STUDIES IN HYPERTHERMIA II. THE ACIDBASE EQUILIBRIUM IN HYPERTHERMIA INDUCED BY SHORT RADIO WAVES BY FRITZ BISCHOFF, M. LOUISA LONG, AND ELSIE HILL (From the Chemical Laboratory of the Potter Metabolic Clinic, Santa Barbara Cottage Hospital, Santa Barbara) (Received for publication, October 30, 1930) INTRODUCTION In an earlier paper (1) the effect of a hyperthermia induced in human subjects by the high frequency electric current was studied. The effects of hyperthermia produced by short radio waves are reported in the present paper. The machine utilizing the high frequency electric current was in principle the same as the ordinary diathermy machine in general use, with the exception that it was designed to give an especially smooth high frequency wave to prevent the subject from suffering any disagreeable sensations due to passage of current. In the radio wave machine, the subject rests between the plates without any part of his body s being in contact with the plates so that the waves oscillate through the body from one side to the other. A detailed description of the machine used in our experiments has been given by Carpenter and Page (2). The present study was made to determine whether there was any difference in effect between the hyperthermia induced by radio waves and that induced by the diathermy principle or by the other well known methods of producing artificial fevers such as hot baths or vaccine injections. Carpenter and Page (2) believe... that the development of heat [by the short radio waves] is due to the resistance of the body to the conduction of current between the surfaces adjacent to the opposedplates. At each alternation of polarity of the plates the corresponding polarities are induced upon the adjacent boundaries of the interposed body and current is conducted through the material for a brief interval. The heating of solutions similar to the blood serum is dependent directly upon their electrical resistance. 321
322 Hyperthermia by Radio Waves If this explanation be accepted (we do not feel qualified to pass a critical judgment on the various theories) there would be little reason for supposing that the effect of the high frequency current (diathermy) would be different from the effect of the short radio wave. The explanation of Carpenter and Boak (3), however, led us to believe that there were theoretical grounds for a possible difference in physiological effect. These authors state, That such a rise in temperature accompanies the passage of the short radio waves through the organism in such a field may be explained in a number of ways, such as that it is conducting induced alternating currents and the heat developed is proportional to the current squared times the resistance of the body. Hosmer s conception is that the heating is due to the increased rate of vibration of the molecules of the cells produced by their alternate attraction to each of the plates in turn. Others consider it analogous to dielectric hysteresis, i.e., a resistance to the changing of the molecules. Plan of Experiment The plan of experimentation was essentially the same as that followed in our studies with the high frequency electric current. In addition, a study of the perspiration was made. Collection of PerspirationAn attempt was made to collect the constituents of the perspiration quantitatively for the entire heating period. The subject was washed with soap and water prior to heating and rinsed with distilled water. He was then wrapped in a sheet and placed upon a cotton blanket, under which was a rubber sheet. He was covered with a cotton blanket. The blankets, sheet, and rubber had previously been rinsed three times in distilled water. The blankets and sheet were dried in a clothes vacuum centrifuge. After the heating the sheets and blankets were washed four times in distilled water. The subject, as well as his hair, was washed with distilled water, gauze sponges being used. All the washings were combined, 1 cc. of concentrated sulfuric acid was added, and the solution was concentrated below 500 cc. Insoluble material was filtered off and washed with dilute acid. The total concentrate was made to a volume of 500 cc. The washings from the rubber were concentrated separately. The amount of perspiration collected from the rubber was not significant. The concentrate gave no precipitate with tungstic acid. Standard methods of blood analysis were used for the determination of non
