Therapeutic hypothermia improves the chances of babies with moderate or severe hypothermia of surviving without serious disability; referrals for evaluation for therapeutic hypothermia have exploded in our center, and many others, now that this advance is widely acknowledged. Many of the babies referred had a difficult start in life, needing resuscitation and having low umbilical cord blood pH, but have only mild encephalopathy, often with a combination of signs of Sarnat stage 1 and 2.

I actually think it is a mistake to believe that we can clearly classify infants into stage 1, 2 or 3 encephalopathy, although it is a very useful classification there are many babies that have some features of stage 2 and some of stage 3, or some of stage 1 and some of stage 2. We have developed a local evaluation system that will often give babies a stage of “1.7” for example, and then are not sure whether we should cool them or not. Are they a “mild” or a “moderate”?

In general, as the randomized trials show very little adverse effect, and the benefits are clear for moderate encephalopathy, we tend to cool babies who are possibly eligible. Occasionally a decision in the other direction has come back to haunt us, when a baby who seemed to just have classical stage 1 encephalopathy then has a convulsion at 12 hours of age (for example) and we have missed the boat.

One thing that has recently given me pause is the idea that induced hypothermia in non-asphyxiated animal models might have adverse effects on cerebral development. There is at least one study (in neonatal rats) showing a decrease in hippocampal cell proliferation following therapeutic hypothermia in non-asphyxiated animals. (I thought there was another study in piglets also, but I can’t find it right now (please send it to me if you find such an article)). If that is also the case in human babies, and there are adverse CNS effects in the non-asphyxiated, but beneficial effects in the asphyxiated, then there may be babies that we are currently treating with hypothermia who are not having a benefit, but may, rather, be having a negative effect.

But also, it may well be that mild encephalopathy is not as benign as we used to think. I was taught, based on good data (published by my mentor and great friend Neil Finer), that stage 1 encephalopathy did not increase impairment, stage 3 babies were all either dead or seriously impaired at 1 year of age, and stage 2 babies were in between (about 40% serious impairment). If stage 1, mild encephalopathy babies all do well, then we should spare them the rigours of therapeutic hypothermia, and the possible theoretical risks: is this true?

My concerns about this situation are obviously shared by others, there is an explosion of articles about babies with mild encephalopathy recently.

Murray DM, et al. Early EEG Grade and Outcome at 5 Years After Mild Neonatal Hypoxic Ischemic Encephalopathy. Pediatrics. 2016. This well-done study (from the great group in Cork) compared outcomes among 22 babies with mild encephalopathy who were evaluated at 5 years of age to 30 controls. The mild encephalopathy group had significantly lower IQ scores (99 on average) compared to the controls (mean=117, smart kids, the Irish!), the mean IQs for the moderate encephalopathy group were similar to the mild infants, but they had a range of other problems, so fewer of them were considered “non-impaired” at 5 years. The EEG at 24 hours (but not so much at 6 hours) helped to predict the full scale IQ at 5 years.

Gagne-Loranger M, et al. Newborns Referred for Therapeutic Hypothermia: Association between Initial Degree of Encephalopathy and Severity of Brain Injury (What About the Newborns with Mild Encephalopathy on Admission?). American journal of perinatology. 2016;33(2):195-202. This study from Pia Wintermark and the group at McGill (the second best group in Montreal ;-)), showed that, of the babies referred for possible hypothermia, there were 50 who had mild encephalopathy at admission who had an MRI, 20 of them had MRI abnormalities and 5 of those had very severe abnormalities. In the figure below BG/W score is a score for MRI abnormalities in the basal ganglia and white matter.

The authors note that many of the mild encephalopathy babies worsened clinically during the first hours of life.

Walsh BH, et al. The Frequency and Severity of Magnetic Resonance Imaging Abnormalities in Infants with Mild Neonatal Encephalopathy. The Journal of pediatrics. 2017. This study from Terrie Inder’s group in Boston examined the prevalence of MRI abnormalities among babies who were cooled; they had 48 babies with mild encephalopathy, more than half of whom had an MRI abnormality during the first week. They were just as likely to have watershed injuries as babies with more severe encephalopathy, but less likely to have basal ganglia injuries.

One thing that happens when you cool babies with mild encephalopathy is that they often appear uncomfortable, they are irritable and cry a great deal, and may seem to need sedation. We sometimes, therefore, consider interrupting the cooling, or add potentially toxic sedatives to their therapy. Sometimes the babies improve so much that they don’t have many signs of encephalopathy, and we think they no longer qualify for hypothermia. Although we don’t know for sure what to do for such babies, this study is informative. Lally PJ, et al. Residual brain injury after early discontinuation of cooling therapy in mild neonatal encephalopathy. Archives of disease in childhood Fetal and neonatal edition. 2017. This article reports 10 babies in whom hypothermia was discontinued early, in each case because they had improved so much they no longer seemed eligible for the treatment. Half of them nevertheless had MRI abnormalities, and 20% had abnormal long-term outcomes at 2 years of age.

Prempunpong C, et al. Prospective research on infants with mild encephalopathy: the PRIME study. J Perinatol. 2017. This is a prospective multi-center cohort of babies with mild encephalopathy who were not treated with hypothermia, led by my friend and former fellow Guilherme Sant’anna. Their definition of an adverse neurological outcome was an abnormal aEEG within the first 9 hours of life, an abnormal MRI, or an abnormal neurological exam at discharge. Of the 54 babies with adequate data, just over half, (n=28) had abnormalities.

I am still not sure how to put all this together. The studies used for my own training, when you examine the data more closely, do show, even 40 years ago, a small signal suggesting worse outcomes for babies who had mild, Sarnat stage 1, HIE.

This now seems to be confirmed. Mild encephalopathy following perinatal adverse events is probably not benign; even serious outcomes may sometimes follow. For the moment, I think if I am unsure about whether to cool a baby, and they have clear signs of being at least a Sarnat stage 1 HIE, then I will start therapeutic hypothermia, and try to continue for 72 hours. What to do for the babies that are very uncomfortable and seem to need sedation isn’t clear to me, I think a morphine infusion is probably the least toxic alternative, but I am not at all sure about that.

But…. the studies showing the greatest proportion of adversely affected infants after mild HIE are those of babies who were treated with hypothermia, when you compare them to studies of mild HIE babies who were not cooled.

One interpretation of this could be that hypothermia worsens the outcomes of mild HIE. Another might well be that we are good at selecting the babies, among the mildly affected, who are more severely impacted, and that we don’t cool the babies at lowest risk. This is always a problem with observational studies, causation is impossible to ascribe.

There is really only one way to answer these unknowns.

You probably don’t need to guess…

A large multi-center RCT of therapeutic hypothermia is essential; criteria for cooling in such a trial need to be exquisitely clearly defined, so that they can be applied prospectively for future generations.