Nitroglycerin-induced Severe Hypotension and Bradycardiain Patients with Acute Myocardial Infarction

PATRICIA C. COME, M.D., AND BERTRAM PITT, M.D.

SUMMARY Seven episodes of simultaneous severe systemic arte-rial hypotension and absolute or relative bradycardia were observedin five patients receiving either sublingual nitroglycerin (two patients)or intravenous nitroglycerin (three patients) within the first 24 hoursof onset of symptoms of acute myocardial infarction. Left ventric-ular filling pressure, measured as pulmonary artery diastolicpressure, decreased simultaneously in all four patients in whom

SINCE THE FIRST REPORT of its efficacy in the treat-ment of angina pectoris in 1879,' nitroglycerin has becomethe most commonly used drug in the therapy of chronicangina. Nitrates are currently being investigated for theirpotential role in the limitation of infarct size2-5 and for thetreatment of congestive heart failure complicating acutemyocardial infarction.6 Side effects of nitroglycerin admin-istration, such as pulsatile headache, nausea, vomiting,flushing, lightheadedness and palpitations, often associatedwith minor decreases in systemic arterial pressure and com-pensatory tachycardia, are well recognized.7 Only a fewreports are available, however, concerning severe complica-tions such as syncope, documented severe hypotension, andserious arrhythmias occurring subsequent to nitroglycerinadministration in patients with cardiac disease.9-"

During the past three years, we have observed sevenepisodes of severe hypotension associated with sinus brady-cardia, occurring in five patients receiving sublingual or in-travenous nitroglycerin within the first 24 hours of onset ofsymptoms of acute myocardial infarction. This reportpresents our experience with this complication of nitro-glycerin administration and emphasizes the need for carefulobservation of patients receiving nitroglycerin during acutemyocardial infarction.

MethodsDuring a three year period from 1972 to 1975, 54 patients

received either sublingual (14 patients) or intravenous (40patients) nitroglycerin during clinical research studies in-vestigating hemodynamic effects of nitroglycerin in patientswith acute myocardial infarction. The diagnosis of acutemyocardial infarction was based on electrocardiographicchanges, coincident with enzyme elevations typical of acuteinfarction. The electrocardiographic changes were indicativeof transmural myocardial infarction in 49 patients and sub-endocardial infarction in the remaining five patients.A #7 Swan Ganz catheter was positioned in the pulmo-

nary artery via antecubital vein cutdown. A short plastic

From the Department of Medicine, Cardiovascular Division, The JohnsHopkins University and Johns Hopkins Hospital, Baltimore, Maryland.

Supported by the MIRU Contract PH 43 NHLI 167-1444 from theNational Institutes of Health. Dr. Come is a Research Fellow of theAmerican Heart Association, Maryland Affiliate.

Address for reprints: Bertram Pitt, M.D., Department of Medicine, Car-diovascular Division, The Johns Hopkins University School of Medicine,Baltimore, Maryland 21205.

Received March 3, 1976; revision accepted May 13, 1976.

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pulmonary artery pressures were monitored. No initial increase inheart rate was observed in any of the five patients prior to the develop-ment of bradycardia. Possible mechanisms producing simultaneousbradycardia and hypotension during nitroglycerin administration areconsidered. The patient studies emphasize the importance of carefulhemodynamic monitoring during administration of sublingual or in-travenous nitroglycerin to patients with acute myocardial infarction.

catheter was inserted via cutdown or percutaneously into theradial artery. Pulmonary and systemic arterial pressureswere measured with Statham P37b and P23Db transducers,respectively.

Fourteen patients received 0.3 mg nitroglycerin sub-lingually according to a previously described protocol."2Nitroglycerin, prepared as an aqueous solution,' was ad-ministered intravenously to 40 patients as previously de-scribed.4 Consent was obtained from all patients prior todrug administration.

Severe systemic arterial hypotension, associated withsinus bradycardia, was observed in one of the 14 patientsfollowing sublingual nitroglycerin administration and inthree of the 40 patients receiving nitroglycerin infusion. Afifth patient, admitted to the Coronary Care Unit for acutemyocardial infarction, developed hypotension and bradycar-dia after receiving 0.4 mg nitroglycerin sublingually for painrecurring shortly after admission. Those five patients devel-oping hypotension and bradycardia with nitroglycerin ad-ministration are described in the case reports which follow.

