Association of preoperative coronavirus disease 2019 with mortality, respiratory morbidity and extrapulmonary complications after elective, noncardiac surgery: An observational cohort study.

STUDY OBJECTIVE: To assess the impact of preoperative infection with the contemporary strain of severe acute respiratory coronavirus 2 (SARS-CoV-2) on postoperative mortality, respiratory morbidity and extrapulmonary complications after elective, noncardiac surgery. DESIGN: An ambidirectional observational cohort study. SETTING: A tertiary and teaching hospital in Shanghai, China. PATIENTS: All adult patients (≥ 18 years of age) who underwent elective, noncardiac surgery under general anesthesia at Huashan Hospital of Fudan University from January until March 2023 were screened for eligibility. A total of 2907 patients were included. EXPOSURE: Preoperative coronavirus disease 2019 (COVID-19) positivity. MEASUREMENTS: The primary outcome was 30-day postoperative mortality. The secondary outcomes included postoperative pulmonary complications (PPCs), myocardial injury after noncardiac surgery (MINS), acute kidney injury (AKI), postoperative delirium (POD) and postoperative sleep quality. Multivariable logistic regression was used to assess the risk of postoperative mortality and morbidity imposed by preoperative COVID-19. MAIN RESULTS: The risk of 30-day postoperative mortality was not associated with preoperative COVID-19 [adjusted odds ratio (aOR), 95% confidence interval (CI): 0.40, 0.13-1.28, P = 0.123] or operation timing relative to diagnosis. Preoperative COVID-19 did not increase the risk of PPCs (aOR, 95% CI: 0.99, 0.71-1.38, P = 0.944), MINS (aOR, 95% CI: 0.54, 0.22-1.30; P = 0.168), or AKI (aOR, 95% CI: 0.34, 0.10-1.09; P = 0.070) or affect postoperative sleep quality. Patients who underwent surgery within 7 weeks after COVID-19 had increased odds of developing delirium (aOR, 95% CI: 2.26, 1.05-4.86, P = 0.036). CONCLUSIONS: Preoperative COVID-19 or timing of surgery relative to diagnosis did not confer any added risk of 30-day postoperative mortality, PPCs, MINS or AKI. However, recent COVID-19 increased the risk of POD. Perioperative brain health should be considered during preoperative risk assessment for COVID-19 survivors.

Anesthesia and Sedation Exposure and Neurodevelopmental Outcomes in Infants Undergoing Congenital Cardiac Surgery: A Retrospective Cohort Study.

BACKGROUND: Children undergoing complex cardiac surgery are exposed to substantial cumulative doses of sedative medications and volatile anesthetics and are more frequently anesthetized with ketamine, compared with healthy children. This study hypothesized that greater exposure to sedation and anesthesia in this population is associated with lower neurodevelopmental scores at 18 months of age. METHODS: A secondary analysis was conducted of infants with congenital heart disease who participated in a prospective observational study of environmental exposures and neurodevelopmental outcomes to assess the impact of cumulative volatile anesthetic agents and sedative medications. Cumulative minimum alveolar concentration hours of exposure to volatile anesthetic agents and all operating room and intensive care unit exposures to sedative and anesthesia medications were collected before administration of Bayley Scales of Infant and Toddler Development, 3rd edition (Bayley III), at 18 months of age. RESULTS: The study cohort included 41 (37%) single-ventricle and 69 (63%) two-ventricle patients. Exposures to volatile anesthetic agents, opioids, benzodiazepines, and dexmedetomidine were not associated with abnormal Bayley III scores. At 18-month follow-up, after adjusting for confounders, each mg/kg increase in ketamine exposure was associated with a 0.34 (95% CI, -0.64 to -0.05) point decrease in Bayley III motor scores (P = 0.024). CONCLUSIONS: Total cumulative exposures to volatile anesthetic agents were not associated with neurodevelopmental impairment in infants with congenital heart disease undergoing various imaging studies and procedures, whereas higher ketamine doses were associated with poorer motor performance.

Effect of dexmedetomidine on sevoflurane-induced neurodegeneration in neonatal rats.

