Oxygen Cost and Efficiency of Respiratory System in Hypoxia and in Congeste Heart ailure By Robert J. Hoeschen,.D., Lawrence H. A. Gold, Thomas E. Cuddy,.D.,.R.C.P. (C), and Reuben. Cherniack,.D.,.Sc,.R.C.P. (C),.A.C.P. The oxygen cost of an increase in ventilation is high, and the efficiency of the respiratory system is low in such disease states as chronic obstructe pulmonary emphysema and obesity. 2 ' 3 Since hypoxia is common to both conditions, it is possible that the high oxygon cost and low efficiency are a result of tissue hypoxia because of either arterial hypoxemia or reduced bld flow. It was, therefore, of interest to determine whether the oxygen consumption and efficiency of the respiratory system were t altered in other conditions in which hypoxia was present. This paper reports measurements of the oxygen cost of an ventilation and the efficiency with which added inspiratory loads were handled in () subjects breathing hypoxic gas mixtures and (2) patients with congeste heart failure. ethods Nine subjects and twenty patients with cardiac disease and clinical evidence of congeste heart failure were studied. Their physical characteristics and measurements of ventilatory function are presented in table. The clinicnl grading of the patients with eongesto heart failure was based on the severity of the dyspnea as suggested by the New York Heart Association. 4 Arterial gns tensions wero measured by a modification "' of the technique of Riley, Proemmel, and ranke. 0 The vital capacity, maximum midexpi r a- tory flow rate, and maximum breathing capacity were measured with a 9-L. Collins spirometer from which the carbon dioxide absorber and valves had been removed and into which a high-speed rotating rom tlio Department of edicine, "Unersity of anitoba, and the Clinical Investigation Unit of the Winnipeg General Hospital, Winnipeg, Canada. Supported in part by the edical Research Council of Canada and the anitoba Heart oundation. Dr. Hsehen is a edical Research Council ellow, and Dr. Cuddy is a Rosearch ellow, Tlie Hoart oundation of Canada. Receed for publication ay 6, 962. Circulation Remearoh, Volume XI, November 96X drum had been incorporated. The maximum of at least three trials was recorded. Predicted values were obtained from Baldwin et al. 7 nnd Leunllen and owler. 8 OXYGEN COST O INCREASED VENTILATION The oxygen cost of ventilation was measured by a closed-circuit technique employing a modification of the method of Campbell, Westlake, and Cherniack. 0 The subject breathed into and out of a 9-L. Collins respirometer with a carbon dioxide absorber incorporated. A cam on the pulley of the spirometer actated a microswitch which in turn opened and closed a solenoid valve through which oxygen could be delered from a second spirometer. The microswitch was actated toward end-inspiration so that a nonsloping record of tidal volumes and the integrated minute ventilation were obtained on the first spirometer, while the oxygen being consumed was recorded on the second spirometer. All subjects were studied in the sitting position, having fasted for at least nine hours and having rested in a comfortable chair for at least one-hall' hour prior to the study. All breathed into and out of the spirometer circuit for eight to ten minutes before any measurements were taken in order to reach a steady state for oxygen consumption. our- to eight-minute measurements of oxygen consumption and ventilation were made at resl and during ventilation. Oxygen consumption was expressed in milliliters per minute standard temperature pressure dry (S.T.P.D.) and ventilation in liters per minute body temperature pressure saturated (B.T.P.S.). At least two levels of ventilation were achieved by the interposition of dead spaces consisting of thick-walled rubber tubing (2.5 cm. internal diameter) between the subject and the spirometer, the smaller of the dead spaces producing an increase in ventilation of to 23 L. per minute and the larger from 7 to 34 L. per minute. The resistance of the whole dead spaee-spirometer system was less than em. H 2 O per L. per second at a flow rate of.5 L. per second. s were allowed to increase their ventilation spontaneously with no control of rate or depth while breathing through a dead space. The sequence in which the various levels of ventilation were studied was altered at random. 8
