Mitochondrial CypD Acetylation Promotes Endothelial Dysfunction and Hypertension.

BACKGROUND: Nearly half of adults have hypertension, a major risk factor for cardiovascular disease. Mitochondrial hyperacetylation is linked to hypertension, but the role of acetylation of specific proteins is not clear. We hypothesized that acetylation of mitochondrial CypD (cyclophilin D) at K166 contributes to endothelial dysfunction and hypertension. METHODS: To test this hypothesis, we studied CypD acetylation in patients with essential hypertension, defined a pathogenic role of CypD acetylation in deacetylation mimetic CypD-K166R mutant mice and endothelial-specific GCN5L1 (general control of amino acid synthesis 5 like 1)-deficient mice using an Ang II (angiotensin II) model of hypertension. RESULTS: Arterioles from hypertensive patients had 280% higher CypD acetylation coupled with reduced Sirt3 (sirtuin 3) and increased GCN5L1 levels. GCN5L1 regulates mitochondrial protein acetylation and promotes CypD acetylation, which is counteracted by mitochondrial deacetylase Sirt3. In human aortic endothelial cells, GCN5L1 depletion prevents superoxide overproduction. Deacetylation mimetic CypD-K166R mice were protected from vascular oxidative stress, endothelial dysfunction, and Ang II-induced hypertension. Ang II-induced hypertension increased mitochondrial GCN5L1 and reduced Sirt3 levels resulting in a 250% increase in GCN5L1/Sirt3 ratio promoting CypD acetylation. Treatment with mitochondria-targeted scavenger of cytotoxic isolevuglandins (mito2HOBA) normalized GCN5L1/Sirt3 ratio, reduced CypD acetylation, and attenuated hypertension. The role of mitochondrial acetyltransferase GCN5L1 in the endothelial function was tested in endothelial-specific GCN5L1 knockout mice. Depletion of endothelial GCN5L1 prevented Ang II-induced mitochondrial oxidative stress, reduced the maladaptive switch of vascular metabolism to glycolysis, prevented inactivation of endothelial nitric oxide, preserved endothelial-dependent relaxation, and attenuated hypertension. CONCLUSIONS: These data support the pathogenic role of CypD acetylation in endothelial dysfunction and hypertension. We suggest that targeting cytotoxic mitochondrial isolevuglandins and GCN5L1 reduces CypD acetylation, which may be beneficial in cardiovascular disease.

Oxidative stress mediates associations between preoperative psychosocial phenotype and pain-related outcomes at 6 months following total knee arthroplasty: a longitudinal cohort study.

OBJECTIVE: Greater preoperative depression, anxiety, and pain catastrophizing are associated with more severe long-term pain following total knee arthroplasty (TKA). In a secondary analysis of previously reported data, we tested the hypothesis that these associations are mediated by oxidative stress (OS). DESIGN: A mixed between/within-subjects longitudinal cohort design. SETTING: A single academic medical center. SUBJECTS: Osteoarthritis patients (n = 91; 62.6% female) undergoing unilateral TKA. METHODS: We assessed depression, anxiety, and catastrophizing, as well as markers of central sensitization (widespread pain, temporal summation of pain) preoperatively. Blood samples were then obtained immediately prior to intraoperative tourniquet placement for quantification of in vivo biomarkers of systemic OS, F2-isoprostanes and isofurans. Post-TKA pain intensity (numeric rating scale worst pain [NRS], McGill Pain Questionnaire-2 [MPQ-2]) and function (PROMIS Pain Interference) were assessed at 6 months following TKA. RESULTS: Greater preoperative depression, catastrophizing, and widespread pain were associated with higher intraoperative combined OS (F2-isoprostanes+isofurans/2), which was in turn associated with higher post-TKA pain intensity and worse function (P < .05). All preoperative phenotype predictors except anxiety were correlated positively with post-TKA pain and/or function (P < .05). Bootstrapped mediation analyses revealed significant (P < .05) indirect (mediated) effects of depression (NRS Worst Pain, MPQ-2, PROMIS Pain Interference), anxiety (MPQ-2, PROMIS Pain Interference), and catastrophizing (PROMIS Pain Interference) on adverse long-term post-TKA outcomes via elevated OS. Central sensitization-related predictors demonstrated only direct effects (P < .05) on post-TKA outcomes that were independent of OS mechanisms. CONCLUSIONS: Results suggest that the adverse impact of depression, anxiety, and pain catastrophizing on post-TKA pain and functional outcomes are mediated in part by elevated OS.

Hyperoxia Increases Kidney Injury During Renal Ischemia and Reperfusion in Mice.

