Robert T. Wilder

Early Exposure to Anesthesia and Learning Disabilities in a Population-based Birth Cohort

Background:Anesthetic drugs administered to immature animals may cause neurohistopathologic changes and alterations in behavior. The authors studied association between anesthetic exposure before age 4 yr 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 to 1982 and who remained in the community at 5 yr 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, sex, and birth weight. Results:Of the 5,357 children in this cohort, 593 received general anesthesia before age 4 yr. Compared with 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% confidence interval, 0.79–1.27). However, children receiving two anesthetics (n = 100) or three or more anesthetics (n = 44) were at increased risk for LD (hazard ratio = 1.59; 95% confidence interval, 1.06–2.37, and hazard ratio = 2.60; 95% confidence interval, 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. These data cannot reveal whether anesthesia itself may contribute to LD or whether the need for anesthesia is a marker for other unidentified factors that contribute to LD.

Cognitive and Behavioral Outcomes After Early Exposure to Anesthesia and Surgery

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 = 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 = 350) before the age of 2 were matched to unexposed controls (n = 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 group-administered 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 group-administered 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.

Reflex sympathetic dystrophy in children. Clinical characteristics and follow-up of seventy patients.

We report on the experience with our first seventy patients who had reflex sympathetic dystrophy and were less than eighteen years old (average age, 12.5 years). In our series, the patients were predominantly girls (male to female ratio, 11:59) and the lower extremity was involved most often (sixty-one of the seventy patients). The average time from the initial injury to the diagnosis was one year, which indicates that the syndrome remains under-recognized in patients in this age-group. Conservative treatment with physical therapy, transcutaneous electrical nerve stimulation, psychological therapies including cognitive-behavioral management and relaxation training, and tricyclic anti-depressants was effective in improving the average scores for pain and function for forty patients. Sympathetic blocks were helpful for twenty-eight of thirty-seven patients. Thirty-eight of the seventy patients in the series continued to have some degree of residual pain and dysfunction. Reflex sympathetic dystrophy in children differs in presentation and clinical course from the syndrome in adults. It is best treated in a multidisciplinary fashion.

Attention-Deficit/Hyperactivity Disorder After Early Exposure to Procedures Requiring General Anesthesia

OBJECTIVE To study the association between exposure to procedures performed under general anesthesia before age 2 years and development of attention-deficit/hyperactivity disorder (ADHD). PATIENTS AND METHODS Study patients included all children born between January 1, 1976, and December 31, 1982, in Rochester, MN, who remained in Rochester after age 5. Cases of ADHD diagnosed before age 19 years were identified by applying stringent research criteria. Cox proportional hazards regression assessed exposure to procedures requiring general anesthesia (none, 1, 2 or more) as a predictor of ADHD using a stratified analysis with strata based on a propensity score including comorbid health conditions. RESULTS Among the 5357 children analyzed, 341 ADHD cases were identified (estimated cumulative incidence, 7.6%; 95% confidence interval [CI], 6.8%-8.4%). For children with no postnatal exposure to procedures requiring anesthesia before the age of 2 years, the cumulative incidence of ADHD at age 19 years was 7.3% (95% CI, 6.5%-8.1%). For single and 2 or more exposures, the estimates were 10.7% ( 95% CI, 6.8%-14.4%) and 17.9% ( 95% CI, 7.2%-27.4%), respectively. After adjusting for gestational age, sex, birth weight, and comorbid health conditions, exposure to multiple (hazard ratio, 1.95; 95% CI, 1.03-3.71), but not single (hazard ratio,1.18; 95% CI, 0.79-1.77), procedures requiring general anesthesia was associated with an increased risk for ADHD. CONCLUSION 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.

Anesthesia for Cesarean Delivery and Learning Disabilities in a Population-Based Birth Cohort

Background:Anesthetics administered to immature brains may cause histopathological changes and long-term behavioral abnormalities. The association between perinatal exposure to anesthetics during Cesarean delivery (CD) and development of learning disabilities (LD) was determined in a population-based birth cohort. Methods:The educational and medical records of all children born to mothers residing in five townships of Olmsted County, Minnesota from 1976–1982 and remaining in the community at age 5 were reviewed to identify those with LDs. Cox proportional hazards regression was used to compare rates of LD between children delivered vaginally and via CD (with general or regional anesthesia). Results:Of the 5,320 children in this cohort, 497 were delivered via CD (under general anesthesia n = 193, and regional anesthesia n = 304). The incidence of LD depended on mode of delivery (P = 0.050, adjusted for sex, birth weight, gestational age, exposure to anesthesia before age 4 yr, and maternal education). LD risk was similar in children delivered by vagina or CD with general anesthesia, but was reduced in children receiving CD with regional anesthesia (hazard ratio = 0.64, 95% confidence interval 0.44 to 0.92; P = 0.017 for comparison of CD under regional anesthesia compared to vaginal delivery). Conclusion:Children exposed to general or regional anesthesia during CD are not more likely to develop LD compared to children delivered vaginally, suggesting that brief perinatal exposure to anesthetic drugs does not adversely affect long-term neurodevelopmental outcomes. The risk of LD may be lower in children delivered by CD whose mothers received regional anesthesia.

