a more accurate and
definitive procedure for patients.25 Today’s surgeons should
RCSIsmjperspective
According to the President of
the Royal College of
Anaesthetists, 37% of medics
are against using checklists;
they find that there is
insufficient time in operating
theatres.
familiarise themselves with these techniques in order to raise the
standard of patient safety.
Robotic surgery is another area being tested and implemented in
some institutions. This provides several advantages, including the
minimisation of human error, which should correlate with
monitoring of blood flow – used to analyse organ viability after
procedures such as kidney transplants.32,33 The prohibitive cost
of this technology means that in NHS hospitals, traditional
ultrasound is still being used.
increased accuracy and precision.26 However, the associated cost
and increased operation lengths are disadvantages.27
Nevertheless, if investment in robotic technology means a
significant reduction in surgical error, then it is definitely worth
developing.
Over the past decade, surgical instruments – including staplers,
scalpels and endoscopes – have also been redesigned to reduce
Conclusion
surgical complications. The use of HemoStaseTM, a powdered
polysaccharide haemostat, is an example of new technology used
transfused during operations.11 These figures emphasise the
need for action against risk. Associations such as the UK’s Patient
First, the stated purpose of which is to “reduce death and harm
in the NHS and to force the UK Government to create policies
and laws that ensure the NHS becomes open and
to control bleeding during surgical procedures.28 During
2009-2010, a study was done at the West London Renal and
Transplant Centre (Imperial College Healthcare) to demonstrate
the benefits of HemoStaseTM; 44 consecutive patients who
underwent live donor nephrectomies had a 100% haemostasis
success rate when the powder was administered. None
experienced postoperative bleeding, fluid collection or infection,
site.29
or required re-exploration of the surgical
Unfortunately, the NHS has been hesitant to invest in equipment
that has been adopted in the private sector. For example, some
NHS hospitals do not use the harmonic scalpel.
This instrument both cuts and coagulates tissue
instantaneously;30 instead, NHS hospitals use traditional methods
such as electrocautery.31 Another example is the Cook-Swartz
doppler flow monitoring system – a 1.0mm Doppler probe
attached to a cuff of expanded polytetrafluoroethylene
(GORE-TEX; WL Gore and Associates, Flagstaff, Arizona), which is
secured around a vessel and sutured in place providing real-time
Unfortunately, the truth is that we are falling short of our
patients’ safety expectations. 2011-2012 saw thousands of
surgical incidents reported to the UK’s National Patient Safety
Agency: 161 patients left operating theatres with surgical
instruments still inside them; 41 patients had the wrong implant
or prosthetic inserted; and, 10 people had incompatible blood
accountable”34 continue to support and promote the goal of
surgical safety, reminding us that patient safety is always the top
priority. �Never events’ should at no time be tolerated and are
eminently preventable in the NHS.35 This is a global issue,
demanding the authority of the WHO, which has produced
schemes to try and reduce surgical risks.
We sadly cannot say that we have done enough to reduce
surgical complications; however, the initiatives taken in recent
years have proven to be effective. With further work and
determination our doctors and future doctors can and will reduce
the risks involved with surgery. Hippocrates stated 2,500 years
ago, “… a great doctor has the value and strength of many other
people together…” This is something that must be proven right.
The only way to do this is to continue to reduce the risks
involved in this life-saving occupation.
Volume 7: Number 1. 2014 | Page 75
RCSIsmjperspective
References
1. Sokol DK, Wilson J. What is a surgical complication? World J Surg.
2008;32(6):942-4.
2. Keogh B, Durkin M. Safer Surgery – the continuing challenge.
London: NHS, 2012.
3. Fry DE. The economic costs of surgical site infection. Surg infect.
2002;3(Suppl. 1):S37-43.
4. Bruce J, Russell EM, Mollison J, Krukowski ZH. The measurement and
monitoring of surgical adverse events. Health Technol Assess.
2001;5(22):1-194.
5. National Quality Forum (NQF). Serious Reportable Events In
Healthcare – 2011 Update: A Consensus Report. NQF; Washington,
DC, 2011.
6. Haynes AB, Weiser TG et al. A surgical safety checklist to reduce
morbidity and mortality in a global population. N Engl J Med.
2009;360(5):491-9.
7. Walker IA, Reshamwalla S, Wilson IH. Surgical safety checklists; do
they improve outcomes? Br J Anaesth. 2012;109(1):47-54.
8. Gawande A. The Checklist Manifesto. Available at:
http://gawande.com/the-checklist-manifesto.
9. World Health Organisation. Atul Gawande. Available at:
http://www.who.int/patientsafety/about/atul_gawande/en/index.html.
10. Haynes A, Weiser T, Berry WR et al. Changes in safety attitude and
relationships to decreased postoperative morbidity and mortality
following implementation of a checklist-based surgical safety
intervention. BMJ Qual Saf. 2011;20(1):102-7.
11. Safer Practice in Surgery – a professional responsibility. [Web
Seminar] Professor Norman Williams, President, Royal College of
Surgeons, Dr J-P van Besouw, President, Royal College of
18. BBC. NHS staff’s poor English is �potential danger to patients’. BBC
News Health. [Internet] 2011 September 15. Available at:
http://www.bbc.co.uk/news/health-14921565.
19. Way LW. General surgery in evolution: technology and competence.
Am J Surg. 1996;171(1):2-9.
20. Rosen M, Ponsky J. Minimally invasive surgery. Endoscopy.
2001;33(04):358-66.
21. Cohn LH, Adams DH, Couper GS et al. Minimally invasive cardiac
valve surgery improves patient satisfaction while reducing costs of
cardiac valve replacement and repair. Ann Surg. 1997;226(4):421-6.
22. Wolf JS Jr, Tchetgen MB, Merion RM. Hand-assisted laparoscopic live
donor nephrectomy. Urology. 1998;52(5):885-7.
23. Hu JC, Gu X et al. Comparative effectiveness of minimally invasive
vs open radical prostatectomy. JAMA. 2009;302(14):1557-64.