BACKGROUND: Renal ischemia and reperfusion (IR) contribute to perioperative acute kidney injury, and oxygen is a key regulator of this process. We hypothesized that oxygen administration during surgery and renal IR would impact postoperative kidney function and injury in mice. METHODS: Mice were anesthetized, intubated, and mechanically ventilated with a fraction of inspired oxygen (F io2 ) 0.10 (hypoxia), 0.21 (normoxia), 0.60 (moderate hyperoxia), or 1.00 (severe hyperoxia) during 67 minutes of renal IR or sham IR surgery. Additional mice were treated before IR or sham IR surgery with 50 mg/kg tempol, a superoxide scavenger. At 24 hours, mice were sacrificed, and blood and kidney collected. We assessed and compared kidney function and injury across groups by measuring blood urea nitrogen (BUN, primary end point), renal histological injury, renal expression of neutrophil gelatinase-associated lipocalin (NGAL), and renal heme oxygenase 1 ( Ho-1 ), peroxisome proliferator-activated receptor gamma coactivator 1-α ( Pgc1-α ), and glutathione peroxidase 4 ( Gpx-4 ) transcripts, to explore potential mechanisms of any effect of oxygen. RESULTS: Hyperoxia and hypoxia during renal IR surgery decreased renal function and increased kidney injury compared to normoxia. Baseline median (interquartile range) BUN was 22.2 mg/dL (18.4-26.0), and 24 hours after IR surgery, BUN was 17.5 mg/dL (95% confidence interval [CI], 1.3-38.4; P = .034) higher in moderate hyperoxia-treated animals, 51.8 mg/dL (95% CI, 24.9-74.8; P < .001) higher in severe hyperoxia-treated animals, and 64.9 mg/dL (95% CI, 41.2-80.3; P < .001) higher in hypoxia-treated animals compared to animals treated with normoxia ( P < .001, overall effect of hyperoxia). Hyperoxia-induced injury, but not hypoxia-induced injury, was attenuated by pretreatment with tempol. Histological injury scores, renal NGAL staining, and renal transcription of Ho-1 and suppression of Pgc1- α followed the same pattern as BUN, in relation to the effects of oxygen treatment. CONCLUSIONS: In this controlled preclinical study of oxygen treatment during renal IR surgery, hyperoxia and hypoxia impaired renal function, increased renal injury, and impacted expression of genes that affect mitochondrial biogenesis and antioxidant response. These results might have implications for patients during surgery when high concentrations of oxygen are frequently administered, especially in cases involving renal IR.

Preoperative Predictors of Prolonged Opioid Use in the 6 Months After Total Knee Arthroplasty.

OBJECTIVES: Prolonged postoperative opioid use increases the risk for new postsurgical opioid use disorder. We evaluated preoperative phenotypic factors predicting prolonged postoperative opioid use. METHODS: We performed a secondary analysis of a prospective observational cohort (n=108) undergoing total knee arthroplasty (TKA) for osteoarthritis with 6-week and 6-month follow-up. Current opioid use and psychosocial, pain, and opioid-related characteristics were assessed at preoperative baseline. Primary outcomes were days/week of opioid use at follow-up. RESULTS: At 6 weeks, preoperative opioid use and greater cumulative opioid exposure, depression, catastrophizing, anxiety, pain interference, sleep disturbance, and central sensitization were significantly associated with more days/week of opioid use after controlling for contemporaneous pain intensity. Prior euphoric response to opioids were also significant predictors at 6 months. All 6-week predictors except anxiety remained significant after controlling for preoperative opioid use; at 6 months, cumulative opioid exposure, catastrophizing, pain interference, and sleep disturbance remained significant after this adjustment ( P <0.05). In multivariable models, a psychosocial factor reflecting negative affect, sleep, and pain accurately predicted 6-week opioid use (area under the curve=0.84). A combined model incorporating psychosocial factor scores, opioid-related factor scores, and preoperative opioid use showed near-perfect predictive accuracy at 6 months (area under the curve=0.97). DISCUSSION: Overall, preoperative psychosocial, pain-related, and opioid-related phenotypic characteristics predicted prolonged opioid use after total knee arthroplasty.

Targeting Soluble Guanylyl Cyclase during Ischemia and Reperfusion.

Ischemia and reperfusion (IR) damage organs and contribute to many disease states. Few effective treatments exist that attenuate IR injury. The augmentation of nitric oxide (NO) signaling remains a promising therapeutic target for IR injury. NO binds to soluble guanylyl cyclase (sGC) to regulate vasodilation, maintain endothelial barrier integrity, and modulate inflammation through the production of cyclic-GMP in vascular smooth muscle. Pharmacologic sGC stimulators and activators have recently been developed. In preclinical studies, sGC stimulators, which augment the reduced form of sGC, and activators, which activate the oxidized non-NO binding form of sGC, increase vasodilation and decrease cardiac, cerebral, renal, pulmonary, and hepatic injury following IR. These effects may be a result of the improved regulation of perfusion and decreased oxidative injury during IR. sGC stimulators are now used clinically to treat some chronic conditions such as heart failure and pulmonary hypertension. Clinical trials of sGC activators have been terminated secondary to adverse side effects including hypotension. Additional clinical studies to investigate the effects of sGC stimulation and activation during acute conditions, such as IR, are warranted.

