Key Papers from the Most Recent Literature Relevant to Anesthesiologists
The glucocorticoid dexamethasone is widely used for prophylaxis of postoperative nausea and vomiting. Glucocorticoids may depress immune function and cause hyperglycemia, potentially increasing the risk of surgical-site infection. This was a triple-blind (patient, anesthesiologist, assessor), pragmatic, international, noninferiority trial randomly assigning 8,880 adult patients undergoing nonurgent, noncardiac surgery (at least 2 h duration, skin incision length longer than 5 cm, overnight hospital stay), to receive 8 mg of intravenous dexamethasone or placebo intraoperatively. The primary outcome was surgical-site infection within 30 days after surgery. A total of 8,725 participants were included in the modified intention-to-treat population (4,372 in the dexamethasone group and 4,353 in the placebo group); 13% were diabetic. Of the 8,678 patients included in the primary analysis, surgical-site infection occurred in 8% randomized to dexamethasone versus 9% placebo (risk difference adjusted for diabetes status, −0.9 percentage points [95.6% CI, −2.1 to 0.3]; P < 0.001 for noninferiority). Postoperative nausea and vomiting in the first 24 h after surgery occurred in 42% of patients in the dexamethasone group versus 54% in the placebo group (risk ratio, 0.78 [95% CI, 0.75 to 0.82]).
Take home message: Dexamethasone administered intraoperatively for postoperative nausea and vomiting prophylaxis was noninferior to placebo with regards to the incidence of surgical-site infection within 30 days after nonurgent, noncardiac surgery.
Spatial mapping of SARS-CoV-2 and H1N1 lung injury identifies differential transcriptional signatures. Cell Rep Med 2021; 2:100242. PMID: 33778787.
Acute respiratory distress syndrome (ARDS) may occur after viral infection such as with influenza and most recently with SARS-CoV-2 infection. Gene expression profiles of the latter, relative to other viral infections, have not been characterized. The authors compared gene expression profiles from alveolar epithelium, pulmonary vasculature, and macrophage populations in lungs obtained at autopsy from three patients with H1N1 influenza infection, three patients with SARS-CoV-2 infection, and one patient with dual infections who died with ARDS, sampled in discrete lung regions with diffuse alveolar damage. Viral immune activation pathways dominated in the H1N1-infected (and the dual-infected patient), whereas greater markers of tissue remodeling and coagulation dominated in the SARS-CoV-2–infected lungs. Vascular tissue demonstrated greater gene expression related to tissue remodeling including extracellular matrix–related genes and proteases, which correlated with a higher deposition of collagen in the SARS-CoV-2–infected lungs compared to H1N1-infected lungs. Vascular structures in lungs from SARS-CoV-2–infected patients demonstrated greater gene expression consistent with hypercoagulability. Epithelial regions of lungs from SARS-CoV-2–infected patients demonstrated greater remodeling genes and genes associated with epithelial proliferation and squamous metaplasia of type II pneumocytes. Macrophage transcriptional analysis revealed enhanced gene expression associated with tissue remodeling as well as differential activation of innate immune signaling.
Take home message: SARS-CoV-2– and H1N1-induced ARDS show unique transcriptional signatures providing evidence for a fibroproliferative ARDS phenotype in SARS-CoV-2 compared to an exudative inflammatory phenotype in H1N1 infection.
Left atrial appendage occlusion during cardiac surgery to prevent stroke. N Engl J Med 2021; 384:2081–91. PMID: 33999547.
In patients with atrial fibrillation undergoing cardiac surgery, surgical occlusion of the left atrial appendage is thought to decrease the risk of postoperative ischemic stroke. In this multicenter study, the authors randomized patients with atrial fibrillation and a CHA2DS2-VASc score of at least 2 to undergo occlusion of the left atrial appendage during their cardiac surgery or not. Subjects, assessors, and primary care physicians were blinded to treatment. Other details of perioperative management, including anticoagulation, were per usual care. The primary outcome was the occurrence of ischemic stroke (including transient ischemic attack with positive neuroimaging) or systemic embolism. The study population included 2,379 participants in the occlusion group and 2,391 in the control group, with a mean age of 71 yr and a mean CHA2DS2-VASc score of 4.2. Approximately two thirds underwent valve surgery and one third underwent surgical ablation of atrial fibrillation. The participants were followed for a mean of 4 yr and approximately 75% were taking oral anticoagulants at 3 yr. The primary endpoint occurred in 114 participants (4.8%) in the occlusion group and in 168 (7.0%) in the control group (hazard ratio, 0.67 [95% CI, 0.53 to 0.85]; P = 0.001). Safety outcomes did not differ significantly.
