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Hemodynamic effects of steroids in cardiac disease
Clinical communications Hemodynamic effects of steroids in cardiac disease Lawrence Gould, M.D. C. V. Ramona Reddy, M.D. C. R. Narayana Swamy, M.D. Windell Chua, M.D. Jean-Claude Dorismond, M.D. Brooklyn, N. Y.
Recently Maroko and his co-workers 1 observed that various therapeutic manipulations can reduce the extent of myocardial necrosis in dogs after coronary arterial occlusion. Steroids were found to be particularly effective in preserving the jeopardized myocardium. Further, the beneficial actions of steroids have been observed in man. Maley and associates 2 administered 2 gm. of methylprednisolone to 15 patients with an acute myocardial infarction. T h e y evaluated infarct size by serial serum creatinine phosphokinase determinations, and observed an apparent salvage of the myocardium. In spite of the interest in steroids, there is still limited information on the hemodynamic effects of large dosage of corticosteroids in acute uncomplicated myocardial infarction. T he following study was designed and performed to answer this unresolved question. Methods Studies were performed in two groups of patients: seven patients who had recently sustained an acute transmural myocardial infarction and six cardiac patients who were undergoing a diagnostic cardiac catheterization. Acute myocardial infarction group. Hemodynamic studies were performed from 1 to 9 days after the onset of symptoms in seven patients who had an acute transmural myocardial infarction documented by a typical history, electrocardio-
From the Department of Medicine, The Methodist Hospital, Brooklyn, N.Y. Received for publication May 22, 1975. Reprint requests: Lawrence Gould, M.D., Department of Medicine, The Methodist Hospital, 506 Sixth St., Brooklyn, N. Y. 11215.
August, 1976, Vol. 92, No. 2, pp. 133-138
graphic (ECG) findings, and serum enzyme changes. Six of the seven patients were males. The average age of the group was 52 years. Most of the patients had received therapy, when needed, in the form of oxygen, narcotics, sedatives, diuretics, and lidocaine before the study. The procedure was carefully explained to the patient and informed consent was obtained. Right heart catheterization was performed with a Swan-Ganz flow-directed balloon-type catheter inserted through the right antecubital vein. Arterial pressure was measured through a Cournand needle in the brachial artery. Pressures were measured with St at ham transducers and recorded with the ECG on an Electronics for Medicine DR 12 machine. T he left v e n t r i c u l a r filling pressure was taken as the mean of the pulmonary capillary wedge pressure. Cardiac output was determined by the Fick technique. Mixed venous blood was obtained from the pulmonary artery and arterial blood from the brachial artery. Arterial and mixed venous oxygen contents were determined by the method of Van Slyke and Neill. Oxygen consumption was determined by measuring ventilation with a spirometer and analyzing the expired gas with a Micro-Scholander apparatus. After recording the control hemodynamic measurements, 2 gm. of methylprednisolone were infused over a 20 minute period. One hour after the termination of the infusion, the pressures and cardiac o u t p u t were again measured. Diagnostic cardiac catheterization group. A group of six hospitalized patients underwent right and in three cases left heart catheterizations, primarily as an aid to other clinical management. The conditions of the patients are listed in Table
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Table I. Acute myocardial infarction group
Patient No. and condition
Sex age
R.A. R. V. (mean) S / D (mm. (mm. Hg) Hg)
9xygen conP.A. P.A. Wedge B.A. B.A. sump. S / D (mean mean S / D (mean) A- Vo2 (c.c./ (ram. (mm. (ram. (mm. (mm. Rate diff. rain.~ Hg) Hg) Hg) Hg) Hg) (b.p.m (rot %) M.9
Peripheral T T I / C.L (L./ nin./ M.9
resis- rain. S.I. tance "mm. (ml./ (dynes- Hg beat seesec. / M.9 em..-~) min.)
li Ant. wall myo. inf. 6 days old Control F/63 0 28/0 28/6 Steroids 4 27-35/4 35/15
13 22
2 13
130/62 135142/72
84 94
85 83
4.2 4.0
125 135
2.98 3.36
35 40
1,332 2,430 1,290 2,960
2. Inf. wall myo. inf. 9 days old Control M/48 7 Steroids 11
25/7 25/12 3 3 / 1 1 33/18
16 23
12 18
105/62 115/65
76 81
88 86
3.9 2.0
124 111
3.19 5.60
36 65
1,000 2,400 610 2,960
3. Inf. wall myo. inf. 3 days old Control M/73 14 Steroids 14
35/14 35/18 40/14 40/22
24 28
17 18
105/60 128/72
75 91
80 75
7.3 6.3
143 163
1.94 2.59
14 34
1,780 2,180 1,620 2,680
4. Ant. wall myo. inf. 3 days old Control M/47 15 Steroids 15
40/15 40/30 40/15 40/17
33 24
30 16
100/72 125/80
81 95
107 107
4.9 5.2
100 109
2.00 2.10
19 20
1,680 2,360 1,860 3,070
5. Ant. wall myo. inf. 2 days old Control M/46 0 Steroids 0
18/0 30/0
18/8 30/15
11 20
3 10
140/80 150/85
100 107
75 75
3.5 5.0
129 98
3.69 1.96
49 26
1,050 2,940 1,830 3,370
6. Inf. wall myo. inf. 1 day old Control M/44 1 3 Steroids 18
40/13 38/18 40/18 40/20
25 26
18 20
110/62 97/50
78 65
75 72
4.9 4.2
98 130
1.89 3.12
25 44
1,800 2,140 830 1,820
7. Inf. wall myo. inf. 3 days old Control M/42 6 Steroids 12
30/6 30/16 32/12 32/18
21 23
15 18
110/65 145/75
80 98
80 88
3.8 3.0
130 140
3.44 4.96
43 54
970 2,460 830 3,580
20 24 N.S.
13.9 16.1 N.S.
82 90 N.S.
84 84 N.S.
4.6 4.2 N.S.
121 118 N.S.
2.59 3.38 N.S.
Mean values p value
7.9 10.6 < 0.05
II. Five of t h e six p a t i e n t s were f e m a l e s . T h e a v e r a g e age of t h e g r o u p w a s 49 years. Right heart c a t h e t e r i z a t i o n was performed w i t h a No. 7 G o o d a l e - L u b i n c a t h e t e r i n s e r t e d i n t o t h e r i g h t a n t e c u b i t a l vein. C a t h e t e r i z a t i o n of t h e left v e n t r i c l e was p e r f o r m e d b y i n s e r t i n g a No. 8 G e n s i n i c a t h e t e r i n t o t h e r i g h t f e m o r a l a r t e r y via the Seldinger approach. Pressures and cardiac o u t p u t were d e t e r m i n e d before a n d a f t e r t h e steroid a d m i n i s t r a t i o n as d e s c r i b e d i n t h e a c u t e myocardial infarction study. Calculations. T h e s y s t o l i c e j e c t i o n t i m e i n m i l l i s e c o n d s was m e a s u r e d f r o m t h e b e g i n n i n g of t h e u p s t r o k e to t h e d i c r o t i c n o t c h of t h e a r t e r i a l p r e s s u r e r e c o r d e d a t 100 m m . per s e c o n d . T h e t e n s i o n t i m e i n d e x ( T T I ) per m i n u t e i n millim e t e r s of m e r c u r y p e r s e c o n d p e r m i n u t e is t h e p r o d u c t of t h e h e a r t r a t e , m e a n s y s t o l i c a r t e r i a l pressure, a n d s y s t o l i c e j e c t i o n r a t e . T h e s y s t e m i c
1 34
32 1,373 2,416 40 1,261 2,920 N . S . N.S. < 0.02
v a s c u l a r r e s i s t a n c e i n d y n e s - s e c . - c m . -5 w a s c a l c u lated from the formula: m e a n arterial pressure X 1,332/cardiac o u t p u t ( m i l l i l i t e r s per s e c o n d ) . T h e s t a t i s t i c a l s i g n i f i c a n c e of t h e d i f f e r e n c e (P value) b e t w e e n t h e c o n t r o l v a l u e s a n d t h e s t e r o i d v a l u e s was c a l c u l a t e d w i t h t h e p a i r e d t test.
