Daren K. Heyland

Corticosteroid treatment for sepsis: a critical appraisal and meta-analysis of the literature.

OBJECTIVE To determine the effect of corticosteroid therapy on morbidity and mortality in patients with sepsis. DATA SOURCES We searched for published and unpublished research using MEDLINE, EMBASE, and the Science Citation Index, manual searching of Index Medicus, citation review of relevant primary and review articles, personal files, and contact with primary investigators. STUDY SELECTION From a pool of 124 potentially relevant articles, duplicate independent review identified nine relevant, randomized, controlled trials of corticosteroid therapy in sepsis and septic shock among critically ill adults. DATA EXTRACTION In duplicate, independently, we abstracted key data on population, intervention, outcome, and methodologic quality of the randomized controlled trials. DATA SYNTHESIS Corticosteroids appear to increase mortality in patients with overwhelming infection (relative risk 1.13, 95% confidence interval 0.99 to 1.29), and have no beneficial effect in the subgroup of patients with septic shock (relative risk 1.07, 95% confidence interval 0.91 to 1.26). Studies with the highest methodologic quality scores also suggest a trend toward increased mortality overall (relative risk 1.10, 95% confidence interval 0.94 to 1.29). A similar trend was observed for patients with septic shock (relative risk 1.12, 95% confidence interval 0.95 to 1.32). No difference in secondary infection rates was demonstrated in corticosteroid-treated patients with sepsis or septic shock. However, there was a trend toward increased mortality from secondary infections in patients receiving corticosteroids (relative risk 1.70, 95% confidence interval 0.70 to 4.12). The occurrence rate of gastrointestinal bleeding was increased slightly in the treatment group (relative risk 1.17, 95% confidence interval 0.79 to 1.73). CONCLUSIONS Current evidence provides no support for the use of corticosteroids in patients with sepsis or septic shock, and suggests that their use may be harmful. These trials underscore the need for future methodologically rigorous trials evaluating new immune-modulating therapies in well-defined critically ill patients with overwhelming infection.

Enteral nutrition in the critically ill patient : a prospective survey

OBJECTIVES To describe current enteral nutrition-prescribing practices for critically ill patients, and to identify factors associated with initiation of, and tolerance to, enteral nutrition. DESIGN A prospective, cohort study. SETTING Two tertiary care medical-surgical intensive care units (ICU) in Ontario, Canada. PATIENTS We enrolled 99 consecutive patients who were expected to stay in the ICU for > 3 days and who were unable to tolerate oral nutrition. We followed patients for 21 days or until they tolerated enteral nutrition, tolerated oral nutrition, were discharged from the ICU, or died. MEASUREMENTS AND MAIN RESULTS We recorded time elapsed from ICU admission to initiation and tolerance of enteral feedings, and examined factors associated with these events. We defined tolerance as receiving 90% of estimated daily energy requirements for > 48 hrs without gastrointestinal dysfunction (i.e., high gastric residuals, vomiting, diarrhea, abdominal distention). Seventy-three (74%) of 99 patients were started on enteral feedings an average 3.1 days (range 1 to 18) after ICU admission. Of 26 patients never started on enteral nutrition, three (12.5%) patients eventually tolerated oral nutrition, 14 (54.0%) patients were discharged from the ICU, and seven (27.0%) patients died. Reasons for not initiating enteral nutrition included absence of bowel sounds (27.0%), high nasogastric drainage (16.9%), contraindication to enteral nutrition (16.7%), tolerance of oral nutrition (6.8%), and no apparent reason (5.1%). Abdominal surgery, use of vasoactive drugs, and admission to one hospital made initiation of enteral nutrition less likely, whereas presence of bowel sounds and admission to the other hospital made initiation of enteral nutrition more likely. Thirty-five (42.9%) of 73 patients started on enteral nutrition achieved tolerance of the regimen. The average time from ICU admission to tolerance of feedings was 5.8 days (range 1 to 14). Once started on enteral nutrition, the most common reasons for decreasing or discontinuing feedings included high gastric residuals (51.0%), mechanical feeding tube problems (15.4%), medical or surgical procedures (5.4%), and vomiting (5.1%). Use of paralytic agents and the presence of high gastric residuals were associated with intolerance. Of 38 patients who did not achieve tolerance, 20 (52.6%) patients were discharged from the ICU, eight (21.0%) patients died, and eight (21.0%) patients eventually tolerated oral nutrition. CONCLUSIONS Enteral nutrition is not started in all eligible ICU patients. Approximately half of those patients receiving enteral nutrition achieved tolerance of the regimen. Gastrointestinal dysfunction causing intolerance to enteral nutrition is a common reason for not starting, or discontinuing, feedings.

