Science, Medicine, and the Anesthesiologist

Key Papers from the Most Recent Literature Relevant to Anesthesiologists ACC/AHA/ASE/ASNC/HFSA/HRS/SCAI/SCCT/SCMR/STS 2024 Appropriate use criteria for multimodality imaging in cardiovascular evaluation of patients undergoing nonemergent, noncardiac surgery. J Am Coll Cardiol 2024; 84:1455–91. PMID: 39207318.Article Selection: Martin J. London, M.D. Image: Adobe Stock.This appropriate use criteria document is part of an ongoing series of documents developed by the American College of Cardiology (ACC) using standardized methodology as part of their “solution set” approach to key clinical problems faced by healthcare teams particularly with regard to the use of potentially expensive cardiac imaging and diagnostic tools. The approach involves a multidisciplinary content development group tasked with developing common clinical scenarios and an independent rating panel using a modified Delphi process to rate the use of such technologies in scenarios as appropriate, may be appropriate, or rarely appropriate. This document is the first dealing with the use of multimodality imaging and diagnostic techniques in preoperative evaluation of patients presenting for elective noncardiac surgery including echocardiographic, electrocardiographic, nuclear, computerized tomography, magnetic resonance, and angiographic approaches. A total of 182 clinical scenarios were developed and rated based on combinations of the presence or absence of prior testing data within a standardized time window of 90 to 220 days before surgery, symptom burden (ischemic, valvular, or heart failure based), functional status (metabolic equivalents), and surgical risk stratification (including a variety of noncardiac organ transplants). When available, definitions were based on existing ACC guideline documents. Take home message: This multidisciplinary appropriate use criteria document for the use of multimodality imaging in the preoperative evaluation of patients undergoing nonemergent, noncardiac surgery (affirmed by the American Society of Anesthesiologists) provides guidance to clinicians and care teams on a wide variety of commonly encountered clinical scenarios over a wide range of patient conditions and surgical procedures. Super-relaxed myosins contribute to respiratory muscle hibernation in mechanically ventilated patients. Sci Transl Med 2024; 16:eadg3894. PMID: 39083588.Article Selection: Michael Zaugg, M.D., M.B.A. Image: Adobe Stock.Mechanical ventilation is used to treat acute respiratory failure in the intensive care unit (ICU). However, 80% of ventilated patients develop respiratory weakness and one in five patients experiences difficult and prolonged weaning. There is incomplete understanding of the underlying molecular mechanisms, and no treatment is available so far. In this study, diaphragm biopsies from mechanically ventilated ICU patients (N = 54) and non-ICU patients undergoing thoracic surgery (control group; N = 27) were compared using contractile force measurements and myosin conformation studies based on x-ray diffraction. In ventilated ICU patients, the maximum force of slow-twitch and fast-twitch myofibers was approximately 50% and 30% lower, respectively. X-ray diffraction revealed that the percentage of myosin heads in the super-relaxed state, where myosin heads are not available for binding with actin, were increased by 10% in ICU patients. In silico simulations confirmed reduced contractile force with an increased population of super-relaxed myosins. Mechanistically, it was found that a hypophosphorylation of serine residues of myosin regulatory light chains contributed to the increased occurrence of super-relaxed myosins in the diaphragm (but not in other muscles) of ventilated ICU patients. This study suggests that small-molecule troponin activators might be used to restore physiologic force generation. Take home message: This observational study suggests that diaphragmatic weakness in mechanically ventilated patients is caused by super-relaxed myosins, which can be potentially reversed by pharmacologic means using troponin activators. Risk of adverse outcomes during gabapentinoid therapy and factors associated with increased risk in UK primary care using the clinical practice research datalink: A cohort study. Pain 2024; 165:2282–90. PMID: 38662459.Article Selection: Steven P. Cohen, M.D. Image: J. P. Rathmell.There is growing evidence for the misuse of gabapentinoids such that pregabalin is considered a controlled substance in the United States, and gabapentin is controlled in a handful of states as well as several other countries. To better understand the risks associated with gabapentinoid use, a matched cohort study was performed in primary care patients prescribed gabapentin or pregabalin between 1997 and 2018 using the United Kingdom Clinical Practice Research Datalink, comparing adverse event rates to an unexposed cohort matched for age, sex, general practice, and follow-up period. A total of 391,655 and 226,685 patients were prescribed gabapentin and pregabalin, respectively, and matched to a control cohort. It was found that substance misuse was similarly common for gabapentin and pregabalin (adjusted hazard ratio for pregabalin, 3.32 [3.12 to 3.52]), but the likelihood of overdose was greater for pregabalin (8.71 [7.51 to 10.11] versus 4.96 [4.33 to 5.67]. The risk of major trauma from 2.5 to 10 yr was also higher in exposed patients (1.73 [1.56 to 1.95]), increasing with older age, male sex, and those living in less-deprived neighborhoods. All adverse events were more common in smokers, those with a psychiatric history