Jean-Charles Preiser

Effects of Fluid Resuscitation With Colloids vs Crystalloids on Mortality in Critically Ill Patients Presenting With Hypovolemic Shock The CRISTAL Randomized Trial

IMPORTANCE Evidence supporting the choice of intravenous colloid vs crystalloid solutions for management of hypovolemic shock remains unclear. OBJECTIVE To test whether use of colloids compared with crystalloids for fluid resuscitation alters mortality in patients admitted to the intensive care unit (ICU) with hypovolemic shock. DESIGN, SETTING, AND PARTICIPANTS A multicenter, randomized clinical trial stratified by case mix (sepsis, trauma, or hypovolemic shock without sepsis or trauma). Therapy in the Colloids Versus Crystalloids for the Resuscitation of the Critically Ill (CRISTAL) trial was open label but outcome assessment was blinded to treatment assignment. Recruitment began in February 2003 and ended in August 2012 of 2857 sequential ICU patients treated at 57 ICUs in France, Belgium, North Africa, and Canada; follow-up ended in November 2012. INTERVENTIONS Colloids (n = 1414; gelatins, dextrans, hydroxyethyl starches, or 4% or 20% of albumin) or crystalloids (n = 1443; isotonic or hypertonic saline or Ringer lactate solution) for all fluid interventions other than fluid maintenance throughout the ICU stay. MAIN OUTCOMES AND MEASURES The primary outcome was death within 28 days. Secondary outcomes included 90-day mortality; and days alive and not receiving renal replacement therapy, mechanical ventilation, or vasopressor therapy. RESULTS Within 28 days, there were 359 deaths (25.4%) in colloids group vs 390 deaths (27.0%) in crystalloids group (relative risk [RR], 0.96 [95% CI, 0.88 to 1.04]; P = .26). Within 90 days, there were 434 deaths (30.7%) in colloids group vs 493 deaths (34.2%) in crystalloids group (RR, 0.92 [95% CI, 0.86 to 0.99]; P = .03). Renal replacement therapy was used in 156 (11.0%) in colloids group vs 181 (12.5%) in crystalloids group (RR, 0.93 [95% CI, 0.83 to 1.03]; P = .19). There were more days alive without mechanical ventilation in the colloids group vs the crystalloids group by 7 days (mean: 2.1 vs 1.8 days, respectively; mean difference, 0.30 [95% CI, 0.09 to 0.48] days; P = .01) and by 28 days (mean: 14.6 vs 13.5 days; mean difference, 1.10 [95% CI, 0.14 to 2.06] days; P = .01) and alive without vasopressor therapy by 7 days (mean: 5.0 vs 4.7 days; mean difference, 0.30 [95% CI, -0.03 to 0.50] days; P = .04) and by 28 days (mean: 16.2 vs 15.2 days; mean difference, 1.04 [95% CI, -0.04 to 2.10] days; P = .03). CONCLUSIONS AND RELEVANCE Among ICU patients with hypovolemia, the use of colloids vs crystalloids did not result in a significant difference in 28-day mortality. Although 90-day mortality was lower among patients receiving colloids, this finding should be considered exploratory and requires further study before reaching conclusions about efficacy. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00318942.

Toward Understanding Tight Glycemic Control in the ICU: A Systematic Review and Metaanalysis

