Pierre-Edouard Bollaert

Reversal of late septic shock with supraphysiologic doses of hydrocortisone

OBJECTIVESnPreliminary studies have suggested that low doses of corticosteroids might rapidly improve hemodynamics in late septic shock treated with catecholamines. We examined the effect of hydrocortisone on shock reversal, hemodynamics, and survival in this particular setting.nnnDESIGNnProspective, randomized, double-blind, placebo-controlled study.nnnSETTINGnTwo intensive care units of a University hospital.nnnPATIENTSnForty-one patients with septic shock requiring catecholamine for >48 hrs.nnnINTERVENTIONSnPatients were randomly assigned either hydrocortisone (100 mg i.v. three times daily for 5 days) or matching placebo.nnnMEASUREMENTS AND MAIN RESULTSnReversal of shock was defined by a stable systolic arterial pressure (>90 mm Hg) for > or =24 hrs without catecholamine or fluid infusion. Of the 22 hydrocortisone-treated patients and 19 placebo-treated patients, 15 (68%) and 4 (21%) achieved 7-day shock reversal, respectively, a difference of 47% (95% confidence interval 17% to 77%; p = .007). Serial invasive hemodynamic measurements for 5 days did not show significant differences between both groups. At 28-day follow-up, reversal of shock was higher in the hydrocortisone group (p = .005). Crude 28-day mortality was 7 (32%) of 22 treated patients and 12 (63%) of 19 placebo patients, a difference of 31% (95% confidence interval 1% to 61%; p = .091). Shock reversal within 7 days after the onset of corticosteroid therapy was a very strong predictor of survival. There were no significant differences in outcome in responders and nonresponders to a short corticotropin test. The respective rates of gastrointestinal bleeding and secondary infections did not differ between both groups.nnnCONCLUSIONSnAdministration of modest doses of hydrocortisone in the setting of pressor-dependent septic shock for a mean of >96 hrs resulted in a significant improvement in hemodynamics and a beneficial effect on survival. These beneficial effects do not appear related to adrenocortical insufficiency.

Comparison of norepinephrine and dobutamine to epinephrine for hemodynamics, lactate metabolism, and gastric tonometric variables in septic shock: a prospective, randomized study

Objectives: To compare the effects of norepinephrine and dobutamine to epinephrine on hemodynamics, lactate metabolism, and gastric tonometric variables in hyperdynamic dopamine-resistant septic shock. Design: A prospective, intervention, randomized clinical trial. Setting: Adult medical/surgical intensive care unit in a university hospital. Patients: 30 patients with a cardiac index (CI) > 3.5 l · min–1· m–2 and a mean arterial pressure (MAP) ≤ 60 mmHg after volume loading and dopamine 20 μg/kg per min and either oliguria or hyperlactatemia. Interventions: Patients were randomized to receive an infusion of either norepinephrine-dobutamine or epinephrine titrated to obtain an MAP greater than 80 mmHg with a stable or increased CI. Measurements and main results: Baseline measurements included: hemodynamic and tonometric parameters, arterial and mixed venous gases, and lactate and pyruvate blood levels. These measurements were repeated after 1, 6, 12, and 24 h. All the patients fulfilled the therapeutic goals. No statistical difference was found between epinephrine and norepinephrine-dobutamine for systemic hemodynamic measurements. Considering metabolic and tonometric measurements and compared to baseline values, after 6 h, epinephrine infusion was associated with an increase in lactate levels (from 3.1 ± 1.5 to 5.9 ± 1.0 mmol/l; p < 0.01), while lactate levels decreased in the norepinephrine-dobutamine group (from 3.1 ± 1.5 to 2.7 ± 1.0 mmol/l). The lactate/pyruvate ratio increased in the epinephrine group (from 15.5 ± 5.4 to 21 ± 5.8; p < 0.01) and did not change in the norepinephrine-dobutamine group (13.8 ± 5 to 14 ± 5.0). Gastric mucosal pH (pHi) decreased (from 7.29 ± 0.11 to 7.16 ± 0.07; p < 0.01) and the partial pressure of carbon dioxide (PCO2) gap (tonometer PCO2– arterial PCO2) increased (from 10 ± 2.7 to 14 ± 2.7 mmHg; p < 0.01) in the epinephrine group. In the norepinephrine-dobutamine group pHi (from 7.30 ± 0.11 to 7.35 ± 0.07) and the PCO2 gap (from 10 ± 3.0 to 4 ± 2.0 mmHg) were normalized within 6 h (p < 0.01). The decrease in pHi and the increase in the lactate/pyruvate ratio in the epinephrine group was transient, since it returned to normal within 24 h. Conclusions: Considering the global hemodynamic effects, epinephrine is as effective as norepinephrine-dobutamine. Nevertheless, gastric mucosal acidosis and global metabolic changes observed in epinephrine-treated patients are consistent with a markedly inadequate, although transient, splanchnic oxygen utilization. The metabolic and splanchnic effects of the combination of norepinephrine and dobutamine in hyperdynamic dopamine-resistant septic shock appeared to be more predictable and more appropriate to the current goals of septic shock therapy than those of epinephrine alone.

