Copeptin levels and commonly used laboratory parameters in hospitalised patients with severe hypernatraemia - the "Co-MED study".

BACKGROUND: Hypernatraemia is common in inpatients and is associated with substantial morbidity. Its differential diagnosis is challenging, and delayed treatment may have devastating consequences. The most important hormone for the regulation of water homeostasis is arginine vasopressin, and copeptin, the C-terminal portion of the precursor peptide of arginine vasopressin, might be a reliable new parameter with which to assess the underlying cause of hypernatraemia. METHODS: In this prospective, multicentre, observational study conducted in two tertiary referral centres in Switzerland, 92 patients with severe hyperosmolar hypernatraemia (Na+ > 155 mmol/L) were included. After a standardised diagnostic evaluation, the underlying cause of hypernatraemia was identified and copeptin levels were measured. RESULTS: The most common aetiology of hypernatraemia was dehydration (DH) (n = 65 [71%]), followed by salt overload (SO) (n = 20 [22%]), central diabetes insipidus (CDI) (n = 5 [5%]) and nephrogenic diabetes insipidus (NDI) (n = 2 [2%]). Low urine osmolality was indicative for patients with CDI and NDI (P < 0.01). Patients with CDI had lower copeptin levels than patients with DH or SO (both P < 0.01) or those with NDI. Copeptin identified CDI with an AUC of 0.99 (95% CI 0.97-1.00), and a cut-off value ≤ 4.4pmol/L showed a sensitivity of 100% and a specificity of 99% to predict CDI. Similarly, urea values were lower in CDI than in DH or SO (P < 0.05 and P < 0.01, respectively) or NDI. The AUC for diagnosing CDI was 0.98 (95% CI 0.96-1.00), and a cut-off value < 5.05 mmol/L showed high specificity and sensitivity for the diagnosis of CDI (98% and 100%, respectively). Copeptin and urea could not differentiate hypernatraemia induced by DH from that induced by SO (P = 0.66 and P = 0.30, respectively). CONCLUSIONS: Copeptin and urea reliably identify patients with CDI and are therefore helpful tools for therapeutic management in patients with severe hypernatraemia. TRIALS REGISTRATION: ClinicalTrials.gov, NCT01456533 . Registered on 20 October 2011.

Characteristics and outcomes of patients with profound hyponatraemia due to primary polydipsia.

OBJECTIVE: Hyponatraemia due to excessive fluid intake (ie primary polydipsia [PP]) is common. It may culminate in profound hyponatraemia-carrying considerable risk of morbidity. However, data on patients with PP leading to hyponatraemia are lacking. Herein, we describe the characteristics of polydiptic patients hospitalized with profound hyponatraemia and assess 1-year outcomes. DESIGN: Substudy of the prospective observational Co-MED Study. PATIENTS: Patients with an episode of profound hyponatraemia (≤125 mmol/L) due to PP in the medical emergency were eligible and classified into psychogenic polydipsia (PsyP), dipsogenic polydipsia (DiP) and beer potomania (BP). MEASUREMENTS: Symptoms, laboratory findings and factors contributing to hyponatraemia (comorbidities, medication and liquid intake) were assessed. A 1-year follow-up was performed to evaluate recurrence of hyponatraemia, readmission rate and mortality. RESULTS: Twenty-three patients were included (median age 56 years [IQR 50-65], 74% female), seven had PsyP, eight had DiP and eight had BP. Median serum sodium of all patients was 121 mmol/L (IQR 114-123), median urine osmolality 167 mmol/L (IQR 105-184) and median copeptin 3.6 mmol/L (IQR 1.9-5.5). Psychiatric diagnoses, particularly dependency disorder (43%) and depression (35%), were highly prevalent. Factors provoking hyponatraemia were found in all patients (eg acute water load, medication, stress). During the follow-up period, 67% of patients were readmitted, 52% of these with rehyponatraemia, and three patients (38%) with BP died. CONCLUSION: Patients with PP are more likely to be female and to have addictive and affective disorders. Given the high recurrence, rehospitalization and mortality rate, careful monitoring and long-term follow-up including controls of serum sodium, education and behavioural therapy are needed.

