Science, Medicine, and the Anesthesiologist

Key Papers from the Most Recent Literature Relevant to AnesthesiologistsThe potent µ-opioid receptor (µOR)–specific agonist, fentanyl, has devastating consequences on public health, increasing opioid addiction-related deaths. Fentanyl is highly addictive, with robust withdrawal symptoms leading to negative reinforcement behaviors where individuals retake the drug to avoid withdrawal effects. However, the neurobiologic mechanisms underlying fentanyl positive and negative reinforcement remain to be described. This study, using sophisticated biologic approaches alongside behavioral analysis, involved conducting innovative experiments to address this gap. Increased neuronal activity in the central amygdala (CeA) was observed during precipitated withdrawal in fentanyl-treated animals. Oprm1, expressed in a distinct neuronal population in CeA, was found to modulate fentanyl withdrawal when deleted. Retrograde viral tracing indicated that CeA primarily projected to the bed nucleus of the stria terminalis and the parabrachial lateral nucleus, associated with aversive and pain-related processes, respectively. Monitoring neural activities associated with positive and negative reinforcement revealed that fentanyl reduced GABAergic neuronal activity while increasing dopamine activity in the ventral tegmental area (VTA). Deleting µOR in VTA abolished dopamine neuronal activity but did not prevent fentanyl withdrawal. Additionally, increased µOR neuron activity in CeA was observed during withdrawal. Optogenetic manipulation of VTAGABA or CeAMOR neurons, combined with operant behavior, confirmed their roles in fentanyl positive and negative reinforcement, respectively.Take home message: The study sheds light on distinct brain neural circuits for fentanyl positive and negative reinforcement. These findings may help in improving the management of opioid addiction by specifically targeting those brain circuits for reducing both the rewarding and aversive aspects of fentanyl addiction.Several human observational studies have found an association between exposure to anesthesia in early childhood and poorer neurobehavioral outcomes, with the association being stronger with multiple exposures. The impact of these studies is limited due to the strong likelihood of confounding. Randomized trials can mitigate the risk of confounding. This study enrolled children from a previously completed randomized trial in which infants with cystic fibrosis were randomized to multiple bronchoalveolar lavages under general anesthesia (n = 52) or standard of care (n = 45), up to 5 yr of age. The children received a battery of neurobehavioral tests and magnetic resonance imaging brain scans at a median age of 12.8 yr. The primary outcome was a composite score of performance on a standardized, computer-based assessment of child attention, processing speed, and response inhibition skills (Conners Continuous Performance test). By 5 yr of age, the bronchoalveolar lavage group had a median of six general anesthesia exposures while the standard of care arm had a median of two exposures. There was no difference in mean ± SD Conners score: 51 ± 8.1 in the bronchoalveolar lavage arm and 53 ± 8.8 in the standard of care arm with a difference –1.7 (95% CI, –5.2 to 1.7; P = 0.32). There was also no difference in other neurobehavioral measures and brain imaging.Take home message: This randomized trial found that children exposed to a greater number of general anesthetics did not have different neurobehavioral outcomes compared to children exposed to fewer anesthetics.Previous work has shown the significance of electrical stimulation of the vagal nerve to attenuate inflammation. To decipher how the brain regulates the body’s immune response, activities of neurons in the brain stems of mice were monitored after infliction of a peripheral immune insult by intraperitoneal injection of endotoxin (lipopolysaccharide). Activation of c-fos, a proxy for neuronal activity, was strong in the caudal nucleus of the solitary tract (cNST). Lipopolysaccharide-evoked neural activity in the cNST was blocked by subdiaphragmatic transection of the vagus nerve. Chemogenetic activation and inhibition of lipopolysaccharide-sensitive cNST neurons, single-cell RNA sequencing, and functional imaging were used to identify the components of the interaction between immune system and the brain. Activation of lipopolysaccharide-sensitive cNST neurons reduced the proinflammatory response by 70% and increased the anti-inflammatory response 10-fold, while their inhibition dramatically increased the proinflammatory response by 300%. Additional experiments showed that specific vagal nerve fibers, mainly from the small intestine, were activated by cytokines and transmitted the inflammatory signal to cNST neurons. The significance of this body–brain circuit could be demonstrated in mice where this circuit had been activated chemogenetically and subsequently injected with lethal doses of lipopolysaccharide, resulting in an astonishing survival rate of 90%.Take