Effect of oral melatonin and wearing earplugs and eye masks on nocturnal sleep in healthy subjects in a simulated intensive care unit environment: which might be a more promising strategy for ICU sleep deprivation?

IntroductionSleep deprivation is common in critically ill patients in the intensive care unit (ICU). Noise and light in the ICU and the reduction in plasma melatonin play the essential roles. The aim of this study was to determine the effect of simulated ICU noise and light on nocturnal sleep quality, and compare the effectiveness of melatonin and earplugs and eye masks on sleep quality in these conditions in healthy subjects.MethodsThis study was conducted in two parts. In part one, 40 healthy subjects slept under baseline night and simulated ICU noise and light (NL) by a cross-over design. In part two, 40 subjects were randomly assigned to four groups: NL, NL plus placebo (NLP), NL plus use of earplugs and eye masks (NLEE) and NL plus melatonin (NLM). 1 mg of oral melatonin or placebo was administered at 21:00 on four consecutive days in NLM and NLP. Earplugs and eye masks were made available in NLEE. The objective sleep quality was measured by polysomnography. Serum was analyzed for melatonin levels. Subjects rated their perceived sleep quality and anxiety levels.ResultsSubjects had shorter total sleep time (TST) and rapid eye movement (REM) sleep, longer sleep onset latency, more light sleep and awakening, poorer subjective sleep quality, higher anxiety level and lower serum melatonin level in NL night (P <0.05). NLEE had less awakenings and shorter sleep onset latency (P <0.05). NLM had longer TST and REM and shorter sleep onset latency (P <0.05). Compared with NLEE, NLM had fewer awakenings (P = 0.004). Both NLM and NLEE improved perceived sleep quality and anxiety level (P = 0.000), and NLM showed better than NLEE in perceived sleep quality (P = 0.01). Compared to baseline night, the serum melatonin levels were lower in NL night at every time point, and the average maximal serum melatonin concentration in NLM group was significantly greater than other groups (P <0.001).ConclusionsCompared with earplugs and eye masks, melatonin improves sleep quality and serum melatonin levels better in healthy subjects exposed to simulated ICU noise and light.

Trial registration

Chinese Clinical Trial Registry ChiCTR-IPR-14005458. Registered 10 November 2014.     

Sleep and circadian rhythm disturbances in intensive care unit (ICU)-acquired delirium: a case–control study

ObjectiveThe relationships among sleep, circadian rhythm, and intensive care unit (ICU)-acquired delirium are complex and remain unclear. This study aimed to examine the pathophysiological mechanisms of sleep and circadian rhythm disturbances in patients with ICU-acquired delirium.MethodsThis study included critical adult patients aged 18 to 75 years who were treated in the ICU. Twenty-four-hour polysomnography was performed and serum melatonin and cortisol levels were measured six times during polysomnography. Receiver operating characteristic curves and binomial logistic regression were used to evaluate the potential of sleep, melatonin, and cortisol as indicators of delirium in the ICU.ResultsPatients with delirium (n = 24) showed less rapid eye movement (REM) sleep compared with patients without delirium (n = 24, controls). Melatonin levels were lower and cortisol levels were higher in the delirium group than in the control group. REM sleep, melatonin, and cortisol were significantly associated with delirium. The optimal cutoff values of REM sleep and mean melatonin and cortisol levels that predicted delirium were ≤1.05%, ≤422.09 pg/mL, and ≥212.14 ng/mL, respectively.ConclusionsREM sleep, and melatonin and cortisol levels are significantly associated with the risk of ICU-acquired delirium. Improved sleep and readjustment of circadian rhythmicity may be therapeutic targets of ICU-acquired delirium.     

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.     

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.     

Copeptin levels are associated with organ dysfunction and death in the intensive care unit after out-of-hospital cardiac arrest