BACKGROUND: Structural brain abnormalities in newborn animals after prolonged exposure to all routinely used general anaesthetics have raised substantial concerns for similar effects occurring in millions of children undergoing surgeries annually. Combining a general anaesthetic with non-injurious sedatives may provide a safer anaesthetic technique. We tested dexmedetomidine as a mitigating therapy in a sevoflurane dose-sparing approach. METHODS: Neonatal rats were randomised to 6 h of sevoflurane 2.5%, sevoflurane 1% with or without three injections of dexmedetomidine every 2 h (resulting in 2.5, 5, 10, 25, 37.5, or 50 µg kg-1 h-1), or fasting in room air. Heart rate, oxygen saturation, level of hypnosis, and response to pain were measured during exposure. Neuronal cell death was quantified histologically after exposure. RESULTS: Sevoflurane at 2.5% was more injurious than at 1% in the hippocampal cornu ammonis (CA)1 and CA2/3 subfields; ventral posterior and lateral dorsal thalamic nuclei; prefrontal, retrosplenial, and somatosensory cortices; and subiculum. Although sevoflurane 1% did not provide complete anaesthesia, supplementation with dexmedetomidine dose dependently increased depth of anaesthesia and diminished responses to pain. The combination of sevoflurane 1% and dexmedetomidine did not reliably reduce neuronal apoptosis relative to an equianaesthetic dose of sevoflurane 2.5%. CONCLUSIONS: A sub-anaesthetic dose of sevoflurane combined with dexmedetomidine achieved a level of anaesthesia comparable with that of sevoflurane 2.5%. Similar levels of anaesthesia caused comparable programmed cell death in several developing brain regions. Depth of anaesthesia may be an important factor when comparing the neurotoxic effects of different anaesthetic regimens.

Standards for preclinical research and publications in developmental anaesthetic neurotoxicity: expert opinion statement from the SmartTots preclinical working group.

In March 2019, SmartTots, a public-private partnership between the US Food and Drug Administration and the International Anesthesia Research Society, hosted a meeting attended by research experts, anaesthesia journal editors, and government agency representatives to discuss the continued need for rigorous preclinical research and the importance of establishing reporting standards for the field of anaesthetic perinatal neurotoxicity. This group affirmed the importance of preclinical research in the field, and welcomed novel and mechanistic approaches to answer some of the field's largest questions. The attendees concluded that summarising the benefits and disadvantages of specific model systems, and providing guidance for reporting results, would be helpful for designing new experiments and interpreting results across laboratories. This expert opinion report is a summary of these discussions, and includes a focused review of current animal models and reporting standards for the field of perinatal anaesthetic neurotoxicity. This will serve as a practical guide and road map for novel and rigorous experimental work.

Immature murine hippocampal neurones do not develop long-term structural changes after a single isoflurane exposure.

BACKGROUND: Studies in developing animals show that a clinically relevant anaesthesia exposure increases neuronal death and alters brain structure. In the hippocampal dentate gyrus, the anaesthetic isoflurane induces selective apoptosis among roughly 10% of 2-week-old hippocampal granule cells in 21-day-old mice. In this work, we queried whether the 90% of granule cells surviving the exposure might be 'injured' and integrate abnormally into the brain. METHODS: The long-term impact of isoflurane exposure on granule cell structure was studied using a transgenic mouse model fate-mapping approach to identify and label immature granule cells. Male and female mice were exposed to isoflurane for 6 h when the fate-mapped granule cells were 2 weeks old. The morphology of the fate-mapped granule cells was quantified 2 months later. RESULTS: The gross structure of the dentate gyrus was not affected by isoflurane treatment, with granule cells present in the correct subregions. Individual isoflurane-exposed granule cells were structurally normal, exhibiting no changes in spine density, spine type, dendrite length, or presynaptic axon terminal structure (P>0.05). Granule cell axon terminals were 13% larger in female mice relative to males; however, this difference was evident regardless of treatment (difference of means=0.955; 95% confidence interval, 0.37-1.5; P=0.010). CONCLUSIONS: A single, prolonged isoflurane exposure did not impair integration of this age-specific cohort of granule cells, regardless of the animal's sex. Nonetheless, although 2-week-old cells were not affected, the results should not be extrapolated to other age cohorts, which may respond differently.

