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Therapeutic hypothermia following intrapartum hypoxia-ischemia. An advisory statement from the Neonatal Task Force of the International Liaison Committee on Resuscitation

      Abstract

      2010 ILCOR Recommendation

      On the basis of the published data to date the Neonatal Task Force of the International Liaison Committee on Resuscitation (ILCOR) made the following recommendation on February 2010 with regard to therapeutic hypothermia: Newly born infants born at term or near-term with evolving moderate to severe hypoxic-ischemic encephalopathy should be offered therapeutic hypothermia. whole-body cooling and selective head cooling are both appropriate strategies. Cooling should be initiated and conducted in neonatal intensive care facilities using protocols consistent with those used in the randomized clinical trials i.e. commence within 6 h, continue for 72 h and rewarm over at least 4 h. Carefully monitor for known adverse effects of cooling – thrombocytopenia and hypotension. All treated infants should be followed longitudinally.

      Keywords

      1. Introduction

      Experimental and pilot studies in humans indicated that modest hypothermia initiated following a hypoxic-ischemic insult reduced the extent of brain injury following hypoxia-ischemia.
      • Gunn A.J.
      • Gunn T.R.
      • deHaan H.H.
      • Williams C.E.
      • Glucman P.D.
      Dramatic neuronal rescue with prolonged selective head cooling after ischemia in fetal lambs.
      • Gunn A.J.
      • Gluckman P.D.
      • Gunn T.R.
      Selective head cooling in newborn infants after perinatal asphyxia: a safety study.
      • Gunn A.J.
      • Gunn T.R.
      • Gunning M.I.
      • Williams C.E.
      • Gluckman P.D.
      Neuroprotection with prolonged head cooling started before postischemic seizures in fetal sheep.
      • Simbruner G.
      • Haberl C.
      • Harrison V.
      • Linley L.
      • Willeitner A.E.
      Induced brain hypothermia in asphyxiated human newborn infants: a retrospective chart analysis of physiological and adverse effects.
      • Gunn A.J.
      • Bennet L.
      • Gunning M.I.
      • Gluckman P.D.
      • Gunn T.R.
      Cerebral hypothermia is not neuroprotective when started after postischemic seizures in fetal sheep.
      • Laptook A.R.
      • Corbett R.J.T.
      • Burns D.K.
      • Sterett R.
      A limited interval of delayed modest hypothermia for ischemic brain resuscitation is not beneficial in neonatal swine.
      • Azzopardi D.
      • Robertson N.J.
      • Cowan F.M.
      • Rutherford M.A.
      • Rampling M.
      • Edwards D.A.
      Pilot study of treatment with whole body hypothermia for neonatal encephalopathy.
      • Battin M.R.
      • Dezoete J.A.
      • Gunn T.R.
      • Gluckman P.D.
      • Gunn A.J.
      Neurodevelopmental outcome of infants treated with head cooling and mild hypothermia after perinatal asphyxia.
      • Thoresen M.
      • Satas S.
      • Loberg E.M.
      • et al.
      Twenty-four hours of mild hypothermia in unsedated newborn pigs starting after a severe global hypoxic-ischemic insult is not neuroprotective.
      • Compagnoni G.
      • Pogliani L.
      • Lista G.
      • Castoldi F.
      • Fontana P.
      • Mosca F.
      Hypothermia reduces neurological damage in asphyxiated newborn infants.
      • Kilani R.A.
      The safety and practicality of selective head cooling in asphyxiated human newborn infants, a retrospective study.
      • Shankaran S.
      • Laptook A.
      • Wright L.L.
      • et al.
      Whole-body hypothermia for neonatal encephalopathy: animal observations as a basis for a randomized, controlled pilot study in term infants.
      • Battin M.R.
      • Penrice J.
      • Gunn T.R.
      • Gunn T.R.
      Treatment of term infants with head cooling and mild systemic hypothermia (35.0 degrees C and 34.5 degrees C) after perinatal asphyxia.
      • Akisu M.
      • Huseyinov A.
      • Yalaz M.
      • Cetin H.
      • Kultursay N.
      Selective head cooling with hypothermia suppresses the generation of platelet-activating factor in cerebrospinal fluid of newborn infants with perinatal asphyxia.
      • Debillon T.
      • Daoud P.
      • Durand P.
      • et al.
      Whole-body cooling after perinatal asphyxia: a pilot study in term neonates.
      • Gluckman P.D.
      • Wyatt J.S.
      • Azzopardi D.
      • et al.
      Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial.
      • Eicher D.J.
      • Wagner C.L.
      • Katikaneni L.P.
      • et al.
      Moderate hypothermia in neonatal encephalopathy: efficacy outcomes.
      However at the time of publication of the Guidelines 2005 for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care, there was insufficient evidence to recommend routine implementation until additional controlled randomized studies in humans had been performed.
      The International Liaison Committee on Resuscitation (ILCOR) Consensus on Science with Treatment Recommendations for Pediatric and Neonatal Patients: Neonatal Resuscitation.