Results C o m p l e t e d a t a of all 13 p a t i e n t s are p r e s e n t e d i n T a b l e s I a n d II. I n a d d i t i o n , t h e a v e r a g e v a l u e s before a n d a f t e r t h e s t e r o i d i n f u s i o n are l i s t e d i n these t a b l e s w i t h t h e s t a t i s t i c a l a n a l y s i s . Acute myocardial infarction group. As a r e s u l t of t h e s t e r o i d i n f u s i o n , t h e a v e r a g e c a r d i a c i n d e x i n c r e a s e d f r o m 2.59 to 3.38 L. per m i n u t e p e r s q u a r e m e t e r (N.S.) a n d t h e s t r o k e i n d e x i n c r e a s e d f r o m 32 to 40 ml. p e r b e a t p e r s q u a r e m e t e r (N.S.). T h e a r t e r i o v e n o u s (A-V) o x y g e n difference d e c r e a s e d f r o m 4.6 t o 4.2 v o l u m e s p e r
A u g u s t , 1976, Vol. 92, No. 2
Hemodynamic effects of steroids in cardiac disease
Table
II. D i a g n o s t i c c a r d i a c c a t h e t e r i z a t i o n g r o u p
Patient No. and condition
R.A. (mean) Sex (ram. age Hg)
1. Cor pulm0nale Control F/52 Steroids
R. V. S/D (ram. Hg)
P.A. P:A. Wedge S/D /mean) mean (ram. (mm. (mm. Hg) Hg) Hg)
)xygen consump. C.I.
Peri- 'TTI / pheral [ resis- min. S.I. I tance I(mm.
B.A. B.A. L.V. A-i o. le.c./ (L./ (ml./l(dynes- ,He/ S/D (mean) S/D diff. rain.~ mm./ beat sec(mm. (mm. (ram. Rate Hg) (b.p.m.) (vol %) M. ~) M. 2) M. 2) Cm. ~) Imin.) Hg) Hg)
68 74
7 10
118/68 128/72
84 91
--
85 83
4.2 6.2
114 184
2.66 3.03
36 37
1,415 2,607 1,345 2,975
2. Arteriosclerotic heart disease Control F/62 2 25/2 20/8 Steroids 0 22/0 18/6
12 9
5 2
130/70 110/60
89 77
130/5 110/0
115 115
3.6 4.1
122 186
3.38 4.54
29 45
1,235 3,588 795 3,289
3. Mitral stenosis Control F/50 Steroids
75/5 75/32 100/6 100/50
46 66
20 32
148/68 130/65
94 86
115/5 120/10
90 61
7.6 6.9
126 178
1.66 2.58
19 42
21504 2,277 1,469 2,050
4. Arteriosclerotic heart disease Control M/68 1 35/1 35/15 Steroids 3 38/3 38/22
22 28
13 22
135/68 93/50
90 64
--
75 68
5.9 7.8
123 170
2.07 1.38
28 14
2,305 2,531 2,507 1,644
5. Idiopathic pulmonary hypertension Control F/32 0 95/0 95/40 0 110/0 110/50 Steroids
60 70
2 4
160/82 107 125/68 87
--
79 83
3.4 5.7
123 126
3.62 2.21
46 27
1,601 3,539 2,107 2,905
6. Mitral stenosis Control F/32 Steroids
16 15
12 11
120/2 118/3
75 79
4.1 4.7
144 167
3.52 3.67
47 45
1,277 2,880 1,238 2,983
2.81 2.90
34 35
1,722 2,903 1,576 2,641
5 7
5 6
1
2
115/5 115/45 128/7 128/47
28/1 26/11 25/2 25/10
140/70 135/70
93 92
Mean values
2.3 3.0
37 44
9.8 13.5
93 83
87 82
4.8 5.9
125 169
p value
N.S.
N.S.
N.S.
N.S.
N.S.
N.S.
<0.01
c e n t (N.S.) a n d t h e o x y g e n c o n s u m p t i o n w a s e s s e n t i a l l y u n c h a n g e d . T h e left v e n t r i c u l a r f i l l i n g p r e s s u r e i n c r e a s e d i n six of s e v e n p a t i e n t s f r o m a m e a n of 13.9 m m . H g i n t h e c o n t r o l p e r i o d t o 16.1 mm. Hg during the steroid infusion. T h e right v e n t r i c u l a r filling p r e s s u r e i n c r e a s e d i n f o u r p a t i e n t s f r o m a c o n t r o l v a l u e of'7.9 m m . H g to a t r e a t m e n t v a l u e of 10.6 m m . H g (p < 0.05). Steroids i n c r e a s e d t h e a r t e r i a l p r e s s u e f r o m a m e a n of 82 to 90 m m . H g (N.S.) a n d t h e T T I p e r m i n u t e f r o m a c o n t r o l of 2,416 to 2,920 m m . H g per s e c o n d per m i n u t e (p < 0:02). O n c l o s e r i n s p e c t i o n of t h e d a t a , t h e b r a c h i a l a r t e r y m e a n p r e s s u r e rose i n t h e six p a t i e n t s w i t h a n i n f a r c t i o n older t h a n 24 h o u r s a n d fell i n t h e o n e p a t i e n t with a 1-day-old m y o c a r d i a l infarction. T h e systemic peripheral resistance was m i n i m a l l y decreased a f t e r t h e s t e r o i d i n f u s i o n . A t t h e c o n c l u s i o n of t h e h e m o d y n a m i c s t u d i e s P a t i e n t 7 d e v e l o p e d severe c h e s t p a i n a s s o c i a t e d w i t h a 35 m m . H g rise i n t h e b r a c h i a l a r t e r y systolic p r e s s u r e a n d m a r k e d S T - s e g m e n t eleva-
American Heart Journal
N.S.N.S.
N.S.
