Science, Medicine, and the Anesthesiologist

Abstract

Key Papers from the Most Recent Literature Relevant to AnesthesiologistsProthrombin complex concentrate (PCC) is increasingly used to treat coagulopathy after cardiac surgery. In this single-institution, open-label randomized trial, adult patients preferentially undergoing complex cardiac surgical procedures developing excessive microvascular bleeding, a prothrombin time (PT) greater than 16.6 s, and an international normalized ratio (INR) greater than 1.6 after cardiopulmonary bypass received either PCC (15 IU/kg) or plasma (10 to 15 ml/kg). The primary outcome was chest tube output volume through midnight on day 1. Secondary outcomes were PT/INR, intraoperative and postoperative (day 1) transfusions, and adverse events. One hundred patients (mean age 67 yr, male 61%) met criteria for entry (49 received plasma, 51 received PCC). There was no significant difference in chest tube output (median [interquartile range], 1022 [799 to 1,575] ml for plasma vs. 937 [708 to 1443] ml for PCC), although allogenic transfusion was avoided in 14% of PCC subjects. After treatment, patients in the PCC arm had a greater improvement in PT (effect estimate, −1.37 s [95% CI, −1.91 to −0.84]; P < 0.001) and INR (effect estimate, −0.12 [95% CI, −0.16 to −0.07]; P < 0.001). Fewer patients in the PCC group required intraoperative red blood cell transfusion after treatment (14% vs. 31%; P = 0.04), although total intraoperative blood component transfusion rates were not different. There were no significant differences in postoperative bleeding, transfusions, or adverse events.Take home message: In this randomized trial of high-risk adult cardiac surgical patients, intraoperative PCC administration versus plasma in response to bleeding and altered coagulation parameters did not alter early postoperative chest tube output but did result in fewer intraoperative red blood cell transfusions after treatment and greater improvement in coagulation parameters without more adverse events.While outcomes between general and spinal anesthesia for hip fracture have not been reported to differ for ambulation, survival, delirium, or hospital length of stay, less is known about pain- and opioid-related outcomes between these two techniques. This planned secondary analysis of a pragmatic randomized trial of these techniques across 46 U.S. and Canadian hospitals (Regional versus General Anesthesia for Promoting Independence after Hip Fracture [REGAIN] trial; n = 1,600) compared postoperative pain, analgesic use, and patient satisfaction between the groups. Using a 0 to 10 numeric rating scale for pain, pain over the first 24 h was greater with spinal anesthesia (mean difference, 0.4 [95% CI, 0.12 to 0.68]); however, this difference did not meet the threshold for a clinically meaningful difference. No other between-group differences for pain at later time points (postoperative days 2, 3, 60, 180, or 365) were noted. Prescription analgesic use at 60 days postoperatively was higher in the spinal anesthesia group (25%) compared with general anesthesia (19%; relative risk, 1.33 [CI, 1.06 to 1.65]). Notably, patient satisfaction, willingness to recommend the same approach to a family member, and exploratory cognitive status evaluations were not different between groups.Take home message: After surgery for hip fracture, patients receiving spinal anesthesia reported statistically higher, yet not clinically meaningful worse pain scores in the first 24 h and greater analgesic use 60 days after surgery when compared with those receiving general anesthesia.Age-associated decline in muscle mass may result from mitochondrial dysfunction. Mitophagy stimulating agents such as urolithin A, a gut-microbiome-derived metabolite of the polyphenolic compounds ellagitannins, might attenuate this decline. This randomized controlled trial evaluated 88 healthy, overweight, middle-aged subjects comparing 500 mg/day urolithin A orally (n = 29), 1,000 mg/day urolithin A (n = 30), and oral placebo (n = 29) for 4 months. The primary endpoint was peak muscle power output by lower- and upper-body muscle strength testing by dynamometry. Secondary endpoints included aerobic endurance (peak oxygen consumption [V̇o2]), physical performance (6-min walk test), and biomarkers of muscle/mitochondrial status and inflammation. Peak power output was comparable in the three groups, whereas muscle strength of the lower-body muscles was greater in both urolithin A groups compared to placebo (hamstring muscle strength: 12% greater in the 500 mg/day group [P = 0.027] and 10% greater in the 1,000 mg/day group [P = 0.029]; leg flexion: 11% greater in the 500 mg/day group [P = 0.017] and 11% greater in the 1,000 mg/day group [P = 0.022]). Peak V̇o2 and walking ability were similar in the urolithin A intervention and placebo groups. Acylcarnitines were lesser in the urolithin A 500 mg/day group, consistent with greater fatty acid oxidation. C-reactive protein plasma concentration was lower in the urolithin A 1,000 mg/day arm compared to placebo along with inflammatory mediators