Benoit Veber

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.

Diagnostic accuracy of protected specimen brush and bronchoalveolar lavage in nosocomial pneumonia: impact of previous antimicrobial treatments.

OBJECTIVE To determine whether the diagnostic accuracy of bronchoscopy samples in patients with suspected ventilator-associated pneumonia is affected by prior antibiotic treatment given for a previous infection, and/or by antibiotic treatment recently started to treat suspected ventilator-associated pneumonia. DESIGN Study of critically ill patients. SETTING Intensive care unit in a university hospital. PATIENTS Sixty-three episodes of suspected ventilator-associated pneumonia were prospectively evaluated. Based on prior antibiotic treatment, three groups were defined: no antibiotic group (no previous antibiotic treatments), n = 12; current antibiotic group (antibiotic treatment initiated >72 hrs earlier), n = 31; and recent antibiotic group (new antibiotic treatment class started within the last 24 hrs), n = 20. INTERVENTIONS Fiberoptic bronchoscopy with quantitative protected specimen brush cultures, bronchoalveolar lavage cultures, and intracellular organism counts of bronchoalveolar lavage cells. MEASUREMENTS AND MAIN RESULTS The diagnosis of ventilator-associated pneumonia was made in 35 cases, based on histology (n = 2), cavitation (n = 2), blood cultures (n = 4), or outcome under appropriate antibiotic treatment (n = 27). The discriminative value of the tests, based on the area under the receiver operating characteristic curve, was high (> or =0.85) in both current antibiotic treatment and recent antibiotic treatment patients. Sensitivities for a 5% intracellular organism count of bronchoalveolar lavage cells, a protected specimen brush culture threshold of 10(3) colony-forming units (cfu)/mL, and a bronchoalveolar lavage culture threshold of 10(5) cfu/mL were as follows, respectively, in the three groups: 0.71, 0.88, and 0.71 (no antibiotic treatment group); 0.5, 0.77, and 0.83 (current antibiotic group); and 0.67, 0.40, and 0.38 (recent antibiotic group). Specificity was consistently > or =0.9. In the recent antibiotic group, protected specimen brush and bronchoalveolar lavage cultures had lower sensitivities (p < .05), and the best threshold values for these two tests were 10(2) cfu/mL and 10(3) cfu/mL, respectively. CONCLUSIONS After recent introduction of an antibiotic treatment for suspected ventilator-associated pneumonia, protected specimen brush and bronchoalveolar lavage culture thresholds must be decreased to maintain good accuracy. In contrast, current antibiotic treatment prescribed for a prior infectious disease does not modify the diagnostic accuracy of protected specimen brush or bronchoalveolar lavage.

Candida as a risk factor for mortality in peritonitis.

Objective:The clinical significance of Candida cultured from peritoneal fluid specimens remains a matter of debate. None of the studies that have addressed this issue have clearly distinguished between community-acquired peritonitis and nosocomial peritonitis. The current study tried to differentiate the pathogenic role of Candida in these two clinical settings and assess its importance on outcome. Design:A multiple-center, retrospective, case-control study was conducted in intensive care unit patients. The interaction between mortality rates and type of patients was assessed. In the case of a significant interaction, a separate analysis of mortality and morbidity was planned. Setting:Seventeen intensive care units in teaching and nonteaching hospitals. Patients:Cases were patients operated on for peritonitis with Candida cultured from the peritoneal fluid, whereas controls were operated patients free from yeast. Cases and controls were matched for type of infection, Simplified Acute Physiology Score II, age, and time period of hospitalization. Interventions:None. Measurements and Main Results:The following characteristics were collected: demographic variables, underlying disease, severity score, site of infection, microbiological features, and anti-infective treatments. Survival was defined as the main outcome criterion and morbidity variables as secondary criteria. Odds ratios of mortality were calculated. Matching was achieved in 91 cases and 168 controls. Matching criteria, clinical characteristics, and mortality rate were not statistically different between cases and controls. A significant interaction was demonstrated between mortality rates and type of infection, leading to separate analysis of patients with community-acquired peritonitis and nosocomial peritonitis. The subgroup analysis demonstrated an increased mortality rate only in nosocomial peritonitis with fungal isolates (48% vs. 28% in controls, p < .01). Upper gastrointestinal tract site (odds ratio, 4.9; 95% confidence interval, 1.6–14.8) and isolation of Candida species (odds ratio, 3.0; 95% confidence interval, 1.3–6.7, p < .001) were found to be independent risk factors of mortality in nosocomial peritonitis patients. Conclusions:Isolation of Candida species appears to be an independent risk factor of mortality in nosocomial peritonitis but not in community-acquired peritonitis.

