Science, Medicine, and the Anesthesiologist

Key Papers from the Most Recent Literature Relevant to AnesthesiologistsOpioid-sparing analgesia is an important clinical objective and many nonopioid receptors are involved in pain processing, including the α2A-adrenergic receptor. While classic α2A-agonists like dexmedetomidine and clonidine are known to be analgesic, they are also sedating, which limits their use. α2A-Receptor ligands that differentially couple to distinct intracellular signaling pathways have the potential to separate analgesic from sedative effects. An in silico screen of more than 301 million molecules from the ZINC15 compound library (https://zinc15.docking.org) was performed to identify compounds predicted to bind to the highly similar α2B receptor that were chemically unrelated to known drugs. Lead compounds were screened in cells expressing α2A-adrenergic receptors to define binding and activation of distinct heterotrimeric G protein family members that regulate different intracellular signaling pathways, including the recruitment of β-arrestin. The key intracellular signaling events that appeared to differentiate these new lead compounds from traditional α2A-agonists were restricted coupling different G protein family members and a reduced ability to recruit β-arrestin, a protein involved in G protein–coupled receptor desensitization and internalization. Structural optimization of lead compounds for low-nanomolar potency and selectivity of G protein signaling revealed several compounds that provided analgesia in neuropathic, inflammatory, and acute thermal nociception models in mice without sedative effects.Take home message: The development of α2A-adrenergic receptor ligands that differentially activate distinct G protein–mediated intracellular signaling pathways may identify novel nonopioid analgesics acting at the α2A-adrenergic receptor devoid of undesirable sedative effects.Although reports highlight certain fluctuations in pain intensity during the day, the exact mechanism is not known. This study was performed in 12 healthy males. Participants were habituated on day 1 and then subjected to an 8-h sleep episode, followed by a 34-h awake phase. In the episode without sleep, pain was triggered every 2 h by thermal stimuli on the forearm (2-s heat stimuli at 42°C, 44°C, and 46°C), and pain intensity was defined using the visual analogue scale. Results showed that circadian processes regulate pain rhythmicity with a maximal pain experienced in the middle of the night (around 3:30 am). Pain sensitivity was accentuated with greater sleep deprivation with the higher two temperatures, but not with 42°C. The effects of time as well as sleep and sleep deprivation were evaluated using a modeling approach wherein the circadian component accounted for 78% of the magnitude of pain sensitivity changes over a 24-h period and the sleep-related homeostatic component for only 22%.Take home message: Pain sensitivity is driven by the circadian process while sleep and sleep deprivation have only a weak influence. Analgesic treatment could potentially be optimized by considering circadian cycles.Lean body mass is associated with functional and metabolic health and is sexually dimorphic. This observational study assesses the potential sex-specific association of lean body mass with cardiovascular capacity. Healthy, nonsmoking, and nonobese women (n = 33; mean ± SD age, 60 ± 12 yr) and men (n = 37; mean ± SD age, 58 ± 15 yr) matched on age, physical activity, and aerobic capacity underwent dual-energy x-ray absorptiometry to assess body composition (lean body mass, fat body mass, and bone). Cardiac structure and function were assessed via transthoracic ultrasound at rest and during peak exercise, with a focus on transmitral inflow velocities, left ventricular mass, left ventricular relative wall thickness, stroke volume, and total peripheral vascular resistance. Blood pressure was measured continuously by volume-clamp method and finger plethysmography and used to calculate total peripheral vascular resistance. Baseline blood pressure, heart rate, and aerobic capacity were similar between sexes, but regional (leg, arm, trunk) and total lean body mass was lower in women versus men (P < 0.001). In women only, the leg, arm, and total lean body mass were positively associated with left ventricular relaxation (r ≥ 0.43, P ≤ 0.013). All lean body mass variables in women were positively associated with left ventricular volumes at peak exercise (r ≥ 0.54, P ≤ 0.001) and negatively associated with total peripheral resistance (r ≥ 0.43, P ≤ 0.023). Results remained consistent after adjustment for cardiovascular risk factors, menopause or hormonal therapy, and adiposity.Take home message: Lean body mass represents a potentially modifiable factor associated with cardiovascular health in women but not in men. These