Key Papers from the Most Recent Literature Relevant to Anesthesiologists
Effect of high-dose baclofen on agitation-related events among patients with unhealthy alcohol use receiving mechanical ventilation: A randomized clinical trial. JAMA 2021; 325:732–41. PMID: 33620407.
Prophylactic pharmacologic therapy for potential alcohol withdrawal or agitation in patients admitted to intensive care units (ICUs) for other reasons is controversial. This multicenter, double-blind, placebo-controlled trial (18 French ICUs) investigated whether prophylactic use of high-dose baclofen, a γ-aminobutyric acid type B receptor agonist that may suppress alcohol craving (dosed from 50 to 150 mg per day), would result in fewer agitation events in mechanically ventilated adult patients with a history of heavy alcohol use (defined as 14 or more drinks per week for men or 7 or more for women or those over age 65). Patients were monitored for at least one agitation event (primary endpoint) as well as 18 prespecified secondary outcomes. Of the 314 randomized patients (baclofen 159, placebo 155; mean age 57 yr; 17% women; approximately 80% admitted for medical reasons), treated patients were less likely to have experienced at least one primary endpoint (19.7% vs. 29.7%; difference –9.93% [95% CI, –19.45 to –0.42%]; adjusted odds ratio, 0.59 [95% CI, 0.35 to 0.99]. However, treated patients were mechanically ventilated longer (9 vs. 8 days, 2 days difference [95% CI, 0 to 3]), and had longer ICU stays (14 vs. 11 days, 2 days difference [95% CI, 0 to 4]).
Take home message: The prophylactic use of baclofen in addition to standard care in patients with underlying heavy alcohol use requiring mechanical ventilation resulted in modestly fewer agitation events but deeper sedation, greater duration of mechanical ventilation, and longer ICU stay.
Association of adoption of transcarotid artery revascularization with center-level perioperative outcomes. JAMA Netw Open 2021; 4:e2037885. PMID: 33616666.
Transcarotid artery revascularization allows flow-reversal embolic protection before manipulation of a carotid atherosclerotic lesion and facilitates repair of surgically challenging lesions. A comparative-effectiveness study of transcarotid artery revascularization in relation to carotid endarterectomy using a difference-in-difference analysis (a technique capturing combined associations of the ability of the operator to select the best procedure for each patient and of the potential outcomes of each patient) from 86,027 patients who underwent revascularization for carotid artery stenosis (2015 to 2019) used the North American Vascular Quality Initiative registry (excluding transfemoral carotid stenting). The primary outcome was the rate of major adverse cardiovascular events. A total of 7,664 patients (9%) underwent transcarotid artery revascularization (mean age, 73 ± 10 yr); 78,363 patients (91.1%) underwent carotid endarterectomy (mean age, 71 ± 9 yr). The number of centers performing both transcarotid artery revascularization and carotid endarterectomy increased from 15 in 2015 to 247 in 2019. Transcarotid artery revascularization use increased from 1 to 17% as well. Difference-in-difference analysis demonstrated that centers that adopted transcarotid artery revascularization had a 10% lesser likelihood of major adverse cardiovascular events at 12 months after transcarotid artery revascularization adoption versus if those centers had continued to perform carotid endarterectomy alone (odds ratio, 0.90 [95% CI, 0.81 to 0.99]; P = 0.04).
Take home message: Transcarotid artery revascularization availability at a center performing carotid revascularization is associated with fewer perioperative major adverse cardiovascular events.
Early initiation of prophylactic anticoagulation for prevention of coronavirus disease 2019 mortality in patients admitted to hospital in the United States: Cohort study. BMJ 2021; 372:n311. PMID: 33574135.
COVID-19 infection is associated with high incidence of thrombotic complications. Several scientific societies have recommended prophylactic anticoagulation for hospitalized patients to reduce the risk of thromboembolism. In this observational cohort study, the authors evaluated the impact of early initiation of prophylactic anticoagulation, compared with none, on 30-day mortality in 4,297 patients with COVID-19 (without previous anticoagulation) admitted to U.S. Veterans Administration hospitals from March 1 to July 31, 2020. Of these patients, 84% received prophylactic anticoagulation within 24 h of admission, either with subcutaneous heparin or enoxaparin. Most deaths (510 of 622, 82%) occurred during the hospital stay. Using inverse probability of treatment weighted propensity-score analyses, the cumulative incidence of mortality at 30 days was 14% (95% CI, 13 to 16%) among those who received prophylactic anticoagulation and 19% (95% CI, 15 to 23%) among those who did not. Patients receiving prophylactic anticoagulation had 27% less risk for 30-day mortality (hazard ratio, 0.73 [95% CI, 0.66 to 0.81]). Prophylactic anticoagulation was not associated with greater risk of bleeding requiring transfusion (hazard ratio, 0.87 [95% CI, 0.71 to 1.05]).
