René Chioléro

Fluconazole prophylaxis prevents intra-abdominal candidiasis in high-risk surgical patients

OBJECTIVE To evaluate the efficacy and safety of intravenous fluconazole for the prevention of intra-abdominal Candida infections in high-risk surgical patients. DESIGN Randomized, prospective, double-blind, placebo-controlled study. SETTING Two university-affiliated hospitals in Switzerland. PATIENTS Forty-nine surgical patients with recurrent gastrointestinal perforations or anastomotic leakages. INTERVENTIONS Prophylaxis with intravenous fluconazole (400 mg per day) or placebo continued until resolution of the underlying surgical condition. MEASUREMENTS AND MAIN RESULTS Patients were evaluated daily, and specimens for culture were obtained three times per week during prophylaxis. The primary study end points were the frequency of and the time to intra-abdominal Candida infections. Secondary end points were the frequency of candidiasis (intra-abdominal and extra-abdominal) and the emergence or persistence of Candida colonization. Among patients who were not colonized at study entry, Candida was isolated from surveillance cultures during prophylaxis in 15% of the patients in the fluconazole group and in 62% of the patients in the placebo group (relative risk, 0.25; 95% confidence interval, 0.07 to 0.96; p = .04). Candida peritonitis occurred in one of 23 patients (4%) who received fluconazole and in seven of 20 patients (35%) who received placebo (relative risk, 0.12; 95% confidence interval, 0.02 to 0.93; p = .02). In addition, one catheter-related Candida albicans sepsis occurred in a fluconazole-treated patient. Thus, overall, candidiasis developed in two fluconazole patients and seven placebo patients (relative risk, 0.25; 95% confidence interval, 0.06 to 1.06; p = .06). C. albicans accounted for 87% of the Candida species isolated before or during prophylaxis, and all C. albicans strains were susceptible to fluconazole. Fluconazole was well tolerated, and adverse events occurred at similar frequencies in both treatment groups. CONCLUSIONS Fluconazole prophylaxis prevents colonization and invasive intra-abdominal Candida infections in high-risk surgical patients.

PREVENTION OF GRAM-NEGATIVE SHOCK AND DEATH IN SURGICAL PATIENTS BY ANTIBODY TO ENDOTOXIN CORE GLYCOLIPID

The prophylactic effect of antibody to endotoxin core glycolipid was studied in surgical patients at high risk of gram-negative infection. At randomisation (on admission to intensive care unit), every 5 days thereafter, and at onset of septic shock, patients received plasma taken from donors before (control) or after immunisation with Escherichia coli J5, a mutant with only core determinants in its endotoxin. Gram-negative shock occurred in 15 of 136 controls and 6 of 126 J5 antibody recipients and related deaths in 9 of 136 and 2 of 126, respectively. J5 antibody was most effective in abdominal surgery patients, in whom shock occurred in 13 of 83 controls and 2 of 71 antibody recipients. Although antibody prophylaxis did not lower the infection rate, it prevented the serious consequences of gram-negative infections and thus improved the overall prognosis.

Nosocomial Pneumonia in Mechanically Ventilated Patients Receiving Antacid, Ranitidine, or Sucralfate as Prophylaxis for Stress Ulcer A Randomized Controlled Trial

