Hydrocortisone plus fludrocortisone for community acquired pneumonia-related septic shock: a subgroup analysis of the APROCCHSS phase 3 randomised trial.

BACKGROUND: Glucocorticoids probably improve outcomes in patients hospitalised for community acquired pneumonia (CAP). In this a priori planned exploratory subgroup analysis of the phase 3 randomised controlled Activated Protein C and Corticosteroids for Human Septic Shock (APROCCHSS) trial, we aimed to investigate responses to hydrocortisone plus fludrocortisone between CAP and non-CAP related septic shock. METHODS: APROCCHSS was a randomised controlled trial that investigated the effects of hydrocortisone plus fludrocortisone, drotrecogin-alfa (activated), or both on mortality in septic shock in a two-by-two factorial design; after drotrecogin-alfa was withdrawn on October 2011, from the market, the trial continued on two parallel groups. It was conducted in 34 centres in France. In this subgroup study, patients with CAP were a preselected subgroup for an exploratory secondary analysis of the APROCCHSS trial of hydrocortisone plus fludrocortisone in septic shock. Adults with septic shock were randomised 1:1 to receive, in a double-blind manner, a 7-day treatment with daily administration of intravenous hydrocortisone 50 mg bolus every 6h and a tablet of 50 µg of fludrocortisone via the nasogastric tube, or their placebos. The primary outcome was 90-day all-cause mortality. Secondary outcomes included all-cause mortality at intensive care unit (ICU) and hospital discharge, 28-day and 180-day mortality, the number of days alive and free of vasopressors, mechanical ventilation, or organ failure, and ICU and hospital free-days to 90-days. Analysis was done in the intention-to-treat population. The trial was registered at ClinicalTrials.gov (NCT00625209). FINDINGS: Of 1241 patients included in the APROCCHSS trial, CAP could not be ruled in or out in 31 patients, 562 had a diagnosis of CAP (279 in the placebo group and 283 in the corticosteroid group), and 648 patients did not have CAP (329 in the placebo group and 319 in the corticosteroid group). In patients with CAP, there were 109 (39%) deaths of 283 patients at day 90 with hydrocortisone plus fludrocortisone and 143 (51%) of 279 patients receiving placebo (odds ratio [OR] 0·60, 95% CI 0·43-0·83). In patients without CAP, there were 148 (46%) deaths of 319 patients at day 90 in the hydrocortisone and fludrocortisone group and 157 (48%) of 329 patients in the placebo group (OR 0·95, 95% CI 0·70-1·29). There was significant heterogeneity in corticosteroid effects on 90-day mortality across subgroups with CAP and without CAP (p=0·046 for both multiplicative and additive interaction tests; moderate credibility). Of 1241 patients included in the APROCCHSS trial, 648 (52%) had ARDS (328 in the placebo group and 320 in the corticosteroid group). There were 155 (48%) deaths of 320 patients at day 90 in the corticosteroid group and 186 (57%) of 328 patients in the placebo group. The OR for death at day 90 was 0·72 (95% CI 0·53-0·98) in patients with ARDS and 0·85 (0·61-1·20) in patients without ARDS (p=0·45 for multiplicative interaction and p=0·42 for additive interaction). The OR for observing at least one serious adverse event (corticosteroid group vs placebo) within 180 days post randomisation was 0·64 (95% CI 0·46-0·89) in the CAP subgroup and 1·02 (0·75-1·39) in the non-CAP subgroup (p=0·044 for multiplicative interaction and p=0·042 for additive interaction). INTERPRETATION: In a pre-specified subgroup analysis of the APROCCHSS trial of patients with CAP and septic shock, hydrocortisone plus fludrocortisone reduced mortality as compared with placebo. Although a large proportion of patients with CAP also met criteria for ARDS, the subgroup analysis was underpowered to fully discriminate between ARDS and CAP modifying effects on mortality reduction with corticosteroids. There was no evidence of a significant treatment effect of corticosteroids in the non-CAP subgroup. FUNDING: Programme Hospitalier de Recherche Clinique of the French Ministry of Health, by Programme d'Investissements d'Avenir, France 2030, and IAHU-ANR-0004.

Fluid balance control in critically ill patients: results from as-treated analyses of POINCARE-2 randomized trial.

