[Natriuretic peptides in intensive care medicine]. / Natriuretische Peptide in der Intensivmedizin.

Natriuretic peptides must be interpreted in their clinical context, especially in intensive care medicine. This overview presents the diagnostic, prognostic, and therapeutic significance of B­type natriuretic peptide (BNP) and N­terminal pro B­type natriuretic peptide (NT-proBNP) in patients with cardiac dysfunction, kidney failure, sepsis, pulmonary embolism, acute respiratory distress syndrome (ARDS), acute exacerbations of chronic obstructive pulmonary disease (AECOPD), and weaning from a respirator.

D-dimers as an early marker for oxygenator exchange in extracorporeal membrane oxygenation.

PURPOSE: Early markers of oxygenator dysfunction during prolonged use of extracorporeal membrane oxygenation (ECMO) are important for timely exchange to avoid sudden loss of function due to clot formation within the system. The measurement of D-dimers (DDs) in plasma might be a marker for early diagnosis of thrombus formation and dysfunction of heparin-coated membrane oxygenators (MOs). METHODS: This is a retrospective study on prospectively collected data of 24 adult acute respiratory distress syndrome patients requiring long-term veno-venous ECMO with at least 1 MO exchange. Kinetics of coagulation, inflammation, and oxygenator function were analyzed before and after MO exchange. RESULTS: Median (interquartile range) support duration is 20 (15-29) days. Thirty-four MOs had to be replaced. Exchange occurred due to visible thrombus formation in the MO (n=16), worsening gas exchange (n=11), increased blood flow resistance (n=1), and activation of coagulation with diffuse bleeding (n=6). In 15 cases, DDs were continuously elevated and, therefore, not suitable as marker for MO exchange. In the remaining 19 cases, DDs increased significantly within 3 days before exchange from 15 (9-20) to 30 (21-35) mg/dL (P=.002) and declined significantly within 1 day thereafter to 13 (7-17) mg/dL (P=.003). CONCLUSIONS: An increase in plasma DD concentration in absence of other explaining pathology can be helpful in predicting an MO exchange in miniaturized heparin-coated ECMO systems.

Acute haemodynamic effects of continuous positive airway pressure in awake patients with heart failure.

BACKGROUND AND OBJECTIVE: Continuous positive airway pressure (CPAP) has been used to treat patients with chronic heart failure (CHF) and sleep-disordered breathing (SDB). CPAP treatment in severe CHF with concomitant SDB and atrial fibrillation has been linked to impairment of cardiac output (CO) as a potential cause for adverse outcome. The aim of the present study was to test whether incremental CPAP application in awake CHF patients with SDB, with and without atrial fibrillation, induces acute alterations of blood pressure (BP), heart rate (HR) and CO. METHODS: During daytime, we applied incremental CPAP (4-10 cmH2O) in 37 stable patients with CHF and SDB. BP and HR were assessed after each 1 cmH2O CPAP increase in 5-min intervals in the entire sample, and CO was assessed at one centre (n = 11). RESULTS: Neither mean BP, HR nor CO changed significantly with incremental CPAP (at 0 and 10 cmH2O: 85 ± 2 and 84 ± 2 mm Hg, P = 1.0, 63 ± 1 to 61 ± 2 b.p.m., P = 0.88 and 2.03 ± 0.5 and 2.35 ± 0.8 L/min/m2 , P = 0.92, respectively). No significant differences in maximum BP drop or HR drop between patients with sinus rhythm and atrial fibrillation were found. In 1 of 37 patients, a prespecified event of haemodynamic compromise (drop of mean BP >15 mm Hg) without clinical signs occurred. CONCLUSIONS: These results contribute to the evidence that CPAP does not cause haemodynamic compromise in the vast majority of normotensive CHF patients with SDB.

Impact of right ventricular reserve on exercise capacity and survival in patients with pulmonary hypertension.

