Following the publication of the above evidence,
cooling for infants with NE has been recommended or adopted as a standard
of care in neonatal units in some countries(8-10). Yet the translation of
this research into practice has been associated with significant debate
and controversy(11-14), and the implementation of TH is associated with a
number of ethical issues(13). There are issues relating particularly to
the transition from experimental therapy to practice and the extrapolation
of research evidence to clinical care. These issues may be even more
apparent in developing countries like India. But there are also several
issues relating to treatment limitation decisions in encephalopathic
newborn infants, and the way in which these are potentially influenced by
new treatments. This paper outlines some of the ethical considerations
that may arise in relation to TH in an Indian setting.
Standard of Care
As the randomized controlled trials of TH were
published in the mid 2000s, and it became clear that cooling was
effective, a debate emerged about whether further trials were necessary,
or whether, indeed, it was even ethical to continue to randomise patients
to normothermia(11-15). The stakes were particularly high because of the
lack of other available treatments and the high rates of death and
disability in infants with moderate or severe NE.
This debate was fundamentally about the level of
certainty that is required of scientific evidence before it is sufficient
to ground a change in standard practice(14). Mistakes can be made by the
overenthusiastic or premature adoption of treatments that may be
ineffective or even harmful, for example the liberal use of oxygen for
premature infants, or steroids for chronic lung disease(16). On the other
hand, delay in adopting treatments that have been proven to be effective
and safe can lead to substantial preventable morbidity and
morta-lity(17,18) (one example includes the considerable delay after
evidence of benefit was demonstrated before antenatal steroids were used
routinely for mothers at risk of premature delivery).
The standard of care debate about TH appears to have
resolved, since normothermia-controlled trials have been stopped in
developed countries(9); albeit TH has not been universally adopted(19).
However, the issue of therapeutic cooling for transitional and developing
countries raises several issues and dilemmas.
The biggest issue is that it may not be acceptable or
safe to extrapolate evidence from trials performed in developed countries
to Third World and transitional countries(20-21). There are differences in
the epidemiology and outcome of NE in low-resource settings(22). For
example, infants may have had a longer time since brain injury because of
obstructed labor or out-of hospital delivery. There is a high incidence of
bacterial sepsis and pneumonia in encephalopathic infants in India(23).
Many of the more severely affected infants who require respiratory support
and who were enrolled in previous trials would not survive in a
transitional country setting(20-21). These differences, and others, could
alter the safety or effectiveness of TH. Given the possibility that the
new treatment would, in fact, cause harm, some have recommended that TH
should not be adopted in India except in controlled trials, citing
the ethical principle of non-maleficence(24).
Nevertheless, there may be a desire on the part of some
pediatricians in India to adopt cooling in the hope that it would be
effective(24). The greatest burden of NE falls in transitional and
developing countries, where it is responsible for a large number of deaths
and neuromotor disabilities(22,25). Doctors may be understandably
reluctant to with-hold a treatment simply on the basis that it has not
been proven effective in low resource settings. After all, performing
randomised controlled trials is expensive, and many medical treatments are
never tested separately in developing countries. With-holding all medical
treatments that hadn’t been shown specifically to be effective in low
resource settings would potentially exacerbate existing health care
inequalities between developed and developing countries.
The issue becomes more complicated since in
transitional economies like India there are sub-stantial differences
across the country in the standards of neonatal units, in the populations
that they service and the resources available for care. In some tertiary
care private centres in urban areas, the quality of NICU care in India may
be at par with some neonatal units in the West where TH trials were
conducted. And clinicians in these centres may feel justified in treating
selected or suitable infants with TH, (there may also be perceived
commercial advantages in offering this new treatment). Within the public
health care system, particularly in level 2 neonatal centres, the concerns
about extrapolating evidence from previous trials have greater relevance.
However, this inconsistency in management proto-cols between various
centres may, in itself, give rise to concerns, since some may worry that
poorer patients are being given sub-standard care.
