Preclinical evidence for anaesthesia-induced neurotoxicity.

Preclinical research concerning anaesthesia-induced neurotoxicity was initiated in 1999. A decade later, the earliest clinical observational data showed mixed results in neurodevelopmental outcomes following anaesthesia exposure at a young age. Hence to date, preclinical studies remain the cornerstone of research in this field, primarily because of the vulnerability of clinical observational studies to confounding bias. This review summarises current preclinical evidence. Most studies used rodent models, although non-human primates have also been employed. Across all gestational and postnatal ages, there is evidence that all commonly used general anaesthetics induce neuronal injury (e.g. apoptosis) and cause neurobehavioural impairment (e.g. learning and memory deficits). These deficits were more pronounced when animals were subjected to either repeated exposure, prolonged durations of exposure or higher doses of anaesthesia. To interpret these results in the clinical context, the strengths and limitations of each model and experiment should be carefully considered, as these preclinical studies were often biased by supraclinical durations and a lack of control with regard to physiological homeostasis.

Introduction and history of anaesthesia-induced neurotoxicity and overview of animal models.

Brain development is initiated at around 3 weeks of gestation. The peak velocity of brain weight gain occurs around birth, with the neural circuitry subsequently being refined until at least 20 years of age. Antenatal and postnatal general anaesthesia suppresses neuronal firing during this critical period and may therefore impair brain development, referred to as "anaesthesia-induced neurotoxicity". Whilst up to 1% of children are exposed to general anaesthesia antenatally (e.g., as an innocent bystander to maternal laparoscopic appendectomy), 15% of children under 3 years of age undergo general anaesthesia postnatally (e.g., otorhinolaryngologic surgery). In this article, the history of preclinical and clinical research in anaesthesia-induced neurotoxicity will be reviewed, starting from the pioneering preclinical study in 1999 until the most recent systematic reviews. The mechanisms of anaesthesia-induced neurotoxicity are introduced. Finally, an overview of the methods used in preclinical studies will be provided, with a comparison of the different animal models that have been employed to investigate this phenomenon.

Anesthetic management of patients with peripartum cardiomyopathy.

PURPOSE OF REVIEW: Cardiovascular disease is increasingly emerging as a cause of peripartum morbidity and mortality. Peripartum cardiomyopathy (PPCM) is defined as pregnancy-related heart failure with a reduced left ventricular ejection fraction <45%. PPCM develops in the peripartum phase and is not an aggravation of an existing prepregnancy cardiomyopathy. Anesthesiologists typically encounter these patients in the peripartum phase in a variety of settings and should be aware of this pathology and its implications for the perioperative management of parturients. RECENT FINDINGS: PPCM has been investigated increasingly over the last few years. Significant progress has been made in the assessment of global epidemiology, pathophysiological mechanisms, genetics and treatment. SUMMARY: Although PPCM is an overall rare pathology, patients can potentially be encountered by any anesthesiologist in many different settings. Therefore, it is important to be aware of this disease and understand the basic implications for anesthetic management. Severe cases often require early referral to specialized centers for advanced hemodynamic monitoring and pharmacological or mechanical circulatory support.

Effects of cumulative duration of repeated anaesthesia exposure on foetal brain development in the ovine model.

OBJECTIVE: Anaesthesia is required in 0.4-1% of pregnant women, and prolonged and repeated exposures to anaesthesia may be required. It is unknown whether these exposures may result in foetal neurotoxicity in humans. As sheep have a gestation comparable to that of humans, the objective of this study was to analyse the neurodevelopmental outcome of ovine foetuses that had been exposed in utero to repeated and prolonged anaesthesia. DESIGN: Randomized controlled preclinical study. SETTING: Anaesthesia for non-obstetric surgery during pregnancy. ANIMALS: Twenty-four healthy pregnant Swifter ewes. INTERVENTIONS: The ewes were randomized to no anaesthesia exposure (control-group), single exposure (at gestational age 68-70 days), or repeated exposure (at gestational age 68-70 days and 96-98 days) to 2.5 h of sevoflurane anaesthesia and maternal laparotomy. All lambs were delivered at approximately term gestation (gestational age: 140-143 days). MEASUREMENTS: The primary outcome was neuron density in the frontal cortex 24 h after birth for the control-group versus the repeated-exposure-group. Key secondary outcome was the time needed to achieve the milestone of standing. Secondary outcomes included other neurobehavioural assessments (e.g., motoric milestones) and histological parameters quantified in multiple brain regions (neuron density, total cell density, proliferation, inflammation, synaptogenesis, astrocytes and myelination). MAIN RESULTS: Neuron density in the frontal cortex did not differ between groups (mean ±â€¯standard deviation: control-group: 403 ±â€¯39, single-exposure group: 436 ±â€¯23 and repeated-exposure-group: 403 ±â€¯40 neurons/mm2, control-group versus repeated-exposure-group: p = 0.986, control-group versus single-exposure-group: p = 0.097). No significant difference was observed for the time needed to achieve the milestone of standing. Only very limited differences were observed for other histological outcome parameters and neurobehavioural assessments. CONCLUSIONS: There is no evidence for foetal neuronal injury or neurobehavioural impairments after a cumulative duration of 5 h repetitive prenatal anaesthesia in sheep.

