Ellen de Kort

120 Chapter 7 DISCUSSION This dose-finding trial was designed to find the optimal single propofol dose for non- emergency endotracheal intubation providing effective sedation without significant side effects in neonates of different GAs and PNAs. To the best of our knowledge, this is the largest drug dose-finding study performed in the neonatal population. Unfortunately, dose finding could only be completed in two of the eight defined age groups without determination of the optimal propofol dose. Our results show a dose-dependent relationship for propofol to reach effective sedation. However, we also found the sedative effect to be unpredictable in the individual patient, and propofol is associated with a high incidence of hypotension. Based on these results, propofol might probably be not the most suitable premedication prior to endotracheal intubation in all neonates. In contrast to our results, Smits et al. were able to calculate specific propofol doses for preterm newborns in the first days of life that increased with GA. 21 Their suggested propofol doses were lower than the doses that resulted in adequate sedation in our study. This difference could be explained by different ways of analyses and outcome parameters in both studies. We did not calculate the EC 50 , but showed that 2.0 mg/kg propofol starting dose is effective in 86% of patients. The available literature shows conflicting results on the sedative effect of propofol. Doses of 1.0 and 2.5 mg/kg are found to provide sufficient sedation in some studies, 16,18 while other studies found insufficient sedation with doses of 1.0, 2.0 and 2.5 mg/kg. 17,19 These conflicting data underline that the sedative effect of propofol is difficult to predict. The indication for intubation could also play a role. For the Intubation-SURfactant-Extubation (INSURE) procedure, duration of sedation should be very short. 26 Therefore, clinicians might accept lower levels of sedation to diminish the risk of insufficient respiratory drive after the administration of surfactant and, therefore, the inability to immediately extubate the patient. However, regardless of the procedures that follow intubation, the act of laryngoscopy is equally stressful and equal levels of sedation should in our opinion be pursued. GA and PNA are known covariates in propofol pharmacokinetics. 20 Therefore, we hypothesized that infants of different GAs and PNAs would need different propofol doses. Logistic regression analysis did not show a statistically significant effect of GA and PNA on the outcomes effective sedation and hypotension. Although unclear, the extended inter-individual variability in the effect of propofol seems much more important than GA and PNA in predicting the effect. Titrating propofol until the desired effect is achieved in the individual patient is probably the only way to ensure effective sedation in every patient. This, however, might still lead to a high incidence of hypotension.