Evaluation of copeptin and commonly used laboratory parameters for the differential diagnosis of profound hyponatraemia in hospitalized patients: 'The Co-MED Study'.

OBJECTIVE: Hyponatraemia is common and its differential diagnosis is challenging. Commonly used diagnostic algorithms have limited diagnostic accuracy. Copeptin, the c-terminal portion of the precursor peptide of arginine vasopressin might help in the differential diagnosis of hyponatraemia. DESIGN: Prospective multicentre observational study. PATIENTS/METHODS: A total of 298 patients admitted with profound hypoosmolar hyponatraemia (Na < 125 mmol/l) were evaluated. Three experts uninvolved in the patients' care determined the aetiology of hyponatraemia after standardized diagnostic evaluation. RESULTS: Hyponatraemia differential diagnoses were as follows: syndrome of inappropriate antidiuresis (SIAD), 106 patients (35·6%); 'diuretic-induced', 72 (24·2%); 'hypovolaemic', 59 (19·8%); 'hypervolaemic', 33 (11·1%); primary polydipsia (PP), 24 (8·1%); and cortisol deficiency, 4 (1·3%). Copeptin levels <3·9 pmol/l identified patients with PP with high specificity (91%). Further, copeptin levels >84 pmol/l were highly predictive for hypovolaemic hyponatraemia (specificity: 90%). Urinary sodium levels and copeptin/urinary sodium ratio in patients with SIAD were higher and lower as compared to other hyponatraemia aetiologies (P < 0·0001). However, the specificity to identify SIAD was moderate for both parameters (31% and 61%). Fractional uric acid excretion (FEUA ) and fractional urea excretion (FEurea ) were higher in patients with SIAD compared to other hyponatraemia aetiologies (both P < 0·0001). FEurea values >55% and FEUA values >12% had a specificity of 96% and 77% to detect patients with SIAD. These results remained similar after excluding patients taking diuretics. CONCLUSIONS: Overall, there is only limited diagnostic utility of copeptin in the differential diagnosis of profound hyponatraemia. Very low copeptin levels are seen in patients with PP and highest copeptin levels in hypovolaemic hyponatraemia. To discriminate between SIAD and other hyponatraemia aetiologies, FEurea and FEUA levels are valuable irrespective of diuretics use.

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.

Predictors for length of hospital stay in patients with community-acquired pneumonia: results from a Swiss multicenter study.

BACKGROUND: Length of hospital stay (LOS) in patients with community-acquired pneumonia (CAP) is variable and directly related to medical costs. Accurate estimation of LOS on admission and during follow-up may result in earlier and more efficient discharge strategies. METHODS: This is a prospective multicenter study including patients in emergency departments of 6 tertiary care hospitals in Switzerland between October 2006 and March 2008. Medical history, clinical data at presentation and health care insurance class were collected. We calculated univariate and multivariate cox regression models to assess the association of different characteristics with LOS. In a split sample analysis, we created two LOS prediction rules, first including only admission data, and second including also additional inpatient information. RESULTS: The mean LOS in the 875 included CAP patients was 9.8 days (95%CI 9.3-10.4). Older age, respiratory rate >20 pm, nursing home residence, chronic pulmonary disease, diabetes, multilobar CAP and the pneumonia severity index class were independently associated with longer LOS in the admission prediction model. When also considering follow-up information, low albumin levels, ICU transfer and development of CAP-associated complications were additional independent risk factors for prolonged LOS. Both weighted clinical prediction rules based on these factors showed a high separation of patients in Kaplan Meier Curves (p logrank <0.001 and <0.001) and a good calibration when comparing predicted and observed results. CONCLUSIONS: Within this study we identified different baseline and follow-up characteristics to be strong and independent predictors for LOS. If validated in future studies, these factors may help to optimize discharge strategies and thus shorten LOS in CAP patients.

