Caleb Ing

Long-term Differences in Language and Cognitive Function After Childhood Exposure to Anesthesia

BACKGROUND: Over the past decade, the safety of anesthetic agents in children has been questioned after the discovery that immature animals exposed to anesthesia display apoptotic neurodegeneration and long-term cognitive deficiencies. We examined the association between exposure to anesthesia in children under age 3 and outcomes in language, cognitive function, motor skills, and behavior at age 10. METHODS: We performed an analysis of the Western Australian Pregnancy Cohort (Raine) Study, which includes 2868 children born from 1989 to 1992. Of 2608 children assessed, 321 were exposed to anesthesia before age 3, and 2287 were unexposed. RESULTS: On average, exposed children had lower scores than their unexposed peers in receptive and expressive language (Clinical Evaluation of Language Fundamentals: Receptive [CELF-R] and Expressive [CELF-E]) and cognition (Colored Progressive Matrices [CPM]). After adjustment for demographic characteristics, exposure to anesthesia was associated with increased risk of disability in language (CELF-R: adjusted risk ratio [aRR], 1.87; 95% confidence interval [CI], 1.20–2.93, CELF-E: aRR, 1.72; 95% CI, 1.12–2.64), and cognition (CPM: aRR, 1.69; 95% CI, 1.13–2.53). An increased aRR for disability in language and cognition persisted even with a single exposure to anesthesia (CELF-R aRR, 2.41; 95% CI, 1.40–4.17, and CPM aRR, 1.73; 95% CI, 1.04–2.88). CONCLUSIONS: Our results indicate that the association between anesthesia and neuropsychological outcome may be confined to specific domains. Children in our cohort exposed to anesthesia before age 3 had a higher relative risk of language and abstract reasoning deficits at age 10 than unexposed children.

Association Between a Single General Anesthesia Exposure Before Age 36 Months and Neurocognitive Outcomes in Later Childhood.

IMPORTANCE Exposure of young animals to commonly used anesthetics causes neurotoxicity including impaired neurocognitive function and abnormal behavior. The potential neurocognitive and behavioral effects of anesthesia exposure in young children are thus important to understand. OBJECTIVE To examine if a single anesthesia exposure in otherwise healthy young children was associated with impaired neurocognitive development and abnormal behavior in later childhood. DESIGN, SETTING, AND PARTICIPANTS Sibling-matched cohort study conducted between May 2009 and April 2015 at 4 university-based US pediatric tertiary care hospitals. The study cohort included sibling pairs within 36 months in age and currently 8 to 15 years old. The exposed siblings were healthy at surgery/anesthesia. Neurocognitive and behavior outcomes were prospectively assessed with retrospectively documented anesthesia exposure data. EXPOSURES A single exposure to general anesthesia during inguinal hernia surgery in the exposed sibling and no anesthesia exposure in the unexposed sibling, before age 36 months. MAIN OUTCOMES AND MEASURES The primary outcome was global cognitive function (IQ). Secondary outcomes included domain-specific neurocognitive functions and behavior. A detailed neuropsychological battery assessed IQ and domain-specific neurocognitive functions. Parents completed validated, standardized reports of behavior. RESULTS Among the 105 sibling pairs, the exposed siblings (mean age, 17.3 months at surgery/anesthesia; 9.5% female) and the unexposed siblings (44% female) had IQ testing at mean ages of 10.6 and 10.9 years, respectively. All exposed children received inhaled anesthetic agents, and anesthesia duration ranged from 20 to 240 minutes, with a median duration of 80 minutes. Mean IQ scores between exposed siblings (scores: full scale = 111; performance = 108; verbal = 111) and unexposed siblings (scores: full scale = 111; performance = 107; verbal = 111) were not statistically significantly different. Differences in mean IQ scores between sibling pairs were: full scale = -0.2 (95% CI, -2.6 to 2.9); performance = 0.5 (95% CI, -2.7 to 3.7); and verbal = -0.5 (95% CI, -3.2 to 2.2). No statistically significant differences in mean scores were found between sibling pairs in memory/learning, motor/processing speed, visuospatial function, attention, executive function, language, or behavior. CONCLUSIONS AND RELEVANCE Among healthy children with a single anesthesia exposure before age 36 months, compared with healthy siblings with no anesthesia exposure, there were no statistically significant differences in IQ scores in later childhood. Further study of repeated exposure, prolonged exposure, and vulnerable subgroups is needed.

