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Propofol as an Adjunct for Neonatal Intubation: The Contribution of Clinical Pharmacology

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natal age had sufficient numbers of neonates to identify the nalgosedation often is used before (semi-)elective neodose judged to be initially effective in 50% of the participants.3 natal intubation, which raises a number of imporThus, the propofol dose of 0.8-1.8 mg/kg that was effective in tant questions, including (1) whether medicines should 50% of participants was lower than doses used in other clinibe used to support neonatal intubation at all, (2) which drug(s) cal trials in preterm neonates.6 Many treated should be used, (3) what dose of each drug See related article, p ••• infants, however, did not recover quickly and should be given, and (4) which adverse effects needed to be ventilated for a prolonged can be anticipated?1 There are 2 approaches to answering these questions: opinion-based and period, interfering with the intended INSURE (ie, intubaevidence-based.2 Here, we focus on making evidence-based detion, surfactant administration, extubation) approach. cisions as demonstrated in the study by Smits et al3 of propofol, Second, some neonates developed hypotension that the a drug used widely to facilitate neonatal intubation. authors did not treat and attributed to propofol-induced vaThe relevant systematic review states: “No practice recomsodilatation. Mean arterial blood pressure decreased between mendation can be made based on the available evidence re29% and 39% of baseline, lasting between 2 and 3 hours after garding the use of propofol in neonates. Further research is propofol administration. Last, near-infrared spectroscopy needed on the pharmacokinetics of propofol in neonates, and showed that there was a significant reduction in regional ceonce a relatively safe dose is identified, randomized conrebral oxygen saturation and a trend towards lower cerebral trolled trials (RCTs) assessing the safety and efficacy of propofol fractional tissue oxygen extraction in some neonates for more are needed.”4 Thus, propofol provides a good example of the than 3 hours, which may represent reduced brain activity as need for foundational work about dosage regimens before RCTs an intended effect of the sedation or an adverse effect due to should be performed. A weaker example is inhaled nitric oxide reduced oxygen delivery. to prevent pulmonary hypertension in extremely premature From the clinical pharmacology perspective, the key inforneonates: thousands of infants were randomized in large studies mation gap is generalizability: can these dosing recommenwithout a proper understanding of optimal dosage.5 dations be validated in other populations? This will be facilitated Propofol is a sedative that appears to work on multiple reby relating the circulating concentrations of propofol (pharceptors. It has a rapid onset of action and typically wears off macokinetics) to the effects (pharmacodynamics). This is necquickly. It is important to note that the short duration of action essary to identify the covariates that affect how the dose relates partly to the metabolism of the molecule by the liver is related to the outcomes and to test the resulting and partly to the distribution in the body.6 In this context, Smits pharmacokinetic/pharmacodynamic model in another related et al3 report an elegant study that provides the foundations for population. From the clinical perspective, the risk-benefit understanding a potential role of propofol in neonatal pracbalance deserves further attention. Even though the authors tice. Key elements of the study are the conduct in a real clinisuggest that preintubation sedation is the standard of care in cal setting (intubations by trainees), multiple strata of neonates, many neonatal units in the US and abroad do not postmenstrual age, a predefined starting dose within each use this approach. Also, the authors conclude that propofol is stratum, rules for adjusting the dose during a procedure, rules efficacious without clinically important short-term side effects. for selecting doses in subsequent neonates in the light of exAre the changes, however, in mean arterial blood pressure and perience with the first infant in each stratum, and multivaribrain oxygen extraction safe and not associated with any longable monitoring of intended and unintended sequelae. This term neurodevelopmental abnormalities? How do the effects approach is an excellent example of “clinical pharmacology,” of propofol compare with the effects of intubation without sewhere there is careful observation of the relationship between dation? The Journal recently published a retrospective report the dose administered and the effects of the medicine, espeof 308 neonates with birth weights

Propofol as an Adjunct for Neonatal Intubation: The Contribution of Clinical Pharmacology.

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