Amit Bardia

PGC-1α promotes recovery after acute kidney injury during systemic inflammation in mice.

Sepsis-associated acute kidney injury (AKI) is a common and morbid condition that is distinguishable from typical ischemic renal injury by its paucity of tubular cell death. The mechanisms underlying renal dysfunction in individuals with sepsis-associated AKI are therefore less clear. Here we have shown that endotoxemia reduces oxygen delivery to the kidney, without changing tissue oxygen levels, suggesting reduced oxygen consumption by the kidney cells. Tubular mitochondria were swollen, and their function was impaired. Expression profiling showed that oxidative phosphorylation genes were selectively suppressed during sepsis-associated AKI and reactivated when global function was normalized. PPARγ coactivator-1α (PGC-1α), a major regulator of mitochondrial biogenesis and metabolism, not only followed this pattern but was proportionally suppressed with the degree of renal impairment. Furthermore, tubular cells had reduced PGC-1α expression and oxygen consumption in response to TNF-α; however, excess PGC-1α reversed the latter effect. Both global and tubule-specific PGC-1α-knockout mice had normal basal renal function but suffered persistent injury following endotoxemia. Our results demonstrate what we believe to be a novel mechanism for sepsis-associated AKI and suggest that PGC-1α induction may be necessary for recovery from this disorder, identifying a potential new target for future therapeutic studies.

Combined Epidural-General Anesthesia vs General Anesthesia Alone for Elective Abdominal Aortic Aneurysm Repair

Importance Epidural analgesia (EA) is used as an adjunct procedure for postoperative pain control during elective abdominal aortic aneurysm (AAA) surgery. In addition to analgesia, modulatory effects of EA on spinal sympathetic outflow result in improved organ perfusion with reduced complications. Reductions in postoperative complications lead to shorter convalescence and possibly improved 30-day survival. However, the effect of EA on long-term survival when used as an adjunct to general anesthesia (GA) during elective AAA surgery is unknown. Objective To evaluate the association between combined EA-GA vs GA alone and long-term survival and postoperative complications in patients undergoing elective, open AAA repair. Design, Setting, and Participants A retrospective analysis of prospectively collected data was performed. Patients undergoing elective AAA repair between January 1, 2003, and December 31, 2011, were identified within the Vascular Society Group of New England (VSGNE) database. Kaplan-Meier curves were used to estimate survival. Cox proportional hazards regression models and multivariable logistic regression models assessed the independent association of EA-GA use with postoperative mortality and morbidity, respectively. Data analysis was conducted from March 15, 2015, to September 2, 2015. Interventions Combined EA-GA. Main Outcomes and Measures The primary outcome measure was all-cause mortality. Secondary end points included postoperative bowel ischemia, respiratory complications, myocardial infarction, dialysis requirement, wound complications, and need for surgical reintervention within 30 days of surgery. Results A total of 1540 patients underwent elective AAA repair during the study period. Of these, 410 patients (26.6%) were women and the median (interquartile range) age was 71 (64-76) years; 980 individuals (63.6%) received EA-GA. Patients in the 2 groups were comparable in terms of age, comorbidities, and suprarenal clamp location. At 5 years, the Kaplan-Meier-estimated overall survival rates were 74% (95% CI, 72%-76%) and 65% (95% CI, 62%-68%) in the EA-GA and GA-alone groups, respectively (P < .01). In adjusted analyses, EA-GA use was associated with significantly lower hazards of mortality compared with GA alone (hazard ratio, 0.73; 95% CI, 0.57-0.92; P = .01). Patients receiving EA-GA also had lower odds of 30-day surgical reintervention (odds ratio [OR], 0.65; 95% CI, 0.44-0.94; P = .02) as well as postoperative bowel ischemia (OR, 0.54; 95% CI, 0.31-0.94; P = .03), pulmonary complications (OR, 0.62; 95% CI, 0.41-0.95; P = .03), and dialysis requirements (OR, 0.44; 95% CI, 0.23-0.88; P = .02). No significant differences were noted for the odds of wound (OR, 0.88; 95% CI, 0.38-1.44; P = .51) and cardiac (OR, 1.08; 95% CI, 0.59-1.78; P = .82) complications. Conclusions and Relevance Combined EA-GA was associated with improved survival and significantly lower HRs and ORs for mortality and morbidity in patients undergoing elective AAA repair. The survival benefit may be attributable to reduced immediate postoperative adverse events. Based on these findings, EA-GA should be strongly considered in suitable patients.