BACKGROUND: Intention-to-treat analyses of POINCARE-2 trial led to inconclusive results regarding the effect of a conservative fluid balance strategy on mortality in critically ill patients. The present as-treated analysis aimed to assess the effectiveness of actual exposure to POINCARE-2 strategy on 60-day mortality in critically ill patients. METHODS: POINCARE­2 was a stepped wedge randomized controlled trial. Eligible patients were ≥ 18 years old, under mechanical ventilation and had an expected length of stay in ICU > 24 h. POINCARE-2 strategy consisted of daily weighing over 14 days, and subsequent restriction of fluid intake, administration of diuretics, and/or ultrafiltration. We computed a score of exposure to the strategy based on deviations from the strategy algorithm. We considered patients with a score ≥ 75 as exposed to the strategy. We used logistic regression adjusted for confounders (ALR) or for an instrumental variable (IVLR). We handled missing data using multiple imputations. RESULTS: A total of 1361 patients were included. Overall, 24.8% of patients in the control group and 69.4% of patients in the strategy group had a score of exposure ≥ 75. Exposure to the POINCARE-2 strategy was not associated with 60-day all-cause mortality (ALR: OR 1.2, 95% CI 0.85-1.55; IVLR: OR 1.0, 95% CI 0.76-1.33). CONCLUSION: Actual exposure to POINCARE-2 conservative strategy was not associated with reduced mortality in critically ill patients. Trial registration POINCARE-2 trial is registered at ClinicalTrials.gov (NCT02765009). Registered 29 April 2016.

Fluid balance control in critically ill patients: results from POINCARE-2 stepped wedge cluster-randomized trial.

BACKGROUND: In critically ill patients, positive fluid balance is associated with excessive mortality. The POINCARE-2 trial aimed to assess the effectiveness of a fluid balance control strategy on mortality in critically ill patients. METHODS: POINCARE-2 was a stepped wedge cluster open-label randomized controlled trial. We recruited critically ill patients in twelve volunteering intensive care units from nine French hospitals. Eligible patients were ≥ 18 years old, under mechanical ventilation, admitted to one of the 12 recruiting units for > 48 and ≤ 72 h, and had an expected length of stay after inclusion > 24 h. Recruitment started on May 2016 and ended on May 2019. Of 10,272 patients screened, 1361 met the inclusion criteria and 1353 completed follow-up. The POINCARE-2 strategy consisted of a daily weight-driven restriction of fluid intake, diuretics administration, and ultrafiltration in case of renal replacement therapy between Day 2 and Day 14 after admission. The primary outcome was 60-day all-cause mortality. We considered intention-to-treat analyses in cluster-randomized analyses (CRA) and in randomized before-and-after analyses (RBAA). RESULTS: A total of 433 (643) patients in the strategy group and 472 (718) in the control group were included in the CRA (RBAA). In the CRA, mean (SD) age was 63.7 (14.1) versus 65.7 (14.3) years, and mean (SD) weight at admission was 78.5 (20.0) versus 79.4 (23.5) kg. A total of 129 (160) patients died in the strategy (control) group. Sixty-day mortality did not differ between groups [30.5%, 95% confidence interval (CI) 26.2-34.8 vs. 33.9%, 95% CI 29.6-38.2, p = 0.26]. Among safety outcomes, only hypernatremia was more frequent in the strategy group (5.3% vs. 2.3%, p = 0.01). The RBAA led to similar results. CONCLUSION: The POINCARE-2 conservative strategy did not reduce mortality in critically ill patients. However, due to open-label and stepped wedge design, intention-to-treat analyses might not reflect actual exposure to this strategy, and further analyses might be required before completely discarding it. Trial registration POINCARE-2 trial was registered at ClinicalTrials.gov (NCT02765009). Registered 29 April 2016.

Astrocyte-neuron crosstalk through Hedgehog signaling mediates cortical synapse development.

Neuron-glia interactions play a critical role in the regulation of synapse formation and circuit assembly. Here we demonstrate that canonical Sonic hedgehog (Shh) pathway signaling in cortical astrocytes acts to coordinate layer-specific synaptic connectivity. We show that the Shh receptor Ptch1 is expressed by cortical astrocytes during development and that Shh signaling is necessary and sufficient to promote the expression of genes involved in regulating synaptic development and layer-enriched astrocyte molecular identity. Loss of Shh in layer V neurons reduces astrocyte complexity and coverage by astrocytic processes in tripartite synapses; conversely, cell-autonomous activation of Shh signaling in astrocytes promotes cortical excitatory synapse formation. Furthermore, Shh-dependent genes Lrig1 and Sparc distinctively contribute to astrocyte morphology and synapse formation. Together, these results suggest that Shh secreted from deep-layer cortical neurons acts to specialize the molecular and functional features of astrocytes during development to shape circuit assembly and function.

