Science, Medicine, and the Anesthesiologist

Key Papers from the Most Recent Literature Relevant to Anesthesiologists Acetaminophen for prevention and treatment of organ dysfunction in critically ill patients with sepsis: The ASTER randomized clinical trial. JAMA 2024; 332:390–400. PMID: 38762798.Article Selection: Beatrice Beck-Schimmer, M.D. Image: J. P. Rathmell.The majority of critically ill patients present with increased cell-free hemoglobin levels, inducing lipid peroxidation that is associated with organ dysfunction and death. In various studies including phase 2a trials, acetaminophen reduced oxidative stress and improved organ function. This phase 2b randomized, double-blind, placebo-controlled clinical trial was performed to evaluate whether acetaminophen increases survival and improves organ dysfunction in a larger cohort of sepsis patients. Between October 2021 and April 2023, 447 adult patients (51% female; mean age, 64 yr; mean Sequential Organ Failure Assessment score, 5.4) at 40 U.S. academic hospitals with sepsis and either respiratory or circulatory organ dysfunction were randomized to either intravenous acetaminophen 1 g every 6 h (n = 227) or placebo (n = 220) over 5 days. The primary outcome was days alive and free of organ support (assisted ventilation, vasopressors, and dialysis) through day 28. There was no difference in the primary outcome between groups days alive and free of organ support to day 28 (20.2 days; 95% CI, 18.8 to 21.6) versus placebo (19.6 days; 95% CI, 18.2 to 21.0; P = 0.56; difference, 0.6; 95% CI, –1.4 to 2.6). A significant interaction between cell-free hemoglobin and acetaminophen was not found. Take home message: This multicenter, randomized, double-blind, placebo-controlled phase 2b clinical trial comparing intravenous acetaminophen over 5 days versus placebo in critically ill patients with sepsis with either respiratory or circulatory organ dysfunction did not show any improvement in days alive and free of organ support to day 28. Effectiveness and cost-effectiveness of an individualised, progressive walking and education intervention for the prevention of low back pain recurrence in Australia (WalkBack): A randomised controlled trial. Lancet 2024; 404:134–44. PMID: 38908392.Article Selection: Steven P. Cohen, M.D. Image: Adobe Stock.Low back pain is the leading cause of global disability, with few reliable treatments. Although there is some literature showing that exercise and education may prevent back pain, programs evaluated tend to be group based and labor and cost intensive. In this study, 701 sedentary Australians randomized (81% female) with an episode of nonspecific low back pain within 6 months to a physical therapist–supervised progressive walking and education program consisting of pain education, reduction of fear-avoidance, and simple steps to prevent recurrence, or to no treatment. Trained physiotherapists provided six sessions over the study course to confirm adherence via accelerometers, track engagement, and adjust the walking program. Over the 12-to 36-month follow-up, the protocol reduced the number of activity-limiting low back pain compared to the no-treatment group (hazard ratio, 0.72 [95% CI, 0.60 to 0.85]; P = 0.0002). The median days to recurrence, the primary outcome measure, was 208 days (95% CI, 149 to 295) in the intervention group versus 112 days (89 to 140) in the control group. The incremental cost per quality-of-life year gained was AU $7,802 (U.S. $5,204), significantly lower than the AU $28,000 willingness-to-pay threshold. In the exercise group, there was a higher number of adverse events affecting the lower extremities (100 vs. 54). Take home message: A supervised light exercise program in conjunction with education prevented the recurrence of nonspecific low back pain for up to 3 yr. Future research should determine whether fewer (or no) supervisory sessions, or different supervisors, can achieve similar results. Tirzepatide for the treatment of obstructive sleep apnea and obesity. N Engl J Med 2024 [Epub ahead of print June 21]. PMID: 38912654.Article Selection: William G. Tharp, M.D., Ph.D. Image: Adobe Stock.Obstructive sleep apnea disrupts