AIMS: Pulmonary hypertension is a clinical syndrome characterized by a progressive increase in pulmonary vascular resistance leading to right ventricular failure and death. Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are key subgroups of this disorder with comparable clinical and pathological findings. Resting pulmonary haemodynamics correlate only moderately with functional parameters and do not predict prognosis in these patients sufficiently accurately. We therefore correlated exercise haemodynamics with peak oxygen uptake (peakVO2) and determined their prognostic significance. METHODS AND RESULTS: Thirty-six consecutive patients (21 female, 54 ± 15 years) with PAH (n = 21) or inoperable CTEPH were studied. The mean follow-up period was 1709 ± 837 days. All patients underwent right heart catheterization at rest and during exercise, and cardiopulmonary exercise testing. Patients had severe pulmonary hypertension at rest (mean pulmonary artery pressure 46 + 11 mmHg, cardiac index 2.2 ± 0.6 L/min/m(2), pulmonary vascular resistance 861 ± 330 dynes/s/cm(5)). Exercise cardiac index correlated with peakVO2 (r = 0.59, P < 0.001) and was the only independent predictor of peakVO2 on multivariate stepwise linear regression analyses (P < 0.001). PeakVO2 was the strongest predictor of survival (χ(2) = 14.5, P = 0.003). Among haemodynamic variables, only exercise cardiac index (χ(2) = 5.6, P = 0.018) and the slope of the pressure/flow relationship (χ(2) = 4.1, P = 0.04) were significant prognostic indicators. CONCLUSION: The ability of the right ventricle to increase the cardiac index during exercise is an important determinant of exercise capacity in patients with pulmonary hypertension. It also predicts prognosis and might therefore be useful in the clinical assessment of these patients.

Auto-servoventilation in heart failure with sleep apnoea: a randomised controlled trial.

We tested the hypotheses that in patients with congestive heart failure (CHF) and sleep disordered breathing (SDB) auto-servoventilation (ASV) improves cardiac function and quality of life. Between March 2007 and September 2009, patients with stable CHF (left ventricular ejection fraction (LVEF) ≤ 40%) and SDB (apnoea/hypopnoea index ≥ 20 events · h(-1)) were randomised to receive either ASV (BiPAP ASV (Philips Respironics, Murrysville, PA, USA), n=37) and optimal medical management, or optimal medical management alone (n=35). Outcomes were assessed at baseline and 12 weeks. The apnoea/hypopnoea index assessed with polysomnography scored in one core laboratory was significantly more reduced in the ASV group (-39 ± 16 versus -1 ± 13 events · h(-1); p<0.001) with an average use of 4.5 ± 3.0 h · day(-1). Both groups showed similar improvements of the primary end-point LVEF (+3.4 ± 5 versus +3.5 ± 6%; p=0.915) assessed with echocardiography. In the ASV group, reduction of N-terminal pro-brain natriuretic peptide (NT-proBNP) was significantly greater (-360 ± 569 versus +135 ± 625 ng · mL(-1); p=0.010). No differences were observed between the groups in subjective quality of life. In patients with CHF and SDB, ASV reduced NT-proBNP levels, but improvement of LVEF or quality of life was not greater than in the control group. The data support that such patients can be randomised in large-scale, long-term trials of positive airway pressure therapy versus control to determine effects on cardiovascular outcome.

Improvement of exercise capacity in monocrotaline-induced pulmonary hypertension by the phosphodiesterase-5 inhibitor Vardenafil.

