Any method of determining the volume of the cardiac output in man which requires intelligent, alert and active cooperation by the subject can scarcely be regarded as suited to the study of this most important aspect of cardiac function in the clinic. Errors are sure to arise from ignorance, lack of training, excitement, apprehension, etc., of such magnitude as to render results worthless. When the ethyl iodide method of Henderson and Haggard (1) was devised, in which the sole requirement of the subject is that he breathe through a mouthpiece, it appeared that a long step had been taken toward the attainment of quantitative information concerning the heart's output under the various circumstances of disease. Impressed by these possibilities Starr and Gamble, at the suggestion of Professor A. N. Richards and with generous assistance from Professor Henderson, learned to use the method and began the study of normal subjects in order to accumulate the experience and the data requisite for its profitable application to patients. Unfortunately discrepancies were soon encountered between their experiences and those which Henderson and Haggard had published.It was soon evident that, by means of the analytical method of Henderson and Haggard, known concentrations of ethyl iodide could not be estimated with satisfactory accuracy. It was therefore necessary to devise new methods which met this requirement (2). Employing these methods Starr and Gamble were unable to verify certain of the conceptions on which the original method was based, namely the absence of ethyl iodide from blood returning to the lungs, and the size of the distribution coefficient for ethyl iodide between air and blood (3). They were therefore confronted with the question of abandoning the project altogether or of so altering the plan of the method that it should yield results in which they could have confidence. The latter alternative was chosen, the distribution coefficient was redetermined and the method was redesigned so that the relatively large amount of ethyl iodide in venous blood could be estimated at each determination of cardiac output. By means of this new method it was found possible to make satisfactory estimations of the flow of blood perfused through the lungs of dogs at a known rate 13

In a previous communication the results of duplicate estimations of cardiac output on 50 persons, the majority hospital patients in the basal condition, have been ret)orted (1). The opportunity to extend this investigation rapidly was provided by the development, by Donal and Gamble, of a physical method for the estimation of ethyl iodide by means of its thermal conductivity in a katharometer (2). This improvement so increased the rapidity with which the cardiac output could be estimated, that about two hundred hospital cases, four hundred estimations of cardiac output, were added to the series with the expenditure of less time and effort than had been required to secure the results in the first fifty cases by the chemical technique. When the new series was combined with the old, over 200 cases were secured in which satisfactory estimations of basal cardiac output, metabolism, blood pressure, and pulse rate, had been made on resting patients 15 or more hours after the last meal; and in which orthodiagrams had been secured also. The analysis of these results forms the subject of this paper.As soon as results, secured by any cardiac output method, are examined a difficulty appears which can best be set forth by an example. The average cardiac output of 31 healthy persons is 2.9 liters per minute per 100 pounds, that of 8 cases of anemia 3.2 liters; should the difference be considered significant or not? An estimation of the validity of differences is based on knowledge of the relative accuracy of the methods involved. One may try to ascertain the accuracy of a cardiac output method, when applied to man, by the agreement of duplicate estimations, and by comparison of the results with those obtained by other methods, preferably based on different physiological principles. But it should be emphasized that cardiac output procedures have not attained the position of those methods the accuracy of which can be tested by estimation of known quantities. Therefore, we have fallen back on another way of approaching the problem and have estimated the significance of our differences by statistical procedures. 561

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