( : I - I A P T E R V I

A Critical View of the Anoxemia Test.

In every tolerance test the strain imposed on the patient should be chosen so that it creates a characteristic and objectively recordable reaction in as great a number of pathologic cases as possible. In normal cases it should not create a change that may be mistaken for a pathologic reaction. The method must be harm- less for the patient. I t is therefore necessary to dose tlie strain in order to avoid a too heavy stress on the examined organ which could be dangerous and in order to accomplish standardized conditions which is a pre-requisite for an accurate interpretation of the reaction. I n the cardiologic anoxemia test, the strain is represented by the induced decrease of tlie oxygen tension of the arterial blood. In order to be able to compare tlie results of two different tests, one must ensure that this decrease is of the same size in both cases. When deciding whether or not a person reacts "normally" one must know tlie degree of liypoxemia to which the person has been subjected. Then the recorded reaction should be compared with the same reaction in a number of clinically healthy persons subjected to the same degree of h ypoxemia.

Most investigators, however, have not controlled the resulting decrease of the arterial oxygen tension. Instead, they have con- sidered i t sufficient to keep an approximately constant oxygen tension in the inspired gas. This would be correct if a certain low oxygen tension in the inspired gas corresponded to an approx- imately constant valne of the alveolar and thereby the arterial oxygen tension. This has not been proven. On the contrary, the findings of several investigators support the view that the oxygen tension in the inspired gas is a poor index of the resulting arterial oxygen tension. For example, KROGH and HoHw~Y-CHRIS-

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TENSEN (1935) examined 50 healthy flyers by letting them rebreathe in a gas tank of 200 liters while simultaneously absorb- ing carbon dioxide. The test continued till the subject8 became so strained that they were not capable of performing qualified work. When the test had to be interrupted, the alveolar oxygen tension was found to be approximately the same (about 30 mm Hg) in all subjects. The oxygen percentage in the inspired gas varied a great deal at that moment: between 5.93 and 9.9i volumes per cent. This means that the person who had the best ability of adaption tolerated a decrease of the oxygen percentage in the inspired gas to 5.9 volumes per cent before the decrease of alveolar and arterial oxygen tension became so extreme that the tolerance limit was reached. The person with the smallest adap- tion arrived at the same tolerance limit with the same alveolar oxygen tension already at a percentage of 9.79 volumes per cent in the inspirad gas. Had the usual anoxemia test according to LARSEN or LEVY been performed with the subject who arrived at the critical alveolar oxygen tension at an oxygen percentage of 9 . i ~ volumes per cent in the inspired gas, one must presume that the strain would have become maximal or nearly maximal in an early stage of the test. But if the same test had been per., formed with the person reaching the critical alveolar tension at an oxygen percentage of 5.93 volumes per cent in the inspired gas, the strain in the later case would probably have been rela- tively less. For this person apparently can adapt himself to a much lower oxygen percentage in the inspired gas than the one used at the test. I t is most likely that the factor limiting the tolerance against the hypoxemia, in the majority of these cases was the sensitivity of the central nervous system and not of the circulatory organs to the hypoxemia. But that does not change the fact that the oxygen percentage in the inspired gas is a bad index of the resulting alveolar oxygen pressure in tests of this kind. In usual clinical anoxemia tests performed with inhalation of 9 or 10 per cent oxygen in nitrogen at normal pressure, it must be supposed that the induced hypoxemia varies consider- ably in different cases, even if the oxygen percentage is kept strictly constant in the inspired gas and even i f the lungs and

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the regulation of respiration are normal. In those cases where rebreathing tests are used, another unknown factor is brought in, viz. the individually varying oxygen consumption. This diminishes the oxygen percentage of the inspired gas differently in different cases.

I t is remarkable that Krogh's and Hohwii-Christensen's inves- tigations have but infrequently been taken into consideration in clinical work. LEVY et al. (1938), in a preliminary work checked the resulting arterial oxygen saturation at the end of a great number of examinations and found considerably varying values from 83 to 67 per cent. In a couple of later papers, however, (1941 and 1942) no consideration was taken to this varying decrease of the arterial oxygen percentage. On the contrary, they laid down general standards for the evaluation of the electrocardio- graphic reaction in anoxemia tests disregarding the quantitative extent of the hypoxemia. No explanation was advanced as to this but according to a personal communication by Doctor GUNNAR BIORCK, who has had the opportunity to discuss the problem with Doctor LEVY, it is because LEVY et al. could not find any corre- lation between the decrease of the arterial oxygen saturation and the electrocardiographic changes. The standards laid down by LEVY et al. have been critisized but seem to have been used extensively in cardiologic practice. ( BURNETT et al. 1942, W.4R- BURG 1943, BIORCK 1945, PRUITT et aZ. 1945.)

