Pilot Study of Endothelin Receptor Blockade in Heart Failure with Diastolic Dysfunction and Pulmonary Hypertension (BADDHY-Trial).

BACKGROUND: In this multi-centre, randomised, placebo-controlled pilot trial, we investigated the clinical and haemodynamic effects of the endothelin-receptor blocker Bosentan in patients with heart failure, preserved ejection fraction and pulmonary hypertension (PH-HFpEF). MATERIALS AND METHODS: Eligible patients received either 12 weeks of Bosentan therapy, or a placebo drug. Patients were thereafter followed for a further period of 12 weeks without the study medication. At three points during the study (study Commencement, Week 12 and Week 24), a six-minute walk test (6MWT), echocardiographic and laboratory assessments were performed, as well as a quality of life survey. Right heart catheterisation (RHC) was undertaken at commencement only. The study was aborted early, after an interim analysis favoured the placebo. RESULTS: Six-minute walk distance (6MWD) did not change in the Bosentan group (309.7±96.3m (Commencement), 317.0±126.1m (Week 12), 307.0±84.4m (Week 24); p=0.86), but almost reached statistical significance in the placebo group from 328.8±79.6m, to 361.6±98.2m and 384.0±74.9m (Week 24); p=0.075. In the placebo group, estimated systolic pulmonary artery pressure (measured via echocardiography) significantly decreased (from 62.3±16.7mmHg [Commencement], 45.3±13.9mmHg [Week 12], to 44.6±14.5mmHg [Week 24]; p=0.014) as did right atrial pressure (13.1±5.3 [Commencement], 10.0±3.8 [Week 12], to 9.4±3.2 [Week 24]; p=0.046). CONCLUSION: Despite this study's limited sample size and premature cessation, it nevertheless suggests that endothelin receptor blockade in patients with PH-HFpEF may have no beneficial effects and could even be detrimental in comparison to a placebo.

[Malignant hyperthermia syndrome in the intensive care unit : Differential diagnosis and acute measures]. / Maligne hypertherme Syndrome auf der Intensivstation : Differenzialdiagnostik und Akutmaßnamen.

Malignant hyperthermia is a life-threatening disease caused by derangement of the autonomic nerve system and hypermetabolism of the peripheral musculature. Commonly body core temperatures of more than 40 °C will be found in this disease which is caused mostly by psychopharmacological drugs like antidepressants, neuroleptics but also antibiotics, pain killers, anti-Parkinson drugs, and volatile anesthetics. The inducers of malignant hyperthermia interact with postsynaptic receptors (serotonin, anticholinergics) or muscular intracellular structures responsible for calcium utilization (volatile anesthetics, succinylcholine). Rarely malignant hyperthermia is a consequence of mental stress or vigorous exercise and or heat. Malignant hyperthermic syndromes lead to a severe dysbalance of the autonomic nerve system accompanied by rhabdomyolysis, disseminated intravascular coagulopathy, and finally multi-organ failure. Accordingly, medical management is primarily directed to stabilize vital functions, withdrawal of the causing drug, and if possible antagonizing toxic substances. The leading symptom hyperthermia needs to be treated physically with available cooling systems.

Effects of exercise and hypoxia on heart rate variability and acute mountain sickness.

