Download Nitroglycerin-induced Severe Hypotension and

Nitroglycerin-induced Severe Hypotension and Bradycardia
in Patients with Acute Myocardial Infarction
PATRICIA C. COME, M.D.,
AND
BERTRAM PITT, M.D.
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SUMMARY Seven episodes of simultaneous severe systemic arterial hypotension and absolute or relative bradycardia were observed
in five patients receiving either sublingual nitroglycerin (two patients)
or intravenous nitroglycerin (three patients) within the first 24 hours
of onset of symptoms of acute myocardial infarction. Left ventricular filling pressure, measured as pulmonary artery diastolic
pressure, decreased simultaneously in all four patients in whom
pulmonary artery pressures were monitored. No initial increase in
heart rate was observed in any of the five patients prior to the development of bradycardia. Possible mechanisms producing simultaneous
bradycardia and hypotension during nitroglycerin administration are
considered. The patient studies emphasize the importance of careful
hemodynamic monitoring during administration of sublingual or intravenous nitroglycerin to patients with acute myocardial infarction.
SINCE THE FIRST REPORT of its efficacy in the treatment of angina pectoris in 1879,' nitroglycerin has become
the most commonly used drug in the therapy of chronic
angina. Nitrates are currently being investigated for their
potential role in the limitation of infarct size2-5 and for the
treatment of congestive heart failure complicating acute
myocardial infarction.6 Side effects of nitroglycerin administration, such as pulsatile headache, nausea, vomiting,
flushing, lightheadedness and palpitations, often associated
with minor decreases in systemic arterial pressure and compensatory tachycardia, are well recognized.7 Only a few
reports are available, however, concerning severe complications such as syncope, documented severe hypotension, and
serious arrhythmias occurring subsequent to nitroglycerin
administration in patients with cardiac disease.9-"
During the past three years, we have observed seven
episodes of severe hypotension associated with sinus bradycardia, occurring in five patients receiving sublingual or intravenous nitroglycerin within the first 24 hours of onset of
symptoms of acute myocardial infarction. This report
presents our experience with this complication of nitroglycerin administration and emphasizes the need for careful
observation of patients receiving nitroglycerin during acute
catheter was inserted via cutdown or percutaneously into the
radial artery. Pulmonary and systemic arterial pressures
were measured with Statham P37b and P23Db transducers,
respectively.
Fourteen patients received 0.3 mg nitroglycerin sublingually according to a previously described protocol."2
Nitroglycerin, prepared as an aqueous solution,' was administered intravenously to 40 patients as previously described.4 Consent was obtained from all patients prior to
drug administration.
Severe systemic arterial hypotension, associated with
sinus bradycardia, was observed in one of the 14 patients
following sublingual nitroglycerin administration and in
three of the 40 patients receiving nitroglycerin infusion. A
fifth patient, admitted to the Coronary Care Unit for acute
myocardial infarction, developed hypotension and bradycardia after receiving 0.4 mg nitroglycerin sublingually for pain
recurring shortly after admission. Those five patients developing hypotension and bradycardia with nitroglycerin administration are described in the case reports which follow.
Cases
Case I
myocardial infarction.
HR, a 78-year-old normotensive male with a history of
myocardial infarction, angina pectoris responsive to nitroglycerin, and stable symptoms of mild left ventricular congestive failure treated with digitalis and diuretics, was admitted following three weeks of increasing angina. Physical
examination revealed a regular pulse of 120, a cuff blood
pressure of 155/80 mm Hg, and signs of both right and left
ventricular failure. The initial ECG revealed ST-segment
depression in the anterolateral leads. The patient complained of recurrent chest pain and was given 0.4 mg nitroglycerin sublingually. Five minutes later a sinus bradycardia of 56 was observed on his bedside monitor. Over the next
four minutes his sinus rate slowed to 38 per minute and
emergence of a nodal bradycardia at a rate of 33 was subsequently observed (fig. 1). Systolic blood pressure was
palpable at 90 mm Hg. Administration of 1 mg of intravenous atropine and leg elevation was associated with a
rapid return of his heart rate to 120 (sinus) and gradual
return 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 the
posterior left ventricle and anterior papillary muscle.
