Key Papers from the Most Recent Literature Relevant to Anesthesiologists

Preoperative intravenous iron to treat anaemia before major abdominal surgery (PREVENTT): A randomised, double-blind, controlled trial. Lancet 2020; 396:1353–61. PMID: 32896294.

Article Selection: David Faraoni, M.D., Ph.D. Image: Heme molecule by Yikrazuul - Own Work, Public Domain, https://commons.wikimedia.org/w/index.php?curid=11081791/Adobe Stock/J. P. Rathmell.

Article Selection: David Faraoni, M.D., Ph.D. Image: Heme molecule by Yikrazuul - Own Work, Public Domain, https://commons.wikimedia.org/w/index.php?curid=11081791/Adobe Stock/J. P. Rathmell.

Preoperative anemia is common in patients undergoing elective surgery and is associated with adverse outcome. In this double- blind, parallel-group randomized trial, subjects with a preoperative diagnosis of anemia before elective open abdominal surgery at 46 hospitals in the United Kingdom were randomized to receive either intravenous iron (a single 1,000-mg dose of ferric carboxymaltose) or placebo 10 to 42 days before surgery. Coprimary endpoints were a composite of blood transfusion or death and the number of blood transfusions from randomization to 30 days postoperatively. Of 487 participants assigned to placebo (n = 243) or intravenous iron (n = 244), anemia was more frequently corrected in the treated group (21% vs. 10%, risk ratio 2.06 [95% CI, 1.27 to 3.35]), yet hemoglobin values were not significantly different in the early postoperative period. Blood transfusion or death occurred in 28% of the patients in the placebo group and 29% of the intravenous iron group (risk ratio 1.03 [95% CI, 0.78 to 1.37], P = 0.84); blood transfusion occurred in 111 versus 105 patients, respectively (rate ratio 0.98 [95% CI, 0.68 to 1.43], P = 0.93). No differences were noted for any of the prespecified safety endpoints.

Take home message: Preoperative intravenous iron in patients with preoperative anemia 10 to 42 days before elective major abdominal surgery was not superior to placebo to reduce the need for perioperative blood transfusion or death.

Effect of out-of-hospital tranexamic acid vs placebo on 6-month functional neurologic outcomes in patients with moderate or severe traumatic brain injury. JAMA 2020; 324:961–74. PMID: 32897344.

Article Selection: David Faraoni, M.D., Ph.D. Image: J. P. Rathmell.

Article Selection: David Faraoni, M.D., Ph.D. Image: J. P. Rathmell.

Early administration of tranexamic acid has been shown to decrease mortality in patients with trauma. In this multicenter, double-blind, randomized study performed across 20 trauma centers in the United States and Canada, patients with traumatic brain injury, Glasgow Coma Scale score less than or equal to 12 and systolic blood pressure greater than or equal to 90 mmHg were randomized to receive either: (1) out-of-hospital tranexamic acid (1 g) bolus initiated within 2 h of injury followed by in-hospital tranexamic acid (1 g) 8-h infusion (n = 312); (2) out-of-hospital tranexamic acid (2 g) bolus and in-hospital placebo (n = 345); or (3) both placebos (n = 309). Among 966 analyzed participants, 819 (85%) were available for the primary outcome analysis (favorable neurologic function at 6 months), which occurred in 65% of patients in the tranexamic acid groups versus 62% in the placebo group (difference 3.5% [90% one-sided confidence limit for benefit, –0.9%], P = 0.16; [97.5% one-sided confidence limit for harm, 10.2%], P = 0.84). There was no significant difference in 28-day mortality between the tranexamic acid and the placebo groups (14% vs. 17%, P = 0.26), 6-month Disability Rating Scale score (6.8% vs. 7.6%, P = 0.29), or progression of intracranial hemorrhage (16% vs. 20%, P = 0.16).

Take home message: In patients with moderate to severe traumatic brain injury, administration of tranexamic acid within 2 h of injury did not significantly improve 6-month neurologic outcome compared to placebo.

Sex differences in neutrophil biology modulate response to type I interferons and immunometabolism. Proc Natl Acad Sci USA 2020; 117:16481–91. PMID: 32601182.

