Frederic T. Billings

Transcatheter aortic valve implantation: anesthetic considerations.

Aortic valvular stenosis remains the most common debilitating valvular heart lesion. Despite the benefit of aortic valve (AV) replacement, many high-risk patients cannot tolerate surgery. AV implantation treats aortic stenosis without subjecting patients to sternotomy, cardiopulmonary bypass (CPB), and aorta cross-clamping. This transcatheter procedure is performed via puncture of the left ventricular (LV) apex or percutaneously, via the femoral artery or vein. Patients undergo general anesthesia, intense hemodynamic manipulation, and transesophageal echocardiography (TEE). To elucidate the role of the anesthesiologist in the management of transcatheter AV implantation, we review the literature and provide our experience, focusing on anesthetic care, intraoperative events, TEE, and perioperative complications. Two approaches to the aortic annulus are performed today: transfemoral retrograde and transapical antegrade. Iliac artery size and tortuosity, aortic arch atheroma, and pathology in the area of the (LV) apex help determine the preferred approach in each patient. A general anesthetic is tailored to achieve extubation after procedure completion, whereas IV access and pharmacological support allow for emergent sternotomy and initiation of CPB. Rapid ventricular pacing and cessation of mechanical ventilation interrupts cardiac ejection and minimizes heart translocation during valvuloplasty and prosthesis implantation. Although these maneuvers facilitate exact prosthesis positioning within the native annulus, they promote hypotension and arrhythmia. Vasopressor administration before pacing and cardioversion may restore adequate hemodynamics. TEE determines annulus size, aortic pathology, ventricular function, and mitral regurgitation. TEE and fluoroscopy are used for positioning the introducer catheter within the aortic annulus. The prosthesis, crimped on a valvuloplasty balloon catheter, is implanted by inflation. TEE immediately measures aortic regurgitation and assesses for aortic dissection. After repair of femoral vessels or LV apex, patients are allowed to emerge and assessed for extubation. Observed and published complications include aortic regurgitation, prosthesis embolization, mitral valve disruption, hemorrhage, aortic dissection, CPB, stroke, and death. Transcatheter AV implantation relies on intraoperative hemodynamic manipulation for success. Transfemoral and transapical approaches pose unique management challenges, but both require rapid ventricular pacing, the management of hypotension and arrhythmias during beating-heart valve implantation, and TEE. Anesthesiologists will care for debilitated patients with aortic stenosis receiving transcatheter AV implantation.

High-Dose Perioperative Atorvastatin and Acute Kidney Injury Following Cardiac Surgery: A Randomized Clinical Trial

IMPORTANCE Statins affect several mechanisms underlying acute kidney injury (AKI). OBJECTIVE To test the hypothesis that short-term high-dose perioperative atorvastatin would reduce AKI following cardiac surgery. DESIGN, SETTING, AND PARTICIPANTS Double-blinded, placebo-controlled, randomized clinical trial of adult cardiac surgery patients conducted from November 2009 to October 2014 at Vanderbilt University Medical Center. INTERVENTIONS Patients naive to statin treatment (n = 199) were randomly assigned 80 mg of atorvastatin the day before surgery, 40 mg of atorvastatin the morning of surgery, and 40 mg of atorvastatin daily following surgery (n = 102) or matching placebo (n = 97). Patients already taking a statin prior to study enrollment (n = 416) continued taking the preenrollment statin until the day of surgery, were randomly assigned 80 mg of atorvastatin the morning of surgery and 40 mg of atorvastatin the morning after (n = 206) or matching placebo (n = 210), and resumed taking the previously prescribed statin on postoperative day 2. MAIN OUTCOMES AND MEASURES Acute kidney injury defined as an increase of 0.3 mg/dL in serum creatinine concentration within 48 hours of surgery (Acute Kidney Injury Network criteria). RESULTS The data and safety monitoring board recommended stopping the group naive to statin treatment due to increased AKI among these participants with chronic kidney disease (estimated glomerular filtration rate <60 mL/min/1.73 m2) receiving atorvastatin. The board later recommended stopping for futility after 615 participants (median age, 67 years; 188 [30.6%] were women; 202 [32.8%] had diabetes) completed the study. Among all participants (n = 615), AKI occurred in 64 of 308 (20.8%) in the atorvastatin group vs 60 of 307 (19.5%) in the placebo group (relative risk [RR], 1.06 [95% CI, 0.78 to 1.46]; P = .75). Among patients naive to statin treatment (n = 199), AKI occurred in 22 of 102 (21.6%) in the atorvastatin group vs 13 of 97 (13.4%) in the placebo group (RR, 1.61 [0.86 to 3.01]; P = .15) and serum creatinine concentration increased by a median of 0.11 mg/dL (10th-90th percentile, -0.11 to 0.56 mg/dL) in the atorvastatin group vs by a median of 0.05 mg/dL (10th-90th percentile, -0.12 to 0.33 mg/dL) in the placebo group (mean difference, 0.08 mg/dL [95% CI, 0.01 to 0.15 mg/dL]; P = .007). Among patients already taking a statin (n = 416), AKI occurred in 42 of 206 (20.4%) in the atorvastatin group vs 47 of 210 (22.4%) in the placebo group (RR, 0.91 [0.63 to 1.32]; P = .63). CONCLUSIONS AND RELEVANCE Among patients undergoing cardiac surgery, high-dose perioperative atorvastatin treatment compared with placebo did not reduce the risk of AKI overall, among patients naive to treatment with statins, or in patients already taking a statin. These results do not support the initiation of statin therapy to prevent AKI following cardiac surgery. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00791648.