Epidemiology and outcome of patients admitted to intensive care after anaphylaxis in France: a retrospective multicentre study.

BACKGROUND: Few data are available on patients who have experienced anaphylaxis and were admitted to ICUs. The purpose of this observational study was to describe the epidemiology and management of these patients. METHODS: This was a multicentre retrospective study carried out in 23 French ICUs between 2012 and 2017. All patients who suffered anaphylaxis and were transferred to an ICU were included. Data were collected using an electronic database after approval by an ethics committee. RESULTS: A total of 339 patients were included, and 17 (5%) died secondary to anaphylaxis. The main triggers were drugs (77%), contrast media (11%), and food (7%). Epinephrine was administered before ICU admission in 88% of patients with Grade III anaphylaxis and 100% of patients with Grade IV anaphylaxis. Most patients with Grades III and IV anaphylaxes did not receive the recommended dose of i.v. fluid of 30 ml kg-1 within the first 4 h of ICU admission. The time to epinephrine administration was not statistically different between survivors and non-survivors, but non-survivors received a higher dose of epinephrine (median: 5 [3-10] vs 3 [2-7] mg; P<0.0001), which suggests that some forms of anaphylactic shock may be resistant to epinephrine. In multivariate analysis, only lactate concentration at ICU admission was a predictor of death (odds ratio: 1.47 [1.15-1.88]; P=0.002). CONCLUSIONS: Lactate concentration at ICU admission appeared to be the most reliable criterion for assessing prognosis. Epinephrine is widely used during anaphylaxis, but the volume of fluid resuscitation was consistently lower than recommended. CLINICAL TRIAL REGISTRATION: NCT04290507.

Sex Differences in Biophysical Signatures across Molecularly Defined Medial Amygdala Neuronal Subpopulations.

The medial amygdala (MeA) is essential for processing innate social and non-social behaviors, such as territorial aggression and mating, which display in a sex-specific manner. While sex differences in cell numbers and neuronal morphology in the MeA are well established, if and how these differences extend to the biophysical level remain unknown. Our previous studies revealed that expression of the transcription factors, Dbx1 and Foxp2, during embryogenesis defines separate progenitor pools destined to generate different subclasses of MEA inhibitory output neurons. We have also previously shown that Dbx1-lineage and Foxp2-lineage neurons display different responses to innate olfactory cues and in a sex-specific manner. To examine whether these neurons also possess sex-specific biophysical signatures, we conducted a multidimensional analysis of the intrinsic electrophysiological profiles of these transcription factor defined neurons in the male and female MeA. We observed striking differences in the action potential (AP) spiking patterns across lineages, and across sex within each lineage, properties known to be modified by different voltage-gated ion channels. To identify the potential mechanism underlying the observed lineage-specific and sex-specific differences in spiking adaptation, we conducted a phase plot analysis to narrow down putative ion channel candidates. Of these candidates, we found a subset expressed in a lineage-biased and/or sex-biased manner. Thus, our results uncover neuronal subpopulation and sex differences in the biophysical signatures of developmentally defined MeA output neurons, providing a potential physiological substrate for how the male and female MeA may process social and non-social cues that trigger innate behavioral responses.

Outcomes of Stenotrophomonas maltophilia hospital-acquired pneumonia in intensive care unit: a nationwide retrospective study.