Take home message: In patients with atrial fibrillation undergoing cardiac surgery, surgical occlusion of the left atrial appendage, when added to standard of care, significantly reduces the risk of ischemic stroke.
Tranexamic acid for the prevention of blood loss after cesarean delivery. N Engl J Med 2021; 384:1623–34. PMID: 33913639.
Administration of tranexamic acid has been shown to reduce death due to bleeding in women with postpartum hemorrhage after vaginal or caesarean delivery. In the present multicenter, double-blind, placebo-controlled randomized trial, women undergoing caesarean delivery were randomized to receive intravenous tranexamic acid (1 g) or placebo in addition to a uterotonic agent. The primary endpoint was postpartum hemorrhage, defined as a calculated estimated blood loss greater than 1,000 ml or requirement for erythrocyte transfusion within 2 days after delivery. Secondary outcomes included gravimetrically estimated blood loss, provider-assessed clinically significant postpartum hemorrhage, use of additional uterotonic agents, and postpartum blood transfusion. The primary outcome occurred in 556 of 2,086 women (27%) in the tranexamic acid group versus 653 of 2,067 women (32%) in the placebo group (adjusted risk ratio, 0.84 [95% CI, 0.75 to 0.94]; P = 0.003). There were no statistically significant differences in any of the secondary endpoints. Thromboembolic events in the 3 months after delivery occurred in 0.4% of the tranexamic acid group versus 0.1% in the placebo group (adjusted risk ratio, 4.01 [95% CI, 0.85 to 18.92]; P = 0.08).
Take home message: In this large prospective randomized study, the administration of 1 g tranexamic acid significantly reduced the incidence of postpartum hemorrhage without difference in transfusion or other clinical outcomes.
Sotatercept for the treatment of pulmonary arterial hypertension. N Engl J Med 2021; 384:1204–15. PMID: 33789009.
Pulmonary arterial hypertension is characterized by pulmonary vascular remodeling, high pulmonary artery pressure, and progressive right ventricular dysfunction. Despite the progress made in slowing progression of disease, the 5-yr survival rate is only 60%. Sotatercept, a novel fusion protein, binds activins and growth differentiation factors, which may restore balance between growth-promoting and growth-inhibiting signaling pathways. The PULSAR trial was a 24-week randomized, placebo-controlled, multicenter trial in which 106 adults receiving conventional therapy received either subcutaneous sotatercept (0.3 mg/kg or 0.7 mg/kg every 3 weeks) or placebo. The primary endpoint was the change from baseline to week 24 in pulmonary vascular resistance. The least-squares mean difference between the 0.3 mg/kg sotatercept group and placebo was −145.8 dyn · s · cm−5 (95% CI, −241.0 to −50.6; P = 0.003), while the least-squares mean difference between the sotatercept 0.7 mg/kg group and the placebo was −239.5 dyn · s · cm−5 (95% CI, −329.3 to −149.7; P < 0.001). The authors also reported an improvement in exercise capacity (as assessed by 6-min walk distance) and NT-proBNP concentration.
Take home message: Treatment with subcutaneous sotatercept reduced pulmonary vascular resistance and improved exercise capacity among patients with pulmonary arterial hypertension receiving conventional therapy.
High-dimensional characterization of post-acute sequalae of COVID-19. Nature 2021; 594:259–64. PMID: 33887749.
The incidence and range of persistent postacute sequelae of COVID-19 infection have not been comprehensively described. The diagnoses, medication use, and laboratory abnormalities of 73,435 nonhospitalized enrollees of the U.S. Veterans Health Administration who had survived at least 30 days after an initial COVID-19 diagnosis, were compared with 4,990,835 non–COVID-19 controls to evaluate outcomes at 6 months. Data were obtained from the Veterans Health Administration’s Corporate Data Warehouse. Beyond the first 30 days, COVID-19 patients had a 1.59-fold greater risk of death and showed larger hazard ratios for a wide spectrum of diseases, medication usage, and abnormal laboratory results. These hazard ratios were even greater in COVID-19 patients who required hospitalization and were about fivefold greater with intensive care unit admission. At 6 months, excess death was estimated at 8.39 per 1,000 COVID-19 patients. To see if these adverse outcomes could be explained as part of a nonspecific postviral syndrome, 13,654 COVID-19 patients were compared with 13,997 hospitalized influenza patients. The post–COVID-19 group had a 1.5-fold greater death rate and a substantially greater burden of illnesses, medication usage, and abnormal laboratory results for most of the disease categories.
Take home message: Veterans with a COVID-19 diagnosis suffer a substantial burden of health loss in pulmonary and other organ systems and excess mortality over a subsequent 6-month period.