Defining the Vulnerability Window of Anesthesia-Induced Neuroapoptosis in Developing Dentate Gyrus Granule Cells - A Transgenic Approach Utilizing POMC-EGFP Mice.

Exposure to commonly used anesthetics is associated with widespread neuroapoptosis in neonatal animals. Vulnerability of developing hippocampal dentate gyrus granule cells to anesthetic neurotoxicity peaks approximately 2 weeks after cell birth, as measured by bromodeoxyuridine birth dating, regardless of the age of the animal. The present study examined whether the vulnerable window can be further characterized by utilizing a transgenic approach. Proopiomelanocortin enhanced green fluorescent protein (POMC-EGFP) mice (postnatal day 21) were exposed to 3% sevoflurane for 6 h. Following exposure, cleaved caspase 3, expression of EGFP and differential maturational markers were quantified and compared with unanesthetized littermates. Electrophysiological properties of EGFP+ and EGFP- cells in the subgranular zone and the inner half of the granule cell layer were recorded by whole-cell patch-clamp. We found that sevoflurane significantly increased apoptosis of POMC-EGFP+ granule cells that accounted for approximate 1/3 of all apoptotic cells in dentate gyrus. Apoptotic EGFP- granule cells more frequently expressed the immature neuronal marker calretinin (75.4% vs 45.0%, P < 0.001) and less frequently the late progenitor marker NeuroD1 (21.9% vs 87.9%, P < 0.001) than EGFP+ granule cells. Although EGFP- granule cells were more mature in immunostaining than EGFP+ granule cells, their electrophysiological properties partially overlapped in terms of input resistance, resting membrane potential and action potential amplitude. Our results revealed the POMC stage, when GABA acts as an excitatory neurotransmitter, only partly captures susceptibility to anesthetic neurotoxicity, suggesting the vulnerable window of anesthesia-induced neuroapoptosis extends from the end of POMC+ stage to the post-POMC+ stage when depolarizing glutamatergic inputs emerge.

Anesthesia and the developing brain: A way forward for laboratory and clinical research.

All commonly used general anesthetics have been shown to cause neurotoxicity in animal models, including nonhuman primates. Opinion, however, remains divided over how cumulative evidence from preclinical and human studies in this field should be interpreted and its translation to current practices in pediatric anesthesia and surgery. A group of international experts in laboratory and clinical sciences recently convened in Genoa, Italy, to evaluate the current state of both laboratory and clinical research and discuss future directions for basic, translational, and clinical studies in this field. This paper describes those discussions and conclusions. A central goal identified was the importance of continuing to pursue laboratory research efforts to better understand the biological pathways underlying anesthesia neurotoxicity. The distinction between basic and translational experimental designs in this field was highlighted, and it was acknowledged that it will be important for future animal research to try to causally link structural changes with long-term cognitive abnormalities. While inherent limitations will continue to affect the ability of even large observational cohorts to determine if anesthesia impacts neurodevelopment or behavioral outcomes, the importance of conducting further large well-designed cohort studies was also emphasized. Adequately powered cohorts could clarify which populations are at increased risk, provide information on environmental and healthcare-related risk modifiers, and guide future interventional trials. If anesthetics cause structural or functional adverse neurological effects in young children, alternative or mitigating strategies need to be considered. While protective or mitigating strategies have been repeatedly studied in animals, there are currently no human data to support alternative anesthetic strategies in clinical practice. Lastly, it was noted that there is still considerable debate over the clinical relevance of anesthesia neurotoxicity, and the need to evaluate the impact of other aspects of perioperative care on neurodevelopment must also be considered.

Does pediatric anesthesia cause brain damage? - Addressing parental and provider concerns in light of compelling animal studies and seemingly ambivalent human data.

