Impact of Various Estimated Glomerular Filtration Rate Equations on the Pharmacokinetics of Meropenem in Critically Ill Adults.

IMPORTANCE: Meropenem dosing is typically guided by creatinine-based estimated glomerular filtration rate (eGFR), but creatinine is a suboptimal GFR marker in the critically ill. OBJECTIVES: This study aimed to develop and qualify a population pharmacokinetic model for meropenem in critically ill adults and to determine which eGFR equation based on creatinine, cystatin C, or both biomarkers best improves model performance. DESIGN SETTING AND PARTICIPANTS: This single-center study evaluated adults hospitalized in an ICU who received IV meropenem from 2018 to 2022. Patients were excluded if they had acute kidney injury, were on kidney replacement therapy, or were treated with extracorporeal membrane oxygenation. Two cohorts were used for population pharmacokinetic modeling: a richly sampled development cohort (n = 19) and an opportunistically sampled qualification cohort (n = 32). MAIN OUTCOMES AND MEASURES: A nonlinear mixed-effects model was developed using parametric methods to estimate meropenem serum concentrations. RESULTS: The best-fit structural model in the richly sampled development cohort was a two-compartment model with first-order elimination. The final model included time-dependent weight normalized to a 70-kg adult as a covariate for volume of distribution (Vd) and time-dependent eGFR for clearance. Among the eGFR equations evaluated, eGFR based on creatinine and cystatin C expressed in mL/min best-predicted meropenem clearance. The mean (se) Vd in the final model was 18.2 (3.5) liters and clearance was 11.5 (1.3) L/hr. Using the development cohort as the Bayesian prior, the opportunistically sampled cohort demonstrated good accuracy and low bias. CONCLUSIONS AND RELEVANCE: Contemporary eGFR equations that use both creatinine and cystatin C improved meropenem population pharmacokinetic model performance compared with creatinine-only or cystatin C-only eGFR equations in adult critically ill patients.

Posthospital Multidisciplinary Care for AKI Survivors: A Feasibility Pilot.

Rationale & Objective: Innovative models are needed to address significant gaps in kidney care follow-up for acute kidney injury (AKI) survivors. Study Design: This quasi-experimental pilot study reports the feasibility of the AKI in Care Transitions (ACT) program, a multidisciplinary approach to AKI survivor care based in the primary care setting. Setting & Participants: The study included consenting adults with stage 3 AKI discharged home without dialysis. Interventions: The ACT intervention included predischarge education from nurses and coordinated postdischarge follow-up with a primary care provider and pharmacist within 14 days. ACT was implemented in phases (Usual Care, Education, ACT). Outcomes: The primary outcome was feasibility. Secondary outcomes included process and clinical outcomes. Results: In total, 46 of 110 eligible adults were enrolled. Education occurred in 18/18 and 14/15 participants in the Education and ACT groups, respectively. 30-day urine protein evaluation occurred in 15%, 28%, and 87% of the Usual Care, Education, and ACT groups, respectively (P < 0.001). Cumulative incidence of provider (primary care or nephrologist) and laboratory follow-up at 14 and 30 days was different across groups (14 days: Usual care 0%, Education 11%, ACT 73% [P < 0.01]; 30 days: 0%, 22%, and 73% [P < 0.01]). 30-day readmission rates were 23%, 44%, and 13% in the Usual Care, Education, and ACT groups, respectively (P = 0.13). Limitations: Patients were not randomly assigned to treatment groups. The sample size limited the ability to detect some differences or perform multivariable analysis. Conclusions: This study demonstrated the feasibility of multidisciplinary AKI survivor follow-up beginning in primary care. We observed a higher cumulative incidence of laboratory and provider follow-up in ACT participants. Trial Registration: ClinicalTrials.gov (NCT04505891). Plain-Language Summary: Abrupt loss of kidney function in hospitalized patients, acute kidney injury (AKI), increases the chances of long-term kidney disease and a worse health care experience for patients. One out of 3 people who experience AKI do not get the follow-up kidney care they need. We performed a pilot study to test whether a program that facilitates structured AKI follow-up in primary care called the AKI in Care Transitions (ACT) program was possible. ACT brings together the unique expertise of nurses, doctors, and pharmacists to look at the patient's kidney health plan from all angles. The study found that the ACT program was possible and led to more complete kidney care follow-up after discharge than the normal approach to care.