Etomidate versus ketamine for rapid sequence intubation in acutely ill patients: a multicentre randomised controlled trial

BACKGROUNDnCritically ill patients often require emergency intubation. The use of etomidate as the sedative agent in this context has been challenged because it might cause a reversible adrenal insufficiency, potentially associated with increased in-hospital morbidity. We compared early and 28-day morbidity after a single dose of etomidate or ketamine used for emergency endotracheal intubation of critically ill patients.nnnMETHODSnIn this randomised, controlled, single-blind trial, 655 patients who needed sedation for emergency intubation were prospectively enrolled from 12 emergency medical services or emergency departments and 65 intensive care units in France. Patients were randomly assigned by a computerised random-number generator list to receive 0.3 mg/kg of etomidate (n=328) or 2 mg/kg of ketamine (n=327) for intubation. Only the emergency physician enrolling patients was aware of group assignment. The primary endpoint was the maximum score of the sequential organ failure assessment during the first 3 days in the intensive care unit. We excluded from the analysis patients who died before reaching the hospital or those discharged from the intensive care unit before 3 days (modified intention to treat). This trial is registered with ClinicalTrials.gov, number NCT00440102.nnnFINDINGSn234 patients were analysed in the etomidate group and 235 in the ketamine group. The mean maximum SOFA score between the two groups did not differ significantly (10.3 [SD 3.7] for etomidate vs 9.6 [3.9] for ketamine; mean difference 0.7 [95% CI 0.0-1.4], p=0.056). Intubation conditions did not differ significantly between the two groups (median intubation difficulty score 1 [IQR 0-3] in both groups; p=0.70). The percentage of patients with adrenal insufficiency was significantly higher in the etomidate group than in the ketamine group (OR 6.7, 3.5-12.7). We recorded no serious adverse events with either study drug.nnnINTERPRETATIONnOur results show that ketamine is a safe and valuable alternative to etomidate for endotracheal intubation in critically ill patients, and should be considered in those with sepsis.nnnFUNDINGnFrench Ministry of Health.

Evolution of lactate/pyruvate and arterial ketone body ratios in the early course of catecholamine-treated septic shock

Objectives: To measure arterial lactate/pyruvate (L/P) and arterial ketone body ratios as reflection of cytoplasmic and mitochondrial redox state at different stages of catecholamine‐treated septic shock and compare them with normal and pathologic values obtained in patients in shock who have decreased oxygen transport (cardiogenic shock), and to assess the relationship between the time course of lactate, L/P ratio, and mortality in septic shock. Design: Prospective, observational human study. Setting: A university intensive care unit. Patients: Sixty consecutive adult patients who developed septic shock and lactic acidosis requiring the administration of vasopressors. Twenty patients in the intensive care unit without shock, sepsis, and hypoxia and with normal lactate values and 10 patients with cardiogenic shock were also studied. Measurements: Hemodynamic measurements, arterial and mixed venous blood gases, arterial lactate and pyruvate concentrations, and arterial ketone body ratio were measured within 4 hrs after the introduction of catecholamine and 24 hrs later. Main Results: Fifteen patients (25%) died within the first 24 hrs of septic shock, and these early fatalities had a higher blood lactate (12.2 ± 3 versus 4.6 ± 1.3 mmol/L; p < .01) concentration and a higher L/P ratio (37 ± 4 versus 20 ± 1; p < .01) than those who died later. No difference was found for arterial ketone body ratio (0.41 ± 0.1 versus 0.50 ± 0.06). Forty‐five patients survived >24 hrs including 25 survivors and 20 nonsurvivors. Although there was no difference between survivors and nonsurvivors in initial lactate concentration (4.1 ± 0.4 and 4.6 ± 0.3, respectively), L/P ratio (19 ± 1 and 20 ± 1, respectively), and arterial ketone body ratio (0.5 ± 0.06 and 0.52 ± 0.07, respectively), blood lactate and L/P ratio significantly decreased during the first 24 hrs in the survivors (2.8 ± 0.4 and 14 ± 1, respectively; p < .05). and were stable in the nonsurvivors (4 ± 0.3 and 22 ± 1, respectively) Although returning to normal values after 24 hrs in survivors and nonsurvivors, arterial ketone body ratio was higher in survivors (1.72 ± 0.17 versus 1.09 ± 0.15; p < .05). Lactate and L/P ratio were closely correlated (r2 = .8, p < .0001). In the cardiogenic shock group, lactate concentration was 4 ± 1 mmol/L, L/P ratio was 40 ± 6, and arterial ketone body ratio was 0.2 ± 0.05. The mortality rate was 60%. Conclusions: The main result of the present study is that hemodynamically unstable patients with sepsis needing catecholamine therapy had a lactic acidosis with an elevated L/P ratio and a decreased arterial ketone body ratio, suggesting a decrease in cytoplasmic and mitochondrial redox state. The duration of lactic acidosis is associated with the development of multiple organ failure and death.