      1.1 Randomized studies (2005–2009)

      Since the completion of the guidelines in February 2005 there have been two additional large randomized studies.
      • Shankaran S.
      • Laptook A.R.
      • Ehrenkranz R.A.
      • et al.
      Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy.
      • Azzopardi D.V.
      • Strohm B.
      • Edwards A.D.
      • et al.
      Moderate hypothermia to treat perinatal asphyxial encephalopathy.
      with follow-up through 18 months both demonstrating that induced hypothermia (33.5–34.5 °C) initiated within 6 h versus no treatment is associated with significantly less death and neurodevelopment disability. The criteria for entry into these studies were relatively similar: gestational age ≥36 weeks, with either perinatal complications or severe acidosis and resuscitation at birth and who had moderate or severe encephalopathy as determined clinically ± amplitude integrated EEG (aEEG) and who were admitted to the hospital at or before 6 h of age. Hypothermia was achieved via selective head cooling to a temperature of 34.5 °C or whole-body cooling to a core temperature of 33.5 °C for 72 h with rewarming to occur over at least 4 h.
      Shankaran et al. randomly assigned infants to usual care (control group) or whole-body cooling to an esophageal temperature of 33.5 °C for 72 h, followed by slow rewarming (hypothermia group) with a primary neurodevelopmental outcome of a combined end point of death or moderate or severe disability assessed at 18–22 months of age.
      • Shankaran S.
      • Laptook A.R.
      • Ehrenkranz R.A.
      • et al.
      Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy.
      Of 239 eligible infants, 102 were assigned to the hypothermia group and 106 to the control group. Death or moderate or severe disability occurred in 45 of 102 infants (44%) in the hypothermia group and 64 of 103 infants (62%) in the control group (risk ratio, 0.72; 95 percent CI, 0.54 to 0.95; P = 0.01). Twenty-four infants (24%) in the hypothermia group and 38 (37%) in the control group died (risk ratio, 0.68; 95% CI, 0.44 to 1.05; P = 0.08) with a number needed to treat (NNT) of 6. There was no increase in major disability among survivors; the rate of cerebral palsy was 15 of 77 (19%) in the hypothermia group as compared with 19 of 64 (30%) in the control group (risk ratio, 0.68; 95 percent confidence interval (CI), 0.38–1.22; P = 0.20). Adverse events were similar in the two groups during the 72 h of cooling.
      Azzopardi et al. compared intensive care plus whole-body cooling to 33.5 °C versus intensive care alone.
      • Azzopardi D.V.
      • Strohm B.
      • Edwards A.D.
      • et al.
      Moderate hypothermia to treat perinatal asphyxial encephalopathy.
      The primary outcome was death or severe disability at 18 months of age. Of 325 infants enrolled, 163 underwent intensive care with cooling, and 162 underwent intensive care alone. In the cooled group, 42 infants died and 32 survived with severe neurodevelopmental disability, whereas in the noncooled group, 44 infants died and 42 had severe disability (relative risk for either outcome, 0.86; 95% CI, 0.68 to 1.07; P = 0.17). Infants in the cooled group had an increased rate of survival without neurologic abnormality (relative risk (RR), 1.57; 95% CI, 1.16–2.12; P = 0.003). Among survivors, cooling resulted in reduced risks of cerebral palsy (RR, 0.67; 95% CI, 0.47–0.96; P = 0.03) and improved scores on the Mental Developmental Index and Psychomotor Developmental Index of the Bayley Scales of Infant Development II (P = 0.03 for each) and the Gross Motor Function Classification System (P = 0.01). Adverse events were mostly minor and not associated with cooling.
      A smaller trial with no long-term follow-up was conducted by Lin et al. Full-term newborns who had a 5 minute Apgar scores <6, first arterial blood gas pH < 7.10 or base deficit >15 mEq/l, and with the clinical signs of encephalopathy were enrolled within 6 h after birth.
      • Lin Z.L.
      • Yu H.M.
      • Lin J.
      • Chen S.Q.
      • Liang Z.Q.
      • Zhang Z.Y.
      Mild hypothermia via selective head cooling as neuroprotective therapy in term neonates with perinatal asphyxia: an experience from a single neonatal intensive care unit.
      Patients were randomized to receive mild hypothermia treatment via selective head cooling for a total of 72 h or receive routine treatment as a control. A head computed tomographic scan (CT scan) at postnatal age 5–7 days and a Neonatal Behavioral Neurological Assessment (NBNA) score at 7–10 days of life was used to quantify hypoxic-ischemic injury. A total of 58 patients (30 hypothermia, 28 controls) completed the study. Head CT scan demonstrated moderate to severe hypoxic-ischemic changes in only 4/30 cases from the hypothermic group as compared to 18/28 cases in the control group (χ2 15.97, P < 0.01). The NBNA score was improved i.e. 32 ± 2 in the hypothermic group versus 28 ± 3 in the control group, P < 0.01 (Fig. 1).
      Figure thumbnail gr1
      Fig. 1Forest plot of the effect of therapeutic hypothermia compared with standard care (normothermia) on death or disability (“events”). All infants randomly assigned to either study arm were included in the analysis. A Mantel-Haenszel fixed effects model was used to calculate risk ratios and 95% confidence intervals. Test for heterogeneity: χ2 = 0.82, degrees of freedom = 2 (P = 0.66); I2 = 0%. Test for overall effect: Z = 3.03 (P = 0.002). Studies shown are the Total Body Hypothermia (TOBY) trial,
      • Azzopardi D.V.
      • Strohm B.
      • Edwards A.D.
      • et al.
      Moderate hypothermia to treat perinatal asphyxial encephalopathy.
      the National Institute of Child Health and Human Development (NICHD) trial,
      • Shankaran S.
      • Laptook A.R.
      • Ehrenkranz R.A.
      • et al.
      Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy.
      and the Cool Cap trial.
      • Gluckman P.D.
      • Wyatt J.S.
      • Azzopardi D.
      • et al.
      Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial.
      Adapted from Ref.
      • Edwards A.D.
      • Brocklehurst P.
      • Gunn A.J.
      • et al.
      Neurological outcomes at 18 months of age after moderate hypothermia for perinatal hypoxic ischaemic encephalopathy: synthesis and meta-analysis of trial data.
      .