N.S.
tions. N i t r o g l y c e r i n was a d m i n i s t e r e d s u b l i n g u a l l y w i t h a r e s u l t a n t fall in t he b l o o d p r e s s u r e to 125/70 m m . H g a n d a ' d i s a p p e a r a n c e of t h e chest p a i n . S t e r o i d s p r o d u c e d a p u l s u s a l t e r n a n s in t h e r i g h t v e n t r i c l e a n d b r a c h i a l a r t e r y in P a t i e n t 1. Diagnostic cardiac catheterization group. After m e t h y l p r e d n i s o l o n e i n f u s i o n , t h e a v e r a g e c a r d i a c i n d e x i n c r e a s e d m i n i m a l l y f r o m 2.81 t o 2.90 L. per m i n u t e per s q u a r e m e t e r (N.S.~. F o u r of t h e p a t i e n t s s h o w e d a rise i n t h i s p a r m e t e r a n d t w o a fall. S i m i l a r l y t h e s t r o k e i n d e x a n d c a r d i a c rate showed m i n i m a l nonsignificant changes. T h e A-V o x y g e n difference i n c r e a s e d f r o m 4.8 to 5.9 v o l u m e s per c e n t (N.S.) a n d t h e o x y g e n c o n s u m p t i o n also i n c r e a s e d f r o m 125 to 169 c.c. p e r m i n u t e per s q u a r e m e t e r (p < 0.01). T h e left v e n t r i c u l a r filling pressure i n c r e a s e d in four of t h e p a t i e n t s from a m e a n of 9.8 m m . H g i n t h e c o n t r o l p e r i o d to 13.5 m m . H g d u r i n g t h e s t e r o i d i n f u s i o n . T h e r i g h t v e n t r i c u l a r filling p r e s s u r e also i n c r e a s e d i n f o u r p a t i e n t s f r o m a c o n t r o l v a l u e o f 2.3 to a
1 35
G o u l d et al.
treatment value of 3.0 mm. Hg (N.S.). Steroids decreased the arterial pressure from a mean of 93 to 83 mm. Hg (N.S.) and the T T I from a control of 2,903 to 2,641 mm. Hg per second per minute (N.S.). The systemic peripheral resistance was minimally decreased after the steroid administration. Discussion
The present study revealed t ha t methylprednisolone administration produced, in the patients with a recent myocardial infarction, an average increase in the cardiac index, left ventricular filling pressure, and mean brachial artery mean pressure. In the patients without a myocardial infarction minimal increases in the cardiac index and left ventricular filling pressures were also observed; however the mean brachial artery pressure fell in this group. There have been a number of hemodynamic studies evaluating corticosteroids. Sambhi and his co-workers :~studied the hemodynamic effects of corticosteroids in 12 normal hum an subjects. Following the injection of 500 mg. of hydrocortisone, 100 mg. of prednisone, or 22 mg. of dexamethasone, the cardiac index rose from 3.0 to 3.9 L. per minute per square meter, the arterial pressure changed insignificantly, the peripheral resistance declined, and the venous pressure was unaltered. Dietzman and his associates "~ s u b s e q u e n t l y administered 30 mg. of methylprednisolone per kilogram of body weight to 23 dogs with an experimentally produced myocardial infarction. A significant increase in the cardiac index was observed with evidence of reduced peripheral vasoconstriction. The blood pressure increased in the control surviving dogs as well as the steroidtreated dogs. Thus, the effect of this dose of methylprednisolone on the systemic blood pressure could not be ascertained. The authors concluded, however, that methylprednisolone is a peripheral vasodilating agent. These same workers also administered 30 mg. of methylprednisolone to 12 patients with recent cardiac valve replacement; however, they also received is0proterenol and volume replacement. Thus it was not possible to evaluate the effect of steroids alone in this group, deMello and his associates '~ recently administered methylprednisolone in, single or multiple doses, 30 mg. per kilogram, to 22 patients in the first day of their infarction. The cardiac
136
output, wedge pressure, and systemic arterial pressures were not significantly altered. Vyden and his colleagues ~ studied the effects of large-dose corticosteroids, 50 mg. per kilogram of methylprednisolone intravenously, to assess which of the regional circulations benefits from the vasodilating action of steroids. T h e y administered the drug to 12 dogs with experimentally produced cardiogenic shock. Ninety minutes after the steroid administration, a marked vasodilating effect on the coronary circulation was observed, with a doubling of the coronary arterial blood flow. The cardiac index also increased, whereas the arterial blood pressure and left ventricular end diastolic pressure were not affected. These workers also reported that methylprednisolone at a concentration level up to 400 mg. per liter had no effect,on the contractile state of 15 isolated cat papillary muscles. Thus, in our study the hemodynamic effects of steroids in the patients without a myocardial infarction were not unexpected, similarly the decline in blood pressure produced by steroids in the patient with the l-day-old myocardial infarction was compatible with the reports in the literature. The increase in the systemic pressure in the six infarction patients who received steroids after the first day was an unexpected finding. T h e rise in the systemic pressure in these six patiehts was highly significant (p < 0.01). An examination of the literature reveals that no group has administered steroids to infarct patients after the first day since it is presumed that any limitation of the infarction must be accomplished shortly after the onset of the infarction. The mechanism for this blood pressure elevation is obscure since steroids are considered to be vasodilating agents. Perhaps the steroids produce an augmented pressure response to sympathomimetic amines. When a patient sustains a myocardial infarction the catecholamines are increased on the first day of the infarction but can increase over the ensuing 5 days. 7 Many workers ~-~~ have reported t h a t steroids can augment the pressure response to catecholamines; other workers have rejected this concept.~. 15 The raise in the systemic pressure should theoretically be associated with an increase in the myocardial oxygen consumption requirements, which may be detrimental. Indeed, Patient 7 developed severe chest pain and STsegment elevation with the steroid-induced raise
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Hemodynamic effects of steroids in cardiac disease
in blood pressure. T h i s experience p r o m p t e d us to t e r m i n a t e the a d m i n i s t r a t i o n of steroids to infarction p a t i e n t s a f t e r the first d a y of their illness. Steroids can still be of benefit if a d m i n i s t e r e d during the first d a y of the m y o c a r d i a l infarction. T h e r e have been a n u m b e r of studies to e v a l u a t e the beneficial effect of corticoid a d m i n i s t r a t i o n on infarct size. In 1952 C h a p m a n and his associates, 1~ using a dose of 3 to 7 rag. per k i l o g r a m of cortisone, found t h a t corticosteroids given to dogs with e x p e r i m e n t a l l y induced m y o c a r d i a l infarction did not deleteriously affect t h e size of the infarction or the r a t e or q u a l i t y of m y o c a r d i a l healing. J o h n s o n a n d colleagues TM showed a reduction in the area of infarcts e x p e r i m e n t a l l y produced in dogs t r e a t e d with cortisone (1 to 2 mg. per kilogram) i n t r a m u s c u l a r l y each d a y for 2 to 3 weeks a f t e r c o r o n a r y ligation. T h e y also noted evidence of increased i n t e r c o r o n a r y a n a s t o moses. T w o other groups TM 