Use of a Continuous Local Anesthetic Infusion for Pain Management after Median Sternotomy

Background The use of large doses of opioid analgesics to treat pain after cardiac surgery can prolong the time to tracheal extubation and interfere with recovery of bowel and bladder function in the postoperative period. Therefore, the authors investigated the efficacy of a continuous infusion of bupivacaine 0.25% or 0.5%, at the median sternotomy site, for 48 h after cardiac surgery in reducing the opioid analgesic requirement and improving the recovery process. Methods In this prospective, randomized, placebo-controlled, double-blind clinical trial, 36 consenting patients undergoing open-heart surgery with a standardized general anesthetic technique had two indwelling infusion catheters placed at the median sternotomy incision site at the end of surgery. The patients were randomly assigned to receive normal saline (control), bupivacaine 0.25% or bupivacaine 0.5%via an elastomeric infusion pump at a constant rate of 4 ml/h for 48 h. Patients evaluated their chest pain using an 11-point verbal rating scale, with 0 = no pain to 10 = worst pain imaginable. In addition, the postoperative opioid analgesic requirements and opioid-related adverse effects were recorded. Patient satisfaction with their pain management was assessed at specific intervals during the postoperative period using a 100-point verbal rating scale, with 1 = highly dissatisfied to 100 = highly satisfied. Finally, serum bupivacaine concentrations were measured 24 and 48 h after surgery. Results Compared with the control group, there was a statistically significant reduction in verbal rating scale pain scores and patient-controlled analgesia morphine use in the bupivacaine-0.5% group. Patient satisfaction with their pain management was also improved in the bupivacaine-0.5% (vs. control) group. However, there were no significant differences in patient-controlled analgesia morphine use between the bupivacaine-0.25% and control groups. Although the duration of the intensive care unit stay (30 vs. 34 h, respectively) was not significantly decreased, the time to ambulation (1 ± 0.5 vs. 2 ± 1 days, respectively) and the duration of hospital stay (4.2 vs. 5.7 days, respectively) were lower in the bupivacaine-0.5% group than in the control group. Mean ± SD serum bupivacaine concentrations at 48 h in the bupivacaine-0.25% and bupivacaine-0.5% groups were 0.5 ± 0.5 and 1.3 ± 0.7 &mgr;g/ml, respectively. Conclusion A continuous infusion of bupivacaine 0.5% at 4 ml/h is effective for decreasing pain and the need for opioid analgesic medication as well as for improving patient satisfaction with their pain management after cardiac surgery. Patients in the bupivacaine-0.5% group were able to ambulate earlier, leading to a reduced length of hospital stay.

Comparative Efficacy of Acustimulation (ReliefBand®) versus Ondansetron (Zofran®) in Combination with Droperidol for Preventing Nausea and Vomiting

Background Antiemetic drugs are costly, are associated with variable efficacy, and can produce unwanted side effects when used for prophylaxis against postoperative nausea and vomiting. This clinical study was designed to compare the efficacy of transcutaneous electrical acupoint stimulation using a ReliefBand® to ondansetron (Zofran®) when utilized alone or in combination for preventing postoperative nausea and vomiting after plastic surgery. Methods A single-center, randomized, double-blind, placebo- and sham-controlled study design was conducted to compare three prophylactic antiemetic treatment regimens in 120 outpatients undergoing plastic surgery procedures with routine low-dose droperidol prophylaxis: (1) ondansetron (n = 40), 4 mg intravenous ondansetron and a sham ReliefBand®; (2) acustimulation (n = 40), 2 ml intravenous saline and an active ReliefBand®; and (3) combination (n = 40), 4 mg intravenous ondansetron and an active ReliefBand®. The incidences of postoperative nausea and vomiting, as well as the need for “rescue” antiemetics, were determined at specific time intervals for up to 72 h after surgery. The outcome variables assessed included recovery times, quality of recovery score, time to resumption of normal diet, and patient satisfaction with the prophylactic antiemetic therapy. Results Use of the ReliefBand® in combination with ondansetron significantly reduced nausea (20 vs. 50%), vomiting (0 vs. 20%), and the need for rescue antiemetics (10 vs. 37%) compared with ondansetron alone at 24 h after surgery. Furthermore, the ability to resume a normal diet (74 vs. 35%) within 24 h after surgery was significantly improved when the ReliefBand® was used to supplement ondansetron (vs. ondansetron alone). Finally, the quality of recovery (90 ± 10 vs. 70 ± 20) and patient satisfaction (94 ± 10 vs. 75 ± 22) scores were significantly higher in the combination group versus the ondansetron group. There were no significant differences between the ReliefBand® and ondansetron when administered as adjuvants to droperidol for antiemetic prophylaxis. Conclusions The ReliefBand® compared favorably to ondansetron (4 mg intravenously) when used for prophylaxis against postoperative nausea and vomiting. Furthermore, the acustimulation device enhanced the antiemetic efficacy of ondansetron after plastic surgery.

