Dominique Perrotin

Effect of Eritoran, an Antagonist of MD2-TLR4, on Mortality in Patients With Severe Sepsis: The ACCESS Randomized Trial

IMPORTANCE Eritoran is a synthetic lipid A antagonist that blocks lipopolysaccharide (LPS) from binding at the cell surface MD2-TLR4 receptor. LPS is a major component of the outer membrane of gram-negative bacteria and is a potent activator of the acute inflammatory response. OBJECTIVE To determine if eritoran, a TLR4 antagonist, would significantly reduce sepsis-induced mortality. DESIGN, SETTING, AND PARTICIPANTS We performed a randomized, double-blind, placebo-controlled, multinational phase 3 trial in 197 intensive care units. Patients were enrolled from June 2006 to September 2010 and final follow-up was completed in September 2011. INTERVENTIONS Patients with severe sepsis (n = 1961) were randomized and treated within 12 hours of onset of first organ dysfunction in a 2:1 ratio with a 6-day course of either eritoran tetrasodium (105 mg total) or placebo, with n = 1304 and n = 657 patients, respectively. MAIN OUTCOME MEASURES The primary end point was 28-day all-cause mortality. The secondary end points were all-cause mortality at 3, 6, and 12 months after beginning treatment. RESULTS Baseline characteristics of the 2 study groups were similar. In the modified intent-to-treat analysis (randomized patients who received at least 1 dose) there was no significant difference in the primary end point of 28-day all-cause mortality with 28.1% (366/1304) in the eritoran group vs 26.9% (177/657) in the placebo group (P = .59; hazard ratio, 1.05; 95% CI, 0.88-1.26; difference in mortality rate, -1.1; 95% CI, -5.3 to 3.1) or in the key secondary end point of 1-year all-cause mortality with 44.1% (290/657) in the eritoran group vs 43.3% (565/1304) in the placebo group, Kaplan-Meier analysis of time to death by 1 year, P = .79 (hazard ratio, 0.98; 0.85-1.13). No significant differences were observed in any of the prespecified subgroups. Adverse events, including secondary infection rates, did not differ between study groups. CONCLUSIONS AND RELEVANCE Among patients with severe sepsis, the use of eritoran, compared with placebo, did not result in reduced 28-day mortality. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00334828.

Recombinant tissue factor pathway inhibitor in severe community-acquired pneumonia: a randomized trial.

RATIONALE Severe community-acquired pneumonia (sCAP) is a leading cause of death worldwide. Adjunctive therapies for sCAP are needed to further improve outcome. A systemic inhibitor of coagulation, tifacogin (recombinant human tissue factor pathway inhibitor) seemed to provide mortality benefit in the sCAP subgroup of a previous sepsis trial. OBJECTIVES Evaluate the impact of adjunctive tifacogin on mortality in patients with sCAP. METHODS A multicenter, randomized, placebo-controlled, double-blind, three-arm study was conducted from July 2005 to June 2008 at 188 centers in North and South America, Europe, South Africa, Asia, Australia, and New Zealand. Adults with sCAP were randomized to receive a continuous intravenous infusion of tifacogin 0.025 mg/kg/h, tifacogin 0.075 mg/kg/h, or matching placebo over 96 hours. MEASUREMENTS AND MAIN RESULTS Severity-adjusted 28-day all-cause mortality. Of 2,138 randomized patients, 946, 238, and 918 received tifacogin 0.025 mg/kg/h, tifacogin 0.075 mg/kg/h, and placebo, respectively. Tifacogin 0.075 mg/kg/h was discontinued after the first interim analysis according to prespecified futility criterion. The 28-day all-cause mortality rates were similar between the 0.025 mg/kg/h (18%) and placebo groups (17.9%) (P = 0.56). Greater reduction in prothrombin fragment 1+2 and thrombin antithrombin complexes levels relative to baseline throughout the first 96 hours was found with tifacogin 0.025 mg/kg/h than with placebo. The incidence of adverse events and serious adverse events were comparable between the tifacogin 0.025 mg/kg/h and placebo groups. CONCLUSIONS Tifacogin showed no mortality benefit in patients with sCAP despite evidence of biologic activity.

