The use of copeptin, the stable peptide of the vasopressin precursor, in the differential diagnosis of sodium imbalance in patients with acute diseases.

BACKGROUND: Sodium imbalance is common in-hospital electrolyte disturbance and is largely related to inequalities in water homeostasis. An important mechanism leading to dysnatraemic disorders is inadequately secreted plasma arginine vasopressin (AVP). Unfortunately, AVP measurement is cumbersome and not reliable. Copeptin is secreted in an equimolar ratio to AVP and is a promising marker in the differential diagnosis of hyponatraemia and possibly hypernatraemia in stable hospitalised patients. This study assessed copeptin concentrations in sick patients with serum sodium imbalance of different aetiology on admission to the emergency department. METHODS: This is a secondary analysis of three previous prospective studies including patients with lower respiratory tract infections (LRTI) and acute cerebrovascular events. Patients were classified into different aetiological groups of hyponatraemia and hypernatraemia based on gold standard diagnostic algorithms. Copeptin levels were compared between different volaemic states and different aetiologies, firstly within the different study populations and secondly in an overall pooled analysis using hierarchical regression analysis adjusted for age and gender. RESULTS: In LRTI, hyponatraemia was found in 10.6% (58/545) and hypernatraemia in 3.7% (20/545). For acute cerebrovascular events, the corresponding numbers were 4.3% (22/509) and 8.4% (43/509). In LRTI patients with hyponatraemia, copeptin levels were only lower in the subgroup of patients with gastrointestinal losses compared to the group of patients with renal failure (mean difference: -73.6 mmol/l, 95%CI -135.0, -12.3). For hypernatraemic patients and stoke patients with hypo- and hypernatraemia, no differences were observed. In the combined analysis, copeptin levels in the hyponatraemic population were higher in patients with a hypervolaemic volume state and in patients with heart failure and renal failure. When focusing on severity, copeptin levels increased with increasing severity of disease, as classified by the Pneumonia Severity Index (p < 0.0001) or the National Institute of Health Stroke Scale Score (p < 0.0001). CONCLUSION: Although limited by small sample size, this study found that plasma copeptin level appears to add very little information to the work up of sodium imbalance in this cohort of medical inpatients. It is likely that the non-osmotic "stress"-stimulus in acute hospitalised patients is a major confounder and overrules the osmotic stimulus.

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

INTRODUCTION: Measurement of prohormones representing different pathophysiological pathways could enhance risk stratification in patients with community-acquired pneumonia (CAP) and other lower respiratory tract infections (LRTI). METHODS: We 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. RESULTS: During 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. CONCLUSIONS: Five 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 REGISTRATION: NCT00350987.

Dexamethasone suppression test predicts later development of an impaired adrenal function after a 14-day course of prednisone in healthy volunteers.

BACKGROUND: Suppression of the adrenal function after glucocorticoid treatment is common, potentially dangerous, and unpredictable. Identification of patients at risk is of clinical importance. We hypothesized that the dexamethasone suppression test predicts the development of corticosteroid-induced impaired adrenal function. METHODS: We included 39 healthy male volunteers. After a 1-microg ACTH test, all participants underwent an overnight 0.5-mg dexamethasone suppression test. Participants then took prednisone, 0.5 mg/kg body weight, for 14-day. After the withdrawal of prednisone, a 1-microg ACTH test was performed and a clinical score was assessed on days 1, 3, 7, and 21. RESULTS: On days 1, 3, 7, and 21, 100, 50, 26.5 and 32.4% of the participants had a suppressed adrenal function. The risk of developing suppressed adrenal function decreased from 44 to 0% in patients with cortisol levels after the administration of dexamethasone in the lowest and highest quartiles respectively. Receiver operating curve (ROC) analysis performed to predict a suppressed adrenal function on day 7 after the withdrawal of prednisone showed an area under the curve (AUC) of 0.76 (95% confidence interval (CI) 0.58-0.89) for cortisol after the administration of dexamethasone, which was in the range of the AUC of 0.78 (95% CI 0.6-0.9) for pre-intervention cortisol after the administration of ACTH. Basal cortisol before intake of prednisone (AUC 0.62 (95% CI 0.44-0.78)) and the clinical score (AUC 0.64 (95% CI 0.45-0.79)) had significantly lower AUCs. CONCLUSION: Circulating cortisol levels after a dexamethasone suppression test and a pre-intervention-stimulated cortisol level are predictive of later development of a suppressed adrenal function after a 14-day course of prednisone, and are superior to a clinical score or basal cortisol levels. This may allow a more targeted concept for the need of stress prophylaxis after cessation of steroid therapy.

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.

Procalcitonin guided antibiotic therapy and hospitalization in patients with lower respiratory tract infections: a prospective, multicenter, randomized controlled trial.

BACKGROUND: Lower respiratory tract infections like acute bronchitis, exacerbated chronic obstructive pulmonary disease and community-acquired pneumonia are often unnecessarily treated with antibiotics, mainly because of physicians' difficulties to distinguish viral from bacterial cause and to estimate disease-severity. The goal of this trial is to compare medical outcomes, use of antibiotics and hospital resources in a strategy based on enforced evidence-based guidelines versus procalcitonin guided antibiotic therapy in patients with lower respiratory tract infections. METHODS AND DESIGN: We describe a prospective randomized controlled non-inferiority trial with an open intervention. We aim to randomize over a fixed recruitment period of 18 months a minimal number of 1002 patients from 6 hospitals in Switzerland. Patients must be >18 years of age with a lower respiratory tract infections <28 days of duration. Patients with no informed consent, not fluent in German, a previous hospital stay within 14 days, severe immunosuppression or chronic infection, intravenous drug use or a terminal condition are excluded. Randomization to either guidelines-enforced management or procalcitonin-guided antibiotic therapy is stratified by centre and type of lower respiratory tract infections. During hospitalization, all patients are reassessed at days 3, 5, 7 and at the day of discharge. After 30 and 180 days, structured phone interviews by blinded medical students are conducted. Depending on the randomization allocation, initiation and discontinuation of antibiotics is encouraged or discouraged based on evidence-based guidelines or procalcitonin cut off ranges, respectively. The primary endpoint is the risk of combined disease-specific failure after 30 days. Secondary outcomes are antibiotic exposure, side effects from antibiotics, rate and duration of hospitalization, time to clinical stability, disease activity scores and cost effectiveness. The study hypothesis is that procalcitonin-guidance is non-inferior (i.e., at worst a 7.5% higher combined failure rate) to the management with enforced guidelines, but is associated with a reduced total antibiotic use and length of hospital stay. DISCUSSION: Use of and prolonged exposure to antibiotics in lower respiratory tract infections is high. The proposed trial investigates whether procalcitonin-guidance may safely reduce antibiotic consumption along with reductions in hospitalization costs and antibiotic resistance. It will additionally generate insights for improved prognostic assessment of patients with lower respiratory tract infections. TRIAL REGISTRATION: ISRCTN95122877.