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Effects of fluorocarbons with and without oxygen supplementation on cardiac hemodynamics and energetics
Effects of Fluorocarbons With and Without Oxygen Supplementation on Cardiac Hemodynamics and Energetics ROBERT E. RUDE, MD, LARRY R. BUSH, PhD, and GREGORY D. TILTON, MD
Because of uncertainty about the mechanism by which fluorocarbons ameliorate myocardial ischemia, the effects of a fluorocarbon emulsion, perfluorodecalin and perfluorotripropylamine (Fluosel-DA 2 0 % TM) with and without 100% 02 inhalation, on cardiac hemodynamics and energetics were studied in the anesthetized dog. Left ventricular (LV) intramural partial pressure of oxygen (PmO2) was measured by mass spectrometry before and after intravenous infusion of FIuosol-DA 20% (40 ml/kg), and was compared with measurements made in another group of dogs receiving the volume expander dextran (36 ml/kg). Both groups of dogs were then ventilated with 100% 02 and repeat measurements were performed. In the 11 animals receiving fluorocarbons, there were increases in left atrial pressure, LV myocardial blood flow, and LV myocardial 02 consumption (MY02) compati.ble with volume expansion. After 1 0 0 % 02, L V M V O 2 decreased to control values, while Pro02 increased to 127 4- 48 mm Hg (p <0.001). There were no significaM changes in heart rate, arterial pressure or first derivative of LV pressure (dP/dt) during the study, in 10 dogs treated
with dextran there was no change in heart rate or dP/dt, but arterial and left atrial pressures were higher after dextran infusion and remained elevated after 100 % 02 inhalation. LV MVO2 increased with volume expansion, and remained increased after 100% 02. PmO2 (66 -t- 18 mm Hg) after 100% 02 was lower (p <0.02) than in the fluorocarbontreated dogs after 02 inhalation. Thus, the acute hemodynamic effects of FIuosoI-DA 20 % are similar to those of a volume expander alone, but elevated left atrial pressure and LV MVO2 tend to be shorter lived than in dogs treated with dextran. After 100 % O2, LV MVO2 remained elevated in the dogstreated with dextran, but not in the fluorocarbon grouP. The extraordinarily high PmO2 attained in dogs treated with fluorocarbon-O2 is greater than thaf produced by volume expansion alone, and is not due to a measurable decrease in LV myocardial 02 demand. Thus, any beneficial effect of this fluorocarbon preparation on myocardial ischemla is likely due to enhanced O2 delivery rather than to reduced 02 demand.
Recent studies have shown that perfluorochemicals or fluorocarbons, inert organic compounds in which 02 and C02 are highly soluble, can substitute adequately for the gas transport functions of blood in both animals and man. 1-3 Perfluorochemicals are now being tested as "blood substitutes" in anemic patients who are not candidates for transfusion with blood or blood products. 4,5 Several workers6-1° have taken advantage of the unique properties of fluorocarbon emulsions to demonstrate potentially beneficial effects of these agents
in animal models of disease states, including cerebral and myocardial ischemia. However, the mechanism by which fluorocarbons ameliorate the severity of myocardial ischemia is not clear. Oxygenated fluorocarbons might improve 02 supply-demand mismatches by (1) enhancing the diffusion of 02 into ischemic segments or (2) reducing myocardial 02 requirements by intrinsic hemodynamic effects, s The latter possibility was proposed after demonstration that certain fluorocarbon emulsions have favorable effects on myocardial ischemic damage even in the absence of supplemental 02 administration, a setting in which fluorocarbon mediated increases in 02 transport should not be quantitatively sufficient to decrease the severity of ischemia, s,9 Because of these mechanistic uncertainties we investigated the effects of fluorocarbons with and without O2 supplementation on cardiac hemodynamics and energetics. The fluorocarbon emulsion utilized contained perfluorodecalin and perfluorotripropylamine Fluosol-DA 20%TM (Alpha Therapeutics Corporation),
(Am J Cardiol 1984;54:880-883)
From the Department of Internal Medicine, University of Texas Health Science Center at Dallas, Dallas, Texas. This study was supported by Clinical InvestigatorAward 1-K08-HL-0882-02from the NationalHeart, Lung, and Blood Instituteand SCOR Grant HL-17669 from the National Institutes of Health, Bethesda, Maryland, and by funds from the Harry S. Moss Heart Center, Dallas, Texas. Manuscript received March 16, 1984; revised manuscript received June 11, 1984, accepted June 14, 1984. Address for reprints: Robert E. Rude, MD, Department of Internal Medicine, University of Texas Health Science Center at Dallas, 5323 Harry Hines Boulevard, Dallas, Texas 75235. 880
October 1, 1984 THE AMERICAN JOURNAL OF CARDIOLOGY Volume 54
TABLE I
881
Hemodynamlc and Gas Tension Data ( M e a n -4- Standard Deviation) In Dogs Treated with Fluorocarbons Control Values
HR (beats/min) SAP (mm Hg) DAP (mm Hg) MAP (mm Hg) LAP (mm Hg) dP/dt (mm Hg/s) RMBFTM (ml/mln/g) A .-~SO2~ (ml O2/100 ml) MVO2 (ml O2/min/100 g) PaO2 (mm Hg) PaCO2 (mm Hg) PmO2 (mm Hg) PmCO2 (mm Hg)
143 114 94 102 4 1754 0.79 10.2
4- 18 -I- 16 4- 16 -I- 17 -I- 2a 4- 583 -I- 0.30 a 4- 2.5 7.8 4- 2.5 a 117 4- 20 a 36 4- 3 33 4- 13" 39 4- 8
60 Minutes"
After FC 131 136 104 120 8 2473 1.63 8.0 12.4 104
4- 30 -I- 22 4- 19 4- 21 4- 4b -I- 707 4- 0.60b -I- 2.6 -I- 4.6 b -I- 23 a
42 4- 8 33 4- I0 a 38 -I- 7
FC -I- O21" 131 126 97 110 6 2054 1.17 7.8 7.9 546
4- 17 4- 30 4- 27 4- 28 4- 3 c 4- 451 4- 0.71 c 4- 2.8 4- 2.6 a 4- 21 b 42 4- 16 127 4- 48 b 38 4- 8
• Values obtained 60 minutes after onset of fluorocarbon administration during room air inhalation. 1" Values obtained 30 minutes after the beginning of 100% 02 inhalation. Intergroup statistical comparison of data from different time periods is represented by lettered super-
scripts (a, b and c). Data from different time periods with different superscripts are statistically different (p <0,05), whereas data with the same or no superscript are not statistically different. Exact p values for selected comparisons are given in the text. Group data represent results from 11 dogs except for dP/dt, where n = 9; and PmO2 and PmCO2, where
n=8. A-CSO2 A = arterial coronary oxygen content difference; DAP = diastolic arterial pressure; dP/dt = maximal rate of rise of left ventricular pressure; FC = fluorocarbons; HR = heart rate; LAP = left atrial pressure; MAP = mean arterial pressure; MVO2 = calculated left ventrlcular myocardial oxygen consumpUon; 02 = oxygen; PaCO2 = arterial carbon dioxide tension; PaO2= partial pressure of oxygen; PmCO2 = intramural partial pressure of carbon dioxide; PmO2 = intramural partial pressure of oxygen; RMBFTM = transmural left ventrlcular myocardial blood flow; SAP = systolic arterial pressure.