Enteral nutrition in the critically ill patient: A critical review of the evidence

ObjectiveTo examine the relationship between enteral nutrition (EN) and infection in the critically ill.Setting: Computerized search of published research and review of relevant reference lists.Study selection: 151 citations were reviewed and 39 articles met selection criteria. Primary studies were included if they evaluated EN in critically ill humans and its effect on infectious morbidity and mortality.Measurements and resultsRelevant data were abstracted on the timing and impact of EN on morbidity, the optimal route of administration, composition and pH of EN, and bacterial contamination of EN. The evidence from human studies that EN, particularly early EN, results in reduced septic morbidity as compared to parenteral nutrition is limited to small, unblinded studies with non-rigorous definitions of pneumonia. There is no evidence to support a preference of feeding into the stomach versus the small bowel. The addition of fish oil, arginine, glutamine and fiber to enteral feeds has a variable impact on survival in animal models; there are no trials in critically ill patients that demonstrate a reduction in infectious morbidity and mortality. Acidification of enteral nutrition results in decreased bacterial colonization of the stomach in critically ill patients. Bacterial contamination of enteral nutrition is an important source of infection.ConclusionsEvidence from experimental data in critically ill patients suggests that enteral nutrition may have a favourable impact on gastrointestinal immunological function and infectious morbidity.

Impaired gastric emptying in mechanically ventilated, critically ill patients

ObjectiveTo measure gastric emptying in critically ill patients using an acetaminophen absorption model and determine which variables are associated with impaired gastric emptying.DesignA prospective, cohort study.SettingA medical/surgical ICU at a tertiary care hospital: Hamilton General Hospital, Hamilton, Ontario.Patients and participantsWe recruited 72 mechanically ventilated patients expected to remain in the ICU for more than 48h. Our results were compared to those in healthy volunteers.InterventionWithin 48 h of admission to the ICU, 1.6 g acetaminophen suspension were administered via a nasogastric tube into the stomach. Blood samples were drawn at=0, 30, 60, 90, and 120 min for measurement of plasma acetaminophen levels determined by the enzymatic degradation method.Measurements and resultsMaximal concentration of acetaminophen was 94.1 (75.3) μmol/l compared to 208.4 (33.1) μmol/l in a control population (p<0.0001). The time to reach the maximal concentration was 105 min (60–180) compared to 30 min (15–90) in controls (p<0.0001). The area under the time-acetaminophen concentration curvet=120 was 9301 (7343) μmol/min per 1 compared to 11644 (1336) μmol/min per 1 in the controls (p=0.28). The variables associated with delayed gastric emptying were age, sex and use of opioids for analgesia and sedation.ConclusionsGastric emptying is delayed in critically ill patients. The important consequences of this phenomenon include intolerance to enteral nutrition and gastric colonization. Strategies to minimize the use of narcotics may improve gastric emptying. Studies to examine the effect of gastrointestinal prokinetic agents on gastric emptying are needed.

Randomized trial of combination versus monotherapy for the empiric treatment of suspected ventilator-associated pneumonia.

