(Anesthesiology. 2017;127(5):788–799) In the United States, >250,000 infants are exposed to anesthesia each year. While general anesthesia causes functional and histopathologic changes in the central nervous systems (CNS) of late fetal and neonatal animals, it is not clear if these findings apply to humans. This study assessed possible associations of surgery and anesthesia in infants with later brain structure abnormalities in children who have no potential confounding risk factors. They hypothesized anesthesia and surgery may be associated with decreased white and gray matter volumes and and white matter integrity.

This study evaluated the relationship between exposure to anesthesia and previously identified differences in cognitive functioning, growth, and volumetric brain measures among a sample of children, adolescents, and young adults with isolated oral clefts. Data from a cross-sectional study were combined with a retrospective chart review. Data were obtained for 87 participants with isolated cleft lip and/or palate (55% male), ranging from 7.5 to 27 years old (mean = 15.78, standard deviation = 4.58). Measures of interest included cognitive functioning, growth measures, and brain volumes. Number of surgeries and time under anesthesia were obtained through systematic medical record review. Potential sex and cleft type differences in exposure as well as relationships between anesthesia exposure and outcome measures were evaluated. Participants with isolated cleft lip and palate had more surgeries and were under anesthesia longer. For participants with isolated cleft lip only, more surgeries were correlated to lower verbal IQ and higher frontal lobe volume.

233 July 2013 To the Editor: I read with interest the recent report from Block et al.,1 examining the relation between anesthetic exposure in the first year of life and academic achievement, but have concerns that their analysis inappropriately emphasizes the post hoc observation of an excess of subjects with extremely low achievement scores rather than overall academic achievements. The authors do not explicitly state their Null (Alternative) Hypotheses; however, based on the title of their report and its Introduction, I suspect that they were of the form “the distribution of achievement test scores in children exposed to anesthesia before age 1 yr does not (does) differ from that seen in children not so exposed.” The analysis presented by the authors would be appropriate only to the far more specific Null (Alternative) Hypotheses that “children exposed to anesthesia before 1 yr of age are not (are) more likely to score in the lowest fifth percentile on tests of academic achievement.” The authors’ analysis unnecessarily discards almost all the informations available from the distribution of scores. When considering distributions of outcomes, a more appropriate analysis would be the chi-square goodness-of-fit test. Based on a minimum cell expected value of 5, we can divide the authors’ data from figure 1 into 10 deciles, each with an expected value of 5.8 (table 1). For this distribution, chi-square test is equal to 8.55 with 9 degrees of freedom (df; P = 0.48). This should be interpreted as meaning that the probability of randomly drawing a sample of 58 subjects from a uniformly distributed population, at least this extreme, is 48%. In other words, the distribution of the achievement scores for the authors’ subjects is entirely consistent with a randomly selected sample from the population of all children taking the test. A similar analysis of subjects’ percentile ranks converted to z-scores yields the even less significant result of chi-square test of 2.16 for df = 5 (P = 0.83). An analogy may be helpful. We are given an icosahedral (12-sided) die and wish to determine if it is fair. The die is rolled 60 times so that the expected value for each possible outcome is five; the results are recorded in a table similar to that in the preceding paragraph (table 2). It is tempting to interpret the excess number of 4’s rolled as evidence that the die is unfair; the result is certainly statistically “significant” for the binomial outcome “4” versus “not 4” (the 95% CI for the observed frequency for each result based on 60 rolls of a fair 12-sided die is 0–9, which does not include the observed value of 10). This conclusion would be incorrect. There was no a priori reason to suspect that the die would roll more 4’s than any other number. Because we had neither specified nor predicted the outcome of interest, we must be prepared to analyze every possible outcome, including an appropriate adjustment to the test-wise level of α to maintain an experiment-wise level of α of 0.05. Because this adjustment can result in an extremely conservative test-wise α, we instead look at the overall distribution of rolls; based on this (chisquare test = 9.60; df = 11; P = 0.57), we conclude that there is no evidence based on this experiment that the die is unfair. Of course, we may wish to repeat the experiment with the hypothesis that the die favors 4’s, especially given the relative deficit of rolls on the side opposite the 4 (the 9). In a similar way, it seems obvious that the excess number of subjects observed in the lowest fifth percentile must mean that the academic achievement was lower in the group exposed to anesthesia in the first year of life. However, there are other deciles whose deviation from the expected is more extreme (50–60 and 60–70%); we are not free to pick and choose which extreme deviations to treat as random chance and which to analyze as meaningful unless we have included a specific deviation in the Null and Alternative Hypotheses. There are many ways that exposure to anesthetics might impact academic achievement. Exposure might decrease each subject’s achievement by a fairly consistent amount relative to that which would have been seen absent exposure, in effect shifting the entire normal curve to the left. Although this would indeed result in an excess of subjects in the lowest fifth percentile, it would also result in a relative deficit in the higher percentiles. This is not seen in the authors’ results; indeed, two subjects scored at the 100th percentile, far above the expected 0.58 subjects. Alternatively, anesthetic exposure might result in disparate impact on the subjects with the highest potential achievement, resulting in a dearth of subjects with high scores, but no major alteration in the distribution of low scores; again, this is not seen. Examination of the authors’ figure 1 shows that their results are almost entirely dependent on the presence of an unexpectedly large number of subjects (five) scoring at the second percentile; indeed, if we remove one of these subjects by excluding the four subjects who had additional surgical procedures beyond those in the inclusion criteria (authors’ figs. 2 and 3 and related discussion; see next paragraph), the resulting distribution falls nicely along the line of identity with the expected uniform distribution (chi-square test = 8.96; df = 9; P = 0.44) and the mean percentile score of the remaining 54 subjects is 49.8. As per the authors' discussion, their results seem most consistent with a mechanism that leads to minimal or no impact in the vast majority of subjects and severe, pervasive neurocognitive impairment in a very small subset of subjects. Finally, some observations about their figures 2 and 3: it seems that the significance of the linear relations reported is entirely dependent on the presence of subjects who either Anesthetic Exposure and Academic Achievement: Missing the Forest for the Trees

