Benjamin Zuber

Is Hypothermia After Cardiac Arrest Effective in Both Shockable and Nonshockable Patients? Insights From a Large Registry

Background— Although the level of evidence of improvement is significant in cardiac arrest patients resuscitated from a shockable rhythm (ventricular fibrillation or pulseless ventricular tachycardia [VF/VT]), the use of therapeutic mild hypothermia (TMH) is more controversial in nonshockable patients (pulseless electric activity or asystole [PEA/asystole]). We therefore assessed the prognostic value of hypothermia for neurological outcome at hospital discharge according to first-recorded cardiac rhythm in a large cohort. Methods and Results— Between January 2000 and December 2009, data from 1145 consecutive out-of-hospital cardiac arrest patients in whom a successful resuscitation had been achieved were prospectively collected. The association of TMH with a good neurological outcome at hospital discharge (cerebral performance categories level 1 or 2) was quantified by logistic regression analysis. TMH was induced in 457/708 patients (65%) in VF/VT and in 261/437 patients (60%) in PEA/asystole. Overall, 342/1145 patients (30%) reached a favorable outcome (cerebral performance categories level 1 or 2) at hospital discharge, respectively 274/708 (39%) in VF/VT and 68/437 (16%) in PEA/asystole (P<0.001). After adjustment, in VF/VT patients, TMH was associated with increased odds of good neurological outcome (adjusted odds ratio, 1.90; 95% confidence interval, 1.18 to 3.06) whereas in PEA/asystole patients, TMH was not significantly associated with good neurological outcome (adjusted odds ratio, 0.71; 95% confidence interval, 0.37 to 1.36). Conclusions— In this large cohort of cardiac arrest patients, hypothermia was independently associated with an improved outcome at hospital discharge in patients presenting with VF/VT. By contrast, TMH was not associated with good outcome in nonshockable patients. Further investigations are needed to clarify this lack of efficiency in PEA/asystole.

Impact of case volume on survival of septic shock in patients with malignancies.

Objective:Septic shock is a frequent and severe complication in the course of malignancies. In a large multicenter cohort of septic shock patients with hematologic malignancies and solid tumors, we assessed the temporal trend in survival and the prognostic factors, with particular emphasis on case volume. Design:A 12-yr multicenter retrospective cohort study of prospectively collected data. Patients and Methods:Cancer patients with septic shock were selected over a 12-yr period (1997–2008) from a French regional database (CUB-Réa). The following variables were extracted: demographic characteristics, type of malignancy, characteristics of infection, severity-of-illness score (Simplified Acute Physiology Score II), organ failure supports, and vital status. For each unit, a running mean annual volume of admissions was calculated for the purpose of categorization into volume tertiles. Prognostic factors were analyzed by a conditional multivariate logistic model after matching on a propensity score of being admitted to a high-volume unit and on the year of admission. Interventions:None. Measurements and Main Results:A total of 3,437 patients were included in the study. The intensive care unit mortality rate dramatically dropped over time (from 70.4% in 1997 to 52.5% in 2008, relative decrease 25.4%, p < .001). Participating units were distributed into low-volume (< five patients per year), medium-volume (five to 12 patients per year), and high-volume (≥13 patients per year) tertiles. A medical cause for intensive care unit admission, Simplified Acute Physiology Score II, invasive mechanical ventilation, renal replacement therapy, fungal infections, and unknown microorganism were identified as poor prognostic factors. Case volume demonstrated a strong influence on survival, admission in a high-volume unit being associated with a marked decrease in mortality as compared to low-volume units (adjusted odds ratio 0.63; 95% confidence interval [0.46–0.87], p = .002). Conclusions:Survival of septic shock patients with malignancies markedly increased over the recent years. Furthermore, we identified case volume as a major prognostic factor in this setting.

Dendritic Cells Modulate Lung Response to Pseudomonas aeruginosa in a Murine Model of Sepsis-Induced Immune Dysfunction