Cases

Case I

HR, a 78-year-old normotensive male with a history ofmyocardial infarction, angina pectoris responsive to nitro-glycerin, and stable symptoms of mild left ventricular con-gestive failure treated with digitalis and diuretics, was ad-mitted following three weeks of increasing angina. Physicalexamination revealed a regular pulse of 120, a cuff bloodpressure of 155/80 mm Hg, and signs of both right and leftventricular failure. The initial ECG revealed ST-segmentdepression in the anterolateral leads. The patient com-plained of recurrent chest pain and was given 0.4 mg nitro-glycerin sublingually. Five minutes later a sinus bradycar-dia of 56 was observed on his bedside monitor. Over the nextfour minutes his sinus rate slowed to 38 per minute andemergence of a nodal bradycardia at a rate of 33 was subse-quently observed (fig. 1). Systolic blood pressure waspalpable at 90 mm Hg. Administration of 1 mg of intra-venous atropine and leg elevation was associated with arapid return of his heart rate to 120 (sinus) and gradualreturn of his blood pressure to 130/70 mm Hg.The patient died following cardiac arrest on the fourth

hospital day. Autopsy revealed recent infarction of theposterior left ventricle and anterior papillary muscle.

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NITROGLYCERIN HYPOTENSION AND BRADYCARDIA/Come, Pitt

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Case 2*

JC, a 67-year-old male without a history of hypertensionor ischemic symptoms was admitted with severe substernalchest pressure. Physical examination revealed signs of leftventricular failure. The ECG revealed ST-segment eleva-tion in the inferior leads. Subsequent enzyme analysis con-firmed the diagnosis of myocardial infarction. Initial hemo-dynamic measurements were stable over a 30 minute controlperiod and included mean arterial pressure of 124 mm Hg, apulmonary artery diastolic pressure of 20 mm Hg and heartrate of 87 beats/minute. Nitroglycerin (0.3 mg) was ad-ministered sublingually. Five minutes later, the pulmonaryartery diastolic pressure had decreased to 15 mm Hg with nochange in heart rate and a minor decrease in mean arterialpressure. Six minutes later the pulmonary artery pressurehad decreased further to 3 mm Hg, the heart rate to 68beats/minute and the mean arterial pressure to 59 mm Hg.No initial tachycardia was noted, and during the bradycar-dia the patient remained in normal sinus rhythm with a rarepremature ventricular contraction. He developed chest painduring the period of hypotension and relative bradycardia.Elevation of the legs, followed by I mg of intravenousatropine, was associated with a rapid return of the heart rateto 92 beats/minute, mean arterial pressure to 104 mm Hgand disappearance of chest pain.

Case 3

JA, a 77-year-old hypertensive male with chronic mildcongestive failure and angina pectoris treated with digitalis,alpha-methyl dopa, a thiazide and nitroglycerin, was ad-mitted after one hour of severe left chest pressure. Cardio-pulmonary examination was remarkable only for a fewbibasilar rales. ST-segment elevation was noted in theanterior leads on the ECG. Cardiac enzyme analysis subse-quently confirmed the diagnosis of acute infarction. Initialhemodynamic parameters were stable over a 30 minute con-

*The hemodynamic data from this patient have previously been reported."2

trol period and included a heart rate of 60 beats/minute,mean arterial pressure of 100 mm Hg and pulmonary arterydiastolic pressure of 4 mm Hg. Intravenous nitroglycerin in-fusion was begun at 17.6 ,ug/min and discontinued fourminutes later when the mean arterial pressure decreasedabruptly to 56 and then to 53 mm Hg. Sinus rhythm con-tinued but the rate decreased to 54 beats/minute. Pul-monary artery diastolic pressure decreased minimally to 3mm Hg. After spontaneous increases in mean arterialpressure to 90 mm Hg and pulmonary artery diastolicpressure to 8 mm Hg and stabilization of the sinus brady-cardia at a heart rate of 55, infusion of nitroglycerin wasrestarted at 5 jug/min and subsequently increased to 7jug/min. Nine minutes later, a sudden decrease in meanarterial pressure to 64 mm Hg, associated with further slow-ing of the sinus rate to 50 and a decrease in pulmonaryartery diastolic pressure to 3 mm Hg, prompted cessation ofinfusion. Mean arterial pressure, heart rate, and pulmonaryartery diastolic pressure increased over the next ten minutes.