Anesthesia facilitates surgery in millions of young children every year. Structural brain abnormalities and functional impairment observed in animals have created substantial concerns among clinicians, parents, and government regulators. Clinical studies seemed ambivalent; it remains unclear whether differential species effects exist towards anesthetic exposure. The current literature search and analysis attempts to unify the available clinical and animal studies, which currently comprise of > 530 in vivo animal studies and > 30 clinical studies. The prevalence of abnormalities was lowest for exposures < 1 hour, in both animals and humans, while studies with injurious findings increased in frequency with exposure time. Importantly, no exposure time, anesthetic technique, or age during exposure was clearly identifiable to be entirely devoid of any adverse outcomes. Moreover, the age dependence of maximum injury clearly identified in animal studies, combined with the heterogeneity in age in most human studies, may impede the discovery of a specific human neurological phenotype. In summary, animal and human research studies identify a growing prevalence of injurious findings with increasing exposure times. However, the existing lack of definitive data regarding safe exposure durations, unaffected ages, and non-injurious anesthetic techniques precludes any evidence-based recommendations for drastically changing current clinical anesthesia management. Animal studies focusing on brain maturational states more applicable to clinical practice, as well as clinical studies focusing on prolonged exposures during distinct developmental windows of vulnerability, are urgently needed to improve the safety of perioperative care for thousands of young children requiring life-saving and quality of life-improving procedures daily.

Comparison of Intranasal Dexmedetomidine and Oral Pentobarbital Sedation for Transthoracic Echocardiography in Infants and Toddlers: A Prospective, Randomized, Double-Blind Trial.

BACKGROUND: Acquisition of transthoracic echocardiographic (TTEcho) images in children often requires sedation. The optimal sedative for TTEcho has not been determined. Children with congenital heart disease are repeatedly exposed to sedatives and anesthetics that may affect brain development. Dexmedetomidine, which in animals alters brain structure to a lesser degree, may offer advantages in this vulnerable population. METHODS: A prospective, randomized, double-blind trial enrolled 280 children 3-24 months of age undergoing outpatient TTEcho, comparing 2.5 µg·kg intranasal dexmedetomidine to 5 mg·kg oral pentobarbital. Rescue sedation, for both groups, was intranasal dexmedetomidine 1 µg·kg. The primary outcome was adequate sedation within 30 minutes without rescue sedation, assessed by blinded personnel. Secondary outcomes included number of sonographer pauses, image quality in relation to motion artifacts, and parental satisfaction. RESULTS: Success rates with a single dose were not different between sedation techniques; 85% in the pentobarbital group and 84% in the dexmedetomidine group (P = .8697). Median onset of adequate sedation was marginally faster with pentobarbital (16.5 [interquartile range, 13-21] vs 18 [16-23] minutes for dexmedetomidine [P = .0095]). Time from drug administration to discharge was not different (P = .8238) at 70.5 (64-83) minutes with pentobarbital and 70 (63-82) minutes with dexmedetomidine. Ninety-five percent of sedation failures with pentobarbital and 100% of dexmedetomidine failures had successful rescue sedation with intranasal dexmedetomidine. CONCLUSIONS: Intranasal dexmedetomidine was comparable to oral pentobarbital sedation for TTEcho sedation in infants and did not increase the risk of clinically important adverse events. Intranasal dexmedetomidine appears to be an effective "rescue" sedative for both failed pentobarbital and dexmedetomidine sedation. Dexmedetomidine could be a safer option for repeated sedation in children, but further studies are needed to assess long-term consequence of repeated sedation in this high-risk population.

Sedation methods for transthoracic echocardiography in children with Trisomy 21-a retrospective study.