results may be explained by the lean body mass gap between sexes and its effect on total peripheral vascular resistance.Current guidelines for defibrillation of ventricular fibrillation recommend use of a single arrangement of pads (most commonly anterolateral) and a single defibrillator. Double sequential external defibrillation (rapid sequential shocks from two defibrillators using different pad configurations) and vector-change defibrillation (switching pads to an anterior-posterior position) have been proposed as alternative approaches. This crossover, cluster-randomized trial (six Canadian paramedic services) evaluated the use of these two techniques versus standard defibrillation in adults sustaining out-of-hospital cardiac arrest. The primary outcome was survival to hospital discharge. Secondary outcomes included termination of ventricular fibrillation, return of spontaneous circulation, and a favorable neurologic outcome at hospital discharge (modified Rankin scale score of 2; no symptoms to slight disability). After enrollment of 405 subjects, the trial was terminated by the data and safety monitoring board due to the COVID-19 pandemic. Of these, 34% had standard, 31% had double sequential, and 36% had vector change defibrillation. The primary outcome was more common in two treatment groups relative to standard therapy (double sequential 30% vs. 13%; relative risk, 2.21; 95% CI, 1.33 to 3.67) and vector change (22% vs. 13%; relative risk, 1.71; 95% CI, 1.01 to 2.88). Of the secondary outcomes, double sequential subjects had better neurologic outcome at discharge (relative risk, 2.21; 95% CI, 1.26 to 3.88).Take home message: In this cluster-randomized trial of subjects with out-of-hospital cardiac arrest with refractory ventricular fibrillation, both double sequential and vector-change defibrillation approaches resulted in a greater percentage of patients surviving to hospital discharge.Transvenous implantable cardioverter–defibrillators significantly reduce cardiac mortality among patients at risk for ventricular arrhythmias, but their use can be complicated by serious vascular, thoracic, and potential long-term complications. Subcutaneous implantable cardioverter–defibillator placement over the sternum has been attempted but suffers from greater energy requirements and limited pacing capabilities. Thus, a minimally invasive substernal mediastinal system using a small subxiphoid incision deploying a wire array contacting both atria and ventricles with connection tunneled subcutaneously to a battery placed in the left midaxillary region (all done under general anesthesia in the cardiac catheterization suite) was developed. This prospective, single-group, premarket clinical study (46 centers, 17 countries) of patients with a class I or IIa American Heart Association guideline indication for an implantable cardioverter–defibrillator evaluated medical benefit (primary: successful defibrillation at time of implantation) and safety (primary: freedom from major system- or procedure-related complications at 6 months) outcomes of this system in 316 patients having an implantation attempt (of 356 enrolled). The medical benefit outcome occurred in 99% (lower boundary of the one-sided 98% CI, 97%; P < 0.001 for comparison with the performance goal of 88%) and safety in 93% (lower boundary of the one-sided 98% CI, 89%; P < 0.001 for the comparison with the performance goal of 79%).Take home message: A minimally invasive substernal implantable cardioverter–defibrillator system placed using general anesthesia appears to be beneficial for defibrillation with an acceptable short- and longer-term safety profile.The use of prophylactic steroids before cardiopulmonary bypass to blunt inflammatory responses in infants undergoing congenital heart surgery remains controversial and is hampered by high costs of adequately powered studies. A registry-based (Society of Thoracic Surgeons Congenital Heart Surgery Database), pragmatic, multicenter (24 U.S. sites), placebo-controlled trial design randomized 1,263 infants younger than 1 yr of age undergoing cardiac surgery with cardiopulmonary bypass to either methylprednisolone (30 mg/kg in the cardiopulmonary bypass priming fluid) or placebo. The primary outcome was a ranked composite of death, heart transplantation, or any of 13 major perioperative complications, while those without such events were ranked based on postoperative length of stay. Ranked outcomes were compared between treatment groups adjusting for clinical risk factors. Secondary outcomes included unadjusted analyses, a pair win-loss ratio analysis, and safety outcomes. Of the 1,200 infants studied (599 vs. 601), no difference was noted in the primary outcome (adjusted odds ratio, 0.86; 95% CI, 0.71 to 1.05; P = 0.14). In contrast, the secondary analysis suggested a potential treatment benefit (unadjusted odds