Case 4

RH, a 63-year-old normotensive male, with a history ofinferior infarction and subsequent exertional angina pectorisresponsive to sublingual nitroglycerin, was admitted withchest pain of 12 hours duration, unresponsive to nitro-glycerin. Physical examination was remarkable for bilateralbasilar rales and S3 and S, gallops. The ECG revealed STdepression in leads V3-V5 and T wave inversion in leads II,III, F and V4-V6. Subsequent enzyme analysis confirmed adiagnosis of myocardial infarction. Initial hemodynamicmeasurements included a mean arterial pressure of 76 mmHg and pulmonary artery diastolic pressure of 21 mm Hg.The initial heart rate was 99 beats/minute. Figure 2 showshis subsequent hemodynamic changes. Nitroglycerin infu-sion was begun at 5 ,ug/min and gradually increased over thenext ten minutes to 26.6 jig/min. The heart rate subse-quently decreased suddenly to a low of 47 beats/minute andthe mean arterial pressure to a low of 33 mm Hg. Con-tinuous electrocardiographic recordings, available for the

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VOL 54, No 4, OCTOBER 1976

HeartRate

(beats/min)

MeanArterialPressure(mmHg)

PulmonoryArtery

DiastolicPressure(mmHg)

IntravenousNitroglycerin(mcg /min)

R.H.100908070-6050

2015105

300F0~~~~~~~~E LEVATION

5 10 IS 20 25 30 35 40Minutes

FIGURE 2. Graphic illustration of the hemodynamic changes oc-curring during intravenous nitroglycerin administration to patient 4.

entire infusion period, revealed a rapid, progressive slowingof the heart rate, without initial tachycardia and withmaintenance of normal sinus rhythm, coincident with thedevelopment of hypotension. Pulmonary artery diastolicpressure was not measured at the time of maximal brady-cardia and hypotension but was 8 mm Hg three minutesafter the peak fall in mean arterial pressure. The patientcomplained of nausea. With cessation of nitroglycerin infu-sion and leg elevation, mean arterial pressure, pulmonaryartery diastolic pressure and heart rate rapidly returnedtoward control levels.

Case 5

MF, a 45-year-old hypertensive male with a history of in-ferior myocardial infarction and subsequent angina pectorisresponsive to nitroglycerin, was admitted after prolongedsubsternal pain. Physical examination was remarkable forsigns of left ventricular failure. The ECG revealed changesof acute transmural anteroseptal infarction. Subsequent en-zyme analysis confirmed acute infarction. During the periodof hemodynamic study the patient was maintained on con-tinuous intravenous lidocaine and procainamide infusions,which were started on admission for treatment of ventric-ular ectopic activity. Baseline hemodynamic measure-ments, stable over a 30 minute control period, included amean arterial pressure of 84 mm Hg and pulmonary arterydiastolic pressure of 23 mm Hg. Initial heart rate was 120beats/minute. Figures 3 and 4 illustrate the subsequenthemodynamic changes and the bradycardia, respectively. In-travenous nitroglycerin infusion was begun at 5 ,g/min andgradually increased over the next 25 minutes to 56.5 ,ug/min.Sinus bradycardia with an occasional ventricular ectopic

M.F.

HeartRate

(beats/min)

MeanArterialPressure(mmHg)

PulmonaryArtery

DiastolicPressure(mmHg)

ntravenousNitroglycerin(mcg /min)

60-

40

20 itZAtropine20, 0.5mg IV/ I

0 10 20 30 50 60 70 80 90 100 120Minutes

FIGURE 3. Graphic illustration of the hemodynamic changes oc-curring during repeated infusions of intravenous nitroglycerin topatient 5.

beat was then observed. The rate of infusion was decreasedto 36.5 ,ug/min. However, a further decrease in heart rate to45 beats/minute was noted and mean arterial pressuredecreased to 38 mm Hg. Pulmonary artery diastolic pres-sure was 7 mm Hg at the time of maximal hypotension.Continuous electrocardiographic recordings revealed a rapidprogressive slowing of the heart rate without initial tachy-cardia and with maintenance of normal sinus rhythm. Afterabrupt discontinuation of nitroglycerin infusion and ad-ministration of 0.5 mg atropine intravenously, mean arterialpressure, heart rate, and pulmonary artery diastolic pressurereturned toward control levels. Reinfusion of nitroglycerinwas begun 24 minutes after initial discontinuation and wasincreased from 10 to 36.5 ,ug/min over the next thirtyminutes. Mean arterial pressure and pulmonary arterydiastolic pressure again decreased to 62 and 8 mm Hg,respectively, and a relative slowing of the heart rate to 92beats/minute was observed. Mean arterial pressure,pulmonary artery diastolic pressure and heart rate returnedtoward control levels with cessation of the infusion.