Intensive care patients are at risk for bleeding from stress ulcers of the upper gastrointestinal tract [1]. Despite the decline of this complication over the last two decades [2], certain patients, such as those requiring prolonged mechanical ventilation, remain at high risk and may benefit from stress ulcer prophylaxis [1, 3-5]. Over the last few years, studies have shown that agents that raise the gastric pH may promote proliferation of bacteria in the stomach, particularly gram-negative bacilli that may originate in the duodenum [6-10]. Passive esophageal reflux and microaspiration of the gastric content along the endotracheal tube may lead to the colonization of the trachea and then to pneumonia [6, 7, 10-18]. Thus, concerns have arisen that the risk for nosocomial pneumonia may outweigh the benefit of stress ulcer prophylaxis when agents raising the gastric pH are used. Sucralfate is a complex salt of sucrose sulfate and aluminum hydroxide that appears to be as effective as antacids or histamine-2 (H2) antagonists for stress ulcer prophylaxis [2, 19, 20] but by mechanisms of action that do not result in clinically relevant gastric pH modification. Several studies have documented that gastric colonization is less frequent and of a lesser magnitude in ventilated patients treated with this agent compared with antacids or H2-antagonists [8, 21-23]. However, whether this would result in a decreased risk for nosocomial pneumonia is controversial [18, 24] because a reduction was found in some [21-23, 25] but not all [17, 21-23, 25-29] comparative studies. Methodologic differences among these studies might explain these conflicting findings [18]. For example, small numbers of patients for analysis [17, 26], low risk for pneumonia in the study patients [27, 28], periods of observation that were too brief [28], insufficient dosages of the agents that raise pH [27, 29], and wide use of enteral feeding [17] might account for the absence of reduction in the incidence of pneumonia noted in some studies. On the other hand, differences in the distribution of the base-line characteristics among the patients [22, 23], the grouping of patients receiving antacids and H2-antagonists, and analysis of subgroups of patients not randomly assigned to a treatment group [21, 25] may have biased the studies in which sucralfate was associated with lower rates of pneumonia. In addition, in two of these latter studies, the reduction of pneumonia developing in patients treated with sucralfate compared with other treatment did not reach the usual 0.05 level of significance [21, 23]. Furthermore, previous studies did not distinguish between pneumonia occurring early or late after intubation. This may be important because it is likely that early-onset pneumonia may be related to the introduction of bacteria in the trachea at the time of intubation [30-32], a process that is not expected to be influenced by the type of anti-stress ulcer prophylaxis. Therefore, we compared three anti-stress ulcer prophylaxis regimens (antacid, ranitidine, and sucralfate) in a large group of ventilated patients for the occurrence of bacterial colonization, early and late-onset nosocomial pneumonia, and overt gastrointestinal bleeding. Methods Patients The Centre Hospitalier Universitaire Vaudois is a 1100-bed hospital serving both as a municipal facility and a tertiary referral center. During a 2-year period (January 1989 to January 1991), all patients admitted to the adult medical and surgical intensive care units who were receiving mechanical ventilation and had a nasogastric tube in place were eligible for the study. Exclusion criteria were as follows: active upper gastrointestinal bleeding; treatment with antacids, H2-blockers, or sucralfate during the preceding 48 hours; creatinine levels greater than 200 mol/L; esogastric surgery; cardiac surgery; or organ transplantations. Patients likely to be extubated within 24 hours were also excluded. At intubation, patients were stratified into five categories according to the following underlying conditions: trauma (surgical intensive care unit), intervention after surgery (surgical intensive care unit), cardiac disease (medical intensive care unit), pulmonary disease (medical intensive care unit), and other medical conditions [medical intensive care unit]. Randomization was done using a random permutable table to generate a random treatment list. Treatment regimens were included in opaque, sealed envelopes. The patients were assigned to one of the following anti-stress ulcer prophylactic regimens: 1) antacid, a hospital-made suspension containing 5.4% aluminum hydroxide and 1.5% magnesium hydroxide with a buffer capacity of 1.2 mEq/mL, administered every 2 hoursthe standard dose of 20 mL was doubled if the gastric pH (tested with pH-indicator strips [Merck and Co., Darmstadt, Germany] before each administration) was less than 4.0; 2) ranitidine (Zantac, Glaxo, Bern, Switzerland) administered as a continuous intravenous infusion of 150 mg/d [100 mg/d if the blood creatinine level was between 150 and 200 mol/L]; or 3) sucralfate (Ulcogant, Merck and Co., Zurich, Switzerland) administered every 4 hours as 1 gram of suspension diluted in 20 mL of sterile water. After antacid or sucralfate was administered, the nasogastric tube was flushed with 10 mL of sterile water and clamped for 30 minutes. Each prophylactic regimen was continued until extubation unless interrupted earlier for any of the following predetermined reasons: an increase of the blood creatinine level to more than 200 mol/L, removal of the nasogastric tube, moribund state, discharge from the intensive care units, or side effects likely to be related to the stress ulcer regimen. Data Collection and Definitions For all eligible patients, demographic characteristics, diagnosis, underlying diseases, physical signs, laboratory tests, and medications were recorded prospectively by one of the investigators. However, only patients eventually intubated for more than 24 hours were followed and included in the final analysis. Glasgow coma and Acute Physiology and Chronic Health Evaluation (APACHE II) scoring systems were used to assess the severity of the acute illness [33]. The adult respiratory distress syndrome was defined by the following criteria: acute bilateral diffuse pulmonary infiltrates and severe hypoxemia without evidence of cardiogenic edema [34]. Gastric aspirates were examined for the macroscopic presence of blood (coffee ground material or fresh blood). The severity of gastric hemorrhage was assessed by clinical criteria (physical signs, blood transfusion requirements, and outcome). Chest radiographs were obtained on a daily basis or more often if clinically indicated. They were interpreted by a pneumologist who had knowledge of all relevant data except for the patients stress ulcer prophylactic regimen, gastric pH, or colonization data. Criteria for the diagnosis of ventilator-associated pneumonia were predetermined and derived from those of Salata and colleagues [35]: presence of a new or progressive infiltrate on the chest radiograph consistent with pneumonia, without other obvious cause, and associated with conditions A or B or both, defined as follows. Condition A refers to any of the following findings: pleural fluid or blood culture positive for an organism also isolated in the tracheal aspirate, radiographic cavitation, or histopathologic evidence of pneumonia. Condition B includes at least two of the following: tracheal aspirates with more than 25 leukocytes per low-power field (x 100) on a Gram stain, new leukocytosis defined as a leukocyte count greater than 10 109/L with an increase of at least 25% over baseline, or body temperature greater than 38.5 C with an increase of at least 1 C above baseline. The latter two criteria were considered only when other causes for these findings were excluded. Pneumonia was considered to be caused by a pathogen when it was cultured in high counts as the sole or predominant microorganism in the tracheal aspirate culture. Using the criteria of Langer and colleagues [30], early-onset and late-onset pneumonia were diagnosed if they occurred during the first 4 days of or 4 days after the initiation of mechanical ventilation, respectively. Consequently, only patients observed for more than 4 days could be evaluated for the development of late-onset pneumonia. A second episode of pneumonia was diagnosed when it was clearly temporally distinct from the first episode and when it involved other areas of the lungs. Pneumonia was attributed to a given anti-stress ulcer prophylactic regimen if it developed during treatment or within 2 days after extubation or treatment interruption. Death was considered to be directly related to nosocomial pneumonia when it occurred during the episode and when no other major contributing cause was present. Bacteriologic Investigations and pH Measurements Gastric and tracheal aspirates and oropharyngeal swabs were obtained twice daily and cultured quantitatively (gastric juice) or semi-quantitatively in aerobic conditions. Aerobic bacteria were identified by standard microbiologic methods. Cultures for Chlamydia species, Legionella pneumophila, or Mycoplasma pneumoniae were not done. Blood or pleural fluid cultures were ordered by the primary care physician according to the clinical situation. Gastric pH was measured twice a day using a pH meter (except in 11 patients for whom values were derived only from pH-indicator strips [Merck and Co.]). A cut-off value of 4.0 for median pH was chosen for further analysis within the three treatment groups because it has been shown to be a critical value for the growth of gram-negative bacilli in the stomach [6, 7, 25]. Colonization was defined by the presence of one microorganism at a given site on at least two occasions. A patient was considered to have gastric colonization with high counts when quantitative culture of at least one speci

