Myocardial oxygen availability and cardiac failure in hemorrhagic shock J o h n C. Lee, Ph.D. S. E v a n s Downing, M.D. New Haven, Conn.
Wiggers and Werle 1 were probably the first to suggest t h a t a reduction in coronary blood flow m a y be responsible for irreversibility of the hemorrhagic shock syndrome. T h e i m p o r t a n c e of low perfusion pressure and insufficient coronary flow leading to cardiac deterioration in shock animals has subsequently been emphasized by Sarnoff and associates 2 and others2 -7 T h e appearance of cardiotoxic factors ~ and depression of the s y m p a t h o a d r e n a l system 9 have also been implicated as c o n t r i b u t o r y to ultimate deterioration of cardiac function in shock. B u t the relative contrib u t i o n of myocardial failure to the severity and irreversibi!ity of this process has been questioned20. 11 Earlier studies in our l a b o r a t o r y d e m o n s t r a t e d a progressive reduction of myocardial contractility in shock which was a t t r i b u t e d to the interplay of three key factors. These included metabolic acidosis, reduced coronary perfusion pressure, and loss of s y m p a t h e t i c support. 19. 13 More recent work TM has suggested from indirect evidence t h a t myocardial oxygen availability m a y be closely related to the e x t e n t of myocardial depression. T h e present s t u d y was u n d e r t a k e n to ascertain by more direct m e t h o d s the interrelationships between left ventricular function and myocardial oxygen availability and metabolism in sustained hemorrhagic hypotension. A second objective was to determine w h e t h e r the progressive and ultiFrom the Department of Pathology, Yale University School of Medicine, New Haven, Conn. This study was supported in part by grant HL-08659 from the National Heart and Lung Institute and the Connecticut Heart Association. Received for publication April 1, 1975. Reprint requests: John C. Lee, Ph.D., Department of Pathology, Yale University School of Medicine, 310 Cedar St., New Haven, Conn. 06510.
August, 1976, Vol. 92, No. 2, pp. 201-209
m a t e l y irreversible myocardial failure is related to i m p a i r m e n t of myocardial metabolism, and if this can be ascribed to i n a d e q u a t e coronary flow and oxygen delivery to the myocardium. Methods
T h e studies were carried out on 18 adult mongrel cats of both sexes, varying in weight from 2.2 to 4.5 kilograms, and an additional 54 cats were used for donor blood. A right heart bypass preparation was used (Fig. 1). All animals were anesthetized by intraperitoneal sodium pentobarbital (30 mg. per kilogram). T h e trachea was exposed and intubated. T h e chest was opened in the midline and ventilation was m a i n t a i n e d with a H a r v a r d c o n s t a n t - v o l u m e positive pressure pump. Heparin (1,000 units) was given intravenously. T h e descending thoracic aorta was c a n n u l a t e d (Fig. 1) and aortic flow was measured with a S t a t h a m 6.0 ram. O.D. extracorporeal flow transducer and a Medicon K-2000 electromagnetic flow meter. T h e aortic flow was then passed t h r o u g h a Sarns heat exchanger and r e t u r n e d to the descending aorta. T h e azygous vein was ligated and the superior and inferior vena cavae were cannulated. Systemic venous return, including coronary, was diverted to a venous reservoir (Fig. 1) and t h e n p u m p e d t h r o u g h a specially constructed glass heat exchanger (MacalasterBicknell Co.) and back into the main p u l m o n a r y artery. C o r o n a r y venous drainage was accomplished b y passing a c a t h e t e r into the right ventricular c h a m b e r t h r o u g h a stab wound in the wall and secured with a purse string stitch. A " T " connector was placed in the line to permit temporary diversion of flow into a graduated cylinder for timed collections and for sampling. T h e extracorporeal tubing, h e a t exchanger, and
A m e r i c a n H e a r t Journal
201
Lee and D o w n i n g
PACE ELECTRODE
"r
AIR
WATER BATH
EXCHANGER
VENOUS RESEI~/OIR
'~
" .
--
,
ELECTRODEASSEMBLY p ~
R.PUMP
Fig. 1. Diagram of right heart bypass preparation. T R = pressure transducer; R . p u m p = roller pump; I V C = inferior vena cava; L S A = left subclavian artery; R A = right atrium; R V = right ventricle; A O = aorta; F V = femoral vein; G C = graduate cylinder; S V C = superior vena cava; B C = brachiocephalic artery; A Z = azygous vein; L A = left atrium; L V = left ventricle; P A = pulmonary artery. See text for detailed description.
reservoirs were primed with freshly d r a w n heparinized (5 mg. per kilogram) blood f r o m d o n o r cats. C e p h a l i c blood flow was abolished by ligating the brachiocephalic and left subclavian arteries. Pulm o n a r y a n d systemic flows were controlled indep e n d e n t l y b y two roller pumps. Aortic pressure was controlled with an a d j u s t a b l e c o n s t a n t pressure reservoir. All pressure m e a s u r e m e n t s were m a d e with S a n b o r n t r a n s d u c e r s (267 series). T h e midlevel of the h e a r t was used as zero reference. Left v e n t r i c u l a r pressure was m e a s u r e d by passing a 15 gauge needle t h r o u g h the apex into t h e left v e n t r i c u l a r cavity. T h e m a x i m a l r a t e of rise of left v e n t r i c u l a r pressure ( d P / d t m a x ) was o b t a i n e d with a R-C differentiating circuit (time c o n s t a n t 0.268 msec.). T h e h e a r t r a t e was controlled by electrically pacing the left a t r i u m with a Grass SD-5 stimulator. Pressures, aortic flow, h e a r t rate, and left v e n t r i c u l a r d P / d t m e a -
202
s u r e m e n t s were recorded s i m u l t a n e o u s l y on a m u l t i c h a n n e l oscillograph ( S a n b o r n m o d e l 358) at a c h a r t speed of 0.5 or 100 ram. per second. Blood t e m p e r a t u r e was m a i n t a i n e d at 38 ~ ___ 1 ~ C. a n d m e a s u r e d with a Yellow-Springs p r o b e and t e l e t h e r m o m e t e r . Arterial pH, Po2 a n d Pco~ were c o n t i n u o u s l y m o n i t o r e d w i t h a flow-through electrode a s s e m b l y with three B e c k m a n 160 physiological gas analyzers a n d were f r e q u e n t l y checked with a blood gas a n a l y z e r and p H s y s t e m {Instrum e n t a t i o n Laboratories). Arterial and c o r o n a r y venous blood samples were w i t h d r a w n simultaneously f r o m the aortic and right v e n t r i c u l a r c a n n u l a s for d e t e r m i n a t i o n of oxygen c o n t e n t 15 and for m e a s u u r e m e n t of pH, Po~, Pco2, and h e m a t o c r i t . T h e h e m a t o c r i t ratio was d e t e r m i n e d i n duplicate by the m e t h o d of m i c r o h e m a t o c r i t t u b e s (Clay Adams). M y o c a r d i a l oxygen cons u m p t i o n (MVo2) a n d per cent oxygen e x t r a c t i o n
August,
1976,
Vol.
92, No.
2
Myocardial 02 metabolism and shock Table I. H e m o d m a m i c s
30 60 90
and
AP
L VEDP
LV dP/dt max
75.0 • 5.0 75.0 • 5.0 75.0 _+ 5.0 75.0 • 5.0
4.1 • 0.3 3.9 • 0.4 4.1 • 0.4 5.5 _+ 1.0
2,210 • 126 2,310 • 63 2,332 • 41 2,090 • 84
Time (min.) 0
values
oxygen
metabolism
in normotensive
cats
(N
= 4)*
Oxygen CF
Myoc. O~ avail.
Art. conc.
33.4 • 1.7 41.9 • 4.8 42.1 + 8.8 37.6 • 6.4
22.19 • 2.76 26.73 • 3.28 30.30 • 5.06 28.46 • 5.17
7:77 + 0.40 7.79 • 0.64 8.93 • 0.75 8.68 • 0.91
Arterial
C. ext. 57.89 • 3.61 54.69 • 2.03 51.39 • 6.65 46.29 • 10.42
MV02
pH
Po.~
Pco2
Hct.
13.73 • 0.80 15.54 • 0.80 14.28 • 1.14 11.38 • 2.08
7.40 • 0.03 7A1 • 0.01 7.42 • 0.02 7.38 • 0.03
106.8 • 14.1 104.8 • 10.0 89.8 • 11.8 98.3 • 11.4
24.0 • 2.2 22.8 • 2.9 24.4 • 4.7 24.6 • 3.1
16.9 • 0.4 16.3 _+ 1.3 17.3 • 1.5 18.1 • 2.3
*Values are means + standard error of the mean. AP = mean aortic pressure in mm. Hg. LVEDP = left ventricular end-diastolic pressure in cm. H~O. LV dP/dt max = maximal rate of rise of left ventricular pressure in mm. Hg/sec. CF = Coronary blood flow in ml./min. Myoc. O2 avail. = myocardial oxygen availability in ml./min./100 Gm. heart weight. Art. conc. = arterial oxygen content in vol.%. C. ext. = myocardial coefficient of extraction; (A-V/(A) • 100 in %. MVo~ = myocardial oxygen consumption in ml./min./100 Gin. heart weight, pH in units. Po2 and Pco~ in mm. Hg. Hct. = hematocrit in %.
