International Experience with Nitrates Cardiology !991;79(suppl 2):70-77

© 1991 S. Karger AG. Basel 0008-6312/91/0796-0070S2.75/0

Hemodynamic Mechanisms of the Effect of Nitroglycerin in Patients with Acute Myocardial Infarction Dzenana E. Rezakovic, Jr., Miodrag Popadic, Gjuro Popovic, Leo Pavicic, Janez Stalec Department of Medicine, University Hospital, Faculty of Medicine, Zagreb; Institute of Radiology, Department of Medicine, Faculty of Medicine, Sarajevo; Faculty of Sciences and Mathematics, Faculty of Kinesiology, University of Zagreb, Yugoslavia

Key Words. Nitroglycerin • Acute myocardial infarction • Acute heart failure

Introduction Intravenous nitroglycerin (NTG) is found to be a very effective therapy in patients with acute myocardial infarction due to its multiple beneficial effects in reducing in­ farct size, major infarct complications and

improving global left ventricular function [1-5], Several studies demonstrated NTGinduced hypotension in some patients with acute myocardial infarction [2, 6, 7] and the others showed that low mean arterial pres­ sure could abolish these beneficial effects [3, 8],

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Abstract. We studied the hemodynamic response to intravenous nitroglycerin (NTG) in 40 patients with and without acute heart failure (hemodynamic subsets I-IV) during acute myocardial infarction. Hemodynamic measurements were performed by right heart cathe­ terization. The results showed that NTG response influenced mainly the preload and to a lesser extent the afterload, however these changes were dependent on initial hemodynamic status. The changes in mean arterial pressure and cardiac index were predominantly related to pretreatment pulmonary wedge pressure and slightly to systemic vascular resistance. Response to NTG could be predicted with 85% probability as a decrease of pulmonary wedge pressure, with 58% probability as a decrease in mean arterial pressure and cardiac index, and with 32% probability as an increase in cardiac index and a decrease in systemic vascular resistance. These results indicate that NTG therapy could have optimal results in patients with elevated pulmonary wedge pressure and normal cardiac index, while in the subsets with low mean arterial pressure or low cardiac index potentially deleterious decrease in these values could occur. Therefore the optimal condition for use of intravenous nitro­ glycerin in the patients with acute heart failure is isolated pulmonary congestion.

Nitroglycerin Hemodynamics in Acute Myocardial Infarction

Patients and Methods Patients The study was performed in 40 males with an average age of 56 years (range 43-65). An anterior and inferior location of myocardial infarction were found in 26 and 14 patients, respectively. Patients of all hemodynamic subsets (I, II, III and IV; fig. la-d), i.e., with and without acute heart fail­ ure were included in the trial. Patients were randomly chosen upon admission in the coronary care unit according to clinical signs of pulmonary congestion and peripheral hypoperfusion as well as to hemody­ namic values of pulmonary wedge pressure (PWP) and cardiac index (Cl). Hemodynamic subsets were determined according to Forrester’s classification: subset I - PWP < 18 mm Hg, Cl > 2 .2 liter/min/m2; subset II - PWP > 18 mm Hg, Cl > 2.2 liter/min/m2; subset III - PWP < 1 8 mm Hg, Cl < 2.2 liter/min/ m2; subset IV - PWP > 18 mm Hg, Cl < 2 .2 liter/ min/m2 [10]. In hemodynamic subset I were included the patients with angina pectoris persisting after sub­ lingual nitroglycerin. Exclusion criteria were: systolic arterial pressure < 100 mm Hg; heart rate > 120 < 5 5 beats/min; sig­ nificant arrhythmia requiring intervention (supraven­ tricular or ventricular tachycardia, ventricular fibril­ lation, heart block requiring pace-maker); hyperten­ sion over 180/110 mm Hg; preexisting valvular heart disease; mechanical complications (pericardial effu­ sion or constriction); pulmonary obstructive disease; cardiomyopathy; age > 7 0 years; beta-adrenergic blocking therapy administered within 48 h; severe life-threatening disease of other organ systems; acute intercurrent disease.

