Prophylactic Intra-Aortic Balloon Counterpulsation in High Risk Cardiac Surgery: The PINBALL Pilot Multicentre, Registry-Linked, Randomised, Controlled Feasibility Trial.

BACKGROUND: Prophylactic intra-aortic balloon counterpulsation (IABC) is commonly used in selected patients undergoing coronary artery bypass graft (CABG) surgery, but definitive evidence is lacking. The aim of the multicentre PINBALL Pilot randomised controlled trial (RCT) was to assess the feasibility of performing a definitive trial to address this question. METHODS: Patients listed for CABG surgery with impaired left ventricular function and at least one additional risk factor for postoperative low cardiac output syndrome were eligible for inclusion if the treating surgical team was uncertain as to the benefit of prophylactic IABC. The primary outcome of feasibility was based on exceeding a pre-specified recruitment rate, protocol compliance and follow-up. RESULTS: The recruitment rate of 0.5 participants per site per month did not meet the feasibility threshold of two participants per site per month and the study was stopped early after enrolment of 24 out of the planned sample size of 40 participants. For 20/24 (83%) participants, preoperative IABC use occurred according to study assignment. Six (6)-month follow-up was available for all enrolled participants, [IABC 1 death (8%) vs. control 1 death (9%), p = 0.95]. CONCLUSION: The PINBALL Pilot recruitment rate was insufficient to demonstrate feasibility of a multicentre RCT of prophylactic IABC in high risk patients undergoing CABG surgery.

Higher versus Lower Continuous Renal Replacement Therapy Intensity in Critically ill Patients with Liver Dysfunction.

AIMS: To study the association between higher versus lower continuous renal replacement therapy (CRRT) intensity and mortality in critically ill patients with combined acute kidney injury and liver dysfunction. METHODS: Post-hoc analysis of patients with liver dysfunction (Sequential Organ Failure Assessment liver score ≥2 or diagnosis of liver failure/transplant) included in the Randomized Evaluation of Normal versus Augmented Level renal replacement therapy (RENAL) trial. RESULTS: Of 444 patients, 210 (47.3%) were randomized to higher intensity (effluent flow 40 mL/kg/h) and 234 (52.7%) to lower intensity (effluent flow 25 mL/kg/h) therapy. Overall, 79 and 86% of prescribed effluent flow was delivered in the higher-intensity and lower-intensity groups, respectively (p < 0.001). In total, 113 (54.1%) and 120 (51.3%) patients died in each group. On multivariable Cox regression analysis, we found no independent association between higher CRRT intensity and mortality (HR 0.93, 95% CI 0.70-1.24; p = 0.642). CONCLUSIONS: In RENAL patients with liver dysfunction, higher CRRT intensity was not associated with reduced mortality.

Transfusion Requirements in Cardiac Surgery III (TRICS III): Study Design of a Randomized Controlled Trial.

OBJECTIVES: To determine if a restrictive transfusion threshold is noninferior to a higher threshold as measured by a composite outcome of mortality and serious morbidity. DESIGN: Transfusion Requirements in Cardiac Surgery (TRICS) III was a multicenter, international, open-label randomized controlled trial of two commonly used transfusion strategies in patients having cardiac surgery using a noninferiority trial design (ClinicalTrials.gov number, NCT02042898). SETTING: Eligible patients were randomized prior to surgery in a 1:1 ratio. PARTICIPANTS: Potential participants were 18 years or older undergoing planned cardiac surgery using cardiopulmonary bypass (CPB) with a preoperative European System for Cardiac Operative Risk Evaluation (EuroSCORE I) of 6 or more. INTERVENTIONS: Five thousand patients; those allocated to a restrictive transfusion group received a red blood cell (RBC) transfusion if the hemoglobin concentration (Hb) was less than 7.5 g/dL intraoperatively and/or postoperatively. Patients allocated to a liberal transfusion strategy received RBC transfusion if the Hb was less than 9.5 g/dL intraoperatively or postoperatively in the intensive care unit or less than 8.5 g/dL on the ward. MEASUREMENTS AND MAIN RESULTS: The primary outcome was a composite of all-cause mortality, myocardial infarction, stroke, or new onset renal dysfunction requiring dialysis at hospital discharge or day 28, whichever comes first. The primary outcome was analyzed as a per-protocol analysis. The trial monitored adherence closely as adherence to the transfusion triggers is important in ensuring that measured outcomes reflect the transfusion strategy. CONCLUSION: By randomizing prior to surgery, the TRICS III trial captured the most acute reduction in hemoglobin during cardiopulmonary bypass.

