Marc Decramer

Physiological basis of improvement after lung volume reduction surgery for severe emphysema : where are we?

Lung volume reduction surgery has become an accepted therapeutic option to relieve the symptoms of selected patients with severe emphysema. In a majority of these patients, it causes objective as well as subjective functional improvement. A proper understanding of the physiological determinants underlying these beneficial effects appears very important in order to better select patients for the procedure that is currently largely carried out on an empirical basis. Lung volume reduction surgery has two distinct effects. Firstly, it causes an increased elastic recoil, which at least partially explains the enhanced maximal expiratory flow. Secondly, it is associated with a reduction of hyperinflation which allows for an increase in global inspiratory muscle strength and in diaphragmatic contribution to tidal volume as well as a decrease in the inspiratory elastic load imposed by the chest wall. Taken together, these effects result in a reduced work of breathing and in an enhanced maximal ventilation which both contribute to the increased exercise capacity and reduced dyspnoea after surgery. The improved lung recoil and the reduced hyperinflation after volume reduction surgery were the primary postulates upon which the usual selection criteria for the procedure were based. It is now likely that these are correct. Nevertheless, some patients do not benefit from lung volume reduction surgery and the current literature does not allow for a refinement of the selection process from a physiological point of view. The exact mechanisms underlying the improvement in lung recoil, lung mechanics, and respiratory muscle function remain incompletely understood. Moreover, the effects of lung volume reduction surgery on gas exchange and pulmonary haemodynamics still need to be more fully investigated. An analysis of the characteristics of patients who do not benefit from the procedure and the development of an animal model for lung volume reduction surgery would probably help address these important issues.

The TERT-CLPTM1L locus for lung cancer predisposes to bronchial obstruction and emphysema

Clinical studies suggest that bronchial obstruction and emphysema increase susceptibility to lung cancer. We assessed the possibility of a common genetic origin and investigated whether the lung cancer susceptibility locus on chromosome 5p15.33 increases the risk for bronchial obstruction and emphysema. Three variants in the 5p15.33 locus encompassing the TERT and CLPTM1L genes were genotyped in 777 heavy smokers and 212 lung cancer patients. Participants underwent pulmonary function tests and computed tomography of the chest, and completed questionnaires assessing smoking behaviour. The rs31489 C-allele correlated with reduced forced expiratory volume in 1 s (p=0.006). Homozygous carriers of the rs31489 C-allele exhibited increased susceptibility to bronchial obstruction (OR 1.82, 95% CI 1.24–2.69; p=0.002). A similar association was observed for diffusing capacity of the lung for carbon monoxide (p=0.004). Consistent with this, CC-carriers had an increased risk of emphysema (OR 2.04, 95% CI 1.41–2.94; p=1.73×10−4) and displayed greater alveolar destruction. Finally, CC-carriers also had an increased risk for lung cancer (OR 1.90, 95% CI 1.21–2.99; p=0.005), and were more susceptible to developing both lung cancer and bronchial obstruction than lung cancer alone (OR 2.11, 95% CI 1.04–4.26; p=0.038). The rs31489 variant on 5p15.33 is associated with bronchial obstruction, presence and severity of emphysema, and lung cancer.

Different effects of corticosteroid-induced muscle wasting compared with undernutrition on rat diaphragm energy metabolism

Abstract An important adverse effect of corticosteroid treatment is respiratory muscle weakness with diaphragm muscle wasting, but little is known about the underlying pathophysiological processes involved. In order to differentiate between the effects of nutrition depletion and corticosteroids on diaphragm muscle metabolism, a study was performed to investigate the effects of triamcinolone (TR) for 2 weeks and of chronic undernutrition in a pair-weight (PW) group on the structure and energy metabolism of the diaphragm in male Wistar rats compared with a free-fed (FF) group. Diaphragm mass was reduced in TR and PW rats to a similar degree, but the extent of type-IIx/b atrophy was more pronounced in TR rats than in PW rats. No myopathic features were observed after either treatment. ATP in absolute terms as well as the ATP/ADP ratio, total adenine nucleotides, the phosphocreatine (PCr) level and the ratio between PCr and creatine (PCr/Cr) were decreased in the diaphragm of both TR and PW rats. In contrast to the PW group, the total Cr pool was reduced and pyruvate and lactate levels were elevated in the diaphragm of the TR group compared with the FF group. In conclusion, the results of this study indicate that severe undernutrition causes a decrease in muscle energy status resulting in a new metabolic equilibrium, while chronic low-dose TR treatment (0.25 mg/kg per day i.m.) causes a decrease in muscle energy status together with a mismatch between glycolysis and oxidative metabolism.

Influence of hypercapnia on rabbit intrapulmonary neuroepithelial bodies: microfluorimetric and morphometric study

The present investigation was undertaken to investigate the influence of hypercapnia on intrapulmonary neuroepithelial bodies (NEB). Rabbits were mechanically ventilated with a hypercapnic gas mixture (7% carbon dioxide, 20% oxygen, 73% nitrogen). Lung samples were examined by a microspectrographical analysis of the NEB formaldehyde-induced fluorescence to quantify the cytoplasmic 5-hydroxy-tryptamine (5HT) content and by electron microscopy to determine morphometrically the extent of the secretory exocytosis at the basal poles of the NEB epithelial cells. In contrast to our earlier studies on the effects of hypoxia and/or vagal stimulation, hypercapnia did not alter significantly the NEB cytoplasmic fluorescence nor did it affect the corpuscular epithelial exocytosis. NEB appear not to be influenced by hypercapnia to discharge their contents of 5HT and peptides. This investigation appears to support a high selectivity of the intrapulmonary NEB to local hypoxia and changes in vagal efferent output.