The Association Between Enhanced Recovery After Cardiac Surgery-Guided Analgesics and Postoperative Delirium.

OBJECTIVES: Delirium is a common postoperative complication associated with death and long-term cognitive impairment. The authors studied the association between opioid-sparing anesthetics, incorporating Enhanced Recovery After Cardiac Surgery (ERACS)-guided analgesics and postoperative delirium. DESIGN: The authors performed a retrospective review of nonemergent coronary, valve, or ascending aorta surgery patients. SETTING: A tertiary academic medical institution. PARTICIPANTS: The study authors analyzed a dataset of elective adult cardiac surgical patients. All patients ≥18 years undergoing elective cardiac surgery from November 2, 2017 until February 2, 2021 were eligible for inclusion. INTERVENTIONS: The ERACS-guided multimodal pain regimen included preoperative oral acetaminophen and gabapentin, and intraoperative intravenous lidocaine, ketamine, and dexmedetomidine. MEASUREMENTS AND MAIN RESULTS: Delirium was measured by bedside nurses using the Confusion Assessment Method for the intensive care unit (ICU). Delirium occurred in 220 of the 1,675 patients (13.7%). The use of any component of the multimodal pain regimen was not associated with delirium (odds ratio [OR]: 0.85 [95% CI: 0.63-1.16]). Individually, acetaminophen was associated with reduced odds of delirium (OR: 0.60 [95% CI: 0.37-0.95]). Gabapentin (OR: 1.36 [95% CI: 0.97-2.21]), lidocaine (OR: 0.86 [95% CI: 0.53-1.37]), ketamine (OR: 1.15 [95% CI: 0.72-1.83]), and dexmedetomidine (OR: 0.79 [95% CI: 0.46-1.31]) were not individually associated with postoperative delirium. Individual ERACS elements were associated with secondary outcomes of hospital length of stay, ICU duration, postoperative opioid administration, and postoperative intubation duration. CONCLUSIONS: The use of an opioid-sparing perioperative ERACS pain regimen was not associated with reduced postoperative delirium, opioid consumption, or additional poor outcomes. Individually, acetaminophen was associated with reduced delirium.

Perioperative oxidative stress predicts subsequent pain-related outcomes in the 6 months after total knee arthroplasty.

ABSTRACT: Total knee arthroplasty (TKA) is effective for pain reduction in most patients, but 15% or more report unsatisfactory long-term pain outcomes. We tested whether oxidative stress (OS) related to extended tourniquet application during TKA and subsequent ischemic reperfusion (IR) contributed to adverse post-TKA pain outcomes. Blood samples were obtained in 91 patients with osteoarthritis (63% female) undergoing TKA before tourniquet placement (T1), 45 minutes after tourniquet inflation (T2), and 15 minutes after tourniquet removal (T3). Plasma levels of F 2 -isoprostanes and isofurans, the most specific measures of in vivo OS, were quantified. Pain intensity and function were assessed at baseline and again at 6 weeks and 6 months after TKA. Results indicated that higher Combined OS (F 2 -isoprostanes + isofurans/2) at T1 baseline and larger increases in Combined OS from T1 to T2 were associated with higher baseline-corrected past 24-hour worst and average pain intensity (numeric rating scale) and higher past week McGill Pain Questionnaire-2 total scores at 6-month follow-up ( P 's < 0.05). Increases in Combined OS from T1 to T3, which should most directly capture OS and IR injury related to tourniquet use, were not associated with short-term or long-term post-TKA pain outcomes. Longer ischemia duration was unexpectedly associated with lower baseline-corrected pain intensity at 6-month follow-up. Combined OS was not linked to functional outcomes at either follow-up. Elevated perioperative OS seems to exert small but significant adverse effects on long-term post-TKA pain outcomes, although this OS seems unrelated to IR injury associated with extended tourniquet use.

Perioperative Acute Kidney Injury: Implications, Approach, Prevention.

Acute kidney injury remains a common and significant contributor to perioperative morbidity. Acute kidney injury worsens patient outcomes, and anesthesiologists should make significant efforts to prevent, assess, and treat perioperative renal injury. The authors discuss the impact of renal injury on patient outcomes and putative underlying mechanisms, evidence underlying treatments for acute kidney injury, and practices that may prevent the development of perioperative renal injury.

Oxygen administration during surgery and postoperative organ injury: observational cohort study.