18F-Fluorocholine-PET combined with contrast-enhanced CT for localizing hyperfunctioning parathyroid glands and optimizing surgical treatment in patients with hyperparathyroidism.

PURPOSE: Hyperparathyroidism (HPT) is a common disorder. A cure can only be achieved by removing all diseased glands. It is critical to localize the hyperfunctioning glands exactly to prevent extensive surgical exploration. The number of false negative/inconclusive results in standard imaging techniques is high. We aimed to evaluate the diagnostic accuracy of 18F-Fluorocholine-PET in combination with contrast-enhanced CT (FCH-PET/CT) and its sensitivity in patients with primary, secondary/tertiary, and familial HPT with negative and/or discordant findings in ultrasound and/or 99mTc-sestamibi scintigraphy/SPECT/CT. METHODS: A total of 96 patients with HPT and negative/equivocal conventional imaging were referred for FCH-PET/CT. In this retrospective, single institution study, 69 patients, who have undergone surgery and histopathologic workup, were analyzed. Of the 69 patients included, 60 patients suffered from primary HPT, four from secondary or tertiary HPT, and five from familial HPT. Sensitivities, positive predictive values, and accuracies were calculated. RESULTS: Sensitivity/positive predictive value (PPV) per lesion was 87.5/98.3% for primary HPT, 75/100% for secondary/tertiary HPT and 25/66.7% for familial HPT. Sensitivity/PPV per patient was 91.5/98.2% for primary HPT, 100/100% for secondary/tertiary HPT and 50/100% for familial HPT. All patients showed normalized serum calcium levels in the postoperative period. The follow-up rate was 97%. Of the patients included in the study, 58 of 60 patients with primary HPT, and four of four patients with secondary/tertiary HPT showed normal calcium and parathyroid hormone (PTH) levels after six months and were cured. Of the patients with familial HPT, four of five patients were cured. CONCLUSION: Diagnostic accuracy of 18F-Fluorocholine-PET/CT for patients with pHPT is excellent. 18F-Fluorocholine-PET/CT is a valuable tool for endocrine surgeons to optimize the surgical treatment of patients with hyperparathyroidism.

[Primary hyperparathyroidism]. / Primärer Hyperparathyreoidismus.

Primary hyperparathyroidism is frequently an incidental finding in asymptomatic patients. Often the diagnosis of primary hyperparathyroidism is made in evaluation for osteoporosis, rarely in the context of hypercalcemic crisis, myopathy, kidney stones, nephrocalcinosis, and osteitis fibrosa. The most frequent cause for primary hyperparathyroidism is benign parathyroid adenoma, reminders have hyperplasia. Primary hyperparathyroidism is defined as hypercalcemia with inappropriately high parathyroid hormone levels. Surgery is the definitive treatment for patients with symptomatic primary hyperparathyroidism and asymptomatic patients, who meet one of the following criteria: serum calcium>0.25 mmol/L (1.0 mg/dl) above the accepted normal reference range, renal failure (GFR<60 ml/min) and presence of osteoporosis (T-score<-2.5 or fracture). Parathyroidectomy should be performed by an experienced surgeon. As an alternative in inoperable patients or preoperatively in severe hypercalcemia cinacalcet successfully reduces calcium levels. In asymptomatic patients not meeting the above mentioned criteria serum calcium and creatinin levels should be measured once a year and DXA every two years, since 30% of the patients with asymptomatic primary hyperparathyroidism are progressive.

The Significance of 18F-Fluorocholine-PET/CT as Localizing Imaging Technique in Patients with Primary Hyperparathyroidism and Negative Conventional Imaging.

