Peter C. Hou

A Randomized Trial of Protocol-Based Care for Early Septic Shock

BACKGROUND In a single-center study published more than a decade ago involving patients presenting to the emergency department with severe sepsis and septic shock, mortality was markedly lower among those who were treated according to a 6-hour protocol of early goal-directed therapy (EGDT), in which intravenous fluids, vasopressors, inotropes, and blood transfusions were adjusted to reach central hemodynamic targets, than among those receiving usual care. We conducted a trial to determine whether these findings were generalizable and whether all aspects of the protocol were necessary. METHODS In 31 emergency departments in the United States, we randomly assigned patients with septic shock to one of three groups for 6 hours of resuscitation: protocol-based EGDT; protocol-based standard therapy that did not require the placement of a central venous catheter, administration of inotropes, or blood transfusions; or usual care. The primary end point was 60-day in-hospital mortality. We tested sequentially whether protocol-based care (EGDT and standard-therapy groups combined) was superior to usual care and whether protocol-based EGDT was superior to protocol-based standard therapy. Secondary outcomes included longer-term mortality and the need for organ support. RESULTS We enrolled 1341 patients, of whom 439 were randomly assigned to protocol-based EGDT, 446 to protocol-based standard therapy, and 456 to usual care. Resuscitation strategies differed significantly with respect to the monitoring of central venous pressure and oxygen and the use of intravenous fluids, vasopressors, inotropes, and blood transfusions. By 60 days, there were 92 deaths in the protocol-based EGDT group (21.0%), 81 in the protocol-based standard-therapy group (18.2%), and 86 in the usual-care group (18.9%) (relative risk with protocol-based therapy vs. usual care, 1.04; 95% confidence interval [CI], 0.82 to 1.31; P=0.83; relative risk with protocol-based EGDT vs. protocol-based standard therapy, 1.15; 95% CI, 0.88 to 1.51; P=0.31). There were no significant differences in 90-day mortality, 1-year mortality, or the need for organ support. CONCLUSIONS In a multicenter trial conducted in the tertiary care setting, protocol-based resuscitation of patients in whom septic shock was diagnosed in the emergency department did not improve outcomes. (Funded by the National Institute of General Medical Sciences; ProCESS ClinicalTrials.gov number, NCT00510835.).

Early Identification of Patients at Risk of Acute Lung Injury: Evaluation of Lung Injury Prediction Score in a Multicenter Cohort Study

RATIONALE Accurate, early identification of patients at risk for developing acute lung injury (ALI) provides the opportunity to test and implement secondary prevention strategies. OBJECTIVES To determine the frequency and outcome of ALI development in patients at risk and validate a lung injury prediction score (LIPS). METHODS In this prospective multicenter observational cohort study, predisposing conditions and risk modifiers predictive of ALI development were identified from routine clinical data available during initial evaluation. The discrimination of the model was assessed with area under receiver operating curve (AUC). The risk of death from ALI was determined after adjustment for severity of illness and predisposing conditions. MEASUREMENTS AND MAIN RESULTS Twenty-two hospitals enrolled 5,584 patients at risk. ALI developed a median of 2 (interquartile range 1-4) days after initial evaluation in 377 (6.8%; 148 ALI-only, 229 adult respiratory distress syndrome) patients. The frequency of ALI varied according to predisposing conditions (from 3% in pancreatitis to 26% after smoke inhalation). LIPS discriminated patients who developed ALI from those who did not with an AUC of 0.80 (95% confidence interval, 0.78-0.82). When adjusted for severity of illness and predisposing conditions, development of ALI increased the risk of in-hospital death (odds ratio, 4.1; 95% confidence interval, 2.9-5.7). CONCLUSIONS ALI occurrence varies according to predisposing conditions and carries an independently poor prognosis. Using routinely available clinical data, LIPS identifies patients at high risk for ALI early in the course of their illness. This model will alert clinicians about the risk of ALI and facilitate testing and implementation of ALI prevention strategies. Clinical trial registered with www.clinicaltrials.gov (NCT00889772).

