Ronald A. Schoenenberger

Effect of procalcitonin-based guidelines vs standard guidelines on antibiotic use in lower respiratory tract infections: the ProHOSP randomized controlled trial

CONTEXT In previous smaller trials, a procalcitonin (PCT) algorithm reduced antibiotic use in patients with lower respiratory tract infections (LRTIs). OBJECTIVE To examine whether a PCT algorithm can reduce antibiotic exposure without increasing the risk for serious adverse outcomes. DESIGN, SETTING, AND PATIENTS A multicenter, noninferiority, randomized controlled trial in emergency departments of 6 tertiary care hospitals in Switzerland with an open intervention of 1359 patients with mostly severe LRTIs randomized between October 2006 and March 2008. INTERVENTION Patients were randomized to administration of antibiotics based on a PCT algorithm with predefined cutoff ranges for initiating or stopping antibiotics (PCT group) or according to standard guidelines (control group). Serum PCT was measured locally in each hospital and instructions were Web-based. MAIN OUTCOME MEASURES Noninferiority of the composite adverse outcomes of death, intensive care unit admission, disease-specific complications, or recurrent infection requiring antibiotic treatment within 30 days, with a predefined noninferiority boundary of 7.5%; and antibiotic exposure and adverse effects from antibiotics. RESULTS The rate of overall adverse outcomes was similar in the PCT and control groups (15.4% [n = 103] vs 18.9% [n = 130]; difference, -3.5%; 95% CI, -7.6% to 0.4%). The mean duration of antibiotics exposure in the PCT vs control groups was lower in all patients (5.7 vs 8.7 days; relative change, -34.8%; 95% CI, -40.3% to -28.7%) and in the subgroups of patients with community-acquired pneumonia (n = 925, 7.2 vs 10.7 days; -32.4%; 95% CI, -37.6% to -26.9%), exacerbation of chronic obstructive pulmonary disease (n = 228, 2.5 vs 5.1 days; -50.4%; 95% CI, -64.0% to -34.0%), and acute bronchitis (n = 151, 1.0 vs 2.8 days; -65.0%; 95% CI, -84.7% to -37.5%). Antibiotic-associated adverse effects were less frequent in the PCT group (19.8% [n = 133] vs 28.1% [n = 193]; difference, -8.2%; 95% CI, -12.7% to -3.7%). CONCLUSION In patients with LRTIs, a strategy of PCT guidance compared with standard guidelines resulted in similar rates of adverse outcomes, as well as lower rates of antibiotic exposure and antibiotic-associated adverse effects. TRIAL REGISTRATION isrctn.org Identifier: ISRCTN95122877.

Prohormones for prediction of adverse medical outcome in community-acquired pneumonia and lower respiratory tract infections

IntroductionMeasurement of prohormones representing different pathophysiological pathways could enhance risk stratification in patients with community-acquired pneumonia (CAP) and other lower respiratory tract infections (LRTI).MethodsWe assessed clinical parameters and five biomarkers, the precursor levels of adrenomedullin (ADM), endothelin-1 (ET1), atrial-natriuretic peptide (ANP), anti-diuretic hormone (copeptin), and procalcitonin in patients with LRTI and CAP enrolled in the multicenter ProHOSP study. We compared the prognostic accuracy of these biomarkers with the pneumonia severity index (PSI) and CURB65 (Confusion, Urea, Respiratory rate, Blood pressure, Age 65) score to predict serious complications defined as death, ICU admission and disease-specific complications using receiver operating curves (ROC) and reclassification methods.ResultsDuring the 30 days of follow-up, 134 serious complications occurred in 925 (14.5%) patients with CAP. Both PSI and CURB65 overestimated the observed mortality (X2 goodness of fit test: P = 0.003 and 0.01). ProADM or proET1 alone had stronger discriminatory powers than the PSI or CURB65 score or any of either score components to predict serious complications. Adding proADM alone (or all five biomarkers jointly) to the PSI and CURB65 scores, significantly increased the area under the curve (AUC) for PSI from 0.69 to 0.75, and for CURB65 from 0.66 to 0.73 (P < 0.001, for both scores). Reclassification methods also established highly significant improvement (P < 0.001) for models with biomarkers if clinical covariates were more flexibly adjusted for. The developed prediction models with biomarkers extrapolated well if evaluated in 434 patients with non-CAP LRTIs.ConclusionsFive biomarkers from distinct biologic pathways were strong and specific predictors for short-term adverse outcome and improved clinical risk scores in CAP and non-pneumonic LRTI. Intervention studies are warranted to show whether an improved risk prognostication with biomarkers translates into a better clinical management and superior allocation of health care resources.Trial RegistrationNCT00350987.

