Key Papers from the Most Recent Literature Relevant to Anesthesiologists

Better detection of heart failure with reduced ejection fraction, particularly in the outpatient setting, may improve long-term outcome. Previous research using a neural network (named AI-ECG) trained on the 12-lead electrocardiogram (ECG) has demonstrated useful sensitivity and specificity for detection of reduced ejection fraction. This observational, prospective, multicenter UK study used the AI-ECG algorithm retrained to interpret single-lead ECG input alone via two electrodes mounted on a stethoscope capable of wireless transmission. Fifteen seconds of supine ECG were recorded at four anatomical positions for cardiac auscultation, plus one additional position, comparing data to echocardiogram-derived ejection fraction. The primary outcome was performance of AI-ECG at classifying reduced left ventricular ejection fraction (40% or lower) using the area under the receiver operating characteristic curve (ROC). The cohort included 1,050 patients (mean age 62 yr, 51% male, 41% non-White), 10% with ejection fraction 40% or lower. ECG signal quality was best at the pulmonary position (93%). Quality was lowest for the aortic position (81%). AI-ECG performed best at the pulmonary valve position (P = 0.02), with a ROC area of 0.85 (95% CI, 0.81 to 0.89), sensitivity of 84.8% (76.2 to 91.3), and specificity of 69.5% (66.4 to 72.6). Diagnostic odds ratios did not differ by age, sex, or non-White ethnicity. Further improvements in ROC area were noted using two positions as well as a weighted logistic regression approach.

Take home message: Single-lead ECG tracings obtained using a specially designed stethoscope and processed using a neural network algorithm facilitated detection of left ventricular ejection fraction of 40% or lower in ambulatory primary care subjects.

The results of spinal cord stimulation studies vary tremendously, with concerns of bias in the mostly industry-sponsored trials. The controversy around the therapeutic effect of spinal cord stimulation has led to an emphasis on objective measures of effectiveness such as requirement for supplemental opioid utilization. This case-control study included 552,937 patients with previous spine surgery and compared the incidence of chronic opioid therapy over a 12-month period after implantation (4.7% of the cohort) or a matched index date, in those without spinal cord stimulation in opioid-naïve patients or those on chronic opioid therapy. In the study period, similar proportions in the spinal cord stimulation and non–spinal cord stimulation groups receiving baseline opioid therapy remained on opioids (70.3% vs. 69.2%). In opioid-naïve patients, spinal cord stimulation was associated with a statistically lower likelihood of patients receiving subsequent opioid therapy (7.6% vs. 7.0%, P = 0.003). In multivariable analysis, spinal cord stimulation was associated with a greater likelihood of not being on opioids in both opioid-naïve (adjusted odds ratio 0.90; 95% CI, 0.85 to 0.96; P < 0.001) and chronic opioid therapy patients (adjusted odds ratio 0.93; 95% CI, 0.88 to 0.99; P = 0.02).

Take home message: In a large case-control study, spinal cord stimulation in patients with previous spinal surgery is associated with a clinically questionable reduction in chronic opioid therapy in opioid-naïve patients, but not in individuals already on chronic opioid therapy.

Standard of care for the duration of anticoagulation after a first episode of venous thromboembolism in patients younger than 21 yr is a 3-month course of anticoagulation. However, recent practice has shifted toward a 6-week course. The Kids-DOTT Randomized Clinical Trial enrolled 417 patients younger than 21 yr with acute provoked venous thromboembolism at 42 centers in five countries between 2008 and 2021 comparing the two strategies. The primary therapeutic and safety endpoints were symptomatic recurrent venous thromboembolism and clinically relevant bleeding events within 1 yr of treatment initiation. The choice of anticoagulant was left at the discretion of the physician. Among 417 randomized patients, 297 (median age, 8 yr) met criteria for the primary per-protocol population analysis. The Kaplan-Meier estimate for the 1-yr cumulative incidence of the primary therapeutic outcome was 0.66% (95% CI, 0 to 1.95%) in the 6-week therapy group and 0.70% (95% CI, 0 to 2.07%) in the 3-month therapy group. For the primary safety outcome, the incidence was 0.65% (95% CI, 0 to 1.91%) and 0.70% (95% CI, 0 to 2.06%).

