Dylan W. de Lange

Efficacy and safety of procalcitonin guidance in reducing the duration of antibiotic treatment in critically ill patients: a randomised, controlled, open-label trial

BACKGROUND In critically ill patients, antibiotic therapy is of great importance but long duration of treatment is associated with the development of antimicrobial resistance. Procalcitonin is a marker used to guide antibacterial therapy and reduce its duration, but data about safety of this reduction are scarce. We assessed the efficacy and safety of procalcitonin-guided antibiotic treatment in patients in intensive care units (ICUs) in a health-care system with a comparatively low use of antibiotics. METHODS We did a prospective, multicentre, randomised, controlled, open-label intervention trial in 15 hospitals in the Netherlands. Critically ill patients aged at least 18 years, admitted to the ICU, and who received their first dose of antibiotics no longer than 24 h before inclusion in the study for an assumed or proven infection were eligible to participate. Patients who received antibiotics for presumed infection were randomly assigned (1:1), using a computer-generated list, and stratified (according to treatment centre, whether infection was acquired before or during ICU stay, and dependent on severity of infection [ie, sepsis, severe sepsis, or septic shock]) to receive either procalcitonin-guided or standard-of-care antibiotic discontinuation. Both patients and investigators were aware of group assignment. In the procalcitonin-guided group, a non-binding advice to discontinue antibiotics was provided if procalcitonin concentration had decreased by 80% or more of its peak value or to 0·5 μg/L or lower. In the standard-of-care group, patients were treated according to local antibiotic protocols. Primary endpoints were antibiotic daily defined doses and duration of antibiotic treatment. All analyses were done by intention to treat. Mortality analyses were completed for all patients (intention to treat) and for patients in whom antibiotics were stopped while being on the ICU (per-protocol analysis). Safety endpoints were reinstitution of antibiotics and recurrent inflammation measured by C-reactive protein concentrations and they were measured in the population adhering to the stopping rules (per-protocol analysis). The study is registered with ClinicalTrials.gov, number NCT01139489, and was completed in August, 2014. FINDINGS Between Sept 18, 2009, and July 1, 2013, 1575 of the 4507 patients assessed for eligibility were randomly assigned to the procalcitonin-guided group (761) or to standard-of-care (785). In 538 patients (71%) in the procalcitonin-guided group antibiotics were discontinued in the ICU. Median consumption of antibiotics was 7·5 daily defined doses (IQR 4·0-12·7) in the procalcitonin-guided group versus 9·3 daily defined doses (5·0-16·6) in the standard-of-care group (between-group absolute difference 2·69, 95% CI 1·26-4·12, p<0·0001). Median duration of treatment was 5 days (3-9) in the procalcitonin-guided group and 7 days (4-11) in the standard-of-care group (between-group absolute difference 1·22, 0·65-1·78, p<0·0001). Mortality at 28 days was 149 (20%) of 761 patients in the procalcitonin-guided group and 196 (25%) of 785 patients in the standard-of-care group (between-group absolute difference 5·4%, 95% CI 1·2-9·5, p=0·0122) according to the intention-to-treat analysis, and 107 (20%) of 538 patients in the procalcitonin-guided group versus 121 (27%) of 457 patients in the standard-of-care group (between-group absolute difference 6·6%, 1·3-11·9, p=0·0154) in the per-protocol analysis. 1-year mortality in the per-protocol analysis was 191 (36%) of 538 patients in the procalcitonin-guided and 196 (43%) of 457 patients in the standard-of-care groups (between-group absolute difference 7·4, 1·3-13·8, p=0·0188). INTERPRETATION Procalcitonin guidance stimulates reduction of duration of treatment and daily defined doses in critically ill patients with a presumed bacterial infection. This reduction was associated with a significant decrease in mortality. Procalcitonin concentrations might help physicians in deciding whether or not the presumed infection is truly bacterial, leading to more adequate diagnosis and treatment, the cornerstones of antibiotic stewardship. FUNDING Thermo Fisher Scientific.

