Effect of eritoran, an antagonist of MD2-TLR4, on mortality in patients with severe sepsis: the ACCESS randomized trial.

IMPORTANCE: Eritoran is a synthetic lipid A antagonist that blocks lipopolysaccharide (LPS) from binding at the cell surface MD2-TLR4 receptor. LPS is a major component of the outer membrane of gram-negative bacteria and is a potent activator of the acute inflammatory response. OBJECTIVE: To determine if eritoran, a TLR4 antagonist, would significantly reduce sepsis-induced mortality. DESIGN, SETTING, AND PARTICIPANTS: We performed a randomized, double-blind, placebo-controlled, multinational phase 3 trial in 197 intensive care units. Patients were enrolled from June 2006 to September 2010 and final follow-up was completed in September 2011. INTERVENTIONS: Patients with severe sepsis (n = 1961) were randomized and treated within 12 hours of onset of first organ dysfunction in a 2:1 ratio with a 6-day course of either eritoran tetrasodium (105 mg total) or placebo, with n = 1304 and n = 657 patients, respectively. MAIN OUTCOME MEASURES: The primary end point was 28-day all-cause mortality. The secondary end points were all-cause mortality at 3, 6, and 12 months after beginning treatment. RESULTS: Baseline characteristics of the 2 study groups were similar. In the modified intent-to-treat analysis (randomized patients who received at least 1 dose) there was no significant difference in the primary end point of 28-day all-cause mortality with 28.1% (366/1304) in the eritoran group vs 26.9% (177/657) in the placebo group (P = .59; hazard ratio, 1.05; 95% CI, 0.88-1.26; difference in mortality rate, -1.1; 95% CI, -5.3 to 3.1) or in the key secondary end point of 1-year all-cause mortality with 44.1% (290/657) in the eritoran group vs 43.3% (565/1304) in the placebo group, Kaplan-Meier analysis of time to death by 1 year, P = .79 (hazard ratio, 0.98; 0.85-1.13). No significant differences were observed in any of the prespecified subgroups. Adverse events, including secondary infection rates, did not differ between study groups. CONCLUSIONS AND RELEVANCE: Among patients with severe sepsis, the use of eritoran, compared with placebo, did not result in reduced 28-day mortality. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00334828.

Risk of contrast induced nephropathy in the critically ill: a prospective, case matched study.

INTRODUCTION: Computerized tomography is frequently employed in the critically ill, often using intravenous radiocontrast material. Many of these patients have clinical features that are considered risk factors for contrast induced nephropathy, but are simultaneously at risk for renal injury from other factors related to their acute illnesses. The attributable risk for renal dysfunction from radiocontrast exposure has not been well quantified in this population. METHODS: A prospective matched cohort study was conducted of patients scanned with or without radiocontrast enhancement while receiving intensive care in a Veterans Affairs Medical Center. Patients were matched for pre-scan measured creatinine clearance, diabetes, mechanical ventilation, and vasopressor use. Measured clearance was followed for three days after scanning. Evolution of nephropathy, as determined by change in measured clearance, was compared within matched pairs. RESULTS: Fifty-three pairs of patients satisfied matching criteria. Unmatched characteristics were similar among the pairs, including serum creatinine variability during the week preceding scanning (67 ± 85% among contrast recipients, 63 ± 62% among others) and clinical risk factors for renal failure. In 29 pairs, pre-scan measured clearances were less than 60 mL/minute/1.73 m2. Following scanning, measured clearance declined by at least 33% in 14 contrast and 19 non-contrast patients (95% confidence interval for contrast associated difference in nephropathy rates -27% to 9%), while a 50% reduction in clearance persisted three days after scanning in three contrast and nine non-contrast patients (95% confidence interval for difference in rates -25% to 2%). CONCLUSIONS: Among established intensive care unit patients declines in glomerular filtration following contrast-enhanced scanning are common, but these changes are far more likely to be attributable to factors other than the contrast exposure itself. The upper bound for the incidence of contrast induced renal injury lasting even three days was 2% in the population studied.

Intensity of renal support in critically ill patients with acute kidney injury.