Dobutamine improves the adequacy of gastric mucosal perfusion in epinephrine-treated septic shock

OBJECTIVEnTo assess the effects of dobutamine at a rate of 5 micrograms/kg/min on hemodynamics and gastric intramucosal acidosis in patients with hyperdynamic septic shock treated with epinephrine.nnnDESIGNnA prospective, interventional, clinical trial.nnnSETTINGnAn adult, 16-bed medical/surgical intensive care unit of a university hospital.nnnPATIENTSnTwenty septic shock patients with a mean arterial pressure of > 75 mm Hg and a cardiac index of > 3.5 L/min/m2.nnnINTERVENTIONSnAfter baseline measurements (H0), each patient received dobutamine at a rate of 5 micrograms/kg/min. Baseline measurements included: hemodynamic parameters, tonometric parameters, arterial and mixed venous gases, and arterial lactate concentrations. These measurements were repeated after 1 (H1), 2 (H2), and 3 (H3) hrs. After H2 measurements, dobutamine was stopped. The patients were separated into two groups according to their PCO2 gap (tonometer PCO2-PaCO2). The increased PCO2 gap group was defined by a PCO2 gap > 8 torr (> 1.1 kPa) (n = 13), and the normal PCO2 gap group by a PCO2 gap < or = 8 torr (< or = 1.1 kPa)(n = 7).nnnMEASUREMENTS AND MAIN RESULTSnDobutamine at 5 micrograms/kg/min had no significant effects on mean arterial pressure, heart rate, cardiac index, systemic vascular resistance, oxygen delivery, and oxygen consumption in epinephrine-treated septic shock. No patients developed arrhythmia or electrocardiographic signs of myocardial ischemia. During dobutamine infusion, arterial lactate concentration decreased from 5.1 +/- 0.4 in the increased PCO2 gap group and 4.2 +/- 0.4 in the normal PCO2 gap group to 3.9 +/- 0.3 and 3.5 +/- 0.3 mmol/L, respectively (p < .01). The PCO2 gap decreased and gastric intramucosal pH increased in the increased PCO2 gap group from 12 +/- 0.8 (1.6 +/- 0.1 kPa) to 3.5 +/- 0.8 torr (0.5 +/- 0.1 kPa) (p < .01) and from 7.11 +/- 0.03 to 7.18 +/- 0.02 (p < .01), respectively, and did not change in the normal PCO2 gap group. After stopping dobutamine infusion, the PCO2 gap and intramucosal pH returned to baseline values in the increased PCO2 gap group.nnnCONCLUSIONnThe addition of 5 micrograms/kg/min of dobutamine added to epinephrine in hyperdynamic septic shock selectively improved the adequacy of gastric mucosal perfusion without modification in systemic hemodynamics.

