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Summary: Up to 1% of pregnant women undergo anaesthesia for non‐obstetric surgery. This study investigated neurodevelopmental outcomes after prenatal anaesthesia for maternal surgery. A bidirectional cohort study of children born between 2001 and 2018 was performed: neurodevelopmental outcomes of children who had received prenatal anaesthesia for maternal surgery were prospectively compared with unexposed children, with exposure status being assessed retrospectively. Children exposed to anaesthesia for obstetric and fetal surgery were excluded. The primary outcome was the global executive composite of the behaviour rating inventory of executive function score. Our secondary outcomes were: total problems; internalising problems and externalising problems derived from the child behaviour checklist; psychiatric diagnoses; and learning disorders. In 90% of exposed children, there was a single mean (SD) antenatal anaesthesia exposure lasting 91(94) min. There was a broad spectrum of indications, with abdominal surgery being most frequent. Parents of 129 exposed (response rate 68%) and 453 unexposed (response rate 63%) children participated. There were no arguments for non‐response bias. After propensity weighting, there were no statistically significant differences in primary outcome, with a weighted mean difference (95%CI) of exposed minus unexposed children of 1.9 (−0.4–4.2), p = 0.10; or any of the secondary outcomes. Sensitivity analyses confirmed the robustness. Exploratory analyses, however, showed significant differences in certain subgroups for the primary outcome, (e.g. for intra‐abdominal surgery, exposure duration > 1 h) and some cognitive subdomains (e.g. working memory and attention). This bidirectional cohort study, the largest investigation on the subject to date, has found no evidence in the general population for an association between prenatal exposure to anaesthesia and impaired neurodevelopmental outcomes. [ABSTRACT FROM AUTHOR]

Background: General anesthesia during pregnancy is not uncommon, for example, for trauma surgery, cerclage, or cesarean delivery. Current recommendations are to maintain maternal partial pressure of carbon dioxide in arterial blood (paCO2) at 30 mm Hg, which is based solely on the average maternal paCO2 in awake pregnant women. However, there is no evidence that this target, compared to other targets, would enable optimal conditions for the fetus during general anesthesia. Maternal paCO2 can affect uterine blood flow, affinity of hemoglobin for oxygen, and fetal CO2 elimination. In this study, a range of potential targets of maternal paCO2 was investigated in the ovine model, aiming to determine which target is most conducive to physiological fetal blood gas values during laparotomy with general anesthesia., Methods: Ten time-mated pregnant Swifter ewes with a gestational age of 93 to 104 days were used. During the first phase of the experiment, anesthesia was induced, all ewes were ventilated to target a physiological maternal paCO2 of 30 mm Hg, a maternal laparotomy was performed, and a fetal microcatheter was inserted surgically to enable blood sampling from the fetal aorta. Thereafter, in the second phase of the experiment, the 10 pregnant ewes were randomized to 10 different targets of maternal paCO2 between 27 and 50 mm Hg (1 target for each ewe), and maternal ventilation was adjusted accordingly. Forty-five minutes later, maternal and fetal arterial blood gas samples were analyzed. Linear regression models were used to estimate maternal paCO2 enabling physiologic fetal parameters, including fetal paCO2 (primary outcome)., Results: A maternal paCO2 of 27.4 mm Hg (95% confidence interval, 23.1-30.3) enabled physiological fetal paCO2. Each increase in maternal paCO2 by 1 mm Hg, on average, increased fetal paCO2 by 0.94 mm Hg (0.69-1.19). This relationship had a strong correlation (r² = 0.906). No fetuses died during the experiment., Conclusions: This study provides experimental support for the clinical recommendation to maintain maternal paCO2 close to the physiologic value of 30 mm Hg during general anesthesia for maternal laparotomy in pregnancy as it is conducive to physiological fetal blood gas values. Given the lower bound of the 95% confidence interval, the possibility that a lower maternal paCO2 would improve fetal gas exchange cannot be excluded., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2025 International Anesthesia Research Society.)

The aim of this pragmatic approach to retrospective observational study was to identify the end-tidal concentration of sevoflurane which was associated with optimal surgical conditions (i.e., absence of any movement, coughing and straining) in 127 pregnant sheep. Optimal surgical conditions were observed in 90% of the ewes with an end-tidal concentration of sevoflurane of 2.4 Vol-% [95% CI: 2.2; 2.8] during minimal-mild nociceptive stimuli (placement of arterial catheter, bladder catheter, shaving), with 4.4 Vol-% [95% CI: 4.0; 5.2] during maternal laparotomy and hysterotomy and with 4.4 Vol-% [95% CI: 3.9; 5.8] during subsequent manipulation of the uterus and fetal surgery.