Population pharmacokinetic model of cefepime for critically ill adults: a comparative assessment of eGFR equations.

Cefepime exhibits highly variable pharmacokinetics in critically ill patients. The purpose of this study was to develop and qualify a population pharmacokinetic model for use in the critically ill and investigate the impact of various estimated glomerular filtration rate (eGFR) equations using creatinine, cystatin C, or both on model parameters. This was a prospective study of critically ill adults hospitalized at an academic medical center treated with intravenous cefepime. Individuals with acute kidney injury or on kidney replacement therapy or extracorporeal membrane oxygenation were excluded. A nonlinear mixed-effects population pharmacokinetic model was developed using data collected from 2018 to 2022. The 120 included individuals contributed 379 serum samples for analysis. A two-compartment pharmacokinetic model with first-order elimination best described the data. The population mean parameters (standard error) in the final model were 7.84 (0.24) L/h for CL1 and 15.6 (1.45) L for V1. Q was fixed at 7.09 L/h and V2 was fixed at 10.6 L, due to low observed interindividual variation in these parameters. The final model included weight as a covariate for volume of distribution and the eGFRcr-cysC (mL/min) as a predictor of drug clearance. In summary, a population pharmacokinetic model for cefepime was created for critically ill adults. The study demonstrated the importance of cystatin C to prediction of cefepime clearance. Cefepime dosing models which use an eGFR equation inclusive of cystatin C are likely to exhibit improved accuracy and precision compared to dosing models which incorporate an eGFR equation with only creatinine.

Adequacy of cefepime concentrations in the early phase of critical illness: A case for precision pharmacotherapy.

STUDY OBJECTIVE: In critically ill patients, adequacy of early antibiotic exposure has been incompletely evaluated. This study characterized factors associated with inadequate cefepime exposure in the first 24 h of critical illness. DESIGN: Prospective cohort study. SETTING: Academic Medical Center. PATIENTS: Critically ill adults treated with cefepime. Patients with acute kidney injury or treated with kidney replacement therapy or extracorporeal membrane oxygenation were excluded. INTERVENTION: None. MEASUREMENTS: A nonlinear mixed-effects pharmacokinetic (PK) model was developed to estimate cefepime concentrations for each patient over time. The percentage of time the free drug concentration exceeded 8 mg/L during the first 24 h of therapy was calculated (%ƒT>8; appropriate for the susceptible breakpoint for Pseudomonas aeruginosa). Factors predictive of low %ƒT>8 were explored with multivariable regression. MAIN RESULTS: In the 100 included patients, a one-compartment PK model was developed with first-order elimination with covariates for weight and estimated glomerular filtration rate based on creatinine and cystatin C (eGFRSCr-CysC). The median (interquartile range) %ƒT>8 for cefepime in the first 24 h of therapy based on this model was 85% (66%, 100%). Less than 100% ƒT>8 during first 24 h of therapy occurred in 70 (70%) individuals. Lower Sequential Organ Failure Assessment score (p = 0.032) and higher eGFRSCr-CysC (p < 0.001) predicted a lower %ƒT>8. Central nervous system infection source was protective (i.e., associated with a higher %ƒT>8; p = 0.008). CONCLUSIONS: During early critical illness, cefepime concentrations were inadequate in a significant proportion of patients. Antimicrobial optimization is needed to improve the precision of pharmacotherapy in the critically ill patients.

Pharmacist-provider collaborative visits after hospital discharge in a comprehensive acute kidney injury survivor model.