OBJECTIVE: To examine whether supraphysiological oxygen administration during surgery is associated with lower or higher postoperative kidney, heart, and lung injury. DESIGN: Observational cohort study. SETTING: 42 medical centers across the United States participating in the Multicenter Perioperative Outcomes Group data registry. PARTICIPANTS: Adult patients undergoing surgical procedures ≥120 minutes' duration with general anesthesia and endotracheal intubation who were admitted to hospital after surgery between January 2016 and November 2018. INTERVENTION: Supraphysiological oxygen administration, defined as the area under the curve of the fraction of inspired oxygen above air (21%) during minutes when the hemoglobin oxygen saturation was greater than 92%. MAIN OUTCOMES: Primary endpoints were acute kidney injury defined using Kidney Disease Improving Global Outcomes criteria, myocardial injury defined as serum troponin >0.04 ng/mL within 72 hours of surgery, and lung injury defined using international classification of diseases hospital discharge diagnosis codes. RESULTS: The cohort comprised 350 647 patients with median age 59 years (interquartile range 46-69 years), 180 546 women (51.5%), and median duration of surgery 205 minutes (interquartile range 158-279 minutes). Acute kidney injury was diagnosed in 19 207 of 297 554 patients (6.5%), myocardial injury in 8972 of 320 527 (2.8%), and lung injury in 13 789 of 312 161 (4.4%). The median fraction of inspired oxygen was 54.0% (interquartile range 47.5%-60.0%), and the area under the curve of supraphysiological inspired oxygen was 7951% min (5870-11 107% min), equivalent to an 80% fraction of inspired oxygen throughout a 135 minute procedure, for example. After accounting for baseline covariates and other potential confounding variables, increased oxygen exposure was associated with a higher risk of acute kidney injury, myocardial injury, and lung injury. Patients at the 75th centile for the area under the curve of the fraction of inspired oxygen had 26% greater odds of acute kidney injury (95% confidence interval 22% to 30%), 12% greater odds of myocardial injury (7% to 17%), and 14% greater odds of lung injury (12% to 16%) compared with patients at the 25th centile. Sensitivity analyses evaluating alternative definitions of the exposure, restricting the cohort, and conducting an instrumental variable analysis confirmed these observations. CONCLUSIONS: Increased supraphysiological oxygen administration during surgery was associated with a higher incidence of kidney, myocardial, and lung injury. Residual confounding of these associations cannot be excluded. TRIAL REGISTRATION: Open Science Framework osf.io/cfd2m.

Role of Axl in target organ inflammation and damage due to hypertensive aortic remodeling.

We have shown that excessive endothelial cell stretch causes release of growth arrest-specific 6 (GAS6), which activates the tyrosine kinase receptor Axl on monocytes and promotes immune activation and inflammation. We hypothesized that GAS6/Axl blockade would reduce renal and vascular inflammation and lessen renal dysfunction in the setting of chronic aortic remodeling. We characterized a model of aortic remodeling in mice following a 2-wk infusion of angiotensin II (ANG II). These mice had chronically increased pulse wave velocity, and their aortas demonstrated increased mural collagen. Mechanical testing revealed a marked loss of Windkessel function that persisted for 6 mo following ANG II infusion. Renal function studies showed a reduced ability to excrete a volume load, a progressive increase in albuminuria, and tubular damage as estimated by periodic acid Schiff staining. Treatment with the Axl inhibitor R428 beginning 2 mo after ANG II infusion had a minimal effect on aortic remodeling 2 mo later but reduced the infiltration of T cells, γ/δ T cells, and macrophages into the aorta and kidney and improved renal excretory capacity, reduced albuminuria, and reduced evidence of renal tubular damage. In humans, circulating Axl+/Siglec6+ dendritic cells and phospho-Axl+ cells correlated with pulse wave velocity and aortic compliance measured by transesophageal echo, confirming chronic activation of the GAS6/Axl pathway. We conclude that brief episodes of hypertension induce chronic aortic remodeling, which is associated with persistent low-grade inflammation of the aorta and kidneys and evidence of renal dysfunction. These events are mediated at least in part by GAS6/Axl signaling and are improved with Axl blockade.NEW & NOTEWORTHY In this study, a brief, 2-wk period of hypertension in mice led to progressive aortic remodeling, an increase in pulse wave velocity, and evidence of renal injury, dysfunction, and albuminuria. This end-organ damage was associated with persistent renal and aortic infiltration of CD8+ and γ/δ T cells. We show that this inflammatory response is likely due to GAS6/Axl signaling and can be ameliorated by blocking this pathway. We propose that the altered microvascular mechanical forces caused by increased pulse wave velocity enhance GAS6 release from the endothelium, which in turn activates Axl on myeloid cells, promoting the end-organ damage associated with aortic stiffening.

SOLUBLE GUANYLYL CYCLASE ACTIVATION RESCUES HYPEROXIA-INDUCED DYSFUNCTION OF VASCULAR RELAXATION.