BACKGROUND: There is little descriptive data on Stenotrophomonas maltophilia hospital-acquired pneumonia (HAP) in critically ill patients. The optimal modalities of antimicrobial therapy remain to be determined. Our objective was to describe the epidemiology and prognostic factors associated with S. maltophilia pneumonia, focusing on antimicrobial therapy. METHODS: This nationwide retrospective study included all patients admitted to 25 French mixed intensive care units between 2012 and 2017 with hospital-acquired S. maltophilia HAP during intensive care unit stay. Primary endpoint was time to in-hospital death. Secondary endpoints included microbiologic effectiveness and antimicrobial therapeutic modalities such as delay to appropriate antimicrobial treatment, mono versus combination therapy, and duration of antimicrobial therapy. RESULTS: Of the 282 patients included, 84% were intubated at S. maltophilia HAP diagnosis for duration of 11 [5-18] days. The Simplified Acute Physiology Score II was 47 [36-63], and the in-hospital mortality was 49.7%. Underlying chronic pulmonary comorbidities were present in 14.1% of cases. Empirical antimicrobial therapy was considered effective on S. maltophilia according to susceptibility patterns in only 30% of cases. Delay to appropriate antimicrobial treatment had, however, no significant impact on the primary endpoint. Survival analysis did not show any benefit from combination antimicrobial therapy (HR = 1.27, 95%CI [0.88; 1.83], p = 0.20) or prolonged antimicrobial therapy for more than 7 days (HR = 1.06, 95%CI [0.6; 1.86], p = 0.84). No differences were noted in in-hospital death irrespective of an appropriate and timely empiric antimicrobial therapy between mono- versus polymicrobial S. maltophilia HAP (p = 0.273). The duration of ventilation prior to S. maltophilia HAP diagnosis and ICU length of stay were shorter in patients with monomicrobial S. maltophilia HAP (p = 0.031 and p = 0.034 respectively). CONCLUSIONS: S. maltophilia HAP occurred in severe, long-stay intensive care patients who mainly required prolonged invasive ventilation. Empirical antimicrobial therapy was barely effective while antimicrobial treatment modalities had no significant impact on hospital survival. TRIAL REGISTRATION: clinicaltrials.gov, NCT03506191.

Effect of fluid balance control in critically ill patients: Design of the stepped wedge trial POINCARE-2.

A high number of recent studies have shown that a positive fluid balance is independently associated with impaired prognosis in specific populations of patients hospitalized in intensive care unit (ICU): acute kidney injury, acute respiratory distress syndrome (ARDS), sepsis, high risk surgery. However, to date, there is no evidence that control of fluid overload reduces mortality in critically ill patients. The main objective is to assess the efficacy of a strategy limiting fluid overload on mortality in unselected critically ill patients hospitalized in ICU. We hypothesized that a strategy based on a weight-driven recommendation of restricted fluid intake, diuretics, and ultrafiltration initiated from 48 h up to 14 days after admission in critically ill patients would reduce all-cause mortality as compared to usual care. We use a stepped wedge cluster randomized controlled trial combined with a quasi-experimental (before-and-after) study. Patients under mechanical ventilation, admitted since >48 h and < 72 h in ICU, and with no discharge planned for the next 24 h are eligible. A total of 1440 patients are expected to be enrolled in 12 ICUs. Sociodemographic and clinical data are collected at inclusion, and outcomes are collected during the follow-up. Primary outcome is all-cause mortality at 60 days after admission. Secondary outcomes are patients weight differences between admission and day7 (or day 14), 28-day, in-hospital, and 1-year mortality, end-organ damages, and unintended harmful events. Analyses will be held in intention-to-treat. If POINCARE-2 strategy proves effective, then guidelines on fluid balance control might be extended to all critically ill patients. Trial registration: ClinicalTrials.govNCT02765009.

Hydrocortisone plus Fludrocortisone for Adults with Septic Shock.

BACKGROUND: Septic shock is characterized by dysregulation of the host response to infection, with circulatory, cellular, and metabolic abnormalities. We hypothesized that therapy with hydrocortisone plus fludrocortisone or with drotrecogin alfa (activated), which can modulate the host response, would improve the clinical outcomes of patients with septic shock. METHODS: In this multicenter, double-blind, randomized trial with a 2-by-2 factorial design, we evaluated the effect of hydrocortisone-plus-fludrocortisone therapy, drotrecogin alfa (activated), the combination of the three drugs, or their respective placebos. The primary outcome was 90-day all-cause mortality. Secondary outcomes included mortality at intensive care unit (ICU) discharge and hospital discharge and at day 28 and day 180 and the number of days alive and free of vasopressors, mechanical ventilation, or organ failure. After drotrecogin alfa (activated) was withdrawn from the market, the trial continued with a two-group parallel design. The analysis compared patients who received hydrocortisone plus fludrocortisone with those who did not (placebo group). RESULTS: Among the 1241 patients included in the trial, the 90-day mortality was 43.0% (264 of 614 patients) in the hydrocortisone-plus-fludrocortisone group and 49.1% (308 of 627 patients) in the placebo group (P=0.03). The relative risk of death in the hydrocortisone-plus-fludrocortisone group was 0.88 (95% confidence interval, 0.78 to 0.99). Mortality was significantly lower in the hydrocortisone-plus-fludrocortisone group than in the placebo group at ICU discharge (35.4% vs. 41.0%, P=0.04), hospital discharge (39.0% vs. 45.3%, P=0.02), and day 180 (46.6% vs. 52.5%, P=0.04) but not at day 28 (33.7% and 38.9%, respectively; P=0.06). The number of vasopressor-free days to day 28 was significantly higher in the hydrocortisone-plus-fludrocortisone group than in the placebo group (17 vs. 15 days, P<0.001), as was the number of organ-failure-free days (14 vs. 12 days, P=0.003). The number of ventilator-free days was similar in the two groups (11 days in the hydrocortisone-plus-fludrocortisone group and 10 in the placebo group, P=0.07). The rate of serious adverse events did not differ significantly between the two groups, but hyperglycemia was more common in hydrocortisone-plus-fludrocortisone group. CONCLUSIONS: In this trial involving patients with septic shock, 90-day all-cause mortality was lower among those who received hydrocortisone plus fludrocortisone than among those who received placebo. (Funded by Programme Hospitalier de Recherche Clinique 2007 of the French Ministry of Social Affairs and Health; APROCCHSS ClinicalTrials.gov number, NCT00625209 .).

