Myocardial Oxygen Delivery After Experimental Hemorrhagic Shock JOSEPH P. ARCHIE, JR., PH.D., M.D., WALDON R. MERTZ, M.S.

The two components of myocardial oxygen delivery, coronary blood flow to capillaries and diffusion from capillaries to mitochondria, were studied in six dogs, (1) prior to shock, (2) after three hours of hemorrhagic shock at a mean systemic arterial pressure of 40 torr, (3) after reinfusion of shed blood, and (4) during the irreversible late posttransfusion stage. There was a maldistribution of left ventricular coronary flow during late shock consistent with subendocardial ischemia. Cardiac performance was significantly impaired after resuscitation and all dogs became irreversible. Total and regional left ventricular coronary blood flow and myocardial oxygen delivery to capillaries were significantly greater than preshock values in (3) but not different from preshock values in (4). However, the myocardial oxygen diffusion area to distance ratio was significantly lower than preshock values in (3), and slightly lower in (4). These data suggest that myocardial oxygen diffusion may be impaired in the early post transfusion period, (3). Accordingly, the probable etiology of left ventricular dysfunction and possibly irreversibility after resuscitation from hemorrhagic shock is subendocardial ischemia during shock with either post-resuscitation impairment of myocardial oxygen diffusion, or in cellular oxygen utilization, or both. HE MECHANISM OF IRREVERSIBLE cardiovascular

dysfunction after hemorrhagic shock remains unclear. It is known that irreversibility and cardiac failure8 characterized by impaired myocardial contractility1"4 occur concurrently, but the question of whether cardiac failure is due to inadequate oxygen delivery to myocardial mitochondria, to an impairment in myocardial cellular oxidative metabolism, to circulating myocardial depressant factors, or to some combination of these, is unanswered. The hypothesis that hemorrhagic hypotension produces myocardial injury in dogs has been questioned because of the coexistance of left ventricular coronary vascular reserve and left ventricular myocardial ischemia.20 However, this paradox has recently been explained Supported by American Heart Association Grant-in-Aid No. 76 7661.

Reprint requests: Joseph P. Archie, Jr., M.D., Department of Surgery, Carraway Methodist Medical Center and Norwood Clinic, Birmingham, Alabama 35234. Submitted for publication: May 23, 1977.

From the Department of Surgery, School of Medicine and Medical Center, University of Alabama Birmingham, Alabama

by evidence of a maldistribution of left ventricular coronary blood flow with subepicardial coronary reserve and subendocardial ischemia.7" 0 Thus, it is quite likely that myocardial ischemic injury occurs during hemorrhagic shock, but the role this injury plays in impaired cardiac function and irreversibility after attempted resuscitation from shock is unclear. One possibility is that ischemic injury during hypotension causes endothelial injury and myocardial edema with subsequent impairment of oxygen delivery during or after resuscitation. Myocardial oxygen delivery is a two step process: first, coronary blood flow to capillaries, and second, diffusion of oxygen from capillaries to mitochondria. In this study, we measured coronary flow and calculated diffusion parameters to see if myocardial oxygen delivery is impaired during and after hemorrhagic shock. Methods Six adult mongrel dogs of both sexes weighing 17-31 kg were anesthetized with sodium pentobarbital, 25 mg/kg intravenously, intubated with an endotracheal tube and ventilated with room air using a Harvard pump. Large polyvinyl catheters were placed in a femoral artery and vein for pressure measurement and rapid removal and infusion of blood and crystalloid solutions. A bilateral thoracotomy was made in the fifth intercostal space, the pericardium opened, and SF polyvinyl catheters placed in the coronary sinus, the left atrium, and a small branch of the left pulmonary artery. A two centimeter section of the left anterior descending coronary artery was mobilized, and a noncannulating cuff-type electromagnetic flow probe placed on it. Measurements were made (1) prior to shock, control, (2) after three hours of hemorrhragic shock with mean systemic arterial pressure maintained at 40 torr, (3) ten