Maternal sepsis.

Maternal sepsis is a life-threatening condition defined as organ dysfunction resulting from infection that can arise during pregnancy, childbirth, postabortion, or in the postpartum period. Validated diagnostic criteria of maternal sepsis and septic shock may reduce the impact of this condition on maternal health worldwide, but the lack of consensus on adequate tools due to the overlap between physiological adaptations that occur during pregnancy and signs and symptoms of infection and sepsis can delay both diagnosis and treatment. In the absence of evidence-based guidelines for obstetric populations, the WHO recommends the use of the "Surviving Sepsis Campaign" sepsis protocols for maternal care adapted to the local obstetric population. Interventions within the first hour from diagnosis have been proposed in 2021 to emphasize the state of emergency of a maternal sepsis. This review will highlight the utility of standardized diagnostic criteria, the implemented approaches for the prevention and treatment of maternal infections, and the strategies for early management of critically ill parturients.

Cardiac disease in pregnancy.

In the developed world, cardiovascular disease has become the most frequent cause of death during pregnancy and postpartum, outnumbering by far obstetric causes of death such as bleeding or thromboembolism. Many factors contribute to this phenomenon, including an increasing age of pregnant women, co-morbidities, and an unhealthy lifestyle. The cardiovascular system is not only significantly challenged by physiological alterations in pregnancy but also by obstetric medication. Depending upon the severity of the underlying condition, pregnant women with cardiovascular disease should be managed by a multidisciplinary heart team in which anaesthesiologists play an important role. Profound knowledge of the cardiac pathophysiology is a prerequisite for the successful anaesthesiologic management of pregnant patients with cardiovascular disease. As there is no difference in general and regional anaesthesia regarding maternal outcomes, neuraxial anaesthesia using incremental techniques should be preferred for labour and (caesarean) delivery if not contraindicated by non-cardiac issues.

Neurodevelopmetal effects of maternal blood pressure management with noradrenaline during general anaesthesia for nonobstetric surgery in the pregnant rabbit model.

In pregnant women, anaesthesia-induced hypotension is commonly treated using phenylephrine or noradrenaline, the rationale being to maintain uterine perfusion pressure and thereby uterine blood flow. Evidence for this strategy during general anaesthesia for nonobstetric surgery is absent. To analyse the effects of treating anaesthesia-induced hypotension with noradrenaline on brain development of rabbit foetuses of mothers subjected to general anaesthesia for nonobstetric surgery. We hypothesised that treatment of maternal hypotension would improve foetal outcomes. Randomised controlled laboratory study using 21 pregnant rabbits (does) at 28 days of gestation. Two hours of sevoflurane anaesthesia for a laparotomy without treatment of anaesthesia-induced hypotension (hypotension group) or with maintaining maternal mean arterial pressure above 80% of the awake value using noradrenaline (noradrenaline group). In the control group, does remained untouched. At term, all pups were delivered by caesarean section. One day later, the neurobehaviour of the pups was assessed and brains were harvested. Neuron density in the frontal cortex for the comparison of noradrenaline groups versus hypotension groups was the primary outcome; the neurobehavioural scores and other histological outcomes were secondary outcomes. In the noradrenaline groups and hypotension groups, neuron density in the frontal cortex was similar (1181 ±â€Š162 versus 1189 ±â€Š200 neurons mm-2, P  = 0.870). However, significantly less foetal survival, lower sensory scores in neurobehavioural assessment and less proliferation were observed in the noradrenaline group when compared with the hypotension group. Neuron densities in other regions, total cell densities, biometrics and synaptogenesis were not affected. There were no differences between the control group and hypotension group. During general anaesthesia for nonobstetric surgery in rabbits, treatment of anaesthesia-induced hypotension using noradrenaline did not affect neuron densities but was associated with impaired foetal outcomes according to several secondary outcome parameters. Further studies are needed to investigate any clinical relevance and to determine the target blood pressure in pregnant women during general anaesthesia.KEY POINTSIn pregnant women, anaesthesia-induced hypotension is commonly treated using phenylephrine or noradrenaline, with the rationale to maintain uterine perfusion pressure and thereby uterine blood flow.Evidence for this strategy during general anaesthesia for nonobstetric surgery is absent.We investigated the effects of treating anaesthesia-induced hypotension with noradrenaline on the brain development of rabbit foetuses, of mothers subjected to general anaesthesia for nonobstetric surgery.We hypothesised that treatment of maternal hypotension would improve foetal outcomes.Neuron densities were similar but significantly less foetal survival, impaired neurobehaviour and less proliferation were observed after treatment of anaesthesia-induced hypotension with noradrenaline, compared with untreated hypotension.