Table II. H e m o d y n a m i c
values
and
myocardial
oxygen
metabolism
in hypotensive
cats*
Oxygen ~ e r i a l
C. ext. I MVO, I pH
L VEDP S h o c k w i t h LV failure (AP=30• Hg)
3
0
6.0 • 0.9
28.3 • 3.0 6
32.3** • 3.0
409* _+ 88
17.2 • 0.6
12.14 • 1.66
73.42 • 3.36
9.54 • 0.50
7.36 -+ 0.07
15.0 • 1.2
11.5" • 0.9
8.18 • 0.87
65.73* • 2.59
5.29* _+ 0.22
7.25 + 0.07
15.3 • 1.5
0
5.5 • 1.0
1,203 • 145
15.9 + 1.6
12.94 • 1.26
76.12 • 3.33
9.62 _+ 0.71
7.37 • 0.03
18.5 • 1.7
30
9.0 • 0.9
974 _+ 86
13.4 • 1.5
11.82 • 1.21
73.04 • 2.05
7.99 -+ 0.70
7.26 • 0.05
18.7 • 1.4
22.6** • 3.9
536** • 111
11.5" _+ 1.2
9.44 • 1.10
56.15" • 4.90
5.28** • 0.71
7.25 • 0.07
19.8 + 1.7
0
2.8 • 0.2
1,509 • 275
13.5 • 0.4
13.37 • 1.27
70.06 • 0.13
9.36 • 0.86
7.36 • 0.07
23.0 • 0.0
30
3.0 -+ 0.7
1,581 • 3,222
12.5 _+ 1.1
13.05 • 1.00
67.05 • 0.67
8.77 • 1.11
7.23 • 0.05
23.5 • 0.4
60
2.8 • 0.2
1,520 • 360
11.8 • 0.2
13.26 • 0.46
74.31 • 3.99
9.91 • 0.87
7.14 • 0.06
23.5 • 1.1
9 90
3.0 • 0.7
1,432 • 358
11.5 _+ 0.4
12.62 • 0.56
73.20 • 7.35
9.36 • 1.35
7.09 -+ 0.05
55.2 • 2.8 S h o c k w i t h o u t LV failure(AP= 30• 5 m m . Hg)
1,238 • 131
I Hct.
2
~
24.5 • 0.4
* V a l u e s a r e m e a n + s t a n d a r d e r r o r o f m e a n . A b b r e v i a t i o n s s a m e a s i n T a b l e I. A s t e r i s k s ( ) i n d i c a t e s t a t i s t i c a l l y s i g n i f i c a n t d i f f e r e n c e b e t w e e n t i m e
periods in each group: *p < 0.05, **p < 0.01.
were was
calculated. estimated
concentration In effects
order
16 M y o c a r d i a l as the and
to
coronary
more
of limitation
oxygen
product
blood
readily
oxygen
flow.
demonstrate
of myocardial
American Heart Journal
availability
of arterial
oxygen
ability the
the avail-
on ventricular
oxygen-carrying donor
blood
performance
capacity with
an
in shock,
was reduced equal
cent glucose
in saline. The
preparation
was in the range
the
by diluting
volume
final hematocrit
of 5 per of the
o f 15 t o 2 5 p e r c e n t
203
Lee and D o w n i n g
( " n o r m a l " hematoci~t for the cat is approximately 30 per cent). After completion of all surgical procedures a period of 15 minutes was allowed for stabilization and control m e a s u r e m e n t s were obtained with a m e a n aortic pressure of 75 +_ 5 mm. Hg. Shock was induced by rapid bleeding from the aorta into the constant-pressure reservoir and aortic pressure was set at 30 +_ 5 mm. Hg. Samples were obtained every 30 minutes following the onset of h y p o t e n s i o n (zero time) for a period of 90 minutes or until severe cardiac failure t e r m i n a t e d the experiment. F o u r animals were studied in a m a n n e r similar to those described above, except t h a t m e a n aortic pressure was m a i n t a i n e d at 75 +_ 5 mm. Hg t h r o u g h o u t t h e experimental period. These animals served as controls. All data in this s t u d y were processed and analyzed by s t a n d a r d statistical methods. 17 T h e difference was considered significant when the p value was less t h a n 5 per cent. Results Left ventricular performance and myocardial oxygen metabolism in normotensive animals. T h e t o t a l right h e a r t bypass preparation involves extensive surgical and cannulation procedures. T h e relative stability and other characteristics of the preparation were therefore determined by studying four animals in which m e a n aortic pressure was maintained at 75 mm. Hg for the full duration of the 90 m i n u t e study period. T h e results are presented in T a b l e I. It is evident t h a t there were no significant changes in left h e a r t performance which might suggest failure. Coron a r y flow increased modestly during the first 30 minutes and then showed little change. Myocardial oxygen extraction and consumption showed small b u t statistically insignificant changes with time. Arterial blood gases, pH, and h e m a t o c r i t values also remained stable over the 11/2 hour interval. Left ventricular performance and myocardial oxygen metabolism during hemorrhagic shock. In 13 animals hemorrhagic shock was produced by lowering the m e a n aortic pressure to 30 mm. Hg. Of these, two died with ventrieular fibrillation shortly after the onset of hypotension. Table II summarizes the h e m o d y n a m i c and metabolic d a t a obtained in the remaining 11 preparations. Nine developed LV f a i l u r e and two showed no
204
evidence of failure during the 11~ h o u r shock period. Within 30 minutes of the onset of shock, three animals showed a sharp reduction of b o t h left ventricular function and myocardial oxygen metabolism. L V E D P rose to 32 cm. H~O and LV d P / d t max fell to a b o u t 30 per cent of time 0 values. Coronary flow fell from 17.2 (_+ 0.6 S.E.) to 11.5 (_+ 0.9 S.E.) ml. per m i n u t e and myocardial O2 availability declined fl'om 12.14 (_+ 1.66 S.E.) to 8.18 (_+ 0.87 S.E.) ml. per m i n u t e per 100 Gm. HW. MVo2 and O2 extraction also fell significantly (Table II). Six animals d e m o n s t r a t e d a progressive reduction of ventricular function with sustained hypotension, but a level of severity comparable to the above was not reached until a b o u t 1 hour of shock (55.2 _+ 2.8 S.E. minutes). T h e m e a n values for L V E D P and LV d P / d t max at time 0 were 5.5 cm. H20 and 1,208 ram. Hg per second, respectively. C o r o n a r y flow was 15.9 ml. per minute and myocardial O2 availability was 12i9 ml. per m i n u t e 100 Gm. HW. E x t r a c t i o n was 76.12 per cent and MVo2 averaged 9.62 ml. per m i n u t e per 100 Gin. HW. After 30 minutes, however, L V E D P rose to 9.0 cm. H20 and LV d P / d t max, coronary flow, myocardial O2 extraction, and MVo2 were all somewhat reduced. Within i h o u r of sustained hypotension the animals showed m a r k e d deterioration of left ventricular function. L V E D P increased t o 22.6 cm. H20 (p < 0.01) and LV d P / dt max fell to 536 mm. Hg per second (p < 0.01). C o r o n a r y flow fell to 11.5 ml. per minute and myocardial O2 availability was reduced to 9.45 ml. per minute per 100 Gin. HW. Concomitantly, O2 extraction and MVo2 were m a r k e d l y decreased to 56 per cent (p < 0.05) and 5.28 ml. per m i n u t e per 100 Gm. H W (p < 0.01), respectively. T w o animals (Table II) showed no significant reduction of left ventricular function during 90 minutes of sustained hypotension as indicated by little change in L V E D P or d P / d t max. Coronary flow showed a small progressive decrease. B u t myocardial O2 availability, extraction, and MVo2 were unchanged over the 11/2h o u r period. It m a y be noted t h a t the arterial oxygen content and h e m a t o e r i t in these animals were significantly higher t h a n in those which developed mechanical failure (Table II). Relationship of ventricular performance to myocardial oxygen availability. T h e d a t a were f u r t h e r analyzed by examining relationship
August, 1976, Vol. 92, No. 2
Myocardial 02 metabolism and shock I
I
I
i
I
I
I
I
I
I
I
I
I
I
I
9 - HYPOTENSIVES(AP=30 mmHg ) N 9 32 (11 animals)
3,000
y 9 t3~J.95X- 5 0 8 . 5 3
3,000
o
r 9 0.75 0
E E
0
~ o
X
g
p < 0.001
9.:.//
o
2,000
0 0
0
E E X
2,000
~= 'o
"S.
.J
I'Z W
O-NORMOTENSIVES ( A P - 7 5 m m H g )
>
N - 16 (4animals)
1,000
F-
|9
I--Z I11
t,000
9
lb. UJ ..J
Y = 2.11X- 2 1 7 6 . 8 0
W J
ql[ _J
r - 0.10 p>O.!
0
i 10
0
I 20
I 30
I 40
I 50
I
0
2
/I
4
MYOCARDIAL OXYGEN AVAILABILITY
I
I
6
8
I f I I I I I 10 12 14 16 18 20 22
(mllmin/1OOgm HW)
Fig. 2. Relationship of myocardial oxygen availability to maximal rate of rise of left ventricular pressure (LV dP/ dt max). Closed circles = shock animals (right panel); open circles = control animals (left panel). See text for further description.
b e t w e e n the left v e n t r i c u l a r d P / d t m a x a n d m y o c a r d i a l 02 availability. Values from the 11 shock cats (32 observations) are p l o t t e d in the r i g h t - h a n d p a n e l of Fig. 2. T h e calculated linear regression line is also shown. A highly significant correlation b e t w e e n LV d P / d t m a x and O~ availability was found (r -- 0.75, p < 0.01), indicating t h a t v e n t r i c u l a r p e r f o r m a n c e in these p r e p a r a tions was closely linked with oxygen availability during shock. In s h a r p contrast, no correlation was found between LV d P / d t m a x and m y o c a r dial 02 availability in n o r m o t e n s i v e controls (r = 0.1, p > 0.1). T h e d a t a from 16 observations are shown in t h e left-hand panel of Fig. 2. Relationship perfusion
of
aortic
pressure
pressure) to ventricular
(coronary
mechanics
and
T h e above findings suggest a close relationshi p b e t w e e n c o r o n a r y flow, a m a j o r d e t e r m i n a n t of m y o c a r d i a l 02 availability, a n d changes in left v e n t r i c u l a r p e r f o r m a n c e a n d m y o c a r d i a l oxygen m e t a b o l i s m in h e m o r r h a g i c shock. T h i s point is f u r t h e r d e m o n s t r a t e d by t h e d a t a f r o m two a n i m a l s shown in T a b l e I I I . W i t h aortic flow a n d h e a r t r a t e held constant, oxygen oxygen
metabolism.