ABSTRACT: Introduction: Perioperative alterations in perfusion lead to ischemia and reperfusion injury, and supplemental oxygen is administered during surgery to limit hypoxic injury but can lead to hyperoxia. We hypothesized that hyperoxia impairs endothelium-dependent and endothelium-independent vasodilation but not the vasodilatory response to heme-independent soluble guanylyl cyclase activation. Methods: We measured the effect of oxygen on vascular reactivity in mouse aortas. Mice were ventilated with 21% (normoxia), 60% (moderate hyperoxia), or 100% (severe hyperoxia) oxygen during 30 minutes of renal ischemia and 30 minutes of reperfusion. After sacrifice, the thoracic aorta was isolated, and segments mounted on a wire myograph. We measured endothelium-dependent and endothelium-independent vasodilation with escalating concentrations of acetylcholine (ACh) and sodium nitroprusside (SNP), respectively, and we measured the response to heme-independent soluble guanylyl cyclase activation with cinaciguat. Vasodilator responses to each agonist were quantified as the maximal theoretical response ( Emax ) and the effective concentration to elicit 50% relaxation (EC 50 ) using a sigmoid model and nonlinear mixed-effects regression. Aortic superoxide was measured with dihydroethidium probe and high-performance liquid chromatography quantification of the specific superoxide product 2-hydroxyethidium. Results: Hyperoxia impaired endothelium-dependent (ACh) and endothelium-independent (SNP) vasodilation compared with normoxia and had no effect on cinaciguat-induced vasodilation. The median ACh Emax was 76.4% (95% confidence interval = 69.6 to 83.3) in the normoxia group, 53.5% (46.7 to 60.3) in the moderate hyperoxia group, and 53.1% (46.3 to 60.0) in the severe hyperoxia group ( P < 0.001, effect across groups), while the ACh EC 50 was not different among groups. The SNP Emax was 133.1% (122.9 to 143.3) in normoxia, 128.3% (118.1 to 138.6) in moderate hyperoxia, and 114.8% (104.6 to 125.0) in severe hyperoxia ( P < 0.001, effect across groups), and the SNP EC 50 was 0.38 log M greater in moderate hyperoxia than in normoxia (95% confidence interval = 0.18 to 0.58, P < 0.001). Cinaciguat Emax and EC 50 were not different among oxygen treatment groups (median range Emax = 78.0% to 79.4% and EC 50 = -18.0 to -18.2 log M across oxygen groups). Aorta 2-hydroxyethidium was 1419 pmol/mg of protein (25th-75th percentile = 1178-1513) in normoxia, 1993 (1831-2473) in moderate hyperoxia, and 2078 (1936-2922) in severe hyperoxia ( P = 0.008, effect across groups). Conclusions: Hyperoxia, compared with normoxia, impaired endothelium-dependent and endothelium-independent vasodilation but not the response to heme-independent soluble guanylyl cyclase activation, and hyperoxia increased vascular superoxide production. Results from this study could have important implications for patients receiving high concentrations of oxygen and at risk for ischemia reperfusion-mediated organ injury.

Society of Cardiovascular Anesthesiologists Clinical Practice Update for Management of Acute Kidney Injury Associated With Cardiac Surgery.

Cardiac surgery-associated acute kidney injury (CS-AKI) is common and is associated with increased risk for postoperative morbidity and mortality. Our recent survey of the Society of Cardiovascular Anesthesiologists (SCA) membership showed 6 potentially renoprotective strategies for which clinicians would most value an evidence-based review (ie, intraoperative target blood pressure, choice of specific vasopressor agent, erythrocyte transfusion threshold, use of alpha-2 agonists, goal-directed oxygen delivery on cardiopulmonary bypass [CPB], and the "Kidney Disease Improving Global Outcomes [KDIGO] bundle of care"). Thus, the SCA's Continuing Practice Improvement Acute Kidney Injury Working Group aimed to provide a practice update for each of these strategies in cardiac surgical patients based on the evidence from randomized controlled trials (RCTs). PubMed, EMBASE, and Cochrane library databases were comprehensively searched for eligible studies from inception through February 2021, with search results updated in August 2021. A total of 15 RCTs investigating the effects of the above-mentioned strategies on CS-AKI were included for meta-analysis. For each strategy, the level of evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology. Across the 6 potentially renoprotective strategies evaluated, current evidence for their use was rated as "moderate," "low," or "very low." Based on eligible RCTs, our analysis suggested using goal-directed oxygen delivery on CPB and the "KDIGO bundle of care" in high-risk patients to prevent CS-AKI (moderate level of GRADE evidence). Our results suggested considering the use of vasopressin in vasoplegic shock patients to reduce CS-AKI (low level of GRADE evidence). The decision to use a restrictive versus liberal strategy for perioperative red cell transfusion should not be based on concerns for renal protection (a moderate level of GRADE evidence). In addition, targeting a higher mean arterial pressure during CPB, perioperative use of dopamine, and use of dexmedetomidine did not reduce CS-AKI (a low or very low level of GRADE evidence). This review will help clinicians provide evidence-based care, targeting improved renal outcomes in adult patients undergoing cardiac surgery.