1~ could not confirm these beneficial results. Similarly, several clinical investigations showed a reduced m o r t a l i t y r a t e in patients with acute m y o c a r d i a l infarction t r e a t e d with hydrocortisone, 17 1~ whereas o t h e r studies have not confirmed this observation. TM L i b b y a n d his co-workers ~~ r e c e n t l y h a v e studied the effect of 50 rag. per kilogram of h y d r o c o r t i s o n e on t h e size of e x p e r i m e n t a l m y o c a r d i a l infarction in 28 dogs. Using e p i c a r d i a l E C G ' s , these workers showed t h a t the a v e r a g e S T - s e g m e n t e l e v a t i o n and n u m b e r of sites with S T elevation g r e a t e r t h a n 2 mV., which are indices of the e x t e n t a n d m a g n i t u d e of m y o c a r d i a l ischemic injury, were relieved by hydrocortisone t r e a t m e n t following acute coronary arterial occlusion. T w e n t y - f o u r hours after infarction, t r a n s m u r a l m y o c a r d i a l specimens were o b t a i n e d for histologic a n d e n z y m e analysis. T h e y found t h a t m y o c a r d i a l creatine phosphokinase activity was less depressed by steroid t r e a t m e n t a n d the areas of m y o c a r d i u m undergoing necrosis were diminished. T h e y concluded t h a t p h a r m a c o l o g i c a l doses of hydrocortisone p r e v e n t m y o c a r d i a l cells from progressing to ischemic necrosis even w h e n administration is initiated 6 h o u r s a f t e r c o r o n a r y occlusion. deMello and associates ~ h a v e r e c e n t l y r e p o r t e d the deleterious effects of m e t h y l p r e d n i s o l o n e in p a t i e n t s with an evolving m y o c a r d i a l infarction. T h e y administered m e t h y l p r e d n i s o l o n e (30 mg. per kilogram) in single or m u l t i p l e doses to 22
American Heart Journal
patients with an a c u t e m y o c a r d i a l infarction beginning 7 h o u r s after the initial C P K elevation. These workers concluded t h a t h i g h doses of methylprednisolone led to an extension of the infarction in patients, reflected b y (1) observed serum C P K values exceeding those projected, (2) persistent elevations of M B - C P K , a n d (3) exacerbations of v e n t r i c u l a r d y s r h y t h m i a . In view of these varying results the e x a c t role of corticosteroid t h e r a p y in h u m a n m y o c a r d i a l infarction still r e m a i n s to be d e t e r m i n e d . T h e d e v e l o p m e n t of new t e c h n i q u e s t h a t allow q u a n titation of infarct size in m a n , t o g e t h e r with the availability of precise h e m o d y n a m i c m e a s u r e ment, m a y clarify this issue. Summary T h e h e m o d y n a m i c effects of i n t r a v e n o u s methylprednisolone were d o c u m e n t e d b y right h e a r t c a t h e t e r i z a t i o n in seven p a t i e n t s with an acute u n c o m p l i c a t e d t r a n s m u r a l m y o c a r d i a l infarction 1 to 9 days a f t e r the onset of s y m p t o m s . I n t r a c a r d i a c pressures, b r a c h i a l a r t e r y pressure, and cardiac o u t p u t were d e t e r m i n e d before a n d 1 hour after the t e r m i n a t i o n of the m e t h y l p r e d n i s o lone infusion. T w o g r a m s of m e t h y l p r e d n i s o l o n e were infused over a 20 m i n u t e period. T h e bracbial pressure rose f r o m a m e a n of 82 to 90 ram. H g (N.S.). T h e b r a c h i a l a r t e r y m e a n pressure fell in the one p a t i e n t with a l - d a y - o l d infarction, and it rose in the six p a t i e n t s with an older infarction, f r o m 83 to 94 m m . H g (p < 0.01). As the brachial a r t e r y pressure rose in one patient, chest pain a n d m a r k e d S T - s e g m e n t elevation occurred which were relieved b y nitroglycerin. This experience p r o m o t e d us to terminate the Steroid study. T h e r e was a nonsignificant increase in the cardiac index and wedge pressure. The raise in the brachial a r t e r y pressure with an infarction older t h a n 1 d a y was an u n e x p e c t e d finding, since steroids are p r e s u m e d to be vasodilating agents. REFERENCES 1, Maroko, P. R., Kjekshus, J. K., Sobel, B. E., Watanobe, T., Covell, J. W., Ross, J., Jr., and Braunwald, E.: Factors influencing infarct size following experimental coronary artery occlusion, Circulation 43:67, 1971. 2. Maley, T., Gulotta, S., and Morrison, J.: Effect of methylpredniso[one on predicted myocardial infarct size in man, Clin. Res. 22:288, 1974. 3. Sambhi, M. P., Well, M. H., and Udhoji, V. N.: Acute pharmacodynamic effects of glucocorticoids. Cardiac
137
G o u l d et al.
4.
5. 6.
7.
8. 9.
10. 11.
138
output and related hemodynamic changes in normal subjects and patients in shock, Circulation 31:523, 1965. Dietzman, R. H., Castaneda, A. R., Lillehei, C. W., Ersek, R. A., Motsay, G. J., and Lillehei, C.: Corticosteroids as effective vasodilators in the t r e a t m e n t of low output syndrome, Chest 5:440, 1970. deMello, V. R., Roberts, R., and Sobel, B. E.: Deleterious effects of methylprednisolone in patients with evolving myocardial infarction, Clin. Res. 33:179, 1975. Vyden, J. K., Tomoda, H., Prakash, R., Chuck, L., Parmley, W. W., and Corday, E.: Effect of corticosteroids in shock secondary to myocardial infarction, Circulation 44:II-237, 1971. Valori, C., Thomas, M., and Shillingford, J.: Free noradrenaline and adrenaline excretion in relation to clinical syndromes following myocardial infarction, Am. J. Cardiol. 20:605, 1967. Raab, W.: Cardiovascular effects of desoxycorticosterone acetate in man, AM. HEART J. 24:365, 1942. Kurland, G. S., and Freedberg, H. S.: Potentiating effects of ACTH and cortisone on pressor response to intravenous infusion of l-norepinephrine, Proc. Soc. Exp. Biol. Med. 78:28, 1951. Spink, W. W.: The pathogenesis and management of shock due to infection, Arch. Intern. Med. 106:433, 1970. Dustan, H., Corcoran, A. C., Taylor, R. D., and Page, I. H.: Cortisone and ACTH in essential hypertension; establishment of renal glycosuria, Arch. Intern. Med. 87:627, 1950.
12. Sambhi, M. P., Weil, M. H., and Udhoji, V. N.: Pressor responses to norepinephrine in h u m a n s before and after corticoids, Am. J. Physiol. 203:961, 1962. 13. Chapman, D. W., Skaggs, R. H., Thomas, J. R., and Greene, J. A~: The effect of cortisone in experimental myocardial infarction, Am. J. Med. Sci. 223:41, 1952. 14. Johnson, A. S., Scheinberg, S. R., Gerisch, R. A., and Saltzstein, H. C.: The effect of cortisone on the size of experimentally produced myocardial infarcts, Circulation 7:224, 1953. 15. Opdyke, D. F., Lambert, A., Stoerk, H. C., Zanetti, M. E., and Kuna, S.: Failure to reduce the size of experimentally produced myocardial infarcts by cortisone treatment, Circulation 8:544, 1953. 16. Hepper, N. G., Pruitt, R. D., Donald, D. E., and Edwards, J. E.: The effect of cortisone on experimentally produced infarcts, Circulation 1 1:742, 1955. 17. Dall, J. L. C., and Peel, A. A. F.: A trial of hydrocortisone in acute myocardial infarction, Lancet 2:1097, 1963. 18. Barzilai, D., Plavnick, J., Hazani, A., Einath, R., Kleinhaus, N., and Kanter, Y.: Use of hydrocortisone in the treatment of myocardial infarction, Chest 61:488, 1972. 19. Scientific subcommittee of the Scottish Society of Physicians: Hydrocortisone in severe myocardial infarction, Lancet 2:785, 1964. 20. Libby, P., Maroko, P. R., Bloor, C. M., Sobel, B. E., and Braunwaldl E.: Reduction of experimental myocardial infarct size by corticosteroid administration, J. Clin. Invest. 52:599, 1973.
