Copeptin for risk stratification in non-traumatic headache in the emergency setting: a prospective multicenter observational cohort study.

BACKGROUND: In the emergency setting, non-traumatic headache is a benign symptom in 80% of cases, but serious underlying conditions need to be ruled out. Copeptin improves risk stratification in several acute diseases. Herein, we investigated the value of copeptin to discriminate between serious secondary headache and benign headache forms in the emergency setting. METHODS: Patients presenting with acute non-traumatic headache were prospectively enrolled into an observational cohort study. Copeptin was measured upon presentation to the emergency department. Primary endpoint was serious secondary headache defined by a neurologic cause requiring immediate treatment of the underlying disease. Secondary endpoint was the combination of mortality and hospitalization within 3 months. Two board-certified neurologist blinded to copeptin levels verified the endpoints after a structured 3-month-telephone interview. RESULTS: Of the 391 patients included, 75 (19%) had a serious secondary headache. Copeptin was associated with serious secondary headache (OR 2.03, 95%CI 1.52-2.70, p < 0.0001). Area under the curve (AUC) for copeptin to identify the primary endpoint was 0.70 (0.63-0.76). After adjusting for age > 50, focal-neurological abnormalities, and thunderclap onset of symptoms, copeptin remained an independent predictive factor for serious secondary headache (OR 1.74, 95%CI 1.26-2.39, p = 0.001). Moreover, copeptin improved the AUC of the multivariate logistic clinical model (p-LR-test < 0.001). Even though copeptin values were higher in patients reaching the secondary endpoint, this association was not significant in multivariate logistic regression. CONCLUSIONS: Copeptin was independently associated with serious secondary headache as compared to benign headaches forms. Copeptin may be a promising novel blood biomarker that should be further validated to rule out serious secondary headache in the emergency department. TRIAL REGISTRATION: Study Registration on 08/02/2010 as NCT01174901 at clinicaltrials.gov.

Adjunct prednisone therapy for patients with community-acquired pneumonia: a multicentre, double-blind, randomised, placebo-controlled trial.

BACKGROUND: Clinical trials yielded conflicting data about the benefit of adding systemic corticosteroids for treatment of community-acquired pneumonia. We assessed whether short-term corticosteroid treatment reduces time to clinical stability in patients admitted to hospital for community-acquired pneumonia. METHODS: In this double-blind, multicentre, randomised, placebo-controlled trial, we recruited patients aged 18 years or older with community-acquired pneumonia from seven tertiary care hospitals in Switzerland within 24 h of presentation. Patients were randomly assigned (1:1 ratio) to receive either prednisone 50 mg daily for 7 days or placebo. The computer-generated randomisation was done with variable block sizes of four to six and stratified by study centre. The primary endpoint was time to clinical stability defined as time (days) until stable vital signs for at least 24 h, and analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00973154. FINDINGS: From Dec 1, 2009, to May 21, 2014, of 2911 patients assessed for eligibility, 785 patients were randomly assigned to either the prednisone group (n=392) or the placebo group (n=393). Median time to clinical stability was shorter in the prednisone group (3·0 days, IQR 2·5-3·4) than in the placebo group (4·4 days, 4·0-5·0; hazard ratio [HR] 1·33, 95% CI 1·15-1·50, p<0·0001). Pneumonia-associated complications until day 30 did not differ between groups (11 [3%] in the prednisone group and 22 [6%] in the placebo group; odds ratio [OR] 0·49 [95% CI 0·23-1·02]; p=0·056). The prednisone group had a higher incidence of in-hospital hyperglycaemia needing insulin treatment (76 [19%] vs 43 [11%]; OR 1·96, 95% CI 1·31-2·93, p=0·0010). Other adverse events compatible with corticosteroid use were rare and similar in both groups. INTERPRETATION: Prednisone treatment for 7 days in patients with community-acquired pneumonia admitted to hospital shortens time to clinical stability without an increase in complications. This finding is relevant from a patient perspective and an important determinant of hospital costs and efficiency. FUNDING: Swiss National Science Foundation, Viollier AG, Nora van Meeuwen Haefliger Stiftung, Julia und Gottfried Bangerter-Rhyner Stiftung.

Validity of different copeptin assays in the differential diagnosis of the polyuria-polydipsia syndrome.