t h e only fluorocarbon c u r r e n t l y a p p r o v e d for experim e n t a l h u m a n use in the U.S. Methods
Twenty-one mongrel dogs, weighing 15.9 to 31.4 kg, were anesthetized with intravenous pentobarbital (30 mg/kg), intubated with a cuffed endotracheal tube and ventilated with room air with a Harvard respirator. A left thoracotomy was performed to expose the anterolateral surface of the heart. Cannulas were placed in the left atrium, left common carotid artery, left jugular vein, left femoral vein, and coronary sinus for blood sampling, injections and pressure measurement. A Konigsberg P22 catheter-tip micromanometer was placed in the left ventricular (LV) cavity through the cardiac apex. Hemodynamic measurements included phasic and mean arterial and left atrial mean pressures, maximal rate of increase in LV intracavitary pressure (dP/dt) and a lead II electrocardiogram. A 22-gauge stainless steel tissue-mass spectrometer probe (Chemetron 40-22-1052), the distal end of which consists of a 1.5-cm Teflon®-coated sensing surface, was inserted intramurally in the anterolateral LV wall through an epicardial incision and sutured in place. 11-14 Mass spectrometer probes were calibrated before and after each use by exposure to known 02 and CO2 tensions. Intramyocardial partial pressures of 02 (PmO2) and CO2 (PmCO2) were measured in the beating heart with a mass spectrometer (Perkin-Elmer 1100B). 11-14 Regional myocardial blood flow (RMBF) to the left ventricle was determined by the radioactive microsphere technique. Two to 6 million microspheres, 8 to 10 #m in diameter, were injected into the left atrium at 3 predetermined points in each protocol. Transmural samples of left ventricle surrounding the mass spectrometer probe were taken after the dog was killed, and were counted along with standard and arterial reference samples in a Packard GAmma Counter with appropriate window settings for each isotope. After background and energy-crossover corrections, RMBF was calculated by standard methods, 15 and expressed as milliliters per gram of LV tissue per minute.
LV myocardial oxygen consumption (M~O2) was calculated as the product of transmural LV myocardial blood flow (RMBF, ml/min/g) and the arterial-coronary sinus 02 content differenc~ (A-CS02 A, ml 02/ml blood), and was expressed as milliliters of 02/min/100 g of LV tissue. The 02 content of arterial and coronary venous samples was analyzed on either a Lex-O2-Con (Lexington Instruments) or ABL-3 (Radiometer). Experimental protocols: After 45 minutes of stabilization of the mass spectrometer probe and confirmation of physiologic arterial and intramyocardial gas tensions, the dogs were randomly classified into 2 groups. Either Fluosol-DA 20% (average 40 ml/kg) or dextran (average 36 ml/kg) was infused over 30 minutes to a target dose of 1,000 ml or that sufficient to consistently elevate left atrial mean pressure to 18 nun Hg. Thirty minutes after the end of either Fluosol-DA or dextran infusion, 100% 02 was administered through an endotracheal tube. Hemodynamic measurements were obtained immediately before Fluosol-DA or dextran infusion (control values), 60 minutes later (after volume expansion with either Fluosol-DA or dextran), and 30 minutes after beginning 100% 02 inhalation. Thus, the effects of Fluosol-DA infusion during both room air and 100% 02 inhalation, could be compared with effects of a volume expander (dextran) under identical conditions. Statistical analyses: All group data are presented as mean ± 1 standard deviation. Data from successive time points in the 2 groups were tested by analyses of variance, and followed by the Newman-Keuls multiple range test. 16 Intergroup comparison of PmO2 values after 100% 02 inhalation was performed by the Student t test for unpaired data. A 2-tailed p <0.05 was required for inference of statistical differences. Results
A n i m a l s treated with fluorocarbons: T h e r e were no significant changes in heart rate, arterial pressure or d P / d t after infusion of fluorocarbons or after the addition of O2 inhalation (Table I). L e f t atrial m e a n pressure increased from 4 + 2 to 8 + 4 m m Hg (p
882
EFFECTSOF FLUOROCARBONS ON CARDIAC ENERGETICS
T A B L E II
Hemodynamic and Gas Tension Data In Dogs Treated with Dextran Control
HR (beats/min) SAP (mm Hg) DAP (mm Hg) MAP (mm Hg) LAP (mm Hg) dP/dt (mm Hg/s) RMBFTM .(ml/min/g) A-.CSO2 A (ml O2/100 ml) MVO2 (ml O2/min/100 g) PaO2 (mm Hg) PaCO2 (mm Hg) PmO2 (mm Hg) PmCO2 (mm Hg)
137 102 83 92 5 1458 0.90 10.2 8.8 102 34 32 39
4- 28 4- 14a -I- 15a 4- 16a 4- 3 a 4- 342 4- 0.41 a 4- 2.2a 4- 3.7 a 4- 11a 4- 5 4- 19a 4- 15
Dextran (60 min) ° 131 140 108 124 11 1955 2.36 6.2 13.9 130 36 32 36
4- 30 -I- 28 b 4- 25 b 4- 28 b 4- 6 b 4- 505 4- 0.88 b 4- 1.2 b 4- 3.7 b 4- 50a 4- 8 4- 18a 4- 13
Dextran + 021 120 144 114 129 9 1795 1.71 7.0 12.0 490 30 66 35
4- 28 4- 32 b 4- 28 b 4- 30 b 4- 5 b 4- 387 4- 0.83 c 4- 1.2 b 4- 5.7 b 4- 42 b 4- 5 4- 18b 4- 16
" Control values obtained 60 minutes after onset of dextran infusion during room air inhalation. 1 Values obtained 30 minutes after beginning 100% 02 inhalation. Abbreviations as in Table I.
