Carole Schwebel

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.

Chlorhexidine-impregnated sponges and less frequent dressing changes for prevention of catheter-related infections in critically ill adults: a randomized controlled trial.

CONTEXT Use of a chlorhexidine gluconate-impregnated sponge (CHGIS) in intravascular catheter dressings may reduce catheter-related infections (CRIs). Changing catheter dressings every 3 days may be more frequent than necessary. OBJECTIVE To assess superiority of CHGIS dressings regarding the rate of major CRIs (clinical sepsis with or without bloodstream infection) and noninferiority (less than 3% colonization-rate increase) of 7-day vs 3-day dressing changes. DESIGN, SETTING, AND PATIENTS Assessor-blind, 2 x 2 factorial, randomized controlled trial conducted from December 2006 through June 2008 and recruiting patients from 7 intensive care units in 3 university and 2 general hospitals in France. Patients were adults (>18 years) expected to require an arterial catheter, central-vein catheter, or both inserted for 48 hours or longer. INTERVENTIONS Use of CHGIS vs standard dressings (controls). Scheduled change of unsoiled adherent dressings every 3 vs every 7 days, with immediate change of any soiled or leaking dressings. MAIN OUTCOME MEASURES Major CRIs for comparison of CHGIS vs control dressings; colonization rate for comparison of 3- vs 7-day dressing changes. RESULTS Of 2095 eligible patients, 1636 (3778 catheters, 28,931 catheter-days) could be evaluated. The median duration of catheter insertion was 6 (interquartile range [IQR], 4-10) days. There was no interaction between the interventions. Use of CHGIS dressings decreased the rates of major CRIs (10/1953 [0.5%], 0.6 per 1000 catheter-days vs 19/1825 [1.1%], 1.4 per 1000 catheter-days; hazard ratio [HR], 0.39 [95% confidence interval {CI}, 0.17-0.93]; P = .03) and catheter-related bloodstream infections (6/1953 catheters, 0.40 per 1000 catheter-days vs 17/1825 catheters, 1.3 per 1000 catheter-days; HR, 0.24 [95% CI, 0.09-0.65]). Use of CHGIS dressings was not associated with greater resistance of bacteria in skin samples at catheter removal. Severe CHGIS-associated contact dermatitis occurred in 8 patients (5.3 per 1000 catheters). Use of CHGIS dressings prevented 1 major CRI per 117 catheters. Catheter colonization rates were 142 of 1657 catheters (7.8%) in the 3-day group (10.4 per 1000 catheter-days) and 168 of 1828 catheters (8.6%) in the 7-day group (11.0 per 1000 catheter-days), a mean absolute difference of 0.8% (95% CI, -1.78% to 2.15%) (HR, 0.99; 95% CI, 0.77-1.28), indicating noninferiority of 7-day changes. The median number of dressing changes per catheter was 4 (IQR, 3-6) in the 3-day group and 3 (IQR, 2-5) in the 7-day group (P < .001). CONCLUSIONS Use of CHGIS dressings with intravascular catheters in the intensive care unit reduced risk of infection even when background infection rates were low. Reducing the frequency of changing unsoiled adherent dressings from every 3 days to every 7 days modestly reduces the total number of dressing changes and appears safe. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00417235.

Is Methicillin Resistance Associated with a Worse Prognosis in Staphylococcus aureus Ventilator-Associated Pneumonia?

