Patient selection and prognostication with hypothermia treatment

https://doi.org/10.1016/j.siny.2010.05.008Get rights and content

Summary

For infants with perinatal hypoxia–ischaemia, the ability to give an accurate prognosis at different ages enables the clinician to make decisions on the continuation of management, and also assists in discussions regarding further treatment and prognosis with parents and families. This review suggests which outcome markers are still valid, which need new ‘cut-off values’ and which can no longer be used in cooled infants. The main focus is on convenient bedside technologies such as the amplitude-integrated electroencephalogram that can be easily applied in routine clinical practice.

Introduction

There is a considerable literature evaluating the positive predictive value (PPV) of clinical signs and examinations from birth onwards in cases of hypoxic–ischaemic encephalopathy (HIE, Table 1).1 A combination of early predictors such as condition at birth, blood gas values, neurological examination and single channel electroencephalography (EEG) were used to select eligible infants in the first large cooling trials. In trying out a new treatment with potential severe adverse effects it is conventional to select a group of patients who, without treatment, have a very poor prognosis. A combination of clinical biochemical and neurological and electrophysiological data (Table 2) have been used successfully in recent trials of hypothermia (HT) for neonatal HIE to select a group of infants who are at high risk of death or disability. For example, in the CoolCap trial, poor outcome (death or severe disability) was predicted to occur in 70% of the infants and indeed 66% of those receiving standard care subsequently had a poor outcome.2 The three large published cooling trials2, 3, 4 reported that there were no differences between cooled and non-cooled infants in other, systemic, adverse effects that would be likely to affect infants’ neurological prognosis, acutely or up to 18 months of age.

Section snippets

How consistent are current selection criteria?

It is very important that published data from normothermic (NT) infants are transferable to other populations as well as valid over time. There are some interesting discrepancies between trials that are still unexplained. The recent TOBY trial recruited 90% from a UK population and CoolCap (CC) 90% from a US population. The entry criteria were identical apart from TOBY allowing entry until 6.0 h and CoolCap 5.5 h (Table 1), and yet TOBY observed only a 53% poor outcome compared to 66% in CoolCap (

Whom have we cooled?

The infants selected in the major trials were nearly all ≥36 weeks of gestation, aged <6 h and did not have physical or chromosomal anomalies. This is of course necessary in a trial since having other medical problems potentially affecting outcome may confound any effect of HT. Before 1999 we did not know the potential for adverse effects with HT, and hence the primary outcomes and exclusion criteria were decided based upon caution. The duration, degree and therapeutic time window of HT were

Who else may be suitable for cooling?

The demographics of the patients who have been included in the large scale cooling trials are outlined in Table 2. As explained earlier, these trials exclude preterm infants, and often other significant underlying medical problems. However, this obviously excludes a significant proportion of infants who may benefit from HT.

Mild, Sarnat grade 1 asphyxia: do they all do well? Should we consider cooling this group?

In the CoolCap trial, infants with grade 1 asphyxia were excluded from entry, although a small proportion of included patients (∼5%) were classified as grade 1 (with or without seizures) and one-third of these did not develop normally.2 In our recent study of aEEG in NT and HT infants, we also found in the NT group that one-third of those with grade 1 encephalopathy did not develop normally.18 It has recently been shown that there is a relationship between Apgar score at 1 min and IQ at 18 years

Chromosomal abnormalities

We (Bristol, UK) offer HT to all children who would otherwise receive intensive care to support their survival after birth. We have no experience in cooling a child with Down syndrome, only one with a translocation and deletion of the long arm on chromosome 4. This child had normal magnetic resonance imaging. The child developed a pattern of developmental24 delay typical for this chromosomal disorder.

Surgical abnormalities

An infant born with moderate asphyxia was cooled and a tracheal–oesophageal fistula was

Infants with seizures and neonatal stroke

There is no curative treatment available for this group of infants. It has been argued that the time period from ischaemia/haemorrhage until seizures present is so long that HT is unlikely to be protective after neonatal stroke. We do not know however the delay between the insult and the presentation of seizures. Experimentally animals can seize within minutes after an insult. In the cooling trials (Table 1) >50% of infants developed seizures before recruitment, at a mean of 4.7 h after birth.

Prognostic markers in HIE

Robust, reliable early predictors are very important to determine as they may both select infants for therapy and guide withdrawal of care. There are currently three major predictors of mortality and morbidity in cases of HIE, namely the Apgar score, aEEG and Sarnat score (see Table 1). These tools are vital in both assisting in decisions regarding who should be cooled, and in determining their overall prognosis. It is therefore vital to understand the relationship between Apgar scores, aEEG,

Apgar scores

One predictor of short term outcomes that has stood the test of time is the Apgar score. First published in 195328 and revalidated in 2001,29 no other clinical marker has proven better in predicting neonatal survival. A pertinent question is therefore whether Apgar scores change prediction when the infants go on to be cooled after birth. The full five-item Apgar score has not been evaluated in HT versus NT infants, whereas the heart rate element of the score has.

