Intraoperative and postoperative analgesia in neonates
It has long been thought that newborn infants do not feel pain the way older children and adults do and therefore do not require anesthetic or analgesic agents (Lippman et al., 1976). Thus, in the past, neonates undergoing surgery were often not afforded the benefits of anesthesia. Later studies, however, indicated that pain experienced by neonates can affect behavioral development (Dixon et al., 1984; Taddio et al., 1995, 2005). Rats exposed to chronic pain without the benefit of anesthesia or analgesia showed varying degrees of neuroapoptosis (Anand et al., 2007). However, to add further controversy to the issue of adequate anesthesia for infants, concerns regarding the neurotoxic effects of both intravenous and inhalational anesthetic agents (GABAminergic and NMDA antagonists) have been raised. Postoperative cognitive dysfunction (POCD) has been noted in adult surgical patients (Johnson et al., 2002; Monk et al., 2008). In adults, POCD may also be a marker for 1-year survival after surgery. Although POCD is an adult phenomenon, animal studies by multiple investigators have raised concerns about anesthetic agents being toxic to the developing brains of infants and small children (Jevtovic-Todorovic et al., 2003, 2008; Mellon et al., 2007; Wang and Slikker, 2008). Early work by Uemura and others (1985) noted that synaptic density was decreased in rats exposed to halothane in utero. Further work with rodents, by multiple investigators, has shown evidence of apoptosis in multiple areas of the central nervous system during the rapid synaptogenesis period. This window of vulnerability appears to be a function of time, dose, and duration of anesthetic exposure. In addition to the histochemical changes of apoptosis, the exposed animals also demonstrated learning and behavioral deficits later in life.
In addition to apoptotic changes that occurred in rodents, Slikker and colleagues have demonstrated neuroapoptotic changes in nonhuman primates (rhesus monkeys) exposed to ketamine (an NMDA antagonist). As with the rodents, ketamine exposure in monkeys resulted in long-lasting deficits in brain function (Dr. Merle Poule, personal communication on the Safety of Key Inhaled and Intravenous Drugs in Pediatric Anesthesia [SAFEKIDS] Scientific Workshop, November 2009, White Oaks Campus Symposium). How these animal studies relate to human findings is unclear to date. However, three clinical studies have been reported, and all three studies are retrospective. Wilder et al. (2009) studied a cohort group of children from Rochester, Minnesota, and noted that children exposed to two or more anesthetics in the first 4 years of life were more likely to have learning disabilities, compared with children exposed to one anesthetic or none at all. Kalkman and others (2009) studied a group of children undergoing urologic surgery before age 6 years and reported that there was a tendency for parents to report more behavioral disturbances than those operated on at a later age. However, in a twin cohort study from the Netherlands, Bartels and coworkers (2009) reported no causal relationship between anesthesia and learning deficits in 1,143 monozygotic twin pairs.
In an effort to determine the impact of anesthetic agents or neurocognitive development, a collaborative partnership between the U.S. Food and Drug Administration (FDA) and the International Anesthesia Research Society has formed Safety of Key Inhaled and Intravenous Drugs in Pediatric Anesthesia (SAFEKIDS), a program designed to fund and promote research in this area.