Science, Medicine, and the Anesthesiologist

Key Papers from the Most Recent Literature Relevant to Anesthesiologists Buprenorphine/naloxone vs methadone for the treatment of opioid use disorder. JAMA 2024; 332:1822–31. PMID: 39418046.Article Selection: Chad M. Brummett, M.D. Image: J. P. Rathmell.Whereas opioid agonist medications for treatment of opioid use disorder are known to reduce morbidity and mortality, there are few studies comparing the effectiveness of methadone to buprenorphine. This population-based retrospective cohort study linking medication dispensing with healthcare administrative data from British Colombia, Canada (January 2010 to March 2020) evaluated adults treated for opioid use disorder. The primary outcome was opioid agonist treatment discontinuation and all-cause mortality during treatment. Subjects initiated on buprenorphine/naloxone had higher rates of treatment discontinuation when compared to those initiated with methadone (88.8% vs. 81.5% discontinued at 24 months; adjusted hazard ratio, 1.58 [95% CI, 1.53 to 1.63]). Outcomes were assessed until the earliest of 24 months of follow-up, primary outcome occurrence, or end of the study period. When evaluated at optimal dose in per-protocol analysis of guideline-recommended dosing, the results for discontinuation were higher for buprenorphine/naloxone versus methadone (42.1% vs. 30.7%; adjusted hazard ratio, 1.67 [95% CI, 1.58 to 1.76]). Per-protocol analyses of mortality while receiving treatment were similar between the two treatments (0.08% vs. 0.13% mortality at 24 months; adjusted hazard ratio, 0.57 [95% CI, 0.24 to 1.35]). Results were consistent after the start of the fentanyl crisis, and the results were consistent in subgroup and sensitivity analyses. Take home message: This population-based retrospective study demonstrated that methadone was associated with a lower risk of treatment discontinuation when compared to buprenorphine/naloxone with a similar risk of mortality. However, treatment discontinuation was high in both groups. Embolization of the middle meningeal artery for chronic subdural hematoma. N Engl J Med 2024 [Epub ahead of print Nov 20]. PMID: 39565980.Article Selection: Jamie Sleigh, M.D. Image: Adobe Stock.Both surgical and nonsurgical treatment of chronic subdural hematoma have high failure rates, so embolization of the middle meningeal artery to reduce intravascular pressure within the meningeal neovascular ingrowth of the hematoma may plausibly have a useful role in increasing hematoma resolution. A multicenter, international randomized trial (32 sites, United States and Europe) was done comparing outcomes when adding adjunctive embolization to standard treatment (n = 149; 91 undergoing surgery, 58 nonsurgical) with standard treatment alone (n = 161; 98 undergoing surgery, 63 nonsurgical). Mean (range) age was 73 (39 to 97) yr, 70% male. The composite primary 180-day outcome reflected persistence, progression, or recurrence of the hematoma (larger than 10 mm); or disabling stroke, myocardial infarction, and death from neurologic causes. The primary safety outcome was short-term major disabling stroke or death from any cause within 30 days. Embolization was done using a nonadhesive liquid embolic agent, within 24 h of randomization, and before surgery. Middle meningeal artery embolization reduced the primary composite adverse outcome from 36% to 16% (odds ratio, 0.36; 95% CI, 0.20 to 0.66; P = 0.001). However, this was mainly driven by a reduction in reoperation or surgical rescue, and there was no change in overall risk of death. Take home message: The addition of middle meningeal artery embolization to standard treatments for chronic subdural hematoma approximately halves the incidence of treatment failure. Intravenous lidocaine for gut function recovery in colonic surgery: A randomized clinical trial. JAMA 2024; 333:39–48. PMID: 39602290.Article Selection: Beatrice Beck-Schimmer, M.D. Image: J. P. Rathmell.Even with minimally invasive surgical approaches, delayed return of gut function after colectomy is still an issue to timely discharge patients. In this trial, it was hypothesized