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.

Energy metabolism in sepsis and injury.

The development of malnutrition is often rapid in critically ill patients with sepsis and severe trauma. In such patients, a wide array of hormonal and nonhormonal mediators are released, inducing complex metabolic changes. Hypermetabolism, associated with protein and fat catabolism, negative nitrogen balance, hyperglycemia, and resistance to insulin, constitute the hallmark of this response. Critically ill patients demonstrate a marked alteration in the adaptation to prolonged starvation: resting metabolic rate and tissue catabolism stay elevated, while ketogenesis remains suppressed. The response to nutrition support is impaired. Substrate use is modified in septic and traumatized patients. Glucose administration during severe aggression does not suppress the enhanced hepatic glucose production and the lipolysis. This phenomenon, related to tissue insulin resistance, ensures a high flow of glucose to the predominantly glucose-consuming cells, such as the wound, the inflammatory, and immune cells, all insulin-independent cells. In addition, the elevated protein catabolism is difficult to abolish, even during aggressive nutrition support. Thus, in patients with prolonged aggression, these alterations produce a progressive loss of body cell mass and foster the development of malnutrition and it dire complications. In this review, the relevant physiologic data and the nutritional implications related to energy metabolism in septic and injured patients are discussed, while potential therapeutic strategies are proposed.

Early predictors of outcome in comatose survivors of ventricular fibrillation and non-ventricular fibrillation cardiac arrest treated with hypothermia: a prospective study.