Assessment of White Matter Injury and Outcome in Severe Brain Trauma: A Prospective Multicenter Cohort

Background:Existing methods to predict recovery after severe traumatic brain injury lack accuracy. The aim of this study is to determine the prognostic value of quantitative diffusion tensor imaging (DTI). Methods:In a multicenter study, the authors prospectively enrolled 105 patients who remained comatose at least 7 days after traumatic brain injury. Patients underwent brain magnetic resonance imaging, including DTI in 20 preselected white matter tracts. Patients were evaluated at 1 yr with a modified Glasgow Outcome Scale. A composite DTI score was constructed for outcome prognostication on this training database and then validated on an independent database (n = 38). DTI score was compared with the International Mission for Prognosis and Analysis of Clinical Trials Score. Results:Using the DTI score for prediction of unfavorable outcome on the training database, the area under the receiver operating characteristic curve was 0.84 (95% CI: 0.75–0.91). The DTI score had a sensitivity of 64% and a specificity of 95% for the prediction of unfavorable outcome. On the validation-independent database, the area under the receiver operating characteristic curve was 0.80 (95% CI: 0.54–0.94). On the training database, reclassification methods showed significant improvement of classification accuracy (P < 0.05) compared with the International Mission for Prognosis and Analysis of Clinical Trials score. Similar results were observed on the validation database. Conclusions:White matter assessment with quantitative DTI increases the accuracy of long-term outcome prediction compared with the available clinical/radiographic prognostic score.

Diagnostic and therapeutic management of nosocomial pneumonia in surgical patients: results of the Eole study.

Objective To assess clinical, microbiological, and therapeutic features of nosocomial pneumonias in surgical patients. Design Prospective (October 1997 through May 1998), consecutive case series analysis of patients suspected of having pneumonia during the fortnight after a surgical procedure or trauma and receiving antibiotic therapy prescribed by the attending physician for this diagnosis. Setting A total of 230 study centers in teaching (n = 66) and nonteaching hospitals (n = 164) (surgical wards and intensive care units). Patients A total of 837 evaluable patients (mean age 61 ± 18 yrs) including 629 intensive care unit patients. Intervention None. Measurements and Main Results The diagnostic and therapeutic procedures followed were based on guidelines. Antibiotics and any changes of therapy and duration of treatment were decided by the attending physician. The charts were reviewed by a panel of experts that classified the cases according to clinical, radiologic, and microbiological criteria (when available). The efficacy of treatment was evaluated over a 30-day period following the index episode. The patients were classified into three groups: definite pneumonia (n = 261), possible pneumonia (n = 392), or low-probability pneumonia (n = 184). Ventilator-acquired pneumonia was reported in 303 patients. Early onset pneumonia was reported in 512 cases. Microbiological sampling was performed in 718 patients, by bronchoscopy in 367 cases, recovering 450 organisms in 328 patients, including 94 polymicrobial specimens. High proportions of Gram-negative bacteria and staphylococci were cultured, even in early onset pneumonias. Antibiotic therapy was administered for 13 ± 4 days, using monotherapy in 254 cases. Changes in the initial antibiotic therapy (135 monotherapies) were decided in 517 patients (including clinical failure or persistent infection, n = 171; organisms resistant to initial therapy, n = 177; pulmonary superinfection, n = 68). Death occurred in 180 patients, related to pneumonia in 53 cases. Conclusions Nosocomial pneumonias in surgical patients are characterized by high frequency of early onset pneumonia, high proportion of nosocomial organisms even in these early onset pneumonias, and moderate mortality rate.