Take home message: Among patients younger than 21 yr with provoked venous thromboembolism, anticoagulant therapy for 6 weeks was noninferior to anticoagulant therapy for 3 months for the therapeutic endpoint of recurrent venous thromboembolism and the safety endpoint of bleeding episodes.

Sex discordance between physicians and patients has been associated with worse clinical outcomes in primary care and acute cardiac care, particularly for male physicians treating female patients. This population-based, retrospective cohort study conducted in Ontario was designed to evaluate the effect of sex discordance between surgeons and patients in perioperative care. It focused on adults undergoing one of 21 common elective or emergency surgeries. The primary outcome was a composite of death, readmission, or complication within 30 days after surgery. Among 1,320,108 patients who underwent surgery by one of 2,937 surgeons in Ontario between January 2007 and December 2019, 602,560 (46%) were sex concordant with their surgeon and 717,548 (54%) were sex discordant. Sex discordance was associated with a greater likelihood of the primary outcome (adjusted odds ratio 1.07; 95% CI, 1.04 to 1.09). This association was different for male versus female patients: sex discordance was associated with worse outcomes for female patients (adjusted odds ratio, 1.11; 95% CI, 1.06 to 1.16) and better outcomes for male patients (adjusted odds ratio, 0.96; 95% CI, 0.93 to 0.99; P for interaction = 0.004). This effect was consistent across all surgical subspecialties and robust to subgroup analyses assessing procedure-, patient-, physician-, and hospital-level characteristics.

Take home message: Sex discordance between patients and surgeons, primarily when female patients are treated by male surgeons, may play a role in worse surgical outcomes.

Up to two thirds of COVID-19 patients develop “post-acute sequelae of COVID-19,” also known as long COVID. These terms refer to health problems that persist for more than a month after an initial SARS-CoV-2 infection, such as fatigue, memory loss, gastrointestinal distress, and dyspnea. Long COVID is a poorly understood, heterogeneous condition, and generally symptoms cluster into one of four systems: neurological, gastrointestinal, respiratory, or nasal. A better understanding of this condition may allow for early intervention or prevention. In this longitudinal study of 309 COVID-19 patients (primary cohort n = 209; independent validation cohort n = 100) followed from initial diagnosis for 2 to 3 months and compared with 457 healthy controls, a systems biology approach was undertaken to elucidate, quantify, and immunologically characterize biological associations that may predict the development of long COVID. Four risk factors at initial COVID-19 diagnosis were identified: type 2 diabetes, Epstein-Barr viremia, SARS-CoV-2 RNAemia, and specific autoantibodies. Analyses of immune-transcriptomes revealed four convalescent immunological endotypes that were associated with varying acute disease severity and long COVID subtype. All four long COVID risk factors are detectable at initial COVID-19 diagnosis, which highlights the importance of prompt and thorough assessments and may allow for risk stratification.

Take home message: Long COVID is common and may be associated with risk factors that are easily identifiable at initial COVID-19 diagnosis, allowing for early risk stratification and more precise treatment plans.

There is almost always an investigation after high-profile public disasters. The expectation is that, by uncovering early warning signs, we might prevent a recurrence of the disaster and make us safer. Unfortunately, the process of the inquiry usually just replicates the same political pressures and poor social science methods that originally led to the occurrence of the disaster in the first place, leading inevitably to biased and misleading conclusions. It is necessary to recognize that there is not a perfect correlation between the process and the outcome. From which it follows that terrible outcomes can sometimes arise from correct judgements in the presence of incomplete knowledge. People can be wrong for the right reasons. To avoid arriving at flawed conclusions, the subsequent inquiry has to have the humility to recognize: the difference between necessary and sufficient causation; the cost of false positives; the dangers of cherry-picking ideas; the problem that there are many “dots” that can be connected in many different ways; and at least considering whether the facts were also consistent with alternative explanations.

Take home message: Although derived from the political and social sphere, these principles clearly also apply to the investigation of medical disasters.