American Heart Journal
delivery to the m y o c a r d i u m was reduced by sequentially lowering c o r o n a r y perfusion pressure. T h e r e was a progressive reduction of c o r o n a r y flow a c c o m p a n i e d by increasing oxygen extraction. LV d P / d t m a x also fell. p r o b a b l y as a mechanical consequence of lowering v e n t r i c u l a r afterloading. However, in b o t h a n i m a l s L V E D P and MVo2 changed little until aortic pressure was reduced to 30 m m . H g a n d m y o c a r d i a l O~ availability fell to a b o u t 11 ml. per m i n u t e per 100 Gm. HW. U n d e r these conditions L V E D P rose sharply to a b o u t 10 cm. H~O a n d d P / d t m a x declined further. I m p r o v e m e n t of m y o c a r d i a l function and oxygen m e t a b o l i s m was observed in each preparation u p o n re-elevation of aortic pressure. This increase in mechanical p e r f o r m a n c e paralleled an increase of c o r o n a r y flow and m y o c a r d i a l 05 availability. Discussion
Previous work f r o m this l a b o r a t o r y 14 h a s s h o w n t h a t sustained h e m o r r h a g i c h y p o t e n s i o n (AP = 30 ram. Hg) a c c o m p a n i e d b y periodic episodes of h y p o x e m i a leads to a m o r e rapid deterioration of
205
Lee and D o w n i n g
Table III. Effects of aortic pressure (coronary perfusion pressure) on v e n t r i c u l a r mechanics and oxygen
metabolism AP
CF
Myoc. 02 ext.
Myoc. 02 avail.
MVO,~
L VEDP
LV dP/dt max
Cat No. 21: 100 75 50 30 50
body weight, 3 . 6 K g ; 22 67.04 20 73.03 17 81.60 14 80.87 20 72.50
h e a r t rate. 226 b.p.m. ~ 10.27 10.07 10.87 8.95 10.63
a ort i c flow. 235 m l . / m i n . : 15.35 4.0 15.10 3.5 13.32 4.0 11.07 10.0 14.66 4.5
h e m a t o c r i t , 20%; 2.279 1.671 1.103 882 1.323
Cat No. 23: 75 35 30 70
body weight, 3.2Kg.; 20 48.09 14 69.88 9 82.90 30 41.47
heart race. 222 b.p.m,; 10.34 10.57 9.43 10.64
a ort i c flow. 250 m l / m i n . : 21.46 3.0 15.16 3.0 11.42 9.5 32.80 3.5
h e m a t o c r i t . 24%. 3.158 1.658 1,188 3,504
Abbreviations same as in Table L *b.p,m. = beats per minute.
m y o c a r d i a l function t h a n when Pao~ is k e p t normal. T h i s s t u d y also d e m o n s t r a t e d t h a t cardiac deterioration during severe h y p o t e n s i o n m a y be delayed by employing less severe hypoxia. observing the "critical P a o ." T h e s e observations s u p p o r t e d the concep~ of c u m u l a t i v e hypoxic tissue d a m a g e in shock a n d suggested t h a t oxygen availability is a p r i m a r y factor in d e t e r m i n i n g reversibility of m y o c a r d i a l depression. T h e present s t u d y was u n d e r t a k e n to obtain m o r e direct evidence for the relationship b e t w e e n these two events. M y o c a r d i a l oxygen availability m a y be simply expressed as the p r o d u c t of c o r o n a r y blood flow and arterial oxygen concentration. Under n o r m a l conditions, the a m o u n t of oxygen that can be carried by p l a s m a in blood is very small, a b o u t 0.3 v o l u m e per cent. Therefore, the oxygen carrying c a p a c i t y of blood is largely d e p e n d e n t on the h e m a t o c r i t ratio. T h e i m p o r t a n c e of the h e m a t o crit to susceptibility to irreversible h e m o r r h a g i c shock has been d e m o n s t r a t e d b y Crowell and associates28 T h e y showed t h a t in dogs the t i m e required for the d e v e l o p m e n t of irreversible shock was p r o p o r t i o n a l to the h e m a t o c r i t in the range of 12 to 35 per cent. However, above 35 per cent the likelihood for survival of the a n i m a l was proportionally decreased. T h e y suggested that this m i g h t be due to an increase of " a p p a r e n t viscosit y " in the blood which f u r t h e r reduces blood flow to the tissues. T h e o p t i m u m h e m a t o c r i t in anesthetized dogs for surviving h e m o r r h a g i c shock was found to be 30 to 35 per cent. 19 Similar conclusions were reached by Chien and asso-
206
ciates. ~~ T h e relationship of c o r o n a r y perfusion pressure a n d left v e n t r i c u l a r function to h e m a t o crit ratio h a s also been d e m o n s t r a t e d by B e n e k e n and associatesF 1 Earlier studies of Sarnoff and associates ~ presented evidence t h a t insufficient c o r o n a r y flow is a m a j o r cause for m y o c a r d i a l failure in late h e m o r r h a g i c shock. M y o c a r d i a l depression could be reversed b y a u g m e n t i n g c o r o n a r y flow with an external p u m p or p h a r m a c o l o g i c a l l y induced v a s o d i l a t a t i o n with Armine. ~ R e c e n t work of B e t h e a a n d associates 22 also d e m o n s t r a t e d t h a t cardiac deterioration during h e m o r r h a g i c hypotension could be reduced by p r e t r e a t m e n t of a n i m a l s with the c o r o n a r y vasodilator, dipyridamole (0.15 mg. per kilogram). T h e y suggested t h a t since d i p y r i d a m o l e h a d no direct effect on m y o c a r d i a l contractility ~ it m u s t exert a protective action through its effect on c o r o n a r y blood flow. 22 T h i s is consistent with earlier work from this l a b o r a t o r y 13 in which a n i m a l s were subjected to h e m o r r h a g i c shock {30 m m . Hg) but c o r o n a r y perfusion pressure was m a i n t a i n e d at n o r m a l levels (100 mm. Hg) to provide a d e q u a t e c o r o n a r y flow. A f t e r 2 hours of shock severe m e t a b o l i c acidosis developed, b u t v e n t r i c u l a r function did not differ f r o m control animals. T h o s e with shock level c o r o n a r y perfusion pressure showed progressive reduction in c o n t r a c t i l i t y to a b o u t 45 per cent of control. T h e observations cited above suggest t h a t the a p p e a r a n c e of left v e n t r i c u l a r failure in hemorrhagic shock m a y be related to an i n a d e q u a t e m y o c a r d i a l oxygen supply. This concept is con-
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Myocardial 02 metabolism and shock
sistent with our present findings. D u r i n g the course of sustained h y p o t e n s i o n , a n i m a l s with the highest arterial oxygen c o n c e n t r a t i o n and h e m a tocrit were m o s t resistant to changes in cardiac p e r f o r m a n c e or oxygen m e t a b o l i s m (Table III. M y o c a r d i a l 02 availability r e m a i n e d relatively high ( a p p r o x i m a t e l y 13 ml. per m i n u t e per 100 Gm. HWJ. On the o t h e r hand. in a n i m a l s where m y o c a r d i a l O~ availability fell below 10 ml. per m i n u t e per 100 Gm. H W cardiac failure c o n s t a n t ly a p p e a r e d and this was a c c o m p a n i e d by a reduction in m y o c a r d i a l O2 e x t r a c t i o n and c o n s u m p t i o n ~Table II). Moreover. two a n i m a l s with m a r g i n a l 02 delivery to the m y o c a r d i u m (10.6 ~- 0.7 S.E. ml. per m i n u t e per 100 Gm. HW~ prior to h e m o r r h a g e were u n a b l e to tolerate h y p o t e n s i o n and died with v e n t r i c u l a r fibrillation shortly a f t e r the onset of shock. T h e close relationship between v e n t r i c u l a r function and myocardial Oz availability during h e m o r r h a g i c shock is clear f r o m the d a t a s h o w n in Fig. 2. As m y o c a r dial O~ availability diminished, there was a c o n c o m i t a n t reduction of left v e n t r i c u l a r d P / d t max. Regression analysis indicates a highly significant association. T h e s e findings m a y be compared with control a n i m a l s ( A P = 7 5 m m . Hg) with equally low h e m a t o c r i t values (Table II. No significant changes in m y o c a r d i a l O~ m e t a b o l i s m or p e r f o r m a n c e occurred over the 90 m i n u t e period. I t should be noted t h a t average 02 delivery to the m y o c a r d i u m r e m a i n e d well above 10 m l per m i n u t e per 100 Gm. H W in these animals. T h e progressive reduction of m y o c a r d i a l 0z availability during shock was p r i m a r i l y conseq u e n t to a reduction of c o r o n a r y flow. T h i s was u n e x p e c t e d since m e t a b o l i c acidosis also appeared (Table I I ) and would p r e s u m a b l y contribute to dilatation of the c o r o n a r y tree. Indeed. mos~ studies h a v e r e p o r t e d a fall of c o r o n a r y resistance during h e m o r r h a g i c hypotension. ~ ~0. 2 4 . 2 6 Others, however, h a v e found in b o t h isolated h e a r t ~ and intact p r e p a r a t i o n s ~' 2~ increased resistance, as in the p r e s e n t study. T h e reason r e m a i n s unclear. S o m e h a v e suggested t h a t it m a y relate to reduced m y o c a r d i a l oxygen d e m a n d 2s or increased c e n t r a l l y m e d i a t e d alphaadrenergic activityY ~ I t would seem unlikely t h a t the decrease in MVo2 a n d m y o c a r d i a l Oz e x t r a c t i o n associated with deterioration of v e n t r i c u l a r function can be a t t r i b u t e d merely to a reduction in contractility
American Heart Journal