826 HOESOHEN, GOLD, CUDDY, CHEENIAOK TABLE Physical Characteristics and Pulmonary unction of Normals and Patients with Congeste Heart ailure no. i* o# 3* 4* 5* 6* 7* 8* 9* * 2 3 4 5* 6 7 IS 9* 20* 2 23 24 26 27* 28* * Age (yr.) 22 35 2 20 3 7 55 49 33 37 53 59 55 60 30 44 47 70 52 78 62 83 75 50 Sex B.S.A.t.».78.95.56.70.55 2.04.73 2.00 2.05 2..88.77.68.9.G2.74.97.34.85.68.92.60.66.44.49.33.67.55.78 'Studied breathing 0 per cent Oi. tb.s.a. = Body surface area. Diagnosis myxoma i i i i i i i Observations at rest with no added space were made at the beginning and end of each series of measurements. The lower of the two resting determinations was used in the calculation of the oxygon cost of ventilation. Ten minutes of rest were allowed between observations, during which time rm air was breathed. or each subject, the difference in oxygen consumption at the resting ventilation and at ventilations was dided by the difference in ventilations and expressed as the oxygen cost of ventilation in milliliters per liter of ventilation. Vital capacity e. 4.65 4.4 3.42 4.2 3.8 5.50 5.43 6.6 6.2 5.4 5.4 3.78 3.45 3.87 4.20 3.47 2.4 4.75 2.09.34 2.36.6 a* 8 7 98 9 23 35 37 22 2 20 90 39 92 9 3 84 43 8 53 aximal breathing capacity o i 83 20 96 43 23 20 77 29 o 9 46 68 98 93 73 34 43 28 62 a 2 42 2 99 8 38 46 39 68 55 82 0 20 82 79 38 92 0 52 45 42 67 b S If *> 4.78 3. 2.60 4.79 2.43 4.46 3.93 5.2 6.80 2.73 4.97 3.30.5 2.8 2.37.32.76 4.86 2.99.37 0.43 0.S3 "3 SO 93 94 95 95 75 85 8 S4 8 80 73 84 Arterial ~~!H o c o^ i 36 36 36 35 4 28 38 55 44 38 X H EICIENCY O THE RESPIRATORY SYSTE The efficiency of the respiratory system was determined by measuring the extra oxygen consumption associated with the performance of a known added respiratory load using the same respirometer. Work was added by having the subject inspire through a metal tube that projected down under a water seal. This produced a constant additional alveolar-spirometer pressure difference throughout inspiration which was relately independent of the rate of air flow and left expiration unimpeded. The added was calculated by multiplying the minute ventilation in liters by the depth of the water seal in centimeters by " 2 and was expressed in Kg../min. The extra oxygen consumption associated with the added load was converted to its enei^gy equalent, assuming a respiratory quotient of 0.82, and expressed in Kg../min. The added dided by the Circulation Reaearch, Volume X/, Novombor 96t
HYPOXIA AND CONGESTIVE HEABT ATLTJBE 827 TABLE 2 0, Cost and Efficiency Breathing Rm Air and 0 Per Cent Oxygen o 8 Diagnosis utrinl myxoma Oicoct 0% Oi 0.69.6.85 (ml./l.) Rm air 0.73.4.48 Efficiency 0% Oi..7.28 (%) Rm air 8.8 9.8.82 Effect of Hypoxia on the O, s TABLE 3 Cost, Efficiency, and Total echanical Work in Normal ubject 2 3 4 5 6 7 8 9 ean 8.D. V Ojcoet i Efficiency (%) 0% O: Hypoxia 0% O: Hypoxia 0.69.6.2S.32.9 0.60 0.89.2.26.05 ±0.27 <0.0 2.3 o or 2.59 3.24 2.44 3.3 3.03 2. 3.86 2.8 ±0.58..7 7.8.0 6.4 8. 6.3 6.0 2.0 8.6 ± 2.6 <o'.0 2.7 4.3 4.2 3.2 2.4 2. 3.4 ±0.85 Total mechanical (Kg../L.) 0% Hypoxia 0.46 0.8 0.4 0.277 0.60 0.2 0.8 0.2 0.3S 0.94 ±0.077 >0.2 0.33 0.203 0.099 0.272 0.64 0.67 0.5 0.228 0.324 0.98 ±0.072 energy equalent of the extra oxygen consumption yielded the efficiency of the respiratory system for handling added loads. The inability to handle the added inspiratory resistance precluded the detenination of efficiency in seven patients with congeste heart failure. TOTAL ECHANICAL WORK O BREATHING It has been shown that the efficiency of the respiratory system for handling added remains essentially unchanged over a large range of added loads. 