Methods
During a three year period from 1972 to 1975, 54 patients
received either sublingual (14 patients) or intravenous (40
patients) nitroglycerin during clinical research studies investigating hemodynamic effects of nitroglycerin in patients
with acute myocardial infarction. The diagnosis of acute
myocardial infarction was based on electrocardiographic
changes, coincident with enzyme elevations typical of acute
infarction. The electrocardiographic changes were indicative
of transmural myocardial infarction in 49 patients and subendocardial infarction in the remaining five patients.
A #7 Swan Ganz catheter was positioned in the pulmonary artery via antecubital vein cutdown. A short plastic
From the Department of Medicine, Cardiovascular Division, The Johns
Hopkins University and Johns Hopkins Hospital, Baltimore, Maryland.
Supported by the MIRU Contract PH 43 NHLI 167-1444 from the
National Institutes of Health. Dr. Come is a Research Fellow of the
American Heart Association, Maryland Affiliate.
Address for reprints: Bertram Pitt, M.D., Department of Medicine, Cardiovascular Division, The Johns Hopkins University School of Medicine,
Baltimore, Maryland 21205.
Received March 3, 1976; revision accepted May 13, 1976.
624
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Case 2*
JC, a 67-year-old male without a history of hypertension
or ischemic symptoms was admitted with severe substernal
chest pressure. Physical examination revealed signs of left
ventricular failure. The ECG revealed ST-segment elevation in the inferior leads. Subsequent enzyme analysis confirmed the diagnosis of myocardial infarction. Initial hemodynamic measurements were stable over a 30 minute control
period and included mean arterial pressure of 124 mm Hg, a
pulmonary artery diastolic pressure of 20 mm Hg and heart
rate of 87 beats/minute. Nitroglycerin (0.3 mg) was administered sublingually. Five minutes later, the pulmonary
artery diastolic pressure had decreased to 15 mm Hg with no
change in heart rate and a minor decrease in mean arterial
pressure. Six minutes later the pulmonary artery pressure
had decreased further to 3 mm Hg, the heart rate to 68
beats/minute and the mean arterial pressure to 59 mm Hg.
No initial tachycardia was noted, and during the bradycardia the patient remained in normal sinus rhythm with a rare
premature ventricular contraction. He developed chest pain
during the period of hypotension and relative bradycardia.
Elevation of the legs, followed by I mg of intravenous
atropine, was associated with a rapid return of the heart rate
to 92 beats/minute, mean arterial pressure to 104 mm Hg
and disappearance of chest pain.
Case 3
JA, a 77-year-old hypertensive male with chronic mild
congestive failure and angina pectoris treated with digitalis,
alpha-methyl dopa, a thiazide and nitroglycerin, was admitted after one hour of severe left chest pressure. Cardiopulmonary examination was remarkable only for a few
bibasilar rales. ST-segment elevation was noted in the
anterior leads on the ECG. Cardiac enzyme analysis subsequently confirmed the diagnosis of acute infarction. Initial
hemodynamic parameters were stable over a 30 minute con*The hemodynamic data from this patient have previously been reported."2
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trol period and included a heart rate of 60 beats/minute,
mean arterial pressure of 100 mm Hg and pulmonary artery
diastolic pressure of 4 mm Hg. Intravenous nitroglycerin infusion was begun at 17.6 ,ug/min and discontinued four
minutes later when the mean arterial pressure decreased
abruptly to 56 and then to 53 mm Hg. Sinus rhythm continued but the rate decreased to 54 beats/minute. Pulmonary artery diastolic pressure decreased minimally to 3
mm Hg. After spontaneous increases in mean arterial
pressure to 90 mm Hg and pulmonary artery diastolic
pressure to 8 mm Hg and stabilization of the sinus bradycardia at a heart rate of 55, infusion of nitroglycerin was
restarted at 5 jug/min and subsequently increased to 7
jug/min. Nine minutes later, a sudden decrease in mean
arterial pressure to 64 mm Hg, associated with further slowing of the sinus rate to 50 and a decrease in pulmonary
artery diastolic pressure to 3 mm Hg, prompted cessation of
infusion. Mean arterial pressure, heart rate, and pulmonary
artery diastolic pressure increased over the next ten minutes.
