Julien Charpentier

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.

Detrimental role of delayed antibiotic administration and penicillin-nonsusceptible strains in adult intensive care unit patients with pneumococcal meningitis: The PNEUMOREA prospective multicenter study*

Objective:To identify factors associated with mortality and morbidity among adults admitted to intensive care units (ICUs) for pneumococcal meningitis, particularly the impact of delayed antibiotic administration. Design:We conducted a prospective, multicenter, observational study of 156 consecutive adults hospitalized for pneumococcal meningitis. We analyzed parameters associated with 3-month survival. Setting:Fifty-six medical and medical-surgical ICUs in France. Intervention:None. Results:Of the 148 strains isolated, 56 (38%) were nonsusceptible to penicillin G. At 3 months after ICU admission, the mortality rate was 33% (51/156), and 34% of survivors (36/105) had neurologic sequelae. Multivariate analysis identified three variables as independently associated with 3-month mortality: Simplified Acute Physiology Score II (odds ration [OR], 1.12; 95% confidence interval [CI], 1.072–1.153; p = .002); isolation of a nonsusceptible strain (OR, 6.83; 95% CI, 2.94–20.8; p < 10−4), and an interval of >3 hrs between hospital admission and administration of antibiotics (OR, 14.12; 95% CI, 3.93–50.9; p < 10−4). In contrast, a cerebrospinal fluid leukocyte count >103 cells/&mgr;L had a protective effect (OR, 0.30; 95% CI, 0.10–0.944; p = 0.04). Conclusions:Independent of severity at the time of ICU admission, isolation of penicillin-nonsusceptible strains and a delay in antibiotic treatment following admission were predictors of mortality among patients with pneumococcal meningitis.

Temporal changes in management and outcome of septic shock in patients with malignancies in the intensive care unit.

Objective:Septic shock is a severe, often terminal, complication of malignancy. For patients without malignancy, outcome from septic shock has improved with new advances in care. We wished to explore whether outcome from septic shock has similarly improved for cancer patients, with regard to implementation of recent adjuvant therapies. Design:An 8-yr retrospective observational study. Setting:A 24-bed medical intensive care unit in a university hospital. Patients:Patients were 238 consecutive cancer patients (solid tumors or hematologic malignancies) with septic shock admitted to the intensive care unit within two consecutive 4-yr periods: 1998–2001 and 2002–2005. Interventions:None. Measurements and Main Results:Septic shock occurred in 90 patients in 1998–2001 and 148 in 2002–2005. Management of septic shock between the two periods mostly differed by emergence of adjuvant therapies of sepsis (mainly low-dose glucocorticoids) and intensive insulin therapy and a more frequent use of renal replacement therapy in the recent period. Short-term survival rates were significantly higher during 2002–2005 compared with the previous 4-yr period: 28-day, intensive care unit, and hospital survival rates were 47.3% vs. 27.8% (p = .003), 41.2% vs. 26.7% (p = .02), and 36.5% vs. 21.1% (p = .01), respectively. After adjustment, intensive care unit admission between 2002 and 2005 was an independent favorable prognostic factor for short-term outcome. Improved survival was mainly observed in patients who did not require renal replacement therapy during their stay in the intensive care unit (hospital survival 65% in 2002–2005 vs. 21.4% in 1998–2001, p < .001). Conclusions:Improved outcome in critically ill cancer patients extended to the subgroup of patients with septic shock. This might be ascribed both to a better selection of patients and to improvements in the care and management, including new therapeutic strategies for sepsis.

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.

Transforming growth factor-β: A mediator of cell regulation in acute respiratory distress syndrome