Preoperative Predictors of Complex Regional Pain Syndrome Outcomes in the 6 Months Following Total Knee Arthroplasty.

This prospective observational study evaluated preoperative predictors of complex regional pain syndrome (CRPS) outcomes in the 6 months following total knee arthroplasty (TKA). Participants were n = 110 osteoarthritis patients (64.5% female) undergoing unilateral TKA with no prior CRPS history. Domains of negative affect (depression, anxiety, catastrophizing), pain (intensity, widespread pain, temporal summation of pain [TSP]), pain interference, sleep disturbance, and pro-inflammatory status (tumor necrosis factor-alpha [TNF-a]) were assessed preoperatively. CRPS outcomes at 6-week and 6-month follow-up included the continuous CRPS Severity Score (CSS) and dichotomous CRPS diagnoses (2012 IASP criteria). At 6 months, 12.7% of participants met CRPS criteria, exhibiting a "warm CRPS" phenotype. Six-week CSS scores were predicted by greater preoperative depression, anxiety, catastrophizing, TSP, pain intensity, sleep disturbance, and TNF-a (P's < .05). Provisional CRPS diagnosis at 6 weeks was predicted by higher preoperative TSP, sleep disturbance, and TNF-a (P's < .05). CSS scores at 6 months were predicted by more widespread and intense preoperative pain, and higher preoperative TSP, pain interference, and TNF-a (P's < .01). CRPS diagnosis at 6 months was predicted only by more widespread and intense pain preoperatively (P's < .05). Risk for CRPS following TKA appears to involve preoperative central sensitization and inflammatory mechanisms. Preoperative negative affect is unlikely to directly influence long-term CRPS risk. PERSPECTIVE: This article identifies preoperative predictors of CRPS features at 6 months following total knee arthroplasty, including more widespread pain and higher pain intensity, temporal summation of pain, pain interference, and tumor necrosis factor-alpha levels. Findings suggest the importance of central sensitization and inflammatory mechanisms in CRPS risk following tissue trauma.

Assessment of Awake Prone Positioning in Hospitalized Adults With COVID-19: A Nonrandomized Controlled Trial.

Importance: Awake prone positioning may improve hypoxemia among patients with COVID-19, but whether it is associated with improved clinical outcomes remains unknown. Objective: To determine whether the recommendation of awake prone positioning is associated with improved outcomes among patients with COVID-19-related hypoxemia who have not received mechanical ventilation. Design, Setting, and Participants: This pragmatic nonrandomized controlled trial was conducted at 2 academic medical centers (Vanderbilt University Medical Center and NorthShore University HealthSystem) during the COVID-19 pandemic. A total of 501 adult patients with COVID-19-associated hypoxemia who had not received mechanical ventilation were enrolled from May 13 to December 11, 2020. Interventions: Patients were assigned 1:1 to receive either the practitioner-recommended awake prone positioning intervention (intervention group) or usual care (usual care group). Main Outcomes and Measures: Primary outcome analyses were performed using a bayesian proportional odds model with covariate adjustment for clinical severity ranking based on the World Health Organization ordinal outcome scale, which was modified to highlight the worst level of hypoxemia on study day 5. Results: A total of 501 patients (mean [SD] age, 61.0 [15.3] years; 284 [56.7%] were male; and most [417 (83.2%)] were self-reported non-Hispanic or non-Latinx) were included. Baseline severity was comparable between the intervention vs usual care groups, with 170 patients (65.9%) vs 162 patients (66.7%) receiving oxygen via standard low-flow nasal cannula, 71 patients (27.5%) vs 62 patients (25.5%) receiving oxygen via high-flow nasal cannula, and 16 patients (6.2%) vs 19 patients (7.8%) receiving noninvasive positive-pressure ventilation. Nursing observations estimated that patients in the intervention group spent a median of 4.2 hours (IQR, 1.8-6.7 hours) in the prone position per day compared with 0 hours (IQR, 0-0.7 hours) per day in the usual care group. On study day 5, the bayesian posterior probability of the intervention group having worse outcomes than the usual care group on the modified World Health Organization ordinal outcome scale was 0.998 (posterior median adjusted odds ratio [aOR], 1.63; 95% credibility interval [CrI], 1.16-2.31). However, on study days 14 and 28, the posterior probabilities of harm were 0.874 (aOR, 1.29; 95% CrI, 0.84-1.99) and 0.673 (aOR, 1.12; 95% CrI, 0.67-1.86), respectively. Exploratory outcomes (progression to mechanical ventilation, length of stay, and 28-day mortality) did not differ between groups. Conclusions and Relevance: In this nonrandomized controlled trial, prone positioning offered no observed clinical benefit among patients with COVID-19-associated hypoxemia who had not received mechanical ventilation. Moreover, there was substantial evidence of worsened clinical outcomes at study day 5 among patients recommended to receive the awake prone positioning intervention, suggesting potential harm. Trial Registration: ClinicalTrials.gov Identifier: NCT04359797.

