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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. 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. 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. 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.

With the advent of sepsis-3, it is important to consider whether there is still a place for the systemic inflammatory response syndrome (SIRS) (1, 2). In 1991, a conference was convened to develop consensus definitions of sepsis (3). Additionally, the term “SIRS” was coined (3) to recognize the comm

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.

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 0.50). 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.

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 Study9s 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.

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.

Objective: In the multinational PROWESS trial, drotrecogin alfa (activated) significantly reduced mortality rate in patients with severe sepsis compared with placebo. The use of large multiple-enter trials can potentially complicate interpretation of results in severe sepsis populations because of variability in medical attitudes and practices and the frequency of confounding events such as protocol violations. The objective of this study was to perform a blinded, critical, integrated review of data from the 1,690 severe sepsis patients from 164 medical centers enrolled in the PROWESS trial using a Clinical Evaluation Committee. Design: Blinded, critical, integrated review of data. Setting: Participating sites. Patients: The 1,690 severe sepsis patients from 164 medical centers enrolled in the PROWESS trial. Interventions: We performed analyses of the optimal cohort, defined as patients who had full compliance with the protocol, had evidence of an infection, and received adequate anti-infective therapy. We also performed other analyses, including significant underlying disorders, life support measures, and causes of death. Measurements and Main Results: The optimal cohort of 81.4% of the intention-to-treat population [drotrecogin alfa (activated), n = 695; placebo, n = 680] had similar baseline severity of illness between the two groups, a similar pharmacodynamic effect, and a relative risk of death estimate consistent with that observed in the overall PROWESS trial (0.83, 95% confidence interval 0.69-0.99 vs. 0.806, 95% confidence interval 0.69-0.94). A beneficial effect of drotrecogin alfa (activated) similarly was observed in patients with significant underlying disorders (0.73, 95% confidence interval 0.57-0.93) who were more severely ill and had a higher percentage of patients forgoing life-sustaining therapy. In contrast with the original investigator determinations, a benefit associated with drotrecogin alfa (activated) treatment in urinary tract infection adjudicated by the Clinical Evaluation Committee was observed. Conclusions: The survival benefit associated with drotrecogin alfa (activated) use was consistent with the results of the overall trial regardless of whether patients met criteria of the optimal cohort or had a significant underlying disorder.

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.

OBJECTIVE: To determine whether measures of inpatient care utilization from the year preceding admission to a medical intensive care unit (MICU) improve physiology-based predictions of hospital and 1-yr survival. DESIGN: Inception cohort study with a validation cohort. SETTING: The MICU in university-affiliated Department of Veterans Affairs Medical Center. PATIENTS: A total of 1,200 consecutive patients admitted to the MICU. MEASUREMENTS AND MAIN RESULTS: Increased use of inpatient health care before MICU admission was associated with increased mortality. However, inpatient utilization data failed to improve physiology-based logistic models for hospital and 1-yr survival (p > .15 for improvement in the area under the receiver operating characteristic curve for both end points in the validation cohort), whereas physiologic data improved models derived from measures of inpatient care (p < .001 for both end points). Empirically derived inpatient care models used only information from the few days preceding MICU admission, despite the availability of a full year of data. CONCLUSIONS: Chronic illness, as gauged by a need for frequent inpatient care in the year before MICU admission, is not independently predictive of poor short- or long-term survival. Clinicians should not attempt to predict survival of prospective MICU patients by the extent of previous inpatient care.

ObjectivesThe objective was to compare the clinical and physiologic characteristics of febrile septic patients with hypothermic septic patients; and to examine plasma levels of cytokines tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6) and the lipid mediators thromboxane B2 (TxB2) an

Background In patients with sepsis the production of arachidonic acid metabolites by cyclooxygenase increases, but the pathophysiologic role of these prostaglandins is unclear. In animal models, inhibition of cyclooxygenase by treatment with ibuprofen before the onset of sepsis reduces physiologic abnormalities and improves survival. In pilot studies of patients with sepsis, treatment with ibuprofen led to improvements in gas exchange and airway mechanics. Methods From October 1989 to March 1995, we conducted a randomized, double-blind, placebo-controlled trial of intravenous ibuprofen (10 mg per kilogram of body weight [maximal dose, 800 mg], given every six hours for eight doses) in 455 patients who had sepsis, defined as fever, tachycardia, tachypnea, and acute failure of at least one organ system. Results In the ibuprofen group, but not the placebo group, there were significant declines in urinary levels of prostacyclin and thromboxane, temperature, heart rate, oxygen consumption, and lactic acidosis....

