[Diabetes, hypoglycemia and driving instructions in Switzerland]. / Diabetes mellitus: Hypoglykämien und Strassenverkehr.

Diabetes, hypoglycemia and driving instructions in Switzerland Abstract. Many individuals with diabetes participate in road traffic in a regular and safe manner. Studies suggest that type 1 diabetes leads to more traffic accidents. Hypoglycemia is a risk factor for driving mishaps. Therefore, patients with diabetes medication, which can cause hypoglycemia, have to be informed and adhere to the guidelines regarding suitability for driving. These guidelines are summarized in this review.

Cosyntropin testing does not predict response to glucocorticoids in community-acquired pneumonia in a randomized controlled trial.

OBJECTIVE: Glucocorticoids have been shown to improve outcome in community-acquired pneumonia (CAP). However, glucocorticoids have potential side-effects, and treatment response may vary. It is thus crucial to select patients with high likelihood to respond favourably. In critical illness, cosyntropin testing is recommended to identify patients in need for glucocorticoids. We investigated whether cosyntropin testing predicts treatment response to glucocorticoids in CAP. DESIGN: Predefined secondary analysis of a randomized controlled trial. PATIENTS: Hospitalized patients with CAP. MEASUREMENTS: We performed 1 µg cosyntropin tests in a randomized trial comparing prednisone 50 mg for 7 days to placebo. We investigated whether subgroups based on baseline and stimulated cortisol levels responded differently to glucocorticoids with regard to time to clinical stability (TTCS) and other outcomes by inclusion of interaction terms into statistical models. RESULTS: A total of 326 patients in the prednisone and 309 patients in the placebo group were evaluated. Neither basal cortisol nor a Δcortisol <250 nmol/L after stimulation nor the combination of basal cortisol and Δcortisol predicted treatment response as measured by TTCS (all P for interaction >0.05). Similarly, we found no effect modification with respect to mortality, rehospitalization, antibiotic treatment duration or CAP-related complications (all P for interaction >0.05). However, glucocorticoids had a stronger effect on shortening length of hospital stay in patients with a baseline cortisol of ≥938 nmol/L (P for interaction = 0.015). CONCLUSIONS: Neither baseline nor stimulated cortisol after low-dose cosyntropin testing at a dose of 1 µg predicted glucocorticoid responsiveness in mild to moderate CAP. A treatment decision for or against adjunct glucocorticoids in CAP should not be made depending on cortisol values or cosyntropin testing results.

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.

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.

Plasma Apelin Concentrations in Patients With Polyuria-Polydipsia Syndrome.

CONTEXT: Apelin and arginine vasopressin are antagonists in the regulation of body fluid and osmotic homeostasis. There are no data about apelin levels in patients with polyuria-polydipsia syndrome (PPS). OBJECTIVE: To investigate plasma apelin levels and plasma apelin to copeptin ratios in patients with PPS and healthy volunteers using copeptin as a surrogate marker for arginine vasopressin. DESIGN, PARTICIPANTS, AND SETTING: We included 41 patients with PPS in this post hoc analysis of a prospective study performed in tertiary care hospitals in Switzerland and Germany and 113 healthy volunteers as a control group. OUTCOME MEASURES: Plasma apelin and copeptin levels were measured in 15 patients with complete central diabetes insipidus (DI), seven patients with complete nephrogenic DI, 19 patients with primary polydipsia (PP), and 113 healthy volunteers. RESULTS: Plasma apelin levels were highest in patients with complete nephrogenic DI (413 pmol/L; interquartile range, 332-504 pmol/L; P = .01) and lower in patients with PP (190 [172-215] pmol/L; P < .001) or complete central DI (209 [174-241] pmol/L; P = .02) as compared to healthy volunteers (254 [225-311] pmol/L). Plasma apelin to copeptin ratio in patients with PP (53 [38-92] pmol/pmol; P > .9) was similar to healthy volunteers (57 [37-102] pmol/pmol). In contrast, the apelin to copeptin ratio was higher in patients with complete central DI (89 [73-135] pmol/pmol; P = .02) and lower in patients with complete nephrogenic DI (7 [6-10] pmol/pmol; P < .001) compared to healthy volunteers. CONCLUSION: In PP, normal plasma apelin to copeptin ratio attests a normal water homeostasis. In contrast, in patients with central or nephrogenic DI, the increased or decreased apelin to copeptin ratio, respectively, reflects a disturbed osmotic and body fluid homeostasis.

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.

Diagnostic Accuracy of Copeptin in the Differential Diagnosis of the Polyuria-polydipsia Syndrome: A Prospective Multicenter Study.