DiscussionAdministration of sublingual and oral nitrates to normal

volunteers and to patients with ischemic heart diseaseusually results in an increase in heart rate,'8-"8 which isthought to be mediated by reflex sympathetic discharge inresponse to decreases in systemic arterial pressure."9 Thepatients with acute myocardial infarction reported in thisstudy developed severe systemic arterial hypotension inassociation with decreases in LVFP and the development ofabsolute or relative bradycardia following administration of

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NITROGLYCERIN HYPOTENSION AND BRADYCARDIA/Come, Pitt

A

B

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demonstrate the sinu th r(p.e.l A).wic wa present

FIGURE 4. Electrocardiographic recordings from patient 5demonstrate the sinus tachycardia (panel A) whech was presentprior to nitroglycerin administration and the sinusbradyiardia(panel B) which was observed coincident with arterial hypotensionduring nitroglycerin administration.

nitroglycerin. The sinus bradycardia observed in the pres-ent study was not preceded by transient tachycardia andappeared to be vagally mediated as evidenced by the re-sponse to intravenous atropine. Recurrence of hemody-namic changes with reinfusion of nitroglycerin in patients 3and 5 suggests that the bradycardia and hypotension weredue to nitroglycerin administration rather than to changeswhich might have occurred independent of drug therapy dur-ing the course of acute myocardial infarction.

There have been other documented instances of severehypotension and bradycardia occurring after sublingualnitroglycerin administration to patients with hypertension orischemic heart disease.9-' Sprague and White in 1933," in areview of approximately 900 patients with angina pectoris,reported three cases of syncope following administration ofsublingual nitroglycerin for chest pain. Two of their patientsfainted while under observation and were noted to becomediaphoretic, bradycardic and hypotensive prior to loss ofconsciousness. Prodger and Ayman'0 observed four in-stances of bradycardia and hypotension occurring in a groupof 110 patients with hypertension given sublingual nitro-glycerin. All four patients developed hypotension and brady-cardia, including one patient who developed transient com-plete heart block. One of their patients had a documentedinitial increase in heart rate prior to the onset of bradycar-dia. Oral and sublingual nitrate administration followed bytilting has also been associated with hypotension, bradycar-dia and syncope.15 20 21 An initial increase in heart rate isfrequently observed, coincident with the onset of hypoten-

sion, in this situation.'5' 20 Bradycardia often occurs late, justprior to loss of consciousness.'5' 20 Prior treatment with in-travenous atropine has been shown to eliminate the brady-cardia, but has been reported to have no effect on the in-cidence of syncope or hypotension.'5' 20, 21 Tilting alone can,however, produce hypotension and bradycardia independentof nitrate administration20' 21 and the additional effect ofnitroglycerin under these circumstances is therefore difficultto assess.

Intravenous nitroglycerin has been studied during acutemyocardial infarction.2-5 Heart rate changes have, however,been variable. In the dog with experimental coronary arteryligation, significant decreases in mean arterial pressureresulting from intravenous nitroglycerin are accompanied bysignificant increases in heart rate.2 In contrast, in humanswith acute myocardial infarction, intravenous nitroglycerinadministration has not been associated with a significantmean change in heart rate, despite significant decreases inmean arterial pressure.2

Carotid and aortic body baroreceptors normally cause areflex increase in heart rate in response to a decrease inarterial pressure.22 23 The development of bradycardia asso-ciated with hypotension following nitroglycerin admin-istration appears to represent a failure of normal compen-sation by the baroreceptor mechanisms and may involveboth a partial failure of sympathetic activity as well as anenhancement of vagal tone. Similar mechanisms have beenpostulated for vasovagal syncope.24 25 Experimentally, si-multaneous bradycardia and hypotension have been pro-duced by chemical stimulation of the myocardium (theBezold-Jarish reflex)26-28 and by electrical stimulation ofspecific areas in the nervous system.26' 29, 30 Variations inheart rate can be effected by manipulation of venous returnto the right and left heart.3' Bradycardia, which can beeliminated by vagotomy, has been produced experimentallyby volume-induced elevation of right atrial or left ven-tricular pressures, suggesting that pressure or length recep-tors in the myocardial walls may elicit reflex changes inheart rate.31 33 In contrast, Sjostrand has recently suggestedthat bradycardia may be elicited by a decrease in centralblood volume.'2 In his experiments, the bradycardia pro-duced by rapid arterial hemorrhage in the rat was lesspronounced and appeared later when simultaneous venousinfusions were given, despite similar decreases in meanarterial pressure. Those experiments suggest that decreasesin venous return may be more important than decreases insystemic arterial pressure in eliciting reflex bradycardia.Although ventricular volume measurements were not per-formed in our patients, it is likely that ventricular volumediminished after nitroglycerin, in association with the potentvasodilatory effects of nitroglycerin on the venous circula-tion.34 The magnitude of changes in ventricular volume can-not be predicted, however, from changes in left ventricularfilling pressures in the patients reported above because ofchanges in left ventricular compliance which may followacute myocardial infarction. The possibility also exists thatnitroglycerin may result in afferent sympathetic stimulationwhich elicits an efferent vagal response. Afferent sym-pathetic reflexes have been shown to be associated withvagally mediated bradycardia.35

