Behavior and Development in Children and Age at the Time of First Anesthetic Exposure

Abstract

SEVERAL experimental studies have suggested that early exposure to anesthetic agents i.e. , before completion of synaptogenesis, can result in widespread apoptotic neuronal degeneration and late cognitive impairment.1–6Much debate is going on regarding the influence of timing of exposure to anesthetics (window of vulnerability) and the possibility of a dose-response relationship.7Initial data were limited to rodents, in which a clear window of vulnerability appears to exist within the first days after birth. However, rodents are born at a much less developed stage of maturity than primates.8Slikker et al. recently found that ketamine administered to rhesus monkeys at gestational day 122 or at day 5 or 35 after birth may cause neuronal cell death that was “age” (developmental stage)–dependent.9The vulnerability window was within the first week of life; 24-h exposure to ketamine at day 35 did not result in demonstrable neuronal loss. Although 24-h ketamine infusions resulted in significant increases in the number of caspase 3–, Fluoro-Jade C–, and silver stain–positive cells in the frontal cortex of postnatal day 5 monkeys, 3-h exposures did not. This suggests that apart from the vulnerability window there could also be a dose-response relationship (i.e. , deeper levels of anesthesia would be more harmful) or a threshold phenomenon in which duration of anesthetic exposure needs to exceed a particular duration before a clinical effect becomes detectable.If, given a particular set of conditions (patient age, duration of anesthesia, and perhaps dose), anesthetic exposure in human neonates and/or infants could produce sufficient neurodegeneration to result in disturbed neurobehavioral development, the consequences for pediatric surgery and pediatric anesthesia would be considerable. In each case in which surgery is indicated, clinicians and parents would need to weigh the risk of exposure of the infant to anesthesia against the possibilities and risks of postponing surgery. Although several authors have argued that human data are urgently needed, clinical studies are scarce.10Various studies have reported short-term alterations in cognitive abilities and behavior after surgery and anesthesia in young children (see Loepke et al. 11for an overview). Long-term neurocognitive impairment has been investigated in specific patient groups such as critically ill neonates, young children undergoing congenital cardiac surgery, and children with prenatal exposure to anesthetics. However, larger studies focusing on the influence of anesthetic exposure at an early age on later cognitive development are lacking.11In this epidemiologic study, we focused on the relationship between age at the time of first anesthetic exposure and disturbed behavioral development at least 4 yr after surgery, hypothesizing that children who underwent anesthesia at a younger age show more deviant behavior. We have chosen the domain of pediatric urological procedures because in this area many solitary urogenital anomalies exist unaccompanied by general illness. Furthermore, the timing of surgery in many cases depends mainly on the age at which a diagnosis is made, and postponing the procedure can be an option in selected cases. The results of this initial study are used to determine the feasibility and the required number of patients of a large-scale study.This retrospective cohort study included children undergoing pediatric urological surgery in the years 1987, 1991, 1993, and 1995 in the academic pediatric hospital of the University Medical Center Utrecht. Individuals in the cohort were between ages 0 and 6 yr at the time of surgery. Surgery was predominantly done for obstructive uropathy like ureteropelvic junction obstruction, obstructive megaureter, or posterior urethral valves. Hypospadias surgery was routinely planned at 12–14 months of age. All children were operated by one of the two Pediatric Urologic surgeons.The anesthetic techniques used in the years studied were predominantly inhalation-based and consisted of mask induction with a volatile agent (halothane, enflurane, or isoflurane) combined with nitrous oxide and an opioid (fentanyl or sufentanil). Total intravenous anesthesia with propofol and an opioid was rarely used. For selected procedures, general anesthesia was sometimes supplemented with a caudal epidural block.On the basis of records kept by the Pediatric Urologic surgeons, the hospital database was queried for medical history to determine initial eligibility. If the patients met one of the following exclusion criteria, parents were not contacted: presence of congenital diseases other than the (congenital) malformation requiring the urological surgery (e.g. , spina bifida, congenital heart surgery, congenital psychomotor retardation), other events in medical history that are known or suspected to be related to later cognitive impairment (e.g. , peripartum cerebral ischemia, hypoxic brain injury, or metabolic events; having be