0 This suggests that the value for efficiency obtained under such conditions may be applied to situations where there is no added load. The mechanical of breathing at rest, therefore, can be calculated from the oxygen cost of breathing at rest and the efficiency. Thus, the total mechanical of breathing was calculated from the product of the efficiency and the energy equalent of the oxygen cost of breathing per liter of ventilation at rest and was expressed in kilogram meters per liter of ventilation. The subjects wore studied while breuthing 0 per cent oxygen and a hypoxic gas mixture of to 2 per cent oxygen in nitrogen. An ear oximeter was used as a monitor in order to insure that the patients were in a steady state and that the arterial oxygen saturation was stable during the hypoxic studies. The oxygen saturations CircutfUion Research, VtAumtj XI, November I96t ranged from 55 to S5 per cent during hypoxic studies. Some of the patients with congeste heart failure were studied while breathing 0 per cent oxygen, and the others were studied breathing rm air. Table 2 presents the values obtained for the oxygen cost and efficiency studies in two subjects and one patient with congeste heart failure, who were studied twice, once while breathing rm air and, on the other occasion, while breathing 0 per cent oxygen. It will be seen that in these three subjects, similar values were obtained utilizing either rm air or 0 per cent oxygen. Results HYPOXIA Table 3 presents the values obtained for the oxygen cost of ventilation, the efficiency with which added inspiratory loads were handled and the total mechanical of breathing in nine subjects, while breathing 0 per cent oxygen and the hypoxic gas mixture. The measurements were made over the same range of ventilation during inhalation of either 0 per cent oxygen or the hypoxic gas mixture. Resting ventilation slightly while subjects breathed
828 HOESOHEN, GOLD, OTJBDY, OHEKNIAOK TABLE 4 Oxygen Cost of Increased Ventilation Using the Open and Closed-Cimtit Techniques Oxygen cost of Increased ventilation (l/l) Cloeed-circuit method Open-circuit method Rm air Hypoxla Rm air Hypoxla 0.87 O.7.",.4.07 2.43 2.20 2.30 2.9 2.0.74.75.89.92.7.87.96 2.7 2.5 2.8 2.97 2.82 3.09 2.95 2.96 the hypoxic gas mixture. It will be seen that the oxygen cost of ventilation rose (I' <0.0) during breathing of the hypoxic gas mixture. This increase was apparently due to a decrease in the efficiency with which added inspiratory loads were handled (P <0.0) for there was no change in the total mechanical of breathing (P > 0.2). These findings could not be attributed to a change in respiratory pattern since there was no consistent change while subjects breathed the hypoxic gas mixture. In order to insure that the rise in oxygen cost was related to the hypoxia rather than the inhalation of carbon dioxide which was inherent in the closed-circuit technique, the oxygen cost of ventilation was measured during voluntary hyperventilation in two of the subjects while breathing rm air and the hypoxic gas mixture, using the open-circuit technique of Cournand et al. n The respiratory rates selected were those at which the subject had breathed during the studies with the closed-circuit technique. The end-tidal carbon dioxide tension was monitored continuously with an infrared carbon dioxide analyzer, sufficient carbon dioxide being added to the inspired gas to maintain a end-tidal pcoo throughout the periods of hyperventilation. In table 4, the results obtained with both the open and closed-circuit techniques are compared. In each subject, the closed-circuit technique was used on two occasions and the open-circuit technique on four occasions. It can be seen that hypoxia TABLE S 0, Cost; Efficiency, and Total echanical Work in Patients icith Congeste Heart ailure 2 3 4 5 6 7 8 9 20 2 23 24 2fi 27 28 ean 3.D. Oncost fml./l.) 2.67 2.67 3.23 2.2] 2.00.59.7] 2.37.48 2.55.43 4.72 2.66 2.06.48 3.90 4.46. 3.3 2.56 2.5 ±.00 Efficiency (%) 5. 4.3 3.6 0.9 2.5.8 7.8 2.3.9 2.]. 