David Gurka

Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock

Objective:To determine the prevalence and impact on mortality of delays in initiation of effective antimicrobial therapy from initial onset of recurrent/persistent hypotension of septic shock. Design:A retrospective cohort study performed between July 1989 and June 2004. Setting:Fourteen intensive care units (four medical, four surgical, six mixed medical/surgical) and ten hospitals (four academic, six community) in Canada and the United States. Patients:Medical records of 2,731 adult patients with septic shock. Interventions:None. Measurements and Main Results:The main outcome measure was survival to hospital discharge. Among the 2,154 septic shock patients (78.9% total) who received effective antimicrobial therapy only after the onset of recurrent or persistent hypotension, a strong relationship between the delay in effective antimicrobial initiation and in-hospital mortality was noted (adjusted odds ratio 1.119 [per hour delay], 95% confidence interval 1.103–1.136, p < .0001). Administration of an antimicrobial effective for isolated or suspected pathogens within the first hour of documented hypotension was associated with a survival rate of 79.9%. Each hour of delay in antimicrobial administration over the ensuing 6 hrs was associated with an average decrease in survival of 7.6%. By the second hour after onset of persistent/recurrent hypotension, in-hospital mortality rate was significantly increased relative to receiving therapy within the first hour (odds ratio 1.67; 95% confidence interval, 1.12–2.48). In multivariate analysis (including Acute Physiology and Chronic Health Evaluation II score and therapeutic variables), time to initiation of effective antimicrobial therapy was the single strongest predictor of outcome. Median time to effective antimicrobial therapy was 6 hrs (25–75th percentile, 2.0–15.0 hrs). Conclusions:Effective antimicrobial administration within the first hour of documented hypotension was associated with increased survival to hospital discharge in adult patients with septic shock. Despite a progressive increase in mortality rate with increasing delays, only 50% of septic shock patients received effective antimicrobial therapy within 6 hrs of documented hypotension.

Intensive Nutrition in Acute Lung Injury A Clinical Trial (INTACT)

BACKGROUND Despite extensive use of enteral (EN) and parenteral nutrition (PN) in intensive care unit (ICU) populations for 4 decades, evidence to support their efficacy is extremely limited. METHODS A prospective randomized trial was conducted evaluate the impact on outcomes of intensive medical nutrition therapy (IMNT; provision of >75% of estimated energy and protein needs per day via EN and adequate oral diet) from diagnosis of acute lung injury (ALI) to hospital discharge compared with standard nutrition support care (SNSC; standard EN and ad lib feeding). The primary outcome was infections; secondary outcomes included number of days on mechanical ventilation, in the ICU, and in the hospital and mortality. RESULTS Overall, 78 patients (40 IMNT and 38 SNSC) were recruited. No significant differences between groups for age, body mass index, disease severity, white blood cell count, glucose, C-reactive protein, energy or protein needs occurred. The IMNT group received significantly higher percentage of estimated energy (84.7% vs 55.4%, P < .0001) and protein needs (76.1 vs 54.4%, P < .0001) per day compared with SNSC. No differences occurred in length of mechanical ventilation, hospital or ICU stay, or infections. The trial was stopped early because of significantly greater hospital mortality in IMNT vs SNSC (40% vs 16%, P = .02). Cox proportional hazards models indicated the hazard of death in the IMNT group was 5.67 times higher (P = .001) than in the SNSC group. CONCLUSIONS Provision of IMNT from ALI diagnosis to hospital discharge increases mortality.

Nutrition assessment: The reproducibility of subjective global assessment in patients requiring mechanical ventilation

Background/Objectives:The detection of malnutrition in the intensive care unit (ICU) is critical to appropriately address its contribution on outcomes. The primary objective of this investigation was to determine if nutritional status could be reliably classified using subjective global assessment (SGA) in mechanically ventilated (MV) patients.Subjects/Methods:Fifty-seven patients requiring MV >48 h in a university-affiliated medical ICU were evaluated in this cross-sectional study over a 3-month period. Nutritional status was categorized independently by two registered dietitians using SGA. Frequencies, means (+ s.d.), χ 2 and t-tests were used to describe the population characteristics; agreement between raters was evaluated using the κ statistic.Results:On admission, the average patient was 50.4 (±14.2) years of age, overweight (body mass index: 29.0±9.2kg/m2), had an acute physiology and chronic health evaluation II score of 24 (±10) and respiratory failure. Fifty percent (n=29) of patients were categorized as malnourished. Agreement between raters was 95% before consensus, reflecting near perfect agreement (κ=0.90) and excellent reliability. Patients categorized as malnourished were more often admitted to the hospital floor before the ICU (n=32; 56%), reported decreased dietary intake (69 vs 46%, P=0.02) and exhibited signs of muscle wasting (45 vs 7%, P<0.001, respectively) and fat loss (52 vs 7%, P<0.001, respectively) on physical exam when compared with normally nourished individuals.Conclusions:SGA can serve as a reliable nutrition assessment technique for detecting malnutrition in patients requiring MV. Its routine use should be incorporated into future studies and clinical practice.