The chemokine receptor CCR4 has several ligands, including CCL2, CCL5, CCL17, and CCL22. This study investigated the role of dendritic cells and CCR4 in postoperative pain in a mouse model of plantar incision. Several interesting findings were reported. First, paw incision increased the expression of CCL17 and CCL22 in skin-resident dendritic and Langerhans cells. Second, exogenous injection of CCL17 and CCL22 was sufficient to induce acute mechanical and thermal hypersensitivity when administered subcutaneously; however, this behavioral response is abrogated by pharmacological blockade or genetic silencing of CCR4, suggesting that CCR4 is required for producing mechanical and thermal nociception elicited by these two cytokines. Third, electrophysiological assessment of dissociated sensory neurons from naïve and postoperative mice revealed that CCL22 was able to directly activate sensory neurons and enhance their excitability after injury. Fourth, postoperative nociception is reduced in mice lacking CCR4 or in wild-type animals treated with CCR4 antagonist. Finally, postoperative nociception is reduced in transgenic mice depleted of dendritic cells.

Take home message: This study demonstrates an essential role of dendritic cells in postoperative nociception in animals and reveals CCR4 as a potential drug target for the development of new pain therapeutics.

Prognosis of recovery in unresponsive, brain-injured patients is of utmost clinical importance but definitive clinical tools for prognostication are lacking. Propofol induces distinctive neural network reconfiguration in the healthy brain as consciousness is lost, such as anteriorization of a network hubs and neutralization of feedback-dominant connectivity. This case series utilized an adaptive reconfiguration index, metrics of a network hubs and directed functional connectivity, to predict patients who would regain full consciousness within 3 months. High-density electroencephalograms (EEGs) were recorded before, during, and after the administration of propofol at a target effect site concentration of 2 ug/min in 12 adult patients, 7 with acute (less than 6 months) and 5 with chronic (more than 6 months) unconsciousness. The chronic patients were considered as negative controls since a low adaptive reconfiguration index was predicted reflecting a low likelihood of recovery of consciousness. In 3 of the 6 acute patients who recovered consciousness by 3 months, the network hub topography and the directed functional connectivity patterns paralleled those of healthy subjects who receive propofol. The three acute patients who completed the study and did not recover consciousness at 3 months demonstrated minimal hub reconfiguration during propofol exposure and little to no reconfiguration in directed functional connectivity.

Take home message: In this small case series, the propofol-induced adaptive reconfiguration index, an EEG measured alteration of a network hubs and directed functional connectivity, was predictive of those unresponsive brain-injured patients who regained consciousness within 3 months.

In critically ill patients, the optimal type and composition of intravenous fluids remain controversial with balanced multielectrolyte solutions increasingly preferred over saline. Critically ill patients were randomized to receive either a balanced multielectrolyte solution or 0.9% sodium chloride for fluid therapy in the intensive care unit (ICU) for up to 90 days after randomization. The primary endpoint was the incidence of 90-day all-cause mortality. Secondary endpoints included new renal-replacement therapy and the maximum increase in creatinine concentration. Among the 5,037 patients recruited from 53 ICUs in Australia and New Zealand, 2,515 patients were assigned to the balanced multielectrolyte solution group and 2,522 to the 0.9% sodium chloride group. Death within 90 days after randomization occurred in 21.8% of the patients treated with balanced multielectrolyte solution and in 22.0% of the patients treated with 0.9% sodium chloride (difference of −0.15 percentage points [95% CI, −3.60 to 3.30]). The incidence of new renal-replacement therapy was 12.7% in the balanced multielectrolyte solution group and 12.9% in the saline group (difference of −0.20 percentage points [95% CI, −2.96 to 2.56]). No difference was reported in the mean increase in creatinine concentrations between the two groups.

Take home message: In this randomized study of critically ill adults who received fluid therapy with a balanced multielectrolyte solution for up to 90 days, there was no difference in the risk of mortality or acute kidney injury when compared to 0.9% sodium chloride.

Myocardial infarction (MI) is a major cause of heart failure. Although fibroblasts, macrophages, and endothelial cells play a pivotal role in postischemic regeneration, the role of cardiomyocytes in wound healing is poorly understood. Using a murine model of ischemic cardiac injury and an arsenal of pharmacological and genetic approaches, the critical role of the ectonucleotidase (ENPP1) in the process of myocardial regeneration was identified. Cardiac damage increased expression of ENPP1 selectively in nonmyocytes, namely fibroblasts, macrophages, and endothelial cells, which was found to metabolize adenosine triphosphate (ATP) derived from cardiomyocytes to adenosine monophosphate (AMP). Cardiomyocytes in response to AMP released adenine and other purine nucleosides, which inhibited the cell cycle and induced apoptotic cell death in cycling nonmyocytes by blocking pyrimidine biosynthesis (UMP synthase) and upregulating the p53-signaling pathway. A knockout model for ENPP1 showed improved cardiac function and decreased chamber size after permanent ligation of the coronary artery. Only 6% of mice in the ENPP1 knockout group showed ejection fractions less than 20%, compared with 50% in control littermates. Peri-infarct histology exhibited increased capillary density and reduced scar formation. By screening a library of 200,000 compounds, a polyphenolic flavonoid named myricetin was identified as potent ENPP1 inhibitor, which also improved post-MI outcome in mice.

