Ewoudt M.W. van de Garde

Dexamethasone and length of hospital stay in patients with community-acquired pneumonia: a randomised, double-blind, placebo-controlled trial

BACKGROUND Whether addition of corticosteroids to antibiotic treatment benefits patients with community-acquired pneumonia who are not in intensive care units is unclear. We aimed to assess effect of addition of dexamethasone on length of stay in this group, which might result in earlier resolution of pneumonia through dampening of systemic inflammation. METHODS In our double-blind, placebo-controlled trial, we randomly assigned adults aged 18 years or older with confirmed community-acquired pneumonia who presented to emergency departments of two teaching hospitals in the Netherlands to receive intravenous dexamethasone (5 mg once a day) or placebo for 4 days from admission. Patients were ineligible if they were immunocompromised, needed immediate transfer to an intensive-care unit, or were already receiving corticosteroids or immunosuppressive drugs. We randomly allocated patients on a one-to-one basis to treatment groups with a computerised randomisation allocation sequence in blocks of 20. The primary outcome was length of hospital stay in all enrolled patients. This study is registered with ClinicalTrials.gov, number NCT00471640. FINDINGS Between November, 2007, and September, 2010, we enrolled 304 patients and randomly allocated 153 to the placebo group and 151 to the dexamethasone group. 143 (47%) of 304 enrolled patients had pneumonia of pneumonia severity index class 4-5 (79 [52%] patients in the dexamethasone group and 64 [42%] controls). Median length of stay was 6·5 days (IQR 5·0-9·0) in the dexamethasone group compared with 7·5 days (5·3-11·5) in the placebo group (95% CI of difference in medians 0-2 days; p=0·0480). In-hospital mortality and severe adverse events were infrequent and rates did not differ between groups, although 67 (44%) of 151 patients in the dexamethasone group had hyperglycaemia compared with 35 (23%) of 153 controls (p<0·0001). INTERPRETATION Dexamethasone can reduce length of hospital stay when added to antibiotic treatment in non-immunocompromised patients with community-acquired pneumonia. FUNDING None.

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.

Statins and prevention of infections: systematic review and meta-analysis of data from large randomised placebo controlled trials

Objective To evaluate whether the potential of statins to lower the risk of infections as published in observational studies is causal. Design Systematic review and meta-analysis of randomised placebo controlled trials. Data sources Medline, Embase, and the Cochrane Library. Study selection Randomised placebo controlled trials of statins (up to 10 March 2011) enrolling a minimum of 100 participants, with follow-up for at least one year. Data extraction Infection or infection related death. Results The first study selection yielded 632 trials. After screening of the corresponding abstracts and full text papers, 11 trials totalling 30 947 participants were included. 4655 of the participants (2368 assigned to statins and 2287 assigned to placebo) reported an infection during treatment. Meta-analysis showed no effect of statins on the risk of infections (relative risk 1.00, 95% confidence interval 0.96 to 1.05) or on infection related deaths (0.97, 0.83 to 1.13). Conclusion These findings do not support the hypothesis that statins reduce the risk of infections. Absence of any evidence for a beneficial effect in large placebo controlled trials reduces the likelihood of a causal effect as reported in observational studies.

Addition of Vitamin D Status to Prognostic Scores Improves the Prediction of Outcome in Community-Acquired Pneumonia

BACKGROUND Vitamin D plays a role in host defense against infection. Vitamin D deficiency is common worldwide. The prognostic value of vitamin D levels in pneumonia is unknown. In this study, we aimed to investigate the impact of vitamin D status on outcome in community-acquired pneumonia (CAP). METHODS We conducted a prospective cohort study in 272 hospitalized patients with CAP. Levels of 25-hydroxyvitamin D, leukocytes, C-reactive protein, and total cortisol and the Pneumonia Severity Index (PSI) and CURB-65 scores were measured on admission. Major outcome measures were intensive care unit (ICU) admission and 30-day mortality. RESULTS One hundred forty-three patients (53%) were vitamin D deficient (<50 nmol/L), 79 patients (29%) were vitamin D insufficient (50-75 nmol/L), and 50 patients (18%) were vitamin D sufficient (>75 nmol/L). Vitamin D deficiency was associated with an increased risk of ICU admission and 30-day mortality. Vitamin D status was an independent predictor of 30-day mortality (area under the curve [AUC] =0.69; 95% confidence interval [CI], .57-.80). Multivariate regression analysis including all predictors for outcome resulted in a final model including vitamin D status and the PSI score, with a significantly higher prognostic accuracy compared with the PSI score alone (AUC=0.83; 95% CI, .71-.94). CONCLUSIONS Vitamin D deficiency is associated with adverse outcome in CAP. Vitamin D status is an independent predictor of 30-day mortality and adds prognostic value to other biomarkers and prognostic scores, in particular the PSI score. CLINICAL TRIALS REGISTRATION NCT00471640.

Postoperative Interleukin-6 Level and Early Detection of Complications After Elective Major Abdominal Surgery.