Oxidative stress is associated with characteristic features of the dysfunctional chronic pain phenotype.

ABSTRACT: The dysfunctional chronic pain (Dysfunctional CP) phenotype is an empirically identifiable CP subtype with unclear pathophysiological mechanisms that cuts across specific medical CP diagnoses. This study tested whether the multidimensional pain and psychosocial features that characterize the dysfunctional CP phenotype are associated broadly with elevated oxidative stress (OS). Measures of pain intensity, bodily extent of pain, catastrophizing cognitions, depression, anxiety, sleep disturbance, pain interference, and function were completed by 84 patients with chronic osteoarthritis before undergoing total knee arthroplasty. Blood samples were obtained at the initiation of surgery before incision or tourniquet placement. Plasma levels of F2-isoprostanes and isofurans, the most highly specific measures of in vivo OS, were quantified using gas chromatography/negative ion chemical ionization mass spectrometry. The results indicated that controlling for differences in age, sex, and body mass index, higher overall OS (mean of isoprostanes and isofurans) was associated with significantly (P < 0.05) greater pain intensity, more widespread pain, greater depressive symptoms and pain catastrophizing, higher pain interference, and lower function. OS measures were not significantly associated with sleep disturbance or anxiety levels (P >0.10). The results build on prior case-control findings suggesting that presence of a CP diagnosis is associated with elevated OS, highlighting that it may specifically be individuals displaying characteristics of the dysfunctional CP phenotype who are characterized by elevated OS. Clinical implications of these findings remain to be determined.

Impact of Intraoperative Data on Risk Prediction for Mortality After Intra-Abdominal Surgery.

BACKGROUND: Risk prediction models for postoperative mortality after intra-abdominal surgery have typically been developed using preoperative variables. It is unclear if intraoperative data add significant value to these risk prediction models. METHODS: With IRB approval, an institutional retrospective cohort of intra-abdominal surgery patients in the 2005 to 2015 American College of Surgeons National Surgical Quality Improvement Program was identified. Intraoperative data were obtained from the electronic health record. The primary outcome was 30-day mortality. We evaluated the performance of machine learning algorithms to predict 30-day mortality using: 1) baseline variables and 2) baseline + intraoperative variables. Algorithms evaluated were: 1) logistic regression with elastic net selection, 2) random forest (RF), 3) gradient boosting machine (GBM), 4) support vector machine (SVM), and 5) convolutional neural networks (CNNs). Model performance was evaluated using the area under the receiver operator characteristic curve (AUROC). The sample was randomly divided into a training/testing split with 80%/20% probabilities. Repeated 10-fold cross-validation identified the optimal model hyperparameters in the training dataset for each model, which were then applied to the entire training dataset to train the model. Trained models were applied to the test cohort to evaluate model performance. Statistical significance was evaluated using P < .05. RESULTS: The training and testing cohorts contained 4322 and 1079 patients, respectively, with 62 (1.4%) and 15 (1.4%) experiencing 30-day mortality, respectively. When using only baseline variables to predict mortality, all algorithms except SVM (area under the receiver operator characteristic curve [AUROC], 0.83 [95% confidence interval {CI}, 0.69-0.97]) had AUROC >0.9: GBM (AUROC, 0.96 [0.94-1.0]), RF (AUROC, 0.96 [0.92-1.0]), CNN (AUROC, 0.96 [0.92-0.99]), and logistic regression (AUROC, 0.95 [0.91-0.99]). AUROC significantly increased with intraoperative variables with CNN (AUROC, 0.97 [0.96-0.99]; P = .047 versus baseline), but there was no improvement with GBM (AUROC, 0.97 [0.95-0.99]; P = .3 versus baseline), RF (AUROC, 0.96 [0.93-1.0]; P = .5 versus baseline), and logistic regression (AUROC, 0.94 [0.90-0.99]; P = .6 versus baseline). CONCLUSIONS: Postoperative mortality is predicted with excellent discrimination in intra-abdominal surgery patients using only preoperative variables in various machine learning algorithms. The addition of intraoperative data to preoperative data also resulted in models with excellent discrimination, but model performance did not improve.

Potential Renoprotective Strategies in Adult Cardiac Surgery: A Survey of Society of Cardiovascular Anesthesiologists Members to Explore the Rationale and Beliefs Driving Current Clinical Decision-Making.