Predicting Risk of Postoperative Lung Injury in High-risk Surgical Patients: A Multicenter Cohort Study

Background: Acute respiratory distress syndrome (ARDS) remains a serious postoperative complication. Although ARDS prevention is a priority, the inability to identify patients at risk for ARDS remains a barrier to progress. The authors tested and refined the previously reported surgical lung injury prediction (SLIP) model in a multicenter cohort of at-risk surgical patients. Methods: This is a secondary analysis of a multicenter, prospective cohort investigation evaluating high-risk patients undergoing surgery. Preoperative ARDS risk factors and risk modifiers were evaluated for inclusion in a parsimonious risk-prediction model. Multiple imputation and domain analysis were used to facilitate development of a refined model, designated SLIP-2. Area under the receiver operating characteristic curve and the Hosmer–Lemeshow goodness-of-fit test were used to assess model performance. Results: Among 1,562 at-risk patients, ARDS developed in 117 (7.5%). Nine independent predictors of ARDS were identified: sepsis, high-risk aortic vascular surgery, high-risk cardiac surgery, emergency surgery, cirrhosis, admission location other than home, increased respiratory rate (20 to 29 and ≥30 breaths/min), FIO2 greater than 35%, and SpO2 less than 95%. The original SLIP score performed poorly in this heterogeneous cohort with baseline risk factors for ARDS (area under the receiver operating characteristic curve [95% CI], 0.56 [0.50 to 0.62]). In contrast, SLIP-2 score performed well (area under the receiver operating characteristic curve [95% CI], 0.84 [0.81 to 0.88]). Internal validation indicated similar discrimination, with an area under the receiver operating characteristic curve of 0.84. Conclusions: In this multicenter cohort of patients at risk for ARDS, the SLIP-2 score outperformed the original SLIP score. If validated in an independent sample, this tool may help identify surgical patients at high risk for ARDS.

Acute Respiratory Distress Syndrome After Spontaneous Intracerebral Hemorrhage

Objectives:Acute respiratory distress syndrome develops commonly in critically ill patients in response to an injurious stimulus. The prevalence and risk factors for development of acute respiratory distress syndrome after spontaneous intracerebral hemorrhage have not been reported. We sought to determine the prevalence of acute respiratory distress syndrome after intracerebral hemorrhage, characterize risk factors for its development, and assess its impact on patient outcomes. Design:Retrospective cohort study at two academic centers. Patients:We included consecutive patients presenting from June 1, 2000, to November 1, 2010, with intracerebral hemorrhage requiring mechanical ventilation. We excluded patients with age less than 18 years, intracerebral hemorrhage secondary to trauma, tumor, ischemic stroke, or structural lesion; if they required intubation only during surgery; if they were admitted for comfort measures; or for a history of immunodeficiency. Interventions:None. Measurements and Main Results:Data were collected both prospectively as part of an ongoing cohort study and by retrospective chart review. Of 1,665 patients identified by database query, 697 met inclusion criteria. The prevalence of acute respiratory distress syndrome was 27%. In unadjusted analysis, high tidal volume ventilation was associated with an increased risk of acute respiratory distress syndrome (hazard ratio, 1.79 [95% CI, 1.13–2.83]), as were male sex, RBC and plasma transfusion, higher fluid balance, obesity, hypoxemia, acidosis, tobacco use, emergent hematoma evacuation, and vasopressor dependence. In multivariable modeling, high tidal volume ventilation was the strongest risk factor for acute respiratory distress syndrome development (hazard ratio, 1.74 [95% CI, 1.08–2.81]) and for inhospital mortality (hazard ratio, 2.52 [95% CI, 1.46–4.34]). Conclusions:Development of acute respiratory distress syndrome is common after intubation for intracerebral hemorrhage. Modifiable risk factors, including high tidal volume ventilation, are associated with its development and in-patient mortality.

Urinary Catheter Use and Appropriateness in U.S. Emergency Departments, 1995–2010