including substance misuse, patients with a lower body mass index (nonobese), and those prescribed opioids, benzodiazepines, antidepressants, or hypnotics. Take home message: This large observational cohort study highlights the risks of prescribing gabapentinoids and the need to educate patients and prescribers but also warrants follow-up studies comparing the risks of gabapentinoids to alternative medications. Risk assessment with gene expression markers in sepsis development. Cell Rep Med 2024; 5:101712. PMID: 39232497.Article Selection: Charles Emala, M.D. Image: Adobe Stock.Sepsis is associated with high morbidity and mortality with limited improvements in clinical outcomes over recent decades. Although demographic and laboratory preoperative risk factors have been identified for predicting the risk of developing postoperative sepsis, the genetic underpinnings of these risk factors are poorly understood. In the present study, preoperative blood samples from 267 patients undergoing major elective surgery were subjected to whole-blood RNA sequencing in an attempt to identify preoperative transcriptomic signatures that predict the risk of developing sepsis compared to an infection without sepsis or an uncomplicated postoperative course. Machine learning approaches using the RNA-sequenced data identified 776 differentially expressed genes that predicted postoperative sepsis with high accuracy. Large sex differences existed such that 421 genes were unique to male patients and 271 genes unique to female patients with 72 genes common to both sexes. Network analysis identified the predominant molecular pathways regulated by these genes, which included genes involved in cellular defense, T-cell activation, epithelial cell adhesion, and taste receptor activity. Confirmation of the RNA-sequenced results were performed using reverse transcriptase-quantitative polymerase chain reaction from 72 genes from 77 patients, which revealed concordance between predictive genes using these two RNA identification approaches in whole human blood. Take home message: Preoperative transcriptome analysis of blood samples of patients undergoing major elective surgery may allow for predictive risk assessment for the subsequent development of sepsis in the postoperative period. Important differences between male and female patients were demonstrated in the panel of genes identified in preoperative samples that predicted postoperative sepsis. Tranexamic acid in patients undergoing liver resection: The HeLiX randomized clinical trial. JAMA 2024; 332:1080–9. PMID: 39158894.Article Selection: Beatrice Beck-Schimmer, M.D. Image: J. P. Rathmell.Liver resection for a cancer-related indication may lead to red blood cell transfusion, which is correlated to a higher postoperative morbidity and mortality. Tranexamic acid was shown to reduce the probability of receiving blood transfusions during surgical procedures. However, evidence is missing for liver resection, particularly for cancer patients at higher risk for thromboembolic events. This multicenter randomized clinical trial was designed to evaluate whether tranexamic acid reduces the need of red blood cell transfusion up to 7 days after liver resection (primary outcome). This two-arm study intervention (N = 1,245 patients, mean age 63 yr, 40% female) with 1 g tranexamic acid bolus followed by a 1-g infusion over 8 h or placebo was performed at 10 Canadian centers and 1 U.S. center (December 2014 to November 2022). No difference was noted in the primary outcome: 16.3% in the tranexamic acid group (total N = 619) versus 14.5% in the placebo group (total N = 626) (odds ratio, 1.15 [95% CI, 0.84 to 1.56]; P = 0.38). The major complication rate (Clavien-Dindo grade III or higher) within 90 days was higher in the tranexamic acid group (odds ratio, 1.42 [95% CI, 1.03 to 1.95]; P = 0.03), although no difference was found for venous thromboembolic events (odds ratio, 1.68 [95% CI, 0.95 to 3.07]; P = 0.08). Take home message: This multicenter randomized clinical trial demonstrates that use of tranexamic acid during liver resection in cancer patients did not reduce red blood transfusion requirements and increased perioperative complications, suggesting that its use should be carefully considered. Propofol disrupts the functional core-matrix architecture of the thalamus in humans. Nat Comm 2024; 15:7496. PMID: 39251579.Article Selection: Jamie Sleigh, M.D. Image: J. P. Rathmell.Based on conventional anatomic definitions of thalamic nuclei, previous neuroimaging studies have investigated how the thalamocortical system may mediate changes in consciousness caused by anesthetic drugs. An alternative approach is to define the functional framework of the thalamus as broadly consisting of two classes of cells. Core cells predominate in the specific nuclei of the posterior thalamus; they are involved in sensory relays, project to middle layers of unimodal cortical regions, and are marked by the presence of parvalbumin-expressing neurons. In contrast, matrix cells predominate in nonspecific medial and anterior thalamic nuclei; they project to the superficial layer of transmodal (association) cortical regions and contain calbindin neurons. Functional gradient mapping is a way of simplifying the description of the functional connectivity of the brain, based on whether the particular region of the brain has a predominance of integrative, transmodal functions. In 53 subjects receiving progressively increasing propofol infusions until loss of responsiveness, an overall decrease in thalamic functional connectivity was seen. More importantly, there was a shift from a balance between