Association between administered oxygen, arterial partial oxygen pressure and mortality in mechanically ventilated intensive care unit patients

IntroductionThe aim of this study was to investigate whether in-hospital mortality was associated with the administered fraction of oxygen in inspired air (FiO2) and achieved arterial partial pressure of oxygen (PaO2).MethodsThis was a retrospective, observational study on data from the first 24 h after admission from 36,307 consecutive patients admitted to 50 Dutch intensive care units (ICUs) and treated with mechanical ventilation. Oxygenation data from all admission days were analysed in a subset of 3,322 patients in 5 ICUs.ResultsMean PaO2 and FiO2 in the first 24 h after ICU admission were 13.2 kPa (standard deviation (SD) 6.5) and 50% (SD 20%) respectively. Mean PaO2 and FiO2 from all admission days were 12.4 kPa (SD 5.5) and 53% (SD 18). Focusing on oxygenation in the first 24 h of admission, in-hospital mortality was shown to be linearly related to FiO2 value and had a U-shaped relationship with PaO2 (both lower and higher PaO2 values were associated with a higher mortality), independent of each other and of Simplified Acute Physiology Score (SAPS) II, age, admission type, reduced Glasgow Coma Scale (GCS) score, and individual ICU. Focusing on the entire ICU stay, in-hospital mortality was independently associated with mean FiO2 during ICU stay and with the lower two quintiles of mean PaO2 value during ICU stay.ConclusionsActually achieved PaO2 values in ICU patients in The Netherlands are higher than generally recommended in the literature. High FiO2, and both low PaO2 and high PaO2 in the first 24 h after admission are independently associated with in-hospital mortality in ICU patients. Future research should study whether this association is causal or merely a reflection of differences in severity of illness insufficiently corrected for in the multivariate analysis.

Mortality After Hospital Discharge in ICU Patients

Objectives:To assess the mortality risk of ICU patients after hospital discharge and compare it to mortality of the general Dutch population. Design:Cohort study of ICU admissions from a national ICU registry linked to administrative records from an insurance claims database. Setting:Eighty-one Dutch ICUs. Patients:ICU patients (n = 91,203) who were discharged alive from the hospital between January 1, 2007, and October 1, 2010. Interventions:None. Measurements and Main Results:The unadjusted observed survival was inspected by Kaplan-Meier curves. Mortality risk at 1, 2, and 3 years after hospital discharge was 12.5%, 19.3%, and 27.5%, respectively. The 3-year mortality after hospital discharge in ICU patients was higher than the weighted average of the gender and age-specific death risks of the general Dutch population (27.5% versus 8.2%). The 1-year mortality after hospital discharge was adjusted for case-mix differences by a set of determinants which showed a statistically significant influence on the outcome in a 10-fold cross validation. The elective and cardiac surgical patients have statistically significantly better mortality outcomes (adjusted hazard ratio, 0.73 and 0.28, respectively), whereas medical patients and patients admitted for cancer have statistically significantly worse mortality outcomes (adjusted hazard ratio, 1.41, 1.94, respectively) compared with other ICU patients. Urgent surgery patients and patients with a subarachnoid hemorrhage, trauma, acute renal failure, or severe community-acquired pneumonia did not differ statistically from the other ICU patients after adjustment for case-mix differences. Conclusions:In-hospital mortality underestimates the true mortality of ICU patients as the mortality in the first months after hospital discharge is substantial. Most ICU patients still have an increased mortality risk in the subsequent years after hospital discharge compared with the general Dutch population. The mortality after hospital discharge differs widely between ICU subgroups. Future studies should focus on the analysis of mortality after hospital discharge that is attributable to the former ICU admission.

Blood glucose amplitude variability as predictor for mortality in surgical and medical intensive care unit patients: a multicenter cohort study ☆,☆☆

PURPOSE The aim of this study was to test the hypothesis that blood glucose amplitude variability (BGAV) is associated with mortality in critically ill patients. METHOD A prospectively collected multicenter data set including all glucose measurements during intensive care unit (ICU) treatment and outcome was analyzed. We used logistic regression to assess the association between hospital mortality and standard deviation (SD), mean amplitude of glycemic excursions (MAGE), mean absolute glucose change per hour (MAG), and glycemic lability index (GLI). The analysis was adjusted for ICU, Acute Physiology And Chronic Health Evaluation IV-expected mortality, the presence of severe hypoglycemia, mean glucose, mean glucose measurement interval, and interaction between the latter 2. RESULTS There were 855,032 glucose measurements included of 20,375 patients admitted to 37 Dutch ICUs in 2008 and 2009. Median Acute Physiology And Chronic Health Evaluation IV-predicted mortality was 14%, and median glucose was 7.3 mmol/L. In all patients combined, adjusted hospital mortality was associated with SD and MAGE, but not with MAG and GLI. In surgical patients, adjusted hospital mortality was associated with SD, MAGE, and MAG, but not GLI. In medical patients, adjusted mortality was associated with SD but not with other BGAV measures. CONCLUSION Not all BGAV measures were associated with mortality. Blood glucose amplitude variability as quantified by SD was consistently independently associated with hospital mortality.

