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We previously showed that severe inspiratory resistive loads cause acute (<1 h) cardiorespiratory failure characterized by arterial hypotension, multifocal myocardial infarcts, and diaphragmatic fatigue. The mechanisms responsible for cardiovascular failure are unknown, but one factor may be the increased ventricular afterload caused by the large negative intrathoracic pressures generated when breathing against an inspiratory load. Because expiratory threshold loads increase intrathoracic pressure and decrease left ventricular afterload, we hypothesized that anesthetized rats forced to breathe against such a load would experience only diaphragmatic failure. Loading approximately doubled end-expiratory lung volume, halved respiratory frequency, and caused arterial hypoxemia and hypercapnia, respiratory acidosis, and increased inspiratory drive. Although hyperinflation immediately reduced the diaphragm's mechanical advantage, fatigue did not occur until near load termination. Mean arterial pressure progressively fell, becoming significant (cardiovascular failure) midway through loading despite tachycardia. Loading was terminated (endurance 125 +/- 43 min; range 82-206 min) when mean arterial pressure dropped below 50 mmHg. Blood samples taken immediately after load termination revealed hypoglycemia, hyperkalemia, and cardiac troponin T, the last indicating myocardial injury that was, according to histology, mainly in the right ventricle. This damage probably reflects a combination of decreased O(2) delivery (decreased venous return and arterial hypoxemia) and greater afterload due to hyperinflation-induced increase in pulmonary vascular resistance. Thus, in rats breathing at an increased end-expiratory lung volume, cardiorespiratory, not just respiratory, failure still occurred. Right heart injury and dysfunction may contribute to the increased morbidity and mortality associated with acute exacerbations of obstructive airway disease.

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Respiratory loads can cause respiratory pump failure but the underlying causes, often assumed to be asphyxia and inspiratory muscle fatigue, remain unresolved. In rat, we hypothesized that breathing at an increased end-expiratory lung volume would cause not just respiratory but cardiovascular failure. Rats breathed at an increased lung volume until inspiratory pressure generation decreased to half the loaded values (respiratory pump failure) or mean arterial pressure dropped below 60 mmHg (cardiovascular failure). Loading resulted in immediate arterial hypoxemia and hypercapnia, as well as a decrease in diaphragmatic contractility (ratio of transdiaphragmatic pressure to integrated phrenic activity). Contractility remained at this level during loading, despite arterial hypoxemia and hypercapnia/acidosis, until decreasing again at the time of respiratory pump failure. Respiratory drive was maintained and heart rate increased but blood pressure declined steadily. At termination of loading, cardiac troponin T was detected in the blood, indicating myocardial injury; moreover, the rats were hyperkalemic and hypoglycemic. Thus, in rats forced to breathe at an increased lung volume, cardiorespiratory, not just respiratory, failure occurs and factors other than fatigue, hypoxia and hypercapnia/ acidosis, such as hypoglycemia and hyperkalemia, may contribute. [ABSTRACT FROM AUTHOR]