breathing during sleep and leads to intermittent hypoxemia and increased cardiovascular disease risk. Obesity is a reversible risk factor for obstructive sleep apnea. Glucagon-like peptide-1 receptor agonists such as tirzepatide are effective treatments for obesity and associated comorbidities. This industry-sponsored, international, multicenter, double-blinded, placebo-controlled trial randomized 469 obese, nondiabetic subjects (106 female/363 male; 49.8 ± 11.5 yr) to treatment with either tirzepatide (10 or 15 mg; n = 234) or placebo (n = 235) for 52 weeks to evaluate effects on obstructive sleep apnea symptoms. All subjects received positive airway pressure therapy. The primary outcome was change in the apnea–hypopnea index from baseline. A key secondary outcome was change in body weight. After 52 weeks, the apnea–hypopnea index decreased from 51.5 events/h by –27.3 (95% CI, –32.3 to –23.3) with tirzepatide versus –5.4 (95% CI, –9.7 to –1.2) with placebo. Subjects given tirzepatide lost more body weight (–18.6%; 95% CI, –20.0 to –17.3) than those given placebo (–2.0%; 95% CI, –3.4 to –0.6) but experienced more mild-to-moderate gastrointestinal side effects. Take home message: In this randomized controlled trial of obese, nondiabetic subjects with obstructive sleep apnea maintained on chronic positive airway pressure therapy, tirzepatide led to clinically meaningful decreases in obstructive sleep apnea symptoms and body weight versus placebo. A randomized trial of intravenous amino acids for kidney protection. N Engl J Med 2024; 391:687–98. PMID: 38865168.Article Selection: Martin J. London, M.D. Image: J. P. Rathmell.Acute kidney injury (AKI) is common after cardiac surgery and may have long-term consequences with renal hypoperfusion a postulated mechanism. Intravenous amino acid infusion in animal and small human pilot studies has been suggested to enhance perfusion and recruit renal reserve. This multinational (22 centers in Italy, Croatia, and Singapore), double-blind trial randomized 3,511 adult patients undergoing cardiac surgery (2019 to 2024) with cardiopulmonary bypass to intravenous infusion of either a balanced mixture of amino acids (n = 1,759) (2 g/kg ideal body weight per day) or placebo (n = 1,752) for up to 3 days. The primary outcome was AKI, defined according to the Kidney Disease: Improving Global Outcomes creatinine criteria. Secondary outcomes included AKI severity, kidney-replacement therapy, and all-cause 30-day mortality. The primary outcome was significantly reduced in the treated group (26.9% vs. 31.7%, respectively; relative risk, 0.85; 95% CI, 0.77 to 0.94; P = 0.002). Significant reductions were noted in stage 1 and stage 3 AKI (24.4% vs. 28.1%; relative risk, 0.87; 95% CI, 0.78 to 0.97 and 1.6% vs. 3.0%; relative risk, 0.56; 95% CI, 0.35 to 0.87). No difference was noted in the use of renal replacement therapy (1.4% vs. 1.9%) or in other secondary outcomes or adverse events. Take home message: This large, multicenter, double-blind, placebo-controlled randomized trial of amino acid infusion for up to 3 days in adult patients undergoing cardiac surgery demonstrated a significant reduction in the overall incidence of AKI with treatment. Brain clearance is reduced during sleep and anesthesia. Nat Neurosci 2024; 27:1046–50. PMID: 38741022.Article Selection: Michael Zaugg, M.D., M.B.A. Image: Adobe Stock.It has been postulated from previous research that sleep is required for clearing toxins from the brain via the glymphatic system and not by simple diffusion. However, this has never been conclusively demonstrated. In this study, movements of tracer dyes were used to directly measure the bulk flow of brain fluid in male mice. In a first set of experiments, the diffusion rate was measured by injecting fluorescein isothiocyanate–dextran (4 kD) into the caudate putamen and monitored for arrival in the prefrontal cortex. No change in the diffusion coefficient with vigilance state was observed, confirming previous findings that the diffusion rate does not change during sleep or anesthesia. To measure brain clearance, the novel dye AF488 was used, which moves freely in brain parenchyma due to its small