Article Selection: Beatrice Beck-Schimmer, M.D., Ph.D. Image: Adobe Stock.

Article Selection: Beatrice Beck-Schimmer, M.D., Ph.D. Image: Adobe Stock.

Neutrophils play a major role in innate immunity. In the blood of human males, neutrophils have been shown to be less mature and less activated than those of females. However, the underlying mechanisms are still incompletely understood. In this in vitro study, RNA-sequencing and functional approaches were used for experiments on neutrophils from young healthy adult females and males (20 to 31 yr old) to determine differences in neutrophil biology between sexes. The authors found that type I interferon-stimulated genes were significantly upregulated in female neutrophils. Female neutrophils were also hyperresponsive to type I interferons, which promoted increased responses to toll-like receptor agonists. These mechanisms lead to a more pronounced proinflammatory response to danger signals. On the other hand, male neutrophils had higher mitochondrial metabolism, a mechanism modulated by estradiol. Differences in neutrophil phenotype between males and females were attributed to in vivo exposure of sex hormones, and not to X chromosome gene dosage.

Take home message: Neutrophils of young human females are more activated and mature than male neutrophils, a difference that is primarily mediated by sex hormones, a finding which may lead to the tailoring of treatment options in a variety of diseases based on the patient’s sex.

Association of race, health insurance status, and household income with location and outcomes of ambulatory surgery among adult patients in 2 US states. JAMA Surg 2020 Sep 9 [Epub ahead of print]. PMID: 32902630.

Article Selection: Marilyn D. Michelow, M.D. Image: Getty Images.

Article Selection: Marilyn D. Michelow, M.D. Image: Getty Images.

Millions of surgical procedures are performed yearly in ambulatory surgical centers, which may be less costly than hospital- based centers. The authors of this cohort study used data from the State Ambulatory Surgery and Services Databases of Healthcare Cost and Utilization Project (Florida and New York), accounting for 13 million patients receiving 12 types of ambulatory surgery from 2011 to 2013, to evaluate associations between location of care (ambulatory center vs. hospital surgical department) and race, insurance status, and patient income. After adjusting for covariates, Black patients compared with White patients were less likely to receive care at an ambulatory surgical center than a hospital surgery department in New York (adjusted odds ratio 0.82 [95% CI, 0.81 to 0.83], P < 0.001) and Florida (adjusted odds ratio 0.65 [95% CI, 0.65 to 0.66], P < 0.001). Patients with public health insurance, either Medicaid or Medicare, were also less likely to have surgery at an ambulatory center in either state: Medicaid in New York (adjusted odds ratio 0.22 [95% CI, 0.22 to 0.22], P < 0.001); Medicaid in Florida (adjusted odds ratio 0.40 [95% CI, 0.40 to 0.41], P < 0.001). In either state, living in a rural area was associated with significantly less use of ambulatory surgical centers compared with a hospital surgery department.

Take home message: In a large cohort of surgical patients in Florida and New York, Black patients, those with public insurance, and those living in rural areas were less likely to receive outpatient surgical care in a freestanding ambulatory clinic than a hospital surgical department.

Multitasking and time pressure in the operating room: Impact on surgeons’ brain function. Ann Surg 2020; 272:648–57. PMID: 32657937.

Article Selection: Marilyn D. Michelow, M.D. Image: J. P. Rathmell.

Article Selection: Marilyn D. Michelow, M.D. Image: J. P. Rathmell.

Intraoperative stress (such as time pressure or cognitive loads while operating) can lead to decreased surgical technical performance, an effect possibly related to deactivation of the prefrontal cortex of the brain, which is involved in executive functioning. The authors evaluated the impact of simultaneous motor and cognitive stress on 29 surgical residents’ performance of a simulated laparoscopic suturing task under four conditions: (1) no time pressure; (2) time pressure; (3) no time pressure with a surgical cognitive task; and (4) time pressure with a surgical cognitive task. Functional near-infrared spectroscopy (dorso- and ventrolateral) was used to assess subjective workload, technical performance, and measured prefrontal cortex activation during each task. Compared with task completion without time pressure, time limited suturing and time limited suturing paired with a cognitive task both increased subjective workload (measured by the surgical task load index in arbitrary units [au]) for residents (146 au vs. 196 au vs. 227 au, respectively, P < 0.001). Objective technical performance also worsened with the cognitive load conditions and optical imaging detected significant deactivation of the prefrontal cortex; this effect was confirmed with a random-effects regression analysis.

