Several retrospective reports demonstrate an association between surgery and anesthesia and subsequent learning and behavioral disorders. In a series of retrospective reports, the Mayo Clinic group examined a cohort born from 1976 to 1982 for learning disabilities. The patients who were exposed to surgery and anesthesia before the age of four had increased incidence of learning disability at age 19 years [63]. Risk factors included more than one anesthetic exposure and general anesthesia lasting longer than 2 h. A similar study was done using matched cohort revealed that children under the age of two who had more than one anesthetic were almost twice as likely to have speech and language disabilities than those who had a single or no anesthetic exposure [64]. In contrast, cohort study from a birth registry reported that even a single exposure to general anesthesia before age 3 years was related to decreased performance on receptive and expressive language and cognitive testing done at 10 years [65]. A similar retrospective report derived from Iowa revealed a negative correlation between the duration of surgery/anesthesia and scores on academic achievement tests [66]. Data analysis from the Medicaid database indicates that, even after adjustment for potential confounding factors, children who underwent hernia repair before the age of 3 years were twice as likely as children in the comparison group to be subsequently diagnosed with a developmental or behavioral disorder [67]. When this group was controlled for gender and birth weight, there was still a nearly twofold increase in these issues. A follow-up study that matched patients with non-anesthetic-exposed siblings found that the former had a 60 % greater association between exposure to anesthesia and later neurologic and developmental problems [68].

Meanwhile other investigators report no evidence of an association between exposure to general anesthesia at a young age and later school problems. An analysis of a twin-twin registry from the Netherlands compared with the educational achievements of identical twin pairs revealed that twin pairs exposed to general anesthesia had lower educational achievements than unexposed twin pairs [69]. However, when one twin was exposed and the other was not, there were no differences in educational achievements. These findings imply that exposure to general anesthesia was not associated with impaired educational performance. A Danish birth cohort compared average test scores at ninth grade in infants who have inguinal hernia study and reported no statistically significant differences from naïve cohorts after adjusting for known confounders [70]. A similar analysis of infants undergoing pyloromyotomies revealed no difference in their educational performance to a surgery naïve cohort [71]. Since these retrospective reports are based on patients undergoing surgery and presumably general anesthesia, they may not be relevant in the setting of procedural sedation.

Several reports have been published on the effect of sedation on neurocognitive parameters in intensive care patients. In a review of premature neonates receiving sedation for mechanical ventilation, prolonged sedation was not associated with a poor neurological outcome [72]. A similar report examining the impact of perioperative administration of sedatives in pediatric cardiac surgery found no association between the dose and duration of these drugs and adverse neurodevelopmental outcome at 18–24 months [73]. A reevaluation of these children at kindergarten age demonstrated that the number of days on chloral hydrate was associated with lower performance intelligence quotient and the cumulative dose of benzodiazepines was associated with lower visual motor integration (VMI) score s [74]. The Beery-Buktenica VMI scores reflect the ability to integrate visual and motor abilities and screens for possible learning and neuropsychological and behavioral problems [75]. These sedation studies in the intensive care unit may reveal a mild association between GABA agonists and neurodevelopmental deficits. However, the overwhelming impact of severe illness and prolonged administration of the sedative drugs cannot be discounted [76].

The limitations of retrospective studies are well known and prompt the need for prospective investigations into the impact of sedative and anesthetic drugs on neurocognitive development in humans. There is at least one prospective ongoing study (the GAS study), which is comparing the neurodevelopmental outcomes of 2- and 5-year-old children who were randomized to either regional or general anesthesia for inguinal herniorrhaphies at age 6 months or less [77]. The 2-year neurocognitive interim results reveal no differences between infants exposed to either general anesthesia or regional anesthesia [78]. Other prospective studies are underway [79, 80]. The EUROPAIN consortium reported a prospective cohort study on sedation and analgesia in neonatal intensive care units [81]. They observed a wide variation in practice among the participating centers, which highlight the potential for confounding factors as the cause for altered neurocognition.

The acute effects of sedation have been investigated. A prospective comparison of preterm and term children undergoing procedural sedation revealed that the former had a twofold increased risk of an adverse event [82]. These include increased oxygen desaturations and apnea in the preterm patients. The overall rate of oxygen desaturation and apnea/upper airway obstruction were 154 and 575 per 10,000 respective in a general cohort of pediatric patients undergoing procedural sedation with propofol [83]. An intravenous bolus of propofol for procedural sedation in neonates undergoing brief painful intervention resulted in a period of hypotension up to 60 min with a transient decrease in cerebral tissue oxygenation index [84]. Morphine infusions and boluses administered to mechanically ventilated preterm neonates were associated with hypotension [85]. The impact of these transient events on neurocognitive is unknown but has the potential to affect neurocognition.