Prognosis and 1-year mortality of intensive care unit patients with severe hepatic encephalopathy ☆

PURPOSE Data regarding outcome of patients with chronic liver disease with severe hepatic encephalopathy in intensive care unit are currently scarce. METHODS This study is a retrospective observational case series in a medical intensive care unit (ICU) in a university hospital from 1995 to 2005. Patients with hepatic encephalopathy (HE) (admitted with or developing) were identified. Clinical and laboratory parameters were analyzed to determinate predictors of ICU and 1-year mortality. RESULTS Seventy-one patients were included (53 male). Median Simplified Acute Physiology Score was 56 with Child-Pugh score 11 +/- 2. Seventy-six percent of patients were admitted with coma (Glasgow Coma Scale, 7.7 +/- 4). Eighty-two percent of patients required intubation, and 28% vasopressors. Thirty-five percent died during ICU stay. At 1 year, mortality was 54%. Univariate analysis identified arterial hypotension, mechanical ventilation, vasopressors at any time, acute renal failure, Simplified Acute Physiology Score, and sepsis associated with ICU mortality. In multivariate analysis, vasopressor use or acute renal failure was the main independent predictor of ICU death and 1-year mortality. Patients free of these risk factors, even requiring intubation, were identified as isolated HE, with lower mortality rates. CONCLUSION Predictors of outcome were similar to other groups of patients with liver disease admitted for other reasons. Intensive care unit mortality was lower than reported for other groups of patients with similar illness. Patients with severe HE admitted to ICU with no organ dysfunction other than mechanical ventilation had a better outcome and may require ICU admission.

Acute Kidney Injury in the Critically Ill: Is Iodinated Contrast Medium Really Harmful?*

Objectives:To assess whether the use of iodinated contrast medium increases the incidence of acute kidney injury in ICU patients, compared with patients not receiving iodinated contrast medium. Design:Prospective observational matched cohort study. Setting:Two ICUs in two tertiary teaching hospitals. Patients:A total of 380 adults were included (20% more than once), before an iodinated contrast medium infusion (contrast inclusions, n = 307) or before an intrahospital transfer without iodinated contrast medium infusion (control inclusions, n = 170). Interventions:None. Measurements and Main Results:Among contrast inclusions, iodinated contrast medium–associated acute kidney injury occurred after 23 administrations (7.5%) according to the Acute Kidney Injury Network definition (stage ≥ 1, over 48 hr). As expected, a broader definition (≥ 25% increase in serum creatinine over 72 hr) yielded a greater incidence (16%). In 146 pairs of contrast and control inclusions, matched on propensity for iodinated contrast medium infusion, the incidence of acute kidney injury was similar (absolute difference in incidence, 0%; 95% confidence interval, –5.2; 5.2%), Acute Kidney Injury Network definition). Hospital mortality was also similar in 71 contrast and 71 control patients included only once and matched the same way. Contrary to iodinated contrast medium infusion (odds ratio, 1.57; 95% confidence interval, 0.69–3.53), the Sequential Organ Failure Assessment score at inclusion (odds ratio, 1.18; 95% confidence interval, 1.07–1.31) and the number of other nephrotoxic agents (odds ratio, 1.38; 95% confidence interval, 1.03–1.85) were independent risk factors for acute kidney injury. Conclusions:The specific toxic effect of monomeric nonionic low-osmolar iodinated contrast medium in ICU patients with multiple renal aggressions seemed minimal. Severity of disease and the global nephrotoxic burden were risk factors for acute kidney injury, regardless of iodinated contrast medium infusion.

Population pharmacokinetics of ceftriaxone in critically ill septic patients: a reappraisal

AIMS To investigate the population pharmacokinetics of ceftriaxone in critically ill patients suffering from sepsis, severe sepsis or septic shock. METHODS Blood samples were collected at preselected times in 54 adult patients suffering from sepsis, severe sepsis or septic shock in order to determine ceftriaxone concentrations using high-performance liquid chromatography-ultraviolet detection. The pharmacokinetics of ceftriaxone were assessed on two separate occasions for each patient: on the second day of ceftriaxone therapy and 48 h after catecholamine withdrawal in patients with septic shock, or on the fifth day in patients with sepsis. The population pharmacokinetics of ceftriaxone were studied using nonlinear mixed effects modelling. RESULTS The population estimates (interindividual variability; coefficient of variation) for ceftriaxone pharmacokinetics were: a clearance of 0.88 l h(-1) (49%), a mean half-life of 9.6 h (range 0.83-28.6 h) and a total volume of distribution of 19.5 l (range 6.48-35.2 l). The total volume of distribution was higher than that generally found in healthy individuals and increased with the severity of sepsis. However, the only covariate influencing the ceftriaxone pharmacokinetics was creatinine clearance. Dosage simulations showed that the risk of ceftriaxone concentrations dropping below the minimum inhibitory concentration threshold was low. CONCLUSIONS Despite the wide interpatient variability of ceftriaxone pharmacokinetic parameters, our results revealed that increasing the ceftriaxone dosage when treating critically ill patients is unnecessary. The risk of ceftriaxone concentrations dropping below the minimum inhibitory concentration threshold is limited to patients with high glomerular filtration rates or infections with high minimum inhibitory concentration pathogens (>1 mg l(-1)).