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

To determine if passive immunization could decrease the incidence or severity of Klebsiella and Pseudomonas aeruginosa infections, patients admitted to intensive care units of 16 Department of Veterans Affairs and Department of Defense hospitals were randomized to receive either 100 mg/kg intravenous hyperimmune globulin (IVIG), derived from donors immunized with a 24-valent Klebsiella capsular polysaccharide plus an 8-valent P. aeruginosa O-polysaccharide-toxin A conjugate vaccine, or an albumin placebo. The overall incidence and severity of vaccine-specific Klebsiella plus Pseudomonas infections were not significantly different between the groups receiving albumin and IVIG. There was some evidence that IVIG may decrease the incidence (2.7% albumin vs. 1.2% IVIG) and severity (1.0% vs. 0.3%) of vaccine-specific Klebsiella infections, but these reductions were not statistically significant. The trial was stopped because it was statistically unlikely that IVIG would be protective against Pseudomonas infections at the dosage being used. Patients receiving IVIG had more adverse reactions (14.4% vs. 9.2%).

Background A recombinant, soluble fusion protein that is a dimer of an extracellular portion of the human tumor necrosis factor (TNF) receptor and the Fc portion of IgG1 (TNFR:Fc) binds and neutralizes TNF-α and prevents death in animal models of bacteremia and endotoxemia. Methods To evaluate the safety and efficacy of TNFR:Fc in the treatment of septic shock, we conducted a randomized, double-blind, placebo-controlled, multicenter trial. A total of 141 patients were randomly assigned to receive either placebo or a single intravenous infusion of one of three doses of TNFR:Fc (0.15, 0.45, or 1.5 mg per kilogram of body weight). The primary end point was mortality from all causes at 28 days. Results There were 10 deaths among the 33 patients in the placebo group (30 percent mortality), 9 deaths among the 30 patients receiving the low dose of TNFR:Fc (30 percent mortality), 14 deaths among the 29 receiving the middle dose (48 percent mortality), and 26 deaths among the 49 receiving the high dose (53 percent...

Objective The development of practice parameters for intravenous analgesia and sedation for adult patients in the intensive care unit (ICU) setting for the purpose of guiding clinical practice.Participants A task force of more than 40 experts in disciplines related to the use of analgesic and sedati

Objective : The development of practice parameters for achieving sustained neuromuscular blockade in the adult critically ill patient for the purpose of guiding clinical practice. Participants : A task force of more than 40 experts in disciplines related to the use of neuromuscular blocking agents in the intensive care unit was convened from the membership of the American College of Critical Care Medicine (ACCM) and the Society of Critical Care Medicine (SCCM). Evidence : The task force members provided the personal experience and determined the published literature (MEDLINE articles, textbooks, pharmacopeias, etc.) from which consensus would be sought. Published literature was reviewed and classified into one of four predetermined categories, according to study design and scientific value. Consensus Process : The task force met several times as a whole, and numerous times in smaller groups by teleconference, over a 1-yr period to identify the pertinent literature and arrive at consensus recommendations for the whole task force to discuss. Consideration was given to the relationship between the weight of scientific information and the experts' viewpoints. Over the next year, draft documents were composed by a task force steering committee and debated by the task force members until consensus was reached by nominal group process. The task force draft was then reviewed, assessed, and edited by the Board of Regents of the ACCM. After steering committee approval, the draft document was reviewed and approved by the SCCM Council. Data Synthesis : To facilitate rapid communication of the three recommendations contained within the complete and unabridged practice parameter document, an executive was prepared for publication by the ACCM Board of Regents, and this executive was approved by the task force steering committee and the SCCM Executive Council. Conclusions : A consensus of experts provided three recommendations with supporting data for achieving sustained neuromuscular blockade in critically ill patients : a) pancuronium is the preferred neuromuscular blocking agent for most critically ill patients ; b) vecuronium is the preferred neuromuscular blocking agent for those patients with cardiac disease or hemodynamic instability in whom tachycardia may be deleterious ; c) patients receiving neuromuscular blocking agents should be appropriately assessed for the degree of blockade that is being sustained. This executive summary selectively presents supporting information and is not intended as a substitute for the complete document. (Crit Care Med 1995 ; 23 :1601-1605)