Nowadays, widespread antenatal ultrasound screenings detect congenital anomalies earlier and more frequently. This has sparked research into foetal surgery, offering treatment options for various conditions. These surgeries aim to correct anomalies or halt disease progression until after birth. Minimally invasive procedures can be conducted under local anaesthesia (with/without maternal sedation), while open mid-gestational procedures necessitate general anaesthesia. Anaesthesia serves to prevent maternal and foetal pain, to provide immobilization, and to optimize surgical conditions by ensuring uterine relaxation. As early as 12 weeks after conception, the foetus may experience pain. Thus, in procedures involving innervated foetal tissue or requiring foetal immobilization, anaesthetic drugs can be administered directly to the foetus (intramuscular or intravenous) or indirectly (transplacental) to the mother. However, animal studies have indicated that exposure to prenatal anaesthesia might impact foetal brain development, translating these findings to the clinical setting remains difficult., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Prenatal spina bifida aperta repair improves neurologic outcomes yet comes with a significant risk of prematurity and uterine scar-related complications. To reduce such complications, different fetoscopic techniques, for example, with varying numbers of ports, are being explored. This has an effect on the duration of the procedure, potentially affecting central nervous system development. Both the condition and anesthesia can affect the central nervous system, particularly the hippocampus, a region crucial for prospective and episodic memory. Previous animal studies have shown the potential influence of anesthesia, premature delivery, and maternal surgery during pregnancy on this area., Objective: This study aimed to compare the effects of 2- vs 3-port fetoscopic spina bifida aperta repair in the fetal lamb model using neuron count of the hippocampus as the primary outcome., Study Design: Based on the hippocampal neuron count from previous lamb experiments, we calculated that we required 5 animals per group to achieve a statistical power of ≥ 80%. A spina bifida aperta defect was developed in fetal lambs at 75 days of gestation (term: 145 days). At 100 days, fetuses underwent either a 2-port or 3-port fetoscopic repair. At 143 days, all surviving fetuses were delivered by cesarean delivery, anesthetized, and transcardially perfused with a mixture of formaldehyde and gadolinium. Next, they underwent neonatal brain and spine magnetic resonance imaging after which these organs were harvested for histology. Hippocampus, frontal cortex, caudate nucleus, and cerebellum samples were immunostained to identify neurons, astrocytes, microglia, and markers associated with cell proliferation, myelination, and synapses. The degree of hindbrain herniation and the ventricular diameter were measured on magnetic resonance images and volumes of relevant brain and medulla areas were segmented., Results: Both treatment groups included 5 fetuses and 9 unoperated littermates served as normal controls. The durations for both skin-to-skin (341±31 vs 287±40 minutes; P=.04) and fetal surgery (183±30 vs 128±22; P=.01) were longer for the 2-port approach than for the 3-port approach. There was no significant difference in neuron density in the hippocampus, frontal cortex, and cerebellum. In the caudate nucleus, the neuron count was higher in the 2-port group (965±156 vs 767±92 neurons/mm 2 ; P=.04). There were neither differences in proliferation, astrogliosis, synaptophysin, or myelin. The tip of the cerebellar vermis was closer to the foramen magnum in animals undergoing the 2-port approach than in animals undergoing the 3-port approach (-0.72±0.67 vs -2.47±0.91 mm; P=.009). There was no significant difference in the ratio of the hippocampus, caudate nucleus, or cerebellar volume to body weight. For the spine, no difference was noted in spine volume-to-body weight ratio for the lower (L1-L2), middle (L3-L4), and higher (L5-L6) levels. Compared with controls, in repaired animals, the cerebellar vermis tip laid closer to the foramen magnum, parietal ventricles were enlarged, and medulla volumes were reduced., Conclusion: In the experimental spina bifida fetal lamb model, a 2-port repair took 40% longer than a 3-port repair. However, there was no indication of any relevant morphologic differences in the fetal brain., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: Surgical patients are asked to adhere to preoperative fasting guidelines to minimize gastric contents. Large fluid volumes or solid content can still be present as shown with gastric ultrasound. It has been suggested that additional rating of patients' satiety, measured as the feeling of hunger and thirst, could help clinicians to better judge emptying of the stomach., Methods: We performed a prospective observational study in fasted elective surgical patients. The primary objective was to investigate the correlation between hunger measured on a 0-10 numeric rating scale and total gastric fluid volume measured with gastric ultrasonography. Secondary objectives included the correlation between 1) thirst and total gastric fluid volume and 2) hunger, thirst, and the Perlas grading scale score., Results: We included 515 patients. The exam was inconclusive in 14 individuals (2.7%). The Spearman correlation coefficient between gastric fluid volumes and hunger was 0.11 (95% confidence interval [CI], 0.02 to 0.20) (P = 0.01). The correlation between gastric fluid volumes and thirst was 0.11 (95% CI, 0.02 to 0.20) (P = 0.02). Between antral grades and numeric rating scale, the correlation coefficient was 0.00 (95% CI, -0.09 to 0.09) (P = 1.00) for thirst and 0.00 (95% CI, -0.08 to 0.09) (P = 0.94) for hunger. Ten patients (2.0%) had solid content, 24 presented a grade 2 antrum (4.8%)., Conclusion: This study suggests that the correlation between total gastric fluid volume and satiety sensation is very weak. Satiety did not reliably predict total gastric fluid volume., Study Registration: ClinicalTrials.gov (NCT04884373); registered 13 May 2021., (© 2023. Canadian Anesthesiologists' Society.)