IntroductionWe studied associations of the stress hormones copeptin and cortisol with outcome and organ dysfunction after out-of-hospital cardiac arrest (OHCA).MethodsPlasma was obtained after consent from next of kin in the FINNRESUSCI study conducted in 21 Finnish intensive care units (ICUs) between 2010 and 2011. We measured plasma copeptin (pmol/L) and free cortisol (nmol/L) on ICU admission (245 patients) and at 48 hours (additional 33 patients). Organ dysfunction was categorised with 24-hour Sequential Organ Failure Assessment (SOFA) scores. Twelve-month neurological outcome (available in 276 patients) was classified with cerebral performance categories (CPC) and dichotomised into good (CPC 1 or 2) or poor (CPC 3 to 5). Data are presented as medians and interquartile ranges (IQRs). A Mann–Whitney U test, multiple linear and logistic regression tests with odds ratios (ORs) 95% confidence intervals (CIs) and beta (B) values, repeated measure analysis of variance, and receiver operating characteristic curves with area under the curve (AUC) were performed.ResultsPatients with a poor 12-month outcome had higher levels of admission copeptin (89, IQR 41 to 193 versus 51, IQR 29 to 111 pmol/L, P = 0.0014) and cortisol (728, IQR 522 to 1,017 versus 576, IQR 355 to 850 nmol/L, P = 0.0013). Copeptin levels fell between admission and 48 hours (P <0.001), independently of outcome (P = 0.847). Cortisol levels did not change between admission and 48 hours (P = 0.313), independently of outcome (P = 0.221). The AUC for predicting long-term outcome was weak for copeptin (0.62, 95% CI 0.55 to 0.69) and cortisol (0.62, 95% CI 0.54 to 0.69). With logistic regression, admission copeptin (standard deviation (SD) increase OR 1.4, 95% CI 1.03 to 1.98) and cortisol (SD increase OR 1.5, 95% CI 1.1 to 2.0) predicted ICU mortality but not 12-month outcome. Admission factors correlating with SOFA were shockable rhythm (B −1.3, 95% CI −2.2 to −0.5), adrenaline use (B 1.1, 95% CI 0.2 to 2.0), therapeutic hypothermia (B 1.3 95% CI 0.4-2.2), and copeptin (B 0.04, 95% CI 0.02 to 0.07).ConclusionsAdmission copeptin and free cortisol were not of prognostic value regarding 12-month neurological outcome after OHCA. Higher admission copeptin and cortisol were associated with ICU death, and copeptin predicted subsequent organ dysfunction.

Electronic supplementary material

The online version of this article (doi:10.1186/s13054-015-0831-y) contains supplementary material, which is available to authorized users.     

Platelet mitochondrial dysfunction in critically ill patients: comparison between sepsis and cardiogenic shock

IntroductionPlatelet mitochondrial respiratory chain enzymes (that produce energy) are variably inhibited during human sepsis. Whether these changes occur even during other acute critical illness or are associated with impaired platelet aggregation and secretion (that consume energy) is not known. The aims of this study were firstly to compare platelet mitochondrial respiratory chain enzymes activity between patients with sepsis and those with cardiogenic shock, and secondly to study the relationship between platelet mitochondrial respiratory chain enzymes activity and platelet responsiveness to (exogenous) agonists in patients with sepsis.MethodsThis was a prospective, observational, case–control study. Platelets were isolated from venous blood of 16 patients with severe sepsis or septic shock (free from antiplatelet drugs) and 16 others with cardiogenic shock, within 48 hours from admission to Intensive Care. Platelet mitochondrial respiratory chain enzymes activity was measured with spectrophotometry and expressed relative to citrate synthase activity, a marker of mitochondrial density. Platelet aggregation and secretion in response to adenosine di-phosphate (ADP), collagen, U46619 and thrombin receptor activating peptide were measured with lumiaggregometry only in patients with sepsis. In total, 16 healthy volunteers acted as controls for both spectrophotometry and lumiaggregometry.ResultsPlatelets of patients with sepsis or cardiogenic shock similarly had lower mitochondrial nicotinamide adenine dinucleotide dehydrogenase (NADH) (P < 0.001), complex I (P = 0.006), complex I and III (P < 0.001) and complex IV (P < 0.001) activity than those of controls. Platelets of patients with sepsis were generally hypo-responsive to exogenous agonists, both in terms of maximal aggregation (P < 0.001) and secretion (P < 0.05). Lower mitochondrial NADH (R² 0.36; P < 0.001), complex I (R² 0.38; P < 0.001), complex I and III (R² 0.27; P = 0.002) and complex IV (R² 0.43; P < 0.001) activity was associated with lower first wave of aggregation with ADP.ConclusionsSeveral platelet mitochondrial respiratory chain enzymes are similarly inhibited during human sepsis and cardiogenic shock. In patients with sepsis, mitochondrial dysfunction is associated with general platelet hypo-responsiveness to exogenous agonists.