OBJECTIVES: The authors sought to (1) characterize the rationale underpinning anesthesiologists' use of various perioperative strategies hypothesized to affect renal function in adult patients undergoing cardiac surgery, (2) characterize existing belief about the quality of evidence addressing the renal impact of these strategies, and (3) identify potentially renoprotective strategies for which anesthesiologists would most value a detailed, evidence-based review. DESIGN: Survey of perioperative practice in adult patients undergoing cardiac surgery. SETTING: Online survey. PARTICIPANTS: Members of the Society of Cardiovascular Anesthesiologists (SCA). INTERVENTIONS: None. MEASUREMENTS & MAIN RESULTS: The survey was distributed to more than 2,000 SCA members and completed in whole or in part by 202 respondents. Selection of target intraoperative blood pressure (and relative hypotension avoidance) was the strategy most frequently reported to reflect belief about its potential renal effect (79%; 95% CI: 72-85). Most respondents believed the evidence supporting an effect on renal injury of intraoperative target blood pressure during cardiac surgery was of high or moderate quality. Other factors, including a specific nonrenal rationale, surgeon preference, department- or institution-level decisions, tradition, or habit, also frequently were reported to affect decision making across queried strategies. Potential renoprotective strategies most frequently requested for inclusion in a subsequent detailed, evidence-based review were intraoperative target blood pressure and choice of vasopressor agent to achieve target pressure. CONCLUSIONS: A large number of perioperative strategies are believed to variably affect renal injury in adult patients undergoing cardiac surgery, with wide variation in perceived quality of evidence for a renal effect of these strategies.

Intraoperative venous congestion and acute kidney injury in cardiac surgery: an observational cohort study.

BACKGROUND: Increased intravascular volume has been associated with protection from acute kidney injury (AKI), but in patients with congestive heart failure, venous congestion is associated with increased AKI. We tested the hypothesis that intraoperative venous congestion is associated with AKI after cardiac surgery. METHODS: In patients enrolled in the Statin AKI Cardiac Surgery trial, venous congestion was quantified as the area under the curve (AUC) of central venous pressure (CVP) >12, 16, or 20 mm Hg during surgery (mm Hg min). AKI was defined using Kidney Disease Improving Global Outcomes (KDIGO) criteria and urine concentrations of tissue inhibitor of metalloproteinase-2 and insulin-like growth factor binding protein 7 ([TIMP-2]⋅[IGFBP7]), a marker of renal stress. We measured associations between venous congestion, AKI and [TIMP-2]⋅[IGFBP7], adjusted for potential confounders. Values are reported as median (25th-75th percentile). RESULTS: Based on KDIGO criteria, 104 of 425 (24.5%) patients developed AKI. The venous congestion AUCs were 273 mm Hg min (81-567) for CVP >12 mm Hg, 66 mm Hg min (12-221) for CVP >16 mm Hg, and 11 mm Hg min (1-54) for CVP >20 mm Hg. A 60 mm Hg min increase above the median venous congestion AUC above each threshold was independently associated with increased AKI (odds ratio=1.06; 95% confidence interval [CI], 1.02-1.10; P=0.008; odds ratio=1.12; 95% CI, 1.02-1.23; P=0.013; and odds ratio=1.30; 95% CI, 1.06-1.59; P=0.012 for CVP>12, >16, and >20 mm Hg, respectively). Venous congestion before cardiopulmonary bypass was also associated with increased [TIMP-2]⋅[IGFBP7] measured during cardiopulmonary bypass and after surgery, but neither venous congestion after cardiopulmonary bypass nor venous congestion throughout surgery was associated with postoperative [TIMP-2]⋅[IGFBP7]. CONCLUSION: Intraoperative venous congestion was independently associated with increased AKI after cardiac surgery.

Perioperative high density lipoproteins, oxidative stress, and kidney injury after cardiac surgery.

Oxidative stress promotes acute kidney injury (AKI). Higher HDL cholesterol concentrations are associated with less AKI. To test the hypothesis that HDL antioxidant activity is associated with AKI after cardiac surgery, we quantified HDL particle (HDL-P) size and number, paraoxonase-1 (PON-1) activity, and isofuran concentrations in 75 patients who developed AKI and 75 matched control patients. Higher preoperative HDL-P was associated with less AKI (OR: 0.80; 95% CI, 0.71-0.91; P = 0.001), higher PON-1 activity ( P < 0.001), and lower plasma concentrations of isofurans immediately after surgery (P = 0.02). Similarly, higher preoperative small HDL-P was associated with less AKI, higher PON-1 activity, and lower isofuran concentrations. Higher intraoperative particle losses were associated with less AKI (OR: 0.79; 95% CI 0.67-0.93; P = 0.005), and with decreased postoperative isofuran concentrations (P = 0.04) . Additionally, higher preoperative small HDL-P and increased intraoperative small particle loss were associated with improved long-term renal function (P = 0.003, 0.01, respectively). In conclusion, a higher preoperative concentration of HDL-P, particularly small particles, is associated with lower oxidative damage and less AKI. Perioperative changes in HDL-P concentrations are also associated with AKI. Small HDL-P may represent a novel modifiable risk factor for AKI.