Comparative analysis of outcome measures used in examining neurodevelopmental effects of early childhood anesthesia exposure

Introduction:Immature animals exposed to anesthesia display apoptotic neurodegeneration and neurobehavioral deficits. The safety of anesthetic agents in children has been evaluated using a variety of neurodevelopmental outcome measures with varied results. Methods:The authors used data from the Western Australian Pregnancy Cohort (Raine) Study to examine the association between exposure to anesthesia in children younger than 3 yr of age and three types of outcomes at age of 10 yr: neuropsychological testing, International Classification of Diseases, 9th Revision, Clinical Modification–coded clinical disorders, and academic achievement. The authors’ primary analysis was restricted to children with data for all outcomes and covariates from the total cohort of 2,868 children born from 1989 to 1992. The authors used a modified multivariable Poisson regression model to determine the adjusted association of anesthesia exposure with outcomes. Results:Of 781 children studied, 112 had anesthesia exposure. The incidence of deficit ranged from 5.1 to 7.8% in neuropsychological tests, 14.6 to 29.5% in International Classification of Diseases, 9th Revision, Clinical Modification–coded outcomes, and 4.2 to 11.8% in academic achievement tests. Compared with unexposed peers, exposed children had an increased risk of deficit in neuropsychological language assessments (Clinical Evaluation of Language Fundamentals Total Score: adjusted risk ratio, 2.47; 95% CI, 1.41 to 4.33, Clinical Evaluation of Language Fundamentals Receptive Language Score: adjusted risk ratio, 2.23; 95% CI, 1.19 to 4.18, and Clinical Evaluation of Language Fundamentals Expressive Language Score: adjusted risk ratio, 2.00; 95% CI, 1.08 to 3.68) and International Classification of Diseases, 9th Revision, Clinical Modification–coded language and cognitive disorders (adjusted risk ratio, 1.57; 95% CI, 1.18 to 2.10), but not academic achievement scores. Conclusions:When assessing cognition in children with early exposure to anesthesia, the results may depend on the outcome measure used. Neuropsychological and International Classification of Diseases, 9th Revision, Clinical Modification–coded clinical outcomes showed an increased risk of deficit in exposed children compared with that in unexposed children, whereas academic achievement scores did not. This may explain some of the variation in the literature and underscores the importance of the outcome measures when interpreting studies of cognitive function.

Feasibility and Pilot Study of the Pediatric Anesthesia NeuroDevelopment Assessment (PANDA) Project

Background: Animal studies have documented that exposure of the developing brain to commonly used anesthetic agents induces neurotoxicity and late abnormal neurobehavioral functions as adults. Results from clinical studies have all been analyzed using existing data sets, and these studies produced inconsistent results. To provide more definitive evidence to address the clinical relevance of anesthetic neurotoxicity in children, an interdisciplinary team of investigators designed and developed the Pediatric Anesthesia NeuroDevelopment Assessment (PANDA) project. We present pilot study results in 28 sibling pairs recruited and tested at the Columbia University Medical Center (CUMC) and Children’s Hospital of Boston (CHB) for the PANDA project. Methods: The PANDA project uses an ambidirectional cohort design. We performed prospective neuropsychological assessment in 28 exposed-unexposed sibling pairs from 6 to 11 years of age. The exposed siblings were ASA 1 or 2 and had received a single episode of anesthesia for inguinal hernia repair before the age of 36 months and the unexposed siblings had no anesthesia before the age of 36 months. All the sibling pairs were English speaking and were 36 weeks of gestational age or older. Each sibling pair underwent a direct testing using the Wechsler Abbreviated Scale of Intelligence (WASI) and the NEuroPSYchological Assessment, second edition (NEPSY II), and the parents completed questionnaires related to behavior using CBCL and Conners rating. Data are presented as means±SD. We conducted descriptive analyses of the demographic data. We compared both the exposed and the unexposed sibling groups on WASI and NEPSY II, and total and T scores from CBCL and Conners rating were analyzed as continuous data using the paired t test between the two groups. A P<0.05 was considered significant. Results: After the Institutional Review Board approval for the study at both CUMC and CHB, the full PANDA study protocol was implemented to perform a pilot feasibility study. Our success rate was 96.7% in obtaining detailed medical and anesthesia records in our historical cohort. The scores for verbal IQ (exposed=106.1±16.3, unexposed=109.2±17.9), performance IQ (exposed=109.1±16.0, unexposed=113.9±15.9), and full IQ (exposed=108.2±14.0, unexposed=112.8±16.8) were comparable between the siblings. There were no differences between the two groups in T scores for any of the NEPSY II subdomains, CBCL, or Conners rating. An abstraction protocol with web-based electronic data capture forms also was developed in conjunction with the International Center for Health Outcomes and Innovation Research (InCHOIR). Conclusions: The pilot study provided useful information for feasibility to recruit the sample size and to obtain relevant clinical data. For the final study protocol, both the neuropsychological battery and the age range for testing were revised. Our results confirmed the feasibility of our study approach and yielded pilot data from neuropsychological testing.