a n d decreased oxygen demand. V e n t r i c u l a r wall tension m u s t h a v e increased significantly with the a p p e a r a n c e of cardiac failure as reflected by the elevation of L V E D P in these e x p e r i m e n t s (Table II). This would be expected to increase the O2 r e q u i r e m e n t s of the m y o c a r d i u m . A m o r e likely e x p l a n a t i o n m a y be the d e v e l o p m e n t of a progressive shift in m e t a b o l i c p a t h w a y s toward anaerobic m e t a b o l i s m followed by the inability of m y o c a r d i a l tissues to e x t r a c t oxygen. Thus, the decrease in MVo2 would a p p e a r m o s t reasonably relatable to the a p p e a r a n c e of a defect in m y o c a r dial cellular m e t a b o l i s m . T h e s e conclusions are consistent with the findings of E d w a r d s and associates 2~ and others. 3. . . . . . . . . 3 , ~9-31 Evidence for m y o c a r d i a l s t r u c t u r a l a l t e r a t i o n s which a p p e a r in the course of h e m o r r h a g i c shock s u p p o r t s this concept. 32-~4 Recent studies 3~-~ have shown t h a t following severe h e m o r r h a g e and prior to biochemical m a n i f e s t a t i o n s for m y o c a r d i a l hypoxia, preferential s u b s t r a t e utilization of m y o c a r d i u m shifts from free f a t t y acid to c a r b o h y d r a t e a n d t h a t this shift precedes a n y functional deterioration. ~ This change of preference was a t t r i b u t e d to a limitation of 02 supply a n d t h o u g h t to c o n t r i b u t e to the s u b s e q u e n t irreversible deterioration of circulat o r y function. 3~ T h e pathophysiological changes observed in e x p e r i m e n t a l h e m o r r h a g i c shock are complex and likely depend to some e x t e n t on t h e protocol and e x p e r i m e n t a l conditions. Our results d e m o n s t r a t e a close relationship between m e c h a n i c a l function a n d oxygen m e t a b o l i s m of the h e a r t during the course of h e m o r r h a g i c shock in the cat model. W h e n m y o c a r d i a l 02 availability fell below 10 ml. per m i n u t e per 100 Gm. H W during shock, cardiac failure c o n s t a n t l y a p p e a r e d a n d was a c c o m p a n i e d by a reduction in m y o c a r d i a l O~ e x t r a c t i o n and consumption. T h e i m p o r t a n c e of O~ availability in determining cardiac function has been established but it is n o t certain f r o m these d a t a w h e t h e r reduced 02 m e t a b o l i s m is the cause or the result of destruction of m y o c a r d i a l metabolic pathways.
Summary T h e relationships between left v e n t r i c u l a r function and m y o c a r d i a l O2 availability and m e t a b o l i s m were studied in cats with hemorrhagic shock t A P = 30 mm. Hg) with the use of a right h e a r t b y p a s s preparation. Aortic flow and
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heart rate were held constant. Oxygen-carrying capacity was reduced by diluting donor blood w i t h a n e q u a l v o l u m e o f 5 p e r c e n t g l u c o s e in saline. O x y g e n a v a i l a b i l i t y w a s e s t i m a t e d as t h e p r o d u c t of a r t e r i a l O2 c o n t e n t a n d c o r o n a r y b l o o d flow. A l l s h o c k a n i m a l s s h o w e d a p r o g r e s sive m e t a b o l i c a c i d e m i a w i t h t i m e , a n d a fall in c o r o n a r y flow c o n c o m i t a n t l y . Four control a n i m a l s ( A P = 7 5 m m . H g ) as w e l l as t w o s h o c k animals with high arterial oxygen content and h e m a t o c r i t s h o w e d n o s i g n i f i c a n t c h a n g e s in m y o c a r d i a l O2 m e t a b o l i s m or p e r f o r m a n c e o v e r a p e r i o d o f 90 m i n u t e s . N i n e s h o c k a n i m a l s w i t h reduced hematocrit demonstrated a progressive r e d u c t i o n in v e n t r i c u l a r f u n c t i o n , m y o c a r d i a l O2 m e t a b o l i s m , a n d 02 a v a i l a b i l i t y . As 02 a v a i l a b i l i t y fell b e l o w i 0 ml. p e r m i n u t e p e r 100 Gin. of heart weight, cardiac failure uniformly appeared a n d was a c c o m p a n i e d b y a r e d u c t i o n in 02 e x t r a c tion and consumption. The correlation between l e f t v e n t r i c u l a r d P / d t m a x a n d O2 a v a i l a b i l i t y w a s h i g h l y s i g n i f i c a n t (r = 0.75, p < 0.01) in s h o c k a n i m a l s b u t n o t in c o n t r o l s . T h u s a close r e l a t i o n s h i p b e t w e e n m y o c a r d i a l O2 m e t a b o l i s m and function during the course of h e m o r r h a g i c shock has been demonstrated. Reduced myocard i a l 02 a v a i l a b i l i t y is d i r e c t l y l i n k e d w i t h t h e a p p e a r a n c e of c a r d i a c failure.
9. 10.
11. 12. 13.
14. 15. 16. 17. 18.
19. 20.
The authors acknowledge the expert technical assistance provided by Mr. Ronald Gordon, Mr. Victor Hardaswick, and Mrs. Alyce Rawlins. 21. REFERENCES
1. Wiggers, C. J., and Werle, J. M.: Cardiac and peripheral resistance factors as determinants of circulatory failure in hemorrhagic shock, Am. J. Physiol. 136:421, 1942. 2. Sarnoff, S. J., Case, R. B., Waithe, P. E., and Isaacs, J. P.: Insufficient coronary flow and myocardial failure as a complicating factor in later hemorrhagic shock, Am. J. Physiol. 176:439, 1954. 3. Crowell, J. W., and Guyton, A. C.: Evidence favoring a cardiac mechanism in irreversible hemorrhagic shock, Am. J. Physiol. 201:893, 1961. 4. Hinshaw, L. B., Archer, T. L., Greenfield, L. J., and Guenter, C. A.: Effect of endotoxin on myocardial hemodynamics, performance and metabolism, Am. J. Physiol. 221:504, 1971. 5. Jones, C. E., Bethea, H. L., Smith, E. E., and Crowell, J. W.: Effect of a coronary vasodilator.on the development of irreversible hemorrhagic shock, Surgery 68:356, 1970. 6. Opdyke, D. F., and Foreman, R. C.: A study of coronary flow under conditions of hemorrhagic hypotension and shock, Am. J. Physiol. 148:726, 1947. 7. Mazor, A. M., and Rogel, S.: Cardiac aspects of shockEffects of an ischemic body on a non-ischemic heart, Ann. Surg. 1 78:128, 1973. 8. Lefer, A. M.: Blood borne humoral factors in the patho-
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22. 23.
24.
25. 26. 27. 28. 29.
physiology of circulatory shock, Circ. Res. 32:129, 1973. Glaviano, V. V., and Coleman, B.: Myocardial depletion of norepinephrine in hemorrhagic hypotension, Proc. Soc. Exp. Biol. Med. 107:761, 1961. Bond, R. F., Manningi E. A., Gonzalez, N. M., Gonzalez, R. R., and Becker, V. E.: Myocardial and skeletal muscle responses to hemorrhage and shock during adrenergic blockade, Am. J. Physiol. 225:247, 1973. Rother, C. F.: Heart failure and fluid loss in hemorrhagic shock, Fed. Proc. 29:1854, 1970. Siegel, H~ W., and Downing, S. E.: Reduction of left ventricular contractility during acute hemorrhagic shock, Am. J. Physiol. 218:772, 1970. Siegel, H. W., and Downing, S. E.: Contributions of coronary perfusion pressure, metabolic acidosis and adrenergic factors to the reduction of myocardial contractility during hemorrhagic shock in the cat, Circ. Res. 27:875, 1970. Lee, J. C., and Downing, S. E.: Critical oxygen tension and left ventricular performance during shock, Am. J. Physiol. 226:9, 1974. Roughton, F. J. W., and Scholander, P. F.: Microgasmetric estimation of the blood gases. I. Oxygen, J. Biol. Chem. 148:542, 1943. Hackel, D. B., Goodale, W. T., and Kleinerman, J.: Effects of hypoxia on myocardial metabolism of intact dogs, Circ. Res. 2:169, 1954. Lewis, A. F.: Biostatistics, New York, 1966, Reinhold Publishing Company. Crowell, J. W., Bounds, S. H., and Johnson, W. W.: Effect of varying the hematocrit ratio on the susceptibility to hemorrhagic shock, Am. J. Physiol. 192:171, 1958. Crowell, J. W.: Oxygen transport in the hypotensive state, Fed. Proc. 29:1848, 1970. Chien, S., Dellenbeck, R. J., Usami, S., Burton, D. A., Gustavson, P. F., and Magazinovic, V.: Blood volume hemodynamic and metabolic changes in hemorrhagic shock in normal and splenectomized dogs, Am. J. Physiol. 225:866, 1973. Beneken, J. E. W., Guyton, A. C., and Sagawa, K.: Coronary perfusion pressure and left ventricular function, Pflugers Arch. 305:76, 1969. Bethea, H. L., Jones, C. E., and Crowe!l, J. W.: Effect of pharmacologic coronary flow augmentation on cardiac function in hypotension, Am. J. Physiol. 222:95, 1972. West, J. W., Bellet, S., Manzoli, U. C., and Muller, O. F.: Effects of persantin (RA8) a new coronary vasodilator, on coronary blood flow and cardiac dynamics in the dog, Circ. Res. 10:35, 1961. Edwards, W. S., Siegel, A., and Bing, R: J.: Studies on myocardial metabolism. III. Coronary blood flow, myocardial oxygen consumption and carbohydrate metabolism in experimental hemorrhagic shock, J. Clin. Invest. 33:1646, 1954: Hackel, D. B., and Goodale, W. T.: Effects of hemorrhagic shock on the heart and circulation of intact dogs, Circulation 1 1:628, 1955. Horvath, S. M., Farrand, E. A., and Hutt, B. K.: Cardiac dynamics and coronary blood flow consequent to acute hemorrhage, Am. J. Cardiol. 2:357, 1958. Granata, L., Huvos, A., Pasque, A., and Gregg, D. E.: Left coronary hemodynamics during hemorrhagic hypotension and shock, Am. J. Physiol. 216:1583, 1969. Vatner, S. F.: Effects of hemorrhage on regional blood flow distribution in dogs and primates, J. Clin. Invest. 54:225, 1974. Baue, A. E., and Sayeed, M. M.: Alterations in the
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30. 31.