BACKGROUND Following publication of the Leuven Intensive Insulin Therapy Trial in 2001, tight glycemic control became the standard of care in ICUs around the world. Recent studies suggest that this approach may be flawed. The goal of this systematic review was to determine the benefits and risks of tight glycemic control in ICU patients and to explain the differences in outcomes among reported trials. METHODS Prospective, randomized controlled clinical trials (RCTs) that studied the impact of tight glycemic control (blood glucose 80-110 mg/dL) on mortality in ICU patients were identified through a search of MEDLINE, EMBASE, and the Cochrane Database of Systematic Reviews, and a citation review of relevant primary and review articles. Data were abstracted on study design, study size, and patient characteristics, as well as on the mean (or median) and SD of the ICU blood glucose level, mean daily dose of insulin administered, average daily caloric intake, percentage of calories given intravenously (parenteral nutrition), incidence of hypoglycemia, need for dialysis, and 28-day/hospital mortality. Metaanalytic techniques were used to analyze the data; subgroup analysis and metaregression were used to explain differences in the treatment effect. RESULTS We identified seven RCT studies that included 11,425 patients. Overall, tight glycemic control did not reduce the 28-day mortality (odds ratio [OR] 0.95; 95% CI, 0.87-1.05), the incidence of blood stream infections (OR 1.04; 95% CI, 0.93-1.17), or the requirement for renal replacement therapy (OR 1.01; 95% CI, 0.89-1.13). The incidence of hypoglycemia was significantly higher in patients randomized to tight glycemic control (OR 7.7; 95% CI, 6.0-9.9; P < .001). Metaregression demonstrated a significant relationship between the treatment effect (28-day mortality) and the proportion of calories provided parenterally (P = .005). This suggests that the difference in outcome between the two Leuven Intensive Insulin Therapy Trials and the subsequent trials could be related to the use of parenteral nutrition. When the two Leuven Intensive Insulin Therapy Trials were excluded from the metaanalysis, mortality was lower in the control patients (OR 0.90; 95% CI, 0.81-0.99; P = .04; I(2) = 0%). CONCLUSIONS There is no evidence to support the use of intensive insulin therapy in general medical-surgical ICU patients who are fed according to current guidelines. Tight glycemic control is associated with a high incidence of hypoglycemia and an increased risk of death in patients not receiving parenteral nutrition.

Glucose variability and mortality in patients with sepsis

Objective:Treatment and prevention of hyperglycemia has been advocated for subjects with sepsis. Glucose variability, rather than the glucose level, has also been shown to be an important factor associated with in-hospital mortality, in general, critically ill patients. Our objective was to determine the association between glucose variability and hospital mortality in septic patients and the expression of glucose variability that best reflects this risk. Design:Retrospective, single-center cohort study. Setting:Academic, tertiary care hospital. Patients:Adult subjects hospitalized for >1 day, with a diagnosis of sepsis were included. Interventions:None. Measurements:Glucose variability was calculated for all subjects as the average and standard deviation of glucose, the mean amplitude of glycemic excursions, and the glycemic lability index. Hospital mortality was the primary outcome variable. Logistic regression was used to determine the odds of hospital death in relation to measures of glucose variability after adjustment for important covariates. Main results:Of the methods used to measure glucose variability, the glycemic lability index had the best discrimination for mortality (area under the curve = 0.67, p < 0.001). After adjustment for confounders, including the number of organ failures and the occurrence of hypoglycemia, there was a significant interaction between glycemic lability index and average glucose level, and the odds of hospital mortality. Higher glycemic lability index was not independently associated with mortality among subjects with average glucose levels above the median for the cohort. However, subjects with increased glycemic lability index, but lower average glucose values had almost five-fold increased odds of hospital mortality (odds ratio = 4.73, 95% confidence interval = 2.6-8.7) compared with those with lower glycemic lability index. Conclusions:Glucose variability is independently associated with hospital mortality in septic patients. Strategies to reduce glucose variability should be studied to determine whether they improve the outcomes of septic patients.

Original ResearchCritical Care MedicineToward Understanding Tight Glycemic Control in the ICU: A Systematic Review and Metaanalysis

