Nitroprusside therapy in acute and chronic coronary heart disease

Nitroprusside Therapy in Acute and Chronic Coronary Heart Disease

RICHARD R. MILLER, M.D. Houston, Texas NAJAM A. AWAN,

M.D.

DEAN T. MASON,

M.D.

Davis, California

From the Section of Cardiology, Depertment of Medicine, Baylor College of Medicine, Houstcn, Texas;andtheSectionofCardlobgjy,Department of fbbdiclne. University of Callfornla School of Medicine, Davis, California. Requests for reprints should be addressed to Dr. Richard R. Miller, Sectlcll of Cwdkkgy, Baylor wlegs of Msdkine. The Methodist Hcspltal, 6516 Bertner Boulevard. Houston, Texas 77030.

To elucidate the effects of nitroprusside on the relations between systemic pressure, coronary blood flow and regional myocardial ischemla, dogs were subjected to constriction of the proximal left anterlor descending (LAD) artery to induce ischemla determined by lntramyocardlal S-T segments and intramyocardial mass spectrometric oxygen tension (PO,) and carbon dioxide tension ( PCOp). Nltroprusside was infused to incrementally lower mean blood pressure from 137 to 62 mm Hg. A decrease in mean blood pressure to 87 mm Hg lowered (p KO.05) intramyocardial S-T segment elevations and dlminished left ventricular filling pressure, but It dld not alter (p >0.05) poststenotk flow In the LAD artery, intramyocardial PC02 and PDs, and cardiac oxygen uptake. With a further decrease in systemic arterial blood pressure below nofmal, S-T segments rose, LAD artery flow decreased, intramyocardlal PCOs increased and intramyocardial PDs decreased. In addition, 12 patlents wtth acute anterior infarction had 35lead S-T segment maps before and after a 10 minute infusion of nitroprusslde. Heart rate was unchanged, left ventricular pressure decreased from 139/19 to 115/l 1 mm Hg (p
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r

,

C

AP

F&ure 1. lhe effect of nitroprusside (NP) during the control (C) period and during atria/ pacing (AP) on heart rate (HR) shown in panel A; mean arterial pressure (MAP), panel 6; left ventricular end-diastolic pressure (L VEDP), panel C; and cardiac index (Cl), panel 0.

the extent of acute myocardial infarction [g-27]. Importantly, it is unresolved whether the action of nitroprusside to reduce myocardial oxygen needs is offset by its potentially deleterious effect of decreasing coronary perfusion pressure and total coronary blood flow

WI.

Previous experimental studies concerning the action of nitroprusside on myocardial ischemia produced by coronary artery ligation in canine models have yielded variable results [9,13,15,16,26]. Thus, following coronary occlusion, nitroprusside improves mechanical performance of the acutely ischemic myocardium [9,13,16]. Furthermore, the agent increases blood flow to the ischemic myocardium and results in improved regional myocardial energetics [ 13,161. Other experimental studies, however, have indicated that concomitant with significant reductions in systemic pressure, nitroprusside aggravates the extent of ischemic injury suggesting a decline in perfusion of the myocardium rendered ischemic [ 141. Experimental Animal Studies. The present series of investigations were carried out to evaluate the effects on myocardial ischemia of nitroprusside-induced incremental reductions in systemic blood pressure following partial coronary artery occlusion in dogs. Multiple indices of myocardial ischemia were evaluated including measurement of S-T segment elevation obtained from myocardial electrodes inserted into the ischemic myocardium, intramyocardial POP and intramyocardial PC02 measured by mass spectrometry, and myocardial oxygen extraction [ 271. Following production of myocardial ischemia induced by stenosis of the proximal left anterior descending coronary artery in dogs, nitroprusside was infused to gradually lower mean aortic pressure from 137 to 62

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mm Hg. The results were compared to those in control animals instrumented in an identical manner which did not receive nitroprusside. Poststenotic flow in the left anterior descending coronary artery was not significantly (p >0.05) decreased by incremental reductions in aor-tic pressure from 137 to 87 mm Hg. Further decline lowered poststenotic flow in the left anterior descending artery slightly (p <0.05) [27]. lntramyocardial electrocardiographic S-T segment elevation in the ischemic myocardium perfused by the stenotic left anterior descending artery was lowered (p <0.05 versus control animals) during the initial nitroprusside infusion. In contrast, with further decline in mean aortic pressure from 87 to 62 mm Hg, intramyocardial S-T segments increased (p <0.05) indicating worsening myocardial ischemia. Left ventricular enddiastolic pressure declined (p 0.05) altered by the nitroprusside-induced decline in systemic pressure from 137 to 87 mm Hg. However, with a further decrease in aortic pressure from 87 to 62 mm Hg, intramyocardial PCOs increased and myocardial oxygen extraction was augmented (p <0.05) [27]. These experimental studies carried out in animal models of acute myocardial ischemia in which multiple indices of ischemia were determined, indicated that nitroprusside infused to gradually lower systemic blood pressure produces very little decline in poststenotic coronary flow through a wide range of systemic blood pressures. Most measured indices of myocardial ischemia were improved consequent to the nitroprusside