The effect of xenon on fetal neurodevelopment following maternal sevoflurane anesthesia and laparotomy in rabbits.

BACKGROUND: There is concern that maternal anesthesia during pregnancy impairs brain development of the human fetus. Xenon is neuroprotective in pre-clinical models of anesthesia-induced neurotoxicity in neonates. It is not known if xenon also protects the developing fetal brain when administered in addition to maternal sevoflurane-anesthesia during pregnancy. OBJECTIVE: To investigate the effects of sevoflurane and xenon on neurobehaviour and neurodevelopment of the offspring in a pregnant rabbit model. METHODS: Pregnant rabbits on post-conception day 28 (term = 31d) underwent two hours of general anesthesia with 1 minimum alveolar concentration (MAC) of sevoflurane in 30% oxygen (n = 17) or 1 MAC sevoflurane plus 50-60 % xenon in 30% oxygen (n = 10) during a standardized laparotomy while receiving physiological monitoring. A sham-group (n = 11) underwent monitoring alone for two hours. At term, the rabbits were delivered by caesarean section. On the first postnatal day, neonatal rabbits underwent neurobehavioral assessment using a validated test battery. Following euthanasia, the brains were harvested for neurohistological analysis. A mixed effects-model was used for statistical analysis. RESULTS: Maternal cardiopulmonary parameters during anesthesia were within the reference range. Fetal survival rates were significantly higher in the sham-group as compared to the sevoflurane-group and the fetal brain/body weight ratio was significantly lower in the sevoflurane-group as compared with the sham- and xenon-group. Pups antenatally exposed to anesthesia had significantly lower motor and sensory neurobehavioral scores when compared to the sham-group (mean ± SD; sevo: 22.70 ± 3.50 vs. sevo+xenon: 22.74 ± 3.15 vs. sham: 24.37 ± 1.59; overall p = 0.003; sevo: 14.98 ± 3.00 vs. sevo+xenon: 14.80 ± 2.83 vs. sham: 16.43 ± 2.63; overall p = 0.006; respectively). Neuron density, neuronal proliferation and synaptic density were reduced in multiple brain regions of the exposed neonates. The co-administration of xenon had no measurable neuroprotective effects in this model. CONCLUSIONS: In rabbits, sevoflurane anesthesia for a standardized laparotomy during pregnancy resulted in impaired neonatal neurobehavior and a decreased neuron count in several regions of the neonatal rabbit brain. Co-administration of xenon did not prevent this effect.

Effects of general anaesthesia during pregnancy on neurocognitive development of the fetus: a systematic review and meta-analysis.

BACKGROUND: The US Food and Drug Administration warned that exposure of pregnant women to general anaesthetics may impair fetal brain development. This review systematically evaluates the evidence underlying this warning. METHODS: PubMed, EMBASE, and Web of Science were searched from inception until April 3, 2020. Preclinical and clinical studies were eligible. Exclusion criteria included case reports, in vitro models, chronic exposures, and exposure only during delivery. Meta-analyses were performed on standardised mean differences. The primary outcome was overall effect on learning/memory. Secondary outcomes included markers of neuronal injury (apoptosis, synapse formation, neurone density, and proliferation) and subgroup analyses. RESULTS: There were 65 preclinical studies included, whereas no clinical studies could be identified. Anaesthesia during pregnancy impaired learning and memory (standardised mean difference -1.16, 95% confidence interval -1.46 to -0.85) and resulted in neuronal injury in all experimental models, irrespective of the anaesthetic drugs and timing in pregnancy. Risk of bias was high in most studies. Rodents were the most frequently used animal species, although their brain development differs significantly from that in humans. In a minority of studies, anaesthesia was combined with surgery. Monitoring and strict control of physiological homeostasis were below preclinical and clinical standards in many studies. The duration and frequency of exposure and anaesthetic doses were often much higher than in clinical routine. CONCLUSION: Anaesthesia-induced neurotoxicity during pregnancy is a consistent finding in preclinical studies, but translation of these results to the clinical situation is limited by several factors. Clinical observational studies are needed. PROSPERO REGISTRATION NUMBER: CRD42018115194.