BACKGROUND: Postdischarge follow-up in primary care is an opportunity for pharmacists to re-evaluate medication use in acute kidney injury (AKI) survivors. Of the emerging AKI survivor care models described in literature, only one involved a pharmacist with limited detail about the direct impact. OBJECTIVE: This study aimed to describe pharmacist contributions to a comprehensive postdischarge AKI survivorship program in primary care (the AKI in Care Transitions [ACT] program). METHODS: The ACT program was piloted from May to December of 2021 at Mayo Clinic as a bundled care strategy for patients who survived an episode of AKI and were discharged home without the need for hemodialysis. Patients received education and care coordination from nurses before discharge and later completed postdischarge laboratory assessment and clinician follow-up in primary care. During the follow-up encounter, patients completed a 30-minute comprehensive medication management visit with a pharmacist focusing on AKI survivorship considerations. Medication therapy recommendations were communicated to a collaborating primary care provider (PCP) before a separate 30-minute visit with the patient. PCPs had access to clinical decision support with evidence-based post-AKI care recommendations. Medication-related issues were summarized descriptively. RESULTS: Pharmacists made 28 medication therapy recommendations (median 3 per patient, interquartile range 2-3) and identified 14 medication discrepancies for the 11 patients who completed the pilot program, and 86% of the medication therapy recommendations were acted on by the PCP within 7 days. Six recommendations were made to initiate renoprotective medications, and 5 were acted on (83%). CONCLUSION: During the pilot phase of a multifaceted transitional care program for AKI survivors, pharmacists' successfully identified and addressed multiple medication therapy problems, including for renally active drugs. These results demonstrate the potential for pharmacist-provider collaborative visits in primary care to improve safe and effective medication use in AKI survivors.

Practical Anemia Bundle for Sustained Blood Recovery (PABST-BR) in critical illness: a protocol for a randomised controlled trial.

INTRODUCTION: Anaemia is highly prevalent in critical illness and is associated with impaired outcomes during and after hospitalisation. However, the impact of interventions designed to attenuate or treat anaemia during critical illness on post-hospitalisation haemoglobin recovery and functional outcomes is unclear. METHODS AND ANALYSIS: The Practical Anemia Bundle for Sustained Blood Recovery (PABST-BR) clinical trial is a pragmatic, open-label, parallel group, single-centre, randomised clinical trial assessing the impact of a multifaceted anaemia prevention and treatment strategy versus standard care for improvement of haemoglobin concentrations and functional outcomes after critical illness. The intervention, which will be delivered early in critical illness for those with moderate-to-severe anaemia (ie, haemoglobin <100 g/L), includes three components: (1) optimised phlebotomy, (2) clinical decision support and (3) pharmacological anaemia treatment directed at the underlying aetiology of anaemia. In-person assessments will occur at 1 and 3 months post-hospitalisation for laboratory evaluations and multidimensional functional outcome assessments. The primary outcome is differences in haemoglobin concentrations between groups, with secondary endpoints of anaemia-related fatigue, physical function, cognition, mental health, quality of life, phlebotomy volumes and frequency, transfusions, readmissions and mortality through 1-year post-hospitalisation. ETHICS AND DISSEMINATION: The study has been approved by the Institutional Review Board of the Mayo Clinic in Minnesota, USA. A Data Safety Monitoring Plan has been created in accordance with the policies of the Institutional Review Board and the study funder, the National Heart, Lung and Blood Institute of the National Institutes of Health (NIH). The study will comply with NIH data sharing and dissemination policies. Results will be presented at national and international meetings and published in peer-reviewed journals. Designing and testing strategies to optimise haemoglobin recovery and improve functional outcomes after critical illness remain important research gaps. The PABST-BR trial will inform the development of a larger multicentre clinical trial. TRIAL REGISTRATION NUMBER: NCT05167734.

Development and Feasibility of a Multidisciplinary Approach to AKI Survivorship in Care Transitions: Research Letter.

