Evidence is weak for the ability of long-term non-invasive positive pressure ventilation (NPPV) to improve survival in patients with stable hypercapnic chronic obstructive pulmonary disease (COPD). ...Previous prospective studies did not target a reduction in hypercapnia when adjusting ventilator settings. This study investigated the effect of long-term NPPV, targeted to markedly reduce hypercapnia, on survival in patients with advanced, stable hypercapnic COPD.
This investigator-initiated, prospective, multicentre, randomised, controlled clinical trial enrolled patients with stable GOLD stage IV COPD and a partial carbon dioxide pressure (PaCO2) of 7 kPa (51.9 mm Hg) or higher and pH higher than 7.35. NPPV was targeted to reduce baseline PaCO2 by at least 20% or to achieve PaCO2 values lower than 6.5 kPa (48.1 mm Hg). Patients were randomly assigned (in a 1:1 ratio) via a computer-generated randomisation sequence with a block size of four, to continue optimised standard treatment (control group) or to receive additional NPPV for at least 12 months (intervention group). The primary outcome was 1-year all-cause mortality. Analysis was by intention to treat. The intervention was unblinded, but outcome assessment was blinded to treatment assignment. This study is registered with ClinicalTrials.gov, number NCT00710541.
Patients were recruited from 36 respiratory units in Germany and Austria, starting on Oct 29, 2004, and terminated with a record of the vital status on July 31, 2011. 195 patients were randomly assigned to the NPPV group (n=102) or to the control group (n=93). All patients from the control group and the NPPV group were included in the primary analysis. 1-year mortality was 12% (12 of 102 patients) in the intervention group and 33% (31 of 93 patients) in the control group; hazard ratio 0.24 (95% CI 0.11-0.49; p=0.0004). 14 (14%) patients reported facial skin rash, which could be managed by changing the type of the mask. No other intervention-related adverse events were reported.
The addition of long-term NPPV to standard treatment improves survival of patients with hypercapnic, stable COPD when NPPV is targeted to greatly reduce hypercapnia.
German Lung Foundation; ResMed, Germany; Tyco Healthcare, Germany; and Weinmann, Germany.
Summary α1-Antitrypsin (AAT) is the archetype member of the serine protease inhibitor ( SERPIN ) supergene family. The AAT deficiency is most often associated with the Z mutation, which results in ...abnormal Z AAT folding in the endoplasmic reticulum of hepatocytes during biogenesis. This causes intra-cellular retention of the AAT protein rather than efficient secretion with consequent deficiency of circulating AAT. The reduced serum levels of AAT contribute to the development of chronic obstructive pulmonary disease (COPD) and the accumulation of abnormally folded AAT protein increases risk for liver diseases. In this review we show that with the discovery of AAT deficiency in the early 60s as a genetically determined predisposition to the development of early-onset emphysema, intensive investigations of enzymatic mechanisms that produce lung destruction in COPD were pursued. To date, the role of AAT in other than lung and liver diseases has not been extensively examined. Current findings provide new evidence that, in addition to protease inhibition, AAT expresses anti-inflammatory, immunomodulatory and antimicrobial properties, and highlight the importance of this protein in health and diseases. In this review co-occurrence of several diseases with AAT deficiency is discussed.
Advanced chronic obstructive pulmonary disease (COPD) might result in chronic hypercapnic ventilatory failure. Similar to neuromuscular and restrictive chest wall diseases, long-term non-invasive ...positive pressure ventilation (NPPV) is increasingly used in chronic hypercapnic COPD. This review describes the methods, patient selection, ventilatory strategies, and therapeutic effects of long-term Home-NPPV based on randomized controlled clinical trials published since 1985 in English language retrieved from the databases PubMed and Scopus. Long-term NPPV is feasible and effective in stable, non-exacerbated COPD patients with daytime hypercapnia with arterial pressure of carbon dioxide (PaCO2) levels ≥50 mm Hg (6.6 kPa), if the applied ventilatory pressures and application times improve baseline hypercapnia by at least 20%. Patients who survived an acute hypercapnic exacerbation might benefit from long-term NPPV if hypercapnia persists 2-4 weeks after resolution of the exacerbation. Pressure-controlled ventilation or pressure-support ventilation with adequate minimum backup breathing frequencies, in combination with nasal masks or oronasal masks have been successfully used in all larger clinical trials. Ventilatory strategies with mean inspiratory pressures of up to 28 cm H2O are well-tolerated by patients, but limitations exist in patients with impaired cardiac performance. Home-NPPV with a PaCO2-reductive approach might be considered as an additional treatment option in patients with stable chronic hypercapnic COPD.
Abstract Alpha-1 antitrypsin deficiency is an inherited disease affecting the lung and liver. The typical pulmonary manifestation is chronic obstructive pulmonary disease and emphysema. Severe ...chronic obstructive pulmonary disease may occur in young adulthood, and terminal respiratory insufficiency causes premature death in many patients. In the liver, alpha-1 antitrypsin deficiency may manifest as benign neonatal hepatitis syndrome; a small percentage of adults develop liver fibrosis, with progression to cirrhosis and hepatocellular carcinoma. The alpha-1 antitrypsin molecule is a serine protease inhibitor that is predominantly produced in the liver. Its most important physiologic functions are the protection of pulmonary tissue from aggressive proteolytic enzymes and regulation of pulmonary immune processes. Diagnosis of alpha-1 antitrypsin deficiency can be established by measurement of the serum alpha-1 antitrypsin concentration or by genetic analysis. Treatment is similar to the usual treatment for patients with chronic obstructive pulmonary disease. A further option is substitution therapy with human alpha-1 antitrypsin. The targets of treatment are the prevention of the accelerated decline of pulmonary function, reduction of lung infections, and improvements in exercise capacity.
