Science, Medicine, and the Anesthesiologist

In this Lancet Commission report, experts from the United States and Canada created recommendations to help address the opioid crisis. Many of the recommendations are supported by empirical data in a review of the vast literature. A list of recommendations broken into seven domains was created with detailed reviews for each: (1) description of the United States and Canada as a case study for multisystem regulatory failure due to industry influence of prescribers, regulators, and political processes; (2) dual nature of opioids as both a benefit and a risk to health needs to be considered to ensure opioid stewardship while allowing for treatment of pain; (3) integrated and enduring systems for education and care of substance use disorder should be developed and supported permanently; (4) changes should be made to the criminal justice system’s involvement with opioids (addiction services during and after jail; ending penalties); (5) healthy environments need to be created to decrease incidence of addiction (drug disposal, youth prevention programs); (6) stimulate innovation in response to addiction (new molecules to treat pain; policies for patent law and marketing incentives; disrupt fentanyl transactions); (7) prevent opioid crises beyond the United States and Canada.

Take home message: A Lancet Commission report presents a detailed evaluation of factors leading to opioid crisis in North America and proposes solutions domestically and efforts to stop its spread internationally.

Although moderate intraoperative hypothermia has been associated with adverse outcomes, the degree to which body temperature should be maintained remains controversial. This study reports a multicenter (12 sites in China, 1 in the United States), parallel group superiority trial, randomly assigning patients to receive either aggressive warming (core temperature 37°C; aggressive group) or routine management (35.5°C; routine group) during general anesthesia for noncardiac surgery. Patients (aged 45 yr and older) had at least one cardiovascular risk factor. The primary outcome was a composite of myocardial injury (troponin elevation), nonfatal cardiac arrest, and 30-day all-cause mortality. A total of 5,013 subjects were included in the intention-to-treat population. Patients assigned to aggressive warming had a mean final intraoperative core temperature of 37.1°C (SD, 0.3), whereas the routine thermal management group averaged 35.6°C (SD, 0.3). No statistically significant difference was noted for the primary outcome between groups (9.9% aggressive vs. 9.6% routine; common effect relative risk, 1.04; 95% CI, 0.87 to 1.24; P = 0.69). Of 47 serious adverse events in both groups, only one in the aggressive group was considerably possibly related to the protocol.

Take home message: A large, multicenter, randomized trial found no significant difference in key perioperative outcomes at 30 days when patients were maintained at either 35.5°C or 37°C during surgery.

Up to 75% of people worldwide suffer low back pain in their lifetime, and many turn to yoga for relief. Studies support this option, but a 2016 Cochrane Review reported the evidence to be low to moderate quality. This article presents a meta-analysis utilizing more recent data, considering 27 randomized controlled trials conducted between 2004 and 2021. Studies compared yoga with a passive (e.g., waitlist) or active (e.g., exercise) comparator among 2,702 participants with low back pain. All trials reported pain intensity or pain-related disability as a primary outcome. The minimal clinically important difference was defined as a mean difference –1.50 points or less. Yoga was associated with statistically significant, but clinically unimportant, lower short-term (mean difference [MD], –0.74 points; 95% CI, –1.04 to –0.44; standardized mean difference [SMD], –0.37; 95% CI, –0.52 to –0.22) and long-term pain (MD, –0.58; 95% CI, –0.94 to 0.22) compared to passive controls. It had no effect when compared to exercise. Yoga was associated with statistical but clinically unimportant lessening of short-term (MD, –2.28; 95% CI, –3.30 to –1.26; SMD, –0.38; 95% CI, –0.55 to –0.21) and long-term (MD, –2.34; 95% CI, –3.30 to –1.38) pain-related disability compared to passive controls. Compared to exercise, it was associated with a clinically unimportant lower rate of short-term disability and had no effect on long-term disability.

Take home message: While yoga was associated with statistically significantly less short- and long-term pain intensity and disability related to lower back pain when compared to a passive control group, these results did not meet the minimal clinically important difference. Comparing yoga to active control groups showed no difference or failed to meet clinical importance.

