A prospective evaluation of the prevalence of CO2 retention and its relationship to lung mechanics and inspiratory muscle strength was carried out in 311 clinically stable patients with chronic obstructive pulmonary disease (COPD). Of these patients 32.8% had hypercapnia (PaCO2 greater than or equal to 43 mm Hg). PaCO2 was directly related to lung resistance (RL; r = 0.53) and inversely related to FEV1 (r = 0.53) and to an expression of the dead space/tidal volume ratio (1 - VD/VT) (r = 0.48). RL was found to be a major determinant of the mean intrathoracic pressure swing developed during inspiration (PI) at rest (r = 0.85). Maximal inspiratory pressure (PImax) was found to improve the predictive value for PaCO2 of several mechanical loads, with RL/PImax the best predictor (r = 0.57). The prevalence of hypercapnia increased from virtually 0 to 100% with increases in the RL/PImax value and was higher in the obese subjects at intermediate RL/PImax values, probably because of the burden placed on the respiratory muscles by chest wall mass loading. Our results show that chronic alveolar hypoventilation is likely to develop in COPD patients who have a combination of high inspiratory loads and inspiratory muscle weakness. hypercapnia may be one strategy available to avoid overloading of the inspiratory muscles leading to fatigue and possible irreversible failure.
PMID: 2024841 DOI: 10.1164/ajrccm/143.5_Pt_1.905

Pulmonary emphysema impairs lung and respiratory muscle function leading to restricted physical capacity and accelerated morbidity and mortality consequent to respiratory muscle failure. In the absence of direct evidence, an O2 supply-demand imbalance within the diaphragm and other respiratory muscles in emphysema has been considered the most likely explanation for this failure. To test this hypothesis, we utilized phosphorescence quenching techniques to measure mean microvascular PO2 (PO2m) within the medial costal diaphragm of control (C, n = 10) and emphysematous (E, elastase instilled, n = 7) hamsters. PO2m and mean arterial pressure (MAP) were measured in the spontaneously breathing anesthetized hamster at inspired O2 percentages of 10, 21, and 100, and across a range of mean MAPs from 40 to 115 mm Hg. At each inspired O2, diaphragm PO2m was significantly (p < 0.05) lower in E animals (10%: C, 19 +/- 3; E, 9 +/- 2; 21%: C, 32 +/- 2; E, 21 +/- 2; 100%: C, 60 +/- 8; E, 36 +/- 9 mm Hg). At 21% inspired O2, the PO2m decrease was correlated with reduced MAP in both C (r = 0.968) and E (r = 0.976) animals. We conclude that diaphragmatic PO2m (and therefore microvascular O2 content) is decreased in emphysematous hamsters reflecting a greater diaphragmatic O2 utilization at rest and a lower O2 extraction reserve. According to Fick's law, this lower PO2m will mandate an exaggerated fall in intramyocyte PO2, which is expected to accelerate muscle glycogen depletion and consequently fatigue. This provides empirical evidence in support of one possible mechanism for respiratory muscle failure in emphysema.
PMID: 11316639 DOI: 10.1164/ajrccm.163.5.2008065

The validity of peak inspiratory mouth pressure (P.PI-max) as a measure of inspiratory muscle strength was investigated by comparing it with sniff Pes in patients with COPD with respect to (1) learning effect, (2) reproducibility, and (3) measures of agreement. To assess the discriminating capacity of P.PImax, we compared the values in patients with COPD with those of healthy elderly subjects. Thirty-four patients (mean age, 62.5 years) with severe airways obstruction (FEV1, 44% predicted; FEV1/IVC, 37% predicted) and 149 healthy subjects (age > or = 55 years) were included. P.PImax was assessed during a maximal static inspiratory maneuver, while sniff Pes was assessed during a maximal sniff maneuver. Both maneuvers were performed from residual volume ten times on the same day. P.PImax showed no learning effect, while the sniff maneuver used seven attempts to obtain a maximal value. The intraindividual coefficients of variation of P.PImax and sniff Pes were 11.2% and 6.0%, respectively. Measures of agreement showed no significant discrepancies between the mean P.PImax and mean sniff Pes (0.29 kPa, p = 0.49). There was a significant correlation (r = 0.57, p < 0.001) between both measurements. P.PImax was significantly (p < 0.001) lower in both male (8.2 kPa) and female (6.2 kPa) patients with COPD compared with healthy men (11.0 kPa) and healthy women (8.8 kPa). We conclude that P.PImax is a valid and noninvasive assessment of inspiratory muscle strength.
PMID: 7874932 DOI: 10.1378/chest.107.3.652

Inspiratory muscle weakness in patients with COPD is of major clinical relevance. For instance, maximum inspiratory pressure generation is an independent determinant of survival in severe COPD. Traditionally, inspiratory muscle weakness has been ascribed to hyperinflation-induced diaphragm shortening. However, more recently, invasive evaluation of diaphragm contractile function, structure, and biochemistry demonstrated that cellular and molecular alterations occur, of which several can be considered pathologic of nature. Whereas the fiber type shift towards oxidative type I fibers in COPD diaphragm is regarded beneficial, rendering the overloaded diaphragm more resistant to fatigue, the reduction of diaphragm fiber force generation in vitro likely contributes to diaphragm weakness. The reduced diaphragm force generation at single fiber level is associated with loss of myosin content in these fibers. Moreover, the diaphragm in COPD is exposed to oxidative stress and sarcomeric injury. This review postulates that the oxidative stress and sarcomeric injury activate proteolytic machinery, leading to contractile protein wasting and, consequently, loss of force generating capacity of diaphragm fibers in patients with COPD. Interestingly, several of these presumed pathologic alterations are already present early in the course of the disease (GOLD I/II), although these patients appear not limited in their daily life activities. Treatment of diaphragm dysfunction in COPD is complex since its etiology is unclear, but recent findings indicate the ubiquitin-proteasome pathway as a prime target to attenuate diaphragm wasting in COPD.
PMCID: PMC2248576 PMID: 18218129

Inspiratory muscle weakness in patients with chronic obstructive pulmonary disease (COPD) is of major clinical relevance; maximum inspiratory pressure generation is an independent determinant of survival in severe COPD. Traditionally, inspiratory muscle weakness has been ascribed to hyperinflation-induced diaphragm shortening. However, more recently, invasive evaluation of diaphragm contractile function, structure, and biochemistry demonstrated that cellular and molecular alterations occur, of which several can be considered of pathologic nature. Although the fiber-type shift toward oxidative type I fibers in COPD diaphragm is regarded as beneficial, rendering the overloaded diaphragm more resistant to fatigue, the reduction of diaphragm fiber force generation in vitro likely contributes to diaphragm weakness. The reduced diaphragm force generation at single-fiber level is associated with loss of myosin content. Moreover, the diaphragm in COPD is exposed to oxidative stress and sarcomeric injury. The current Pulmonary Perspective postulates that the oxidative stress and sarcomeric injury activate proteolytic machinery, leading to contractile protein wasting and, consequently, loss of force-generating capacity of diaphragm fibers in patients with COPD. Interestingly, several of these presumed pathologic alterations are already present early in the course of the disease (GOLD I/II), although these patients do not appear to be limited in their daily-life activities. Therefore, investigating in vivo diaphragm function in mild to moderate COPD should be the focus of future research. Treatment of diaphragm dysfunction in COPD is complex because its etiology is unclear, but recent findings show promise for the use of proteasome inhibitors in syndromes associated with muscle wasting, such as the diaphragm in COPD.
PMID: 17413128 DOI: 10.1164/rccm.200701-020PP