BACKGROUND: Many children with Trisomy 21 have neurologic or behavioral problems that make it difficult for them to remain still during noninvasive imaging studies, such as transthoracic echocardiograms (TTEcho). Recently, intranasal dexmedetomidine sedation has been introduced for this purpose. However, dexmedetomidine has been associated with bradycardia. Children with Trisomy 21 have been reported to have a higher risk of bradycardia and airway obstruction with sedation or anesthesia compared to children without Trisomy 21. OBJECTIVE: Our aim was to quantify the incidence of age-defined bradycardia and other adverse effects in patients with Trisomy 21 under sedation for TTEcho using a variety of sedation and anesthesia techniques available and utilized at our institution in this challenging patient population, including intranasal dexmedetomidine, oral pentobarbital, general anesthesia with propofol, and general anesthesia with sevoflurane. Our primary hypothesis was that intranasal dexmedetomidine sedation would result in a significantly higher risk of bradycardia in patients with Trisomy 21, compared with other sedative or anesthetic regimens. METHODS: This is a retrospective, observational study of 147 consecutive patients with Trisomy 21 who were sedated or anesthetized for transthoracic echocardiography. Efficacy of sedation was defined as no need for rescue sedation or conversion to an alternate technique. Lowest and highest heart rate, systolic blood pressure, oxygen saturation, and PR interval from formal electrocardiograms were extracted from the electronic medical record. These data were compared to age-defined normal values to determine adverse events. RESULTS: Four methods of sedation or anesthesia were utilized to perform sedated transthoracic echocardiography: general anesthesia with sevoflurane by mask, general anesthesia with sevoflurane induction followed by intravenous propofol maintenance, oral pentobarbital, and intranasal dexmedetomidine. Intranasal dexmedetomidine 2.5 mcg·kg-1 was an effective sedative as a single dose for TTEcho in 37 of 41 (90%) cases. Oral pentobarbital 5 mg·kg-1 as a single dose for young children with Trisomy 21 was effective in 55 of 75 (73%) cases. Intranasal dexmedetomidine sedation was not associated with a significantly higher risk of bradycardia in patients with Trisomy 21, compared with other sedative or anesthetic regimens, when compared to oral pentobarbital for patients under 2 years of age and general anesthesia for children 3 years and older. The two general anesthesia groups showed lowest heart rates of 66.9 ± 15.9 min-1 for sevoflurane and 69.0 ± 11.5 min-1 for sevoflurane-propofol. Hypotension was present in all groups ranging between an incidence of 56% in the sevoflurane group to 11% in the oral pentobarbital group. Oxygen saturation and clinically significant desaturation occurred in 14% of the oral pentobarbital group. CONCLUSION: Intranasal dexmedetomidine sedation was not associated with a significantly higher risk of bradycardia in patients with Trisomy 21, compared with other sedative or anesthetic regimens.

Do anesthetics harm the developing human brain? An integrative analysis of animal and human studies.

Anesthetics that permit surgical procedures and stressful interventions have been found to cause structural brain abnormalities and functional impairment in immature animals, generating extensive concerns among clinicians, parents, and government regulators regarding the safe use of these drugs in young children. Critically important questions remain, such as the exact age at which the developing brain is most vulnerable to the effects of anesthetic exposure, whether a particular age exists beyond which anesthetics are devoid of long-term effects on the brain, and whether any specific exposure duration exists that does not lead to deleterious effects. Accordingly, the present analysis attempts to put the growing body of animal studies, which we identified to include >440 laboratory studies to date, into a translational context, by integrating the preclinical data on brain structure and function with clinical results attained from human neurocognitive studies, which currently exceed 30 studies. Our analysis demonstrated no clear exposure duration threshold below which no structural injury or subsequent cognitive abnormalities occurred. Animal data did not clearly identify a specific age beyond which anesthetic exposure did not cause any structural or functional abnormalities. Several potential mitigating strategies were found, however, no general anesthetic was identified that consistently lacked neurodegenerative properties and could be recommended over other anesthetics. It therefore is imperative, to expand efforts to devise safer anesthetic techniques and mitigating strategies, even before long-term alterations in brain development are unequivocally confirmed to occur in millions of young children undergoing anesthesia every year.

Long-term Fate Mapping to Assess the Impact of Postnatal Isoflurane Exposure on Hippocampal Progenitor Cell Productivity.