Background: Acute kidney injury (AKI) survivors are at heightened risk for poor short- and long-term health outcomes. Even among those who recover after an AKI episode, the risk for chronic kidney disease is 4- to 6-fold higher than in patients without AKI, underscoring the importance of identifying methods to improve AKI survivorship. Objective: The purpose of this report was to describe the development and feasibility of a novel multidisciplinary approach to caring for AKI survivors at care transitions (ACT). Design: Observational process improvement initiative. Setting: Single academic medical center in the United States. Patients: The studied population was adults with stage 3 AKI not discharging on dialysis who were established with a primary care provider (PCP) at our institution. Methods: An electronic health record tool was developed prior to implementation to identify AKI survivors. The ACT program encompassed engaging patients in the hospital, delivering education by nephrology-trained nurses before discharge, completing recommended laboratory testing after discharge, and conducting structured kidney-focused follow-up with a pharmacist and a PCP within 7 to 14 days after discharge. Patients could be referred for nephrology evaluation at the discretion of the PCP. Results: Preliminary data demonstrated that most AKI survivors of interest could be identified, educated, and followed up with this model. This strategy appeared feasible, scalable, and maximized the unique expertise of each member of the multidisciplinary team. Limitations: Small sample size, future assessment of process, clinical, and patient-reported outcomes needed. Conclusions: The multidisciplinary ACT workflow supported by clinical decision support was feasible and addressed gaps in existing care transition models. Team-based care delivery in primary care appears to be a mechanism to extend the capacity for kidney health monitoring for AKI survivors.

Contexte: Les patients qui survivent à un épisode d'insuffisance rénale aiguë (IRA) courent un risque plus élevé de mauvais résultats cliniques à court et à long terme. Même chez les patients qui se rétablissent, le risque de progression vers l'insuffisance rénale chronique (IRC) demeure de quatre à six fois plus élevé que chez les patients n'ayant jamais eu d'épisode d'IRA. Il est donc essentiel d'identifier des méthodes permettant d'améliorer la survie à un épisode d'IRA. Objectif: L'objectif de cette étude était de décrire l'élaboration et la faisabilité d'une nouvelle approche multidisciplinaire pour la prise en charge des survivants d'un épisode d'IRA en transition de soins (Approche multidisciplinaire en Transition de Soins­AmTS). Type d'étude: Initiative d'amélioration des processus menée par observation. Cadre: Un seul centre médical universitaire aux États-Unis. Sujets: La population étudiée était constituée d'adultes atteints d'IRA de stade 3 sans traitements de dialyse à leur sortie et qui avaient été mis en contact avec un fournisseur de soins primaires (FSP) dans l'établissement. Méthodologie: Avant la mise en œuvre de l'intervention, un outil de dossier de santé électronique a été développé pour identifier les survivants à un épisode d'IRA. Le programme de l'AmTS comprenait la participation des patients pendant leur séjour à l'hôpital, une formation donnée par des infirmières formées en néphrologie avant le congé, les tests de laboratoire recommandés après la sortie de l'hôpital et un suivi structuré axé sur la santé rénale avec un pharmacien et un FSP dans les 7 à 14 jours suivant la sortie de l'hôpital. Il a été laissé à la discrétion des FSP d'aiguiller ou non leurs patients pour une évaluation en néphrologie. Résultats: Des données préliminaires ont démontré qu'il était possible d'identifier, d'informer et d'assurer le suivi de la plupart des sujets d'intérêt (des survivants à un épisode d'IRA) avec ce modèle. Cette stratégie a semblé réalisable, évolutive et apte à optimiser l'expertise individuelle des membres de l'équipe multidisciplinaire. Limites: Faible taille de l'échantillon; une évaluation future du processus, des résultats cliniques et des résultats rapportés par les patients est nécessaire. Conclusion: Le processus de cette AmTS soutenue par une aide à la prise de décision clinique s'est avéré réalisable et a permis de combler les lacunes des modèles de transition des soins existants. Dans le contexte des soins primaires, la prestation de soins en équipe semble être un mécanisme permettant d'étendre la capacité de surveillance de la santé rénale des survivants à un épisode d'IRA.