ObjectiveTo review recent advances in the use of transforming growth factor (TGF)-&bgr; in acute lung injury and to apply this knowledge to understanding the pathophysiology of this syndrome. Data Sources and Study SelectionPublished research and review articles in the English language related to the role of TGF-&bgr; in acute lung injury. Data Extraction and SynthesisThe cytokine TGF-&bgr; plays a critical role in the resolution of tissue injury in multiple organs, including the lung. Following injury, TGF-&bgr; has been most thoroughly evaluated during the late phases of tissue repair, where it plays a critical role in the development of pulmonary fibrosis. In contrast, recent animal studies showed that expression levels of several TGF-&bgr;-inducible genes were dramatically increased as early as 2 days after the induction of injury. The integrin &agr;v&bgr;6 activates latent TGF-&bgr; in the lungs. Mice lacking this integrin were completely protected from pulmonary edema in a model of bleomycin-induced acute lung injury. Pharmacologic inhibition of TGF-&bgr; also protected wild-type mice from pulmonary edema induced by bleomycin or Escherichia coli endotoxin. Similar findings also have been reported in patients in a clinical study evaluating TGF-&bgr; in the bronchoalveolar lavage fluid during the course of acute respiratory distress syndrome (ARDS). Indeed, the bronchoalveolar lavage concentrations were dramatically increased as early as 1 day after the initiation of ARDS criteria and were correlated with decreases in the Pao2/Fio2 ratio, suggesting an important role for TGF-b1 in the development of ARDS in humans. ConclusionsThese studies suggest that TGF-&bgr; not only participates in the late phase of acute lung injury, but also might be active early in acute lung injury and potentially could contribute to the development of pulmonary edema. Integrin-mediated local activation of TGF-&bgr; is critical to the development of pulmonary edema in ARDS, and blocking TGF-&bgr; or its activation could be an effective treatment for this disorder.

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.

Benefit of an early and systematic imaging procedure after cardiac arrest: Insights from the PROCAT (Parisian Region Out of Hospital Cardiac Arrest) registry ☆

AIMS Identification of the cause of out-of-hospital cardiac arrest (OHCA) is of paramount importance. We investigated the ability of our imaging strategy to provide an early etiological diagnosis of OHCA and the influence of this strategy on ICU survival. METHODS Retrospective review of a prospectively acquired ICU database (01/2000-12/2010) including all OHCA patients without obvious extracardiac cause, for which an early diagnosis research was conducted (coronary angiography and/or brain and chest CT scan) within 24h after resuscitation. These procedures could be performed separately or be combined, according to a decision algorithm. RESULTS Of the 1274 patients admitted after OHCA during this 10-year period, the imaging strategy was applied in 896 patients. Patients who benefited from coronary angiography and/or CT scan were admitted to our ICU after a median delay of 180 [130-220]min after resuscitation. Seven hundred and forty-five coronary angiographies were performed, of which 452 (61%) identified at least one significant coronary lesion deemed responsible for the OHCA. CT-scan was performed in 355 patients and provided a diagnosis in 72 patients (20%), mainly stroke (n=38) and pulmonary embolism (n=19). Overall, this strategy allowed early diagnosis in 524 patients (59%). ICU survival was significantly higher for patients with a diagnosis identified by coronary angiography as compared with CT-scan (43% vs 10%, p<0.001). CONCLUSION The use of an early diagnosis protocol with immediate coronary angiography and/or CT scan provided the etiology of nearly two thirds of OHCA cases. In this large retrospective database, coronary angiography yielded a better diagnostic value than brain and/or chest CT-scan.

Determinants of recovery from severe posterior reversible encephalopathy syndrome.

Objective Few outcome data are available about posterior reversible encephalopathy syndrome (PRES). We studied 90-day functional outcomes and their determinants in patients with severe PRES. Design 70 patients with severe PRES admitted to 24 ICUs in 2001–2010 were included in a retrospective cohort study. The main outcome measure was a Glasgow Outcome Scale (GOS) of 5 (good recovery) on day 90. Main Results Consciousness impairment was the most common clinical sign, occurring in 66 (94%) patients. Clinical seizures occurred in 57 (81%) patients. Median mean arterial pressure was 122 (105–143) mmHg on scene. Cerebral imaging abnormalities were bilateral (93%) and predominated in the parietal (93%) and occipital (86%) white matter. Median number of brain areas involved was 4 (3–5). Imaging abnormalities resolved in 43 (88%) patients. Ischaemic and/or haemorrhagic complications occurred in 7 (14%) patients. The most common causes were drug toxicity (44%) and hypertensive encephalopathy (41%). On day 90, 11 (16%) patients had died, 26 (37%) had marked functional impairments (GOS, 2 to 4), and 33 (56%) had a good recovery (GOS, 5). Factors independently associated with GOS<5 were highest glycaemia on day 1 (OR, 1.22; 95%CI, 1.02–1.45, p = 0.03) and time to causative-factor control (OR, 3.3; 95%CI, 1.04–10.46, p = 0.04), whereas GOS = 5 was associated with toxaemia of pregnancy (preeclampsia/eclampsia) (OR, 0.06; 95%CI, 0.01–0.38, p = 0.003). Conclusions By day 90 after admission for severe PRES, 44% of survivors had severe functional impairments. Highest glycaemia on day 1 and time to causative-factor control were strong early predictors of outcomes, suggesting areas for improvement.

