Christian Brun-Buisson

Incidence of and Risk Factors for Ventilator-Associated Pneumonia in Critically Ill Patients

A recent international prevalence study involving more than 1000 intensive care units indicated that pneumonia is responsible for almost half of the infections in critically ill patients in Europe [1]. Ventilator-associated pneumonia accounts for approximately 90% of infections in patients requiring assisted ventilation [2, 3]. An independent contribution to mortality conferred by ventilator-associated pneumonia was recently suggested [4, 5]. Although debate persists about the mortality attributable to ventilator-associated pneumonia among other causes of death in critically ill patients [1, 4-7], there is little doubt that ventilator-associated pneumonia causes substantial morbidity by increasing the duration of mechanical ventilation and intensive care unit stay [4, 5]. It is therefore important to understand the factors that are predictive of ventilator-associated pneumonia, to identify patients at highest risk, and to target these patients for the most effective preventive strategies as determined by randomized trials [8, 9]. Risk factors for nosocomial pneumonia have been evaluated in hospitalized elderly persons [10], heterogeneous groups of hospitalized patients breathing spontaneously or requiring assisted ventilation [11], and similar mixed populations admitted to the intensive care unit [2, 12-15]. Investigations in ventilated critically ill patients only are needed to identify independent predictors of ventilator-associated pneumonia. Most studies of risk factors for ventilator-associated pneumonia have been conducted at single institutions, and different predictors have been examined. In cohort studies using multivariable analyses [16-21], only reintubation [17, 19, 21] and antibiotic use [18, 20] were identified as risk factors in more than one report. However, a direct relation between antibiotics and pneumonia was found in one study [18], whereas an inverse relation was found in another [20]. We examined factors associated with ventilator-associated pneumonia. We explored baseline and time-dependent characteristics, including measures of illness severity, factors relating to mechanical ventilation, variables in the gastropulmonary route of infection, and drug exposure. Methods Patients We used a multicenter national database of 1200 patients who received mechanical ventilation for 48 hours or more and were enrolled from October 1992 to May 1996 in a double-blind, concealed, randomized trial of sucralfate compared with ranitidine to determine rates of ventilator-associated pneumonia and gastrointestinal bleeding [22]. Patients were followed until death, discharge, or clinical suspicion of ventilator-associated pneumonia as determined by the attending intensivist. Bronchoalveolar lavage or protected specimen brush was indicated for patients with a clinical suspicion of ventilator-associated pneumonia. A diagnosis of ventilator-associated pneumonia was considered only in patients who were receiving mechanical ventilation or who stopped receiving ventilation for less than 48 hours. In the absence of a reference standard for diagnosing pneumonia in critically ill patients [23, 24], each patients clinical, laboratory, and radiographic data were independently reviewed by one of four pairs of adjudicators blinded to treatment group. The readers in each adjudication pair decided on the presence or absence of ventilator-associated pneumonia, resolving any disagreement through discussion. Consensus was achieved on all cases. The adjudicated outcome was used for the primary analysis [177 cases]. However, each case of pneumonia was classified according to four additional definitions: 1) the bedside clinicians diagnosis [233 cases]; 2) the modified Centers for Disease Control and Prevention criteria [25], which require a new radiographic infiltrate persistent for 48 hours or more plus a body temperature greater than 38.5 C or less than 35.0 C, a leukocyte count of more than 10 cells 109/L or less than 3 cells 109/L, purulent sputum or change in character of sputum, or isolation of pathogenic bacteria from an endotracheal aspirate [211 cases]; 3) a Clinical Pulmonary Infection score of 7 or more [26] [194 cases]; or 4) a positive culture from bronchoalveolar lavage (>104 colony-forming units/mL) or protected specimen brush (<103 colony-forming units/mL) (97 cases). Statistical Analysis We expressed continuous variables as the mean (SD) or as the median and interquartile range if their distribution was skewed. We used the Student t-test to compare continuous variables and the chi-square test to compare proportions. All statistical tests were two-tailed. We performed a forward stepwise Cox proportional-hazards regression analysis to evaluate potential risk factors for ventilator-associated pneumonia. The Cox model assesses the effect of each risk factor on the hazard rate of ventilator-associated pneumonia over time, adjusted for other factors in the