Characterization of Platelet Biologic Markers in the Early Pathogenesis of Postoperative Acute Respiratory Distress Syndrome.

Animal models and limited human studies have suggested a plausible role for platelets in the pathogenesis and resolution of acute respiratory distress syndrome (ARDS). However, there are little data regarding the role of platelets in ARDS development. OBJECTIVES: The objective of this study was to characterize the role of platelets in a postoperative ARDS model through an analysis of two platelet-specific biologic markers: thromboxane A2 (TxA2) and soluble CD-40-ligand (sCD40L). DESIGN SETTING AND PARTICIPANTS: This was a nested case-control study of ARDS cases matched to non-ARDS controls. Blood samples were collected from a cohort of 500 patients undergoing thoracic, aortic vascular, or cardiac surgery that placed them at high-risk of developing postoperative ARDS. MAIN OUTCOMES AND MEASURES: TxA2 and sCD40L were analyzed at baseline (prior to surgical incision) as well as 2 hours and 6 hours after the key intraoperative events believed to be associated with increased risk of postoperative ARDS. RESULTS: Of 500 patients enrolled, 20 ARDS cases were matched 1:2 to non-ARDS controls based on age, sex, surgical procedure, and surgical lung injury prediction score. Those who developed ARDS had longer surgeries, greater fluid administration, and higher peak inspiratory pressures. There were no significant differences in levels of TxA2 or sCD40L at baseline, at 2 hours, or at 6 hours. There was also no difference in the change in biomarker concentration between baseline and 2 hours or baseline and 6 hours. CONCLUSIONS: Two novel platelet-associated biologic markers (TxA2 and sCD40L) were not elevated in patients who developed ARDS in a postoperative ARDS model. Although limited by the relatively small study size, these results do not support a clear role for platelets in the early pathogenesis of postoperative ARDS.

Bedside Allogeneic Erythrocyte Washing with a Cell Saver to Remove Cytokines, Chemokines, and Cell-derived Microvesicles.

BACKGROUND: Removal of cytokines, chemokines, and microvesicles from the supernatant of allogeneic erythrocytes may help mitigate adverse transfusion reactions. Blood bank-based washing procedures present logistical difficulties; therefore, we tested the hypothesis that on-demand bedside washing of allogeneic erythrocyte units is capable of removing soluble factors and is feasible in a clinical setting. METHODS: There were in vitro and prospective, observation cohort components to this a priori planned substudy evaluating bedside allogeneic erythrocyte washing, with a cell saver, during cardiac surgery. Laboratory data were collected from the first 75 washed units given to a subset of patients nested in the intervention arm of a parent clinical trial. Paired pre- and postwash samples from the blood unit bags were centrifuged. The supernatant was aspirated and frozen at -70°C, then batch-tested for cell-derived microvesicles, soluble CD40 ligand, chemokine ligand 5, and neutral lipids (all previously associated with transfusion reactions) and cell-free hemoglobin (possibly increased by washing). From the entire cohort randomized to the intervention arm of the trial, bedside washing was defined as feasible if at least 75% of prescribed units were washed per protocol. RESULTS: Paired data were available for 74 units. Washing reduced soluble CD40 ligand (median [interquartile range]; from 143 [1 to 338] ng/ml to zero), chemokine ligand 5 (from 1,314 [715 to 2,551] to 305 [179 to 488] ng/ml), and microvesicle numbers (from 6.90 [4.10 to 20.0] to 0.83 [0.33 to 2.80] × 106), while cell-free hemoglobin concentration increased from 72.6 (53.6 to 171.6) mg/dl to 210.5 (126.6 to 479.6) mg/dl (P < 0.0001 for each). There was no effect on neutral lipids. Bedside washing was determined as feasible for 80 of 81 patients (99%); overall, 293 of 314 (93%) units were washed per protocol. CONCLUSIONS: Bedside erythrocyte washing was clinically feasible and greatly reduced concentrations of soluble factors thought to be associated with transfusion-related adverse reactions, increasing concentrations of cell-free hemoglobin while maintaining acceptable (less than 0.8%) hemolysis.

