Bayesian methods: a potential path forward for sepsis trials.

BACKGROUND: Given the success of recent platform trials for COVID-19, Bayesian statistical methods have become an option for complex, heterogenous syndromes like sepsis. However, study design will require careful consideration of how statistical power varies using Bayesian methods across different choices for how historical data are incorporated through a prior distribution and how the analysis is ultimately conducted. Our objective with the current analysis is to assess how different uses of historical data through a prior distribution, and type of analysis influence results of a proposed trial that will be analyzed using Bayesian statistical methods. METHODS: We conducted a simulation study incorporating historical data from a published multicenter, randomized clinical trial in the US and Canada of polymyxin B hemadsorption for treatment of endotoxemic septic shock. Historical data come from a 179-patient subgroup of the previous trial of adult critically ill patients with septic shock, multiple organ failure and an endotoxin activity of 0.60-0.89. The trial intervention consisted of two polymyxin B hemoadsorption treatments (2 h each) completed within 24 h of enrollment. RESULTS: In our simulations for a new trial of 150 patients, a range of hypothetical results were observed. Across a range of baseline risks and treatment effects and four ways of including historical data, we demonstrate an increase in power with the use of clinically defensible incorporation of historical data. In one possible trial result, for example, with an observed reduction in risk of mortality from 44 to 37%, the probability of benefit is 96% with a fixed weight of 75% on prior data and 90% with a commensurate (adaptive-weighting) prior; the same data give an 80% probability of benefit if historical data are ignored. CONCLUSIONS: Using Bayesian methods and a biologically justifiable use of historical data in a prior distribution yields a study design with higher power than a conventional design that ignores relevant historical data. Bayesian methods may be a viable option for trials in critical care medicine where beneficial treatments have been elusive.

Endothelial fate mapping in mice with pulmonary hypertension.

BACKGROUND: Pulmonary endothelial injury triggers a reparative program, which in susceptible individuals is characterized by neointima formation, vascular narrowing, and the development of pulmonary arterial hypertension. The neointimal cells in human pathological plexiform lesions frequently coexpress smooth muscle α-actin and the endothelial von Willebrand antigen, creating a question about their cellular lineage of origin. METHODS AND RESULTS: Experimental pulmonary hypertension with neointima formation develops in C57Bl/6 mice subjected to left pneumonectomy followed 1 week later by jugular vein injection of monocrotaline pyrrole (20 µg/µL and 1 µL/g; group P/MCTP). Compared with the group vehicle, by day 35, group P/MCTP developed higher right ventricular systolic pressure (54±5 versus 25±2 mm Hg; P<0.01) and right ventricular hypertrophy (0.58±0.16 versus 0.26±0.05; P<0.01). Transgenic vascular endothelial-cadherin Cre recombinase or Tie-2 Cre mice were intercrossed with mTomato/mGreen fluorescent protein double-fluorescent Cre reporter mice to achieve endothelial genetic lineage marking with membrane-targeted green fluorescent protein. In control mice, few endothelial lineage-marked cells lining the lumen of small pulmonary arteries demonstrate expression of smooth muscle α-actin. Concurrent with the development of pulmonary hypertension, endothelial lineage-marked cells are prominent in the neointima and exhibit expression of smooth muscle α-actin and smooth muscle myosin heavy chain. Human pulmonary arterial hypertension neointimal lesions contain cells that coexpress endothelial CD31 or von Willebrand antigen and smooth muscle α-actin. CONCLUSION: Neointimal cells in pulmonary hypertension include contributions from the endothelial genetic lineage with induced expression of smooth muscle α-actin and smooth muscle myosin heavy chain.

Obstructive Sleep Apnea Is an Independent Predictor of Postoperative Atrial Fibrillation in Cardiac Surgery.

OBJECTIVE: To test the hypothesis that obstructive sleep apnea (OSA) is a risk factor for development of postoperative atrial fibrillation (POAF) after cardiac surgery. DESIGN: Retrospective analysis. SETTING: Single-center university hospital. PARTICIPANTS: Five hundred forty-five patients in sinus rhythm preoperatively undergoing coronary artery bypass grafting (CABG), aortic valve replacement, mitral valve replacement/repair, or combined valve/CABG surgery from January 2008 to April 2011. INTERVENTIONS: Retrospective review of medical records. MEASUREMENTS AND MAIN RESULTS: Postoperative atrial fibrillation was defined as atrial fibrillation requiring therapeutic intervention. Of 545 cardiac surgical patients, 226 (41%) patients developed POAF. The risk was higher in 72 OSA patients than 473 patients without OSA (67% v 38%, adjusted hazard ratio 1.83 [95% CI: 1.30-2.58], p<0.001). Of the 32 OSA patients who used home positive airway pressure (PAP) therapy, 18 (56%) developed POAF compared with 29 of 38 (76%) patients who did not use PAP at home (unadjusted hazard ratio 0.63 [95% CI: 0.35-1.15], p = 0.13). CONCLUSION: OSA is significantly associated with POAF in cardiac surgery patients. Further investigation is needed to determine whether or not use of positive airway pressure in OSA patients reduces the risk of POAF.