24. Hakim N, Aboutaleb E, Syed A, Rajagopal P, Herbert P, Canelo R et
al. A fast and safe living donor “finger-assisted” nephrectomy
technique: results of 359 cases. Transplant Proc. 2010;42(1):165-70.
25. University of Chicago. Benefits of miminally invasive procedures.
[Internet] 2012. Available at:
http://www.uchospitals.edu/specialties/minisurgery/benefits/index.h
tml.
26. Hanly EJ, Talamini MA. Robotic abdominal surgery. Am J Surg.
2004;188(Suppl. 4a):19S-26S.
27. Lanfranco AR, Castellanos AE, Desai JP, Meyers WC. Robotic surgery:
a current perspective. Ann Surg. 2004;239(1):14-21.
28. HemoStase™ – Cryolife HemoStase™ Absorbable Haemostatic
Particles. Available at: http://www.obex.co.nz/Product/Index/533.
29. Rajagopal P, Hakim N. The use of a powdered polysaccharide
Anaesthetists, Dr William Harrop-Griffiths, President, The Association
hemostat (HemoStase) in live donor nephrectomies controls
of Anaesthetist of Great Britain & Ireland. Safer Surgery Week. Royal
bleeding and reduces postoperative complications. Transplant Proc.
College of Ophthalmologists. 2012 Sept 27.
12. Leonard M, Graham S, Bonacum D. The human factor: the critical
2011;43(2):424-6.
30. The Harmonic Scalpel. EBME Biomedical Engineering. [Internet]
importance of effective teamwork and communication in providing
2011 January. Available at:
safe care. Qual Saf Health Care. 2004;13(Suppl. 1):i85-90.
http://www.ebme.co.uk/articles/clinical-engineering/91-the-harmoni
13. Healey AN, Undre S, Vincent CA. Developing observational measures
of performance in surgical teams. Qual Saf Health Care.
2004;13(Suppl. 1):i33-40.
14. Williams RG, Silverman R, Schwind C et al. Surgeon information
transfer and communication: factors affecting quality and efficiency
of inpatient care. Ann Surg. 2007;245(2):159-69.
15. Awad SS, Fagan SP, Bellows C, Albo D et al. Bridging the
communication gap in the operating room with medical team
training. Am J Surg. 2005;190(5):770-4.
16. Yule S, Flin R, Paterson-Brown S, Maran N. Non-technical skills for
surgeons in the operating room: a review of the literature. Surgery.
2006;139(2):140-9.
17. Daily Mail. The doctor and nurses putting lives at risk because they
can’t speak English. [Internet] 2012 March 30. Available at:
http://www.dailymail.co.uk/news/article-2123044/The-doctor-nursesputting-lives-risk-speak-English.html.
Page 76 | Volume 7: Number 1. 2014
c-scalpel.
31. Armstrong DN, Ambroze WL, Schertzer ME, Orangio GR. Harmonic
ScalpelВ® vs. electrocautery hemorrhoidectomy: a prospective
evaluation. Dis Colon Rectum. 2001;44(4):558-64.
32. Cook-Swartz Doppler Flow Monitoring. Available at:
http://www.cookmedical.com/sur/familyListingAction.do?family=Co
ok-Swartz+Doppler+Flow+Monitoring.
33. Guillemaud JP, Seikaly H, Cote D, Allen H, Harris JR. The implantable
Cook-Swartz Doppler probe for postoperative monitoring in head
and neck free flap reconstruction. Arch Otolaryngol Head Neck
Surg. 2008;134(7):729-34.
34. Patientsfirst.org.uk. 2014. Patients First. [online] Available at:
http://www.patientsfirst.org.uk.
35. The “Never Events” List 2011/12. National Health Service – United
Kingdom Department of Health.
RCSIsmjperspective
The white coat:
DOES IT HAVE A FUTURE IN IRELAND?
EOIN KELLEHER explores the future of the white coat in Irish hospitals,
and what a doctor should wear.
Introduction
The white coat and stethoscope are the most recognisable
symbols of our profession. The white coat rose to popularity
among surgeons because of its association with groundbreaking
important in all cultures, medicine being no different. �White
coat ceremonies’ have become a rite of passage in modern
medical schools. The first was held in Columbia University, New
scientific achievements that characterised the 19th century.1 It
came to be associated with science, cleanliness and
professionalism. It maintained its popularity among the
profession through tradition; symbols and traditions are
York2,3 in 1993, and spread to Ireland, with the Royal College of
Surgeons in Ireland (RCSI) holding the first such ceremony
(Figure 1). They are now a part of the culture in many medical
schools on the island and elsewhere.
Volume 7: Number 1. 2014 | Page 77
RCSIsmjperspective
The white coat falls out of favour
FIGURE 1: RCSI
students at the 2011
white coat ceremony.
A consequence of the 2007 UK law – and
changing worldwide fashions – has been
a lively debate in the profession about
what a doctor should wear. Many
patients complain that they cannot
identify who in the hospital is a
doctor, and among doctors they
cannot tell what their rank is.
In recent years, however, the white coat has fallen out of fashion
in hospitals. It began with paediatrics and psychiatry, which
eliminated the use of the white coat because it was felt it
presented a barrier to the doctor-patient relationship. Public
health doctors and pathologists soon followed. Physicians
themselves gradually dropped the garment, and now even many
surgeons do not wear them. In 2007, the UK Government
instituted a �bare below the elbows’ (BBE) policy across the
National Health Service (NHS), which effectively sounded the
death knell for the white coat, which joined neckties and cuffs in
the realm of obsolescence in the UK.4
Even in most Irish hospitals you would be hard pressed to find
even one qualified doctor who regularly wears a white coat. In
fact, medical students are the one remaining group who wear
the white coat regularly.5 However, this is also going out of
fashion, with many hospitals in Ireland banning the white coat
from their wards, notably the children’s hospitals.
What should a doctor wear?
A consequence of the 2007 UK law – and changing worldwide
fashions – has been a lively debate in the profession about what
a doctor should wear.
Many patients complain that they cannot identify who in the
hospital is a doctor, and among doctors they cannot tell what
their rank is.6 With many medical students no longer wearing
white coats, this adds to the confusion.