BACKGROUND: Exposure to isoflurane increases apoptosis among postnatally generated hippocampal dentate granule cells. These neurons play important roles in cognition and behavior, so their permanent loss could explain deficits after surgical procedures. METHODS: To determine whether developmental anesthesia exposure leads to persistent deficits in granule cell numbers, a genetic fate-mapping approach to label a cohort of postnatally generated granule cells in Gli1-CreER::GFP bitransgenic mice was utilized. Green fluorescent protein (GFP) expression was induced on postnatal day 7 (P7) to fate map progenitor cells, and mice were exposed to 6 h of 1.5% isoflurane or room air 2 weeks later (P21). Brain structure was assessed immediately after anesthesia exposure (n = 7 controls and 8 anesthesia-treated mice) or after a 60-day recovery (n = 8 controls and 8 anesthesia-treated mice). A final group of C57BL/6 mice was exposed to isoflurane at P21 and examined using neurogenesis and cell death markers after a 14-day recovery (n = 10 controls and 16 anesthesia-treated mice). RESULTS: Isoflurane significantly increased apoptosis immediately after exposure, leading to cell death among 11% of GFP-labeled cells. Sixty days after isoflurane exposure, the number of GFP-expressing granule cells in treated animals was indistinguishable from control animals. Rates of neurogenesis were equivalent among groups at both 2 weeks and 2 months after treatment. CONCLUSIONS: These findings suggest that the dentate gyrus can restore normal neuron numbers after a single, developmental exposure to isoflurane. The authors' results do not preclude the possibility that the affected population may exhibit more subtle structural or functional deficits. Nonetheless, the dentate appears to exhibit greater resiliency relative to nonneurogenic brain regions, which exhibit permanent neuron loss after isoflurane exposure.

Biomarkers, Genetics, and Epigenetic Studies to Explore the Neurocognitive Effects of Anesthesia in Children.

Exposure to commonly used anesthetic agents causes widespread neuronal degeneration in the developing mammalian brain and has been shown to impair neurodevelopment in a variety of newborn vertebrate animal species. Although retrospective studies have suggested an association between anesthesia exposure in childhood and subsequent neurodevelopmental abnormalities, a causal relationship in humans has yet to be demonstrated. Unfortunately, translation of findings from bench to bedside is limited by several factors and histologic assessment in healthy children following exposure to anesthesia is not possible. Therefore, to prove that anesthesia-induced neurotoxicity occurs in humans, alternative approaches are necessary. Here we present the summary of a focus group discussion regarding the utility of biomarkers in translational studies of anesthetic neurotoxicity as part of The 2016 Pediatric Anesthesia NeuroDevelopmental Assessment (PANDA) Symposium at Columbia University Medical Center. The experts agreed that defining intermediate phenotypes using advanced neuroimaging as a biomarker is a highly feasible and reasonable modality to provide new insights into the deleterious effects of anesthetic exposure in the developing human brain and could illuminate a viable investigative path forward. Ultimately, well-defined intermediate phenotypes may allow us to fully understand the neurodevelopmental impact of anesthesia-induced neurotoxicity and permit us to develop the safest and most effective anesthetic strategies for the infants and children we care for.

Dosing and efficacy of intranasal dexmedetomidine sedation for pediatric transthoracic echocardiography: a retrospective study.

PURPOSE: We designed this retrospective observational study on the use of α2-agonist dexmedetomidine to determine the optimum intranasal dose to achieve sedation for pediatric transthoracic echocardiography and to identify any dose-related adverse effects. METHODS: Outpatient children aged three months to three years with diverse diagnoses of congenital heart disease, including cyanotic cardiac defects, underwent transthoracic echocardiography under dexmedetomidine sedation. Aerosolized intranasal dexmedetomidine was administered with initial doses ranging from 1-3 µg·kg(-1). A rescue dose of 1 µg·kg(-1) was administered if adequate sedation was not achieved within 45 min following the first dose. The primary study outcome was the achievement of adequate sedation to allow transthoracic echocardiography (TTE) scanning, including subxiphoid and suprasternal probe manipulation. RESULTS: Sedation with intranasal dexmedetomidine for transthoracic echocardiography was successful in 62 of the 63 (98%) patients studied, with an intranasal rescue dose required in 13 (21%) patients. Intranasal doses of dexmedetomidine 2.5-3.0 µg·kg(-1) were required for tolerating TTE probe placement, including subxiphoid and suprasternal manipulation, with minimal response and a 90% success rate. Excluding patients who required a second dose of dexmedetomidine, the mean (standard deviation) time from administration to achieving such sedation (onset time) was 26 (8) min for low-dose (1-2 µg·kg(-1)) dexmedetomidine and 28 (8) min for moderate-dose (2.5-3.0 µg·kg(-1)) dexmedetomidine (P = 0.33). Time from administration of low-dose dexmedetomidine to discharge, including TTE scan time, was 80 (14) min, and it increased with moderate-dose dexmedetomidine to 91 (22) min (P = 0.05). Mild to moderate bradycardia and hypotension were observed, but no interventions were required. CONCLUSION: We found that aerosolized intranasal dexmedetomidine offers satisfactory conditions for TTE in children three months to three years of age with an optimal dose of 2.5-3.0 µg·kg(-1)administered under the supervision of a pediatric cardiac anesthesiologist.