Vardenafil, a phosphodiesterase-5 inhibitor, is approved for the therapy of erectile dysfunction. However, in contrast to Sildenafil and Tadalafil, little is known about its effects on pulmonary hypertension. Four weeks after monocrotaline-administration rats exhibited a significant increase in right ventricular pressure (RVSP, 94mmHg vs. 25mmHg; p=0.001) right ventricular weight (right ventricle/left ventricle+septum, 59 vs. 23; p=0.001) and pulmonary vascular remodeling (medial wall area 104% vs. 66%; p<0.05) as compared to controls, with a corresponding reduction in exercise capacity (% from baseline value: 67%; p<0.05). Vardenafil treatment resulted in decreased RVSP (56mmHg vs. 95mmHg; p=0.008), right ventricular weight (41 vs. 59; p=0.013), pulmonary vascular remodeling (medial wall area 64% vs. 104%; p<0.05) and a significant better exercise capacity (% from baseline value: 84% vs. 67%; p<0.05) compared to monocrotaline only treated animals. In conclusion, Vardenafil exerts beneficial effects on monocrotaline-induced pulmonary hypertension in rats. Whether it is a treatment option for patients with pulmonary hypertension needs to be elucidated.

Prognostic impact of sleep disordered breathing and its treatment in heart failure: an observational study.

AIMS: Sleep disordered breathing (SDB) may contribute to disease progression in patients with chronic heart failure (CHF). The objective of this observational study was to evaluate whether SDB is a risk factor for mortality in CHF patients and whether this risk can be attenuated by treatment with positive airway pressure (PAP). METHODS AND RESULTS: We studied 296 CHF patients (median left ventricular ejection fraction 33%) who underwent in-lab polysomnography between January 2002 and December 2009. We compared (i) mortality between patients with severe SDB [apnoea-hypopnoea index (AHI) ≥ 22.5 h(-1)] vs. those without severe SDB (AHI < 22.5 h(-1)) and (ii) evaluated the impact of PAP treatment on mortality in those with severe SDB. After accounting for significant confounding factors (age, NYHA class, cause of CHF, diabetes, and PAP treatment), patients with severe SDB (n= 176) had a 2.0-fold increased hazard ratio for death compared with those without severe SDB [95% confidence interval (CI) 1.1-3.5, P= 0.023]. In an adjusted on-treatment analysis of the group with severe SDB, mortality was significantly less in patients using PAP (18%) compared with those with untreated SDB (52%; hazard ratio 0.4, 95% CI 0.2-0.6, P= 0.001). Mortality in the PAP-treated group was lower compared with the untreated group at any time-point of the follow-up period. CONCLUSION: The presence of severe SDB in CHF patients constitutes a significantly increased risk for death, independent of established risk factors. In CHF patients with SDB, use of PAP therapy was associated with a decreased mortality rate at any time point of the follow-up, suggesting that PAP can be safely used in such patients.

Improvement of bleomycin-induced pulmonary hypertension and pulmonary fibrosis by the endothelin receptor antagonist Bosentan.

RATIONALE: There is evidence that endothelin plays a key role in the development of pulmonary hypertension (PH) in pulmonary fibrosis (PF). However, the functional consequence of the unselective endothelin receptor antagonist Bosentan in PH and PF has not yet been studied. Therefore, we investigated the effects of Bosentan on the development of PH in the model of Bleomycin-induced PF in rats. METHODS: Adult male Wistar rats were randomly assigned to the following groups: untreated animals (controls), Bleomycin-induced PF (Bleomycin) and Bleomycin-induced PF treated with Bosentan (Bleomycin+Bosentan). Exercise capacity was evaluated by treadmill exercise testing. PH was assessed by right ventricular systolic pressure (RVSP) and right ventricular hypertrophy. For quantification of PF the hydroxyproline content in lung tissue (HPC) was measured. RESULTS: Compared to controls, animals with Bleomycin-induced PF showed a significant reduction in exercise capacity (44% vs. 100%), significantly higher RVSP (65 mmHg vs. 23 mmHg), significantly more right ventricular hypertrophy (0.55 vs. 0.24) and significantly higher HPC (60.5 vs. 14.8). Bosentan treatment in animals with Bleomycin-induced PF resulted in significantly greater exercise capacity (98% vs. 44%) and a trend towards lower RVSP (52 mmHg vs. 65 mmHg), significantly less right ventricular hypertrophy (0.34 vs. 0.55) and significantly lower HPC (16.7 vs. 60.5) compared to untreated Bleomycin-induced PF. CONCLUSION: Application of Bosentan in Bleomycin rats resulted in significantly higher exercise capacity as a result of improvements in PH and PF.