In addition, the casual clothing that has replaced coats,
particularly in UK hospitals, has given rise to complaints about a
lack of professionalism.6,7
A symbol of elitism
However, many are happy to see the white coat go. To some, it
symbolises the elitism and privilege associated with stereotypes of
doctors.3,8 They fear doctors �become the coat’ and fail to
empathise with their patient as a fellow human being. The white
coat, it is argued, represents a hierarchy of care that places the
consultant physician at the pinnacle and everyone else beneath
them. It is partially for these reasons that paediatricians and
psychiatrists long ago lost the coat. The length and weight of a
white coat used to be a marker of seniority. An interesting study
from Edinburgh demonstrated an inverse correlation between the
mean weights of white coats and physicians’ seniority. A junior
house officer had 1.7kg weighing him down on average,
compared to 1kg for a consultant.9
Bare below the elbows
Along less philosophical lines, many argue that the white coat
should be abandoned because it is unhygienic. Studies have
shown white coats to harbour pathogens, and that long sleeves
FIGURE 2: Example of the medical student white coat in Guy’s and St
Thomas’ NHS Foundation Trust. The coat is made from a light material,
has short sleeves, zip, and the logo of the trust on it.
Page 78 | Volume 7: Number 1. 2014
may transmit these to patients.10 In addition, since most
hospitals in the UK and Ireland have stopped providing laundry
services for workers’ uniforms, white coats are not being
washed as frequently.
RCSIsmjperspective
FIGURE 3: Doctors’
uniform in West
Middlesex NHS Trust
hospitals: navy blue
with �Doctor’ printed on
the chest pocket.
A study of London medical students (prior to the BBE policy)
found that the vast majority only washed their coats
occasionally, and that the sleeves and pockets were
contaminated with organisms such as Staphylococcus aureus.5
White coats, in addition to neckties,11 lanyards,12 watches13
and long sleeves,14 it is argued, should be discarded.
However, the evidence to support changing clothing policy for
hygiene reasons is scanty.
A review on the topic, commissioned by the Department of
Health in the UK, stated that: “Although it has been
hypothesised that contaminated uniforms are a potential vehicle
for the transmission of pathogens, no studies demonstrated the
transfer of micro-organisms from uniforms to patients in the
clinical situation”.15
Indeed, it has not been reliably demonstrated that the white
coat, or indeed any item of clothing, contributes to
hospital-acquired infections.14 The impact of the BBE policy in
the UK has also been mixed. One argument in its favour is that,
even if shirtsleeves themselves do not cause transmission of
hospital-acquired infections, having bare arms and wrists
promotes better hand hygiene. However, this has not been
borne out by evidence, with one study showing no difference in
hand hygiene between doctors who followed the BBE policy
not.16
and those who did
In the UK, many argue that the BBE policy was introduced as a
public relations exercise to demonstrate that action was being
taken against �hospital superbugs’, which were being portrayed
in the media. It is easy and cheap to issue clothing policies,
while it is more difficult to tackle more fundamental causes of
hospital-acquired infections, such as patient overcrowding and
antibiotic misuse.17
On balance, it seems prudent to regard long-sleeved white
coats as reservoirs of pathogens, particularly when they reside
solely on medical students who are in frequent close contact
with patients, have yet to develop a strong sense of hand
hygiene, and who are not given to regularly washing their
coats.5
Does it matter what a doctor wears?
Doctors are one of the few groups in healthcare who do not
wear uniforms. With more and more hospitals discarding the
white coat, one can ask, does it really matter what a doctor
wears? The answer, it seems, is yes (Figure 2).
There are many studies that demonstrate that patients prefer
their doctors to look professional.6 Many show that patients
prefer doctors to wear white coats, while many are equivocal.
A study by Au et al.18 asked family members of ICU patients to
complete a questionnaire rating the importance of different
aspects of doctors’ appearance.
They then asked them to select the best physician from a panel
of four photographs, which depicted doctors in clothing that
ranged from jeans to a business suit, a white coat, and scrubs.
Unsurprisingly, jeans fared worst, with only 10% favouring
them. Surprisingly, the business suit (commonly worn by many
doctors in Ireland), fared next worst, being preferred by only
12%. The white coat was the overall favourite, being favoured
by over half of family members, with scrubs being favoured by
one-quarter. What is interesting is that the white coat and
scrubs are both the most specific garments associated with
doctors, and both were most associated with being �caring’ and
�competent’. Other studies have shown similar results, with
garments specific to doctors, such as the white coat and scrubs,
being preferred.7,19,20
Why might this be the case? First, these items of clothing
clearly identify the person as a doctor, which carries with it
associations of competency, caring and professionalism. These
create a vital good first impression with a patient. First
impressions are important in medicine because most clinical
encounters are very brief. With most consultations lasting a
matter of minutes, it is vital to establish a good rapport.
Additionally, it can be difficult for a patient to identify who is a
doctor, and among doctors to identify who is a student, who is
the intern and who is their consultant, particularly if everyone is
wearing his or her own clothes.
ID badges are often cited as an answer to this, but the vast
majority of patients report that ID badges are not visible, or
that the writing is too small.7 Additionally, lanyards – much like
neckties – are a source of infection and so are not ideal for
advertising one’s rank.12
A uniform for doctors?
So far we have identified several themes. The white coat, which
was once the brand image of the medical profession, is
disappearing; it is now effectively extinct among doctors and is
in decline among medical students.
Patients want their doctors to look professional, and prefer
items of clothing specific to healthcare, rather than business
suits. Indeed, new infection control measures mean that
neckties and long shirtsleeves are also not likely to be a feature
of Irish hospitals much longer, much like the UK. However,
these same infection control measures mean that the traditional
long-sleeved, billowing white coat is unlikely to stage a
comeback. So what are medics to wear?
Perhaps it is time to consider uniforms for doctors in Irish
hospitals. These would have a number of advantages. First, and
most importantly, it would mean that all grades, from student
to consultant, are easily identifiable to patients and other staff.