Take home message: In surgical residents engaging in high workload conditions, interruptions involving simultaneous motor and cognitive engagement may result in deactivation of the frontal cortex, leading to performance degradation.

Detailed perioperative risk among patients with extreme obesity undergoing nonbariatric general surgery. Surgery 2020; 168:462–70. PMID: 32418709.

Article Selection: Beatrice Beck-Schimmer, M.D., Ph.D. Image: Getty Images.

Article Selection: Beatrice Beck-Schimmer, M.D., Ph.D. Image: Getty Images.

In the United States more than two thirds of the population are obese (body mass index [BMI] ≥ 30 kg/m2). Patients with class III obesity are subcategorized into morbid obesity (BMI 40.0 to 49.9), super obesity (BMI 50.0 to 59.9), and super- super obesity (BMI ≥ 60.0). The perioperative risks of each group remain unclear. Using the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) the authors employed multivariable linear and logistic regression to analyze associations of BMI in 1,378,711 patients undergoing elective nonbariatric general surgery between 2012 and 2016 with a battery of ACS-NSQIP predefined 30-day postoperative outcomes. Super and super-super obesity were associated with the highest mortality risk (odds ratio 2.31 [95% CI, 1.93 to 2.78], P < 0.001 and odds ratio 2.63 [95% CI, 1.96 to 3.53], P < 0.001, respectively) adjusted by procedure, while morbid obesity was associated with a moderate mortality risk (odds ratio 1.37 [95% CI, 1.24 to 1.52], P < 0.001). Patients classified as overweight, obesity class I, or obesity class II had lower or equivocal risk of mortality compared to patients with a normal BMI. The risk of perioperative mortality, infections, and intensive care complications increased progressively with the degree of class III obesity.

Take home message: Extreme obesity is associated with greater perioperative risks including mortality, which increase progressively with the degree of obesity.

Considerations for reduction of risk of perioperative stroke in adult patients undergoing cardiac and thoracic aortic operations: A scientific statement from the American Heart Association. Circulation 2020; 142:e193–e209. PMID: 32842767.

Article Selection: Jamie Sleigh, M.D. Image: B. Leslie-Mazwi.

Article Selection: Jamie Sleigh, M.D. Image: B. Leslie-Mazwi.

This scientific statement presents a contemporary literature review and expert consensus of perioperative stroke, which occurs in 1 to 2% of cardiac surgery patients, but at least twofold more in aortic procedures with a 14.7-fold increased risk if the patient has had a stroke within the preceding 3 months. Mortality is high for intraoperative (28.8%) or postoperative (17.9%) stroke. Seventy to eighty percent of intraoperative strokes arise from thromboembolism secondary to surgical aortic manipulation, and the remainder from hypoperfusion. Early postoperative strokes are usually caused by postoperative arrhythmias, whereas late postoperative strokes reflect the atherosclerotic risk profile. Intraoperative preventative measures include surgical control of embolism sources (epi-aortic scanning, left atrial appendage ligation, and thrombectomy), hemoglobin and blood pressure targets, and neuromonitoring (electroencephalography and near field infrared spectroscopy techniques). A stroke diagnosis requires a full neurological examination and computed tomography/computed tomography angiography, and it is facilitated by rapid emergence from anesthesia. Treatment includes immediate engagement of a Stroke Team, optimizing cerebral oxygenation and perfusion, and consideration of early thrombolysis or thrombectomy. Prevention is largely contingent on adequate control of atrial fibrillation and anticoagulation.

Take home message: Maintaining a high suspicion for perioperative stroke risk will ensure the appropriate use of a wide range of effective measures for stroke prevention, diagnosis, and treatment, which can significantly reduce disease burden.