Short-term effects of methylene blue on hemodynamics and gas exchange in humans with septic shock

ObjectiveThe aim of this study was to investigate the acute effects of methylene blue (MB), an inhibitor of thel-arginine nitric oxide pathway, in patients with septic shock.DesignA prospective, open, single-dose study.SettingThe medical ICU of a university hospital.PatientsSix patients with severe septic shock.InterventionsComplete hemodynamic values were recorded before and 20 min after the infusion of intravenous MB (3 mg kg−1). Arterial pressure was then monitored during the next 24 h or until death.Measurements and resultsMethylene blue increased the mean arterial pressure from 69.7±4.5 to 83.7±5.1 mmHg (p=0.028) and the mean pulmonary artery pressure, from 34.3±7.2 to 38.7±8.0 mmHg (p=0.023). Systemic vascular resistance index was increased from 703.1±120.6 to 903.7±152.2 dyne.s.cm−5.m−2 (p=0.028) and pulmonary vascular resistance index, from 254.6±96.9 to 342.2±118.9 dyne.s.cm−5.m−2 (p=0.027). The PaO2/FIO2 decreased from 229.2±54.4 to 162.2±44.1 mmHg (p=0.028), without significant modification of intrapulmonary shunting. Heart rate, cardiac index, right atrial pressure, DO2, VO2, oxygen extraction and arterial lactate were essentially unchanged. Sequential measurements of arterial pressure demonstrated a return to baseline level in 2–3 h. All but one patients died, three in shock and two in multiple organ failure.ConclusionsMB induces systemic and pulmonary vasoconstriction in patients with septic shock, without significant decrease in cardiac index. The worsening of arterial oxygenation following MB injection may limit its use in patients with the adult respiratory distress syndrome. Larger studies are required to determine whether MB improves the outcome of patients with septic shock.

Pneumocystis carinii pneumonia requiring intensive care management: Survival and prognostic study in 110 patients with human immunodeficiency virus

OBJECTIVE To perform a descriptive study of patients with acute respiratory failure secondary to acquired immunodeficiency syndrome-related Pneumocystis carinii pneumonia and to identify variables that are predictive of death within 3 months. DESIGN Case series study. SETTING Infectious disease intensive care unit (ICU) in a university hospital. PATIENTS Detailed clinical, laboratory, and ventilatory data were collected prospectively within 48 hrs of admission and during the ICU stay in 110 consecutive human immunodeficiency virus-infected patients requiring ICU management with or without mechanical ventilation for P. carinii pneumonia-related acute respiratory failure. MEASUREMENTS AND MAIN RESULTS Continuous positive airway pressure was used initially in 66 (60%) patients. Among the 34 patients (31%) who required mechanical ventilation, including 12 at admission and 22 after failure of continuous positive airway pressure, 76% died. The 3-month mortality rate after ICU admission was estimated at 34.6% (95% confidence interval [CI], 25%-44%). The 1-yr survival rate was estimated at 47% (95% CI, 36%-58%). With successive multiple logistic regression models analyzing the relative prognostic importance of baseline clinical and laboratory tests variables, ventilation variables, and events in the ICU, only delayed mechanical ventilation after 3 days (odd ratio [OR], 6.7; 95% CI, 1.9-23.9), duration of mechanical ventilation of > or = 5 days (OR, 2.8; 95% CI, 1.1-6.9), nosocomial infection (OR, 5.2; 95% CI, 2.1-12.9), and pneumothorax (OR, 5; 95% CI, 1.7-14.7) were predictive of death within 3 months of ICU admission. Among patients with delayed mechanical ventilation on day 3 or later and with a pneumothorax associated or not associated with a nosocomial infection, the predicted probability of 3-month death was close to 100%. CONCLUSIONS Our data suggest that the most significant predictive factors of death were identifiable during the course of P. carinii pneumonia-related acute respiratory failure rather than at admission and can help in bedside decisions to withdraw intensive care support in such patients.

Effect of oropharyngeal povidone-iodine preventive oral care on ventilator-associated pneumonia in severely brain-injured or cerebral hemorrhage patients: a multicenter, randomized controlled trial.