Time course of continuous positive airway pressure effects on central sleep apnoea in patients with chronic heart failure.

Continuous positive airway pressure (CPAP) causes a variable immediate reduction in the frequency of central apnoeas and hypopnoeas in patients with congestive heart failure (CHF) and central sleep apnoea (CSA), but has beneficial mid-term effects on factors known to destabilize the ventilatory control system. We, therefore, tested whether CPAP therapy leads, in addition to its short-term effects on CSA, to a significant further alleviation of CSA after 12 weeks of treatment on the same CPAP level in such patients. CPAP therapy was initiated in 10 CHF patients with CSA. During the first night on CPAP, the pressure was stepwise increased to a target pressure of 8-12 cmH(2)O or the highest level the patients tolerated (<12 cmH(2)O). Throughout the second night (baseline CPAP), the achieved CPAP of the first night was applied. After 12 weeks of CPAP treatment, we performed a follow-up polysomnography (12 weeks CPAP) on the same CPAP level (8.6 +/- 1.1 cmH(2)0). We found a significant reduction of the apnoea-hypopnoea index (AHI) between the diagnostic polysomnography and baseline CPAP night (41.8 +/- 19.2 versus 22.2 +/- 12.6 events per hour; P = 0.005). The AHI further significantly decreased between the baseline CPAP night and the 12 weeks CPAP night on the same CPAP level (22.2 +/- 12.6 versus 12.8 +/- 11.0 events per hour; P = 0.028). We conclude that, in addition to its immediate effects, CPAP therapy leads to a time-dependent alleviation of CSA in some CHF patients, indicating that in such patients neither clinical nor scientific decisions should be based on a short-term trial of CPAP.

Predictive significance of the six-minute walk distance for long-term survival in chronic hypercapnic respiratory failure.

BACKGROUND: The 6-min walk distance (6-MWD) is a global marker of functional capacity and prognosis in chronic obstructive pulmonary disease (COPD), but less explored in other chronic respiratory diseases. OBJECTIVE: To study the role of 6-MWD in chronic hypercapnic respiratory failure (CHRF). METHODS: In 424 stable patients with CHRF and non-invasive ventilation (NIV) comprising COPD (n = 197), restrictive diseases (RD; n = 112) and obesity-hypoventilation-syndrome (OHS; n = 115), the prognostic value of 6-MWD for long-term survival was assessed in relation to that of body mass index (BMI), lung function, respiratory muscle function and laboratory parameters. RESULTS: 6-MWD was reduced in patients with COPD (median 280 m; quartiles 204/350 m) and RD (290 m; 204/362 m) compared to OHS (360 m; 275/440 m; p < 0.001 each). Overall mortality during 24.9 (13.1/40.5) months was 22.9%. In the 424 patients with CHRF, 6-MWD independently predicted mortality in addition to BMI, leukocytes and forced expiratory volume in 1 s (p < 0.05 each). In COPD, 6-MWD was strongly associated with mortality using the median [p < 0.001, hazard ratio (HR) = 3.75, 95% confidence interval (CI): 2.24-6.38] or quartiles as cutoff levels. In contrast, 6-MWD was only significantly associated with impaired survival in RD patients when it was reduced to 204 m or less (1st quartile; p = 0.003, HR = 3.31, 95% CI: 1.73-14.10), while in OHS 6-MWD had not any prognostic value. CONCLUSIONS: In patients with CHRF and NIV, 6-MWD was predictive for long-term survival particularly in COPD. In RD only severely reduced 6-MWD predicted mortality, while in OHS 6-MWD was relatively high and had no prognostic value. These results support a disease-specific use of 6-MWD in the routine assessment of patients with CHRF.

Effects of dynamic bilevel positive airway pressure support on central sleep apnea in men with heart failure.