Systolic Anterior Motion of the Mitral Valve and Three-Dimensional Echocardiography

From the *Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA; †Department of Anesthesia and Pain Medicine, Peking University People’s Hospital, Beijing, China; and ‡Department of Anesthesiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. Address reprint requests to Luyang Jiang, MD, Department of Anesthesia and Pain Medicine, Peking University People’s Hospital, 11 Xi Zhi Men South Street, Beijing, China 100044. E-mail: jiangly1018@hotmail.com

Effect of Preoperative Angina Pectoris on Cardiac Outcomes in Patients With Previous Myocardial Infarction Undergoing Major Noncardiac Surgery (Data from ACS-NSQIP)

The impact of preoperative stable angina pectoris on postoperative cardiovascular outcomes in patients with previous myocardial infarction (MI) who underwent major noncardiac surgery is not well studied. We studied patients with previous MI who underwent elective major noncardiac surgeries within the American College of Surgeons-National Surgical Quality Improvement Program (2005 to 2011). Primary outcome was occurrence of an adverse cardiac event (MI and/or cardiac arrest). Multivariable logistic regression models evaluated the impact of stable angina on outcomes. Of 1,568 patients (median age 70 years; 35% women) with previous MI who underwent major noncardiac surgery, 5.5% had postoperative MI and/or cardiac arrest. Patients with history of preoperative angina had significantly greater incidence of primary outcome compared to those without anginal symptoms (8.4% vs 5%, p = 0.035). In secondary outcomes, reintervention rates (22.5% vs 11%, p <0.001) and length of stay (median 6-days vs 5-days; p <0.001) were also higher in patients with preoperative angina. In multivariable analyses, preoperative angina was a significant predictor for postoperative MI (odds ratio 2.49 [1.20 to 5.58]) and reintervention (odds ratio 2.40 [1.44 to 3.82]). In conclusion, our study indicates that preoperative angina is an independent predictor for adverse outcomes in patients with previous MI who underwent major noncardiac surgery, and cautions against overreliance on predictive tools, for example, the Revised Cardiac Risk Index, in these patients, which does not treat stable angina and previous MI as independent risk factors during risk prognostication.

Cardiopulmonary Bypass Decreases Activation of the Signal Transducer and Activator of Transcription 3 (STAT3) Pathway in Diabetic Human Myocardium

BACKGROUND Cardiopulmonary bypass (CPB) is associated with increased myocardial oxidative stress and apoptosis in diabetic patients. A mechanistic understanding of this relationship could have therapeutic value. To establish a possible mechanism, we compared the activation of the cardioprotective signal transducer and activator of transcription 3 (STAT3) pathway between patients with uncontrolled diabetes (UD) and nondiabetic (ND) patients. METHODS Right atrial tissue and serum were collected before and after CPB from 80 patients, 39 ND and 41 UD (HbA1c ≥ 6.5), undergoing cardiac operations. The samples were evaluated with Western blotting, immunohistochemistry, and microarray. RESULTS On Western blot, leptin levels were significantly increased in ND post-CPB (p < 0.05). Compared with ND, the expression of Janus kinase 2 and phosphorylation (p-) of STAT3 was significantly decreased in UD (p < 0.05). The apoptotic proteins p-Bc12/Bc12 and caspase 3 were significantly increased (p < 0.05), antiapoptotic proteins Mcl-1, Bcl-2, and p-Akt were significantly decreased (p < 0.05) in UD compared with ND. The microarray data suggested significantly increased expression of interleukin-6 R, proapoptotic p-STAT1, caspase 9, and decreased expression of Bc12 and protein inhibitor of activated STAT1 antiapoptotic genes (p = 0.05) in the UD patients. The oxidative stress marker nuclear factor-κB was significantly higher (p < 0.05) in UD patients post-CPB compared with the pre-CPB value, but was decreased, albeit insignificantly, in ND patients post-CPB. CONCLUSIONS Compared with ND, UD myocardium demonstrated attenuation of the cardioprotective STAT3 pathway. Identification of this mechanism offers a possible target for therapeutic modulation.