Effect of high-frequency (10-kHz) spinal cord stimulation in patients with painful diabetic neuropathy: A randomized clinical trial. JAMA Neurol 2021; 78:687–98. PMID: 33818600.
Approximately 20% of patients with diabetes will develop painful diabetic neuropathy and the prevalence of such patients continues to grow. In previous observational studies, high-frequency spinal cord stimulation (10 kHz) has been shown to provide substantial pain relief without additional paresthesias in a variety of chronic pain syndromes. This prospective, multicenter, open-label randomized trial compared the effectiveness of conventional medical management alone to medical management with high-frequency spinal cord stimulation in providing pain relief to patients with painful diabetic neuropathy (at least 1 yr duration). The primary endpoint was the percentage of patients achieving 50% pain relief 3 months after initiating treatment. A total of 216 patients were randomized. At 3 months, 5 of 94 patients in the conventional medical management group and 75 of 95 patients in the high-frequency spinal cord stimulation plus medical management group were successful in meeting the primary endpoint (79%; difference, 73.6% [95% CI, 64.2 to 83.0]; P < 0.001). In those implanted with spinal cord stimulators, visual analog pain scores decreased by a mean of 76% (95% CI, 71 to 82), and improvements were stable for 6 months. Patients in the spinal cord stimulation group displayed better neurological and health-related quality of life outcomes.
Take home message: High-frequency (10 kHz) spinal cord stimulation provides substantial pain relief and improved quality of life in patients with refractory painful diabetic neuropathy relative to conventional medical therapy.
Positive allosteric modulation of the mu-opioid receptor produces analgesia with reduced side effects. Proc Natl Acad Sci USA 2021; 118:e2000017118. PMID: 33846240.
Despite troubling side effects (e.g., constipation and respiratory depression), μ-opioid receptor agonists are critically important to the practice of anesthesiology. Developing positive allosteric modulators of this receptor is attractive as the analgesic effects of endogenous opioid peptides might be augmented without enhancing side effects. Positive allosteric modulators increase an agonist’s affinity or efficacy, such as benzodiazepines that interact with γ-aminobutyric acid type A receptors. It was first observed in these studies that the positive allosteric modulator BMS-986122 potentiates Methionine-enkephalin (Met-Enk)–stimulated G protein activity in mouse brain homogenates while having no opioid receptor agonist effect on its own. Furthermore, these effects were biased toward analgesia-related G protein activation rather than side effect–related β arrestin activation. Similarly, BMS-986122 augmented Met-Enk’s effects in the periaqueductal gray matter of the brain, a major site for opioid analgesic activity. When tested in mice, BMS-986122 provided analgesia in two models of inflammatory pain (injection of carrageenan and complete Freund’s adjuvant). Additional experiments in mice showed no constipating effect, no rewarding effects, and little respiratory depression, although morphine administration caused robust responses in all three tests.
Take home message: Positive allosteric μ-opioid receptor agonists may provide opioid-level analgesia with limited side effects, thus offering a novel new approach to pain relief.
Racial disparities in the use of surgical procedures in the US. JAMA Surg 2021; 156:274–81. PMID: 33439237.
In the United States, racial disparities in healthcare exist. This case-control study using data from the National Inpatient Sample database assessed if disparities between Black and White patients undergoing surgery in the United States changed after implementation of Department of Health and Human Services initiatives in 2011 aimed at reducing disparity focusing on rates of use of nine major inpatient procedures (percutaneous coronary transluminal angioplasty, spinal fusion, coronary artery bypass grafting, carotid endarterectomy, total knee and hip arthoplasties, valve replacement, appendectomy, and colorectal resection) from 2012 to 2017. Significant disparity in utilization was observed in all procedures, although by 2017 reductions were noted in angioplasty (−20.1/100,000 persons in males, −4.2/100,000 persons in females), spinal fusion (−7.7 male, −15.0 females), carotid endarterectomy (−4.3 males, −4.6 females), appendectomy (−12.3 males, −12.2 females), and colorectal resection (−9.0 males, −12.7 females). For coronary artery bypass grafting, the disparity remained similar, but it was greater for total hip (+11.6 males, +20.8 females) and knee arthroplasty (+19.9 males, +12.0 females) and heart valve replacement (+12.4 males, +9.2 females). Disparities remained present after adjustment for U.S. census division, hospital teaching status, or insurance status, and in Medicare, Medicaid, and private insurance populations.
Take home message: Despite national initiatives starting in 2011, racial disparities in rates of major surgical utilization have persisted and worsened in one third of procedures studied.
Increased beat-to-beat variability of cerebral microcirculatory perfusion during atrial fibrillation: A near-infrared spectroscopy study. Europace 2021 Apr 13 [Epub ahead of print]. PMID: 33846732.