Measurements The trial was conducted in coronary care unit. A flow-directed thermodilution catheter was inserted in the pulmonary artery under waveform monitoring

control via a percutaneous approach to the right sub­ clavian vein following local anaesthesia with lignocain 2%. All pressures were measured with the zero reference point at axillary line. Systemic arterial pres­ sures were measured via insertion of a cannula to the radialis artery or. if not possible, by sphygmomanom­ eter. The following hemodynamic values were mea­ sured: heart rate (beats/min); systolic/diastolic/mean arterial pressures; central venous pressure; pulmo­ nary systolic/diastolic/mean artery pressures; pulmo­ nary wedge pressure; cardiac output. The values of Cl (1/min/m2) and systemic vascular resistance index (dyn sec cm~5/m 2) were calculated.

Protocol This open trial was approved by the hospital com­ mittee on drug research and the patients gave an informed consent. Control hemodynamic parameters were measured three times over 45 min to confirm a stable hemody­ namic condition and to determine hemodynamic sub­ set. A titration period was started with 0.5-1.0 mg (816 pg/min) NTG (Perlinganit®, Schwarz Pharma) in­ fusion per hour, with augmenting of dosage for l.Omg/h each 10-20 min. When hemodynamic val­ ues approached to prestated criteria of NTG efficacy, a continuous infusion was commenced at a fixed dose. Infusion period was continued over 2.0 h in the range of 2.0-10.0 mg NTG/hour (mean 6.8 mg/h). NTG infusion was not interrupted during titration and infusion periods, i.e. during approximately 4.0 h. Hemodynamic measurements were performed each 15 min. Optimal NTG dosage was determined during ti­ tration period with the aim to achieve the following prestated criteria of clinical and hemodynamic pa­ tients’ improvement: a disappearance or significant attenuation of angina pectoris in subset I; decrease of elevated pulmonary wedge pressure at 16-18 mm Hg and/or an increase of low Cl by at least 15 % or over 2.2 liter/min/m2. The additional endpoints were also taken into account: a 10% decrease in mean arterial pressure but not below 80 mm Hg; a 10% decrease in normal and 30-40 mm Hg in elevated systolic arterial pressure but not below 90 mm Hg; an increase of heart rate of no more than 20 beats/min and a de­ crease not below 50 beats/min. When the hemodynamic effects during NTG infu­ sion were considered clinically unfavorable, the treat-

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The aim of this study was to investigate NTG mechanisms in different hemody­ namic subsets of the patients with and with­ out acute heart failure during acute myocar­ dial infarction and to define those subsets with the optimal hemodynamic results.

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SUBSET

I

I

I CONTROL

mcnt was discontinued and other vasodilator and ino­ tropic therapy started. The undesirable effects would include an increasing severe angina pectoris; an in­ crease of pulmonary wedge pressure by 20%; a de­ crease of Cl by > 15 %; a decrease of systolic arterial pressure below 90 mm Hg; either marked tachycardia

or bradycardia. Whenever MAP fell below 80 mm Hg. NTG infusion rate was decreased or completely stopped. All hemodynamic measurements were performed twice in a standardized manner by a physician, to improve the accuracy and reproducibility of the re-

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Fig. 1. Hemodynamic values of patients in the subsets I—IV. PWP = Pulmonary wedge pressure; Cl «* cardiac index; MAP = mean arterial pressure; SVRI = systemic vascular resistance index, a Hemodynamic subset I: NTG values of PWP. Cl. MAP and SVRI compared with ini­ tial control values. * p < 0.01 in multivariate analysis, b Hemody­ namic subset II: NTG values of PWP. Cl. MAP and SVRI com­ pared with initial control values. * p < 0.01 in multivariate analy­ sis.

Nitroglycerin Hemodynamics in Acute Myocardial Infarction

73

suits that were finally calculated as a mean of at least 2 values in each time period. No other drugs were given during NTG hemody­ namic investigation, except previous or newly started antiarrhythmic or anticoagulant therapy. Long-acting nitrates and calcium antagonist therapy were with­

drawn within 6-12 h and diuretics 4-6 h prior to the beginning of trial. When sublingual nitroglycerin was administered for persistent angina at the beginning of the trial, the first hemodynamic measurement was performed after 30 min at the earliest.

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Fig. I. c Hemodynamic subset III: NTG values of PWP, Cl, MAP and SVRI compared with initial control values. * p < 0.01 in multi­ variate analysis, d Hemodynamic subset IV: NTG values of PWP, Cl, MAP and SVRI compared with ini­ tial control values. *p < 0.01 in multivariate analysis.