Patients with acute myocardial infarction, especially in-ferior infarction, not infrequently develop hypotension and

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628 CIRCULATION

bradycardia, responsive to intravenous atropine, during theearly phases of acute infarction.36' It is possible that nitro-glycerin administration may enhance underlying mecha-nisms responsible for the development of bradycardia andhypotension in such patients. It should, however, be notedthat four of the five patients in the present study had ECGevidence of acute anterior transmural or subendocardial,rather than inferior, myocardial infarctions.

In animals subjected to acute coronary occlusion, Costan-tin has demonstrated a transient, vagally-mediated sym-patho-inhibitory reflex resulting in blunting of the expectedperipheral vasoconstrictor and cardiac sympathetic responseto hypotension.38 Although it has not been demonstrated inman nor in animals subjected to prolonged periods of ische-mia or infarction, such a reflex mechanism might possiblyexplain the failure of normal compensation by the aortic andcarotid body baroreceptors to the hypotension observed withnitroglycerin infusion in our five patients.

Although the mechanism of bradycardia in associationwith nitrate-induced hypotension remains unclear, the casespresented above re-emphasize the potentially serious adverseeffects of nitroglycerin. They underscore the need for carefulobservation during its use, particularly in the setting of acutemyocardial infarction.

Acknowledgment

We are indebted to Miss Lisa Grue for her secretarial assistance and toMyron L. Weisfeldt, M.D. for review of the manuscript.

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151, 18792. Smith ER, Redwood DR, McCarron WE, Epstein SE: Coronary artery

occlusion in the conscious dog: Effects of alterations in arterial pressureproduced by nitroglycerin, hemorrhage and alpha-adrenergic agonists onthe degree of myocardial ischemia. Circulation 47: 51, 1973

3. Flaherty JT, Reid PR, Kelly DT, Taylor DR, Weisfeldt ML, Pitt B: In-travenous nitroglycerin in acute myocardial infarction. Circulation 51:132, 1975

4. Come PC, Flaherty JT, Baird MG, Rouleau JR, Weisfeldt ML, GreeneHL, Becker L, Pitt B: Reversal by phenylephrine of the beneficial effectsof intravenous nitroglycerin in patients with acute myocardial infarction.N Engl J Med 293: 1003, 1975

5. Flaherty JT, Come PC, Baird MG, Rouleau JR, Taylor DR, WeisfeldtML, Greene HL, Becker LC, Pitt B: Effect of afterload reduction with in-travenous nitroglycerin on left ventricular function and ST segmentchanges in acute myocardial infarction. Br Heart J 38: 612, 1976

6. Gold HK, Leinbach RC, Sanders CA: Use of sublingual nitroglycerin incongestive failure following acute myocardial infarction. Circulation 46:839, 1972

7. AMA Drug Evaluations. Chicago, American Medical Association, 1971,p 16

8. Nickerson M: Vasodilator drugs. In The Pharmacological Basis ofTherapeutics, edited by Goodman LS, Gilman A. Toronto, MacMillanCompany, 1970, p 750

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10. Prodger SH, Ayman D: Harmful effects of nitroglycerin. With special

VOL 54, No 4, OCTOBER 1976

reference to coronary thrombosis. AmJ Med Sci 184: 480, 193211. Sprague HB, White PD: Nitroglycerin collapse - A potential danger in

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16. Najmi M, Griggs DM, Kasparian H, Novack P: Effects of nitroglycerinon hemodynamics during rest and exercise in patients with coronary in-sufficiency. Circulation 35: 46, 1967

17. Hoeschen RJ, Bousuaros GA, Klassen GA, Fam WM, McGregor M:Haemodynamic effects of angina pectoris and of nitroglycerin in normaland anginal subjects. Br Heart J 28: 221, 1966

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P C Come and B Pittmyocardial infarction.

Nitroglycerin-induced severe hypotension and bradycardia in patients with acute

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