tumor necrosis factor-α and interferon-γ. Oral administration of urolithin A was well tolerated.Take home message: In this randomized, placebo-controlled trial, overweight middle-aged subjects taking urolithin A (present in berries, walnuts, and pomegranates) for 4 months had significantly greater lower-extremity strength compared to placebo.The use of cannabis-based products has continued to surge in the United States and worldwide for medical indications, including chronic pain, despite persistent concerns regarding abuse and questions regarding effectiveness. This systematic review included 18 randomized, placebo-controlled trials (n = 1,740) and 7 cohort studies (n = 13,095) evaluating the effectiveness of the cannabinoids tetrahydrocannabinol (THC) or cannabidiol (CBD, which is devoid of psychoactive effects) for chronic pain. Studies were primarily short term (less than 8 weeks), with 56% enrolling patients with neuropathic pain. No study was at low risk for bias. Synthetic products with high THC:CBD ratios (more than 98% THC, n = 10) were associated with moderate improvement in pain severity and binary treatment response (greater than or equal to 30% improvement) but also a greater risk for dizziness. Within this class, the effect for nabilone was statistically significant (mean difference, 1.59 [95% CI, 2.49 to 0.82], while the effect for dronabinol was not. Medications with comparable THC:CBD ratios were associated with smaller improvements in pain (mean difference, 0.54 [95% CI, 0.95 to 0.19]) and function (mean difference, 0.42 [95% CI, 0.73, 0.16]). There was insufficient evidence to assess compounds containing only CBD and no data were provided on misuse.Take home message: Oral synthetic cannabinoids with high THC:CBD ratios and sublingual cannabis products with comparable THC:CBD ratios may be associated with short-term improvements in chronic pain but also greater risk for dizziness and sedation relative to placebo. Studies are needed to evaluate long-term outcomes.Heat sensation is a fundamental perception necessary for the detection of potentially harmful stimuli. However, its spinal mechanisms, especially the identity of heat-processing neurons, is unknown. Using genetic manipulation and electrophysiologic and behavioral approaches, this study explored the responsible spinal network in mice, in particular a group of excitatory neurons that are ErbB4+ responding to noxious heat stimulation. ErB4 is a receptor tyrosine kinase of the epidermal growth factor receptor (EGFR) family, which is activated by the growth factor neuregulin 1 (NRG1). Specific ablation of spinal ErbB4 neurons reduced heat perception, whereas mechanical sensation was unchanged. The ErbB4 neurons receive inputs from heat nociceptor-containing C and A delta fibers, especially TRPV1 nociceptors and not by mechanosensory neurons. The expression in spinal ErbB4 neurons, of an engineered chemogenetic receptor, which solely responds to a synthetic ligand designed to activate or inhibit ErbB4 neurons, confirmed the role of ErbB4 in heat sensation. Spinal NRG1 and the phosphorylated active form of ErbB4 were increased after noxious heat stimulus, inflammation, and nerve injury. This demonstrates the involvement of NRG1-ErbB4 signaling in heat sensation in physiologic and pathologic conditions via regulation of the glutamatergic transmission. Blockade of either ErbB4 or NRG1 reduced thermal pain hypersensitivity produced by inflammatory or neuropathic pain.Take home message: NRG1 activates spinal ErbB4 excitatory interneurons that are necessary for heat sensation and not involved in mechanosensitivity. NRG1-ErbB4 signaling is also responsible for thermal pain hypersensitivity produced by either inflammatory or neuropathic pain.Preclinical and clinical studies suggest that nitric oxide added to the gas inflow of the cardiopulmonary bypass oxygenator may decrease the incidence of low cardiac output syndrome in young children. In this double-blind, multicenter, randomized clinical trial, a total of 1,371 children younger than 2 yr of age were randomized to receive either nitric oxide (20 ppm) delivered into the cardiopulmonary bypass oxygenator (n = 679) or standard care (n = 685). The primary endpoint was the number of ventilator-free days from bypass until day 28. Secondary endpoints include a composite of low cardiac output syndrome, extracorporeal life support, or death; intensive care and hospital length of stay; and postoperative troponin levels. The number of ventilator-free days did not differ between groups (median, 26.6 days with nitric oxide [interquartile range, 24.4 to 27.4] vs. 26.4 days without [24.0 to 27.2]; absolute difference of −0.01 days [95% CI, −0.25 to 0.22]). No statistical difference was noted for the composite secondary endpoint (adjusted odds ratio for age at randomization, surgical lesion type, and study site 1.12 [95% CI, 0.85 to 1.47]), intensive care or hospital length of stay (adjusted odds ratio, 1.00 [95% CI, 0.90 to 1.12]; 0.97 [95% CI, 0.87 to 1.09]), and postoperative troponin levels (adjusted odds ratio, –0.23 [95% CI, –0.88 