Science, Medicine, and the Anesthesiologist

Neck pain is one of the top five leading causes of disability, with more than one-third being neuropathic in nature. Since 2000, the use of cervical epidural steroid injections has more than tripled, leading to increased scrutinization. The presence of nonorganic (Waddell) signs has been shown to be associated with treatment failure for back pain but has never been validated for neck pain. In a multicenter study, Waddell signs were adapted for cervical pain, with nine signs in five categories validated in a small pilot. Seventy-eight patients with cervical radiculopathy scheduled for epidural steroid injection were then evaluated with these signs for their association with outcome, with a positive outcome defined as a greater-than 2-point decrease in arm pain and a score greater than 5 on a 7-point improvement scale. Seventy-one percent had at least one nonorganic sign and 40% had at least one sign in three categories, with noncorrelative tenderness being most common (51%). Mean number of positive nonorganic categories was higher in individuals with negative outcomes (2.5 ± 1.8; 95% CI, 2.0 to 3.1) versus those with positive outcomes (1.1 ± 1.3; 95% CI, 0.7 to 1.5; P = 0.0002). Positive associations were noted between nonorganic signs and multiple pain (P = 0.011) and multiple psychiatric (P = 0.028) conditions.

Take home message: In this observational analysis, the number of cervical nonorganic exam signs correlated with negative treatment outcome as well as comorbid pain and psychiatric morbidities, and their use as screening tools may improve patient selection.

Close coordination between surgeons and anesthesiologists in a team manner is generally felt to result in optimal patient outcome, although the dynamics of such a relation have not been well studied. This Canadian population-based, retrospective cohort study evaluated 7,893 adults (median age, 65 yr; 66% male) undergoing gastrointestinal oncologic surgery cancer (2007 to 2018) considering “dyad familiarity” (the annual volume of procedures of the dyad in the 4 yr before the index surgery) in relation to the primary outcome of 90-day major morbidity (any Clavien-Dindo complication grade 3 to 5) using multivariable logistic regression. Dyads included 737 anesthesiologists and 163 surgeons; median surgeon-anesthesiologist dyad volume was 1 (range, 0 to 12.2) procedures per year. Ninety-day major morbidity occurred in 43% of patients. A linear association between dyad volume and the primary outcome was observed. After adjustment, annual dyad volume associated with improved outcomes (odds ratio, 0.95 [95% CI, 0.92 to 0.98; P = 0.01) for each incremental procedure per year, per dyad. Similar results were noted for 30-day major morbidity.

Take home message: This retrospective cohort analysis suggests that increasing familiarity between anesthesiologists and surgeons on a case basis was associated with greater short-term patient outcomes. The implications for this in surgical case scheduling require additional consideration.

The informational theory of aging states that the accumulation of genetic changes leads to decreased cellular function and ultimately death. Classically, double-stranded DNA breaks were thought to be the primary genetic change facilitating aging, but studies in yeast suggest that the loss of epigenetic information may underlie aging. Mouse fibroblasts were modified by inducible changes to the epigenome (ICE), induced by a limited number of DNA breaks that were insufficient to induce mutations or to initially effect cell cycle, apoptosis, or senescence measurements. However, at 4 days, ICE fibroblasts were epigenetically older, demonstrated by increased age-associated DNA methylation sites. Cells were more susceptible to subsequent DNA-damaging agents and had reduced lamin B1 levels and increased senescence, all indicators of aging. ICE was induced in vivo, which yielded mice with accelerated aging at 10 months, including increased frailty, alopecia, pigment loss, reduced body weight, fewer kidney glomeruli, and subepithelial thinning of skin. Remarkably, these accelerated aging changes in ICE cells or mice could be reversed by the expression of a collection of transcription factors, classically used to reprogram mature cells to pluripotent cells. Five weeks after these factors were induced in mice, aging markers in kidney, muscle, and retina recovered to control levels.

Take home message: Mammalian cellular aging is accelerated by the loss of epigenetic information, and genetic reprogramming with transcription factors can reverse or accelerate aging in isolated murine fibroblasts and in mice in vivo.

