Acta anaesth. scand. 1975, 19, 1-7
Changes in Systolic Time Intervals During Stepwise Increasing Hypoxia J. P. RASMUSSEN, P. BECH-JANSEN and T. KANN Department of Anaesthesia 11, Gentofte Hospital, Copenhagen, Denmark
Determinations of the reciprocal value of the square of the pre-ejection period (l/PEP2) and the pre-ejection period/left ventricular ejection time-ratio (PEP,’ LVET-ratio) during stepwise increasing hypoxia showed in seven mongrel dogs a decrease in PEP/LVET-ratio and an increase in l/PEPZ as an expression of a stimulation of the cardiac function. Significant changes were not observcd before the arterial oxygen tension (Pa,,) was below 40 mmHg. During severe hypoxia (Pao, 15-20 mmHg), some deterioration in the systolic time intervals occurs with time, but a stimulation persists at the time of death compared to the prehypoxic values.
Received 27 December 1973, accepted for publication 5374 1974
The influence of hypoxia on cardiac function has been discussed for several years. Part of this discussion has been due to differences in experimental methods and parameters chosen by the various investigators concerned about cardiac performance (DOWNING 1966, NOBLE et al. 1966). Using aortic flow and maximum blood flow acceleration and left ventricular stroke volume as parameters to assess cardiac performance, NOBLEet al. (1966) found that changes in arterial blood oxygen tension (Pao,) over the range 40-500 mmHg had no effect on cardiac performance. In a previous paper, RASMUSSEN & BECHJANSEN (1974) have described the changes in the pre-ejection period (PEP) and the left ventricular ejection time (LVET) of the heart during transient hypoxia and reoxygenation. A decrease in PEPILVET-ratio and an increase in 1/PEP2during short term hypoxia were observed, and both parameters returned to prehypoxic values after reoxygenation. Evaluation of myocardial functionis still under discussion (SHIMOSATO et al. 1971, BRAUNWALD1972), but it is commonly
agreed upon that the systolic time intervals (STI) of the left ventricular systole are useful as non-invasive expressions of cardiac function (HARRIS et al. 1967, REITANet al. 1972, WEISSLER & GARRARD 1971a, 1971b). PEP and LVET estimated from central aortic catheterizations and from non-invasively derived carotid pulse tracings have demonet al. strated a close correlation (TALLEY 1971, WEISSLER et al. 1961). METZCER et al. et al. (1971) found (1970) and TALLEY significant close correlation between PEP and the first derivatives of the left ventricular pressure (dp/dt, dp/dt,,,) over a wide range of inotropic stimuli. This study was planned to evaluate the changes in 1/PEP2 and PEP/LVET-ratio in anesthetized dogs during stepwise increasing hypoxia to determine the relation between different arterial oxygen tensions and the function of the myocardium.
MATERIAL AND METHODS Anesthesia Seven unpremedicated mongrel dogs weighing 14-2 1 kg were anesthetized with a nitrous oxide (NzO)/
2
J. P. RASMUSSEN, P. BECH-JANSEN AND T . KANN
ECG
ECG
ECG
A : Catheter 'in left ventricle
B: W i t h d r a w a l -
of
catheter
Fig. 1. Electrocardiograms (ECG) related to pressure curves from the left ventricle (LV) and the ascending aorta (AO).
C : Catheter i n place
oxygen (0,)-mixture after halothane induction. After 2-4 min, a 15 gauge plastic needle was inserted into the bracheocephalic-vein. Succinylcholine chloride (50 mg) was injected, and following muscle relaxation, the dogs were intubated. The animals were ventilated with an intermittent positive pressure non-rebreathing system utilizing an Air-Shield@ ventilator. The tidal volume and respiratory rate were kept constant. Carbon dioxide (COZ)was added to the inspired NzO/ O2-mixture to maintain a steady arterial carbon dioxide tension (PacoZ) of 3 5 4 2 mmHg throughout the study. After halothane vapor was discontinued, the nitrous oxide was administered in mixture with oxygen to provide a controlled arterial oxygen tension (Pa ) O2 of 130 mmHg. Nitrous oxide was used as an anesthetlc agent because it does not possess any direct myocardial depressant or stimulant properties (GOLDBERG et al. 1972). Muscle relaxation was maintained with succinylcholine chloride.
