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The potential for harmful effects of general anesthesia on the developing brain has been described as pediatric anesthesiology’s greatest current challenge.1 Anesthetic agents appear to have the greatest neurodegenerative impact when exposure occurs during the period of rapid synaptogenesis.2-15 Among species, peak synaptogenesis occurs at different rates and at different parts of the life cycle. This critical period of synaptogenesis in the rat lasts from roughly day of birth to day 10, peaking in cortex at day 7. In humans, this corresponds roughly to a period from the third trimester of gestation and the initial 3 yr of postnatal life. In rats and mice, brain growth is most rapid during the first 2 weeks of postnatal life. The brain’s maturational state in postnatal day 7 mice is comparable to 7-day-old rats and corresponds to premature human neonates.16,17 Studies in infant rat models have shown that exposure to a number of classes of sedative-hypnotic medications, including benzodiazepines, n-methyl-d-aspartate receptor antagonists, and inhalation anesthetics produce striking degrees of apoptotic neurodegeneration, particularly at 7 days postnatal age (P7) but not at postnatal days 21 (P21). Similar concerns have been raised by studies in other species, including infant mice young primates and in brain slice preparations in vitro.2-15 Conversely, other investigators, including one of us (S.S.), have found increased brain apoptosis in sections of parietal and temporal cortex and thalamus in P7 rats with prolonged (6-h) ketamine exposure, but not with brief (1-h) exposure.4,18 During programmed cell death, also termed apoptosis, a cascade of autodigestive enzymes known as caspases are activated. Cleavage of the final member of this cascade, caspase-3, will leads to activation of endonucleases, resulting in apoptotic cell death.19 Case-control studies have shown that infants undergoing surgery under general anesthesia, especially with more than one procedure20 may have a higher frequency of neurodevelopmental difficulties than infants who did not require anesthesia in infancy.20 Conversely, a recent twin study did not find evidence for harmful sequelae of anesthesia in infancy.21 Case-control studies do not fully answer the question of whether the anesthesia per se is associated with increased risk, due to the confounding effect of surgery, postsurgical stress, and other comorbidities that may be more common among infants requiring surgery. To address these concerns, a large international randomized controlled trial is in progress examining neurodevelopmental outcomes at 2 and 5 years of age in a group of infants undergoing inguinal hernia repairs under spinal or general anesthesia.22 The rationale for this trial is based in part on the assumption that spinal anesthesia would not be expected to produce harmful effects on neurodevelopment. Nevertheless, this assumption has not previously been examined in infant animal surrogate models. The present study describes a technique for spinal anesthesia in the young rat. Our general hypothesis is that spinal anesthesia is neurologically benign in young rats. In particular, we hypothesized that (1): a spinal bupivacaine dose could be identified that produced signs of lower body blockade without signs of high spinal blockade, severe physiologic instability, or high mortality, (2) these doses would not increase apoptotic neurodegeneration in the brain or spinal cord (as assayed by cleaved caspase-3 staining), as seen with prolonged exposure to a volatile anesthetic, (3) spinal anesthesia would not produce long-term deficits in motor performance in those rats when tested as adults, and (4) histologic effects of spinal anesthesia on lumbar spinal cord would appear benign. |