BACKGROUND: Treatment with continuous positive airway pressure (CPAP) improves cardiac function in chronic heart failure (CHF) patients with central sleep apnea (CSA)-Cheyne-Stokes respiration (CSR) by stabilizing ventilation, but frequently central apneas and hypopneas persist. Our objective was to test the hypothesis that flow-targeted dynamic bilevel positive airway pressure (BPAP) support (BiPAP autoSV; Respironics; Murrysville, PA) effectively suppresses CSR-CSA in CHF patients. METHODS: We studied 14 CHF patients with CSR-CSA (and residual CSA on positive airway pressure therapy) during 3 consecutive nights: (1) diagnostic polysomnography, (2) CPAP (n=10) or BPAP (n=4) titration, and (3) dynamic flow-targeted dynamic BPAP support with an expiratory positive airway pressure (EPAP) set to suppress obstructive respiratory events, and an inspiratory positive airway pressure (IPAP) dynamically ranging between 0 and 15 cm H2O above the EPAP. RESULTS: CPAP or BPAP significantly reduced the apnea-hypopnea index (AHI) [mean+/-SD, 46+/-4 events/h to 22+/-4 events/h; p=0.001] compared to the first night without treatment. Flow-targeted dynamic BPAP support (mean EPAP, 6.5+/-1.7 cm H2O; maximal IPAP, 21.9+/-2.1 cm H2O) further reduced the AHI to 4+/-1/h of sleep compared to the untreated (p<0.001) and CPAP or BPAP night (p=0.002). After the first night of flow-targeted dynamic BPAP support, patients rated on an analog scale (range, 0 to 10) the treatment as comfortable (6.9+/-0.6), and the sleep quality as improved compared to previous nights (7.4+/-0.6). CONCLUSION: Flow-targeted dynamic BPAP support effectively suppresses CSR-CSA in patients with CHF and is well tolerated.

Activation of bronchial epithelial cells in smokers without airway obstruction and patients with COPD.

STUDY OBJECTIVE: The aim of this study was to investigate the basal level as well as the tumor necrosis factor (TNF)-alpha- and interferon (IFN)-gamma-induced expression and release of the neutrophil chemoattractants interleukin (IL)-8 and growth-related oncogene (GRO)-alpha in primary bronchial epithelial cells (PBECs) from smokers without airflow obstruction and patients with COPD. In addition, the expression of both TNF-alpha-receptor subtypes--p55 TNF-receptor subtype (TNF-R55) and p75 TNF-receptor subtype (TNF-R75)--was quantified in PBECs. DESIGN: PBECs from eight smokers without airflow limitation and eight patients with COPD were stimulated with 50 ng/mL of TNF and 200 U/mL of IFN-gamma for 4 h along with unstimulated time controls. The transcriptional expression and protein release were quantitatively assessed by means of real-time polymerase chain reaction and enzyme-linked immunosorbent assay. RESULTS: Basal level messenger RNA (mRNA) expression and protein release of IL-8 and GRO-alpha were not significantly different between both groups, although a trend toward higher IL-8 levels was seen in patients with COPD. TNF-alpha induced significantly higher mRNA amounts of IL-8 (p = 0.005) and GRO-alpha (p = 0.007) in patients with COPD. This was accompanied by higher protein release data for IL-8 (p = 0.005) and GRO-alpha (p = 0.007). IFN-gamma had no significant effect on the mRNA expression and protein release of IL-8 and GRO-alpha in either group. TNF-R55 and TNF-R75 were detectable in PBECs. However, no significant differences were found between both groups with respect to steady-state mRNA levels of TNF-alpha-receptor subtypes. CONCLUSION: PBECs from patients with COPD show significantly higher TNF-alpha-induced release of the neutrophil chemoattractant CXC-chemokines IL-8 and GRO-alpha compared to smokers without airflow limitation. This increased activation of PBECs may contribute to the predominance of neutrophils seen in the airway lumen of patients with COPD.