Recordings and measurements
Arterial blood gas tensions (Pao2, Paco2) and p H were monitored continuously using an artificial external femoral arterial-venous shunt as previously described (RASMUSSEN & BECH-JANSEN 1974). Via the right carotid artery, a catheter with one end-
A0
C
hole (Lehman no. 7, USCI) was placed in the ascend ing aorta just outside the aortic valves (Fig. 1). The aortic pressure curve was recorded using a Statham P-23 Db strain gauge transducer, the output of which was recorded on a multichannel stripchart recorder (Ultralette) with a frequency response of 1700 cycles per s. The Statham P-23 dB strain gauge transducer plus the aortic catheter has a 100 Hz flat amplitudefrequency response. The central venous pressure (CVP) was recorded from the superior vena cava via a catheter placed in the right external jugular vein connected to a waterfilled Venometer. Lead I1 of the electrocardiogram (ECG) was recorded on the same stripchart recorder. The dogs were kept heparinized throughout the study. The experimental protocol consisted of a 20-minute normoxic stabilization period (i.e., Pao2 130 mmHg, Paco, 35-42 mmHg and stable blood pressure (BP), heart rate (HR) and CVP). At the end of this period, blood gas values, EGG, CVP and aortic pressure curve were recorded. Then the normoxic period was changed to stepwise increasing hyjoxia with a decrease in Pao2 of 10 mmHg every 5 min. The decrease in Paoz was obtained by changing the inspired Oz-percentage. Every 5 min blood gas values, ECG, CVP and
3
SYSlOLIC TIME INTERVALS DURING INCREASING HYPOXIA
aortic pulse curve were recorded throughout the experiment. At a Pao2 of 20 mmHg, the stepwise hypoxic period was changed to steady hypoxia with a Pao2 of 15-20 mmHg which was maintained until the death of the animal. The pre-ejection period was measured as the interval from the Q-wave of the ECG to the onset of the upstroke from the aortic pressure tracing. The left ventricular ejection time was measured from the aortic pulse curve as the interval between the onset of upstroke and the dicrotic notch as previously described (RASMUSSEN & BECH-JANSEN 1974). The measurements were all done manually on rectilinear paper tracings at a paper-speed of 100 mm/s. During sinus rhythm, 10 consecutive heartbeats and during arrhythmias, 20 consecutive heartbeats were analyzed and averaged for each determination of PEP and LVET. From these values PEP/LVET-ratio and l/PEPZwere calculated.
values. During increasing hypoxia at a constant PacOz (38 mmHg) and a constant pH (7.34), no changes in PEP/LVET-ratio and I/PEP2 are observed until PaO2is below 40 mmHg; then a decrease in PEP/LVETratio occurs. The maximum changes are reached at a PaOzof 20 mmHg. A concomitant increase in 1/PEP2 is observed, and by comparison of PEP/LVET-ratio and 1/PEP2 using linear regression analysis, a correlation coefficient of -0.994 is found. Because of this good correlation, further statistic analysis will be carried out only for the parameter PEP/LVET-ratio. T o evaluate whether the change in PEP/LVET-ratio caused by increasing hypoxia was statistically significant the Wilcoxon test was performed (see Table RESULTS 1). The changes in PEPiLVET and 1/PEP2 Table 1 shows control values during the are shown graphically in Fig. 2. normoxic stabilization period, and the effect From Table 1 it is possible to recognize the of the stepwise increasing hypoxia on PEP/ hypoxic response, i.e., bradycardia and LVET-ratio and 1/PEP2 values. The values hypertension. pH remains unchanged are presented as mean values of PEPiLVET throughout this part of the experiment. T h e and 1/PEP2 in percent of the uniform values. changes in PEPiLVET and l/PEP2 precede The uniformation is obtained by dividing all the increase in central venous pressure and calculated values of PEPiLVET and 1/PEP2 the changes in heart rate and blood pressure. in each dog experiment by the single control In Table 2 are shown the parameters durvalue of the experiment times 100. S.d. and ing steady hypoxia at a PaOzof 15-20 mmHg s.e. mean are calculated from the uniformed and a PacO2of 35-42 mmHg. The responses Table 1 PEP/LVET, ]/PEP2 and the observations of Pao2, Paco2, pH, blood pressure (BP), heart rate (HR) and central venous pressure (CVP) during increasing hypoxia. Values of PEPiLVET and l/PEPZare mean values in percent of the uniform values. Results are mean values from seven dogs. PEP/LVET-values with significant changes are marked * P V
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about 25 min after the onset of the severe hypoxia (Pa,, = 20 mmHg). Then a decrease in l/PEPZ and an increase in PEP/ LVET-ratio are found, but the dogs die even before the values reach control levels. The changes in the two parameters are shown graphically in Fig. 3. From Table 2 it is also seen that the hypoxic bradycardia continues, but there is a transitory increase in heart rate at the end of the experiment. The hypertension gradually decreases towards the end of the experiment, where the dogs die under hypotension. The central venous pressure increases just before the dogs die.