Erythropoietin and organ protection: lessons from negative clinical trials.

Based on its pleiotropic effects, erythropoietin can decrease inflammation, oxidative stress, and apoptosis. Erythropoietin provides organ protection for the heart, brain, and kidney in diverse preclinical animal studies, especially models that include ischemia-reperfusion injury and/or inflammation. However, large clinical studies in coronary reperfusion, heart failure, stroke, acute kidney injury, and chronic renal disease have failed to demonstrate improved outcomes. A study in a previous issue of Critical Care examining the ability of erythropoietin to prevent or ameliorate acute kidney injury in patients undergoing complex valvular heart surgery is similarly negative. The failure of erythropoietin in clinical studies may be due to an inadequate dose, since the receptors responsible for organ protection may require higher concentrations than those responsible for erythropoiesis. However, as has occurred in studies in sepsis and acute respiratory distress syndrome, the negative studies probably reflect an inadequate understanding of the complexity of the underlying processes with multiple redundant and interacting pathways that may differ among the large number of different cell types involved. As tools to understand this complexity and integrate it on an organismal basis continue to evolve, we will develop the ability to use erythropoietin and related nonhematopoietic agents for organ protection.

Focused transthoracic echocardiography during critical care medicine training: curriculum implementation and evaluation of proficiency*.

OBJECTIVES: We designed and implemented a focused transthoracic echocardiography curriculum for critical care medicine fellows participating in 1- and 2-year training programs. We quantitatively evaluated their proficiency in focused transthoracic echocardiography. DESIGN: Prospective study evaluating curriculum implementation and objective assessment of focused transthoracic echocardiography proficiency. SETTING: Medical and surgical ICUs at an academic teaching hospital. Simulation laboratory. SUBJECTS: Eighteen critical care medicine fellows. INTERVENTIONS: Training in focused transthoracic echocardiography followed by proficiency testing. MEASUREMENTS AND MAIN RESULTS: We assessed the ability of critical care medicine fellows to obtain and interpret focused transthoracic echocardiography images from critically ill patients and a from transthoracic echocardiography simulator. Using a cognitive examination test, we also evaluated each fellow's knowledge with regard to focused transthoracic echocardiography and each fellow's ability to interpret prerecorded focused transthoracic echocardiography images. After training, critical care medicine fellows were able to rapidly obtain five essential focused transthoracic echocardiography views: parasternal long axis, parasternal short axis, apical four chamber, subcostal four chamber, and subcostal inferior vena cava. Fellows were also able to expeditiously identify four important abnormalities: asystole, left ventricular dysfunction, right ventricular dilation and dysfunction, and a large pericardial effusion. CONCLUSIONS: A focused transthoracic echocardiography curriculum that includes quantitative measures of proficiency can be integrated into critical care medicine fellowship training programs.

Tezosentan and right ventricular failure in patients with pulmonary hypertension undergoing cardiac surgery: the TACTICS trial.

OBJECTIVE: To evaluate the efficacy of tezosentan in reducing the incidence of right ventricular (RV) failure and associated mortality in patients with pre-existing pulmonary hypertension. The primary endpoint was the proportion of patients with RV failure during weaning from cardiopulmonary bypass (CPB), assessed 30 minutes after the end of CPB. DESIGN: Multicenter, double-blind, randomized, placebo-controlled trial. SETTING: Thirty-one cardiac surgical centers in 14 countries. PARTICIPANTS: Two hundred seventy-four patients with pulmonary hypertension aged ≥ 18 years scheduled to undergo cardiac surgery. INTERVENTION: Intravenous tezosentan (5 mg/h) during surgery and up to 24 hours afterwards (1 mg/h), or matched placebo. MEASUREMENTS AND MAIN RESULTS: One-hundred thirty-three patients received tezosentan and 141 placebo. RV failure occurred in 30 patients (10.9%), 37% of whom died. There was no difference in the incidence of RV failure between the two treatment groups (relative risk reduction: 0.07 [95% CI-0.83, 0.53; P = 0.8278]). CONCLUSION: A reduction in RV failure with tezosentan was not observed in this study.(Current Controlled Trials, identifier NCT00458276).