Trial registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00541827","term_id":"NCT00541827"}}NCT00541827. Registered 8 October 2007.     

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.     

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.     

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.     

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.     

Hydroxyethyl starch versus other fluids for non-septic patients in the intensive care unit: a meta-analysis of randomized controlled trials

IntroductionUse of hydroxyethyl starch (HES) in septic patients is reported to increase the mortality and incidence of renal replacement therapy (RRT). However, whether or not use of HES would induce the same result in non-septic patients in the intensive care unit (ICU) remains unclear. The objective of this meta-analysis was to evaluate 6% HES versus other fluids for non-septic ICU patients.MethodsRandomized controlled trials (RCTs) were searched from Pubmed, OvidSP, Embase database and Cochrane Library, published before November, 2013. A meta-analysis was made on the effect of 6% HES versus other fluids for non-septic ICU patients, including mortality, RRT incidence, bleeding volume, red blood cell (RBC) transfusion and fluid application for non-septic patients in ICU.ResultsTwenty-two RCTs were included, involving 6,064 non-septic ICU patients. Compared with the other fluids, 6% HES was not associated with decreased overall mortality (RR = 1.03, 95%CI: 0.09 to 1.17; P = 0.67; I² = 0). There was no significant difference in RRT incidence, bleeding volume and red blood cell transfusion between 6% HES group and the other fluid groups. However, patients in HES group received less total intravenous fluids than those receiving crystalloids during the first day in ICU (SMD = −0.84; 95%CI: −1.39 to −0.30; P = 0.003, I² = 74%).ConclusionsThis meta-analysis found no increased mortality, RRT incidence, bleeding volumes or RBC transfusion in non-septic ICU patients, but the sample sizes were small and the studies generally were of poor quality.

Electronic supplementary material

The online version of this article (doi:10.1186/s13054-015-0833-9) contains supplementary material, which is available to authorized users.     

Erythropoietin improves long-term neurological outcome in acute ischemic stroke patients: a randomized,prospective, placebo-controlled clinical trial

IntroductionMortality and disability following ischemic stroke (IS) remains unacceptably high with respect to the conventional therapies. This study tested the effect of erythropoietin (EPO) on long-term neurological outcome in patients after acute IS. This study aimed to evaluate the safety and efficacy of two consecutive doses of EPO (5,000 IU/dose, subcutaneously administered at 48 hours and 72 hours after acute IS) on improving the 90-day combined endpoint of recurrent stroke or death that has been previously reported. A secondary objective was to evaluate the long-term (that is, five years) outcome of patients who received EPO.MethodsThis was a prospective, randomized, placebo-controlled trial that was conducted between October 2008 and March 2010 in a tertiary referral center. IS stroke patients who were eligible for EPO therapy were enrolled into the study.ResultsThe results showed that long-term recurrent stroke and mortality did not differ between group 1 (placebo-control; n = 71) and group 2 (EPO-treated; n = 71).Long-term Barthel index of <35 (defining a severe neurological deficit) was lower in group 2 than group 1 (P = 0.007). Multiple-stepwise logistic-regression analysis showed that EPO therapy was significantly and independently predictive of freedom from a Barthel index of <35 (P = 0.029). Long-term major adverse neurological event (MANE; defined as: death, recurrent stroke, or long-term Barthel index < 35) was lower in group 2 than group 1 (P = 0.04). Log-Rank test showed that MANE-free rate was higher in group 2 than group 1 (P = 0.031). Multiple-stepwise Cox-regression analysis showed that EPO therapy and higher Barthel Index at day 90 were independently predictive of freedom from long-term MANE (all P <0.04).ConclusionEPO therapy significantly improved long-term neurological outcomes in patients after IS.

Trial registration

ISRCTN71371114. Registered 10 October 2008.     