August, 1976, Vol. 92, No. 2
Recently Maroko and his co-workers 1 observed that various therapeutic manipulations can reduce the extent of myocardial necrosis in dogs after coronary arterial occlusion. Steroids were found to be particularly effective in preserving the jeopardized myocardium. Further, the beneficial actions of steroids have been observed in man. Maley and associates 2 administered 2 gm. of methylprednisolone to 15 patients with an acute myocardial infarction. T h e y evaluated infarct size by serial serum creatinine phosphokinase determinations, and observed an apparent salvage of the myocardium. In spite of the interest in steroids, there is still limited information on the hemodynamic effects of large dosage of corticosteroids in acute uncomplicated myocardial infarction. T he following study was designed and performed to answer this unresolved question. Methods Studies were performed in two groups of patients: seven patients who had recently sustained an acute transmural myocardial infarction and six cardiac patients who were undergoing a diagnostic cardiac catheterization. Acute myocardial infarction group. Hemodynamic studies were performed from 1 to 9 days after the onset of symptoms in seven patients who had an acute transmural myocardial infarction documented by a typical history, electrocardio-
From the Department of Medicine, The Methodist Hospital, Brooklyn, N.Y. Received for publication May 22, 1975. Reprint requests: Lawrence Gould, M.D., Department of Medicine, The Methodist Hospital, 506 Sixth St., Brooklyn, N. Y. 11215.
August, 1976, Vol. 92, No. 2, pp. 133-138
graphic (ECG) findings, and serum enzyme changes. Six of the seven patients were males. The average age of the group was 52 years. Most of the patients had received therapy, when needed, in the form of oxygen, narcotics, sedatives, diuretics, and lidocaine before the study. The procedure was carefully explained to the patient and informed consent was obtained. Right heart catheterization was performed with a Swan-Ganz flow-directed balloon-type catheter inserted through the right antecubital vein. Arterial pressure was measured through a Cournand needle in the brachial artery. Pressures were measured with St at ham transducers and recorded with the ECG on an Electronics for Medicine DR 12 machine. T he left v e n t r i c u l a r filling pressure was taken as the mean of the pulmonary capillary wedge pressure. Cardiac output was determined by the Fick technique. Mixed venous blood was obtained from the pulmonary artery and arterial blood from the brachial artery. Arterial and mixed venous oxygen contents were determined by the method of Van Slyke and Neill. Oxygen consumption was determined by measuring ventilation with a spirometer and analyzing the expired gas with a Micro-Scholander apparatus. After recording the control hemodynamic measurements, 2 gm. of methylprednisolone were infused over a 20 minute period. One hour after the termination of the infusion, the pressures and cardiac o u t p u t were again measured. Diagnostic cardiac catheterization group. A group of six hospitalized patients underwent right and in three cases left heart catheterizations, primarily as an aid to other clinical management. The conditions of the patients are listed in Table
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133
G o u l d et al.
Table I. Acute myocardial infarction group
Patient No. and condition
Sex age
R.A. R. V. (mean) S / D (mm. (mm. Hg) Hg)
9xygen conP.A. P.A. Wedge B.A. B.A. sump. S / D (mean mean S / D (mean) A- Vo2 (c.c./ (ram. (mm. (ram. (mm. (mm. Rate diff. rain.~ Hg) Hg) Hg) Hg) Hg) (b.p.m (rot %) M.9
Peripheral T T I / C.L (L./ nin./ M.9
resis- rain. S.I. tance "mm. (ml./ (dynes- Hg beat seesec. / M.9 em..-~) min.)
li Ant. wall myo. inf. 6 days old Control F/63 0 28/0 28/6 Steroids 4 27-35/4 35/15
13 22
2 13
130/62 135142/72
84 94
85 83
4.2 4.0
125 135
2.98 3.36
35 40
1,332 2,430 1,290 2,960
2. Inf. wall myo. inf. 9 days old Control M/48 7 Steroids 11
25/7 25/12 3 3 / 1 1 33/18
16 23
12 18
105/62 115/65
76 81
88 86
3.9 2.0
124 111
3.19 5.60
36 65
1,000 2,400 610 2,960
3. Inf. wall myo. inf. 3 days old Control M/73 14 Steroids 14
35/14 35/18 40/14 40/22
24 28
17 18
105/60 128/72
75 91
80 75
7.3 6.3
143 163
1.94 2.59
14 34
1,780 2,180 1,620 2,680
4. Ant. wall myo. inf. 3 days old Control M/47 15 Steroids 15
40/15 40/30 40/15 40/17
33 24
30 16
100/72 125/80
81 95
107 107
4.9 5.2
100 109
2.00 2.10
19 20
1,680 2,360 1,860 3,070
5. Ant. wall myo. inf. 2 days old Control M/46 0 Steroids 0
18/0 30/0
18/8 30/15
11 20
3 10
140/80 150/85
100 107
75 75
3.5 5.0
129 98
3.69 1.96
49 26
1,050 2,940 1,830 3,370
6. Inf. wall myo. inf. 1 day old Control M/44 1 3 Steroids 18
40/13 38/18 40/18 40/20
25 26
18 20
110/62 97/50
78 65
75 72
4.9 4.2
98 130
1.89 3.12
25 44
1,800 2,140 830 1,820
7. Inf. wall myo. inf. 3 days old Control M/42 6 Steroids 12
30/6 30/16 32/12 32/18
21 23
15 18
110/65 145/75
80 98
80 88
3.8 3.0
130 140
3.44 4.96
43 54
970 2,460 830 3,580
20 24 N.S.
13.9 16.1 N.S.
82 90 N.S.
84 84 N.S.
4.6 4.2 N.S.
121 118 N.S.
2.59 3.38 N.S.
Mean values p value
7.9 10.6 < 0.05
II. Five of t h e six p a t i e n t s were f e m a l e s . T h e a v e r a g e age of t h e g r o u p w a s 49 years. Right heart c a t h e t e r i z a t i o n was performed w i t h a No. 7 G o o d a l e - L u b i n c a t h e t e r i n s e r t e d i n t o t h e r i g h t a n t e c u b i t a l vein. C a t h e t e r i z a t i o n of t h e left v e n t r i c l e was p e r f o r m e d b y i n s e r t i n g a No. 8 G e n s i n i c a t h e t e r i n t o t h e r i g h t f e m o r a l a r t e r y via the Seldinger approach. Pressures and cardiac o u t p u t were d e t e r m i n e d before a n d a f t e r t h e steroid a d m i n i s t r a t i o n as d e s c r i b e d i n t h e a c u t e myocardial infarction study. Calculations. T h e s y s t o l i c e j e c t i o n t i m e i n m i l l i s e c o n d s was m e a s u r e d f r o m t h e b e g i n n i n g of t h e u p s t r o k e to t h e d i c r o t i c n o t c h of t h e a r t e r i a l p r e s s u r e r e c o r d e d a t 100 m m . per s e c o n d . T h e t e n s i o n t i m e i n d e x ( T T I ) per m i n u t e i n millim e t e r s of m e r c u r y p e r s e c o n d p e r m i n u t e is t h e p r o d u c t of t h e h e a r t r a t e , m e a n s y s t o l i c a r t e r i a l pressure, a n d s y s t o l i c e j e c t i o n r a t e . T h e s y s t e m i c
1 34
32 1,373 2,416 40 1,261 2,920 N . S . N.S. < 0.02
v a s c u l a r r e s i s t a n c e i n d y n e s - s e c . - c m . -5 w a s c a l c u lated from the formula: m e a n arterial pressure X 1,332/cardiac o u t p u t ( m i l l i l i t e r s per s e c o n d ) . T h e s t a t i s t i c a l s i g n i f i c a n c e of t h e d i f f e r e n c e (P value) b e t w e e n t h e c o n t r o l v a l u e s a n d t h e s t e r o i d v a l u e s was c a l c u l a t e d w i t h t h e p a i r e d t test.