New treatment strategies for severe sepsis and septic shock.

Purpose of reviewSevere sepsis and septic shock are common causes of morbidity and mortality in critically ill patients. The complexities of the septic cascade continue to emerge and may identify new targets for innovative patient management. This review will highlight some of the recent advances in our management of the patient with sepsis. Recent findingsThe early administration of adequate antibiotic therapy, effective source control, and goal-directed hemodynamic resuscitation are the cornerstone of successful management. Prevention of the complications of critical illness and maintenance of normal glucose levels are also important elements of effective management. In patients with vasopressor-dependent septic shock, evaluation for inadequate cortisol response and the provision of physiologic doses of replacement steroids for those found to be deficient may result in improved survival. Administration of drotrecogin alfa (activated), (activated protein C) has been shown to improve survival in patients with severe sepsis and septic shock who have a high risk of mortality. Because of its anticoagulant properties, caution must be exercised with the use of activated protein C in those patients who meet the contraindications for its use or who have risk factors for increased bleeding complications. SummarySignificant advances have been made in our understanding of the septic cascade and our ability to manage patients with severe sepsis and septic shock. Despite these advances, significant morbidity and mortality continue. In addition, there is also considerable impact on the financial and overall function of the patient.

Activated protein C and septic shock: a propensity-matched cohort study*.

Background:Septic shock is a highly inflammatory and procoagulant state associated with significant mortality. In a single randomized controlled trial, recombinant human activated protein C (drotrecogin alfa) reduced mortality in patients with severe sepsis at high risk of death. Further clinical trials, including a recently completed trial in patients with septic shock, failed to reproduce these results. Objective:To evaluate the effectiveness of recombinant human activated protein C on mortality in a cohort of patients with septic shock and to explore possible reasons for inconsistent results in previous studies. Design:Retrospective, 2:1 propensity-matched, multicenter cohort study. Setting:Twenty-nine academic and community intensive care units in three countries. Patients:Seven thousand three hundred ninety-two adult patients diagnosed with septic shock, of which 349 received recombinant human activated protein C within 48 hrs of intensive care unit admission between 1997 and 2007. Measurements and Main Results:Our primary outcomes were mortality over 30 days and mortality stratified by Acute Physiology and Chronic Health Evaluation II quartile. Using a propensity-matched Cox proportional hazard model, we observed a 6.1% absolute reduction in 30-day mortality associated with the use of recombinant human activated protein C (108/311 [34.7%] vs. 254/622 [40.8%], hazard ratio 0.72, 95% confidence interval 0.52–1.00, p = .05) and noted consistent reductions in mortality among Acute Physiology and Chronic Health Evaluation II quartiles. A time to event analysis showed that the time to appropriate antimicrobials after documented hypotension decreased for each year of study (p = .003), a finding that was congruent with a decrease in annual mortality over the study period (odds ratio 0.96 per year [95% confidence interval 0.93–0.99], p = .003). Conclusions:In this retrospective, propensity-matched, multicenter cohort study of patients with septic shock, early use of recombinant human activated protein C was associated with reduced mortality. Improvements in general quality of care such as speed of antimicrobial delivery leading to decreasing mortality of patients with septic shock may have contributed to the null results of the recently completed trial of recombinant human activated protein C in patients with septic shock.

Intensive Medical Nutrition Therapy: Methods to Improve Nutrition Provision in the Critical Care Setting

Patients requiring mechanical ventilation in an intensive care unit commonly fail to attain enteral nutrition (EN) infusion goals. We conducted a cohort study to quantify and compare the percentage of energy and protein received between standard care (n=24) and intensive medical nutrition therapy (MNT) (n=25) participants; to assess the percentage of energy and protein received varied by nutritional status, and to identify barriers to EN provision. Intensive MNT entailed providing energy at 150% of estimated needs, using only 2.0 kcal/cc enteral formula and 24-hour infusions. Estimated energy and protein needs were calculated using 30 kcal/kg and 1.2 g protein/kg actual or obesity-adjusted admission body weight. Subjective global assessment was completed to ascertain admission intensive care unit nutritional status. Descriptive statistics and survival analyses were conducted to examine time until attaining 100% of feeding targets. Patients had similar estimated energy and protein needs, and 51% were admitted with both respiratory failure and classified as normally nourished (n=25/49). Intensive MNT recipients achieved a greater percentage of daily estimated energy and protein needs than standard care recipients (1,198±493 vs 475±480 kcal, respectively, P<0.0001; and 53±25 vs 29±32 g, respectively, P=0.007) despite longer intensive care unit stays. Cox proportional hazards models showed that intensive MNT patients were 6.5 (95% confidence interval 2.1 to 29.0) and 3.6 (95% confidence interval 1.2 to 15.9) times more likely to achieve 100% of estimated energy and protein needs, respectively, controlling for confounders. Malnourished patients (n=13) received significantly less energy (P=0.003) and protein (P=0.004) compared with normally nourished (n=11) patients receiving standard care. Nutritional status did not affect feeding intakes in the intensive MNT group. Clinical management, lack of physician orders, and gastrointestinal issues involving ileus, gastrointestinal hemorrhage, and EN delivery were the most frequent clinical impediments to EN provision. It was concluded that intensive MNT could achieve higher volumes of EN infusion, regardless of nutritional status. Future studies are needed to advance this methodology and to assess its influence on outcomes.