Postoperative acute kidney injury is associated with hemoglobinemia and an enhanced oxidative stress response

Acute kidney injury (AKI) frequently afflicts patients undergoing cardiopulmonary bypass and independently predicts death. Both hemoglobinemia and myoglobinemia are independent predictors of postoperative AKI. Release of free hemeproteins into the circulation is known to cause oxidative injury to the kidneys. This study tested the hypothesis that postoperative AKI is associated with both enhanced intraoperative hemeprotein release and increased lipid peroxidation assessed by measuring F₂-isoprostanes and isofurans. In a case-control study nested within an ongoing randomized trial of perioperative statin treatment and AKI, we compared levels of F₂-isoprostanes and isofurans with plasma levels of free hemoglobin and myoglobin in 10 cardiac surgery AKI patients to those of 10 risk-matched controls. Peak plasma free hemoglobin concentrations were significantly higher in AKI subjects (289.0 ± 37.8 versus 104.4 ± 36.5mg/dl, P = 0.01), whereas plasma myoglobin concentrations were similar between groups. The change in plasma F₂-isoprostane and isofuran levels (repeated-measures ANOVA, P = 0.02 and P = 0.001, respectively) as well as the change in urine isofuran levels (P = 0.04) was significantly greater in AKI subjects. In addition, change in peak plasma isofuran levels correlated not only with peak free plasma hemoglobin concentrations (r² = 0.39, P = 0.001) but also with peak change in serum creatinine (r² = 0.20, P = 0.01). Postoperative AKI is associated with both enhanced intraoperative hemeprotein release and enhanced lipid peroxidation. The correlations among hemoglobinemia, lipid peroxidation, and AKI indicate a potential role for hemeprotein-induced oxidative damage in the pathogenesis of postoperative AKI.

Obesity and Oxidative Stress Predict AKI after Cardiac Surgery

Obesity increases oxidative stress, endothelial dysfunction, and inflammation, but the effect of obesity on postoperative AKI is not known. We examined the relationship between body mass index (BMI) and AKI in 445 patients undergoing cardiac surgery and whether oxidative stress (F(2)-isoprostanes), inflammation (IL-6), or antifibrinolysis (plasminogen activator inhibitor-1 [PAI-1]) contribute to any identified relationship. Overall, 112 (25%) of the 445 patients developed AKI. Higher BMI was independently associated with increased odds of AKI (26.5% increase per 5 kg/m(2) [95% confidence interval, 4.3%-53.4%]; P=0.02). Baseline F(2)-isoprostane (P=0.04), intraoperative F(2)-isoprostane (P=0.003), and intraoperative PAI-1 (P=0.04) concentrations also independently predicted AKI. BMI no longer predicted AKI after adjustment for the effect of F(2)-isoprostanes, suggesting that obesity may affect AKI via effects on oxidative stress. In contrast, adjustment for IL-6 or PAI-1 did not substantially alter the association between BMI and AKI. Further, deconstruction of the obesity-AKI relationship into direct (i.e., independent of candidate pathways) and indirect (i.e., effect of BMI on AKI via each candidate pathway) effects indicated that F(2)-isoprostanes, but not IL-6 or PAI-1, partially mediate the relationship between obesity and AKI (P=0.001). In conclusion, obesity independently predicts AKI after cardiac surgery, and oxidative stress may partially mediate this association.