Non-invasive ventilation (NIV) has been shown to improve survival and quality of life in COPD patients with chronic hypercapnic respiratory failure. However, the proportion of COPD patients with ...chronic hypercapnia is not yet known and clinical data enabling better identification of patients are scarce. The HOmeVent registry was initiated to determine the prevalence of chronic hypercapnia in COPD in an outpatient setting and to evaluate the predictors of hypercapnia.
HOmeVent is a multicenter, prospective, observational, non-interventional patient registry that includes COPD patients in GOLD stage 3 or 4. Eligible patients were identified and enrolled in an outpatient setting during routine clinic visits. Assessments included blood gas analyses, pulmonary function testing and quality of life assessment.
Ten outpatient clinics in Germany enrolled 231 COPD patients in the registry (135 in GOLD stage 3 (58%) and 96 in GOLD stage 4 (42%)). Arterial carbon dioxide pressure (PaCO
) was ≥45 mmHg in 58 patients (25%); of these, 20 (9%) had PaCO
≥50 mmHg. The prevalence of hypercapnia at both cut-off values was numerically higher for patients in GOLD stage 4 versus 3. An increased body mass index, a decreased forced vital capacity and an increased bicarbonate level were significant independent predictors of hypercapnia. The proportion of patients who received NIV was 6% overall and 22% of those with hypercapnia.
A relevant proportion of COPD patients in GOLD stage 3 and 4 exhibits chronic hypercapnia and might, therefore, be candidates for long-term domiciliary NIV treatment.
Not all hypercapnic COPD patients benefit from home noninvasive ventilation (NIV), and mechanisms through which NIV improves clinical outcomes remain uncertain. We aimed to identify "responders" to ...home NIV, denoted by a beneficial effect of NIV on arterial partial pressure of carbon dioxide (
), health-related quality of life (HRQoL) and survival, and investigated whether NIV achieves its beneficial effect through an improved
.
We used individual patient data from previous published trials collated for a systematic review. Linear mixed-effect models were conducted to compare the effect of NIV on
, HRQoL and survival, within subgroups defined by patient and treatment characteristics. Secondly, we conducted a causal mediation analysis to investigate whether the effect of NIV is mediated by a change in
.
Data of 1142 participants from 16 studies were used. Participants treated with lower pressure support (<14
≥14 cmH
O) and with lower adherence (<5
≥5 h·day
) had less improvement in
(mean difference (MD) -0.30 kPa, p<0.001 and -0.29 kPa, p<0.001, respectively) and HRQoL (standardised MD 0.10, p=0.002 and 0.11, p=0.02, respectively), but this effect did not persist to survival.
improved more in patients with severe dyspnoea (MD -0.30, p=0.02), and HRQoL improved only in participants with fewer than three exacerbations (standardised MD 0.52, p=0.03). The results of the mediation analysis showed that the effect on HRQoL is mediated partially (23%) by a change in
.
With greater pressure support and better daily NIV usage, a larger improvement in
and HRQoL is achieved. Importantly, we demonstrated that the beneficial effect of home NIV on HRQoL is only partially mediated through a reduction in diurnal
.
Abstract Patients with alpha-1-antitrypsin deficiency (AATD) and a PI-ZZ genotype are at high risk to develop severe emphysema during adulthood. However, little is known about early stages of ...emphysema and disease manifestation in other PI-types. Spirometry is commonly used for monitoring although early manifestation of emphysema is suspected within the peripheral airways that are not accessible by forced expiratory manoeuvres. We hypothesized that the Lung Clearance Index (LCI) derived from multiple breath nitrogen-washout (N2 -washout) is useful to bridge this diagnostic gap. Patients from age 4 years onward and different PI-types performed N2 -washout and spirometry. Results were compared to controls. 193 patients (4–79 years, 75% PI-ZZ) and 33 controls (8–60 years) were included. Mean (SD) LCI in patients was 9.1 (3.1) and 6.3 (0.6) in controls ( p =<0.001). 47% of adult patients with other than PI-ZZ genotypes and 39% of all patients with normal spirometry had abnormal LCIs. The LCI measured by N2 -washout discriminates between patients with AATD and controls, reflects AATD related lung disease in all stages and appears to identifiy early peripheral lung changes in younger age than spirometry. We conclude that a normal spirometry does not exclude presence of AATD related lung disease even in genotypes other than PI-ZZ.
Background: Alpha-1 antitrypsin deficiency (AATD) is one of the most prevalent inherited diseases in Whites, but identification of affected patients and establishment of the diagnosis is still ...unsatisfactory. This study assessed the latencies and numbers of physicians involved in identifying AATD patients, and the importance of smoking, vaccination status, and specific augmentation therapy on the course of the disease.
Method: Patients from Germany and Austria underwent a single written interview with 28 items. Five hundred and ninety-six patients were addressed and 44.9% replied.
Results: The age at symptom onset was 39.1±10.1 years, and the diagnosis was established at the age of 45.1±10.9 years. From the 6-year delay in establishing the diagnosis, 1.4±1.7 (range 0.5—10.5) years were due to patients’ reluctance to seek medical attention. There were 3.2±2.4 (range 1—13) physicians involved in establishing the diagnosis. Smoking was associated with an earlier onset of respiratory symptoms and lower exercise capacity. Vaccination against pneumococci and/or influenza, and augmentation therapy resulted in significantly fewer exacerbations and fewer emergency room visits. Airway infections and passive smoking during childhood were not found to influence the onset of respiratory symptoms.
Conclusions: In conclusion, there is still a large delay between symptom onset and AATD diagnosis. Smoking history, vaccination status, and augmentation therapy have an important impact on the course of the disease.
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