model and allowing for censoring because of death or discharge. The hazard function in the Cox model can be used to estimate the event rate per day over the duration of stay in the intensive care unit. Independent variables recorded at baseline included age; sex; primary diagnosis; medical or surgical status; hospital admission in the fall or winter compared with spring or summer; location before admission to the intensive care unit; treatment center; Acute Physiology and Chronic Health Evaluation II score; Acute Physiology score; Multiple Organ Dysfunction score [27]; Glasgow Coma Scale score; and chronic comorbid conditions, such as alcoholism, a smoking history of 10 or more pack-years, asthma, bronchiectasis, pulmonary fibrosis, cancer, and HIV infection; organ transplantation; and recent corticosteroid therapy or chemotherapy. Additional independent variables evaluated daily throughout the intensive care unit stay were classified as illness severity measures (daily Multiple Organ Dysfunction score and change in Multiple Organ Dysfunction score from baseline), ventilation variables (mechanical ventilation, change or reinsertion of endotracheal tube, discontinuation and reinstitution of mechanical ventilation, and tracheostomy), nutritional variables (nasoenteral nutrition, gastrostomy feeding, jejunostomy feeding, enteral nutrition through any route, central parenteral nutrition, peripheral parenteral nutrition, and insulin requirement of more than 15 U/d), witnessed aspiration, and drug exposure (stress-ulcer prophylaxis with ranitidine or sucralfate, paralytic agents, and antibiotics). The Multiple Organ Dysfunction Score combines measures of physiologic dysfunction in six domains: the cardiovascular system (heart rate x right atrial pressure/mean arterial pressure), pulmonary system (Pao 2:Fio 2 ratio), the renal system (serum creatinine concentration), the hepatic system (serum bilirubin level), the hematologic system (platelet count), and the central nervous system (Glasgow Coma Scale score) [25]. These continuous variables are constructed in 5 categories so that 0 represents normal function and 4 reflects marked physiologic derangement and is associated with a mortality rate greater than 50%. Composite scores provide a quantitative measure of global physiologic dysfunction at a discrete point in the intensive care unit stay. For individual domains, either the raw data or their score provides a measure of dysfunction in the system of interest. Variables that were associated with ventilator-associated pneumonia in the univariable analysis and had a P value less than 0.10 were entered into a multivariable regression analysis. Factors were considered significant if the P value was less than 0.05 in the multivariable analysis. We calculated risk ratios and 95% CIs for all significant predictors of ventilator-associated pneumonia in the multivariable analysis using all five definitions. We tested for all pairwise interactions between significant risk factors in the multivariable model. We also tested for interactions between predictors in the multivariable model and factors that were significant in the univariable analysis. Finally, we investigated the possibility that the effects of risk factors may vary over the duration of stay in the intensive care unit; this was done by using a nonproportional Cox model testing the interaction of each variable in the final model with time. For example, we hypothesized that the influence of antibiotics on ventilator-associated pneumonia may vary over time. Time was considered both a continuous variable and a discretized variable by using 3-day and 5-day intervals. We did not consider antibiotics administered 24 hours before the diagnosis of ventilator-associated pneumonia, so that drugs prescribed in response to early ventilator-associated pneumonia would be excluded [28]. Role of Study Sponsor Our funding sources had no role in the acquisition, analysis, or interpretation of data or in the submission of this report. Results Of the 1200 patients enrolled in this study, 186 were excluded (85 were discharged, 71 died, and 30 had pneumonia in the first 48 hours), leaving 1014 patients ventilated for 48 hours or more who were free of pneumonia at admission to the intensive care unit. Of these patients, 177 (17.5%) developed ventilator-associated pneumonia 9.0 5.9 days after admission (median, 7 days [interquartile range, 5 to 10 days]). The characteristics of patients with and without ventilator-associated pneumonia are shown in Table 1. The total duration of mechanical ventilation among patients with ventilator-associated pneumonia was 19.3 16.0 days (median, 15 days [interquartile range, 9 to 23 days]) compared with 10.2 10.5 days (median, 7 days [interquartile range, 4 to 11 days]) in other patients (P < 0.001). Among the 177 patients with ventilator-associated pneumonia, 131 (74.0%) had bronchoscopic testing with bronchoalveolar lavage or protected specimen brush. Patients in the following admitting diagnostic categories

