Ubiquinol (reduced Coenzyme Q10) in patients with severe sepsis or septic shock: a randomized,double-blind,placebo-controlled,pilot trial

IntroductionWe previously found decreased levels of Coenzyme Q10 (CoQ10) in patients with septic shock. The objective of the current study was to assess whether the provision of exogenous ubiquinol (the reduced form of CoQ10) could increase plasma CoQ10 levels and improve mitochondrial function.MethodsWe performed a randomized, double-blind, pilot trial at a single, tertiary care hospital. Adults (age ≥18 years) with severe sepsis or septic shock between November 2012 and January 2014 were included. Patients received 200 mg enteral ubiquinol or placebo twice a day for up to seven days. Blood draws were obtained at baseline (0 h), 12, 24, 48, and 72 h. The primary outcome of the study was change in plasma CoQ10 parameters (total CoQ10 levels, CoQ10 levels relative to cholesterol levels, and levels of oxidized and reduced CoQ10). Secondary outcomes included assessment of: 1) vascular endothelial biomarkers, 2) inflammatory biomarkers, 3) biomarkers related to mitochondrial injury including cytochrome c levels, and 4) clinical outcomes. CoQ10 levels and biomarkers were compared between groups using repeated measures models.ResultsWe enrolled 38 patients: 19 in the CoQ10 group and 19 in the placebo group. The mean patient age was 62 ± 16 years and 47 % were female. Baseline characteristics and CoQ10 levels were similar for both groups. There was a significant increase in total CoQ10 levels, CoQ10 levels relative to cholesterol levels, and levels of oxidized and reduced CoQ10 in the ubiquinol group compared to the placebo group. We found no difference between the two groups in any of the secondary outcomes.ConclusionsIn this pilot trial we showed that plasma CoQ10 levels could be increased in patients with severe sepsis or septic shock, with the administration of oral ubiquinol. Further research is needed to address whether ubiquinol administration can result in improved clinical outcomes in this patient population.

Trial registration

Clinicaltrials.gov identifier {"type":"clinical-trial","attrs":{"text":"NCT01948063","term_id":"NCT01948063"}}NCT01948063. Registered on 18 February 2013.     

Clinical impact of stress dose steroids in patients with septic shock: insights from the PROWESS-Shock trial

IntroductionThe aim of our study was to evaluate the clinical impact of the administration of intravenous steroids, alone or in conjunction with drotrecogin-alfa (activated) (DrotAA), on the outcomes in septic shock patients.MethodsWe performed a sub-study of the PROWESS-Shock trial (septic shock patients who received fluids and vasopressors above a predefined threshold for at least 4 hours were randomized to receive either DrotAA or placebo for 96 hours). A propensity score for the administration of intravenous steroids for septic shock at baseline was constructed using multivariable logistic regression. Cox proportional hazards model using inverse probability of treatment weighting of the propensity score was used to estimate the effect of intravenous steroids, alone or in conjunction with DrotAA, on 28-day and 90-day all-cause mortality.ResultsA total of 1695 patients were enrolled of which 49.5% received intravenous steroids for treatment of septic shock at baseline (DrotAA + steroids N = 436; DrotAA + no steroids N = 414; placebo + steroids N = 403; placebo + no steroids N = 442). The propensity weighted risk of 28-day as well as 90-day mortality in those treated vs. those not treated with steroids did not differ among those randomized to DrotAA vs. placebo (interaction p-value = 0.38 and p = 0.27, respectively) nor was a difference detected within each randomized treatment. Similarly, the course of vasopressor use and cardiovascular SOFA did not appear to be influenced by steroid therapy. In patients with lung infection (N = 744), abdominal infection (N = 510), Gram-positive sepsis (N = 420) and Gram-negative sepsis (N = 461), the propensity weighted risk of 28-day as well as 90-day mortality in those treated vs. those not treated with steroids did not differ among those randomized to DrotAA vs. placebo nor was a difference detected within each randomized treatment.ConclusionsIn the present study of septic shock patients, after adjustment for treatment selection bias, we were unable to find noticeable positive impact from intravenous steroids for treatment of septic shock at baseline either in patients randomized for DrotAA or placebo.

Trial registration

Clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00604214","term_id":"NCT00604214"}}NCT00604214. Registered 24 January 2008.     

Effect of high-dose dexamethasone on perioperative lactate levels and glucose control: a randomized controlled trial

IntroductionBlood lactate levels are increasingly used to monitor patients. Steroids are frequently administered to critically ill patients. However, the effect of steroids on lactate levels has not been adequately investigated. We studied the effect of a single intraoperative high dose of dexamethasone on lactate and glucose levels in patients undergoing cardiac surgery.MethodsThe Dexamethasone for Cardiac Surgery (DECS) trial was a multicenter randomized trial on the effect of dexamethasone 1 mg/kg versus placebo on clinical outcomes after cardiac surgery in adults. Here we report a pre-planned secondary analysis of data from DECS trial participants included at the University Medical Center Groningen. The use of a computer-assisted glucose regulation protocol—Glucose Regulation for Intensive care Patients (GRIP)—was part of routine postoperative care. GRIP aimed at glucose levels of 4 to 8 mmol/L. Primary outcome parameters were area under the lactate and glucose curves over the first 15 hours of ICU stay (AUC₁₅). ICU length of stay and mortality were observed as well.ResultsThe primary outcome could be determined in 497 patients of the 500 included patients. During the first 15 hours of ICU stay, lactate and glucose levels were significantly higher in the dexamethasone group than in the placebo group: lactate AUC₁₅ 25.8 (13.1) versus 19.9 (11.2) mmol/L × hour, P <0.001 and glucose AUC₁₅ 126.5 (13.0) versus 114.4 (13.9) mmol/L × hour, P <0.001. In this period, patients in the dexamethasone group required twice as much insulin compared with patients who had received placebo. Multivariate and cross-correlation analyses suggest that the effect of dexamethasone on lactate levels is related to preceding increased glucose levels. Patients in the placebo group were more likely to stay in the ICU for more than 24 hours (39.2%) compared with patients in the dexamethasone group (25.0%, P = 0.001), and 30-day mortality rates were 1.6% and 2.4%, respectively (P = 0.759).ConclusionsIntraoperative high-dose dexamethasone increased postoperative lactate and glucose levels in the first 15 hours of ICU stay. Still, patients in the dexamethasone group had a shorter ICU length of stay and similar mortality compared with controls.