32. 33.
functional capacity of mitochondria in hemorrhagic shock, Surgery 68:40, 1970. Cowsert, M. K., Carrier, O., and Crowell, J. W.: The effect of hemorrhagic shock on blood uric acid level, Can. J. Physiol. Pharmacol. 44:861, 1966. McShan, W. H., Potter, V. R., Goldman, A., Shipley, E. A., and Meyer, R. K.: Biological energy transformations during shock as shown by blood chemistry, Am. J. Physiol. 145:93, 1945. Chang, J., and Hackel, D. B.: Comparative study of myocardial lesions in hemorrhagic shock, Lab. Invest. 28:641, 1973. Kajihara, H., Hara, H., Seyama, S., Iijima, S., and Yoshidoa: Light and electron microscopic observations of the myocardium of dogs in hemorrhagic shock, Acta Pathol Jap. 23:315, 1973.
American Heart Journal
34. Martin, A. M., and Hackel, D. B.: The myocardium of the dog in hemorrhagic shock. A. Histochemical study, Lab. Invest. 12:77, 1963. 35. Spitzer, J. J., Bechtel, A. A., Archer, L. T., Black, M. R., and Hinshaw, L. B.: Myocardial substrate utilization in dogs following endotoxin administration, Am. J. Physiol. 227:132, 1974. 36. Spitzer, J. J., and Spitzer, J. A.: Myocardial metabolism in dogs during hemorrhagic shock, Am. J. Physiol. 222:101, 1972. 37. Wiener, R., and Spitzer, J. J.: Lactate metabolism following severe hemon'hage in the conscious dog, Am. J. Physiol. 227:58, 1974. 38. Wiener, R., and Spitzer, J. J.: Glucose metabolism following severe hemorrhage in the conscious dog, Am. J. Physiol. 227:63, 1974.
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Wiggers and Werle 1 were probably the first to suggest t h a t a reduction in coronary blood flow m a y be responsible for irreversibility of the hemorrhagic shock syndrome. T h e i m p o r t a n c e of low perfusion pressure and insufficient coronary flow leading to cardiac deterioration in shock animals has subsequently been emphasized by Sarnoff and associates 2 and others2 -7 T h e appearance of cardiotoxic factors ~ and depression of the s y m p a t h o a d r e n a l system 9 have also been implicated as c o n t r i b u t o r y to ultimate deterioration of cardiac function in shock. B u t the relative contrib u t i o n of myocardial failure to the severity and irreversibi!ity of this process has been questioned20. 11 Earlier studies in our l a b o r a t o r y d e m o n s t r a t e d a progressive reduction of myocardial contractility in shock which was a t t r i b u t e d to the interplay of three key factors. These included metabolic acidosis, reduced coronary perfusion pressure, and loss of s y m p a t h e t i c support. 19. 13 More recent work TM has suggested from indirect evidence t h a t myocardial oxygen availability m a y be closely related to the e x t e n t of myocardial depression. T h e present s t u d y was u n d e r t a k e n to ascertain by more direct m e t h o d s the interrelationships between left ventricular function and myocardial oxygen availability and metabolism in sustained hemorrhagic hypotension. A second objective was to determine w h e t h e r the progressive and ultiFrom the Department of Pathology, Yale University School of Medicine, New Haven, Conn. This study was supported in part by grant HL-08659 from the National Heart and Lung Institute and the Connecticut Heart Association. Received for publication April 1, 1975. Reprint requests: John C. Lee, Ph.D., Department of Pathology, Yale University School of Medicine, 310 Cedar St., New Haven, Conn. 06510.
August, 1976, Vol. 92, No. 2, pp. 201-209
m a t e l y irreversible myocardial failure is related to i m p a i r m e n t of myocardial metabolism, and if this can be ascribed to i n a d e q u a t e coronary flow and oxygen delivery to the myocardium. Methods
T h e studies were carried out on 18 adult mongrel cats of both sexes, varying in weight from 2.2 to 4.5 kilograms, and an additional 54 cats were used for donor blood. A right heart bypass preparation was used (Fig. 1). All animals were anesthetized by intraperitoneal sodium pentobarbital (30 mg. per kilogram). T h e trachea was exposed and intubated. T h e chest was opened in the midline and ventilation was m a i n t a i n e d with a H a r v a r d c o n s t a n t - v o l u m e positive pressure pump. Heparin (1,000 units) was given intravenously. T h e descending thoracic aorta was c a n n u l a t e d (Fig. 1) and aortic flow was measured with a S t a t h a m 6.0 ram. O.D. extracorporeal flow transducer and a Medicon K-2000 electromagnetic flow meter. T h e aortic flow was then passed t h r o u g h a Sarns heat exchanger and r e t u r n e d to the descending aorta. T h e azygous vein was ligated and the superior and inferior vena cavae were cannulated. Systemic venous return, including coronary, was diverted to a venous reservoir (Fig. 1) and t h e n p u m p e d t h r o u g h a specially constructed glass heat exchanger (MacalasterBicknell Co.) and back into the main p u l m o n a r y artery. C o r o n a r y venous drainage was accomplished b y passing a c a t h e t e r into the right ventricular c h a m b e r t h r o u g h a stab wound in the wall and secured with a purse string stitch. A " T " connector was placed in the line to permit temporary diversion of flow into a graduated cylinder for timed collections and for sampling. T h e extracorporeal tubing, h e a t exchanger, and
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PACE ELECTRODE
"r
AIR
WATER BATH
EXCHANGER
VENOUS RESEI~/OIR
'~
" .
--
,
ELECTRODEASSEMBLY p ~
R.PUMP
Fig. 1. Diagram of right heart bypass preparation. T R = pressure transducer; R . p u m p = roller pump; I V C = inferior vena cava; L S A = left subclavian artery; R A = right atrium; R V = right ventricle; A O = aorta; F V = femoral vein; G C = graduate cylinder; S V C = superior vena cava; B C = brachiocephalic artery; A Z = azygous vein; L A = left atrium; L V = left ventricle; P A = pulmonary artery. See text for detailed description.
reservoirs were primed with freshly d r a w n heparinized (5 mg. per kilogram) blood f r o m d o n o r cats. C e p h a l i c blood flow was abolished by ligating the brachiocephalic and left subclavian arteries. Pulm o n a r y a n d systemic flows were controlled indep e n d e n t l y b y two roller pumps. Aortic pressure was controlled with an a d j u s t a b l e c o n s t a n t pressure reservoir. All pressure m e a s u r e m e n t s were m a d e with S a n b o r n t r a n s d u c e r s (267 series). T h e midlevel of the h e a r t was used as zero reference. Left v e n t r i c u l a r pressure was m e a s u r e d by passing a 15 gauge needle t h r o u g h the apex into t h e left v e n t r i c u l a r cavity. T h e m a x i m a l r a t e of rise of left v e n t r i c u l a r pressure ( d P / d t m a x ) was o b t a i n e d with a R-C differentiating circuit (time c o n s t a n t 0.268 msec.). T h e h e a r t r a t e was controlled by electrically pacing the left a t r i u m with a Grass SD-5 stimulator. Pressures, aortic flow, h e a r t rate, and left v e n t r i c u l a r d P / d t m e a -
202
s u r e m e n t s were recorded s i m u l t a n e o u s l y on a m u l t i c h a n n e l oscillograph ( S a n b o r n m o d e l 358) at a c h a r t speed of 0.5 or 100 ram. per second. Blood t e m p e r a t u r e was m a i n t a i n e d at 38 ~ ___ 1 ~ C. a n d m e a s u r e d with a Yellow-Springs p r o b e and t e l e t h e r m o m e t e r . Arterial pH, Po2 a n d Pco~ were c o n t i n u o u s l y m o n i t o r e d w i t h a flow-through electrode a s s e m b l y with three B e c k m a n 160 physiological gas analyzers a n d were f r e q u e n t l y checked with a blood gas a n a l y z e r and p H s y s t e m {Instrum e n t a t i o n Laboratories). Arterial and c o r o n a r y venous blood samples were w i t h d r a w n simultaneously f r o m the aortic and right v e n t r i c u l a r c a n n u l a s for d e t e r m i n a t i o n of oxygen c o n t e n t 15 and for m e a s u u r e m e n t of pH, Po~, Pco2, and h e m a t o c r i t . T h e h e m a t o c r i t ratio was d e t e r m i n e d i n duplicate by the m e t h o d of m i c r o h e m a t o c r i t t u b e s (Clay Adams). M y o c a r d i a l oxygen cons u m p t i o n (MVo2) a n d per cent oxygen e x t r a c t i o n
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Myocardial 02 metabolism and shock Table I. H e m o d m a m i c s
30 60 90
and
AP
L VEDP
LV dP/dt max
75.0 • 5.0 75.0 • 5.0 75.0 _+ 5.0 75.0 • 5.0
4.1 • 0.3 3.9 • 0.4 4.1 • 0.4 5.5 _+ 1.0
2,210 • 126 2,310 • 63 2,332 • 41 2,090 • 84
Time (min.) 0
values
oxygen
metabolism
in normotensive
cats
(N
= 4)*
Oxygen CF
Myoc. O~ avail.