Objective:To evaluate the efficacy and safety of oral care with povidone-iodine on the occurrence of ventilator-associated pneumonia in a high-risk population. Design:A multicenter, placebo-controlled, randomized, double-blind, two-parallel-group trial performed between May 2008 and May 2011. Setting:Six ICUs in France. Patients:One hundred seventy-nine severely brain-injured patients (Glasgow Coma Scale ⩽ 8) or cerebral hemorrhage expected to be mechanically ventilated for more than 24 hours. Interventions:Participants were randomly assigned to receive oropharyngeal care with povidone-iodine (n = 91) or placebo (n = 88) six times daily until mechanical ventilation withdrawal. Measurements and Main Results:Primary endpoint was the rate of ventilator-associated pneumonia. Secondary endpoint included the rates of ventilator-associated tracheobronchitis and acute respiratory distress syndrome and patient’s outcome. The number of patients evaluable for the primary endpoint (preplanned modified intention-to-treat population) was 150 (78 in the povidone-iodine group, 72 in the placebo group). Ventilator-associated pneumonia occurred in 24 patients (31%) in the povidone-iodine group and 20 (28%) in the placebo group (relative risk, 1.11 [95% CI, 0.67–1.82]; p = 0.69). There was no significant difference between the two groups for ventilator-associated tracheobronchitis: eight patients (10%) in the povidone-iodine group and five patients (7%) in the placebo group (relative risk, 1.48 [95% CI, 0.51–4.31]; p = 0.47). Acute respiratory distress syndrome occurred in five patients in the povidone-iodine group but not in the placebo group (p = 0.06). There was no difference between groups for ICU and hospital lengths of stay, as well as ICU and 90-day mortality. Conclusions:There is no evidence to recommend oral care with povidone-iodine to prevent ventilator-associated pneumonia in high-risk patients. Furthermore, this strategy seems to increase the rate of acute respiratory distress syndrome.

Comparison of direct examination of three types of bronchoscopy specimens used to diagnose nosocomial pneumonia.

Objective: To compare direct examination of bronchial aspirate and plugged telescopic catheter specimens (PTC) with infected cell counts in bronchoalveolar lavage (BAL) specimens for the diagnosis of nosocomial pneumonia. Design: Prospective study of critically ill patients. Setting: Intensive care unit in a university hospital. Patients: A total of 64 patients hospitalized for >48 hrs with suspected nosocomial pneumonia. Interventions: Fiberoptic bronchoscopy with bronchial aspirate and quantitative protected specimen brush, PTC, and BAL cultures. PTC and bronchial aspirate specimens were Gram‐stained. BAL specimens for infected cell counts were examined as described previously in the literature. Measurements and Main Results: Nosocomial pneumonia was diagnosed by the medical staff based on all available clinical, radiologic, laboratory test, and microbiological data and on the course before and after appropriate therapy. A total of 71% of patients were ventilated, and 70.1% were receiving antibiotics. Nosocomial pneumonia was diagnosed in 54% of the cases. On direct examination, sensitivity (Se) and specificity (Sp) of bronchial aspirate specimens were Se, 82% and Sp, 60%; of BAL with 5% infected cells, Se, 56% and Sp, 100%; of BAL with 3% infected cells, Se, 74% and Sp, 96%; of PTC specimens, Se, 65% and Sp, 76%; and of PTC specimens plus BAL with 3% infected cells, Se, 83% and Sp, 78%. BAL with 3% infected cells was significantly better for predicting nosocomial pneumonia than direct examination of bronchial aspirate or PTC specimens (p = .0012). When the BAL showed 3% infected cells, neither direct examination of bronchial aspirate nor direct examination of PTC specimens was useful (p = .24 and p = .38, respectively). Combined use of direct examination of PTC specimens plus BAL with 3% infected cells markedly improved sensitivity. The total cost of each procedure was taken into account for the final evaluation. Conclusions: Our data suggest that BAL with 3% infected cells is currently the only test whose predictive value for nosocomial pneumonia is sufficiently high to be of use for guiding the initial choice of antimicrobial class while waiting for quantitative culture results.

Nosocomial Cerebral Aspergillosis: A Report of 3 Cases

Cerebral aspergillosis carries a mortality rate close to 100%, especially in immunocompromised patients. We describe 3 patients who contracted cerebral aspergillosis after neurosurgery, 2 of whom survived after exhaustive surgical treatment and medical treatment with high doses of amphotericin B (once liposomal), 5-fluorocytosine and itraconazole. We review the few non-fatal cases of cerebral aspergillosis reported. We consider that surgical excision must be complete and repeated if necessary, always in combination with medical treatment.