F. Bischoff, M. L. Long, and E. Hill 323 protein, urea, ammonia, and creatinine nitrogen and uric acid. Ammonia was separated with permutit. AnalysesThe analytical methods were the same as described in a former paper. The ph, as previously described, was determined by the quinhydrone electrode upon the separated plasma of blood as drawn. The ph was determined at room temperatures. The ph values are reported corrected to the oral temperature of the patient, with the temperature coefficient 0.010. Laug (4) has recently determined the temperature coefficient by the quinhydrone electrode as 0.013 ph per degree for dog plasma. Our value (5) was obtained for two human plasma samples at 25 and 37. For rabbit plasma we obtained a coefficient of 0.012. The value obtained depends somewhat upon the method of extrapolation of the drifting potential to zero time. For the present we are using our value of 0.010 until more is known regarding the behavior of the electrode the first 15 seconds of the determination. EXPERIMENTAL SubjectsWe have not felt justified in raising the body temperature of normal individuals above 39. In the present series, one normal individual was heated on three occasions. The quantitative collection of perspiration was made for this individual. In addition two paretics were subjected to the hyperthermia. One of these showed an initial high temperature of 37.8. Her temperature was raised to 39.6. The changes in oral temperature, pulse rate, and respiration rate are given in the protocols. Blood Volume ChangesWith the increase in the oxygen capacity of the blood as a measure of volume change, an appreciable loss in blood volume during the radio wave hyperthermia is noted. Reductions in blood volume amounting to 3.5, 15.0, 6.5, and 7.0 per cent were noted. In hyperthermia induced by the high frequency electric current, the changes in the oxygen capacity approached the error of the analytical determination, increases of 1 and 2 per cent in blood volume being noted in three cases and decreases in 1 and 4 per cent in two others. The data for total hemoglobin are given in Table I. Blood ph and Alkali ReserveThere was a decided increase in the plasma ph in three of the experiments during the hyperthermia. Shifts of ph from 7.47 to 7.59, from 7.44 to 7.70, and
324 Hyperthermia by Radio Waves from 7.46 to 7.55 were noted. As the normal range for the plasma ph by the quinhydrone electrode is 7.40 to 7.50, the increases are above the upper limits of normal. In a fourth experiment, the ph remained within normal limits, shifting from 7.40 to 7.44. TABLE Blood Changes Following Rise in Body Temperature The values for total Hb, HbOs, and total COz are measured in volumes per cent; those for urea N, nonprotein N, cholesterol, creatinine, uric acid, and amino acid N are measured in mg. per 100 cc. Subject A. I( L. D. Date 1950 Apr. 15 Sept. 23 July 12 June 7 Oral temperature C. 36.8 38.9 36.9 38.9 37.5 39.2 37.8 39.4 I. _ lasma PH 7.47 7.59 7.46 7.55 7.44 7.70 7.40 7.44 6 2 $ 24.0 24.9 21.0 22.6.0 23.5 18.8.1 TABLE I Whole blood findings 13.757.9 21.046.1 10.656.9 151 19.0 50.0 151 9.154.9 31.2 23.037.5 34.5 7.7 52.123.7 8.655.425.0 II 7.5 7.5 1.3 3.5 8.0 1.3 3.2 7.0 1.2 1.8 1.5 2.2 Changes in Distribution of Base Bound by Bu$ers of Blood During Heatin.g Subject A. L. D. A. ABHCOs AB(Hb) ABP,?nM pm 1. rnm per 2. mdb per 1. 5.8 +5.4 +0.8 10.0 +9.2 +1.7 0.5 +1.1 +0.3 4.0 +4.3 +0.6 ZAB 11261 per 1. +0.4 +0.9 +0.9 $0.9 4 correction was applied for the change in blood volume during heating. This subject had a fever at the time the experimental hyperthermia was induced. The significance of her condition will be discussed later. An appreciable fall in the whole blood total CO2 was noted in
F. Bischoff, M. L. Long, and E. Hill 325 the three experiments in which the plasma ph was markedly increased. A 3 volume per cent rise was noted for the subject whose plasma ph did not change during the hyperthermia. The hemoglobin became highly oxygenated in the three experiments in which the ph rose, and remained unchanged in the experiment in which the plasma ph was unchanged. In order to determine whether the fall in the total CO2 could be accounted for by a shift of base to the blood proteins in accordance with the increased ph, the base bound by the blood buffers has been calculated. The results are given in Table II. The method of calculation is given in an earlier paper (1). These calculations can be considered only semiquantitatively. In the present instance, they have been complicated by the changes in blood volume. Since the interest is TABLE Quantitative Estimation of Perspiratory Elimination of Subject A Nitrogen as nonprotein N Urea, NHIN... N... NHaN.... Creatinine N.... Amino acid N... P.............................. III 2.25 hr. period, 36.937.6 2.5 