2.7 3. ±.89 Total mechanical (Kg../L.) 0.286 0.244 0.72 0.069 0.09 0.056 0.420 0.062 0.9 0.39 0.050 0.3 0.27 0.6 ±0. led to an increase in oxygen cost during both voluntary hyperventilation and carbon dioxide-induced hypercapnia. This indicates that the rise in oxygen cost of ventilation during hypoxia, which was demonstrated with the closed-circuit technique, was not due to the associated hypercapnia. It can also be seen that the values for the oxygen cost of ventilation were higher when the ventilation was voluntarily. This is in agreement with other investigators, as reported by Otis. 2 CONGESTIVE HEART AILURE The oxygen cost of ventilation, the efficiency with which added loads were handled, and the total mechanical of breathing at rest in the patients with congeste heart failure are presented in table 5. The measurements were made over the same range of ventilation as in the subjects. The resting respiratory rate was generally higher in the patients with congeste heart failure but showed similar changes with ventilation, the respiratory rate rising Circulation Retaroh, Volu-me XI, ivouomfw Itlt
HYPOXIA AND CONGESTIVE HEART AXLTJBE 8 fe to six breaths per minute. It is seen that the oxygen cost of ventilation was higher than (P < 0.0) in the patients with congeste heart failure. In 3 patients, the mean efficiency for handling added inspiratory loads was 3. per cent which was lower than (P < 0.0). On the other hand, the mean value for mechanical of breathing in these patients was 0.6 Kg../L., which was not significantly different from the (P > 0.2). Discussion The data presented indicate that the oxygen cost of ventilation was high in patients with congeste heart failure and in subjects who were breathing a hypoxic gas mixture. The oxygen cost of breathing at resting ventilation is probably similarly elevated. The high oxygen cost found in the patients with congeste heart failure is in agreement with the data of Cournand et al., who studied one patient with mitral stenosis and clinical evidence of congeste heart failure, but differs from that of cgregor and Becklake, 8 who found that the oxygen cost in patients with congeste heart failure was not above. However, the values for the oxygen cost of breathing in the latter study were higher than those reported by most investigators. 2i Oi > 4> B ' The high oxygen cost of breathing in hypoxia and in congeste heart failure may be attributed to either an increase in total mechanical done, or to a less efficient respiratory system, or both. Table 3 demonstrates that the rise in oxygen cost which developed when the subjects breathed a hypoxic gas mixture was due to a fall in the efficiency of the respiratory system, rather than to a change in total mechanical done. Since elastic resistance and mechanical done on the lungs are in patients with congeste heart failure, "~ it is surprising that the total respiratory mechanical done was not in the present series of patients with congeste heart TABU 6 Effect of Added Inspiratory Work on the Compliance of the Lungs no. Normal 8 Condition rest veutilation rest ventilation Congeste heart failure 28 rest ventilation rest ventilation (a) (b) (a) (b) (a) (b) Ventllatlon (L./min.) 7.65.85 8.75.08 7.56.2 8.7 4.4 9.77 9.02 9.78 9.57 9.87 2.95 20.5 Respiratory frequency.0 3.5 2.5 4.5 4.5 22.5 22.5 7.5 23 Compliance HjO (L./min.) 0.234 0.2 0.2 0.24 0.244 0.5 0.3 0.280 0.098 0.095 0.074 0.059 0.045 0.043 0.038 failure. However, calculation of the total mechanical of breathing was dependent on the estimated efficiency for handling added inspiratory loads. The added load was dered from the knowledge of the minute ventilation and the depth of the water seal through which the subjects inspired. Since the added inspiratory resistance may have led to pulmonary congestion and thereby the elastic resistance of the lungs, the additional load may have been underestimated. In this way, the efficiency of the respiratory system would also have been underestimated. In order to determine whether the elastic resistance of the lungs was altered during measurements of efficiency, the compliance of the lungs was determined by measuring simultaneous changes in esophageal pressure and tidal volume at rest, at different levels of ventilation, and when added inspiratory was imposed in two subjects and in two patients with heart failure. The mean of breaths was calculated for each of these situations. Table 6 shows that in the two subjects, the lung compliance was unaltered at approximately equalent respiratory rates and minute ventilations when inspira- Circulation Remearch, Volume XI. November leet