Long-term outcome of delirium during intensive care unit stay in survivors of critical illness: a prospective cohort study

IntroductionDelirium is associated with impaired outcome, but it is unclear whether this relationship is limited to in-hospital outcomes and whether this relationship is independent of the severity of underlying conditions. The aim of this study was to investigate the association between delirium in the intensive care unit (ICU) and long-term mortality, self-reported health-related quality of life (HRQoL), and self-reported problems with cognitive functioning in survivors of critical illness, taking severity of illness at baseline and throughout ICU stay into account.MethodsA prospective cohort study was conducted. We included patients who survived an ICU stay of at least a day; exclusions were neurocritical care patients and patients who sustained deep sedation during the entire ICU stay. Delirium was assessed twice daily with the Confusion Assessment Method for the ICU (CAM-ICU) and additionally, patients who received haloperidol were considered delirious. Twelve months after ICU admission, data on mortality were obtained and HRQoL and cognitive functioning were measured with the European Quality of Life – Six dimensions self-classifier (EQ-6D). Regression analyses were used to assess the associations between delirium and the outcome measures adjusted for gender, type of admission, the Acute Physiology And Chronic Health Evaluation IV (APACHE IV) score, and the cumulative Sequential Organ Failure Assessment (SOFA) score throughout ICU stay.ResultsOf 1101 survivors of critical illness, 412 persons (37%) had been delirious during ICU stay, and 198 (18%) died within twelve months. When correcting for confounders, no significant association between delirium and long-term mortality was found (hazard ratio: 1.26; 95% confidence interval (CI) 0.93 to 1.71). In multivariable analysis, delirium was not associated with HRQoL either (regression coefficient: -0.04; 95% CI -0.10 to 0.01). Yet, delirium remained associated with mild and severe problems with cognitive functioning in multivariable analysis (odds ratios: 2.41; 95% CI 1.57 to 3.69 and 3.10; 95% CI 1.10 to 8.74, respectively).ConclusionsIn this group of survivors of critical illness, delirium during ICU stay was not associated with long-term mortality or HRQoL after adjusting for confounding, including severity of illness throughout ICU stay. In contrast, delirium appears to be an independent risk factor for long-term self-reported problems with cognitive functioning.

Effect of procalcitonin-guided antibiotic treatment on mortality in acute respiratory infections: a patient level meta-analysis

BACKGROUND In February, 2017, the US Food and Drug Administration approved the blood infection marker procalcitonin for guiding antibiotic therapy in patients with acute respiratory infections. This meta-analysis of patient data from 26 randomised controlled trials was designed to assess safety of procalcitonin-guided treatment in patients with acute respiratory infections from different clinical settings. METHODS Based on a prespecified Cochrane protocol, we did a systematic literature search on the Cochrane Central Register of Controlled Trials, MEDLINE, and Embase, and pooled individual patient data from trials in which patients with respiratory infections were randomly assigned to receive antibiotics based on procalcitonin concentrations (procalcitonin-guided group) or control. The coprimary endpoints were 30-day mortality and setting-specific treatment failure. Secondary endpoints were antibiotic use, length of stay, and antibiotic side-effects. FINDINGS We identified 990 records from the literature search, of which 71 articles were assessed for eligibility after exclusion of 919 records. We collected data on 6708 patients from 26 eligible trials in 12 countries. Mortality at 30 days was significantly lower in procalcitonin-guided patients than in control patients (286 [9%] deaths in 3336 procalcitonin-guided patients vs 336 [10%] in 3372 controls; adjusted odds ratio [OR] 0·83 [95% CI 0·70 to 0·99], p=0·037). This mortality benefit was similar across subgroups by setting and type of infection (pinteractions>0·05), although mortality was very low in primary care and in patients with acute bronchitis. Procalcitonin guidance was also associated with a 2·4-day reduction in antibiotic exposure (5·7 vs 8·1 days [95% CI -2·71 to -2·15], p<0·0001) and a reduction in antibiotic-related side-effects (16% vs 22%, adjusted OR 0·68 [95% CI 0·57 to 0·82], p<0·0001). INTERPRETATION Use of procalcitonin to guide antibiotic treatment in patients with acute respiratory infections reduces antibiotic exposure and side-effects, and improves survival. Widespread implementation of procalcitonin protocols in patients with acute respiratory infections thus has the potential to improve antibiotic management with positive effects on clinical outcomes and on the current threat of increasing antibiotic multiresistance. FUNDING National Institute for Health Research.

