Key Papers from the Most Recent Literature Relevant to Anesthesiologists

Continuation versus discontinuation of renin–angiotensin system inhibitors in patients admitted to hospital with COVID-19: A prospective, randomised, open-label trial. Lancet Respir Med 2021 Jan 7 [Epub ahead of print]. PMID: 33422263.

Article Selection: Martin J. London, M.D. Image: M. Lane-Fall/Adobe Stock/Noun Project.

Article Selection: Martin J. London, M.D. Image: M. Lane-Fall/Adobe Stock/Noun Project.

Concerns have been voiced regarding the safety of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers in patients hospitalized with COVID-19 given their potential effects on tissue ACE2 expression, the receptor whereby SARS-CoV-2 enters host cells. The authors report a prospective, randomized, open-label trial at 20 hospitals in seven countries. Eligible subjects were hospitalized with COVID-19 and were receiving a renin–angiotensin system inhibitor before admission. Participants were randomly assigned (1:1) to continuation or discontinuation of their renin–angiotensin system inhibitor. The primary outcome was a global rank score across four hierarchical tiers incorporating time to death, duration of mechanical ventilation, time on renal replacement or vasopressor therapy, and multiorgan dysfunction. Between March 31 and August 20, 2020, 152 participants were randomized to either the continuation group (n = 75) or discontinuation group (n = 77). The mean age was 62 yr (SD 12), 45% were female, mean body mass index was 33 kg/m2 (SD 8), and 52% had diabetes. Medication continuation had no effect on the global rank score (median rank 73 [interquartile range, 40 to 110] for continuation versus 81 [interquartile range, 38 to 117] for discontinuation; β-coefficient 8 [95% CI, –13 to 29]). No significant differences were noted in any secondary (all-cause death, length of hospital or intensive care unit stay, sequential organ failure score) or exploratory (intensive care unit admission, invasive mechanical ventilation, hypotension requiring support) outcomes.

Take home message: This small randomized trial provides evidence consistent with international society recommendations that renin–angiotensin system inhibitors can be safely continued in patients hospitalized with COVID-19.

Effect of laparoscopic sleeve gastrectomy vs Roux-en-Y gastric bypass on weight loss and quality of life at 7 years in patients with morbid obesity: The SLEEVEPASS randomized clinical trial. JAMA Surg 2021; 156:137–46. PMID: 33295955.

Article Selection: J. David Clark, M.D., Ph.D. Image: M. Lane-Fall/Adobe Stock/Noun Project.

Article Selection: J. David Clark, M.D., Ph.D. Image: M. Lane-Fall/Adobe Stock/Noun Project.

Morbid obesity is a worldwide epidemic linked to many comorbidities. Bariatric surgery is one of the few effective treatments demonstrated, although the optimal technique has not been defined. It is not clear whether laparoscopic sleeve gastrectomy provides long-term results similar to laparoscopic Roux-en-Y gastric bypass. The authors report 7-yr follow-up results from a randomized trial comparing the two, originally involving 240 patients in Finland. Although the primary endpoint of percentage excess weight loss was greater in the Roux-en-Y group (55% [95% CI, 52 to 59%]) versus sleeve gastrectomy (47% [95% CI, 43 to 50%]), this difference was not deemed clinically relevant based on prespecified equivalence margins. Another key measure, quality of life, was greatly improved in both groups, but the results between groups were not significantly different. Importantly, greater weight loss was associated with greater improvement in quality of life. The 7-yr morbidity rates were also similar between the groups.

Take home message: Laparoscopic sleeve gastrectomy or Roux-en-Y gastric bypass appear to provide equivalent beneficial long-term impact on weight loss, quality of life, and morbidity.

Lower or higher oxygenation targets for acute hypoxemic respiratory failure. N Engl J Med 2021 Jan 20 [Epub ahead of print]. PMID: 33471452.

Article Selection: Martin J. London, M.D. Image: M. Lane-Fall/Adobe Stock.

Article Selection: Martin J. London, M.D. Image: M. Lane-Fall/Adobe Stock.