Take home message: Early initiation of prophylactic anticoagulation among hospitalized COVID-19 patients was associated with a lower risk of 30-day mortality without greater risk of serious bleeding events.
One-year Medicare costs associated with delirium in older patients undergoing major elective surgery. JAMA Surg 2021 Feb 24 [Epub ahead of print]. PMID: 33625501.
Postoperative delirium is a common problem in older adults and is associated with prolonged hospital stays, functional and cognitive decline, and death. The authors prospectively evaluated healthcare costs associated with delirium in 497 patients, age 70 yr or older, who underwent hip or knee replacements, colectomies, laminectomies, lower extremity bypasses, or abdominal aneurysm repairs from 2010 to 2013 and were enrolled in the Successful Aging after Elective Surgery study. Healthcare costs were evaluated for the index hospitalization and at 30 days, 90 days, and 1 yr of follow-up using Medicare administrative claims. Delirium was rated using the Confusion Assessment Method while delirium severity was measured using the Confusion Assessment Method-Severity long form. Twenty-five percent of patients developed delirium while hospitalized with significantly higher unadjusted healthcare costs ($146,358) compared to patients without ($94,609). After adjustments for confounders, the cumulative costs associated with delirium were $44,291 per patient per year. Increased costs were associated with an increased severity of delirium. An extrapolation to national healthcare costs suggests an estimated $33 billion annual cost.
Take home message: This study suggests that the healthcare costs of delirium in older patients undergoing major noncardiac surgery is associated with the severity of delirium and rival those annual costs associated with cardiovascular disease or diabetes.
Glycemic index, glycemic load, and cardiovascular disease and mortality. N Engl J Med 2021; 384:1312–22. PMID: 33626252.
The association between cardiovascular disease and glycemic index was assessed in 137,851 participants (ages 35 to 70 yr) using country-specific food questionnaires. The glycemic index is a value of how specific foods increase blood glucose. Glycemic load is the mean net carbohydrate intake (measured in grams per day) multiplied by the glycemic index. Foods were classified as low, medium, or high load. Participants were from 20 high-, middle-, and low-income countries on five continents. Enrollees reported consumption of seven categories of carbohydrate foods; median follow-up was 9.5 yr. The primary outcome was a composite of major cardiovascular events (cardiovascular death, nonfatal myocardial infarction, stroke, and heart failure) or death from any cause. During the follow-up period, 8,780 deaths and 8,252 major cardiovascular events occurred. A high glycemic index diet was associated with greater risk of major cardiovascular events or death among participants with pre-existing cardiovascular disease (hazard ratio, 1.51 [95% CI, 1.25 to 1.82]) and among those without cardiovascular disease (hazard ratio, 1.21 [95% CI, 1.11 to 1.34]). A significant association between glycemic load alone and outcome was seen only among those with pre-existing cardiovascular disease (hazard ratio, 1.34 [95% CI, 1.08 to 1.67]).
Take home message: In a large multinational cohort, a high glycemic index diet was associated with a greater risk of cardiovascular disease and death.
Dexmedetomidine or propofol for sedation in mechanically ventilated adults with sepsis. N Engl J Med 2021; 384:1424–36. PMID: 33528922.
Dexmedetomidine and propofol are widely used for sedation of intubated critically ill patients. A multicenter (13 U.S. hospitals), double-blind trial randomly assigned mechanically ventilated adults with sepsis to either intravenous infusions of dexmedetomidine or propofol to achieve light sedation using the Richmond Agitation–Sedation Scale (−2 to 0). The primary endpoint was days alive without delirium or coma over the 14-day study period. Secondary endpoints were ventilator-free days at 28 days, death at 90 days, and total score on a cognitive status questionnaire at 6 months. Of 422 analyzed subjects, 51% received dexmedetomidine (median dose of 0.27 μg · kg–1 · h–1), and 49% propofol (10 μg · kg–1 · min–1) for a median duration of 3 days (interquartile range, 2 to 6), and median Richmond Agitation–Sedation Scale score −2 (interquartile range, −3 to −1). Comparing dexmedetomidine to propofol, no differences between groups in the primary outcome (adjusted median 10.7 vs. 10.8 days; odds ratio, 0.96 [95% CI, 0.74 to 1.26]), ventilator-free days (adjusted median 23.7 vs. 24.0 days; odds ratio, 0.98 [95% CI, 0.63 to 1.51]), death at 90 days (38% vs. 39%; hazard ratio, 1.06 [95% CI, 0.74 to 1.52]), or cognitive status at 6 months (adjusted median score, 40.9 vs. 41.4; odds ratio, 0.94 [95% CI, 0.66 to 1.33]) were noted. Safety endpoints were similar.