Use of procalcitonin to reduce patients' exposure to antibiotics in intensive care units (PRORATA trial): a multicentre randomised controlled trial

BACKGROUND Reduced duration of antibiotic treatment might contain the emergence of multidrug-resistant bacteria in intensive care units. We aimed to establish the effectiveness of an algorithm based on the biomarker procalcitonin to reduce antibiotic exposure in this setting. METHODS In this multicentre, prospective, parallel-group, open-label trial, we used an independent, computer-generated randomisation sequence to randomly assign patients in a 1:1 ratio to procalcitonin (n=311 patients) or control (n=319) groups; investigators were masked to assignment before, but not after, randomisation. For the procalcitonin group, antibiotics were started or stopped based on predefined cut-off ranges of procalcitonin concentrations; the control group received antibiotics according to present guidelines. Drug selection and the final decision to start or stop antibiotics were at the discretion of the physician. Patients were expected to stay in the intensive care unit for more than 3 days, had suspected bacterial infections, and were aged 18 years or older. Primary endpoints were mortality at days 28 and 60 (non-inferiority analysis), and number of days without antibiotics by day 28 (superiority analysis). Analyses were by intention to treat. The margin of non-inferiority was 10%. This trial is registered with ClinicalTrials.gov, number NCT00472667. FINDINGS Nine patients were excluded from the study; 307 patients in the procalcitonin group and 314 in the control group were included in analyses. Mortality of patients in the procalcitonin group seemed to be non-inferior to those in the control group at day 28 (21.2% [65/307] vs 20.4% [64/314]; absolute difference 0.8%, 90% CI -4.6 to 6.2) and day 60 (30.0% [92/307] vs 26.1% [82/314]; 3.8%, -2.1 to 9.7). Patients in the procalcitonin group had significantly more days without antibiotics than did those in the control group (14.3 days [SD 9.1] vs 11.6 days [SD 8.2]; absolute difference 2.7 days, 95% CI 1.4 to 4.1, p<0.0001). INTERPRETATION A procalcitonin-guided strategy to treat suspected bacterial infections in non-surgical patients in intensive care units could reduce antibiotic exposure and selective pressure with no apparent adverse outcomes. FUNDING Assistance Publique-Hôpitaux de Paris, France, and Brahms, Germany.

Reversal of acute exacerbations of chronic obstructive lung disease by inspiratory assistance with a face mask.

BACKGROUND Patients with acute exacerbations of chronic obstructive pulmonary disease may require endotracheal intubation with mechanical ventilation. We designed, and here report on the efficacy of, a noninvasive ventilatory-assistance apparatus to provide inspiratory-pressure support by means of a face mask. METHODS We assessed the short-term (45-minute) physiologic effects of the apparatus in 11 patients with acute exacerbations of chronic obstructive pulmonary disease and evaluated its therapeutic efficacy in 13 such patients (including 3 of the 11 in the physiologic study) who were treated for several days and compared with 13 matched historical-control patients. RESULTS In the physiologic study, after 45 minutes of inspiratory positive airway pressure by face mask, the mean (+/- SD) arterial pH rose from 7.31 +/- 0.08 to 7.38 +/- 0.07 (P less than 0.01), the partial pressure of carbon dioxide fell from 68 +/- 17 mm Hg to 55 +/- 15 mm Hg (P less than 0.01), and the partial pressure of oxygen rose from 52 +/- 12 mm Hg to 69 +/- 16 mm Hg (P less than 0.05). These changes were accompanied by marked reductions in respiratory rate (from 31 +/- 7 to 21 +/- 9 breaths per minute, P less than 0.01). Only 1 of the 13 patients treated with inspiratory positive airway pressure needed tracheal intubation and mechanical ventilation, as compared with 11 of the 13 historical controls (P less than 0.001). Two patients in each group died. As compared with the controls, the treated patients had a more transient need for ventilatory assistance (3 +/- 1 vs. 12 +/- 11 days, P less than 0.01) and a shorter stay in the intensive care unit (7 +/- 3 vs. 19 +/- 13 days, P less than 0.01). CONCLUSIONS Inspiratory positive airway pressure delivered by a face mask can obviate the need for conventional mechanical ventilation in patients with acute exacerbations of chronic obstructive pulmonary disease.