Take home message: The discovery of a key cardiomyocyte–nonmyocyte crosstalk, which disrupts nonmyocyte cell function and deteriorates postischemic wound healing, has potential implications as a newly identified small molecular inhibitor of ENPP1 to improve post-MI outcomes in mice.

The rapid and diverse accrual of mutations in the Omicron variant of SARS-CoV-2 has raised the question of whether its origin occurred in humans or an alternative mammalian host. Three hypotheses have been proposed for Omicron’s many and divergent mutations compared to previous variants: (1) it circulated in a human population with insufficient viral surveillance and sequencing; (2) it evolved in a chronically infected and immunocompromised human host allowing for long-term intra-host viral interactions; (3) it evolved in a nonhuman host and jumped species to humans. Results demonstrate that the Omicron spike protein was subjected to stronger positive selection than any previously reported variants and that the molecular spectrum of the mutations was different from those mutations previously acquired by other viruses in humans. This is based on previous research demonstrating that the patterns of mutations in RNA viruses are highly dependent on host-specific cellular environments and that the pattern of mutations in Omicron more closely resembled virus evolution in a murine host. Moreover, molecular docking experiments predicted that the acquired mutations resulted in a higher binding affinity of Omicron for the mouse ACE2 than the receptor binding domains of the reference SARS-CoV-2 genome.

Take home message: The molecular spectrum of pre-outbreak mutations of the SARS-CoV-2 Omicron variant is inconsistent with evolution in humans but is more consistent with mutations accumulating in murine hosts for more than 1 yr before jumping back to humans.

Identifying patients at risk for opioid-related overdose remains a critical priority. In this retrospective, observational cohort study, data from the Oregon Comprehensive Risk Registry containing linked all payer claims with other health data were used to assess risk factors associated with overdose after the first (index) opioid prescription. Of the 236,921 patients, 667 (0.3%) experienced opioid overdose. Risk of overdose was highest among individuals 75 yr or older (adjusted hazard ratio, 3.22; 95% CI, 1.94 to 5.36) compared with young age groups; male sex (adjusted hazard ratio, 1.29; 95% CI, 1.10 to 1.51); dual eligible Medicare/Medicaid beneficiaries (adjusted hazard ratio, 4.37; 95% CI, 3.09 to 6.18), Medicaid (adjusted hazard ratio, 3.77; 95% CI, 2.97 to 4.80), or Medicare Advantage (adjusted hazard ratio, 2.18; 95% CI, 1.44 to 3.31) compared with commercial insurance; those with comorbid substance use disorder (adjusted hazard ratio, 2.74; 95% CI, 2.15 to 3.50), with depression (adjusted hazard ratio, 1.26; 95% CI, 1.03 to 1.55), or with one to two comorbidities (adjusted hazard ratio, 1.32; 95% CI, 1.08 to 1.62) or three or more comorbidities (adjusted hazard ratio, 1.90; 95% CI, 1.42 to 2.53) compared with none. Patients were at a greater overdose risk if they filled oxycodone (adjusted hazard ratio, 1.70; 95% CI, 1.04 to 2.77) or tramadol (adjusted hazard ratio, 2.80; 95% CI, 1.34 to 5.84) compared with codeine; used benzodiazepines (adjusted hazard ratio, 1.06; 95% CI, 1.01 to 1.11); used concurrent opioids and benzodiazepines (adjusted hazard ratio, 2.11; 95% CI, 1.70 to 2.62); or filled opioids from three or more pharmacies over 6 months (adjusted hazard ratio, 1.38; 95% CI, 1.09 to 1.75).

Take home message: Although opioid overdose is uncommon after first prescriptions, there are patient and prescribing factors associated with overdose that may aid in medical decision making and patient education.