OBJECTIVES Catheter-associated urinary tract infection (CAUTI) is the most prevalent hospital-acquired infection, yet little is known about emergency department (ED) use of urinary catheters. The objective was to describe use of urinary catheters in U.S. EDs and determine the proportion that was potentially avoidable. METHODS The National Hospital Ambulatory Medical Care Survey (NHAMCS), a weighted probability sample of U.S. ED visits, was analyzed from 1995 through 2010 for use of urinary catheters in adults. Use of a urinary catheter was a specific chart review element and was classified as potentially avoidable if none of the Centers for Disease Control and Prevention (CDC) list of appropriate indications were met by ED visit diagnoses or patient disposition. Annual frequency of urinary catheter use and appropriateness were calculated. Predictors of ED-placed urinary catheters for admitted patients were assessed with multivariate logistic regression. RESULTS The annual rate of ED-placed urinary catheters varied from 2.2 to 3.3 per 100 adult ED visits. Among admitted patients, 8.5% (95% confidence interval [CI] = 8.0% to 9.1%) received urinary catheters; 64.9% (95% CI = 56.9% to 72.9%) were potentially avoidable. Among discharged patients 1.6% (95% CI = 1.5% to 1.7%) received urinary catheters. There was no significant trend over time in the use of urinary catheters or potentially avoidable urinary catheters (PAUCs). Predictors of catheter use in admitted patients included indicators of patient severity, female sex, and race/ethnicity. Hospital characteristics predicting catheter use included region, ownership type, and urban location. Predictors of potentially avoidable urinary catheter use were lower patient severity, female sex, care by a midlevel practitioner, and nonurban location. CONCLUSIONS Reducing use of urinary catheters outside of CDC guideline criteria in ED patients is a promising strategy to reduce CAUTIs.

Implementation of a Hospital-wide Protocol for Induced Hypothermia Following Successfully Resuscitated Cardiac Arrest.

Permanent neurologic impairment following cardiac arrest is often severely debilitating, even after successful resuscitation. Therapeutic hypothermia decreases anoxic brain injury and subsequent cognitive deficits. Current practice guidelines recommend therapeutic hypothermia in comatose survivors of cardiac arrest. To address the multifacets of therapeutic hypothermia, we assembled a multidisciplinary task force including members from various specialties to create an evidence-based guideline with transparency across disciplines and consistency of care. We describe our institutional guidelines for the initiation and management of induced hypothermia in patients successfully resuscitated from a cardiac arrest.

Vasopressors in septic shock: a systematic review and network meta-analysis

Objective Vasopressor agents are often prescribed in septic shock. However, their effects remain controversial. We conducted a systematic review and Bayesian network meta-analysis to compare the effects among different types of vasopressor agents. Data sources We searched for relevant studies in PubMed, Embase, and the Cochrane Library databases from database inception until December 2014. Study selection Randomized controlled trials in adults with septic shock that evaluated different vasopressor agents were selected. Data extraction Two authors independently selected studies and extracted data on study characteristics, methods, and outcomes. Data synthesis Twenty-one trials (n=3,819) met inclusion criteria, which compared eleven vasopressor agents or vasopressor combinations (norepinephrine [NE], dopamine [DA], vasopressin [VP], epinephrine [EN], terlipressin [TP], phenylephrine [PE], TP+NE, TP + dobutamine [DB], NE+DB, NE+EN, and NE + dopexamine [DX]). Except for the superiority of NE over DA, the mortality of patients treated with any vasopressor agent or vasopressor combination was not significantly different. Compared to DA, NE was found to be associated with decreased cardiac adverse events, heart rate (standardized mean difference [SMD]: −2.10; 95% confidence interval [CI]: −3.95, −0.25; P=0.03), and cardiac index (SMD: −0.73; 95% CI: −1.14, −0.03; P=0.004) and increased systemic vascular resistance index (SVRI) (SMD: 1.03; 95% CI: 0.61, 1.45; P<0.0001). This Bayesian meta-analysis revealed a possible rank of probability of mortality among the eleven vasopressor agents or vasopressor combinations; from lowest to highest, they are NE+DB, EN, TP, NE+EN, TP+NE, VP, TP+DB, NE, PE, NE+DX, and DA. Conclusion In terms of survival, NE may be superior to DA. Otherwise, there is insufficient evidence to suggest that any other vasopressor agent or vasopressor combination is superior to another. When compared to DA, NE is associated with decreased heart rate, cardiac index, and cardiovascular adverse events, as well as increased SVRI. The effects of vasopressor agents or vasopressor combinations on mortality in patients with septic shock require further investigation.

Endothelial Permeability and Hemostasis in Septic Shock: Results from the ProCESS Trial.