Objectives:Current indications for therapeutic hypothermia (TH) are restricted to comatose patients with cardiac arrest (CA) due to ventricular fibrillation (VF) and without circulatory shock. Additional studies are needed to evaluate the benefit of this treatment in more heterogeneous groups of patients, including those with non-VF rhythms and/or shock and to identify early predictors of outcome in this setting. Design:Prospective study, from December 2004 to October 2006. Setting:32-bed medico-surgical intensive care unit, university hospital. Patients:Comatose patients with out-of-hospital CA. Interventions:TH to 33 ± 1°C (external cooling, 24 hrs) was administered to patients resuscitated from CA due to VF and non-VF (including asystole or pulseless electrical activity), independently from the presence of shock. Measurements and Main Results:We hypothesized that simple clinical criteria available on hospital admission (initial arrest rhythm, duration of CA, and presence of shock) might help to identify patients who eventually survive and might most benefit from TH. For this purpose, outcome was related to these predefined variables. Seventy-four patients (VF 38, non-VF 36) were included; 46% had circulatory shock. Median duration of CA (time from collapse to return of spontaneous circulation [ROSC]) was 25 mins. Overall survival was 39.2%. However, only 3.1% of patients with time to ROSC >25 mins survived, as compared to 65.7% with time to ROSC ≤25 mins. Using a logistic regression analysis, time from collapse to ROSC, but not initial arrest rhythm or presence of shock, independently predicted survival at hospital discharge. Conclusions:Time from collapse to ROSC is strongly associated with outcome following VF and non-VF cardiac arrest treated with therapeutic hypothermia and could therefore be helpful to identify patients who benefit most from active induced cooling.

Cefepime versus Imipenem-Cilastatin for Treatment of Nosocomial Pneumonia in Intensive Care Unit Patients: a Multicenter, Evaluator-Blind, Prospective, Randomized Study

ABSTRACT In a randomized, evaluator-blind, multicenter trial, we compared cefepime (2 g three times a day) with imipenem-cilastatin (500 mg four times a day) for the treatment of nosocomial pneumonia in 281 intensive care unit patients from 13 centers in six European countries. Of 209 patients eligible for per-protocol analysis of efficacy, favorable clinical responses were achieved in 76 of 108 (70%) patients treated with cefepime and 75 of 101 (74%) patients treated with imipenem-cilastatin. The 95% confidence interval (CI) for the difference between these response rates (−16 to 8%) failed to exclude the predefined lower limit for noninferiority of −15%. In addition, therapy of pneumonia caused by an organism producing an extended-spectrum β-lactamase (ESBL) failed in 4 of 13 patients in the cefepime group but in none of 10 patients in the imipenem group. However, the clinical efficacies of both treatments appeared to be similar in a secondary intent-to-treat analysis (95% CI for difference, −9 to 14%) and a multivariate analysis (95% CI for odds ratio, 0.47 to 1.75). Furthermore, the all-cause 30-day mortality rates were 28 of 108 (26%) patients in the cefepime group and 19 of 101 (19%) patients in the imipenem group (P = 0.25). Rates of documented or presumed microbiological eradication of the causative organism were similar with cefepime (61%) and imipenem-cilastatin (54%) (95% CI, −23 to 8%). Primary or secondary resistance of Pseudomonas aeruginosa was detected in 19% of the patients treated with cefepime and 44% of the patients treated with imipenem-cilastatin (P = 0.05). Adverse events were reported in 71 of 138 (51%) and 62 of 141 (44%) patients eligible for safety analysis in the cefepime and imipenem groups, respectively (P = 0.23). Although the primary end point for this study does not exclude the possibility that cefepime was inferior to imipenem, some secondary analyses showed that the two regimens had comparable clinical and microbiological efficacies. Cefepime appeared to be less active against organisms producing an ESBL, but primary and secondary resistance to imipenem was more common for P. aeruginosa. Selection of a single agent for therapy of nosocomial pneumonia should be guided by local resistance patterns.

Antioxidant supplementation in sepsis and systemic inflammatory response syndrome

Objective:Summarize the current knowledge about oxidative stress-related organ dysfunction in inflammatory and septic conditions, and its potential prevention and treatment by antioxidants in critically ill patients, focusing on naturally occurring antioxidants and clinical trials. Study Selection:PubMed, MEDLINE, and personal database search. Synthesis:Plasma concentrations of antioxidant micronutrients are depressed during critical illness and especially during sepsis. The causes of these low levels include losses with biological fluids, low intakes, dilution by resuscitation fluids, as well as systemic inflammatory response syndrome-mediated redistribution of micronutrients from plasma to tissues. Numerous clinical trials have been conducted, many of which have shown beneficial effects of supplementation. Interestingly, among the candidates, glutamine, glutathione, and selenium are linked with the potent glutathione peroxidase enzyme family at some stage of their synthesis and metabolism. Conclusions:Three antioxidant nutrients have demonstrated clinical benefits and reached level A evidence: a) selenium improves clinical outcome (infections, organ failure); b) glutamine reduces infectious complication in large-sized trials; and c) the association of eicosapentaenoic acid and micronutrients has significant anti-inflammatory effects. Other antioxidants are still on the clinical benchmark level, awaiting well-designed clinical trials.

