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Meta-Analysis
. 2013 Jan 31;2013(1):CD003311.
doi: 10.1002/14651858.CD003311.pub3.

Cooling for newborns with hypoxic ischaemic encephalopathy

Susan E Jacobs  1 , Marie Berg, Rod Hunt, William O Tarnow-Mordi, Terrie E Inder, Peter G Davis
Affiliations
Meta-Analysis

Cooling for newborns with hypoxic ischaemic encephalopathy

Susan E Jacobs et al. Cochrane Database Syst Rev. .

Abstract

Background: Newborn animal studies and pilot studies in humans suggest that mild hypothermia following peripartum hypoxia-ischaemia in newborn infants may reduce neurological sequelae without adverse effects.

Objectives: To determine the effect of therapeutic hypothermia in encephalopathic asphyxiated newborn infants on mortality, long-term neurodevelopmental disability and clinically important side effects.

Search methods: We used the standard search strategy of the Cochrane Neonatal Review Group as outlined in The Cochrane Library (Issue 2, 2007). Randomised controlled trials evaluating therapeutic hypothermia in term and late preterm newborns with hypoxic ischaemic encephalopathy were identified by searching the Oxford Database of Perinatal Trials, the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, 2007, Issue 2), MEDLINE (1966 to June 2007), previous reviews including cross-references, abstracts, conferences, symposia proceedings, expert informants and journal handsearching. We updated this search in May 2012.

Selection criteria: We included randomised controlled trials comparing the use of therapeutic hypothermia with standard care in encephalopathic term or late preterm infants with evidence of peripartum asphyxia and without recognisable major congenital anomalies. The primary outcome measure was death or long-term major neurodevelopmental disability. Other outcomes included adverse effects of cooling and 'early' indicators of neurodevelopmental outcome.

Data collection and analysis: Four review authors independently selected, assessed the quality of and extracted data from the included studies. Study authors were contacted for further information. Meta-analyses were performed using risk ratios (RR) and risk differences (RD) for dichotomous data, and weighted mean difference for continuous data with 95% confidence intervals (CI).

Main results: We included 11 randomised controlled trials in this updated review, comprising 1505 term and late preterm infants with moderate/severe encephalopathy and evidence of intrapartum asphyxia. Therapeutic hypothermia resulted in a statistically significant and clinically important reduction in the combined outcome of mortality or major neurodevelopmental disability to 18 months of age (typical RR 0.75 (95% CI 0.68 to 0.83); typical RD -0.15, 95% CI -0.20 to -0.10); number needed to treat for an additional beneficial outcome (NNTB) 7 (95% CI 5 to 10) (8 studies, 1344 infants). Cooling also resulted in statistically significant reductions in mortality (typical RR 0.75 (95% CI 0.64 to 0.88), typical RD -0.09 (95% CI -0.13 to -0.04); NNTB 11 (95% CI 8 to 25) (11 studies, 1468 infants) and in neurodevelopmental disability in survivors (typical RR 0.77 (95% CI 0.63 to 0.94), typical RD -0.13 (95% CI -0.19 to -0.07); NNTB 8 (95% CI 5 to 14) (8 studies, 917 infants). Some adverse effects of hypothermia included an increase sinus bradycardia and a significant increase in thrombocytopenia.

Authors' conclusions: There is evidence from the 11 randomised controlled trials included in this systematic review (N = 1505 infants) that therapeutic hypothermia is beneficial in term and late preterm newborns with hypoxic ischaemic encephalopathy. Cooling reduces mortality without increasing major disability in survivors. The benefits of cooling on survival and neurodevelopment outweigh the short-term adverse effects. Hypothermia should be instituted in term and late preterm infants with moderate-to-severe hypoxic ischaemic encephalopathy if identified before six hours of age. Further trials to determine the appropriate techniques of cooling, including refinement of patient selection, duration of cooling and method of providing therapeutic hypothermia, will refine our understanding of this intervention.

PubMed Disclaimer

Conflict of interest statement

Dr Sue Jacobs is the principal investigator for one of the included randomised controlled trials, the Infant Cooling Evaluation (ICE) trial.

