Background Anesthetic drugs administered to immature animals may cause neurohistopathologic changes and alterations in behavior. We studied association between anesthetic exposure prior to age 4 and the development of reading, written language and math learning disabilities (LD). Methods This was a population-based, retrospective birth cohort study. The educational and medical records of all children born to mothers residing in five townships of Olmsted County, Minnesota from 1976–1982 and who remained in the community at 5 years of age were reviewed to identify children with LD. Cox proportional hazards regression was used to calculate hazard ratios for anesthetic exposure as a predictor of LD, adjusting for gestational age at birth, gender, and birth weight. Results Of the 5,357 children in this cohort, 593 received general anesthesia before age 4. Compared to those not receiving anesthesia (N=4,764), a single exposure to anesthesia (N=449) was not associated with an increased risk of LD (hazard ratio =1.0, 95% CI 0.79–1.27). However, children receiving 2 anesthetics (N=100) or ≥3 anesthetics (N=44) were at increased risk for LD (hazard ratio =1.59, 95% CI 1.06–2.37, and hazard ratio =2.60, 95% CI 1.60–4.24, respectively). The risk for LD increased with longer cumulative duration of anesthesia exposure (expressed as a continuous variable) (P=0.016). Conclusion Exposure to anesthesia was a significant risk factor for the later development of LD in children receiving multiple, but not single anesthetics. We cannot determine whether anesthesia itself may contribute to LD, or whether the need for anesthesia is a marker for other unidentified factors that contribute to LD.

WHAT'S KNOWN ON THIS SUBJECT:Exposure to virtually all anesthetic drugs has been shown to cause neurodegeneration in young animals. Studies of learning and cognition in children exposed to anesthesia and surgery have been few, have relied on single outcome measures, and have not controlled for comorbidity. WHAT THIS STUDY ADDS:In this study of children exposed to anesthesia/surgery before the age of 2, multiple group and individual measures of learning and behavior are examined by using a matched design with adjustment for comorbidity using 2 separate methods. abstract + BACKGROUND: Annually, millions of children are exposed to anesthetic agents that cause apoptotic neurodegeneration in immature animals. To explore the possible significance of these findings in children, we investigated the association between exposure to anesthesia and subsequent (1) learning disabilities (LDs), (2) receipt of an individualized education program for an emotional/behavior disorder (IEP-EBD), and (3) scores of group-administered achievement tests. METHODS:This was a matched cohort study in which children (N ϭ 8548) born between January 1, 1976, and December 31, 1982, in Rochester, Minnesota, were the source of cases and controls. Those exposed to anesthesia (n ϭ 350) before the age of 2 were matched to unexposed controls (n ϭ 700) on the basis of known risk factors for LDs. Multivariable analysis adjusted for the burden of illness, and outcomes including LDs, receipt of an IEP-EBD, and the results of groupadministered tests of cognition and achievement were outcomes. RESULTS:Exposure to multiple, but not single, anesthetic/surgery significantly increased the risk of developing LDs (hazard ratio: 2.12 [95% confidence interval: 1.26 -3.54]), even when accounting for health status. A similar pattern was observed for decrements in groupadministered tests of achievement and cognition. However, exposure did not affect the rate of children receiving an individualized education program. CONCLUSIONS:Repeated exposure to anesthesia and surgery before the age of 2 was a significant independent risk factor for the later development of LDs but not the need for educational interventions related to emotion/behavior. We cannot exclude the possibility that multiple exposures to anesthesia/surgery at an early age may adversely affect human neurodevelopment with lasting consequence.

Background Few studies of how exposure of children to anesthesia may affect neurodevelopment employ comprehensive neuropsychological assessments. This study tested the hypothesis that exposure to multiple, but not single, procedures requiring anesthesia before age 3 yr is associated with adverse neurodevelopmental outcomes. Methods Unexposed, singly exposed, and multiply exposed children born in Olmsted County, Minnesota, from 1994 to 2007 were sampled using a propensity-guided approach and underwent neuropsychological testing at ages 8 to 12 or 15 to 20 yr. The primary outcome was the Full-Scale intelligence quotient standard score of the Wechsler Abbreviated Scale of Intelligence. Secondary outcomes included individual domains from a comprehensive neuropsychological assessment and parent reports. Results In total, 997 children completed testing (411, 380, and 206 unexposed, singly exposed, and multiply exposed, respectively). The primary outcome of intelligence quotient did not differ significantly according to exposure status; multiply exposed and singly exposed children scoring 1.3 points (95% CI, −3.8 to 1.2; P = 0.32) and 0.5 points (95% CI, −2.8 to 1.9; P = 0.70) lower than unexposed children, respectively. For secondary outcomes, processing speed and fine motor abilities were decreased in multiply but not singly exposed children; other domains did not differ. The parents of multiply exposed children reported increased problems related to executive function, behavior, and reading. Conclusions Anesthesia exposure before age 3 yr was not associated with deficits in the primary outcome of general intelligence. Although secondary outcomes must be interpreted cautiously, they suggest the hypothesis that multiple, but not single, exposures are associated with a pattern of changes in specific neuropsychological domains that is associated with behavioral and learning difficulties.