Impact of fremanezumab on disability outcomes in patients with episodic and chronic migraine: a pooled analysis of phase 3 studies

BackgroundMigraine is the second leading cause of disability worldwide. Although many preventive treatments reduce migraine frequency and severity, it is unclear whether these treatments reduce migraine-related disability in a clinically meaningful way. This pooled analysis evaluated the ability of fremanezumab to reduce migraine-related disability, based on responses and shifts in severity in patient-reported disability outcomes.MethodsThis pooled analysis included 3 double-blind phase 3 trials (HALO EM, HALO CM, FOCUS) in which patients with episodic or chronic migraine were randomly assigned 1:1:1 to quarterly or monthly fremanezumab or matched placebo for 12 weeks. Migraine-related disability was assessed using the 6-item Headache Impact Test (HIT-6) and Migraine Disability Assessment (MIDAS) questionnaires. A clinically meaningful improvement in disability was defined per American Headache Society guidelines: for HIT-6, a ≥ 5-point reduction; for MIDAS, a ≥ 5-point reduction when baseline score was 11 to 20 or ≥ 30% reduction when baseline score was > 20. Proportions of patients who demonstrated shifts in severity for each outcome were also evaluated.ResultsFor patients with baseline MIDAS scores of 11 to 20 (n = 234), significantly higher proportions achieved 5-point reductions from baseline in MIDAS scores with fremanezumab (quarterly, 71%; monthly, 70%) compared with placebo (49%; both P ≤ 0.01). For patients with baseline MIDAS scores of > 20 (n = 1266), proportions achieving ≥30% reduction from baseline in MIDAS scores were also significantly higher with fremanezumab (quarterly, 69%; monthly, 79%) compared with placebo (58%; both P < 0.001). For HIT-6 scores, proportions of patients achieving 5-point reductions from baseline were significantly higher with fremanezumab (quarterly, 53%; monthly, 55%) compared with placebo (39%; both P < 0.0001). Proportions of patients with shifts of 1 to 3 grades down in MIDAS or HIT-6 disability severity were significantly greater with quarterly and monthly fremanezumab compared with placebo (all P < 0.0001).ConclusionFremanezumab demonstrated clinically meaningful improvements in disability severity in this pooled analysis.Trial registrationsHALO 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.     

The diagnostic and prognostic significance of monitoring blood levels of immature neutrophils in patients with systemic inflammation

IntroductionIn this cohort study, we investigated whether monitoring blood levels of immature neutrophils (myelocytes, metamyelocytes and band cells) differentiated patients with sepsis from those with the non-infectious (N-I) systemic inflammatory response syndrome (SIRS). We also ascertained if the appearance of circulating immature neutrophils was related to adverse outcome.MethodsBlood samples were routinely taken from 136 critically ill patients within 48 hours of ICU entry and from 20 healthy control subjects. Clinical and laboratory staff were blinded to each other’s results, and patients were retrospectively characterised into those with SIRS (n = 122) and those without SIRS (n = 14). The patients with SIRS were further subdivided into categories of definite sepsis (n = 51), possible sepsis (n = 32) and N-I SIRS (n = 39). Two established criteria were used for monitoring immature white blood cells (WBCs): one where band cells >10% WBCs and the other where >10% of all forms of immature neutrophils were included but with a normal WBC count. Immature neutrophils in blood smears were identified according to nuclear morphology and cytoplasmic staining.ResultsWith the first criterion, band cells were present in most patients with SIRS (mean = 66%) when compared with no SIRS (mean = 29%; P <0.01) and with healthy subjects (0%). The prevalence of band cells was higher in definite sepsis (mean = 82%) than in patients with possible sepsis (mean = 63%; P <0.05) or with N-I SIRS (mean = 39%; P <0.001), and they had a sensitivity of 84% and a specificity of 71% for the detection of definite sepsis. With the second criterion (that is, patients with normal WBC counts), we noted that immature neutrophils did not differentiate any of the patient groups from one another. Patients who died within 1 week of blood sample provision had higher levels of myelocytes and metamyelocytes (median = 9%; P <0.05) than patients who died at 2 to 4 weeks (median =0.5%).ConclusionsRaised blood levels of band cells have diagnostic significance for sepsis, provided that measurements are not confined to patients with normal WBC counts, whereas an increased prevalence of myelocytes and metamyelocytes may have prognostic application.     