To evaluate the electrocardiographic reaction disregarding the quantitative extent of the hypoxemia must, in principle, be con- sidered wrong. From a practical viewpoint, it may be defended if one can show that the appearing variations of the arterial hypoxemia are relatively small in anoxemia tests used in practice which, in contradistinction to those performed by KROGH and HOHWU-CHRISTENSEN, do not intend to strain the patient to the tolerance limit, and if it can be shown that these variations lie within a range where the test in itself causes no injuries, but where injuried myocards in most cases give marked electrocardio- graphic changes while healthy hearts do not present changes of the same magnitude. With these assumptions the method may

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give an important contribution to the diagnostics of latent myo- cardial injuries.

Whether or not the test as it is performed now fills these con- ditions is an open question. As for the risks, extensive clinical experience shows that, in isolated cases, one may get complica- tions such as headache and dizziness, convulsive seizures, mental confusion and ”vasovagal attacks” characterized by a sensation usually described as ”faintness” accompanied by slowing of the pulse rate, fall in blood pressure, coldness of the skin, pallor and sweating (LEVY 1941). EARLIER, LEVY et al. have observed a few cases of pulmonary edema and a few such cases have also been reported by other investigators. All cases could be mastered with the usual treatment. According to LEVY, this complication has not been observed after they had made use of certain pre- ventive measures. These consisted of never subjecting incompen- sated persons to anoxemia tests, nor persons who were supposed to have had an acute infarction for the last four month . Also, they never tested a person more than once a day. Other investigators, as a rule, have made similar observations. As a rule, no serious complications have been observed in tests performed Zege artis. A slight pulmonary edema described by LINDGREN (1946) possibly is an exception. The method, therefore, is harmless i f performed according to LEVY’S directions and with the individuals for which it is intended.

The degree of variation of the resulting hypoxemia was fixed already by LEVY et a,?. (1938) who found arterial oxygen satura- tion values varying between 82 and 50 per cent in 17 heart patients at the end of anoxemia tests with inhalation of 12 per cent oxygen in nitrogen. Similar investigations have been per- formed by LINDCREN (1946), MALMSTROM (1946) and SJOSTRAND, WAHLUND (1946). The results unanimously have shown that the resulting oxygen saturation varies considerably in different tests even if the tests are performed under most carefully standardized conditions. LINDCREN has shown that the oxygen saturation decreases with varying speed in these tests. In some cases there is a continous slow decrease of the saturation values, in others a steep decrease at the beginning of the tests and then slowly

sinking values. Two identical saturation values at the end of two anoxemia tests performed according to LARSEN or LEVY with identical external conditions and over equal intervals of time do not guarantee the strain to have been of the same size in both cases.

In addition to this, the oxygen saturation cannot be simply accepted as a quantitative measure of the hypoxemia. The gap exchange between the alveoli and the blood and between the blood and the tissues are processess of diffusion and follow phy- sical laws. The partial pressure of the oxygen in the arterial blood therefore is of decisive importance for the nutrition of the tissues. This does not go for certain special states, such as pro- nounced anemias where the oxygen supply may suffer despite normal oxygen tension because of the decreased capacity of the blood to combine and transport oxygen. Aside from such special cases, however, it seems to be more correct to use the oxygen tension as a measure of the quantitative extent of the hypoxemia. Earlier investigations indicate that the pH changes vary con- siderably in different anoxemia tests. This means that the oxygen saturation in these tests is a bad index of the oxygen tension (MALRISTROM 1946), a fact limiting the value of earlier investi- gations where the oxygen saturation is used as a measure of the hypoxemia. The tension values should also be preferred because, on direct determination, they indicate minute lowerings of the normal oxygen values of the blood better than do the saturation values. This fact is of no importance in this work, however, where the tension is calculated indirectely and where the lowerings of the oxygen content of the blood are relatively marked.