<0.001) 60 minutes after fluorocarbon infusion, and decreased thereafter, being 6 ± 3 mm Hg at the end of the study after 30 minutes of 100% 02 inhalation (p <0.05 vs other 2 measurement points). RMBF increased from 0.79 ± 0.30 ml/min/g in the control state to 1.63 q0.60 ml/min/g (p <0.001), and decreased to an intermediate value (1.17 ± 0.71 ml/min/g) after the administration of 02 (p <0.05 vs control; p <0.025 vs after fluorocarbon infusion). Calculated LV MV02 was increased 60 minutes after fluorocarbon infusion vs the control value (12.4 ± 4.6 vs 7.8 ± 2.5 ml 02/min/100 g, respectively, p <0.01). After administration of 100% 02, MV02 decreased to the control value. Arterial and LV intramural P02 (Pa02 and P~02, respectively) were significantly increased only after 100% 02 in the presence of circulating fluorocarbons. Pa02 increased to 546 q- 21 mm Hg (p <0.001 vs preceding values) and Pro02 increased to 127 ± 48 mm Hg (p <0.001 vs preceding values). There was no significant change in arterial or intramural PCO2 (PaC02 and PmCO2, respectively) during the study. Dogs treated with dextran: Although there was no significant change in heart rate or dP/dt at any measurement point, arterial and left atrial mean pressures were all higher after dextran infusion, and after 100% 02 inhalation (Table II). Similar to the response in the fluorocarbon group, RMBF increased after volume loading with dextran (from 0.90 + 0.41 to 2.36 + 0.88 ml/min/g, p <0.001), and decreased to an intermediate value (1.71 ± 0.83 ml/min/g, p <0.01 vs preceding values) after administration of 100% 02. A-CSO2 A narrowed from a control value of 10.2 ± 2.2 ml O2/100 ml to 6.2 ± 1.2 ml O2/100 ml after dextran infusion (p <0.001), and to 7.0 ± 1.2 m102/100 ml after the addition of 100% 02 (p <0.001 vs control, difference not significant [NS] vs values after dextran). As in dogs receiving fluorocarbons, calculated LV M'~O2 increased with volume loading (from 8.8 + 3.7 to 13.9 ± 3.7 ml 02/ min/100 g, p <0.01) after dextran; however, LV MV02 remained higher after 02 inhalation--12.0 ± 5.7 ml 02/rain/100 g (p <0.01 vs control value; NS vs values after dextran infusion). There were no changes in PaC02 and P=CO2 at any measurement point. Pa02 and PmO2 were significantly (p <0.001) increased only after 02
inhalation 490 4- 42 and 66 ± 18 mm Hg, respectively; this PmO2 value was significantly lower (p <0.02) than that obtained in the dogs treated with fluorocarbon after 02 inhalation (127 4- 48 mm Hg, Table I). Discussion
These studies were designed to determine the effects of a fluorocarbon emulsion on cardiac hemodynamics and energetics in the anesthetized opened-chest dog. Myocardial ischemia was not produced in these experiments, so that analyses of hemodynamic changes after the experimental interventions would not be confounded by another variable. The effects of similar amounts of a volume expander (dextran) and a fluorocarbon emulsion Fluosol-DA 20%, before and after inhalation of 100% 02, were compared. Left atrial pressure, LV transmural RMBF, and LV M'~02 were increased by the administration of both agents, while heart rate, dP/dt, and arterial and LV intramural PO2 and PCO2 were not changed. Dextran infusion clearly increased systolic, diastohc and mean arterial pressures; after 100% 02 inhalation, arterial and left atrial pressures remained more elevated in dogs treated with dextran, but decreased to or toward control values in the fluorocarbon group. LV RMBF in both groups remained elevated after 100% 02, at values intermediate between the control state and after acute volume loading with either agent. After 02 administration, LV M~'02 remained higher than in the control state in dogs treated with dextran, but decreased to control values in the fluorocarbon group. Arterial P02 increased dramatically after 100% 02 administration in both groups; LV Pro02 also increased in both groups, but more so in the animals with circulating fluorocarbons (P=O2 in dextran and fluorocarbon groups, 66 ± 18 and 127 ± 48 mm Hg, respectively, p <0.02). The hemodynamic effects of Fluosol-DA 20% are significantly shorter-lived than those of a pure volume expander (dextran) when infusion of either agent is followed by 100% 02 inhalation. Thus, the extraordinarily high PmO2 attained in the fluorocarbon-treated dogs is very unlikely to be due solely to the effects of volume expansion. Similarly, it is not likely to be due to a major decrease in LV myocardial 02 demand, be-
October 1, 1984 THE AMERICAN JOURNAL OF CARDIOLOGY Volume 54