BACKGROUND Following publication of the Leuven Intensive Insulin Therapy Trial in 2001, tight glycemic control became the standard of care in ICUs around the world. Recent studies suggest that this approach may be flawed. The goal of this systematic review was to determine the benefits and risks of tight glycemic control in ICU patients and to explain the differences in outcomes among reported trials. METHODS Prospective, randomized controlled clinical trials (RCTs) that studied the impact of tight glycemic control (blood glucose 80-110 mg/dL) on mortality in ICU patients were identified through a search of MEDLINE, EMBASE, and the Cochrane Database of Systematic Reviews, and a citation review of relevant primary and review articles. Data were abstracted on study design, study size, and patient characteristics, as well as on the mean (or median) and SD of the ICU blood glucose level, mean daily dose of insulin administered, average daily caloric intake, percentage of calories given intravenously (parenteral nutrition), incidence of hypoglycemia, need for dialysis, and 28-day/hospital mortality. Metaanalytic techniques were used to analyze the data; subgroup analysis and metaregression were used to explain differences in the treatment effect. RESULTS We identified seven RCT studies that included 11,425 patients. Overall, tight glycemic control did not reduce the 28-day mortality (odds ratio [OR] 0.95; 95% CI, 0.87-1.05), the incidence of blood stream infections (OR 1.04; 95% CI, 0.93-1.17), or the requirement for renal replacement therapy (OR 1.01; 95% CI, 0.89-1.13). The incidence of hypoglycemia was significantly higher in patients randomized to tight glycemic control (OR 7.7; 95% CI, 6.0-9.9; P < .001). Metaregression demonstrated a significant relationship between the treatment effect (28-day mortality) and the proportion of calories provided parenterally (P = .005). This suggests that the difference in outcome between the two Leuven Intensive Insulin Therapy Trials and the subsequent trials could be related to the use of parenteral nutrition. When the two Leuven Intensive Insulin Therapy Trials were excluded from the metaanalysis, mortality was lower in the control patients (OR 0.90; 95% CI, 0.81-0.99; P = .04; I(2) = 0%). CONCLUSIONS There is no evidence to support the use of intensive insulin therapy in general medical-surgical ICU patients who are fed according to current guidelines. Tight glycemic control is associated with a high incidence of hypoglycemia and an increased risk of death in patients not receiving parenteral nutrition.

Methylene blue administration in septic shock: A clinical trial

OBJECTIVE: A release of nitric oxide has been incriminated in the cardiovascular alterations of septic shock. Since guanylate cyclase is the target enzyme in the endothelium-dependent relaxation mediated by nitric oxide, we studied the acute effects of methylene blue, a potent inhibitor of guanylate cyclase in patients with septic shock. DESIGN: Prospective clinical trial. SETTING: Medical-surgical intensive care unit in a university hospital. PATIENTS: Fourteen patients with severe septic shock requiring adrenergic therapy. INTERVENTIONS: Short-term intravenous infusion of methylene blue. MEASUREMENTS AND MAIN RESULTS: Hemodynamic measurements were obtained at baseline, and 30, 60, and 90 mins after the infusion of 2 mg/kg of methylene blue. Methylene blue administration was followed by a progressive increase in mean arterial pressure (from 61.1 +/- 7.6 to 71.7 +/- 12.0 mm Hg at 60 mins, p < .01). Pulmonary arterial pressure, cardiac filling pressures, cardiac output oxygen delivery, and oxygen consumption were not significantly affected. Left ventricular stroke work increased from 42.5 +/- 17.9 to 48.9 +/- 14.5 g.m after 60 mins (p < .05). Arterial lactate concentration decreased from 3.4 +/- 1.4 to 2.7 +/- 1.3 mmol/L (p < .05). Since these effects were transient, a second dose of methylene blue was administered 90 mins later to six patients and was followed by a similar response. No adverse effect was observed. CONCLUSIONS: In septic shock patients, the administration of methylene blue results in a transient and reproducible increase in arterial pressure, associated with an improvement in cardiac function, but does not increase cellular oxygen availability. The significant reduction in blood lactate concentration is probably related to the reductor effect of methylene blue, rather than to an improvement in tissue oxygenation.

Enteral nutrition in intensive care patients: a practical approach

Severe protein-calorie malnutrition is a major problem in many intensive care (ICU) patients due to the increased catabolic state often associated with acute severe illness and the frequent presence of prior chronic wasting conditions. Nutritional support is thus an important part of the management of these patients. Over the years, enteral nutrition (EN) has gained considerable popularity, due to its favorable effects on the digestive tract and its lower cost and rate of complications compared to parenteral nutrition. However, clinicians caring for ICU patients are often faced with contradictory data and difficult decisions when having to determine the optimal timing and modalities of EN administration, estimation of patient requirements, and choice of formulas. The purpose of this paper is to provide practical guidelines on these various aspects of enteral nutritional support, based on presently available evidence.