Development of the Modern Cardiothoracic Intensive Care Unit and Current Management.

The modern cardiothoracic intensive care unit (CTICU) developed as a result of advances in critical care, cardiology, and cardiac surgery. Patients undergoing cardiac surgery today are sicker, frailer, and have more complex cardiac and noncardiac morbidities. CTICU providers need to understand postoperative implications of different surgical procedures, complications that can occur in CTICU patients, resuscitation protocols for cardiac arrest, and diagnostic and therapeutic interventions such as transesophageal echocardiography and mechanical circulatory support. Optimum CTICU care requires a multidisciplinary team with collaboration between cardiac surgeons and critical care physicians with training and experience in the care of CTICU patients.

Evaluation of the efficacy and safety of amustaline/glutathione pathogen-reduced RBCs in complex cardiac surgery: the Red Cell Pathogen Inactivation (ReCePI) study-protocol for a phase 3, randomized, controlled trial.

BACKGROUND: Red blood cell (RBC) transfusion is a critical supportive therapy in cardiovascular surgery (CVS). Donor selection and testing have reduced the risk of transfusion-transmitted infections; however, risks remain from bacteria, emerging viruses, pathogens for which testing is not performed and from residual donor leukocytes. Amustaline (S-303)/glutathione (GSH) treatment pathogen reduction technology is designed to inactivate a broad spectrum of infectious agents and leukocytes in RBC concentrates. The ReCePI study is a Phase 3 clinical trial designed to evaluate the efficacy and safety of pathogen-reduced RBCs transfused for acute anemia in CVS compared to conventional RBCs, and to assess the clinical significance of treatment-emergent RBC antibodies. METHODS: ReCePI is a prospective, multicenter, randomized, double-blinded, active-controlled, parallel-design, non-inferiority study. Eligible subjects will be randomized up to 7 days before surgery to receive either leukoreduced Test (pathogen reduced) or Control (conventional) RBCs from surgery up to day 7 post-surgery. The primary efficacy endpoint is the proportion of patients transfused with at least one study transfusion with an acute kidney injury (AKI) diagnosis defined as any increased serum creatinine (sCr) level ≥ 0.3 mg/dL (or 26.5 µmol/L) from pre-surgery baseline within 48 ± 4 h of the end of surgery. The primary safety endpoints are the proportion of patients with any treatment-emergent adverse events (TEAEs) related to study RBC transfusion through 28 days, and the proportion of patients with treatment-emergent antibodies with confirmed specificity to pathogen-reduced RBCs through 75 days after the last study transfusion. With ≥ 292 evaluable, transfused patients (> 146 per arm), the study has 80% power to demonstrate non-inferiority, defined as a Test group AKI incidence increase of no more than 50% of the Control group rate, assuming a Control incidence of 30%. DISCUSSION: RBCs are transfused to prevent tissue hypoxia caused by surgery-induced bleeding and anemia. AKI is a sensitive indicator of renal hypoxia and a novel endpoint for assessing RBC efficacy. The ReCePI study is intended to demonstrate the non-inferiority of pathogen-reduced RBCs to conventional RBCs in the support of renal tissue oxygenation due to acute anemia and to characterize the incidence of treatment-related antibodies to RBCs.

Effect of adenosine-regulating agent acadesine on morbidity and mortality associated with coronary artery bypass grafting: the RED-CABG randomized controlled trial.