OBJECTIVE: The essential prerequisite for focused parathyroidectomy in patients with primary hyperparathyroidism (pHPT) is proper localization of all autonomic tissue. Sensitivity of conventional imaging modalities (ultrasound, 99mTc-sestamibi scintigraphy/SPECT/CT) is influenced by different factors (i.e., size/weight and position of autonomic tissue) and decreases in the presence of a multinodular goiter. Therefore, a considerable percentage of pHPT patients have negative or equivocal localization studies before surgery. The aim of this study is to evaluate the utility of FCH-PET/CT for preoperative localization in patients with pHPT and negative/equivocal 99mTc-sestamibi scintigraphy/SPECT/CT and/or ultrasound. METHODS AND MEASUREMENTS: Between 2014 and 2017, a total of 39 patients with pHPT and negative/equivocal conventional imaging were referred for FCH-PET/CT. In the analysis, we included those (n = 23) who had surgery and a histopathologic workup of the lesions. RESULTS: 19 of 23 patients demonstrated no tracer uptake with 99mTc-sestamibi scintigraphy/SPECT/CT, 6 patients had an equivocal sonographic lesion, and multinodular goiter was present in 43% (10/23). In 21 of 23 patients, hyperfunctioning parathyroid tissue was identified correctly by FCH-PET/CT [21 true positive, 1 false negative, and 1 false positive; per-patient sensitivity 95.5% (95% confidence interval {CI}, 77.2-99.9)]. 29 lesions were resected [21 true positives, 3 false negatives, 1 false positive, and 4 true negatives; per-lesion sensitivity 87.5% (95% CI, 67.6-97.3)]. All patients were classified as having surgical success according to a decrease of intraoperative parathyroid hormone of ≥50% and normalization of postoperative serum calcium levels. CONCLUSION: Despite a high prevalence of multinodular goiter, diagnostic accuracy of FCH-PET/CT in our patient group was excellent. Therefore, FCH-PET/CT is a promising new imaging tool in patients with pHPT and negative/equivocal results by conventional imaging techniques.

Long-term outcome of profound hyponatremia: a prospective 12 months follow-up study.

BACKGROUND: Hyponatremia is the most common electrolyte abnormality in hospitalized patients and given its impact on mortality and morbidity, a relevant medical condition. Nevertheless, little is known about factors influencing long-term outcome. METHODS: This is a prospective observational 12-month follow-up study of patients with profound hyponatremia (≤125 mmol/L) admitted to the emergency department of two tertiary care centers between 2011 and 2013. We analyzed the predictive value of clinical and laboratory parameters regarding the following outcomes: 1-year mortality, rehospitalization and recurrent profound hyponatremia. RESULTS: Median (IQR) initial serum sodium (s-sodium) level of 281 included patients was 120 mmol/L (116-123). During the follow-up period, 58 (20.6%) patients died. The majority (56.2%) were rehospitalized at least once. Recurrent hyponatremia was observed in 42.7%, being profound in 16%. Underlying comorbidities, assessed by the Charlson Comorbidity Index, predicted 1-year mortality (odds ratio (OR) 1.43, 95% confidence interval (CI) 1.25-1.64, P < 0.001). Furthermore, 's-sodium level at admission' (OR 1.14, 95% CI 1.01-1.29, P = 0.036) and 'correction of hyponatremia' defined as s-sodium ≥135 mmol/L at discharge were associated with mortality (OR 0.47, 95% CI 0.23-0.94, P = 0.034). Mortality rate fell with decreasing baseline s-sodium levels and was lower in the hyponatremia category ≤120 mmol/L vs >120 mmol/L (14.8% and 27.8%, P < 0.01). Patients with s-sodium level ≤120 mmol/L were more likely to have drug-induced hyponatremia, whereas hypervolemic hyponatremia was more common in patients with s-sodium >120 mmol/L. CONCLUSION: Hyponatremia is associated with a substantial 1-year mortality, recurrence and rehospitalization rate. The positive correlation of s-sodium and mortality emphasizes the importance of the underlying disease, which determines the outcome besides hyponatremia itself.