As in the debate about cooling trials in developed
countries, the key question relates to balancing risks, benefits and
uncertainty. One approach to uncertainty, and one way of analysing the
debate is to draw on Bayesian theory(14). Briefly, our response to an
intervention depends on the ‘prior probability’. Where there is a high
prior probability that a given treatment is effective, we are more likely
to respond positively to the trial evidence that appears to support it.
Conversely, where the prior probability is low, a single positive trial
result may not be enough (and should not be enough) to convince us to
change an established practice. In developed countries the evidence from
multiple clinical trials builds on existing (and strongly supportive)
pre-clinical evidence(26). It is appropriate that hypothermia is used
routinely for infants who would have met the criteria of previous trials.
On the other hand, in developing countries there is considerable evidence
that "non-therapeutic" hypothermia is associated with an increased risk of
mortality in newborns(23, 27,28). Furthermore, the significant differences
in the epidemiology of NE in these settings raise the distinct possibility
that the safety and efficacy of TH in Indian neonatal units would be
different from that evident in the trials conducted in developed
There are two approaches that are of potential use in
resolving debates about treatments that may or may not be effective. The
first draws on the importance of patient autonomy - it involves informing
patients (or parents in this case) about the uncertainty relating to new
treatments, and the arguments for and against its use(29). This approach
is particularly challenging for populations with little formal education
and no prior exposure to concepts of research, statistical testing, or
medical uncertainty. Even in developed countries parents involved in a
controlled trial may have several misconceptions about randomisation and
the research process despite informed consent having been obtained(30).
The second approach would be to draw on the disagreement about treatment
and the concept of clinical equipoise(32,32). In this setting, the best
way to ensure that doubts are put to rest and Indian infants with NE are
treated appropriately (either with or without cooling) would be to perform
an appropriately powered, controlled trial.
Ethical Issues in Cooling Trials
Given the genuine uncertainties about whether cooling
would be effective and safe in less well resourced settings, there is a
strong case for performing further randomised controlled trials(29). But
some might have concerns that this would conflict with existing guidelines
for performing trials in developing countries. The recently revised World
Medical Association Declaration of Helsinki specifically indicates that
comparisons with no treatment or placebo are only appropriate where there
is no current proven intervention(33). However, the Declaration itself has
been criticised on the grounds that it would prevent research that has the
potential to improve the health and well being of patients in developing
countries(34,35). Instead of a universal standard some have proposed that
research participants should be offered, as a minimum, the best
intervention currently available as part of a national public health
system(36). In any case, as noted above, it could be argued that in low
resource settings there is no currently proven treatment for NE(21).
If cooling trials are conducted in Indian centres,
trial participants should be made aware of the results of previous
research as part of the informed consent process. One issue worth
considering is whether parents who do not consent to enrolment in such
trials should be allowed to choose that their infant be cooled or given
the conventional treatment. This may jeopardise enrolment, however, or
even render a trial unworkable. Patients and parents are often biased
towards new treatments – particularly where there is little or no existing
therapy. The majority of parents interviewed following the UK extracorpo-real
membrane oxygenation (ECMO) trial had a preference for ECMO at the time of
consent(30). Those who were allocated to conventional treatment exhibited
intense disappointment and anger(30). In an Indian setting, enrolment may
also be threatened if some centres offer (and advertise) cooling outside a
A further question relates to the likely substantial
cost of an adequately powered Indian cooling trial with appropriate
follow-up. Such a trial would need to compete with other health priorities
for funding. Some may feel that it would be better, for example, to devote
resources to improving antenatal care and reducing the incidence of NE. On
the other hand, given that infants are going to continue to be affected by
NE even if antenatal care is improved, there is good reason to seek
simple, effective ways of reducing the burden of this illness and the
considerable ongoing health care costs for survivors. If a low-cost form
of TH were shown to be effective and safe in an Indian trial it would have
enormous significance for the large number of infants with NE, both in
India, and in other transitional and developing countries.