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 ± standard deviation: control-group: 403 ± 39, single-exposure group: 436 ± 23 and repeated-exposure-group: 403 ± 40 neurons/mm 2 , 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., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

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., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Introduction: Children with congenital diaphragmatic hernia (CDH) are at risk for neurodevelopmental delay. Some changes are already present prenatally. Herein, we further examined how the brain develops in fetal rabbits with surgically created DH., Methods: Two fetuses underwent surgical DH creation on day 23 (term = d31). DH pups and littermate controls were harvested at term. Ten DH pups and 11 controls underwent transcardial perfusion for brain fixation and measurement of brain volume, brain folding, neuron and synaptic density, pre-oligodendrocyte count, proliferation, and vascularization. Twelve other DH and 11 controls had echocardiographic assessment of cardiac output and aortic and cerebral blood flow, magnetic resonance imaging (9.4 T) for cerebral volumetry, and molecular assessment of vascularization markers., Results: DH pups had lower lung-to-body weight ratio (1.3 ± 0.3 vs. 2.4 ± 0.3%; p < 0.0001) and lower heart-to-body weight ratio (0.007 ± 0.001 vs. 0.009 ± 0.001; p = 0.0006) but comparable body weight and brain-to-body weight ratio. DH pups had a lower left ventricular ejection fraction, aortic and cerebral blood flow (39 ± 8 vs. 54 ± 15 mm/beat; p = 0.03) as compared to controls but similar left cardiac ventricular morphology. Fetal DH-brains were similar in volume but the cerebellum was less folded (perimeter/surface area: 25.5 ± 1.5 vs. 26.8 ± 1.2; p = 0.049). Furthermore, DH brains had a thinner cortex (143 ± 9 vs. 156 ± 13 μm; p = 0.02). Neuron densities in the white matter were higher in DH fetuses (124 ± 18 vs. 104 ± 14; p = 0.01) with comparable proliferation rates. Pre-oligodendrocyte count was lower, coinciding with the lower endothelial cell count., Conclusion: Rabbits with DH had altered brain development compared to controls prenatally, indicating that brain development is already altered prenatally in CDH., (© 2023 John Wiley & Sons Ltd.)