Effects of Maternal Abdominal Surgery on Fetal Brain Development in the Rabbit Model.

INTRODUCTION: Anesthesia during pregnancy can impair fetal neurodevelopment, but effects of surgery remain unknown. The aim is to investigate effects of abdominal surgery on fetal brain development. Hypothesis is that surgery impairs outcome. METHODS: Pregnant rabbits were randomized at 28 days of gestation to 2 h of general anesthesia (sevoflurane group, n = 6) or to anesthesia plus laparoscopic appendectomy (surgery group, n = 13). On postnatal day 1, neurobehavior of pups was assessed and brains harvested. Primary outcome was neuron density in the frontal cortex, and secondary outcomes included neurobehavioral assessment and other histological parameters. RESULTS: Fetal survival was lower in the surgery group: 54 versus 100% litters alive at birth (p = 0.0442). In alive litters, pup survival until harvesting was 50 versus 69% (p = 0.0352). No differences were observed for primary outcome (p = 0.5114) for surviving pups. Neuron densities were significantly lower in the surgery group in the caudate nucleus (p = 0.0180), but not different in other regions. No differences were observed for secondary outcomes. Conclusions did not change after adjustment for mortality. CONCLUSION: Abdominal surgery in pregnant rabbits at a gestational age corresponding to the end of human second trimester results in limited neurohistological changes but not in neurobehavioral impairments. High intrauterine mortality limits translation to clinical scenario, where fetal mortality is close to zero.

Successful resuscitation after hyperkalemic cardiac arrest during liver transplantation by converting veno-venous bypass to veno-arterial ECMO.

INTRODUCTION: Intraoperative cardiac arrest (ICA) is a feared complication during liver transplantation (LTx), typically occurring during reperfusion. Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) has been used for post-reperfusion cardiac arrest. CASE REPORT: We present a case of successful resuscitation after hyperkalemic ICA during the pre-anhepatic phase of a second liver transplantation by converting veno-venous bypass (VVB) to VA-ECMO. DISCUSSION: While this technique has been recommended for ICA during reperfusion, it has never been reported during the pre-anhepatic phase. VA-ECMO can be a lifesaving extension to cardiopulmonary resuscitation for ICA during LTx with beneficial neurological outcome by providing perfusion while the cause of ICA is reversed. CONCLUSION: Conversion of VVB to VA-ECMO should be considered in all patients who suffer from ICA during LTx with use of VVB. With VVB installed, conversion to VA-ECMO is fast and effective. If VVB is not used, early VA-ECMO should be considered for ICA.

Effect of xenon and dexmedetomidine as adjuncts for general anesthesia on postoperative emergence delirium after elective cardiac catheterization in children: study protocol for a randomized, controlled, pilot trial.

BACKGROUND: Emergence delirium, a manifestation of acute postoperative brain dysfunction, is frequently observed after pediatric anesthesia and has been associated with the use of sevoflurane. Both xenon and dexmedetomidine possess numerous desirable properties for the anesthesia of children with congenital heart disease, including hemodynamic stability, lack of neurotoxicity, and a reduced incidence of emergence delirium. Combining both drugs has never been studied as a balanced-anesthesia technique. This combination allows the provision of anesthesia without administering anesthetic drugs against which the Food and Drug Administration (FDA) issued a warning for the use in young children. METHODS/DESIGN: In this phase-II, mono-center, prospective, single-blinded, randomized, controlled pilot trial, we will include a total of 80 children aged 0-3 years suffering from congenital heart disease and undergoing general anesthesia for elective diagnostic and/or interventional cardiac catheterization. Patients are randomized into two study groups, receiving either a combination of xenon and dexmedetomidine or mono-anesthesia with sevoflurane for the maintenance of anesthesia. The purpose of this study is to estimate the effect size for xenon-dexmedetomidine versus sevoflurane anesthesia with respect to the incidence of emergence delirium in children. We will also describe group differences for a variety of secondary outcome parameters including peri-interventional hemodynamics, emergence characteristics, incidence of postoperative vomiting, and the feasibility of a combined xenon-dexmedetomidine anesthesia in children. DISCUSSION: Sevoflurane is the most frequently used anesthetic in young children, but has been indicated as an independent risk factor in the development of emergence delirium. Xenon and dexmedetomidine have both been associated with a reduction in the incidence of emergence delirium. Combining xenon and dexmedetomidine has never been described as a balanced-anesthesia technique in children. Our pilot study will therefore deliver important data required for future prospective clinical trials. TRIAL REGISTRATION: EudraCT, 2018-002258-56. Registered on 20 August 2018. https://www.clinicaltrialsregister.eu.