Also, it seems to be necessary to take into consideration the alkalotic effect upon the electrocardiographic reaction. This has been neglected; but after CHRISTENSEN investigations (1946) it is no longer justifiable to neglect this factor which may well be the reason for occasional "pathologic" reactions which some investigators have observed in clinically healthy persons.

The appearing tachycardia represents another possible source of errors which may cause difficulties on evaluation of the electro- cardiographic reaction. It seems that this has not, up till now,

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been sufficiently observed. I t is a well known fact that a marked increase of heart rate often is combined with a depression of the S-T interval which also may appear in clinically healthy persons. This depression may partly be caused by a T, wave interfering with the S-T interval. Normally the T, wave is negative and there- fore may push the S-T interval in a negative direction. The depression may also be caused by a disturbance of blood flow. The current opinion is that the coronary blood flow during systole is much less than during diastole because of the pressure; and probably is very little or non-existing in the inner parts of the left chamber’s apical parts (HARRISON 1939). In tachycardia, diastole is especially shortened and systole will occupy a relatively greater part of the heart cycle than normal; also, the oxygen requirements of the heart will increase. So even normally, a none-too-good oxygen supply of the mentioned inner parts of the heart must be expected at increased heart rate. In anoxemia tests with its marked decrease of the arterial oxygen tension this defective oxygen supply must necessarily be more pronounced. It is true that the normal myocardium shows great resistance to hypoxemia, at least judging from experiments on animals. There degenerative changes can be shown - preferably in the papillar muscles and adjoining parts of the walls of the left chamber - but not until the animals have inhaled 4-5 per cent oxygen mixtures for one or two days (LORBER, EVANS 1943, BARNES, ESSEX 1944). I t is not certain, either, that a disturbance of blood flow which mainly affects the inner parts of the myocardium gives electrocardiographic changes aa long as the remaining parts of the cardiac muscle is intact. We do not know for certain the importance of an increased heart rate for the normal electrocar- diographic reaction. Such knowledge can be obtained only by an empirical investigation of a large material.

The results cited above definitely indicate that the hypoxemic strain varies very much in size in anoxemia tests according to LEVY and LARSEN despite indentical outside conditions. In addi- tion to this, it is evident that at least two other factors, namely the alkalosis and the increased heart rate may influence the ECG.

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This influence pobably varies and affects the electrocardiogra- phic reaction considerably.

Theoretically, it is still possible that the variations in size of the induced strain do not affect the electrocardiographic reaction so much that we cannot fix pracital limits between ’’normal” and ”pathologic” values. In order to be able to decide whether or not this is the case, we must scrutinize the practical results of these methods.

I t is remarkable that only a relatively small part of the cases which clinically were supposed to have myocardial in juries showed a positive reaction. This also applies to the large and thoroughly examined materials published by BIORCIC, LARSEN, LEVY and NYLIN. For an explanation, one may assume that indi- viduals who reacted normally despite clinical symptoms of myo- cardial injuries are persons who in this test have a great capacity of increasing their alveolar ventilation and thus keep their alveolar and arterial oxygen tension on a relatively high level during the test. Owing to this fact, the liypoxemia may not become sufficiently extreme to cause electrocardiographic changes in some cases of myocardial injuries. Possibly, electrocardiographic changes could have been demonstrated, had the decrease of the arterial oxygen tension been more normal. Possibly, also, the pathological electrocardiographic changes in BURNETT’S et al. material express the fact that the oxygen tension was lowered to a greater extent than in LEVY’S et al. investigations, since BUR- NETT et al. performed their examinations at an atmospheric pres- sure of only 630 mm Hg but with the same oxygen mixture which is otherwise used at normal atmospheric pressure. Since, on the whole, the increase in ventilation is proportional to the decrease in oxygen tension one must presume that the hyperventilation and thus the arterial alkalosis also were more pronounced in these cases. The added effect of the alkalosis and the extremely lowered oxygen pressure may possibly have caused the patho- logic changes in clinically healthy persons in BURNETT’S pt at?. material. This may also explain the few cases with the corres- ponding changes in normal subjects which have been observed

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by other investigators using LEVY’S et al. original method or the rebreathing method.

It is apparent that the anoxemia test according to LARSEN and LEVY at present seems to be impaired by a number of uncertain factors-each a source of possible error-which probably in- fluence the results. consequently, it is important to try to elimi- nate these or at least to decrease their influence; thus the diagnostic usefulness of the method may increase.

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