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The authors investigated the effect of manual hyperinflation (MHI) with set parameters applied to patients on mechanical ventilation on hemodynamics, respiratory mechanics, and gas exchange. Sixteen critically ill patients post-septic shock, with acute lung injury, were studied. Heart rate, arterial pressure, and mean pulmonary artery pressure were recorded every minute. Pulmonary artery occlusion pressure, cardiac output, arterial blood gases, and dynamic compliance (Cdyn) were recorded pre-and post-MHI. From this, systemic vascular resistance index (SVRI), cardiac index, oxygen delivery, and partial pressure of oxygen:fraction of inspired oxygen (PaO2:FiO2) ratio were calculated. There were significant increases in SVRI (P < 0.05) post-MHI and diastolic arterial pressure (P < 0.01) during MHI. Cdyn increased post-MHI (P < 0.01) and was sustained at 20 minutes post-MHI (P < 0.01). Subjects with an intrapulmonary cause of lung disease had a significant decrease (P = 0.02) in PaO2:FiO2, and those with extrapulmonary causes of lung disease had a significant increase (P < 0.001) in PaO2:FiO2 post-MHI. In critically ill patients, MHI resulted in an improvement in lung mechanics and an improvement in gas exchange in patients with lung disease due to extrapulmonary events and did not result in impairment of the cardiovascular system.