Results C o m p l e t e d a t a of all 13 p a t i e n t s are p r e s e n t e d i n T a b l e s I a n d II. I n a d d i t i o n , t h e a v e r a g e v a l u e s before a n d a f t e r t h e s t e r o i d i n f u s i o n are l i s t e d i n these t a b l e s w i t h t h e s t a t i s t i c a l a n a l y s i s . Acute myocardial infarction group. As a r e s u l t of t h e s t e r o i d i n f u s i o n , t h e a v e r a g e c a r d i a c i n d e x i n c r e a s e d f r o m 2.59 to 3.38 L. per m i n u t e p e r s q u a r e m e t e r (N.S.) a n d t h e s t r o k e i n d e x i n c r e a s e d f r o m 32 to 40 ml. p e r b e a t p e r s q u a r e m e t e r (N.S.). T h e a r t e r i o v e n o u s (A-V) o x y g e n difference d e c r e a s e d f r o m 4.6 t o 4.2 v o l u m e s p e r
A u g u s t , 1976, Vol. 92, No. 2
Hemodynamic effects of steroids in cardiac disease
Table
II. D i a g n o s t i c c a r d i a c c a t h e t e r i z a t i o n g r o u p
Patient No. and condition
R.A. (mean) Sex (ram. age Hg)
1. Cor pulm0nale Control F/52 Steroids
R. V. S/D (ram. Hg)
P.A. P:A. Wedge S/D /mean) mean (ram. (mm. (mm. Hg) Hg) Hg)
)xygen consump. C.I.
Peri- 'TTI / pheral [ resis- min. S.I. I tance I(mm.
B.A. B.A. L.V. A-i o. le.c./ (L./ (ml./l(dynes- ,He/ S/D (mean) S/D diff. rain.~ mm./ beat sec(mm. (mm. (ram. Rate Hg) (b.p.m.) (vol %) M. ~) M. 2) M. 2) Cm. ~) Imin.) Hg) Hg)
68 74
7 10
118/68 128/72
84 91
--
85 83
4.2 6.2
114 184
2.66 3.03
36 37
1,415 2,607 1,345 2,975
2. Arteriosclerotic heart disease Control F/62 2 25/2 20/8 Steroids 0 22/0 18/6
12 9
5 2
130/70 110/60
89 77
130/5 110/0
115 115
3.6 4.1
122 186
3.38 4.54
29 45
1,235 3,588 795 3,289
3. Mitral stenosis Control F/50 Steroids
75/5 75/32 100/6 100/50
46 66
20 32
148/68 130/65
94 86
115/5 120/10
90 61
7.6 6.9
126 178
1.66 2.58
19 42
21504 2,277 1,469 2,050
4. Arteriosclerotic heart disease Control M/68 1 35/1 35/15 Steroids 3 38/3 38/22
22 28
13 22
135/68 93/50
90 64
--
75 68
5.9 7.8
123 170
2.07 1.38
28 14
2,305 2,531 2,507 1,644
5. Idiopathic pulmonary hypertension Control F/32 0 95/0 95/40 0 110/0 110/50 Steroids
60 70
2 4
160/82 107 125/68 87
--
79 83
3.4 5.7
123 126
3.62 2.21
46 27
1,601 3,539 2,107 2,905
6. Mitral stenosis Control F/32 Steroids
16 15
12 11
120/2 118/3
75 79
4.1 4.7
144 167
3.52 3.67
47 45
1,277 2,880 1,238 2,983
2.81 2.90
34 35
1,722 2,903 1,576 2,641
5 7
5 6
1
2
115/5 115/45 128/7 128/47
28/1 26/11 25/2 25/10
140/70 135/70
93 92
Mean values
2.3 3.0
37 44
9.8 13.5
93 83
87 82
4.8 5.9
125 169
p value
N.S.
N.S.
N.S.
N.S.
N.S.
N.S.
<0.01
c e n t (N.S.) a n d t h e o x y g e n c o n s u m p t i o n w a s e s s e n t i a l l y u n c h a n g e d . T h e left v e n t r i c u l a r f i l l i n g p r e s s u r e i n c r e a s e d i n six of s e v e n p a t i e n t s f r o m a m e a n of 13.9 m m . H g i n t h e c o n t r o l p e r i o d t o 16.1 mm. Hg during the steroid infusion. T h e right v e n t r i c u l a r filling p r e s s u r e i n c r e a s e d i n f o u r p a t i e n t s f r o m a c o n t r o l v a l u e of'7.9 m m . H g to a t r e a t m e n t v a l u e of 10.6 m m . H g (p < 0.05). Steroids i n c r e a s e d t h e a r t e r i a l p r e s s u e f r o m a m e a n of 82 to 90 m m . H g (N.S.) a n d t h e T T I p e r m i n u t e f r o m a c o n t r o l of 2,416 to 2,920 m m . H g per s e c o n d per m i n u t e (p < 0:02). O n c l o s e r i n s p e c t i o n of t h e d a t a , t h e b r a c h i a l a r t e r y m e a n p r e s s u r e rose i n t h e six p a t i e n t s w i t h a n i n f a r c t i o n older t h a n 24 h o u r s a n d fell i n t h e o n e p a t i e n t with a 1-day-old m y o c a r d i a l infarction. T h e systemic peripheral resistance was m i n i m a l l y decreased a f t e r t h e s t e r o i d i n f u s i o n . A t t h e c o n c l u s i o n of t h e h e m o d y n a m i c s t u d i e s P a t i e n t 7 d e v e l o p e d severe c h e s t p a i n a s s o c i a t e d w i t h a 35 m m . H g rise i n t h e b r a c h i a l a r t e r y systolic p r e s s u r e a n d m a r k e d S T - s e g m e n t eleva-
American Heart Journal
N.S.N.S.
N.S.