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., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objectives: Primary graft dysfunction resulting from ischaemia-reperfusion injury remains a major obstacle after lung transplantation (LTx) and is associated with morbidity and mortality. Continuous release of inflammatory cytokines, due to the process of ischaemia and reperfusion, triggers a complex cascade of apoptosis and necrosis resulting in graft dysfunction. Previous studies demonstrated successful graft improvement by cytokine filtration during ex vivo lung perfusion. We hypothesize that plasma cytokine filtration with CytoSorb® during in vivo graft perfusion immediately after implantation may attenuate ischaemia-reperfusion injury after left LTx in a porcine model., Methods: Left porcine LTx was performed with allografts preserved for 24 h at 4°C. In the treatment group [T] (n = 7), a veno-venous shunt was created to insert the cytokine filter (CytoSorbents, Berlin, Germany). In the sham group [S] (n = 4), the shunt was created without the filter. Haemodynamic parameters, lung mechanics, blood gases and plasma cytokines were assessed during 6 h in vivo reperfusion., Results: During 6 h of reperfusion, significant differences in plasma pro-inflammatory cytokine [interferon (IFN)-α, IFN-γ and interleukin (IL)-6] concentrations were observed between [T] and [S], but surprisingly with higher plasma levels in the [T] group. Plasma concentrations of other pro-inflammatory cytokines (IL-1β, IL-12p40, IL-4, IL-6, IL-8, IFN-α, IFN-γ and tumour necrosis factor-α) and anti-inflammatory cytokines (IL-10) did not find any evidence for a difference. Furthermore, our study failed to show meaningful difference in haemodynamics and blood gases. Also, no statistically significant differences were found between [T] and [S] in biopsies and wet-to-dry ratio at the end of the experiment., Conclusions: In our porcine left LTx model cytokine filtration did not achieve the intended effect. This is in contrast to previous studies with CytoSorb use during ex vivo lung perfusion as a surrogate LTx model. Our findings might highlight the fact that the theoretical benefit of inserting an additional cytokine adsorber to improve graft function in clinical practice should be critically evaluated with further studies., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Nonobstetric surgery may be required in up to 1% of pregnancies. Most common procedures are urgent abdominal surgeries requiring general anaesthesia. Maintaining normal maternal physiology during anaesthesia is vital. Left lateral tilt position prevents aortocaval compression and preserves normal venous return. Preparation for a difficult airway is required in all obstetric patients due to the known anatomical and physiological changes. Aspiration prophylaxis and a rapid sequence induction are traditionally recommended to avoid the (probably overestimated) risk of aspiration. Although the minimum alveolar concentration (MAC) of volatile anaesthetic agents is reduced by 30 to 40%, awareness occurs more frequently in the obstetric population. Maternal outcomes from surgery are comparable with those of nonpregnant women, but increased incidences of foetal loss, preterm delivery, low birth weight and caesarean section have been reported. Although animal studies have observed impaired foetal brain development after antenatal exposure to anaesthesia, the translational value of these studies remain controversial. Clinical evidence is nearly absent. Withholding urgent/essential procedures is certainly more threatening than proceeding with the surgery. To increase the safety of mother and foetus, nonurgent or nonessential procedures should be postponed until after delivery, and if procedures cannot wait, locoregional anaesthesia should be used if possible. Where general anaesthesia cannot be avoided, the duration of exposure should be kept to a minimum. This narrative review summarises the literature of the past 20 years concerning the anaesthetic management and outcomes of nonobstetric surgery under general anaesthesia during pregnancy., Competing Interests: Conflicts of interest: None., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Society of Anaesthesiology and Intensive Care.)

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 ± 162 versus 1189 ± 200 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., (Copyright © 2022 European Society of Anaesthesiology and Intensive Care. Unauthorized reproduction of this article is prohibited.)

Background: Fetal surgery is part of modern fetal medicine, and some procedures, such as fetal spina bifida repair, are performed under general anesthesia. Fetuses are operated on in a time window when the developing brain is extremely vulnerable to external, potentially harmful factors. To date, little is known about the effect of fetal surgery on fetal brain development., Objective: This study aimed to assess the effect of fetal surgery on the developing fetal brain in the rabbit model., Study Design: This was a randomized, sham-controlled study in time-mated pregnant does at 28 days' gestation (term, 31 days), which corresponds to the start of the peak of brain development and end of the second trimester of pregnancy in humans. We included 4 different groups in this experiment: no-surgery, general anesthesia, general anesthesia+hysterotomy, and general anesthesia+fetal surgery. In 11 does, anesthesia was induced using propofol and maintained for 75 minutes with 3.6 vol% (4% is the equivalent of 1 minimum alveolar concentration) sevoflurane. Maternal blood pressure, heart rate, oxygen saturation, temperature, end-tidal CO 2 were continuously monitored. For each operated doe, 6 fetuses were part of the experiment. Randomization determined which cornual sac and what opposing third sac were assigned to fetal surgery: hysterotomy, fetal injection (atropine, fentanyl, and cisatracurium), fetal skin incision, and suturing. Only hysterotomy was performed on the opposing cornual and third amniotic sacs of the does. The fetus in these experimental sacs was used as internal unmanipulated control (general anesthesia). All fetuses (n=38) from unmanipulated does (n=4) served as external controls (no-surgery). At term, the does were delivered by cesarean delivery under ketamine-medetomidine sedation and local anesthesia. The pups underwent standardized motoric and sensory neurologic testing on day 1 followed by euthanasia and brain harvesting for histologic assessment of neurons, synapses, proliferation, and glial cells., Results: Maternal vital signs were stable during surgery. Survival was similar in the 4 groups (75%-94%), and brain-to-body weight ratio was comparable; only the no-surgery pups had a higher brain weight. On postnatal day 1, the pups in the 4 groups had a comparable neurobehavioral outcome on both motoric and sensory testing. In the prefrontal cortex, no-surgery pups had significantly higher neuron density than pups who underwent maternal surgery, but there was no difference among pups that underwent general anesthesia, hysterotomy, or fetal surgery. The measurements of proliferation had a similar outcome: a higher proliferation rate in the prefrontal cortex of no-surgery pups. Moreover, synaptic density values were higher in the no-surgery pups, but there was no difference observed among pups who underwent general anesthesia, hysterotomy, and fetal surgery. Lastly, there was no difference in gliosis among the 4 groups., Conclusion: In rabbits, fetal surgery through hysterotomy under maternal general anesthesia did not affect brain development, in addition to the effects of general anesthesia per se., (Copyright © 2021 Elsevier Inc. All rights reserved.)