that a perioperative lidocaine infusion would improve gut function as a direct or indirect effect through a reduction of opioid requirements. This multicenter, placebo-controlled, double-blind trial (27 United Kingdom hospitals) randomized 557 patients (44.7% female, mean ± SD age 66 ± 10.9 yr) undergoing elective minimally invasive colon resection for benign or malignant disease evaluating the effect of a 2% lidocaine infusion (bolus of 1.5 mg/kg at induction of anesthesia, followed by an infusion of 1.5 mg · kg–1 · h–1 for 6 to 12 h) versus placebo (0.9% saline). The primary outcome was defined as the proportion of patients with return of gut function within 72 h after surgery, a composite outcome of tolerating diet (food and drink uptake without nausea or vomiting for three consecutive meals), and flatus or stool. Eleven secondary outcomes included opioid consumption and quality of recovery. There was no significant difference in the primary outcome between groups (57.3% lidocaine vs. 59.0% placebo; adjusted absolute difference, –1.9% [95% CI, –8.0 to 4.2%]; relative risk, 0.97 [95% CI, 0.88 to 1.07]; P = 0.54). Secondary outcomes were also comparable. Take home message: In this multicenter, randomized trial of patients undergoing elective minimally invasive colonic surgery, perioperative lidocaine infusion did not improve return of gut function relative to placebo. Intratracheal budesonide mixed with surfactant for extremely preterm infants: The PLUSS randomized clinical trial. JAMA 2024; 332:1889–99. PMID: 39527075.Article Selection: William G. Tharp, M.D., Ph.D. Image: Adobe Stock.Bronchopulmonary dysplasia (BPD) is common in extremely preterm infants, and while systemic corticosteroid therapy may prevent BPD, it may adversely affect outcome. Alternative routes of corticosteroid administration may be more effective and safer, but concrete data are lacking. Testing the hypothesis that intratracheal administration of corticosteroids prevents BPD when coadministered with surfactant, 1,059 infants were enrolled (mean ± SD gestational age 25.6 ± 1.3 weeks, mean birth weight 775 ± 197 g, 44.6% female) born at 25.7 ± 1.4 weeks’ gestation (January 2018 to March 2023) at 21 neonatal units in an international, double-blinded, randomized controlled trial of 0.25 mg/kg intratracheal budesonide plus surfactant (n = 524) or surfactant only (n = 535). Infants were eligible if they were born before 28 weeks’ gestation, were less than 48 h of age, were receiving mechanical ventilation or advanced noninvasive respiratory support, had received up to 1 surfactant dose, and were receiving no postnatal corticosteroids. The primary outcome was survival without BPD at 36 weeks’ postmenstrual age by ventilatory or oxygen requirements. Survival without BPD at 36 weeks’ postmenstrual age occurred in 25.6% of infants treated with budesonide and 22.6% in those treated with surfactant only (adjusted risk difference, 2.7% [95% CI, –2.1 to 7.4%]). No significant differences were noted in secondary outcomes or adverse events. Take home message: In this multicenter, randomized trial of extremely premature infants receiving surfactant, the additional of intratracheal budesonide did not improve survival free of BPD. Hypovolaemic phlebotomy in patients undergoing hepatic resection at higher risk of blood loss (PRICE-2): A randomised controlled trial. Lancet Gastroenterol Hepatol 2024:S2468-1253(24)00307-8. PMID: 39667380.Article Selection: Daniel I. McIsaac, M.D., M.P.H. Image: Adobe Stock.Liver resections carry substantial risk of blood loss. Intraoperative bleeding can complicate parenchymal resection and lead to adverse intraoperative events. Observational data suggest that perioperative allogenic red blood cell transfusions are associated with worsened oncologic outcomes for patients with liver and biliary tract cancers. This multicenter patient-, surgeon-, and assessor-blinded, parallel-arm randomized trial was conducted in adults at four Canadian centers and evaluated the impact of hypovolemic phlebotomy (removal of 7 to 10 ml/kg of whole blood prior to parenchymal resection without volume replacement, with