ESPEN guidelines on nutrition in cancer patients

Cancers are among the leading causes of morbidity and mortality worldwide, and the number of new cases is expected to rise significantly over the next decades. At the same time, all types of cancer treatment, such as surgery, radiation therapy, and pharmacological therapies are improving in sophistication, precision and in the power to target specific characteristics of individual cancers. Thus, while many cancers may still not be cured they may be converted to chronic diseases. All of these treatments, however, are impeded or precluded by the frequent development of malnutrition and metabolic derangements in cancer patients, induced by the tumor or by its treatment. These evidence-based guidelines were developed to translate current best evidence and expert opinion into recommendations for multi-disciplinary teams responsible for identification, prevention, and treatment of reversible elements of malnutrition in adult cancer patients. The guidelines were commissioned and financially supported by ESPEN and by the European Partnership for Action Against Cancer (EPAAC), an EU level initiative. Members of the guideline group were selected by ESPEN to include a range of professions and fields of expertise. We searched for meta-analyses, systematic reviews and comparative studies based on clinical questions according to the PICO format. The evidence was evaluated and merged to develop clinical recommendations using the GRADE method. Due to the deficits in the available evidence, relevant still open questions were listed and should be addressed by future studies. Malnutrition and a loss of muscle mass are frequent in cancer patients and have a negative effect on clinical outcome. They may be driven by inadequate food intake, decreased physical activity and catabolic metabolic derangements. To screen for, prevent, assess in detail, monitor and treat malnutrition standard operating procedures, responsibilities and a quality control process should be established at each institution involved in treating cancer patients. All cancer patients should be screened regularly for the risk or the presence of malnutrition. In all patients - with the exception of end of life care - energy and substrate requirements should be met by offering in a step-wise manner nutritional interventions from counseling to parenteral nutrition. However, benefits and risks of nutritional interventions have to be balanced with special consideration in patients with advanced disease. Nutritional care should always be accompanied by exercise training. To counter malnutrition in patients with advanced cancer there are few pharmacological agents and pharmaconutrients with only limited effects. Cancer survivors should engage in regular physical activity and adopt a prudent diet.

Diabetic status and the relation of the three domains of glycemic control to mortality in critically ill patients: an international multicenter cohort study.

IntroductionHyperglycemia, hypoglycemia, and increased glycemic variability have each beenindependently associated with increased risk of mortality in critically illpatients. The role of diabetic status on modulating the relation of these threedomains of glycemic control with mortality remains uncertain. The purpose of thisinvestigation was to determine how diabetic status affects the relation ofhyperglycemia, hypoglycemia, and increased glycemic variability with the risk ofmortality in critically ill patients.MethodsThis is a retrospective analysis of prospectively collected data involving 44,964patients admitted to 23 intensive care units (ICUs) from nine countries, betweenFebruary 2001 and May 2012. We analyzed mean blood glucose concentration (BG),coefficient of variation (CV), and minimal BG and created multivariable models toanalyze their independent association with mortality. Patients were stratifiedaccording to the diagnosis of diabetes.ResultsAmong patients without diabetes, mean BG bands between 80 and 140 mg/dl wereindependently associated with decreased risk of mortality, and mean BG bands> 140 mg/dl, with increased risk of mortality. Among patients withdiabetes, mean BG from 80 to 110 mg/dl was associated with increased risk ofmortality and mean BG from 110 to 180 mg/dl with decreased risk of mortality. Aneffect of center was noted on the relation between mean BG and mortality.Hypoglycemia, defined as minimum BG <70 mg/dl, was independently associatedwith increased risk of mortality among patients with and without diabetes andincreased glycemic variability, defined as CV > 20%, was independentlyassociated with increased risk of mortality only among patients without diabetes.Derangements of more than one domain of glycemic control had a cumulativeassociation with mortality, especially for patients without diabetes.ConclusionsAlthough hyperglycemia, hypoglycemia, and increased glycemic variability is eachindependently associated with mortality in critically ill patients, diabeticstatus modulates these relations in clinically important ways. Our findingssuggest that patients with diabetes may benefit from higher glucose target rangesthan will those without diabetes. Additionally, hypoglycemia is independentlyassociated with increased risk of mortality regardless of the patients diabeticstatus, and increased glycemic variability is independently associated withincreased risk of mortality among patients without diabetes.See related commentary by Krinsley,http://ccforum.com/content/17/2/131See related commentary by Finfer and Billot,http://ccforum.com/content/17/2/134