Symptoms and characteristics of individuals with profound hyponatremia: a prospective multicenter observational study.

OBJECTIVES: To assess symptoms and characteristics of hyponatremia, the most common electrolyte disturbance in hospitalized individuals and a condition that is associated with substantial morbidity and mortality. DESIGN: Prospective observational multicenter study. SETTING: Two Swiss academic centers. PARTICIPANTS: Individuals with profound hypoosmolar hyponatremia (sodium<125 mmol/L) (N=298). MEASUREMENTS: All symptoms and complete medical history including current medications, therapy management, and in-hospital outcomes were recorded. RESULTS: The median age of all participants was 71 (interquartile range (IQR) 60-80), 195 (65%) were female, and mean serum sodium value on admission was 120 mmol/L (IQR 116-123 mmol/L). Frequent clinical symptoms were nausea (n=130, 44%), acute vomiting (n=91, 30%), generalized weakness (n=205, 69%), fatigue (n=175, 59%), gait disturbance (n=92, 31%), recurrent falls (n=47, 16%), and acute falls (n=60, 20%). Fractures were reported in 11 participants (4%). More-severe symptoms such as acute epileptic seizures and focal neurological deficits were identified in 16 (5%) and 17 (5%) participants, respectively. The most common comorbidities were hypertension (n=199, 67%), congestive heart failure (n=44, 15%), chronic renal failure (n=64, 21%), pulmonary disease (82, 28%), and central nervous system disease (n=114, 38%). During hospitalization, 12 (4%) participants died, and 103 (35%) needed treatment in the intensive care unit. CONCLUSION: A wide spectrum of symptoms accompanies profound hyponatremia. Most participants had moderate symptoms mirroring chronic hyponatremia with brain cell adaptation. Participants with profound hyponatremia had several comorbidities.

Corticosteroid treatment for community-acquired pneumonia--the STEP trial: study protocol for a randomized controlled trial.

BACKGROUND: Community-acquired pneumonia (CAP) is the third-leading infectious cause of death worldwide. The standard treatment of CAP has not changed for the past fifty years and its mortality and morbidity remain high despite adequate antimicrobial treatment. Systemic corticosteroids have anti-inflammatory effects and are therefore discussed as adjunct treatment for CAP. Available studies show controversial results, and the question about benefits and harms of adjunct corticosteroid therapy has not been conclusively resolved, particularly in the non-critical care setting. METHODS/DESIGN: This randomized multicenter study compares a treatment with 7 days of prednisone 50 mg with placebo in adult patients hospitalized with CAP independent of severity. Patients are screened and enrolled within the first 36 hours of presentation after written informed consent is obtained. The primary endpoint will be time to clinical stability, which is assessed every 12 hours during hospitalization. Secondary endpoints will be, among others, all-cause mortality within 30 and 180 days, ICU stay, duration of antibiotic treatment, disease activity scores, side effects and complications, value of adrenal function testing and prognostic hormonal and inflammatory biomarkers to predict outcome and treatment response to corticosteroids. Eight hundred included patients will provide an 85% power for the intention-to-treat analysis of the primary endpoint. DISCUSSION: This largest to date double-blind placebo-controlled multicenter trial investigates the effect of adjunct glucocorticoids in 800 patients with CAP requiring hospitalization. It aims to give conclusive answers about benefits and risks of corticosteroid treatment in CAP. The inclusion of less severe CAP patients will be expected to lead to a relatively low mortality rate and survival benefit might not be shown. However, our study has adequate power for the clinically relevant endpoint of clinical stability. Due to discontinuing glucocorticoids without tapering after seven days, we limit duration of glucocorticoid exposition, which may reduce possible side effects. TRIAL REGISTRATION: 7 September 2009 on ClinicalTrials.gov: NCT00973154.