150
DISCUSSION
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The primary cardiovascular responses to total body hypoxia have been shown mainly to be due to activation of the sympathetic nervous system and a release of catechol50. amines (DOWNING 1966, WOODS & RICHARDSON 1959, MILLAR1960). I n dogs whose ventilation was kept cont stant, KONTOS et al. (1965) found decreased heart rate and increased mean arterial blood Fig. 3. The effects of maintained hypoxia (Pa,, 15-20 mmHg) on the parameters, PEP/LVET and I/PEP2. pressure when the Paoz was around 30 Values are mean values of two dog experiments. mmHg. These findings are in agreement with those reported here. Our findings can in part be explained as a in the STI during this part of the hypoxic stress are identical in trend, but the changes result of a combined sympathetic and vagal do not occur at the same time in all dogs, for effect on the cardiovascular system. During which reason the results from two typical the stepwise increasing hypoxia, both hyperexperiments (dogs nos. 4 and 5) are demon- tension and bradycardia were present, and strated. Dogs nos. 4 and 5 both correspond to the contractile state of the myocardium the mean values of all seven dogs as concerns showed an increase expressed by a fall in body weight (mean 17 kg), minutes to the PEP/LVET-ratio and an increase in 1/PEP2. DOWNINGin 1966 also found a rise in cessation of decrease in PEP/LVET-ratio (mean 27 min, range 10-35 min), minutes to arterial blood pressure and a slowing in heart the termination of increase in 1/PEP2 (mean rate when dogs were exposed to severe 30 min, range 15-35 min) and minutes to hypoxia during controlled ventilation. Downing explains this as a stimulation of the death (mean 45 min, range 30-60 min). During the steady hypoxia (Table 2) at a chemoreceptors due to the low Pao2 resulting Paoz level of 15-20 mmHg, an increasing in peripheral vasoconstriction and bradymetabolic acidosis is evident. The p H drops cardia. The arterial hypertension is caused by from 7.32 to 6.89. PEPiLVET and l/PEPZ a direct stimulation by the low PaO, of the continue the changes already seen during vasomotor center in the central nervous stepwise increasing hypoxia (Table 1 and system via the sympathetic nerves. The Fig. 2), but reach the maximum changes hypertension per se might cause an additional 100.
6
J. P. RASMUSSEN, P. BECH-JANSEN AND T. KANN
decrease in heart rate via the baroreceptor in PEP/LVET-ratio are seen as soon as the PaO2decreases from 120 mmHg to 80 mmHg. reflex mechanism. A decrease in the pre-ejection period like The changes in PEP/LVET-ratio precede the we found during severe hypoxia due to changes in central venous pressure, heart rate sympathetic activation is in agreement with and arterial blood pressure. Our experiments do not explain why the HARRIS et al. (1967) who showed a shortening of the pre-ejection period during P-adrenergic dogs all die during the final steady hypoxic receptor activation. Increase in l/PEP2 and period before the systolic time intervals of decrease in PEP/LVET-ratio are seen from the heart approach normoxic levels, i.e., a the beginning of stepwise decrease in arteriaI persisting stimulation or “improvement” in oxygen tension, but the maximum changes cardiac function at the time of death. were reached at a PaO2level of about 20 mmHg. When this low arterial oxygen tension was maintained without change in ACKNOWLEDGMENTS arterial carbon dioxide tension, the heart was The authors wish to thank M. SCHEELLARSENfor able to decrease the pre-ejection period even typing this manuscript and B. SAURBREY, L. MOHRand further in spite of an evident metabolic SOLENIELSEN for their technical assistance. acidosis, and not until this low Pao2 had lasted 25 min did the heart show a decrease in the contractile state. At that point the arterial ZUSAMENFASSUNG p H was 7.02. Bestimmungen des Reziprokwertes des Quadrates Endogenous corticoids in some way pro- der Vor-Auswurfsperiode ( l/PEP2) und der Relation tect against hypoxia. ROOSEVELTet al. zwischen der Vor-Auswurfsperiode und linksventri(1972) showed a corticoid-induced decrease kularen Auswurfzeit (PEP/LVET) wahrend schrittin lactic acid formation during exposure to weise verstarkter Hypoxie zeigted bei 7 Bastardhunden eine Abnahme von PEPiLVET und eine Zunahme hypoxia and postulated the protective effect von l/PEP2 als Ausdruck einer Stimulation der to be through a facilitation of aerobic metab- Herzfunktion. Signifikante Veranderungen wurden olism. The hypoxic stress in this study must erst unter einer arteriellen Sauerstoffspannung (Pao2) have reduced the amounts of corticoids, but von 40 mmHg beobachtet. Bei schwerer Hypoxie this alone does not explain why the heart is (Pao2 15-20 mmHg) kommt es mit der Zeit zu einer Verschlechterung des Systolenzeitintervalls, aber im affected. Even though stepwise increasing Vergleich zu den vor-hypoxischen Werten bleibt hypoxia resulting in a PaO, below 30-40 sogar zum Zeitpunkt des Todes noch eine Stimulation mmHg increases coronary blood flow (VANCE bestehen. et al. 1970), it is probably more important that there is a decrease in coronary blood flow due to a low p H as demonstrated by REFERENCES WANG & KATZ (1965) and attributed to BRAUNWALD, E. (1972) Myocardial function- 1972. intracellular acidosis and marked decrease of Anesth. Analg. Curr. Res. 51, 489. myocardial contractile force. Also, the acido- DOWNING, S. E. (1966) Autonomic influences on cardiac function in systemic hypoxia. Proceedings of the Intersis exerts a depressant action on the cardiovascular response to catecholamines (WOODS national Symposium on the Cardiovascular and Respiratory Effects of Hypoxia. Kingston, Ontario 1965, pp. 208et al. 1963). 23 1. Karger, Base1 and New York. We may conclude that the essential changes GOLDBERG, A., SOHN,Y. Z. & PHEAR,W. P. C. (1972) in 1/PEP2 and PEP/LVET-ratio occur at Direct myocardial effects of nitrous oxide. Anesthesiology 37, 373. arterial oxygen tensions below 40 mmHg HARRIS, W. S., SCHOENFELD, C. D. & WEISSLER, A. M. during stepwise increasing hypoxia. Hypoxia (1967) Effects of adrenergic receptor activation and with arterial oxygen tensions down to 40 blockade on the systolic pre-ejection period, heart mmHg causes no specific changes in the rate, and arterial pressure in man. 3. din. ItrveJt. 46, cardiovascular response, although alterations 1704.