Trial registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00293592","term_id":"NCT00293592"}}NCT00293592. Registered 16 February 2006.

Electronic supplementary material

The online version of this article (doi:10.1186/s13054-015-0736-9) contains supplementary material, which is available to authorized users.     

A high mean arterial pressure target is associated with improved microcirculation in septic shock patients with previous hypertension: a prospective open label study

IntroductionThe effect of mean arterial pressure titration to a higher level on microcirculation in septic shock patients with previous hypertension remains unknown. Our goal is to assess the effect of mean arterial pressure titration to a higher level on microcirculation in hypertensive septic shock patients.MethodsThis is a single-center, open-label study. Hypertensive patients with septic shock for less than 24 hours after adequate fluid resuscitation and requiring norepinephrine to maintain a mean arterial pressure of 65 mmHg were enrolled. Mean arterial pressure was then titrated by norepinephrine from 65 mmHg to the normal level of the patient. In addition to hemodynamic variables, sublingual microcirculation was evaluated by sidestream dark field imaging.ResultsNineteen patients were enrolled in the study. Increasing mean arterial pressure from 65 mmHg to normal levels was associated with increased central venous pressure (from 11 ± 4 to 13 ± 4 mmHg, P = 0.002), cardiac output (from 5.4 ± 1.4 to 6.4 ± 2.1 l/minute, P = 0.001), and central venous oxygen saturation (from 81 ± 7 to 83 ± 7%, P = 0.001). There were significant increases in small perfused vessel density (from 10.96 ± 2.98 to 11.99 ± 2.55 vessels/mm², P = 0.009), proportion of small perfused vessels (from 85 ± 18 to 92 ± 14%, P = 0.002), and small microvascular flow index (from 2.45 ± 0.61 to 2.80 ± 0.68, P = 0.009) when compared with a mean arterial pressure of 65 mmHg.ConclusionsIncreasing mean arterial pressure from 65 mmHg to normal levels is associated with improved microcirculation in hypertensive septic shock patients.

Trial registration

Clinicaltrials.gov: {"type":"clinical-trial","attrs":{"text":"NCT01443494","term_id":"NCT01443494"}}NCT01443494; registered 28 September 2011.

Electronic supplementary material

The online version of this article (doi:10.1186/s13054-015-0866-0) contains supplementary material, which is available to authorized users.     

Efficacy and safety of citrate-based anticoagulation compared to heparin in patients with acute kidney injury requiring continuous renal replacement therapy: a randomized controlled trial

IntroductionA systemic anticoagulation is often required to prevent circuit and filter clotting in ICU patients undergoing continuous renal replacement therapy (CRRT). A regional citrate-based anticoagulation (RCA) does not induce a systemic anticoagulation and prolongs the filter lifespan, but metabolic side-effects have been associated with this therapy. We conducted a randomized controlled trial with patients requiring CRRT to determine whether RCA using a balanced predilution replacement fluid is more effective than heparin in terms of renal replacement delivered dose and safety profile.MethodsOne hundred and three patients with AKI requiring CRRT were included. The patients were randomized to either CRRT with RCA or heparin anticoagulation. Primary endpoints were effective daily delivered RRT dose during the first 3 days of CRRT and filter lifespan. Secondary endpoints were 28-day and 90-day survival and severe metabolic complications and bleeding disorders.ResultsMedian CRRT duration was 3.0 (2–6) days. Effective delivered daily RRT doses were 29 ± 3 and 27 ± 5 mL/kg/hr in the RCA and heparin groups, respectively (p = 0.005). Filter lifespans were 49 ± 29 versus 28 ± 23 hrs in the RCA and heparin groups (p = 0.004). Survival rates at 28 and 90 days were 80-74% in the RCA and 74-73% in the heparin group. Electrolytes and acid–base disturbances were uncommon and transient in patients treated with RCA.ConclusionsThese results show that RCA is superior to heparin-based anticoagulation in terms of delivered RRT dose and filter life span and is a safe and feasible method. This does not translate into an improvement in short term survival.

Trial registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01269112","term_id":"NCT01269112"}}NCT01269112. Registered 3rd January 2011.     