Cardiopulmonary resuscitation in the prone position: Kouwenhoven revisited

Sir: It has been proposed that severely hypoxemic patients be ventilated in the prone position, in an attempt to improve gas exchange [1]. Testing this position in patients with the acute respiratory distress syndrome (ARDS) is recommended [21. However, no guidelines are available for cases of life-threatening events occurring with the patient in the prone position especially cardiac arrest. We report a case of successful cardiopulmonary resuscitation of a patient ventilated in the prone position, without changing the patients position. A 48-year-old man was being ventilated for community-acquired pneumonia. His gas exchange (partial pressure of oxygen in arterial blood 4.3 kPa and of carbon dioxide 16.4 kPa and pH 7.14) deteriorated despite controlmode ventilation with 10 cmH20 positive end-expiratory pressure, 100 p. 100 fractional inspired oxygen, and 20 ppm inhaled nitric oxide. He was then turned to the prone position. A few minutes later, asytole developed and blood pressure became unobtainable. Cardiac massage was begun immediately with the patient in the prone position. One physician placed the flat of one hand under the patients sternum, while another physician compressed the mid-thoracic spine rhythmically with both hands (Fig. 1). Arterial radial blood pressure was maintained at least at 80/35 mmHg throughout resuscitation. Epinephrine (1 mg i.v.) was injected twice at a 3-min interval. Five minutes after starting cardiac compression, sinus rhythm resumed and blood pressure was maintained at 140/85 mmHg. Gas exchange dramatically improved a few hours later. Seven days after the incident, the patient was awake and well oriented. The conventional approach of closed chest compression is well established with the patient in the supine position [3]. However, cardiac massage might be required for patients in the prone position, e.g., during anesthesia for spinal or posterior fossa surgery. Three cases of successful resuscitation have been reported in these circumstances [4, 5] in which resuming the supine position might have injured the brain or spinal cord. Changing the position has some other drawbacks for ARDS patients ventilated in the prone position: (a) it is time consuming and delays initiation of cardiac massage; (b) moving the patient into the supine position without proper protection may induce certain complications, e.g., accidental extubation, dislodging the venous catheter, or shoulder injury to the patient; (c) turning a patient from one position into another requires at least four members of staff, who are not always immediately available in emergency situations. For these reasons, we suggest trying the

Randomized comparison of 2 protocols to prevent acquisition of methicillin-resistant Staphylococcus aureus: results of a 2-center study involving 500 patients.

OBJECTIVE To compare an interventional protocol with a standard protocol for preventing the acquisition of methicillin-resistant Staphylococcus aureus (MRSA) in the intensive care unit (ICU). DESIGN Prospective, randomized, controlled, parallel-group, nonblinded clinical trial. SETTING Medical ICUs of 2 French university hospitals. PARTICIPANTS Five hundred adults with an expected length of stay in the ICU greater than 48 hours. INTERVENTIONS For the intervention group, the protocol required repeated MRSA screening, contact and droplet isolation precautions for patients at risk for MRSA at ICU admission and for MRSA-positive patients, and decontamination with nasal mupirocin and chlorhexidine body wash for MRSA-positive patients. For the standard group, the standard precautions protocol was used, and the results of repeated MRSA screening in the standard group were not communicated to investigators. MAIN OUTCOME MEASURE MRSA acquisition rate in the ICU. An audit was conducted to assess compliance with hygiene and isolation precautions. RESULTS In the intent-to-treat analysis ([Formula: see text]), the MRSA acquisition rate in the ICU was similar in the standard (13 [5.3%] of 243) and intervention (16 [6.5%] of 245) groups ([Formula: see text]). The audit showed that the overall compliance rate was 85.5% in the standard group and 84.1% in the intervention group ([Formula: see text]), although compliance was higher when isolation precautions were absent than when they were in place (88.2% vs 79.1%; [Formula: see text]). MRSA incidence rates were higher without isolation precautions (7.57‰) than with isolation precautions (2.36‰; [Formula: see text]). CONCLUSIONS Individual allocation to MRSA screening, isolation precautions, and decontamination do not provide individual benefit in reducing MRSA acquisition, compared with standard precautions, although the collective risk was lower during the periods of isolation. TRIAL REGISTRATION Clinicaltrials.gov identifier: NCT00151606.