Gene expression profile of blood cells for the prediction of delayed cerebral ischemia after intracranial aneurysm rupture: a pilot study in humans.

BACKGROUND: Delayed cerebral ischemia (DCI) is a potentially devastating complication after intracranial aneurysm rupture and its mechanisms remain poorly elucidated. Early identification of the patients prone to developing DCI after rupture may represent a major breakthrough in its prevention and treatment. The single gene approach of DCI has demonstrated interest in humans. We hypothesized that whole genome expression profile of blood cells may be useful for better comprehension and prediction of aneurysmal DCI. METHODS: Over a 35-month period, 218 patients with aneurysm rupture were included in this study. DCI was defined as the occurrence of a new delayed neurological deficit occurring within 2 weeks after aneurysm rupture with evidence of ischemia either on perfusion-diffusion MRI, CT angiography or CT perfusion imaging, or with cerebral angiography. DCI patients were matched against controls based on 4 out of 5 criteria (age, sex, Fisher grade, aneurysm location and smoking status). Genome-wide expression analysis of blood cells obtained at admission was performed by microarrays. Transcriptomic analysis was performed using long oligonucleotide microarrays representing 25,000 genes. Quantitative PCR: 1 µg of total RNA extracted was reverse-transcribed, and the resulting cDNA was diluted 10-fold before performing quantitative PCR. Microarray data were first analyzed by 'Significance Analysis of Microarrays' software which includes the Benjamini correction for multiple testing. In a second step, microarray data fold change was compared using a two-tailed, paired t test. Analysis of receiver-operating characteristic (ROC) curves and the area under the ROC curves were used for prediction analysis. Logistic regression models were used to investigate the additive value of multiple biomarkers. RESULTS: A total of 16 patients demonstrated DCI. Significance Analysis of Microarrays software failed to retrieve significant genes, most probably because of the heterogeneity of the patients included in the microarray experiments and the small size of the DCI population sample. Standard two-tailed paired t test and C-statistic revealed significant associations between gene expression and the occurrence of DCI: in particular, the expression of neuroregulin 1 was 1.6-fold upregulated in patients with DCI (p = 0.01) and predicted DCI with an area under the ROC curve of 0.96. Logistic regression analyses revealed a significant association between neuroregulin 1 and DCI (odds ratio 1.46, 95% confidence interval 1.02-2.09, p = 0.02). CONCLUSIONS: This pilot study suggests that blood cells may be a reservoir of prognostic biomarkers of DCI in patients with intracranial aneurysm rupture. Despite an evident lack of power, this study elicited neuroregulin 1, a vasoreactivity-, inflammation- and angiogenesis-related gene, as a possible candidate predictor of DCI. Larger cohort studies are needed but genome-wide microarray-based studies are promising research tools for the understanding of DCI after intracranial aneurysm rupture.

Effects of fluid resuscitation with colloids vs crystalloids on mortality in critically ill patients presenting with hypovolemic shock: the CRISTAL randomized trial.