A Computer-Based Intervention for Improving the Appropriateness of Antiepileptic Drug Level Monitoring

We designed and implemented 2 automated, computerized screens for use at the time of antiepileptic drug (AED) test order entry to improve appropriateness by reminding physicians when a potentially redundant test was ordered and providing common indications for monitoring and pharmacokinetics of the specific AED. All computerized orders for inpatient serum AED levels during two 3-month periods were included in the study. During the 3-month period after implementation of the automated intervention, 13% of all AED tests ordered were canceled following computerized reminders. For orders appearing redundant, the cancellation rate was 27%. For nonredundant orders, 4% were canceled when information on specific AED monitoring and pharmacokinetics was provided. The cancellation rate was sustained after 4 years. There has been a 19.5% decrease in total AED testing volume since implementation of this intervention, despite a 19.3% increase in overall chemistry test volume. Inappropriateness owing to repeated testing before pharmacologic steady state was reached decreased from 54% of all AED orders to 14.6%. A simple, automated, activity-based intervention targeting a specific test-ordering behavior effectively reduced inappropriate laboratory testing. The sustained benefit supports the idea that computerized interventions may durably affect physician behavior. Computerized delivery of such evidence-based boundary guidelines can help narrow the gap between evidence and practice.

Acyclovir-induced neurotoxicity: Concentration-side effect relationship in acyclovir overdose

PURPOSE To investigate the concentration-side effect relationship in a patient with severe acyclovir-induced neurotoxicity and to summarize the information available in the literature about central nervous system side effects due to acyclovir. METHODS Repeated blood samples were drawn in a patient with severe acyclovir overdose who developed coma and nonoliguric renal failure. The acyclovir levels measured by radioimmunoassay were related to the level of consciousness. RESULTS We measured the highest acyclovir serum levels reported so far (229.9 mumol/L = 51.8 mg/L). Impairment of consciousness developed with a remarkable temporal delay of 24 to 48 hours after occurrence of peak serum concentrations and resolved with a comparable delay after reaching the therapeutic range (anticlockwise hysteresis). Six days after discontinuation of the drug, central nervous system symptoms had resolved, and, 4 days later, renal function returned to pretreatment values. CONCLUSIONS The observation that neurotoxicity developed with a delay of 24 to 48 hours after acyclovir peak serum concentrations could explain the wide range of acyclovir levels reported in similar cases. Single drug level measurements may therefore be of little diagnostic value. Since toxicity develops with a remarkable delay, early removal of the drug (by hemodialysis) could possibly prevent central nervous toxicity.

Quality of care delivered by fee-for-service and DRG hospitals in Switzerland in patients with community-acquired pneumonia

PRINCIPLES Reimbursement for inpatient treatment in Switzerland is in transition. While hospitals in some cantons already use Diagnosis Related Groups (DRG) based systems for hospital financing, others use fee-for-service (FFS) based systems, a situation that provides the opportunity to perform a head-to-head comparison between the two reimbursement systems. The aim of this analysis was to compare reimbursement systems with regard to length of hospital stay (LOS) and patient outcomes in a cohort of community-acquired pneumonia patients from a previous prospective multicentre study in Switzerland. METHODS This is a post-hoc analysis of 925 patients with community-acquired pneumonia from a previous randomised-controlled trial. We calculated multivariate regression models adjusted for age, gender, comorbidities and severity of illness (using the Pneumonia Severity Index) and accounting for clustering within hospitals to compare LOS and outcomes between FFS (n = 4) or DRG hospitals (n = 2). RESULTS LOS in DRG hospitals was significantly shorter compared to FFS hospitals (8.4 vs 10.3 days, absolute difference 1.9 days [95%CI 0.8-3.1]). This was confirmed in multivariate adjusted Cox models (hazard ratio 1.2 [95% 1.1-1.3]). There were no differences in 30-day and 18-month mortality rates (adjusted odds ratio 1.7 [95% 0.9-3.2] and 1.3 [95% 0.9-1.9]) or recurrence rates within 30 days (adjusted odds ratio 0.8 [95% 0.4-1.7]). Also, no differences were found in the rate of still ongoing clinical symptoms at 30 days, satisfaction with the discharge process and quality of life measures at 30 days of follow-up. CONCLUSIONS This study focusing on community-acquired pneumonia patients with different severities found a 20% shorter LOS in hospitals with DRG financing compared to FFS hospitals without apparent harmful effects on patient outcomes, satisfaction with care and different quality of life measures. Further studies are required to validate these findings for other medical and surgical patient populations.

Variation in the management of deep vein thrombosis: Implications for the potential impact of a critical pathway

PURPOSE To evaluate the potential impact of a practice guideline in the form of a critical pathway on variation and quality of care in patients with deep vein thrombosis (DVT). METHODS Goals were identified for key steps and processes that were believed to be important for meeting a length-of-stay (LOS) goal of 5.5 days, and for improving quality of care for patients with DVT. Data collected via chart review were used to determine the percentage o patients with uncomplicated DVT admitted in the year after October 1, 1992, whose management would have met these goals. RESULTS Only 11 (12%) of 92 eligible patients with a primary discharge diagnosis of DVT met the LOS goal. In 30%, the activated partial thromboplastin time (aPTT) was >60 seconds within a target of 12 hours after admission. The goals for the initiation of warfarin (within 12 hours after aPTT >60 seconds) and the achievement of a therapeutic international normalized ratio (INR) level (within 120 hours) were met in 51% and 58% of patients, respectively. The target duration of intravenous heparin therapy was achieved in 78% of patients. Only 18% of patients, however, were discharged within 12 hours after 96 hours of heparin therapy had been given and a therapeutic INR had been achieved. CONCLUSIONS These data demonstrate considerable variation in management of uncomplicated DVT at a single hospital, suggesting that a critical pathway could have impact on both LOS and quality of care.