Prolonged mild-to-moderate hypothermia has been shown to be efficacious in reducing post-ischaemic neurological injury in the term newborn population. Infants subjected to a hypoxic insult demonstrate variable multi-organ impairment which may impact on drug pharmacokinetics and pharmacodynamics, for example drugs excreted by the kidneys may accumulate due to the renal impairment. However, hypothermia itself may impact on the responses to drugs.
Hypothermia causes the redistribution of regional blood flow, which may significantly impact on both drug distribution and clearance. It has been associated with decreased GFR in a number of animal studies, and may, therefore, impair the renal excretion of drugs in humans.
Many drugs, especially those metabolised in the liver, are modulated by enzymes that exhibit a temperature dependency that can be affected by therapeutic hypothermia. Depending on the action of the enzyme on the drug metabolism, therapeutic hypothermia can lead to lack of action of some drugs and accumulation of others. The additional difficulty is that whilst drug metabolism may be affected by hypothermia, it can also change during re-warming 72 hours after hypothermia has elapsed. Drugs with a large volume of distribution given before the start of hypothermia can be sequestered in peripheral tissues at the onset of hypothermia and may undergo recirculation upon re-warming, exposing the patient to higher serum concentrations and a greater risk of toxicity. It should not be forgotten that the baby undergoing therapeutic hypothermia will have, in many cases, suffered hepatic and renal injuries and that this too can greatly impact on how the baby handles the drugs that are given.
Table 4 lists most of the drugs that are used in asphyxiated infants undergoing therapeutic hypothermia; it explains where there is a known significant effect on that drug’s efficacy due to altered metabolism. This list is not exhaustive but instead reflects merely those drugs in frequent use in this population and also those drugs for which information is available. Further information is available on the website commentary.
Table 4 Effects of therapeutic hypothermia on medications.
| Drug | Effect of hypothermia | Suggested dose adjustments during hypothermia |
| Antibiotics | ||
| Gentamicin | Conflicting reports because of co-existing renal injury. Data suggest a 25–33% reduction in renal clearance | Give a dose of 4 mg/kg every 36 hours |
| Measure serum levels | ||
| Vancomycin | No data in neonates (in adults undergoing cardiac by-pass, there appears to be no effect). It is unusual for this drug to be used in treating early onset sepsis. | No data in neonates |
| Penicillin and other β-lactam antibiotics | The pharmacokinetics of these antibiotics during hypothermia have not yet been studied, however, because of their safe profiles, any effect, if there is one, is unlikely to be of any clinical significance. | No dose adjustment necessary |
| Anticonvulsants | ||
| Phenobarbital | Reduced clearance during hypothermia, some reports suggest a doubling of the half-life; however, this does not appear to have a clinically relevant effect. | Give single loading dose of 20 mg/kg |
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