Premedication for intubation in newborn infants; pain assessment, pharmacokinetics and pharmacodynamics

Abstract: Preterm infants undergo intensive care during a vulnerable period with hemodynamic instability and a rapidly developing and immature CNS. Adequate pain management is essential, since pain experience might lead to acute physiological reactions as well as neurological and neuropsychological sequels. There is no “golden standard” for objective pain assessment, and no evidence-based recommendations for premedication before endotracheal intubation in newborn infants. The aims of the research project were to investigate the possibilities to objectively assess pain with amplitude-integrated EEG (aEEG), to develop a safe and effective strategy for premedication before tracheal intubation, and to study pharmacokinetics and pharmacodynamics of the chosen drugs in the preterm infant population. The responses to three different types of noxious stimuli in healthy term infants were measured with aEEG/EEG and pain scales. Thiopental pharmacokinetics was assessed in maternal and cord blood after caesarean section in thiopental anesthesia, and in newborn infants receiving thiopental before neonatal surgery. Preterm infants needing semi-urgent intubation were enrolled to receive either Rapid Sequence Induction (RSI) with glycopyrrolate, thiopental, suxamethonium and remifentanil or atropine and morphine in a blinded randomized controlled trial (RCT). The main outcome measure was good intubation conditions, secondary were procedural duration, as well as changes in physiological and biochemical parameters, aEEG and pain scales that were monitored during and after the intubation. There were no changes in frontal EEG asymmetry to the different noxious stimuli. Thiopental placental transfer ratio was 0.7, and the median terminal half-life of thiopental in the infants was 8 hours depending on weight and postnatal age. The RCT demonstrated superior intubation conditions and shorter duration in the RSI group. Compared to RSI, the morphine group had prolonged heart rate decrease and mean arterial blood pressure (MABP) increase during intubation, and a progressive MABP decrease concomitant with neurophysiologic depression for 6 h afterwards. Neurophysiologic parameters were significantly depressed for 24 h. The results of these studies indicate that responses in cortical activity, registered as EEG frontal asymmetry, are not useful for clinical assessment of pain responses in newborn infants. Further, thiopental can be used as premedication for intubation in preterm and term infants, with dose adjustments for maternal dosage and infant weight when administered during the first four hours after birth. The RSI used in the trial can be implemented in clinical practice. Morphine should be avoided because of circulatory and neurophysiologic depression during and after the intubation.