SYSTOLIC TIME INTERVALS DURING INCREASING HYPOXIA
7
KONTOS, H. A., PAGEMAUCK,H., Jr., RICHARDSON,WANG,H. & KATZ,R. L. (1965) Effects of changes in coronary blood pH on the heart. Circ. Res. 17, 115. J. L., Jr. (1965) Mechanism D. W. & PATTERSON, A. M., PEELER,R. G. & ROCHLL, W. I1 of circulatory response to systemic hypoxia in the WEISSLER, (1961) Relationships between left ventricular anesthetized dog. Amer.3. Physiol. 209, 397. rjection time, stroke volume, and heart rate in METZGER, C. C., CHOUGH, C. B., KROETZ,F. W. & normal individuals and patients with cardiovascular LEONARD, J. J. (1970) True isovolumic contraction disease. Amer. Heart 3. 62, 367. time. Amer. J . Cardiol. 25, 434. A. M. & GARRARD, C. L. (1971a) Systolic MILLAR,R . A. (1960) Plasma adrenaline and nor- WEISSLER, time intervals in cardiac disease (I). Mod. Conc. adrenaline during diffusion respiration. 3. Physiol. cardiouasc. Dis. 15, 1. (Lond.) 150, 79. A. M. & GARRARD, C . L. (1971b) Systolic NOBLE,M. I. M., TRENCHARD, D. & Guz, A. (1966) WEISSLER, time intervals in cardiac disease 11. Mod. Conc. Effects of changes in Paco2 and PaoL on cardiac Cardiouasc. Dis. 15, 5. performance in conscious dogs. 3. aj@. Physiol. 22, WOODS,E. F. & RICHARDSON, J. A. (1959) Effect of 147. acute anoxia on cardiac contractility. Amer. 3. J. P. & BECH-JANSEN, P. (1974) Influence RASMUSSEN, Physiol. XX, 203. of transient hypoxia and reoxygenation on the preE. S. & WOODBURY, R. A. ejection period of the heart. Acta anaesth. scand. 18, WOODS,W. B., MANLEY, (1963) The effects of C02-induced respiratory 5. acidosis on the depressor and pressor components of REITAN, J. A., SMITH,N. T., BORISON, V. S. & KADIS, the dog’s blood pressure response to epinephrine. L. B. (1972) The cardiac pre-ejection period. 3. Pharmacol. exp. Ther. 139, 238. Anesthesiology 36, 76. T. S., RUHMANN-WENNHOLD, A. & NELSON, ROOSEVELT, D. H. (1972) A protective effect on glucocorticoids in hypoxic stress. Amer. 3. Physiol. 223, 30. S. & ETSTEN,B. E. (1971) Evaluating Address : SHIMOSATO, myocardial contractility. Anesthesiolopy 35, 327. TALLEY, R. C., MEYER, J. F. & MCNAY,J. L. (1971) 3. Peter Rasmussen, M.D. Evaluation of the pre-ejection period as an estimate of myocardial contractility in dogs. Amer. 3. Cardiol. 27, 384. J. R., MCBRIDE,T. I. & VANCE,J. P., PARRATT, LEDINGHAM, I. McA. (1970) The effects of hypoxia on myocardial blood flow and oxygen consumption. Brit. 3. Anaesth. 42, 558.
Case Western Reserve University School of Medicine Departments of Anesthesiology University Hospitals 2065 Adelbert Road Cleveland, Ohio 44106 U.S.A.
