Key Papers from the Most Recent Literature Relevant to AnesthesiologistsThe utility of acetazolamide, a carbonic anhydrase inhibitor that reduces proximal tubular sodium reabsorption enhancing the efficiency of loop diuretics in patients with acute decompensated heart failure with volume overload, is controversial. This multicenter (27 sites in Belgium), double-blind, placebo-controlled trial of 519 patients with clinical signs of volume overload and N-terminal pro–B-type natriuretic peptide concentrations of more than 1,000 pg/ml or a B-type natriuretic peptide concentrations of more than 250 pg/ml randomized patients (stratified by left ventricular ejection fraction [less than or equal to 40% or greater than 40%]) to receive IV acetazolamide (500 mg once daily) or placebo added to standardized IV loop diuretics (at a dose equivalent to twice the oral maintenance dose). The primary end point was successful decongestion (absence of signs of volume overload), within 3 days after randomization. Secondary end points were a composite of death from any cause or rehospitalization for heart failure. The primary outcome was significantly greater in the treatment group (42% vs. 31%, risk ratio, 1.46; 95% CI, 1.17 to 1.82; P < 0.001). There was no difference in the composite secondary outcome (30% vs. 28%). Safety outcomes (worsening kidney function, hypokalemia, hypotension, and adverse events) were similar between groups.Take home message: In this randomized, placebo-controlled trial, addition of acetazolamide to loop diuretic therapy in patients with acute decompensated heart failure had greater clinical signs of decongestion relative to placebo.SARS-CoV-2 is an airborne pathogen, which is transmitted via aerosol particles. This descriptive study measured the concentration of aerosol particles in exhaled air as well as the overall emission of aerosol particles during rest and during graded exercise to exhaustion. Eight healthy women and 8 healthy men between ages 18 and 40 yr were studied. Particle concentration in expired air was 56 ± 53 particles/l at rest. At maximal intensity, an increase to 633 ± 422 particles/l was measured (P < 0.001). Similarly, aerosol particle emission per subject increased from 580 ± 489 particles/min at rest to 76,200 ± 48,000 at maximal intensity (P < 0.001). Endurance-trained subjects presented with much higher emission than untrained subjects (85% more particles exhaled, P = 0.02), with an exponential increase at exercise intensities of 2 W/kg and higher. No sex difference was observed.Take home message: These data suggest that in times of high COVID-19 prevalence, avoidance of high-intensity group exercise indoors could be an efficient target for data-based mitigation measures.High-flow nasal oxygen has greatly been used during the COVID-19 pandemic. However, its impact on mortality is controversial. This multicenter clinical trial (34 French intensive care units [ICUs] during 2021) of 711 patients (mean ± SD age, 61 ± 12 yr; 214 women [30%]) with COVID-19 respiratory failure (with a ratio of partial pressure of arterial oxygen to fraction of inspired oxygen equal to or below 200 mm) randomized to receive either high-flow oxygen (n = 357) or standard oxygen via a nonrebreathing mask initially set at a 10 l/min (n = 354). The primary outcome was mortality at day 28. Thirteen secondary outcomes were also considered. There was no difference in the primary outcome between groups (10% vs. 11%, absolute difference, –1% [95% CI, –6 to 3%]; P = 0.60). There were no significant differences in 12 of the 13 secondary outcomes, including length of stay, ICU mortality, and 90-day mortality. However, the rate of intubation was significantly lower with high-flow oxygen (45% vs. 53%; absolute difference, –8% [95% CI, –15 to –0.4%]; P = 0.04), although the number of ventilator-free days at day 28 was not significantly different between groups (median, 28 [interquartile range, 11 to 28] vs. 23 [interquartile range, 10 to 28] days; P = 0.07).Take home message: In this randomized multicenter trial, use of high-flow nasal cannula oxygen did not significantly affect 28-day mortality when compared with standard oxygen therapy.Safer and more effective analgesics for acute and chronic pain treatment are