Navigating Between Scylla and Charybdis; Sevoflurane for Difficult Sedation at the PICU.

Adequate analgosedation is considered as one of the main quality issues in daily PICU cure and care, which is unfortunately not reached in all children. A number of guidelines have been published over the years (1) and specific populations following cardiac surgery or laryngotracheal reconstruction (2, 3). Especially if longer duration of sedation is needed, tachyphylaxis due to changes in pharmacokinetics or pharmacodynamics related to the disease state or when signs of withdrawal and even delirium occur optimal dosing of sedatives can be an increasing challenge in mechanically ventilated children (4). Genetic variation in the metabolism of drugs complicates the dosing required for adequate sedation. Often a varied mixture of opioids, benzodiazepines, and other sedatives like α2 agonists (clonidine and dexmedetomidine) are used with or without the use of validated assessment instruments (5). In this issue of Pediatric Critical Care Medicine, Mencía et al (6) present the use of an inhalation anesthetic sevoflurane in 23 patients admitted during a 6-year period to two Spanish PICUs when the achievement of an optimal sedation level was difficult with their conventional sedation strategy. The authors included a large variety of patients of mainly infants (median age, 7 mo): 1) who did not reach an adequate level of sedation with maximal doses of conventional sedative drugs, 2) when the patient required sedatives’ doses greater than usual to achieve optimal sedation, or 3) when problems arose with the usual sedation weaning. Inhalation of sevoflurane around minimum alveolar concentration awake level (end-tidal concentration sevoflurane varying between 0.8% and 1.6%) in combination with (an unknown dose of) morphine resulted in a significant reduction of conventional sedatives (midazolam, fentanyl, propofol, ketamine, remifentanil, dexmedetomidine, etc). The question is whether or not this is the way to go under these circumstances? Knowledge of sevoflurane across PICUs varies considerably due to differences in background training of the specialists of the staff. People primarily trained as pediatricians are often unfamiliar with the properties of sevoflurane, whereas sevoflurane is part of the basic clinical practice for (pediatric) anesthesiologists. Sevoflurane is the agent of choice for mask induction in pediatric anesthesia because of its lack of airway irritation, pleasant odor, and stable hemodynamic properties. Furthermore, sevoflurane has a low blood/gas partition coefficient, which results in a rapid equilibration of the alveolarto-inspiratory fraction and therapeutic range. Most of the sevoflurane is exhaled, and only a small fraction is metabolized in the liver. The measurement of end-tidal sevoflurane gives a direct continuous feedback on the concentration in the patient. Furthermore, it has virtually no side effects on other organs, and the dosing is independent of other drugs (7). However, one of the most important side effects of anesthesia with sevoflurane is the increased emergence agitation, which is probably attributable to the fast recovery and increased pain awareness compared with other anesthetics (8). Sevoflurane has also been shown to be clinically effective when used in PICUs to treat mechanically ventilated children with life-threatening asthma who fail to respond to conventional treatment (9). In adults, sevoflurane is increasingly used, and a recent systematic review showed a reduction in time to extubation, with no increase in short-term adverse outcomes (10). However, long-term effects in adults and children have not been evaluated yet, and larger clinical trials are required to evaluate the role of inhalation anesthetics for critically ill patients especially in the pediatric age group. The U.S. Food and Drug Administration (FDA) is warning that “repeated or lengthy use of general anesthetic and sedation drugs during surgeries or procedures in children younger than 3 years.may affect the development of children’s brains” (https://www.fda.gov/Drugs/DrugSafety/ucm532356.htm) (11). This official warning of the FDA is based on animal studies showing that anesthesia and sedation for more than 3 hours with virtually all anesthetic drugs cause widespread apoptosis of nerve cells in the brain. More than 1,000 publications in pregnant and neonatal and young animals showed that exposure to anesthesia cause increased neuroapoptosis and deficits in hippocampal synaptic functioning (12). Furthermore, these histologic changes are associated with functional and cognitive problems at adultery of these animals; animals exposed to anesthesia at early age showed learning deficits, abnormal social behavior, and induced long-term memory impairment *See also p. e335.