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Rezakovié/Popadic/Popovic/PaviCic/Stalcc

Statislics Statistical analysis of the quantitative and qualita­ tive changes during NTG administration was per­ formed by multivariate analysis of differences; the model of differences was based on the analysis of the matrix of differences. In this analysis each subject served as its own control. The quantitative and qualitative of the relation­ ships between initial control and NTG hemodynamic status were performed by a canonical correlation analysis. This multivariate analysis determines ca­ nonical factors, i.e. significant combinations of two systems of variables [11-13], The significance of the analyses was determined at the level of p < 0.01.

Results The analysis of differences between initial control and NTG-induced hemodynamic status showed significant (p < 0 .0 1 ) but dif­ ferent changes in each hemodynamic subset of patients. In subset I, NTG demonstrated significant decrease in Cl, mean arterial pressure and pulmonary wedge pressure with increased heart rate. In subset II, a signifi­ cant decrease in pulmonary wedge pressure, pulmonary artery mean pressure, central ve­ nous pressure and mean arterial pressure and an increase in heart rate occurred. In subset III, a significant decrease in mean arterial pressure and systemic vascular resistance index was found, while in the sub­ set IV, a significant decrease in pulmonary wedge pressure, pulmonary artery mean pressure, central venous pressure and sys­ temic vascular resistance index was shown. Testing the hypothesis that NTG action is related to initial hemodynamic status three significant canonical factors were extracted

by the canonical correlation analysis (ta­ ble 1). Canonical factor 1 shows that the higher are initial values of central venous pressure, pulmonary artery mean pressure and pulmo­ nary wedge pressure the greater will be their decrease during NTG administration. These two systems of variables have a very high correlation coefficient (0.92) and 85% of common variability. Canonical factor 2 is defined by the rela­ tionship of initial low mean arterial pressure, low Cl and high pulmonary wedge pressure with NTG-induced decrease in mean arterial pressure, Cl, pulmonary wedge pressure and an increase in heart rate, with high correla­ tion coefficient (0.70) and moderately high common variability (58%). Canonical factor 3 demonstrated that ini­ tially elevated systemic vascular resistance, high pulmonary wedge pressure and low Cl are related to NTG increase in Cl with low­ ering of pulmonary wedge pressure and sys­ temic vascular resistance index. This rela­ tionship has a moderately high correlation coefficient (0.61 ) with low common variabil­ ity (32%). Canonical factors 1 and 2 have a high cor­ relation coefficient, meaning that initial combination of high preload values with or without low mean arterial pressure and low Cl is related to NTG decrease of all these values with augmentation in heart rate (ta­ ble 2).

Discussion This study demonstrated that NTG re­ sponse in acute myocardial infarction is sig­ nificantly related to initial hemodynamic condition of the treated patients. It is shown

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All patients had continuous electrocardiographic monitoring during the investigation as well as CKactivity measurements repeated serially each 3 h.

Nitroglycerin Hemodynamics in Acute Myocardial Infarction

75

Table I. Analysis of the relationships between initial control and NTG hemodynamic values in 40 patients Variables

Factor 11

Factor I control

CVP PAMP PWP HR MAP Cl SVRI

NTG

0.54 0.65 0.70

-0.48 -0.54 -0.69

0.14 0.18 0.11 0.06

0.20 -0.22 -0.13 -0.09

Factor 111

control

NTG

control

NTG

0.14 0.24

-0.16 -0.28

0.20 0.26

0.30

0.38

-0.29 -0.41

-0.55 -0.40

-0.60 0.44 -0.53 -0.38

0.12 0.14

0.12 -0.10

0.13

-0.09

-0.36 0.46

0.50 -0.30

0.12

-0.18

Correlation coefficient

0.92

0.70

0.61

Percent of common variabilty

85% p < 0.01

58% p < 0.01

32% p < 0.01

Italics: factor correlation coefficient p < 0.01; all others: factor correlation coefficient NS. CVP - Central venous pressure; PAMP = pulmonary artery mean pressure; HR = heart rate; MAP = mean arterial pressure; SVRI = systemic vascular resistance index.