necessary. PD-1 (programmed cell death protein 1) is a transmembrane protein, which is also expressed in neurons and suppresses neuronal activity via Src homology 2 domain–containing protein tyrosine phosphatase 1 (SHP-1) and concomitant modulation of ion channel function. PD-1 knockout mice are more sensitive to nociception than wild-type mice, and the interaction of PD-1 with its natural ligand potently diminishes acute and chronic nociception. Hence, targeting PD-1 with small-molecule peptides is a promising therapeutic approach for pain treatment. This study used a peptide database for PD-1 and molecular dynamics simulation to identify H-20, an oligopeptide consisting of nine amino acids, that interacts with PD-1 with high affinity and inhibits the activity of nociceptive neurons, specifically dorsal ganglion neurons, providing analgesia with fewer adverse effects than opioid-based analgesics. Spinal and IV H-20 administration led to pain reduction in multiple preclinical murine nociception models and curtailed the occurrence of tolerance, addiction, itching, adverse gastrointestinal effects, and depression.Take home message: H-20, a small peptide, inhibits acute and chronic nociception via the PD-1 pathway with few adverse effects in an animal nociception model.There is little evidence for any treatments of persistent post-concussion syndrome, but recently some benefit has been shown for hyperbaric oxygen therapy in adults. This randomized, controlled, double-blind trial examined the effects of 60 sessions of either hyperbaric oxygen therapy (n = 15) or sham treatment (n = 10), on children (age 8 to 15 yr) who had suffered mild traumatic brain injury from 6 months to 10 yr previously. In the treatment group, there was greater overall cognitive function (effect size, d = 0.598, P = 0.01), but especially in the memory domain (a mean ± SD score change of 12 ± 12, P = 0.017), compared to a change of only 3 ± 9 (P = 0.39) in the sham treatment group. There were also fewer emotional (d = −0.676, P = 0.04) and behavioral (d = 0.244, P = 0.03) symptoms of persistent post-concussion syndrome. These changes in clinical scores (phonemic fluency) correlated with changes in the microstructure of the lingual (r = −0.817, P < 0.02), insula (r = −0.686, P < 0.0001), inferior frontal, supramarginal, and fusiform gyri, as measured by magnetic resonance imaging (n = 8 from each group).Take home message: This small study suggests that even long-delayed hyperbaric oxygen treatment might increase quality of life in children with persistent post-concussion syndrome.Glutamine is a vital component of stress-response pathways, and its concentration is known to drop after severe burn injuries, with low concentration associated with worse outcomes. International guidelines recommend enteral glutamine supplementation for burn-associated critical illness based on the results of single-center clinical trials. However, glutamine has been associated with greater mortality among nonburned critically ill populations. This international, double-blinded, placebo-controlled trial randomized 1,209 patients at 54 burn hospitals with severe second- or third-degree burns (mean size 33% of body surface area) to receive 0.5 g · kg–1 · day–1 enteral glutamine (n = 596; 28% female; mean age, 50 yr) versus placebo (n = 604; 24% female; mean age, 49 yr). The primary outcome was changed after 4 years of recruitment, from 6-month mortality to days to hospital discharge alive, due to poor enrollment. The study found no difference in time to hospital discharge alive between the glutamine group (median, 40 days; interquartile range, 24 to 87) and placebo (median, 38 days; interquartile range, 22 to 75). Six-month mortality did not differ between the groups (17% vs. 16%), with a reported hazard ratio for death of 1.06 (95% CI, 0.80 to 1.41).Take home message: In this multicenter trial, enteral glutamine supplementation did not improve time to discharge from hospital alive or 6-month mortality in severely burned critically ill patients. These results highlight the importance of large multicenter clinical trials before the creation or implementation of international guidelines.Multimodal, opioid-sparing approaches to postoperative pain management have rapidly