Background We studied patients from the Protocolized Care in Early Septic Shock (ProCESS) trial to determine the effects of alternative resuscitation strategies on circulating markers of endothelial cell permeability and hemostasis and the association between biomarkers and mortality. Methods This was a prospective study of biomarkers of endothelial cell permeability (vascular endothelial growth factor [VEGF], soluble fms‐like tyrosine kinase 1 [sFLT‐1], angiopoietin 2 [Ang‐2]) and biomarkers of hemostasis (von Willebrand factor [vWF], thrombomodulin [TM], tissue plasminogen activator [tPA] in 605 of the 1,341 ProCESS participants in a derivation cohort and 305 participants in a validation cohort. Analyses assessed (1) the impact of varying resuscitation strategies on biomarker profiles and (2) the association of endothelial biomarkers with 60‐day in‐hospital mortality. The study was conducted in 31 US EDs in adult patients with septic shock. Patients were randomly assigned to one of three resuscitation strategies. Blood samples were collected at enrollment, at 6 h, and at 24 h. Results There were 116 (19.2%) and 52 (17.0%) deaths in the derivation and validation cohorts, respectively. There was no significant association between treatment strategy and any biomarker levels. Permeability (Ang‐2 and sFLT‐1) and hemostasis (vWF, TM, tPA) biomarkers were higher and VEGF levels were lower in nonsurvivors (P < .05 for all). At baseline, sFLT‐1 had the highest point estimate for mortality discrimination (derivation area under the curve [AUC], 0.74; validation, 0.70), similar to lactate (AUC, 0.74) and Sequential Organ Failure Assessment score (AUC, 0.73). In an analysis including all time points and adjusted for age, presence of cancer, and Charlson comorbidity score, the adjusted AUC for sFLT‐1 was 0.80. Conclusions We found no relationship between different resuscitation strategies and biomarker profiles in sepsis, but we did find that elevated levels of endothelial cell biomarkers of permeability and hemostasis were associated with increased mortality. Trial Registry ClinicalTrials.gov; No.: NCT00510835 and NCT00793442; URL: www.clinicaltrials.gov

Design and Rationale of the Reevaluation of Systemic Early Neuromuscular Blockade Trial for Acute Respiratory Distress Syndrome

&NA; The Reevaluation of Systemic Early Neuromuscular Blockade (ROSE) trial is a multicenter, randomized trial designed to assess the efficacy and safety of early neuromuscular blockade in patients with moderate to severe acute respiratory distress syndrome. This document provides background for interpretation of the trial results, and highlights unique design approaches that may inform future trials of acute illness. We describe the process by which ROSE was chosen as the inaugural trial of the multidisciplinary Prevention and Early Treatment of Acute Lung Injury Network, provide the trial methodology using the Consolidated Standards of Reporting Trials framework, and discuss key design challenges and their resolution. Four key design issues proved challenging—feasibility, choice of sedation depth in the control group, impact of emphasizing early treatment on enrollment criteria and protocol execution, and choice of positive end‐expiratory pressure strategy. We used literature, an iterative consensus model, and internal surveys of current practice to inform design choice. ROSE will provide definitive, Consolidated Standards of Reporting Trials adherent data on early neuromuscular blockade for future patients with acute respiratory distress syndrome. Our multidisciplinary approach to trial design may be of use to other trials of acute illness. Clinical trial registered with www.clinicaltrials.gov (NCT02509078).

Towards Prevention of Acute Lung Injury: Frequency and Outcomes of Emergency Department Patients At-Risk: A Multicenter Cohort Study

BackgroundFew emergency department (ED) evaluations on acute lung injury (ALI) have been carried out; hence, we sought to describe a cohort of hospitalized ED patients at risk for ALI development.MethodsPatients presenting to the ED with at least one predisposing condition to ALI were included in this study, a subgroup analysis of a multicenter observational cohort study (USCIITG-LIPS 1). Patients who met ALI criteria within 6 h of initial ED assessment, received end-of-life care, or were readmitted during the study period were excluded. Primary outcome was frequency of ALI development; secondary outcomes were ICU and hospital mortality.ResultsTwenty-two hospitals enrolled 4,361 patients who were followed from the ED to hospital discharge. ALI developed in 303 (7.0 %) patients at a median onset of 2 days (IQR 2–5). Of the predisposing conditions, frequency of ALI development was highest in patients who had aortic surgery (43 %) and lowest in patients with pancreatitis (2.8 %). Compared to patients who did not develop ALI, those who did had higher ICU (24 % vs. 3.0 %, p < 0.001) and hospital (28 % vs. 4.6 %, p < 0.001) mortality, and longer hospital length of stay (16 vs. 5 days, p < 0.001). Among the 22 study sites, frequency of ALI development varied from less than 1 % to more than 12 % after adjustment for APACHE II.ConclusionsSeven percent of hospitalized ED patients with at least one predisposing condition developed ALI. The frequency of ALI development varied significantly according to predisposing conditions and across institutions. Further research is warranted to determine the factors contributing to ALI development.