On the Importance of Serendipity


Professor Alistair Gunn, Departments of Physiology and Paediatrics, University of Auckland, Auckland, New Zealand.

Therapeutic hypothermia is a dream revisited, first suggested in antiquity (1). The possibility that it could improve recovery after a period of hypoxia-ischemia at birth was first tested in small uncontrolled studies in the 1950s and 1960s (2). In those first studies, infants who were not breathing spontaneously at 5 minutes after birth were immersed in cold water until respiration began and then allowed to spontaneously rewarm over many hours. Unfortunately, the concept was abandoned because of Silverman’s finding of greater mortality in preterm infants who were allowed to become even mildly hypothermic (3). Thus, for a long time hypothermia was discounted as a dangerous fad.

In the 1980’s the new fashion was excitotoxicity, and many new, highly specific drugs were developed. The excitatory neurotransmitter glutamate is central to seizures of all kinds, and there was a growing evidence base that this group of drugs was highly neuroprotective during and in hypoxia-ischemia. Thus, as a trainee in Paediatrics, I thought it would be wonderful to see if one of these new drugs could both stop seizures and reduce brain damage. This was not in anyway an original concept, but potentially useful. We had already established animal models of hypoxia-ischemia that led to delayed seizures, so I started with the simplest, using baby rats. In the first, preliminary studies, I found that the drug given after hypoxia did seem to be reducing brain infarction but also caused apneoa and mortality in the rats. Not good. I tried different doses; same problem. During this, I noticed by accident that the baby rats felt cold during recovery. Brain wave; hypothermia increases mortality, so if we keep the rats warm, we can have neuroprotection without the drug related risks! To cut a long story short what actually happened was that the apparent neuroprotection went away.

At that point, it struck me that it would be a lot simpler to cut out the middleman and just study hypothermia directly, and that this should be done in a more controlled setting such as our fetal model of ischemic injury. This protocol seemed ideal because it leads to a stable pattern of evolving injury with delayed onset of brain cell swelling, energy failure and then seizures (4). More important, the in utero environment would avoid inadvertent cooling in controls. Many people contributed to this work, but the most critical, was my late mother, Tania Gunn an experienced neonatologist and researcher in the birth transition. She had already worked out how to cool a fetus in utero as part of physiological studies, so I had the privilege of asking her to collaborate. I was enough of a clinician to understand that there was no way that we would ever be able to start any new treatment immediately after birth so in my first trials I planned to cooling at the earliest time that seemed remotely possible, 90 minutes after reperfusion. We continued hypothermia for 72h as an initial guess, until the period of delayed seizures and brain swelling had settled down. By the second study it was obvious to both of us that this delayed cooling totally stopped the delayed cell swelling and improved recovery of EEG activity (5). We then tested even greater delay to 5.5 h and 8.5 h after reperfusion, and showed that cooling was still partially protective, but only if it could be started before the onset of delayed seizures (6).

We found only minor other effects of head cooling in the fetal sheep. What about babies? We knew that sick babies would be at risk of low blood sugars and respiratory problems? Still, clinicians manage side effects all the time, provided that they understand what will happen. What we did was to undertake the most cautious randomized safety study ever, in babies with encephalopathy to define the point at which these effects would need to be managed. The first group were cooled just the low end of normal, then the next group to 0.5 deg C, and so forth. To our extreme surprise none of the anticipated problems emerged; that is to say, for example some babies had hypoglycemia and many had severe respiratory distress, but no different from the randomized controls (7). As part of this study, follow showed that the clinical Sarnat neurological examination before starting cooling was, not perfect, but still acceptably predictive of outcomes (8). This combination of findings; a potentially dramatically protective intervention, good safety and a reasonable criteria for recruitment led to the first large, randomised trial of head cooling, in collaboration with an American company (9), and other trials around the world. Together these trials have shown that cooling reduces brain damage in about one in six babies, providing the first practical and effective treatment for this devastating problem (10). The key to this progress was taking advantage of the serendipitous finding that drug associated neuroprotection was often confounded by hypothermia.

 

  • 1. Floyer J 1722 An essay to restore the dipping of infants in their baptism; with a dialogue betwixt a curate and a practitioner, concerning the manner of immersion. Holland, London, p 79.
  • 2. Miller JA, Jr., Miller FS. Mechanisms of hypothermic protection against anoxia. Adv Exp Med Biol 1972; 33:571-586.
  • 3. Silverman WA, Fertig JW, Berger AP. The influence of the thermal environment upon the survival of newly born premature infants. Pediatrics 1958; 22:876-886.
  • 4. Williams CE, Gunn AJ, Mallard C, Gluckman PD. Outcome after ischemia in the developing sheep brain: an electroencephalographic and histological study. Ann Neurol 1992; 31:14-21.
  • 5. Gunn AJ, Gunn TR, de Haan HH, Williams CE, Gluckman PD. Dramatic neuronal rescue with prolonged selective head cooling after ischemia in fetal lambs. J Clin Invest 1997; 99:248-256.
  • 6. Gunn AJ, Gunn TR, Gunning MI, Williams CE, Gluckman PD. Neuroprotection with prolonged head cooling started before postischemic seizures in fetal sheep. Pediatrics 1998; 102:1098-1106.
  • 7. Gunn AJ, Gluckman PD, Gunn TR. Selective head cooling in newborn infants after perinatal asphyxia: a safety study.
  • 8. Battin MR, Dezoete JA, Gunn TR, Gluckman PD, Gunn AJ. Neurodevelopmental outcome of infants treated with head cooling after perinatal asphyxia. Pediatrics 2001; 107:480-484.
  • 9. Gluckman PD, Wyatt JS, et al. Selective head cooling with mild systemic hypothermia to improve neurodevelopmental outcome following neonatal encephalopathy. Lancet 2005; 365:663-670.
  • 10. Gunn AJ, Gluckman PD. Head cooling for neonatal encephalopathy: the state of the art. Clin Obstet Gynecol 2007; 50:636-651.

 

 

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