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minutes after reinfusion of shed blood, early resuscitation, and (4) when mean systemic arterial pressure decreased below 65 torr, approximately 90 minutes after reinfusion of shed blood and infusion of 100 ml/kg of normal saline, late resuscitation. Left atrial, pulmonary artery and systemic arterial pressures were measured with P23Db Statham transducers and recorded on a Hewlett Packard oscillograph. The electrocardiogram was recorded throughout. The flow reactive hyperemic response to an eight second occlusion of the left anterior descending coronary artery was measured with a Statham model SP2201 electromagnetic flowmeter. Systemic arterial, pulmonary artery and coronary sinus blood samples were taken for duplicate measurement of hematocrit, pH, PCO2, Po2, and oxygen content (Lex-O2-Con oxygen content analyzer). Regional myocardial blood flow5 9 and cardiac output2 were measured by the radioactive microsphere method by injecting 400,000-500,000 microspheres (9 + 1.2 micron diameter) labeled with 46Sc, 85Sr, 141Ce, or 1251, into the left atrium while simultaneously collecting arterial reference samples from the femoral artery and from the pulmonary artery. In one dog, myocardial shunting of microspheres2 was measured by collecting coronary sinus reference samples. The dogs were systemically heparinized, and following control measurements, hemorrhagic hypotension was rapidly produced by adjusting the height of a blood reservoir connected to the femoral arterial cannula to approximately 50 cm above the left atrial level. Mean systemic arterial blood pressure was maintained at 40 ± 3 torr for three hours and a second complete set of measurements made at the end of this time. The shed blood that had not been taken up by the dog from the reservoir by the end of three hours was reinfused over a 15-20 minute period, and measurements were repeated ten minutes post reinfusion. Two ampules of sodium bicarbonate (44.4 meq/amp) were given intravenously during blood reinfusion. After the third set of measurements, infusion of normal saline was begun at 35 ± 10 ml/min (total of 100 ml/kg body weight) for approximately one hour. When systemic blood pressure began to decrease, the fourth set of measurements were made. Following completion of measurements, the dogs were killed with intravenous potassium chloride, and the hearts removed. The hearts were divided into right ventricle, septum and left ventricle, and the fat, superficial coronary vessels, and valve structures removed. The left ventricular free wall section was divided into inner (subendocardial), middle and outer regions. Gamma radioactivity in the arterial blood reference samples and heart regions was counted with a Picker Autowell Spectrometer and isotope activity calculated by the

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method of Rudolph and Heymann. 18 Regional coronary blood flow,6'9 cardiac output,2 and total body and heart arterial-venous shunting,2 were calculated using the reference sample technique. Left ventricular myocardial oxygen consumption per unit weight was calculated by multiplying left ventricular coronary blood flow per unit weight times the arterial-coronary sinus blood oxygen content difference. Myocardial oxygen diffusion area (A) to distance (d) ratio was calculated from the diffusion equation: MVO2 = (kA/d) (Po2cap - Po2ceil); where k is the diffusion coefficient for oxygen in myocardium; A is the surface area of functioning capillaries per unit mass of myocardium; d is the mean diffusion distance from myocardial capillaries to mitochondria; P02cap is the mean capillary Po2 which is calculated by integrating the oxyhemoglobin dissociation curve of Hill13 between the measured arterial and coronary sinus Po2 end points; and Po2cell is the partial pressure of oxygen in mitochondria which is estimated to be less than one torr and, therefore, negligible. Left ventricular coronary vascular resistance (R) was calculated from the equation: R = AP/q; where l\P is the coronary pressure gradient and q is left ventricular myocardial blood flow per unit weight. Resistance was calculated in two ways. First, by assuming that AP is equal to the mean systemic arterial pressure (R) and second, by assuming that AP is equal to coronary perfusion pressure minus mean diastolic intramyocardial pressure (R'), where the mean diastolic intramyocardial pressure was taken to be 18 torr.3 Minimum coronary vascular resistance (Rmin) was calculated from both the R and the R' values by dividing resistance by the ratio of maximum reactive hyperemic flow to preocclusion flow measured by the electromagnetic flowmeter. Results

After the fourth set of measurements in the late post resucitation period, all six dogs had progression of systemic hypotension and three developed ventricular arrythemias. The mean and one SE of measurements of systemic hemodynamics, systemic arterial-venous shunting, and blood gas and oxygen content data for the preshock control, three hour shock, and early and late resuscitation periods are given in Table 1. Early after blood reinfusion mean aortic pressure returned to within control levels, but cardiac index and total body oxygen consumption were significantly lower than control values and cardiac index decreased even further during late resuscitation. Systemic arterialvenous shunting of microspheres was less than 11% in all study periods in all but one dog, where

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TABLE 1. Systemic Hemodvnamics