I

I

-I-

PTM (mmHg.sec

C

AP

Figure 2. The effect of nitroprusside (NP) on the index of myocardL4 oxygen demand. pressur&itns per minute (PTM), during control and with atria/ pacing.

NITROPRUSSIDE

infusion at rates which lowered blood pressure from 137 to 87 mm Hg. More pronounced decreases in blood pressure, however, lead to significant reduction in poststenotic coronary flow with consequent worsening of myocardial ischemia [27]. Clinical Investigation of Nitroprusside During Atrial Pacing. To evaluate the actions of nitroprusside in clinical myocardial ischemia, eight patients with arteriographically documented coronary artery disease and electrocardiographic S-T segment depression during atrial pacing received nitroprusside infusion during repeat atrial pacing to the identical heart rate as achieved during control. Following control atrial pacing to ischemia, hemodynamic variables, electrocardiographic alterations and heart rate were allowed to return to control levels. Nitroprusside was then infused to lower left ventricular end-diastolic pressure to 8 to 12 mm Hg and systolic aortic pressure to 110 to 115 mm Hg. The nitroprusside infusion was then maintained constant, and atrial pacing was repeated utilizing incremental rate increases in an identical manner and over the same time interval as during the control pacing [ 121. With peak pacing heart rates, mean arterial pressure was lowered by nitroprusside from 95 to 75 mm Hg (p 0.05) (Figure I), and the index of myocardial oxygen demand, pressure time per minute, was reduced from 3,221 to 2,370 mm Hg/sec/min (p
C

AP

STC (mm)

i?%‘JP Figure 3.

The action of nitroprusside (NP) on maximal average S-T segment depression (ST) on lead VI with maximal atrial pacing (AP) rate. Nitropnrssi& significantly (p < 0.00 1) reduced the extent of S-T segment depression during atria/ pacing.

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F&II@ 4. The effect of nitroprussik on total coronary blood flow (CSF) determined by coronary sinus thermodilution during control (C) and with atria/ pacing.


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TABLE I

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Hemodynamic Responses to Nitroprusside in Acute Myocardiai infraction (N = 12) Meanf SEM C

Parameter Blood pressure (mm Hg) Mean arterial pressure (mm Heart rate (beatslmin)

Pulmonary arterywedge pressure(mmHg)

NP

139174

Hg)

f 612 115165’ f 512 6O’f2 94 f 2 96 f 6 95 f 7 19f 2 ll’f2

2.2 f 0.2 2.1 f 0.2 Cardiac index (liters/min/m2) 2690 f 186 2,372’ f 171 Pressure-time per minute (mmHg-sec/min) 2,045 f 158 1,621’ f 122 Totalsystemicvascular resistance(dynes-set-cm-5) NOTE:C = control;NP = nihoprusside. p value0.001. l

second or more) Q waves in at least three precordial leads of the standard 1Blead electrocardiogram

1111. The patients underwent right heart catheterization in the coronary care unit with use of a balloon-tipped flow-directed Swan-Ganz catheter. The height of the S-T segment above the isoelectric line was measured for six consecutive beats in each lead and averaged. Measurement of the S-T segment was made 60 msec after the J junction of the QRS-T complex. When the J junction could not be well defined, S-T segment elevation was measured 120 msec after the initial Q or R deflection. The following data were determined from the 35lead precordial electrode blanket: sum of all S-T segment elevations @ST), number of leads with S-T segment elevation greater than 1 mm (NST) and average S-T segment elevation (ST) as determined by (ZST/NST). After control hemodynamic variables and S-T segment maps were recorded, sodium nitroprusside was infused intravenously at an initial rate of 16 pg/min. The rate of infusion (range 20 to 100 pg/min) was individually adjusted to reduce systemic systolic arterial pressure to 100 to 115 mm Hg in eight of the 12 patients. in the remaining four patients, left ventricular filling pressures were reduced with nitroprusside to the mid-normal levels of 6 and 7 mm Hg, thus preventing use of increased doses of nitroprusside to reduce systolic pressures to 115 mm Hg. After a stable optimal rate of nitroprusside infusion had been maintained for 10 to 15 minutes in all 12 patients, hemodynamic measurements and S-T segment recordings were repeated. The hemodynamic responses to nitroprusside are shown in Table I. There were significant reductions (p X0.05) in systolic and diastolic blood pressures, mean arterial pressure, increased mean pulmonary capillary wedge pressure (PAW), total systemic vascular resis-