Do corticosteroids have a role in preventing or reducing acute toxic lung injury caused by inhalation of chemical agents

Objective. To assess the evidence that treatment with corticosteroids improves the outcome in those exposed to lung-damaging agents. Methods.  We searched Pubmed, Toxnet, Cochrane database, Google Scholar, and Embase from 1966 to January 2010 using the search terms “steroid”, “corticosteroid”, “lung injury”, “lung damage”, and “inhalation”. These searches identified 287 papers of which 118 contained information on animal studies. However, most were reviews or case reports and only a few were controlled animal experiments of which 13 were considered relevant. Role of corticosteroids: animal studies.  Corticosteroids have no beneficial effect at the alveolar level on acute lung injury, which is caused by inhalation of poorly water-soluble compounds (e.g. nitrogen dioxide, ozone, phosgene) or following severe exposure to water-soluble compounds (e.g. chlorine, ammonia). In the recovery phase, corticosteroids may even be harmful, because corticosteroids hamper the division of type II alveolar cells and hamper the differentiation from type II into type I alveolar cells. The latter is important for the re-epithelialization of the alveolus and removal of excess of water in the alveolus. Furthermore, the quality of animal studies does not always allow extrapolation to human exposures. Differences between humans and animals in anatomy, pulmonary defense systems, breathing physiology, as well as the way the animals have been exposed, and the timing and route of corticosteroids in animal studies make predictions difficult. Role of corticosteroids: human studies.  An abundance of uncontrolled case reports and a few human crossover studies have evaluated the outcome of human volunteers exposed to various lung-damaging agents. Only a few reports contained systematic information on corticosteroid treatment. Data on the efficacy of corticosteroids after human exposure to lung-damaging agents are inconclusive. Often the number of patients involved is small or the severity of exposure is unclear or not well determined. These reports are therefore limited in their ability to establish a cause–effect relationship for the treatments involved. In some studies involving mild to moderate exposure to water-soluble agents (e.g. chlorine, ammonia), corticosteroid treatment was beneficial for some physiological parameters, such as airway resistance or arterial oxygen tension. However, severe lung injury and inflammation appear not to be improved by corticosteroid treatment. The optimal duration of treatment to obtain these beneficial effects has not been assessed adequately, but it only seems to be useful in the first hours after exposure. Generally, studies evaluating exposure to water-soluble compounds have too short a follow-up, which hampers the evaluation of the efficacy of corticosteroid treatment. The results of studies with longer follow-up suggest that the initial slight improvement in some variables is lost several hours after exposure. Conclusions.  Clinical data on the efficacy of corticosteroids after human exposure to lung-damaging agents are inconclusive as the number of well-structured controlled studies is small and the indications for administration of corticosteroids are unclear. There have been no human controlled studies of high-dose exposure to lung-damaging agents. Furthermore, treatment with corticosteroids is limited by the potential side effects, such as prolonged neuromuscular weakness, deregulation of glucose metabolism, superinfection, and sepsis, which could diminish the chances for recovery.

Rapid Intake of Alcohol (Binge Drinking) Inhibits Platelet Adhesion to Fibrinogen Under Flow