Evidence-based clinical practice guideline for the prevention of ventilator-associated pneumonia.

Critically ill patients in the intensive care unit (ICU) are at high risk for infections associated with increased morbidity, mortality, and health care costs (1-3). The overall infection rate in critically ill patients approaches 40% and may be as high as 50% or 60% in patients who remain in the ICU for more than 5 days (4, 5). Respiratory tract infections account for 30% to 60% of all such infections. The incidence of pneumonia acquired in the ICU ranges from 10% to 65% (6-11). Among patients at high risk for ventilator-associated pneumonia (VAP) are those who have chronic obstructive pulmonary disease, burns, neurosurgical conditions, the acute respiratory distress syndrome, and witnessed aspiration; those who are reintubated; and those who receive paralytic agents or enteral nutrition (12, 13). The attributable morbidity and mortality of VAP are clinically important. In a prospective, matched cohort study, patients with VAP remained in the ICU 4.3 days (95% CI, 1.5 to 7.0 days) longer than patients who did not have VAP and had a trend toward an increased risk for death (absolute risk increase, 5.8% [CI, 2.4% to 14.0%]) (14). Six other studies using a matching strategy found a prolonged length of ICU stay associated with VAP (range, 5 to 13 days) and attributable mortality ranging from an absolute risk increase of 0% to 50% (15-20). Therefore, strategies to decrease the incidence of VAP could decrease morbidity, mortality, and health care costs and improve patient safety. A survey of the use of VAP prevention strategies identified differences across countries (21). For example, changing the ventilator circuit for each new patient was reported more frequently by French ICU directors than those in Canada (21). This survey also showed that some effective strategies were used infrequently, suggesting inadequate translation of randomized trial results into practice. One potential catalyst for knowledge translation is an evidence-based clinical practice guideline. Therefore, a Joint Planning Group of the Canadian Critical Care Society and Canadian Critical Care Trials Group commissioned the development of an evidence-based clinical practice guideline for the prevention of VAP. In this paper, we describe the methods used to create the guideline and the recommendations generated. Methods The Joint Planning Group selected an 11-member VAP Prevention Guideline Panel made up of 9 intensivists from university-affiliated and community hospitals, an ICU nurse, and an ICU respiratory therapist. Panel members were experts in critical care medicine (n= 9), VAP (n= 4), evidence-based medicine (n= 4), and guideline development (n= 3). The context was mechanically ventilated adult patients cared for in the ICU. The target audience was ICU clinicians in university-affiliated and community hospitals. To identify potentially relevant evidence, we searched 3 bibliographic databases (MEDLINE, EMBASE, and the Cochrane Database of Systematic Reviews) to 1 April 2003 for randomized trials that evaluated interventions influencing VAP (Appendix). We had no language restrictions. We also reviewed personal files and practice guidelines on this subject previously published by the Centers for Disease Control and Prevention (22) and the American Thoracic Society (23). We included randomized trials and systematic reviews of randomized trials that 1) studied adult critically ill patients; 2) had VAP as an outcome; and 3) evaluated any of the following interventions: physical strategies (route of endotracheal intubation, systematic search for maxillary sinusitis, frequency of ventilator circuit changes, type of airway humidification, frequency of humidifier changes, endotracheal suctioning system, subglottic secretion drainage, chest physiotherapy, and tracheostomy timing), positional strategies (kinetic beds, semi-recumbent positioning, and prone positioning), and pharmacologic strategies (stress ulcer prophylaxis and prophylactic antibiotics, including selective decontamination of the digestive tract). Since study authors used various definitions of VAP, we used the definitions they provided. The most common definition was a new or persistent radiographic infiltrate plus fever, leukocytosis, change in the volume or color of sputum, or isolation of a pathogen. If available, histologic evidence of pneumonia was also used. A priori, we decided to review only systematic reviews of randomized clinical trials for antibiotic prophylaxis and only randomized clinical trials for all other topics. We excluded crossover and beforeafter studies. We also excluded randomized trials of ventilator weaning, including noninvasive mechanical ventilation, and nutritional interventions evaluating VAP because guidelines addressing these topics have recently been published (24, 25). In duplicate and independently, 3 pairs of panel members critically appraised each trial (26, 27) and systematic review (28). Each