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tance, and pressure-time per minute [ 111. There were no significant changes (p >0.05) in heart rate, cardiac index (Cl) or stroke work index (SWI). The ratios SWI: PAW and CI:PAW increased significantly during nitroprusside therapy from 1.66 f 0.32 (SEM) to 2.95 f 0.66 (p <0.005) and from 0.14 f 0.02 to 0.25 f 0.05 (p
2

IE I

C

NP

C

NP

F:I#ure 5. Theeffectsof constant nitmpmssk& (NP) infusion on the sum of S-T segment elevation (E ST), panel A; the number of leads with S-Tsegment elevation 5 1 mm (ND, panel B; and the mean S-T segment elevation per NST (ST), panel C. S-T segments were measured from the 354ead precordial electrode blanket. C on horizontal base line = control.

NITROPRUSSIDE

jective. Thus our investigations assessed in patients with acute anterior wall myocardial infarction the effects of sodium nitroprusside infusion on cardiac hemodynamics and on the extent of ischemic injury as determined by precordial S-T segment mapping. This use of the potent unloading agent was prompted by previous studies in which nitroprusside substantially improved hemodynamic variables and concomitantly reduced the principal determinants of myocardial oxygen requirements in patients with acute and chronic coronary heart disease with congestive heart failure [3,6]. Moreover, nitroprusside has been shown to reduce the extent of pacing-induced myocardial ischemia quantified by electrocardiographic and metabolic assessments in patients with coronary artery disease [ 121. Additionally, experimental studies have indicated that nitroprusside improves the mechanical performance of the ischemic ventricle, while increasing regional perfusion and diminishing lactate production in ischemic myocardium after coronary arterial occlusion [ 131. Previous work in experimental animals with coronary occlusion in which direct epicardial electrodes were used to assess the extent of ischemic injury have supported the importance of maintaining mean arterial pressure, and hence coronary perfusion, to limit the ischemic area [ 181. Whereas systemically administered nitroprusside decreases myocardial perfusion pressure, the reduction in total coronary blood flow observed with the agent may reflect a decrease in myocardial oxygen needs that predominates over the reduction of blood pressure [ 11,121. Further, an increase in the reduced myocardial flow in ischemic areas has been reported in patients at the time of coronary bypass surgery [ 191. Our clinical investigations as well as other studies [ 18-251 in patients examining the actions of intrave-

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nously administered nitroglycerin, phentolamine and trimethaphan in acute myocardial infarction, have demonstrated that cardiac unloading accompanied by substantial reduction in systemic blood pressure reduced ischemic injury associated with acute anterior myocardial infarction. These studies have thereby suggested that over-all reduction of myocardial oxygen consumption generally overrides the potentially deleterious effect of decreases in total coronary blood flow. A potentially beneficial effect of cardiac unloading agents in improving reduced myocardial perfusion in coronary disease would appear to be the result of the considerable reduction in intraventricular diastolic pressure produced by nitroprusside. Consequently, the reduced intramyocardial pressure provides an increased transmural pressure gradient facilitating subendocardial blood flow despite reduced aortic pressure. Our clinical findings are in agreement with the aforementioned experimental evidence that nitroprusside may exert a beneficial action in enhancing blood flow to ischemic heart muscle. Further, our observation that improvement in S-T segment mapping indices of ventricular ischemia was not closely correlated with the magnitude of reduction in indexes of total myocardial oxygen consumption is consistent with this postulation. Thereby the clinical and experimental data reported herein are consonant with the work of da Luz et al. [ 13,161 in providing indirect evidence that nitroprusside may possess a separate action of augmenting regional blood flow to ischemic myocardium in patients with coronary artery disease, and thus the drug may improve myocardial energetics in this manner as well as by reducing myocardial oxygen needs through peripheral cardiac unloading mechanisms.

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