830 HOESOHEN, GOLD, OTJDDT, 0HEENIA0K tory was added. In the two patients with congeste heart failure, however, the lung compliance decreased when the inspiratory resistance was added. This suggests that in the patients with congeste heart failure, the additional done may have been greater than that used for the calculation of efficiency so that the actual efficiency was underestimated. In addition, the calculated values for the total mechanical of breathing might also have been underestimated. Although it is difficult to draw any conclusions about the efficiency of the respiratory system in the patients with: congeste heart failure, it is nevertheless possible that the efficiency is decreased in congeste heart failure and that this inefficiency may be partly responsible for the high oxygen cost of breathing. A high oxygen cost has been found in other disease states in which hypoxia was present, such as chronic obstructe pulmonary emphysema and obesity. 2 ' 3 The present paper demonstrates that the oxygen cost of breathing was high in two other situations in which hypoxia was present, namely, congeste heart failure and subjects breathing a hypoxic gas mixture. Although arterial hypoxemia was not a consistent finding in the patients with congeste heart failure, it is possible that the high oxygen cost of breathing in this situation was the result of tissue hypoxia due to inadequate bld flow. Conclusions. The oxygen cost of ventilation and the "efficiency of the respiratory system" were measured in nine subjects and 20 patients with cardiac disease and clinical evidence of congeste heart failure. 2. The oxygen cost of ventilation rose, and the efficiency of the respiratory system fell in subjects when they breathed a hypoxic gas mixture. 3. The oxygen cost of ventilation was high and "the efficiency of the respiratory system" low in patients with cardiac disease and clinical evidence of congeste heart failure. It is suggested that the '' added " and the efficiency may be underestimated in this condition. 4. The presence of hypoxia results in a rise of the oxygen cost of ventilation and a fall in "the efficiency of the respiratory system.'' Acknowledgment The authors wish to express their appreciation of the technical assistance of r. Stefan Eedka and iss ary Louise Van den Brand. References. CHERNIACK, E..: Oxygen consumption anil efficiency of the respiratory muscles in health and emphysema.,t. Clin. Invest. 38: 494, 959. 2. KAUAN, B. J., EBGUSON,. H., AND CHER- NIACK, B..: Hypoventilation in obesity. J. din. Invest. 38: 500, 959. 3. CHEKNIAOK, E.., AND GUENTER, C. A.: Efficiency of the respiratory muscles in obesity. ' Canad. J. Biochem. 39: 25, 96. 4. Nomenclature and Criteria for Diagnosis of Diseases of the Heart. New York, New York Heart Association, 947. 5. BWNKAN, G. L., JOHNS, C..., DONOSO, H., AND ETLET, E. L.: odification of the method of Eiley, Proemmel and ranke for determination of oxygen and carbon dioxide tensions in bld. J. Appl. Physiol. 7: 3, 954. 6. BILEY, E. L., PROEEL, D. D., AND RANKK, B. E.: Direct method for determination of oxygen and carbon dioxide tensions in bld. J. Biol. Cliem. 6: 62, 945. 7. BALDWIN, B. DE., COURNAND, A., AND BlCHARDS, D. W., JR.: Pulmonary insufficiency: I. Physiological classification, clinical methods of analysis, standard values in subjects. edicine 27: 243, 948. 8. LUEALLEN, E. C, AND OWLER, W. S.: aximal mid-expiratory flow. Am. E«v. Tuberc. 72: 783, 955. 9. CAPBELL, E. J.., WESTLAKE, E. K., AND CHERNIAOK, E..: Simple methods of estimating oxygen consumption and efficiency of the muscles of breathing. J. Appl. Physiol. : 303, 957.. URRAY, J..: Oxygen cost of voluntary hyper ventilation. J. Appl. Physiol. 4: 87, 959.. COURNAND, A., RICHARDS, D. W., BADER, H. A., BADER,. E., AND ISHHAN", A. P.: Oxygen cost of breatlng. Tr. A. Am. Physicians 67: 62, 954. 2. OTIS, A. B.: "Work of breathing. Physiol. Rev. 34: 449, 954. Circulation Retearth, Volume XI, November 96