Art. conc.
33.4 • 1.7 41.9 • 4.8 42.1 + 8.8 37.6 • 6.4
22.19 • 2.76 26.73 • 3.28 30.30 • 5.06 28.46 • 5.17
7:77 + 0.40 7.79 • 0.64 8.93 • 0.75 8.68 • 0.91
Arterial
C. ext. 57.89 • 3.61 54.69 • 2.03 51.39 • 6.65 46.29 • 10.42
MV02
pH
Po.~
Pco2
Hct.
13.73 • 0.80 15.54 • 0.80 14.28 • 1.14 11.38 • 2.08
7.40 • 0.03 7A1 • 0.01 7.42 • 0.02 7.38 • 0.03
106.8 • 14.1 104.8 • 10.0 89.8 • 11.8 98.3 • 11.4
24.0 • 2.2 22.8 • 2.9 24.4 • 4.7 24.6 • 3.1
16.9 • 0.4 16.3 _+ 1.3 17.3 • 1.5 18.1 • 2.3
*Values are means + standard error of the mean. AP = mean aortic pressure in mm. Hg. LVEDP = left ventricular end-diastolic pressure in cm. H~O. LV dP/dt max = maximal rate of rise of left ventricular pressure in mm. Hg/sec. CF = Coronary blood flow in ml./min. Myoc. O2 avail. = myocardial oxygen availability in ml./min./100 Gm. heart weight. Art. conc. = arterial oxygen content in vol.%. C. ext. = myocardial coefficient of extraction; (A-V/(A) • 100 in %. MVo~ = myocardial oxygen consumption in ml./min./100 Gin. heart weight, pH in units. Po2 and Pco~ in mm. Hg. Hct. = hematocrit in %.
Table II. H e m o d y n a m i c
values
and
myocardial
oxygen
metabolism
in hypotensive
cats*
Oxygen ~ e r i a l
C. ext. I MVO, I pH
L VEDP S h o c k w i t h LV failure (AP=30• Hg)
3
0
6.0 • 0.9
28.3 • 3.0 6
32.3** • 3.0
409* _+ 88
17.2 • 0.6
12.14 • 1.66
73.42 • 3.36
9.54 • 0.50
7.36 -+ 0.07
15.0 • 1.2
11.5" • 0.9
8.18 • 0.87
65.73* • 2.59
5.29* _+ 0.22
7.25 + 0.07
15.3 • 1.5
0
5.5 • 1.0
1,203 • 145
15.9 + 1.6
12.94 • 1.26
76.12 • 3.33
9.62 _+ 0.71
7.37 • 0.03
18.5 • 1.7
30
9.0 • 0.9
974 _+ 86
13.4 • 1.5
11.82 • 1.21
73.04 • 2.05
7.99 -+ 0.70
7.26 • 0.05
18.7 • 1.4
22.6** • 3.9
536** • 111
11.5" _+ 1.2
9.44 • 1.10
56.15" • 4.90
5.28** • 0.71
7.25 • 0.07
19.8 + 1.7
0
2.8 • 0.2
1,509 • 275
13.5 • 0.4
13.37 • 1.27
70.06 • 0.13
9.36 • 0.86
7.36 • 0.07
23.0 • 0.0
30
3.0 -+ 0.7
1,581 • 3,222
12.5 _+ 1.1
13.05 • 1.00
67.05 • 0.67
8.77 • 1.11
7.23 • 0.05
23.5 • 0.4
60
2.8 • 0.2
1,520 • 360
11.8 • 0.2
13.26 • 0.46
74.31 • 3.99
9.91 • 0.87
7.14 • 0.06
23.5 • 1.1
9 90
3.0 • 0.7
1,432 • 358
11.5 _+ 0.4
12.62 • 0.56
73.20 • 7.35
9.36 • 1.35
7.09 -+ 0.05
55.2 • 2.8 S h o c k w i t h o u t LV failure(AP= 30• 5 m m . Hg)
1,238 • 131
I Hct.
2
~
24.5 • 0.4
* V a l u e s a r e m e a n + s t a n d a r d e r r o r o f m e a n . A b b r e v i a t i o n s s a m e a s i n T a b l e I. A s t e r i s k s ( ) i n d i c a t e s t a t i s t i c a l l y s i g n i f i c a n t d i f f e r e n c e b e t w e e n t i m e
periods in each group: *p < 0.05, **p < 0.01.
were was
calculated. estimated
concentration In effects
order
16 M y o c a r d i a l as the and
to
coronary
more
of limitation
oxygen
product
blood
readily
oxygen
flow.
demonstrate
of myocardial
American Heart Journal
availability
of arterial
oxygen
ability the
the avail-
on ventricular
oxygen-carrying donor
blood
performance
capacity with
an
in shock,
was reduced equal
cent glucose
in saline. The
preparation
was in the range
the
by diluting
volume
final hematocrit
of 5 per of the
o f 15 t o 2 5 p e r c e n t
203
Lee and D o w n i n g
( " n o r m a l " hematoci~t for the cat is approximately 30 per cent). After completion of all surgical procedures a period of 15 minutes was allowed for stabilization and control m e a s u r e m e n t s were obtained with a m e a n aortic pressure of 75 +_ 5 mm. Hg. Shock was induced by rapid bleeding from the aorta into the constant-pressure reservoir and aortic pressure was set at 30 +_ 5 mm. Hg. Samples were obtained every 30 minutes following the onset of h y p o t e n s i o n (zero time) for a period of 90 minutes or until severe cardiac failure t e r m i n a t e d the experiment. F o u r animals were studied in a m a n n e r similar to those described above, except t h a t m e a n aortic pressure was m a i n t a i n e d at 75 +_ 5 mm. Hg t h r o u g h o u t t h e experimental period. These animals served as controls. All data in this s t u d y were processed and analyzed by s t a n d a r d statistical methods. 17 T h e difference was considered significant when the p value was less t h a n 5 per cent. Results Left ventricular performance and myocardial oxygen metabolism in normotensive animals. T h e t o t a l right h e a r t bypass preparation involves extensive surgical and cannulation procedures. T h e relative stability and other characteristics of the preparation were therefore determined by studying four animals in which m e a n aortic pressure was maintained at 75 mm. Hg for the full duration of the 90 m i n u t e study period. T h e results are presented in T a b l e I. It is evident t h a t there were no significant changes in left h e a r t performance which might suggest failure. Coron a r y flow increased modestly during the first 30 minutes and then showed little change. Myocardial oxygen extraction and consumption showed small b u t statistically insignificant changes with time. Arterial blood gases, pH, and h e m a t o c r i t values also remained stable over the 11/2 hour interval. Left ventricular performance and myocardial oxygen metabolism during hemorrhagic shock. In 13 animals hemorrhagic shock was produced by lowering the m e a n aortic pressure to 30 mm. Hg. Of these, two died with ventrieular fibrillation shortly after the onset of hypotension. Table II summarizes the h e m o d y n a m i c and metabolic d a t a obtained in the remaining 11 preparations. Nine developed LV f a i l u r e and two showed no
204
evidence of failure during the 11~ h o u r shock period. Within 30 minutes of the onset of shock, three animals showed a sharp reduction of b o t h left ventricular function and myocardial oxygen metabolism. L V E D P rose to 32 cm. H~O and LV d P / d t max fell to a b o u t 30 per cent of time 0 values. Coronary flow fell from 17.2 (_+ 0.6 S.E.) to 11.5 (_+ 0.9 S.E.) ml. per m i n u t e and myocardial O2 availability declined fl'om 12.14 (_+ 1.66 S.E.) to 8.18 (_+ 0.87 S.E.) ml. per m i n u t e per 100 Gm. HW. MVo2 and O2 extraction also fell significantly (Table II). Six animals d e m o n s t r a t e d a progressive reduction of ventricular function with sustained hypotension, but a level of severity comparable to the above was not reached until a b o u t 1 hour of shock (55.2 _+ 2.8 S.E. minutes). T h e m e a n values for L V E D P and LV d P / d t max at time 0 were 5.5 cm. H20 and 1,208 ram. Hg per second, respectively. C o r o n a r y flow was 15.9 ml. per minute and myocardial O2 availability was 12i9 ml. per m i n u t e 100 Gm. HW. E x t r a c t i o n was 76.12 per cent and MVo2 averaged 9.62 ml. per m i n u t e per 100 Gin. HW. After 30 minutes, however, L V E D P rose to 9.0 cm. H20 and LV d P / d t max, coronary flow, myocardial O2 extraction, and MVo2 were all somewhat reduced. Within i h o u r of sustained hypotension the animals showed m a r k e d deterioration of left ventricular function. L V E D P increased t o 22.6 cm. H20 (p < 0.01) and LV d P / dt max fell to 536 mm. Hg per second (p < 0.01). C o r o n a r y flow fell to 11.5 ml. per minute and myocardial O2 availability was reduced to 9.45 ml. per minute per 100 Gin. HW. Concomitantly, O2 extraction and MVo2 were m a r k e d l y decreased to 56 per cent (p < 0.05) and 5.28 ml. per m i n u t e per 100 Gm. H W (p < 0.01), respectively. T w o animals (Table II) showed no significant reduction of left ventricular function during 90 minutes of sustained hypotension as indicated by little change in L V E D P or d P / d t max. Coronary flow showed a small progressive decrease. B u t myocardial O2 availability, extraction, and MVo2 were unchanged over the 11/2h o u r period. It m a y be noted t h a t the arterial oxygen content and h e m a t o e r i t in these animals were significantly higher t h a n in those which developed mechanical failure (Table II). Relationship of ventricular performance to myocardial oxygen availability. T h e d a t a were f u r t h e r analyzed by examining relationship
August, 1976, Vol. 92, No. 2
Myocardial 02 metabolism and shock I
I
I
i
I
I
I
I
I
I
I
I
I
I
I
9 - HYPOTENSIVES(AP=30 mmHg ) N 9 32 (11 animals)
3,000
y 9 t3~J.95X- 5 0 8 . 5 3
3,000
o
r 9 0.75 0
E E
0
~ o
X
g
p < 0.001
9.:.//
o
2,000
0 0
0
E E X
2,000
~= 'o
"S.