Low-molecular-weight heparin for thromboprophylaxis in patients with fractures is widely used, but its effectiveness relative to aspirin, a less expensive and more easily administered drug, has not been studied. This pragmatic, multicenter (21 U.S. and Canadian centers), noninferiority trial randomized adults (mean ± SD age, 45 ± 18 yr) with a fracture of an extremity (hip to midfoot or shoulder to wrist) treated operatively or any pelvic or acetabular fracture to either low- molecular-weight heparin (30 mg enoxaparin twice daily; N = 6,110) or 81 mg aspirin twice daily (N = 6,101) while in the hospital (mean 8.8 ± 10.6 doses) followed as outpatients by the clinical protocol of each hospital. The primary outcome was all-cause mortality at 90 days. Secondary outcomes included nonfatal pulmonary embolism, bleeding complications, and deep-vein thrombosis. No significant difference was noted in the primary outcome between groups (difference, 0.05 percentage points; 96% CI, −0.27 to 0.38; P < 0.001 for a noninferiority margin of 0.75 percentage points). Of the secondary outcomes, the incidence of nonfatal pulmonary embolism was identical (1%), bleeding complications were similar (14% aspirin vs. 14% enoxaparin) as was deep-vein thrombosis (3% vs. 2%). Other serious adverse events were similar as well.

Take home message: In this randomized, multicenter study of patients with extremity fractures treated operatively or with any pelvic or acetabular fracture, in-hospital thromboprophylaxis with aspirin was noninferior to low-molecular-weight heparin with regard to 90-day all-cause mortality as were the incidences of deep-vein thrombosis and pulmonary embolism.

Prior reports have documented higher mortality and morbidity in women undergoing coronary artery bypass in the United States compared with men, although data from the past decade have not been reported. This retrospective cohort study of 1,297,204 patients undergoing primary isolated coronary artery bypass (mean age, 66 yr; 25% women) from 2011 to 2020 utilized data from hospitals participating in the Adult Cardiac Surgery Database of the Society of Thoracic Surgeons analyzing the association with this procedure and the primary outcome of operative mortality. Secondary outcomes included a composite of operative mortality and morbidity outcomes. The attributable risk (the association of female sex with coronary artery bypass grafting outcomes) for the primary and secondary outcomes was calculated. The primary outcome was significantly higher in women (3%; 95% CI, 2.8 to 2.9 vs. 2%; 95% CI, 1.7 to 1.7; P < 0.001) as was the composite secondary outcome (23%; 95% CI, 22.7 to 23.0 vs. 17%; 95% CI, 16.6 to 16.8; P < 0.001) compared to men. The attributable risk of female sex for the primary outcome and the composite secondary variable varied from 1.28 and 1.08, respectively, in 2011 to 1.41 and 1.08, respectively, in 2020, with no significant change over the study period (P for trends = 0.38 and 0.71).

Take home message: This large-scale retrospective cohort analysis demonstrates ongoing elevated risk for women undergoing coronary artery bypass surgery with regard to operative mortality that has not changed over the past decade.

The opioid crisis remains a serious issue in the United States, with an estimated 30% of deaths related to long-term opioid prescriptions. Several epidemiologists suggest an association with opioid prescriptions from acute care visits. In the perioperative population, an estimated 5 to 10% of opioid-naïve patients will become long-term opioid users. This single-center (Dartmouth-Hitchcock Medical Center) prospective study prospectively evaluated 221 opioid-naïve surgical patients, 88% undergoing cancer-related surgery. Long-term opioid prescriptions, identified using the New Hampshire Prescription Drug Monitoring Program, were defined as a prescription filled 3 to 12 months after surgery. Patients with a history of opioid dependence or misuse, or opioid use before surgery, were excluded. Fifteen percent of the subjects filled a prescription 3 to 12 months after surgery. The median days of opioid supplied was 7 (interquartile range, 5 to 27). Fifty-one percent of these were for a new painful medical condition (e.g., cancer related) and 40% were for a new surgical procedure. Only 2% developed persistent opioid use, all for medical or surgical reasons. No significant differences were observed for demographics, surgical service, length of stay, discharge opioid prescription, or postdischarge complications between patients who received a long-term opioid prescription compared with those who did not.

Take home message: This prospective, single-center analysis of opioid-naïve surgical patients demonstrated a very low rate of persistent opioid use, all for well-defined reasons when use is directed by institutional guidelines.

