Thermopharmacology of anticonvulsive treatment after perinatal asphyxia

Therapeutic hypothermia in the immediate postnatal period has been shown to be a successful strategy for neuroprotection in encephalopathic newborns in clinical trials. Due to the effect of hypothermia on physiological functions, such as heart rate and liver enzyme metabolic capacity, as well as effects on physico-chemical properties of the drugs, such as lipophilicity, pharmacokinetic and pharmacodynamic parameters may change. Depending on the mode of action and the route of inactivation/elimination, drugs are affected in a different way. We called the discipline that involves the investigation of drug effects as a function of body temperature, the effect of body temperature on drug disposition as well as the investigation of drug effects upon temperature homeostasis (or thermoregulation), “thermopharmacology”. The effect of therapeutic hypothermia on the clinical efficacy and safety of anticonvulsive treatment with phenobarbital, midazolam and lidocaine were studied in the prospective SHIVER study on the NICUs of the UMC Utrecht and the Isala Clinics, Zwolle. Clinicians are reluctant to prescribe (high) doses of phenobarbital in asphyxiated newborns because suppression of the aEEG background pattern has been noted to occur. We developed a pharmacokinetic-pharmacodynamic model using a multi-level Markov transition model to evaluate the safety and efficacy. Administration of phenobarbital under hypothermia seems to reduce the transition rate from Continuous Normal Voltage to Discontinuous Normal Voltage aEEG background level in hypothermic asphyxiated newborns, which may be attributed to additional neuroprotection. No (clinically relevant) thermopharmacological effect of moderate therapeutic hypothermia on phenobarbital pharmacokinetics could be identified. The observed responsiveness in our study population was 66%, which may be further increased if phenobarbital dosages in all newborns are increased to 40 mg/kg before switching to a second-line antiepileptic drug. Midazolam is notorious for its hypotensive adverse effects. Hypotension should be avoided, since it may cause neurological effects due to transient cerebral hypoperfusion, in particular during pressure-passive circulation in asphyxiated neonates. In our study population, 64% of the newborns experienced at least one hypotensive episode under midazolam treatment. With the developed pharmacokinetic-pharmacodynamic model we identified a relationship between the midazolam plasma concentration and decrease from baseline Mean Arterial Pressure. No effect of therapeutic hypothermia on drug exposure could be identified, but concomitant use of inotropes was identified as a significant covariate that decreased midazolam clearance by 33%. With a typical half-life of 5.2 hours for midazolam, neonatologists should be aware that the midazolam plasma concentration accumulates considerably over the first 12-24 hours. Add-on seizure control with midazolam was limited (23% seizure control). Lidocaine toxicity, mainly in the form of bradycardia and arrhythmias, is life-threatening and should be avoided. A reduced clearance of 24% was observed in the hypothermic newborn population. A response of 92% on epileptiform activity on the aEEG was observed under hypothermia for lidocaine add-on therapy in our population, which is better than the effect of other anti-epileptic drugs. No infants experienced cardiac arrhythmias. A lidocaine dosing regimen under hypothermia was developed in order to obtain comparable plasma concentrations as in normothermic patients accounting for the reduced clearance.