The safety of various levels of inspired oxygen therapy in patients presenting to the intensive care unit (ICU) with acute hypoxemic respiratory failure is uncertain with conflicting study data. The authors report a randomized multicenter trial (35 ICUs in Northern Europe) in 2,928 adult ICU patients (less than or equal to 12 h before randomization) requiring at least 10 l of oxygen per minute (open system) or a fraction of inspired oxygen of at least 0.50 in a closed system (mechanical or noninvasive ventilation) to receive oxygen therapy targeting a Pao2 of 60 mmHg (low) versus 90 mmHg (high) for a maximum of 90 days. The primary outcome was death within 90 days. The cohort was primarily medical ICU patients (86%), with pneumonia (57.7% vs. 57.4%); invasive ventilation was used in 57.4% vs. 59.7%, noninvasive in 13.7% vs. 12.1%, and open systems in 28.9 vs. 28.2%, respectively. There was no difference in the primary outcome (42.9% vs. 42.4%; adjusted risk ratio, 1.02 [95% CI, 0.94 to 1.11]; P = 0.64), and no significant between-group difference in patients alive without life support or in days alive after hospital discharge. The incidence of episodes of shock, myocardial ischemia, ischemic stroke, or intestinal ischemia were not different (P = 0.24).

Take home message: In adult patients admitted to the ICU for respiratory failure, randomization to a lower oxygenation target did not result in lower mortality than a higher target at 90 days.

Mortality with paclitaxel-coated devices in peripheral artery disease. N Engl J Med 2020; 383:2538–46. PMID: 33296560.

Article Selection: Martin J. London, M.D. Image: M. Lane-Fall/Adobe Stock.

Article Selection: Martin J. London, M.D. Image: M. Lane-Fall/Adobe Stock.

A 2018 meta-analysis of 28 randomized clinical trials involving 4,663 patients suggested a late mortality signal associated with the use of paclitaxel-coated angioplasty balloons and stents in lower-limb endovascular interventions for symptomatic peripheral artery disease resulting in suspension of enrollment in ongoing studies. The authors report an unplanned interim analysis of data from a multicenter, randomized, open-label, registry-based clinical trial (Swedish Drug Elution Trial in Peripheral Arterial Disease). At the time of the analysis, 2,289 patients had been randomly assigned to paclitaxel-coated devices (1,149 patients) or uncoated devices (1,140 patients). Randomization was stratified according to disease severity on the basis of whether patients had chronic limb-threatening ischemia (1,480 patients) or intermittent claudication (809 patients). The primary outcome was all-cause mortality. At a mean follow-up of 2.5 yr, mortality was not different between groups (25.5% paclitaxel vs. 24.6% uncoated; hazard ratio, 1.06 [95% CI, 0.92 to 1.22]). At 1 yr, all-cause mortality was 10.2% in the paclitaxel group and 9.9% in the uncoated group. There was no significant difference in primary outcome between the treatment groups in patients with chronic limb-threatening ischemia (33.4% paclitaxel vs. 33.1% uncoated) or in those with intermittent claudication (10.9% and 9.4%, respectively).

Take home message: An interim analysis of a large ongoing randomized clinical trial comparing use of paclitaxel-coated to uncoated endovascular devices in patients with peripheral arterial disease did not show a difference between groups in the incidence of all-cause mortality during 1 to 4 yr of follow-up, failing to confirm a recent meta-analysis suggesting greater risk with paclitaxel-coated devices.

Advanced reperfusion strategies for patients with out-of-hospital cardiac arrest and refractory ventricular fibrillation (ARREST): A phase 2, single centre, open-label, randomised controlled trial. Lancet 2020; 396:1807–16. PMID: 33197396.

Article Selection: Meghan Prin, M.D., M.S. Image: M. Lane-Fall/Adobe Stock.

Article Selection: Meghan Prin, M.D., M.S. Image: M. Lane-Fall/Adobe Stock.

More than half of patients who suffer out-of-hospital cardiac arrest associated with refractory ventricular fibrillation are refractory to advanced cardiac life support (ACLS). Extracorporeal membrane oxygenation (ECMO) has shown promise for the resuscitation of these patients in observational studies. In this phase 2, single-center, open-label, adaptive randomized clinical trial of safety and benefit, 30 patients (83% men; mean age 59 yr [range, 36 to 73 yr]) with out-of-hospital cardiac arrest and ventricular fibrillation refractory to three shocks, use of an automated cardiopulmonary resuscitation device, and estimated transfer time to the hospital of less than 30 min were assigned to either routine ACLS (n = 15) or early ECMO (n = 15) on arrival. Survival to hospital discharge (the primary outcome) was 43% (95% CI, 21 to 68%) in the ECMO group versus 7% (95% CI, 1.6 to 30%) in the ACLS group (risk difference, 36.2% [95% CI, 3.7 to 59.2]), and cumulative 6-month survival was better in the ECMO group (hazard ratio, 0.16 [95% CI, 0.06 to 0.41]). No unexpected serious adverse events occurred. The study was terminated at the first interim analysis by recommendation of the Data Safety Monitoring Board based on ECMO superiority.