Case 4
RH, a 63-year-old normotensive male, with a history of
inferior infarction and subsequent exertional angina pectoris
responsive to sublingual nitroglycerin, was admitted with
chest pain of 12 hours duration, unresponsive to nitroglycerin. Physical examination was remarkable for bilateral
basilar rales and S3 and S, gallops. The ECG revealed ST
depression in leads V3-V5 and T wave inversion in leads II,
III, F and V4-V6. Subsequent enzyme analysis confirmed a
diagnosis of myocardial infarction. Initial hemodynamic
measurements included a mean arterial pressure of 76 mm
Hg and pulmonary artery diastolic pressure of 21 mm Hg.
The initial heart rate was 99 beats/minute. Figure 2 shows
his subsequent hemodynamic changes. Nitroglycerin infusion was begun at 5 ,ug/min and gradually increased over the
next ten minutes to 26.6 jig/min. The heart rate subsequently decreased suddenly to a low of 47 beats/minute and
the mean arterial pressure to a low of 33 mm Hg. Continuous electrocardiographic recordings, available for the
626
CIRCULATION
VOL 54, No 4, OCTOBER 1976
R.H.
100
90
Heart
80
Rate
(beats/min) 7060
50
M.F.
Heart
Rate
(beats/min)
Mean
Pressure
(mmHg)
Arterial
Mean
Arterial
Pressure
(mmHg)
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Pulmonory
Artery
Diastolic
Pressure
(mmHg)
Intravenous
Nitroglycerin
(mcg /min)
20
15
10
5
300F
0~~~~~~~~E LEVATION
5 10 IS 20 25 30 35 40
Minutes
FIGURE 2. Graphic illustration of the hemodynamic changes occurring during intravenous nitroglycerin administration to patient 4.
entire infusion period, revealed a rapid, progressive slowing
of the heart rate, without initial tachycardia and with
maintenance of normal sinus rhythm, coincident with the
development of hypotension. Pulmonary artery diastolic
pressure was not measured at the time of maximal bradycardia and hypotension but was 8 mm Hg three minutes
after the peak fall in mean arterial pressure. The patient
complained of nausea. With cessation of nitroglycerin infusion and leg elevation, mean arterial pressure, pulmonary
artery diastolic pressure and heart rate rapidly returned
toward control levels.
Case 5
MF, a 45-year-old hypertensive male with a history of inferior myocardial infarction and subsequent angina pectoris
responsive to nitroglycerin, was admitted after prolonged
substernal pain. Physical examination was remarkable for
signs of left ventricular failure. The ECG revealed changes
of acute transmural anteroseptal infarction. Subsequent enzyme analysis confirmed acute infarction. During the period
of hemodynamic study the patient was maintained on continuous intravenous lidocaine and procainamide infusions,
which were started on admission for treatment of ventricular ectopic activity. Baseline hemodynamic measurements, stable over a 30 minute control period, included a
mean arterial pressure of 84 mm Hg and pulmonary artery
diastolic pressure of 23 mm Hg. Initial heart rate was 120
beats/minute. Figures 3 and 4 illustrate the subsequent
hemodynamic changes and the bradycardia, respectively. Intravenous nitroglycerin infusion was begun at 5 ,g/min and
gradually increased over the next 25 minutes to 56.5 ,ug/min.
Sinus bradycardia with an occasional ventricular ectopic
Pulmonary
Artery
Diastolic
Pressure
(mmHg)
60-
ntravenous
Nitroglycerin
(mcg /min)
40
2020 ,
itZAtropine
0.5mg IV
/
I
10 20 30
50 60 70 80 90 100 120
Minutes
FIGURE 3. Graphic illustration of the hemodynamic changes occurring during repeated infusions of intravenous nitroglycerin to
patient 5.