CONTEXT: Ischemia/reperfusion injury remains an important cause of morbidity and mortality after coronary artery bypass graft (CABG) surgery. In a meta-analysis of randomized controlled trials, perioperative and postoperative infusion of acadesine, a first-in-class adenosine-regulating agent, was associated with a reduction in early cardiac death, myocardial infarction, and combined adverse cardiac outcomes in participants undergoing on-pump CABG surgery. OBJECTIVE: To assess the efficacy and safety of acadesine administered in the perioperative period in reducing all-cause mortality, nonfatal stroke, and severe left ventricular dysfunction (SLVD) through 28 days. DESIGN, SETTING, AND PARTICIPANTS: The Reduction in Cardiovascular Events by Acadesine in Patients Undergoing CABG (RED-CABG) trial, a randomized, double-blind, placebo-controlled, parallel-group evaluation of intermediate- to high-risk patients (median age, 66 years) undergoing nonemergency, on-pump CABG surgery at 300 sites in 7 countries. Enrollment occurred from May 6, 2009, to July 30, 2010. INTERVENTIONS: Eligible participants were randomized 1:1 to receive acadesine (0.1 mg/kg per minute for 7 hours) or placebo (both also added to cardioplegic solutions) beginning just before anesthesia induction. MAIN OUTCOME MEASURE: Composite of all-cause mortality, nonfatal stroke, or need for mechanical support for SLVD during and following CABG surgery through postoperative day 28. RESULTS: Because results of a prespecified futility analysis indicated a very low likelihood of a statistically significant efficacious outcome, the trial was stopped after 3080 of the originally projected 7500 study participants were randomized. The primary outcome occurred in 75 of 1493 participants (5.0%) in the placebo group and 76 of 1493 (5.1%) in the acadesine group (odds ratio, 1.01 [95% CI, 0.73-1.41]). There were no differences in key secondary end points measured. CONCLUSION: In this population of intermediate- to high-risk patients undergoing CABG surgery, acadesine did not reduce the composite of all-cause mortality, nonfatal stroke, or SLVD. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00872001.

Self-reported information needs of anesthesia residency applicants and analysis of applicant-related web sites resources at 131 United States training programs.

BACKGROUND: Despite the use of web-based information resources by both anesthesia departments and applicants, little research has been done to assess these resources and determine whether they are meeting applicant needs. Evidence is needed to guide anesthesia informatics research in developing high-quality anesthesia residency program Web sites (ARPWs). METHODS: We used an anonymous web-based program (SurveyMonkey, Portland, OR) to distribute a survey investigating the information needs and perceived usefulness of ARPWs to all 572 Stanford anesthesia residency program applicants. A quantitative scoring system was then created to assess the quality of ARPWs in meeting the information needs of these applicants. Two researchers independently analyzed all 131 ARPWs in the United States to determine whether the ARPWs met the needs of applicants based on the scoring system. Finally, a qualitative assessment of the overall user experience of ARPWs was developed to account for the subjective elements of the Web site's presentation. RESULTS: Ninety-eight percent of respondents reported having used ARPWs during the application process. Fifty-six percent reported first visiting the Stanford ARPW when deciding whether to apply to Stanford's anesthesia residency program. Multimedia and Web 2.0 technologies were "very" or "most" useful in "learning intangible aspects of a program, like how happy people are" (42% multimedia and Web 2.0 versus 14% text and photos). ARPWs, on average, contained only 46% of the content items identified as important by applicants. The average (SD) quality scores among all ARPWs was 2.06 (0.59) of 4.0 maximum points. The mean overall qualitative score for all 131 ARPWs was 4.97 (1.92) of 10 points. Only 2% of applicants indicated that the majority (75%-100%) of Web sites they visited provided a complete experience. CONCLUSION: Anesthesia residency applicants rely heavily on ARPWs to research programs, prepare for interviews, and formulate a rank list. Anesthesia departments can improve their ARPWs by including information such as total hours worked and work hours by rotation (missing in 96% and 97% of ARPWs) and providing a valid web address on the Fellowship and Residency Electronic Interactive Database Access System (FREIDA) (missing in 28% of ARPWs).

Efficacy and safety of epoetin alfa in critically ill patients.

BACKGROUND: Anemia, which is common in the critically ill, is often treated with red-cell transfusions, which are associated with poor clinical outcomes. We hypothesized that therapy with recombinant human erythropoietin (epoetin alfa) might reduce the need for red-cell transfusions. METHODS: In this prospective, randomized, placebo-controlled trial, we enrolled 1460 medical, surgical, or trauma patients between 48 and 96 hours after admission to the intensive care unit. Epoetin alfa (40,000 U) or placebo was administered weekly, for a maximum of 3 weeks; patients were followed for 140 days. The primary end point was the percentage of patients who received a red-cell transfusion. Secondary end points were the number of red-cell units transfused, mortality, and the change in hemoglobin concentration from baseline. RESULTS: As compared with the use of placebo, epoetin alfa therapy did not result in a decrease in either the number of patients who received a red-cell transfusion (relative risk for the epoetin alfa group vs. the placebo group, 0.95; 95% confidence interval [CI], 0.85 to 1.06) or the mean (+/-SD) number of red-cell units transfused (4.5+/-4.6 units in the epoetin alfa group and 4.3+/-4.8 units in the placebo group, P=0.42). However, the hemoglobin concentration at day 29 increased more in the epoetin alfa group than in the placebo group (1.6+/-2.0 g per deciliter vs. 1.2+/-1.8 g per deciliter, P<0.001). Mortality tended to be lower at day 29 among patients receiving epoetin alfa (adjusted hazard ratio, 0.79; 95% CI, 0.56 to 1.10); this effect was also seen in prespecified analyses in those with a diagnosis of trauma (adjusted hazard ratio, 0.37; 95% CI, 0.19 to 0.72). A similar pattern was seen at day 140 (adjusted hazard ratio, 0.86; 95% CI, 0.65 to 1.13), particularly in those with trauma (adjusted hazard ratio, 0.40; 95% CI, 0.23 to 0.69). As compared with placebo, epoetin alfa was associated with a significant increase in the incidence of thrombotic events (hazard ratio, 1.41; 95% CI, 1.06 to 1.86). CONCLUSIONS: The use of epoetin alfa does not reduce the incidence of red-cell transfusion among critically ill patients, but it may reduce mortality in patients with trauma. Treatment with epoetin alfa is associated with an increase in the incidence of thrombotic events. (ClinicalTrials.gov number, NCT00091910 [ClinicalTrials.gov].).