BACKGROUND: The optimal intensity of renal-replacement therapy in critically ill patients with acute kidney injury is controversial. METHODS: We randomly assigned critically ill patients with acute kidney injury and failure of at least one nonrenal organ or sepsis to receive intensive or less intensive renal-replacement therapy. The primary end point was death from any cause by day 60. In both study groups, hemodynamically stable patients underwent intermittent hemodialysis, and hemodynamically unstable patients underwent continuous venovenous hemodiafiltration or sustained low-efficiency dialysis. Patients receiving the intensive treatment strategy underwent intermittent hemodialysis and sustained low-efficiency dialysis six times per week and continuous venovenous hemodiafiltration at 35 ml per kilogram of body weight per hour; for patients receiving the less-intensive treatment strategy, the corresponding treatments were provided thrice weekly and at 20 ml per kilogram per hour. RESULTS: Baseline characteristics of the 1124 patients in the two groups were similar. The rate of death from any cause by day 60 was 53.6% with intensive therapy and 51.5% with less-intensive therapy (odds ratio, 1.09; 95% confidence interval, 0.86 to 1.40; P=0.47). There was no significant difference between the two groups in the duration of renal-replacement therapy or the rate of recovery of kidney function or nonrenal organ failure. Hypotension during intermittent dialysis occurred in more patients randomly assigned to receive intensive therapy, although the frequency of hemodialysis sessions complicated by hypotension was similar in the two groups. CONCLUSIONS: Intensive renal support in critically ill patients with acute kidney injury did not decrease mortality, improve recovery of kidney function, or reduce the rate of nonrenal organ failure as compared with less-intensive therapy involving a defined dose of intermittent hemodialysis three times per week and continuous renal-replacement therapy at 20 ml per kilogram per hour. (ClinicalTrials.gov number, NCT00076219.)

Use of intensive care, mechanical ventilation, both, or neither by patients with acute lung injury.

OBJECTIVE: Reports of acute lung injury and acute respiratory distress syndrome have generally been restricted to mechanically ventilated intensive care unit patients, creating an incomplete picture of the epidemiologies of the syndromes. We sought to determine the incidence and outcomes of acute lung injury and acute respiratory distress syndromes throughout an entire hospital population. DESIGN: Retrospective cohort study. SETTING: A Department of Veterans Affairs medical center. PATIENTS: All patients satisfying criteria for acute lung injury or acute respiratory distress syndrome during a 2-yr period. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: There were 11,465 acute medical and surgical admissions during the study period; 156 patients had acute lung injury or acute respiratory distress syndrome. Only 74 (47%) were invasively ventilated in an intensive care unit for acute lung injury. Another 15 (10%) patients were ventilated for other reasons, 41 (26%) were admitted to an intensive care unit at approximately the time of acute lung injury onset but were not invasively ventilated, and 26 (17%) were managed with neither invasive ventilation nor admission to an intensive care unit. Four-week mortality differed by group (p = .023), ranging from 22% among those managed in an intensive care unit without invasive ventilation to 50% among those ventilated for acute lung injury or acute respiratory distress syndrome. By 2 yrs, differences in survival between groups were no longer significant. Notably, only 53 (34%) patients would have been eligible for widely cited acute lung injury intervention trials. Ten patients had a second episode of acute lung injury during the study period, equating to a 16%-per-year risk of recurrence. CONCLUSIONS: Acute lung injury and acute respiratory distress syndrome studies restricted to patients mechanically ventilated in intensive care units substantially underestimate the incidence of the syndromes. Nonventilated patients and those cared for outside of intensive care units may still be at substantial risk for death. Further characterization of previously overlooked acute lung injury and acute respiratory distress syndrome patients may suggest new therapeutic opportunities.

Influence of critical illness on physicians' prognoses for underlying disease: a randomized study using simulated cases.

OBJECTIVE: During critical illness, physicians often provide estimates of the severity of underlying disease to aid patients and families when formulating care directives. We sought to determine whether factors such as the superimposed acute illness, the prognoses of other patients cared for by the same physician, or the phrasing of inquiry influence these assessments of underlying disease. DESIGN, SETTING, AND SUBJECTS: Internal medicine attending and resident physicians participated in a computerized, Web-available survey that described two case vignettes, one with cardiomyopathy and the other with lung cancer as underlying diseases. Using random assignment, each respondent was presented one case as having septic shock, and the other as an uneventful clinic visit. Respondents were explicitly asked to ignore the context and to assess the severity of the underlying disease alone to predict survival time and quality of life. The order in which subjects encountered the cases and phrasing of the survival question also were varied through randomization. MEASUREMENTS AND MAIN RESULTS: Mortality predictions for the cardiomyopathy case at 5 yrs were sensitive to both context (predicted survival, 39% +/- 23% when presented as septic vs. 52% +/- 24% when presented as a clinic patient; p < .001) and to whether a lung cancer case was presented before it (39% +/- 23% when presented after lung cancer vs. 52% +/- 24% when presented before; p < .001). These effects were independent and led to mean predicted 5-yr survival probabilities ranging from 31% to 59%. Predicted 1-yr survival from lung cancer was sensitive to phrasing (p < .05) but not to context. Quality of life predictions were also sensitive to context and case order. CONCLUSIONS: Physician appraisal of underlying disease severity is potentially vulnerable to a number of biases that may be relevant in the critical care setting. These biases appear to vary with the nature of the underlying disease.