The aim of this study was to correlate three commercially available copeptin assays and their diagnostic accuracy in the differential diagnosis of the polyuria-polydipsia syndrome. Analyzed data include repeated copeptin measures of 8 healthy volunteers and 40 patients with polyuria-polydipsia syndrome undergoing osmotic stimulation and of 40 patients hospitalized with pneumonia. Copeptin was measured using the automated Brahms KRYPTOR, the manual Brahms LIA and the manual Cloud Clone ELISA assay. Primary outcome was the interrater correlation coefficient (ICC) and diagnostic accuracy in the polyuria-polydipsia syndrome of the three assays. In healthy volunteers, there was a moderate correlation for the KRYPTOR and LIA (ICC 0.74; 95% CI 0.07 to 0.91), and a poor correlation for the KRYPTOR and ELISA (ICC 0.07; 95% CI - 0.06 to 0.29), as for the LIA and ELISA (ICC 0.04; 95% CI - 0.04 to 0.17). The KRYPTOR had the highest diagnostic accuracy (98% (95% CI 83 to100)), comparable to the LIA (88% (95% CI 74 to 100)), while the ELISA had a poor diagnostic accuracy (55% (95% CI 34 to 68)) in the differential diagnosis of the polyuria-polydipsia syndrome. The KRYPTOR and LIA yield comparable copeptin concentrations and high diagnostic accuracy, while the ELISA correlates poorly with the other two assays and shows a poor diagnostic accuracy for polyuria-polydipsia patients. The current copeptin cut-off is valid for the KRYPTOR and LIA assay. Our results indicate that interpretation with other assays should be performed with caution and separate validation studies are required before their use in differentiating patients with polyuria-polydipsia syndrome.Trial registration: NCT02647736 January 6, 2016/NCT01940614 September 12, 2013/NCT00973154 September 9, 2009.

Outcomes of Hospitalized Patients with Glucocorticoid-Induced Hyperglycemia-A Retrospective Analysis.

BACKGROUND: Glucocorticoid (GC)-induced hyperglycemia is a frequent side effect in hospitalized patients. Guidelines recommend treat-to-target treatment between 6-10 mmol/L (108-180 mg/dL) with insulin, but data on outcome is scarce. We investigated the 30-day outcome in hospitalized patients receiving GCs. METHODS: All patient records of hospitalized patients between January 2014 and April 2018 were screened for GC administration and consecutive hyperglycemia. The primary combined endpoint consisted of death, cardiovascular events, and infections until 30 days after admission. Hypoglycemia was a secondary outcome. RESULTS: Of the 2424 hospitalized patients (9.6% of all hospitalized patients) who received systemic GCs and met inclusion criteria, the overall incidence for GC-induced hyperglycemia was 812 (33.5%), and 89 (3.7%) had at least one documented hypoglycemia during their hospital stay. Compared to patients with normoglycemia, GC-induced hyperglycemia had an adjusted-odds ratio of 1.68 (95% CI 1.25-2.26) for the combined primary endpoint. Hypoglycemia even had an odds ratio of 1.95 (95% CI 1.2-3.17). CONCLUSIONS: Mortality, cardiovascular events, and rate of infections were markedly higher in patients with GC-induced hyperglycemia as compared to patients with normoglycemia. Importantly, hypoglycemia was associated with a doubled risk for adverse outcome. Future studies should evaluate whether optimized glucose control by minimizing the risk for hypoglycemia has a beneficial effect on clinical outcomes in patients with GC-induced hyperglycemia.

Mild to moderate hyponatremia at discharge is associated with increased risk of recurrence in patients with community-acquired pneumonia.

BACKGROUND: Hyponatremia is the most common electrolyte disorder in hospitalized patients with pneumonia. Different studies have shown an association of hyponatremia on admission and worse patient's outcome. Yet, the impact of hyponatremia at discharge or of hyponatremia correction on patient's prognosis is unknown. METHODS: This is a preplanned secondary data analysis from a double-blind, randomized, placebo-controlled trial of hospitalized patients with community-acquired pneumonia and prednisone treatment. The primary outcome was the impact of hyponatremia on admission and at discharge on patient relevant outcomes (i.e. mortality, rehospitalization and recurrence rate) within 180 days. RESULTS: Of the 708 included patients, 185 (26.1%) were hyponatremic on admission. Of these, 28 (15.1%) were still hyponatremic at discharge. 34 (4.8%) patients developed hyponatremia during hospitalization despite being normonatremic on admission. Patients with hyponatremia at discharge had a higher rate of pneumonia recurrence as compared to normonatremic patients (OR 2.68; 95%-CI 1.09-6.95; p = 0.037). Among patients with hyponatremia at discharge, patients who were already hyponatremic on admission showed the strongest association with increased recurrence rate (OR 4.01; 95%-CI 1.08-12.64; p = 0.022). In contrast, recurrence rate was not affected in patients who were hyponatremic on admission but had normalized serum sodium levels at discharge (p = 0.73). CONCLUSION: Mild to moderate hyponatremia at discharge is associated with an increased risk of recurrence in hospitalized patients with pneumonia. This association is particularly strong for patients who are hyponatremic both on admission and at discharge, emphasizing the importance of hyponatremia correction during hospitalization.

Retrospective assessment of resource use and costs in two investigator-initiated randomized trials exemplified a comprehensive cost item list.