Shared structural mechanisms of general anaesthetics and benzodiazepines. Nature 2020; 585:303–8. PMID: 32879488.

Article Selection: Meghan E. Prin, M.D., M.S. Image: A. Johnson, Vivo Visuals.

Article Selection: Meghan E. Prin, M.D., M.S. Image: A. Johnson, Vivo Visuals.

Most intravenous anesthetic drugs are known to potentiate or activate the γ-aminobutyric acid type A (GABAA) receptor, which leads to their sedative, anxiolytic, and hypnotic effects. Benzodiazepines and intravenous anesthetics such as propofol, etomidate, and phenobarbital act as positive allosteric modulators at the GABAA receptor. The transmembrane sites at which the anesthetics act were thought to be distinct from those at which benzodiazepines act, but this study provides cryo-electron microscopy evidence of both shared and distinct GABAA binding sites for propofol, phenobarbital, etomidate, and benzodiazepines. These structures were solved in a lipidic environment and reinforced by electrophysiology and molecular dynamic simulations. This study also identified an additional diazepam membrane binding site and suggests an allosteric mechanism of action for flumazenil. All potentiating structures formed by intravenous anesthetics (phenobarbital, etomidate, propofol, and diazepam) at binding sites clustered in a region along the dominant principal components of motion for the transmembrane domain that was distinct from that of inhibitor complexes (bicuculline or picrotoxin), flumazenil, or with GABA alone.

Take home message: These in vitro data contribute to a better understanding of both the diversity and overlap of pharmacologic actions by intravenous anesthetic agents and benzodiazepines at GABAA receptors.

Association of new-onset atrial fibrillation after noncardiac surgery with subsequent stroke and transient ischemic attack. JAMA 2020; 324:871–8. PMID: 32870297.

Article Selection: BobbieJean Sweitzer, M.D. Image: J. P. Rathmell.

Article Selection: BobbieJean Sweitzer, M.D. Image: J. P. Rathmell.

Although new postoperative onset atrial fibrillation is associated with increased risk of neurologic outcomes, the risk factors and long-term outcomes have not been well delineated. The authors report a retrospective cohort study of 550 residents of Olmstead County, Minnesota, with newly documented (persistent or paroxysmal) atrial fibrillation within 30 days of major noncardiac surgery. Subjects were matched 1:1 on age, sex, and year and type of surgery with 452 subjects without atrial fibrillation. Outcomes were transient ischemic attack and ischemic stroke, subsequent atrial fibrillation, all-cause mortality, and cardiovascular mortality. Administrative codes were used, with manual verification of outcomes. Subjects were primarily Caucasian with a median age of 75 yr; 52% were men. The median follow-up was 5.4 yr. Those with postoperative atrial fibrillation had significantly higher CHA2DS2-VASc (congestive heart failure, hypertension, age 75 yr or older, diabetes, previous stroke or transient ischemic attack–vascular disease, age 65 to 74 yr, sex category) scores compared to those without (median, 4 vs. 3; P < 0.001). Patients with atrial fibrillation had significantly higher risk of ischemic stroke and transient ischemic attack (hazard ratio 2.69 [95% CI, 1.35 to 5.37]), subsequently documented atrial fibrillation (hazard ratio 7.94 [95% CI, 4.85 to 12.98]), and all-cause death (hazard ratio 1.66 [95% CI, 1.32 to 2.09]) versus those without atrial fibrillation. Cardiovascular deaths were not significantly different between groups.

Take home message: New-onset postoperative atrial fibrillation (persistent or paroxysmal) was associated with a significantly greater long-term risk of stroke or transient ischemic attack as well as subsequently documented atrial fibrillation and all-cause mortality in patients undergoing major noncardiac surgery.

Ten-year differences in women’s awareness related to coronary heart disease: Results of the 2019 American Heart Association national survey: A special report from the American Heart Association. Circulation 2020 Sep 21 [Epub ahead of print]. PMID: 32954796.

Article Selection: BobbieJean Sweitzer, M.D. Image: Adobe Stock.

Article Selection: BobbieJean Sweitzer, M.D. Image: Adobe Stock.