Objective:To compare a strategy of combination therapy with a strategy of monotherapy with broad-spectrum antibiotics for suspected late ventilator-associated pneumonia. Design:Randomized trial. Setting:Twenty-eight intensive care units in Canada and the United States. Patients:The study included 740 mechanically ventilated patients who developed suspected ventilator-associated pneumonia after 96 hrs in the intensive care unit. Patients known to be colonized or infected with Pseudomonas or methicillin-resistant Staphylococcus aureus or who were immunocompromised were excluded from the study. Interventions:As initial unblinded therapy, patients were allocated to receive meropenem (1 g every 8 hrs) and ciprofloxacin (400 mg every 12 hrs) or meropenem alone. Before starting antibiotics, patients were also randomized to bronchoalveolar lavage with quantitative cultures or endotracheal aspirates. When culture results were available, physicians were encouraged to adjust antibiotics. Adequacy of antibiotics was defined as the organism present in the enrollment culture having in vitro susceptibility to one or more of the study antibiotics. Measurements and Main Results:Baseline characteristics and etiologies of ventilator-associated pneumonia were similar in the two groups. There was no difference in 28-day mortality between the combination and monotherapy groups (relative risk = 1.05, 95% confidence interval 0.78–1.42, p = .74). Duration of intensive care unit and hospital stay, clinical and microbiological treatment response, emergence of antibiotic-resistant bacteria, isolation of Clostridium difficile in stool, and fungal colonization were also similar in the two groups. In a subgroup of patients who had infection due to Pseudomonas species, Acinetobacter species, and multidrug-resistant Gram-negative bacilli at enrollment (n = 56), the adequacy of initial antibiotics (84.2% vs. 18.8%, p < .001) and microbiological eradication of infecting organisms (64.1% vs. 29.4%, p = .05) was higher in the combination group compared with the monotherapy group, but there were no differences in clinical outcomes. Conclusions:For critically ill patients who have suspected late ventilator-associated pneumonia and who are at low risk for difficult-to-treat Gram-negative bacteria, monotherapy is associated with similar outcomes compared with combination therapy. For those patients at high risk of difficult-to-treat Gram-negative bacteria, combination therapy is safe and may be associated with better microbiological and clinical outcomes.

REducing Deaths due to OXidative Stress (The REDOXS© Study): rationale and study design for a randomized trial of glutamine and antioxidant supplementation in critically-ill patients

Critically-ill patients experience an extent of hyperinflammation, cellular immune dysfunction, oxidative stress and mitochondrial dysfunction. Supplementation with key nutrients, such as glutamine and antioxidants, is most likely to have a favourable effect on these physiological derangements, leading to an improvement in clinical outcomes. The results of two meta-analyses suggest that glutamine and antioxidants may be associated with improved survival. The purpose of the present paper is to report the background rationale and study protocol for the evaluation of the effect of high-dose glutamine and antioxidant supplementation on mortality in a large-scale randomized trial in 1200 mechanically-ventilated, critically-ill patients. Patients admitted to an intensive care unit (ICU) with clinical evidence of severe organ dysfunction will be randomized to one of four treatments in a 2 x 2 factorial design: (1) glutamine; (2) antioxidant therapy; (3) glutamine and antioxidant therapy; (4) placebo. The primary outcome for this study is 28 d mortality. The secondary outcomes are duration of stay in ICU, adjudicated diagnosis of infection, multiple organ dysfunction, duration of mechanical ventilation, length of stay in hospital and health-related quality of life at 3 and 6 months. A novel design feature is the combined use of parenteral and enteral study nutrients dissociated from the nutrition support. The therapeutic strategies tested in the randomized trial may lead to less morbidity and improved survival in critically-ill patients. The trial will be conducted in approximately twenty tertiary-care ICU in Canada and the first results are expected in 2009.

Metabolic and nutritional support of critically ill patients: consensus and controversies

The results of recent large-scale clinical trials have led us to review our understanding of the metabolic response to stress and the most appropriate means of managing nutrition in critically ill patients. This review presents an update in this field, identifying and discussing a number of areas for which consensus has been reached and others where controversy remains and presenting areas for future research. We discuss optimal calorie and protein intake, the incidence and management of re-feeding syndrome, the role of gastric residual volume monitoring, the place of supplemental parenteral nutrition when enteral feeding is deemed insufficient, the role of indirect calorimetry, and potential indications for several pharmaconutrients.

Reduction of nosocomial pneumonia after major burns by trace element supplementation: aggregation of two randomised trials.