Induced Hypothermia in Severe Bacterial Meningitis: A Randomized Clinical Trial

IMPORTANCEnDespite advances in care, mortality and morbidity remain high in adults with acute bacterial meningitis, particularly when due to Streptococcus pneumoniae. Induced hypothermia is beneficial in other conditions with global cerebral hypoxia.nnnOBJECTIVEnTo test the hypothesis that induced hypothermia improves outcome in patients with severe bacterial meningitis.nnnDESIGN, SETTING, AND PATIENTSnAn open-label, multicenter, randomized clinical trial in 49 intensive care units in France, February 2009-November 2011. In total, 130 patients were assessed for eligibility and 98 comatose adults (Glasgow Coma Scale [GCS] score of ≤8 for <12 hours) with community-acquired bacterial meningitis were randomized.nnnINTERVENTIONSnHypothermia group received a loading dose of 4°C cold saline and were cooled to 32°C to 34°C for 48 hours. The rewarming phase was passive. Controls received standard care.nnnMAIN OUTCOMES AND MEASURESnPrimary outcome measure was the Glasgow Outcome Scale score at 3 months (a score of 5 [favorable outcome] vs a score of 1-4 [unfavorable outcome]). All patients received appropriate antimicrobial therapy and vital support. Analyses were performed on an intention-to-treat basis. The data and safety monitoring board (DSMB) reviewed severe adverse events and mortality rate every 50 enrolled patients.nnnRESULTSnAfter inclusion of 98 comatose patients, the trial was stopped early at the request of the DSMB because of concerns over excess mortality in the hypothermia group (25 of 49 patients [51%]) vs the control group (15 of 49 patients [31%]; relative risk [RR], 1.99; 95% CI, 1.05-3.77; Pu2009=u2009.04). Pneumococcal meningitis was diagnosed in 77% of patients. Mean (SD) temperatures achieved 24 hours after randomization were 33.3°C (0.9°C) and 37.0°C (0.9°C) in the hypothermia and control group, respectively. At 3 months, 86% in the hypothermia group compared with 74% of controls had an unfavorable outcome (RR, 2.17; 95% CI, 0.78-6.01; Pu2009=u2009.13). After adjustment for age, score on GCS at inclusion, and the presence of septic shock at inclusion, mortality remained higher, although not significantly, in the hypothermia group (hazard ratio, 1.76; 95% CI, 0.89-3.45; Pu2009=u2009.10). Subgroup analysis on patients with pneumococcal meningitis showed similar results. Post hoc analysis showed a low probability to reach statistically significant difference in favor of hypothermia at the end of the 3 planned sequential analyses (probability to conclude in favor of futility, 0.977).nnnCONCLUSIONS AND RELEVANCEnModerate hypothermia did not improve outcome in patients with severe bacterial meningitis and may even be harmful. Careful evaluation of safety issues in future trials on hypothermia are needed and may have important implications in patients presenting with septic shock or stroke.nnnTRIAL REGISTRATIONnclinicaltrials.gov Identifier: NCT00774631.

Probiotics in the critically ill patient: a double blind, randomized, placebo-controlled trial

PurposeProbiotics have been shown to be able to restore a non-pathogenic digestive flora, to prevent digestive colonization by pathogenic bacteria, and to modulate immunity. The aim of this study was to assess the effects of prophylactic probiotic administration in patients ventilated for up to 2xa0days.MethodsThis study was performed as a double-blind, concealed randomized, placebo-controlled trial in a French medical intensive care unit (ICU). Adult patients mechanically ventilated for a period of more than 48xa0h received enterally administered probiotics (Ergyphilus®, 2xa0×xa01010 lactic acid bacteria, mostly Lactobacillus rhamnosus GG, once a day) or placebo until successful weaning.ResultsA total of 167 patients were included. The two groups were comparable at baseline. The 28-day mortality rates were not different in the probiotic (25.3%) and placebo groups (23.7%). Mortality rates in ICU and at 90xa0days were also unaffected by the treatment. The incidence of ICU-acquired infections did not differ significantly except for that of catheter-related bloodstream infections that was lowered by probiotics. On a prespecified subgroup analysis, we found a reduction of the 28-day mortality among severe sepsis patients (total nxa0=xa0101) treated with probiotics (nxa0=xa052) with an odds ratio (OR) for death at 0.38 (95% CI 0.16–0.93, pxa0=xa00.035). By contrast, probiotics were associated with a higher mortality rate in non-severe sepsis patients (OR 3.09, 95% CI 0.87–11.01, pxa0=xa00.08).ConclusionsAlthough numerous uncertainties remain (type and the number of strains to use, delay and length of administration), and despite an acceptable safety profile, the daily prophylactic administration of probiotics cannot be encouraged in the critically ill patient.

Differential Quantitative Blood Cultures in the Diagnosis of Catheter-Related Sepsis in Intensive Care Units

The aim of this prospective study was to compare differential blood cultures and quantitative catheter tip cultures for the diagnosis of catheter-related sepsis. Over a period of 2 years, 283 central venous catheters were inserted in 190 adult patients. Catheters were removed when they were no longer needed or when infection was suspected. Immediately before removal of the central venous catheters, blood cultures were performed, with blood drawn simultaneously from the catheter and the peripheral vein. After removal, quantitative catheter culture was performed according to the Brun-Buisson modified Cleri technique. Fifty-five quantitative catheter cultures were positive. They were classified as contaminated (n = 18), colonized (n = 23), or infected (n = 14). Differential blood cultures correctly identified 13 infections. With a catheter/peripheral cfu ratio of 8, differential blood cultures had a sensitivity of 92.8% and a specificity of 98.8%. When the catheters were removed because of suspected infection, differential blood cultures had a sensitivity of 92.8% and a specificity of 100%. Differential blood culture, a technique that does not necessitate catheter removal, seems effective in the diagnosis of catheter-related sepsis in patients in the intensive care unit.