HYPOXIA AND CONGESTIVE HEABT AILURE 83 8. CGREGOR,., AND BECKLAKE,. R.: Relationship of oxygen cost of breathing to respiratory mechanical and respiratory force. J. Cliu. Invest. : 97, 96. 4. LILJESTRAND, G.: Untersuchungen fiber die Atmungearbeit. Skandin. Arch. f. Physiol. Leipz. 36: 99, 98. 5. CAPBELL, E. 0.., AVESTLAKE, B. K., AND CHERNIACK, R..: Oxygen consumption and efficiency of the respiratory muscles of young male subjects. Clin. Sc. 8: 55, 959. 6. CHERNIACK, R.., CUDDY, T. E., AND AR- STRONG,.T. B.: Significance of pulmonary elastic and viscous resistance in orthopna. Circulation 5: 859, 957. 7. HAYWOOD, G. W., AXD KNOTT, J.. S.: Effect of exercise on lung distensibility and respiratory in mitral stenosis. Brit. Heart J. 7: 303, 955. 8. SHARP, J. T., GRIITH, G. T., BUNNELL, J.., AND GREENE, D. G.: Ventilatory mechanics in pulmonary oedema in man. J. Clin. Invest. 37:, 958. 9. BROWN, C. C, RY, D. L., AND EBSRT, H. V.: echanics of pulnionarj' ventilation in patients with heart disease. Am. J. ed. 7: 438, 954. Bk Reviews Nnkleannedizin in der Klinik (Clinical Aspects of Nuclear edicine). Symposium with Special Reference to Cancer and Cardiovascular Diseases, Leo K. arr, IT. W. Knifrping and T/Zlmi H. Lewi*. Oplnden, Germany, Westdentseher Verlag, 96, 486 pages, illustrated. The 33 papers presented in this monograph nre published in English, German, or rench, with a translation of the summary in the two other languages. The ehapter on cerebral bld flow is a brief summary of the recent performed by the late 0. Nylin. The use of rndioisotopes in the measurement of cardiovascular function is reviewed by H. Ludes. The estimation of regional ventilation of the lungs by means of xenon 3 is described by H. Venrnth and H. Rink. The other chaptei-s pertain to th,e use of isotopes in the investigation of cancer. A Survey of Cardiac G-lycosides and Genins, J. Hampton Tfoch. Columbia, South Carolina, l, T neraity of South Carolina Press, 96, 93 pages. $3.50. This is a survey of the botanical, chemical, and pharmacological aspects of the cardiac glycosides. The data are presented in three tables and have been gathered both from the original literature and from abstract sources. The table on animal assay doses is particularly useful to the investigator who is interested in comparing the potency of various glycosides. About 300 glycosides are listed. or each of these, there is a lethal dose and a dose that is effecte in influencing cardiac function in various animal species. One shortcoining of the available literature is clearly emphasized in these tables. It would be desirnble to know for most glycosides the relate ratios between the effecte dose that will improve ventricular function, the dose that will induce cardiac an-hythinias, and the lethal dose. L'apparato Oardiovascolare nelle alattie da Virus Noti, Endemiche in Italia (The Cardiovascular System in the Course of Known Viral Diseases of Common Occurrence in Italy),. arcolongo and U. Carcassi. Rome, Atti della Soeieta Itnlinn di Cardiologia, XX Congresso, June 958, vol. I, 47 pnges, illustrated. During the last 20 years, clinicians have become increasingly aware of myoenrdial involvement in the course of viral diseases, such as influenza, measles, mumps, atypical pneumonia, etc. The most common features of cardiac pathology in these diseases nre the lack of specific anatomical localization and the absence of a definite eleetrocnrdiographic picture, except for the usual alterations of the S-T segment and the occasional appearance of conduction defects. This extense review of the problem and related literature restates the most important features of the problem and contributes in some measure to a clearer understanding of the pathogenetie relationship between systemic viral invasion and myocardial involvement. Unfortunately, it provides no basic information on the existence of a specific tropism of viruses for cardiac muscle. Until such information is available, efforts of this kind are necessarily inconcluse and, therefore, serve to emphasize the need for further study rather than provide definite explanations. Circulation Retearch, Volume XI, November 9tt