size (0.5 kD). Time course recordings of the dye movement throughout the brain were obtained during different vigilance states. The flow was markedly reduced in mice treated with dexmedetomidine, ketamine-xylazine, and pentobarbital as well as in sleeping mice. Similar to fluorescein isothiocyanate–dextran experiments, the diffusion coefficient for this dye did not change. There was a negative correlation between depth of sedation and sleep, as measured by the delta power spectra, and fluid movement. Take home message: In contrast to previous research, this murine study demonstrates that brain clearance is reduced during sleep and anesthesia, rejecting the hypothesis that clearance of toxins by increased bulk flow of brain fluid is the purpose of sleep. Hypertension and kidney function after living kidney donation. JAMA 2024; 332:287–99. PMID: 38780499.Article Selection: BobbieJean Sweitzer, M.D. Image: J. P. Rathmell.Long-term health outcomes of living kidney donors are important. This prospective cohort study of 924 normotensive adult kidney donors (66% female; mean age, 47 yr) from 17 Canadian and Australian transplant centers determined onset of hypertension (systolic blood pressure of 140 mmHg, diastolic blood pressure of 90 mmHg, or antihypertensive medication), estimated glomerular filtration rate (eGFR) decline, and albuminuria during a median follow-up of 7.3 yr (interquartile range, 6.0 to 9.0) compared to 396 nondonors from the same centers followed in a similar manner. Propensity score techniques were used to balance groups. Baseline characteristics were similar between the groups. Hypertension developed in 17% of donors and 17% of nondonors (weighted hazard ratio, 1.11 [95% CI, 0.75 to 1.66]). Longitudinal changes in mean blood pressure were similar in both groups. The eGFR decreased in donors after nephrectomy (mean, 32 ml · min–1 · 1.73 m–2); subsequently, donors had a 1.4 ml · min–1 · 1.73 m–2 (95% CI, 1.2 to 1.5) per year lesser eGFR decline than nondonors. However, more donors had an eGFR of 30 to 60 ml · min–1 · 1.73 m–2 at least once in follow-up (47% vs. 5%). Albuminuria occurred in 15% of donors and 11% of nondonors (weighted hazard ratio, 1.46 [95% CI, 0.97 to 2.21]). The albumin-to-creatinine ratio weighted difference between groups was 1.02 (95% CI, 0.88 to 1.19). Take home message: This multinational prospective cohort study comparing living kidney donors to comparable nondonors over a median follow-up period of 7.3 yr demonstrated that eGFR decreases after nephrectomy, and donors are more likely to have an eGFR between 30 and 60 ml · min–1 · 1.73 m–2 but have a slower mean rate of eGFR decline than nondonors and no significantly increased risk of hypertension or albuminuria. Electroencephalography-guided anesthesia and delirium in older adults after cardiac surgery: The ENGAGES-Canada randomized clinical trial. JAMA 2024; 332:112–23. PMID: 38857019.Article Selection: Jamie Sleigh, M.D. Image: J. P. Rathmell.It is unclear whether the occurrence of delirium after cardiac surgery is reduced if the general anesthetic is titrated to avoid pathologic intraoperative electroencephalogram (EEG) patterns such as burst suppression. Accordingly, a randomized trial of 1,140 cardiac surgical patients (inclusion older than 60 yr age; median [interquartile range] age, 70 [65 to 75] yr; 24.7% female) was performed at four Canadian centers, comparing EEG-guided anesthesia (commercially available processed EEG displaying suppression ratio, spectral edge frequency, electromyography, signal quality index, and proprietary index) versus usual care (sensor placed but clinician blind to EEG data). The aim of the EEG-guided hypnotic drug titration was to minimize the intraoperative burst suppression pattern. The primary outcome was the development of delirium within the first 5 postoperative days as scored by the Confusion Assessment Method or chart review. The primary outcome was similar between groups (18.2% vs. 18.1%, respectively; difference, 0.05% [95% CI, −4.57 to 4.67%]). The EEG-guided group had a 0.14% (95% CI, 0.15 to 0.13) lower median alveolar concentration of volatile anesthetic drug, and a 7.7-min (95% CI, 10.6 to 