Second, a well-designed uniform would reinforce the image
that the profession wants to convey: trust, hygiene and
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RCSIsmjperspective
competence. Third, a uniform would provide pockets (a not
inconsiderable advantage, as anyone who has had to go
without the white coat is aware). What would such a uniform
look like? Two such possibilities exist in the NHS. Guy’s and St
Thomas’ Hospitals in London recently introduced a uniform for
all staff, fashioned on the white coat.21 The garment is shorter
than a traditional white coat, has short sleeves, large pockets
and a zip at the front. Medical students have “medical student”
emblazoned on the front, along with the NHS logo. Junior
doctors have “Doctor” in big, identifiable writing on the chest,
and consultants have their name and specialty embroidered.
The coats are laundered by the hospital for staff, much as
hospital scrubs are, to maintain hygiene. Another example is
West Middlesex NHS Trust, which introduced similar uniforms
based on scrubs rather than the white coat, again with the title
of the individual labelled clearly (Figure 3).
Conclusion
Many are sorry to see the white coat in its current form
disappear, particularly as it is an integral part of the �brand’ of
being a doctor. However, brands can change, and if the
disadvantages of the white coat – be they hygienic or elitist –
outweigh their benefits, we should change the brand. There is
no reason the white coat cannot be adapted, much as some
NHS trusts in the UK have done, to make them acceptable to
both patients and doctors alike.
However, it is also important to remember that there is more to
professionalism than a professional appearance. A professional
appearance contributes to a good first impression and helps
establish rapport, but professional behaviour is important to
continue that, and is ultimately more valued by patients and
their families.
References
1. Blumhagen DW. The doctor’s white coat. The image of the physician
in modern America. Ann Intern Med. 1979;91(1):111-6.
2. Branch WT Jr. Deconstructing the white coat. Ann Intern Med.
1998;129(9):740-42.
3. Wear D. On white coats and professional development: the formal
and the hidden curricula. Ann Intern Med. 1998;129(9):734-7.
4. Department of Health UK. Uniforms and workwear: an evidence base
for developing local policy. 2007:10.
5. Loh W, Ng VV, Holton J. Bacterial flora on the white coats of medical
students. J Hosp Infect. 2000;45(1):65-8.
6. Palazzo S, Hocken DB. Patients’ perspectives on how doctors dress. J
Hos Infect. 2010;74(1):30-4.
7. Gallagher J, Waldron Lynch F, Stack J, Barragry J. Dress and address:
patient preferences regarding doctor’s style of dress and patient
interaction. Ir Med J. 2008;101(7):211-3.
8. Huber SJ. The white coat ceremony: a contemporary medical ritual. J
Med Ethics. 2003;29(6):364-6.
9. Hone S, Mackle T, Keogh I, Colreavy M, Walsh M. Junior hospital
doctors: a weighty issue. Ir Med J. 2001;94(7):208,210.
10. Butler DL, Major Y, Bearman G, Edmond MB. Transmission of
nosocomial pathogens by white coats: an in-vitro model. J Hosp
Infect. 2010;75(2):137-38.
11. McGovern B, Doyle E, Fenelon LE, FitzGerald SF. The necktie as a
potential vector of infection: are doctors happy to do without? J
Hosp Infect. 2010;75(2):138-9.
12. Alexander R, Volpe NG, Catchpole C, Allen R, Cope S. Are lanyards a
risk for nosocomial transmission of potentially pathogenic bacteria? J
Hosp Infect. 2008;70(1):92-3.
13. Jeans AR, Moore J, Nicol C, Bates C, Read RC. Wristwatch use and
hospital-acquired infection. J Hosp Infect. 2010;74(1):16-21.
Page 80 | Volume 7: Number 1. 2014
14. Weber RL, Khan PD, Fader RC, Weber RA. Prospective study on the
effect of shirt sleeves and ties on the transmission of bacteria to
patients. J Hosp Infect. 2012;80(3):252-4.
15. Wilson JA, Loveday HP, Hoffman PN, Pratt RJ. Uniform: an evidence
review of the microbiological significance of uniforms and uniform
policy in the prevention and control of healthcare-associated
infections. Report to the Department of Health (England). Journal
Hosp Infect. 2007;66(4):301-7.
16. Willis-Owen CA, Subramanian P, Kumari P, Houlihan-Burne D. Effects
of �bare below the elbows’ policy on hand contamination of 92
hospital doctors in a district general hospital. J Hosp Infection.
2010;75(2):116-9.
17. Dancer SJ. Pants, policies and paranoia… J Hosp Infect.
2010;74(1):10-15.
18. Au S, Khandwala F, Stelfox HT. Physician attire in the intensive care
unit and patient family perceptions of physician professional
characteristics. JAMA Intern Med. 2013;173(6):465-7.
19. Gherardi G, Cameron J, West A, Crossley M. Are we dressed to
impress? A descriptive survey assessing patients’ preference of
doctors’ attire in the hospital setting. Clin Med. 2009;9(6):519-24.
20. Anvik T. Doctors in a white coat – what do patients think and what
do doctors do? Scand J Prim Health Care. 1990;8(2):91-4.
21. Trust GsaSTNF. Dress code and uniform protocol. v2.6. 2009:16.
RCSIsmjperspective
Miraculous, malevolent
or misunderstood:
KNOWLEDGE AND ATTITUDES REGARDING
ELECTROCONVULSIVE THERAPY
IOLANDA TIEDT makes the case for this often
controversial treatment method.
“I wondered what terrible thing it was that I had done.”
Sylvia Plath, The Bell Jar.1
Electroconvulsive therapy (ECT) is an emotive topic. The debate
about its use is one that no one comes to neutral. The above
quote by Sylvia Plath is a line from Esther Greenwood, the main
character in her novel The Bell Jar, as she is having ECT for the
first time. It exemplifies the negativity and fear characteristically
displayed in popular fiction when the protagonists are faced with
the prospect of this treatment. There is no doubt that the stigma
still surrounding mental health disorders and their treatment
weighs heavily on our society. One treatment that bears the
brunt of this stigma is ECT.