0
beat was then observed. The rate of infusion was decreased
,ug/min. However, a further decrease in heart rate to
45 beats/minute was noted and mean arterial pressure
decreased to 38 mm Hg. Pulmonary artery diastolic pressure was 7 mm Hg at the time of maximal hypotension.
Continuous electrocardiographic recordings revealed a rapid
progressive slowing of the heart rate without initial tachycardia and with maintenance of normal sinus rhythm. After
abrupt discontinuation of nitroglycerin infusion and administration of 0.5 mg atropine intravenously, mean arterial
pressure, heart rate, and pulmonary artery diastolic pressure
returned toward control levels. Reinfusion of nitroglycerin
was begun 24 minutes after initial discontinuation and was
increased from 10 to 36.5 ,ug/min over the next thirty
minutes. Mean arterial pressure and pulmonary artery
diastolic pressure again decreased to 62 and 8 mm Hg,
respectively, and a relative slowing of the heart rate to 92
beats/minute was observed. Mean arterial pressure,
pulmonary artery diastolic pressure and heart rate returned
toward control levels with cessation of the infusion.
to 36.5
Discussion
Administration of sublingual and oral nitrates to normal
volunteers and to patients with ischemic heart disease
usually results in an increase in heart rate,'8-"8 which is
thought to be mediated by reflex sympathetic discharge in
response to decreases in systemic arterial pressure."9 The
patients with acute myocardial infarction reported in this
study developed severe systemic arterial hypotension in
association with decreases in LVFP and the development of
absolute or relative bradycardia following administration of
NITROGLYCERIN HYPOTENSION AND BRADYCARDIA/Come, Pitt
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FIGURE 4. Electrocardiographic recordings from patient 5
demonstrate the sinus tachycardia (panel A) whech was present
prior to nitroglycerin administration and the sinusbradyiardia
(panel B) which was observed coincident with arterial hypotension
during nitroglycerin administration.
nitroglycerin. The sinus bradycardia observed in the present study was not preceded by transient tachycardia and
appeared to be vagally mediated as evidenced by the response to intravenous atropine. Recurrence of hemodynamic changes with reinfusion of nitroglycerin in patients 3
and 5 suggests that the bradycardia and hypotension were
due to nitroglycerin administration rather than to changes
which might have occurred independent of drug therapy during the course of acute myocardial infarction.
There have been other documented instances of severe
hypotension and bradycardia occurring after sublingual
nitroglycerin administration to patients with hypertension or
ischemic heart disease.9- ' Sprague and White in 1933," in a
review of approximately 900 patients with angina pectoris,
reported three cases of syncope following administration of
sublingual nitroglycerin for chest pain. Two of their patients
fainted while under observation and were noted to become
diaphoretic, bradycardic and hypotensive prior to loss of
consciousness. Prodger and Ayman'0 observed four instances of bradycardia and hypotension occurring in a group
of 110 patients with hypertension given sublingual nitroglycerin. All four patients developed hypotension and bradycardia, including one patient who developed transient complete heart block. One of their patients had a documented
initial increase in heart rate prior to the onset of bradycardia. Oral and sublingual nitrate administration followed by
tilting has also been associated with hypotension, bradycardia and syncope.15 20 21 An initial increase in heart rate is
frequently observed, coincident with the onset of hypoten-
627
sion, in this situation.'5' 20 Bradycardia often occurs late, just
prior to loss of consciousness.'5' 20 Prior treatment with intravenous atropine has been shown to eliminate the bradycardia, but has been reported to have no effect on the incidence of syncope or hypotension.'5' 20, 21 Tilting alone can,
however, produce hypotension and bradycardia independent
of nitrate administration20' 21 and the additional effect of
nitroglycerin under these circumstances is therefore difficult
to assess.