Although the clinical benefit of tranexamic acid in reducing bleeding and transfusion requirements has been previously demonstrated, the risk of cardiovascular complications associated with tranexamic use in noncardiac surgery has not been studied. In the 2 × 2 factorial POISE-3 study, 9,535 patients undergoing noncardiac surgery at 114 hospitals in 22 countries who were at risk for bleeding and cardiovascular events were randomized to receive either tranexamic acid (1-g bolus at the start and end of surgery) or a placebo. A hypotension avoidance strategy was the other randomized arm. The objective was to assess whether tranexamic would result in a lower incidence of life-threatening bleeding, major bleeding, or bleeding into a critical organ than placebo (clinical endpoint) without increasing the incidence of major cardiovascular complications within 30 days (noninferiority safety endpoint). The composite bleeding outcome event was significantly lower in the tranexamic acid group (9.1% vs. 11.7%; hazard ratio, 0.76; 95% CI, 0.67 to 0.87; two-sided P < 0.001 for superiority). A composite cardiovascular outcome event occurred in 14.2% versus 13.9%, respectively (hazard ratio, 1.02; 95% CI, 0.92 to 1.14; one-sided P = 0.04 for noninferiority).

Take home message: Among patients undergoing noncardiac surgery, a 1-g tranexamic acid bolus at the start and end of surgery resulted in a lower incidence of the composite bleeding outcome. The between-group difference in the composite cardiovascular outcome was small, and noninferiority of tranexamic acid was not established.

It is unknown whether the benefits of aspirin and heparin use during endovascular treatment of stroke outweigh risks of symptomatic intracranial hemorrhage. This study reports an open-label, multicenter, randomized controlled trial with a 2 × 3 factorial design (15 Netherlands centers). Six hundred twenty-eight adult patients with large-vessel ischemic stroke were randomized and analyzed to receive either periprocedural intravenous aspirin (1:1; 300-mg bolus) or no aspirin, and randomly assigned (1:1:1) to receive moderate-dose unfractionated heparin (UFH) (5,000-IU bolus followed by 1,250 IU/h for 6 h), low-dose UFH (5,000-IU bolus followed by 500 IU/h for 6 h), or no UFH. The primary outcome was the score on the modified Rankin Scale (0 = no deficit, 6 = death) at 90 days. Symptomatic intracranial hemorrhage was the main safety outcome. The trial was prematurely stopped over safety concerns. The risk of symptomatic intracranial hemorrhage was higher in patients allocated to receive aspirin (14% vs. 7% [no aspirin]; adjusted odds ratio, 1.95 [95% CI, 1.13 to 3.35]) and those receiving UFH (13% vs. 7% [no UFH]; 1.98 [1.14 to 3.46]). Neither aspirin (adjusted odds ratio, 0.91 [95% CI, 0.69 to 1.21]) nor UFH (0.81 [0.61 to 1.08]) were significantly associated with modified Rankin Scale scores.

Take home message: Intravenous aspirin and heparin administration during endovascular stroke treatment are associated with significantly greater risk of symptomatic intracranial hemorrhage without beneficial effect on functional outcome, suggesting that avoidance of routine treatment may be warranted.

The association of SARS-CoV-2 infection with the risk of serious obstetric morbidity is uncertain. This article reports a retrospective cohort study of 14,104 pregnant and postpartum patients undergoing delivery between March 2020 and December 2020 at 17 U.S. hospitals. SARS-CoV-2–positive (nucleic acid or antigen test) patients were compared to negative patients who delivered on randomly selected dates. The primary outcome was a composite of maternal death or serious morbidity related to hypertensive disorders of pregnancy, postpartum hemorrhage, or other infections. The main secondary outcome was cesarean birth. SARS-CoV-2 infection was noted in 16.6% of 14,104 subjects (mean age, 30 yr) and was significantly associated with the primary outcome (13.4% vs. 9.2%; difference, 4.2% [95% CI, 2.8 to 5.6%]; adjusted relative risk [aRR], 1.41 [95% CI, 1.23 to 1.61]) with five maternal deaths occurring in the SARS-CoV-2 group. It was not significantly associated with cesarean birth (34.7% vs. 32.4%; aRR, 1.05 [95% CI, 0.99 to 1.11]). Moderate or higher COVID-19 severity (n = 586) was significantly associated with the primary outcome (26.1% vs. 9.2%; difference, 16.9% [95% CI, 13.3 to 20.4%]; aRR, 2.06 [95% CI, 1.73 to 2.46]) and cesarean birth (45.4% vs. 32.4%; difference, 12.8% [95% CI, 8.7 to 16.8%]; aRR, 1.17 [95% CI, 1.07 to 1.28]), whereas mild or asymptomatic infection (n = 1766) was not.

Take home message: In a large, retrospective cohort of pregnant and postpartum individuals, SARS-CoV-2 infection was associated with greater risk for a composite outcome of maternal mortality or serious morbidity from obstetric complications.