Cardiac interventions in pregnancy and peripartum - a narrative review of the literature.

In the UK, mortality rate during pregnancy/in the peripartal period is 14.1 per 100,000 maternities with heart disease being the leading cause of non-obstetric maternal mortality (10% to 15% of all maternal deaths). Owing to the advances in the treatment of congenital heart disease (CHD), an increasing percentage of women has reached childbearing age, making CHD nowadays the most frequent cardiovascular disease during pregnancy in the Western world. In the pregnant woman, several adaptive changes occur in the cardiovascular and pulmonary system that in the worst case can lead to cardiovascular collapse in women with pre-existing heart disease. If medical management is not sufficient, cardiac interventions have to be considered, including percutaneous endovascular interventions, cardiac surgery, the use of extracorporeal membrane oxygenation or the placement of assist devices. While all these interventions seem to be relatively safe for the mother, fetal mortality remains considerably high. A thorough understanding of maternal physiology during pregnancy and of the perfusion of the feto-maternal unit is mandatory for the successful management of pregnant patients in need of cardiac (surgical) interventions.

Maternal surgery during pregnancy has a transient adverse effect on the developing fetal rabbit brain.

BACKGROUND: Recently, the US Food and Drug Administration called for cautious use of anesthetic drugs during pregnancy. In 0.2-2% of pregnancies, nonobstetric surgery is being performed. The consequences of anesthesia during pregnancy on fetal development remain unclear, and preclinical studies in relevant animal models may help to elucidate them. OBJECTIVE: To assess the effect of maternal anesthesia and surgery during pregnancy on the developing fetal brain, using a rabbit model. MATERIALS AND METHODS: This is a randomized, sham-controlled study in time-mated pregnant does at 28 days of gestation (term = 31 days), which corresponds to the end of the second trimester in humans. Anesthesia was induced in 14 does (155 pups) with propofol and maintained with 4 vol% (equivalent to 1 minimum alveolar concentration) sevoflurane for 2 hours, and a laparotomy with minimal organ manipulation was performed (surgery group). Maternal vital signs (blood pressure, heart rate, peripheral and cerebral oxygen saturation, temperature, end-tidal CO2, pH, lactate) were continuously monitored. Sham controls consisted of 7 does (74 pups) undergoing invasive hemodynamic monitoring for 2 hours without sedation. At term, does underwent cesarean delivery under ketamine-medetomidine sedation and local anesthesia. Pups either underwent motor and sensory neurologic testing followed by euthanasia at day 1 or daily neurodevelopment testing for 2 weeks and extensive neurologic assessment at 5 and 7 weeks (open field and object recognition test, T-maze, and radial-arm maze). Brains were harvested for histologic assessment of neuron density and synaptophysin expression. RESULTS: Blood gases and vital parameters were stable in both groups. On postnatal day 1, surgery pups had significant lower motor (25 ± 1 vs 23 ± 3; P = .004) and sensory (16 ± 2 vs 15 ± 2; P = .005) neurobehavioral scores and lower brain-to-body weight ratios (3.7% ± 0.6% vs 3.4% ± 0.6%; P = .001). This was accompanied by lower neuron density in multiple brain regions (eg, hippocampus 2617 ± 410 vs 2053 ± 492 neurons/mm2; P = .004) with lower proliferation rates and less synaptophysin expression. Furthermore, surgery pups had delayed motor development during the first week of life, for example with hopping appearing later (6 ± 5 vs 12 ± 3 days; P = .011). Yet, by 7 weeks of age, neurobehavioral impairment was limited to a reduced digging behavior, and no differences in neuron density or synaptophysin expression were seen. CONCLUSION: In rabbits, 2 hours of maternal general anesthesia and laparotomy, with minimal organ and no fetal manipulation, had a measurable impact on neonatal neurologic function and brain morphology. Pups had a slower motoric neurodevelopment, but by 7 weeks the effect became almost undetectable.