N.S.
tions. N i t r o g l y c e r i n was a d m i n i s t e r e d s u b l i n g u a l l y w i t h a r e s u l t a n t fall in t he b l o o d p r e s s u r e to 125/70 m m . H g a n d a ' d i s a p p e a r a n c e of t h e chest p a i n . S t e r o i d s p r o d u c e d a p u l s u s a l t e r n a n s in t h e r i g h t v e n t r i c l e a n d b r a c h i a l a r t e r y in P a t i e n t 1. Diagnostic cardiac catheterization group. After m e t h y l p r e d n i s o l o n e i n f u s i o n , t h e a v e r a g e c a r d i a c i n d e x i n c r e a s e d m i n i m a l l y f r o m 2.81 t o 2.90 L. per m i n u t e per s q u a r e m e t e r (N.S.~. F o u r of t h e p a t i e n t s s h o w e d a rise i n t h i s p a r m e t e r a n d t w o a fall. S i m i l a r l y t h e s t r o k e i n d e x a n d c a r d i a c rate showed m i n i m a l nonsignificant changes. T h e A-V o x y g e n difference i n c r e a s e d f r o m 4.8 to 5.9 v o l u m e s per c e n t (N.S.) a n d t h e o x y g e n c o n s u m p t i o n also i n c r e a s e d f r o m 125 to 169 c.c. p e r m i n u t e per s q u a r e m e t e r (p < 0.01). T h e left v e n t r i c u l a r filling pressure i n c r e a s e d in four of t h e p a t i e n t s from a m e a n of 9.8 m m . H g i n t h e c o n t r o l p e r i o d to 13.5 m m . H g d u r i n g t h e s t e r o i d i n f u s i o n . T h e r i g h t v e n t r i c u l a r filling p r e s s u r e also i n c r e a s e d i n f o u r p a t i e n t s f r o m a c o n t r o l v a l u e o f 2.3 to a
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treatment value of 3.0 mm. Hg (N.S.). Steroids decreased the arterial pressure from a mean of 93 to 83 mm. Hg (N.S.) and the T T I from a control of 2,903 to 2,641 mm. Hg per second per minute (N.S.). The systemic peripheral resistance was minimally decreased after the steroid administration. Discussion
The present study revealed t ha t methylprednisolone administration produced, in the patients with a recent myocardial infarction, an average increase in the cardiac index, left ventricular filling pressure, and mean brachial artery mean pressure. In the patients without a myocardial infarction minimal increases in the cardiac index and left ventricular filling pressures were also observed; however the mean brachial artery pressure fell in this group. There have been a number of hemodynamic studies evaluating corticosteroids. Sambhi and his co-workers :~studied the hemodynamic effects of corticosteroids in 12 normal hum an subjects. Following the injection of 500 mg. of hydrocortisone, 100 mg. of prednisone, or 22 mg. of dexamethasone, the cardiac index rose from 3.0 to 3.9 L. per minute per square meter, the arterial pressure changed insignificantly, the peripheral resistance declined, and the venous pressure was unaltered. Dietzman and his associates "~ s u b s e q u e n t l y administered 30 mg. of methylprednisolone per kilogram of body weight to 23 dogs with an experimentally produced myocardial infarction. A significant increase in the cardiac index was observed with evidence of reduced peripheral vasoconstriction. The blood pressure increased in the control surviving dogs as well as the steroidtreated dogs. Thus, the effect of this dose of methylprednisolone on the systemic blood pressure could not be ascertained. The authors concluded, however, that methylprednisolone is a peripheral vasodilating agent. These same workers also administered 30 mg. of methylprednisolone to 12 patients with recent cardiac valve replacement; however, they also received is0proterenol and volume replacement. Thus it was not possible to evaluate the effect of steroids alone in this group, deMello and his associates '~ recently administered methylprednisolone in, single or multiple doses, 30 mg. per kilogram, to 22 patients in the first day of their infarction. The cardiac
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output, wedge pressure, and systemic arterial pressures were not significantly altered. Vyden and his colleagues ~ studied the effects of large-dose corticosteroids, 50 mg. per kilogram of methylprednisolone intravenously, to assess which of the regional circulations benefits from the vasodilating action of steroids. T h e y administered the drug to 12 dogs with experimentally produced cardiogenic shock. Ninety minutes after the steroid administration, a marked vasodilating effect on the coronary circulation was observed, with a doubling of the coronary arterial blood flow. The cardiac index also increased, whereas the arterial blood pressure and left ventricular end diastolic pressure were not affected. These workers also reported that methylprednisolone at a concentration level up to 400 mg. per liter had no effect,on the contractile state of 15 isolated cat papillary muscles. Thus, in our study the hemodynamic effects of steroids in the patients without a myocardial infarction were not unexpected, similarly the decline in blood pressure produced by steroids in the patient with the l-day-old myocardial infarction was compatible with the reports in the literature. The increase in the systemic pressure in the six infarction patients who received steroids after the first day was an unexpected finding. T h e rise in the systemic pressure in these six patiehts was highly significant (p < 0.01). An examination of the literature reveals that no group has administered steroids to infarct patients after the first day since it is presumed that any limitation of the infarction must be accomplished shortly after the onset of the infarction. The mechanism for this blood pressure elevation is obscure since steroids are considered to be vasodilating agents. Perhaps the steroids produce an augmented pressure response to sympathomimetic amines. When a patient sustains a myocardial infarction the catecholamines are increased on the first day of the infarction but can increase over the ensuing 5 days. 7 Many workers ~-~~ have reported t h a t steroids can augment the pressure response to catecholamines; other workers have rejected this concept.~. 15 The raise in the systemic pressure should theoretically be associated with an increase in the myocardial oxygen consumption requirements, which may be detrimental. Indeed, Patient 7 developed severe chest pain and STsegment elevation with the steroid-induced raise
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Hemodynamic effects of steroids in cardiac disease
in blood pressure. T h i s experience p r o m p t e d us to t e r m i n a t e the a d m i n i s t r a t i o n of steroids to infarction p a t i e n t s a f t e r the first d a y of their illness. Steroids can still be of benefit if a d m i n i s t e r e d during the first d a y of the m y o c a r d i a l infarction. T h e r e have been a n u m b e r of studies to e v a l u a t e the beneficial effect of corticoid a d m i n i s t r a t i o n on infarct size. In 1952 C h a p m a n and his associates, 1~ using a dose of 3 to 7 rag. per k i l o g r a m of cortisone, found t h a t corticosteroids given to dogs with e x p e r i m e n t a l l y induced m y o c a r d i a l infarction did not deleteriously affect t h e size of the infarction or the r a t e or q u a l i t y of m y o c a r d i a l healing. J o h n s o n a n d colleagues TM showed a reduction in the area of infarcts e x p e r i m e n t a l l y produced in dogs t r e a t e d with cortisone (1 to 2 mg. per kilogram) i n t r a m u s c u l a r l y each d a y for 2 to 3 weeks a f t e r c o r o n a r y ligation. T h e y also noted evidence of increased i n t e r c o r o n a r y a n a s t o moses. T w o other