Glucocorticoids Prolong Rat Sciatic Nerve Blockade In Vivo from Bupivacaine Microspheres

Background Previous work showed that incorporation of dexamethasone (0.05 weight/weight percentage) into bupivacaine microspheres prolonged blockade by eight to 13 times compared with that produced by bupivacaine microspheres alone. The determinants of dexamethasones block-prolonging effect were examined and reported here. Methods Polylactic-co-glycolic acid polymer microspheres (65/35) with 75 weight/weight percentage bupivacaine were prepared. Microspheres were injected adjacent to the rat sciatic nerve, and sensory and motor blockade were assessed. A procedure was developed to test drugs for block-prolonging ability in vivo by placing test drugs in the injection fluid along with a suspension of bupivacaine microspheres. Results Dexamethasone alone in suspension did not produce blockade, nor did it prolong blockade induced by aqueous bupivacaine. Bupivacaine microspheres (150 mg drug/kg rat weight) produced blockade for 6 to 10 h. Dexamethasone in the suspending solution of microspheres prolonged block by up to five times. Glucocorticoids prolonged block in proportion to glucocorticoid/antiinflammatory potency. The corticosteroid antagonist cortexolone inhibited dexamethasones blockade-prolonging action. Durations of blockade with or without dexamethasone were unaltered by hydroxyurea-induced neutrophil depletion. Microspheres were extracted from rats at time points ranging from 7 h to 7 days, and residual microsphere dry weight and bupivacaine content were similar in groups of rats injected with either bupivacaine microspheres or bupivacaine microspheres containing dexamethasone, respectively. Conclusions Glucocorticoids prolong blockade from bupivacaine microspheres. The mechanism appears unrelated to the kinetics of bupivacaine release in vivo.

The risk of infection from epidural analgesia in children: a review of 1620 cases.

We reviewed cases to determine whether suspected or confirmed epidural infection was associated with epidural analgesia for 1620 infants, children, and adolescents treated over a 6-yr period at Childrens Hospital, Boston. Postoperative patients (1458/1620) received epidural infusions for a median of 2 days (range, 0-8 days). No postoperative patient had an epidural abscess. One 10-yr-old with terminal malignancy received thoracic epidural analgesia via two successive catheters over a 4-wk period. She had Candida colonization of the epidural space along with necrotic epidural tumor. A second oncology patient and two patients with reflex sympathetic dystrophy were evaluated for epidural abscess, but none was found. We conclude that the risk of epidural infection is quite low in pediatric postoperative patients receiving short-term catheterization. Use of prolonged epidural analgesia in the management of chronic pain in children requires careful monitoring of warning signs of infection. (Anesth Analg 1995;80:234-8)

Risk factors for laryngospasm in children during general anesthesia

Background:  Laryngospasm is a common and often serious adverse respiratory event encountered during anesthetic care of children. We examined, in a case control design, the risk factors for laryngospasm in children.

Regional anesthesia for pain associated with terminal pediatric malignancy

&NA; The objectives of this study were to identify the characteristics of children who required regional anesthesia for pain associated with terminal malignancy and to identify the safety, tolerability and effectiveness of regional anesthesia as an analgesic modality in terminal pediatric malignancy. A retrospective examination was made of the medical records of children who died of malignancy following treatment at the Dana‐Farber Cancer Institute and Childrens Hospital, Boston, Massachusetts, and who required either epidural or subarachnoid infusions, or neurolytic blockade for pain management (June, 1936 – April, 1994) during the terminal phase of their illness. Eleven patients were identified, with a duration of epidural or subarachnoid infusions ranging from 3 days to 7 weeks. Indications for this intervention included limiting side effects of opioids, neuropathic pain unresponsive to either rapid escalation of opioids or massive opioid infusions, analgesia for thoracocenteses for the drainage of malignant pleural effusions and instillation of intrapleural chemotherapy. Pain was localized to one area in all patients. Analgesia was judged to be satisfactory in all cases after regional anesthesia was instituted and remained satisfactory in all cases throughout the treatment course. Complications associated with regional anesthesia included dural puncture headache and mild respiratory depression. Five patients were nursed at home with either epidural or subarachnoid infusions.

Neurodevelopment of children exposed to anesthesia: Design of the Mayo Anesthesia Safety in Kids (MASK) study

There is increasing evidence that exposure of developing brains in animals, including nonhuman primates, to commonly-utilized anesthetic agents may cause adverse effects on cognition and behavior. In this paper, we summarize our methodology for a population-based, propensity-matched study to evaluate possible anesthesia-related sequelae in preschool children when evaluated in elementary or high school. A cohort of all children born in Olmsted County, Minnesota between the years 1994 and 2007 who are currently local residents has been identified. Existing medical records are being used to identify all episodes of exposure to general anesthesia prior to the age of 3 years (i.e., prior to their 3rd birthday). Children with multiple, single, and no anesthesia exposure are sampled for testing between the ages of 8 and 12 years or 15 and 19 years during the period 2012-2016. To match children in different exposure groups as closely as possible, sampling is guided by propensity-matching for the likelihood of receiving anesthesia. Selected children are invited to participate in a single 4-hour session of neuropsychological testing, including the National Center for Toxicological Research-Operant Test Battery, which has been used to study anesthetic neurotoxicity in nonhuman primates. The results of this testing will be compared among children with different anesthetic exposure histories. The expected products of this research will be a detailed phenotype of possible anesthetic-associated neurotoxicity in humans, utilizing a robust patient database and neuropsychological testing battery, and the first comparison of effects of anesthetic exposure in children and nonhuman primates performing nearly identical behavioral tasks.