Current 2005 International

Lactate as a biochemical hypoxia marker

Lactate, an anaerobic end product of glucose metabolism, is a direct marker of global tissue hypoxia. Although both single and serial lactate measurements have been used to predict the degree of encephalopathy in HIE, and sustained lactic acidosis has been correlated with ‘seizure burden’, lactate values are not used in prediction of outcome.43 With regard to cooling therapy it is relevant whether temperature per se affects the metabolism of lactate, hence affects the values measured. We have

Early predictors by 1.5 h of age

In a retrospective single centre study we assessed whether HT changes the validity of outcome predictors derived from normothermic encephalopathic term infants. Clinical or biochemical parameters at 1.5–6 h were assessed in 47 non-cooled and 49 cooled infants with neonatal encephalopathy included in pilot and RCTs. Outcome was assessed at 18 months of age.

In the ‘cooled’ group at 1.5 h of age, out of 12 predictors and a 50% event rate, two factors were independently predictive; base deficit at 1.5

References (43)

  • S. Shankaran et al.

    Whole-body hypothermia for neonates with hypoxic–ischemic encephalopathy

    N Engl J Med

    (2005)
  • S. Thayyil et al.

    Therapeutic hypothermia for neonatal encephalopathy. Implications for neonatal units in India

    Indian Pediatr

    (2009)
  • M. Thoresen et al.

    Twenty-four hours of mild hypothermia in unsedated newborn pigs starting after a severe global hypoxic–ischemic insult is not neuroprotective

    Pediatr Res

    (2001)
  • S.A. Bernard et al.

    Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia

    N Engl J Med

    (2002)
  • Group HaCAS

    Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest

    N Engl J Med

    (2002)
  • Chakkarapani E, Liu X, Hoque N, et al. Xenon hypothermia combination enhances neuroprotection after perinatal asphyxia....
  • A.J. Gunn et al.

    Dramatic neuronal rescue with prolonged selective head cooling after ischemia in fetal lambs

    J Clin Invest

    (1997)
  • G. Compagnoni et al.

    Safety of deep hypothermia in treating neonatal asphyxia

    Neonatology

    (2008)
  • M. Karlsson et al.

    Delayed hypothermia as selective head cooling or whole body cooling does not protect brain or body in newborn pig subjected to hypoxia–ischemia

    Pediatr Res

    (2008)
  • G.L. Clifton et al.

    Hypothermia on admission in patients with severe brain injury

    J Neurotrauma

    (2002)
  • A.D. Edwards et al.

    Neurological outcome at 18 months of age following moderate hypothermia in newborn infants with hypoxic ischaemic encephalopathy

    BMJ

    (2010)

    • Cited by (24)

    • Volumetric changes in brain MRI of infants with hypoxic-ischemic encephalopathy and abnormal neurodevelopment who underwent therapeutic hypothermia

      2024, Brain Research

    • MRI combined with early clinical variables are excellent outcome predictors for newborn infants undergoing therapeutic hypothermia after perinatal asphyxia

      2021, EClinicalMedicine
      Citation Excerpt :

      We summated these regional scores as a Total Injury Score (TIS) providing a continuum from 0 (all normal) to 11 (maximum lesion load) to quantify injury and predict outcome on a binary basis [21]. We have previously explored traditional clinical/biochemical factors as outcome predictors [22,23]. These are the severity pattern of aEEG, [21,24] the peak LDH (LDHpeak), LDH value at 72h (LDH72h), [25,26] time for plasma lactate to fall below 5 mmol (lactatehrs<5mmol) [21] and the number of inotropic and anticonvulsant drugs used during TH [27] as proxy-markers for hypotension and seizure burden respectively.

    • Therapeutic hypothermia for neonates with hypoxic ischemic encephalopathy

      2017, Pediatrics and Neonatology
      Citation Excerpt :

      Sustained lactic acidosis has been correlated with so-called seizure burden, but lactate values were not used to predict outcomes.57 In a subset of patients in a clinical asphyxia database, at least five plasma samples were obtained during the 1st 24 hours of life from each of 33 NT and 21 TH infants; data showed that at all time points the plasma lactate values were similar between NT and HT infants.41 A small study found that higher serum levels of lactate following TH were associated with poor neurodevelopmental outcomes in neonates with HIE.4

    • Electroencephalography in the Preterm and Term Infant

      2017, Fetal and Neonatal Physiology, 2-Volume Set

    • Use of therapeutic hypothermia in sudden unexpected postnatal collapse

      2014, Archives de Pediatrie

    • Therapeutic hypothermia in at term or near term newborns with hypoxic-ischemic encephalopathy

      2013, Anales de Pediatria Continuada
    View all citing articles on Scopus
    View full text
    Copyright © 2010 Elsevier Ltd. All rights reserved.