Safe and effective
ECT is a relatively safe, effective treatment for severe depression. It
uses a small amount of electricity to induce a generalised seizure
under general anaesthetic. The seizure is modified by the use of
muscle relaxants. The patient is usually given a course of about
eight to 12 treatments over a number of weeks. Patients may
experience side effects such as acute confusion, headaches and
memory loss. Some of the memory loss may be permanent. Stigma
is undoubtedly the single greatest obstacle to the appropriate use
of ECT.2
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Patients may experience side effects
such as acute confusion, headaches
and memory loss. Some of the memory
loss may be permanent. Stigma is
undoubtedly the single greatest
obstacle to the appropriate
use of ECT.2
While on my psychiatry rotation as a fourth-year medical student,
the first patient that I met was Mrs M. She was tearful, apathetic
and essentially bedbound due to her crippling depression. She
could neither sleep nor eat and was tortured by persistent,
inescapable thoughts of killing herself. Although she loved
reading, she could not focus enough to do so anymore. She had
been in hospital for two months. This was her second admission;
she had been hospitalised once before, ten years previously. This
time, all of the medications available had been tried – nothing
was working. Mrs M was due to start ECT the day after I met her.
She was worried but felt that this was her last hope.
Prejudices
Literature and film have often portrayed ECT as a cruel, primitive
procedure. Much of the fear surrounding the treatment seems to
stem from the misconception that this therapy is portrayed
realistically in films such as One Flew over the Cuckoo’s Nest.
This is one example of a film that has almost irreparably
tarnished ECT’s image. In it, we see a patient undergoing
unmodified ECT, i.e., without the use of a general anaesthetic or
a muscle relaxant, therefore producing a violent grand mal
seizure. This is neither a true representation of the way the
therapy is carried out now, nor of how it was carried out in 1975
when the film was released, yet it had a catastrophic effect on
the public image of ECT. When we think of ECT in film, it is
difficult to come up with positive examples. Instead, our heads
are filled with images of institutions like the one in the film
Shutter Island. This makes it easy to understand the negativity
surrounding this treatment.
The negativity and fear associated with ECT seems out of
proportion when compared to public opinion of other medical
procedures. For example, in 2011 Senator Niall Г“ BrolchГЎin said
he personally believed ECT was “absolutely barbaric”.3 This word,
by definition, means savagely cruel, primitive and
unsophisticated. These are not words that we are used to
associating with modern medicine. The idea of interfering with
the brain, the most sacred of organs, in what people perceive as
a non-lifethreatening situation, is taboo.
Any form of brain surgery carries this same risk, yet it is ECT that
is described as barbaric. Yes, induction of a seizure as a form of
treatment seems paradoxical. It could be seen as callous or
uncivilised. But is it any more crude than drilling a hole in
someone’s skull in order to relieve the pressure caused by a
Page 82 | Volume 7: Number 1. 2014
subdural haematoma? Is it more invasive than performing an
appendicectomy to treat appendicitis? The scientific answer is no.
ECT does carry risks, but the main risk is that general anaesthetic
is used. Why, then, is ECT seen in such a negative light when
compared to other life-saving procedures?
The key words here are �life saving’. Perhaps depression is not
viewed as life threatening, but this is not the case.4 Perhaps the
potential for some memory loss5 post procedure is what scares
people the most. We need to weigh up a small degree of
memory loss against being trapped in your own mind, unable to
care for yourself, with no quality of life and a distinct risk of
death. When we do this, I believe that it quickly becomes clear
what most people suffering from severe depression would
choose.
ECT tends to be viewed more negatively by people who have
had little contact with it; knowledge of the procedure is
associated with lower levels of fear.6 Most patients experience
anxiety about their first treatment.
Despite this, a 2005 study by Dowman et al. found that 98% of
the patients treated with ECT said that they would avail of ECT if
they became unwell again. After having completed the
treatment, 62% of patients surveyed found ECT to be less
frightening than visiting the dentist. It has been shown that a
reduction in fear of ECT was only achieved by a doctor
explaining the procedure to the patient.7 For this reason, it is
very important that doctors have a thorough understanding and
unbiased view of the treatment.
Knowledge of ECT among health professionals
On the first day of my six-week psychiatry rotation, my class was
given a lecture on ECT. Up until this point, I wasn’t aware that
the therapy was still in use and was shocked by this discovery.
Upon conducting research, I found that I was not alone.
Healthcare workers’ opinions and knowledge of ECT have been
shown to vary hugely. A 2001 study of second-year medical
students in the US showed that 40% of those surveyed felt that
ECT was misused, and 31% actually thought that it was used as a
punishment.7 Another study found that 92% of final-year
Hungarian medical students surveyed rated their knowledge of
ECT as poor; 35% of this group believed that ECT was used to
control violent patients.6 Closer to home, a 2006 study showed
that 39% of Irish medical students surveyed thought that ECT
could cause brain damage. In the same study, 25% of doctors
RCSIsmjperspective
Most patients experience anxiety about
their first treatment. Despite this, a 2005
study by Dowman et al. found that 98%
of the patients treated with ECT said
that they would avail of ECT if they
became unwell again.
linked ECT and brain damage, and 10% overestimated
ECT-related mortality. This study showed even worse figures for
nurses. One-third of those surveyed overestimated ECT-related
mortality and did not know if it caused permanent brain damage.
Only one psychiatric nurse (2.9%) surveyed expressed positive
attitudes towards its use.8 It is important for the healthcare
professionals working with these patients to be able to give
factual information and reassurance to someone considering the
procedure. Is it really surprising that the public has fears about
ECT when the professionals responsible for it are so divided in
their knowledge and opinions?
Like any other medical procedure that uses general anaesthetic,
ECT is a treatment that carries risks. However, it has a higher
efficacy than treatment with antidepressant medication.5 I have
come to believe that this treatment can hold the life-changing
potential to free a patient from their torment and place them
back among the living.
The barbaric procedures displayed by mass media have had a
significant negative impact on public opinion surrounding ECT.
This, however, does not represent the opinions of those who
have actually had the treatment, or the opinions of their friends
and relatives.9 Perhaps if public focus was shifted from the
negative aspects of ECT in the past to the positive impact that it
can potentially have, the stigma surrounding it would be
successfully shaken.