member of a pair compared his or her independent appraisal of a given trial or systematic review with that of the other member of the pair. For each randomized trial, we abstracted sample, allocation, intervention, co-interventions, exclusions after randomization, blinding of outcome assessment, definition of VAP, crude VAP events, relative risk for VAP, and other outcomes. For each intervention, we summarized the risk differences and calculated a pooled risk difference. For each systematic review, we abstracted number of trials, population, intervention, selection criteria, search strategy, validity assessment, method of pooling results, homogeneity assessment, VAP definition, pooled event rates, and other outcomes. Before the panel meeting, each pair of appraisers achieved consensus on the validity and results of the trials they reviewed. One month before the panel meeting, panel members received the evidence tables for review prepared by the 3 pairs of appraisers. A priori, panel members agreed to read all circulated documents and evidence tables in advance, to use levels of evidence to generate a status statement for each item, and to abide by the group process and consensus methods. The Canadian Critical Care Society appointed a chair to ensure that the panel achieved its objectives through group process (29). At the panel meeting, each member recorded any potential conflicts of interest (30). The pair of panel members responsible for critical appraisal of each intervention provided a structured written and oral presentation of the evidence. After the panel discussion, the initial evidence summary was revised if necessary. The panel members assigned levels of evidence, semi-quantitative scores to summarize the evidence and describe the intervention, and a status statement. We classified trials as level 1 if they had all of the following: concealed randomization, blinded outcome adjudication, an intention-to-treat analysis, and an explicit definition of VAP. Trials were classified as level 2 if any one of these characteristics was unfulfilled and as level 3 if allocation was not strictly randomized. We used a semi-quantitative score (0, 1, 2, or 3) to evaluate each intervention with respect to the validity of the randomized trials; the effect size of each intervention; the confidence intervals around the estimate of effect; the homogeneity of the trial results; and the safety, feasibility, and economic consequences of the intervention. The language of the status statement for each item was keyed to the levels of evidence and the semi-quantitative scores. We used the term recommended if there were no reservations about endorsing an intervention and the term considered if the evidence supported an intervention but there were minor uncertainties about the benefits, harms, or costs. No recommendation was made if evidence regarding an intervention was inadequate or if there were major uncertainties about the benefits, harms, or costs. After the panel meeting, the chair compiled the summaries and status statements and sent them to all panel members to check accuracy and clarity. In addition, the pairs of evidence appraisers wrote background documents for the interventions they appraised, including the rationale for each intervention, appraisal of randomized trials and systematic reviews, and harms and costs of the interventions. The chair and the writing committee organized the background documents, the evidence summaries, a table of the semi-quantitative scores, and the status statement for each item. We formatted the document with a structured abstract (31), a summary of the evidentiary basis for each recommendation, and a status statement for each item. We also created a quick reference guide. The draft guideline document was submitted for structured external review by the executives of the Canadian Critical Care Society and the Canadian Critical Care Trials Group and the respective executives of the Canadian Association of Critical Care Nurses, Canadian Society of Respiratory Therapists, Canadian Infectious Disease Society, and Canadian Thoracic Society. External reviewers were asked to critique whether the guideline was logical, clear, and practical and to critique the guideline development process. The panel revised the document on the basis of this feedback. The final guideline was returned to the external reviewers for further comments and official endorsement by their respective organizations. The final guideline was then piloted in 2 institutions. To record the agreement of each panel member with the final status statement for each item, we sent the final document to all panel members. Independently, blinded to each others ratings, panel members used a Likert scale from 1 to 9 that was anchored by disagree completely at the low end and agree completely at the high end. The panel will formally review and update this guideline every 2 years (32). The funding source played no role in study selection for this guideline and had no role in its development