Contrast-associated acute kidney injury in the critically ill: systematic review and Bayesian meta-analysis.

PURPOSE: Critically ill patients, among whom acute kidney injury is common, are often considered particularly vulnerable to iodinated contrast medium nephrotoxicity. However, the attributable incidence remains uncertain given the paucity of observational studies including a control group. This study assessed acute kidney injury incidence attributable to iodinated contrast media in critically ill patients based on new data accounting for sample and effect size and including a control group. METHODS: Systematic review of studies measuring incidence of acute kidney injury in critically ill patients following contrast medium exposure compared to matched unexposed patients. Patient-level meta-analysis implementing a Bayesian nested mixed effects multiple logistic regression model. RESULTS: Ten studies were identified; only four took into account the baseline acute kidney injury risk, three by patient matching (560 patients). Objective meta-analysis of these three studies (vague and impartial a priori hypothesis concerning attributable acute kidney injury risk) did not find that iodinated contrast media increased the incidence of acute kidney injury (odds ratio 0.95, 95% highest posterior density interval 0.45-1.62). Bayesian analysis demonstrated that, to conclude in favor of a statistically significant incidence of acute kidney injury attributable to contrast media despite this observed lack of association, one's a priori belief would have to be very strongly biased, assigning to previous uncontrolled reports 3-12 times the weight of evidence strength provided by the matched studies including a control group. CONCLUSIONS: Meta-analysis of matched cohort studies of iodinated contrast medium exposure does not support a significant incidence of acute kidney injury attributable to iodinated contrast media in critically ill patients.

Relationship of baseline glucose homeostasis to hyperglycemia during medical critical illness.

STUDY OBJECTIVE: To elucidate the relationship of baseline glucose control and acute stimuli with hyperglycemia during medical critical illness. DESIGN: Prospective cohort study. SETTING: Medical ICU (MICU) of a university affiliated hospital. PATIENTS: Convenience sample of 100 medical patients meeting criteria for severity of illness and anticipated length of stay and not admitted to the hospital for diabetic ketoacidosis or a hyperglycemic hyperosmolar state. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients were categorized as having normal, abnormal, or unevaluable baseline glucose control based on history and glycosylated hemoglobin (HbA1c). Data collection included blood glucose measurements within 120 h of MICU admission, and dosing of norepinephrine, corticosteroids, propofol, and carbohydrates. Average blood glucose and times over glycemic thresholds were calculated using linear interpolation. Hyperglycemia (glucose > 110 mg/dL) was pervasive in all groups. Among the 51 patients with normal baseline glucose control, HbA1c was correlated with hyperglycemic time (p < 0.01, R(2) = 0.15). Multiple regression found HbA1c, age, corticosteroid dose, and carbohydrate administration independently associated with hyperglycemic time (p < 0.05 for each, total R(2) = 0.49) in these patients, while body mass index, APACHE (acute physiology and chronic health evaluation) II, norepinephrine dose, propofol dose, gender, and sepsis were not associated with time > 110 mg/dL. Among normal subjects, HbA1c was independently predictive of peak and average glucose, and the fraction of time glucose was > 150 mg/dL and > 200 mg/dL (p < 0.05 for each). Patients with abnormal baseline glucose control had significantly more hyperglycemia than patients with normal baseline control. CONCLUSIONS: Even in patients without evidence of abnormal glucose homeostasis at baseline, hyperglycemia is common during critical illness. Time exposure to hyperglycemia is correlated with acute stressors and baseline glucose regulation, as characterized by HbA1c. Patients with low HbA1c levels are less disposed to hyperglycemia during severe illness than patients with higher, but still normal, HbA1c.

Risk-benefit analysis for drotrecogin alfa (activated).