Right-to-left interatrial shunt in ARDS: dramatic improvement in prone position

Abstract The mechanisms leading to shunting through a patent foramen ovale include high right-sided cardiac pressures and respiratory factors due to mechanical ventilation and also anatomical changes in the right atrium as described in the platypnea-orthodeoxia syndrome. We report a patient with the adult respiratory distress syndrome (ARDS) who had a right-to-left atrial shunt which decreased in the prone position, after which oxygenation improved. The patient was admitted to the intensive care unit because of ARDS due to an invasive fungal infection. He had a history of chronic lymphocytic leukemia and paradoxical embolisms through a patent foramen ovale. Despite mechanical ventilation and antifungal treatment he developed severe ARDS. He was therefore turned to the prone position. Blood gas values improved dramatically (arterial oxygen tension/fractional inspired oxygen ratio increasing from 59 to 278 torr). Transcranial Doppler sonography was performed with bubble study, which confirmed a massive right-to-left shunt in the supine position and which instantaneously decreased in the prone position. This case suggests that a decrease in right-to-left shunt in patients who have a patent foramen ovale could partly explain the improvement in hypoxemia in the prone position.

Acquiring procedural skills in ICUs: a prospective multicenter study*.

Objectives:Providing appropriate training of procedural skills to residents while ensuring patient safety through trainee supervision is a difficult and constant challenge. We sought to determine how effective and safe procedural skill acquisition is in French ICUs and to identify failure and complication risk factors. Design:Multicenter prospective observational study. Invasive procedures performed by residents were recorded during two consecutive semesters. Setting:Eighty-four residents. Subjects:Eighty-four residents. Intervention:None. Measurements and Main Results:Number of invasive procedures performed, failure and complication rates, supervision, and assistance provided. Five thousand six hundred seventeen procedures were prospectively studied: 1,007 tracheal intubations, 1,272 arterial and 2,586 central venous catheter insertions, 457 fiberoptic bronchoscopies, and 295 chest tube insertions. During the semesters, residents performed a median of 10 intubations, 14 arterial catheter insertions, and 26 central venous catheter insertions. Complication rates were low, similar to those in the literature: 8.6% desaturation and 7.4% esophageal placement during intubation; 0.4% and 2.3% pneumothorax with jugular and subclavian central venous catheter insertions, respectively. We identified risk factors for failure and complications. Higher rates of failure and complications for intubation were associated with residents with no or little previous experience (p < 0.001); failure of internal jugular vein catheterization was associated with left-side insertion (p = 0.005) and absence of mechanical ventilation (p = 0.007). Supervision and assistance were more frequent at the beginning of the semester and for intubation and chest tube insertion. Finally, residents had less access to fiberoptic bronchoscopy and chest tube insertion. Conclusion:Procedural skills acquisition by residents in the ICU appears feasible and safe with complication rates comparable to what has previously been reported. We identified specific procedures and situations associated with higher failure and complication rates that could require proactive training. Questions still remain regarding minimal numbers of procedures to attain competence and how best to provide procedural training.

Atteinte respiratoire sévère et choc septique à Mycobacterium bovis: Une complication rare de la BCG thérapie intravésicale

INTRODUCTION Intravesical bacillus Calmette-Guerin (BCG) therapy, recommended for superficial bladder tumors, triggers side effects in fewer than 5% of patients. The most severe side effects, however, are septic shock and acute respiratory failure. CASE A 70-year-old man was hospitalized for septic shock with acute respiratory and renal failure after intravesical instillation of BCG, which was identified in the gastric aspiration sample. Treatment with rifampicin, ethambutol, isoniazid, and corticosteroid therapy, as well as standard reanimation measures, led to the patients recovery. DISCUSSION This case shows the potentially severe side effects of intravesical BCG instillation. Although this treatment is well tolerated in more than 95% of patients and its systemic complications can be effectively treated, these side effects can be life-threatening.