hr. period, 36.938.9 gm. 0.315 0.190 0.115 0.065 0.010 0.012 Less than 0.5 mg. 0.400 0.160 0.260 0.003 Less than 0.5 mg. primarily whether or not the alkali reserve as a whole is increased, the data obtained during the heating period have been corrected for changes in blood volume. The results indicate a slight increase in the alkali reserve. These results are in harmony with data obtained by us in hyperthermia induced by the high frequency electric current and by Cajori et al. (6), who used the electric bake and determined the change in alkali reserve by absorption curves. Cajori obtained increases ranging from 0 to 6.0 millimols per liter. Nitrogenous Blood ConstituentsA slight increase in the blood nonprotein nitrogen and urea nitrogen during hyperthermia was noted. The increases were comparable to the change in the oxygen capacity. Increases of 1.8 and 1.3 mg. per 100 cc. for urea nitrogen
326 Hyperthermia by Radio Waves and 3.3 mg. per 100 cc. for nonprotein nitrogen were observed. There was no change and a slight decrease in the amino acid nitrogen for two cases studied. Changes noted in blood uric acid and creatinine were within the error of the analytical determination. There was likewise no change in the whole blood cholesterol. The data are given in Table I. Nitrogenous Constituents of PerspirationThe high percentage of NH3 nitrogen as compared with the total nitrogen is perhaps the most interesting observation of the perspiration analyses. The sum of the urea, ammonia, creatinine, and amino acid nitrogen values does not account for the nonprotein nitrogen. The data are given in Table III. Urine phin the present study the urine ph was followed at intervals for the preheating, heating, cooling, and recovery periods for three individuals. There was no indication of the urine s becoming alkaline during the period of increased alkalinity of the blood. There was a tendency of the ph to become more acid during the recovery period. The results are given in Table II of the companion paper (7). DISCUSSION Concerning the effect upon the acidbase equilibrium, there is apparently no difference whether the rise in temperature is induced by the external application of heat (hot water or air baths) or by the generation of heat within the body (high frequency current or radio wave). Of fundamental importance is the loss of COS with rise in the blood ph. The fall in the CO2 content of the blood is readily accounted for by a shift of base to the blood proteins due to the increase in ph. Cajori et al. (6) found no significant change in the blood volume as measured by the oxygen capacity in their studies with the electric bake. We found none in our studies with the high frequency electric current, though the concentration in blood volume following the radio wave hyperthermia was significant. When the high frequency current was used it was necessary to insulate the subject from loss of heat by wrapping him in blankets. In the radio wave series, the effect of the machine was so powerful that the subject was covered with only a thin cotton blanket. It is probable that in the radio wave experiments there was a greater evaporation of
F. Bischoff, M. L. Long, and E. Hill 327 perspiration, while with the high frequency current the subject became bathed in his own perspiration. Since the radio wave hyperthermia is now under investigation for possible clinical use, a warning is sounded as to the change in blood volume it may bring about. In our experiments the subjects drank over a liter of water during the heating and still showed a fall in blood volume. Donath and Heilig (8) have divided hyperthermias into two classes: those which bring about an increase in the blood amino acid nitrogen with increased nitrogen excretion in the urine and those which do not affect these constituents. According to this classification the radio wave hyperthermia is analogous to the manipulation of the heat centers, which brings about no changes, in contrast to the injection of nucleic acids or vaccines. The present series of experiments have confirmed our impression that there is little reason for believing that the body is attempting to compensate for the lowered CO, tension by lowering the alkali reserve. In experiments with forced breathing and those in which the body temperature is raised very rapidly by immersion in hot water, very alkaline urines and falls in urine ammonia are observed. In our series with the high frequency electric current, some alkaline urines were observed, but they were in no case as alkaline as the blood. In the present series the urine ph at the peak of the heating