CONTEXT: The polyuria-polydipsia syndrome comprises primary polydipsia (PP) and central and nephrogenic diabetes insipidus (DI). Correctly discriminating these entities is mandatory, given that inadequate treatment causes serious complications. The diagnostic "gold standard" is the water deprivation test with assessment of arginine vasopressin (AVP) activity. However, test interpretation and AVP measurement are challenging. OBJECTIVE: The objective was to evaluate the accuracy of copeptin, a stable peptide stoichiometrically cosecreted with AVP, in the differential diagnosis of polyuria-polydipsia syndrome. DESIGN, SETTING, AND PATIENTS: This was a prospective multicenter observational cohort study from four Swiss or German tertiary referral centers of adults >18 years old with the history of polyuria and polydipsia. MEASUREMENTS: A standardized combined water deprivation/3% saline infusion test was performed and terminated when serum sodium exceeded 147 mmol/L. Circulating copeptin and AVP levels were measured regularly throughout the test. Final diagnosis was based on the water deprivation/saline infusion test results, clinical information, and the treatment response. RESULTS: Fifty-five patients were enrolled (11 with complete central DI, 16 with partial central DI, 18 with PP, and 10 with nephrogenic DI). Without prior thirsting, a single baseline copeptin level >21.4 pmol/L differentiated nephrogenic DI from other etiologies with a 100% sensitivity and specificity, rendering a water deprivation testing unnecessary in such cases. A stimulated copeptin >4.9 pmol/L (at sodium levels >147 mmol/L) differentiated between patients with PP and patients with partial central DI with a 94.0% specificity and a 94.4% sensitivity. A stimulated AVP >1.8 pg/mL differentiated between the same categories with a 93.0% specificity and a 83.0% sensitivity. LIMITATION: This study was limited by incorporation bias from including AVP levels as a diagnostic criterion. CONCLUSION: Copeptin is a promising new tool in the differential diagnosis of the polyuria-polydipsia syndrome, and a valid surrogate marker for AVP. Primary Funding Sources: Swiss National Science Foundation, University of Basel.

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.

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.

Effectiveness of Proadrenomedullin Enhanced CURB65 Score Algorithm in Patients with Community-Acquired Pneumonia in "Real Life", an Observational Quality Control Survey.

BACKGROUND: An intervention trial found a trend for shorter length of stay (LOS) in patients with community-acquired pneumonia (CAP) when the CURB65 score was combined with the prognostic biomarker proadrenomedullin (ProADM) (CURB65-A). However, the efficacy and safety of CURB65-A in real life situations remains unclear. METHODS: From September, 2011, until April, 2012, we performed a post-study prospective observational quality control survey at the cantonal Hospital of Aarau, Switzerland of consecutive adults with CAP. The primary endpoint was length of stay (LOS) during the index hospitalization and within 30 days. We compared the results with two well-defined historic cohorts of CAP patients hospitalized in the same hospital with the use of multivariate regression, namely 83 patients in the observation study without ProADM (OPTIMA I) and the 169 patients in the intervention study (OPTIMA II RCT). RESULTS: A total of 89 patients with confirmed CAP were included. As compared to patients with CURB65 only observed in the OPTIMA I study, adjusted regression analysis showed a significant shorter initial LOS (7.5 vs. 10.4 days; -2.32; 95% CI, -4.51 to -0.13; p = 0.04) when CURB65-A was used in clinical routine. No significant differences were found for LOS within 30 days. There were no significant differences in safety outcomes in regard to mortality and ICU admission between the cohorts. CONCLUSION: This post-study survey provides evidence that the use of ProADM in combination with CURB65 (CURB65-A) in "real life" situations reduces initial LOS compared to the CURB65 score alone without apparent negative effects on patient safety.

Biomarker-enhanced triage in respiratory infections: a proof-of-concept feasibility trial.

Concerns about inadequate performance and complexity limit routine use of clinical risk scores in lower respiratory tract infections. Our aim was to study feasibility and effects of adding the biomarker proadrenomedullin (proADM) to the confusion, urea>7 mmol·L(-1), respiratory rate≥30 breaths·min(-1), blood pressure<90 mmHg (systolic) or ≤60 mmHg (diastolic), age≥65 years (CURB-65) score on triage decisions and length of stay. In a randomised controlled proof-of-concept intervention trial, triage and discharge decisions were made for adults with lower respiratory tract infection according to interprofessional assessment using medical and nursing risk scores either without (control group) or with (proADM group) knowledge of proADM values, measured on admission, and on days 3 and 6. An adjusted generalised linear model was calculated to investigate the effect of our intervention. On initial presentation the algorithms were overruled in 123 (39.3%) of the cases. Mean length of stay tended to be shorter in the proADM (n=154, 6.3 days) compared with the control group (n=159, 6.8 days; adjusted regression coefficient -0.19, 95% CI -0.41-0.04; p=0.1). This trend was robust in subgroup analyses and for overall length of stay within 90 days (7.2 versus 7.9 days; adjusted regression coefficient -0.18, 95% CI -0.40-0.05; p=0.13). There were no differences in adverse outcomes or readmission. Logistic obstacles and overruling are major challenges to implement biomarker-enhanced algorithms in clinical settings and need to be addressed to shorten length of stay.

[Successful treatment of thrombotic thrombocytopenic purpura (TTP) with rituximab]. / Erfolgreiche Behandlung einer Thrombotisch Thrombozytopenischen Purpura mit Rituximab.

A 15-year-old female patient with TTP was admitted to our hospital for further evaluation after the initial treatment with IVIG and prednisone failed. With the detection of anti-ADAMTS13 antibodies the acquired form of TTP could be diagnosed. Despite of therapeutic plasma exchange and high dose steroids no sustained remission could be achieved. However, application of rituximab led to a normalisation of platelet counts within one week allowing the termination of plasma exchanges and reduction of oral steroids. No side effects of rituximab were observed and the patient remained in clinical remission during the following months.