Host infection by pathogens triggers an innate immune response leading to a systemic inflammatory response, often followed by an immune dysfunction which can favor the emergence of secondary infections. Dendritic cells (DCs) link innate and adaptive immunity and may be centrally involved in the regulation of sepsis-induced immune dysfunction. We assessed the contribution of DCs to lung defense in a murine model of sublethal polymicrobial sepsis (cecal ligature and puncture, CLP). In this model, bone marrow-derived DCs (BMDCs) retained an immature phenotype, associated with decreased capacity of IL-12p70 release and impaired priming of T cell lymphocytes. Eight days after CLP surgery, we induced a secondary pulmonary infection through intratracheal instillation of 5 × 106 CFUs of Pseudomonas aeruginosa. Whereas all sham-operated mice survived, 80% of post-CLP mice died after secondary pneumonia. Post-CLP mice exhibited marked lung damage with early recruitment of neutrophils, cytokine imbalance with decreased IL-12p70 production, and increased IL-10 release, but no defective bacterial lung clearance, while systemic bacterial dissemination was almost constant. Concomitant intrapulmonary administration of exogenous BMDCs into post-CLP mice challenged with P. aeruginosa dramatically improved survival. BMDCs did not improve bacterial lung clearance, but delayed neutrophil recruitment, strongly attenuated the early peak of TNF-α and restored an adequate Il-12p70/IL-10 balance in post-CLP mice. Thus, adoptive transfer of BMDCs reversed sepsis-induced immune dysfunction in a relevant model of secondary P. aeruginosa pneumonia. Unexpectedly, the mechanism of action of BMDCs did not involve enhanced antibacterial activity, but occurred by dampening the pulmonary inflammatory response.

Can early cardiac troponin I measurement help to predict recent coronary occlusion in out-of-hospital cardiac arrest survivors?

Objective:Recent guidelines recommend the immediate performance of a coronary angiography when an acute myocardial infarction is suspected as a cause of out-of-hospital cardiac arrest. However, prehospital factors such as postresuscitation electrocardiogram pattern or clinical features are poorly sensitive in this setting. We searched to evaluate if an early measurement of cardiac troponin I can help to detect a recent coronary occlusion in out-of-hospital cardiac arrest. Design:Retrospective analysis of a prospective electronic registry database. Setting:University cardiac arrest center. Patients:Between January 2003 and December 2008, 422 out-of-hospital cardiac arrest survivors without obvious extra-cardiac cause have been consecutively studied. An immediate coronary angiography has been systematically performed. The primary outcome was the finding of a recent coronary occlusion. Intervention:First, blood cardiac troponin I levels at admission were analyzed to assess the optimum cutoff for identifying a recent coronary occlusion. Second, a logistic regression was performed to determine early predictive factors of a recent coronary occlusion (including cardiac troponin I) and their respective contribution. Measurements and Main Results:An ST-segment elevation was present in 127 of 422 patients (30%). During coronary angiography, a recent occlusion has been detected in 193 of 422 patients (46%). The optimum cardiac troponin I threshold was determined at 4.66 ng·mL−1 (sensitivity 66.7%, specificity 66.4%). In multivariate analyses, in addition of smoking and epinephrine initial dose, cardiac troponin I (odds ratio 3.58 [2.03–6.32], p < .001) and ST-segment elevation (odds ratio 10.19 [5.39–19.26], p < .001) were independent predictive factors of a recent coronary occlusion. Conclusions:In this large cohort of out-of-hospital cardiac arrest patients, isolated early cardiac troponin I measurement is modestly predictive of a recent coronary occlusion. Furthermore, the contribution of this parameter even in association with other factors does not seem helpful to predict recent occlusion. As a result and given the high benefit of percutaneous coronary intervention for such patients, the dosage of cardiac troponin I at admission could not help in the decision of early coronary angiogram.

Short- and long-term outcome in elderly patients after out-of-hospital cardiac arrest: a cohort study.

Objective: Determinants of outcome and long-term survival are unknown in elderly patients successfully resuscitated after out-of-hospital cardiac arrest. Our aim was to identify factors associated with short- and long-term neurologic outcome in such patients. Design: Retrospective cohort study. Setting: Tertiary hospital in Paris, France. Patients: Patients aged over 75 admitted in our ICU after an out-of-hospital cardiac arrest between 2000 and 2009. Interventions: None. Measurements and Main Results: Two hundred twenty-five patients were included in the study. Fifty-seven patients (25.3%) had a good neurologic outcome at ICU discharge (Cerebral Performance Category 1–2). By multivariate logistic regression analysis, factors associated with good short-term outcome were time from collapse to cardiopulmonary resuscitation less than or equal to 3 minutes (odds ratio = 4.06; 95% CI, 1.49–11.09, p = 0.006) and blood lactate level less than or equal to 5.1 mmol/L (odds ratio = 3.30; 95% CI, 1.05–10.39, p = 0.04), but age less than or equal to 79.5 years and use of induced hypothermia were not. Long-term survivors were assessed for cognitive and functional status (using Cerebral Performance Category and Overall Performance Category scales), and their survival was compared with a large community–based cohort of participants over 75 years. The 1-year survival of ICU survivors (mean follow-up, 28.4 mo) was 69.3% (95% CI, 55.8–79.5) as compared with 95.3% (95% CI, 93.3–97.3) in the control community–based cohort (p< 0.001), resulting in a standardized mortality ratio of 3.49 (95% CI, 2.42–4.85). By multivariate Cox proportional hazard model, factors associated with long-term survival were initial shockable rhythm (hazard ratio = 1.41; 95% CI, 1.01–1.96; p = 0.04), epinephrine cumulate dose less than or equal to 3 mg (hazard ratio = 1.48; 95% CI, 1.06–2.08; p = 0.02), and blood lactate level less than or equal to 5.1 mmol/L (hazard ratio = 2.11; 95% CI, 1.5–2.96; p < 0.001). When available at end of follow-up, 91% and 74% of the patients were classified Cerebral Performance Category 1 and Overall Performance Category 1, respectively. Conclusions: Neurologic outcome in successfully resuscitated elderly patients depends on cardiac arrest characteristics rather than age. Short-term survival is 25% with acceptable long-term outcome among survivors.