The Association Between Preoperative Hemoglobin A1C and Postoperative Glycemic Variability on 30-Day Major Adverse Outcomes Following Isolated Cardiac Valvular Surgery.

BACKGROUND: Preoperative hemoglobin A1c (HbA1c) and postoperative glycemic variability predict major adverse events (MAEs) after coronary artery bypass grafting in a protocolized glycemic control setting. However, the influence of preoperative HbA1c and postoperative glycemic variability in isolated cardiac valvular surgery is unknown. In this study, we sought to establish (a) whether preoperative HbA1c could identify patients at increased risk of MAEs and (b) whether postoperative glycemic variability was associated with MAEs after isolated cardiac valvular surgery. METHODS: Patients >18 years of age undergoing isolated valve surgery from January 2008 to December 2013 were enrolled in this prospective, single-center, observational cohort study with IRB approval. Patient demographics, intraoperative data, and postoperative MAEs were extracted from the institutional Society of Thoracic Surgery (STS) database. The primary outcome, MAEs, was a composite of in-hospital death, myocardial infarction, reoperations, sternal infection, cardiac tamponade, pneumonia, stroke, or renal failure. Glycemic variability in the postoperative period was assessed by the coefficient of variation. Patents were stratified by HbA1c levels (<6.5% or ≥6.5%) and assessed using multivariable logistic regression. RESULTS: Of the enrolled 763 patients, 109 (14.3%) had a preoperative HbA1c level ≥6.5%. Patients with HbA1c ≥6.5% were older (70 [63–79] vs 66 [56–75], P < .001) and had a higher incidence of dyslipidemia (83.5% vs 57.0%, P < .001) and congestive heart failure (39.5% vs 27.8%, P = .01). The calculated STS risk score for morbidity and mortality was also statistically higher in this group (0.18 [0.13–0.27] vs 0.13 [0.09–0.21], P < .001). The occurrence of MAEs was similar between the 2 groups (13.8% in HbA1c ≥6.5% vs 11.0% in HbA1c <6.5%, P = .40). Multivariate logistic regression analysis revealed that neither preoperative HbA1c ≥ 6.5% (odds ratio [OR] 1.48, 95% confidence interval [CI]: 0.78–2.82; P = .23) nor postoperative glycemic variability (CV per quartile; OR 1.05, 95% CI: 0.85–1.30; P = .67) was found to be associated with MAEs. An HbA1c ≥ 6.5% was associated with the increased glycemic variability in the postoperative period (0.173 [0.129–0.217] vs 0.141 [0.106–0.178], P < .0001). CONCLUSIONS: This study did not show an association between preoperative HbA1c and postoperative glycemic variability with MAEs after isolated cardiac valvular surgery. Specifically, lack of association between postoperative glycemic variability and MAEs is noteworthy and is in contrast to our previous finding in CABG patients. Future studies should focus a targeted glycemic variability reduction in CABG patients and evaluate the reduction in MAEs, without risk of employing a one-size fits all approach when approaching other cardiac procedures.

Early Cellular Changes in the Ascending Aorta and Myocardium in a Swine Model of Metabolic Syndrome

Background Metabolic syndrome is associated with pathological remodeling of the heart and adjacent vessels. The early biochemical and cellular changes underlying the vascular damage are not fully understood. In this study, we sought to establish the nature, extent, and initial timeline of cytochemical derangements underlying reduced ventriculo-arterial compliance in a swine model of metabolic syndrome. Methods Yorkshire swine (n = 8 per group) were fed a normal diet (ND) or a high-cholesterol (HCD) for 12 weeks. Myocardial function and blood flow was assessed before harvesting the heart. Immuno-blotting and immuno-histochemical staining were used to assess the cellular changes in the myocardium, ascending aorta and left anterior descending artery (LAD). Results There was significant increase in body mass index, blood glucose and mean arterial pressures (p = 0.002, p = 0.001 and p = 0.024 respectively) in HCD group. At the cellular level there was significant increase in anti-apoptotic factors p-Akt (p = 0.007 and p = 0.002) and Bcl-xL (p = 0.05 and p = 0.01) in the HCD aorta and myocardium, respectively. Pro-fibrotic markers TGF-β (p = 0.01), pSmad1/5 (p = 0.03) and MMP-9 (p = 0.005) were significantly increased in the HCD aorta. The levels of pro-apoptotic p38MAPK, Apaf-1 and cleaved Caspase3 were significantly increased in aorta of HCD (p = 0.03, p = 0.04 and p = 0.007 respectively). Similar changes in coronary arteries were not observed in either group. Functionally, the high cholesterol diet resulted in significant increase in ventricular end systolic pressure and–dp/dt (p = 0.05 and p = 0.007 respectively) in the HCD group. Conclusion Preclinical metabolic syndrome initiates pro-apoptosis and pro-fibrosis pathways in the heart and ascending aorta, while sparing coronary arteries at this early stage of dietary modification.