Take home message: In mechanically ventilated adults with sepsis treated with a light sedation protocol, no differences were noted in a variety of clinically important outcomes between those receiving dexmedetomidine or propofol infusions.
Hypothermic machine perfusion in liver transplantation — A randomized trial. N Engl J Med 2021; 384:1391–1401. PMID: 33626248.
The relationship between hypothermic oxygenated machine perfusion of transplanted livers and the incidence of subsequent biliary complications is not well known. A multicenter (six European centers) controlled trial randomly assigned patients to receive a liver either after hypothermic oxygenated machine perfusion (machine perfusion group) or after conventional static cold storage (control group). The primary outcome was the incidence of nonanastomotic biliary strictures within 6 months. Secondary endpoints included other complications. Of 160 patients, 78 received a machine-perfused and 78 a static cold storage liver (four patients were not transplanted). The primary outcome occurred in 6% of the machine perfusion group versus 18% of the control group (risk ratio, 0.36 [95% CI, 0.14 to 0.94]; P = 0.03). Postreperfusion syndrome occurred in 12% of the machine-perfused group versus 27% of controls (risk ratio, 0.43 [95% CI, 0.20 to 0.91]). Early allograft dysfunction occurred in 26% of the machine-perfused versus 40% of controls (risk ratio, 0.61 [95% CI, 0.39 to 0.96]). Cumulative number of treatments for the primary outcome were lower by a factor of almost 4 in the machine-perfused group.
Take home message: In a randomized study, hypothermic oxygenated machine perfusion of donor livers had a lower risk of subsequent nonanastomotic biliary strictures compared to conventional static cold storage.
Morphine acts on spinal dynorphin neurons to cause itch through disinhibition. Sci Transl Med 2021; 13:eabc3774. PMID: 33536279.
Neuraxial opioid administration frequently causes pruritus, an effect thought to be due to histamine release from mast cells. In a novel set of studies, investigators now document a role for spinal dynorphin, an endogenous opioid peptide closely associated with pain signaling. Using measures demonstrated to be sensitive to itch caused by intrathecal morphine in parturients undergoing Cesarean section, investigators first designed analogous tests for itch in mice. This mouse model helped investigators show using pharmacologic mast cell depletion and knockout experiments that these cells mediate itching caused by systemic morphine. However, mast cells are not required for intrathecal morphine-induced itch. Additional genetic and pharmacologic studies demonstrated that dynorphin acts through kappa opioid receptors expressed on specific inhibitory spinal dorsal horn neurons to limit morphine-induced itch. Finally, the investigators tested a highly selective kappa receptor agonist, nalfurafine, finding that it effectively reduces itching behaviors after intrathecal morphine administration in mice. Although not approved for use in humans, the investigators also showed that in rhesus monkeys, nalfurafine reduces intrathecal morphine-induced itch.
Take home message: This report describes a novel spinal dynorphin-kappa opioid receptor signaling mechanism mediating itch that may be a promising target for treatment of neuraxial opioid-associated pruritis.
An algorithmic approach to reducing unexplained pain disparities in underserved populations. Nat Med 2021; 27:136–40. PMID: 33442014.
Chronic pain is common but is unequally spread across populations, with persons of color often reporting higher pain levels. In subjects with knee pain related to osteoarthritis, standard methods of scoring radiographs predict pain poorly and inconsistently among different races. Using a neural network machine-learning approach and scanned X-ray data from 4,172 participants in the Osteoarthritis Initiative (a multicenter, 10-yr National Institutes of Health–funded observational study of men and women, ages 45 to 79 yr with, or at risk for, symptomatic femoral-tibial knee osteoarthritis), the authors derived an analysis algorithm that reduced race-related scoring differences. In their dataset, 58% of Black patients experienced severe pain compared with 38% overall (P < 0.001). Subjects with lower income and lower education had similar excess severe pain prevalence. Kellgren–Lawrence osteoarthritis scoring, a system developed using a predominantly White population, accounted for only 9% of the racial pain disparity (95% CI, 3 to 16%), whereas the machine-learning algorithm accounted for 43% (95% CI, 33 to 56%). The algorithm also did better in accounting for pain differences related to income and education. Models constructed based on datasets in which data from non-Whites and lower-income patients had been removed performed more poorly.