The epidemiology of the systemic inflammatory response.

Objective: To examine the incidence, risk factors, aetiologies and outcome of the various forms of the septic syndromes (the systemic inflammatory response syndrome [SIRS] sepsis, severe sepsis, and septic shock) and their relationships with infection.¶Design: Review of published cohort studies examining the epidemiology of the septic syndromes, with emphasis on intensive care unit (ICU) patients.¶Results: The prevalence of SIRS is very high, affecting one-third of all in-hospital patients, and > 50 % of all ICU patients; in surgical ICU patients, SIRS occurs in > 80 % patients. Trauma patients are at particularly high risk of SIRS, and most these patients do not have infection documented. The prevalence of infection and bacteraemia increases with the number of SIRS criteria met, and with increasing severity of the septic syndromes. About one-third of patients with SIRS have or evolve to sepsis. Sepsis may occur in approximately 25 % of ICU patients, and bacteraemic sepsis in 10 %. In such patients, sepsis evolves to severe sepsis in > 50 % of cases, whereas evolution to severe sepsis in non-ICU patients is about 25 %. Severe sepsis and septic shock occur in 2 %–3 % of ward patients and 10 %–15 % or more ICU patients, depending on the case-mix; 25 % of patients with severe sepsis have shock. There is a graded severity from SIRS to sepsis, severe sepsis and septic shock, with an associated 28-d mortality of approximately 10 %, 20 %, 20 %–40 %, and 40 %–60 %, respectively. Mortality rates are similar within each stage, whether infection is documented or not, and microbiological characteristics of infection do not substantially influence outcome, although the source of infection does. While about three of four deaths occur during the first months after sepsis, the septic syndromes significantly impact on long-term outcome, with an estimated 50 % reduction of life expectancy over the following five years. The major determinants of outcome, both short-term and long-term, of patients with sepsis are the severity of underlying diseases and comorbidities, the presence of shock and organ failures at onset of sepsis or evolving thereafter. It has been estimated that two-thirds of the overall mortality can be attributed to sepsis.¶Conclusions: The prevalence of sepsis in ICU patients is very high, and most patients have clinically or microbiologically documented infection, except in specific subset of patients. The prognosis of septic syndromes is related to underlying diseases and the severity of the inflammatory response and its sequelae, reflected in shock and organ dysfunction/failures.

TRANSFERABLE ENZYMATIC RESISTANCE TO THIRD-GENERATION CEPHALOSPORINS DURING NOSOCOMIAL OUTBREAK OF MULTIRESISTANT KLEBSIELLA PNEUMONIAE

Klebsiella pneumoniae strains that were resistant to third-generation cephalosporins and amikacin were recovered from 62 of 395 patients (15.7%) during 1986. 25 isolates (40%) caused urinary tract infections. The outbreak involved three intensive care units (54 isolates), and spread from one unit to another and then to four wards (8 isolates). K pneumoniae of various serotypes and strains of different Enterobacteriaceae demonstrating the same antibiotic resistance pattern were isolated, which suggests dissemination of an R-factor. The isolates had low-level resistance to third-generation cephalosporins (mode minimum inhibitory concentration of cefotaxime, 2 mg/l) but remained sensitive to cephamycins. Cefotaxime was effective in cases of uncomplicated urinary tract infection, but failed in major infections at other sites. 1-5 mg/l of the beta-lactamase inhibitors clavulanic acid or sulbactam restored normal activity to cefotaxime against the multiresistant strains. Resistance to third-generation cephalosporins was mediated by a new broad-spectrum enzyme of isoelectric point 6.3. Resistance to beta-lactams and aminoglycosides was transferable to Escherichia coli. The emergence of transferable enzymatic resistance to newer beta-lactams in K pneumoniae strains indicates a major risk of spread of such resistance to otherwise sensitive strains.