An analysis of risks and benefits is an important component of patient care. Drotrecogin alfa (activated), the first approved cogin (a class of recombinant human coagulation inhibitors), provides a clear example of a treatment that requires a careful risk-benefit analysis. Treatment with this novel compound has been shown to reduce significantly the risk of death in patients with sepsis and acute organ dysfunction (severe sepsis). However, the drug is a natural antithrombotic that can increase the risk of bleeding in recipients. We will discuss bleeding and other potential risks associated with drotrecogin alfa (activated) treatment, as well as the survival benefits seen with the use of this therapy in patients with severe sepsis.

Severe pulmonary toxicity in a patient treated with gemcitabine.

Gemcitabine is a pyrimidine analog of deoxycytidine with activity against nonhematologic and hematologic malignancies. Its pulmonary toxicity is usually mild and self-limiting. We describe a male patient with lung cancer in whom severe dyspnea and interstitial infiltrates developed after the administration of gemcitabine.

Acute lung injury outside of the ICU: incidence in respiratory isolation on a general ward.

BACKGROUND: Epidemiologic investigations of acute lung injury (ALI) and ARDS have focused on mechanically ventilated patients in ICUs, and have reported high mortality rates. We sought to determine the incidence and lethality of these syndromes in the respiratory isolation areas of general wards, a non-ICU setting that often serves patients with acute lung processes. METHODS: We prospectively studied all patients who were admitted to respiratory isolation rooms on the general wards of a large tertiary care hospital over a 1-year period. Patients were classified as having ALI or ARDS if they met consensus definitions for the syndromes. Characteristics and outcomes were compared to those of other patients who had been admitted to a respiratory isolation room with infiltrating lung disease but lacking bilateral infiltrates, hypoxemia, or both. RESULTS: Of 715 patients admitted to respiratory isolation rooms on general wards, 474 (66%) had acute infiltrates. ALI criteria were met by 9% of patients (62 of 715 patients), with 2% of patients (15 of 715) satisfying the criteria for ARDS. Respiratory distress was present in 71% of ALI patients (44 of 62 patients) and 32% of patients (130 of 412 patients) with acute infiltrates who did not have ALI (p < 0.001). However, the 90-day survival rates (ALI patients, 88%; patients with acute infiltrates who did not have ALI, 90%) was similar between the two groups (p > 0.50). CONCLUSIONS: ALI and ARDS may be frequent among patients who are admitted to respiratory isolation beds outside of ICUs. Mortality rates are substantially lower than those typically reported from surveys of ventilated ICU patients with ALI and ARDS.

Lessons for successful study enrollment from the Veterans Affairs/National Institutes of Health Acute Renal Failure Trial Network Study.

BACKGROUND AND OBJECTIVES: Design elements of clinical trials can introduce recruitment bias and reduce study efficiency. Trials involving the critically ill may be particularly prone to design-related inefficiencies. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Enrollment into the Veterans Affairs/National Institutes of Health Acute Renal Failure Trial Network Study was systematically monitored. Reasons for nonenrollment into this study comparing strategies of renal replacement therapy in critically ill patients with acute kidney injury were categorized as modifiable or nonmodifiable. RESULTS: 4339 patients were screened; 2744 fulfilled inclusion criteria. Of these, 1034 were ineligible by exclusion criteria. Of the remaining 1710 patients, 1124 (65.7%) enrolled. Impediments to informed consent excluded 21.4% of potentially eligible patients. Delayed identification of potential patients, physician refusal, and involvement in competing trials accounted for 4.4, 2.7, and 2.3% of exclusions. Comfort measures only status, chronic illness, chronic kidney disease, and obesity excluded 11.8, 7.8, 7.6, and 5.9% of potential patients. Modification of an enrollment window reduced the loss of patients from 6.6 to 2.3%. CONCLUSIONS: The Acute Renal Failure Trial Network Study's enrollment efficiency compared favorably with previous intensive care unit intervention trials and supports the representativeness of its enrolled population. Impediments to informed consent highlight the need for nontraditional acquisition methods. Restrictive enrollment windows may hamper recruitment but can be effectively modified. The low rate of physician refusal acknowledges clinical equipoise in the study design. Underlying comorbidities are important design considerations for future trials that involve the critically ill with acute kidney injury.

Levels of endothelial and platelet microparticles and their interactions with leukocytes negatively correlate with organ dysfunction and predict mortality in severe sepsis.