BACKGROUND Excess mortality associated with methicillin resistance in patients with Staphylococcus aureus ventilator-associated pneumonia (SA-VAP), taking into account such confounders as treatment adequacy and time in the intensive care unit (ICU), have not been adequately estimated. METHODS One hundred thirty-four episodes of SA-VAP entered in the Outcomerea database were studied. Patients from whom methicillin-resistant S. aureus (MRSA) was recovered were compared with those from whom methicillin-susceptible S. aureus (MSSA) was recovered, stratified for duration of stay in the ICU at the time of VAP diagnosis and adjusted for confounders (severity at admission, characteristics at VAP diagnosis, and treatment adequacy). RESULTS Treatment was adequate within 24 h after VAP diagnosis for 86% of the 65 MSSA-infected patients and 77% of the 69 MRSA-infected patients (P = .2). Polymicrobial VAP was more commonly associated with MSSA than with MRSA (49.2% vs. 25.7%; P = .01). MRSA infection was associated with a lower prevalence of coma at hospital admission and a higher rate of use of central venous lines and fluoroquinolones during the first 48 h of the ICU stay. The rates of shock, recurrence, and superinfection were similar in both groups. The crude hospital mortality rate was higher for MRSA-infected patients than for MSSA-infected patients (59.4% vs. 40%; P = .024). This difference disappeared after controlling for time in the ICU before VAP and parameters imbalanced at ICU admission (odds ratio [OR], 1.23; 95% confidence interval [CI], 0.49-3.12; P = .7) and remained unchanged after further adjustments for initial treatment adequacy and polymicrobial VAP (OR, 0.98; 95% CI, 0.36-2.66). CONCLUSIONS Differences in patient characteristics, initial ICU treatment, and time in the ICU confounded estimates of excess death due to MRSA VAP. After careful adjustment, methicillin resistance did not affect ICU or hospital mortality rates.

Randomized Controlled Trial of Chlorhexidine Dressing and Highly Adhesive Dressing for Preventing Catheter-related Infections in Critically Ill Adults

RATIONALE Most vascular catheter-related infections (CRIs) occur extraluminally in patients in the intensive care unit (ICU). Chlorhexidine-impregnated and strongly adherent dressings may decrease catheter colonization and CRI rates. OBJECTIVES To determine if chlorhexidine-impregnated and strongly adherent dressings decrease catheter colonization and CRI rates. METHODS In a 2:1:1 assessor-masked randomized trial in patients with vascular catheters inserted for an expected duration of 48 hours or more in 12 French ICUs, we compared chlorhexidine dressings, highly adhesive dressings, and standard dressings from May 2010 to July 2011. Coprimary endpoints were major CRI with or without catheter-related bloodstream infection (CR-BSI) with chlorhexidine versus nonchlorhexidine dressings and catheter colonization rate with highly adhesive nonchlorhexidine versus standard nonchlorhexidine dressings. Catheter-colonization, CR-BSIs, and skin reactions were secondary endpoints. MEASUREMENTS AND MAIN RESULTS A total of 1,879 patients (4,163 catheters and 34,339 catheter-days) were evaluated. With chlorhexidine dressings, the major-CRI rate was 67% lower (0.7 per 1,000 vs. 2.1 per 1,000 catheter-days; hazard ratio [HR], 0.328; 95% confidence interval [CI], 0.174-0.619; P = 0.0006) and the CR-BSI rate 60% lower (0.5 per 1,000 vs. 1.3 per 1,000 catheter-days; HR, 0.402; 95% CI, 0.186-0.868; P = 0.02) than with nonchlorhexidine dressings; decreases were noted in catheter colonization and skin colonization rates at catheter removal. The contact dermatitis rate was 1.1% with and 0.29% without chlorhexidine. Highly adhesive dressings decreased the detachment rate to 64.3% versus 71.9% (P < 0.0001) and the number of dressings per catheter to two (one to four) versus three (one to five) (P < 0.0001) but increased skin colonization (P < 0.0001) and catheter colonization (HR, 1.650; 95% CI, 1.21-2.26; P = 0.0016) without influencing CRI or CR-BSI rates. CONCLUSIONS A large randomized trial demonstrated that chlorhexidine-gel-impregnated dressings decreased the CRI rate in patients in the ICU with intravascular catheters. Highly adhesive dressings decreased dressing detachment but increased skin and catheter colonization. Clinical trial registered with www.clinicaltrials.gov (NCT 01189682).