BACKGROUND Moderate alcohol consumption is associated with decreased mortality from cardiovascular disease. Drinking large amounts in a short period (binge drinking) is associated with increased cardiovascular morbidity. We tested whether rapid consumption of a large dose of alcohol affects platelet aggregation and adhesion. METHODS Healthy volunteers (n = 20) were asked to drink three glasses of alcohol or red wine in a 45-min period. Thereafter, another 45 min was allowed for absorption of alcohol. Ninety minutes after the start of the experiment, blood was collected. This entire cycle was repeated once, resulting in consumption of six alcohol-containing drinks in 3 hr. Adenosine-diphosphate (ADP)-induced aggregation was measured and platelet adhesion to fibrinogen and collagen was measured in a perfusion chamber at shear rates of 300/sec and 1600/sec. Platelet coverage and aggregate size were measured. RESULTS Acute alcohol intake significantly increased platelet aggregation in suspension when stimulated with low concentrations of ADP (0.1 and 0.5 microg/ml). This effect was not observed when consuming red wine. In contrast, adhesion to fibrinogen was significantly inhibited by alcohol but not red wine at high shear rate after six drinks (p = 0.025). The inhibition was accompanied by a reduction in aggregate size at 90 and 180 min after the start of the experiment. Adhesion to collagen was not altered by either alcohol or red wine. CONCLUSIONS Rapid intake of alcohol increases platelet aggregation, which might contribute to the increased mortality associated with binge drinking. Red wine does not show increased platelet aggregation, which might support the reduction of cardiovascular disease in red wine consumers. However, alcohol inhibits platelet adhesion to fibrinogen-coated surface under flow. The diminished adhesion might contribute to the cardioprotective effects of alcohol.

In-hospital mortality and long-term survival of patients with acute intoxication admitted to the ICU

Objective:To assess in-hospital and long-term mortality of Dutch ICU patients admitted with an acute intoxication. Design:Cohort of ICU admissions from a national ICU registry linked to records from an insurance claims database. Setting:Eighty-one ICUs (85% of all Dutch ICUs). Patients:Seven thousand three hundred thirty-one admissions between January 1, 2008, and October 1, 2011. Interventions:None. Measurements and Main Results:Kaplan-Meier curves were used to compare the unadjusted mortality of the total intoxicated population and for specific intoxication subgroups based on the Acute Physiology and Chronic Health Evaluation IV reasons for admission: 1) alcohol(s), 2) analgesics, 3) antidepressants, 4) street drugs, 5) sedatives, 6) poisoning (carbon monoxide, arsenic, or cyanide), 7) other toxins, and 8) combinations. The case-mix adjusted mortality was assessed by the odds ratio adjusted for age, gender, severity of illness, intubation status, recurrent intoxication, and several comorbidities. The ICU mortality was 1.2%, and the in-hospital mortality was 2.1%. The mortality 1, 3, 6, 12, and 24 months after ICU admission was 2.8%, 4.1%, 5.2%, 6.5%, and 9.3%, respectively. Street drugs had the highest mortality 2 years after ICU admission (12.3%); a combination of different intoxications had the lowest (6.3%). The adjusted observed mortality showed that intoxications with street drugs and “other toxins” have a significant higher mortality 1 month after ICU admission (odds ratioadj = 1.63 and odds ratioadj= 1.73, respectively). Intoxications with alcohol or antidepressants have a significant lower mortality 1 month after ICU admission (odds ratioadj = 0.50 and odds ratioadj = 0.46, respectively). These differences were not found in the adjusted mortality 3 months upward of ICU admission. Conclusions:Overall, the mortality 2 years after ICU admission is relatively low compared with other ICU admissions. The first 3 months after ICU admission there is a difference in mortality between the subgroups, not thereafter. Still, the difference between the in-hospital mortality and the mortality after 2 years is substantial.

Active von Willebrand factor predicts 28-day mortality in patients with systemic inflammatory response syndrome

Endothelial dysfunction contributes to the pathology of systemic inflammatory response syndrome (SIRS). However, endothelial biomarkers are not routinely evaluated in this setting. Here, 275 patients with SIRS and plasma levels of von Willebrand factor (VWF), thrombospondin-1, myeloperoxidase, ADAMTS-13, and active VWF (aVWF) were studied in relation to 28-day mortality. On admission, aVWF levels were higher in nonsurvivors vs survivors (0.69 vs 0.47 µg/mL, P = .019). Patients in the highest tertile of aVWF levels had a lower cumulative survival (86% vs 75%, P = .017) and twofold increased hazard ratio (HR). When adjusted for the Acute Physiology and Chronic Health Evaluation IV (APACHE-IV) score, this difference remained significant (HR 1.82, 95% confidence interval, 1.03-3.3). On admission, no significant differences were measured for the other proteins. These observations suggest that the stimulated release of VWF is not predictive for mortality in patients with SIRS, opposite of the processing of VWF after release. aVWF could be used with the APACHE-IV score to stratify SIRS patients at high mortality risk.