Anesthesia-related Neurotoxicity Research Articles

Regions of the basal ganglia and primary olfactory system are most sensitive to neurodegeneration after extended sevoflurane anesthesia in the perinatal rat

Extended general anesthesia early in life is neurotoxic in multiple species. However, little is known about the temporal progression of neurodegeneration after general anesthesia. It is also unknown if a reduction in natural cell death, or an increase in cell creation, occurs as a form of compensation after perinatal anesthesia exposure. The goal of this study was to evaluate markers of neurodegeneration and cellular division at 2, 24, or 72 h after sevoflurane (Sevo) exposure (6 h) in fully oxygenated postnatal day (PND) 7 rats. Neurodegeneration was observed in areas throughout the forebrain, while the largest changes (fold increase above vehicle) were observed in areas associated with either the primary olfactory learning pathways or the basal ganglia. These regions included the indusium griseum (IG, 25-fold), the posterior dorso medial hippocampal CA1 (17-fold), bed nucleus of the stria terminalis (Bed Nuclei STM, 5-fold), the shell of the nucleus accumbens (Acb, 5-fold), caudate/putamen (CPu, 5-fold), globus pallidus (GP, 9-fold) and associated thalamic (11-fold) and cortical regions (5-fold). Sevo neurodegeneration was minimal or undetectable in the ventral tegmentum, substantia nigra, and most of the hypothalamus and frontal cortex. In most brain regions where neurodegeneration was increased 2 h post Sevo exposure, the levels returned to <4-fold above control levels by 24 h. However, in the IG, CA1, GP, anterior thalamus, medial preoptic nucleus of the hypothalamus (MPO), anterior hypothalamic area (AHP), and the amygdaloid nuclei, neurodegeneration at 24 h was double or more than that at 2 h post exposure. Anesthesia exposure causes either a prolonged period of neurodegeneration in certain brain regions, or a distinct secondary degenerative event occurs after the initial insult. Moreover, regions most sensitive to Sevo neurodegeneration did not necessarily coincide with areas of new cell birth, and new cell birth was not consistently affected by Sevo. The profile of anesthesia related neurotoxicity changes with time, and multiple mechanisms of toxicity may exist in a time-dependent fashion.

Acetyl-l-carnitine does not prevent neurodegeneration in a rodent model of prolonged neonatal anesthesia

Many studies have shown that prolonged or repeated use of general anesthesia early in life can cause an increase in neurodegeneration and lasting changes in behavior. While short periods of general anesthesia appear to be safe, there is a concern about the neurotoxic potential of prolonged or repeated general anesthesia in young children. Unfortunately, the use of general anesthesia in children cannot be avoided. It would be a great benefit to develop a strategy to reduce or reverse anesthesia mitigated neurotoxicity.The mechanisms behind anesthesia related neurotoxicity are unknown, but evidence suggests that mitochondrial dysfunction and abnormal energy utilization are involved. Recent research suggests that a class of compounds known as carnitines may be effective at preventing anesthesia related neurotoxicity by influencing fatty acid metabolism in the mitochondria. However, it is unknown if carnitines can provide protection against changes in behavior associated with early life exposure to anesthesia. Accordingly, we evaluated the neuroprotective potential of acetyl-l-carnitine in 7-day old rats. Rat pups were exposed to 6 h of general anesthesia with sevoflurane or a control condition, with and without acetyl-l-carnitine. The oxygenation level of animals was continuously monitored during sevoflurane exposure, and any animal showing signs of hypoxia was removed from the study.Animals exposed to sevoflurane showed clear signs of neurodegeneration 2 h after sevoflurane exposure. The hippocampus, cortex, thalamus, and caudate putamen all had elevated levels of Fluoro-Jade C staining. Despite the elevated levels of Fluoro-Jade C, few behavioral changes were observed in an independent cohort of animals treated with sevoflurane. Furthermore, acetyl-l-carnitine had little impact on levels of Fluoro-Jade C staining in animals treated with sevoflurane. These data suggest that acetyl-l-carnitine may offer little protection again anesthesia related neurotoxicity in fully oxygenated animals.