Selected medical errors in the intensive care unit: results of the IATROREF study: parts I and II.

RATIONALE Although intensive care units (ICUs) were created for patients with life-threatening illnesses, the ICU environment generates a high risk of iatrogenic events. Identifying medical errors (MEs) that serve as indicators for iatrogenic risk is crucial for purposes of reporting and prevention. OBJECTIVES We describe the selection of indicator MEs, the incidence of such MEs, and their relationship with mortality. METHODS We selected indicator MEs using Delphi techniques. An observational prospective multicenter cohort study of these MEs was conducted from March 27 to April 3, 2006, in 70 ICUs; 16 (23%) centers were audited. Harm from MEs was collected using specific scales. MEASUREMENTS AND MAIN RESULTS Fourteen types of MEs were selected as indicators; 1,192 MEs were reported for 1,369 patients, and 367 (26.8%) patients experienced at least 1 ME (2.1/1,000 patient-days). The most common MEs were insulin administration errors (185.9/1,000 d of insulin treatment). Of the 1,192 medical errors, 183 (15.4%) in 128 (9.3%) patients were adverse events that were followed by one or more clinical consequences (n = 163) or that required one or more procedures or treatments (n = 58). By multivariable analysis, having two or more adverse events was an independent risk factor for ICU mortality (odds ratio, 3.09; 95% confidence interval, 1.30-7.36; P = 0.039). CONCLUSIONS The impact of medical errors on mortality indicates an urgent need to develop prevention programs. We have planned a study to assess a program based on our results.

Induced Hypothermia in Severe Bacterial Meningitis: A Randomized Clinical Trial

IMPORTANCE Despite advances in care, mortality and morbidity remain high in adults with acute bacterial meningitis, particularly when due to Streptococcus pneumoniae. Induced hypothermia is beneficial in other conditions with global cerebral hypoxia. OBJECTIVE To test the hypothesis that induced hypothermia improves outcome in patients with severe bacterial meningitis. DESIGN, SETTING, AND PATIENTS An open-label, multicenter, randomized clinical trial in 49 intensive care units in France, February 2009-November 2011. In total, 130 patients were assessed for eligibility and 98 comatose adults (Glasgow Coma Scale [GCS] score of ≤8 for <12 hours) with community-acquired bacterial meningitis were randomized. INTERVENTIONS Hypothermia group received a loading dose of 4°C cold saline and were cooled to 32°C to 34°C for 48 hours. The rewarming phase was passive. Controls received standard care. MAIN OUTCOMES AND MEASURES Primary outcome measure was the Glasgow Outcome Scale score at 3 months (a score of 5 [favorable outcome] vs a score of 1-4 [unfavorable outcome]). All patients received appropriate antimicrobial therapy and vital support. Analyses were performed on an intention-to-treat basis. The data and safety monitoring board (DSMB) reviewed severe adverse events and mortality rate every 50 enrolled patients. RESULTS After inclusion of 98 comatose patients, the trial was stopped early at the request of the DSMB because of concerns over excess mortality in the hypothermia group (25 of 49 patients [51%]) vs the control group (15 of 49 patients [31%]; relative risk [RR], 1.99; 95% CI, 1.05-3.77; P = .04). Pneumococcal meningitis was diagnosed in 77% of patients. Mean (SD) temperatures achieved 24 hours after randomization were 33.3°C (0.9°C) and 37.0°C (0.9°C) in the hypothermia and control group, respectively. At 3 months, 86% in the hypothermia group compared with 74% of controls had an unfavorable outcome (RR, 2.17; 95% CI, 0.78-6.01; P = .13). After adjustment for age, score on GCS at inclusion, and the presence of septic shock at inclusion, mortality remained higher, although not significantly, in the hypothermia group (hazard ratio, 1.76; 95% CI, 0.89-3.45; P = .10). Subgroup analysis on patients with pneumococcal meningitis showed similar results. Post hoc analysis showed a low probability to reach statistically significant difference in favor of hypothermia at the end of the 3 planned sequential analyses (probability to conclude in favor of futility, 0.977). CONCLUSIONS AND RELEVANCE Moderate hypothermia did not improve outcome in patients with severe bacterial meningitis and may even be harmful. Careful evaluation of safety issues in future trials on hypothermia are needed and may have important implications in patients presenting with septic shock or stroke. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00774631.