IMPORTANCE: Evidence supporting the choice of intravenous colloid vs crystalloid solutions for management of hypovolemic shock remains unclear. OBJECTIVE: To test whether use of colloids compared with crystalloids for fluid resuscitation alters mortality in patients admitted to the intensive care unit (ICU) with hypovolemic shock. DESIGN, SETTING, AND PARTICIPANTS: A multicenter, randomized clinical trial stratified by case mix (sepsis, trauma, or hypovolemic shock without sepsis or trauma). Therapy in the Colloids Versus Crystalloids for the Resuscitation of the Critically Ill (CRISTAL) trial was open label but outcome assessment was blinded to treatment assignment. Recruitment began in February 2003 and ended in August 2012 of 2857 sequential ICU patients treated at 57 ICUs in France, Belgium, North Africa, and Canada; follow-up ended in November 2012. INTERVENTIONS: Colloids (n = 1414; gelatins, dextrans, hydroxyethyl starches, or 4% or 20% of albumin) or crystalloids (n = 1443; isotonic or hypertonic saline or Ringer lactate solution) for all fluid interventions other than fluid maintenance throughout the ICU stay. MAIN OUTCOMES AND MEASURES: The primary outcome was death within 28 days. Secondary outcomes included 90-day mortality; and days alive and not receiving renal replacement therapy, mechanical ventilation, or vasopressor therapy. RESULTS: Within 28 days, there were 359 deaths (25.4%) in colloids group vs 390 deaths (27.0%) in crystalloids group (relative risk [RR], 0.96 [95% CI, 0.88 to 1.04]; P = .26). Within 90 days, there were 434 deaths (30.7%) in colloids group vs 493 deaths (34.2%) in crystalloids group (RR, 0.92 [95% CI, 0.86 to 0.99]; P = .03). Renal replacement therapy was used in 156 (11.0%) in colloids group vs 181 (12.5%) in crystalloids group (RR, 0.93 [95% CI, 0.83 to 1.03]; P = .19). There were more days alive without mechanical ventilation in the colloids group vs the crystalloids group by 7 days (mean: 2.1 vs 1.8 days, respectively; mean difference, 0.30 [95% CI, 0.09 to 0.48] days; P = .01) and by 28 days (mean: 14.6 vs 13.5 days; mean difference, 1.10 [95% CI, 0.14 to 2.06] days; P = .01) and alive without vasopressor therapy by 7 days (mean: 5.0 vs 4.7 days; mean difference, 0.30 [95% CI, -0.03 to 0.50] days; P = .04) and by 28 days (mean: 16.2 vs 15.2 days; mean difference, 1.04 [95% CI, -0.04 to 2.10] days; P = .03). CONCLUSIONS AND RELEVANCE: Among ICU patients with hypovolemia, the use of colloids vs crystalloids did not result in a significant difference in 28-day mortality. Although 90-day mortality was lower among patients receiving colloids, this finding should be considered exploratory and requires further study before reaching conclusions about efficacy. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00318942.

Recombinant human activated protein C for adults with septic shock: a randomized controlled trial.

RATIONALE: A decade after drotrecogin alfa (activated) (DAA) was released on the market worldwide, its benefit-to-risk ratio remains a matter of debate. OBJECTIVES: The current investigator-led trial was designed to evaluate the efficacy and safety of DAA, in combination with low-dose steroids, in adults with persistent septic shock. METHODS: This was a multicenter (24 intensive care units), placebo-controlled, double-blind, 2 × 2 factorial design trial in which adults with persistent septic shock and no contraindication to DAA were randomly assigned to DAA alone (24 µg/kg/h for 96 h), hydrocortisone and fludrocortisone alone, their respective combinations, or their respective placebos. Primary outcome was mortality rate on Day 90. MEASUREMENTS AND MAIN RESULTS: On October 25, 2011, the trial was suspended after the withdrawal from the market of DAA. The Scientific Committee decided to continue the trial according to a two parallel group design comparing low-dose steroids with their placebos and to analyze the effects of DAA on patients included before trial suspension. At the time trial was suspended, 411 patients had been recruited, 208 had received DAA, and 203 had received its placebo. There was no significant interaction between DAA and low-dose steroids (P = 0.47). On Day 90, there were 99 deaths (47.6%) among the 208 patients receiving DAA and 94 deaths (46.3%) among the 203 patients receiving placebo (P = 0.79). There was no evidence of a difference between DAA and its placebo for any secondary outcomes or serious adverse events. CONCLUSIONS: In adults with established and severe septic shock, DAA showed no evidence of benefit or harm. Clinical trial registered with www.clinicaltrials.gov (NCT00625209).

