Ursodeoxycholic acid attenuates hepatotoxicity of multidrug treatment of mycobacterial infections: A prospective pilot study.

BACKGROUND: Tuberculosis (TB) remains a global health problem. The application of rifampicin-based regimens for antimycobacterial therapy is hampered by its marked hepatotoxicity which results in poor adherence and may contribute to prolonged therapy or treatment failure. The purpose of this prospective investigation was to evaluate the hepatoprotective effectiveness of oral ursodeoxycholic acid (UDCA) (250-500 mg TID) administered to TB- or non-TB mycobacterial (NTM)-infected patients with drug-induced hepatotoxicity and ongoing therapy. METHODS: Study population: During 2009-2017, 27 patients (11 women, 16 men, aged 19-90 years; median age 44 years, 16 Caucasians, 10 Africans, 1 Asian) out of 285 patients with active TB (24/261) or NTM infections (3/24) treated at our TB Center developed clinically relevant hepatotoxicity. Oral UDCA was administered to treat hepatotoxicity. RESULTS: Twenty-one out of 27 patients (77.8%) showed normalization of elevated enzymes (alanine transferase and aspartate aminotransferase), alkaline phosphatase, and bilirubin while continuing TB treatment and 5 patients demonstrated a significant reduction of liver enzymes (18.5%). No change was observed in 1 patient (3.7%). Drug dose was not reduced in all patients; they all showed radiological and clinical improvement. There were no significant side effects. CONCLUSION: Oral administration of UDCA to TB patients developing anti-TB drug-induced liver injury may reverse hepatotoxicity in adults.

Cardiovascular and respiratory dynamics during normal and pathological sleep.

Sleep is an active and regulated process with restorative functions for physical and mental conditions. Based on recordings of brain waves and the analysis of characteristic patterns and waveforms it is possible to distinguish wakefulness and five sleep stages. Sleep and the sleep stages modulate autonomous nervous system functions such as body temperature, respiration, blood pressure, and heart rate. These functions consist of a sympathetic tone usually related to activation and to parasympathetic (or vagal) tone usually related to inhibition. Methods of statistical physics are used to analyze heart rate and respiration to detect changes of the autonomous nervous system during sleep. Detrended fluctuation analysis and synchronization analysis and their applications to heart rate and respiration during sleep in healthy subjects and patients with sleep disorders are presented. The observed changes can be used to distinguish sleep stages in healthy subjects as well as to differentiate normal and disturbed sleep on the basis of heart rate and respiration recordings without direct recording of brain waves. Of special interest are the cardiovascular consequences of disturbed sleep because they present a risk factor for cardiovascular disorders such as arterial hypertension, cardiac ischemia, sudden cardiac death, and stroke. New derived variables can help to find indicators for these health risks.

Brain natriuretic peptide for prediction of Cheyne-Stokes respiration in heart failure patients.

Cheyne-Stokes respiration (CSR) is indicative of adverse outcome in patients with chronic heart failure (CHF). We evaluated the use of brain natriuretic peptide (BNP) plasma levels to predict CSR in CHF patients. In this cross-sectional study, overnight polygraphy and cardiac work-up were performed and neurohumoral activation was determined in 102 consecutive CHF patients (25-82 years). Demographic characteristics did not significantly differ among patients with (n=38) or without CSR (n=64); BNP (median: 377 vs. 142 pg/ml, p<0.001) and norepinephrine levels (459+/-283 vs. 346+/-204 pg/ml, p=0.02) were significantly increased in patients with CSR. BNP concentrations were significantly associated with the central apnoea/hypopnoea index (y=253+/-5.3x; r=0.26, p=0.01). The area under the ROC curve that used BNP to predict CSR was 0.780 (95% CI: 0.688 to 0.873). Using established cut-off limits of BNP plasma levels, heart failure patients with BNP levels >500 pg/ml displayed a 13 fold increased risk of CSR (95% CI: 2.34-73.50; p=0.03) compared to patients with BNP levels <100 pg/ml. In multiple logistic regression analysis p(a)CO2 (point estimate 0.84, 95% CI: 0.72 to 0.98; p=0.02) and higher BNP class (point estimate 3.14, 95% CI: 1.38-7.144; p=0.006) emerged as parameters independently predicting the presence of CSR in our cohort of CHF patients. In conclusion, CSR is associated with neurohumoral activation in CHF patients. Specifically, BNP levels are associated with the severity of cardiac and sleep-related disease, and may be helpful in the diagnosis of CSR and more appropriate use of polysomnography in CHF patients.