cause of the nearly identical L V M V O 2 values in the control and fluorocarbon-O2-treated states.Any beneficialeffectsof 20% Fluosol-DA-02 treatment on acute myocardial ischemia are therefore more likelyto result from increased 02 delivery to ischemic myocardium than to decreased 02 demands. Fluosol-DA 20% is an emulsion that is differentfrom Decamine 60 (perfluorodecalin--perfluorotributylamine), which was used in our earlier studies of fluorocarbons in acute myocardial ischemia, 8 in which a bradycardic effect of the fluorocarbon preparation was noted. Fluosol-DA 20% did not decrease heart rate in the present study and has not produced significant changes in heart rates in anemic humans. 4,5 Fluorocarbon infusions have been added to the circulating blood volume in our studies. Thus, changes in cardiac hemodynamics and energetics m a y differ, either in magnitude or effect, from situations in which fluorocarbons are used as part of an exchange transfusion I° or in the treatment of intravascular volume depletion or severe anemia. 4,5Our model is more relevant to potential clinicaluse of fluorocarbon compounds in normovolemic and nonanemic patients, such as those with acute myocardial or cerebral infarction. In summary, our studies with an emulsion of Fluosol-DA 20% indicate that its acute hemodynamic effects are similar to those of a volume expander (dextran). After addition of 100% 02 inhalation, cardiac hemodynamics and energetics are similar to those of the control state, except for modest increases in myocardial blood flow and a dramatic increase in LV intramural PO2. This increase in myocardial 02 availability appears to be more related to enhancement of 02 delivery to the left ventricle than to major reductions in myocardial 02 demand. Acknowledgment: We gratefully acknowledgethe expert technical assistance of Janice McNatt, Michael Deguchi,
883
Julius Lamar and Cora Marsaw in the performance of these studies;the assistanceof Paulette Newingham in the preparation of the manuscript;and the thoughtfuladvice of James T. Willerson,MD.
References 1. Clark LC Jr, Gollan F. Survival of mammals breathing organic liquids equilibrated with oxygen at atmospheric pressure. Science 1966;152: 1755-1756. 2. Geyer RP. Fluorocarbon-polyol artificial blood substitutes. N Engl J Med 1973;289:1077-1082. 3. Geyer RP. Oxygen transport in vivo by means of perfluorochemical preparations. N Engl J IVied 1982;307:304-305. 4. Tremper KK, Friedman AE, Levlne EM, Lapin R, and Camarlllo D. The preoperativetreatmentof severely anemic patientswith a perfluorochemical • oxygen--transport fluid, FluosoI-DA. N Engl J Med 1982;307:277283. 5. Mltsuno T, Chyanagl I.I, Nalto R. Clinical studies of a perfluorochemical whole blood substitute (Fluosol.-DA): summary of 186 cases. Ann Surg 1982;195:60-69. 6. Slovlter HA, Kamlmoto T. Erythrocyte substitution for perfusion of brain. Nature 1967;216:458-46• 7. Glogar DH, Kloner RA, Ml~b~erJE, DeBoer LWV, Braunwald E, Clark LC Jr. Fluorocarbons reduce =nyocardial ischemic damage after coronary occlusion. Science 1981;211:1439-1441. 8. Rude RE, Glogar D, Khurl SF, Kloner RA, Karaffa S, Muller JE, Clark LC Jr, Braunwald E. Effects of intravenous fluorocarbons during and without oxygen enhancement on acute myocardial ischemic injury assessed by measurement of Intramyocardial gas tensions. Am Heart J 1982;103: 986-995. 9. Glogar DH, Clark LC Jr, Kloner RA, DeBoer LWV, Muller JE, Braunwald E. Fluorocarbons--synthetic oxygen carrying compounds which reduce myocardial ischamla (abstr). Circulation 1980;62:supp1111-111-144. 10. Nunn GR, Dance G, Peters J, Cohn LH. Effects of fluorocarbon exchange transfusion on myocardial infarction size in dogs. Am J Cardlol 1983;52: 203-205.
11. HIIIIsLD, Khud SF, Braunwald E, Kloear RA, Tow D, Barsandan E, Maroko PR. Assessment of the efficacy of interventions to limit ischemic injury by direct measurement of intramural carbon dioxide tension after coronary artery occlusion in the dog. J Clin Invest 1979;63:99-107. 12. Rude RE, Izqulerdo C, BuJa LM, Wlllerson Jr. Effects of inotropic and chronotropic stimuli on acute myocardial ischemic injury. I. Studies with dobutamine in the anesthetized dog. Circulation 1982;65:1321-1328. 13. Khurl SF, Kloner RA, HIIIIs LD, Tow DE, Barsamlan EM, Maroko PR, Braunwald E. Intramural PCO2:a reliable index of the severity of myocardial ischemic injury. Am J Physiol 1979;237:253-259. 14. Brantlgan JW, Gott VL, Martz MV. A Teflon membrane for measurement of blood and intramyocardlal gas tensions. J Appl Physiol 1972;32:276282. 15. Heymann MA, Payne BD, Hoffman JIE, Rudolph AM. Blood flow measurements with radionuclide labeled particles. Prog Cardiovasc Dis 1977;20:55-79. 16. Zar JR. Biostatistical Analysis. Englewood Cliffs, NJ: Prentlce-Hall, 1974.