4.7) shorter time in an EEG burst suppression pattern. There were no differences in the secondary outcomes (length of stay in intensive care unit, intraoperative awareness, medical complications, and 30-day mortality) between treatment groups. Take home message: In this multicenter randomized trial, the incidence of postoperative delirium in older cardiac surgical patients was not influenced by the use of processed EEG monitoring, which was associated with modestly reduced anesthetic drug delivery. Noninvasive ventilation for preoxygenation during emergency intubation. N Engl J Med 2024; 390:2165–77. PMID: 38869091.Article Selection: Martin J. London, M.D. Image: J. P. Rathmell.Hypoxemia during tracheal intubation in critically ill patients is associated with adverse outcome. Vigorous preoxygenation is a standard approach. There is controversy regarding use of noninvasive ventilatory approach with bilevel positive airway pressure (BIPAP) compared to preoxygenation with an oxygen mask. This multicenter (24 U.S. emergency departments and intensive care units) pragmatic trial randomized 1,301 critically ill adults (median age, 61 yr; 48.1% hypoxemic respiratory failure) requiring tracheal intubation to receive preoxygenation for 3 to 5 min with either BIPAP (n = 637) or an oxygen mask (n = 637). The primary outcome was hypoxemia during intubation (oxygen saturation more than 85% between induction of anesthesia and 2 min after intubation). Patients in the BIPAP group were started at a fraction of inspired oxygen of 100%, an expiratory pressure of at least 5 cm of water, an inspiratory pressure of at least 10 cm of water, and a respiratory rate of at least 10 breaths/min. Use of high-flow nasal cannula oxygenation was not controlled but was used in approximately 25% of each group. The primary outcome was significantly lower in the BIPAP group (9.1% vs. 18.5% [difference, −9.4 percentage points; 95% CI, −13.2 to −5.6; P < 0.001]). Use of BIPAP did not increase the incidence of aspiration. Take home message: This large, multicenter pragmatic trial demonstrated a lower incidence of hypoxemia around the time of intubation in critically ill adult patients requiring endotracheal intubation with the use of BIPAP compared to standard preoxygenation with an oxygen mask. Overdose, behavioral health services, and medications for opioid use disorder after a nonfatal overdose. JAMA Intern Med 2024; 184:954–62. PMID: 38884975.Article Selection: Chad M. Brummett, M.D. Image: Adobe Stock.Nonfatal overdose is a known risk factor for subsequent opioid overdose; however, previous studies have been limited in scope and predated the era of fentanyl. This longitudinal cohort study of people after a nonfatal drug overdose reviewed claims and demographic and mortality data from fee-for-service Medicare beneficiaries between January 2020 and December 2021 to assess subsequent rates of nonfatal and fatal overdoses, as well as receipt of medications for opioid use disorder, naloxone, and behavioral health services in the 12 months to follow the index overdose. In this cohort of 136,762 subjects, 17.4% experienced at least one subsequent nonfatal overdose, and 1.0% died of a fatal drug overdose. Opioids were involved in 72.2% of these fatal overdoses. Only 4.1% received any medications for opioid use disorder and 6.2% had a naloxone prescription fulfillment. Independent risk factors statistically associated with reduced odds of fatal overdose included naloxone prescription fulfillment (adjusted odds ratio, 0.70; 95% CI, 0.56 to 0.89), each percentage of days receiving methadone (adjusted odds ratio, 0.98; 95% CI, 0.98 to 0.99) or buprenorphine (adjusted odds ratio, 0.99; 95% CI, 0.98 to 0.99), or receipt of behavioral assessment or crisis services (adjusted odds ratio, 0.25; 95% CI, 0.22 to 0.28). Take home message: In this retrospective longitudinal cohort analysis of Medicare beneficiaries, despite only a small percentage receiving naloxone or medications to treat opioid use disorder after a nonfatal overdose, these interventions were independently associated with reduced odds of subsequent fatal overdose.

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