Key Papers from the Most Recent Literature Relevant to Anesthesiologists
Hypothermia versus normothermia after out-of-hospital cardiac arrest. N Engl J Med 2021; 384:2283–94. PMID: 34133859.
The role of targeted temperature management for subjects remaining comatose after cardiac arrest remains controversial. This international (Europe and United States) multicenter, randomized, open-label trial (with blinded outcome assessment) included 1,900 adults sustaining out-of-hospital cardiac arrest of presumed cardiac or unknown cause who remained comatose. Subjects underwent either targeted hypothermia at 33°C, followed by controlled rewarming, or targeted normothermia with early treatment of fever (defined as temperature greater than or equal to 37.8°C). The primary outcome was 6-month all-cause mortality with functional outcome at 6 months as assessed by the modified Rankin scale as a secondary outcome. Specific relevant subgroups and adverse events were defined. The primary outcome was evaluable in 1,850 subjects; 50% in the hypothermia group versus 48% in the normothermia group (relative risk ratio, 1.04 [95% CI, 0.94 to 1.14]; P = 0.37). Functional outcome was assessed in 1,747 subjects; 55% in the hypothermia group had moderately severe disability or worse (modified Rankin scale score greater than or equal to 4) versus 55% with normothermia (relative risk ratio, 1.00 [95% CI, 0.92 to 1.09]). Outcomes were consistent across all subgroups. Of the adverse events, only arrhythmia resulting in hemodynamic compromise was significantly greater in the hypothermia group (24% vs. 17%, P < 0.001).
Take home message: Targeted hypothermia was not superior to targeted normothermia in reducing all-cause mortality or functional outcomes in comatose subjects sustaining out-of-hospital cardiac arrest.
Therapeutic versus prophylactic anticoagulation for patients admitted to hospital with COVID-19 and elevated D-dimer concentration (ACTION): An open-label, multicentre, randomised, controlled trial. Lancet 2021; 397:2253–63. PMID: 34097856.
Thrombotic complications associated with COVID-19 are common, yet the effect of therapeutic anticoagulation is controversial. In this pragmatic open-label multicenter randomized controlled trial in Brazil, adult patients hospitalized with COVID-19 (symptoms up to 14 days before randomization) and elevated D-dimers were randomly assigned (1:1) to receive either therapeutic or prophylactic anticoagulation. Therapeutic anticoagulation was started either with oral rivaroxaban (15 to 20 mg daily; stable patients), subcutaneous enoxaparin (1 mg/kg twice per day) or intravenous heparin (to achieve a 0.3 to 0.7 IU/ml anti-Xa concentration; clinically unstable patients) followed by rivaroxaban up to day 30. The prophylactic anticoagulation protocol employed standard in-hospital enoxaparin or unfractionated heparin. The primary endpoint was a hierarchical analysis of time to death, duration of hospitalization, or duration of supplemental oxygen to day 30 using a “win ratio” method. The safety endpoint was the occurrence of bleeding complications. From June 2020 to February 2021, 311 patients were randomized to the therapeutic anticoagulation group and 304 to prophylactic anticoagulation. No difference was noted for the primary endpoint (win ratio 0.86 [95% CI, 0.59 to 1.22], P = 0.40), but the risk of bleeding complications was significantly higher in the therapeutic group (8% vs. 2%, relative risk 3.64 [95% CI, 1.61 to 8.27], P = 0.001).
Take home message: Therapeutic anticoagulation in COVID-19 patients increased the risk of bleeding complications without benefit in survival or recovery when compared to prophylactic anticoagulation.
Neural effects of propofol-induced unconsciousness and its reversal using thalamic stimulation. Elife 2021; 10:e60824. PMID: 33904411.
The electrophysiological effects of propofol are usually recorded using scalp electroencephalography methods, with low spatial resolution. There is a paucity of data obtained with high-resolution techniques. Unresponsiveness was induced in four macaque monkeys using propofol infusions. Neural activity (local field potentials and extracellular spikes) was recorded using 8 × 8 microelectrode arrays from four sites in the cerebral cortex and thalamus. In agreement with previous work, the unresponsive state was characterized in all monkeys by a decrease in high frequencies in the local field potentials; increase in slow waves (~1 Hz); decreased neuronal spike rates (from ~8/s to ~0.5/s); increased spike-slow wave coupling; increased slow- frequency phase synchronization between all areas; anteriorization of extended alpha frequency band power and increased prefrontal-thalamic synchronization. Electrical stimulation of the central thalamus-induced partial arousal as assessed clinically (eyes opening, muscle movement) and electrophysiologically (loss of slow wave power and increased spike rate).