Toll-Like Receptors 2 and 4 Contribute to Sepsis-Induced Depletion of Spleen Dendritic Cells

ABSTRACT Depletion of dendritic cells (DC) in secondary lymphoid organs is a hallmark of sepsis-induced immune dysfunction. In this setting, we investigated if Toll-like receptor (TLR)-dependent signaling might modulate the maturation process and the survival of DC. Using a model of sublethal polymicrobial sepsis induced by cecal ligation and puncture, we investigated the quantitative and functional features of spleen DC in wild-type, TLR2−/−, TLR4−/−, and TLR2−/− TLR4−/− mice. By 24 h, a decrease in the relative percentage of CD11chigh spleen DC occurred in wild-type mice but was prevented in TLR2−/−, TLR4−/−, and TLR2−/− TLR4−/− mice. In wild-type mice, sepsis dramatically affected both CD11c+ CD8α+ and CD11c+ CD8α− subsets. In all three types of knockout mice studied, the CD11c+ CD8α+ subset followed a depletion pattern similar to that for wild-type mice. In contrast, the loss of CD11c+ CD8α− cells was attenuated in TLR2−/− and TLR4−/− mice and completely prevented in TLR2−/− TLR4−/− mice. Accordingly, apoptosis of spleen DC was increased in septic wild-type mice and inhibited in knockout mice. In addition we characterized the functional features of spleen DC obtained from septic mice. As shown by increased expression of major histocompatibility complex class II and CD86, polymicrobial sepsis induced maturation of DC, with subsequent increased capacity to prime T lymphocytes, similarly in wild-type and knockout mice. In response to CpG DNA stimulation, production of interleukin-12 was equally impaired in DC obtained from wild-type and knockout septic mice. In conclusion, although dispensable for the DC maturation process, TLR2 and TLR4 are involved in the mechanisms leading to depletion of spleen DC following polymicrobial sepsis.

Toll-Like Receptor 2 Deficiency Increases Resistance to Pseudomonas aeruginosa Pneumonia in the Setting of Sepsis-Induced Immune Dysfunction

BACKGROUND Sepsis is characterized by a dysregulated inflammatory response followed by immunosuppression that favors the development of secondary infections. Toll-like receptors (TLRs) are major regulators of the hosts response to infections. How variability in TLR signaling may impact the development of sepsis-induced immune dysfunction has not been established. We sought to establish the role of TLR2, TLR4, and TLR5 in postseptic mice with Pseudomonas aeruginosa pneumonia. METHODS We used an experimental model of sublethal polymicrobial sepsis induced by cecal ligation and puncture (CLP). Wild-type, tlr2(-/-), tlr4(-/-), tlr5(-/-), tlr2 4(-/-) mice that underwent CLP were secondarily subjected to P. aeruginosa pulmonary infection. RESULTS Postseptic wild-type and tlr4(-/-) and tlr5(-/-) mice displayed high susceptibility to P. aeruginosa pneumonia. In contrast, TLR2-deficient mice, either tlr2(-/-)or tlr2 4(-/-), that underwent CLP were resistant to the secondary pulmonary infection. As compared to wild-type mice, tlr2(-/-) mice displayed improvement in bacterial clearance, decreased bacteremic dissemination, and attenuated lung damage. Furthermore, tlr2(-/-) mice exhibited a pulmonary proinflammatory cytokine balance, with increased production of tumor necrosis factor α and decreased release of interleukin 10. CONCLUSIONS In a model of secondary P. aeruginosa pneumonia in postseptic mice, TLR2 deficiency improves survival by promoting efficient bacterial clearance and restoring a proinflammatory cytokine balance in the lung.