Acute Hemorrhagic Leukoencephalopathy Associated with Influenza A (H1N1) Virus

BackgroundAcute hemorrhagic leukoencephalopathy (AHLE) is a rare condition associated with H1N1. In this condition the infection triggers an autoimmune response which results in perivascular demyelination and hemorrhage in the brain parenchyma.MethodsWe report a case of a patient who developed brain edema and herniation as a result of AHLE.ResultsA 27-year-old presented to a community hospital with fever, dyspnea, and malaise and was found to have H1N1-associated pneumonia. Despite treatment he progressed to acute respiratory distress syndrome and required mechanical ventilation. Due to failure on conventional ventilation, he was transferred to our hospital and was placed on high-frequency oscillatory ventilation. He was showing improvement until day 6 of transfer to our hospital when he was suddenly noted to have a rise in his blood pressure followed by hypotension. The following morning he was noted to have non-reactive pupils and was declared brain dead. Autopsy of the brain was consistent with AHLE.ConclusionsThis case emphasizes the importance of awareness of this disease. The non-specific signs and symptoms, and the use of sedatives, make diagnosis challenging in the early stages of this disease. If suspected early, appropriate imaging can aid in the diagnosis. Treatment with immunosuppressive agents and plasmapheresis may prevent rapid progression and death. This is the first published case of AHLE in association with H1N1 that has been confirmed pathologically.

Role of timing and dose of energy received in patients with acute lung injury on mortality in the Intensive Nutrition in Acute Lung Injury Trial (INTACT): A post hoc analysis

BACKGROUND Our trial INTACT (Intensive Nutrition in Acute Lung Injury Trial) was designed to compare the impact of feeding from acute lung injury (ALI) diagnosis to hospital discharge, an interval that, to our knowledge, has not yet been explored. It was stopped early because participants who were randomly assigned to energy intakes at nationally recommended amounts via intensive medical nutrition therapy experienced significantly higher mortality hazards than did those assigned to standard nutrition support care that provided energy at 55% of recommended concentrations. OBJECTIVE We assessed the influence of dose and timing of feeding on hospital mortality. DESIGN Participants (n = 78) were dichotomized as died or discharged alive. Associations between the energy and protein received overall, early (days 1-7), and late (days ≥8) and the hazards of hospital mortality were evaluated between groups with multivariable analysis methods. RESULTS Higher overall energy intake predicted significantly higher mortality (OR: 1.14, 95% CI: 1.02, 1.27). Among participants enrolled for ≥8 d (n = 66), higher early energy intake significantly increased the HR for mortality (HR: 1.17, 95% CI: 1.07, 1.28), whereas higher late energy intake was significantly protective (HR: 0.91, 95% CI: 0.83, 1.0). Results were similar for early but not late protein (grams per kilogram) exposure (early-exposure HR: 8.9, 95% CI: 2.3, 34.3; late-exposure HR: 0.15, 95% CI: 0.02, 1.1). Threshold analyses indicated early mean intakes ≥18 kcal/kg significantly increased subsequent mortality. CONCLUSIONS Providing kilocalories per kilogram or grams of protein per kilogram early post-ALI diagnosis at recommended levels was associated with significantly higher hazards for mortality, whereas higher late energy intakes reduced mortality hazards. This time-varying effect violated the Cox proportionality assumption, indicating that feeding trials in similar populations should extend beyond 7 d and use time-varying statistical methods. Future trials are required for corroboration. INTACT was registered at clinicaltrials.gov as NCT01921101.

The impact of obesity in cirrhotic patients with septic shock: A retrospective cohort study

The prevalence of obesity in cirrhosis is rising. The impact of obesity in critically ill cirrhotic patients with sepsis/septic shock has not been evaluated. This study aimed to examine the relationship between obesity and mortality in cirrhotic patients admitted to the intensive care unit with septic shock.

Response to Drs Jeejeebhoy and Bistrian.

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