Take home message: Propofol-induced unresponsiveness is associated with profound disturbances in neural signaling that could be partially reversed with thalamic electrical stimulation.
Antibiotic therapy for 6 or 12 weeks for prosthetic joint infection. N Engl J Med 2021; 384:1991–2001. PMID: 34042388.
The management of prosthetic joint infections may require surgical intervention in addition to antimicrobial therapy; however, the optimal duration of antimicrobial therapy remains unclear. This multicenter (28 sites in France) randomized controlled noninferiority trial compared short (6 weeks) to long (12 weeks) antimicrobial treatment in patients with microbiologically confirmed prosthetic joint infection who had received appropriate surgery. The primary outcome was persistent infection within 2 yr after the completion of antibiotic treatment. The noninferiority margin was defined at 10%. Between November 2011 and January 2015, 205 subjects were randomized to receive short treatment (190 completed 2-yr follow-up with 165 included in the per-protocol analysis) and 205 were randomized to long treatment (188 completed 2-yr follow-up with 160 included in the per-protocol analysis). In the short treatment group, 18% of the patients developed persistent infection, compared to 9% in the long treatment group (risk difference 8.7% [95% CI, 1.8 to 15.6]). Additional per-protocol and sensitivity analyses did not demonstrate noninferiority, and there were no differences between both groups when assessing treatment failure due to new infection, probable treatment failure, or serious adverse events.
Take home message: A duration of 6 weeks’ antimicrobial therapy was not noninferior compared to 12 weeks’ duration in patients with confirmed prosthetic joint infection who had received appropriate surgical treatment and was associated with a higher incidence of unfavorable outcomes.
Patient care and clinical outcomes for patients with COVID-19 infection admitted to African high-care or intensive care units (ACCCOS): A multicentre, prospective, observational cohort study. Lancet 2021; 397:1885–94. PMID: 34022988.
There is a dearth of information on outcomes of critically ill COVID-19 patients in Africa. The African COVID-19 Critical Care Outcomes Study evaluated outcomes and association with resources, comorbidities, and critical care interventions in adults (aged 18 yr or older) with suspected or confirmed COVID-19 infection admitted to intensive care or high-care units in 64 hospitals in 10 African countries. The primary outcome was in-hospital mortality censored at 30 days. Investigators evaluated patient risk and hospital process/structure factors in relation to mortality. From May to December 2020, 3,140 patients were studied (mean age 56 yr; 61% male). Participating hospitals had a median of two intensivists and pulse oximetry was available to patients at 86% of sites. In-hospital mortality within 30 days of admission was 48%. Factors independently associated with mortality were increasing age, HIV/AIDS, diabetes, chronic liver disease, chronic kidney disease, delay in admission due to a shortage of resources, quick sequential organ failure assessment score at admission, high-flow oxygen requirement, continuous positive airway pressure requirement, invasive mechanical ventilation requirement, cardiorespiratory arrest within 24 h of admission, and vasopressor requirement. Steroid therapy was associated with survival (odds ratio 0.55 [97.5% CI, 0.37 to 0.81]; P = 0.003). There was no difference in outcome associated with female sex.
Take home message: Mortality in critically ill patients with COVID-19 in African countries is higher than reported from other continents and independently associated with insufficient critical care resources and prevalent comorbidities.
Randomized trial of fetal surgery for moderate left diaphragmatic hernia. N Engl J Med 2021; 385:119–29. PMID: 34106555.
Fetoscopic endoluminal tracheal occlusion is associated with greater survival of infants with severe congenital diaphragmatic hernia on the left side. Whether it improves survival in infants with moderate disease has not been determined. In this multicenter, international, open-label, adaptive, parallel-group superiority trial, women carrying singleton fetuses with moderate isolated congenital left diaphragmatic hernia were randomly assigned to fetoscopic endoluminal tracheal occlusion at 30 to 32 weeks of gestation or expectant care. The primary outcomes were infant survival to discharge from the neonatal intensive care unit and survival without oxygen at 6 months of age. The trial randomized 196 women; 63% of infants (62 of 98) in the tracheal occlusion group survived to discharge compared to 50% (49 of 98) in the expectant care group (relative risk 1.27 [95% CI, 0.99 to 1.63]). At 6 months of age, 54% of infants in the tracheal occlusion group and 44% of infants in the expectant care group were alive without oxygen supplementation (relative risk 1.23 [95% CI, 0.93 to 1.65]). The incidence of preterm birth was 64% in the tracheal occlusion group and 22% in the expectant care group (relative risk 2.86 [95% CI, 1.94 to 4.34]).
