PICO Summary: Does therapeutic hypothermia decrease the risk of death and long-term neurodevelopmental disabulity in infants with moderate to severe hypoxic ischaemic encephalopathy?


BackgroundIn technically developed countries, peripartum asphyxia affects 3–5 per 1000 live births with subsequent moderate or severe hypoxic ischaemic encephalopathy (HIE) in 0.5–1 per 1000 live births. 10–60% of affected infants die, and at least 25% of survivors have long-term neurodevelopmental sequelae (Ferriero, 2004). Hypothermia is a clinically feasible manoeuvre that may improve the outcome of neonates with HIE. Therapeutic hypothermia aims to lower the temperature of the vulnerable deep brain structures, the basal ganglia, to 32–34 degrees Celsius. Two methods are being evaluated in newborn infants with HIE: whole body cooling and selective head cooling with mild systemic hypothermia.
Participants• Term or near term newborn infants.
 • Evidence of peripartum asphyxia including at least one of the following criteria:
  - Apgar score of 5 or less at 10 min;
  - Mechanical ventilation or resuscitation at 10 min;
  - Cord pH < 7.1, or an arterial pH < 7.1 or base deficit of 12 or more within 60 min of birth.
 • Evidence of encephalopathy according to Sarnat staging:
  - Stage 1 (Mild): hyperalertness, hyperreflexia, dilated pupils, tachycardia, absence of seizures;
  - Stage 2 (Moderate): lethargy, hyperreflexia, miosis, bradycardia, seizures, hypotonia with weak suck and Moro;
  - Stage 3 (Severe): stupor, flaccidity, small to midposition pupils which react poorly to light, decreased stretch reflexes, hypothermia and absent Moro.
 • No major congenital abnormalities recognizable at birth.
InterventionCooling (whole body or selective head cooling).
ComparisonNo cooling (standard care).
Outcome(s)Death or long-term (>18 months) major neurodevelopmental disability [cerebral palsy, developmental delay (Bayley or Griffith assessment more than 2 SD below the mean) or intellectual impairment (IQ more than 2 SD below mean), blindness (vision < 6/60 in both eyes), sensorineural deafness requiring amplification].
StudiesAll randomized and quasi-randomized studies comparing the use of therapeutic hypothermia with standard care were included.
Study description and settingEight randomized controlled trials were included in the review of Jacobs and coworkers (Jacobs 2007), comprising 638 term infants with moderate/severe encephalopathy and evidence of intrapartum asphyxia.
ResultsTherapeutic 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 0.76, 95% CI 0.65, 0.89; typical RD −0.15 95% CI −0.24, −0.07; NNT 7, 95% CI 4, 14). Cooling also resulted in statistically significant reductions in mortality (typical RR 0.74, 95% CI 0.58, 0.94; typical RD −0.09, 95% CI −0.16, −0.02; NNT 11, 95% CI 6, 50) and in neurodevelopmental disability in survivors (typical RR 0.68, (95% CI 0.51, 0.92), typical RD −0.13, (95% CI −0.23, −0.03) NNT 7 (4–33)). Adverse effects of hypothermia included an increase in the need for inotrope support of borderline significance and a significant increase in thrombocytopenia.
Confidence in resultsAlthough unblinded, the trials represent high quality evidence for all primary outcomes reported.
Key figure(s)Thumbnail image of
Figure captionDeath or major disability in survivors assessed, by method of cooling
Search for eligible studiesCENTRAL, MEDLINE, EMBASE, CINAHL, abstracts from scientific meetings published in Pediatric Research and reference lists of identified trials and reviews were searched through June 2007.
ConclusionTherapeutic hypothermia in infants with moderate to severe hypoxic ischaemic encephalopathy resulted in a statistically significant and clinically important reduction in mortality and major neurodevelopmental disability to 18 months of age. Some adverse effects of hypothermia included an increase in the need for inotrope support of borderline significance and a significant increase in thrombocytopenia.
CitationJacobs SE, Hunt R, Tarnow-Mordi WO, Inder TE, Davis PG. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database of Systematic Reviews 2007, Issue 4. Art. No.: CD003311. DOI: 10.1002/14651858.CD003311.pub2.
Date completed20 February 2010
People who helped prepare this Cochrane PICO:Roger Soll and Martin Offringa, editors

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