Nonrandom variability of respiration during sleep in healthy humans.

STUDY OBJECTIVES: Breath-to-breath variability is not purely random but is, instead, characterized by correlations on short- and long-term scales. Short-term correlations might reflect intact metabolic-control mechanisms. To investigate whether the higher variability of breathing during rapid eye movement (REM) compared to non-REM (NREM) sleep is of random or nonrandom nature--reflecting an altered respiratory control--short-term and long-term correlations of respiratory drive and timing were determined. DESIGN: A full-night polysomnogram with a pneumotachograph attached to a full-face mask was performed. For each breath during NREM and REM sleep, respiratory components were analyzed based on the quantitative airflow. SETTING: Data collection took place in the sleep laboratory. PARTICIPANTS: Twenty-nine healthy subjects (age, 25.8 +/- 3.1 years). MEASUREMENTS AND RESULTS: Long-term correlations are practically absent in respiratory timing and drive components during NREM sleep, whereas they are present during REM sleep. Short-term correlations are present in respiratory drive, tidal volume, and minute ventilation during both NREM and REM sleep. In all timing components, additional short-term correlations are absent. CONCLUSION: We conclude that from NREM to REM sleep, short-term regulation of respiratory drive remains strongly metabolically controlled and clearly different from the short-term regulation of the rhythm-generating function. Regulation of respiratory timing and drive during REM sleep is characterized by additional long-term correlations. We speculate that this is the result of cortical influences during phasic REM sleep. Thus, the variability of breathing during REM sleep contains a nonrandom component, such that breathing components remain dependent upon each other even with large time lags between components.

Association of right ventricular dysfunction and Cheyne-Stokes respiration in patients with chronic heart failure.

Cheyne-Stokes respiration (CSR) is present in up to 40% of patients with congestive heart failure (CHF) and is an independent risk factor for increased overall mortality. We examined whether CSR is associated with right ventricular (RV) dysfunction in CHF patients. Parameters of RV function were assessed by two-dimensional echocardiography and tissue velocity imaging in 42 patients (aged 23-75 years) with a left ventricular (LV) ejection fraction below 40%. Respiratory polygraphy revealed CSR with an central apnea-hypopnea index (CAHI) >10 h-1 in 13 of the 42 patients (31%). Demographic characteristics did not differ among the patient groups. The velocity of the tricuspid annular systolic motion (TASM), a parameter reflecting systolic RV function, was significantly reduced in CHF patients with CSR (10.5 +/- 2.3 cm s-1) compared with those without CSR (15.0 +/- 5.1 cm s-1, P = 0.004), and was inversely associated with the CAHI (y = 15.2-0.2x; r = 0.46, P = 0.003). The RV dimensions were significantly increased and the fractional RV area changes significantly reduced in CHF patients with CSR (33 +/- 17 versus 48 +/- 20%; P = 0.04). Doppler parameters of pulmonary artery flow indicate higher pulmonary artery pressures in CSR patients compared with patients without CSR, which is also reflected by an increased RV free-wall thickness in CSR patients (6.5 +/- 1.1 vs. 5.3 +/- 1.3 mm; P = 0.05). Parameters of systolic LV function, forced expiratory volume in 1 s (FEV1), and PaO2 and PaCO2 were not different among patients with or without CSR. In conclusion, CSR is associated with depressed systolic RV function and increased RV dimensions in CHF patients. Future studies will show whether optimized treatment of CSR will improve RV function.