Between January 2009 and January 2019, online surveys of women older than 25 yr of age in the United States were conducted to assess awareness that cardiovascular disease is the leading cause of death for women. Identification of heart disease as the number one cause of deaths among women declined from 2009 (65%) to 2019 (44%). This occurred despite educational programs to raise awareness. The greatest declines were among Hispanic (odds ratio 0.14 [95% CI, 0.07 to 0.28]) and non-Hispanic Black women (odds ratio 0.31 [95% CI, 0.19 to 0.49]) and 25- to 34-yr-olds (odds ratio 0.19 [95% CI, 0.10 to 0.34]). Awareness was lower in those with less education. Ironically, women with risk factors for heart disease, or diagnosed with diabetes mellitus and hypertension had less awareness than those without these conditions. Primary prevention may be most effective in these demographics. Knowledge of the symptoms of myocardial infarction also declined. A significant number of women (especially younger women) mistakenly identified cancer and specifically breast cancer as the leading causes of female death.

Take home message: Cardiovascular disease is responsible for 28% of all deaths in women and is the leading cause of death among women. Yet awareness of this among women remains low and has decreased over the last decade.

Effect of intravenous acetaminophen on postoperative hypoxemia after abdominal surgery: The FACTOR randomized clinical trial. JAMA 2020; 324:350–8. PMID: 32721009.

Article Selection: J. David Clark, M.D., Ph.D. Image: J. P. Rathmell.

Article Selection: J. David Clark, M.D., Ph.D. Image: J. P. Rathmell.

Postoperative hypoxemia is a potentially serious postoperative adverse event. Opioids may contribute to this problem, highlighting the importance of identifying alternative postoperative analgesic strategies. Acetaminophen, favored for its favorable safety record and lack of effect on ventilation, is widely used in the postoperative setting. The authors randomized 570 patients undergoing abdominal surgery to standard opioid-based patient-controlled analgesia plus 1 g of intravenous acetaminophen or placebo at the beginning of surgery and every 6 h for 48 h postoperatively or until hospital discharge if earlier. The primary outcome was the median duration of hypoxemia (hemoglobin oxygen saturation less than 90%) over the first 48 postoperative h; no significant difference was noted (0.7 min per h treated vs. 1.1 min per h placebo, P = 0.29). There were no significant differences in postoperative pain or sedation scores, postoperative opioid consumption, nausea and vomiting, or other secondary outcomes. Median use of morphine equivalents was 50 mg treated versus 58 mg placebo for postoperative opioid consumption.

Take home message: Perioperative use of intravenous acetaminophen failed to affect duration of hypoxemia in a cohort of patients undergoing abdominal surgery managed with patient-controlled opioid analgesia.

Activation of TRPA1 nociceptor promotes systemic adult mammalian skin regeneration. Sci Immunol 2020; 5:eaba5683. PMID: 32859683.

Article Selection: J. David Clark, M.D., Ph.D. Image: Adobe Stock.

Article Selection: J. David Clark, M.D., Ph.D. Image: Adobe Stock.

Wounds in mammals heal via two mechanisms: the formation of scar or the regeneration of the native tissue. The former process can involve problematic functional and cosmetic results. In a recent set of studies, the authors show unexpectedly that the nociceptive receptor TRPA1 expressed on sensory neurons can shift healing toward regenerative processes. They observed that the drug imiquimod, which induces inflammation via stimulation of the toll-like receptor 7, applied to ear wounds in mice led to enhanced wound closure, an effect blocked in TRPA1 knockout, but not several other types of knockout animals. Pursuing inflammatory mechanisms for these effects, the application of imiquimod was then observed to raise serum IL-17a concentrations in control, but not TRPA1 animals, and the local application of IL-17a after wounding TRPA1 knockout mice rescued the tissue regeneration phenotype, implicating this as a critical cytokine involved in regenerative wound healing. Additional experiments involving flow cytometry of wound edge tissue demonstrated that γδ T cells were the likely source of the critical IL-17a.

Take home message: Topical TRPA1 activators promote adult mammalian tissue regeneration, providing a new avenue for novel therapies.