Heart rate (beats/min) Mean systemic arterial pressure (torr) Systemic arterial pressure systolic/diastolic (torr) Left atrial pressure (torr) Mean pulmonary artery pressure (torr) Cardiac index (ml/min -kg) Oxygen consumption (ml/min kg) Left ventricular stroke work index (torr mlkg beat) Hematocrit Arterial Po2 (torr) Arterial pH Arterial PcO2 (torr) Arterial blood oxygen content (ml/100 nl) Percent systemic microsphere shunting

159 95.7 132 90.7 (5.4 15.6 121 7.35

74.6 34.8 68.1 7.436 25.3 12.7 (5.7

± ± ± ± ± ± ± ±

Early Resuscitation

3 hr Shock

Control 11.5 3.31 4.2 10.86 0.55) 1.43 10.3 1.47

131 40.5 59.3 32.0 2.0 13.2 28.9 3.43

± 8.07 ± 3.82 ± 5.60 ± 0.0178 ± 1.11 ± 1.50 ± 1.48)

± ± ± +

7.9* 3.34t

±

± ± ± ± ± ± +

3.4t 4.96 8.2 7.00t 0.79 1.12t 9.47t ± 0.415t

136 61.5 120 47.8 3.3 12.7 61.9 4.04

± ± ± ± ± ± ± ±

58.3 ± 4.53t 39.7 ± 2.76t 78.3 ± 4.79t 7.187 ± 0.0407§ 36.3 ± 2.46t 14.8 ± 1.36* (7.6 + 3.65)

28.6 (30.9 67.7 7.297 26.1 10.5 (4.5

± ± ± ± ± ± ±

126 83.5 138 59.3 5.2 18.3 89.5 3.81

8.86§

2.10: 0.37: ± 0.40* ± 3.19§

0.665t

9.16 ± 1.510§ 40.8 ± 3.35* 79.4 ± 7.65t 7.082 ± 0.0347§ 24.8 ± 1.87 13.7 ± 1.77 (0.77 ± 0.273)t

Late Resuscitation 6.4 4.01 t(t) 6.5t(*)

4.44t(*) 0.49t(t) 1.45*(t) 7.96t(§) 0.278 4.951(§) 1.49)(*) 6.35(*) 0.0193§(t) 6.35(t) 0.85*(t) 1.67)

All values mean ± 1 SE. Probability of difference from control by paired t test: * 0.05 < p < 0.10, t 0.01 < 0.05, t 0.001 < p < 0.01, § p < 0.001. Symbols in ( ) are paired comparison

between the two resuscitation states. Mean ± SE in ( ) means n = 5, otherwise n = 6.

shunting was 20-30% at all four periods. The latter data is not included in the shunting data of Table 1. Myocardial blood flow per unit weight of the right ventricle, septum and left ventricle is given in Table 2. Flow decreased significantly in all heart regions in late shock, but returned to or exceeded control values during resuscitation. Left ventricular subendocardial flow per unit weight was only slightly less than subepicardial flow in late resuscitation. Table 3 gives the mean and one SE of the left ventricular myocardial hemodynamics for the four study periods. Myocardial oxygen delivery exceeded control values in the early resuscitation period, and was near control values in late resuscitation. Coronary sinus Po2 increased in both resuscitation periods and the per cent extraction of oxygen by the left ventricle decreased significantly in early resuscitation. The left ventricular oxygen diffusion area to distance ratio was significantly less than control during shock and early resuscitation. The left anterior descending coronary

artery reactive hyperemic response to an eight second occlusion was significantly decreased during late shock and resuscitation. Coronary vascular resistance calculated by both techniques was less than control in late shock and during the late resuscitation period. However, minimum coronary vascular resistance was significantly increased in shock and late resuscitation using the mean arterial pressure as coronary perfusion pressure (Rmin), and was essentially unchanged from control values when intramyocardial pressure was used (R'min). In one dog, left ventricular shunting of microspheres was 4.0, 0.84, 0.75, and 1.7% in the control, shock, and early and late resuscitation periods respectively. Figure 1 illustrates cardiac performance, represented by per cent change from control of mean systemic arterial pressure and cardiac index, as contrasted to myocardial oxygen delivery, represented by the per cent change from control of left ventricular myocardial oxygen supply and left ventricular oxygen dif-

/ TABLE 2. Regional Myocardial Blood Flow (mllmin 100 g)

Region Right ventricle Septum Left ventricle Inner Middle Outer Inner/outer ratio

(dimensionless) Total heart

Control 60.0 83.6 90.5 96.5 94.1 86.2

± ± ± ± ± ±

8.35 8.10 9.82 12.17 11.45 9.24

1.20 ± 0.089 82.1 ± 8.89

All values mean ± 1 SE. Symbols per Table 1.