Sepsis survivors are at high risk for adverse events after hospitalization, although associations with rehospitalization or subsequent death are unclear. This retrospective cohort analysis used data from the OptumLabs Data Warehouse of patients hospitalized between February 2009 and December 2019 who survived for at least 2 nights. A multivariable Cox proportional-hazards model was used to estimate and compare rehospitalization in sepsis and nonsepsis survivors, and a Kaplan-Meier survival model to analyze postdischarge events comparing groups by log-rank testing. Of 2,258,464 survivors, a total of 808,673 (36%) were diagnosed with sepsis during hospitalization. Sepsis patients were older with more comorbidities including cardiovascular disease. The risk of all-cause rehospitalization (adjusted hazard ratio, 1.38 [95% CI, 1.37 to 1.39]; P < 0.001) as well as all-cause mortality (adjusted hazard ratio, 1.27 [95% CI, 1.25 to 1.28]; P < 0.001) were greater in patients with sepsis. The risk for hospitalization due to cardiovascular disease was greater as well, with an adjusted hazard ratio of 1.43 (95% CI, 1.41 to 1.44; P < 0.001), especially due to heart failure (adjusted hazard ratio, 1.51 [95% CI, 1.49 to 1.53]; P < 0.001). A sensitivity analysis using the first hospitalization confirmed results for cardiovascular hospitalization (adjusted hazard ratio, 1.78 [95% CI, 1.76 to 1.78]; P < 0.001). Also, a propensity-weighted analysis (adjusted hazard ratio, 1.52 [95% CI, 1.50 to 1.54]; P < 0.001) revealed similar results.

Take home message: This retrospective cohort analysis suggests that patients surviving hospitalization for sepsis experience a greater risk for rehospitalization or death and cardiovascular events than nonsepsis survivors do.

After cardiac surgery, cognitive dysfunction is common and may be related to brain inflammation. It is unclear whether these cognitive deficits are mediated by alterations in brain network functional connectivity. Neuropsychologic testing, blood levels of two inflammatory cytokines (tumor necrosis factor-α, interleukin-6); and functional magnetic resonance imaging scans were done preoperatively and at 7 and 30 days postoperatively in 17 patients undergoing cardiac valve replacement surgery and were compared with 18 healthy age-matched controls. On postoperative day 7, neuropsychologic testing revealed executive function deficits. Therefore, a brain area known to be important for executive function was chosen as a seed to assess changes in functional connectivity. The preoperative patients and healthy controls showed the expected correlations of activity within the executive control network, and negative correlations with other brain networks. The negative correlations with other brain networks were lost on the postoperative day 7 scan but had returned to baseline by postoperative day 30. The inflammatory cytokine levels were maximal on day 7 and correlated with the functional connectivity between and within networks and also with components of the neuropsychology battery.

Take home message: Systemic inflammation is associated with cognitive deficits and disturbed functional connectivity in brain networks after cardiac surgery.

Adverse pregnancy outcomes have been linked to greater risk of maternal cardiovascular disease in later life, but there are no previous data on the prevalence of subclinical coronary atherosclerosis in this cohort. This cross-sectional, population-based cohort study of women in Sweden (n = 10,528) analyzing coronary computed tomography angiography indices in women with more than one delivery in 1973 or later enrolled in the Swedish Cardiopulmonary Bioimage Study (2013 to 2018) at age 50 to 65 yr (median, 57.3 yr) stratified by the presence or absence of prior adverse pregnancy outcomes (19%); specific pregnancy histories ranged from gestational diabetes (1%) to preterm delivery (10%). At a median of 30 yr (interquartile range, 25.0 to 34.9 yr) after their first delivery, the prevalence of coronary artery disease in women with adverse pregnancy outcomes was 32% (95% CI, 30 to 34%), significantly higher (prevalence difference, 4% [95% CI, 2 to 6%]; prevalence ratio, 1.14 [95% CI, 1.06 to 1.22]) than reference women. Gestational hypertension and preeclampsia were significantly associated with higher and similar prevalence of coronary artery disease, significant stenosis, noncalcified plaque, segment involvement score higher than 4, and coronary artery calcium score higher than 100. In adjusted models, for preeclampsia, odds ratios ranged from 1.31 (95% CI, 1.07 to 1.61) for any coronary artery disease to 2.21 (95% CI, 1.42-3.44) for significant stenosis. Of note, similar associations were observed for women with low predicted cardiovascular risk.

Take home message: In this large observational cohort analysis, women with adverse pregnancy outcomes were found to have significantly increased risk of later-life coronary atherosclerosis on coronary computed tomography angiography at either high or low predicted risk for coronary artery disease.