groups TM 1~ could not confirm these beneficial results. Similarly, several clinical investigations showed a reduced m o r t a l i t y r a t e in patients with acute m y o c a r d i a l infarction t r e a t e d with hydrocortisone, 17 1~ whereas o t h e r studies have not confirmed this observation. TM L i b b y a n d his co-workers ~~ r e c e n t l y h a v e studied the effect of 50 rag. per kilogram of h y d r o c o r t i s o n e on t h e size of e x p e r i m e n t a l m y o c a r d i a l infarction in 28 dogs. Using e p i c a r d i a l E C G ' s , these workers showed t h a t the a v e r a g e S T - s e g m e n t e l e v a t i o n and n u m b e r of sites with S T elevation g r e a t e r t h a n 2 mV., which are indices of the e x t e n t a n d m a g n i t u d e of m y o c a r d i a l ischemic injury, were relieved by hydrocortisone t r e a t m e n t following acute coronary arterial occlusion. T w e n t y - f o u r hours after infarction, t r a n s m u r a l m y o c a r d i a l specimens were o b t a i n e d for histologic a n d e n z y m e analysis. T h e y found t h a t m y o c a r d i a l creatine phosphokinase activity was less depressed by steroid t r e a t m e n t a n d the areas of m y o c a r d i u m undergoing necrosis were diminished. T h e y concluded t h a t p h a r m a c o l o g i c a l doses of hydrocortisone p r e v e n t m y o c a r d i a l cells from progressing to ischemic necrosis even w h e n administration is initiated 6 h o u r s a f t e r c o r o n a r y occlusion. deMello and associates ~ h a v e r e c e n t l y r e p o r t e d the deleterious effects of m e t h y l p r e d n i s o l o n e in p a t i e n t s with an evolving m y o c a r d i a l infarction. T h e y administered m e t h y l p r e d n i s o l o n e (30 mg. per kilogram) in single or m u l t i p l e doses to 22
American Heart Journal
patients with an a c u t e m y o c a r d i a l infarction beginning 7 h o u r s after the initial C P K elevation. These workers concluded t h a t h i g h doses of methylprednisolone led to an extension of the infarction in patients, reflected b y (1) observed serum C P K values exceeding those projected, (2) persistent elevations of M B - C P K , a n d (3) exacerbations of v e n t r i c u l a r d y s r h y t h m i a . In view of these varying results the e x a c t role of corticosteroid t h e r a p y in h u m a n m y o c a r d i a l infarction still r e m a i n s to be d e t e r m i n e d . T h e d e v e l o p m e n t of new t e c h n i q u e s t h a t allow q u a n titation of infarct size in m a n , t o g e t h e r with the availability of precise h e m o d y n a m i c m e a s u r e ment, m a y clarify this issue. Summary T h e h e m o d y n a m i c effects of i n t r a v e n o u s methylprednisolone were d o c u m e n t e d b y right h e a r t c a t h e t e r i z a t i o n in seven p a t i e n t s with an acute u n c o m p l i c a t e d t r a n s m u r a l m y o c a r d i a l infarction 1 to 9 days a f t e r the onset of s y m p t o m s . I n t r a c a r d i a c pressures, b r a c h i a l a r t e r y pressure, and cardiac o u t p u t were d e t e r m i n e d before a n d 1 hour after the t e r m i n a t i o n of the m e t h y l p r e d n i s o lone infusion. T w o g r a m s of m e t h y l p r e d n i s o l o n e were infused over a 20 m i n u t e period. T h e bracbial pressure rose f r o m a m e a n of 82 to 90 ram. H g (N.S.). T h e b r a c h i a l a r t e r y m e a n pressure fell in the one p a t i e n t with a l - d a y - o l d infarction, and it rose in the six p a t i e n t s with an older infarction, f r o m 83 to 94 m m . H g (p < 0.01). As the brachial a r t e r y pressure rose in one patient, chest pain a n d m a r k e d S T - s e g m e n t elevation occurred which were relieved b y nitroglycerin. This experience p r o m o t e d us to terminate the Steroid study. T h e r e was a nonsignificant increase in the cardiac index and wedge pressure. The raise in the brachial a r t e r y pressure with an infarction older t h a n 1 d a y was an u n e x p e c t e d finding, since steroids are p r e s u m e d to be vasodilating agents. REFERENCES 1, Maroko, P. R., Kjekshus, J. K., Sobel, B. E., Watanobe, T., Covell, J. W., Ross, J., Jr., and Braunwald, E.: Factors influencing infarct size following experimental coronary artery occlusion, Circulation 43:67, 1971. 2. Maley, T., Gulotta, S., and Morrison, J.: Effect of methylpredniso[one on predicted myocardial infarct size in man, Clin. Res. 22:288, 1974. 3. Sambhi, M. P., Well, M. H., and Udhoji, V. N.: Acute pharmacodynamic effects of glucocorticoids. Cardiac
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output and related hemodynamic changes in normal subjects and patients in shock, Circulation 31:523, 1965. Dietzman, R. H., Castaneda, A. R., Lillehei, C. W., Ersek, R. A., Motsay, G. J., and Lillehei, C.: Corticosteroids as effective vasodilators in the t r e a t m e n t of low output syndrome, Chest 5:440, 1970. deMello, V. R., Roberts, R., and Sobel, B. E.: Deleterious effects of methylprednisolone in patients with evolving myocardial infarction, Clin. Res. 33:179, 1975. Vyden, J. K., Tomoda, H., Prakash, R., Chuck, L., Parmley, W. W., and Corday, E.: Effect of corticosteroids in shock secondary to myocardial infarction, Circulation 44:II-237, 1971. Valori, C., Thomas, M., and Shillingford, J.: Free noradrenaline and adrenaline excretion in relation to clinical syndromes following myocardial infarction, Am. J. Cardiol. 20:605, 1967. Raab, W.: Cardiovascular effects of desoxycorticosterone acetate in man, AM. HEART J. 24:365, 1942. Kurland, G. S., and Freedberg, H. S.: Potentiating effects of ACTH and cortisone on pressor response to intravenous infusion of l-norepinephrine, Proc. Soc. Exp. Biol. Med. 78:28, 1951. Spink, W. W.: The pathogenesis and management of shock due to infection, Arch. Intern. Med. 106:433, 1970. Dustan, H., Corcoran, A. C., Taylor, R. D., and Page, I. H.: Cortisone and ACTH in essential hypertension; establishment of renal glycosuria, Arch. Intern. Med. 87:627, 1950.
12. Sambhi, M. P., Weil, M. H., and Udhoji, V. N.: Pressor responses to norepinephrine in h u m a n s before and after corticoids, Am. J. Physiol. 203:961, 1962. 13. Chapman, D. W., Skaggs, R. H., Thomas, J. R., and Greene, J. A~: The effect of cortisone in experimental myocardial infarction, Am. J. Med. Sci. 223:41, 1952. 14. Johnson, A. S., Scheinberg, S. R., Gerisch, R. A., and Saltzstein, H. C.: The effect of cortisone on the size of experimentally produced myocardial infarcts, Circulation 7:224, 1953. 15. Opdyke, D. F., Lambert, A., Stoerk, H. C., Zanetti, M. E., and Kuna, S.: Failure to reduce the size of experimentally produced myocardial infarcts by cortisone treatment, Circulation 8:544, 1953. 16. Hepper, N. G., Pruitt, R. D., Donald, D. E., and Edwards, J. E.: The effect of cortisone on experimentally produced infarcts, Circulation 1 1:742, 1955. 17. Dall, J. L. C., and Peel, A. A. F.: A trial of hydrocortisone in acute myocardial infarction, Lancet 2:1097, 1963. 18. Barzilai, D., Plavnick, J., Hazani, A., Einath, R., Kleinhaus, N., and Kanter, Y.: Use of hydrocortisone in the treatment of myocardial infarction, Chest 61:488, 1972. 19. Scientific subcommittee of the Scottish Society of Physicians: Hydrocortisone in severe myocardial infarction, Lancet 2:785, 1964. 20. Libby, P., Maroko, P. R., Bloor, C. M., Sobel, B. E., and Braunwaldl E.: Reduction of experimental myocardial infarct size by corticosteroid administration, J. Clin. Invest. 52:599, 1973.
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