Figures

1.1
1.1. Analysis
Comparison 1 Therapeutic hypothermia versus standard care: subgroup analysis by method of cooling, Outcome 1 Death or major disability in survivors assessed, by method of cooling.
1.2
1.2. Analysis
Comparison 1 Therapeutic hypothermia versus standard care: subgroup analysis by method of cooling, Outcome 2 Mortality, by method of cooling.
1.3
1.3. Analysis
Comparison 1 Therapeutic hypothermia versus standard care: subgroup analysis by method of cooling, Outcome 3 Major neurodevelopmental disability by method of cooling.
1.4
1.4. Analysis
Comparison 1 Therapeutic hypothermia versus standard care: subgroup analysis by method of cooling, Outcome 4 Major neurodevelopmental disability in survivors assessed, by method of cooling.
1.5
1.5. Analysis
Comparison 1 Therapeutic hypothermia versus standard care: subgroup analysis by method of cooling, Outcome 5 Neuromotor delay (BSID PDI more than 2 SD below mean) in survivors assessed, by method of cooling.
1.6
1.6. Analysis
Comparison 1 Therapeutic hypothermia versus standard care: subgroup analysis by method of cooling, Outcome 6 Developmental delay (BSID MDI more than 2 SD below mean) in survivors assessed, by method of cooling.
1.7
1.7. Analysis
Comparison 1 Therapeutic hypothermia versus standard care: subgroup analysis by method of cooling, Outcome 7 Neuromotor development (BSID PDI) in survivors assessed.
1.8
1.8. Analysis
Comparison 1 Therapeutic hypothermia versus standard care: subgroup analysis by method of cooling, Outcome 8 Mental development (BSID MDI) in survivors assessed.
1.9
1.9. Analysis
Comparison 1 Therapeutic hypothermia versus standard care: subgroup analysis by method of cooling, Outcome 9 Cerebral palsy in survivors assessed.
1.10
1.10. Analysis
Comparison 1 Therapeutic hypothermia versus standard care: subgroup analysis by method of cooling, Outcome 10 Blindness in survivors assessed.
1.11
1.11. Analysis
Comparison 1 Therapeutic hypothermia versus standard care: subgroup analysis by method of cooling, Outcome 11 Deafness in survivors assessed.
1.12
1.12. Analysis
Comparison 1 Therapeutic hypothermia versus standard care: subgroup analysis by method of cooling, Outcome 12 Outcome at 6 to 7 years of age.
1.13
1.13. Analysis
Comparison 1 Therapeutic hypothermia versus standard care: subgroup analysis by method of cooling, Outcome 13 Sinus bradycardia.
1.14
1.14. Analysis
Comparison 1 Therapeutic hypothermia versus standard care: subgroup analysis by method of cooling, Outcome 14 Major arrhythmia.
1.15
1.15. Analysis
Comparison 1 Therapeutic hypothermia versus standard care: subgroup analysis by method of cooling, Outcome 15 Hypotension (mean arterial pressure < 40 mmHg).
1.16
1.16. Analysis
Comparison 1 Therapeutic hypothermia versus standard care: subgroup analysis by method of cooling, Outcome 16 Hypotension requiring inotropic support.
1.17
1.17. Analysis
Comparison 1 Therapeutic hypothermia versus standard care: subgroup analysis by method of cooling, Outcome 17 Anaemia requiring transfusion.
1.18
1.18. Analysis
Comparison 1 Therapeutic hypothermia versus standard care: subgroup analysis by method of cooling, Outcome 18 Leukopenia.
1.19
1.19. Analysis
Comparison 1 Therapeutic hypothermia versus standard care: subgroup analysis by method of cooling, Outcome 19 Thrombocytopenia.
1.20
1.20. Analysis
Comparison 1 Therapeutic hypothermia versus standard care: subgroup analysis by method of cooling, Outcome 20 Any coagulopathy.
1.21
1.21. Analysis
Comparison 1 Therapeutic hypothermia versus standard care: subgroup analysis by method of cooling, Outcome 21 Coagulopathy resulting in major thrombosis or haemorrhage.
1.22
1.22. Analysis
Comparison 1 Therapeutic hypothermia versus standard care: subgroup analysis by method of cooling, Outcome 22 Hypoglycaemia.
1.23
1.23. Analysis
Comparison 1 Therapeutic hypothermia versus standard care: subgroup analysis by method of cooling, Outcome 23 Hypokalaemia.
