Lena S. Sun

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.

Epidemiology of Anesthesia-related Mortality in the United States, 1999–2005

Background:Previous research on anesthesia-related mortality in the United States was limited to data from individual hospitals. The purpose of this study was to examine the epidemiologic patterns of anesthesia-related deaths at the national level. Methods:The authors searched the International Classification of Diseases, 10th Revision manuals for codes specifically related to anesthesia/anesthetics. These codes were used to identify anesthesia-related deaths from the US multiple-cause-of-death data files for the years 1999–2005. Rates from anesthesia-related deaths were calculated based on population and hospital surgical discharge data. Results:The authors identified 46 anesthesia/anesthetic codes, including complications of anesthesia during pregnancy, labor, and puerperium (O29.0–O29.9, O74.0–74.9, O89.0–O89.9), overdose of anesthetics (T41.0–T41.4), adverse effects of anesthetics in therapeutic use (Y45.0, Y47.1, Y48.0–Y48.4, Y55.1), and other complications of anesthesia (T88.2–T88.5, Y65.3). Of the 2,211 recorded anesthesia-related deaths in the United States during 1999–2005, 46.6% were attributable to overdose of anesthetics; 42.5% were attributable to adverse effects of anesthetics in therapeutic use; 3.6% were attributable to complications of anesthesia during pregnancy, labor, and puerperium; and 7.3% were attributable to other complications of anesthesia. Anesthesia complications were the underlying cause in 241 (10.9%) of the 2,211 deaths. The estimated rates from anesthesia-related deaths were 1.1 per million population per year (1.45 for males and 0.77 for females) and 8.2 per million hospital surgical discharges (11.7 for men and 6.5 for women). The highest death rates were found in persons aged 85 yr and older. Conclusion:Each year in the United States, anesthesia/anesthetics are reported as the underlying cause in approximately 34 deaths and contributing factors in another 281 deaths, with excess mortality risk in the elderly and men.

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.

Prevalence of Malignant Hyperthermia Due to Anesthesia in New York State, 2001-2005

BACKGROUND: Malignant hyperthermia (MH) is a pharmacogenetic syndrome that variably expresses itself on exposure to triggering agents. MH prevalence in the United States is not well documented. In this study, we assessed the prevalence of MH in New York State hospitals. METHODS: Using New York hospital discharge data for the years 2001 through 2005, we identified all patients with a diagnosis of MH due to anesthesia using International Classification of Diseases, Ninth Revision, Clinical Modification code 995.86. MH prevalence was evaluated by demographic and clinical characteristics. RESULTS: Of the 12,749,125 discharges from New York hospitals during the study period, 73 patients had a recorded diagnosis of MH due to anesthesia. Nearly three quarters of the MH patients were male and 71% were patients from emergency/urgent admissions. The estimated prevalence rate of MH was 0.96 (95% confidence interval [CI] 0.67–1.24) per 100,000 surgical discharges and 1.08 (95% CI 0.75–1.41) per 100,000 discharges in which there was any indication of exposure to anesthesia. The estimated prevalence of MH for males was 2.5 to 4.5 times the rate for females. CONCLUSION: The prevalence of MH due to anesthesia in surgical patients treated in New York State hospitals is approximately 1 per 100,000. MH risk in males is significantly higher than in females.

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.

Anesthesia and neurodevelopment in children: time for an answer?

Editor’s Note: This is the first in a three-part series of Editorial Views regarding design of clinical trials to address the effect of anesthesia on the developing brain. Animal studies have suggested that anesthetic exposure could affect neurocognitive development, and there is an urgent need for clinical trials to determine whether this effect occurs in humans. This series presents the opinions of three world thought leaders in the possible designs of such clinical trials.

Sex-based differences in serum cardiac troponin I, a specific marker for myocardial injury, after cardiac surgery

BackgroundPrevalence and causes of sex-based differences in morbidity and mortality secondary to cardiovascular disease remain controversial. Cardiac troponin I (cTnI) is a sensitive and specific marker for myocardial injury. Serial cTnI measurements have been used to identify perioperative myocardial cell injury. ObjectiveTo determine whether sex influences the extent of myocardial injury during cardiac surgery, we measured perioperative cTnI in male and female patients. DesignA total of 17 male and 17 female patients were prospectively studied in an age- and case-matched manner. Arterial cTnI were obtained preinduction, 30 mins after the application of the aortic cross-clamp, at arrival to the intensive care unit, and on postoperative day 1. SettingTertiary cardiac surgery center at a major teaching hospital. ResultsThere was no difference between men and women in body mass index (kg/m2), duration of cardiopulmonary bypass, and aortic cross-clamp times. Preoperative cTnI measurements were similar in men (0.24 ± 0.15 ng/mL) and women (0.25 ± 0.13 ng/mL, mean ± sem). The maximum serum cTnI occurred on postoperative day 1 in all patients, and it was 3-fold higher in men (18.5 ± 5.7 ng/mL) compared with women (6.4 ± 1.0 ng/mL). ConclusionsMen had markedly higher serum cTnI compared with women, although they were case matched with respect to age and cardiac risk factors. Our results may suggest there may be sex-related differences in the myocardial response to ischemia and reperfusion injury or intrinsic differences between the male and female myocardium.