Cooling and Palliative Care
The other potential source of ethical conflicts or
dilemmas relating to cooling is the impact of cooling on decisions about
withdrawal of life-sustaining treatment. The majority of deaths in infants
with HIE in neonatal units in developed countries follow decisions to
withdraw treatment in the face of predicted poor prognosis(3,8,37,38).
There are few studies of treatment limitation decisions in Indian neonatal
units. Withdrawal of treatment appears to be generally accepted(39,40),
though there is considerable legal ambiguity that may lead to confusion in
the minds of doctors and inconsistency in management(41,42). Withdrawal of
treatment in infants with HIE is often cited as particularly difficult
because of uncertainty about outcome(43), but also because such decisions
are based on potentially controversial judgements about future quality of
Firstly, TH may influence withdrawal of treatment by
affecting the timing of decisions. In previous trials cooling was
initiated within 6 hours of birth, continued for 72 hours, followed by
slow rewarming over the next 6 hours. However, there is the possibility
that by 80 hours of age or soon after, infants will have resumed
spontaneous breathing and no longer be ventilator dependent. If
neonatologists wait until cooling has been completed before making
decisions about treatment withdrawal the "window of opportunity" may have
been missed(45). This concern is not borne out in previous trials, since
decisions to withdraw treatment occurred at similar times in cooled and
non-cooled infants(2,3). Furthermore, there were fewer severely impaired
infants among survivors in the three large cooling trials, implying that
overall TH did not lead to the survival of a large number of impaired
infants. Discussions about treatment should be initiated early in the most
severely affected infants, whether or not they are cooled. In some infants
it may be appropriate to withdraw treatment before completing the 72 hours
Secondly, TH may influence decisions about withdrawing
treatment by raising questions about prognosis. The majority of existing
evidence about predicting outcome in infants with NE relates to infants
who have not been cooled. It is possible that factors, previously strongly
associated with adverse outcome, may be less reliable in a population of
infants who are cooled. Doctors and parents usually seek a high degree of
certainty of adverse outcome before deciding to withdraw treatment, and
consequently if an infant has been cooled there may be reluctance to
discontinue intensive care.
Recently published studies are helpful in this regard.
They suggest that early assessment of severity either clinically(46) or
with the help of amplitude integrated electroencephalogram (aEEG)(47) are
less useful in cooled infants. Severe encephalopathy or burst suppression
on aEEG at this stage was not uniformly associated with poor outcome in
infants treated with TH(46,47). However, persistent severely abnormal
neurological findings or aEEG abnormalities were strongly linked to
adverse outcome(46,47). In another recent study cooling did not
substantially change the relationship between various prognostic
parameters including MRI findings. Infants who were cooled were less
likely to have MRI evidence of injury, or had less severe patterns of
injury, but those who had such patterns were still likely to have a poor
Third, TH may raise questions about with-drawing or
withholding treatment in the setting of limited intensive care beds, and
limited support for surviving disabled infants and their families(42,49).
Cooling may make it possible to save the life of infants with severe NE.
This is likely, however, to increase the pressure on neonatal intensive
care capacity. It may mean, for example, that premature infants with
respiratory distress are unable to be supported due to space constraints
in the NICU. It will also highlight the difficult balance between the
interests of the infant, and that of the family. Although TH may reduce
the risk of disability in surviving infants with NE (and it is not clear
yet whether it will in an Indian setting), it may also lead to substantial
burdens on some families by leading to the survival of infants (with
moderate or severe impairment) who would have died previously. TH has been
used in conjunction with monitoring of aEEG and magnetic resonance imaging
for prognostication but these technologies are not available in low
resource settings, or are likely to be in short supply. It is probably
appropriate to provide cooling without these adjuncts, but it potentially
makes prognostication and decision-making more challenging.