The last time I saw Mrs M, she was tearing herself away from her
book in order to go shopping for an outfit for her
granddaughter’s christening. If I had not seen her six weeks
previously, I would not have believed that this was the same
woman. Gone were the thoughts of killing herself. The stifling
apathy had lifted. She was playing an active part in the world
again, rather than just watching life go on around her. I do not
believe that any amount of lectures could have helped me to
completely accept ECT. Seeing the change that it brought about
in this patient did just that. Perhaps, in an effort to dispel the
negativity, those of us who have had exposure to ECT should be
more vocal about how positive an experience it can be for
patients.
Sylvia Plath best describes the effect of the therapy that we
should be trying to highlight, in the quest to throw open the
blackout curtain of fear that has been closed over ECT for so
long.
“All the heat and fear had purged itself. I felt surprisingly at
peace. The bell jar hung, suspended a few feet above my head. I
was open to circulating air.” – Sylvia Plath, The Bell Jar.1
References
1.
Plath S. The Bell Jar. London; Faber and Faber Limited, 1963.
2.
Kellner, C. UpToDate: Overview of Electroconvulsive Therapy for Adults.
5.
2013. [cited 2014 January 12). Available at:
http://www.uptodate.com.proxy.library.rcsi.ie/contents/overview-of-elect
2003;326:1343-4.
6.
roconvulsive-therapy-ect-for-adults?source=search_result&search=electroc
Connors A. Fresh controversy over ECT proposal. Irish Medical Times.
public. J ECT. 2008;24(4):244-53.
7.
2011 March 30. Available at:
http://www.imt.ie/features-opinion/2011/03/fresh-controversy-over-ect-p
8.
Byrne PF, Cassidy B, Higgins P. Knowledge and attitudes toward
electroconvulsive therapy among healthcare professionals and students. J
Coryell W. Unipolar depression in adults: course of illness. (Accessed
2014 January 15). Available from:
Dowman JF, Patel A, Rajput K. Electroconvulsive therapy attitudes and
misconceptions. J ECT. 2005;21(2):84-7.
roposal.html.
4.
Mcfarquhar TF, Thompson J. Knowledge and attitudes regarding
electroconvulsive therapy among medical students and the general
onvulsive+therapy&selectedTitle=1~94#H26.
3.
Carney S, Geddes J. Electroconvulsive therapy: recent recommendations
are likely to improve standards and uniformity of use. BMJ.
ECT. 2006;22(2):133-8.
9.
Grover SK, Chakrabarti S, Khehra N, Rajagopal R. Does the experience of
http://www.uptodate.com.uptodate/contents/unipolar-depression-in-adu
electroconvulsive therapy improve awareness and perceptions of
lts-course-of-illness?source=preview&anchor=H1385544&selectedTitle=2
treatment among relatives of patients? J ECT. 2011;27(1):67-72.
~150#H1385544.
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RCSI medical
student ZACHARY
WIKERD spent two
months in Sewa
Bhawan Hospital in
the Mahasamund
district of
Chhattisgarh in
India.
Medicine
AND MONSOONS
The gap between what I expected and the reality of what I had
signed up for began to dawn on me soon after I arrived at
Kolkata International Airport, mere days after completing my
first-year medical exams. Following an exhausting 14-hour train
trip and a two-hour drive over monsoon-soaked roads, I arrived
at Sewa Bhawan Hospital (SBH), a small rural hospital on the
edge of a jungle. For the next two months, under the guidance
of Dr Tushar and his wife Dr Kanchan Naik, my appointed
mentors, I was thrust into the medical realities of this rural
community. The situation was more dire than I could have
imagined. I observed with awe as very competent and dedicated
medical staff dealt with rural medical demands that would defy
possibility in the �Western’ hospitals I had been acquainted with
to this point.
For starters, I found myself directly involved in assisting in
medical procedures that were often beyond my medical
knowledge, let alone my comfort level. I had not anticipated
routine power outages (even during surgery), severe injuries,
poisonings, and sometimes, and most challenging, the
unexpected demands of cultural customs that often added to the
stress, especially for the uninitiated like myself. However, I
Page 84 | Volume 7: Number 1. 2014
couldn’t help but be struck by the professionalism, competence,
compassion, and patience of the medical staff. I sensed early on
that the level of learning I would attain over the following
months would exceed my highest expectation.
General medicine
SBH was opened in 1928 as a dispensary to serve the people of
the Mahasamund district of Chhattisgarh. Today it is a 50-bed
medical facility, and one of 21 hospitals operating under the
administrative umbrella known as the Emmanuel Hospital
Association (EHA), an organisation committed to providing
medical service first and foremost to the poor of rural Northern
India. The hospital provides essential healthcare for an estimated
population base of nearly 200,000 people across 300 villages. A
husband and wife team – one a general surgeon, the other an
obstetrician/gynaecologist – comprises the hospital’s only
consultants. SBH has the only three operating theatres in the
whole catchment area.
SBH is a Christian hospital. Every day begins with morning
devotions, with rounds commencing promptly thereafter. The
morning rounds provided me with an opportunity to see critically
RCSIsmjelective report
ill patients and develop postoperative management skills. Once
rounds are completed, there is only a quick break for breakfast
before the outpatient department (OPD) opens and the usual
rush of activity begins.
A common case seen at the hospital is sickle cell anaemia crisis,
which is most prevalent during the rainy season, i.e. June to
September. Simple measures like childhood vaccinations,
adequate oral intake of fluids with electrolytes during
vaso-occlusive crises, and avoidance of exposure to extreme
temperatures can mitigate the frequency and severity of these
incidents. Anaemia, due mostly to malnutrition, is common in
pregnant mothers. Malaria from increased mosquito infestation
during the rainy season, typhoid fever due to poor water
sanitation, scorpion bites, and diabetes were also common
presentations.