Diagnosis of catheter-related bacteraemia: a prospective comparison of the time to positivity of hub-blood versus peripheral-blood cultures

BACKGROUND A method of diagnosing catheter-related infection (CRI) without removing the catheter would be useful. An earlier positivity of central compared with peripheral venous-blood cultures may be associated with catheter-related bacteraemia. We evaluated prospectively the differential time to positivity (DTP) of paired blood cultures drawn simultaneously via the catheter hub and from a peripheral venous site. METHODS Over a 14-month period in an intensive-care unit of a cancer referral centre, simultaneous hub-blood and peripheral-blood cultures (a mean of two per patient) were obtained from patients with a suspected CRI. According to clinical criteria and quantitative culture of the catheter tip, cases were classified as CRI or sepsis of other origin. At least one pair of hub-blood and peripheral-blood cultures was obtained within 48 h before catheter removal, and we recorded the DTP between hub-blood and peripheral-blood cultures with an automatic device for detection of blood culture positivity. FINDINGS We analysed 93 catheters removed because of suspicion of CRI. In 28 episodes, the same micro-organisms were found in both hub-blood and peripheral-blood cultures. A diagnosis of definite bacteraemic CRI was made in 16 of the 17 patients in whom a positive hub-blood culture was detected at least 2 hours earlier than peripheral-blood culture. About half (9/17) of these episodes occurred in long-term (>30 days) devices. CRI was excluded in ten of the 11 patients with a DTP lower than 2 h. The DTP of paired blood cultures was significantly greater in patients with CRI than in others (p<10(-4)). A cut-off DTP value of 120 min had 91% specificity and 94% sensitivity for the diagnosis of CRI. Three of 17 episodes with only hub-blood culture positive were associated with CRI. INTERPRETATION This prospective study suggests that measurement of the differential time to positivity between hub-blood and peripheral-blood cultures is a simple and reliable tool for in-situ diagnosis of catheter-related sepsis in cancer patients. Further studies are needed to confirm these data for short-term catheters.

Randomised comparison of thalidomide versus placebo in toxic epidermal necrolysis

BACKGROUND Toxic epidermal necrolysis (TEN) is associated with a 30% death rate. Tumour necrosis factor alpha (TNF-alpha) has been implicated in the pathogenesis of TEN. Thalidomide is a potent inhibitor of TNF-alpha action. We did a double-blind, randomised, placebo-controlled study of thalidomide in TEN. METHODS The patients received a 5-day course of thalidomide 400 mg daily or placebo. The main endpoint was the progression of skin detachment after day 7. Secondary endpoints were the severity of the disease, evaluated with the simplified acute physiology score (SAPS), and the mortality. TNF-alpha and interleukin 6 were measured. FINDINGS The study was stopped because there was excess mortality in the thalidomide group--ten of 12 patients died compared with three of ten in the placebo group (Fishers exact test with Katzs approximation, relative risk=2.78, p=0.03). After adjustment for SAPS, mortality remained significantly higher in the thalidomide group than in the placebo group (exact logistic regression mid-p=0.007; 95% CI for odds ratio 2.7 to infinity). Plasma TNF-alpha concentration was higher in the thalidomide group than the placebo group on day 2, though the difference was not significant (Wilcoxon rank-sum test p=0.07). INTERPRETATION Even though few patients were included, our data suggest that thalidomide is detrimental in TEN, possibly because of a paradoxical enhancement of TNF-alpha production.