Evolution of Validated Biomarkers and Intraoperative Parameters in the Development of Postoperative ARDS.

BACKGROUND: Patients who develop ARDS from medical or traumatic causes typically present after the inciting event has already occurred. Postoperative ARDS is unique in that the inciting insult potentially responsible for ARDS is known ahead of time, which provides an opportunity to study the early pathophysiology of ARDS. The objective of this study was to better understand the early pathophysiology of postoperative ARDS through a temporal analysis of key biomarkers of interest. METHODS: We performed a case-control study of adults undergoing elective thoracic, aortic vascular, or cardiac surgery, which placed them at increased risk of developing postoperative ARDS. Biomarkers were measured at baseline, 2 h, and 6 h after the key intraoperative event believed to be responsible for ARDS. RESULTS: Of the 467 subjects enrolled, 26 developed ARDS and were matched to non-ARDS controls 1:2 based on age, sex, surgical procedure, and surgical lung injury prediction score. Patients with ARDS were more likely to have lower preoperative albumin (P = .029), longer surgery (P = .007), larger amounts of intraoperative fluid (P = .036), and higher intraoperative peak inspiratory pressures (P = .006). Baseline plasminogen activator inhibitor-1 levels were higher in the ARDS group (P = .03). Changes in postoperative biomarker levels from baseline were greater in the ARDS group for interleukin-8 (baseline to 6 h, P = .02) and surfactant protein-D (baseline to 2 h, P = .009). CONCLUSIONS: Our study supported the hypothesis that dysregulated coagulation, inflammation, and epithelial injury are pathophysiologic features of early postoperative ARDS. Interleukin-8, plasminogen activator-1, and surfactant protein-D may help predict development of postoperative ARDS.

Point-of-care washing of allogeneic red blood cells for the prevention of transfusion-related respiratory complications (WAR-PRC): a protocol for a multicenter randomised clinical trial in patients undergoing cardiac surgery.

INTRODUCTION: The transfusion-related respiratory complications, transfusion-related acute lung injury (TRALI) and transfusion-associated circulatory overload (TACO), are leading causes of transfusion-related morbidity and mortality. At present, there are no effective preventive strategies with red blood cell (RBC) transfusion. Although mechanisms remain incompletely defined, soluble biological response modifiers (BRMs) within the RBC storage solution may play an important role. Point-of-care (POC) washing of allogeneic RBCs may remove these BRMs, thereby mitigating their impact on post-transfusion respiratory complications. METHODS AND ANALYSIS: This is a multicenter randomised clinical trial of standard allogeneic versus washed allogeneic RBC transfusion for adult patients undergoing cardiac surgery testing the hypothesis that POC RBC washing is feasible, safe, and efficacious and will reduce recipient immune and physiologic responses associated with transfusion-related respiratory complications. Relevant clinical outcomes will also be assessed. This investigation will enrol 170 patients at two hospitals in the USA. Simon's two-stage design will be used to assess the feasibility of POC RBC washing. The primary safety outcomes will be assessed using Wilcoxon Rank-Sum tests for continuous variables and Pearson chi-square test for categorical variables. Standard mixed modelling practices will be employed to test for changes in biomarkers of lung injury following transfusion. Linear regression will assess relationships between randomised group and post-transfusion physiologic measures. ETHICS AND DISSEMINATION: Safety oversight will be conducted under the direction of an independent Data and Safety Monitoring Board (DSMB). Approval of the protocol was obtained by the DSMB as well as the institutional review boards at each institution prior to enrolling the first study participant. This study aims to provide important information regarding the feasibility of POC washing of allogeneic RBCs and its potential impact on ameliorating post-transfusion respiratory complications. Additionally, it will inform the feasibility and scientific merit of pursuing a more definitive phase II/III clinical trial. REGISTRATION: ClinicalTrials.gov registration number is NCT02094118 (Pre-results).

Extravascular lung water and pulmonary vascular permeability index as markers predictive of postoperative acute respiratory distress syndrome: a prospective cohort investigation.