Prognosis of stroke patients undergoing mechanical ventilation

ObjectiveTo determine the outcome of stroke patients undergoing mechanical ventilation.DesignRetrospective chart review and follow-up telephone interview.SettingMedical ICU in a multidisciplinary university hospital.Patients and participants199 stroke patients from 1984–1989 where the final diagnosis was stroke.InterventionsAll patients were admitted for the need of mechanical ventilation.Measurements and resultsDemographic information, previous relevant diseases, stroke type, general clinical and neurological data, biochemical variables, severity of illness were recorded for the first 24 h following ICU admission. A 1-year follow-up was performed, including mortality and functional status of survivors. Of 170 eventually analyzable patients, 123 (72.4%) died during their ICU stay and 156 (91.8%) during the first year. Three variables were independently associated with one-year mortality: Glasgow score <10 (p<0.03), bradycardia (p<0.001), absence of brainstem reflexes (p<0.0004).ConclusionOverall prognosis of stroke needing mechanical ventilation is poor, strongly linked to symptoms of neurological impairment.

Comparison of systemic and regional effects of dobutamine and dopexamine in norepinephrine-treated septic shock

Objectives: To compare the effects of dobutamine and dopexamine on systemic hemodynamics, lactate metabolism, renal function and the intramucosal-arterial PCO2 gap in norepinephrine-treated septic shock. Design: A prospective, interventional, randomized clinical trial. Setting: Adult medical/surgical intensive care unit in a university hospital. Patients: After volume resuscitation, 24 patients were treated with norepinephrine alone titrated to obtain a mean arterial pressure of 75 mmHg and a cardiac index greater than 3.5 l/min-1· m-2. Interventions: Patients were randomized to receive an infusion of dobutamine (n = 12) (5 μg/kg per min) or dopexamine (n = 12) (1 μg/kg per min). Measurements and main results: Baseline measurements included: hemodynamic parameters, renal parameters (diuresis, creatinine clearance and urinary sodium excretion), gastric mucosal-arterial PCO2 gap, arterial and mixed venous gases and arterial lactate and pyruvate levels. These measurements were repeated after 1 (H1), 4 (H4) and 24 (H24) h. No difference was found between dobutamine and dopexamine among H0 and H1, H4 and H24 values for hemodynamics. Dobutamine and dopexamine at low doses had no significant effect on mean arterial pressure, heart rate, cardiac index, oxygen delivery, oxygen consumption and pulmonary artery occlusion pressure. No patients developed arrhythmia or electrocardiographic signs of myocardial ischemia. After 4 and 24 h lactate concentration decreased in the dobutamine group from 2.4 ± 1 mmol/l to 1.7 ± 0.7 mmol/l and 1.5 ± 0.4 mmol/l, respectively, while it increased in the dopexamine group from 2.3 ± 1 mmol/l to 2.7 ± 1 mmol/l after 4 h and returned to baseline values after 24 h (2.2 ± 0.6). After 24 h the lactate/pyruvate ratio decreased in the dobutamine group from 15 ± 5 to 12 ± 3 (p < 0.05) while it was unchanged in the dopexamine group (from 16 ± 6 to 17 ± 4). Arterial pH increased in the dobutamine group from 7.35 ± 0.05 to 7.38 ± 0.07 (p < 0.05) while it was unchanged in the dopexamine group (from 7.34 ± 0.01 to 7.35 ± 0.10). The PCO2 gap decreased after 1 and 4 h in both the dobutamine and dopexamine groups (p < 0.05 with respect to baseline). When looking at individual responses, however, patients from both groups exhibited an increased gastric PCO2 gap. No difference was found between dobutamine and dopexamine for renal parameters. Conclusions: In norepinephrine-treated septic shock, low doses of neither dobutamine nor dopexamine caused significant effects on systemic hemodynamics and renal function and both dobutamine and dopexamine inconsistently improved the PCO2 gap. The present results support the need for individual measurement of the effects of catecholamine on the PCO2 gap.