High-Protein Enteral Nutrition Enriched With Immune-Modulating Nutrients vs Standard High-Protein Enteral Nutrition and Nosocomial Infections in the ICU: A Randomized Clinical Trial

IMPORTANCE Enteral administration of immune-modulating nutrients (eg, glutamine, omega-3 fatty acids, selenium, and antioxidants) has been suggested to reduce infections and improve recovery from critical illness. However, controversy exists on the use of immune-modulating enteral nutrition, reflected by lack of consensus in guidelines. OBJECTIVE To determine whether high-protein enteral nutrition enriched with immune-modulating nutrients (IMHP) reduces the incidence of infections compared with standard high-protein enteral nutrition (HP) in mechanically ventilated critically ill patients. DESIGN, SETTING, AND PARTICIPANTS The MetaPlus study, a randomized, double-blind, multicenter trial, was conducted from February 2010 through April 2012 including a 6-month follow-up period in 14 intensive care units (ICUs) in the Netherlands, Germany, France, and Belgium. A total of 301 adult patients who were expected to be ventilated for more than 72 hours and to require enteral nutrition for more than 72 hours were randomized to the IMHP (n = 152) or HP (n = 149) group and included in an intention-to-treat analysis, performed for the total population as well as predefined medical, surgical, and trauma subpopulations. INTERVENTIONS High-protein enteral nutrition enriched with immune-modulating nutrients vs standard high-protein enteral nutrition, initiated within 48 hours of ICU admission and continued during the ICU stay for a maximum of 28 days. MAIN OUTCOMES AND MEASURES The primary outcome measure was incidence of new infections according to the Centers for Disease Control and Prevention (CDC) definitions. Secondary end points included mortality, Sequential Organ Failure Assessment (SOFA) scores, mechanical ventilation duration, ICU and hospital lengths of stay, and subtypes of infections according CDC definitions. RESULTS There were no statistically significant differences in incidence of new infections between the groups: 53% (95% CI, 44%-61%) in the IMHP group vs 52% (95% CI, 44%-61%) in the HP group (P = .96). No statistically significant differences were observed in other end points, except for a higher 6-month mortality rate in the medical subgroup: 54% (95% CI, 40%-67%) in the IMHP group vs 35% (95% CI, 22%-49%) in the HP group (P = .04), with a hazard ratio of 1.57 (95% CI, 1.03-2.39; P = .04) for 6-month mortality adjusted for age and Acute Physiology and Chronic Health Evaluation II score comparing the groups. CONCLUSIONS AND RELEVANCE Among adult patients breathing with the aid of mechanical ventilation in the ICU, IMHP compared with HP did not improve infectious complications or other clinical end points and may be harmful as suggested by increased adjusted mortality at 6 months. These findings do not support the use of IMHP nutrients in these patients. TRIAL REGISTRATION trialregister.nl Identifier: NTR2181.

Enteral nutrition in intensive care patients: a practical approach. Working Group on Nutrition and Metabolism, ESICM. European Society of Intensive Care Medicine.

Severe protein-calorie malnutrition is a major problem in many intensive care (ICU) patients due to the increased catabolic state often associated with acute severe illness and the frequent presence of prior chronic wasting conditions. Nutritional support is thus an important part of the management of these patients. Over the years, enteral nutrition (EN) has gained considerable popularity, due to its favorable effects on the digestive tract and its lower cost and rate of complications compared to parenteral nutrition. However, clinicians caring for ICU patients are often faced with contradictory data and difficult decisions when having to determine the optimal timing and modalities of EN administration, estimation of patient requirements, and choice of formulas. The purpose of this paper is to provide practical guidelines on these various aspects of enteral nutritional support, based on presently available evidence.