Therapeutic Hypothermia: How Can We Optimize This Therapy to Further Improve Outcomes?

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Key points

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    Therapeutic hypothermia to 33.0°C to 34.0°C for moderate to severe hypoxic-ischemic encephalopathy has been demonstrated to be safe and efficacious in reducing death and disability.

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    In addition to the biochemical criteria, evidence of moderate or severe encephalopathy on neurologic examination is a prerequisite to cooling; serial examinations have prognostic utility.

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    Avoidance of hypocarbia, hyperoxia, and glucose derangements and detection and control of seizures during cooling are important to

Current rates of mortality and disability following hypothermia therapy

Neonatal encephalopathy is a condition of disordered neonatal brain function and is associated with many risk factors. The incidence of neonatal encephalopathy is estimated to be 3.0 per 1000 live births. Neonatal encephalopathy due to hypoxic-ischemic events is a subset of neonatal encephalopathy and occurs in 1.5 per 1000 livebirths. About 15% to 20% of affected newborns die in the postnatal period, and an additional 25% will sustain childhood disabilities.1 Six randomized clinical trials of

How effective is therapeutic hypothermia?

TH is an effective therapy to reduce death or disability at 18 months of age after moderate or severe neonatal HIE (typical relative risk [RR] 0.75, 95% confidence interval [CI] 0.68–0.83).11 TH was also associated with significant reduction in mortality and in disability in survivors.11 The number needed to treat (NNT) to prevent one case of death or disability is 7,11 much lower than the NNT of adults receiving statins to prevent cardiovascular disease (n = 72)13 or that of neonates receiving

Selection of neonates for therapeutic hypothermia

It is important to select the appropriate neonates for hypothermia therapy; the safety and efficacy of this therapy has been demonstrated only for neonates with moderate or severe HIE.11, 15 All the clinical trials have had a 2-step process of selection, initially with biochemical evidence of hypoxia-ischemia followed by evolving moderate or severe encephalopathy. In the NICHD NRN trials,3, 12 acidosis was required at birth on cord pH or the first blood gas within 1 hour of age (pH <7.0 or base

The neurologic examination for moderate or severe encephalopathy

The clinical trials of hypothermia for neonatal HIE have required 3 or more out of 6 abnormalities in the moderate or severe categories of the neurologic examination or clinical seizures within 6 hours of age for trial eligibility. The CoolCap and TOBY (Total Body Hypothermia for Neonatal Encephalopathy) trials mandated that one of the abnormal categories of the neurologic examination needed to be level of consciousness, and they both also required an abnormal amplitude integrated

Time to initiation of cooling and transport cooling

In both the NICHD NRN and TOBY trials, neither time to initiation of cooling nor location of birth (inborn vs out-born) impacted outcome, although enrollment heavily clustered around 3 to 4 hours.4, 15, 17 However, in the most recent NICHD NRN trial of usual cooling compared with longer and deeper cooling, the mortality and disability rates were lower in the usual care cooled group; time to initiation of cooling was earlier in spite of more out-born infants when compared with the first NICHD

Delivery room management

A persistently low Apgar score at 10 minutes is associated with death or moderate/severe disability at 18 months and also at 6 to 7 years of age.24, 25 However, not all infants with a 10-minute Apgar score of 3 or less had a uniformly poor outcome; 20% of children with a score of 0 at 10 minutes survived without disability at school age.25

Optimum duration of cooling

Early discontinuation of cooling due to clinical improvement has been reported in registry data26; this practice should be discouraged, as evidence of brain injury has been noted with incomplete cooling following mild encephalopathy.27

Management of elevated temperature

Elevated temperature in the control group of the NICHD NRN and CoolCap trials was associated with higher risk of death or disability compared with noncooled infants without elevated temperatures after controlling for stage of encephalopathy, race, and sex.28, 29 In the NICHD NRN childhood follow-up data, the association with elevated temperature and death or IQ less than 70 was still present.30 Brain temperature measured with magnetic resonance spectroscopy reveals a higher temperature among

Hemodynamic stability during therapeutic hypothermia

The link between cerebral ischemia and cardiac dysfunction is unclear; but HIE is associated with multi-organ dysfunction, including myocardial dysfunction.15, 32 Cooling may exacerbate blood pressure and temperature instability, especially in smaller sicker infants during induction and maintenance of cooling,33 hence, the need to provide hemodynamic support during cooling and rewarming.34

Hypocarbia during therapeutic hypothermia

The cumulative exposure to hypocarbia in the early phase of TH was linked with a higher risk of death or disability at 18 months of age in the NICHD NRN’s first randomized controlled trial (RCT).35 The CoolCap data noted that Pco2 during the 72 hours of TH was inversely related to an unfavorable outcome after adjustment for HIE severity and other confounding variables.36 Low carbon dioxide levels may impact cerebral perfusion, thus, exacerbating the risk of brain injury. Thus, it is essential

Hyperoxemia during therapeutic hypothermia

In an evaluation of infants with birth acidosis, hyperoxemia during the first hour of life was associated with a higher incidence of encephalopathy; among infants with HIE who had a brain MRI, there was a higher incidence of brain injury.37 An association between an increased inspired oxygen concentration during the first 6 hours of life and an adverse outcome (death or Bayley II Mental Developmental Index or Psychomotor Index <70) was noted in another study, although no association was found