Lactate and glucose metabolism in severe sepsis and cardiogenic shock

Objective:To evaluate the relative importance of increased lactate production as opposed to decreased utilization in hyperlactatemic patients, as well as their relation to glucose metabolism. Design:Prospective observational study. Setting:Surgical intensive care unit of a university hospital. Patients:Seven patients with severe sepsis or septic shock, seven patients with cardiogenic shock, and seven healthy volunteers. Interventions:13C-labeled sodium lactate was infused at 10 &mgr;mol/kg/min and then at 20 &mgr;mol/kg/min over 120 mins each. 2H-labeled glucose was infused throughout. Measurements and Main Results:Baseline arterial lactate was higher in septic (3.2 ± 2.6) and cardiogenic shock patients (2.8 ± 0.4) than in healthy volunteers (0.9 ± 0.20 mmol/L, p < .05). Lactate clearance, computed using pharmacokinetic calculations, was similar in septic, cardiogenic shock, and controls, respectively: 10.8 ± 5.4, 9.6 ± 2.1, and 12.0 ± 2.6 mL/kg/min. Endogenous lactate production was determined as the initial lactate concentration multiplied by lactate clearance. It was markedly enhanced in the patients (septic 26.2 ± 10.5; cardiogenic shock 26.6 ± 5.1) compared with controls (11.2 ± 2.7 &mgr;mol/kg/min, p < .01). 13C-lactate oxidation (septic 54 ± 25; cardiogenic shock 43 ± 16; controls 65 ± 15% of a lactate load of 10 &mgr;mol/kg/min) and transformation of 13C-lactate into 13C-glucose were not different (respectively, 15 ± 15, 9 ± 18, and 10 ± 7%). Endogenous glucose production was markedly increased in the patients (septic 14.8 ± 1.8; cardiogenic shock 15.0 ± 1.5) compared with controls (7.2 ± 1.1 &mgr;mol/kg/min, p < .01) and was not influenced by lactate infusion. Conclusions:In patients suffering from septic or cardiogenic shock, hyperlactatemia was mainly related to increased production, whereas lactate clearance was similar to healthy subjects. Increased lactate production was concomitant to hyperglycemia and increased glucose turnover, suggesting that the latter substantially influences lactate metabolism during critical illness.

Effects of isoenergetic glucose-based or lipid-based parenteral nutrition on glucose metabolism, de novo lipogenesis, and respiratory gas exchanges in critically ill patients.

OBJECTIVE To compare the effects of isocaloric, isonitrogenous carbohydrate nutrition vs. lipid-based total parenteral nutrition on respiratory gas exchange and intermediary metabolism in critically ill patients. DESIGN Prospective, clinical trial. SETTING Surgical intensive care unit in a major university hospital in Switzerland. PATIENTS Sixteen patients admitted to the surgical intensive care unit. INTERVENTIONS Patients were randomized to receive isocaloric isonitrogenous total parenteral nutrition (TPN) containing 75% (TPN-glucose) or 15% (TPN-lipid) glucose over a 5-day period. MEASUREMENTS AND MAIN RESULTS Indirect glucose metabolism was assessed from plasma carbon-13 (13C)-labeled glucose and 13C-labeled CO2 production during a tracer infusion of uniformly 13C-labeled glucose, and de novo lipogenesis was estimated from the incorporation of 13C into palmitate-very low density lipoproteins (VLDL) during a tracer infusion of 1-(13)C acetate. Compared with TPN-lipid, TPN-glucose increased plasma glucose more (by 26% vs. 7%, p < .05), increased insulin more (by 284% vs. 40%, p < .01), and increased total CO2 more (by 15% vs. 0%, p < .01). Both nutrient mixtures failed to inhibit endogenous glucose production and net protein oxidation, suggesting absence of suppression of gluconeogenesis. Fractional de novo lipogenesis was markedly increased by TPN-glucose to 17.4% vs. 3.3% with TPN lipids. CONCLUSIONS The rate of glucose administration commonly used during TPN of critically ill patients does not suppress endogenous glucose production or net protein loss, but markedly stimulates de novo lipogenesis and CO2 production. Increasing the proportion of fat may be beneficial, provided that lipid emulsion has no adverse effects.