ratio, 0.82 [95% CI, 0.67 to 1.00]; win-loss ratio, 1.15 [95% CI, 1.00 to 1.32]), although a significantly higher percentage of treated infants developed hyperglycemia requiring insulin treatment (19% vs. 7%, P < 0.001).Take home message: This large, multicenter, registry-based, pragmatic randomized trial found no benefit to prophylactic methylprednisolone administered in the cardiopulmonary bypass priming fluid on adverse outcomes in infants younger than 1 yr of age undergoing heart surgery.Acute and chronic pain remain a major public health concern, and opioids remain a common modality for treating pain. The release of the original CDC Guideline for Prescribing Opioids for Chronic Pain in 2016 was associated with an accelerated decrease in high-risk opioid prescribing; however, some of the changes were due to misapplication of the guideline by policy makers and payers, leading to undertreated pain, rapid tapers, and abrupt discontinuation. These factors have been associated with mental health crises and suicide. This updated guideline addresses these concerns and fill some gaps from the original document, including (1) broadened scope to include acute and subacute pain guidance (including surgical pain); (2) specific information on nonopioid treatments; (3) additional information on tapering; (4) updates on benefit:risk of opioids; and (5) direct language to avoid misapplication of the guideline. To this last point, the article clearly notes that the recommendations are voluntary and not intended to replace individualized, patient-centered care. These revisions also included public commentary for the guidelines, noting concerns and challenges related to opioids and pain management. The article states the importance of “safe, effective, individualized and informed pain care.”Take home message: The CDC has released updated clinical practice guidelines for prescribing opioids for chronic pain that place a strong emphasis on individualized, patient-centered care, particularly in avoidance of rigid dose limitations, acute withdrawal, or abandonment that may result in adverse patient outcomes.GTP cyclohydrolase 1 (GCH1) is the rate-limiting enzyme for the synthesis of tetrahydrobiopterin (BH4), a pain mediator that is induced after nerve injury. Previous human genetic study has associated a single polymorphism of GCH1 with pain, and the role of GCH1/BH4 was validated in Gch1 transgenic mice. Furthermore, the epidermal growth factor receptor (EGFR) and Kirsten ras sarcoma virus (KRAS) signaling pathway was implicated as a key signaling pathway for driving pain in humans and mice. This article reports that EGFR/KRAS signaling can induce Gch1 expression in rodent injured dorsal root ganglion neurons, therefore connecting these two important pathways in nociception regulation. Through a phenotypic screening of bioactive compounds, including many of the Food and Drug Association–approved drugs, the article identified several compounds (such as the antipsychotic fluphenazine) that can inhibit GCH1 expression and neuropathic nociception symptoms in mice. Finally, KRAS is an oncogene; it was found that GCH1 promotes tumorigenesis in KRAS-driven lung cancer. It was demonstrated that pharmacologic blockage of the GCH1/BH4 pathway with a specific reductase inhibitor suppressed the KRAS-mediated tumor growth.Take home message: This study identified potential pharmacologic treatment for neuropathic pain, lung cancer, and cancer pain by targeting the GCH1/BH4 or EGFR/KRAS/GCH1/BH4 pathway.Fentanyl is used to relieve severe postsurgical pain but is also a driver of opioid dependence and fatal respiratory arrest. To date, there is no clinical biomarker of opioid-induced respiratory depression, mainly due to large interindividual variability. Current real-time assessments of opioid requirements rely on pharmacokinetic and pharmacodynamic models, potentially resulting in significant under- or overdosing. This was a clinical study of 25 patients (ages 18 to 65 yr) undergoing general anesthesia with fentanyl (three boluses of 2 µg/kg ideal body weight at 2-min intervals) administered before induction. Respiration was measured with the aid of respiratory inductance plethysmography in preoxygenated patients while monitoring pulse oximetry. Sedation was assessed by judging an auditory behavioral task (pressing a button in response to headphone sound). Electroencephalography (EEG) was recorded from four-channel frontal leads. Fentanyl effect site concentrations were estimated by pharmacokinetic/pharmacodynamic modeling using published parameters and compared with changes in EEG spectrogram and power spectrum changes. Exposure to fentanyl correlated with increases in the theta (4 to 8 Hz) band. Minute ventilation decreased with increasing fentanyl concentration by 60% after the third dose correlating with EEG theta power. Respiratory