3 hr Shock 41.1 51.8 50.3 40.2 50.4 55.5

± ± ± ± ± ±

4.48* 7.26t

5.50t 3.37t 5.73t 6.81t

0.736 ± 0.056t 48.3 ± 5.14t

Resuscitationearly

Resuscitationlate

76.5 103 106 123 99.9 104

75.7 103 108 99.3 105 116

± 9.09 ± 6.4t ± 8.Ot ± 10.0 ± 7.06 ± 7.5t

1.19 ± 0.080t 98.3 ± 6.93t

± ± ± ± ± ±

14.43 9.2* 14.1

12.67(*) 13.8 15.7

0.866 ± 0.0221(t) 98.8 ± 12.86

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TABLE 3. Left Ventricular Mvocardial Hemodyvna,mics

Control 18.5 2.75 11.1 8.57 78.2 35.9

Coronary sinus Po2 (torr) Coronary sinus oxygen content (ml/100 ml) Left ventricular oxygen supply (ml/min g)

Leftventricularoxygenconsumption(ml/min g) Per cent myocardial oxygen extraction Mean capillary P02(torr) Left ventricular oxygen diffusion area to distance ratio, kA/d (m102/min 100 g torr) Reactive hyperemic response (max flow/preocclusion flow) Left ventricular coronary resistance, R (torr min g/ml) Corrected coronary resistance, R' (torr min g/ml) Minimum left ventricular coronary resistance, Rmin (torr min g/ml) Corrected minimum resistance, R'min (torr min g/ml)

± 0.89 ± 0.357 ± 1.02 0.696 ± 1.79 ± 2.14

3 hr Shock

18.2 1.38 6.73 6.08 90.2 38.8

± 1.73 ± 0.230t ± 0.905t 0.830t ± 0.87§ ± 3.39

Resuscitation-early 30.2 5.25 15.5 9.94 64.3 47.5

± 1.29§ ± 0.485§ ± 1.30§ 0.781* ± 2.01§ ± 2.79t

Resuscitation-late 23.5 2.77 11.1 6.51 73.1 39.3

± ± ± ± ± ±

1.54t(t) 0.409(t) 1.23(t)

1.281(*) 3.14*(t) 2.22*(t)

0.203 ± 0.020

0.245 ± 0.021

0.167 + 0.031t

0.208 ± 0.023t

3.7 ± 0.41

1.6 ± 0.22t

(2.0 ± 0.18)i

(1.5 ± 0.12)t(t)

112 ± 12.49

87.0 ± 13.69t

80.7 ± 7.44t

61.5 ± 8.08t(t)

90.9 ± 10.25

48.7 ± 10.51t

63.3 ± 6.37

42.7 ± 4.88§(§)

30.6 ± 2.31

58.1 ± I1.20t

(39.6 ± 3.93*

(42.8 ± 7.46)*

24.8 ± 2.00

33.2 ± 8.78

(30.6 ± 3.20)*

(29.5 ± 4.95)

All values mean ± 1 SE. Symbols per Table 1.

fusion surface area to distance ratio. During early resuscitation there is significant cardiac functional impairment, a significantly increased oxygen supply to the capillaries, and a significantly depressed diffusion area to distance ratio. In late resuscitation cardiac function is severely impaired, but oxygen delivery by both flow and diffusion are not significantly different from control, in part, because of variability in the data. Discussion Our findings of a significantly reduced cardiac index and total body oxygen consumption (as compared to MYOCARDIAL OXYGEN TRANSPORT

SYSTEMIC HEMODYNAMICS ,.

1c

Oxygen Supply Mean Systenic Arterial Pressure 25_

75 50 Ii

0

-25-J -50e

ii

-75. iio 75-

It so

le

Diftion Area to Distance Radto A/d

w i

-25-! -75

.-

Cardiac Index

_. -o..l_ SHOCK RESUSCI- RESUC-

,0

TATION EARLY

TATION LATE

SHOCK RESUSCI- RESUSClTATION TATION .. _.. .