      2. Discussion

      Pooled analysis of the outcomes from the three randomized studies with 18 month follow-up (n = 767)
      • Gluckman P.D.
      • Wyatt J.S.
      • Azzopardi D.
      • et al.
      Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial.
      • Shankaran S.
      • Laptook A.R.
      • Ehrenkranz R.A.
      • et al.
      Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy.
      • Azzopardi D.V.
      • Strohm B.
      • Edwards A.D.
      • et al.
      Moderate hypothermia to treat perinatal asphyxial encephalopathy.
      indicate that therapeutic hypothermia significantly reduced the combined rate of death or disability (risk ratio 0.81, 95% CI 0.71–0.93, P = 0.002), with a NNT of nine (95% CI 5–25).
      • Edwards A.D.
      • Brocklehurst P.
      • Gunn A.J.
      • et al.
      Neurological outcomes at 18 months of age after moderate hypothermia for perinatal hypoxic ischaemic encephalopathy: synthesis and meta-analysis of trial data.
      Hypothermia increased survival with normal neurological function at 18 months (risk ratio 1.53, 95% CI 1.22–1.93, P < 0.001), with a NNT of eight (95% CI 5–17), and in survivors reduced the rates of severe disability (P = 0.006), cerebral palsy (P = 0.004), and mental and psychomotor developmental indices <70 (P = 0.01 and P = 0.02, respectively). No significant interaction between severity of encephalopathy and treatment effect was detected.
      The individual trials and the pooled analysis are methodically strong: the enrollment criteria were similar, the studies were randomized (although not blinded) and the outcome of infants (18 months) is at an age where most major motor and/or cognitive deficits should be readily identified. However more subtle cognitive and/or behavioral deficits will require longer follow-up. Adverse events were in general minor (hypotension and thrombocytopenia) and similar in the two groups during the 72 h of cooling.
      Given these characteristics, the findings strongly suggest that in the context of the treatment protocols outlined above, the benefits of treating infants at risk for evolving hypoxic-ischemic brain injury outway the risks irrespective of the method of cooling.

      2.1 Recommendations for offering hypothermia

      2.1.1 Selection of patients

      There is good evidence to recommend the use of mild to moderate hypothermia (33.5–34.5 °C) to newly born infants ≥36 weeks gestation with either perinatal complications or severe acidosis (cord umbilical arterial pH < 7.00, base deficit ≥16 mmol/l or postnatal pH < 7.10) and having received resuscitation at birth. Criteria should include presence of moderate or severe encephalopathy as determined clinically with or without amplitude integrated EEG (aEEG) and who have treatment applied at or before 6 h of age.