to 0.42]).Take home message: In children younger than 2 yr undergoing congenital heart surgery, the use of nitric oxide via cardiopulmonary bypass did not significantly affect the number of ventilator-free days after surgery or composite secondary outcomes.Venous thromboembolism after traumatic injury affects 2 to 20% of patients. Antithrombin, a crucial factor for effective anticoagulation with heparins, has been found to be deficient in 20% of trauma patients. This single-center, prospective cohort study was performed at a level 1 trauma center. The study objective was to assess time-dependent changes in antithrombin activity, responsiveness to enoxaparin (measured by anti–factor Xa levels), and the incidence of venous thromboembolism after severe trauma. In addition, this study examined the effect of ex vivo antithrombin supplementation on responsiveness to enoxaparin measured by anti-factor Xa levels 4 to 6 h after the first daily enoxaparin dose. Among 150 patients enrolled, 28 (19%) developed venous thromboembolism. Patients with venous thromboembolism had significantly lower antithrombin activity on admission compared with patients without (median [interquartile range], 91% [79 to 104%] vs. 100% [88 to 112%]; P = 0.04), as well as lower antithrombin activity on hospital days 5, 6, 7, and 8. Anti-factor Xa levels were significantly lower in patients with venous thromboembolism throughout the study. Multivariable analyses found that for every 10% decrease in antithrombin activity during the first 3 days, the risk of venous thromboembolism increased 1.5-fold. Addition of antithrombin ex vivo improved responsiveness to enoxaparin measured by anti-factor Xa.Take home message: After severe trauma in adults, antithrombin deficiency is common and contributes to enoxaparin resistance and venous thromboembolism.Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used postoperatively to improve pain, decrease inflammation, and limit opioids. NSAIDs previously have been associated with increased risk of acute kidney injury (AKI) and anastomotic leaks. A multicenter, prospective cohort study evaluated patients having elective or emergency major gastrointestinal surgery from September to December 2015 across 173 hospitals in the United Kingdom and Ireland. A secondary analysis evaluated the 7-day postoperative AKI rate and anastomotic leaks in patients administered NSAIDs on postoperative days 0 to 3. Propensity score matching was used to balance treatment groups and estimate treatment effects. Within 3 days of surgery, 20% (1,039 of 5,240) of patients received NSAIDs. AKI occurred in 11% of the early-NSAID group and 15% of the no-NSAID group. After propensity score matching, early use of NSAIDs was not significantly associated with AKI (adjusted odds ratio, 0.80; 95% CI, 0.63 to 1.00; P = 0.057). The finding was consistent in subgroup analyses by NSAID dosage and timing. The anastomotic leak rate was 5% in the NSAID group and 6% in the no-NSAID group. NSAIDs were not associated with anastomotic leak (adjusted odds ratio, 0.85; 95% CI, 0.58 to 1.21; P = 0.382).Take home message: In a large observational cohort, the use of NSAIDs in the early postoperative period after major gastrointestinal surgery was not associated with a greater risk of either acute kidney injury or anastomotic leak.The COVID-19 pandemic led to an unprecedented increase in acute care clinical research. Optimal methodology has been questioned given the challenge of simultaneously treating and researching a novel illness, obtaining consent amid hospital visitor restrictions, and the widespread repurposing of common therapies. The 2020 Critical Care Clinical Trialists Workshop participants reviewed the ORCHID trial of hydroxychloroquine for COVID-19 and the RECOVERY trial of common therapies for COVID-19 to showcase the benefits and drawbacks of explanatory versus pragmatic trials during a public health crisis. Explanatory trials evaluate novel therapies while pragmatic trials assess known therapies in a real-world context. These different goals require different designs. For example, regulatory standards for explanatory trials are likely too restrictive for pragmatic trials. The need for informed consent is controversial for pragmatic trials given that participants receive the intervention as part of standard care and waiting for consent may hamper enrollment targets. Explanatory trials’ stringent enrollment criteria maximize internal validity but compromise generalizability; pragmatic trials include a more representative population to facilitate early application of results. Explanatory trials require experienced research staff while pragmatic trials maximize efficiency by allowing nonresearch staff to enroll, administer interventions, and record data.Take home message: Pragmatic clinical trials offer efficiency and generalizability, which may be more appropriate in the setting of a public health crisis relative to traditional explanatory trials. However, broad adoption of this design will require alignment of institutional stakeholders to match the intensity of regulatory