Table 2. Matrix of factor correlations Factor 1 Factor 1 Factor 2 Factor 3

Factor 2

Factor 3

1.00

0.69 0.38

1.00 -0.06

1.00

ity, being related to a decrease of systemic vascular resistance index. These results demonstrated that NTG re­ sponse was different in each hemodynamic subset. In subset I, major changes occurred in a decrease of Cl and mean arterial pres­ sure, with less lowering of pulmonary wedge pressure and an increase in heart rate. In subset II, pulmonary wedge pressure and pulmonary artery mean pressure values sig­ nificantly decreased with a lowering of the mean arterial pressure and an increase in

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that elevated values of pulmonary wedge pressure and pulmonary artery pressure are the most important variables for prediction of NTG response that is also predominant at the level of preload. Based on these findings, a decrease of preload values could be pre­ dicted with 85% of probability. The combi­ nation of initially elevated preload values with lowered mean arterial pressure and low Cl could predict a further decrease of mean arterial pressure as well as Cl in 58% of these patients, due to a decrease in pulmonary wedge pressure. However, it was shown that the changes in initial preload values were highly related with NTG lowering of mean arterial pressure and Cl, regardless if these values were primarily decreased or not. If elevated pulmonary wedge pressure was combined with high systemic vascular resis­ tance index and low Cl, then an increase of Cl could be predicted with 32% of probabil-

Rezakovi6/Popadic/Popovi6/Pavicic/Stalec

Table 3. Number of patients in the subsets I—IV with no change, increase or decrease in cardiac index and mean arterial pressure values No change Increase Decrease Subset I Subset II Subset III Subset IV Total

Cl MAP Cl MAP Cl MAP Cl MAP

I 1 4 2 2 3

4 2 2 4 2

7 10 5 9 4 6 4 4

Cl MAP

10 6

10 4

20 30

3

Abbreviations as in table I.

heart rate. In subset III, mean arterial pres­ sure decrease was dominant with a minimal fall in systemic vascular resistance index. In subset IV, a dominant decrease of preload values occurred with less lowering of sys­ temic vascular resistance index. However, in both subsets there was no significant Cl change. These differences could not be at­ tributed to NTG dosage, being similar in all subsets. NTG action on preload values was domi­ nant, being greater the higher were initial values. Decrease of mean arterial pressure, found in 75%, and lowering Cl in 50% of all patients (regardless the statistical signifi­ cance), are attributed to this effect. An aug­ mentation of Cl occurred only in 25% of all patients, meaning that NTG action on sys­ temic vascular resistance was of secondary importance (table 3). Other authors also found that cardiac out­ put remained unchanged or increased in the patients with initially elevated left ventricu­ lar filling pressure, but tended to decrease

when it was lower than 18 mm Hg [1, 13, 14], Flaherty [15] found similar results with the most beneficial effects on cardiac output in the patients evidencing the most severe heart failure. However, he also showed that the patients with abnormal baseline ejection fraction had an improvement of ejection fraction with an early NTG administration while those with late NTG had not. Other authors [ 16], too, showed that cardiac output could increase only when pulmonary wedge pressure and systemic vascular resistance were elevated, while it decreased in the pa­ tients with normal or low values. On the con­ trary, Williams [17] found a decrease in pul­ monary wedge pressure, mean arterial pres­ sure and cardiac output regardless of initial pulmonary wedge pressure value. These differences in the findings demon­ strate that NTG response is related to initial hemodynamic status, but also that cardiac output is dependent on multiple parameters: left ventricular filling pressure, myocardial perfusion and afterload changes. The results of this study confirmed our previous findings that NTG action is pre­ dominant on the preload and in second place on the afterload level [18], and clearly showed that optimal indication for NTG ad­ ministration are the patients in subsets I and II, i.e. those with normal or elevated pulmo­ nary wedge pressure and normal mean ar­ terial pressure and Cl. On the contrary, many patients in the subsets III and IV could have modest changes or even potentially del­ eterious decrease in mean arterial pressure or Cl. These findings are important since hemodynamic disturbances are in significant correlation with mortality during acute myo­ cardial infarction [19], Moreover, a low mean arterial pressure could abolish all ben­ eficial NTG effects [3, 8].