retransfusion of phlebotomized blood after liver resection). The primary outcome was receipt of a red blood cell transfusion within 30 days. A total of 486 subjects were randomly assigned to hypovolemic phlebotomy (n = 245) or usual care (n = 241), with 446 (n = 223 per arm) included in the modified intention-to-treat population of randomized patients who underwent planned liver resection. Hypovolemic phlebotomy patients were significantly less likely to receive an allogenic red blood cell transfusion (8% vs. 16% respectively; absolute risk difference, 8.8% [95% CI, –14.8 to –2.8]). There were no differences in the incidence of severe complications, or any complications between groups. No deaths occurred. Take home message: In this randomized study of liver resection patients, phlebotomy of 7 to 10 ml/kg of whole blood without volume replacement before parenchymal resection with retransfusion after resection reduced the risk of allogenic transfusion without increasing risk of complications. Liberal or restrictive transfusion strategy in aneurysmal subarachnoid hemorrhage. N Engl J Med 2024 [Epub ahead of print Dec 9]. PMID: 39655786.Article Selection: Martin J. London, M.D. Image: J. P. Rathmell.The effect of a liberal red-cell transfusion strategy versus a restrictive strategy after acute aneurysmal subarachnoid hemorrhage is unclear. A total of 742 patients at 23 U.S., Canadian, and Australian centers were randomly assigned to either a mandatory liberal (hemoglobin up to 10 g/dl) or optional restrictive strategy (hemoglobin up to 8 g/dl). The primary outcome was unfavorable neurologic outcome (modified Rankin score 4 or higher [range, 0 to 6 higher scores greater disability]) at 12 months. Secondary outcomes included functional independence and quality-of-life assessments. Randomization occurred on median day 3 after hospitalization. The median intervention duration was 17 days (liberal) and 16 days (restrictive). Median pretransfusion hemoglobin levels were 9.6 g/dl (interquartile range, 9.4 to 9.8 g/dl) liberal versus 7.6 g/dl (interquartile range, 7.2 to 7.8 g/dl) restrictive. The primary outcome was assessed in 97.7% of patients (mean ± SD age, 59.4 ± 12.3 y; 82% female). No significant difference in the primary outcome occurred (33.5% liberal strategy vs. 37.7% restrictive; risk ratio, 0.88; 95% CI, 0.72 to 1.09; P = 0.22). The result was consistent in sensitivity analyses of the primary outcome. No significant differences were noted in the secondary outcome assessments or in the incidence of adverse effects. Take home message: This large multicenter randomized trial of a liberal versus restrictive transfusion strategy in patients with acute aneurysmal subarachnoid hemorrhage did not demonstrate lower risks for unfavorable neurologic outcome at 12 months. COVID-19 is a coronary artery disease risk equivalent and exhibits a genetic interaction with ABO blood type. Arterioscler Thromb Vasc Biol 2024; 44:2321–33. PMID: 39381876.Article Selection: BobbieJean Sweitzer, M.D. Image: Adobe Stock.COVID-19 is associated with an acute risk of major adverse cardiac events (MACE) and mortality. Data from the UK Biobank was used to identify COVID-19 cases (n = 10,005) who were positive for SARS-CoV-2 infection (n = 8,062) or had a hospital diagnosis of COVID-19 (n = 1,943) based on International Classification of Diseases version-10 codes between February 1, 2020, and December 31, 2020. Controls (n = 217,730) and propensity score–matched controls (n = 38,860) were obtained from the UK Biobank during the same period. The risk of long-term MACE (more than 1,000 days of follow-up) and whether COVID-19 interacted with genetic determinants to affect the risk of MACE were evaluated. MACE was elevated in COVID-19 cases (hazard ratio, 2.09 [95% CI, 1.94 to 2.25]; P < 0.0005) and higher in patients hospitalized for COVID-19 (hazard ratio, 3.85 [95% CI, 3.51 to 4.24]; P < 0.0005). MACE was higher in patients without cardiovascular disease with COVID-19 than in patients with cardiovascular disease without COVID-19 (hazard ratio, 1.21 [95% CI, 1.08 to 1.37]; P < 0.005). Thrombotic events were increased in