ObjectiveTo evaluate the safety and efficacy of E5, a murine, monoclonal antibody directed against endotoxin, in the treatment of patients with Gram-negative sepsis.DesignA multicenter, randomized, double-blind, placebo-controlled trial.SettingFifty-three hospitals across the United States, includin

OBJECTIVES We sought to determine whether there might be acute changes in hemodynamics attributable to HA-1A, a monoclonal antibody to endotoxin, in patients with presumed Gram-negative sepsis. DESIGN Post hoc analysis of a multicenter, randomized, double-blind, placebo-controlled study. PATIENTS A total of 543 patients with severe sepsis presumed to be caused by Gram-negative bacteria who were enrolled in a clinical trial to evaluate the efficacy and safety of HA-1A human monoclonal antibody. INTERVENTIONS Patients were randomly assigned to receive either 100 mg of HA-1A or placebo. MEASUREMENT AND MAIN RESULTS Patients were grouped by the study drug, HA-1A, or placebo, and the presence or absence of Gram-negative bacteremia. Hemodynamic variables were monitored from before, until 72 hrs after infusion of the study drug. For the entire study population (n = 543), no changes over time attributable to study drug were noted in the mean arterial pressure (p > .19), heart rate (p > .53) or the need for vasopressor administration (p > .62). One hundred ninety-seven patients underwent pulmonary artery catheterization and had hemodynamic data available from before the infusion of HA-1A or placebo until at least 12 hrs after infusion. Evaluating all 197 patients on an intent to treat basis demonstrated no significant differences over time in cardiac index (p > .15), oxygen delivery index (p > .43), or left ventricular stroke work index (p > .48) between patients who received HA-1A and those patients receiving placebo. Grouping patients by the presence of Gram-negative bacteremia and study drug received also failed to demonstrate any significant difference attributable to HA-1A in mean arterial pressure (p > .54), heart rate (p > .84), cardiac index (p > .13), oxygen delivery index (p > .05), or left ventricular stroke work index (p > .48) between populations. CONCLUSION There is no apparent relationship between the administration of HA-1A, the presence of Gram-negative bacteremia, and hemodynamic profiles over the 72-hr study period.

OBJECTIVES To determine the safety, pharmacokinetics, and activity of an anti-tumor necrosis factor (TNF)-alpha monoclonal antibody in severe sepsis. DESIGN Open-label, prospective, phase II multicenter trial with escalating doses of a murine monoclonal antibody (CB0006). SETTING Twelve academic medical center intensive care units in the United States and Europe. PATIENTS Eighty patients with severe sepsis or septic shock who received standard supportive care and antimicrobial therapy in addition to the anti-TNF antibody. INTERVENTIONS Patients were treated intravenously with one of four dosing regimens with CB0006: 0.1 mg/kg, 1.0 mg/kg, 10 mg/kg or two doses of 1 mg/kg 24 hrs apart. MEASUREMENTS AND MAIN RESULTS The murine monoclonal anti-TNF antibody was well tolerated despite the development of anti-murine antibodies in 98% of patients. No survival benefit was found for the total study population, but patients with increased circulating TNF concentrations at study entry appeared to benefit by the high dose anti-TNF antibody treatment. Increased interleukin (IL)-6 levels predicted a fatal outcome (p = .003), but TNF levels were not found to be a prognostic indicator. TNF levels were higher (206.7 +/- 60.7 vs. 85.9 +/- 26.1 pg/mL; p < .001) and outcome was poor (41% vs. 71% survival; p = .007) in patients who were in shock at study entry when compared with septic patients not in shock. CONCLUSIONS The murine anti-TNF-alpha monoclonal antibody CB0006 has proven to be safe in this clinical trial and may prove to be useful in septic patients with increased circulating TNF concentrations. Further studies are needed to determine efficacy and the ultimate clinical utility of this immunotherapeutic agent in sepsis.

An American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference was held in Northbrook in August 1991 with the goal of agreeing on a set of definitions that could be applied to patients with sepsis and its sequelae. New definitions were offered for some terms, while others were discarded. Broad definitions of sepsis and the systemic inflammatory response syndrome were proposed, along with detailed physiologic parameters by which a patient may be categorized. Definitions for severe sepsis, septic shock, hypotension, and multiple organ dysfunction syndrome were also offered. The use of severity scoring methods when dealing with septic patients was recommended as an adjunctive tool to assess mortality. Appropriate methods and applications for the use and testing of new therapies were recommended. The use of these terms and techniques should assist clinicians and researchers who deal with sepsis and its sequelae.