Changes in Systolic Time Intervals During Stepwise Increasing Hypoxia J. P. RASMUSSEN, P. BECH-JANSEN and T. KANN Department of Anaesthesia 11, Gentofte Hospital, Copenhagen, Denmark
Determinations of the reciprocal value of the square of the pre-ejection period (l/PEP2) and the pre-ejection period/left ventricular ejection time-ratio (PEP,’ LVET-ratio) during stepwise increasing hypoxia showed in seven mongrel dogs a decrease in PEP/LVET-ratio and an increase in l/PEPZ as an expression of a stimulation of the cardiac function. Significant changes were not observcd before the arterial oxygen tension (Pa,,) was below 40 mmHg. During severe hypoxia (Pao, 15-20 mmHg), some deterioration in the systolic time intervals occurs with time, but a stimulation persists at the time of death compared to the prehypoxic values.
Received 27 December 1973, accepted for publication 5374 1974
The influence of hypoxia on cardiac function has been discussed for several years. Part of this discussion has been due to differences in experimental methods and parameters chosen by the various investigators concerned about cardiac performance (DOWNING 1966, NOBLE et al. 1966). Using aortic flow and maximum blood flow acceleration and left ventricular stroke volume as parameters to assess cardiac performance, NOBLEet al. (1966) found that changes in arterial blood oxygen tension (Pao,) over the range 40-500 mmHg had no effect on cardiac performance. In a previous paper, RASMUSSEN & BECHJANSEN (1974) have described the changes in the pre-ejection period (PEP) and the left ventricular ejection time (LVET) of the heart during transient hypoxia and reoxygenation. A decrease in PEPILVET-ratio and an increase in 1/PEP2during short term hypoxia were observed, and both parameters returned to prehypoxic values after reoxygenation. Evaluation of myocardial functionis still under discussion (SHIMOSATO et al. 1971, BRAUNWALD1972), but it is commonly
agreed upon that the systolic time intervals (STI) of the left ventricular systole are useful as non-invasive expressions of cardiac function (HARRIS et al. 1967, REITANet al. 1972, WEISSLER & GARRARD 1971a, 1971b). PEP and LVET estimated from central aortic catheterizations and from non-invasively derived carotid pulse tracings have demonet al. strated a close correlation (TALLEY 1971, WEISSLER et al. 1961). METZCER et al. et al. (1971) found (1970) and TALLEY significant close correlation between PEP and the first derivatives of the left ventricular pressure (dp/dt, dp/dt,,,) over a wide range of inotropic stimuli. This study was planned to evaluate the changes in 1/PEP2 and PEP/LVET-ratio in anesthetized dogs during stepwise increasing hypoxia to determine the relation between different arterial oxygen tensions and the function of the myocardium.
MATERIAL AND METHODS Anesthesia Seven unpremedicated mongrel dogs weighing 14-2 1 kg were anesthetized with a nitrous oxide (NzO)/
2
J. P. RASMUSSEN, P. BECH-JANSEN AND T . KANN
ECG
ECG
ECG
A : Catheter 'in left ventricle
B: W i t h d r a w a l -
of
catheter
Fig. 1. Electrocardiograms (ECG) related to pressure curves from the left ventricle (LV) and the ascending aorta (AO).
C : Catheter i n place
oxygen (0,)-mixture after halothane induction. After 2-4 min, a 15 gauge plastic needle was inserted into the bracheocephalic-vein. Succinylcholine chloride (50 mg) was injected, and following muscle relaxation, the dogs were intubated. The animals were ventilated with an intermittent positive pressure non-rebreathing system utilizing an Air-Shield@ ventilator. The tidal volume and respiratory rate were kept constant. Carbon dioxide (COZ)was added to the inspired NzO/ O2-mixture to maintain a steady arterial carbon dioxide tension (PacoZ) of 3 5 4 2 mmHg throughout the study. After halothane vapor was discontinued, the nitrous oxide was administered in mixture with oxygen to provide a controlled arterial oxygen tension (Pa ) O2 of 130 mmHg. Nitrous oxide was used as an anesthetlc agent because it does not possess any direct myocardial depressant or stimulant properties (GOLDBERG et al. 1972). Muscle relaxation was maintained with succinylcholine chloride.