Infectious risk associated with arterial catheters compared with central venous catheters

Background:Scheduled replacement of central venous catheters and, by extension, arterial catheters, is not recommended because the daily risk of catheter-related infection is considered constant over time after the first catheter days. Arterial catheters are considered at lower risk for catheter-related infection than central venous catheters in the absence of conclusive evidence. Objectives:To compare the daily risk and risk factors for colonization and catheter-related infection between arterial catheters and central venous catheters. Methods:We used data from a trial of seven intensive care units evaluating different dressing change intervals and a chlorhexidine-impregnated sponge. We determined the daily hazard rate and identified risk factors for colonization using a marginal Cox model for clustered data. Results:We included 3532 catheters and 27,541 catheter-days. Colonization rates did not differ between arterial catheters and central venous catheters (7.9% [11.4/1000 catheter-days] and 9.6% [11.1/1000 catheter-days], respectively). Arterial catheter and central venous catheter catheter-related infection rates were 0.68% (1.0/1000 catheter-days) and 0.94% (1.09/1000 catheter-days), respectively. The daily hazard rate for colonization increased steadily over time for arterial catheters (p = .008) but remained stable for central venous catheters. Independent risk factors for arterial catheter colonization were respiratory failure and femoral insertion. Independent risk factors for central venous catheter colonization were trauma or absence of septic shock at intensive care unit admission, femoral or jugular insertion, and absence of antibiotic treatment at central venous catheter insertion. Conclusions:The risks of colonization and catheter-related infection did not differ between arterial catheters and central venous catheters, indicating that arterial catheter use should receive the same precautions as central venous catheter use. The daily risk was constant over time for central venous catheter after the fifth catheter day but increased significantly over time after the seventh day for arterial catheters. Randomized studies are needed to investigate the impact of scheduled arterial catheter replacement. (Crit Care Med 2010; 38:1030–1035)

Does catheter-associated urinary tract infection increase mortality in critically ill patients?

OBJECTIVE To produce an accurate estimate of the association between catheter-associated urinary tract infection (UTI) and intensive care unit (ICU) and hospital mortality, controlling for major confounding factors. DESIGN Nested case-control study in a multicenter cohort (the OutcomeRea database). SETTING Twelve French medical or surgical ICUs. METHODS All patients admitted between January 1997 and August 2005 who required the insertion of an indwelling urinary catheter. Patients who developed catheter-associated UTI (ie, case patients) were matched to control patients on the basis of the following criteria: sex, age (+/- 10 years), SAPS (Simplified Acute Physiology Score) II score (+/- 10 points), duration of urinary tract catheterization, and presence or absence of diabetes mellitus. The association of catheter-associated UTI with ICU and hospital mortality was assessed by use of conditional logistic regression. RESULTS Of the 3,281 patients who had an indwelling urinary catheter, 298 (9%) developed at least 1 episode of catheter-associated UTI. The incidence density of catheter-associated UTI was 12.9 infections per 1,000 catheterization-days. Crude ICU mortality rates were higher among patients with catheter-associated UTI, compared with those without catheter-associated UTI (32% vs 25%, P=.02); the same was true for crude hospital mortality rates (43% vs 30%, P<.01). After matching and adjustment, catheter-associated UTI was no longer associated with increased mortality (ICU mortality: odds ratio [OR], 0.846 [95% confidence interval {CI}, 0.659-1.086]; P=.19 and hospital mortality: OR, 0.949 [95% CI, 0.763-1.181]; P=.64). CONCLUSION After carefully controlling for confounding factors, catheter-associated UTI was not found to be associated with excess mortality among our population of critically ill patients in either the ICU or the hospital.