Take home message: Early ECMO-assisted resuscitation for patients with out-of-hospital cardiac arrest and refractory ventricular fibrillation improved survival to hospital discharge and at 6 months compared to standard ACLS.

Effect of a lower vs higher positive end-expiratory pressure strategy on ventilator-free days in ICU patients without ARDS: A randomized clinical trial. JAMA 2020; 324:2509–20. PMID: 33295981.

Article Selection: Martin J. London, M.D. Image: M. Lane-Fall/Adobe Stock.

Article Selection: Martin J. London, M.D. Image: M. Lane-Fall/Adobe Stock.

The optimal level of positive end-expiratory pressure (PEEP) in critically ill patients without acute respiratory distress syndrome (ARDS) requiring mechanical ventilation is uncertain. The authors performed a noninferiority randomized clinical trial in eight intensive care units (ICUs) in The Netherlands, randomizing 980 patients expected not to be extubated within 24 h after intubation. Subjects were randomized to receive lower PEEP (0 to 5 cm H2O, n = 476) or higher PEEP (8 cm H2O, n = 493). The primary outcome was the number of ventilator-free days at day 28, with a noninferiority margin for the difference in ventilator-free days at day 28 of −10%. Secondary outcomes included lengths of stay, complications, and therapeutic rescue strategies. Among 980 patients who were randomized, 99% completed the trial (median age 66 yr [interquartile range, 56 to 74]; 36% female). At day 28, the lower PEEP group had a median of 18 ventilator-free days (interquartile range, 0 to 27) and the higher PEEP group a median of 17 ventilator-free days (interquartile range, 0 to 27; mean ratio, 1.04 [95% CI, 0.95 to infinity]; P = 0.007 for noninferiority). No statistically significant differences were noted in rates of severe hypoxemia, rescue strategies, 28-day mortality, or other secondary outcomes.

Take home message: In a large cohort of ICU patients requiring invasive mechanical ventilation without ARDS, a lower PEEP strategy was noninferior to a higher PEEP strategy for the number of ventilator-free days at day 28.

Effect of digoxin vs bisoprolol for heart rate control in atrial fibrillation on patient-reported quality of life: The RATE-AF randomized clinical trial. JAMA 2020; 324:2497–508. PMID: 33351042.

Article Selection: BobbieJean Sweitzer, M.D., F.A.C.P. Image: M. Lane-Fall/Adobe Stock.

Article Selection: BobbieJean Sweitzer, M.D., F.A.C.P. Image: M. Lane-Fall/Adobe Stock.

Parasympathomimetic actions of digitalis glycosides such as digoxin reduce atrioventricular nodal conduction although their safety in observational studies is debated. The authors conducted the first randomized trial in 160 adults, 60 yr or older, with atrial fibrillation and heart failure symptoms comparing digoxin (mean dose, 161 μg/d) versus bisoprolol (mean dose, 3.2 mg/d). The primary outcome was the 36-item Short Form Health Survey physical component summary (SF-36 PCS) scores at 6 months. Other outcomes included 17 secondary outcomes at 6 months (including heart rate, European Heart Rhythm Association symptom classification, and NT-proBNP concentration), 20 endpoints at 12 months, and adverse events. Quality of life was not significantly different (SF-36 PCS score 32 for the digoxin group vs. 29 in the bisoprolol group) at 6 months. European Heart Rhythm Association class was significantly different at 6 months (53% on digoxin reported a 2-class improvement vs. 9% in bisoprolol group). At 12 months, eight of the 20 outcomes were significantly different, all favoring digoxin. Adverse events were less common with digoxin.

Take home message: Low-dose digoxin therapy appears to be a well-tolerated, viable alternative in achieving heart rate control in patients with permanent atrial fibrillation who are intolerant of or do not reach therapeutic effect with beta or calcium channel blockers.

Ultra-early tranexamic acid after subarachnoid haemorrhage (ULTRA): A randomised controlled trial. Lancet 2021; 397:112–8. PMID: 33357465.

Article Selection: David Faraoni, M.D., Ph.D. Image: M. Lane-Fall/Adobe Stock.