IntroductionNosocomial pneumonia is a major source of morbidity and mortality after severe burns. Burned patients suffer trace element deficiencies and depressed antioxidant and immune defences. This study aimed at determining the effect of trace element supplementation on nosocomial or intensive care unit (ICU)-acquired pneumonia.MethodsTwo consecutive, randomised, double-blinded, supplementation studies including two homogeneous groups of 41 severely burned patients (20 placebo and 21 intervention) admitted to the burn centre of a university hospital were combined. Intervention consisted of intravenous trace element supplements (copper 2.5 to 3.1 mg/day, selenium 315 to 380 μg/day, and zinc 26.2 to 31.4 mg/day) for 8 to 21 days versus placebo. Endpoints were infections during the first 30 days (predefined criteria for pneumonia, bacteraemia, wound, urine, and other), wound healing, and length of ICU stay. Plasma and skin (study 2) concentrations of selenium and zinc were determined on days 3, 10, and 20.ResultsThe patients, 42 ± 15 years old, were burned on 46% ± 19% of body surface: the combined characteristics of the patients did not differ between the groups. Plasma trace element concentrations and antioxidative capacity were significantly enhanced with normalisation of plasma selenium, zinc, and glutathione peroxidase concentrations in plasma and skin in the trace element-supplemented group. A significant reduction in number of infections was observed in the supplemented patients, which decreased from 3.5 ± 1.2 to 2.0 ± 1.0 episodes per patient in placebo group (p < 0.001). This was related to a reduction of nosocomial pneumonia, which occurred in 16 (80%) patients versus seven (33%) patients, respectively (p < 0.001), and of ventilator-associated pneumonia from 13 to six episodes, respectively (p = 0.023).ConclusionEnhancing trace element status and antioxidant defences by selenium, zinc, and copper supplementation was associated with a decrease of nosocomial pneumonia in critically ill, severely burned patients.

Mortality, Attributable Mortality, and Clinical Events as End Points for Clinical Trials of Ventilator- Associated Pneumonia and Hospital-Acquired Pneumonia

Appropriate end points are crucial for the successful interpretation of clinical trials. Choosing end points for therapeutic trials of ventilator-associated pneumonia (VAP) and hospital-acquired pneumonia (HAP) requires careful consideration, because they are complications of critical illness. It may be difficult to distinguish the consequences of VAP and HAP from manifestations of the underlying illnesses, and it is important to determine their incremental magnitude, to plan for possible treatment effects and, thus, sample size calculations. In this article, we discuss mortality, attributable mortality, and time to clinical events as possible end points for HAP and/or VAP trials. Because of the paucity of evidence on HAP, we focus predominantly on VAP. In a systematic review of applicable trials, VAP appears to have slight intensive care unit and low hospital-attributable mortality. VAP is associated with prolonged durations of intensive care unit stay, hospital stay, and mechanical ventilation. Because of these findings, superiority trials of VAP treatment that use mortality as a primary end point are not possible. Equivalency studies are possible, but there are sample size implications. The use of time to clinical event end points, especially when combined with mortality, may be the best option for trial in the future.

Clinical Outcomes Related to Protein Delivery in a Critically Ill Population A Multicenter, Multinational Observation Study

OBJECTIVE Optimal intake of energy and protein is associated with improved outcomes, although outcomes relative to protein intake are very limited. Our purpose was to evaluate the impact of prescribed protein delivery on mortality and time to discharge alive (TDA) using data from the International Nutrition Survey 2013. We hypothesized that greater protein delivery would be associated with lower mortality and shorter TDA. METHODS The sample included patients in the intensive care unit (ICU) ≥ 4 days (n = 2828) and a subsample in the ICU ≥ 12 days (n = 1584). Models were adjusted for evaluable nutrition days, age, body mass index, sex, admission type, acuity scores, and geographic region. Percentages of prescribed protein and energy intake were compared with mortality outcomes using logistic regression and with Cox proportional hazards for TDA. RESULTS Mean intake for the 4-day sample was protein 51 g (60.5% of prescribed) and 1100 kcal (64.1% of prescribed); for the 12-day sample, mean intake was protein 57 g (66.7% of prescribed) and 1200 kcal (70.7% of prescribed). Achieving ≥ 80% of prescribed protein intake was associated with reduced mortality (4-day sample: odds ratio [OR], 0.68; 95% confidence interval [CI], 0.50-0.91; 12-day sample: OR, 0.60; 95% CI, 0.39-0.93), but ≥ 80% of prescribed energy intake was not. TDA was shorter with ≥ 80% prescribed protein (hazard ratio [HR], 1.25; 95% CI, 1.04-1.49) in the 12-day sample but longer with ≥ 80% prescribed energy in the 4-day sample (HR, 0.82; 95% CI, 0.69-0.96). CONCLUSION Achieving at least 80% of prescribed protein intake may be important to survival and shorter TDA in ICU patients. Efforts to achieve prescribed protein intake should be maximized.