OBJECTIVE: Robust markers of subclinical perioperative lung injury are lacking. Extravascular lung water indexed to predicted body weight and pulmonary vascular permeability index are two promising early markers of lung edema. We aimed to evaluate whether extravascular lung water indexed to predicted body weight and pulmonary vascular permeability index would identify patients at risk for clinically significant postoperative pulmonary edema, particularly resulting from the acute respiratory distress syndrome. DESIGN: Prospective cohort study. SETTING: Tertiary care academic medical center. PATIENTS: Adults undergoing high-risk cardiac or aortic vascular surgery (or both) with risk of acute respiratory distress syndrome. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Extravascular lung water indexed to predicted body weight and pulmonary vascular permeability index measurements were obtained intraoperatively and in the early postoperative period. We assessed the accuracy of peak extravascular lung water indexed to predicted body weight and pulmonary vascular permeability index as predictive markers of clinically significant pulmonary edema (defined as acute respiratory distress syndrome or cardiogenic pulmonary edema) using area under the receiver-operating characteristic curves. Associations between extravascular lung water indexed to predicted body weight and pulmonary vascular permeability patient-important with important outcomes were assessed. Of 150 eligible patients, 132 patients (88%) had extravascular lung water indexed to predicted body weight and pulmonary vascular permeability index measurements. Of these, 13 patients (9.8%) had postoperative acute respiratory distress syndrome and 15 patients (11.4%) had cardiogenic pulmonary edema. Extravascular lung water indexed to predicted body weight effectively predicted development of clinically significant pulmonary edema (area under the receiver-operating characteristic curve, 0.79; 95% CI, 0.70-0.89). Pulmonary vascular permeability index discriminated acute respiratory distress syndrome from cardiogenic pulmonary edema alone or no edema (area under the receiver-operating characteristic curve, 0.77; 95% CI, 0.62-0.93). Extravascular lung water indexed to predicted body weight was associated with the worst postoperative PaO2/FIO2, duration of mechanical ventilation, ICU stay, and hospital stay. Peak values for extravascular lung water indexed to predicted body weight and pulmonary vascular permeability index were obtained within 2 hours of the primary intraoperative insult for the majority of patients (> 80%). CONCLUSIONS: Perioperative extravascular lung water indexed to predicted body weight is an early marker that predicts risk of clinically significant postoperative pulmonary edema in at-risk surgical patients. Pulmonary vascular permeability index effectively discriminated postoperative acute respiratory distress syndrome from cardiogenic pulmonary edema. These measures will aid in the early detection of subclinical lung injury in at-risk surgical populations.

Rates and determinants of informed consent: a case study of an international thromboprophylaxis trial.

BACKGROUND: Successful completion of randomized trials depends upon efficiently and ethically screening patients and obtaining informed consent. Awareness of modifiable barriers to obtaining consent may inform ongoing and future trials. OBJECTIVE: The objective of this study is to describe and examine determinants of consent rates in an international heparin thromboprophylaxis trial (Prophylaxis for ThromboEmbolism in Critical Care Trial, clinicaltrials.gov NCT00182143). DESIGN: Throughout the 4-year trial, research personnel approached eligible critically ill patients or their substitute decision makers for informed consent. Whether consent was obtained or declined was documented daily. SETTING: The trial was conducted in 67 centers in 6 countries. MEASUREMENTS AND MAIN RESULTS: A total of 3764 patients were randomized. The overall consent rate was 82.2% (range, 50%-100%) across participating centers. Consent was obtained from substitute decision makers and patients in 90.1% and 9.9% of cases, respectively. Five factors were independently associated with consent rates. Research coordinators with more experience achieved higher consent rates (odds ratio [OR], 3.43; 95% confidence interval, 2.42-4.86; P < .001 for those with >10 years of experience). Consent rates were higher in smaller intensive care units with less than 15 beds compared with intensive care units with 15 to 20 beds, 21 to 25 beds, and greater than 25 beds (all ORs, <0.5; P < .001) and were higher in centers with more than 1 full-time research staff (OR, 1.95; 95% confidence interval, 1.28-2.99; P < .001). Consent rates were lower in centers affiliated with the Canadian Critical Care Trials Group or the Australian and New Zealand Intensive Care Society Clinical Trials Group compared with other centers (OR, 0.57; 95% confidence interval, 0.42-0.77; P < .001). Finally, consent rates were highest during the pilot trial, lowest during the initiation of the full trial, and increased over years of recruitment (P < .001). CONCLUSIONS: Characteristics of study centers, research infrastructure, and experience were important factors associated with successfully procuring informed consent to participate in this thromboprophylaxis trial.