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.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.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 (p0.001). 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 (p0.50).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.

While the outcome of in-hospital cardiopulmonary arrest has been studied extensively, the clinical antecedents of arrest are less well defined. We studied a group of consecutive general hospital ward patients developing cardiopulmonary arrest. Prospectively determined definitions of underlying pathophysiology, severity of underlying disease, patient complaints, and clinical observations were used to determine common clinical features. Sixty-four patients arrested 161 +/- 26 hours following hospital admission. Pathophysiologic alterations preceding arrest were classified as respiratory in 24 patients (38 percent), metabolic in 7 (11 percent), cardiac in 6 (9 percent), neurologic in 4 (6 percent), multiple in 17 (27 percent), and unclassified in 6 (9 percent). Patients with multiple disturbances had mainly respiratory (39 percent) and metabolic (44 percent) disorders. Fifty-four patients (84 percent) had documented observations of clinical deterioration or new complaints within eight hours of arrest. Seventy percent of all patients had either deterioration of respiratory or mental function observed during this time. Routine laboratory tests obtained before arrest showed no consistent abnormalities, but vital signs showed a mean respiratory rate of 29 +/- 1 breaths per minute. The prognoses of patients' underlying diseases were classified as ultimately fatal in 26 (41 percent), nonfatal in 23 (36 percent), and rapidly fatal in 15 (23 percent). Five patients (8 percent) survived to hospital discharge. Patients developing arrest on the general hospital ward services have predominantly respiratory and metabolic derangements immediately preceding their arrests. Their underlying diseases are generally not rapidly fatal. Arrest is frequently preceded by a clinical deterioration involving either respiratory or mental function. These features and the high mortality associated with arrest suggest that efforts to predict and prevent arrest might prove beneficial.

Sepsis, an important cause of hospital mortality, continues to be a diagnostic and therapeutic challenge. To define more clearly the impact of encephalopathy on the course of sepsis, the various clinical signs of sepsis, blood culture results, and mortality rates were examined in relation to mental

To investigate the endogenous adrenocortical response to sepsis, plasma cortisol concentrations were measured in 37 patients (53 +/- 3 yr of age) with septic shock. Patients were studied 11 +/- 2 h after shock commenced. Vasopressor therapy was required in 35 of 37 patients (median dopamine infusion rate of 11 micrograms/kg.min, range 3 to 74). Plasma cortisol concentrations were increased markedly (median 50.7 micrograms/dl, range 15.6 to 400) above normal values (10 to 20 micrograms/dl) in patients with septic shock. Neither patients who reversed their shock nor those who survived to hospital discharge had significantly different plasma cortisol concentrations from those who did not. Patients with Gram-positive infections had increased cortisol levels compared with those who had Gram-negative infections (median 83 micrograms/dl, range 32 to 400 vs. median 44 micrograms/dl, range 16 to 81, respectively; p less than .05). The source of infection, amount of vasopressors infused, and severity of shock were not associated with differences in cortisol concentrations. The length of time in shock before collection of the blood sample for measurements of cortisol and mean arterial pressure at the time of blood collection had significant but weak negative correlations with cortisol concentrations (p less than .05, rs = .37 and p less than .05, rs = -.40, respectively). We conclude that plasma cortisol concentrations are increased in patients with septic shock, but that the degree of increase is variable. This variability may, in part, be related to type of infection, length of time in shock, and BP at the time of blood sampling.(ABSTRACT TRUNCATED AT 250 WORDS)

Background: Data on current practices for management of renal replacement therapy (RRT) in acute kidney injury (AKI) are limited, particularly with regard to the dosing of therapy. Design, setting, participants, and measurements: A survey was conducted of practitioners at the 27 study sites that participate in the Veterans Affairs/National Institutes of Health Acute Renal Trial Network (ATN) Study before initiation of patient enrollment for ascertainment of the local prevailing practices for management of RRT in critically ill patients with AKI. Surveys were returned from 130 practitioners at 26 of 27 study sites; the remaining study site provided aggregate data. Results: Intermittent hemodialysis and continuous RRT were the most commonly used modalities of RRT, with sustained low-efficiency dialysis and other “hybrid” treatments used in fewer than 10% of patients. Intermittent hemodialysis was most commonly provided on a thrice-weekly or every-other-day schedule, with only infrequent assessment of the delivered dosage of therapy. Most practitioners reported that they did not dose continuous RRT on the basis of patient weight. The average prescribed dosage of therapy corresponded to a weight-based dosage of no more than 20 to 25 ml/kg per h. Conclusions: These results provide insight into clinical management of RRT and provide normative data for evaluation of the design of ongoing clinical trials.