OBJECTIVE: Mortality in sepsis is believed to be associated with exaggerated inflammatory responses, but recent evidence suggests that poor outcome is associated with reduced inflammation. To test this hypothesis, we measured several inflammatory markers to determine whether any of them or any combinations are associated with mortality or organ dysfunction. DESIGN: Clinical study. SETTING: School of medicine. PATIENTS: Thirty-five patients with severe sepsis. INTERVENTIONS: Markers of endothelial, platelet, and leukocyte activation were measured on days 1, 2, and 3 after enrollment. The markers were a) endothelial microparticles (EMPs) and their conjugates with monocytes (EMP/MONO); b) platelet microparticles (PMPs) and platelet activation marker CD62P; c) platelet-leukocyte conjugates (PLT/LEU) and leukocyte activation marker CD11b; and d) intracellular nitric oxide in leukocytes. MEASUREMENTS AND MAIN RESULTS: The 28-day mortality rate was 51% (18 of 35). Significant differences between survivors and nonsurvivors on day 1 were found in PLT/LEU (p = .001), CD11b (p = 0.02), and EMP/MONO (p = .02) groups. Using logistic regression to assess if these markers predict mortality on day 1, we found that PLT/LEU had the best predictive value among the markers used (area under receiver operating characteristics curve = 0.82). All markers of cell activation and inflammation were significantly higher among survivors on days 2 and 3, except nitric oxide, which was lower. This marker showed significant negative correlation with the Sequential Organ Failure Assessment score throughout the study. CONCLUSIONS: Our data support the hypothesis that early increased, not decreased, inflammatory response as measured by our markers is associated with improved survival rate. A high negative correlation was found between some of these markers and Sequential Organ Failure Assessment score.

Efficacy and safety of LY315920Na/S-5920, a selective inhibitor of 14-kDa group IIA secretory phospholipase A2, in patients with suspected sepsis and organ failure.

OBJECTIVE: Concentrations of group IIA secretory phospholipase A, an inflammatory response mediator, are increased in the plasma of patients with sepsis and septic shock, and the extent of elevation is correlated with mortality. LY315920Na/S-5920 is a selective inhibitor of group IIA secretory phospholipase A that has been shown to inhibit serum group IIA secretory phospholipase A enzyme activity in patients with severe sepsis. The primary objectives of this study were to determine whether there was a dose-response relationship between two doses of LY315920Na/S-5920 compared with placebo in the reduction of 28-day all-cause mortality in patients with severe sepsis and to determine whether LY315920Na/S-5920 had an acceptable safety profile.(2) (2) (2) DESIGN: Multicenter, double-blind, placebo-controlled trial of two doses of LY315920Na/S-5920 in a parallel design. PATIENTS: A total of 586 patients with severe sepsis at 72 institutions in the United States. INTERVENTIONS Patients enrolled within 72 hrs from onset of first sepsis-induced organ failure were randomized (1:1:1) to low-dose LY315920Na/S-5920 (target plasma concentration of 200 ng/mL, n = 196), high-dose LY315920Na/S-5920 (800 ng/mL, n = 194), or placebo (n = 196). Study medication was administered as a constant-rate intravenous infusion for 168 hrs. MEASUREMENTS AND MAIN RESULTS: The study was stopped prematurely because it was unlikely that a statistically significant difference in mortality between LY315920Na/S-5920 and placebo would be found. There was no effect of LY315920Na/S-5920 on the primary end point of 28-day all-cause mortality across the entire study population. The 28-day all-cause mortality was distributed as follows: placebo group, 33.2% (65/196 patients); low-dose LY315920Na/S-5920, 37.2% (73/196); and high-dose LY315920Na/S-5920, 36.1% (70/194); p = .525. However, in a prospectively planned analysis, there was a favorable overall dose-response effect on 28-day all-cause mortality in patients administered LY315920Na/S-5920 within 18 hrs of onset of the first sepsis-induced organ failure. Among these patients, 28-day all-cause mortality was distributed as follows: placebo group, 43.5% (20/46 patients); low-dose LY315920Na/S-5920, 31.4% (16/51); and high-dose LY315920Na/S-5920, 20.8% (10/48); p = .018. CONCLUSIONS: Administration of LY315920Na/S-5920 had an acceptable safety profile in patients with severe sepsis. There was no overall survival benefit associated with the use of LY315920Na/S-5920 in this study. However, prospectively planned secondary analyses suggested that treatment with LY315920Na/S-5920 was associated with an improvement in survival in patients treated within 18 hrs of the first sepsis-induced organ failure.