Because of uncertainty about the mechanism by which fluorocarbons ameliorate myocardial ischemia, the effects of a fluorocarbon emulsion, perfluorodecalin and perfluorotripropylamine (Fluosel-DA 2 0 % TM) with and without 100% 02 inhalation, on cardiac hemodynamics and energetics were studied in the anesthetized dog. Left ventricular (LV) intramural partial pressure of oxygen (PmO2) was measured by mass spectrometry before and after intravenous infusion of FIuosol-DA 20% (40 ml/kg), and was compared with measurements made in another group of dogs receiving the volume expander dextran (36 ml/kg). Both groups of dogs were then ventilated with 100% 02 and repeat measurements were performed. In the 11 animals receiving fluorocarbons, there were increases in left atrial pressure, LV myocardial blood flow, and LV myocardial 02 consumption (MY02) compati.ble with volume expansion. After 1 0 0 % 02, L V M V O 2 decreased to control values, while Pro02 increased to 127 4- 48 mm Hg (p <0.001). There were no significaM changes in heart rate, arterial pressure or first derivative of LV pressure (dP/dt) during the study, in 10 dogs treated
with dextran there was no change in heart rate or dP/dt, but arterial and left atrial pressures were higher after dextran infusion and remained elevated after 100 % 02 inhalation. LV MVO2 increased with volume expansion, and remained increased after 100% 02. PmO2 (66 -t- 18 mm Hg) after 100% 02 was lower (p <0.02) than in the fluorocarbontreated dogs after 02 inhalation. Thus, the acute hemodynamic effects of FIuosoI-DA 20 % are similar to those of a volume expander alone, but elevated left atrial pressure and LV MVO2 tend to be shorter lived than in dogs treated with dextran. After 100 % O2, LV MVO2 remained elevated in the dogstreated with dextran, but not in the fluorocarbon grouP. The extraordinarily high PmO2 attained in dogs treated with fluorocarbon-O2 is greater than thaf produced by volume expansion alone, and is not due to a measurable decrease in LV myocardial 02 demand. Thus, any beneficial effect of this fluorocarbon preparation on myocardial ischemla is likely due to enhanced O2 delivery rather than to reduced 02 demand.
Recent studies have shown that perfluorochemicals or fluorocarbons, inert organic compounds in which 02 and C02 are highly soluble, can substitute adequately for the gas transport functions of blood in both animals and man. 1-3 Perfluorochemicals are now being tested as "blood substitutes" in anemic patients who are not candidates for transfusion with blood or blood products. 4,5 Several workers6-1° have taken advantage of the unique properties of fluorocarbon emulsions to demonstrate potentially beneficial effects of these agents
in animal models of disease states, including cerebral and myocardial ischemia. However, the mechanism by which fluorocarbons ameliorate the severity of myocardial ischemia is not clear. Oxygenated fluorocarbons might improve 02 supply-demand mismatches by (1) enhancing the diffusion of 02 into ischemic segments or (2) reducing myocardial 02 requirements by intrinsic hemodynamic effects, s The latter possibility was proposed after demonstration that certain fluorocarbon emulsions have favorable effects on myocardial ischemic damage even in the absence of supplemental 02 administration, a setting in which fluorocarbon mediated increases in 02 transport should not be quantitatively sufficient to decrease the severity of ischemia, s,9 Because of these mechanistic uncertainties we investigated the effects of fluorocarbons with and without O2 supplementation on cardiac hemodynamics and energetics. The fluorocarbon emulsion utilized contained perfluorodecalin and perfluorotripropylamine Fluosol-DA 20%TM (Alpha Therapeutics Corporation),
(Am J Cardiol 1984;54:880-883)
From the Department of Internal Medicine, University of Texas Health Science Center at Dallas, Dallas, Texas. This study was supported by Clinical InvestigatorAward 1-K08-HL-0882-02from the NationalHeart, Lung, and Blood Instituteand SCOR Grant HL-17669 from the National Institutes of Health, Bethesda, Maryland, and by funds from the Harry S. Moss Heart Center, Dallas, Texas. Manuscript received March 16, 1984; revised manuscript received June 11, 1984, accepted June 14, 1984. Address for reprints: Robert E. Rude, MD, Department of Internal Medicine, University of Texas Health Science Center at Dallas, 5323 Harry Hines Boulevard, Dallas, Texas 75235. 880
October 1, 1984 THE AMERICAN JOURNAL OF CARDIOLOGY Volume 54
TABLE I
881
Hemodynamlc and Gas Tension Data ( M e a n -4- Standard Deviation) In Dogs Treated with Fluorocarbons Control Values
HR (beats/min) SAP (mm Hg) DAP (mm Hg) MAP (mm Hg) LAP (mm Hg) dP/dt (mm Hg/s) RMBFTM (ml/mln/g) A .-~SO2~ (ml O2/100 ml) MVO2 (ml O2/min/100 g) PaO2 (mm Hg) PaCO2 (mm Hg) PmO2 (mm Hg) PmCO2 (mm Hg)
143 114 94 102 4 1754 0.79 10.2
4- 18 -I- 16 4- 16 -I- 17 -I- 2a 4- 583 -I- 0.30 a 4- 2.5 7.8 4- 2.5 a 117 4- 20 a 36 4- 3 33 4- 13" 39 4- 8
60 Minutes"
After FC 131 136 104 120 8 2473 1.63 8.0 12.4 104
4- 30 -I- 22 4- 19 4- 21 4- 4b -I- 707 4- 0.60b -I- 2.6 -I- 4.6 b -I- 23 a
42 4- 8 33 4- I0 a 38 -I- 7
FC -I- O21" 131 126 97 110 6 2054 1.17 7.8 7.9 546
4- 17 4- 30 4- 27 4- 28 4- 3 c 4- 451 4- 0.71 c 4- 2.8 4- 2.6 a 4- 21 b 42 4- 16 127 4- 48 b 38 4- 8
• Values obtained 60 minutes after onset of fluorocarbon administration during room air inhalation. 1" Values obtained 30 minutes after the beginning of 100% 02 inhalation. Intergroup statistical comparison of data from different time periods is represented by lettered super-
scripts (a, b and c). Data from different time periods with different superscripts are statistically different (p <0,05), whereas data with the same or no superscript are not statistically different. Exact p values for selected comparisons are given in the text. Group data represent results from 11 dogs except for dP/dt, where n = 9; and PmO2 and PmCO2, where
n=8. A-CSO2 A = arterial coronary oxygen content difference; DAP = diastolic arterial pressure; dP/dt = maximal rate of rise of left ventricular pressure; FC = fluorocarbons; HR = heart rate; LAP = left atrial pressure; MAP = mean arterial pressure; MVO2 = calculated left ventrlcular myocardial oxygen consumpUon; 02 = oxygen; PaCO2 = arterial carbon dioxide tension; PaO2= partial pressure of oxygen; PmCO2 = intramural partial pressure of carbon dioxide; PmO2 = intramural partial pressure of oxygen; RMBFTM = transmural left ventrlcular myocardial blood flow; SAP = systolic arterial pressure.