Recordings and measurements
Arterial blood gas tensions (Pao2, Paco2) and p H were monitored continuously using an artificial external femoral arterial-venous shunt as previously described (RASMUSSEN & BECH-JANSEN 1974). Via the right carotid artery, a catheter with one end-
A0
C
hole (Lehman no. 7, USCI) was placed in the ascend ing aorta just outside the aortic valves (Fig. 1). The aortic pressure curve was recorded using a Statham P-23 Db strain gauge transducer, the output of which was recorded on a multichannel stripchart recorder (Ultralette) with a frequency response of 1700 cycles per s. The Statham P-23 dB strain gauge transducer plus the aortic catheter has a 100 Hz flat amplitudefrequency response. The central venous pressure (CVP) was recorded from the superior vena cava via a catheter placed in the right external jugular vein connected to a waterfilled Venometer. Lead I1 of the electrocardiogram (ECG) was recorded on the same stripchart recorder. The dogs were kept heparinized throughout the study. The experimental protocol consisted of a 20-minute normoxic stabilization period (i.e., Pao2 130 mmHg, Paco, 35-42 mmHg and stable blood pressure (BP), heart rate (HR) and CVP). At the end of this period, blood gas values, EGG, CVP and aortic pressure curve were recorded. Then the normoxic period was changed to stepwise increasing hyjoxia with a decrease in Pao2 of 10 mmHg every 5 min. The decrease in Paoz was obtained by changing the inspired Oz-percentage. Every 5 min blood gas values, ECG, CVP and
3
SYSlOLIC TIME INTERVALS DURING INCREASING HYPOXIA
aortic pulse curve were recorded throughout the experiment. At a Pao2 of 20 mmHg, the stepwise hypoxic period was changed to steady hypoxia with a Pao2 of 15-20 mmHg which was maintained until the death of the animal. The pre-ejection period was measured as the interval from the Q-wave of the ECG to the onset of the upstroke from the aortic pressure tracing. The left ventricular ejection time was measured from the aortic pulse curve as the interval between the onset of upstroke and the dicrotic notch as previously described (RASMUSSEN & BECH-JANSEN 1974). The measurements were all done manually on rectilinear paper tracings at a paper-speed of 100 mm/s. During sinus rhythm, 10 consecutive heartbeats and during arrhythmias, 20 consecutive heartbeats were analyzed and averaged for each determination of PEP and LVET. From these values PEP/LVET-ratio and l/PEPZwere calculated.
values. During increasing hypoxia at a constant PacOz (38 mmHg) and a constant pH (7.34), no changes in PEP/LVET-ratio and I/PEP2 are observed until PaO2is below 40 mmHg; then a decrease in PEP/LVETratio occurs. The maximum changes are reached at a PaOzof 20 mmHg. A concomitant increase in 1/PEP2 is observed, and by comparison of PEP/LVET-ratio and 1/PEP2 using linear regression analysis, a correlation coefficient of -0.994 is found. Because of this good correlation, further statistic analysis will be carried out only for the parameter PEP/LVET-ratio. T o evaluate whether the change in PEP/LVET-ratio caused by increasing hypoxia was statistically significant the Wilcoxon test was performed (see Table RESULTS 1). The changes in PEPiLVET and 1/PEP2 Table 1 shows control values during the are shown graphically in Fig. 2. normoxic stabilization period, and the effect From Table 1 it is possible to recognize the of the stepwise increasing hypoxia on PEP/ hypoxic response, i.e., bradycardia and LVET-ratio and 1/PEP2 values. The values hypertension. pH remains unchanged are presented as mean values of PEPiLVET throughout this part of the experiment. T h e and 1/PEP2 in percent of the uniform values. changes in PEPiLVET and l/PEP2 precede The uniformation is obtained by dividing all the increase in central venous pressure and calculated values of PEPiLVET and 1/PEP2 the changes in heart rate and blood pressure. in each dog experiment by the single control In Table 2 are shown the parameters durvalue of the experiment times 100. S.d. and ing steady hypoxia at a PaOzof 15-20 mmHg s.e. mean are calculated from the uniformed and a PacO2of 35-42 mmHg. The responses Table 1 PEP/LVET, ]/PEP2 and the observations of Pao2, Paco2, pH, blood pressure (BP), heart rate (HR) and central venous pressure (CVP) during increasing hypoxia. Values of PEPiLVET and l/PEPZare mean values in percent of the uniform values. Results are mean values from seven dogs. PEP/LVET-values with significant changes are marked * P V
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SYSTOLIC TIME [NTERVALS DURING INCREASING HYPOXIA
5
2 00
about 25 min after the onset of the severe hypoxia (Pa,, = 20 mmHg). Then a decrease in l/PEPZ and an increase in PEP/ LVET-ratio are found, but the dogs die even before the values reach control levels. The changes in the two parameters are shown graphically in Fig. 3. From Table 2 it is also seen that the hypoxic bradycardia continues, but there is a transitory increase in heart rate at the end of the experiment. The hypertension gradually decreases towards the end of the experiment, where the dogs die under hypotension. The central venous pressure increases just before the dogs die.