Cognition and Brain Structure Following Early Childhood Surgery With Anesthesia.

BACKGROUND: Anesthetics induce widespread cell death, permanent neuronal deletion, and neurocognitive impairment in immature animals, raising substantial concerns about similar effects occurring in young children. Epidemiologic studies have been unable to sufficiently address this concern, in part due to reliance on group-administered achievement tests, inability to assess brain structure, and limited control for confounders. METHODS: We compared healthy participants of a language development study at age 5 to 18 years who had undergone surgery with anesthesia before 4 years of age (n = 53) with unexposed peers (n = 53) who were matched for age, gender, handedness, and socioeconomic status. Neurocognitive assessments included the Oral and Written Language Scales and the Wechsler Intelligence Scales (WAIS) or WISC, as appropriate for age. Brain structural comparisons were conducted by using T1-weighted MRI scans. RESULTS: Average test scores were within population norms, regardless of surgical history. However, compared with control subjects, previously exposed children scored significantly lower in listening comprehension and performance IQ. Exposure did not lead to gross elimination of gray matter in regions previously identified as vulnerable in animals. Decreased performance IQ and language comprehension, however, were associated with lower gray matter density in the occipital cortex and cerebellum. CONCLUSIONS: The present findings suggest that general anesthesia for a surgical procedure in early childhood may be associated with long-term diminution of language abilities and cognition, as well as regional volumetric alterations in brain structure. Although causation remains unresolved, these findings nonetheless warrant additional research into the phenomenon's mechanism and mitigating strategies.

Developmental stage-dependent impact of midazolam on calbindin, calretinin and parvalbumin expression in the immature rat medial prefrontal cortex during the brain growth spurt.

BACKGROUND: Human epidemiological data suggest a link between anesthesia exposure in early postnatal life and subsequent lasting neurocognitive alterations. Understanding the underlying mechanisms of this potential association is of paramount importance in an attempt to develop protective strategies. While general anesthetics are powerful modulators of GABAergic neurotransmission, little is known about the impact of these drugs on developing GABAergic networks. Here we addressed this issue by evaluating the impact of a 6-h-long midazolam exposure on the development of calbindin-, calretinin- and parvalbumin-expressing GABAergic interneurons. METHODS: Physiological expression patterns of calbindin-, calretinin-, and parvalbumin-positive neurons as well as the impact of a 6-h-long midazolam exposure on these cell populations were evaluated in the medial prefrontal cortex of Wistar rats at defined stages of the brain growth spurt using stereological analysis. Activated caspase-3 immunohistochemistry was used to quantify apoptotic death in controls and midazolam-treated subjects. RESULTS: In control animals, the number of parvalbumin expressing cells significantly (p<0.01) increased while those of calbindin positive populations significantly (p<0.01) decreased between postnatal day 10 and 20. Expression of calretinin remained constant during this period. Immediately following exposure, midazolam induced neuroapoptosis at both early (postnatal day 5, p=0.016) and later (postnatal day 15, p=0.025) stages of brain development. While this did not diminish overall neuronal density in the medial prefrontal cortex, exposure at P5 led to a subsequent increase in the number of parvalbumin positive neurons in lower cortical layers, and midazolam administration at P15 increased the number of both parvalbumin and calretinin expressing neurons 5 days following exposure. CONCLUSION: These observations demonstrate that midazolam exposure can impair the physiological differentiation patterns of GABAergic interneurons during the brain growth spurt. Considering the important role of GABAergic networks in neuronal physiology, these data provide us with one potential mechanism that could account for the lasting neurobehavioral and cognitive deficits observed in the context of anesthesia exposure in the early postnatal period.