Traditionally, the focus in developing countries has been on
primary prevention of infectious diseases. However, India faces a
dual burden of infectious diseases and increasing prevalence of
non-communicable diseases such as asthma, chronic obstructive
pulmonary disease (COPD), hypertension, diabetes, and
psychiatric problems, to name a few. As such, there is an urgent
need to formulate appropriate policy responses to these diseases
(their prevention, as well as treatment), as they are very
expensive to treat and well beyond the means of the poor. A
range of effective, population-wide approaches for chronic
disease prevention and control exist; however, governments, the
private sector and the community must work together and scale
up their efforts to reach all members of society.
Obstetrics and gynaecology
I had my first exposure to obstetrics and gynaecology under the
guidance of Dr Kanchan Naik. Once I became accustomed to
terms associated with an obstetric and gynaecological history, I
was able to help with multiple deliveries, suture episiotomies, and
assist in caesarean sections and tubal ligations. I encountered
presentations that would rarely be seen in a Western setting.
These included a massive leiomyoma myometrium tumour, foetal
death in utero, retained placentas following village deliveries, and
advanced cases of cervical cancers and pelvic inflammatory
disease. My time in the OB/GYN outpatient department also
brought to my attention the very different gender dynamic in
India, which from a Western perspective seems incredibly archaic.
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RCSIsmjelective report
In Indian culture, immense pressure is placed on new brides to
give birth to a son, as males are more valued than females. It was
difficult to become accustomed to this gender inequality. In
addition, the husbands and fathers accompanying women to the
hospital regarded them as �chattels’, and were very involved in
directing the medical care they received.
Ophthalmology
India has the dubious distinction of having the highest number of
blind people in the world - figures vary from 12-15 million.1 In
the majority of these cases, blindness is a result of cataracts,
which can be corrected through surgery. Because EHA facilities
are, for the most part, located in rural villages, they are able to
reach out to the poor and marginalised members of the Indian
population; however, there is still a lack of qualified
ophthalmologists to service the rural areas. Several hospitals are
without a resident eye surgeon to provide continuous year-round
service. In spite of this difficulty, 12 EHA hospitals provide some
form of eye care, if not year round, then intermittently in the
form of hospital-based camps by inviting EHA teams or eye
surgeons from other organisations. I was fortunate enough to
observe a visiting ophthalmologist perform cataract operations
during one of these eye camp services. Unfortunately, many
people do not reach the EHA eye care clinics; some people are
still unaware of the availability of services, or are inhibited by fear
of surgery, the cost of surgery or other social handicaps.
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RCSIsmjelective report
Mental health
One day, while I was out playing soccer during a recreational
opportunity, one of the hospital staff members called the junior
doctor and me to the intensive care unit.
A quick history and examination revealed a family of five all in
cholinergic crisis. Organophosphate poisoning is common in
developing countries, and especially so in India.2
Often poisoning occurs by voluntary ingestion, according to a
study conducted by the Indira Gandhi Institute of Development
Research, Mumbai.
Major reasons for farmer suicides via organophosphate
ingestion are linked with: the inability to pay debt; crop failure
and low returns; illness of family members; failure to arrange
the marriage of daughters; and, a lack of alternative sources of
income.3 Unfortunately, this was not an isolated case. During
my two-month stay at the hospital, I witnessed over 10 patients
suffering from the same presentation.
The EHA is in the process of performing a research study with
the intent of developing a greater understanding of the
underlying causes and possible remedies of this tragic
phenomenon, in order to offer support and counselling.1
Due to a lack of human resources and inadequate infrastructure,
mental health services are far less available in rural than urban
areas; where they are available, financial constraints and social
issues still act as barriers to access.4
Concluding thoughts
Hospital administration is a major challenge in the present day
environment of private and corporate hospitals, where demands
from the community are ever increasing. Most Indians seek
healthcare in private facilities, as public facilities often suffer from
a variety of problems. These include: worker absence and dual
public-private practice; low demand for their use; and, shortages
of supplies and staff.
In contrast, private healthcare varies greatly in quality across
centres, as it is unregulated and financed largely through
out-of-pocket payments. Smaller rural hospitals face the
challenges of staff retention and financial sustainability, as they
Volume 7: Number 1. 2014 | Page 87
RCSIsmjelective report
continue to fulfil their mission of serving the poor. Despite this,
the number of patients seen in EHA hospitals has been
increasing. The implementation of national health insurance
coverage for below-poverty-line families known as Rashtriya
Swasthya Bima Yojana (RSBY) has enabled EHA hospitals to
provide greater care to those in need. From my limited
experience, my impression is that, while India is moving forward
as a developing nation, it has yet to fully educate its rural
population in matters pertaining to personal healthcare. The
dilemmas they face have as much to do with complex social
barriers and long-held beliefs and customs that interfere with
progress, as with limited medical resources for a rapidly
expanding population. I remain optimistic, given the
resourcefulness and commitment of the medical personnel that I
worked with during my placement, that India will one day be
able to address these challenges more successfully.
References
1. EHA India. Annual Report 2012-2013. The Emmanuel Hospital
Association. 2013.
2. Pandit V, Seshadri S, Rao SN, Samarasinghe C, Kumar A, Valsala R. A case
of organophosphate poisoning presenting with seizure and unavailable
history of parenteral suicide attempt. J Emerg Trauma Shock.
2011;4(1):132-4.
Page 88 | Volume 7: Number 1. 2014
3. Dongre AR, Deshmukh PR. Farmers’ suicides in the Vidarbha region of
Maharashtra, India: a qualitative exploration of their causes. J Inj Violence
Res. 2012;4(1):2-6.
4. Kumar A. Mental health services in rural India: challenges and prospects.
Health. 2011;3(12):757-61.
RCSIsmjbook review
The Rise and Fall of Modern Medicine
by James Le Fanu
Reviewed by Elizabeth Ahern-Flynn, RCSI medical student
Paperback: 608 pages
Publisher: Abacus
Published 2011
ISBN: 978-0349123752
Most students will be familiar with the story of the discovery of
penicillin: a hurried microbiologist by the name of Alexander
Fleming left a petri dish unwashed in the lab as he left for his
holidays. To his surprise, on his return he found that a fungus had
grown, which had killed nearby colonies of the Staphylococcus
bacteria. What followed was the extraction of penicillin from the
fungus, which revolutionised the treatment of infectious diseases
and dramatically reduced mortality from infection. What many
people may not be familiar with is that, had this accident happened
in any other lab in Britain, it is likely that penicillin never would have
been discovered. Penicillum notatum – the fungus that colonised the
petri dish – had wafted up to Fleming’s laboratory from the
laboratory below during a particularly cool period in London, which
provided the perfect growth environment for the fungus to kill the
bacteria. This perfect storm of unlikely events resulted in millions of
lives saved from infectious diseases over the following years.