been adopted for patients undergoing arthroscopic shoulder or knee surgery although their effectiveness is not well documented. This clinical trial (three Canadian sites) of 200 patients (mean age, 43 yr; 38% female) undergoing outpatient arthroscopic shoulder or knee surgery randomized them (1:1) to an opioid-sparing group (prescribed naproxen, acetaminophen, and pantoprazole with a rescue prescription of hydromorphone and an educational infographic) versus a control group (prescribed an opioid analgesic determined by the treating surgeon). The primary outcome was postoperative oral morphine equivalent consumption at 6 weeks postoperatively. Five secondary outcomes were evaluated: pain, patient satisfaction, opioid refills, quantity prescribed at the time of hospital discharge, and adverse events at 6 weeks postoperatively. Ninety-seven percent of patients completed the trial. The primary outcome was significantly different in the multimodal group (median, 0 mg; interquartile range, 0 to 8.0 mg vs. 40.0 mg; interquartile range, 7.5 to 105.0; z = −6.55; P < 0.001). Of the secondary outcomes, only the mean amount of morphine equivalents prescribed differed (40.4 mg [95% CI, 39.6 to 41.2] vs. 341.2 mg [95% CI, 310.2 to 372.2]; mean difference, 300.8 mg [95% CI, 269.4 to 332.3; P < 0.001]). There was no significant difference in adverse events at 6 weeks (2% vs. 3%).Take home message: In this randomized trial, a multimodal opioid-sparing postoperative pain-management protocol resulted in significantly less postoperative opioid consumption over 6 weeks compared with standard opioid prescribing in patients undergoing outpatient arthroscopic knee or shoulder surgery.Early aggressive hydration has been a longstanding mainstay of management of acute pancreatitis despite limited evidence. This randomized trial assigned patients hospitalized with acute pancreatitis at 18 centers (India, Italy, Mexico, Spain) to either goal-directed aggressive or moderate resuscitation with lactated Ringer’s solution. Aggressive fluid resuscitation consisted of a bolus of 20 ml/kg body weight, followed by 3 ml · kg–1 · h–1. Moderate fluid resuscitation consisted of a bolus of 10 ml/kg in patients with hypovolemia (or no bolus in patients with normovolemia), followed by 1.5 ml · kg–1 · h–1. Patients were assessed over a 72-h period, with adjustments based on clinical status. The primary outcome was the development of moderately severe or severe pancreatitis during hospitalization. The main safety outcome was fluid overload. At an interim analysis of 249 patients, the trial was halted due to significant between-group differences in the safety outcome (21% vs. 6%, adjusted relative risk, 2.85; 95% CI, 1.36 to 5.94, P = 0.004) without a significant difference in the primary outcome (22% vs. 17%; adjusted relative risk, 1.30; 95% CI, 0.78 to 2.18; P = 0.32).Take home message: In a randomized trial of patients with acute pancreatitis, early aggressive fluid resuscitation caused a higher incidence of fluid overload with no improvement in clinical outcomes.Gabapentin was increasingly used perioperatively for multimodal analgesia. Its safety in older patients has not been well studied. This retrospective cohort study used the Premier Healthcare Database (2009–2018) examining in-hospital adverse outcomes in patients 65 yr or older having major surgery within 7 days of admission, who did not use gabapentin before surgery, but were prescribed gabapentin within 2 days postoperatively. Before 1:1 propensity score matching, 967,547 patients (mean ± SD age, 76 ± 7 yr; 60% female) were included, 12% of whom were prescribed gabapentin. After propensity score matching, 237,872 (118,936 pairs) gabapentin users and nonusers (74 ± 7 yr; 63% female) were identified. Compared with nonusers, more gabapentin users had delirium (3.4% vs. 2.6%; risk ratio, 1.28 [95% CI, 1.23 to 1.34]), new antipsychotic use (0.8% vs. 0.7%; risk ratio, 1.17 [95% CI, 1.07 to 1.29]), and postoperative pneumonia (1.3% vs. 1.2%; risk ratio, 1.11 [95% CI, 1.03 to 1.20]). There was no difference in in-hospital deaths (0.3% vs. 0.2%; risk ratio, 1.02 [95% CI, 0.88 to 1.18]).Take home message: In this retrospective cohort analysis, patients 65 yr or older undergoing major surgery had a