oversight and human subjects’ protection with potential impacts on trial enrollment.Dexmedetomidine is postulated to have renal protective effects. However, its effects on renal allograft success after renal transplant have not been studied. This single-center, double-blind, placebo-controlled randomized controlled trial included 111 renal transplant patients. The treatment group (n = 56) received a 24-h IV infusion of dexmedetomidine: 0.4 µg · kg–1 · h–1 intraoperatively and 0.1 µg · kg–1 · h–1 postoperatively. Controls (n = 55) received infusions of normal saline. The primary outcome was the need for dialysis in the first week posttransplant. The prespecified secondary outcomes were in-hospital repeated dialysis, in-hospital rejection, serum creatinine and cystatin, estimated glomerular filtration rate, and patient dialysis and survival at day 30. Patients receiving dexmedetomidine had a lower incidence of dialysis in the first week, 35% versus 18% (odds ratio, 0.41; 95% CI, 0.17 to 0.98; P = 0.04), and greater creatinine clearance on days 1 (9.9 [4.9 to 21.2] ml/min vs. 7.9 [2.0 to 10.4] ml/min) and 2 (29.6 [9.7 to 67.4] ml/min vs. 14.6 [3.8 to 45.1] ml/min). Dexmedetomidine had no beneficial effects on other secondary outcomes, and there was no difference in adverse events between the two groups.Take home message: In this single-center, randomized, double-blind, placebo-controlled study, patients receiving a 24-hr perioperative infusion of low-dose dexmedatomidine had a lower incidence of dialysis in the first week postoperatively.Carbon dioxide, a major physiologic gas, is elevated in microenvironments of many inflammatory diseases that impair immune cell function, but little is known about its effects on downstream signaling pathways. This two-part human study (in vitro cell culture, in vivo analysis) demonstrates that higher levels of carbon dioxide (10% vs. 5%) inhibit autocrine inflammatory gene expression in macrophages by changing intracellular pH, which ultimately reduces macrophage activation and migratory functions. Mechanistically, inhibition of carbonic anhydrase 2 (a carbon dioxide–sensing enzyme) by pharmacologic or genetic (siRNA) means was found to prevent carbon dioxide–mediated intracellular pH alterations and attenuated the sensitivity of macrophages to carbon dioxide–mediated inhibition. Ten percent CO2 decreased endotoxin-stimulated NFκB activation and its corresponding cytokine and chemokine response. Intestinal epithelial cells subjected to a scratch assay exhibited decreased simulated “wound closure” when media from 10%, as opposed to 5%, CO2-treated M1 polarized macrophages was added. The significance of these in vitro findings was corroborated in patients undergoing colorectal surgery where macrophages from patients with elevated Pco2 as measured by intraoperative blood gas analysis, exhibited reduced migration. Low intraoperative pH, but not Po2 values, in these patients also correlated with reduced intestinal macrophage infiltration and a higher risk of anastomotic leakage secondary to wound healing problems.Take home message: High levels of carbon dioxide inhibit macrophage differentiation and activation via carbonic anhydrase in an intracellular pH-dependent manner. Hypercapnia and acidosis are associated with increased risk of anastomotic leakage in patients undergoing colorectal surgery.Intraoperative handovers between anesthesia providers are common. Observational data suggest associations between such handovers and adverse events. This parallel-group, randomized clinical trial (12 German centers without standardized handover protocols) enrolled 1,817 patients with American Society of Anesthesiologists (ASA) physical status III or IV undergoing inpatient surgery (duration greater than or equal to 2 h) to receive a complete (n = 908) or no handover of anesthesia care (n = 909). The primary outcome was a 30-day composite of all-cause mortality, hospital readmission, or serious postoperative complications. Nineteen secondary outcomes were collected. A total of 1,772 patients (mean ± SD age, 66 ± 12 yr; 56% male, 97% ASA physical status III, median duration of anesthesia, 267 min [interquartile range, 206 to 351 min], median time from start of anesthesia to first handover, 144 min in the handover group [interquartile range, 105 to 213 min]) completed the study. No difference in the primary outcome was noted (30% handover vs. 33% no handover group; absolute risk difference, −2.5%; 95% CI, −6.8% to 1.9%; odds ratio, 0.89; 95% CI, 0.72 to 1.10; P = 0.27)). There were no statistical differences in the composite components (30-day mortality, 2% vs. 3%; readmission, 13% vs. 16%; postoperative complications, 22% vs. 22%). None of the 19 prespecified secondary endpoints differed significantly.Take home message: In this randomized trial of higher-risk patients undergoing major noncardiac surgery who received a structured intraoperative handover between anesthesia care providers versus no handover, no difference in mortality, readmission, or serious postoperative complications at 30 days after surgery were noted.