t h e only fluorocarbon c u r r e n t l y a p p r o v e d for experim e n t a l h u m a n use in the U.S. Methods
Twenty-one mongrel dogs, weighing 15.9 to 31.4 kg, were anesthetized with intravenous pentobarbital (30 mg/kg), intubated with a cuffed endotracheal tube and ventilated with room air with a Harvard respirator. A left thoracotomy was performed to expose the anterolateral surface of the heart. Cannulas were placed in the left atrium, left common carotid artery, left jugular vein, left femoral vein, and coronary sinus for blood sampling, injections and pressure measurement. A Konigsberg P22 catheter-tip micromanometer was placed in the left ventricular (LV) cavity through the cardiac apex. Hemodynamic measurements included phasic and mean arterial and left atrial mean pressures, maximal rate of increase in LV intracavitary pressure (dP/dt) and a lead II electrocardiogram. A 22-gauge stainless steel tissue-mass spectrometer probe (Chemetron 40-22-1052), the distal end of which consists of a 1.5-cm Teflon®-coated sensing surface, was inserted intramurally in the anterolateral LV wall through an epicardial incision and sutured in place. 11-14 Mass spectrometer probes were calibrated before and after each use by exposure to known 02 and CO2 tensions. Intramyocardial partial pressures of 02 (PmO2) and CO2 (PmCO2) were measured in the beating heart with a mass spectrometer (Perkin-Elmer 1100B). 11-14 Regional myocardial blood flow (RMBF) to the left ventricle was determined by the radioactive microsphere technique. Two to 6 million microspheres, 8 to 10 #m in diameter, were injected into the left atrium at 3 predetermined points in each protocol. Transmural samples of left ventricle surrounding the mass spectrometer probe were taken after the dog was killed, and were counted along with standard and arterial reference samples in a Packard GAmma Counter with appropriate window settings for each isotope. After background and energy-crossover corrections, RMBF was calculated by standard methods, 15 and expressed as milliliters per gram of LV tissue per minute.
LV myocardial oxygen consumption (M~O2) was calculated as the product of transmural LV myocardial blood flow (RMBF, ml/min/g) and the arterial-coronary sinus 02 content differenc~ (A-CS02 A, ml 02/ml blood), and was expressed as milliliters of 02/min/100 g of LV tissue. The 02 content of arterial and coronary venous samples was analyzed on either a Lex-O2-Con (Lexington Instruments) or ABL-3 (Radiometer). Experimental protocols: After 45 minutes of stabilization of the mass spectrometer probe and confirmation of physiologic arterial and intramyocardial gas tensions, the dogs were randomly classified into 2 groups. Either Fluosol-DA 20% (average 40 ml/kg) or dextran (average 36 ml/kg) was infused over 30 minutes to a target dose of 1,000 ml or that sufficient to consistently elevate left atrial mean pressure to 18 nun Hg. Thirty minutes after the end of either Fluosol-DA or dextran infusion, 100% 02 was administered through an endotracheal tube. Hemodynamic measurements were obtained immediately before Fluosol-DA or dextran infusion (control values), 60 minutes later (after volume expansion with either Fluosol-DA or dextran), and 30 minutes after beginning 100% 02 inhalation. Thus, the effects of Fluosol-DA infusion during both room air and 100% 02 inhalation, could be compared with effects of a volume expander (dextran) under identical conditions. Statistical analyses: All group data are presented as mean ± 1 standard deviation. Data from successive time points in the 2 groups were tested by analyses of variance, and followed by the Newman-Keuls multiple range test. 16 Intergroup comparison of PmO2 values after 100% 02 inhalation was performed by the Student t test for unpaired data. A 2-tailed p <0.05 was required for inference of statistical differences. Results
A n i m a l s treated with fluorocarbons: T h e r e were no significant changes in heart rate, arterial pressure or d P / d t after infusion of fluorocarbons or after the addition of O2 inhalation (Table I). L e f t atrial m e a n pressure increased from 4 + 2 to 8 + 4 m m Hg (p
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EFFECTSOF FLUOROCARBONS ON CARDIAC ENERGETICS
T A B L E II
Hemodynamic and Gas Tension Data In Dogs Treated with Dextran Control
HR (beats/min) SAP (mm Hg) DAP (mm Hg) MAP (mm Hg) LAP (mm Hg) dP/dt (mm Hg/s) RMBFTM .(ml/min/g) A-.CSO2 A (ml O2/100 ml) MVO2 (ml O2/min/100 g) PaO2 (mm Hg) PaCO2 (mm Hg) PmO2 (mm Hg) PmCO2 (mm Hg)
137 102 83 92 5 1458 0.90 10.2 8.8 102 34 32 39
4- 28 4- 14a -I- 15a 4- 16a 4- 3 a 4- 342 4- 0.41 a 4- 2.2a 4- 3.7 a 4- 11a 4- 5 4- 19a 4- 15
Dextran (60 min) ° 131 140 108 124 11 1955 2.36 6.2 13.9 130 36 32 36
4- 30 -I- 28 b 4- 25 b 4- 28 b 4- 6 b 4- 505 4- 0.88 b 4- 1.2 b 4- 3.7 b 4- 50a 4- 8 4- 18a 4- 13
Dextran + 021 120 144 114 129 9 1795 1.71 7.0 12.0 490 30 66 35
4- 28 4- 32 b 4- 28 b 4- 30 b 4- 5 b 4- 387 4- 0.83 c 4- 1.2 b 4- 5.7 b 4- 42 b 4- 5 4- 18b 4- 16
" Control values obtained 60 minutes after onset of dextran infusion during room air inhalation. 1 Values obtained 30 minutes after beginning 100% 02 inhalation. Abbreviations as in Table I.