home message: Pharmacologically targeting cNST neurons may provide a powerful treatment of hyperactive immune states such as autoimmune diseases, cytokine storms, and toxic shocks.Patients sustaining acute intracerebral hemorrhage on anticoagulants are at increased risk for hematoma expansion. Factor Xa inhibitors are now widely used for chronic anticoagulation, and before the release of andexanet alfa, no specific reversal agents were available. The effects of andexanet alfa on hematoma volume expansion in a randomized study have not been previously reported. This multicenter study (131 sites, 23 countries) evaluated its use versus usual care (primarily prothrombin complex concentrates). Patients receiving factor Xa inhibitors within 15 h before an acute intracerebral hemorrhage were randomized to either andexanet (N = 263) or usual care (N = 267). The primary outcome was hemostatic efficacy (a composite of radiographic hematoma expansion, increase in National Institutes of Health Stroke Scale score, and receipt of rescue therapy). Safety outcomes included thrombotic events and death. Atrial fibrillation was present in 84 (usual) to 90% (andexanet) of subjects. The primary outcome was significantly lower in the andexanet group (67% vs. 53.1%; adjusted difference, 13.4 percentage points; 95% CI, 4.6 to 22.2; P = 0.003). Adverse safety outcomes were higher with andexanet (thrombosis, 10.3% vs. 5.6%, P = 0.048; ischemic stroke, 6.5% vs. 1.5%). No difference occurred in 30-day mortality.Take home message: In this randomized multicenter trial, reversal of anticoagulation during acute intracerebral hemorrhage in the setting of prior factor Xa inhibitor use with andexanet was associated with improved hemostatic efficacy compared to usual care, although more adverse safety events occurred with its use.Inguinal hernia repair in premature neonates is associated with morbidity, but it is controversial whether repair should be done before or after intensive care unit (ICU) discharge. This multicenter (39 U.S. sites) randomized infants to either early (N = 172) or late (N = 166, age older than 55 postmenstrual weeks). The primary outcome was occurrence of any prespecified serious adverse event during the 10-month observation period. The mean ± SD gestational birth age was 26.6 ± 2.8 weeks; the mean ± SD postnatal age at enrollment was 12 ± 5 weeks. At follow-up, 159 (early) and 149 (late) had complete data. The primary outcome was significantly lower with late repair (18% vs. 28%, risk difference, −7.9% [95% credible interval, −16.9 to 0%]). The median days in the hospital during the 10-month observation period was 19.0 (interquartile range, 9.8 to 35.0) in the early group versus 16.0 (7.0 to 38.0) in the late group (82% posterior probability of benefit with late repair). The probability that late repair reduced the number of infants with at least one serious adverse event was higher in infants younger than 28 weeks’ gestational age and in those with bronchopulmonary dysplasia (99% probability of benefit).Take home message: In this multicenter randomized study of timing of neonatal inguinal hernia repair, late repair after ICU discharge resulted in a significant reduction in serious adverse events over the intervening 10-month period. Benefits appeared to be greatest in younger infants and in those with bronchopulmonary dysplasia.The neuronal mechanisms of general anesthetics are attributed to multiple cellular targets including postsynaptic potentiation of inhibitory ion channels and the inhibition of neurotransmitter release by interference with proteins involved in exocytosis; however, variation may exist in the cellular targets of anesthetics among synapse subtypes. In the current study, isoflurane’s effects on neurotransmitter release at cholinergic neurons in insect mushroom body output neurons (MBON) of female Drosophilia brains was measured. Anesthesia was defined as an absence of behavioral responsiveness to mechanical stimulation. Isoflurane immobilized and clustered syntaxin1a, a key component of the SNARE protein complex, essential for neurotransmitter release. In contrast, isoflurane did not effect syntaxin1a mobility or clustering in GABAergic or glutamatergic synapses in the MBON. The difference between isoflurane’s effects on cholinergic versus GABAergic synapses was not attributable to variation in neuronal stimulation measured by calcium transients. These results suggest that isoflurane inhibits presynaptic release of neurotransmitter at cholinergic neurons while potentiating postsynaptic GABAergic and glutamatergic inhibitory neuronal activity. It is concluded that variations in the specific proteins of the exocytotic protein complex, rather than the specific neurotransmitter released, may account for differential effects of anesthetics on excitatory cholinergic system versus the inhibitory GABAergic and glutamatergic circuits.Take home message: Anesthetics are well known for their potentiation of inhibitory ion channels, but additional cellular targets may result in synergistic presynaptic inhibition