OBJECTIVES: Randomized clinical trials (RCTs) are costly and published information on resource requirements for their conduct is limited. To identify key factors for making RCTs more sustainable, empirical data on resource use and associated costs are needed. We aimed to retrospectively assess resource use and detailed costs of two academic, investigator-initiated RCTs using a comprehensive list of cost items. STUDY DESIGN AND SETTING: The resource use of two investigator-initiated RCTs (Prednisone-Trial [NCT00973154] and Oxantel-Trial [ISRCTN54577342]) was empirically assessed in a standardized manner through semistructured interviews and a systematically developed cost item list. Using information about yearly salaries, resource use was translated into costs. In addition, we collected all "other costs" including fixed priced items. Overall costs as well as cost of different study phases were calculated. RESULTS: The personnel time used in the Prednisone-Trial trial was approximately 2,897 working days and the overall costs were calculated to be USD 2.3 million, which was USD 700,000 more than planned. In the Oxantel-Trial 798 working days were spent and the overall costs were as originally planned USD 100,000. Cost drivers were similar between the two RCTs with recruitment delays explaining the additional costs in the Prednisone-Trial. CONCLUSION: This case study provides an example of how to transparently assess resources and costs of RCTs and presents detailed empirical data on type and magnitude of expenses. In the future, this model approach may serve others to plan, assess, or monitor resource use and costs of RCTs.

Influence of hospital characteristics on quality of care in patients with community-acquired pneumonia.

PRINCIPLES: In-hospital care of patients with community-acquired pneumonia (CAP) varies across hospitals. Understanding of the underlying factors is the basis for tailored quality improvements. Using data from a randomised controlled Swiss-wide multicentre trial, we compared length of stay (LOS) and other patient outcomes according to (A) the use of a procalcitonin (PCT)-based antibiotic stewardship protocol, (B) institution type (university vs non-university), and (C) historical time period in relation to the introduction of Diagnosis Related Group (DRG) reimbursement (2012). METHODS: We included 784 patients hospitalised with CAP from six institutions into this secondary analysis. We used multivariable regression models adjusted for age, comorbidities and disease severity to determine the influence of institution characteristics on LOS and patient outcomes. FINDINGS: LOS was significantly shorter in the institution using a PCT-based antibiotic stewardship protocol (9.2 vs 5.3 days; adjusted mean difference 3.92 days; 95% confidence interval [CI] 5.16-2.68) with shorter antibiotic treatment. There was no difference in LOS in university vs non-university hospitals, but antibiotic courses in university-type hospitals were longer (11.0 vs 8.3 days; adjusted mean difference 2.59 days; 95% CI, 1.69-3.49). No significant difference in LOS was found when comparing the time period before and after the introduction of the DRG system in Switzerland. CONCLUSIONS: We found differences in LOS associated with theuse of a PCT-based antibiotic stewardship protocol, which remained robust after multivariable adjustment. Importantly, the type of institution and model of reimbursement did not influence LOS in our CAP cohort. More health services research studies are needed to establish causal effects.

Postoperative Copeptin Concentration Predicts Diabetes Insipidus After Pituitary Surgery.

CONTEXT: Copeptin is a stable surrogate marker of vasopressin release; the peptides are stoichiometrically secreted from the neurohypophysis due to elevated plasma osmolality or nonosmotic stress. We hypothesized that following stress from pituitary surgery, patients with neurohypophyseal damage and eventual diabetes insipidus (DI) would not exhibit the expected pronounced copeptin elevation. OBJECTIVE: The objective was to evaluate copeptin's accuracy to predict DI following pituitary surgery. DESIGN: This was a prospective multicenter observational cohort study. SETTING: Three Swiss or Canadian referral centers were used. PATIENTS: Consecutive pituitary surgery patients were included. MEASUREMENTS: Copeptin was measured postoperatively daily until discharge. Logistic regression models and diagnostic performance measures were calculated to assess relationships of postoperative copeptin levels and DI. RESULTS: Of 205 patients, 50 (24.4%) developed postoperative DI. Post-surgically, median [25th-75th percentile] copeptin levels were significantly lower in patients developing DI vs those not showing this complication: 2.9 [1.9-7.9] pmol/L vs 10.8 [5.2-30.4] pmol/L; P < .001. Logistic regression analysis revealed strong association between postoperative copeptin concentrations and DI even after considering known predisposing factors for DI: adjusted odds ratio (95% confidence interval) 1.41 (1.16-1.73). DI was seen in 22/27 patients with copeptin <2.5 pmol/L (positive predictive value, 81%; specificity, 97%), but only 1/40 with copeptin >30 pmol/L (negative predictive value, 95%; sensitivity, 94%) on postoperative day 1. LIMITATIONS: Lack of standardized DI diagnostic criteria; postoperative blood samples for copeptin obtained during everyday care vs at fixed time points. CONCLUSIONS: In patients undergoing pituitary procedures, low copeptin levels despite surgical stress reflect postoperative DI, whereas high levels virtually exclude it. Copeptin therefore may become a novel tool for early goal-directed management of postoperative DI.