Patient selection and prognostication with hypothermia treatment Marianne Thoresen * Department of Child Health, University of Bristol, Level D, Child Health, St Michael’s Hospital, Bristol BS2 8EG, UK Keywords: Amplitude-integrated EEG Hypothermia Normothermia Outcome prediction Patient selection Perinatal asphyxia summary For infants with perinatal hypoxiaeischaemia, 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 discus- sions 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. Ó 2010 Elsevier Ltd. All rights reserved. 1. Introduction There is a considerable literature evaluating the positive predictive value (PPV) of clinical signs and examinations from birth onwards in cases of hypoxiceischaemic 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 electro- physiological 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 trials 2e4 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. 2. 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 (P ¼ 0.06). If anything, the clinical markers suggest that the TOBY infants were actually more severely affected at entry than CoolCap because the propor- tion of severely abnormal amplitude-integrated aEEG before ran- domisation was 60% in TOBY 3 compared with just 34% in CC. 2 Population-based variability may explain the findings of rand- omised pilot trials in Africa and India where there was a strong trend towards increased mortality in the cooled groups. 5,6 We do not know whether this effect was due to HT in combination with infection perhaps being less effective than in uninfected infants. However, some experimental work suggests that being stressed and unsedated while cold might counteract the neuroprotective effect of HT. 7 Therefore it appears that at present HT should only be considered in those settings where full intensive care is available. 3. 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 chro- mosomal 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 initially defined based on animal data. 8 Now that we know HT is effective and was not associated with serious adverse effects, we have the possibility of refining the treatment protocols and entry criteria. * Tel.: þ44 1173 425607/5226; fax: þ44 1173 425751. E-mail address: marianne.thoresen@bristol.ac.uk. Contents lists available at ScienceDirect Seminars in Fetal & Neonatal Medicine journal homepage: www.elsevier.com/locate/siny 1744-165X/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.siny.2010.05.008 Seminars in Fetal & Neonatal Medicine 15 (2010) 247e252