was 5.0, 6.2, and 5.8. Moreover, the ratio of ammonia to urea in the perspiration increased with rise of temperature and the urine ph became more acid during the cooling period. The latter observation overrules the possibility that the kidneys may have been unable to secrete alkali during the hyperthermia because of the decrease in urine volume. The findings of the experiment in which the subject had a fever (37.8 ) at the time the artificial hyperthermia was induced were unexpected. Her initial plasma ph was within the lower limits of normal. The induced 2 rise in temperature brought about no significant blood changes with the exception of reduction of blood volume. This subject was given a small dose of morphine before the experiment. It is possible that either the morphine or the paretic condition inhibited the normal response of the heat centers. Since another paretic responded normally the condition is apparently not characteristic of paresis. It is not in the scope of the present study to investigate pathological conditions. The
328 Hyperthermia by Radio Waves results suggest that studies of hyperthermia induced in various pathological conditions would help materially in elucidating the mechanism of heat regulation. A study of the nature reported in this paper is possible only with the cooperation of a large number of people. We are indebted to Dr. H. J. Ullmann for the clinical supervision of the problem, to Dr. R.. F. Atsatt, who was the normal subject studied, to Dr. N. H. Brush for supplying us with suitable human subjects for study, and to Miss Ella M. Ottery for the care of the subjects. Mr. Carl Darnell of the General Electric Company was responsible for the radio wave machine placed at our disposal. SUMMARY With the exception of a fall in blood volume, which is probably not a direct effect, no difference in effect was noted between raising the body temperat.ure by placing the subject in the field of condenser plates in circuit with a short wave radio transmitter and in raising the body temperature by means of diathermy, warmed air, or hot water baths. Of fundamental importance was the loss of coz. The ph of the blood became more alkaline, there was a shift of bases to the blood proteins and an increased oxygenation of t.he hemoglobin of venous blood. No significant change in the nonprotein nitrogen constituents of the blood was noted. No evidence was obtained that the body was attempting to compensate for the condition of alkalosis through the urinary or perspiratory excretions. BIBLIOGRAPHY 1. Bischoff, F., Ullmann, H. J., Hill, E., and Long, M. L., J. Biol. Chem., 86,675 (1930). 2. Carpenter, C. M., and Page, A. B., Science, 71,450 (1930). 3. Carpenter, C. M., and Boak, R. A., Am. J. Syphilis, 14,346 (1930). 4. Laug, E. P., J. Biol. Chem., 88,551 (1930). 5. Bischoff, F., Long, M. L., and Hill, E., J. Pharmacol. and Ezp. Therap., 39,425 (1930). 6. Cajori, F. A., Crouter, C. Y., and Pemberton, R., J. BioZ. Chem., 67, 217 (1923). 7. Bischoff, F., Maxwell, L. C., and Hill, E., J. BioZ. Chem., SO, 331 (1931). 8. Donath, J. D., and Heilig, R., KZin. Woch., 3,834 (1924).
F. Bischoff, M. L. Long, and E. Hill 329 Protocols T = oral temperature in C., P = pulse rate, R = respiration rate. Time 1 T I P I R Time I T 1 P I R p.m. 7.15* 7.30 7.451 8.00 8.30 9.00 9.30 10.05 10.35% 11.15 12.10 A., male, Apr. 15, 1930 t 36.8 72 36.8 80 36.6 76 37.0 80 37.4 92 38.0 38.6 1 38.9 108 38.0 104 37.0 96 A., male, July, 1930 18 22 26 26 16 8.00*? 36.9 88 8.35 37.1 100 9.00 37.5 92 9.1 37.6 9.45 37.2 92 A., male, Sept. 23, 1930 p.m. 7.50*t 36.9 80 8.30 36.7 99 9.05 38.5 116 24 9.30*t 38.9 116 22 9.55 38.4 90 10.10 37.2 88 10.40 37.0 L., male, July 12, 1930 2.30*t 37.5 100 2.55 37.8 100 3.30 38.4 108 3.58 38.6 108 4.30 39.1 118 4.35*t 39.2 118 5.00 39.0 118 5.30 38.4 90 6.30 37.2 116 7.30 37.0 24 24 26 24 * Taking of blood. t Beginning and termination of radio wave heating. D., female. June 7, 1930 p.m. 2.30*f 3.15 3.45 4. 5.03*1 5.43 6.30 7.00 8.00 37.t 38.c 38.1 38.! 39.f 38.f 37.f 37.t 38.: 104 124 126 18 132 24 104 24 100 22 100 22 100 22
STUDIES IN HYPERTHERMIA: II. THE ACIDBASE EQUILIBRIUM IN HYPERTHERMIA INDUCED BY SHORT RADIO WAVES Fritz Bischoff, M. Louisa Long and Elsie Hill J. Biol. Chem. 1931, 90:321329. Access the most updated version of this article at http://www.jbc.org/content/90/1/321.citation Alerts: When this article is cited When a correction for this article is posted Click here to choose from all of JBC's email alerts This article cites 0 references, 0 of which can be accessed free at http://www.jbc.org/content/90/1/321.citation.full.ht ml#reflist1