Efficacy and safety of fremanezumab in patients with migraine and inadequate response to prior preventive treatment: subgroup analyses by country of a randomized,placebo-controlled trial

BackgroundThe FOCUS study evaluated the efficacy of migraine preventive medications across different countries within the same patient population, particularly for patients with difficult-to-treat migraine. These prespecified subgroup analyses evaluated efficacy by country in the FOCUS study of fremanezumab in adults with episodic migraine or chronic migraine and documented inadequate response to 2 to 4 migraine preventive medication classes.MethodsOverall, 838 participants were enrolled in the FOCUS study, a randomized, double-blind, placebo-controlled, parallel-group, phase 3b study performed at 104 sites. For 12 weeks of double-blind treatment, patients were randomized (1:1:1) to quarterly fremanezumab, monthly fremanezumab, or matched placebo. The primary efficacy endpoint was the mean change from baseline in monthly average migraine days over 12 weeks of double-blind treatment, evaluated by country in these subgroup analyses.ResultsOf 14 countries contributing data, the Czech Republic (n = 188/838; 22%), the United States (n = 120/838; 14%), and Finland (n = 85/838; 10%) enrolled the most patients. Changes from baseline in monthly average migraine days over 12 weeks were significantly greater with fremanezumab versus placebo for patients in these countries: Czech Republic (least-squares mean difference versus placebo [95% confidence interval]: quarterly fremanezumab, − 1.9 [− 3.25, − 0.47]; P = 0.009; monthly fremanezumab, − 3.0 [− 4.39, − 1.59]; P < 0.001), the United States (quarterly fremanezumab, − 3.7 [− 5.77, − 1.58]; P < 0.001; monthly fremanezumab, − 4.2 [− 6.23, − 2.13]; P < 0.001), and Finland (quarterly fremanezumab, − 3.0 [− 5.32, − 0.63]; P = 0.014; monthly fremanezumab, − 3.9 [− 6.27, − 1.44]; P = 0.002). Results were comparable for the remaining 9 countries, with the least-squares mean difference versus placebo ranging from – 5.6 to – 2.4 with quarterly fremanezumab and from − 5.3 to − 1.5 with monthly fremanezumab. Incidences of serious adverse events and adverse events leading to discontinuation were low and comparable across countries and treatment groups.ConclusionsMonthly and quarterly fremanezumab significantly reduced the monthly average number of migraine days versus placebo regardless of country and continent (North America versus Europe) in migraine patients with documented inadequate response to 2 to 4 migraine preventive medication classes.Trial registrationClinicalTrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT03308968","term_id":"NCT03308968"}}NCT03308968.Supplementary InformationThe online version contains supplementary material available at 10.1186/s10194-021-01232-8.     

Efficacy of galcanezumab in patients with migraine and history of failure to 3–4 preventive medication categories: subgroup analysis from CONQUER study

BackgroundChronic migraine (CM) and episodic migraine (EM) are associated with substantial headache-related disability, poor quality of life and global societal burden. In this subgroup analysis from the CONQUER study, we report efficacy outcomes from a pre-specified analysis of galcanezumab versus placebo in patients with CM or EM and 3–4 prior preventive medication category failures due to inadequate efficacy (after at least 2 months at maximum tolerated dose), or safety or tolerability reasons. The patient population is of particular interest due to evidence of decreased quality of life and increased economic burden among patients with migraine that is inadequately managed and is of interest to decision-makers globally.MethodsKey outcomes included overall mean change from baseline in monthly migraine headache days and proportions of patients achieving ≥30% (CM), ≥50%, and ≥ 75% reduction (response rates) in monthly migraine headache days across Months 1–3. Patient functioning and disability were evaluated at Month 3.ResultsOf the 462 randomized patients, 186 (40.3%) had a history of 3–4 preventive category failures. Galcanezumab versus placebo resulted in significantly (P ≤ .001) larger overall mean reduction in monthly migraine headache days (total: − 5.49 versus − 1.03; CM: − 6.70 versus − 1.56; EM: − 3.64 versus − 0.65). Similarly, the ≥50% response rate was significantly (P ≤ .001) higher with galcanezumab versus placebo (total: 41.0 versus 12.7; CM: 41.5 versus 8.4; EM: 41.1 versus 16.5). In the CM group, the ≥30% response rate was significantly higher in the galcanezumab group than the placebo group (CM, 57.5 versus 19.8, P ≤ .0001) as was the ≥75% response rate (13.3 versus 2.6, P ≤ .05). Galcanezumab also resulted in significant (P < .0001) improvements in patient functioning and reductions in disability.ConclusionsGalcanezumab was effective in a difficult-to-treat population of patients with CM or EM who had failed 3–4 prior preventive medication categories.Trial registrationCONQUER. Clinicaltrials.gov identifier: {"type":"clinical-trial","attrs":{"text":"NCT03559257","term_id":"NCT03559257"}}NCT03559257.     