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., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: During fetal surgery, fetuses receive medication (atropine-fentanyl-curare) to prevent fetal pain, movement and bradycardia. Although essential there has been no detailed review of potential side effects. Herein we aimed to assess the effects of this medication cocktail on fetal brain development in a rabbit model., Methods: Pregnant does underwent laparotomy at 28 days of gestation. Two pups of each horn were randomized to an ultrasound guided injection with medication (atropine-cisatracurium-fentanyl, as clinically used) or saline (sham). The third pup was used as control. At term, does were delivered by cesarean. Outcome measures were neonatal biometry, neuromotoric functioning and neuro-histology (neuron density, synaptic density and proliferation)., Results: Maternal vital parameters remained stable during surgery. Fetal heart rates did not differ before and after injection, and were comparable for the three groups. At birth, neonatal body weights and brain-to-body weight ratios were also comparable. Both motor and sensory neurobehavioral scores were comparable. There were no differences in neuron density or proliferation. Sham pups, had a lower synaptic density in the hippocampus as compared to the medication group, however there was no difference in the other brain areas., Conclusion: In the rabbit model, fetal medication does not appear to lead to short-term neurocognitive effects., (© 2021 John Wiley & Sons Ltd.)

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., (Copyright © 2021 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

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., (© 2021 S. Karger AG, Basel.)

Histone deacetylase 6 (HDAC6) is a multifunctional cytoplasmic enzyme involved in diverse cellular processes such as intracellular transport and protein quality control. Inhibition of HDAC6 can alleviate defects in cell and rodent models of certain diseases, particularly neurodegenerative disorders, including Alzheimer's disease and amyotrophic lateral sclerosis. However, while HDAC6 represents a potentially powerful therapeutic target, development of effective brain-penetrant HDAC6 inhibitors remains challenging. Recently, [ 18 F]EKZ-001 ([ 18 F]Bavarostat), a brain-penetrant positron emission tomography (PET) radioligand with high affinity and selectivity toward HDAC6, was developed and evaluated preclinically for its ability to bind HDAC6. Herein, we describe the efficient and robust fully automated current Good Manufacturing Practices (cGMP) compliant production method. [ 18 F]EKZ-001 quantification methods were validated in nonhuman primates (NHP) using full kinetic modeling, and [ 18 F]EKZ-001 PET was applied to compare dose-occupancy relationships between two HDAC6 inhibitors, EKZ-317 and ACY-775. [ 18 F]EKZ-001 is cGMP produced with an average decay-corrected radiochemical yield of 14% and an average molar activity of 204 GBq/μmol. We demonstrate that a two-tissue compartmental model and Logan graphical analysis are appropriate for [ 18 F]EKZ-001 PET quantification in NHP brain. Blocking studies show that the novel compound EKZ-317 achieves higher target occupancy than ACY-775. This work supports the translation of [ 18 F]EKZ-001 PET for first-in-human studies.

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 CO 2 , 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/mm 2 ; 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., (Copyright © 2019 Elsevier Inc. All rights reserved.)