Definition of Clinical Outcomes in Pediatric Anesthesia Research: It Is Like the Tower of Babel!

Definition of Clinical Outcomes in Pediatric Anesthesia Research: It Is Like the Tower of Babel!

General Anesthesia-Related Neurotoxicity: Status of Pediatric Surgeries at an Academic Hospital in the North of Iran

Background: Recently, general anesthesia (GA)-related neurotoxicity has turned into a big concern. However, it seems that inadequate attention has been paid to the issue in Iran. Objectives: The aim of this survey was to investigate the frequency of elective surgeries in children under the age of three at an academic hospital in the north of Iran. Methods: This retrospective study was conducted at Alzahra Hospital affiliated to the Guilan University of Medical Sciences (GUMS). The records of all children who had undergone surgeries during 2014 - 2017 were examined by a responsible physician. Then, the records of children under three receiving GA were sorted out. After that, questionnaires with items on gender, habitat, age of receiving GA, type and status (elective or urgency) of surgeries were filled out. Results: According to our results, 670 children underwent surgery under GA during the study period, while 50.4% were elective. The mean age of patients was 15.26 months; 9.9% of them were neonates, 42.4% were infants, 80.3% were boys, and 60.7% were from urban areas. The most affected children were urban boys and the most obviously avoidable surgery was circumcision. Conclusions: More attention should be paid to the issue of GA-related neurotoxicity at our hospital. Future studies are welcome to examine the issue and find practical interventions.

General Anesthesia-Related Neurotoxicity in the Developing Brain and Current Knowledge and Practice of Physicians at Guilan Academic Hospitals.

BackgroundRecent articles about the topic of the anesthetic agents-related neurotoxicity have currently attracted the attention to the issue in the anesthesiology community. However, specialists in other fields should also be aware of this potential risk.ObjectivesThis study aimed to evaluate the knowledge and practice of physicians at Guilan academic hospitals regarding general anesthesia-related neurotoxicity.MethodsFirstly, the responsible anesthesia resident explained the purpose of this work to Guilan faculty and residents and if they agreed to participate a questionnaire containing 12 items was filled via a face to face interview.ResultsA response rate of 100% was achieved (271 responders from 271 eligible study responders). Also, 89 (33.1%) responders were attending, 180 (66.9%) were residents, 112 (41.6%) were female, and 157 (58.4%) were male. The mean years of experience was 8.8 ± 4.82 (2 - 28 years). According to the achieved data, the majority of the precipitants did not believe in GA toxicity.ConclusionsThis paper revealed that the current curriculum does not sufficiently address the anesthesia-related neurotoxicity problem. Indeed, the need for training and communication with non-anesthesia medical colleagues was highlighted.

Oral Clefts and Academic Performance in Adolescence: The Impact of Anesthesia-Related Neurotoxicity, Timing of Surgery, and Type of Oral Clefts.

Early life exposure to anesthesia and surgery is suspected to associate with cognitive impairment later in life. We compared academic achievement among adolescents with cleft lip only (CL), cleft palate only (CP), and cleft lip and cleft palate (CLP) with a noncleft control group to investigate whether outcome depends on timing and number of operations during childhood and/or type of oral cleft. Nationwide register-based follow-up study. Danish birth cohort 1986 to 1990. Five hundred fifty-eight children with isolated CL (n = 171), CLP (n = 222), or CP (n = 195), of which 509 children had been exposed to anesthesia and one or more cleft operation(s), and a 5% sample of the birth cohort (n = 14,677). Test score in the Danish standardized ninth-grade exam and proportion of nonattainment, defined as "results for ninth-grade exam unavailable." Data adjusted for sex, birth weight, parental age, and parental level of education. Compared to controls, children with CL achieved higher scores (mean difference 0.12, 95% CI -0.05; 0.29) and children with CLP presented with lower scores (mean difference -0.06, 95% CI -0.21; 0.09), albeit both statistically insignificant. Children with CP achieved significantly lower scores, mean difference -0.20 (95% CI -0.38; -0.03). Odds ratios for nonattainment at final exam were: CL 0.79 (95% CI 0.46; 1.35), CLP 1.07 (95% CI 0.71; 1.61), CP 2.59 (95% CI 1.78; 3.76). Oral cleft type rather than number and timing of anesthesia and operations associate to poorer academic performance. Although a potential neurotoxic effect due to anesthetic agents is not reflected in the data, it cannot be completely excluded.