Amiodarone versus lidocaine and placebo for the prevention of ventricular fibrillation after aortic crossclamping: a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: Ventricular fibrillation occurs commonly after aortic crossclamping in patients undergoing cardiac surgery. Ventricular fibrillation increases myocardial oxygen consumption, and defibrillation may harm the myocardium. Thus, a pharmacologic approach to decreasing the incidence of ventricular fibrillation or the number of shocks required may be beneficial. The goal of this study was to evaluate whether amiodarone or lidocaine was superior to placebo for the prevention of ventricular fibrillation after aortic crossclamping in patients undergoing a variety of cardiac surgical procedures. METHODS: Patients undergoing cardiac surgery requiring aortic crossclamping were randomized to receive lidocaine 1.5 mg/kg, amiodarone 300 mg, or placebo before aortic crossclamp removal The primary outcomes were the incidence of ventricular fibrillation and the number of shocks required to terminate ventricular fibrillation. RESULTS: A total of 342 patients completed the trial. On multivariate analysis, there was no difference in the incidence of ventricular fibrillation among treatment groups. The number of required shocks was categorized as 0, 1 to 3, and greater than 3. On multivariate analysis, patients receiving amiodarone required fewer shocks to terminate ventricular fibrillation (odds ratio, 0.51; 95% confidence interval, 0.31-0.83; P = .008 vs placebo). There was no difference between lidocaine and placebo in the number of required shocks (odds ratio, 0.86; 95% confidence interval, 0.52-1.41; P = .541). CONCLUSIONS: In patients undergoing a variety of cardiac surgical procedures, neither amiodarone nor lidocaine reduced the incidence of ventricular fibrillation. Amiodarone decreased the number of shocks required to terminate ventricular fibrillation.

Research ethics board approval for an international thromboprophylaxis trial.

BACKGROUND: Research ethics board (REB) review of scientific protocols is essential, ensuring participants' dignity, safety, and rights. The objectives of this study were to examine the time from submission to approval, to analyze predictors of approval time, and to describe the scope of conditions from REBs evaluating an international thromboprophylaxis trial. METHODS: We generated survey items through literature review and investigators' discussions, creating 4 domains: respondent and institutional demographics, the REB application process, and alternate consent models. We conducted a document analysis that involved duplicate assessment of themes from REB critique of the protocol and informed consent forms (ICF). RESULTS: Approval was granted from 65 REB institutions, requiring 58 unique applications. We analyzed 44 (75.9%) of 58 documents and surveys. Survey respondents completing the applications had 8 (5-12) years of experience; 77% completed 4 or more REB applications in previous 5 years. Critical care personnel were represented on 54% of REBs. The time to approval was a median (interquartile range) of 75 (42, 150) days, taking longer for sites with national research consortium membership (89.1 vs 31.0 days, P = .03). Document analysis of the application process and ICF yielded 5 themes: methodology, data management, consent procedures, cataloguing, and miscellaneous. Protocol-specific themes focused on trial implementation, external critiques, and budget. The only theme specific to the ICF was risks and benefits. The most frequent comments on the protocol and ICF were about methodology and miscellaneous issues; ICF comments also addressed study risks and benefits. CONCLUSIONS: More studies on methods to enhance efficiency and consistency of the REB approval processes for clinical trials are needed while still maintaining high ethical standards.