      2.1.2 Specifics of cooling

      The goal should be to initiate cooling using either selective head cooling or whole-body cooling as soon as is feasible once enrollment criteria have been met. Hypothermia should be conducted in neonatal intensive care units with the capacity of providing multidisciplinary care including electroencephalographic (EEG) monitoring, and centers should provide longitudinal follow-up care of treated infants.

      2.1.3 Gaps in knowledge

      Although hypothermia reduces the extent of brain injury, approximately 50% of treated infants still either died or have disability at 18-month follow-up.
      • Gluckman P.D.
      • Wyatt J.S.
      • Azzopardi D.
      • et al.
      Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial.
      • Shankaran S.
      • Laptook A.R.
      • Ehrenkranz R.A.
      • et al.
      Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy.
      • Azzopardi D.V.
      • Strohm B.
      • Edwards A.D.
      • et al.
      Moderate hypothermia to treat perinatal asphyxial encephalopathy.
      The mean time to initiating hypothermia in the three largest studies was approximately 4.5 h. Animal data indicate that the greatest benefit from cooling is derived when treatment is initiated closest to the time of the insult and that the effect is reduced if initiated after 6 h.
      • Gunn A.J.
      • Gunn T.R.
      • deHaan H.H.
      • Williams C.E.
      • Glucman P.D.
      Dramatic neuronal rescue with prolonged selective head cooling after ischemia in fetal lambs.
      • Gunn A.J.
      • Gunn T.R.
      • Gunning M.I.
      • Williams C.E.
      • Gluckman P.D.
      Neuroprotection with prolonged head cooling started before postischemic seizures in fetal sheep.
      • Battin M.R.
      • Penrice J.
      • Gunn T.R.
      • Gunn T.R.
      Treatment of term infants with head cooling and mild systemic hypothermia (35.0 degrees C and 34.5 degrees C) after perinatal asphyxia.
      • Akisu M.
      • Huseyinov A.
      • Yalaz M.
      • Cetin H.
      • Kultursay N.
      Selective head cooling with hypothermia suppresses the generation of platelet-activating factor in cerebrospinal fluid of newborn infants with perinatal asphyxia.
      Thus the focus should be on an earlier initiation of therapy and data should be collected on all cooled infants in order to assess any effect of earlier cooling. The potential benefit of initiating cooling during transport remains unclear
      • Eicher D.J.
      • Wagner C.L.
      • Katikaneni L.P.
      • et al.
      Moderate hypothermia in neonatal encephalopathy: efficacy outcomes.
      pending the findings of the ICE trial.
      • Jacobs S.
      • Hunt R.
      • Tarnow-Mordi W.
      • Inder T.
      • Davis P.
      Cooling for newborns with hypoxic ischemic encephalopathy.
      Conversely avoiding inadvertent hyperthermia appears to be important.
      • Wyatt J.S.
      • Gluckman P.D.
      • Liu P.Y.
      • et al.
      Determinants of outcomes after head cooling for neonatal encephalopathy.
      • Laptook A.
      • Tyson J.
      • Shankaran S.
      • et al.
      Elevated temperature after hypoxic-ischemic encephalopathy: risk factor for adverse outcomes.
      Further research is also needed to determine the optimal target temperature, duration of treatment and the rate of rewarming following hypothermia. Thus there exists a critical need for additional randomized studies to derive the maximum benefit from hypothermia.

      3. Conclusion

      Newly born infants born at term or near-term with evolving moderate to severe hypoxic-ischemic encephalopathy should be offered therapeutic hypothermia. Whole-body cooling and selective head cooling are both appropriate strategies. Cooling should be initiated and conducted under clearly defined protocols with treatment in neonatal intensive care facilities. Treatment should be consistent with the protocols used in the randomized clinical trials unless part of a subsequent randomized trial addressing knowledge gaps. Therefore treatment should commence within 6 h, continue for 72 h and rewarm over at least 4 h. Carefully monitor for known adverse effects of cooling – thrombocytopenia and hypotension. At present there is little evidence to recommend cooling commenced beyond 6 h of age. All treated infants should be followed up with serial neurodevelopmental assessments.

      Conflicts of interest

      Every effort has been made to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship or a personal, professional, or business interest of a member of the writing panel. Specifically, all members of the writing group are required to complete and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest. This statement was approved by the Neonatal Life Support Task Force of the International Liaison Committee on Resuscitation in February 2010.

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