Perioperative goal-directed therapy and postoperative outcomes in patients undergoing high-risk abdominal surgery: a historical-prospective,comparative effectiveness study

IntroductionPerioperative goal-directed therapy (PGDT) may improve postoperative outcome in high-risk surgery patients but its adoption has been slow. In 2012, we initiated a performance improvement (PI) project focusing on the implementation of PGDT during high-risk abdominal surgeries. The objective of the present study was to evaluate the effectiveness of this intervention.MethodsThis is a historical prospective quality improvement study. The goal of this initiative was to standardize the way fluid management and hemodynamic optimization are conducted during high-risk abdominal surgery in the Departments of Anesthesiology and Surgery at the University of California Irvine. For fluid management, the protocol consisted in standardized baseline crystalloid administration of 3 ml/kg/hour and any additional boluses based on PGDT. The impact of the intervention was assessed on the length of stay in the hospital (LOS) and post-operative complications (NSQIP database).ResultsIn the 1 year pre- and post-implementation periods, 128 and 202 patients were included. The average volume of fluid administered during the case was 9.9 (7.1–13.0) ml/kg/hour in the pre-implementation period and 6.6 (4.7–9.5) ml/kg/hour in the post-implementation period (p < 0.01). LOS decreased from 10 (6–16) days to 7 (5–11) days (p = 0.0001). Based on the multiple linear regression analysis, the estimated coefficient for intervention was 0.203 (SE = 0.054, p = 0.0002) indicating that, with the other conditions being held the same, introducing intervention reduced LOS by 18 % (95 % confidence interval 9–27 %). The incidence of NSQIP complications decreased from 39 % to 25 % (p = 0.04).ConclusionThese results suggest that the implementation of a PI program focusing on the implementation of PGDT can transform fluid administration patterns and improve postoperative outcome in patients undergoing high-risk abdominal surgeries.

Trial registration

Clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT02057653","term_id":"NCT02057653"}}NCT02057653. Registered 17 December 2013.

Electronic supplementary material

The online version of this article (doi:10.1186/s13054-015-0945-2) contains supplementary material, which is available to authorized users.     

Resting energy expenditure and substrate oxidation rates correlate to temperature and outcome after cardiac arrest - a prospective observational cohort study

IntroductionTargeted temperature management improves outcome after cardiopulmonary resuscitation. Reduction of resting energy expenditure might be one mode of action. The aim of this study was to correlate resting energy expenditure and substrate oxidation rates with targeted temperature management at 33°C and outcome in patients after cardiac arrest.MethodsThis prospective, observational cohort study was performed at the department of emergency medicine and a medical intensive care unit of a university hospital. Patients after successful cardiopulmonary resuscitation undergoing targeted temperature management at 33°C for 24 hours with subsequent rewarming to 36°C and standardized sedation, analgesic and paralytic medication were included. Indirect calorimetry was performed five times within 48 h after cardiac arrest. Measurements were correlated to outcome with repeated measures ANOVA, linear and logistic regression analysis.ResultsIn 25 patients resting energy expenditure decreased 20 (18 to 27) % at 33°C compared to 36°C without differences between outcome groups (favourable vs. unfavourable: 25 (21 to 26) vs. 21 (16 to 26); P = 0.5). In contrast to protein oxidation rate (favourable vs. unfavourable: 35 (11 to 68) g/day vs. 39 (7 to 75) g/day, P = 0.8) patients with favourable outcome had a significantly higher fat oxidation rate (139 (104 to 171) g/day vs. 117 (70 to 139) g/day, P <0.05) and a significantly lower glucose oxidation rate (30 (−34 to 88) g/day vs. 77 (19 to 138) g/day; P < 0.05) as compared to patients with unfavourable neurological outcome.ConclusionsTargeted temperature management at 33°C after cardiac arrest reduces resting energy expenditure by 20% compared to 36°C. Glucose and fat oxidation rates differ significantly between patients with favourable and unfavourable neurological outcome.

Trial registration

Clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00500825","term_id":"NCT00500825"}}NCT00500825. Registered 11 July 2007.

Electronic supplementary material

The online version of this article (doi:10.1186/s13054-015-0856-2) contains supplementary material, which is available to authorized users.     

Furosemide versus ethacrynic acid in pediatric patients undergoing cardiac surgery: a randomized controlled trial

IntroductionClinical effects of furosemide (F) and ethacrynic acid (EA) continuous infusion on urine output (UO), fluid balance, and renal, cardiac, respiratory, and metabolic function were compared in infants undergoing surgery for congenital heart diseases.MethodsA prospective randomized double-blinded study was conducted. Patients received 0.2 mg/kg/h (up to 0.8 mg/kg/h) of either F or EA.ResultsIn total, 38 patients were enrolled in the F group, and 36, in the EA group. No adverse reactions were recorded. UO at postoperative day (POD) 0 was significantly higher in the EA group, 6.9 (3.3) ml/kg/h, compared with the F group, 4.6 (2.3) ml/kg/h (P = 0.002) but tended to be similar in the two groups thereafter. Mean administered F dose was 0.33 (0.19) mg/kg/h compared with 0.22 (0.13) mg/kg/h of EA (P < 0.0001). Fluid balance was significantly more negative in the EA group at postoperative day 0: −43 (54) ml/kg/h versus −17 (32) ml/kg/h in the F group (P = 0.01). Serum creatinine, cystatin C and neutrophil gelatinase-associated lipocalin levels and incidence of acute kidney injury did not show significant differences between groups. Metabolic alkalosis occurred frequently (about 70% of cases) in both groups, but mean bicarbonate level was higher in the EA group: 27.8 (1.5) M in the F group versus 29.1 (2) mM in the EA group (P = 0.006). Mean cardiac index (CI) values were 2.6 (0.1) L/min/m² in the F group compared with 2.98 (0.09) L/min/m² in the EA group (P = 0.0081). Length of mechanical ventilation was shorter in the EA group, 5.5 (8.8) days compared with the F group, 6.7 (5.9) (P = 0.06). Length of Pediatric Cardiac Intensive Care Unit (PCICU) admission was shorter in the EA group: 14 (19) days compared with 16 (15) in the F group (P = 0.046).ConclusionsIn cardiac surgery infants, EA produced more UO compared with F on POD0. Generally, a smaller EA dose is required to achieve similar UO than F. EA and F were safe in terms of renal function, but EA caused a more-intense metabolic alkalosis. EA patients achieved better CI, and shorter mechanical ventilation and PCICU admission time.

Trial registration

Clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01628731","term_id":"NCT01628731"}}NCT01628731. Registered 24 June 2012.     

A randomized controlled trial on the effects of goal-directed therapy on the inflammatory response open abdominal aortic aneurysm repair

IntroductionGoal-directed therapy (GDT) has been shown in numerous studies to decrease perioperative morbidity and mortality. The mechanism of benefit of GDT, however, has not been clearly elucidated. Targeted resuscitation of the vascular endothelium with GDT might alter the postoperative inflammatory response and be responsible for the decreased complications with this therapy.MethodsThis trial was registered at ClinicalTrials.gov as {"type":"clinical-trial","attrs":{"text":"NCT01681251","term_id":"NCT01681251"}}NCT01681251. Forty patients undergoing elective open repair of their abdominal aortic aneurysm, 18 years of age and older, were randomized to an interventional arm with GDT targeting stroke volume variation with an arterial pulse contour cardiac output monitor, or control, where fluid therapy was administered at the discretion of the attending anesthesiologist. We measured levels of several inflammatory cytokines (C-reactive protein, Pentraxin 3, suppressor of tumorgenicity--2, interleukin-1 receptor antagonist, and tumor necrosis factor receptor-III) preoperatively and at several postoperative time points to determine if there was a difference in inflammatory response. We also assessed each group for a composite of postoperative complications.ResultsTwenty patients were randomized to GDT and twenty were randomized to control. Length of stay was not different between groups. Intervention patients received less crystalloid and more colloid. At the end of the study, intervention patients had a higher cardiac index (3.4 ± 0.5 vs. 2.5 ± 0.7 l/minute per m², p < 0.01) and stroke volume index (50.1 ± 7.4 vs. 38.1 ± 9.8 ml/m², p < 0.01) than controls. There were significantly fewer complications in the intervention than control group (28 vs. 12, p = 0.02). The length of hospital and ICU stay did not differ between groups. There was no difference in the levels of inflammatory cytokines between groups.ConclusionsDespite being associated with fewer complications and improved hemodynamics, there was no difference in the inflammatory response of patients treated with GDT. This suggests that the clinical benefit of GDT occurs in spite of a similar inflammatory burden. Further work needs to be performed to delineate the mechanism of benefit of GDT.

Trial registration

ClinicalTrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT01681251","term_id":"NCT01681251"}}NCT01681251. Registered 18 May 2011.     

Early mobilization and recovery in mechanically ventilated patients in the ICU: a bi-national,multi-centre,prospective cohort study

IntroductionThe aim of this study was to investigate current mobilization practice, strength at ICU discharge and functional recovery at 6 months among mechanically ventilated ICU patients.MethodThis was a prospective, multi-centre, cohort study conducted in twelve ICUs in Australia and New Zealand. Patients were previously functionally independent and expected to be ventilated for >48 hours. We measured mobilization during invasive ventilation, sedation depth using the Richmond Agitation and Sedation Scale (RASS), co-interventions, duration of mechanical ventilation, ICU-acquired weakness (ICUAW) at ICU discharge, mortality at day 90, and 6-month functional recovery including return to work.ResultsWe studied 192 patients (mean age 58.1 ± 15.8 years; mean Acute Physiology and Chronic Health Evaluation (APACHE) (IQR) II score, 18.0 (14 to 24)). Mortality at day 90 was 26.6% (51/192). Over 1,351 study days, we collected information during 1,288 planned early mobilization episodes in patients on mechanical ventilation for the first 14 days or until extubation (whichever occurred first). We recorded the highest level of early mobilization. Despite the presence of dedicated physical therapy staff, no mobilization occurred in 1,079 (84%) of these episodes. Where mobilization occurred, the maximum levels of mobilization were exercises in bed (N = 94, 7%), standing at the bed side (N = 11, 0.9%) or walking (N = 26, 2%). On day three, all patients who were mobilized were mechanically ventilated via an endotracheal tube (N = 10), whereas by day five 50% of the patients mobilized were mechanically ventilated via a tracheostomy tube (N = 18).In 94 of the 156 ICU survivors, strength was assessed at ICU discharge and 48 (52%) had ICU-acquired weakness (Medical Research Council Manual Muscle Test Sum Score (MRC-SS) score <48/60). The MRC-SS score was higher in those patients who mobilized while mechanically ventilated (50.0 ± 11.2 versus 42.0 ± 10.8, P = 0.003). Patients who survived to ICU discharge but who had died by day 90 had a mean MRC score of 28.9 ± 13.2 compared with 44.9 ± 11.4 for day-90 survivors (P <0.0001).ConclusionsEarly mobilization of patients receiving mechanical ventilation was uncommon. More than 50% of patients discharged from the ICU had developed ICU-acquired weakness, which was associated with death between ICU discharge and day-90.

Clinical trial registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01674608","term_id":"NCT01674608"}}NCT01674608. Registered 14 August 2012.     

Preload dependence indices to titrate volume expansion during septic shock: a randomized controlled trial

IntroductionIn septic shock, pulse pressure or cardiac output variation during passive leg raising are preload dependence indices reliable at predicting fluid responsiveness. Therefore, they may help to identify those patients who need intravascular volume expansion, while avoiding unnecessary fluid administration in the other patients. However, whether their use improves septic shock prognosis remains unknown. The aim of this study was to assess the clinical benefits of using preload dependence indices to titrate intravascular fluids during septic shock.MethodsIn a single-center randomized controlled trial, 60 septic shock patients were allocated to preload dependence indices-guided (preload dependence group) or central venous pressure-guided (control group) intravascular volume expansion with 30 patients in each group. The primary end point was time to shock resolution, defined by vasopressor weaning.ResultsThere was no significant difference in time to shock resolution between groups (median (interquartile range) 2.0 (1.2 to 3.1) versus 2.3 (1.4 to 5.6) days in control and preload dependence groups, respectively). The daily amount of fluids administered for intravascular volume expansion was higher in the control than in the preload dependence group (917 (639 to 1,511) versus 383 (211 to 604) mL, P = 0.01), and the same held true for red cell transfusions (178 (82 to 304) versus 103 (0 to 183) mL, P = 0.04). Physiologic variable values did not change over time between groups, except for plasma lactate (time over group interaction, P <0.01). Mortality was not significantly different between groups (23% in the preload dependence group versus 47% in the control group, P = 0.10). Intravascular volume expansion was lower in the preload dependence group for patients with lower simplified acute physiology score II (SAPS II), and the opposite was found for patients in the upper two SAPS II quartiles. The amount of intravascular volume expansion did not change across the quartiles of severity in the control group, but steadily increased with severity in the preload dependence group.ConclusionsIn patients with septic shock, titrating intravascular volume expansion with preload dependence indices did not change time to shock resolution, but resulted in less daily fluids intake, including red blood cells, without worsening patient outcome.

Trial registration

Clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01972828","term_id":"NCT01972828"}}NCT01972828. Registered 11 October 2013.

Electronic supplementary material

The online version of this article (doi:10.1186/s13054-014-0734-3) contains supplementary material, which is available to authorized users.     

A multicenter study on the effect of continuous hemodiafiltration intensity on antibiotic pharmacokinetics

IntroductionContinuous renal replacement therapy (CRRT) may alter antibiotic pharmacokinetics and increase the risk of incorrect dosing. In a nested cohort within a large randomized controlled trial, we assessed the effect of higher (40 mL/kg per hour) and lower (25 mL/kg per hour) intensity CRRT on antibiotic pharmacokinetics.MethodsWe collected serial blood samples to measure ciprofloxacin, meropenem, piperacillin-tazobactam, and vancomycin levels. We calculated extracorporeal clearance (CL), systemic CL, and volume of distribution (Vd) by non-linear mixed-effects modelling. We assessed the influence of CRRT intensity and other patient factors on antibiotic pharmacokinetics.ResultsWe studied 24 patients who provided 179 pairs of samples. Extracorporeal CL increased with higher-intensity CRRT but the increase was significant for vancomycin only (mean 28 versus 22 mL/minute; P = 0.0003). At any given prescribed CRRT effluent rate, extracorporeal CL of individual antibiotics varied widely, and the effluent-to-plasma concentration ratio decreased with increasing effluent flow. Overall, systemic CL varied to a greater extent than Vd, particularly for meropenem, piperacillin, and tazobactam, and large intra-individual differences were also observed. CRRT dose did not influence overall (systemic) CL, Vd, or half-life. The proportion of systemic CL due to CRRT varied widely and was high in some cases.ConclusionsIn patients receiving CRRT, there is great variability in antibiotic pharmacokinetics, which complicates an empiric approach to dosing and suggests the need for therapeutic drug monitoring. More research is required to investigate the apparent relative decrease in clearance at higher CRRT effluent rates.

Trial registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00221013","term_id":"NCT00221013"}}NCT00221013. Registered 14 September 2005.

Electronic supplementary material

The online version of this article (doi:10.1186/s13054-015-0818-8) contains supplementary material, which is available to authorized users.     

Low-dose hydrocortisone reduces norepinephrine duration in severe burn patients: a randomized clinical trial

IntroductionThe aim of this study was to assess the effect of low-dose corticosteroid therapy in reducing shock duration after severe burn.MethodsA placebo-controlled, double-blind, randomized clinical trial (RCT) was performed on two parallel groups in the burn intensive care unit (ICU). Patients were randomized to receive either low-dose corticosteroid therapy or placebo for seven days. A corticotropin test was performed at the time of randomization, before the administration of the treatment dose. Thirty-two severely burned patients with refractory shock (>0.5 μg/kg/min of norepinephrine) were prospectively included in the study.ResultsWe included 12 patients in the hydrocortisone-treated group and 15 patients in the placebo group in the final analysis. Among these patients, 21 were nonresponders to the corticotropin test. Median norepinephrine treatment duration (primary objective) was significantly lower in the corticosteroid-treated versus the placebo group (57 hours versus 120 hours, P = 0.035). The number of patients without norepinephrine 72 hours after inclusion was significantly lower in the treated group (P = 0.003, log-rank test analysis). The total quantities of norepinephrine administered to patients were lower in the hydrocortisone-treated versus the placebo group (1,205 μg/kg (1,079 to 2,167) versus 1,971 μg/kg (1,535 to 3,893), P = 0.067). There was no difference in terms of ICU or hospital length of stay, sepsis incidence, cicatrization or mortality.ConclusionsIn this placebo-controlled, randomized, double-blind clinical trial, we show for the first time that the administration of low-dose hydrocortisone in burn patients with severe shock reduces vasopressor administration.

Trial registration

Clinicaltrial.gov {"type":"clinical-trial","attrs":{"text":"NCT00149123","term_id":"NCT00149123"}}NCT00149123. Registered 6 September 2005.

Electronic supplementary material

The online version of this article (doi:10.1186/s13054-015-0740-0) contains supplementary material, which is available to authorized users.     

Association between biomarkers of endothelial injury and hypocoagulability in patients with severe sepsis: a prospective study

IntroductionPatients with severe sepsis often present with concurrent coagulopathy, microcirculatory failure and evidence of vascular endothelial activation and damage. Given the critical role of the endothelium in balancing hemostasis, we investigated single-point associations between whole blood coagulopathy by thrombelastography (TEG) and plasma/serum markers of endothelial activation and damage in patients with severe sepsis.MethodsA post-hoc multicenter prospective observational study in a subgroup of 184 patients from the Scandinavian Starch for Severe Sepsis/Septic Shock (6S) Trial. Study patients were admitted to two Danish intensive care units. Inclusion criteria were severe sepsis, pre-intervention whole blood TEG measurement and a plasma/serum research sample available from baseline (pre-intervention) for analysis of endothelial-derived biomarkers. Endothelial-derived biomarkers were measured in plasma/serum by enzyme-linked immunosorbent assay (syndecan-1, thrombomodulin, protein C (PC), tissue-type plasminogen activator and plasminogen activator inhibitor-1). Pre-intervention TEG, functional fibrinogen (FF) and laboratory and clinical data, including mortality, were retrieved from the trial database.ResultsMost patients presented with septic shock (86%) and pulmonary (60%) or abdominal (30%) focus of infection. The median (IQR) age was 67 years (59 to 75), and 55% were males. The median SOFA and SAPS II scores were 8 (6 to 10) and 56 (41 to 68), respectively, with 7-, 28- and 90-day mortality rates being 21%, 39% and 53%, respectively. Pre-intervention (before treatment with different fluids), TEG reaction (R)-time, angle and maximum amplitude (MA) and FF MA all correlated with syndecan-1, thrombomodulin and PC levels. By multivariate linear regression analyses, higher syndecan-1 and lower PC were independently associated with TEG and FF hypocoagulability at the same time-point: 100 ng/ml higher syndecan-1 predicted 0.64 minutes higher R-time (SE 0.25), 1.78 mm lower TEG MA (SE 0.87) and 0.84 mm lower FF MA (SE 0.42; all P <0.05), and 10% lower protein C predicted 1.24 mm lower TEG MA (SE 0.31).ConclusionsIn our cohort of patients with severe sepsis, higher circulating levels of biomarkers of mainly endothelial damage were independently associated with hypocoagulability assessed by TEG and FF. Endothelial damage is intimately linked to coagulopathy in severe sepsis.

Trial registration

Clinicaltrials.gov number: {"type":"clinical-trial","attrs":{"text":"NCT00962156","term_id":"NCT00962156"}}NCT00962156. Registered 13 July 2009.     

Assessment of patient-ventilator breath contribution during neurally adjusted ventilatory assist in patients with acute respiratory failure

IntroductionWe previously showed in animals that the ratio of inspired tidal volume (Vt_insp) to inspiratory peak electrical activity of the diaphragm (EAdi_pk) can be used to quantify the respective patient and ventilator breath contributions (PVBCs) during neurally adjusted ventilatory assist (NAVA). The PVBC index has not been tested clinically.MethodsWe studied 12 intubated and mechanically ventilated patients with acute respiratory failure and measured EAdi_pk, airway (Paw) and inspiratory esophageal pressure (Pes) and Vt_insp. We applied 11 different NAVA levels, increasing them every 3 minutes in steps of 0.3 cm H₂O/μV from 0 to 3.0 cmH₂O/μV. At each NAVA level, one breath was non-assisted (NAVA level 0). PVBC indices were calculated by relating Vt_insp/EAdi_pk of the non-assisted breath to Vt_insp/EAdi_pk of the assisted breath(s) using one (^N1PVBC) or the mean value of five preceding assisted breaths (^X5PVBC). During assisted breaths, inspiratory changes in Pes (∆Pes) and transpulmonary (ΔPtp) pressures were used to calculate the relative contribution of patient to total inspiratory lung-distending pressures (ΔPes/ΔPtp). Matching of respiratory drive indices and squaring of the PVBC was evaluated for their effect on the correlation between PVBC and ΔPes/ΔPtp. Linear regression analysis and Bland-Altman analysis were applied to compare indices.ResultsUsing an average of five assisted breaths prior to the non-assisted breath and squaring the PVBC (^X5PVBC²) improved determination coefficients (P <0.05), adjusted the regression slope and intercept between PVBC and ΔPes/ΔPtp toward identity (P <0.05) and reduced bias (P <0.05). Matching EAdi_pk between non-assisted and assisted breaths within the range of 0.77 to 1.30 improved the relationship between ^X5PVBC² and ΔPes/ΔPtp (P <0.05) and abolished the need for EAdi normalization in the PVBC calculation (R² = 0.96; bias = 0.16 ± 0.06; precision = 0.33 ± 0.08 (mean and 95% confidence interval)).ConclusionsThis clinical study confirms previous experimental results showing that the PVBC² predicts the contribution of the inspiratory muscles versus that of the ventilator during NAVA, when differences in effort (EAdi) between non-assisted and assisted breaths are limited. PVBC could help to quantify and standardize the adjustment of the level of assist, and hence reduce the risks of excessive ventilatory assist in patients.

Trial registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01663480","term_id":"NCT01663480"}}NCT01663480. Registered 9 August 2012.     

Incidence of and risk factors for severe cardiovascular collapse after endotracheal intubation in the ICU: a multicenter observational study

IntroductionSevere cardiovascular collapse (CVC) is a life-threatening complication after emergency endotracheal intubation (ETI) in the ICU. Many factors may interact with hemodynamic conditions during ETI, but no study to date has focused on factors associated with severe CVC occurrence. This study assessed the incidence of severe CVC after ETI in the ICU and analyzed the factors predictive of severe CVC.MethodsThis was a secondary analysis of a prospective multicenter study of 1,400 consecutive intubations at 42 ICUs. The incidence of severe CVC was assessed in patients who were hemodynamically stable (mean arterial blood pressure >65 mmHg without vasoactive drugs) before intubation, and the factors predictive of severe CVC were determined by multivariate analysis based on patient and procedure characteristics.ResultsSevere CVC occurred following 264 of 885 (29.8 %) intubation procedures. A two-step multivariate analysis showed that independent risk factors for CVC included simple acute physiologic score II regardless of age (odds ratio (OR) 1.02, p < 0.001), age 60–75 years (OR 1.96, p < 0.002 versus <60 years) and >75 years (OR 2.81, p < 0.001 versus <60 years), acute respiratory failure as a reason for intubation (OR 1.51, p = 0.04), first intubation in the ICU (OR 1.61, p = 0.02), noninvasive ventilation as a preoxygenation method (OR 1.54, p = 0.03) and inspired oxygen concentration >70 % after intubation (OR 1.91, p = 0.001). Comatose patients who required ETI were less likely to develop CVC during intubation (OR 0.48, p = 0.004).ConclusionsCVC is a frequent complication, especially in old and severely ill patients intubated for acute respiratory failure in the ICU. Specific bundles to prevent CVC may reduce morbidity and mortality related to intubation of these high-risk, critically ill patients.

Trial registration

clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01532063","term_id":"NCT01532063"}}NCT01532063; registered 8 February 2012.     

Neurally adjusted ventilatory assist (NAVA) allows patient-ventilator synchrony during pediatric noninvasive ventilation: a crossover physiological study

IntroductionThe need for intubation after a noninvasive ventilation (NIV) failure is frequent in the pediatric intensive care unit (PICU). One reason is patient-ventilator asynchrony during NIV. Neurally adjusted ventilatory assist (NAVA) is a mode of ventilation controlled by the patient’s neural respiratory drive. The aim of this study was to assess the feasibility and tolerance of NIV-NAVA in children and to evaluate its impact on synchrony and respiratory effort.MethodsThis prospective, physiologic, crossover study included 13 patients requiring NIV in the PICU of Sainte-Justine’s Hospital from October 2011 to May 2013. Patients were successively ventilated in conventional NIV as prescribed by the physician in charge (30 minutes), in NIV-NAVA (60 minutes), and again in conventional NIV (30 minutes). Electrical activity of the diaphragm (EAdi) and airway pressure were simultaneously recorded to assess patient-ventilator synchrony.ResultsNIV-NAVA was feasible and well tolerated in all patients. One patient asked to stop the study because of anxiety related to the leak-free facial mask. Inspiratory trigger dys-synchrony and cycling-off dys-synchrony were significantly shorter in NIV-NAVA versus initial and final conventional NIV periods (both P <0.05). Wasted efforts were also decreased in NIV-NAVA (all values expressed as median and interquartile values) (0 (0 to 0) versus 12% (4 to 20) and 6% (2 to 22), respectively; P <0.01). As a whole, total time spent in asynchrony was reduced to 8% (6 to 10) in NIV-NAVA, versus 27% (19 to 56) and 32% (21 to 38) in conventional NIV before and after NIV-NAVA, respectively (P =0.05).ConclusionNIV-NAVA is feasible and well tolerated in PICU patients and allows improved patient-ventilator synchronization. Larger controlled studies are warranted to evaluate the clinical impact of these findings.

Trial registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT02163382","term_id":"NCT02163382"}}NCT02163382. Registered 9 June 2014.     

Daily laxative therapy reduces organ dysfunction in mechanically ventilated patients: a phase II randomized controlled trial

IntroductionConstipation is a common problem in intensive care units. We assessed the efficacy and safety of laxative therapy aiming to promote daily defecation in reducing organ dysfunction in mechanically ventilated patients.MethodsWe conducted a prospective, randomized, controlled, nonblinded phase II clinical trial at two general intensive care units. Patients expected to remain ventilated for over 3 days were randomly assigned to daily defecation or control groups. The intervention group received lactulose and enemas to produce 1–2 defecations per day. In the control group, absence of defecation was tolerated up to 5 days. Primary outcome was the change in Sequential Organ Failure Assessment (SOFA) score between the date of enrollment and intensive care unit discharge, death or day 14.ResultsWe included 88 patients. Patients in the treatment group had a higher number of defecations per day (1.3 ± 0.42 versus 0.7 ± 0.56, p < 0.0001) and lower percentage of days without defecation (33.1 ± 15.7 % versus 62.3 ±24.5 %, p < 0.0001). Patients in the intervention group had a greater reduction in SOFA score (–4.0 (–6.0 to 0) versus –1.0 (–4.0 to 1.0), p = 0.036) with no difference in mortality rates or in survival time. Adverse events were more frequent in the treatment group (4.5 (3.0–8.0) versus 3.0 (1.0–5.7), p = 0.016), including more days with diarrhea (2.0 (1.0–4.0) versus 1.0 (0–2.0) days, p < 0.0001). Serious adverse events were rare and did not significantly differ between groups.ConclusionsLaxative therapy improved daily defecation in ventilated patients and was associated with a greater reduction in SOFA score.

Trial registration

Clinical Trials.gov {"type":"clinical-trial","attrs":{"text":"NCT01607060","term_id":"NCT01607060"}}NCT01607060, registered 24 May 2012.

Electronic supplementary material

The online version of this article (doi:10.1186/s13054-015-1047-x) contains supplementary material, which is available to authorized users.     

Functional outcomes in ICU – what should we be using? - an observational study

IntroductionWith growing awareness of the importance of rehabilitation, new measures are being developed specifically for use in the intensive care unit (ICU). There are currently 26 measures reported to assess function in ICU survivors. The Physical Function in Intensive care Test scored (PFIT-s) has established clinimetric properties. It is unknown how other functional measures perform in comparison to the PFIT-s or which functional measure may be the most clinically applicable for use within the ICU. The aims of this study were to determine (1) the criterion validity of the Functional Status Score for the ICU (FSS-ICU), ICU Mobility Scale (IMS) and Short Physical Performance Battery (SPPB) against the PFIT-s; (2) the construct validity of these tests against muscle strength; (3) predictive utility of these tests to predict discharge to home; and (4) the clinical applicability. This was a nested study within an ongoing controlled study and an observational study.MethodsSixty-six individuals were assessed at awakening and ICU discharge. Measures included: PFIT-s, FSS-ICU, IMS and SPPB. Bivariate relationships (Spearman’s rank correlation coefficient) and predictive validity (logistic regression) were determined. Responsiveness (effect sizes); floor and ceiling effects; and minimal important differences were calculated.ResultsMean ± SD PFIT-s at awakening was 4.7 ± 2.3 out of 10. On awakening a large positive relationship existed between PFIT-s and the other functional measures: FSS-ICU (rho = 0.87, p < 0.005), IMS (rho = 0.81, p < 0.005) and SPPB (rho = 0.70, p < 0.005). The PFIT-s had excellent construct validity (rho = 0.8, p < 0.005) and FSS-ICU (rho = 0.69, p < 0.005) and IMS (rho = 0.57, p < 0.005) had moderate construct validity with muscle strength. The PFIT-s and FSS-ICU had small floor/ceiling effects <11% at awakening and ICU discharge. The SPPB had a large floor effect at awakening (78%) and ICU discharge (56%). All tests demonstrated responsiveness; however highest effect size was seen in the PFIT-s (Cohen’s d = 0.71).ConclusionsThere is high criterion validity for other functional measures against the PFIT-s. The PFIT-s and FSS-ICU are promising functional measures and are recommended to measure function within the ICU.

Trial registration

Clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT02214823","term_id":"NCT02214823"}}NCT02214823. Registered 7 August 2014).

Electronic supplementary material

The online version of this article (doi:10.1186/s13054-015-0829-5) contains supplementary material, which is available to authorized users.     

Multicenter evaluation of a lateral-flow device test for diagnosing invasive pulmonary aspergillosis in ICU patients

IntroductionThe incidence of invasive pulmonary aspergillosis (IPA) in intensive care unit (ICU) patients is increasing, and early diagnosis of the disease and treatment with antifungal drugs is critical for patient survival. Serum biomarker tests for IPA typically give false-negative results in non-neutropenic patients, and galactomannan (GM) detection, the preferred diagnostic test for IPA using bronchoalveolar lavage (BAL), is often not readily available. Novel approaches to IPA detection in ICU patients are needed. In this multicenter study, we evaluated the performance of an Aspergillus lateral-flow device (LFD) test for BAL IPA detection in critically ill patients.MethodsA total of 149 BAL samples from 133 ICU patients were included in this semiprospective study. Participating centers were the medical university hospitals of Graz, Vienna and Innsbruck in Austria and the University Hospital of Mannheim, Germany. Fungal infections were classified according to modified European Organization for Research and Treatment of Cancer/Mycoses Study Group criteria.ResultsTwo patients (four BALs) had proven IPA, fourteen patients (sixteen BALs) had probable IPA, twenty patients (twenty-one BALs) had possible IPA and ninety-seven patients (one hundred eight BALs) did not fulfill IPA criteria. Sensitivity, specificity, negative predictive value, positive predictive value and diagnostic odds ratios for diagnosing proven and probable IPA using LFD tests of BAL were 80%, 81%, 96%, 44% and 17.6, respectively. Fungal BAL culture exhibited a sensitivity of 50% and a specificity of 85%.ConclusionLFD tests of BAL showed promising results for IPA diagnosis in ICU patients. Furthermore, the LFD test can be performed easily and provides rapid results. Therefore, it may be a reliable alternative for IPA diagnosis in ICU patients if GM results are not rapidly available.

Trial registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT02058316","term_id":"NCT02058316"}}NCT02058316. Registered 20 January 2014.