Children repeatedly exposed to procedures requiring general anesthesia before age 2 years are at increased risk for the later development of ADHD even after adjusting for comorbidities.

Context Pancreatic cancer is an aggressive tumor associated with high mortality. Optimal pain control may improve quality of life (QOL) for these patients. Objective To test the hypothesis that neurolytic celiac plexus block (NCPB) vs opioids alone improves pain relief, QOL, and survival in patients with unresectable pancreatic cancer. Design, Setting, and Patients Double-blind, randomized clinical trial conducted at Mayo Clinic, Rochester, Minn. Enrolled (October 1997 and January 2001) were 100 eligible patients with unresectable pancreatic cancer experiencing pain. Patients were followed up for at least 1 year or until death. Intervention Patients were randomly assigned to receive either NCPB or systemic analgesic therapy alone with a sham injection. All patients could receive additional opioids managed by a clinician blinded to the treatment assignment. Main Outcome Measures Pain intensity (0-10 numerical rating scale), QOL, opioid consumption and related adverse effects, and survival time were assessed weekly by a blinded observer. Results Mean (SD) baseline pain was 4.4 (1.7) for NCPB vs 4.1 (1.8) for opioids alone. The first week after randomization, pain intensity and QOL scores were improved (pain intensity, PՅ.01 for both groups; QOL, PϽ.001 for both groups), with a larger decrease in pain for the NCPB group (P = .005). From repeated measures analysis, pain was also lower for NCPB over time (P = .01). However, opioid consumption (P = .93), frequency of opioid adverse effects (all PϾ.10), and QOL (P=.46) were not significantly different between groups. In the first 6 weeks, fewer NCPB patients reported moderate or severe pain (pain intensity rating of Ն5/10) vs opioid-only patients (14% vs 40%, P=.005). At 1 year, 16% of NCPB patients and 6% of opioid-only patients were alive. However, survival did not differ significantly between groups (P=.26, proportional hazards regression). Conclusion Although NCPB improves pain relief in patients with pancreatic cancer vs optimized systemic analgesic therapy alone, it does not affect QOL or survival.

1. Our aim was to determine whether the vasodilating substance nitric oxide (NO) contributes to the rise in forearm blood flow observed during mental stress in humans. We also determined whether the NO might be released as a result of cholinergic stimulation of the vascular endothelium. 2. Blood flow was measured in both forearms using plethysmography during several 3‐5 min bouts of a colour word test. In one forearm the nitric oxide synthase blocker NG‐monomethyl‐L‐arginine (L‐NMMA) and other drugs were infused via a brachial artery catheter. The contralateral forearm served as a control. 3. When L‐NMMA was given prior to mental stress it blunted the rise in blood flow in the treated forearm almost completely. The normal blood flow response returned during a second bout of stress conducted after a wash‐out period. During a third bout of mental stress, administration of more L‐NMMA again blunted the blood flow responses to mental stress. 4. When atropine was given prior to mental stress, the increases in blood flow were reduced in the treated forearm. Subsequent administration of both atropine and L‐NMMA caused a somewhat greater reduction in the blood flow responses than those observed with atropine alone. 5. These data demonstrate that NO plays a role in forearm vasodilatation during mental stress in humans. It is likely that most of the NO is released by cholinergic stimulation of the vascular endothelium.

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The majority of perioperative CAs were caused by factors not attributed to anesthesia, in distinction to some recent reports. The incidence of perioperative CA is many-fold higher in children undergoing cardiac procedures, suggesting that definition of case mix is necessary to accurately interpret epidemiologic studies of perioperative CA in children.