Meta-analysis of the various cooling trials from developed countries has
shown conclusively that therapeutic hypothermia reduces death and
disability following hypoxic ischemic encephalopathy (HIE) and has now
become the standard of care in these countries [1]. There have been doubts
raised as to whether cooling should be practiced in developing countries
like India due to concerns of availability of alternative cheaper
equipment and differences in patient population [2,3]. In a previous
study, we demonstrated the safety and feasibility of cooling babies with
HIE in India using low cost and easily available material [4]. However, in
addition to short term safety and outcome, it is important to look at the
long term outcome of these babies. The present study was conducted to
evaluate the neurodevelopmental outcome of the 20 babies who underwent
whole body cooling for HIE in the neonatal period [4]. We were able to
evaluate at 18-24 months, 14 of the 19 (73.7%) babies who were discharged
alive. A detailed history was taken from all the parents regarding the age
of achievement of important milestones. The Griffith Mental Developmental
Scales (GMDS) and Vineland Social Maturity Scales (VSMS) were done on 11
children.
One child died at 1 month of age with a respiratory
illness. One child had developmental delay. In the remaining 12, parents
had no concern about their development or growth and the age of
achievement of major milestones were within the normal range. All children
had normal anthropometry and head circumference except one child with
developmental delay, who had microcephaly. This child had spastic
quadriplegia with normal vision and hearing and an episode of fever
precipitated seizures. All the other children had normal tone, vision and
hearing. The mean developmental quotient (SD) and mean social quotient
(SD) for normal children were 98.2 (10.79) and 133.6 (14.9), respectively.
The child with developmental delay had a developmental quotient of 35 and
social quotient of 42.
This follow-up evaluation showed only 3/15 (20%) to
have had an adverse outcome (2 death and 1 disability). If all 5 of the
babies who could not be contacted were assumed to have an adverse outcome,
a minimum of 12 children (60%) still would have had a normal
neurodevelopmental outcome. This is a better outcome than the major
cooling trials, where death or disability was seen in 44% to 51% of cooled
babies [5,6,7]. All of our cooled babies had either moderate or severe
encephalopathy, belying the argument that our cohort was not similar to
the western cohorts. However, it is well documented that there is a
process of natural selection in developing countries where babies with
very severe asphyxia are stillborn or die before reaching the hospital
[8]. Thus the better outcome seen in the study may be in part due to the
fact that the very sick babies were not cooled. However, meta-analyses of
the cooling studies from the west have shown that in babies with severe
encephalopathy, cooling did not lead to significant benefit (RR 0.62,
95%CI 0.33-1.18) [9].
This study has established the good outcome at 18-24
month age in cooling babies with HIE in our country. However, the numbers
are small and several questions remain unanswered. Before cooling can
become the standard of care in India, there is an urgent need to conduct
an adequately powered multi-centric RCT to address the questions of
patient population difference and cooling in conditions without intensive
care monitoring, especially as a study from Africa has shown increased
mortality in cooled babies [10].
References
1. 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:c363.
2. Thayyil S, Costello A, Shankaran S, Robertson NJ.
Therapeutic hypothermia for neonatal encephalo-pathy:Implications for
neonatal units in India. Indian Pediatr. 2009;46:283-9.
3. Wilkinson DJ, Singh M, Wyatt J. Ethical challenges
in the use of therapeutic hypothermia in Indian neonatal units. Indian
Pediatr. 2010;47:387-93.
4. Thomas N, George KC, Sridhar S, Kumar M, Kuruvilla
KA, Jana AK. Whole body cooling in newborn infants with perinatal
asphyxial encephalopathy in a low resource setting: A feasibility trial.
Indian Pediatr. 2010;48:445-51.
5. Shankaran S, LaptookAR, Ehrenkranz RA, Tyson JE,
McDonald SA, Donovan EF, et al. Whole-body hypothermia for neonates
with hypoxic-ischemic encephalopathy. N Engl J Med.
2005;353:1574-84.
6. Azzopardi DV, Strohm B, Edwards AD, Dyet L, Halliday
HL, Juszczak E, et al. Moderate hypothermia to treat perinatal
ashyxial encephalopathy. N Engl J Med. 2009;361:1349-58.
7. Jacobs SE, Morley CJ, Inder TE, Stewart MJ, Smith
KR, McNamara PJ, et al. Whole-body hypothermia for term and
near-term newborns with hypoxic-ischemic encephalo-pathy: A randomized
controlled trial. Arch Pediatr Adolesc Med. 2011; published online April
4, 2011. doi 10.1001/archpediatrics.2011.43.
8. Ellis M, Manandhar N, Manandhar D, Costello A. Risk
factors for neonatal encephalopathy in Kathmandu, Nepal, a developing
country: unmatched case control study. BMJ. 2000;320:1229-36.
9. Shah PS. Hypothermia: a systematic review and
meta-analysis of clinical trials. Semin Fetal Neonatal Med.
2010;15:238-46.
10. Robertson NJ, Nakakkeeto M, Hagmann C, Cowan FM, Acolet D, Iwata O,
et al. Therapeutic hypothermia for birth asphyxia in low resource
settingd: a pilot randomized trial. Lancet. 2008;372:801-03.