EARLY

LATE

FIG. 1. The per cent change from preshock control values of systemic hemodynamic and myocardial oxygen transport variables. Bars are mean per cent change + 1 SD.

control) after resuscitation from hypovolemic shock, are similar to those of Carlson et al.,7 and consistent with impaired left ventricular function8 and contractile state'1'4 previously described in this hemorrhagic shock dog model. Subendocardial ischemic injury has been reported after hemorrhagic shock in man and experimental animals." Hackel et al." have pointed out that there are two types of myocardial injuries associated with hypovolemia and hypotension; the "contraction band" injury not believed to be due to ischemia per se, and true subendocardial ischemic necrosis secondary to inadequate coronary perfusion. Sarnoff et al.19 originally suggested inadequate myocardial blood flow as the etiology of impaired cardiac function and irreversibility in hemorrhagic shock. In our study, regional coronary blood flow per unit weight to the right ventricle, septum and left ventricle, and the left ventricular transmural distribution of coronary blood flow prior to and during shock was similar to that reported by Carlson et al.7 The significantly decreased left ventricular inner to outer flow ratio after three hours of hemorrhagic shock at a mean arterial pressure of 40 torr further confirms the findings of Downey et al.10 and Carlson et al.,7 and supports their hypothesis that subendocardial ischemic injury occurs in this dog shock model. However, we found normal or increased total and regional left ventricular myocardial blood flow during both the early and late resuscitation periods. These data suggest that while left ventricular subendocardial ischemia due to inadequate coronary flow probably occurs during hypovolemic shock, it is unlikely that coronary flow is inadequate after resuscitation, or in the irreversibility period. Therefore, impaired left ventricular function

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OXYGEN DELIVERY AFTER SHOCK

after resuscitation is not due to inadequate coronary flow after resuscitation. The left ventricular inner to outer flow ratio decreased late after resuscitation, but the absolute flow to the left ventricular subendocardium remained within the preshock control range. Further, the reactive hyperemic response of the left anterior descending coronary artery was present during hemorrhagic shock and after resuscitation, although significantly lower than control. These latter findings are similar to those of Von Ackern et al.20 and Carlson et al.7 Carlson et al.7 found a significant increase in minimum coronary vascular resistance during and after hypovolemic shock, and suggested that this may be due to myocardial edema, which they also found. However, they did not take into account diastolic intramyocardial pressure which probably was 16-20 torr.3 When diastolic coronary perfusion pressures are normal (7080 torr), neglecting the intramyocardial pressure contribution to coronary perfusion pressure leads to a 20-30% overestimation of coronary vascular resistance. By contrast, if diastolic coronary artery pressure is low, such as during hypovolemic shock or in the irreversible hypotensive period after resuscitation, then the error induced by not accounting for intramyocardial pressure may be on the order of 50% or more. Indeed, when we calculated minimum resistance in the traditional way (Rmin), we found a significant increase above control values during shock, and the increase after resuscitation tended to be significant. When we accounted for diastolic intramyocardial pressure (R'min), differences in resistance from control values were smaller but still slightly larger than control and tended toward statistical significance in early resuscitation (0.05 < p < 0.10). These results support the hypothesis that there. is an increase in minimum coronary vascular resistance during and after shock. Others have demonstrated decreased myocardial oxygen consumption and myocardial oxygen extraction, as well as an increase in coronary sinus Po2, in the post resuscitation period after hypovolemic shock.7'12'15'20 These findings have been interpreted to mean that there may be an impairment in the ability of the myocardium to utilize oxygen. If one examines the diffusion equation, however, it is clear that a defect in oxygen utilization is not the only possible mechanism that would explain these observations. Specifically, if there is a decrease in the myocardial oxygen diffusion surface area to distance ratio; then, in order to maintain myocardial oxygen consumption, mean capillary Po2 must rise. This means an increase in coronary sinus Po2 and a decrease in per cent extraction of oxygen from the blood. Further, coronary flow would increase to maintain

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myocardial oxygen supply. We found that the left ventricular area to distance ratio (kA/d) was significantly below preshock control values during shock and early resuscitation, while oxygen delivery to left ventricular capillaries was significantly increased and oxygen consumption tended to increase (0.05 < p

Myocardial oxygen delivery after experimental hemorrhagic shock.

Myocardial Oxygen Delivery After Experimental Hemorrhagic Shock JOSEPH P. ARCHIE, JR., PH.D., M.D., WALDON R. MERTZ, M.S. The two components of myoca...
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