1.24
1.24. Analysis
Comparison 1 Therapeutic hypothermia versus standard care: subgroup analysis by method of cooling, Outcome 24 Renal impairment.
1.25
1.25. Analysis
Comparison 1 Therapeutic hypothermia versus standard care: subgroup analysis by method of cooling, Outcome 25 Oliguria.
1.26
1.26. Analysis
Comparison 1 Therapeutic hypothermia versus standard care: subgroup analysis by method of cooling, Outcome 26 Sepsis.
1.27
1.27. Analysis
Comparison 1 Therapeutic hypothermia versus standard care: subgroup analysis by method of cooling, Outcome 27 Persistent pulmonary hypertension.
1.28
1.28. Analysis
Comparison 1 Therapeutic hypothermia versus standard care: subgroup analysis by method of cooling, Outcome 28 Treated with inhaled nitric oxide.
1.29
1.29. Analysis
Comparison 1 Therapeutic hypothermia versus standard care: subgroup analysis by method of cooling, Outcome 29 Hepatic dysfunction.
1.30
1.30. Analysis
Comparison 1 Therapeutic hypothermia versus standard care: subgroup analysis by method of cooling, Outcome 30 Gastric tube feeds at discharge.
1.31
1.31. Analysis
Comparison 1 Therapeutic hypothermia versus standard care: subgroup analysis by method of cooling, Outcome 31 Seizures during initial hospitalisation.
1.32
1.32. Analysis
Comparison 1 Therapeutic hypothermia versus standard care: subgroup analysis by method of cooling, Outcome 32 Seizures or need for anticonvulsant treatment at follow‐up.
1.33
1.33. Analysis
Comparison 1 Therapeutic hypothermia versus standard care: subgroup analysis by method of cooling, Outcome 33 MRI abnormalities.
2.1
2.1. Analysis
Comparison 2 Therapeutic hypothermia versus standard care: subgroup analysis by baseline severity of encephalopathy, Outcome 1 Death or major disability in survivors assessed.
2.2
2.2. Analysis
Comparison 2 Therapeutic hypothermia versus standard care: subgroup analysis by baseline severity of encephalopathy, Outcome 2 Mortality.
2.3
2.3. Analysis
Comparison 2 Therapeutic hypothermia versus standard care: subgroup analysis by baseline severity of encephalopathy, Outcome 3 Major disability in survivors assessed.
3.1
3.1. Analysis
Comparison 3 Therapeutic hypothermia versus standard care: subgroup analysis by baseline amplitude‐integrated electroencephalogram (aEEG) findings, Outcome 1 Death or major disability in survivors assessed.
3.2
3.2. Analysis
Comparison 3 Therapeutic hypothermia versus standard care: subgroup analysis by baseline amplitude‐integrated electroencephalogram (aEEG) findings, Outcome 2 Mortality.
3.3
3.3. Analysis
Comparison 3 Therapeutic hypothermia versus standard care: subgroup analysis by baseline amplitude‐integrated electroencephalogram (aEEG) findings, Outcome 3 Major disability in survivors assessed.
4.1
4.1. Analysis
Comparison 4 Therapeutic hypothermia versus standard care: subgroup analysis by quality of follow‐up, Outcome 1 Death or major disability in survivors assessed, by quality of follow‐up.
4.2
4.2. Analysis
Comparison 4 Therapeutic hypothermia versus standard care: subgroup analysis by quality of follow‐up, Outcome 2 Major neurodevelopmental disability, by quality of follow‐up.
4.3
4.3. Analysis
Comparison 4 Therapeutic hypothermia versus standard care: subgroup analysis by quality of follow‐up, Outcome 3 Major neurodevelopmental disability in survivors assessed, by quality of follow‐up.
4.4
4.4. Analysis
Comparison 4 Therapeutic hypothermia versus standard care: subgroup analysis by quality of follow‐up, Outcome 4 Neuromotor delay (BSID PDI more than 2 SD below mean) in survivors assessed, by quality of follow‐up.
4.5
4.5. Analysis
Comparison 4 Therapeutic hypothermia versus standard care: subgroup analysis by quality of follow‐up, Outcome 5 Developmental delay (BSID MDI more than 2 SD below mean) in survivors assessed, by quality of follow‐up.
See this image and copyright information in PMC