This anecdote captures the message of The Rise and Fall of Modern
Medicine: that the major medical discoveries of the 20th century
have resulted from a delicate balance of ingenious logical thinking
and serendipity.
The rise
James Le Fanu made his name as a medical historian with his
columns in the Daily and Sunday Telegraph, The Times, The Spectator,
and GQ magazine. In this, his third book, he charts the course of
modern medicine through his �12 definitive moments’:
developments in fields such as surgery, epidemiology, oncology and
psychiatry that transformed these specialties into the modern
practice we know today. As he takes us through the last century, we
meet the people who translated casual observation about nature
into medical theories; those who strove to make advances in one
area and stumbled into discoveries in another; and those who were
in the right place at the right time.
The fall
The confidence crafted in the first half of the book is challenged in
the second as Le Fanu follows the �fall’ of modern medicine, citing
the decline of new drug discoveries and the new ethical challenges
posed by the 20th century’s rapid medical developments as factors
leading to the end of medicine’s golden age. He skillfully identifies
the hurdles that contemporary medicine will have to overcome if it
is to prevent the momentum built by the previous century from
grinding to a halt.
More history than science, this book is essential reading for anyone
who has ever wondered how medicine functioned before many of
our modern therapies, and the elegant solutions to some of the
most dangerous diseases, were developed. The Rise and Fall of
Modern Medicine grounds many of the biological and clinical
sciences we learn in medical school in a historical and social context,
and puts names and backgrounds to established therapies and
interventions we may take for granted. It is a well-written, accessible
book, which can be as easily read from cover to cover in one
session, as it can be dipped into over time. Le Fanu’s impression of
the future of medicine provides ample food for thought for both
junior medical students beginning their studies of disease, and
senior students about to enter clinical practice.
Volume 7: Number 1. 2014 | Page 89
RCSIsmjabstract
Volume of caudate
nucleus in major
depressive disorder
Sarah Pradhan
RCSI medical student
Background
Major depressive disorder (MDD) is a disabling illness affecting
15-20% of people worldwide.1 It is characterised by low
self-esteem, high self-criticism, symptoms of melancholia and
suicide attempts.2 Studies have shown the caudate nucleus to be
important in emotion and reward, as emotional networks are
localised to the head of the caudate.3 In depressed adolescents,
smaller caudate nuclei volumes have been noted.4 Therefore, a
smaller caudate nucleus may be present in adult patients
suffering from MDD, as proposed by other studies.5
Methods
This study included 19 healthy controls (eight males and 11
females, aged 20-52) and 51 patients with MDD (18 males and
33 females, aged 19-58), who underwent magnetic resonance
imaging (MRI). Volume of the caudate nuclei was determined by
performing manual tracing on MRI images using AnalyzeDirect
10.0 operated by a trained and reliable rater (SP, r=0.93-0.99).
Results
No significant differences were found between healthy controls
and patients with MDD in the right (t=0.058, df=65, p=0.954),
left (t=0.014, df=65, p=0.989) and total caudate volumes
(t=0.024, df=65, p=0.981). No significant difference in the
asymmetry of the caudate was observed in patients with MDD
versus healthy controls (t=0.187, df=65, p=0.852). Furthermore,
in the patients with MDD, right caudate volume correlated with
the change in depression scores with treatment (r=0.34,
p=0.036). Interestingly, when the MDD group was divided into
treatment responders and non-responders, a trend for larger
right caudate volumes in the responder group was observed,
although this did not reach statistical significance (t=1.77, df=37,
p=0.086).
Conclusion
This data suggests that right caudate volume may be predictive
of treatment response. Studies have shown the right caudate
nucleus to have greater availability of dopamine than the left;6
thus, the right caudate could be more sensitive to treatment.
However, this requires further investigation. Although significant
volumetric differences between patients with MDD and controls
were not found, reasons for this may include small sample size,
differing methods of caudate measurement or medication history.
References
1. Rosenberg DR, Keshavan MS, Dick EL, Bagwell WW, MacMaster FP, Birmaher B.
Corpus callosal morphology in treatment-naive pediatric obsessive compulsive
disorder. Prog Neuropsychopharmacol Biol Psychiatry. 1997;21(8):1269-83.
2. Birmaher B, Ryan ND, Williamson DE, Brent DA, Kaufman J. Childhood
and adolescent depression: a review of the past 10 years. Part II. J Am
Acad Child Adolesc Psychiatry. 1996;35(12):1575-83.
3. Robinson JL, Laird AR, Glahn DC, Blangero J, Sanghera MK, Pessoa L et al.
4. Krishnan KR, McDonald WM, Escalona PR, Doraiswamy PM, Na C,
Husain MM et al. Magnetic resonance imaging of the caudate nuclei
in depression. Arch Gen Psychiatry. 1992;49(7):553-7.
5. Shad MU, Muddasani S, Rao U. Gray matter differences between
healthy and depressed adolescents: a voxel-based morphometry
study. J Child Adolesc Psychopharmacol. 2012;22(3):190-7.
6. Kim MJ, Hamilton JP, Gotlib IH. Reduced caudate gray matter volume
The functional connectivity of the human caudate: an application of
in women with major depressive disorder. Psychiatry Res.
meta-analytic connectivity modeling with behavioral filtering. Neuroimage.
2008;164(2):114-22.
2012;60(1):117-29.
Page 90 | Volume 7: Number 1. 2014
RCSI DEVELOPING HEALTHCARE LEADERS WHO MAKE A DIFFERENCE WORLDWIDE
RCSI
[email protected]
[email protected]
www.rcsismj.com.
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Royal College of Surgeons in Ireland
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