The Coanda Effect.

582 www.anesthesia-analgesia.org September 2016 • Volume 123 • Number 3 A 57-year-old man presented for an urgent coronary artery bypass grafting surgery. On routine intraoperative 2-dimensional transesophageal echocardiography (2D TEE), an eccentric mitral regurgitant (MR) jet hugging the left atrial (LA) wall was appreciated in the 2D midesophageal long-axis view. (Figure 1A; Supplemental Digital Content 1, Video 1, left panel, http://links.lww.com/AA/B459) and 3dimensional (3D) TEE (Figure 1B; Supplemental Digital Content 1, Video 1, right panel, http://links.lww.com/AA/B459). The MR was graded as moderate to severe, and mitral valve repair was performed using an annuloplasty ring.

A Right Atrial Echodensity

N 84-YEAR-OLD MAN with a history of coronary artery bypass graft surgery was admitted for the workup of newonset asymptomatic atrial fibrillation. The patient reported a history of a cerebrovascular accident. A chest radiograph revealed mild-to-moderate enlargement of the cardiac silhouette. Transthoracic echocardiographic examination revealed severe aortic stenosis (valve area 0.9 cm2). The patient was scheduled for aortic valve replacement surgery. A precardiopulmonary bypass 2-dimensional (2D) transesophageal echocardiographic examination revealed severe aortic stenosis without other valvular abnormalities and normal ejection fraction. In the right atrial appendage, an echodensity was noticed (Fig 1 and Video 1 [supplementary videos are available online]), with well-defined edges and homogenous in appearance. Although it also appeared to be pedunculated, it was not mobile. There were no echodensities seen in the left atrial appendage. What is the possible diagnosis?

Post-cardiotomy Veno-Arterial Extracorporeal Membrane Oxygenation (VA ECMO) in adult patients – many questions, few answers, and hard choices

Cardiogenic shock after cardiac surgery continues to be a major clinical challenge with an overall reported incidence of 2% to 6%. Along with inotropic support, various mechanical circulatory support devices including intra-aortic balloon pumps, venoarterial membrane oxygenation (VA ECMO), and ventricular assist devices are used as salvage therapy in this scenario. VA ECMO offers the possibility of providing a bridge for maintaining organ perfusion and oxygenation allowing time for the heart and lung function to recover from the original insult or for transfer to more advanced care facilities. However, mortality among patients who receive VA ECMO for shock after cardiac surgery remains high, and perioperative variables that may be useful to predict outcomes remain poorly defined. In the current issue of the Journal of Cardiothoracic and Vascular Anesthesia, Biancari et al report the findings of a meta-analysis on the characteristics and outcomes of patients undergoing postcardiotomy VA ECMO. The authors included prospective and retrospective observational studies since the year 2000 that reported ECMO use for postcardiotomy shock in the adult patient population. They excluded studies on cardiac transplant patients alone. Among the 2,986 patients (31 studies) included in the analysis, the authors report a pooled hospital survival of 36.1% (95% CI, 31.5-40.8) after postcardiotomy VA-ECMO. A majority of the patients underwent peripheral cannulation (79.0%, 95% CI, 73.8-84.3, I 98%, 23 studies including 2,652 patients) and had an intra-aortic balloon pump concomitantly (62.2%, 95% CI, 48.9-75.6, I 99%, 19 studies including 1,910 patients). Their pooled survival estimate is remarkably close to the findings of other recent studies, which found survival rates of 37% to 39%. As reported in prior studies, patient age appears to be an important factor affecting prognosis, with younger patients doing better. The authors also found that lower lactate levels prior to initiation of ECMO were associated with improved hospital survival (pooled mean lactate levels in survivors: