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.     

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.     

Dexmedetomidine versus standard care sedation with propofol or midazolam in intensive care: an economic evaluation

IntroductionDexmedetomidine was shown in two European randomized double-blind double-dummy trials (PRODEX and MIDEX) to be non-inferior to propofol and midazolam in maintaining target sedation levels in mechanically ventilated intensive care unit (ICU) patients. Additionally, dexmedetomidine shortened the time to extubation versus both standard sedatives, suggesting that it may reduce ICU resource needs and thus lower ICU costs. Considering resource utilization data from these two trials, we performed a secondary, cost-minimization analysis assessing the economics of dexmedetomidine versus standard care sedation.MethodsThe total ICU costs associated with each study sedative were calculated on the basis of total study sedative consumption and the number of days patients remained intubated, required non-invasive ventilation, or required ICU care without mechanical ventilation. The daily unit costs for these three consecutive ICU periods were set to decline toward discharge, reflecting the observed reduction in mean daily Therapeutic Intervention Scoring System (TISS) points between the periods. A number of additional sensitivity analyses were performed, including one in which the total ICU costs were based on the cumulative sum of daily TISS points over the ICU period, and two further scenarios, with declining direct variable daily costs only.ResultsBased on pooled data from both trials, sedation with dexmedetomidine resulted in lower total ICU costs than using the standard sedatives, with a difference of €2,656 in the median (interquartile range) total ICU costs—€11,864 (€7,070 to €23,457) versus €14,520 (€7,871 to €26,254)—and €1,649 in the mean total ICU costs. The median (mean) total ICU costs with dexmedetomidine compared with those of propofol or midazolam were €1,292 (€747) and €3,573 (€2,536) lower, respectively. The result was robust, indicating lower costs with dexmedetomidine in all sensitivity analyses, including those in which only direct variable ICU costs were considered. The likelihood of dexmedetomidine resulting in lower total ICU costs compared with pooled standard care was 91.0% (72.4% versus propofol and 98.0% versus midazolam).ConclusionsFrom an economic point of view, dexmedetomidine appears to be a preferable option compared with standard sedatives for providing light to moderate ICU sedation exceeding 24 hours. The savings potential results primarily from shorter time to extubation.

Trial registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00479661","term_id":"NCT00479661"}}NCT00479661 (PRODEX), {"type":"clinical-trial","attrs":{"text":"NCT00481312","term_id":"NCT00481312"}}NCT00481312 (MIDEX).

Electronic supplementary material

The online version of this article (doi:10.1186/s13054-015-0787-y) contains supplementary material, which is available to authorized users.     

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.     

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.     

A randomized controlled proof-of-concept trial of early sedation management using Responsiveness Index monitoring in mechanically ventilated critically ill patients

IntroductionDeep sedation is associated with adverse patient outcomes. We recently described a novel sedation-monitoring technology, the Responsiveness Index (RI), which quantifies patient arousal using processed frontal facial EMG data. We explored the potential effectiveness and safety of continuous RI monitoring during early intensive care unit (ICU) care as a nurse decision-support tool.MethodsIn a parallel-group controlled single centre proof of concept trial, patients requiring mechanical ventilation and sedation were randomized via sequential sealed envelopes following ICU admission. Control group patients received hourly clinical sedation assessment and daily sedation holds; the RI monitor was connected but data were concealed from clinical staff. The intervention group received control group care, but RI monitoring was visible and nurses were asked to adjust sedation to maintain patients with an RI>20 whenever possible. Traffic-light colour coding (RI<20, Red; 20–40, Amber; >40, Green) simplified decision-making. The intervention lasted up to 48 hours. Sixteen nurses were interviewed to explore their views of the novel technology.ResultsWe analysed 74 patients treated per protocol (36 intervention; 38 control). The proportion of patients with RI<20 was identical at the start of monitoring (54 % both groups). Overall, the proportion of time with RI<20 trended to lower values for the intervention group (median 16 % (1–3rd quartile 8–30 %) versus 33 % (10–54 %); P = 0.08); sedation and analgesic use was similar. A post hoc analysis restricted to patients with RI<20 when monitoring started, found intervention patients spent less time with low RI value (16 % (11–45 %) versus 51 % (33–72 %); P = 0.02), cumulative propofol use trended to lower values (median 1090 mg versus 2390 mg; P = 0.14), and cumulative alfentanil use was lower (21.2 mg versus 32.3 mg; P = 0.01). RASS scores were similar for both groups. Sedation related adverse event rates were similar (7/36 versus 5/38). Similar proportions of patients had sedation holds (83 % versus 87 %) and were extubated (47 % versus 44 %) during the intervention period. Nurses valued the objective visible data trends and simple colour prompts, and found RI monitoring a useful adjunct to existing practice.ConclusionsRI monitoring was safe and acceptable. Data suggested potential to modify sedation decision-making. Larger trials are justified to explore effects on patient-centred outcomes.

Trial registration

{"type":"clinical-trial","attrs":{"text":"NCT01361230","term_id":"NCT01361230"}}NCT01361230 (registered April 19, 2010)

Electronic supplementary material

The online version of this article (doi:10.1186/s13054-015-1043-1) contains supplementary material, which is available to authorized users.     

Microvascular reactivity and clinical outcomes in cardiac surgery

IntroductionMicrovascular reactivity is decreased in patients with septic shock; this is associated with worse clinical outcomes. The objectives of the present study were to investigate microvascular reactivity in cardiac surgery patients and to assess any association with clinical outcomes.MethodsWe retrospectively analyzed a prospectively collected registry. In total, 254 consecutive adult patients undergoing cardiac and thoracic aortic surgeries from January 2013 through May 2014 were analyzed. We performed a vascular occlusion test (VOT) by using near-infrared spectroscopy to measure microvascular reactivity. VOT was performed three times per patient: prior to the induction of anesthesia, at the end of surgery, and on postoperative day 1. The primary endpoint was a composite of major adverse complications, including death, myocardial infarction, acute kidney injury, acute respiratory distress syndrome, and persistent cardiogenic shock.ResultsVOT recovery slope decreased during the surgery. VOT recovery slope on postoperative day 1 was significantly lower in patients with composite complications than those without (3.1 ± 1.6 versus 4.0 ± 1.5 %/s, P = 0.001), although conventional hemodynamic values, such as cardiac output and blood pressure, did not differ between the groups. On multivariable regression and linear analyses, low VOT recovery slope on postoperative day 1 was associated with increases of composite complications (odds ratio 0.742; 95 % confidence interval (CI) 0.584 to 0.943; P = 0.015) and hospital length of stay (regression coefficient (B) −1.276; 95 % CI −2.440 to −0.112; P = 0.032).ConclusionMicrovascular reactivity largely recovered on postoperative day 1 in the patients without composite complications, but this restoration was attenuated in patients with composite complications.

Trial registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01713192","term_id":"NCT01713192"}}NCT01713192. Registered 22 October 2012.

Electronic supplementary material

The online version of this article (doi:10.1186/s13054-015-1025-3) contains supplementary material, which is available to authorized users.     

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.     

Efficacy and safety of fremanezumab in clinical trial participants aged ≥60 years with episodic or chronic migraine: pooled results from 3 randomized,double-blind,placebo-controlled phase 3 studies

BackgroundAlthough migraine is less common in older people, preventive treatment of migraine in these individuals may be more challenging due to the presence of multiple comorbidities and polypharmacy. Additionally, evidence for migraine treatment efficacy, safety, and tolerability is limited in this population. We evaluated efficacy, safety, and tolerability of fremanezumab, a fully humanized monoclonal antibody (IgG2Δa) that selectively targets calcitonin gene–related peptide (CGRP), in clinical trial participants aged ≥60 years with episodic migraine (EM) or chronic migraine (CM).MethodsThis analysis included data from 3 randomized, double-blind, placebo-controlled phase 3 studies: the HALO EM study, HALO CM study, and FOCUS study in participants with EM or CM and prior inadequate response to 2–4 migraine preventive medication classes. Participants in all studies were randomized 1:1:1 to receive 12 weeks of subcutaneous treatment with quarterly fremanezumab (Months 1/2/3: EM/CM, 675 mg/placebo/placebo), monthly fremanezumab (Months 1/2/3: EM, 225 mg/225 mg/225 mg; CM, 675 mg/225 mg/225 mg), or matched monthly placebo.ResultsThese pooled analyses included 246 participants aged ≥60 years. Reductions in monthly migraine days from baseline over 12 weeks were significantly greater with fremanezumab (least-squares mean change from baseline [standard error]: quarterly fremanezumab, − 4.3 [0.59]; monthly fremanezumab, − 4.6 [0.54]) versus placebo (placebo, − 2.3 [0.57]; both P < 0.01 vs placebo). As early as Week 1, significant reductions from baseline in weekly migraine days were observed with fremanezumab versus placebo (both P < 0.01). With fremanezumab treatment versus placebo, a significantly higher proportion of participants achieved ≥50% reduction in monthly migraine days, and significant improvements in disability and quality-of-life outcomes were observed (P < 0.05). Proportions of participants experiencing serious adverse events and adverse events leading to discontinuation were low and similar in the fremanezumab and placebo groups. Efficacy and safety results were comparable to the overall pooled population (N = 2843).ConclusionsThis pooled subgroup analysis demonstrates that fremanezumab treatment is efficacious and well-tolerated over 12 weeks in participants aged ≥60 years with EM or CM. These data may help healthcare providers with clinical decision making and preventive treatment selection for older patients with migraine.Trial registrationClinicalTrials.gov identifiers: HALO CM: {"type":"clinical-trial","attrs":{"text":"NCT02621931","term_id":"NCT02621931"}}NCT02621931; HALO EM: {"type":"clinical-trial","attrs":{"text":"NCT02629861","term_id":"NCT02629861"}}NCT02629861; FOCUS: {"type":"clinical-trial","attrs":{"text":"NCT03308968","term_id":"NCT03308968"}}NCT03308968.Supplementary InformationThe online version contains supplementary material available at 10.1186/s10194-021-01351-2.     

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.     

Effect of transfusion of fresh frozen plasma on parameters of endothelial condition and inflammatory status in non-bleeding critically ill patients: a prospective substudy of a randomized trial

IntroductionMuch controversy exists on the effect of a fresh frozen plasma (FFP) transfusion on systemic inflammation and endothelial damage. Adverse effects of FFP have been well described, including acute lung injury. However, it is also suggested that a higher amount of FFP decreases mortality in trauma patients requiring a massive transfusion. Furthermore, FFP has an endothelial stabilizing effect in experimental models. We investigated the effect of fresh frozen plasma transfusion on systemic inflammation and endothelial condition.MethodsA prospective predefined substudy of a randomized trial in coagulopathic non-bleeding critically ill patients receiving a prophylactic transfusion of FFP (12 ml/kg) prior to an invasive procedure. Levels of inflammatory cytokines and markers of endothelial condition were measured in paired samples of 33 patients before and after transfusion. The statistical tests used were paired t test or the Wilcoxon signed-rank test.ResultsAt baseline, systemic cytokine levels were mildly elevated in critically ill patients. FFP transfusion resulted in a decrease of levels of TNF-α (from 11.3 to 2.3 pg/ml, P = 0.01). Other cytokines were not affected. FFP also resulted in a decrease in systemic syndecan-1 levels (from 675 to 565 pg/ml, P = 0.01) and a decrease in factor VIII levels (from 246 to 246%, P <0.01), suggestive of an improved endothelial condition. This was associated with an increase in ADAMTS13 levels (from 24 to 32%, P <0.01) and a concomitant decrease in von Willebrand factor (vWF) levels (from 474 to 423%, P <0.01).ConclusionsA fixed dose of FFP transfusion in critically ill patients decreases syndecan-1 and factor VIII levels, suggesting a stabilized endothelial condition, possibly by increasing ADAMTS13, which is capable of cleaving vWF.

Trial registrations

Trialregister.nl NTR2262, registered 26 March 2010 and Clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01143909","term_id":"NCT01143909"}}NCT01143909, registered 14 June 2010.     

Normalisation of airflow limitation in asthma: Post‐hoc analyses of TRIMARAN and TRIGGER

BackgroundIn asthma, persistent airflow limitation (PAL) is associated with poorer control, lung function decline and exacerbations. Using post‐hoc analyses we evaluated: the relationship between post‐salbutamol PAL at screening, airflow limitation (AL) during 52 weeks treatment with extrafine beclometasone dipropionate/formoterol fumarate/glycopyrronium (BDP/FF/G) versus BDP/FF and the risk of moderate/severe asthma exacerbations.MethodsTRIMARAN and TRIGGER were double‐blind studies comparing BDP/FF/G with BDP/FF (TRIMARAN medium‐dose ICS; TRIGGER high‐dose) in adults with uncontrolled asthma. Patients were subgrouped according to post‐salbutamol PAL status at screening, and AL over the 52‐week treatment period.ResultsMost patients with post‐salbutamol PAL at screening had AL at all on‐treatment visits (TRIMARAN 62.8%; TRIGGER 66.8%). A significantly higher proportion of patients had normalised airflow on ≥1 follow‐up visit when receiving BDP/FF/G than BDP/FF (TRIMARAN 44.1 vs. 33.1% [p = 0.003]; TRIGGER 40.1 vs. 26.0% [p < 0.001]). In patients with post‐salbutamol PAL at screening and normalised AL at ≥1 follow‐up visit, exacerbation rates were 15% (p = 0.105) and 19% (p = 0.039) lower in TRIMARAN and TRIGGER versus those with AL on all visits. There was a trend to lower exacerbation rates in patients receiving BDP/FF/G than BDP/FF, particularly in patients in whom AL was normalised.ConclusionIn these analyses, AL in asthma was associated with an increased exacerbation incidence. Inhaled triple therapy with extrafine BDP/FF/G was more likely to normalise airflow, and was associated with a trend to a lower exacerbation rate than BDP/FF, particularly in the subgroup of patients in whom treatment was associated with airflow normalisation.ClinicalTrials.gov: TRIMARAN, {"type":"clinical-trial","attrs":{"text":"NCT02676076","term_id":"NCT02676076"}}NCT02676076; TRIGGER, {"type":"clinical-trial","attrs":{"text":"NCT02676089","term_id":"NCT02676089"}}NCT02676089.     

Measuring dose-related efficacy of eptinezumab for migraine prevention: post hoc analysis of PROMISE-1 and PROMISE-2

BackgroundEptinezumab 100 mg and 300 mg met the primary efficacy endpoint in both PROMISE clinical trials, significantly reducing frequency of monthly migraine days over Weeks 1‒12. The objective of this analysis was to assess the clinical response to eptinezumab 100 mg and 300 mg within the pivotal phase 3 PROMISE-1 and PROMISE-2 studies to potentially identify subsets of patients with meaningful differences between doses.MethodsPatients from PROMISE-1 ({"type":"clinical-trial","attrs":{"text":"NCT02559895","term_id":"NCT02559895"}}NCT02559895) and PROMISE-2 ({"type":"clinical-trial","attrs":{"text":"NCT02974153","term_id":"NCT02974153"}}NCT02974153) trials were divided into subgroups based on demographic and migraine characteristics, and baseline questionnaire responses. For each subgroup, the overall likelihood of achieving ≥ 50% migraine responder rate (MRR) over Weeks 1–12 and Weeks 13–24 with either eptinezumab 100 mg or 300 mg was calculated using odds ratios (with associated confidence intervals) and compared.ResultsIn PROMISE-1 (episodic migraine) and PROMISE-2 (chronic migraine), the likelihood of achieving ≥ 50% MRR over Weeks 1–12 and Weeks 13–24 was roughly equivalent for patients receiving either dose level of eptinezumab. Given the number of comparisons performed, sporadic apparent differences were seen but no replicated patterns between studies emerged. In PROMISE-1, no differences were observed in any subgroup over Weeks 1–12. In PROMISE-2, patients reporting < 15 monthly migraine days at baseline, any problems with mobility per the EQ-5D-5L, or a social functioning score > 45.0 per the 36-item Short-Form Health Survey (SF-36), appeared more likely to achieve ≥ 50% MRR with 300 mg over Weeks 1–12, with none of these being apparent in PROMISE-1.ConclusionsOverall, these data suggest that across PROMISE-1 and PROMISE-2, there were no meaningful differences in the likelihood of achieving ≥ 50% MRR between the eptinezumab dose levels in the majority of patient subgroups. In the few subgroups that displayed small, but potentially meaningful differences, patients were more likely to achieve ≥ 50% MRR with eptinezumab 300 mg; however, minimal consistency across both studies and time periods was noted.Trial RegistrationClinicalTrials.gov.PROMISE-1: {"type":"clinical-trial","attrs":{"text":"NCT02559895","term_id":"NCT02559895"}}NCT02559895.PROMISE-2: {"type":"clinical-trial","attrs":{"text":"NCT02974153","term_id":"NCT02974153"}}NCT02974153.     

Does walking during chemotherapy impact p16INK4a levels in women with early breast cancer

BackgroundIncreased p16 ^INK4a (p16) expression is directly related to cellular senescence and is a robust biomarker of aging in humans. Prior studies have shown that levels of p16 dramatically increase in breast cancer patients who have received adjuvant chemotherapy. This study investigated whether moderate physical activity during chemotherapy would attenuate the expected rise in p16 expression.MethodsParticipants were women with Stage I–III breast cancer enrolled in a walking study for the duration of their chemotherapy ({"type":"clinical-trial","attrs":{"text":"NCT02167932","term_id":"NCT02167932"}}NCT02167932, {"type":"clinical-trial","attrs":{"text":"NCT02328313","term_id":"NCT02328313"}}NCT02328313, {"type":"clinical-trial","attrs":{"text":"NCT03761706","term_id":"NCT03761706"}}NCT03761706). Participants were asked to walk at least 30 min or 6200 steps/day following a structured walking program and to wear an activity tracker. p16 mRNA levels were measured in peripheral blood T‐cells before chemotherapy initiation and at approximately 6 months after last chemotherapy treatment (mean 200 days, SD 40 days).ResultsIn total, 141 participants met inclusion criteria and 10% (n = 14) averaged > 6200 steps/day. There was no significant association of daily steps with change in p16 levels pre‐ to post‐chemotherapy (Pearson correlation coefficient = 0.11, p = 0.17). After adjusting for age, stage, anthracycline‐based chemotherapy, and baseline p16, the change in log₂ p16 for each 1000 steps was estimated to be 0.03 (p = 0.35). Most participants were sedentary prior to chemotherapy and achieved modest levels of physical activity during treatment.ConclusionA self‐guided walking program achieved only modest levels of physical activity and was unable to ameliorate chemotherapy‐induced change in p16 levels in women undergoing chemotherapy for early‐stage breast cancer. More structured and vigorous exercise programs should be tested for a more definitive exploration of their impact on post‐chemotherapy p16 levels.     

Severe and multiple hypoglycemic episodes are associated with increased risk of death in ICU patients

IntroductionIn a randomized controlled trial comparing tight glucose control with a computerized decision support system and conventional protocols (post hoc analysis), we tested the hypothesis that hypoglycemia is associated with a poor outcome, even when controlling for initial severity.MethodsWe looked for moderate (2.2 to 3.3 mmol/L) and severe (<2.2 mmol/L) hypoglycemia, multiple hypoglycemic events (n ≥3) and the other main components of glycemic control (mean blood glucose level and blood glucose coefficient of variation (CV)). The primary endpoint was 90-day mortality. We used both a multivariable analysis taking into account only variables observed at admission and a multivariable matching process (greedy matching algorithm; caliper width of 10⁻⁵ digit with no replacement).ResultsA total of 2,601 patients were analyzed and divided into three groups: no hypoglycemia (n =1,474), moderate hypoglycemia (n =874, 34%) and severe hypoglycemia (n =253, 10%). Patients with moderate or severe hypoglycemia had a poorer prognosis, as shown by a higher mortality rate (36% and 54%, respectively, vs. 28%) and decreased number of treatment-free days. In the multivariable analysis, severe (odds ratio (OR), 1.50; 95% CI, 1.36 to 1.56; P =0.043) and multiple hypoglycemic events (OR, 1.76, 95% CI, 1.31 to 3.37; P <0.001) were significantly associated with mortality, whereas blood glucose CV was not. Using multivariable matching, patients with severe (53% vs. 35%; P <0.001), moderate (33% vs. 27%; P =0.029) and multiple hypoglycemic events (46% vs. 32%, P <0.001) had a higher 90-day mortality.ConclusionIn a large cohort of ICU patients, severe hypoglycemia and multiple hypoglycemic events were associated with increased 90-day mortality.

Trial registration

Clinicaltrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT01002482","term_id":"NCT01002482"}}NCT01002482. Registered 26 October 2009.     

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.     

Safety and tolerability of erenumab in individuals with episodic or chronic migraine across age groups: a pooled analysis of placebo-controlled trials

BackgroundErenumab, a fully human monoclonal antibody that targets the calcitonin gene-related peptide receptor, has demonstrated efficacy and safety in the prevention of episodic and chronic migraine. There exists an unmet need to establish the safety of erenumab in older individuals, in view of existing multiple comorbidities, polypharmacy, and age-related physiological changes. This pooled analysis of five large migraine-prevention studies examined the safety of erenumab stratified across age groups, particularly in older populations.MethodsPooled and age-stratified analysis of safety data from the 12-week double-blind treatment phase (DBTP) of five randomized, placebo-controlled Phase 2 and 3 studies of erenumab in participants with episodic or chronic migraine across the age groups < 40 years, 40–49 years, 50–59 years, and ≥ 60 years was completed. The safety of erenumab across age groups was determined by assessing safety endpoints including treatment-emergent adverse events (AEs), serious AEs, and events leading to study drug discontinuation.ResultsOverall, 3345 participants across five studies were randomized to receive either placebo (n = 1359), erenumab 70 mg (n = 1132) or erenumab 140 mg (n = 854); 3176 (94.9%) completed the DBTP, and 169 (5.1%) discontinued, mainly due to participant decision (110; 3.3%). Overall, 1349 (40.6%), 1122 (33.8%), and 850 (25.6%) participants received at least one dose of placebo, erenumab 70 mg, and erenumab 140 mg, respectively.Incidence of treatment-emergent AEs was similar across all age groups for both doses of erenumab (70 mg or 140 mg) and placebo (< 40 years, 44.0% vs 44.4%; 40–49 years, 42.5% vs 49.2%; 50–59 years, 46.5% vs 41.6%; ≥ 60 years, 43.8% vs 59.4%). Incidence of treatment-emergent serious AEs overall, and stratified by age groups for both doses and placebo was low (< 40 years, 0.9% vs 1.2%; 40–49 years, 1.7% vs 1.9%; and 50–59 years, 1.6% vs 1.1%), with no serious AEs reported in participants aged ≥ 60 years. No deaths were reported.ConclusionsErenumab (70 mg or 140 mg) exhibited a similar safety profile compared with placebo across age groups in individuals with episodic or chronic migraine, with no increased emergence of events due to age. Erenumab was well tolerated in older participants with multiple comorbidities, polypharmacy, and age-related physiological changes.Trial registration numberClinicalTrials.gov Identifiers: {"type":"clinical-trial","attrs":{"text":"NCT02066415","term_id":"NCT02066415"}}NCT02066415, {"type":"clinical-trial","attrs":{"text":"NCT02456740","term_id":"NCT02456740"}}NCT02456740, {"type":"clinical-trial","attrs":{"text":"NCT02483585","term_id":"NCT02483585"}}NCT02483585, {"type":"clinical-trial","attrs":{"text":"NCT03096834","term_id":"NCT03096834"}}NCT03096834, {"type":"clinical-trial","attrs":{"text":"NCT03333109","term_id":"NCT03333109"}}NCT03333109.Supplementary InformationThe online version contains supplementary material available at 10.1186/s10194-022-01470-4.     

Smart Care? versus respiratory physiotherapy–driven manual weaning for critically ill adult patients: a randomized controlled trial

IntroductionA recent meta-analysis showed that weaning with SmartCare™ (Dräger, Lübeck, Germany) significantly decreased weaning time in critically ill patients. However, its utility compared with respiratory physiotherapist–protocolized weaning is still a matter of debate. We hypothesized that weaning with SmartCare™ would be as effective as respiratory physiotherapy–driven weaning in critically ill patients.MethodsAdult critically ill patients mechanically ventilated for more than 24 hours in the adult intensive care unit of the Albert Einstein Hospital, São Paulo, Brazil, were randomly assigned to be weaned either by progressive discontinuation of pressure support ventilation (PSV) with SmartCare™. Demographic data, respiratory function parameters, level of PSV, tidal volume (VT), positive end-expiratory pressure (PEEP), inspired oxygen fraction (FiO₂), peripheral oxygen saturation (SpO₂), end-tidal carbon dioxide concentration (EtCO₂) and airway occlusion pressure at 0.1 second (P_0.1) were recorded at the beginning of the weaning process and before extubation. Mechanical ventilation time, weaning duration and rate of extubation failure were compared.ResultsSeventy patients were enrolled 35 in each group. There was no difference between the two groups concerning age, sex or diagnosis at study entry. There was no difference in maximal inspiratory pressure, maximal expiratory pressure, forced vital capacity or rapid shallow breathing index at the beginning of the weaning trial. PEEP, VT, FiO₂, SpO₂, respiratory rate, EtCO₂ and P_0.1 were similar between the two groups, but PSV was not (median: 8 vs. 10 cmH₂O; p =0.007). When the patients were ready for extubation, PSV (8 vs. 5 cmH₂O; p =0.015) and PEEP (8 vs. 5 cmH₂O; p <0.001) were significantly higher in the respiratory physiotherapy–driven weaning group. Total duration of mechanical ventilation (3.5 [2.0–7.3] days vs. 4.1 [2.7-7.1] days; p =0.467) and extubation failure (2 vs. 2; p =1.00) were similar between the two groups. Weaning duration was shorter in the respiratory physiotherapy–driven weaning group (60 [50–80] minutes vs. 110 [80–130] minutes; p <0.001).ConclusionA respiratory physiotherapy–driven weaning protocol can decrease weaning time compared with an automatic system, as it takes into account individual weaning difficulties.

Trial registration

Clinicaltrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT02122016","term_id":"NCT02122016"}}NCT02122016. Date of Registration: 27 August 2013.     

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.     

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.