Indian Pediatr 2018;55: 197-198
Cooling Therapy for Neonatal Encephalopathy
in Low- and Middle-income Countries
From the Centre for Perinatal Neuroscience, Imperial
College London, Du Cane Road, London W12 0HS,
escue hypothermic neuroprotection has now
dominated publications related to neonatal encephalopathy for over a
decade. Carefully designed and executed randomized controlled trials in
high-income countries have conclusively shown that a controlled
reduction of body temperature by 3 to 4°C soon after birth for three
days reduces death and neuro-disability, and that the benefits persists
into late childhood . Deeper or longer cooling is not beneficial and
may be harmful , and the benefits of delayed cooling (after 6 hours)
is marginal . In all high-income countries, cooling therapy is now
the standard of care for babies with moderate or severe encephalopathy.
However, the cooling story is far from complete. One
of the biggest unanswered questions is whether this therapy would
benefit babies in low- and middle-income countries (LMICs), which
shoulder the highest disease burden. Undertaking cooling trials in
developing countries is challenging due to the lack of adequate research
governance, and the difficulty in obtaining accurate clinical and
follow-up data. It is unrealistic for clinical teams to obtain accurate
hourly recordings of core body temperature in LMICs, unless data loggers
are used, and the claims of accurate hourly manual temperature recording
have to be taken with a pinch of salt . Thus, although a number of
small and low quality clinical trials have been reported from LMICs, the
published data are inconclusive and the safety and efficacy of cooling
in these settings remain uncertain .
Another key issue is the way cooling is delivered.
Any method that can maintain core body temperature within the target
range without wide fluctuations, in theory, should be adequate for this
purpose. Interestingly, almost every low-tech cooling strategy – ice,
frozen gel packs, water bottles, fans – has been reported to have
similar cooling efficacy as the servo-controlled devices [1,5]. The
latest in this long list is phase changing material.
Phase changing materials (PCM) are made of salt
hydride, fatty acid, and esters or paraffin, and melt at a set point.
During this process they can store or release large amounts of energy,
and hence, have a wide range of applications based on the set points.
The use of PCM as a low-cost cooling method for developing countries was
first proposed by Olsen, as a part of his PhD work at University College
London and Karolinsnka University in 2007. In a piglet model of hypoxic
ischemic injury (where the ambient temperatures were around 18 to 20°C
with air conditioning), PCM effectively induced and maintained cooling
in the target range. The first ever clinical trial of PCM was conducted
at Calicut Medical College – the Peacock (Phase Change Material for
Cooling in Kerala) trial in 2009 [5,6]. The PCM cooling mattress was
manufactured by Climator with a cost of approximately £100 per mattress.
Hourly rectal temperatures were recorded and stored using a data-logger,
and then transferred to a database for analysis. PCM maintained core
temperature within the target range, only when ambient temperature was
low. Given that most tertiary neonatal units in India may have
air-conditioning, this may not prove to be a major hurdle in wider use.
Although it is unclear whether the nursing staff documented hourly
temperature data in real time, and what the ambient temperatures were,
Thomas and colleagues report that PCM can be used to administer cooling
in Indian neonatal units .
The key question is: should we now start routine
cooling therapy in India and other LMICs? Opinions are polarized. Some
feel most neonatal therapies used in LMICs are based on evidence from
high-income countries, and high quality, multicenter neonatal trials are
rarely undertaken in these settings. So, why should this be different in
cooling therapy? Moreover, is it ethical to withhold a highly effective
and proven treatment that is standard of care in high-income countries
 from the babies in LMICs, particularly as there is no alternative
Others argue that differences in population
co-morbidities, infection, and supportive care could alter the
therapeutic response to cooling such that it may even be harmful .
Not uncommonly, direct extrapolation of the evidence from high income
countries to LMICs may cause harm [9,10]. The primary duty of the
clinicians is to ‘do no harm first’. A large multi-country randomized
controlled trial (HELIX) is now nearing completion in many centers in
India, Sri Lanka and Bangladesh, and may well provide a definitive
answer to this important issue.
Funding: None; Competing interests: None
1. Montaldo P, Pauliah SS, Lally PJ, Olson L, Thayyil
S. Cooling in a low-resource environment: lost in translation. Semin
Fetal. Neonatal Med. 2015;20:72-9.
2. Shankaran S, Laptook AR, Pappas A, McDonald SA,
Das A, Tyson JE, et al. Effect of depth and duration of cooling
on death or disability at age 18 months among neonates with
hypoxic-ischemic encephalopathy: A randomized clinical trial. JAMA.
3. Laptook AR, Shankaran S, Tyson JE, Munoz B, Bell
EF, Goldberg RN, et al. Effect of therapeutic hypothermia
initiated after 6 hours of age on death or disability among newborns
with hypoxic-ischemic encephalopathy: A randomized clinical trial. JAMA.
4. Pauliah SS, Shankaran S, Wade A, Cady EB, Thayyil
S. Therapeutic hypothermia for neonatal encephalopathy in low- and
middle-income countries: A systematic review and meta-analysis. PLoS
5. Robertson NJ, Kendall GS, Thayyil S. Techniques
for therapeutic hypothermia during transport and in hospital for
perinatal asphyxial encephalopathy. Semin Fetal Neonatal Med.
6. Thayyil S, Ayer M, Guhan B, et al. Whole
Body Cooling Using Phase Changing Material in Neonatal Encephalopathy: A
Pilot Randomised Control Trial. Pediatric Academic Societies Meeting
, Vancouver 2010.
7. Thomas N, Abiramalatha T, Bhat V, Varanattu M, Rao
S, Wazir S, et al. Phase changing material for therapeutic
hypothermia in neonates with hypoxic ischemic encephalopathy – A
multi-centric study. Indian Pediatr. 2018;55:201-6.
8. Thomas N, Santhanam S, Kumar M, Kuruvilla KA, Jana
AK. Hypothermia for neonatal encephalopathy in resource-poor
environments. J Pediatr. 2012;160:709; author reply 709-10.
9. Klein K, McClure EM, Colaci D, Thorsten V, Hibberd
PL, Esamai F, et al. The Antenatal Corticosteroids Trial (ACT): A
secondary analysis to explore site differences in a multi-country trial.
Reprod Health. 2016;13:64.
10. Maitland K, Kiguli S, Opoka RO, Engoru C,
Olupot-Olupot P, Akech SO, et al. Mortality after fluid bolus in
African children with severe infection. N Engl J Med. 2011;364:2483-95.