Pressure support ventilation attenuates ventilator-induced protein modifications in the diaphragm.

Common medical conditions that require mechanical ventilation include chronic obstructive lung disease, acute lung injury, sepsis, heart failure, drug overdose, neuromuscular disorders, and surgery. Although mechanical ventilation can be a life saving measure, prolonged mechanical ventilation can also present clinical problems. Indeed, numerous well-controlled animal studies have demonstrated that prolonged mechanical ventilation results in diaphragmatic weakness due to both atrophy and contractile dysfunction. Importantly, a recent clinical investigation has confirmed that prolonged mechanical ventilation results in atrophy of the human diaphragm. This mechanical ventilation-induced diaphragmatic weakness is important because the most frequent cause of weaning difficulty is respiratory muscle failure due to inspiratory muscle weakness and/or a decline in inspiratory muscle endurance. Therefore, developing methods to protect against mechanical ventilation-induced diaphragmatic weakness is important.

Guidelines for Physiotherapeutic Management in Chronic Obstructive Pulmonary Disease (COPD)

Abstract A national practice guideline (NPG) for physiotherapy management of patients with chronic obstructive pulmonary disease (COPD) has been developed. This guideline aims to decrease the variation in practice patterns and to increase the efficiency of treatment, thereby increasing the quality of care in this group of patients. The NPG was systematically developed and drafted by clinical experts in the field of COPD. Systematic reviews of the literature were used to assess the efficacy of physiotherapy interventions in COPD. The appropriate interventions were then incorporated in the NPG. Where no evidence-based strategies were found, consensus among the expert group was used. The NPG was approved by the Royal Dutch Physical Therapy Association after being tested in practice. Diagnostic and therapeutic modalities for effective management of patients with COPD are described in the guideline. To improve the quality of care in patients with COPD, the use of this NPG is recommended.

Using dynamics of forced expiration to identify COPD where conventional criteria for the FEV₁ /FVC ratio do not match.

The definition of chronic obstructive pulmonary disease (COPD) based on a fixed forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio or on the lower limits of FEV1/FVC of a healthy reference population is the subject of continuous debate. We explored whether dynamics of forced expiratory flow decline on spirometry can identify subjects with and without COPD when the two key diagnostic criteria are discordant.

Alterations in gene expression in hamster diaphragm after emphysema and lung volume reduction surgery

The authors have demonstrated previously that emphysema and lung volume reduction surgery (LVRS) resulted in a significant shift of type IIx/b to type IIa fibres in the diaphragm of hamsters with elastase-induced emphysema. To explore the mechanisms leading to this fibre switching, the mRNA expression of the myogenic regulatory factors, the inhibitors of DNA binding proteins (Id-proteins) and insulin-like growth factor-I were examined. Ribonucleic acid was extracted from the diaphragm of control, emphysematous, emphysematous and sham operated and LVRS hamsters and subjected to reverse transcriptase polymerase chain reaction. Compared to control, the ratio MyoD to myogenin declined with emphysema, sham and even more after LVRS, due to a decrease in MyoD mRNA and an increase in myogenin mRNA. Similarly, compared to control, Id-1 protein mRNA levels decreased significantly in sham and even more in LVRS. Id-2 protein mRNA levels decreased in all groups, but reached statistical significance in LVRS only, compared to control. In conclusion: 1) the reduced MyoD/myogenin ratio may be the mechanism of the shift to a slower fibre type, 2) the decreased MyoD/myogenin ratio in lung volume reduction surgery animals suggests that lung volume reduction surgery enhances rather than decreases the load placed on the diaphragm and 3) the observed down-regulation of the inhibiting factors may facilitate the diaphragm adaptation to overload.

Effects of lung volume reduction surgery in hamsters with elastase-induced emphysema.

Lung volume reduction surgery (LVRS) has been shown to improve respiratory mechanics in selected patients with severe emphysema. This is thought to be due to an improvement in lung elastic recoil. This study was aimed at gaining further understanding about the effects of LVRS on respiratory mechanics and airway function. Control hamsters instilled with saline (Ctrl; n=8) were compared with emphysematous animals that underwent either a sham operation (Sham; n=7) or an LVRS (LVRS; n=7). As expected, there was a significant increase in the static lung volumes in the Sham as compared to the Ctrl group and a significant decrease of these volumes in LVRS as compared to the Sham group. Surprisingly, emphysema was associated with a significant increase and LVRS with a significant decrease in vital capacity. Despite a tendency toward an increase in lung compliance as compared to Sham, indices of maximal expiratory flows tended to decrease with LVRS. As opposed to humans, there was no change in the distribution of airway diameters in Sham compared to Ctrl. These findings appear to be largely explained by the high compliance of the hamster chest wall. This allows for better matching between the emphysematous lung and the chest-wall sizes than in humans.