Automated drug dispensing system reduces medication errors in an intensive care setting.

Objectives:We aimed to assess the impact of an automated dispensing system on the incidence of medication errors related to picking, preparation, and administration of drugs in a medical intensive care unit. We also evaluated the clinical significance of such errors and user satisfaction. Design:Preintervention and postintervention study involving a control and an intervention medical intensive care unit. Setting:Two medical intensive care units in the same department of a 2,000-bed university hospital. Patients:Adult medical intensive care patients. Interventions:After a 2-month observation period, we implemented an automated dispensing system in one of the units (study unit) chosen randomly, with the other unit being the control. Measurements and Main Results:The overall error rate was expressed as a percentage of total opportunities for error. The severity of errors was classified according to National Coordinating Council for Medication Error Reporting and Prevention categories by an expert committee. User satisfaction was assessed through self-administered questionnaires completed by nurses. A total of 1,476 medications for 115 patients were observed. After automated dispensing system implementation, we observed a reduced percentage of total opportunities for error in the study compared to the control unit (13.5% and 18.6%, respectively; p < .05); however, no significant difference was observed before automated dispensing system implementation (20.4% and 19.3%, respectively; not significant). Before-and-after comparisons in the study unit also showed a significantly reduced percentage of total opportunities for error (20.4% and 13.5%; p < .01). An analysis of detailed opportunities for error showed a significant impact of the automated dispensing system in reducing preparation errors (p < .05). Most errors caused no harm (National Coordinating Council for Medication Error Reporting and Prevention category C). The automated dispensing system did not reduce errors causing harm. Finally, the mean for working conditions improved from 1.0 ± 0.8 to 2.5 ± 0.8 on the four-point Likert scale. Conclusions:The implementation of an automated dispensing system reduced overall medication errors related to picking, preparation, and administration of drugs in the intensive care unit. Furthermore, most nurses favored the new drug dispensation organization.

Prognostic consequences of borderline dysnatremia: pay attention to minimal serum sodium change

IntroductionTo assess the prevalence of dysnatremia, including borderline changes in serum sodium concentration, and to estimate the impact of these dysnatremia on mortality after adjustment for confounders.MethodsObservational study on a prospective database fed by 13 intensive care units (ICUs). Unselected patients with ICU stay longer than 48 h were enrolled over a 14-year period were included in this study. Mild to severe hyponatremia were defined as serum sodium concentration < 135, < 130, and < 125 mmol/L respectively. Mild to severe hypernatremia were defined as serum sodium concentration > 145, > 150, and > 155 mmol/L respectively. Borderline hyponatremia and hypernatremia were defined as serum sodium concentration between 135 and 137 mmol/L or 143 and 145 respectively.ResultsA total of 11,125 patients were included in this study. Among these patients, 3,047 (27.4%) had mild to severe hyponatremia at ICU admission, 2,258 (20.3%) had borderline hyponatremia at ICU admission, 1,078 (9.7%) had borderline hypernatremia and 877 (7.9%) had mild to severe hypernatremia. After adjustment for confounder, both moderate and severe hyponatremia (subdistribution hazard ratio (sHR) 1.82, 95% CI 1.002 to 1.395 and 1.27, 95% CI 1.01 to 1.60 respectively) were associated with day-30 mortality. Similarly, mild, moderate and severe hypernatremia (sHR 1.34, 95% CI 1.14 to 1.57; 1.51, 95% CI 1.15 to 1.99; and 2.64, 95% CI 2.00 to 3.81 respectively) were independently associated with day-30 mortality.ConclusionsOne-third of critically ill patients had a mild to moderate dysnatremia at ICU admission. Dysnatremia, including mild changes in serum sodium concentration, is an independent risk factor for hospital mortality and should not be neglected.