This American Thoracic Society–Fleischner Society workshop report summarizes the fundamental principles and analytic approaches used for linking quantitative thoracic imaging modalities to pulmonary structure, function, and disease pathology. The rapid proliferation of imaging modalities and contrast agents has led to innovative methods for evaluating structural data (e.g., airspace, parenchymal, and vascular volumes and dimensions) and functional information (e.g., regional ventilation-perfusion matching or alveolar-capillary diffusion). Quantitative analyses of computed tomography imaging can provide detailed information on regional lung volumes, tissue density and texture, spatial relationships, anatomic dimensions, and respiratory mechanics. Methods like magnetic resonance imaging or positron emission tomography have less structural resolution than computed tomography but can be used with tracers or specialized acquisition modes to evaluate dynamic physiologic functions, like ventilation-perfusion matching. This report makes recommendations for unbiased study design and analysis, use of standardized imaging guidelines to improve reproducibility, and identify reporting standards (e.g., posture, point in breath cycle) necessary for interpretation of the imaging data.

Take home message: This comprehensive workshop report summarizes the fundamental principles of quantitative thoracic imaging used to assess pulmonary physiology. It is recommended reading for both the researcher and the clinician interested in learning the latest nuances of state-of-the-art pulmonary imaging modalities.

Open lobectomy, video-assisted thoracoscopic surgery, and more recently, robotic-assisted lobectomy is commonly used early-stage lung cancer resection. This retrospective study using data from 21 U.S. centers with experienced surgeons evaluated the relative effectiveness of these approaches. Propensity-score matching (1:1) included age, sex, race, smoking status, FEV1%, Zubrod score, American Society of Anesthesiologists score, tumor size, and clinical T and N stages. From 2013 to 2019, all consecutive cases of lung cancer clinical stage IA to IIIA were included. Both minimally invasive procedures were correlated with fewer postoperative complications (patients %) (Open vs. Robotic: 36% vs. 27%, P < 0.0001; Open vs. Video: 36% vs. 28%, P = 0.001), and a shorter hospital stay (mean days ± SD) (Open vs. Robotic: 6 days ± 5, Robotic 4 days ± 5, P < 0.0001; Open vs. Video: 6 days ± 6 vs. 5 days ± 4; P < 0.0001). Hospital stay for Robotic was lower compared to Video (4 days ± 4 vs. 5 days ± 5, P < 0.0001). The conversion rate to Open from Robotic was lower compared to Video (4% vs. 10%, P < 0.0001). In-hospital mortality and 30-day mortality were comparable between all three groups (0.3 to 0.8%).

Take home message: This retrospective, multi-institutional, propensity-matched analysis suggests that minimally invasive procedures have better outcomes compared to open lobectomy and that the robotic technique was superior to video-assisted approaches with regard to conversion rates and length of hospital stay.

The mechanisms underlying opioid withdrawal are still elusive. In this study, an expanded population of fragile regulatory T cells (fTreg), which are characterized by the loss of their immunosuppressive function and the production of IFN-γ despite expressing the transcription factor Foxp3, was identified in the blood of patients with opioid use disorder. Subsequent experiments in mice revealed that the development of fTreg cells resulted from opioid-induced global hypoxia and was driven by upregulation of hypoxia-inducible factor 1-α. In mice with short- and long-term morphine treatment, fTreg cells infiltrated the nucleus accumbens, the region of the brain serving as the reward center and regulating addictive behavior, remodeled the morphology of neurons and weakened their excitatory synaptic function. The use of IFN-γ–neutralizing antibodies or the deletion of the IFN-γ gene in Treg cells led to lessened withdrawal symptoms. Morphine-exposed neurons produced greater amounts of the chemokine CCL2, and deletion of the CCL2 receptor in Treg cells lowered their infiltration into the nucleus accumbens and the withdrawal symptoms. Morphine treatment was also associated with elevated blood-brain barrier permeability and a lower abundance of astrocyte-derived fatty acid–binding protein 7 (Fabp7). Overexpression of Fabp7 rescued the barrier function and lowered neuroinflammation in the nucleus accumbens and withdrawal symptoms.

Take home message: Opioids increase the expansion of specific T cells, which cross the blood-brain barrier, where they mediate synaptic instability responsible for withdrawal symptoms. This finding opens the development of a novel immunotherapeutic treatment of opioid-dependent patients.