Unusual "flesh-eating" strain of Escherichia coli.

ABSTRACT We report an exceptional case of life-threatening Escherichia coli-induced necrotizing fasciitis. A combined host-pathogen genetic analysis explained the phenotype: the host displayed a susceptibility to intravascular coagulation, and the strain was capable of producing a necrotic toxin (cytotoxic necrotizing factor 1), showing how E. coli can be a dermonecrotic pathogen.

Is Hypothermia After Cardiac Arrest Effective in Both Shockable and Nonshockable Patients

Background— Although the level of evidence of improvement is significant in cardiac arrest patients resuscitated from a shockable rhythm (ventricular fibrillation or pulseless ventricular tachycardia [VF/VT]), the use of therapeutic mild hypothermia (TMH) is more controversial in nonshockable patients (pulseless electric activity or asystole [PEA/asystole]). We therefore assessed the prognostic value of hypothermia for neurological outcome at hospital discharge according to first-recorded cardiac rhythm in a large cohort. Methods and Results— Between January 2000 and December 2009, data from 1145 consecutive out-of-hospital cardiac arrest patients in whom a successful resuscitation had been achieved were prospectively collected. The association of TMH with a good neurological outcome at hospital discharge (cerebral performance categories level 1 or 2) was quantified by logistic regression analysis. TMH was induced in 457/708 patients (65%) in VF/VT and in 261/437 patients (60%) in PEA/asystole. Overall, 342/1145 patients (30%) reached a favorable outcome (cerebral performance categories level 1 or 2) at hospital discharge, respectively 274/708 (39%) in VF/VT and 68/437 (16%) in PEA/asystole (P<0.001). After adjustment, in VF/VT patients, TMH was associated with increased odds of good neurological outcome (adjusted odds ratio, 1.90; 95% confidence interval, 1.18 to 3.06) whereas in PEA/asystole patients, TMH was not significantly associated with good neurological outcome (adjusted odds ratio, 0.71; 95% confidence interval, 0.37 to 1.36). Conclusions— In this large cohort of cardiac arrest patients, hypothermia was independently associated with an improved outcome at hospital discharge in patients presenting with VF/VT. By contrast, TMH was not associated with good outcome in nonshockable patients. Further investigations are needed to clarify this lack of efficiency in PEA/asystole.

High Level of Endotoxemia Following Out-of-hospital Cardiac Arrest Is Associated With Severity and Duration of Postcardiac Arrest Shock*

Objective:To investigate the contribution of endotoxemia to the severity of postcardiac arrest shock. Design:A prospective monocentric study. Setting:A tertiary hospital in Paris, France. Patients:Patients admitted in our ICU after a successfully resuscitated out-of-hospital cardiac arrest. Interventions:None. Measurements and Main Results:Endotoxin measurement was performed in the 12 hours following return of spontaneous circulation using the endotoxin activity assay. Endotoxin level was classified as low (< 0.4 endotoxin activity), intermediate (0.4 to < 0.6 endotoxin activity), or high (≥ 0.6 endotoxin activity) according to manufacture guidelines. Severity of shock was assessed by the vasopressor-free days and by the mean daily dose of vasopressor to insure a mean arterial pressure of 65–75 mm Hg. Among 92 patients included in the study, 60 presented a postcardiac arrest shock. Endotoxemia level was higher in patients with postcardiac arrest shock. Among these patients, by multivariate linear regression, high endotoxin class (adjusted estimate –2.0; 95% CI, –3.90 to –0.11), public place of cardiac arrest (adjusted estimate, 1.47; 95% CI, 0.007 to 2.93), and time to return of spontaneous circulation (adjusted estimate –0.08; 95% CI, –0.13 to –0.03) were independently associated with the number of vasopressor-free days. Furthermore, high endotoxin class (adjusted estimate, 97.95; 95% CI, 20.5 to 175.4) and a nonshockable rhythm (adjusted estimate, 59.9; 95% CI, 6.2 to 113.7) were the sole factors independently associated with the mean daily dose of vasopressors. Conclusions:In patients successfully resuscitated from cardiac arrest with a postcardiac arrest shock, high level of endotoxemia is independently associated with duration of postcardiac arrest shock and the amount of vasopressive drugs. Whether treatment targeting endotoxemia could be beneficial in the management of postcardiac arrest shock needs to be studied in further randomized controlled studies.