Objective:To assess the association of systemic inflammation and outcome after major abdominal surgery. Background:Major abdominal surgery carries a high postoperative morbidity and mortality rate. Studies suggest that inflammation is associated with unfavorable outcome. Methods:Levels of C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-&agr; and the systemic inflammatory response syndrome (SIRS) were assessed in 137 patients undergoing major abdominal surgery. Blood samples were drawn on days 0, 1, 3, and 7, and SIRS was scored during 48 hours after surgery. Primary outcome was a composite of mortality, pneumonia, sepsis, anastomotic dehiscence, wound infection, noncardiac respiratory failure, atrial fibrillation, congestive heart failure, myocardial infarction, and reoperation within 30 days of surgery. Results:An IL-6 level more than 432 pg/mL on day 1 was associated with an increased risk of complications (adjusted odds ratio: 3.3; 95% confidence interval [CI]: 1.3–8.5) and a longer median length of hospital stay (7 vs 12 days, P < 0.001). As a single test, an IL-6 cut-off level of 432 pg/mL on day 1 yielded a specificity of 70% and a sensitivity of 64% for the prediction of complications (area under the curve: 0.67; 95% CI: 0.56–0.77). Levels of CRP started to discriminate from day 3 onward with a specificity of 87% and a sensitivity of 58% for a cut-off level of 203 mg/L (AUC: 0.73; 95% CI: 0.63–0.83). Conclusions:A high IL-6 level on day 1 is associated with postoperative complications. Levels of IL-6 help distinguish between patients at low and high risk for complications before changes in levels of CRP.

Angiotensin-converting enzyme inhibitor use and protection against pneumonia in patients with diabetes

Objectives Because of the high risk of pneumonia in patients with diabetes, we aimed to assess the effect of angiotensin-converting enzyme (ACE) inhibitor use on the occurrence of pneumonia in a general population of patients with diabetes. Methods The study population comprised all patients in the UK General Practice Research Database who had a diagnosis of diabetes (both type 1 and type 2) between 1987 and 2001. Cases were defined as patients with a first diagnosis of pneumonia. For each case, up to four controls were matched by age, gender, practice, and index date. Patients were classified as current ACE inhibitor user when the index date was between the start and end date of ACE inhibitor therapy. Conditional logistic regression analysis was used to estimate the strength of the association between ACE inhibitor use and pneumonia risk. Results ACE inhibitors were used in 12.7% of 4719 cases and in 13.7% of 15 322 matched controls [crude odds ratio (OR) = 0.92, 95% confidence interval (CI) = 0.82–1.01]. After adjusting for confounding, ACE inhibitor therapy was associated with a significant reduction in pneumonia risk (adjusted OR = 0.72, 95% CI = 0.64–0.80). The protective association was consistent across different relevant subgroups with the strongest association in patients with a history of stroke. There was a significant dose–effect relationship (P for trend < 0.001). Conclusions The use of ACE inhibitors is associated with a significant reduction in pneumonia risk and, apart from blood pressure-lowering properties, may be useful in the prevention of pneumonia in patients with diabetes.

Comparative evaluation of atracurium dosed on ideal body weight vs. total body weight in morbidly obese patients

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT Different conflicting reports have been published for the use of atracurium in morbidly obese patients. Dosing of atracurium based on lean body mass, total body weight, and total body weight with a dose reduction for every 10 kg more than 70 kg have been proposed. WHAT THIS STUDY ADDS The current prospective randomized double-blind study compares atracurium 0.5 mg kg(-1) ideal body weight vs. 0.5 mg kg(-1) total body weight when used as a muscle relaxant in morbidly obese patients undergoing bariatric surgery. Based on our results in patients with body weights varying from 112 to 260 kg, we have concluded that atracurium 0.5 mg kg(-1) ideal body weight results in a predictable profile of muscle relaxation allowing for adequate intubation conditions and recovery of muscle strength within 60 min with lack of need for antagonism. A dose-dependent prolongation of action is shown when dosing is based on total body weight. AIMS This double-blind randomized study evaluated atracurium dosing based on ideal body weight vs. total body weight for muscle relaxation in morbidly obese patients undergoing bariatric surgery. METHODS Twenty patients (body weight 112-260 kg, BMI 38-79 kg m(-2) ) were randomized to receive atracurium 0.5 mg kg(-1) ideal body weight vs. 0.5 mg kg(-1) total body weight. Primary endpoint was neuromuscular blockade using train-of-four ratios (TOF ratios) and secondary endpoints were intubation conditions and need for antagonism with neostigmine. RESULTS In the ideal body weight group, times to recovery of TOF ratio from 0 to 5%, 50% and 75% were significantly shorter [TOF ratio from 0 to 5%: mean difference 30 min (95% CI 23, 39 min)] and with lower variability compared with the total body weight group. In the total body weight group there was a significant correlation between atracurium dose and time to a TOF ratio of 5% (r= 0.82, P < 0.001), which was absent in the ideal body weight group (r= 0.24). In both groups, intubation conditions were good while 70% of the patients in the total body weight group needed neostigmine at the end of surgery compared with 0% in the ideal body weight group. CONCLUSION In morbid obesity (112-260 kg), atracurium 0.5 mg kg(-1) ideal body weight results in a predictable profile of muscle relaxation allowing for adequate intubation conditions and recovery of muscle strength to a TOF ratio >90% within 60 min with lack of need for antagonism. A dose-dependent prolongation of action is shown when dosing is based on total body weight.