Electrocardiographic markers of atrial dysfunction have been associated with dementia, although more sensitive and specific measures of left atrial function and size measured on two-dimensional transthoracic echocardiography have not. Using a large U.S.-based, community-based prospective cohort (The Atherosclerosis Risk in Communities [ARIC] study), this exploratory, retrospective analysis included 4,096 enrollees (mean ± SD age, 75 ± 5 yr; 60% female) without prior atrial fibrillation or stroke who underwent two-dimensional transthoracic echocardiography, evaluating measures of left atrial function and size, in 2011 to 2013 followed through the end of 2019. Dementia occurred in 13% of the cohort. After risk factor adjustment, significant associations between the measures of left atrial function and dementia were noted (presented as hazard ratios between the lowest vs. highest quintile): for reservoir strain, 1.98 (95% CI, 1.42 to 2.75); conduit strain, 1.50 (95% CI, 1.09 to 2.06); contractile strain, 1.57 (95% CI, 1.16 to 2.14); emptying fraction, 1.87 (95% CI, 1.31 to 2.65); and active emptying fraction, 1.43 (95% CI, 1.04 to 1.96). Neither left atrial passive emptying fraction (hazard ratio, 1.26 [95% CI, 0.93 to 1.71]) nor measures of atrial size (maximal or minimal volume index) were significantly associated with dementia. Findings were robust to sensitivity analyses excluding participants with incident atrial fibrillation or stroke.

Take home message: In a large, exploratory analysis of a community-based cohort, several echocardiographic measures of impaired left atrial function were significantly associated with a greater risk of subsequent dementia.

Definitions for myocardial infarction and myocardial injury after cardiac surgery vary widely and are based on limited clinical data. To better delineate reference ranges, a prospective cohort study (24 centers in 12 countries) was performed in adults undergoing coronary artery bypass assessing high-sensitivity cardiac troponin I concentrations (upper reference limit, 26 ng/l) at 3 to 12 h after surgery and on postoperative days 1, 2, and 3. Associations between peak troponin measurements and the primary outcome, 30-day mortality (adjusted for the European System for Cardiac Operative Risk Evaluation II score) were analyzed. The primary outcome occurred in 2.1% of the 13,862 enrolled patients. In patients undergoing isolated coronary artery bypass grafting or aortic valve replacement or repair, the threshold troponin concentration (within 1 day after surgery) associated with an adjusted hazard ratio of more than 1.00 for the primary outcome was 5,670 ng/l (95% CI, 1,045 to 8,260), which is 218 times the current upper reference limit. Among patients undergoing all types of cardiac surgery, the threshold troponin concentration was 12,981 ng/l (95% CI, 2,673 to 16,591), which is 499 times the upper reference limit.

Take home message: High-sensitivity troponin I concentrations measured shortly after cardiac surgery that are associated with a greater risk of death within 30 days are substantially higher than concentrations currently used to define periprocedural myocardial injury.

Specialized vasculature constitutes the blood-brain barrier (BBB) excluding cellular and plasma contents from the inner central nervous system environment. Therapies aiming at restoring the BBB, following disruption by neurodegeneration, trauma, stroke, or brain tumors, would be of great benefit. In this study, a molecular approach was used by targeting the Wnt signaling pathway, which is key in the maintenance of the BBB. A unique feature of the BBB was exploited, namely its need to engage the Gpr124 (G protein–coupled receptor 124)/Reck (reversion-inducing cysteine-rich protein with Kazal motifs) membrane complex to bind to Wnt7a, in order to trigger Wnt signaling. A single amino acid mutation (K190A) in Wnt7a caused this ligand to bind exclusively in the presence of the Gpr124/Reck complex conferring Wnt signaling specificity to BBB endothelial cells. Wnt7a-K190A introduced by gene editing (zebrafish models) or adeno-associated virus (mouse models) improved outcomes of BBB pathology caused by stroke and tumor growth by reducing bleeding and inhibiting detrimental immune cell infiltration. In vivo experiments also showed that Wnt7a-K190A is a BBB-specific Wnt signaling agonist with no off-target activity, i.e., no activation of Wnt signaling in other cells or elsewhere in the vascular system.

Take home message: Wnt signaling can be modulated to specifically target the BBB with the aim at restoring it. Such strategies have a great potential in many brain pathologies where a dysfunctional BBB plays a critical role.