CGRP and PACAP-38 play an important role in diagnosing pediatric migraine

BackgroundAn increasing number of studies have suggested that the important role of vasoactive peptides, such as pituitary adenylate cyclase-activating polypeptide-38 (PACAP-38) and calcitonin gene-related peptide (CGRP), in the pathophysiology of migraine seems undeniable in adults, but studies in pediatric migraine patients remain scarce. We prospectively investigated CGRP and PACAP-38 plasma levels in children with migraine during ictal and interictal periods and compared the results between migraine patients with aura and without aura. We were the first to explore the diagnostic value of a combination of CGRP and PACAP-38.MethodsSeventy-six migraine patients aged 4–18 years and seventy-seven age-matched healthy children were included in the study. Plasma vasoactive peptides were measured using the enzyme-linked immunosorbent assay (ELISA). Differences and correlations of groups were analyzed using the independent samples t-test, analysis of variance (ANOVA), Mann-Whitney U test, and multiple linear regression. We also performed logistic regression and receiver operating characteristic curve (ROC) analyses to evaluate the diagnostic value of CGRP and PACAP-38 in pediatric migraine.ResultsPACAP-38 and CGRP levels in migraine patients during the ictal and interictal periods were higher than those in controls (p < 0.001). PACAP-38 and CGRP levels in migraine patients with aura and without aura were higher than those in controls (p < 0.001). PACAP-38 and CGRP were independent risk factors in diagnosing pediatric migraine (adjusted OR (PACAP-38) =1.331, 95% CI: 1.177–1.506, p < 0.001; adjusted OR (CGRP) = 1.113, 95% CI: 1.064–1.165, p < 0.001). Area Under Curve (AUC) comparison: Combination (0.926) > CGRP (0.869) > PACAP-38 (0.867).ConclusionsOur study found almost the same changes in CGRP and PACAP levels in pediatric migraine, suggesting that CGRP and PACAP-38 may work together to play an integral role in pediatric migraine. Higher CGRP levels were found in the ictal phase than in the interictal phase and with aura group than without aura group, indicating that CGRP may take part in the formation of pain and aura. Moreover, ROC and logistic regression analyses suggested that CGRP and PACAP-38 are good indicators to diagnose pediatric migraine, and the combination of CGRP and PACAP-38 was valuable in diagnosing pediatric migraine and differentiating pediatric migraine from non-migraine headaches.Trial registrationThe study has been registered at the Chinese Clinical Trial Registry (ChiCTR2100043157).     

Midazolam and propofol used alone or sequentially for long-term sedation in critically ill,mechanically ventilated patients: a prospective,randomized study

Introduction

Midazolam and propofol used alone for long-term sedation are associated with adverse effects. Sequential use may reduce the adverse effects, and lead to faster recovery, earlier extubation and lower costs. This study evaluates the effects, safety, and cost of midazolam, propofol, and their sequential use for long-term sedation in critically ill mechanically ventilated patients.

Methods

A total of 135 patients who required mechanical ventilation for >3 days were randomly assigned to receive midazolam (group M), propofol (group P), or sequential use of both (group M-P). In group M-P, midazolam was switched to propofol until the patients passed the spontaneous breathing trial (SBT) safety screen. The primary endpoints included recovery time, extubation time and mechanical ventilation time. The secondary endpoints were pharmaceutical cost, total cost of ICU stay, and recollection to mechanical ventilation-related events.

Results

The incidence of agitation following cessation of sedation in group M-P was lower than group M (19.4% versus 48.7%, P = 0.01). The mean percentage of adequate sedation and duration of sedation were similar in the three groups. The recovery time, extubation time and mechanical ventilation time of group M were 58.0 (interquartile range (IQR), 39.0) hours, 45.0 (IQR, 24.5) hours, and 192.0 (IQR, 124.0) hours, respectively; these were significantly longer than the other groups, while they were similar between the other two groups. In the treatment-received analysis, ICU duration was longer in group M than group M-P (P = 0.016). Using an intention-to-treat analysis and a treatment-received analysis, respectively, the pharmaceutical cost of group M-P was lower than group P (P <0.01) and its ICU cost was lower than group M (P <0.01; P = 0.015). The proportion of group M-P with unbearable memory of the uncomfortable events was lower than in group M (11.7% versus 25.0%, P <0.01), while the proportion with no memory was similar (P >0.05). The incidence of hypotension in group M-P was lower than group (P = 0.01).