Muscarinic receptor heterogeneity in neonatal rat ventricular myocytes in culture.

Carbachol increased ventricular automaticity in a concentration-dependent fashion from a control rate of 72 +/- 5 (mean +/- SEM) to 86 +/- 4 beats per minute at 10(-4) M carbachol. Pirenzepine, an M1-selective antagonist, and AFDX 116, an M2-selective antagonist, both at 10(-7) M, did not block the carbachol-induced positive chronotropic response. In contrast, 10(-7) M HHSiD, an M3-selective antagonist, completely blocked the positive chronotropic effect of carbachol. Carbachol stimulated the accumulation of IP1 in a concentration-dependent manner at concentrations > or = 3 x 10(-6) M. AFDX 116 had no effect on carbachol-induced IP1 accumulation. HHSiD significantly inhibited IP1 accumulation at concentrations > or = 3 x 10(-8) M, while pirenzepine inhibited IP1 accumulation only at concentrations > or = 10(-5) M. McN A343 and methacholine, two muscarinic receptor agonists with minimal M2 activities, and carbachol did not alter basal cAMP concentration, but all three agonists significantly attenuated the increase in cAMP accumulation in response to isoproterenol. Carbachol inhibited isoproterenol-mediated cAMP accumulation at concentrations > or = 10(-7) M. AFDX 116, HHSiD, and pirenzepine blocked the carbachol-induced inhibition of isoproterenol-stimulated cAMP accumulation. At equimolar concentrations, the inhibitory effects of HHSiD and AFDX-116 were similar, while that of pirenzepine was much less. Pretreatment with pertussis toxin for 24 h did not prevent the carbachol-mediated positive chronotropic response or accumulation of IP1 but completely abolished the inhibition of isoproterenol-stimulated cAMP accumulation. These results indicate that (a) neonatal ventricular myocytes in culture have a heterogeneous population of muscarinic (M2 and M3) receptors, (b) the M3 receptor is coupled to pertussis toxin-sensitive and pertussis toxin-insensitive G proteins, (c) M3 receptor stimulation activates phosphoinositide hydrolysis and increases automaticity via a pertussis toxin-insensitive G protein-dependent pathway, and (d) both M2 and M3 receptors couple to pertussis toxin-sensitive G protein(s) to mediate the inhibition of intracellular cAMP accumulation in response to isoproterenol stimulation.

The association of tracheal anomalies and tetralogy of fallot

OBJECTIVE To determine the incidence of tracheal anomalies in children with tetralogy of Fallot. DESIGN Retrospective. SETTING A university childrens hospital. PARTICIPANTS Forty-four children with the diagnosis of tetralogy of Fallot who underwent either primary or palliative cardiac surgery. MEASUREMENTS AND MAIN RESULTS Three criteria were used to identify tracheal abnormalities: (1) direct laryngoscopic evidence; (2) radiographic evidence; and/or (3) inability to intubate the trachea with an endotracheal (ET) tube of appropriate size for age, followed by insertion of a 2.5-mm ET tube. An 11% incidence (5/44) of tracheal anomalies was noted. These could be separated into two categories: isolated upper airway pathology (either glottic or subglottic stenosis) and lower tracheal pathology. None of the five children identified with tracheal abnormalities manifested any preoperative signs or symptoms suggestive of airway problems. Four of the children experienced significant perioperative complications resulting directly from the underlying tracheal pathology. This represented a 9% morbidity (4/44) for patients presenting for repair of tetralogy of Fallot. CONCLUSIONS A significant incidence of tracheal anomalies is associated with tetralogy of Fallot, leading to potential perioperative complications.

Tracheobronchial anomalies in children with congenital cardiac disease

OBJECTIVE To perform preoperative airway evaluations, using radiographic analysis, to review the tracheal anatomy in children with congenital cardiac disease. DESIGN Prospective. SETTING A university childrens hospital. PARTICIPANTS One hundred patients. MEASUREMENTS AND MAIN RESULTS One magnified airway film (high kilovoltage filtered) was performed preoperatively on 100 consecutive children presenting for repair of congenital cardiac disease. Events at intubation, with respect to endotracheal tube size (internal diameter in millimeters) and difficulties with placement of the tube, were recorded. Postoperative morbidity, specifically related to underlying airway anomaly, was documented. Eleven children had positive radiographic findings after review of magnified airway films. Six of 11 patients had evidence of tracheobronchial pathology, and five patients had no tracheal pathology. Difficulties with intubation were noted in two children. No perioperative morbidity was noted in any patient. CONCLUSION The use of preoperative magnified airway films for tracheal evaluations in children with cardiac disease should be considered.