of neurotransmitter release from excitatory neurons. These hypotheses will need further investigation in mammalian models in which consciousness can be studied in addition to physical immobilization.Large language models (LLMs) like ChatGPT are widely used, but their use for perioperative care applications is uncertain. This retrospective prognostic study studied six different “prompting strategies” for question-and-answer tasks using GPT-4 Turbo (OpenAI) on 133,500 anesthesia preoperative notes and 226,821 clinical notes from three U.S. academic medical centers. LLMs were asked to predict eight outcomes: inpatient mortality, American Society of Anesthesiologists (ASA) Physical Status, hospital admission, intensive care unit (ICU) admission, unplanned admission, postanesthesia care unit (PACU) phase 1 duration, hospital length of stay, and ICU length of stay. Predictions were validated against labeled data for the outcomes of interest. LLM performance was described using F1 scores, which includes true positive, false positive, and false negative values in a combined metric (ranging from 0 = lowest to 1 = highest performance). Prompting strategies providing more background examples of notes to the LLM (“few-shot”) and those requiring the reasoning behind LLM answers (“chain of thought”) generally performed best. Across outcomes, LLMs performed best at predicting in-hospital mortality (F1 score, 0.86; 95% CI, 0.83 to 0.89), ASA Physical Status (F1 score, 0.50; 95% CI, 0.47 to 0.53), need for hospital admission (F1 score, 0.64; 95% CI, 0.61 to 0.67), need for ICU admission (F1 score, 0.81; 95% CI, 0.78 to 0.83), and unplanned admission (F1 score, 0.61; 95% CI, 0.58 to 0.64). Prediction for duration-specific outcomes such as length of stay and PACU stay was poor.Take home message: This retrospective analysis suggests that commonly used LLMs (like ChatGPT) may be able to aid in perioperative risk stratification for specific outcomes using customized prompting strategies.It is widely accepted that the evacuation of acute supratentorial intracerebral hemorrhages does not improve patient outcomes. However, recent advances in minimally invasive neurosurgical techniques (such as trans-sulcal parafascicular surgery) enable effective hematoma drainage with less damage to the surrounding brain and thus may produce better functional outcomes. Three hundred adult patients suffering from 30- to 80-ml volume hemorrhages in cortical lobar (69.3%) or anterior basal ganglion (30.7%) brain regions were recruited to an adaptive randomized trial at 37 U.S. centers sponsored by the maker of the surgical evacuator used. Patients received either minimally invasive surgical hematoma removal within 24 h of the hemorrhage (surgical group, n = 150) or conservative medical management alone (control group, n = 150). The primary outcome was a utility-weighted modified Rankin scale at 180 days after the hemorrhage. The surgery group had a better Rankin score (0.458) than the control group (0.374; 95% Bayesian credible interval, 0.005 to 0.163; posterior probability of superiority of surgery = 0.981). The difference in outcome was greater in those with cortical lobar hemorrhages than those involving the basal ganglia. Fewer in the surgery group (n = 14) died by 30 days compared to the control group (n = 27).Take home message: In this multicenter, randomized, adaptive trial, the use of minimally invasive hematoma evacuation within 24 h of a supratentorial cerebral hemorrhage results in improved long-term outcomes.In contrast to availability in adults and children, only limited data on the efficacy of video laryngoscopy for neonatal intubation area are available. This single-center trial (tertiary Irish center) randomized neonates (any gestational age) requiring intubation in either the delivery room (29%) or the neonatal intensive care unit (71%) to either video laryngoscopy (N = 107 analyzed) or direct laryngoscopy (N = 107 analyzed). The primary outcome was success on the first intubation attempt. Intubations were performed by pediatric or neonatology residents or a neonatologist; a total of 54 clinicians were involved (trainees compromised 93 to 97% of first attempts). The primary outcome was significantly improved with video laryngoscopy (74% [95% CI, 66 to 82] vs. 45% [95% CI, 35 to 54]; P < 0.001). Of the secondary outcomes, median number of attempts for successful intubation was 1 (95% CI, 1 to 1) versus 2 (95% CI, 1 to 2) respectively. Safety outcomes included median lowest oxygen saturation during intubation 74% (95% CI, 65 to 78) video versus 68% (95% CI, 62 to 74) direct and lowest heart rate 153 beats/min (95% CI, 148 to 158) versus 148 beats/min (95% CI, 140 to 156), respectively.Take home message: This randomized single-center study involving trainees in pediatrics or neonatology at a tertiary care center demonstrated that first-pass success with use of video laryngoscopy for urgent endotracheal intubation in neonates in the delivery room or neonatal intensive care unit was significantly greater relative to use of direct laryngoscopy.