There is a range of other practical questions that are
likely to be faced if TH is adopted. The equipment used for cooling in
previous trials is expensive, and it is important that staff is adequately
trained in its use. In some parts of the world this has led to the
development of regional centres with expertise in cooling and referral of
affected infants to the specialized units. However, such a system requires
adequate infrastructure to transport sick encephalopathic infants to the
cooling centres, which is unlikely to be available in many centres in
developing countries. Furthermore it raises the question of cooling the
infants during transport, something that has not been well studied, and is
associated with a risk of over-cooling(50).
The other requirement for implementation of TH in
developed countries is availability of adequate follow-up facilities and
infrastructure to assess the safety and efficacy of the treatment (9, 51).
However, this facility is unlikely to be available in most centres in
resource poor countries except as part of a funded research protocol.
Although the development of TH for newborn infants with
NE has the potential to prevent death and severe disability, its
implementation is likely to raise a number of ethical challenges. There
are unanswered questions about the safety and effectiveness of cooling in
low resource settings. There is a need to exercise caution in the adoption
of TH in Indian neonatal units until further trials have been performed.
We suggest that there is a strong ethical argument in favour of such
trials given differences in the epidemiology of NE in developing countries
and the possibility that TH may be ineffective or even harmful.
Sudhin Thayyil (Academic Neonatology, University
College London) provided very valuable comments and support in the writing
of this manuscript.
1. Eicher DJ, Wagner CL, Katikaneni LP, Hulsey TC, Bass
WT, Kaufman DA, et al. Moderate hypothermia in neonatal
encephalopathy: efficacy outcomes. Pediatr Neurol 2005;32: 11-17.
2. Gluckman PD, Wyatt JS, Azzopardi D, Ballard R,
Edwards AD, Ferriero DM, et al. Selective head cooling with mild
systemic hypothermia after neonatal encephalopathy: multicentre randomised
trial. Lancet 2005;365: 663-670.
3. Shankaran S, Laptook AR, Ehrenkranz RA, Tyson JE,
McDonald SA, Donovan EF, et al. Whole-body hypothermia for neonates
with hypoxic-ischemic encephalopathy. N Engl J Med 2005; 353: 1574-1584.
4. Azzopardi DV, Strohm B, Edwards AD, Dyet L, Halliday
HL, Juszczak E, et al. Moderate hypothermia to treat perinatal
asphyxial Encephalopathy. N Engl J Med 2009; 361: 1349-1358.
5. Edwards AD, Brocklehurst P, Gunn AJ, Halliday H,
Juszczak E, Levene M, et al. Neurological outcomes at 18 months of
age after moderate hypothermia for perinatal hypoxic ischaemic
encephalopathy: synthesis and meta-analysis of trial data. BMJ 2010; 340:
6. Jacobs S, Hunt R, Tarnow-Mordi W, Inder T, Davis P.
Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane
Database of Systematic Rev 2007; CD003311.
7. Shah P, Ohlsson A, Perlman M. Hypothermia to treat
neonatal hypoxic ischemic encephalopathy: systematic review. Arch Pediatr
Adolesc Med 2007;161: 951-958.
8. Azzopardi D, Strohm B, Edwards AD, Halliday H,
Juszczak E, Levene M, et al. Treatment of asphyxiated newborns with
moderate hypothermia in routine clinical practice: how cooling is managed
in the UK outside a clinical trial. Arch Dis Child Fetal Neonatal Ed 2009;
94: F 260-264.
9. Hoehn T, Hansmann G, Bührer C, Simbruner G, Gunn AJ,
Yager J, et al. Therapeutic hypothermia in neonates. Review of
current clinical data, ILCOR recommendations and suggestions for
implementation in neonatal intensive care units. Resuscitation 2008; 78:
10. Perlman M, Shah PS. Ethics of therapeutic
hypothermia. Acta Paediatr 2009;98: 211-213.