Early Postoperative Statin Therapy Is Associated With a Lower Incidence of Acute Kidney Injury After Cardiac Surgery

OBJECTIVE To test the hypothesis that perioperative statin use reduces acute kidney injury (AKI) after cardiac surgery. DESIGN A retrospective analysis of prospectively collected data from an ongoing clinical trial. SETTING A quaternary-care university hospital. PARTICIPANTS Three hundred twenty-four adult elective cardiac surgery patients. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS The authors assessed the association of preoperative statin use, early postoperative statin use, and acute statin withdrawal with the incidence of AKI. Early postoperative statin use was defined as statin treatment within the first postoperative day. Statin withdrawal was defined as the discontinuation of preoperative statin treatment before surgery until at least postoperative day 2. Logistic regression and propensity score modeling were used to control for AKI risk factors. Sixty-eight of 324 patients (21.0%) developed AKI. AKI patients stayed in the hospital longer (p = 0.03) and were more likely to develop pneumonia (p = 0.002) or die (p = 0.001). A higher body mass index (p = 0.003), higher central venous pressure (p = 0.03), and statin withdrawal (27.4 v 14.7%, p = 0.046) were associated with a higher incidence of AKI, whereas early postoperative statin use was protective (12.5% v 23.8%, p = 0.03). Preoperative statin use did not affect the risk of AKI. In multivariate logistic regression, age (p = 0.03), male sex (p = 0.02), body mass index (p < 0.001), and early postoperative statin use (odds ratio = 0.32; 95% confidence interval, 0.14-0.72; p = 0.006) independently predicted AKI. Propensity score-adjusted risk assessment confirmed the association between early postoperative statin use and reduced AKI (odds ratio = 0.30; 95% confidence interval, 0.13-0.70; p = 0.005). CONCLUSIONS Early postoperative statin use is associated with a lower incidence of AKI among both chronic statin users and statin-naive cardiac surgery patients.

Substance P Increases Sympathetic Activity During Combined Angiotensin-Converting Enzyme and Dipeptidyl Peptidase-4 Inhibition

&NA; Dipeptidyl peptidase-4 inhibitors prevent the degradation of incretin hormones and reduce postprandial hyperglycemia in patients with type 2 diabetes mellitus. Dipeptidyl peptidase-4 degrades other peptides with a penultimate proline or alanine, including bradykinin and substance P, which are also substrates of angiotensin-converting enzyme (ACE). During ACE inhibition, substance P is inactivated primarily by dipeptidyl peptidase-4, whereas bradykinin is first inactivated by aminopeptidase P. This study tested the hypothesis that dipeptidyl peptidase-4 inhibition potentiates vasodilator and fibrinolytic responses to substance P when ACE is inhibited. Twelve healthy subjects participated in this randomized, double-blinded, placebo-controlled crossover study. On each study day, subjects received sitagliptin 200 mg by mouth or placebo. Substance P and bradykinin were infused via brachial artery before and during intra-arterial enalaprilat. Sitagliptin and enalaprilat each reduced forearm vascular resistance and increased forearm blood flow without affecting mean arterial pressure, but there was no interactive effect of the inhibitors. Enalaprilat increased bradykinin-stimulated vasodilation and tissue plasminogen activator release; sitagliptin did not affect these responses to bradykinin. The vasodilator response to substance P was unaffected by sitagliptin and enalaprilat; however, substance P increased heart rate and vascular release of norepinephrine during combined ACE and dipeptidyl peptidase-4 inhibition. In women, sitagliptin diminished tissue plasminogen activator release in response to substance P both alone and during enalaprilat. Substance P increases sympathetic activity during combined ACE and dipeptidyl peptidase-4 inhibition. Clinical Trial Registration:— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01413542.