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.Clinical study.School of medicine.Thirty-five patients with severe sepsis.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.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.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.

To elucidate the relationship of baseline glucose control and acute stimuli with hyperglycemia during medical critical illness.Prospective cohort study.Medical ICU (MICU) of a university affiliated hospital.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.None.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 (glucose110 mg/dL) was pervasive in all groups. Among the 51 patients with normal baseline glucose control, HbA1c was correlated with hyperglycemic time (p0.01, R(2) = 0.15). Multiple regression found HbA1c, age, corticosteroid dose, and carbohydrate administration independently associated with hyperglycemic time (p0.05 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 time110 mg/dL. Among normal subjects, HbA1c was independently predictive of peak and average glucose, and the fraction of time glucose was150 mg/dL and200 mg/dL (p0.05 for each). Patients with abnormal baseline glucose control had significantly more hyperglycemia than patients with normal baseline control.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.

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)Multicenter, double-blind, placebo-controlled trial of two doses of LY315920Na/S-5920 in a parallel design.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.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.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.

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.

Study objectives: Evaluate the safety of filgrastim (recombinant methionyl human granulocyte colony-stimulating factor) administration, combined with standard therapy, in patients with pneumonia and either septic shock or severe sepsis who were receiving mechanical ventilation. Design: Multicenter, double-blind, randomized, placebo-controlled study. Setting: ICU, multicenter. Patients: Eighteen patients with pneumonia and hypotension, or in the absence of shock, two or more end-organ dysfunctions, were enrolled and treated. Baseline acute physiology and chronic health evaluation II scores and median age for the filgrastim (n 5 12) and placebo (n 5 6) groups were 25.0 and 49.5 years and 31.5 and 56.5 years, respectively. Intervention: Filgrastim (300 mg) or placebo was administered IV daily for up to 5 days. Measurements and results: Study end points included safety; biological response, including endogenous cytokine levels, endotoxin levels, and neutrophil counts; and mortality. Cytokine and endotoxin levels were highly variable in both groups. By day 29, 3 of 12 filgrastim-treated patients and 4 of 6 placebo-treated patients had died. There were no differences in types and occurrences of adverse events, including ARDS, or in outcome between the two groups. Three of four placebo-treated patients had persistent bacterial growth on bronchoscopy repeated after 48 h compared with 2 of 10 filgrastim-treated patients. Conclusion: Filgrastim appeared to be well tolerated in this population of patients with pneumonia and severe sepsis or septic shock. Larger studies to determine the benefit of filgrastim in patients with pneumonia and sepsis or organ dysfunction are warranted. (CHEST 2001; 119:523‐529)

Objective We examined the pattern of organ system dysfunction, the evolution of this pattern over time, and the relationship of these features to mortality in patients who had sepsis syndrome. Design Prospective, multicenter, observational study. Setting Intensive care units in tertiary referral teaching hospitals. Patients A total of 287 patients who had sepsis syndrome were prospectively identified in intensive care units. MATERIALS AND MEASUREMENTS: Cardiovascular, pulmonary, neurologic, coagulation, renal, and hepatic dysfunction were assessed at onset and on day 3 of sepsis syndrome. Organ dysfunction was classified as normal, mild, moderate, severe, and extreme dysfunction. We calculated the occurrence rate and associated 30-day mortality rate of organ dysfunction at the onset of sepsis syndrome. We then measured the change in organ dysfunction from onset to day 3 of sepsis syndrome and determined, for individual organ systems, the associated 30-day mortality rate. Results At the onset of sepsis syndrome, clinically significant pulmonary dysfunction was the most common organ failure, but was not related to 30-day mortality. Clinically significant cardiovascular, neurologic, coagulation, renal, and hepatic dysfunction were less common at the onset of sepsis syndrome but were significantly associated with the 30-day mortality rate. Worsening neurologic, coagulation, and renal dysfunction from onset to day 3 of sepsis syndrome were associated with significantly higher 30-day mortality than with improvement or no change in organ dysfunction. Conclusions Increased mortality rate in sepsis syndrome is associated with a pattern characterized by failure of nonpulmonary organ systems and, in particular, worsening neurologic, coagulation, and renal dysfunction over the first 3 days. Although initial pulmonary dysfunction is common in patients with sepsis syndrome, it is not associated with an increased mortality rate.