150
DISCUSSION
100
350
300
2 50
The primary cardiovascular responses to total body hypoxia have been shown mainly to be due to activation of the sympathetic nervous system and a release of catechol50. amines (DOWNING 1966, WOODS & RICHARDSON 1959, MILLAR1960). I n dogs whose ventilation was kept cont stant, KONTOS et al. (1965) found decreased heart rate and increased mean arterial blood Fig. 3. The effects of maintained hypoxia (Pa,, 15-20 mmHg) on the parameters, PEP/LVET and I/PEP2. pressure when the Paoz was around 30 Values are mean values of two dog experiments. mmHg. These findings are in agreement with those reported here. Our findings can in part be explained as a in the STI during this part of the hypoxic stress are identical in trend, but the changes result of a combined sympathetic and vagal do not occur at the same time in all dogs, for effect on the cardiovascular system. During which reason the results from two typical the stepwise increasing hypoxia, both hyperexperiments (dogs nos. 4 and 5) are demon- tension and bradycardia were present, and strated. Dogs nos. 4 and 5 both correspond to the contractile state of the myocardium the mean values of all seven dogs as concerns showed an increase expressed by a fall in body weight (mean 17 kg), minutes to the PEP/LVET-ratio and an increase in 1/PEP2. DOWNINGin 1966 also found a rise in cessation of decrease in PEP/LVET-ratio (mean 27 min, range 10-35 min), minutes to arterial blood pressure and a slowing in heart the termination of increase in 1/PEP2 (mean rate when dogs were exposed to severe 30 min, range 15-35 min) and minutes to hypoxia during controlled ventilation. Downing explains this as a stimulation of the death (mean 45 min, range 30-60 min). During the steady hypoxia (Table 2) at a chemoreceptors due to the low Pao2 resulting Paoz level of 15-20 mmHg, an increasing in peripheral vasoconstriction and bradymetabolic acidosis is evident. The p H drops cardia. The arterial hypertension is caused by from 7.32 to 6.89. PEPiLVET and l/PEPZ a direct stimulation by the low PaO, of the continue the changes already seen during vasomotor center in the central nervous stepwise increasing hypoxia (Table 1 and system via the sympathetic nerves. The Fig. 2), but reach the maximum changes hypertension per se might cause an additional 100.
6
J. P. RASMUSSEN, P. BECH-JANSEN AND T. KANN
decrease in heart rate via the baroreceptor in PEP/LVET-ratio are seen as soon as the PaO2decreases from 120 mmHg to 80 mmHg. reflex mechanism. A decrease in the pre-ejection period like The changes in PEP/LVET-ratio precede the we found during severe hypoxia due to changes in central venous pressure, heart rate sympathetic activation is in agreement with and arterial blood pressure. Our experiments do not explain why the HARRIS et al. (1967) who showed a shortening of the pre-ejection period during P-adrenergic dogs all die during the final steady hypoxic receptor activation. Increase in l/PEP2 and period before the systolic time intervals of decrease in PEP/LVET-ratio are seen from the heart approach normoxic levels, i.e., a the beginning of stepwise decrease in arteriaI persisting stimulation or “improvement” in oxygen tension, but the maximum changes cardiac function at the time of death. were reached at a PaO2level of about 20 mmHg. When this low arterial oxygen tension was maintained without change in ACKNOWLEDGMENTS arterial carbon dioxide tension, the heart was The authors wish to thank M. SCHEELLARSENfor able to decrease the pre-ejection period even typing this manuscript and B. SAURBREY, L. MOHRand further in spite of an evident metabolic SOLENIELSEN for their technical assistance. acidosis, and not until this low Pao2 had lasted 25 min did the heart show a decrease in the contractile state. At that point the arterial ZUSAMENFASSUNG p H was 7.02. Bestimmungen des Reziprokwertes des Quadrates Endogenous corticoids in some way pro- der Vor-Auswurfsperiode ( l/PEP2) und der Relation tect against hypoxia. ROOSEVELTet al. zwischen der Vor-Auswurfsperiode und linksventri(1972) showed a corticoid-induced decrease kularen Auswurfzeit (PEP/LVET) wahrend schrittin lactic acid formation during exposure to weise verstarkter Hypoxie zeigted bei 7 Bastardhunden eine Abnahme von PEPiLVET und eine Zunahme hypoxia and postulated the protective effect von l/PEP2 als Ausdruck einer Stimulation der to be through a facilitation of aerobic metab- Herzfunktion. Signifikante Veranderungen wurden olism. The hypoxic stress in this study must erst unter einer arteriellen Sauerstoffspannung (Pao2) have reduced the amounts of corticoids, but von 40 mmHg beobachtet. Bei schwerer Hypoxie this alone does not explain why the heart is (Pao2 15-20 mmHg) kommt es mit der Zeit zu einer Verschlechterung des Systolenzeitintervalls, aber im affected. Even though stepwise increasing Vergleich zu den vor-hypoxischen Werten bleibt hypoxia resulting in a PaO, below 30-40 sogar zum Zeitpunkt des Todes noch eine Stimulation mmHg increases coronary blood flow (VANCE bestehen. et al. 1970), it is probably more important that there is a decrease in coronary blood flow due to a low p H as demonstrated by REFERENCES WANG & KATZ (1965) and attributed to BRAUNWALD, E. (1972) Myocardial function- 1972. intracellular acidosis and marked decrease of Anesth. Analg. Curr. Res. 51, 489. myocardial contractile force. Also, the acido- DOWNING, S. E. (1966) Autonomic influences on cardiac function in systemic hypoxia. Proceedings of the Intersis exerts a depressant action on the cardiovascular response to catecholamines (WOODS national Symposium on the Cardiovascular and Respiratory Effects of Hypoxia. Kingston, Ontario 1965, pp. 208et al. 1963). 23 1. Karger, Base1 and New York. We may conclude that the essential changes GOLDBERG, A., SOHN,Y. Z. & PHEAR,W. P. C. (1972) in 1/PEP2 and PEP/LVET-ratio occur at Direct myocardial effects of nitrous oxide. Anesthesiology 37, 373. arterial oxygen tensions below 40 mmHg HARRIS, W. S., SCHOENFELD, C. D. & WEISSLER, A. M. during stepwise increasing hypoxia. Hypoxia (1967) Effects of adrenergic receptor activation and with arterial oxygen tensions down to 40 blockade on the systolic pre-ejection period, heart mmHg causes no specific changes in the rate, and arterial pressure in man. 3. din. ItrveJt. 46, cardiovascular response, although alterations 1704.