The medical benefit of sublingual dexmedetomidine in treating acute agitation in patients with bipolar disorder is unclear. This multicenter (15 U.S. sites), randomized, double-blind, placebo-controlled trial enrolled 380 adults (mean age, 46 yr; 55% female) with bipolar disorder and acute agitation (as measured using the Positive and Negative Syndrome Scale-Excited Component score; range, 5 [no agitation] to 35 [very severe]) receiving either placebo or 120 µg or 180 µg dexmedetomidine sublingually. At baseline, moderate agitation was present (mean ± SD score, 18.0 ± 2.9), and treatment effects were noted after 20 min. The mean decrease in agitation score 2 h after treatment were −10.4 ± 4.4 for the 180-µg dose, −9.0 ± 5.3 for the 120-µg dose, and −4.9 ± 4.7 for placebo. Both doses of dexmedetomidine were significantly better than placebo at 2 h. Mean differences were −5.4 (97.5% CI, −6.6 to −4.2) for 180 µg and −4.1 (97.5% CI, −5.3 to −2.9) for 120 µg (both doses, P < 0.001). Although no treatment-related serious or severe adverse events were reported, dexmedetomidine resulted in more somnolence (21.4% and 20.6% vs. 4.8%), dry mouth (4.8% and 7.1% vs. 0.8%), hypotension (6.3% and 4.8% vs. 0%), dizziness (5.6% and 5.6% vs. 0.8%), and bradycardia (2.4% vs. 1.6% vs. 0%).

Take home message: Doses of 120 µg or 180 µg sublingual dexmedetomidine were effective for lessening acute agitation in patients with bipolar disorder compared to placebo, but side effects were prominent.

Recent studies suggest equipoise between functional testing for coronary artery disease (CAD) in patients with chest pain and computed tomography (CT). Limited data suggest CT’s equivalence with invasive coronary angiography. This article reports a pragmatic randomized superiority trial of CT versus invasive coronary angiography in patients with stable chest pain and an intermediate pretest probability of CAD referred for diagnostic imaging at 26 European centers. The primary outcome was major adverse cardiovascular events (cardiovascular death, myocardial infarction, and stroke) over 3.5 yr. Secondary outcomes were procedure-related complications and angina pectoris. Of 3,561 subjects included in the modified intent-to-treat analysis (56% female, median age, 61 yr), there was no difference in the primary outcome (2.1% CT vs. 3.0% invasive coronary angiography; hazard ratio, 0.70; 95% CI, 0.46 to 1.07; P = 0.10). Results were similar between prespecified subgroups and overall were lower than expected. Procedure-related complications were lower in the CT group (0.5% vs. 1.9%; hazard ratio, 0.26; 95% CI, 0.13 to 0.55). During the final 4 weeks of follow-up, there were no differences in the rates of reported angina (8.8% CT vs. 7.5% invasive coronary angiography; odds ratio, 1.17; 95% CI, 0.92 to 1.48).

Take home message: In this multicenter trial of patients with stable chest pain and intermediate pretest probability for CAD, rates of major adverse cardiovascular events were not different between an initial CT or invasive angiographic strategy with lower procedural complication rates after CT.

Ketamine infusions are increasingly used for chronic pain with a dearth of long-term follow-up data. In this prospective cohort study (30 French pain clinics), 256 patients receiving ketamine infusions over 12 months were followed. Infusion protocols were not standardized (single or a series of treatments), but the mean cumulative total dose was 207 ± 115 mg, with those receiving higher doses experiencing greater pain reductions (median dose, 222 mg with a mild pain trajectory vs. 210 mg with a severe trajectory). The mean 0–10 pain score decreased from 6.8 ± 1.8 at baseline to 5.7 ± 1.9 at 1 week after ketamine, 5.7 ± 2.0 at 6 months, and 5.7 ± 1.8 at 12 months (n = 167). Thirty-eight percent of patients were depressed at baseline, and 46% had anxiety. The Hospital Anxiety & Depression Scale depression subscale decreased from 9.2 ± 4.5 at baseline to 8.3 ± 4.6 at 1 week, 7.5 ± 4.4 at 6 months, and 7.2 ± 4.7 at 12 months. Similar reductions were noted for anxiety. Younger male patients without fibromyalgia were more likely to have a mild pain trajectory (greater improvement), while older female patients with fibromyalgia were more likely to experience a severe pain trajectory.

Take home message: Ketamine infusions may provide modest relief of chronic pain, with individuals with more diffuse pain and those with higher baseline depression and anxiety experiencing worse pain trajectories.