Maximizing oxygen delivery in critically ill patients: a methodologic appraisal of the evidence.

OBJECTIVE To systemically review the effect of interventions designed to achieve supraphysiologic values of cardiac index, oxygen delivery (DO2), and oxygen consumption (VO2) in critically ill patients. DATA SOURCES Computerized bibliographic search of published research, citation review of relevant articles, and contact with primary investigators. STUDY SELECTION We included all randomized clinical trials of adult intensive care unit (ICU) patients that evaluated interventions (fluids, inotropes, and vasoactive drugs) designed to achieve supraphysiologic values of cardiac index, DO2, and/or VO2. Independent review of 64 articles identified seven relevant studies of 1,016 patients. DATA EXTRACTION We abstracted data on the population, interventions, outcomes, and methodologic quality of the studies by duplicate independent review. Agreement was high (weighed kappa 0.73); differences were resolved by consensus. DATA SYNTHESIS Targeting therapy to achieve supraphysiologic end points in critically ill patients is associated with a nonstatistically significant trend toward decreased mortality rates (relative risk 0.86, 95% confidence intervals 0.62 to 1.20). For the two studies in which supraphysiologic goals were initiated preoperatively, the relative risk was 0.20 (95% confidence intervals 0.07 to 0.55). This value differed significantly from the combined estimate of the remaining studies, in which the intervention was started after ICU admission (relative risk 0.98, 95% confidence intervals 0.79 to 1.22; p<.01). However, there are several methodologic problems with the primary studies. In no trials were caregivers or outcome assessors blinded to treatment allocation. Only three of seven trials analyzed patients according to the group to which they were allocated. None adequately controlled for cointerventions, and there was considerable crossover between groups (patients in the control group achieved the goals of the intervention group and vice versa). CONCLUSIONS Interventions designed to achieve supraphysiologic goals of cardiac index, DO2, and VO2 did not significantly reduce mortality rates in all critically ill patients. However, there may be a benefit in those patients in which the therapy is initiated preoperatively. Methodologic limitations weaken the inferences that can be drawn from these studies and preclude any evidence-based clinical recommendations.

Intestinal Decontamination for Control of Nosocomial Multiresistant Gram-Negative Bacilli: Study of an Outbreak in an Intensive Care Unit

STUDY OBJECTIVE To study the efficacy of intestinal decontamination by oral nonabsorbable antibiotic agents to control a nosocomial outbreak of intestinal colonization and infection with multiresistant Enterobacteriaceae, and to examine its effects on endemic nosocomial infection rates. DESIGN A 10-week prospective incidence study (group 1), and then an 8-week randomized, open trial of intestinal decontamination (groups 2 and 3). SETTING A medical intensive care unit of a tertiary care university hospital. PATIENTS Consecutive patients with unit stay of over 2 days and a severity score at admission of more than 2; 124 patients were included in group 1, 50 in group 2 (control), and 36 in group 3 (intestinal decontamination). INTERVENTIONS Neomycin, polymyxin E, and nalidixic acid were given to group 3 patients throughout their stay in the unit. MEASUREMENTS AND MAIN RESULTS Intestinal colonization with multiresistant strains occurred in 19.6% of patients in group 1, at a mean of 16 days after admission, and preceded detection in clinical samples by a mean of 11 days. During the decontamination trial, intestinal colonization rates decreased to 10% (group 2), and 3% (group 3) (P = 0.12 and P less than 0.01, compared with group 1, respectively). Corresponding infection rates were 9% (group 1), 3% (group 2), and 0 (group 3). No new cases were detected in the following 4 months. The intestinal colonization rate with gram-positive cocci was higher in group 3 than group 2 (P less than 0.001). The overall rate of nosocomial infections was at 28% (group 1), 33% (group 2), and 32% (group 3). CONCLUSIONS Intestinal decontamination can help to control an outbreak of intestinal colonization and infection with multiresistant gram-negative bacilli in the intensive care unit, but should not be recommended for routine prevention of endemic nosocomial infections.