Effect of Dexmedetomidine Added to Standard Care on Ventilator-Free Time in Patients With Agitated Delirium: A Randomized Clinical Trial.

IMPORTANCE: Effective therapy has not been established for patients with agitated delirium receiving mechanical ventilation. OBJECTIVE: To determine the effectiveness of dexmedetomidine when added to standard care in patients with agitated delirium receiving mechanical ventilation. DESIGN, SETTING, AND PARTICIPANTS: The Dexmedetomidine to Lessen ICU Agitation (DahLIA) study was a double-blind, placebo-controlled, parallel-group randomized clinical trial involving 74 adult patients in whom extubation was considered inappropriate because of the severity of agitation and delirium. The study was conducted at 15 intensive care units in Australia and New Zealand from May 2011 until December 2013. Patients with advanced dementia or traumatic brain injury were excluded. INTERVENTIONS: Bedside nursing staff administered dexmedetomidine (or placebo) initially at a rate of 0.5 µg/kg/h and then titrated to rates between 0 and 1.5 µg/kg/h to achieve physician-prescribed sedation goals. The study drug or placebo was continued until no longer required or up to 7 days. All other care was at the discretion of the treating physician. MAIN OUTCOMES AND MEASURES: Ventilator-free hours in the 7 days following randomization. There were 21 reported secondary outcomes that were defined a priori. RESULTS: Of the 74 randomized patients (median age, 57 years; 18 [24%] women), 2 withdrew consent later and 1 was found to have been randomized incorrectly, leaving 39 patients in the dexmedetomidine group and 32 patients in the placebo group for analysis. Dexmedetomidine increased ventilator-free hours at 7 days compared with placebo (median, 144.8 hours vs 127.5 hours, respectively; median difference between groups, 17.0 hours [95% CI, 4.0 to 33.2 hours]; P = .01). Among the 21 a priori secondary outcomes, none were significantly worse with dexmedetomidine, and several showed statistically significant benefit, including reduced time to extubation (median, 21.9 hours vs 44.3 hours with placebo; median difference between groups, 19.5 hours [95% CI, 5.3 to 31.1 hours]; P < .001) and accelerated resolution of delirium (median, 23.3 hours vs 40.0 hours; median difference between groups, 16.0 hours [95% CI, 3.0 to 28.0 hours]; P = .01). Using hierarchical Cox modeling to adjust for imbalanced baseline characteristics, allocation to dexmedetomidine was significantly associated with earlier extubation (hazard ratio, 0.47 [95% CI, 0.27-0.82]; P = .007). CONCLUSIONS AND RELEVANCE: Among patients with agitated delirium receiving mechanical ventilation in the intensive care unit, the addition of dexmedetomidine to standard care compared with standard care alone (placebo) resulted in more ventilator-free hours at 7 days. The findings support the use of dexmedetomidine in patients such as these. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01151865.

An observational study fluid balance and patient outcomes in the Randomized Evaluation of Normal vs. Augmented Level of Replacement Therapy trial.