unimodal and transmodal thalamic connectivity pattern in the wakeful state to a thalamic pattern characterized by a profound suppression of transmodal functional connectivity, when the subject was unresponsive. Take home message: Anesthetic-induced loss of consciousness is associated with a loss of thalamic matrix cell functional connectivity, and hence impaired transmodal, association-cortex functions. Immunological memory diversity in the human upper airway. Nature 2024; 632:630–6. PMID: 39085605.Article Selection: William G. Tharp, M.D., Ph.D. Image: J. P. Rathmell.The upper respiratory tract is a primary site of infection, but immunologic memory in the airway is poorly understood. In this single-site, longitudinal cohort study, flow cytometry, single-cell sequencing, and transcriptomic techniques were used to define native upper airway immune populations and adaptive responses to SARS-CoV-2 infection. In a cohort of 20 healthy adults, immune cell populations were characterized from monthly nasal swabs for 1 yr (August 2021 to January 2023). The resident memory T- and B-lymphocyte populations identified remained stable over the year and were not detected in blood. In nasal swabs from a cohort of 177 adults with or without SARS-CoV-2 infection in the previous month (August 2021 to February 2024), virus-specific resident memory B-lymphocytes were present along with primed, IgA+ B-lymphocytes during breakthrough infections. Subsequent to infection, resident memory T-lymphocyte and multiple virus-specific T-lymphocyte populations were identified in nasal tissues, none of which were detected in the blood. Resident and virus-specific immune cells demonstrated transcriptional signatures of longevity. Take home message: This observational cohort study used state-of-the-art cellular analyses to document the presence and long-term persistence of resident memory and virus-specific immune cell populations in the upper airway mucosa after SARS-CoV-2 infection. Potassium supplementation and prevention of atrial fibrillation after cardiac surgery: The TIGHT K randomized clinical trial. JAMA 2024; 332:979–88. PMID: 39215972.Article Selection: Martin J. London, M.D. Image: J. P. Rathmell.Intravenous potassium supplementation to maintain high-normal serum concentrations after cardiac surgery is a commonly used clinical strategy to prevent atrial fibrillation, although it has risks, incurs additional costs, and has a limited evidence base. This open-label, noninferiority clinical trial (23 sites in the United Kingdom and Germany) randomized 1,690 patients (mean age, 65 yr; 85% male) with no history of atrial dysrhythmias undergoing isolated coronary artery bypass grafting surgery (CABG) to either tight (serum potassium 4.5 mEq/l and higher; N = 837) or relaxed potassium control (serum potassium 3.6 mEq/l and higher; N = 830). The primary outcome was clinically detected and electrocardiographically confirmed new-onset atrial fibrillation in the first 120 h after CABG surgery or until hospital discharge, whichever occurred first. The noninferiority criteria of relaxed potassium control was a risk difference for the primary outcome with associated upper bound of a one-sided 97.5% CI of less than 10%. Secondary outcomes included other heart rhythm–related events, clinical outcomes, and cost related to the intervention. With regard to the primary endpoint, tight supplementation was noninferior to a relaxed strategy (26.2% vs. 27.8%, respectively; risk difference, 1.7% [95% CI, −2.6 to 5.9%]). No differences were noted in secondary outcomes except for per-patient cost for purchasing, and administering potassium was significantly lower in the relaxed group. Take home message: This large, multicenter, randomized trial found that tight control of serum potassium levels in the first 120 h after isolated CABG was noninferior to a relaxed strategy with respect to new-onset postoperative atrial fibrillation. Invasive treatment strategy for older patients with myocardial infarction. N Engl J Med. 2024; 391:1673–84. PMID: 39225274.Article Selection: BobbieJean Sweitzer, M.D. Image: Adobe Stock.It is unclear whether medical therapy alone or medical therapy plus intervention is better in older adults with non–ST-segment elevation myocardial infarction (NSTEMI). This prospective, multicenter trial at 48 sites in the United Kingdom randomized 1,518 patients (mean age, 82 yr; female 45%, frailty 32%) 75 yr or older with NSTEMI to optimal medical therapy (N = 765) or coronary angiography and revascularization plus medical therapy (N = 753). The primary outcome was a composite of death from cardiovascular causes or nonfatal myocardial infarction. Over a median follow-up of 4.1 yr, there was no difference in the primary outcome between groups (25.6% in the interventional-strategy group vs. 26.3% in the medical-strategy group; hazard ratio, 0.94; 95% CI, 0.77 to 1.14; P = 0.53). Within the composite outcome, there was no difference in cardiovascular death (15.8% vs. 14.2%, respectively; hazard ratio, 1.11; 95% CI, 0.86 to 1.44), although nonfatal myocardial infarction was lower (11.7% vs. 15.0%, respectively; hazard ratio, 0.75; 95% CI, 0.57 to 0.99). Procedural complications were rare, occurring in less than 1% of patients. Take home message: This multicenter, randomized trial of older patients with NSTEMI found no benefit of coronary angiography and revascularization with medical management compared to medical management alone on a composite outcome of death from cardiovascular causes or nonfatal myocardial infarction over a median follow-up of 4.1 yr.

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