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Nitroglycerin Hemodynamics in Acute Myocardial Infarction

1 Bussmann WD. Schöfer H, Kaltenbach M: Wir­ kung von Nitroglycerin beim akuten Myokardin­ farkt. II. Intravenöse Dauerinfusion von Nitro­ glycerin bei Patienten mit und ohne Linksinsuffi­ zienz und ihre Auswirkungen auf die Infarktgrössc. Dtsch mcd Wschr 1976;101:642-648. 2 Jaffe AS, Geltman EM, Tiefenbrunn AJ, Ambos HD, Strauss HD: Reduction of infarct size in patients with inferior infarction with intravenous glyceryl trinitrate. Br Heart J 1983;49:452-460. 3 Jugdutt BI: Myocardial salvage by intravenous nitroglycerin in conscious dogs: loss of beneficial effects with marked nitroglycerin-induced hypo­ tension. Circulation 1983:68:673-684. 4 Flaherty JT, Becker LC, Bulkley BH, Weiss JL, Gerstenblith G: A randomised prospective trial of intravenous nitroglycerin in patients with acute myocardial infarction. Circulation 1983:68:576588. 5 Bussmann WD, Löhner J, Kaltenbach M: Orally administered isosorbide dinitrate in patients with and without left ventricular failure due to acute myocardial infarction. Am J Cardiol 1977;39:91— 96. 6 Lis Y, Bennet D, Lambert G, Robson D: A prelim­ inary double blinded study of intravenous nitro­ glycerin in acute myocardial infarction. Intens Care Med 1984;10:179-184. 7 Come P, Pitt B: Nitroglycerin induced severe hy­ potension and bradycardia in patients with acute myocardial infarction. Circulation 1976,54:624628. 8 Jugdutt BI, Wamica JW: Intravenous nitroglyc­ erin therapy to limit myocardial infarct size, ex­ pansion and complications. Circulation 1988;78: 906-919. 9 Forrester JS, Diamond GA, Chatterjee K, Swan HJC: Medical therapy of acute myocardial infarc­ tion by application of hemodynamic subsets. New Engl J Med 1976;295:1356-1362. 10 Cooley WW, Lohnes PR: Multivariate Data Anal­ ysis. New York. Wiley, 1971.

11 Mulaik SA: The Foundation of Factor Analysis. New York, McGraw Hill. 1972. 12 Zakrajsek E, Stalec J, Momirovic K: SS-program system for multivariate analysis of data. Proceed­ ings of International Symposium Computer on University, Zagreb, 1973, pp C8:1—16. 13 Gold HK. Lcinbach RC. Sanders CA: Use of sub­ lingual nitroglycerin in congestive heart failure following acute myocardial infarction. Circulation 1972;46(5):839—845. 14 Korewicki J, Kraska T, Opolski G, Ostrzycki A, Palynyczko Z: Beneficial effects of intravenous nitroglycerin on hemodynamics and enzymati­ cally estimated infarct size. Eur Heart J 1984:5: 697-704. 15 Flaherty JT: Role of nitrates in acute myocardial infarction. Eur Heart J !988;9(Suppl A): 165— 170. 16 Baligadoo S, Ingrand JC, Maïti D, Derrida JP, Savier CH. Chiche P: La trinitrine intraveineuse chez les malades avec et sans insuffisance cardia­ que. Nouv Presse Méd 1979:8:283-292. 17 Williams DO, Amsterdam EA, Mason DT: Hemo­ dynamic effects of nitroglycerin in acute myocar­ dial infarction. Decrease of ventricular preload at the expense of cardiac output. Circulation 1975; 51:421-427. 18 Rezakovié DE, Rutishauser W, Bloch A. Popadii M: Different hemodynamic actions of trinitro­ glycerin and isosorbide dinitrate in patients with acute myocardial infarction. Eur Heart J 1983;4: 718-723. 19 Forrester JS, Diamond GA, Swan HJC: Correla­ tive classification of clinical and hemodynamic function after acute myocardial infarction. Am J Cardiol 1977;39:137-145.

Dzenana E. Rezakovic, Jr., MD. PhD Proleterskih Brigada 222/11 YU-41000 Zagreb (Yugoslavia)

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References

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Hemodynamic mechanisms of the effect of nitroglycerin in patients with acute myocardial infarction.

We studied the hemodynamic response to intravenous nitroglycerin (NTG) in 40 patients with and without acute heart failure (hemodynamic subsets I-IV) ...
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