Mitochondrial dysfunction and oxidative stress in patients with chronic kidney disease

Mitochondria abnormalities in skeletal muscle may contribute to frailty and sarcopenia, commonly present in patients with chronic kidney disease (CKD). Dysfunctional mitochondria are also a major source of oxidative stress and may contribute to cardiovascular disease in CKD. We tested the hypothesis that mitochondrial structure and function worsens with the severity of CKD. Mitochondrial volume density, mitochondrial DNA (mtDNA) copy number, BNIP3, and PGC1α protein expression were evaluated in skeletal muscle biopsies obtained from 27 subjects (17 controls and 10 with CKD stage 5 on hemodialysis). We also measured mtDNA copy number in peripheral blood mononuclear cells (PBMCs), plasma isofurans, and plasma F2‐isoprostanes in 208 subjects divided into three groups: non‐CKD (eGFR>60 mL/min), CKD stage 3–4 (eGFR 60–15 mL/min), and CKD stage 5 (on hemodialysis). Muscle biopsies from patients with CKD stage 5 revealed lower mitochondrial volume density, lower mtDNA copy number, and higher BNIP3 content than controls. mtDNA copy number in PBMCs was decreased with increasing severity of CKD: non‐CKD (6.48, 95% CI 4.49–8.46), CKD stage 3–4 (3.30, 95% CI 0.85–5.75, P = 0.048 vs. non‐CKD), and CKD stage 5 (1.93, 95% CI 0.27–3.59, P = 0.001 vs. non‐CKD). Isofurans were higher in patients with CKD stage 5 (median 59.21 pg/mL, IQR 41.76–95.36) compared to patients with non‐CKD (median 49.95 pg/mL, IQR 27.88–83.46, P = 0.001), whereas F2‐isoprostanes did not differ among groups. Severity of CKD is associated with mitochondrial dysfunction and markers of oxidative stress. Mitochondrial abnormalities, which are common in skeletal muscle from patients with CKD stage 5, may explain the muscle dysfunction associated with frailty and sarcopenia in CKD. Further studies are required to evaluate mitochondrial function in vivo in patients with different CKD stages.

Angiotensin-converting enzyme inhibition or mineralocorticoid receptor blockade do not affect prevalence of atrial fibrillation in patients undergoing cardiac surgery.

Objective: This study tested the hypothesis that interruption of the renin–angiotensin system with either an angiotensin-converting enzyme inhibitor or a mineralocorticoid receptor antagonist will decrease the prevalence of atrial fibrillation after cardiac surgery. Design: Randomized double-blind placebo-controlled study. Setting: University-affiliated hospitals. Patients: Four hundred forty-five adult patients in normal sinus rhythm undergoing elective cardiac surgery. Interventions: One week to 4 days prior to surgery, patients were randomized to treatment with placebo, ramipril (2.5mg the first 3 days followed by 5mg/day, with the dose reduced to 2.5mg/day on the first postoperative day only), or spironolactone (25mg/day). Measurements: The primary endpoint was the occurrence of electrocardiographically confirmed postoperative atrial fibrillation. Secondary endpoints included acute renal failure, hyperkalemia, the prevalence of hypotension, length of hospital stay, stroke, and death. Main Results: The prevalence of atrial fibrillation was 27.2% in the placebo group, 27.8% in the ramipril group, and 25.9% in the spironolactone group (p = .95). Patients in the ramipril (0.7%) or spironolactone (0.7%) group were less likely to develop acute renal failure than those randomized to placebo (5.4%, p = .006). Patients in the placebo group tended to be hospitalized longer than those in the ramipril or spironolactone group (6.8±8.2 days vs. 5.7±3.2 days and 5.8±3.4 days, respectively, p = .08 for the comparison of placebo vs. the active treatment groups using log-rank test). Compared with patients in the placebo group, patients in the spironolactone group were extubated sooner after surgery (576.4±761.5 mins vs. 1091.3±3067.3 mins, p = .04). Conclusions: Neither angiotensin-converting enzyme inhibition nor mineralocorticoid receptor blockade decreased the primary outcome of postoperative atrial fibrillation. Treatment with an angiotensin-converting enzyme inhibitor or mineralocorticoid receptor antagonist was associated with decreased acute renal failure. Spironolactone use was also associated with a shorter duration of mechanical ventilation after surgery.