.J
I'Z W
O-NORMOTENSIVES ( A P - 7 5 m m H g )
>
N - 16 (4animals)
1,000
F-
|9
I--Z I11
t,000
9
lb. UJ ..J
Y = 2.11X- 2 1 7 6 . 8 0
W J
ql[ _J
r - 0.10 p>O.!
0
i 10
0
I 20
I 30
I 40
I 50
I
0
2
/I
4
MYOCARDIAL OXYGEN AVAILABILITY
I
I
6
8
I f I I I I I 10 12 14 16 18 20 22
(mllmin/1OOgm HW)
Fig. 2. Relationship of myocardial oxygen availability to maximal rate of rise of left ventricular pressure (LV dP/ dt max). Closed circles = shock animals (right panel); open circles = control animals (left panel). See text for further description.
b e t w e e n the left v e n t r i c u l a r d P / d t m a x a n d m y o c a r d i a l 02 availability. Values from the 11 shock cats (32 observations) are p l o t t e d in the r i g h t - h a n d p a n e l of Fig. 2. T h e calculated linear regression line is also shown. A highly significant correlation b e t w e e n LV d P / d t m a x and O~ availability was found (r -- 0.75, p < 0.01), indicating t h a t v e n t r i c u l a r p e r f o r m a n c e in these p r e p a r a tions was closely linked with oxygen availability during shock. In s h a r p contrast, no correlation was found between LV d P / d t m a x and m y o c a r dial 02 availability in n o r m o t e n s i v e controls (r = 0.1, p > 0.1). T h e d a t a from 16 observations are shown in t h e left-hand panel of Fig. 2. Relationship perfusion
of
aortic
pressure
pressure) to ventricular
(coronary
mechanics
and
T h e above findings suggest a close relationshi p b e t w e e n c o r o n a r y flow, a m a j o r d e t e r m i n a n t of m y o c a r d i a l 02 availability, a n d changes in left v e n t r i c u l a r p e r f o r m a n c e a n d m y o c a r d i a l oxygen m e t a b o l i s m in h e m o r r h a g i c shock. T h i s point is f u r t h e r d e m o n s t r a t e d by t h e d a t a f r o m two a n i m a l s shown in T a b l e I I I . W i t h aortic flow a n d h e a r t r a t e held constant, oxygen oxygen
metabolism.
American Heart Journal
delivery to the m y o c a r d i u m was reduced by sequentially lowering c o r o n a r y perfusion pressure. T h e r e was a progressive reduction of c o r o n a r y flow a c c o m p a n i e d by increasing oxygen extraction. LV d P / d t m a x also fell. p r o b a b l y as a mechanical consequence of lowering v e n t r i c u l a r afterloading. However, in b o t h a n i m a l s L V E D P and MVo2 changed little until aortic pressure was reduced to 30 m m . H g a n d m y o c a r d i a l O~ availability fell to a b o u t 11 ml. per m i n u t e per 100 Gm. HW. U n d e r these conditions L V E D P rose sharply to a b o u t 10 cm. H~O a n d d P / d t m a x declined further. I m p r o v e m e n t of m y o c a r d i a l function and oxygen m e t a b o l i s m was observed in each preparation u p o n re-elevation of aortic pressure. This increase in mechanical p e r f o r m a n c e paralleled an increase of c o r o n a r y flow and m y o c a r d i a l 05 availability. Discussion
Previous work f r o m this l a b o r a t o r y 14 h a s s h o w n t h a t sustained h e m o r r h a g i c h y p o t e n s i o n (AP = 30 ram. Hg) a c c o m p a n i e d b y periodic episodes of h y p o x e m i a leads to a m o r e rapid deterioration of
205
Lee and D o w n i n g
Table III. Effects of aortic pressure (coronary perfusion pressure) on v e n t r i c u l a r mechanics and oxygen
metabolism AP
CF
Myoc. 02 ext.
Myoc. 02 avail.
MVO,~
L VEDP
LV dP/dt max
Cat No. 21: 100 75 50 30 50
body weight, 3 . 6 K g ; 22 67.04 20 73.03 17 81.60 14 80.87 20 72.50
h e a r t rate. 226 b.p.m. ~ 10.27 10.07 10.87 8.95 10.63
a ort i c flow. 235 m l . / m i n . : 15.35 4.0 15.10 3.5 13.32 4.0 11.07 10.0 14.66 4.5
h e m a t o c r i t , 20%; 2.279 1.671 1.103 882 1.323
Cat No. 23: 75 35 30 70
body weight, 3.2Kg.; 20 48.09 14 69.88 9 82.90 30 41.47
heart race. 222 b.p.m,; 10.34 10.57 9.43 10.64
a ort i c flow. 250 m l / m i n . : 21.46 3.0 15.16 3.0 11.42 9.5 32.80 3.5
h e m a t o c r i t . 24%. 3.158 1.658 1,188 3,504
Abbreviations same as in Table L *b.p,m. = beats per minute.