<0.001) 60 minutes after fluorocarbon infusion, and decreased thereafter, being 6 ± 3 mm Hg at the end of the study after 30 minutes of 100% 02 inhalation (p <0.05 vs other 2 measurement points). RMBF increased from 0.79 ± 0.30 ml/min/g in the control state to 1.63 q0.60 ml/min/g (p <0.001), and decreased to an intermediate value (1.17 ± 0.71 ml/min/g) after the administration of 02 (p <0.05 vs control; p <0.025 vs after fluorocarbon infusion). Calculated LV MV02 was increased 60 minutes after fluorocarbon infusion vs the control value (12.4 ± 4.6 vs 7.8 ± 2.5 ml 02/min/100 g, respectively, p <0.01). After administration of 100% 02, MV02 decreased to the control value. Arterial and LV intramural P02 (Pa02 and P~02, respectively) were significantly increased only after 100% 02 in the presence of circulating fluorocarbons. Pa02 increased to 546 q- 21 mm Hg (p <0.001 vs preceding values) and Pro02 increased to 127 ± 48 mm Hg (p <0.001 vs preceding values). There was no significant change in arterial or intramural PCO2 (PaC02 and PmCO2, respectively) during the study. Dogs treated with dextran: Although there was no significant change in heart rate or dP/dt at any measurement point, arterial and left atrial mean pressures were all higher after dextran infusion, and after 100% 02 inhalation (Table II). Similar to the response in the fluorocarbon group, RMBF increased after volume loading with dextran (from 0.90 + 0.41 to 2.36 + 0.88 ml/min/g, p <0.001), and decreased to an intermediate value (1.71 ± 0.83 ml/min/g, p <0.01 vs preceding values) after administration of 100% 02. A-CSO2 A narrowed from a control value of 10.2 ± 2.2 ml O2/100 ml to 6.2 ± 1.2 ml O2/100 ml after dextran infusion (p <0.001), and to 7.0 ± 1.2 m102/100 ml after the addition of 100% 02 (p <0.001 vs control, difference not significant [NS] vs values after dextran). As in dogs receiving fluorocarbons, calculated LV M'~O2 increased with volume loading (from 8.8 + 3.7 to 13.9 ± 3.7 ml 02/ min/100 g, p <0.01) after dextran; however, LV MV02 remained higher after 02 inhalation--12.0 ± 5.7 ml 02/rain/100 g (p <0.01 vs control value; NS vs values after dextran infusion). There were no changes in PaC02 and P=CO2 at any measurement point. Pa02 and PmO2 were significantly (p <0.001) increased only after 02
inhalation 490 4- 42 and 66 ± 18 mm Hg, respectively; this PmO2 value was significantly lower (p <0.02) than that obtained in the dogs treated with fluorocarbon after 02 inhalation (127 4- 48 mm Hg, Table I). Discussion
These studies were designed to determine the effects of a fluorocarbon emulsion on cardiac hemodynamics and energetics in the anesthetized opened-chest dog. Myocardial ischemia was not produced in these experiments, so that analyses of hemodynamic changes after the experimental interventions would not be confounded by another variable. The effects of similar amounts of a volume expander (dextran) and a fluorocarbon emulsion Fluosol-DA 20%, before and after inhalation of 100% 02, were compared. Left atrial pressure, LV transmural RMBF, and LV M'~02 were increased by the administration of both agents, while heart rate, dP/dt, and arterial and LV intramural PO2 and PCO2 were not changed. Dextran infusion clearly increased systolic, diastohc and mean arterial pressures; after 100% 02 inhalation, arterial and left atrial pressures remained more elevated in dogs treated with dextran, but decreased to or toward control values in the fluorocarbon group. LV RMBF in both groups remained elevated after 100% 02, at values intermediate between the control state and after acute volume loading with either agent. After 02 administration, LV M~'02 remained higher than in the control state in dogs treated with dextran, but decreased to control values in the fluorocarbon group. Arterial P02 increased dramatically after 100% 02 administration in both groups; LV Pro02 also increased in both groups, but more so in the animals with circulating fluorocarbons (P=O2 in dextran and fluorocarbon groups, 66 ± 18 and 127 ± 48 mm Hg, respectively, p <0.02). The hemodynamic effects of Fluosol-DA 20% are significantly shorter-lived than those of a pure volume expander (dextran) when infusion of either agent is followed by 100% 02 inhalation. Thus, the extraordinarily high PmO2 attained in the fluorocarbon-treated dogs is very unlikely to be due solely to the effects of volume expansion. Similarly, it is not likely to be due to a major decrease in LV myocardial 02 demand, be-
October 1, 1984 THE AMERICAN JOURNAL OF CARDIOLOGY Volume 54