11. Kirpalani H, Barks J, Thorlund K, Guyatt G. Cooling
for neonatal hypoxic ischemic encephalopathy: do we have the answer?
Pediatrics 2007;120: 1126-1130.
12. Perlman M, Shah P. Time to adopt cooling for
neonatal hypoxic-ischemic encephalopathy: response to a previous
commentary. Pediatrics 2008; 121: 616-618.
13. Wilkinson DJ. Cool heads: ethical issues associated
with therapeutic hypothermia for newborns. Acta Paediatrica. 2008; 98:
14. Lantos J, Meadow W. Hot debate about a cool
therapy. NeoReviews 2009;10: e65-e70.
15. Wilkinson DJ, Casalaz D, Watkins A, Andersen CC,
Duke T. Hypothermia: a neuroprotective therapy for neonatal
hypoxic-ischemic encephalopathy. Pediatrics 2007; 422-423.
16. Robertson A. Reflections on errors in neonatology
III. The "experienced" years, 1970 to 2000. J Perinatol 2003; 23: 240-249.
17. Lau J, Schmid CH, Chalmers TC. Cumulative
meta-analysis of clinical trials builds evidence for exemplary medical
care. J Clin Epidemiol. 1995; 48: 45-57; 9-60.
18. Chalmers I. The scandalous failure of science to
cumulate evidence scientifically. Clin Trials 2005; 2: 229-231.
19. Kapetanakis A, Azzopardi D, Wyatt J, Robertson NJ.
Therapeutic hypothermia for neonatal encephalopathy: a UK survey of
opinion, practice and neuro-investigation at the end of 2007. Acta
Paediatr 2009; 98: 631-635.
20. Thayyil S, Costello A, Shankaran S, Robertson NJ.
Therapeutic hypothermia for neonatal encephalo-pathy: Implications for
neonatal units in India. Indian Pediatr 2009; 46: 283-289.
21. Wilkinson D, Thayyil S, Robertson N. Ethical and
practical issues relating to the global use of therapeutic hypothermia for
newborn infants. Arch Dis Child 2010 (In press).
22. Ellis M, Manandhar N, Shrestha PS, Shrestha L,
Manandhar DS, Costello AM. Outcome at 1 year of neonatal encephalopathy in
Kathmandu, Nepal. Dev Med Child Neurol 1999; 41: 689-695.
23. Mathur NB, Krishnamurthy S, Mishra TK. Evaluation
of WHO classification of hypothermia in sick extramural neonates as
predictor of fatality. J Trop Pediatr 2005; 51: 341-345.
24. Thayyil S, Bhutta Z, Ramji S, Costello A, Robertson
N. Global applications of therapeutic hypothermia to treat perinatal
asphyxial encephalopathy. Int Health 2010 (In press).
25. Lawn J, Shibuya K, Stein C. No cry at birth: global
estimates of intrapartum stillbirths and intrapartum-related neonatal
deaths. Bulletin of the World Health Organ. 2005; 83: 409-417.
26. Gunn AJ, Gluckman PD. Head cooling for neonatal
encephalopathy: the state of the art. Clin Obstet Gynecol 2007; 50:
27. Kambarami R, Chidede O. Neonatal hypothermia levels
and risk factors for mortality in a tropical country. Cent Afr J Med 2003;
28. Kumar V, Shearer JC, Kumar A, Darmstadt GL.
Neonatal hypothermia in low resource settings: A review. J Perinatol 2009;
29. Wilkinson D. Therapeutic hypothermia and the ‘equal
air-time’ solution for controversial randomised trials. J Paediatr Child
Health 2010 (In press).
30. Snowdon C, Garcia J, Elbourne D. Making sense of
randomization; responses of parents of critically ill babies to random
allocation of treatment in a clinical trial. Soc Sci Med 1997; 45:
31. Allmark P, Spedding M. Clinical trials in neonates:
Ethical issues. Semin Fetal Neonatal Med 2007;12: 318-323.