Adrenal trauma: medical and surgical emergency.

A 35-year-old man was admitted to hospital in a state of haemorrhagic shock after a road traffic accident. A right adrenal gland injury associated with a retroperitoneal haematoma was diagnosed by CT scan. Haemostatic surgery (without adrenal gland resection) was performed instead of angioembolisation because of an associated abdominal compartment syndrome. The outcome was favourable. The objective of this case report is to illustrate the importance of the early diagnosis of adrenal gland injuries after trauma which, though uncommon and frequently overlooked or discovered fortuitously by CT scan, can be life-threatening. Angioembolisation or surgery may be necessary in cases of uncontrolled bleeding or the development of abdominal compartmental syndrome.

Early-onset ventilator-associated pneumonia in adults randomized clinical trial: comparison of 8 versus 15 days of antibiotic treatment.

PURPOSE: The optimal treatment duration for ventilator-associated pneumonia is based on one study dealing with late-onset of the condition. Shortening the length of antibiotic treatment remains a major prevention factor for the emergence of multiresistant bacteria. OBJECTIVE: To demonstrate that 2 different antibiotic treatment durations (8 versus 15 days) are equivalent in terms of clinical cure for early-onset ventilator-associated pneumonia. METHODS: Randomized, prospective, open, multicenter trial carried out from 1998 to 2002. MEASUREMENTS: The primary endpoint was the clinical cure rate at day 21. The mortality rate was evaluated on days 21 and 90. RESULTS: 225 patients were included in 13 centers. 191 (84.9%) patients were cured: 92 out of 109 (84.4%) in the 15 day cohort and 99 out of 116 (85.3%) in the 8 day cohort (difference = 0.9%, odds ratio = 0.929). 95% two-sided confidence intervals for difference and odds ratio were [-8.4% to 10.3%] and [0.448 to 1.928] respectively. Taking into account the limits of equivalence (10% for difference and 2.25 for odds ratio), the objective of demonstrative equivalence between the 2 treatment durations was fulfilled. Although the rate of secondary infection was greater in the 8 day than the 15 day cohort, the number of days of antibiotic treatment remained lower in the 8 day cohort. There was no difference in mortality rate between the 2 groups on days 21 and 90. CONCLUSION: Our results suggest that an 8-day course of antibiotic therapy is safe for early-onset ventilator-associated pneumonia in intubated patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT01559753.

Norepinephrine plus dobutamine versus epinephrine alone for management of septic shock: a randomised trial.

BACKGROUND: International guidelines for management of septic shock recommend that dopamine or norepinephrine are preferable to epinephrine. However, no large comparative trial has yet been done. We aimed to compare the efficacy and safety of norepinephrine plus dobutamine (whenever needed) with those of epinephrine alone in septic shock. METHODS: This prospective, multicentre, randomised, double-blind study was done in 330 patients with septic shock admitted to one of 19 participating intensive care units in France. Participants were assigned to receive epinephrine (n=161) or norepinephrine plus dobutamine (n=169), which were titrated to maintain mean blood pressure at 70 mm Hg or more. The primary outcome was 28-day all-cause mortality. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00148278. FINDINGS: There were no patients lost to follow-up; one patient withdrew consent after 3 days. At day 28, there were 64 (40%) deaths in the epinephrine group and 58 (34%) deaths in the norepinephrine plus dobutamine group (p=0.31; relative risk 0.86, 95% CI 0.65-1.14). There was no significant difference between the two groups in mortality rates at discharge from intensive care (75 [47%] deaths vs 75 [44%] deaths, p=0.69), at hospital discharge (84 [52%] vs 82 [49%], p=0.51), and by day 90 (84 [52%] vs 85 [50%], p=0.73), time to haemodynamic success (log-rank p=0.67), time to vasopressor withdrawal (log-rank p=0.09), and time course of SOFA score. Rates of serious adverse events were also similar. INTERPRETATION: There is no evidence for a difference in efficacy and safety between epinephrine alone and norepinephrine plus dobutamine for the management of septic shock.

Improvement of donor myocardial function after treatment of autonomic storm during brain death.