patients with non-O blood types (hazard ratio, 1.65 [95% CI, 1.29 to 2.09]; P = 4.8 × 10−5) compared to those with blood type O (hazard ratio, 0.96 [95% CI, 0.66 to 1.39]; P = 0.82). Antiplatelet therapy in patients with COVID-19, but without known cardiovascular disease, reduced the risk of myocardial infarction or strokes. Take home message: Major adverse cardiac events were increased for almost 3 yr in COVID-19 patients, particularly those requiring hospitalization. Myocardial infarctions and strokes were more common in COVID-19 patients with non-O blood types. Intra-channel bi-epitopic crosslinking unleashes ultrapotent antibodies targeting NaV1.7 for pain alleviation. Cell Rep Med 2024; 5:101800. PMID: 39461335.Article Selection: Ru-Rong Ji, Ph.D. Image: Adobe Stock.Genetic evidence from both gain-of-function and loss-of-function studies has strongly implicated sodium channel subtype NaV1.7 (coded by SCN9A) in human pain regulation. However, developing small molecule inhibitors for NaV1. 7 has been limited by their lack of specificity. Efforts in academia and industry have also been focused on developing monoclonal antibodies targeting the voltage domains of the channel, although the limited number of extracellular epitopes on NaV1. 7 has hindered the development of high-affinity antibodies. This study adopted a novel approach by crosslinking two nonoverlapping epitopes on voltage-sensing domains II and IV to construct bispecific antibodies, thereby forming stable ligand-antibody conjugates. Notably, the lead drug candidate, a ligand-antibody conjugate (1080-PEG7-ACDTB), exhibited a high potency, with an IC50 of 0.06 nM and demonstrated exceptional selectivity, being 1,000-fold more selective for NaV1.7. This candidate also demonstrated activity in native sensory neurons and acute pain murine models through intravenous injection (25 to 50 mg/kg). Further studies are required to enhance in vivo efficacy and to evaluate the antibody in chronic pain conditions, such as neuropathic pain. Take home message: The study developed bispecific antibodies that potently inhibited NaV1.7 activity in vitro demonstrating some in vivo activities in murine acute pain models. Myocardial infarction augments sleep to limit cardiac inflammation and damage. Nature 2024; 635:168–77. PMID: 39478215.Article Selection: Michael Zaugg, M.D., M.B.A. Image: Adobe Stock.While sleep is essential to cardiovascular health, the underlying mechanisms remain elusive. These comprehensive studies tested the immune-mediated networks linking an acute ischemic cardiac injury to the brain’s sleep pattern in mice and humans and assessed how the altered sympathetic outflow from the brain affected cardiac healing and recovery. After myocardial infarction (MI), mice spent substantially more time in slow-wave sleep than healthy mice. Single-cell RNA sequencing of murine brain cells after MI revealed activation of microglia via increased plasma cytokine levels (Il1β) and recruitment of macrophages, as confirmed by lineage tracing approaches. Using specialized imaging technology, macrophage accumulation could be localized to the third ventricle (choroid plexus) and thalamic lateral posterior nucleus (mainly excitatory glutamatergic neurons). This finding was confirmed in human brains of patients who died shortly after an ST-elevation MI. Injection of a CCR antagonist into the cisterna magna of mice reduced post-MI macrophage accumulation and normalized the sleep pattern. Experiments in mice also revealed that tumor necrosis factor-α released from these macrophages initiated the change in sleep pattern via the thalamic lateral posterior nucleus, facilitating post-MI recovery by lowering the sympathetic outflow. In patients with acute coronary syndrome, good sleep quality was associated with twofold lower cardiovascular complications during a 2-yr follow-up. Take home message: The immune system, heart, and brain are deeply interconnected. These comprehensive studies in mice and humans demonstrate that MI-induced neuroinflammation initiates restorative sleep to promote cardiac healing.

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