Intravenous nitroglycerin has been studied during acute
myocardial infarction.2-5 Heart rate changes have, however,
been variable. In the dog with experimental coronary artery
ligation, significant decreases in mean arterial pressure
resulting from intravenous nitroglycerin are accompanied by
significant increases in heart rate.2 In contrast, in humans
with acute myocardial infarction, intravenous nitroglycerin
administration has not been associated with a significant
mean change in heart rate, despite significant decreases in
mean arterial pressure.2
Carotid and aortic body baroreceptors normally cause a
reflex increase in heart rate in response to a decrease in
arterial pressure.22 23 The development of bradycardia associated with hypotension following nitroglycerin administration appears to represent a failure of normal compensation by the baroreceptor mechanisms and may involve
both a partial failure of sympathetic activity as well as an
enhancement of vagal tone. Similar mechanisms have been
postulated for vasovagal syncope.24 25 Experimentally, simultaneous bradycardia and hypotension have been produced by chemical stimulation of the myocardium (the
Bezold-Jarish reflex)26-28 and by electrical stimulation of
specific areas in the nervous system.26' 29, 30 Variations in
heart rate can be effected by manipulation of venous return
to the right and left heart.3' Bradycardia, which can be
eliminated by vagotomy, has been produced experimentally
by volume-induced elevation of right atrial or left ventricular pressures, suggesting that pressure or length receptors in the myocardial walls may elicit reflex changes in
heart rate.31 33 In contrast, Sjostrand has recently suggested
that bradycardia may be elicited by a decrease in central
blood volume.'2 In his experiments, the bradycardia produced by rapid arterial hemorrhage in the rat was less
pronounced and appeared later when simultaneous venous
infusions were given, despite similar decreases in mean
arterial pressure. Those experiments suggest that decreases
in venous return may be more important than decreases in
systemic arterial pressure in eliciting reflex bradycardia.
Although ventricular volume measurements were not performed in our patients, it is likely that ventricular volume
diminished after nitroglycerin, in association with the potent
vasodilatory effects of nitroglycerin on the venous circulation.34 The magnitude of changes in ventricular volume cannot be predicted, however, from changes in left ventricular
filling pressures in the patients reported above because of
changes in left ventricular compliance which may follow
acute myocardial infarction. The possibility also exists that
nitroglycerin may result in afferent sympathetic stimulation
which elicits an efferent vagal response. Afferent sympathetic reflexes have been shown to be associated with
vagally mediated bradycardia.35
Patients with acute myocardial infarction, especially inferior infarction, not infrequently develop hypotension and
CIRCULATION
628
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bradycardia, responsive to intravenous atropine, during the
early phases of acute infarction.36' It is possible that nitroglycerin administration may enhance underlying mechanisms responsible for the development of bradycardia and
hypotension in such patients. It should, however, be noted
that four of the five patients in the present study had ECG
evidence of acute anterior transmural or subendocardial,
rather than inferior, myocardial infarctions.
In animals subjected to acute coronary occlusion, Costantin has demonstrated a transient, vagally-mediated sympatho-inhibitory reflex resulting in blunting of the expected
peripheral vasoconstrictor and cardiac sympathetic response
to hypotension.38 Although it has not been demonstrated in
man nor in animals subjected to prolonged periods of ischemia or infarction, such a reflex mechanism might possibly
explain the failure of normal compensation by the aortic and
carotid body baroreceptors to the hypotension observed with
nitroglycerin infusion in our five patients.
Although the mechanism of bradycardia in association
with nitrate-induced hypotension remains unclear, the cases
presented above re-emphasize the potentially serious adverse
effects of nitroglycerin. They underscore the need for careful
observation during its use, particularly in the setting of acute
myocardial infarction.
Acknowledgment
We are indebted to Miss Lisa Grue for her secretarial assistance and to
Myron L. Weisfeldt, M.D. for review of the manuscript.
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VOL 54, No 4, OCTOBER 1976
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Nitroglycerin-induced severe hypotension and bradycardia in patients with acute
myocardial infarction.
P C Come and B Pitt
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Circulation. 1976;54:624-628
doi: 10.1161/01.CIR.54.4.624
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 1976 American Heart Association, Inc. All rights reserved.
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