Take home message: Predictive algorithms derived from datasets representing the diversity of the target patient population may reduce disparities in access to treatments.
Evaluation of exercise interventions and outcomes after hip arthroplasty: A systematic review and meta-analysis. JAMA Netw Open 2021; 4:e210254. PMID: 33635329.
It is widely believed that preoperative and postoperative exercise interventions can improve recovery after total hip arthroplasty. A systematic review and meta-analysis of randomized controlled trials of preoperative and postoperative land-based exercise interventions in hip arthroplasty patients appraised the evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) method. The quantitative synthesis included a total of 26 studies (n = 1,004), and the exercise interventions were typically 4 to 12 weeks in duration. Compared to usual care, postoperative exercise training showed no improvement in self-reported physical function (such as the Harris Hip Score) up to 26 weeks after the operation (standardized mean difference −0.04 [95% CI, −0.31 to 0.24], and moderate level of certainty). Similarly, preoperative exercise interventions also showed no difference in hospital length of stay (mean difference −0.21 [95% CI, −0.74 to 0.31], moderate certainty), or functional benefit up to 1 yr after the operation (standardized mean difference 0.01 [95% CI, −0.37 to 0.40], very low certainty).
Take home message: Both “prehabilitation” and postoperative exercise interventions appear to have minimal benefit on the average patient’s recovery from total hip arthroplasty.
Effect of vitamin C, thiamine, and hydrocortisone on ventilator- and vasopressor-free days in patients with sepsis: The VICTAS randomized clinical trial. JAMA 2021; 325:742–50. PMID: 33620405.
Sepsis remains a common and lethal condition throughout the world. Recently, treatment with vitamin C, thiamine, and hydrocortisone has been proposed but remains controversial. A multicenter (43 U.S. hospitals), placebo-controlled, randomized trial evaluated treatment with intravenous vitamin C (1.5 gm), thiamine (100 mg), and hydrocortisone (50 mg) every 6 h for 96 h (or until discharge from the intensive care unit or until death) in sepsis patients with cardiac or pulmonary dysfunction. The primary outcome was the number of consecutive ventilator- and vasopressor-free days within 30 days of randomization. A secondary outcome was mortality at 30 days. From August 2018 to July 2019, 501 patients were randomized: 252 in the intervention arm and 249 in the placebo arm. The projected sample size (using an adaptive trial design) was 2,000 but the trial was stopped early due to withdrawal of funding by the sponsor. In treated patients, a median of 25 ventilator- and vasopressor-free days (interquartile range, 0 to 29 days) was observed, compared to 26 days (interquartile range, 0 to 28 days) in placebo patients (median difference –1 day [95% CI, –4 to 2 days]; P = 0.85). Mortality at 30 days was similar between groups (22% treated vs. 24% placebo).
Take home message: In sepsis patients with cardiac or pulmonary dysfunction, treatment with intravenous vitamin C, thiamine, and hydrocortisone did not influence the number of ventilator- and vasopressor-free days. Due to early termination the study may have been underpowered.
Association of cryoprecipitate use with survival after major trauma in children receiving massive transfusion. JAMA Surg 2021 Feb 17 [Epub ahead of print]. PMID: 33595600.
Massive transfusion protocols ensure judicious use of blood products to optimize patient outcomes after massive hemorrhage. They often include cryoprecipitate, but evidence for its use in pediatric patients is scarce. This retrospective, multicenter cohort study analyzed 1,948 severely injured children (71% male; median age 16 yr) from the U.S. Pediatric Trauma Quality Improvement Program from January 2014 to December 2017 who received a massive transfusion (defined as at least 40 ml/kg of blood products) within the first 4 h of emergency room arrival. Patients who received cryoprecipitate within the first 4 h (541, 28%) were compared to those who did not. The primary outcome was in-hospital 24-h mortality evaluated using propensity score analyses with inverse probability of treatment weighting to adjust for multiple baseline and injury-related clinical potential confounders. Patients who received early cryoprecipitate had lower adjusted in-hospital 24-h mortality compared to those who did not (–6.9%; 95% CI, –10.6 to –3.2%). Early cryoprecipitate was also associated with lower 7-day mortality but only after penetrating trauma (adjusted difference, −9.2% [95% CI, −15.4 to −3.0%]) and in those who received at least 100 ml/kg of blood products (adjusted difference, −7.7% [95% CI, −15.0 to −0.5%).
Take home message: Early use of cryoprecipitate after pediatric trauma requiring massive transfusion was associated with lower 24-h mortality benefit overall and through 7 days in those with penetrating trauma or very large-volume transfusion.