m y o c a r d i a l function t h a n when Pao~ is k e p t normal. T h i s s t u d y also d e m o n s t r a t e d t h a t cardiac deterioration during severe h y p o t e n s i o n m a y be delayed by employing less severe hypoxia. observing the "critical P a o ." T h e s e observations s u p p o r t e d the concep~ of c u m u l a t i v e hypoxic tissue d a m a g e in shock a n d suggested t h a t oxygen availability is a p r i m a r y factor in d e t e r m i n i n g reversibility of m y o c a r d i a l depression. T h e present s t u d y was u n d e r t a k e n to obtain m o r e direct evidence for the relationship b e t w e e n these two events. M y o c a r d i a l oxygen availability m a y be simply expressed as the p r o d u c t of c o r o n a r y blood flow and arterial oxygen concentration. Under n o r m a l conditions, the a m o u n t of oxygen that can be carried by p l a s m a in blood is very small, a b o u t 0.3 v o l u m e per cent. Therefore, the oxygen carrying c a p a c i t y of blood is largely d e p e n d e n t on the h e m a t o c r i t ratio. T h e i m p o r t a n c e of the h e m a t o crit to susceptibility to irreversible h e m o r r h a g i c shock has been d e m o n s t r a t e d b y Crowell and associates28 T h e y showed t h a t in dogs the t i m e required for the d e v e l o p m e n t of irreversible shock was p r o p o r t i o n a l to the h e m a t o c r i t in the range of 12 to 35 per cent. However, above 35 per cent the likelihood for survival of the a n i m a l was proportionally decreased. T h e y suggested that this m i g h t be due to an increase of " a p p a r e n t viscosit y " in the blood which f u r t h e r reduces blood flow to the tissues. T h e o p t i m u m h e m a t o c r i t in anesthetized dogs for surviving h e m o r r h a g i c shock was found to be 30 to 35 per cent. 19 Similar conclusions were reached by Chien and asso-
206
ciates. ~~ T h e relationship of c o r o n a r y perfusion pressure a n d left v e n t r i c u l a r function to h e m a t o crit ratio h a s also been d e m o n s t r a t e d by B e n e k e n and associatesF 1 Earlier studies of Sarnoff and associates ~ presented evidence t h a t insufficient c o r o n a r y flow is a m a j o r cause for m y o c a r d i a l failure in late h e m o r r h a g i c shock. M y o c a r d i a l depression could be reversed b y a u g m e n t i n g c o r o n a r y flow with an external p u m p or p h a r m a c o l o g i c a l l y induced v a s o d i l a t a t i o n with Armine. ~ R e c e n t work of B e t h e a a n d associates 22 also d e m o n s t r a t e d t h a t cardiac deterioration during h e m o r r h a g i c hypotension could be reduced by p r e t r e a t m e n t of a n i m a l s with the c o r o n a r y vasodilator, dipyridamole (0.15 mg. per kilogram). T h e y suggested t h a t since d i p y r i d a m o l e h a d no direct effect on m y o c a r d i a l contractility ~ it m u s t exert a protective action through its effect on c o r o n a r y blood flow. 22 T h i s is consistent with earlier work from this l a b o r a t o r y 13 in which a n i m a l s were subjected to h e m o r r h a g i c shock {30 m m . Hg) but c o r o n a r y perfusion pressure was m a i n t a i n e d at n o r m a l levels (100 mm. Hg) to provide a d e q u a t e c o r o n a r y flow. A f t e r 2 hours of shock severe m e t a b o l i c acidosis developed, b u t v e n t r i c u l a r function did not differ f r o m control animals. T h o s e with shock level c o r o n a r y perfusion pressure showed progressive reduction in c o n t r a c t i l i t y to a b o u t 45 per cent of control. T h e observations cited above suggest t h a t the a p p e a r a n c e of left v e n t r i c u l a r failure in hemorrhagic shock m a y be related to an i n a d e q u a t e m y o c a r d i a l oxygen supply. This concept is con-
August, 1976, Vol. 92, No. 2
Myocardial 02 metabolism and shock
sistent with our present findings. D u r i n g the course of sustained h y p o t e n s i o n , a n i m a l s with the highest arterial oxygen c o n c e n t r a t i o n and h e m a tocrit were m o s t resistant to changes in cardiac p e r f o r m a n c e or oxygen m e t a b o l i s m (Table III. M y o c a r d i a l 02 availability r e m a i n e d relatively high ( a p p r o x i m a t e l y 13 ml. per m i n u t e per 100 Gm. HWJ. On the o t h e r hand. in a n i m a l s where m y o c a r d i a l O~ availability fell below 10 ml. per m i n u t e per 100 Gm. H W cardiac failure c o n s t a n t ly a p p e a r e d and this was a c c o m p a n i e d by a reduction in m y o c a r d i a l O2 e x t r a c t i o n and c o n s u m p t i o n ~Table II). Moreover. two a n i m a l s with m a r g i n a l 02 delivery to the m y o c a r d i u m (10.6 ~- 0.7 S.E. ml. per m i n u t e per 100 Gm. HW~ prior to h e m o r r h a g e were u n a b l e to tolerate h y p o t e n s i o n and died with v e n t r i c u l a r fibrillation shortly a f t e r the onset of shock. T h e close relationship between v e n t r i c u l a r function and myocardial Oz availability during h e m o r r h a g i c shock is clear f r o m the d a t a s h o w n in Fig. 2. As m y o c a r dial O~ availability diminished, there was a c o n c o m i t a n t reduction of left v e n t r i c u l a r d P / d t max. Regression analysis indicates a highly significant association. T h e s e findings m a y be compared with control a n i m a l s ( A P = 7 5 m m . Hg) with equally low h e m a t o c r i t values (Table II. No significant changes in m y o c a r d i a l O~ m e t a b o l i s m or p e r f o r m a n c e occurred over the 90 m i n u t e period. I t should be noted t h a t average 02 delivery to the m y o c a r d i u m r e m a i n e d well above 10 m l per m i n u t e per 100 Gm. H W in these animals. T h e progressive reduction of m y o c a r d i a l 0z availability during shock was p r i m a r i l y conseq u e n t to a reduction of c o r o n a r y flow. T h i s was u n e x p e c t e d since m e t a b o l i c acidosis also appeared (Table I I ) and would p r e s u m a b l y contribute to dilatation of the c o r o n a r y tree. Indeed. mos~ studies h a v e r e p o r t e d a fall of c o r o n a r y resistance during h e m o r r h a g i c hypotension. ~ ~0. 2 4 . 2 6 Others, however, h a v e found in b o t h isolated h e a r t ~ and intact p r e p a r a t i o n s ~' 2~ increased resistance, as in the p r e s e n t study. T h e reason r e m a i n s unclear. S o m e h a v e suggested t h a t it m a y relate to reduced m y o c a r d i a l oxygen d e m a n d 2s or increased c e n t r a l l y m e d i a t e d alphaadrenergic activityY ~ I t would seem unlikely t h a t the decrease in MVo2 a n d m y o c a r d i a l Oz e x t r a c t i o n associated with deterioration of v e n t r i c u l a r function can be a t t r i b u t e d merely to a reduction in contractility
American Heart Journal
a n d decreased oxygen demand. V e n t r i c u l a r wall tension m u s t h a v e increased significantly with the a p p e a r a n c e of cardiac failure as reflected by the elevation of L V E D P in these e x p e r i m e n t s (Table II). This would be expected to increase the O2 r e q u i r e m e n t s of the m y o c a r d i u m . A m o r e likely e x p l a n a t i o n m a y be the d e v e l o p m e n t of a progressive shift in m e t a b o l i c p a t h w a y s toward anaerobic m e t a b o l i s m followed by the inability of m y o c a r d i a l tissues to e x t r a c t oxygen. Thus, the decrease in MVo2 would a p p e a r m o s t reasonably relatable to the a p p e a r a n c e of a defect in m y o c a r dial cellular m e t a b o l i s m . T h e s e conclusions are consistent with the findings of E d w a r d s and associates 2~ and others. 3. . . . . . . . . 3 , ~9-31 Evidence for m y o c a r d i a l s t r u c t u r a l a l t e r a t i o n s which a p p e a r in the course of h e m o r r h a g i c shock s u p p o r t s this concept. 32-~4 Recent studies 3~-~ have shown t h a t following severe h e m o r r h a g e and prior to biochemical m a n i f e s t a t i o n s for m y o c a r d i a l hypoxia, preferential s u b s t r a t e utilization of m y o c a r d i u m shifts from free f a t t y acid to c a r b o h y d r a t e a n d t h a t this shift precedes a n y functional deterioration. ~ This change of preference was a t t r i b u t e d to a limitation of 02 supply a n d t h o u g h t to c o n t r i b u t e to the s u b s e q u e n t irreversible deterioration of circulat o r y function. 3~ T h e pathophysiological changes observed in e x p e r i m e n t a l h e m o r r h a g i c shock are complex and likely depend to some e x t e n t on t h e protocol and e x p e r i m e n t a l conditions. Our results d e m o n s t r a t e a close relationship between m e c h a n i c a l function a n d oxygen m e t a b o l i s m of the h e a r t during the course of h e m o r r h a g i c shock in the cat model. W h e n m y o c a r d i a l 02 availability fell below 10 ml. per m i n u t e per 100 Gm. H W during shock, cardiac failure c o n s t a n t l y a p p e a r e d a n d was a c c o m p a n i e d by a reduction in m y o c a r d i a l O~ e x t r a c t i o n and consumption. T h e i m p o r t a n c e of O~ availability in determining cardiac function has been established but it is n o t certain f r o m these d a t a w h e t h e r reduced 02 m e t a b o l i s m is the cause or the result of destruction of m y o c a r d i a l metabolic pathways.
Summary T h e relationships between left v e n t r i c u l a r function and m y o c a r d i a l O2 availability and m e t a b o l i s m were studied in cats with hemorrhagic shock t A P = 30 mm. Hg) with the use of a right h e a r t b y p a s s preparation. Aortic flow and
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Lee and D o w n i n g
heart rate were held constant. Oxygen-carrying capacity was reduced by diluting donor blood w i t h a n e q u a l v o l u m e o f 5 p e r c e n t g l u c o s e in saline. O x y g e n a v a i l a b i l i t y w a s e s t i m a t e d as t h e p r o d u c t of a r t e r i a l O2 c o n t e n t a n d c o r o n a r y b l o o d flow. A l l s h o c k a n i m a l s s h o w e d a p r o g r e s sive m e t a b o l i c a c i d e m i a w i t h t i m e , a n d a fall in c o r o n a r y flow c o n c o m i t a n t l y . Four control a n i m a l s ( A P = 7 5 m m . H g ) as w e l l as t w o s h o c k animals with high arterial oxygen content and h e m a t o c r i t s h o w e d n o s i g n i f i c a n t c h a n g e s in m y o c a r d i a l O2 m e t a b o l i s m or p e r f o r m a n c e o v e r a p e r i o d o f 90 m i n u t e s . N i n e s h o c k a n i m a l s w i t h reduced hematocrit demonstrated a progressive r e d u c t i o n in v e n t r i c u l a r f u n c t i o n , m y o c a r d i a l O2 m e t a b o l i s m , a n d 02 a v a i l a b i l i t y . As 02 a v a i l a b i l i t y fell b e l o w i 0 ml. p e r m i n u t e p e r 100 Gin. of heart weight, cardiac failure uniformly appeared a n d was a c c o m p a n i e d b y a r e d u c t i o n in 02 e x t r a c tion and consumption. The correlation between l e f t v e n t r i c u l a r d P / d t m a x a n d O2 a v a i l a b i l i t y w a s h i g h l y s i g n i f i c a n t (r = 0.75, p < 0.01) in s h o c k a n i m a l s b u t n o t in c o n t r o l s . T h u s a close r e l a t i o n s h i p b e t w e e n m y o c a r d i a l O2 m e t a b o l i s m and function during the course of h e m o r r h a g i c shock has been demonstrated. Reduced myocard i a l 02 a v a i l a b i l i t y is d i r e c t l y l i n k e d w i t h t h e a p p e a r a n c e of c a r d i a c failure.
9. 10.
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14. 15. 16. 17. 18.
19. 20.
The authors acknowledge the expert technical assistance provided by Mr. Ronald Gordon, Mr. Victor Hardaswick, and Mrs. Alyce Rawlins. 21. REFERENCES
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