Article Selection: David Faraoni, M.D., Ph.D. Image: M. Lane-Fall/Adobe Stock.

In patients with aneurysmal subarachnoid hemorrhage, acute administration of antifibrinolytics such as tranexamic acid is associated with a reduction in the risk of rebleeding, but effects on long-term outcome are uncertain. In this multicenter prospective, randomized, controlled, open-label trial, adult patients with spontaneous subarachnoid hemorrhage in The Netherlands were randomly assigned to receive either ultra-early tranexamic acid (n = 480) or care as usual/control without tranexamic acid (n = 475). Tranexamic acid was started immediately after diagnosis by noncontrast computed tomography imaging (ultra-early) in the presenting hospital as a 1-g bolus followed by a 1-g continuous infusion every 8 h, continued up to the time of endovascular or surgical treatment or up to 24 h (maximum 4 g total). The primary endpoint was assessed at 6 months using the modified Rankin Scale dichotomized into good or poor outcome groups. In the intent-to-treat analysis, good clinical outcome was observed in 287 (60%) of 475 tranexamic acid patients versus 300 (64%) of 470 control patients (adjusted odds ratio, 0.86 [95% CI, 0.66 to 1.12). Rebleeding after randomization and before aneurysm treatment occurred in 49 (10%) of tranexamic acid patients versus 66 (14%) control patients (odds ratio, 0.71; 95% CI, 0.48 to 1.04). Other serious adverse events were comparable between groups.

Take home message: In patients with aneurysmal subarachnoid hemorrhage, ultra-early and short-term tranexamic acid administration did not improve clinical outcome at 6 months and was comparable to standard care.

Differences in long-term outcomes after coronary artery bypass grafting using single vs multiple arterial grafts and the association with sex. JAMA Cardiol 2020 Dec 23 [Epub ahead of print]. PMID: 33355595.

Article Selection: Beatrice Beck-Schimmer, M.D. Image: M. Lane-Fall/Adobe Stock.

Article Selection: Beatrice Beck-Schimmer, M.D. Image: M. Lane-Fall/Adobe Stock.

The use of multiple arterial grafting has been associated with better outcomes compared to single arterial grafting in patients undergoing coronary artery bypass grafting (CABG). However, these data stem from studies of predominantly male patients, and the benefit of either approach in females is uncertain. This cohort study assessed these associations analyzing data from 63,402 patients from the New York State Cardiac Surgery Reporting System from January 1, 2005, to December 31, 2014. Propensity score matching created 9,512 male pairs and 1,860 female pairs. Preoperatively, females had worse baseline characteristics than males. In males, multiple arterial grafting was associated with lower mortality at 7 yr after CABG (adjusted hazard ratio, 0.80 [95% CI, 0.73 to 0.87]), whereas this was not the case in females (adjusted hazard ratio, 0.99 [95% CI, 0.84 to 1.15]). In general, across both sexes, outcomes including mortality or major adverse cardiac events were better with multiple arterial grafts in low risk (less than 10% 1-yr predicted mortality), but not in high-risk patients (greater than 10%). The percent of females in the high-risk category was greater than males (13% vs. 6%), and in sensitivity analyses the risk cutoff differed between males and females.

Take home message: The use of multiple arterial grafts for CABG is associated with better long-term outcomes compared to single arterial grafts in low-risk patients of both sexes. The observation that the risk cutoff is different suggests the need for female sex–based randomized trials.

Oxygenated versus standard cold perfusion preservation in kidney transplantation (COMPARE): A randomised, double-blind, paired, phase 3 trial. Lancet 2020; 396:1653–62. PMID: 33220737.

Article Selection: Beatrice Beck-Schimmer, M.D. Image: Adobe Stock.

Article Selection: Beatrice Beck-Schimmer, M.D. Image: Adobe Stock.