Hypoglycemia and hyperglycemia during therapeutic hypothermia

In a single-center study conducted between 1994 and 2010, 15 of 94 (16%) neonates with neonatal encephalopathy and early brain imaging studies had hypoglycemia (glucose values <46 mg/dL) in the first 24 hours after birth. TH was provided for 10 infants in the no-hypoglycemia group (n = 79) and one infant in the hypoglycemia group. Among all infants, hypoglycemia was associated with an increased risk of corticospinal tract injury on brain MRI imaging and lower Bayley II Psychomotor Developmental

Seizures during therapeutic hypothermia

In the NICHD NRN RCT, 127 of 208 neonates had clinical seizures at less than 6 hours of age. In the univariate analysis, death or disability at 18 months of age was associated with seizures and severe HIE; on multivariate analysis, seizures no longer had an independent effect on outcomes.41 It should be noted that clinical seizures may not always represent electrographic seizures and instead may be abnormal movements. In another study in 47 neonates with HIE who underwent continuous

Cerebral functioning monitoring at less than 6 hours of age

Both the CoolCap and TOBY trials had an abnormal aEEG as an eligibility criterion, in addition to birth acidosis or need for resuscitation and moderate or severe encephalopathy.2, 4 Death or disability was lower among infants who had a less severely abnormal background aEEG pattern, and an absence of seizures on the aEEG was associated with a better outcome in the CoolCap trial.2 The effect of cooling did not vary according to the severity of the abnormality on the aEEG.29 In an observational

Use of sedation-analgesia during therapeutic hypothermia

The administration of sedation, analgesia, and neuromuscular blockade during TH for neonatal HIE is determined by center and clinician preferences and may be a surrogate of the severity of illness. Of the neonatal trials of TH, only the neo.nEURO.network hypothermia randomized controlled trial treated all infants with morphine (0.1 mg/kg) or an equivalent dose of fentanyl every 4 hours or by continuous infusion.5 In the TOBY trial, all infants underwent sedation with morphine infusions or with

Assessment of serum biomarkers

The assessment of the utility of serum biomarkers in HIE is an area of active research. Two markers, ubiquitin carboxyl-terminal esterase Li (UCHL1), known to be released from neurons following cardiac arrest, and glial fibrillary acidic protein (GFAP), released from astrocytes following possible hypoxia during extracorporeal oxygenation, were measured in neonates with HIE undergoing cooling. The markers were elevated at differing time points; infants with brain injury on MRI had higher UCHL1

Heart rate variability

Monitoring of heart rate variability is a useful adjunct tool to assess the severity of HIE in infants undergoing TH.56 Depressed heart rate variability (the normalized RR interval also known as the NN interval) correlates well with the EEG and the neurodevelopmental outcome; a lower NN value is seen with a more severe EEG grade of HIE and with an abnormal neurodevelopmental outcome at 2 years.57, 58

Neuroimaging for neonates undergoing therapeutic hypothermia

The MRI findings among 131 of 325 infants who participated in the TOBY trial, performed at a mean age of 8 days, demonstrated that TH reduced injury in the basal ganglia and thalamus (BGT) (OR [95% CI] 0.36 [0.15–0.84]), the posterior limb of the internal capsule (PLIC) (0.38 [0.17–0.85]), and white matter (WM), (0.30 [0.12–0.77]) among cooled infants compared with the noncooled group. There was no reduction of signal abnormalities in the cortex. Cooled infants were more likely to have normal

Withdrawal of support or decision to redirect care in the neonatal intensive care unit following therapeutic hypothermia

The mortality rate of neonates undergoing TH for moderate/severe HIE in the first NICHD NRN3 trial was 19% in the cooled arm (72 hours at 33.5°C), whereas the mortality rate in the trial comparing usual depth and duration with longer and deeper cooling was 8 of 92 (9%) in the 33.5°C for 72 hours group.12 Withdrawal of support occurred among 12 of 24 infants who died in the hypothermia group in the first NICHD NRN trial3; in the Optimizing Cooling strategies trial, among the infants assigned to

Follow-up of infants who receive therapeutic hypothermia

The major RCTs of TH for neonatal moderate/severe HIE have all reported outcomes at 18 or 24 months.2, 3, 4, 5, 6, 7 The 6- to 7-year outcome of the CoolCap trial was assessed by parent interview with the WeeFIM, a pediatric functional independence measure, among 62 of 135 surviving children; disability rates at 18 months were strongly associated with WeeFIM ratings in childhood, and there was no significant effect of treatment.8 The NICHD NRN trial evaluated 91% of trial participants at 6 to

Summary

Based on the evidence presented, to optimize TH for neonatal HIE, cooling should be limited to infants with moderate or severe encephalopathy by following the eligibility criteria of the clinical trials. A careful neurologic examination for eligibility should be performed after the infant has been resuscitated and stabilized after birth. Serial neurologic examinations should be performed during TH and at discharge to assess prognosis. During TH, avoid hypocarbia, hypoxemia, and hyperoxemia and

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      This is of critical importance because treatment with hypothermia is not neuroprotective after exposure to severe HI in neonatal rats (Sabir et al., 2012). Treatment of infants after exposure to HIE is often delayed either because the time of the onset of injury before birth is not known and/or because the treatment requires evaluation and stabilization after birth (Higgins et al., 2011; Natarajan et al., 2018). Hypothermic treatment of infants with HIE is most effective when started within six hours after birth (Gunn et al., 1997; Shankaran et al., 2012).

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    Funding: Funded by NIH: U10 HD 21385; U10 HD 27904.

    Disclosures: The authors have no relationship with any commercial company that has a direct financial interest in subject matter or materials discussed in the article or with a company making a competing product.

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