Carbon monoxide incompletely prevents isoflurane-induced defects in murine neurodevelopment

BackgroundCommonly used anesthetics have been shown to disrupt neurodevelopment in preclinical models. It has been proposed that such anesthesia-induced neurotoxicity is mediated by apoptotic neurodegeneration in the immature brain. Low dose carbon monoxide (CO) exerts cytoprotective properties and we have previously demonstrated that CO inhibits isoflurane-induced apoptosis in the developing murine brain. Here we utilized anti-apoptotic concentrations of CO to delineate the role of apoptotic neurodegeneration in anesthesia-induced neurotoxicity by assessing the effect of CO on isoflurane-induced defects in neurodevelopment. MethodsC57Bl/6 mouse pups underwent 1-hour exposure to 0ppm (air), 5ppm, or 100ppm CO in air with or without isoflurane on postnatal day 7. Cohorts were evaluated 5–7weeks post exposure with T-maze cognitive testing followed by social behavior assessment. Brain size, whole brain cellular content, and neuronal density in primary somatosensory cortex and hippocampal CA3 region were measured as secondary outcomes 1-week or 5–7weeks post exposure along with 7-day old, unexposed controls. ResultsIsoflurane impaired memory acquisition and resulted in abnormal social behavior. Low concentration CO abrogated anesthetic-induced defects in memory acquisition, however, it also resulted in impaired spatial reference memory and social behavior abnormalities. Changes in brain size, cellular content, and neuronal density over time related to the age of the animal and were unaffected by either isoflurane or CO. ConclusionsAnti-apoptotic concentrations of CO incompletely prevented isoflurane-induced defects in neurodevelopment, lacked concentration-dependent effects, and only provided protection in certain domains suggesting that anesthesia-related neurotoxicity is not solely mediated by activation of the mitochondrial apoptosis pathway.

Neonatal anesthetic neurotoxicity: Insight into the molecular mechanisms of long-term neurocognitive deficits.

Mounting animal studies have demonstrated that almost all the clinically used general anesthetics could induce widespread neuroapoptosis in the immature brain. Alarmingly, some published findings have reported long-term neurocognitive deficits in response to early anesthesia exposure which deeply stresses the potential seriousness of developmental anesthetic neurotoxicity. However, the connection between anesthesia induced neuroapoptosis and subsequent neurocognitive deficits remains controversial. It should be noted that developmental anesthesia related neurotoxicity is not limited to neuroapoptosis. Early anesthesia exposure caused transient suppression of neurogenesis, ultrastructural abnormalities in synapse and alteration in the development of neuronal networks also could contribute to the long-term neurocognitive dysfunction. Understanding the mechanisms of developmental anesthetic neurotoxicity, especially by which anesthesia impairs brain function months after exposure, may lead to development of rational preventive and therapeutic strategies. The focus of present review is on some of those potential mechanisms that have been proposed for anesthesia induced cognitive decline.

発達期脳への麻酔薬暴露による中枢神経障害─これまでの研究と中枢神経障害をどう防ぐか─

これまでの研究により，動物において発達期の麻酔薬暴露が中枢神経毒性をきたし，成長後の学習・行動異常を引き起こすことがわかった．これらは主に齧歯類での報告で，ヒトに当てはまるかどうかは不明である．近年，霊長類であるアカゲザルを用いた研究により，発達期麻酔薬暴露が齧歯類と同様に毒性をきたすことが報告された．米国において進行中のヒトでの前向き大規模臨床試験の結果は，将来の小児麻酔の方法を大きく変えるかもしれない．これまで，毒性を軽減する方法についてさまざまな議論が交わされてきたが，臨床応用可能な方法は確立されていない．本稿では麻酔薬暴露による毒性研究の歴史を解説し，水素による毒性軽減の可能性について述べる．

Neurotoxicity, general anesthesia in young children, and a survey of current pediatric anesthesia practice at US teaching institutions.