Episodic Monoplane Transesophageal Echocardiography Impacts Postoperative Management of the Cardiac Surgery Patient

OBJECTIVE A new slender, flexible, and miniaturized disposable monoplane transesophageal TEE probe has been approved for episodic hemodynamic transesophageal echocardiographic monitoring. The authors hypothesized that episodic monoplane TEE with a limited examination would help guide the postoperative management of high-risk cardiac surgery patients. DESIGN The authors analyzed the initial consecutive observational experience with the miniaturized transesophageal echocardiography monitoring system (ClariTEE, ImaCor, Uniondale, New York). SETTING Single institution in a university setting. PARTICIPANTS Unstable cardiac surgery patients. INTERVENTIONS The authors assessed fluid responsiveness, echocardiographic data, and concordance among hemodynamic data. MEASUREMENTS AND MAIN RESULTS From June 2010 to February 2011, 21 unstable cardiac surgery patients with postoperative instability were identified. Two patients (10%) required reoperation for bleeding and tamponade physiology. Right ventricular dysfunction was diagnosed by episodic TEE monitoring in 7 patients (33%), while hypovolemia was documented in 12 patients (57%). Volume responsiveness was documented in 11 patients. In this observational study, discordance between hemodynamic monitoring and episodic TEE was qualitatively observed in 14 patients (66%). CONCLUSION The authors demonstrated the ability of episodic monoplane TEE to identify discordance between hemodynamic monitoring to better define clinical scenarios in unstable cardiac surgery patients. For these challenging patients, limited episodic TEE assessment has become a cornerstone of ICU care in this institution.

Early bispectral index and sedation requirements during therapeutic hypothermia predict neurologic recovery following cardiac arrest.

Objectives:To test the hypothesis that low bispectral index scores and low sedative requirements during therapeutic hypothermia predict poor neurologic outcome. Design:Observational study of a prospectively collected cohort. Setting:Cardiovascular ICU. Patients:One hundred sixty consecutive cardiac arrest patients treated with therapeutic hypothermia. Interventions:None. Measurements and Results:Eighty-four of the 141 subjects (60%) who survived hypothermia induction were discharged from the ICU with poor neurologic outcome, defined as a cerebral performance category score of 3, 4, or 5. These subjects had lower bispectral index (p < 0.001) and sedative requirements (p < 0.001) during hypothermia compared with the 57 subjects discharged with good outcome. Early prediction of neurologic recovery was best 7 hours after ICU admission, and median bispectral index scores at that time were 31 points lower in subjects discharged with poor outcome (11 [interquartile range, 4–29] vs 42 [37–49], p < 0.001). Median sedation requirements decreased by 17% (interquartile range, –50 to 0%) 7 hours after ICU admission in subjects with poor outcome but increased by 50% (interquartile range, 0–142%) in subjects with good outcome (p < 0.001). Each 10-point decrease in bispectral index was independently associated with a 59% increase in the odds of poor outcome (95% CI, 32–76%; p < 0.001). The model including bispectral index and sedative requirement correctly reclassified 15% of subjects from good to poor outcome and 1% of subjects from poor to good outcome. The model incorrectly reclassified 1% of subjects from poor to good outcome but did not incorrectly reclassify any from good to poor outcome. Conclusions:Bispectral index scores and sedative requirements early in the course of therapeutic hypothermia improve the identification of patients who will not recover from brain anoxia. The ability to accurately predict nonrecovery after cardiac arrest could facilitate discussions with families, reduce patient suffering, and limit use of ICU resources in futile cases.