Take home message: In fetuses with moderate left diaphragmatic hernia, fetoscopic endoluminal tracheal occlusion at 30 to 32 weeks of gestation is not associated with significant therapeutic benefit but is associated with greater risk of preterm birth.
Randomized trial of fetal surgery for severe left diaphragmatic hernia. N Engl J Med 2021; 385:107–18. PMID: 34106556.
Evidence suggests that fetoscopic endoluminal tracheal occlusion is associated with greater survival among infants with severe left diaphragmatic hernia, but data from randomized trials are lacking. In this open-label, randomized, multicenter, international trial, women carrying singleton fetuses with severe isolated congenital left diaphragmatic hernia were assigned to either fetoscopic endoluminal tracheal occlusion at 27 to 29 weeks of gestation or expectant care using a group- sequential design with five prespecified interim analyses for superiority. Both groups received standardized postnatal care and the primary outcome was infant survival to discharge from the neonatal intensive care unit. The trial was stopped after the third interim analysis and included 80 women; 40% of infants (16 of 40) in the tracheal occlusion group survived to discharge compared to 15% (6 of 40) in the expectant care group (relative risk 2.67 [95% CI, 1.22 to 6.11]). The incidence of preterm, prelabor rupture of membranes was higher among women in the tracheal occlusion group compared to the expectant group (47% vs. 11%, relative risk 4.51 [95% CI, 1.83 to 11.9]) as was the incidence of preterm birth (75% vs. 29%, relative risk 2.59 [95% CI, 1.59 to 4.52]).
Take home message: Despite a higher incidence of preterm birth, fetoscopic endoluminal tracheal occlusion at 27 to 29 weeks of gestation resulted in greater survival of infants with severe left diaphragmatic hernia.
Recovery of consciousness and cognition after general anesthesia in humans. Elife 2021; 10:e59525. PMID: 33970101.
The processes by which the brain recovers wakefulness and cognition after anesthesia are still poorly defined and understood. Thirty normal volunteers received 3 h of 1.3 age-adjusted minimum alveolar concentration (MAC) isoflurane anesthesia with brain activity measured using permutation entropy and Lempel-Ziv complexity of the multichannel electroencephalography. A battery of tests to measure various aspects of cognition were performed preanesthetic, on return of wakefulness, and every 30 min thereafter. Sleep-wake cycles were assessed using actigraphy in the week before and 3 days after the study. A control group consisted of 30 nonanesthetized subjects undergoing similar testing who remained awake and nonsedated. In the recovery period, tests of abstract problem-solving ability resumed quickly after recovery of consciousness, whereas reaction time and attention took longer to return to normal. The anesthetized subjects had full neurocognitive recovery by 3 h. The electroencephalography measures decreased during anesthesia and recovered to preanesthetic readings around, or just before, the time of wakening—but were not correlated with the cognitive tasks during recovery. Anesthesia did not alter subsequent sleep rhythms.
Take home message: Cognitive function returns in a stepwise fashion after anesthesia with executive function returning earliest contrary to previous beliefs.
Manipulating placebo analgesia and nocebo hyperalgesia by changing brain excitability. Proc Natl Acad Sci USA 2021; 118:e2101273118. PMID: 33941677.
Placebo effects (positive expectations producing improved outcomes) and nocebo effects (negative expectations producing negative outcomes) are complementary processes felt to impact subjective responses to medical treatments. This study of 81 volunteers tested the hypothesis that transcranial direct current stimulation of the dorsal lateral prefrontal cortex would affect the magnitude of placebo and nocebo responses to a painful heat stimulus by altering the excitability of endogenous pain control circuitry. Subjects received anodal (anode located above the targeted cortex), cathodal, or sham stimulation. Direct current stimulation did not independently alter pain intensity experienced after a thermal stimulus to the forearm. However, after training participants to experience placebo or nocebo effects to the application of an inert topical cream, it was found that cathodal stimulation significantly boosted placebo analgesia compared with sham stimulation (mean difference 1.16, P = 0.028), while anodal stimulation significantly inhibited nocebo hyperalgesia compared with sham (mean difference −1.39, P = 0.041). Functional magnetic resonance imaging scanning demonstrated that stimulation of the dorsal lateral prefrontal cortex affected coupling of that region with other regions of the prefrontal cortex and the insula.
Take home message: Transcranial direct current stimulation can alter the magnitude of placebo and nocebo responses by altering the excitability of the dorsolateral prefrontal cortex and the activation of other brain regions involved in endogenous pain modulation.
Effect of continuous infusion of hypertonic saline vs standard care on 6-month neurological outcomes in patients with traumatic brain injury: The COBI randomized clinical trial. JAMA 2021; 325:2056–66. PMID: 34032829.