Recent articles in both scholarly journals and the lay press about the topic of anesthetic related neurotoxicity have increased the awareness and discussion of this topic with parents and other pediatric medical specialties (i.e., surgeons, radiologists, and pediatricians). The purpose of the present study was to survey how a subset of pediatric anesthesia departments in the US have responded to the issue of anesthetic related neurotoxicity in terms of clinical practice, training and communication with other medical specialties, and the frequency and timing of discussions with families. A survey consisting of 22 questions was sent to PALC (Pediatric Anesthesia Leadership Council) & PAPDA (Pediatric Anesthesia Program Directors Association) via SurveyMonkey. The survey was divided into sections on Anesthesia Faculty/Trainees, Parents and Non-Anesthesia Providers. Responses to the survey were solicited via email to PALC and PAPDA, and then followed up with reminders to individual emails using the mailing lists of both organizations. The results of this survey demonstrate that pediatric anesthesia programs around the US do not have a consistent approach in managing the topic of anesthesia-related neurotoxicity with pediatric anesthesiologists, anesthesiology residents, pediatric anesthesiology fellows and their non-anesthesia medical and surgical colleagues, as well as the discussion of this topic with parents. A significant need exists to provide information to other pediatric professionals and parents. A consistent message from all providers that includes what is known, and indeed more importantly what is not known may be a useful approach.

A holistic view of anesthesia-related neurotoxicity in children

A holistic view of anesthesia-related neurotoxicity in children

Neonatal anesthesia: how we manage our most vulnerable patients.

Neonates undergoing surgery are at higher risk than older children for anesthesia-related adverse events. During the perioperative period, the maintenance of optimal hemodynamics in these patients is challenging and requires a thorough understanding of neonatal physiology and pharmacology. Data from animals and human cohort studies have shown relation of the currently used anesthetics may associate with neurotoxic brain injury that lead to later neurodevelopmental impairment in the developing brain. In this review, the unique neonatal physiologic and pharmacologic features and anesthesia-related neurotoxicity will be discussed.

The changes of oligodendrocytes induced by anesthesia during brain development.

With the advent of modern techniques, drugs, and monitoring, general anesthesia has come to be considered an unlikely cause of harm, particularly for healthy patients. While this is largely true, newly emerging clinical and laboratory studies have suggested that exposure to anesthetic agents during early childhood may have long-lasting adverse effects on cognitive function. This concern has been the focus of intense study in the field of anesthesia research. A recent high-profile review by Rappaport et al. (2015) concluded that while many questions remain unanswered, there is strong evidence from laboratory studies that commonly used anesthetics interfere with brain development and that clinical studies suggest a correlation between early childhood exposure to these agents and subsequent effects on learning and cognition. The issue is of sufficient public health importance that a public-private partnership known as SmarTots (Strategies for Mitigating Anesthesia-Related Neurotoxicity in Tots) was developed by the FDA to study pediatric anesthetic neurotoxicity. The mechanism of injury underlying this phenomenon has yet to be fully elucidated, and there is evidence to suggest that anesthetics may have direct cytotoxic effects on neurons leading to cell death or suppressed neurogenesis (Stratmann et al., 2010) and that they may interfere with key processes in neuronal growth and development that underlie brain circuit development (Wagner et al., 2014).

Anesthesia-related neurotoxicity and the developing animal brain is not a significant problem in children.

A multitude of animal studies have shown that virtually all general anesthetics used in clinical practice possibly during a vulnerable period of brain development (i.e., brain growth spurt, peak of synaptogenesis) may lead to neurodegeneration (particularly apoptosis) and abnormal synaptic development with functional deficits in learning and behavior later in life. Initial studies were mainly performed in immature rodent pups, but more recent studies have included nonhumans primates (rhesus monkeys). Given the number of neonates, infants, and young children anesthetized annually worldwide, these findings could have significant public health implications. So far, relatively few human (cohort) studies focusing on this topic have been published with inconsistent results. While some studies have indicated an association between exposure to anesthesia and surgery, other studies have indicated no such association. Prospective studies are underway, but the result will not be available for several years. This paper reviews some of the preclinical background behind anesthesia-related neurotoxicity but focuses mainly on the human studies so far. It is concluded that although disturbing, the animal data lack verification in humans. Fortunately, the humans studies performed so far have been unable to confirm these animal data. A single brief anesthetic seems safe in infants. Multiple anesthetic and surgical exposures on the other hand are different. But there may be other reasons for this than merely the anesthetics. Currently, there is no need to change current anesthetic clinical practice or to postpone or cancel truly urgent surgeries in young children.

