Selection Bias in Thrombolytie Trials

We appreciate the keen interest of Broka et al. in our work on the hemodynamic effects of oxygen. They raised two concerns. The first relates to the importance and mechanism of our observation demonstrating a diminished cardiac output in response to supplemental oxygen. The second relates to the calculated oxygen consumption values in our study and the fact that oxygen consumption decreased as supplemental oxygen was added. With regard to the first concern, the majority of subjects did not become symptomatic as we gave supplemental oxygen. However, one subject became short of breath and diaphoretic in response to this intervention. Another subject who was studied after completing this project also became diaphoretic as oxygen was delivered. We did not include these data in the original report because we did not systematically examine symptoms and considered these data to be too anecdotal. However, as we emphasized in our report, pulmonary capillary wedge pressure increased, confirming the finding that oxygen had a detrimental hemodynamic effect. We agree that measurements of plasma lactate would have been useful. Unfortunately, at the time of these studies, we did not think of performing these measurements. What is the mechanism for the decrease in cardiac output? We would expect a change in cardiac output to be associated with either a change in loading conditions or a change in inotropy. As mentioned above, pulmonary capillary wedge pressure increased in response to oxygen, providing evidence that preload increased. This would suggest that cardiac output diminished at a time when Starling forces would dictate that cardiac output should increase. Therefore, one could only conclude that there must be a change in either inotropy or systemic resistance. Although we did not measure inotropy directly, a decrease in inotropy is typically accompanied by evidence of reflex sympathoexcitation. We found no changes in heart rate or peroneal nerve muscle sympathetic nervous system activity. Thus, we would surmise that inotropy did not decrease. We did calculate system vascular resistance and found it to increase fairly dramatically. Therefore, our data support the contention that oxygen acted as a direct vasoconstrictor, thereby increasing peripheral vascular resistance. We have further pursued the issue of changes in systemic resistance in our experiments in patients with a left ventricular assist device. We have performed studies in six such patients and found a consistent relation between increased systemic resistance and the administration of oxygen (unpublished observations). Further, in normal subjects, we have performed experiments on forearm blood flow in response to 10 min of forearm ischemia. We have observed that peak vasodilation is reduced with the administration of supplemental oxygen (1). The exact mechanism for this change in systemic resistance is currently unknown, In terms of the insightful discussion on oxygen delivery of Broca et al., we completely agree that the change in calculated oxygen consumption in our data would bring into question the dependency of oxygen consumption on oxygen delivery. Ideally, one would measure oxygen consumption during such experiments. Measuring oxygen consumption during oxygen delivery is fraught with a number of inaccuracies and, accordingly, we did not pursue these measurements. The work cited in their letter was performed in anesthetized patients with coronary disease (2). These subjects differed considerably from those in our study in that they were anesthetized, and there is no comment on the presence or absence of congestive heart failure. These are important considerations because spontaneous ventilation in the presence of increased filling pressures would substantially increase the work of breathing and total oxygen consumption. This could substantially alter the relation between oxygen consumption and oxygen delivery so aptly described in your letter. With regard to the estimated oxygen consumption values in the letter of Broca et al., there were some assumptions made that would overestimate the calculated oxygen delivery. In reviewing the data in experiment 2, we found that oxygen delivery ranged from 333 ml/min on room air to 270 ml/min with 100% oxygen. Accordingly, we were in the previously described range where there is a dependency of oxygen consumption on oxygen delivery. Additionally, from the data that Broca et al. referenced, one would predict a 21% decrease in oxygen consumption. Based on our patients, a 29% change was observed. As mentioned above, because the patient groups and clinical conditions are different, it would be inappropriate to directly apply the previous data to our patients. In conclusion, our work dealt primarily with the hemodynamic effects of supplemental oxygen in conscious humans with severe heart failure. We agree with Broca et al. that other "clinical" measures during oxygen administration in patients with heart failure are warranted.