Pediatric Anesthesia and Neurodevelopmental Impairments: A Bayesian Meta-Analysis

Experimental evidence of anesthesia-induced neurotoxicity has caused serious concern about the long-term effect of commonly used volatile anesthetic agents on young children. Several observational studies based on existing data have been conducted to address this concern with inconsistent results. We conducted a meta-analysis to synthesize the epidemiologic evidence on the association of anesthesia/surgery with neurodevelopmental outcomes in children. Using Bayesian meta-analytic approaches, we estimated the synthesized odds ratios (OR) and 95% credible interval (CrI) as well as the predictive distribution of a future study given the synthesized evidence. Data on 7 unadjusted and 6 adjusted measures of association were abstracted from 7 studies. The synthesized OR based on the 7 unadjusted measures for the association of anesthesia/surgery with an adverse behavioral or developmental outcome was 1.9 (95% CrI, 1.2-3.0). The most likely unadjusted OR from a future study was estimated to be 2.2 (95% CrI, 0.6-6.1). The synthesized OR based on the 6 adjusted measures for the association of anesthesia/surgery with an adverse behavioral or developmental outcome was 1.4 (95% CrI, 0.9-2.2). The most likely adjusted OR from a future study was estimated to be 1.5 (95% CrI, 0.5-4.0). We conclude that existent epidemiologic evidence suggests a modestly elevated risk of adverse behavioral or developmental outcomes in children who were exposed to anesthesia/surgery during early childhood. The evidence, however, is considerably uncertain.

Cost-efficacy of Rofecoxib versus Acetaminophen for Preventing Pain after Ambulatory Surgery

Background Nonsteroidal antiinflammatory drugs are commonly administered as part of a multimodal regimen for pain management in the ambulatory setting. This randomized, double-blinded, placebo-controlled study was designed to compare the analgesic effect of oral rofecoxib, a cyclooxygenase-2 inhibitor, and acetaminophen when administered alone or in combination prior to outpatient otolaryngologic surgery. Methods A total of 143 healthy outpatients undergoing elective otolaryngologic surgery were assigned to one of four study groups: group 1 = control (500 mg vitamin C); group 2 = 2 g acetaminophen; group 3 = 50 mg rofecoxib; or group 4 = 2 g acetaminophen and 50 mg rofecoxib. The first oral dose of the study medication was taken 15–45 min before surgery, and a second dose of the same medication was administered on the morning after surgery. Recovery times, side effects, and the need for rescue analgesics were recorded. Follow-up evaluations were performed at 24 and 48 h after surgery to assess postdischarge pain, analgesic requirements, nausea, and patient satisfaction with their postoperative pain management and quality of recovery. Peak pain scores and the need for rescue analgesic medication were used as the endpoints for estimating efficacy of the study drugs, while cost to achieve complete satisfaction with analgesia was used in the cost-effectiveness analysis. Results Premedication with rofecoxib (50 mg) was significantly more effective than either placebo or acetaminophen (2 g) in reducing the peak postoperative pain, the need for analgesic medication, and improving the quality of recovery and patient satisfaction. Moreover, the addition of acetaminophen failed to improve its analgesic efficacy. An expenditure for rofecoxib of

Epidemiology of pediatric surgical admissions in US children: data from the HCUP kids inpatient database.

16.76 (95% confidence interval,

Anesthesia for electroconvulsive therapy in obese patients.

7.89 to 21.03) and