OBJECTIVE: To examine associations between mean daily fluid balance during intensive care unit study enrollment and clinical outcomes in patients enrolled in the Randomized Evaluation of Normal vs. Augmented Level (RENAL) replacement therapy study. DESIGN: Statistical analysis of data from multicenter, randomized, controlled trials. SETTING: Thirty-five intensive care units in Australia and New Zealand. PATIENTS: Cohort of 1453 patients enrolled in the RENAL study. INTERVENTIONS: We analyzed the association between daily fluid balance on clinical outcomes using multivariable logistic regression, Cox proportional hazards, time-dependent analysis, and repeated measure analysis models. MEASUREMENTS AND MAIN RESULTS: During intensive care unit stay, mean daily fluid balance among survivors was -234 mL/day compared with +560 mL/day among nonsurvivors (p < .0001). Mean cumulative fluid balance over the same period was -1941 vs. +1755 mL (p = .0003). A negative mean daily fluid balance during study treatment was independently associated with a decreased risk of death at 90 days (odds ratio 0.318; 95% confidence interval 0.24-0.43; p < .000.1) and with increased survival time (p < .0001). In addition, a negative mean daily fluid balance was associated with significantly increased renal replacement-free days (p = .0017), intensive care unit-free days (p < .0001), and hospital-free days (p = .01). These findings were unaltered after the application of different statistical models. CONCLUSIONS: In the RENAL study, a negative mean daily fluid balance was consistently associated with improved clinical outcomes. Fluid balance may be a target for specific manipulation in future interventional trials of critically ill patients receiving renal replacement therapy.

Sex and mortality in septic severe acute kidney injury.

PURPOSE: To investigate the relationship between sex and mortality and whether menopause or the intensity of renal replacement therapy (RRT) modify this relationship in patients with severe septic acute kidney injury (AKI). MATERIALS AND METHODS: Post-hoc analysis of patients with sepsis included in the Randomized Evaluation of Normal versus Augmented Level renal replacement therapy (RENAL) trial. RESULTS: Of 724 patients, 458 (63.3%) were male and 266 (36.7%) were female. The mean delivered effluent flow rate was 25.6 ±â€¯7.4 ml/kg/h (80 ±â€¯15% of prescribed dose) in males and 27.4 ±â€¯7.6 ml/kg/h (83 ±â€¯15% of prescribed dose) in females (p = .01). A total of 237 (51.7%) males and 118 (44.5%) females died within 90 days of randomization (p = .06). The adjusted hazard ratio (HR) for 90-day mortality was significantly decreased in females as compared with males (HR 0.74, 95% CI 0.57 to 0.96, p = .02). The relationship between sex and mortality was not significantly altered by menopausal status (adjusted P value for interaction 0.99) or by RRT intensity allocation (adjusted P value for interaction 0.27). CONCLUSIONS: In a cohort of patients with sepsis and severe AKI, female sex was associated with improved survival. The relationship between sex and survival was not altered by menopausal status or RRT intensity.

The relationship between hypophosphataemia and outcomes during low-intensity and high-intensity continuous renal replacement therapy.

AIM: To identify risk factors for development of hypophosphataemia in patients treated with two different intensities of continuous renal replacement therapy (CRRT) and to assess the independent association of hypophosphataemia with major clinical outcomes. MATERIALS AND METHODS: We performed secondary analysis of data collected from 1441 patients during a large, multicentre randomised controlled trial of CRRT intensity. We allocated patients to two different intensities of CRRT (25mL/kg/hour vs 40 mL/kg/hour of effluent generation) and obtained daily measurement of serum phosphate levels. RESULTS: We obtained 14 115 phosphate measurements and identified 462 patients (32.1%) with hypophosphataemia, with peak incidence on Day 2 and Day 3. With lower intensity CRRT, there were 58 episodes of hypophosphataemia/1000 patient days, compared with 112 episodes/1000 patient days with higher intensity CRRT (P < 0.001). On multivariable logistic regression analysis, higher intensity CRRT, female sex, higher Acute Physiology and Chronic Health Evaluation score and hypokalaemia were independently associated with an increased odds ratio (OR) for hypophosphataemia. On multivariable models, hypophosphataemia was associated with better clinical outcomes, but when analysis was confined to patients alive at 96 hours, hypophosphataemia was not independently associated with clinical outcomes. CONCLUSIONS: Hypophosphataemia is common during CRRT and its incidence increases with greater CRRT intensity. Hypophosphataemia is not a robust independent predictor of mortality. Its greater incidence in the higher intensity CRRT arm of the Randomised Evaluation of Normal vs Augmented Level trial does not explain the lack of improved outcomes with such treatment.