Cardiorespiratory system responses in the critically ill patient were studied with the use of a computer-based simulation which duplicated the major interrelationships between pulmonary ventilation and perfusion, gas transport in blood, and the peripheral metabolism of oxygen, carbon dioxide, and metabolic acid. This simulation produced response patterns reflecting the interactions of the cardiopulmonary system. It was able to generate data compatible with those obtained clinically and to determine the observability of different patterns of respiratory insufficiency from external measurements. A detailed evaluation was carried out examining the coupling between decreases in functional residual capacity, and in pulmonary compliance, and increased resistance, and the increase in pulmonary venoarterial admixture in posttraumatic respiratory insufficiency. By comparing the simulation output with real patient data this technique was also used to study the possible mechanisms resulting in the transition from a metabolically unbalanced septic state to a decompensated septic state in which evidence of pulmonary insufficiency occurs. The results suggest that this transition is most compatible with the major effect being due to ateletasis, rather than multiple septic microemboli, or the production of acute interstitial edema. Potentially these techniques may provide a means of evaluating the nature of pathophysiologic processes in human disease from a reduced set of measurements, and may also provide the possibility of a prospective simulation as a means of evaluation of therapy prior to clinical application. © 1973.