Update of

References

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TOBY Study 2009 {published data only}
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Zhou 2010 {published data only}
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References to studies excluded from this review

Araki 2010 {published data only}
    1. Araki S, Takahashi D, Matsui M, Saito R, Morita H, Ishii M, et al. Brain hypothermia therapy for newborns with severe birth asphyxia: an experience from a single neonatal intensive care unit [in Japanese]. Journal of UOEH 2010;32(2):205‐11. - PubMed
Azzopardi 2000 {published data only}
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Christensen 2012 {published data only}
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Compagnoni 2002 {published data only}
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Compagnoni 2008 {published data only}
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Debillon 2003 {published data only}
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Filippi 2009 {published data only}
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Filippi 2010 {published data only}
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Gucuyener 2012 {published data only}
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Hamelin 2011 {published data only}
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Horan 2004 {published data only}
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Horn 2006 {published data only}
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Ichiba 2003 {published data only}
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Inder 2004 {published data only}
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Kendall 2010 {published data only}
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Kilani 2002 {published data only}
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Lista 2004 {published data only}
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Liu 2010 {published data only}
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Massaro 2010 {published data only}
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Meyn 2010 {published data only}
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Robertson 2008 {published data only}
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Róka 2007 {published data only}
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Rutherford 2005 {published data only}
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Simbruner 1999 {published data only}
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Thomas 2011 {published data only}
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Thoresen 2000 {published data only}
    1. Thoresen M, Whitelaw A. Cardiovascular changes during mild therapeutic hypothermia and rewarming in infants with hypoxic‐ischemic encephalopathy. Pediatrics 2000;106(1 Pt 1):92‐9. - PubMed
Thoresen 2010 {published data only}
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Tusor 2012 {published data only}
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Wusthoff 2011 {published data only}
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Zhou 2002 {published data only}
    1. Zhou WH, Shao XM, Cao Y, Chen C, Zhang XD. Safety study of hypothermia for treatment of hypoxic‐ischemic brain damage in term neonates. Acta Pharmacologica Sinica 2002;23(Supplement):64‐8.
Zhou 2003 {published data only}
    1. Zhou WH, Shao XM, Zhang XD, Chen C, Huang GY. Effects of hypothermia on cardiac function in neonates with asphyxia [in Chinese]. Zhonghua Er Ke Za Zhi 2003;41(6):460‐2. - PubMed

References to studies awaiting assessment

Bharadwaj 2012 {published data only}
    1. Bharadwaj SK, Vishnu Bhat B. Therapeutic hypothermia using gel packs for term neonates with hypoxic ischaemic encephalopathy in resource‐limited settings: a randomized controlled trial. Journal of Tropical Pediatrics 2012;58(5):382‐8. - PubMed
Bhat 2006 {published data only}
    1. Bhat MA. Re: therapeutic hypothermia following perinatal asphyxia. Archives of Diseases in Childhood. Fetal and Neonatal Edition 2006;91(6):F464. - PMC - PubMed
Sun 2012 {published data only}
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Thayyil 2010 {published data only}
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References to ongoing studies

CoolXenon Study {published data only}
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NeoNATI {published data only}
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NEST Study {published data only}
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NICHD: Optimizing Cooling {published data only}
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TOBYXe {published data only}
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Walsh: Preterm Infants {published data only}
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Walsh: Thermal Imaging {published data only}
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References to other published versions of this review

Jacobs 2003
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