depression began at 1,700-fold lower fentanyl concentrations and minutes before noticeable changes in alertness.Take home message: Real-time monitoring of opioid drug effects using the theta band of the EEG could facilitate real-time monitoring and enable safe, precise, and personalized opioid administration in clinical settings.The differential impact of anesthesia services in Medicare beneficiaries undergoing low-risk elective procedures has not been well delineated. This article reports a population-based, retrospective, observational cohort study of 36,652 Medicare beneficiaries (mean age, 75 yr; 59% female, 87% White) undergoing cataract surgery in 2017 evaluating the prevalence of anesthesia services; patient, clinician, and health system characteristics; and systemic complications within 7 days of surgery compared with patients undergoing other low-risk procedures (e.g., colonoscopy, endoscopy, bronchoscopy, cardiac catheterization) where anesthesia services are less routine (90% vs. <1 to 70%). Approximately 6% of ophthalmologists never used anesthesia care, 17% used anesthesia for a subset of patients, and 77% always used anesthesia care. Neither the patient’s age (adjusted odds ratio, 1.01; 95% CI, 1.00 to 1.02; P = 0.01) nor the Charlson Comorbidity Index (CCI) score (CCI of 3: adjusted odds ratio, 1.06; 95% CI, 0.95 to 1.18; P = 0.28; reference, CCI score of 0 to 1) were associated with anesthesia care for cataract surgery; rather, it was associated with the ophthalmologists’ usual approach. Fewer cataract surgery patients had systemic complications within 7 days (8%), even for those patients of ophthalmologists who never used anesthesia care (7%) compared to patients undergoing other low-risk procedures (13 to 52%).Take home message: In this large retrospective analysis of Medicare beneficiaries, anesthesia care for cataract surgery was not associated with lower perioperative systemic complications and the fraction of complications was lower for this group compared with other low-risk, nonophthalmologic procedures for which anesthesia care is less commonly used. The results suggest that a more selective approach to anesthesia care for cataract surgery could potentially result in national health care cost savings.Although haloperidol has been used for many years to treat delirium in intensive care patients, it is unclear how effective it is and whether it has significant adverse effects. A multicenter, randomized, blinded trial was conducted in which intensive care patients with delirium were given either 2.5 mg IV haloperidol three times a day (up to 20 mg) or a placebo. Hypoactive delirium was present in 540 patients, and hyperactive delirium in 447. The primary outcome was the number of days alive and out of the hospital 90 days after randomization. There was no difference in the primary outcome; haloperidol group, 36 days (95% CI, 32.9 to 39 days) versus 33 days (95% CI, 29.9 to 36 days) for the placebo group. The 90-day mortality was 36% in the haloperidol group versus 43% in the placebo group (adjusted absolute difference, −7% [95% CI, −13.0 to −0.6]). Both treatment groups had similar numbers of adverse events (n = 11 for haloperidol vs. n = 9 for placebo) and similar use of rescue propofol, α2-agonists, antipsychotic drugs, or benzodiazepines.Take home message: Routine use of haloperidol to treat ICU patients with delirium did not influence the number of days alive and out of the hospital 90 days after randomization versus placebo. An unexpected difference in 90-day mortality favoring haloperidol remains unexplained.The use of spinal cord stimulation to treat neuropathic and other forms of pain has dramatically increased, with most recent studies being industry sponsored. Results between industry- and non–industry-sponsored studies differ significantly. This article reports a non–industry-sponsored study, in which 50 patients with persistent radicular pain after lumbar spine surgery were randomized to two 3-month periods of spinal cord burst stimulation or placebo, in random order. The burst mode consisted of 40 Hz of constant current stimuli with four spikes per burst; single leads were placed for pain, two leads for pain. The primary outcome was change from in Index between periods of and placebo stimulation recorded at the of The mean score at was and the mean changes in were for burst stimulation periods and for the placebo stimulation periods (mean difference, [95% CI, to P = significant were in secondary outcomes including (mean difference, [95% CI, to P = and (mean difference, [95% CI, to P = pain. A total of experienced adverse including requiring surgical home message: This study found no significant between burst spinal cord stimulation and spinal cord stimulation for lumbar radicular pain, the most common indication for

Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.