32. Weijer C, Shapiro SH, Cranley Glass K. For and
against: clinical equipoise and not the uncertainty principle is the moral
underpinning of the rando-mised controlled trial. BMJ 2000; 321: 756-758.
33. World Medical Association. ‘Declaration of
Helsinki: Ethical Principles For Medical Research Involving Human Subjects
2008. Available from http://www.wma.net/e/policy/b3.htm. Accessed 4
34. Hope RA. Medical ethics: a very short introduction.
Oxford: Oxford University Press; 2004.
35. Wendler D, Emanuel EJ, Lie RK. The standard of care
debate: can research in developing countries be both ethical and
responsive to those countries’ health needs? Am J Public Health 2004; 94:
36. Nuffield Council on Bioethics. The ethics of
research related to healthcare in developing countries. London: Nuffield
Council on Bioethics; 2002.
37. Pierrat V, Haouari N, Liska A, Thomas D, Subtil D,
Truffert P, et al. Prevalence, causes, and outcome at 2 years of
age of newborn encephalopathy: population based study. Arch Dis Child
Fetal Neonatal Ed 2005; 90: F257-261.
38. Verhagen A, Dorscheidt J, Engels B, Hubben J, Sauer
P. End-of-life decisions in Dutch neonatal intensive care units. Arch
Pediatr Adolesc Med 2009; 163: 895-901.
39. Subramanian KN. Caring for newborns: three world
views. In India, Nepal, and Sri Lanka, quality of life weights heavily.
Hastings Cent Rep 1986;16: 20-22.
40. Subramanian KN, Paul VK. Care of critically ill
newborns in India. Legal and ethical issues. J Legal Med 1995; 16:
41. Mani RK. End-of-life care in India. Intensive Care
Med 2006; 32: 1066-1068.
42. Miljeteig I, Norheim OF. My job is to keep him
alive, but what about his brother and sister? How Indian doctors
experience ethical dilemmas in neonatal medicine. Dev World Bioethics
2006; 6: 23-32.
43. McHaffie HE, Fowlie PW. Life, death and decisions:
Doctors and nurses reflect on neonatal practice. Hale: Hochland and
44. Wilkinson D. Death in the Netherlands: evidence and
argument. Arch Pediatr Adolesc Med 2009; 163: 958-959.
45. Wilkinson D. The window of opportunity: decision
theory and the timing of prognostic tests for newborn infants. Bioethics
2009; 23: 503-514.
46. Gunn AJ, Wyatt JS, Whitelaw A, Barks J, Azzopardi
D, Ballard R, et al. Therapeutic hypothermia changes the prognostic
value of clinical evaluation of neonatal encephalopathy. J Pediatr
47. Hallberg B, Grossmann K, Bartocci M, Blennow M. The
prognostic value of early EEG in asphyxiated infants undergoing systemic
hypothermia treatment. Acta Paediatr 2010; 99: 531-536.
48. Rutherford M, Ramenghi LA, Edwards AD, Brocklehurst
P, Halliday H, Levene M, et al. Assessment of brain tissue injury
after moderate hypothermia in neonates with hypoxic-ischaemic
encephalopathy: a nested substudy of a randomised controlled trial. Lancet
Neurol 2010; 9: 39-45.
49. Miljeteig I, Sayeed SA, Jesani A, Johansson KA,
Norheim OF. Impact of ethics and economics on end-of-life decisions in an
Indian neonatal unit. Pediatrics 2009; 124: e322-328.
50. Fairchild K, Sokora D, Scott J, Zanelli S.
Therapeutic hypothermia on neonatal transport: 4-year experience in a
single NICU. J Perinatol 2009 Oct 22 [Epub ahead of print]; doi:
51. Perlman JM. Hypothermia as a therapeutic
intervention in term infants with neonatal encephalopathy-Is it ready for
prime time? Resuscitation 2008; 78: 1-2.