Hypothermic machine perfusion is used in kidney transplantation to preserve the donor kidney as much as possible by reducing its oxygen demand and metabolism. Hypothermic machine perfusion consists of pumping a cold preservation solution, which is usually not oxygenated, through the renal vasculature. However, studies have shown that hypothermic machine perfusion with supplemental oxygen could improve the outcome after kidney transplantation. The authors report a randomized controlled trial at 19 European centers in which kidney pairs retrieved from donors (age greater than 50 yr) after circulatory death were randomly allocated to hypothermic machine perfusion without oxygenation or hypothermic machine perfusion with oxygenation. The primary outcome was the estimated glomerular filtration rate (eGFR) at 12 months in the pairs of donated kidneys, which were successfully transplanted and functioning at the end of the study period. Of the 106 kidney pairs transplanted, and after exclusion due to kidney failure or death, 83 pairs were included in analysis. At 12 months, the eGFR was 50 ± 19 (mean ± SD) ml/min per 1.73 m2 in the hypothermic machine perfusion with oxygenation group compared to 47 ± 17 ml/min per 1.73 m2 in the hypothermic machine perfusion without oxygenation group (mean difference, 3.7; 95% CI, −1.0 to 8.4; P = 0.12). Hypothermic machine perfusion with oxygenation was associated with fewer severe complications (Clavien-Dindo grade IIIb or more) and less graft failure compared to hypothermic machine perfusion without oxygenation.

Take home message: Hypothermic machine perfusion with oxygenation was safe, associated with fewer complications and less graft failure compared to hypothermic machine perfusion without oxygenation, but renal function was not different.

Automated identification of adults at risk for in-hospital clinical deterioration. N Engl J Med 2020; 383:1951–60. PMID: 33176085.

Article Selection: Marilyn D. Michelow, M.D. Image: M. Lane-Fall/Adobe Stock.

Article Selection: Marilyn D. Michelow, M.D. Image: M. Lane-Fall/Adobe Stock.

Utilization of data in electronic health records to facilitate rapid identification of medical-surgical ward inpatients at high risk for clinical deterioration requiring transfer to higher levels of care by triggering a rapid response team intervention is increasing. In previous work, the authors instituted a predictive model, the Automated Alert Monitor score, utilizing vital signs, laboratory data, comorbidities, and severity of illness indicators from the Epic electronic health record at two hospitals in the Kaiser Permanente Northern California healthcare system. They now report results of staggered deployment across its remaining 19 hospitals (2016 to 2019). Thirty-day mortality after an alert was lower in hospitalizations where a clinical alert was triggered (15,487 hospitalizations), compared with those where an alert would have been triggered before implementation (comparison group, 28,462 hospitalizations; relative risk, 0.84 [95% CI, 0.78 to 0.90]; P < 0.001). This difference translated into 520 deaths avoided per year over the 3.5-yr study period (95% CI, 209 to 831) and was associated with lower ICU admission rates and shorter hospital lengths of stay. However, the authors did not observe any significant differences in processes of care between groups to explain the improved outcomes.

Take home message: An electronic health record–based alert system in a large integrated healthcare system was associated with improvements in mortality, ICU utilization, and lengths of stay. Precise reasons for these improvements remain to be determined.

Randomized trial of focused ultrasound subthalamotomy for Parkinson’s disease. N Engl J Med 2020; 383:2501–13. PMID: 33369354.

Article Selection: J. David Clark, M.D., Ph.D. Image: M. Lane-Fall/Adobe Stock.

Article Selection: J. David Clark, M.D., Ph.D. Image: M. Lane-Fall/Adobe Stock.

Deep brain stimulation of the subthalamic nucleus is currently the preferred neurosurgical approach for patients not controlled on medical therapy. Magnetic resonance–guided focused ultrasound ablation of deep brain structures is a newer nonsurgical alternate approach, although less data are available on its effectiveness and safety. In this randomized, double-blind controlled trial, unilateral focused ultrasound subthalamotomy performed under magnetic resonance imaging guidance at two centers (Spain, United States) was compared to a sham procedure in 40 patients with highly asymmetric disease on optimal medications who declined or were ineligible for deep-brain stimulation. Patients were randomized 2:1 (ablation:sham) using 4-month changes in the Movement Disorder Society–Unified Parkinson’s Disease Rating Scale as the primary outcome. The between-group difference at 4 months in the rating scale was 8.1 points (95% CI, 6.0 to 10.3; P < 0.001). Moreover, for the treated patients baseline rating scale scores of 19.9 decreased to 9.9 at 4 months (least-squares mean difference, 9.8 points [95% CI, 8.6 to 11.1]). Patients who crossed over to ablation treatment at 4 months demonstrated improvements similar to randomized patients. Among the 27 active treatment patients, new adverse events including dyskinesia, weakness, speech disturbances, and gait problems occurred in 12 and persisted in 3 at 4 months.

Take home message: Focused ultrasound subthalamotomy to one hemisphere in patients with Parkinson disease with highly asymmetric motor symptoms improves symptoms but is associated with a high incidence of new adverse events.