cause of the nearly identical L V M V O 2 values in the control and fluorocarbon-O2-treated states.Any beneficialeffectsof 20% Fluosol-DA-02 treatment on acute myocardial ischemia are therefore more likelyto result from increased 02 delivery to ischemic myocardium than to decreased 02 demands. Fluosol-DA 20% is an emulsion that is differentfrom Decamine 60 (perfluorodecalin--perfluorotributylamine), which was used in our earlier studies of fluorocarbons in acute myocardial ischemia, 8 in which a bradycardic effect of the fluorocarbon preparation was noted. Fluosol-DA 20% did not decrease heart rate in the present study and has not produced significant changes in heart rates in anemic humans. 4,5 Fluorocarbon infusions have been added to the circulating blood volume in our studies. Thus, changes in cardiac hemodynamics and energetics m a y differ, either in magnitude or effect, from situations in which fluorocarbons are used as part of an exchange transfusion I° or in the treatment of intravascular volume depletion or severe anemia. 4,5Our model is more relevant to potential clinicaluse of fluorocarbon compounds in normovolemic and nonanemic patients, such as those with acute myocardial or cerebral infarction. In summary, our studies with an emulsion of Fluosol-DA 20% indicate that its acute hemodynamic effects are similar to those of a volume expander (dextran). After addition of 100% 02 inhalation, cardiac hemodynamics and energetics are similar to those of the control state, except for modest increases in myocardial blood flow and a dramatic increase in LV intramural PO2. This increase in myocardial 02 availability appears to be more related to enhancement of 02 delivery to the left ventricle than to major reductions in myocardial 02 demand. Acknowledgment: We gratefully acknowledgethe expert technical assistance of Janice McNatt, Michael Deguchi,
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Julius Lamar and Cora Marsaw in the performance of these studies;the assistanceof Paulette Newingham in the preparation of the manuscript;and the thoughtfuladvice of James T. Willerson,MD.
References 1. Clark LC Jr, Gollan F. Survival of mammals breathing organic liquids equilibrated with oxygen at atmospheric pressure. Science 1966;152: 1755-1756. 2. Geyer RP. Fluorocarbon-polyol artificial blood substitutes. N Engl J Med 1973;289:1077-1082. 3. Geyer RP. Oxygen transport in vivo by means of perfluorochemical preparations. N Engl J IVied 1982;307:304-305. 4. Tremper KK, Friedman AE, Levlne EM, Lapin R, and Camarlllo D. The preoperativetreatmentof severely anemic patientswith a perfluorochemical • oxygen--transport fluid, FluosoI-DA. N Engl J Med 1982;307:277283. 5. Mltsuno T, Chyanagl I.I, Nalto R. Clinical studies of a perfluorochemical whole blood substitute (Fluosol.-DA): summary of 186 cases. Ann Surg 1982;195:60-69. 6. Slovlter HA, Kamlmoto T. Erythrocyte substitution for perfusion of brain. Nature 1967;216:458-46• 7. Glogar DH, Kloner RA, Ml~b~erJE, DeBoer LWV, Braunwald E, Clark LC Jr. Fluorocarbons reduce =nyocardial ischemic damage after coronary occlusion. Science 1981;211:1439-1441. 8. Rude RE, Glogar D, Khurl SF, Kloner RA, Karaffa S, Muller JE, Clark LC Jr, Braunwald E. Effects of intravenous fluorocarbons during and without oxygen enhancement on acute myocardial ischemic injury assessed by measurement of Intramyocardial gas tensions. Am Heart J 1982;103: 986-995. 9. Glogar DH, Clark LC Jr, Kloner RA, DeBoer LWV, Muller JE, Braunwald E. Fluorocarbons--synthetic oxygen carrying compounds which reduce myocardial ischamla (abstr). Circulation 1980;62:supp1111-111-144. 10. Nunn GR, Dance G, Peters J, Cohn LH. Effects of fluorocarbon exchange transfusion on myocardial infarction size in dogs. Am J Cardlol 1983;52: 203-205.
11. HIIIIsLD, Khud SF, Braunwald E, Kloear RA, Tow D, Barsandan E, Maroko PR. Assessment of the efficacy of interventions to limit ischemic injury by direct measurement of intramural carbon dioxide tension after coronary artery occlusion in the dog. J Clin Invest 1979;63:99-107. 12. Rude RE, Izqulerdo C, BuJa LM, Wlllerson Jr. Effects of inotropic and chronotropic stimuli on acute myocardial ischemic injury. I. Studies with dobutamine in the anesthetized dog. Circulation 1982;65:1321-1328. 13. Khurl SF, Kloner RA, HIIIIs LD, Tow DE, Barsamlan EM, Maroko PR, Braunwald E. Intramural PCO2:a reliable index of the severity of myocardial ischemic injury. Am J Physiol 1979;237:253-259. 14. Brantlgan JW, Gott VL, Martz MV. A Teflon membrane for measurement of blood and intramyocardlal gas tensions. J Appl Physiol 1972;32:276282. 15. Heymann MA, Payne BD, Hoffman JIE, Rudolph AM. Blood flow measurements with radionuclide labeled particles. Prog Cardiovasc Dis 1977;20:55-79. 16. Zar JR. Biostatistical Analysis. Englewood Cliffs, NJ: Prentlce-Hall, 1974.