Imaging of Fibrogenesis in Patients with Idiopathic Pulmonary Fibrosis with cis-4-[18F]-Fluoro-l-Proline PET

PurposeIdiopathic pulmonary fibrosis (IPF) is a lethal lung disease for which no single diagnostic modality is able to evaluate the activity of the disease process. Cis-4-18F-fluoro-l-proline (18F-proline) was shown in animal studies to be a reliable marker for fibrosis formation. We tested this candidate radioligand for imaging of fibrogenesis in patients with IPF.MethodsFive patients with IPF proven by lung biopsy and computed tomography were included. Furthermore, we also included one patient with non-specific interstitial pneumonia (NSIP) and scleroderma and one with NSIP and organising pneumonia. Positron emission tomography (PET) acquisition was performed 1, 2 and 3h after injection of 400MBq 18F-proline. We scored 18F-proline activity visually and quantitatively by calculating the activity in the regions of interest over lung, liver and mediastinum.ResultsWe found low uptake of 18F-proline in the lungs of all patients with IPF. The highest uptake was seen at 2h post-injection, with a decline at 3h past injection. The differences in lung uptake between patients were small, except for one patient with NSIP and organising pneumonia who had a slightly higher 18F-proline uptake. No significant correlations between 18F-proline uptake and clinical parameters were found.ConclusionsDue to the low pulmonary uptake of 18F-proline in patients with IPF, 18F-proline does not seem to be a suitable radioligand to evaluate the activity of fibrosis formation in patients with IPF. The low uptake in the lungs of patients with interstitial fibrosis may be explained by the slow nature of fibrogenesis or to the relatively low dose of proline that can be used.

Comparative evaluation of propofol 350 and 200 mg for induction of anaesthesia in morbidly obese patients: a randomized double-blind pilot study.

Background and objective The aim of this pilot study was to evaluate efficacy and safety of propofol 350 versus 200 mg for induction of anaesthesia in morbidly obese patients undergoing bariatric surgery. Patients and methods Twenty morbidly obese patients (BMI range 38–60 kg m−2) were randomized to receive propofol 350 or 200 mg over 60 s for induction of anaesthesia. Bispectral index (BIS) values, induction characteristics and haemodynamic parameters were compared. Results At the time of intubation, in the 200 mg group, mean BIS values were more variable and significantly higher [53 (range 27–86) versus 31 (range 18–52), 200 versus 350 mg group (P = 0.01)]. In 20% of the 200 mg group, an additional propofol dose was needed, whereas no additional doses were judged necessary in the 350 mg group. At the time of intubation, six patients in the 200 mg group had systolic arterial pressures above 160 mmHg [mean 162 (range 100–210)], whereas mean pressures in the first 10 min were more in the target range in the 350 mg group [mean 122 (range 90–170)] (P = 0.01). One patient in the 350 mg group experienced a serious decrease in systolic arterial pressure (below 60 mmHg), immediately upon starting the maintenance dose. There were no significant differences in heart rate. Conclusion Although propofol 200 mg proved to be an inadequate induction dose for morbidly obese patients, the 350 mg induction dose deserves further study, provided the maintenance dose is not started within 5 min, thereby preventing temporary cardiovascular instability.

Validation of an automated method for compounding monoclonal antibody patient doses: case studies of Avastin (bevacizumab), Remicade (infliximab) and Herceptin (trastuzumab).

Automation robots have recently come to the market as an alternative for manual compounding of drugs for intravenous administration. Our aim was to assess whether robotic compounding can be performed with monoclonal antibodies (mAbs) without influencing the aggregation state of the proteins. Three frequently used mAbs were studied: infliximab (Remicade®, Janssen Biotech) and trastuzumab (Herceptin®, Roche) in lyophilised form, and bevacizumab (Avastin®, Roche) as a liquid formulation stored at 2°C to 8°C. The effects of different procedures to prepare the patient doses on antibody aggregation were evaluated. Remicade® and Herceptin® were reconstituted both manually and by a robotic arm (i.v.STATION®, Health Robotics). Additionally, the influence of vigorous shaking during reconstitution was investigated. The effects of rapid aspiration and dispensing on antibody aggregation were investigated for all three mAbs. Aggregation state was assessed by UV-Vis absorbance, 90° light scatter, fluorescence spectroscopy, Nile red fluorescence microscopy, and field flow fractionation without cross and focus flow. Robotic reconstituted samples showed similar findings compared with manual reconstitution if performed exactly according to the summary of product characteristics (SPC). Vials that were vigorously shaken showed a significant increase in aggregates. Similarly, rapid aspiration/dispense cycles resulted in a strong increase in the number and sizes of aggregates for all three mAbs; this result was observed after just one rapid aspiration/dispense cycle. Our study showed that robotic compounding of mAbs is feasible if the robot is exactly programmed according to the SPC, indicating that robotic compounding can be used to achieve reproducible high-quality compounding for delicate formulations.