Atrial fibrillation is associated with cognitive decline and dementia, independent of stroke risk, but the underlying etiology is unclear. The authors investigated the beat-to-beat microcirculatory cerebral perfusion changes during atrial fibrillation and after elective cardioversion to sinus rhythm. Patients with atrial flutter were included to compare regular and irregular atrial arrhythmias. Microcirculatory perfusion was assessed using tissue hemoglobin index, a parameter of high-frequency (20 Hz) spatially resolved near-infrared spectroscopy that reflects local changes in cerebral tissue blood volume. Of 53 enrolled patients (79% male, mean age 69 yr, mean CHADS-VASc score 2.5) with atrial fibrillation (n = 39) or flutter (n = 14), signal processing was completed on 44 patients. A significant decrease in interbeat tissue hemoglobin index variability, representing both hypoperfusive and hyperperfusive events, was observed after restoration of sinus rhythm in patients with atrial fibrillation (7.41 x 10–9 to 1.94 x 10–9, P < 0.001 [right tail of distribution of signals] and 4.33 x 10–9 to 1.30 x 10–9, P = 0.047 [left tail]), but not those with atrial flutter (1.25 x 10–9 to 6.51 x 10–10, P = 0.496 [right tail] and 1.12 x 10–9 to 5.71 x 10–10, P = 0.650 [left tail]). No difference in interbeat systemic arterial blood pressure variability was found.
Take home message: Atrial fibrillation exerts detrimental effects on cerebral microperfusion that are not necessarily reflected in the systemic circulation.
Perioperative neurological evaluation and management to lower the risk of acute stroke in patients undergoing noncardiac, nonneurological surgery: A scientific statement from the American Heart Association/American Stroke Association. Circulation 2021; 143:e923–46. PMID: 33827230.
Perioperative stroke is a feared complication in patients undergoing noncardiac, non-neurological surgery. This scientific statement from the American Heart and Stroke Associations summarizes literature within the previous 10 yr based on pertinent MESH search terms covering a range of experimental designs and existing formal guidelines. Specific topics addressed include established risk factors for perioperative stroke, preoperative (including the role of preoperative carotid revascularization in patients with high-grade carotid stenosis and delaying surgery in patients with recent strokes) and intraoperative (focusing on blood pressure control, perioperative goal-directed therapy, blood transfusion, and anesthetic technique strategies to mitigate the risk of stroke), suggestions for postoperative assessments, and treatment approaches for minimizing permanent neurological dysfunction in patients who experience a perioperative stroke (including rapid recognition of strokes and the early use of intravenous thrombolysis and mechanical embolectomy in appropriate patients). Relevant summary tables are provided for the major topics. Of particular interest to anesthesiologists are recommendations for maintenance of a mean arterial pressure greater than 70 mmHg, especially in those at moderate or high risk for stroke, a transfusion threshold of 8 g/dl for high-risk patients, 8 to 9 g/dl for those with acute stroke, and avoidance of intraoperative hypocarbia.
Take home message: A comprehensive literature review with management recommendations for the perioperative neurological evaluation and management of patients to lower risk of acute stroke in patients undergoing noncardiac, non-neurological surgery is now available.
Screening for hypertension in adults: US Preventive Services Task Force reaffirmation recommendation statement. JAMA 2021; 325:1650–6. PMID: 33904861.
The U.S. Preventive Services Task Force’s latest systematic review evaluates the benefits and harms of screening for hypertension in adults and addresses the accuracy of office measurements of blood pressure for initial screening and the accuracy of various measurement methods to confirm hypertension. Hypertension, the most commonly diagnosed condition in outpatients, affects 45% of the population. This U.S. Preventive Services Task Force update recommends annual measurements for those 40 yr and older, or those at high risk such as Black persons, those with high-normal blood pressure, or overweight patients. For low-risk 18- to 39-yr-old persons, measurements can be done at 3- to 5-yr intervals. The U.S. Preventive Services Task Force found convincing evidence that screening and treatment for hypertension with office blood pressure measurements in adults substantially reduces cardiovascular events and has few major harms. The U.S. Preventive Services Task Force recommends continuing to screen for hypertension in adults with blood pressure measurements in medical offices, but before starting treatment confirmation outside of a clinical setting should be obtained. Recommended methods of measurement include ambulatory monitoring with a wearable programmed device that measures blood pressure at intervals over several hours, or home blood pressure monitoring with intermittent measurements by patients over several days.
Take home message: Using a reaffirmation deliberation evidence review process the U.S. Preventive Services Task Force reaffirmed its Grade A 2015 recommendation for hypertension screening in persons 18 yr of age and older.