The occurrence of cardiogenic pulmonary edema following alternating current electrical injury has not been reported. A patient developing severe pulmonary edema immediately following an electrical injury-induced episode of ventricular fibrillation is described. Evidence that the etiology of the pulmonary edema was cardiogenic is derived from both hemodynamic data and the calculation of the pulmonary edema fluid to serum colloid osmotic pressure ratio.

Introduction: Leukostasis is a medical emergency marked by decreased tissue perfusion accompanying capillary obstruction by blasts or large, inelastic immature white cells. It is associated with the hyperleukocytosis of acute myeloid leukemia or with chronic myelogenous leukemia (CML) when blast cou

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.

Objective Numerous reports have appeared describing the effects of intravenous lipid administration on the pulmonary function of the critically ill patient. Our study was undertaken to determine whether the lipid content of an arterial blood gas specimen affects the measurement of arterial pH, PaO2, PaCO2, or arterial oxygen saturation. Design Prospective, in vitro controlled study. Setting Medical and cardiac intensive care units. Patients Critically ill patients undergoing clinically-directed blood gas sampling via indwelling arterial catheters. Interventions None. Measurements Arterial blood gas specimens were modified in vitro by dividing the sample and adding a known amount of lipid emulsion to half of the sample, resulting in a difference between the plasma triglyceride concentrations of the two halves. Two series of experiments were run: one series was run with a predicted plasma triglyceride difference of 400 mg/dL (4.5 mmol/L) between the two samples; the other series was run with a predicted plasma triglyceride difference of 800 mg/dL (9.0 mmol/L) between the two samples. Blood gas measurements were performed on each half of a sample, and the results were compared. Because some studies have only noted changes in patients with the adult respiratory distress syndrome (ARDS), samples from these patients were also analyzed as a separate group. Results No significant changes were found in arterial pH, PaO2, PaCO2, or arterial oxygen saturation between the two halves of the sample. With 95% confidence, differences as small as 1.5 torr (0.2 kPa) for PaO2 and PaCO2, 0.5% for arterial oxygen saturation, and 0.005 for pH, would have been detected. No differences were found in the ARDS subgroup. Conclusions The addition of clinically relevant amounts of lipid to blood samples does not affect blood gas measurements. Any observed changes in blood gas values after lipid feeding are presumably due to products of lipid metabolism or alterations in pulmonary function.

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 renalreplacement 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.)

To evaluate the role of amino acid profiles in septic encephalopathy.Retrospective analysis.Medical wards and medical ICU of a university hospital.Patients with infections and normal mental status were compared with patients with septic shock and altered sensorium.Plasma amino acid levels and Acute Physiology and Chronic Health Evaluation (APACHE II) scores were determined.Patients with septic shock and altered sensorium had higher circulating concentrations of ammonia (425 +/- 55 vs. 127 +/- 7 mmol/L) and the aromatic amino acids phenylalanine (122 +/- 19 vs. 74 +/- 3 mmol/L) and tryptophan (97 +/- 7 vs. 32 +/- 13 mmol/L), and lower levels of the branch-chain amino acid isoleucine (48 +/- 7 vs. 68 +/- 5 mmol/L) than patients with infections and normal sensorium (p less than .05). Aromatic amino acid levels correlated with APACHE II scores (R2 = .4, p less than .001) and mortality. APACHE II scores were higher in the septic shock patients (30 +/- 2 vs. 8 +/- 1, p less than .001), and these patients had a higher mortality rate (71% vs. 12%, p less than .01). Patients with septic shock who died had higher levels of ammonia (524 +/- 58 vs. 227 +/- 40 mmol/L, p less than .05) and sulfur-containing amino acids (172 +/- 31 vs. 61 +/- 7 mmol/L, p less than .05) than patients who survived.Plasma amino acid profiles appear to be important in septic encephalopathy and the severity of septic disease.