Neurosurgical conditions and procedures in infancy are associated with mortality and academic performances in adolescence: a nationwide cohort study.

Few human cohort studies on anesthesia-related neurotoxicity and the developing brain have focused on and compared specific surgeries and conditions. These studies cannot disentangle the effects of anesthesia from those of the surgery and underlying conditions. This study aimed at assessing the impact of specific neurosurgical conditions and procedures in infancy on mortality and academic achievements in adolescence. A nationwide unselected register-based follow-up study of the Danish birth cohorts 1986-1990 compared academic performances of all children having undergone neurosurgeries as infants with a randomly selected, age-matched 5% sample of the same cohorts. The two groups were compared regarding mortality prior to June 1st, 2006, average test scores at ninth grade, and finally the proportion of children not attaining test scores. The exposure group comprised 228 and the control group 14 698 individuals. Hydrocephalus (n = 130), craniotomy (n = 43), and myelomeningocele/encephalocele children (n = 55) had a higher mortality (18.5.0%, 18.6%, and 7.3%, respectively) vs controls (1.3%; P < 0.00001, P < 0.00001, and P = 0.0052, respectively). Average test scores were significantly lower than controls in hydrocephalus and craniotomy (P = 0.0043 and P = 0.0077) but not myelomeningocele/encephalocele children (P = 0.2785); the proportion of available test scores were significantly lower in all three groups (40.8%, 60.0%, and 67.3%, respectively) vs 86.8% in controls (P < 0.00001, P = 0.000077, and P = 0.000064). Neurosurgery in infancy was associated with high mortality and significantly impaired academic achievements in adolescence. When studying anesthesia-related neurotoxicity and the developing brain, focus on specific surgeries/conditions is important. Pooling of major/minor conditions and major/minor surgeries should be avoided.

Dexmedetomidine Ameliorates Histological and Neurological Outcomes after Transient Spinal Ischemia in Rats

Aims: Dexmedetomidine, anα2adrenergicagonist, provides neuroprotection in various cerebral ischemia models and against anesthesia-related neurotoxicity. Dexmedetomidine also improves paraplegia induced by intrathecal morphine after short-term spinal ischemia. In this preliminary study, we investigated whether dexmedetomidine provides spinal protection against transient spinal ischemia in rats. Methodology: Adult male Sprague-Dawley rats were randomly divided into the following 3 groups: 1) intravenous infusion of 0.9% NaCl at a rate of 0.5 mL/h (control), 2) dexmedetomidine 1 μg/kg/h, and 3) intravenous infusion of 0.9% NaCl without spinal ischemia (sham). The rats received saline solution or dexmedetomidine 30 min before spinal cord ischemia and for 24 h. Spinal cord ischemia was induced by intra-aortic balloon occlusion combined with proximal arterial hypotension for 10 min. Ischemic injury was assessed by the neurological deficit score and by the number of viable motor nerve cells in the anterior spinal cord at 24 h of reperfusion. Results: The neurological deficit score was significantly lower in the dexmedetomidine group compared to the control group (p< 0.05). The number of viable motor nerve cells in the dexmedetomidine group was significantly greater than was that in the control group (p< 0.05), but was lower than was that in the sham group. Short Research Article British Journal of Medicine & Medical Research, 4(33): 5238-5247, 2014 5239 Conclusion: Our findings suggest that continuous administration of dexmedetomidine ameliorates short-term neurological and histological outcomes induced by transient spinal cord ischemia and reperfusion in rats; thus, dexmedetomidine appears to protect the spinal as well as the brain.

SmartTots

SmartTots

Translational Research

Translational Research