SYSTOLIC TIME INTERVALS DURING INCREASING HYPOXIA
7
KONTOS, H. A., PAGEMAUCK,H., Jr., RICHARDSON,WANG,H. & KATZ,R. L. (1965) Effects of changes in coronary blood pH on the heart. Circ. Res. 17, 115. J. L., Jr. (1965) Mechanism D. W. & PATTERSON, A. M., PEELER,R. G. & ROCHLL, W. I1 of circulatory response to systemic hypoxia in the WEISSLER, (1961) Relationships between left ventricular anesthetized dog. Amer.3. Physiol. 209, 397. rjection time, stroke volume, and heart rate in METZGER, C. C., CHOUGH, C. B., KROETZ,F. W. & normal individuals and patients with cardiovascular LEONARD, J. J. (1970) True isovolumic contraction disease. Amer. Heart 3. 62, 367. time. Amer. J . Cardiol. 25, 434. A. M. & GARRARD, C. L. (1971a) Systolic MILLAR,R . A. (1960) Plasma adrenaline and nor- WEISSLER, time intervals in cardiac disease (I). Mod. Conc. adrenaline during diffusion respiration. 3. Physiol. cardiouasc. Dis. 15, 1. (Lond.) 150, 79. A. M. & GARRARD, C . L. (1971b) Systolic NOBLE,M. I. M., TRENCHARD, D. & Guz, A. (1966) WEISSLER, time intervals in cardiac disease 11. Mod. Conc. Effects of changes in Paco2 and PaoL on cardiac Cardiouasc. Dis. 15, 5. performance in conscious dogs. 3. aj@. Physiol. 22, WOODS,E. F. & RICHARDSON, J. A. (1959) Effect of 147. acute anoxia on cardiac contractility. Amer. 3. J. P. & BECH-JANSEN, P. (1974) Influence RASMUSSEN, Physiol. XX, 203. of transient hypoxia and reoxygenation on the preE. S. & WOODBURY, R. A. ejection period of the heart. Acta anaesth. scand. 18, WOODS,W. B., MANLEY, (1963) The effects of C02-induced respiratory 5. acidosis on the depressor and pressor components of REITAN, J. A., SMITH,N. T., BORISON, V. S. & KADIS, the dog’s blood pressure response to epinephrine. L. B. (1972) The cardiac pre-ejection period. 3. Pharmacol. exp. Ther. 139, 238. Anesthesiology 36, 76. T. S., RUHMANN-WENNHOLD, A. & NELSON, ROOSEVELT, D. H. (1972) A protective effect on glucocorticoids in hypoxic stress. Amer. 3. Physiol. 223, 30. S. & ETSTEN,B. E. (1971) Evaluating Address : SHIMOSATO, myocardial contractility. Anesthesiolopy 35, 327. TALLEY, R. C., MEYER, J. F. & MCNAY,J. L. (1971) 3. Peter Rasmussen, M.D. Evaluation of the pre-ejection period as an estimate of myocardial contractility in dogs. Amer. 3. Cardiol. 27, 384. J. R., MCBRIDE,T. I. & VANCE,J. P., PARRATT, LEDINGHAM, I. McA. (1970) The effects of hypoxia on myocardial blood flow and oxygen consumption. Brit. 3. Anaesth. 42, 558.
Case Western Reserve University School of Medicine Departments of Anesthesiology University Hospitals 2065 Adelbert Road Cleveland, Ohio 44106 U.S.A.