greater risk of delirium with perioperative gabapentin use.Studies have suggested a beneficial effect of anticoagulation on disease-free survival in patients with cancer. In this prospective, multicenter, randomized study (12 Canadian sites), 614 adults with pathologically confirmed invasive adenocarcinoma of the colon or rectum without evidence of metastatic disease were randomized to receive either extended-duration thromboprophylaxis beginning at decision to operate until 56 days postoperatively or postoperative thromboprophylaxis only. Both groups received daily subcutaneous tinzaparin at a dose of 4,500 IU. The primary outcome was disease-free survival at 3 yr. Secondary outcomes included venous thromboembolism, postoperative major bleeding, and 5-year overall survival. The trial stopped recruitment prematurely after the interim analysis for futility. The primary outcome occurred in 235 of 307 (77%) patients in the extended-duration group and in 243 of 307 (79%) patients in the in-hospital thromboprophylaxis group (hazard ratio, 1.1, 95% CI, 0.90 to 1.33; P = 0.4). None of the secondary endpoints differed between groups.Take home message: Extended duration of anticoagulation using low-molecular-weight heparin did not affect disease-free survival or overall survival in patients with colorectal cancer undergoing surgical resection.Although management of chest wall injury remains mostly nonoperative, that approach could lead to suboptimal outcomes. In this multicenter (15 U.S. and Canadian sites), prospective, randomized controlled study, 207 patients (16 to 85 yr old) with displaced rib fractures with a flail chest or non–flail chest injuries with severe chest wall deformity were randomized to receive operative treatment (plate and screws) or nonoperative treatment. The primary outcome was ventilator-free days in the first 28 days after injury. Secondary outcomes included mortality, length of stay, and rates of complications (pneumonia, ventilator-associated pneumonia, sepsis, tracheostomy). There was no difference in the primary outcome between groups (22.7 ± 7.5 days for the operative group vs. 20.6 ± 9.7 days for the nonoperative group, mean difference, 2.1 days; 95% CI, −0.3 to 4.5 days). Mortality was significantly higher in the nonoperative group (6% vs. 0%, P = 0.01). There were no differences in complications or length of stay between groups. Subgroup analysis of patients mechanically ventilated at the time of randomization demonstrated a mean difference in ventilator-free days of 2.8 (95% CI, 0.1 to 5.5) in favor of operative treatment.Take home message: Operative treatment of unstable chest wall injuries was associated with mortality, but no difference in ventilator-free days and other complications. The effect was limited to patients requiring initial mechanical ventilation.Transcatheter aortic-valve replacement (TAVR) for aortic stenosis is associated with calcific debris from native valve manipulation and deployment of the prosthetic valve potentially leading to stroke or other major embolic complications. Capture of such debris by placement of basketlike devices above the site of valve deployment are thought to reduce the risk of stroke. This randomized trial assigned 3,000 patients with aortic stenosis (1:1 ratio) undergoing transfemoral TAVR to either a cerebral embolic protection or a control group at 521 centers in three continents. The primary outcome was stroke within 72 h after TAVR or before discharge (whichever came first) in an intention-to-treat design. Secondary outcomes included disabling stroke, death, transient ischemic attack, delirium, vascular complications, and acute kidney injury. The cerebral protection device was successfully deployed in 94% of attempts. There was no significant difference in the primary outcome between groups (2% vs. 3% [difference, −0.6 percentage points]; 95% CI, −1.7 to 0.5; P = 0.30). Disabling stroke was lower in the treatment group (0.5% vs. 1.3%, number needed to treat, 125). No other substantial differences were noted in secondary outcomes.Take home message: In patients undergoing transfemoral TAVR, the use of a cerebral protection device did not alter the incidence of periprocedural stroke, although the incidence of disabling stroke was lower.