BACKGROUND: In experimental brain death models, autonomic storm (AS) triggers severe myocardial dysfunction, which can be attenuated by pharmacologic treatment. The aim of this study was to determine the incidence of AS in a cohort of human organ donors and to evaluate the potential interest of AS treatment on myocardial function, cardiac harvesting and transplantation. METHODS: The cohort consisted of 152 patients. Among them, 46 patients were initially considered as potential cardiac donors (main criteria: age < 60 years, no history of cardiac disease). AS diagnosis included increased systolic arterial pressure > 200 mm Hg associated with tachycardia >140 beats/min. Heart acceptance criteria were associated creatine kinase (CK), troponin Ic, and left ventricle ejection fraction (LVEF) estimated by echocardiography and visual inspection. RESULTS: AS was observed in 29 patients (63%). Hypertension was treated in 12 patients (esmolol n = 6, urapidil n = 5, nicardipine). Cardiac harvesting was performed in 28 donors (61%). LVEFs were significantly higher after AS treatment (no AS: 55.4 +/- 13.4%, untreated AS: 49.0 +/- 18.8%, treated AS: 63.9+ +/- 10.3%, P = 0.049). AS treatment was found to be independently associated with LVEF in > 50% of the cases (P = 0.034). Treatment of AS or the lack of AS were associated with an increased probability of successful cardiac transplantation (OR = 8.8; 95% CI 2.1-38.3, P = 0.002). CONCLUSIONS: Treatment of hypertension during AS may attenuate brain death-induced myocardial dysfunction and increase the number of available cardiac grafts.

Baseline cortisol levels, cortisol response to corticotropin, and prognosis in late septic shock.

The prognostic value of basal and corticotropin-stimulated cortisol concentration in patients with sepsis remains a controversial issue. In a retrospective cohort study, 82 consecutive patients with septic shock underwent a short corticotropin test performed more than 24 h after the onset of vasopressor therapy. Forty-one (50%) patients died within 28 days after the onset of septic shock. The mean (SD) basal cortisol level was 22.7 (10.6) microg/dL. With threshold values of 7 and 9 microg/dL maximal increases in cortisol level, 28 (34%) and 31 (38%) patients were, respectively, classified as nonresponders to the short corticotropin test. On multivariate analysis, a cortisol level >20 microg/dL (P = 0.0002), a maximal response to corticotropin <9 microg/dL (P = 0.044), abnormal lactate values (P = 0.0098), and positive blood cultures (P = 0.004) were independent predictors of 28-day mortality. In conclusion, high basal cortisol and low increase on corticotropin stimulation are predictors of a poor outcome in late septic shock. The underlying mechanisms of these prognostic patterns remain to be elucidated.

Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock.

CONTEXT: Septic shock may be associated with relative adrenal insufficiency. Thus, a replacement therapy of low doses of corticosteroids has been proposed to treat septic shock. OBJECTIVE: To assess whether low doses of corticosteroids improve 28-day survival in patients with septic shock and relative adrenal insufficiency. DESIGN AND SETTING: Placebo-controlled, randomized, double-blind, parallel-group trial performed in 19 intensive care units in France from October 9, 1995, to February 23, 1999. PATIENTS: Three hundred adult patients who fulfilled usual criteria for septic shock were enrolled after undergoing a short corticotropin test. INTERVENTION: Patients were randomly assigned to receive either hydrocortisone (50-mg intravenous bolus every 6 hours) and fludrocortisone (50- micro g tablet once daily) (n = 151) or matching placebos (n = 149) for 7 days. MAIN OUTCOME MEASURE: Twenty-eight-day survival distribution in patients with relative adrenal insufficiency (nonresponders to the corticotropin test). RESULTS: One patient from the corticosteroid group was excluded from analyses because of consent withdrawal. There were 229 nonresponders to the corticotropin test (placebo, 115; corticosteroids, 114) and 70 responders to the corticotropin test (placebo, 34; corticosteroids, 36). In nonresponders, there were 73 deaths (63%) in the placebo group and 60 deaths (53%) in the corticosteroid group (hazard ratio, 0.67; 95% confidence interval, 0.47-0.95; P =.02). Vasopressor therapy was withdrawn within 28 days in 46 patients (40%) in the placebo group and in 65 patients (57%) in the corticosteroid group (hazard ratio, 1.91; 95% confidence interval, 1.29-2.84; P =.001). There was no significant difference between groups in responders. Adverse events rates were similar in the 2 groups. CONCLUSION: In our trial, a 7-day treatment with low doses of hydrocortisone and fludrocortisone significantly reduced the risk of death in patients with septic shock and relative adrenal insufficiency without increasing adverse events.