Plasma-induced endothelial oxidative stress is related to the severity of septic shock.

Objective:To estimate the capacity of plasma from septic shock patients to induce in vitro reactive oxygen species (ROS) production by endothelial cells and to analyze whether ROS production is related to the severity of the septic shock. Design:Prospective, observational study. Setting:Medical intensive care unit in a university hospital. Patients:Twenty-one patients with septic shock. Interventions:The in vitro capacity of plasma from septic shock patients to induce ROS production by naive human umbilical vein endothelial cells (HUVEC) was quantified by using a fluorescent probe (2′,7′-dichlorodihydrofluorescein diacetate). Measurements and Main Results:Blood samples were collected on day 1, day 3, and day 5 from 21 consecutive septic shock adult patients and from ten healthy volunteers. Patients mean age was 58 yrs old, mean Sequential Organ Failure Assessment (SOFA) score at admission was 12, mean severity illness assessed by Simplified Acute Physiology Score (SAPS) II was 53, and the mortality rate was 47%. In addition to assessment of in vitro ROS generation by HUVEC, oxidative stress in blood was evaluated by measuring lipid peroxidation products and enzymatic and nonenzymatic antioxidants. Septic shock was associated with oxidative stress and an imbalance in antioxidant status. As compared with controls, plasma-induced ROS production by naïve HUVEC was significantly higher in septic shock. Moreover ROS production was significantly correlated with SAPS II (p = .028) and SOFA values (p = .0012) and was higher in nonsurvivors than in survivors. In contrast, no correlation was found between the severity of the septic shock and any of the levels of lipid peroxidation products or enzymatic and nonenzymatic antioxidants. Conclusion:Plasma from septic shock patients induces ROS formation by naive HUVEC, and the extent of ROS formation correlates with mortality and with criteria of the severity of septic shock as SOFA score and SAPS II.

Endovascular Versus External Targeted Temperature Management for Patients With Out-of-Hospital Cardiac Arrest A Randomized, Controlled Study

Background— Targeted temperature management is recommended after out-of-hospital cardiac arrest. Whether advanced internal cooling is superior to basic external cooling remains unknown. The aim of this multicenter, controlled trial was to evaluate the benefit of endovascular versus basic surface cooling. Methods and Results— Inclusion criteria were the following: age of 18 to 79 years, out-of-hospital cardiac arrest related to a presumed cardiac cause, time to return of spontaneous circulation <60 minutes, delay between return of spontaneous circulation and inclusion <240 minutes, and unconscious patient after return of spontaneous circulation and before the start of cooling. Exclusion criteria were terminal disease, pregnancy, known coagulopathy, uncontrolled bleeding, temperature on admission <30°C, in-hospital cardiac arrest, immediate need for extracorporeal life support or hemodialysis. Patients were randomized between 2 cooling strategies: endovascular femoral devices (Icy catheter, Coolgard, Zoll, formerly Alsius; n=203) or basic external cooling using fans, a homemade tent, and ice packs (n=197). The primary end point, that is, favorable outcome evaluated by survival without major neurological damage (Cerebral Performance Categories 1–2) at day 28, was not significantly different between groups (odds ratio, 1.41; 95% confidence interval, 0.93–2.16; P=0.107). Improvement in favorable outcome at day 90 in favor of the endovascular group did not reach significance (odds ratio, 1.51; 95% confidence interval, 0.96–2.35; P=0.07). Time to target temperature (33°C) was significantly shorter and target hypothermia was more strictly maintained in the endovascular than in the surface group (P<0.001). Minor side effects directly related to the cooling method were observed more frequently in the endovascular group (P=0.009). Conclusion— Despite better hypothermia induction and maintenance, endovascular cooling was not significantly superior to basic external cooling in terms of favorable outcome. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00392639.