Acute mountain sickness (AMS) is a common condition among non-acclimatized individuals ascending to high altitude. Exercise, a characteristic feature of hiking and mountaineering, has been suggested to exacerbate AMS prevalence and to cause modifications of the autonomic nervous system. A reduction of the heart rate variability (HRV) is a common finding during acute hypoxia, however characteristics of HRV during exercise in subjects suffering from AMS are unknown. Therefore, the aim of the present study was to investigate the effects of acute normobaric hypoxia (FiO2=11.0% ≙ 5 500 m) at rest (PHE) and during exercise (AHE) on the cardiac autonomic function and the development of AMS in 20 healthy, male individuals. HRV recordings were performed during normoxia and after 2, 4, 6 and 8 h in hypoxia during PHE and AHE, respectively. AMS was assessed using the Lake Louise Score. During PHE 50% of participants developed AMS and 70% during AHE (p=0.22). The analysis of HRV data showed a significant reduction of total power (TP), high frequency (HF) and low frequency (LF) components and an increase of the LF:HF ratio during PHE, however without further modification during AHE. Exercise did not increase AMS prevalence or severity, but increased "non-gastrointestinal" symptoms including headache, fatigue and dizziness. HRV indices were not related to the overall incidence of AMS or the development of "non-gastrointestinal" symptoms but we detected significant correlations between gastrointestinal complaints and HRV components. Thus, we suggest that the cardiac autonomic modulation during acute normobaric hypoxia does not play an important role in the development of AMS, but seems to be related to gastrointestinal complaints at high altitude. However, the influence of moderate exercise on HRV and AMS is minor, only "non-GI" symptoms seem to be exacerbated when exercise is applied.

Plasma copeptin levels before and during exogenous arginine vasopressin infusion in patients with advanced vasodilatory shock.

BACKGROUND: Plasma copeptin levels before and during exogenous arginine vasopressin infusion (AVP) were evaluated, and the value of copeptin levels before AVP therapy to predict complications during AVP therapy and outcome in vasodilatory shock patients was determined. METHODS: This prospective, observational study was nested in a randomized, controlled trial investigating the effects of two AVP doses (0.033 vs. 0.067 IU/min) on the hemodynamic response in patients with advanced vasodilatory shock due to sepsis, systemic inflammatory response syndrome or after cardiac surgery. Clinical data, plasma copeptin levels and adverse events were recorded before, 24 hours after and 48 hours after randomization. RESULTS: Plasma copeptin levels were elevated before AVP therapy. During AVP, copeptin levels decreased (P<0.001) in both groups (P=0.73). Copeptin levels at randomization predicted the occurrence of ischemic skin lesions (AUC ROC, 0.73; P=0.04), a fall in platelet count (AUC ROC, 0.75; P=0.01) during AVP and intensive care unit mortality (AUC ROC, 0.67; P=0.04). Twenty-five patients (64.1%) exhibited a decrease in copeptin levels. Patients experiencing a decrease in copeptin levels were older (P=0.04), had a higher Sequential Organ Failure Assessment score count before (P=0.03) and during AVP therapy (P=0.04), had a longer intensive care unit stay (P<0.001) and required AVP therapy longer (P=0.008) than patients without a decrease in copeptin levels during AVP. CONCLUSION: Plasma copeptin levels are elevated in patients with advanced vasodilatory shock. During exogenous AVP therapy, copeptin levels decrease, suggesting suppression of the endogenous AVP system.

Bosentan treatment of portopulmonary hypertension related to liver cirrhosis owing to hepatitis C.

Pulmonary arterial hypertension (PAH) with coexisting portal hypertension has been defined as portopulmonary hypertension (PPHTN). It is often related to liver cirrhosis of various aetiologies and is associated with a high mortality rate. Endothelin-1 (ET) is supposed to play an important role in the pathogenesis of PAH as well as portal hypertension. Therefore, therapy with an ET(A)/ET(B) receptor antagonist might be of use in the treatment of PPHTN. We report the case of a 76-year-old male with liver cirrhosis owing to chronic hepatitis C virus infection and PPHTN who was treated with the dual ET(A)/ET(B) receptor antagonist bosentan. The patient showed remarkable improvement of 6-min walking distance from 300 to 480 m after 2 weeks and to 540 m after 14 weeks, respectively. In addition, a significant decline of N-terminal pro B-type natriuretic peptide fraction (NT-proBNP) from 4928 ng mL(-1) to 640 ng mL(-1) was observed. Bosentan might be a promising new therapeutical option for patients suffering from PPHTN.