Conclusion

Sequential use of midazolam and propofol was a safe and effective sedation protocol, with higher clinical effectiveness and better cost-benefit ratio than midazolam or propofol used alone, for long-term sedation of critically ill mechanically ventilated patients.

Trial registration

Current Controlled Trials ISRCTN01173443. Registered 25 February 2014.     

Impact of four sequential measures on the prevention of ventilator-associated pneumonia in cardiac surgery patients

Introduction

Ventilator-associated pneumonia (VAP) is the most frequent infection in patients admitted to intensive care units.The efficacy of individual measures for the prevention of VAP is well documented, and data on the impact of implementing bundle measures have usually been reported from studies in which several measures are implemented simultaneously in the general intensive care unit (ICU).The objective of our work was to evaluate the impact of four sequentially implemented measures for preventing VAP in a major heart surgery ICU. The measures were a specific training program, aspiration of subglottic secretions (ASSs), introduction of an inclinometer to improve the semirecumbent position, and reinforcement of oral care with chlorhexidine.

Methods

We compared rates of VAP, days on mechanical ventilation (MV), and cost of antimicrobial agents before and during implementation.

Results

We collected data from 401 patients before the intervention and from 1,534 patients during the intervention. Both groups were comparable. No significant differences in EuroSCORE were observed between the patients of both periods (6.4 versus 6.3; P = 0.7). The rates of VAP (episodes/1,000 days of ventilation) were, respectively, 23.9 versus 13.5 (P = 0.005). Mean number of days of MV/1,000 days of stay was 507 versus 375 (P = 0.001), and the cost of antimicrobial therapy (Euros/1,000 days of stay) was €70,612 versus €52,775 (P = 0.10). The main effect of sequential application of preventive measures in time achieved a relative-rate reduction of VAP of 41% (IRR, 0.41; 95% CI, 0.28 to 0.62). The mortality rate before and during the intervention was 13.0% and 10.2%, respectively.VAP rate was most significantly reduced by training and the use of the inclinometer.

Conclusions

A sequentially applied bundle of four preventive measures reduces VAP rates, days of MV, and the cost of antimicrobial therapy in patients admitted to the major heart surgery ICU.

Trial registration

Clinical Trials.gov: {"type":"clinical-trial","attrs":{"text":"NCT02060045","term_id":"NCT02060045"}}NCT02060045. Registered 4 February 2014.     

Different dosage regimens of Eptinezumab for the treatment of migraine: a meta-analysis from randomized controlled trials

BackgroundMigraine is one of the most common neurological diseases around the world and calcitonin gene-related peptide (CGRP) plays an important role in its pathophysiology. Therefore, in the present study, we evaluated the efficacy of monoclonal antibodies blocking the CGRP ligand or receptor in episodic and chronic migraine.ObjectiveThe objective of our study is implementing a meta-analysis to systematically evaluate the efficacy and safety of eptinezumab for the treatment of migraine compared with placebo.MethodWe searched the Medline, Embase, Cochrane Library and Clinicaltrials.gov for randomized controlled trials (RCTs) which were performed to evaluate eptinezumab versus placebo for migraine up to September 2020. The data was assessed by Review Manager 5.3 software. The risk ratio (RR) and standard mean difference (SMD) were analyzed using dichotomous outcomes and continuous outcomes respectively with a random effect model.ResultWe collected 2739 patients from 4 RCTs: the primary endpoint of efficacy was the change from baseline to week 12 in mean monthly migraine days (MMDs). We found that eptinezumab (30 mg, 100 mg, 300 mg) led to a significant reduction in MMDs (P = 0.0001,P < 0.00001, P < 0.00001) during 12 weeks compared with placebo, especially with 300 mg. For the safety, we compared and concluded the treatment emergent adverse events (TEAEs) of the 4 RCTs. This indicated no evident statistical difference between eptinezumab and placebo.ConclusionsIn the present study, we found that eptinezumab is safe and has significant efficacy in the treatment of migraine, especially the dose of 300 mg.Supplementary InformationThe online version contains supplementary material available at 10.1186/s10194-021-01220-y.