Finally, because we disagree with Gunter’s arguments as detailed above, we disagree with his statement that our “ . . . results only support a conclusion that the distribution of academic achievement scores in otherwise neurologically normal children with a single exposure to anesthesia in the first year of life for minor, peripheral surgery is completely consistent with that seen in the population at large.” However, for numerous reasons detailed in the Discussion section of our article, we do not believe that our results established that exposure to anesthesia during infancy was causally related to the disproportionate number of children who had very low test scores. We made clear in the article that causation could not be determined from our study and that the findings should be considered tentative until further verification.

BACKGROUND:Although studies in neonatal animals show that anesthetics have neurotoxic effects, relevant human evidence is limited. We examined whether children who had surgery during infancy showed deficits in academic achievement.METHODS:We attempted to contact parents of 577 children who, during infancy, had one of three operations typically performed in otherwise healthy children. We compared scores on academic achievement tests with population norms.RESULTS:Composite scores were available for 287 patients. The mean normal curve equivalent score was 43.0±22.4 (mean±SD), lower than the expected normative value of 50, P<0.0001 by one-sample Student t test; and 35 (12%) had scores below the 5th percentile, more than expected, P<0.00001 by binomial test. Of 133 patients who consented to participate so that their scores could be examined in relation to their medical records, the mean score was 45.9±22.9, P=0.0411; and 15 (11%) scored below the 5th percentile, P=0.0039. Of 58 patients whose medical records showed no central nervous system problems/potential risk factors during infancy, 8 (14%) scored below the 5th percentile, P=0.008; however, the mean score, 47.6±23.4, was not significantly lower than expected, P=0.441. Duration of anesthesia and surgery correlated negatively with scores (r=-0.34, N=58, P=0.0101).CONCLUSIONS:Although the findings are consistent with possible adverse effects of anesthesia and surgery during infancy on subsequent academic achievement, other explanations are possible and further investigations are needed.

Objective: The study aimed to describe the patterns and density of early tracheal colonization among intubated patients and to correlate colonization status with levels of antimicrobial peptides and inflammatory cytokines.Design: The was a prospective cohort study.Setting: The study was conducted in medical and cardiovascular intensive care units of a tertiary referral hospital.Patients: Seventy-four adult patients admitted between March 2003 and May 2006 were recruited for the study.Interventions: Tracheal aspirates were collected daily for the first 4 days of intubation using standardized, sterile technique and sent for quantitative culture and cytokines, lactoferrin and lysozyme measurements.Measurements and Main Results: The mean acute physiology and chronic health evaluation (APACHE II) score in this cohort was 24 +/- 7. Proportion of subjects colonized by any microorganism increased over the first 4 days of intubation (47%, 60%, 70%, 70%, P = .08), but density of colonization for bacteria or yeast did not change significantly. No known risk factors predicted tracheal colonization on day I of intubation. Several patterns of colonization were observed (persistent, transient, new colonization, and clearance of initial colonization). The most common organisms cultured were Candida albicans and coagulase-negative Staphylococcus. Levels of cytokines, lactoferrin, or lysozyme did not change over time and were not correlated with tracheal colonization status. Four subjects (6%) had ventilator-associated pneumonia.Conclusions: The density of tracheal colonization did not change significantly over the first 4 days of intubation in medical intensive care unit patients. There was no correlation between tracheal colonization and the levels of antimicrobial peptides or cytokines. Several different patterns of colonization may have to be considered while planning interventions to reduce airway colonization. (C) 2009 Elsevier Inc. All rights reserved.

The area postrema is a circumventricular organ that plays an important role in neurohumoral regulation of the circulation. We have developed a method to examine permeability and vascular responses of the microcirculation of the area postrema in vivo. A craniotomy was performed over the dorsal brain stem in anesthetized rats, and blood vessels to the area postrema were visualized with fluorescein microscopy. Extravasation of sodium fluorescein (MW, 386), but not 150 kDa (MW) fluorescein isothiocyanate-dextran, occurred in the area postrema under control conditions. There was no extravasation of fluorescein or dextran in the brain stem under control conditions. Acute hypertension produced marked disruption of the barrier to 150 kDa dextran in the area postrema, compared with minimal disruption in the brain stem. We tested the hypothesis that the area postrema has greater permeability to small molecules than the brain stem and that this permeability might be accompanied by distinctive vascular responses. Topical suffusion of adenosine and ADP produced similar dose-related dilation of arterioles to area postrema and dorsal brain stem. Topical and intravenous vasopressin produced similar dose-related constriction of vessels to area postrema and brain stem. Electron microscopy in rats demonstrated that a barrier to horseradish peroxidase, which is absent in capillaries in the area postrema, is present in arterioles that supply the area postrema.(ABSTRACT TRUNCATED AT 250 WORDS)