The impact of the osmolarity of fluid therapy in traumatic brain injury on development and severity of posttraumatic intracranial hypertension is controversial. This multicenter randomized controlled trial at nine French intensive care units evaluated the effects of a continuous 20% hypertonic saline infusion (0.5 to 1.9 gm NaCl per hour) for at least 48 h in addition to standard care in moderate to severe traumatic brain injury (titrated to maintain serum Na+ less than 155 mmol/l) as long as the patient was considered at risk for intracranial hypertension compared to standard care alone (control). The primary outcome was neurological outcome assessed by the Extended Glasgow Outcome Scale score at 6 months after trauma. Secondary outcomes included mortality at 6 months and development of intracranial hypertension. From 2017 to 2020, 185 subjects were randomized to the intervention group and 185 to the control group. At 6 months, no significant difference in the Extended Glasgow Outcome Scale score was found between both groups (adjusted common odds ratio 1.02 [95% CI, 0.71 to 1.47]; P = 0.92). In addition, the development of intracranial hypertension (34% vs. 36%, absolute difference –2.6% [95% CI, –12.3% to 7.2%]) and mortality at 6 months (16% vs. 21%, absolute difference –4.9% [95% CI, –12.8% to 3.1%]) were comparable across both groups.
Take home message: Continuous infusion of hypertonic saline in addition to standard care did not improve neurological outcomes at 6 months in patients after moderate to severe traumatic brain injury compared to standard care alone.
Final report of a trial of intensive versus standard blood-pressure control. N Engl J Med 2021; 384:1921–30. PMID: 34010531.
In 2015 the influential SPRINT trial, which randomized 9,361 participants at increased risk for cardiovascular disease (without diabetes or previous stroke) to intensive (systolic blood pressure [SBP] less than 120 mmHg) or standard (SBP less than 140 mmHg) blood pressure control, reported initial results when the trial was halted due to statistical benefit in the primary outcome (major adverse cardiovascular events) in the intensive group. This report presents the final adjudicated outcomes and data on safety and clinical events with extended median follow-up through July 2016. At a median of 3 yr of follow-up, the rate of the primary outcome during the trial was significantly lower in the intensive treatment group (1.77% vs. 2.40% per year; hazard ratio 0.73 [95% CI, 0.63 to 0.86]). All-cause mortality was also reduced (1.06% vs. 1.41% per year; hazard ratio 0.75 [95% CI, 0.61 to 0.92]). Serious adverse events (hypotension, electrolyte abnormalities, acute kidney injury or failure, and syncope) were significantly higher in the intensive treatment group. Combining trial and post-trial follow-up data (4 yr), similar patterns were found; however, rates of acute decompensated heart failure, initially lower in the intensive group (hazard ratio 0.68 [95% CI, 0.50 to 0.92]) increased significantly in the postintervention period (hazard ratio 1.63 [95% CI, 1.02 to 2.57]).
Take home message: In patients with increased cardiovascular risk (but without diabetes or previous stroke), an intensive blood pressure control strategy was associated with lower rates of major adverse cardiovascular events but was also associated with higher rates of some adverse events.
Association of coronary artery bypass grafting vs percutaneous coronary intervention with memory decline in older adults undergoing coronary revascularization. JAMA 2021; 325:1955–64. PMID: 34003225.
Postoperative neurocognitive dysfunction is an important complication after cardiac surgery in older adults. Its etiology is complex and multifactorial. It has been hypothesized that percutaneous coronary intervention (PCI) avoids many of the etiologic factors contributing to it after coronary artery bypass graft (CABG) surgery. Using participants in the U.S. Health and Retirement Study, a prospective longitudinal cohort started in 1992, the authors studied subjects age 65 yr or older who underwent either CABG or PCI between 1998 and 2015. Data were modeled for up to 5 yr preceding and 10 yr after revascularization or until death, drop out, or the 2016 to 2017 interview wave. The primary outcome was a summary measure of cognitive test scores and proxy cognition reports performed biennially. The current study analyzed 1,680 participants: 665 underwent CABG surgery and 1,015 had PCI. Overall, the between-group difference-in-differences estimate for memory decline for PCI versus CABG was 0.015 memory units per year (95% CI, −0.008 to 0.038; P = 0.21), although a significant worsening was noted in those undergoing off-pump relative to on-pump approaches. The absence of difference between the two therapeutic strategies persisted after balancing the cohort using inverse probability of treatment weighting.
Take home message: This retrospective cohort study did not find any differences in the change of rate of memory decline between CABG and PCI in older adults undergoing coronary revascularization.