A prospective randomized pilot study of near-infrared spectroscopy-directed restricted fluid therapy versus standard fluid therapy in patients undergoing elective colorectal surgery.

There are substantial data supporting the concept that algorithms that effectively limit fluid volumes to patients undergoing elective surgery, particularly intraoperatively, significantly reduce perioperative morbidity. We hypothesized that intraoperative fluid limitation could be safely accomplished when guided by near-infrared spectroscopy (NIRS) monitoring, and that this fluid restriction regimen would result in a reduction in postoperative morbidity when compared with standard monitoring and fluid therapy. The intent of this pilot study was to demonstrate the feasibility and ease of conduct of this study protocol before expanding to the multicenter pivotal trial. We performed a prospective, (2:1) randomized, pilot study at two centers. A total enrollment of 24 fully evaluable patients undergoing elective open colorectal surgery (16 restricted, 8 standard) was planned. After providing informed consent, patients were randomized to standard fluid resuscitation (500 LR induction bolus, then LR 7 mL/kg/h x 1 h, then 5 mL/kg/h) or restricted fluid resuscitation (no induction bolus, then LR 2 mL/kg/h). Subsequent fluid bolus infusions were guided by physiologic parameters (systolic blood pressure < 90 mm Hg, heart rate > 100 bpm, or oliguria) in the standard group, and by tissue oxygen saturation from NIRS (tissue oxygen saturation (StO2) < 75%, or 20% below baseline; or the same physiologic parameters) in the restricted group. Primary endpoints were major postoperative complications. A total of 27 patients were randomized (18 restricted, 9 standard). Age, gender, ethnicity, past medical history, and body mass index were similar. American Society of Anesthesiologists class was somewhat higher in the restricted group (American Society of Anesthesiologists class 3 in 77% of restricted vs 44% of standard patients; P = 0.194). Median total intraoperative fluids were less in the restricted group (1300 mL) when compared with the standard group (3014 mL) (P = 0.021). Total fluids for the hospitalization were also statistically significantly decreased in the restricted group. Complications occurred in about two-thirds of patients, and complication rates were not statistically different between groups (1.6/restricted patient vs 2.1/standard patient; P = 0.333). Primary indications for boluses (n = 93) given to study patients were: hypotension (69%); oliguria (15%); and tachycardia (14%), with multiple indications per bolus. In only two instances did the StO2 drop to less than 75 per cent, or decrease by 20 per cent from baseline in the 3 minutes before bolus as an indication for fluid administration. Patients undergoing elective colorectal surgery with a fluid restricted strategy had only rare episodes of decreased StO2, suggesting that adequate tissue perfusion was maintained in this group. As a result, NIRS monitoring did not significantly influence intraoperative fluid management of patients undergoing colorectal surgery.

Learning management systems and lecture capture in the medical academic environment.

As residents work disparate schedules at multiple locations and because of workweek hour limits mandated by the ACGME, residents may be unable to attend lectures, seminars, or other activities that would enhance their skills. Further, the ACGME requires that residency programs document resident learning in six stated core competencies and provide proof of completion for various other requirements. LMS/LC is a promising technology to provide a means by which residency programs may overcome these obstacles. More studies are needed to show under what conditions an LMS/LC program actually enhances learning, and which elements are most useful to the new generation of learners comfortable with Web 2.0 technologies.