Claude Perret
Jean-François Enrico
Manipulating afterload for the treatment
of acute heart failure
A historical summary
For decades, digitalis and diuretics
presented as the mainstay of the conventional treatment of heart failure.
In the late 1960s, however, the use of
positive inotropic agents was reconsidered on account of several studies
demonstrating a poor hemodynamic
response to digitalis and arrhythmogenic effects in patients with coronary disease. The beneficial effect
of diuretics in relieving pulmonary
congestion and acute pulmonary edema was clearly established. But, it
was also shown that excessive use
could be deleterious, leading to
electrolyte imbalance, hypovolemia,
low cardiac output and shock.
Before the introduction of bedside
hemodynamic investigation in the
early 1970s, the assessment of ventricular performance in man was essentially clinical and radiological. In
patients with acute left ventricular
failure, successive chest X-rays were
used to demonstrate a reduction in
cardiac size or a clearing of pulmonary congestion. In view of the usefulness of assessing ventricular function in experimental animals by relating filling pressure to ventricular
performance during volume expansion, it was thought that a similar approach in man might be of interest.
But the method appeared not to be
convenient due to reflex adjustments
to the change in blood volume.
In 1964, an important paper, by
John Ross and Eugene Braunwald,
was published in Circulation [1] de-
scribing a new method to evaluate
left ventricular function by increasing resistance to ventricular ejection.
They investigated the ventricular response to graded infusions of angiotensin in patients with and without
clinical evidence of impaired left
ventricular function. The method
used consisted in simultaneous measurements of left ventricular pressure, obtained by transseptal left
heart catheterization, and cardiac
output determined by the indicatordilution technique. It was thus possible to construct individual function
curves while relating stroke work to
filling pressure and to compare the
response to a progressive increase in
resistance to ventricular ejection.
It appeared that, in patients with normal or near normal left ventricular
function, there was a steep increase
in ventricular stroke work with small
elevations in left ventricular enddiastolic pressure. By contrast, in
patients with signs of a markedly depressed functional capacity, the initial limb of the curve was flat or
even descending, demonstrating a
fall in cardiac index and stroke volume as the arterial blood pressure
and left ventricular filling pressure
rose.
This study was of primary importance for understanding heart function in disease. It demonstrated that
the left ventricular response to increased resistance to ejection was
highly dependent of its function: in
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normal hearts stroke work increased
with the augmented afterload so that
stroke volume was maintained
constant; by contrast, in severely
depressed hearts, stroke volume
decreased with any increase in aortic
pressure. Surprisingly, this new concept did not give rise to the potential
implications it contained for clinicians and apparently none raised the
question: if an increase in resistance
to ventricular ejection worsens ventricular performance, might its reduction be used to improve this?
Our personal experience with
vasodilators for the treatment of
severe acute left ventricular failure
began in the early 1960s, with an
erroneous diagnosis. It concerned a
60-year-old patient who was hospitalized in the ICU of the university
medical department for severe acute
pulmonary edema. Upon admission,
he was tachypneic and cyanotic.
Blood pressure was extremely unstable oscillating between 150 and
240 mmHg of systolic and 100 and
140 of diastolic pressures. There
were signs of intense peripheral
vasoconstriction with a cold and
clammy skin. Electrocardiogram
showed sinus tachycardia with frequent supraventricular ectopic beats
and diffuse T wave inversions. Chest
X-ray demonstrated marked pulmonary venous congestion and enlarged
cardiac silhouette. The patient was
immediately treated with high concentrations of oxygen, diuretics and
digitalis. The response was poor.
Hypertension and tachypnea persisted
with signs of clinical shock.
A pheochromocytoma was suspected and an intravenous infusion
of phentolamine, an agent with adrenergic and sympathetic blockade properties, was initiated in an attempt to
correct hypertension. The drug produced an immediate and dramatic
clinical improvement: peripheral
signs of shock subsided, blood pressure progressively normalized and
pulmonary venous congestion improved. The infusion was progressively discontinued and the patient recovered uneventfully. The beneficial
response to phentolamine with a
positive test for catecholamines in a
sample of urine collected during the
hypertensive crisis made likely the
diagnosis of pheochromocytoma but
all subsequent urinary tests were negative. The diagnosis could not be confirmed and the excessive excretion of
urinary catecholamines was attributed
to an intense and temporary drive in
sympathetic activity related to acute
left ventricular failure.
The surprising benefit obtained
with phentolamine infusion in a patient with acute pulmonary edema
lead us to investigate further the role
of vasodilation in left ventricular
failure [2]. Seven patients were studied, five of whom had a history of
acute myocardial infarction. All
were admitted to the intensive care
unit for refractory acute pulmonary
edema, associated with hypertension
in six. Arterial blood gas analysis
with repeated lactate determinations
were used as an index of severity of
the patient’s condition. Upon admission, all patients demonstrated
marked hypoxemia in spite of
oxygen therapy (SaO2: 56–76%)
and severe metabolic acidosis
(pH: 7.08–7.33) with a mean lactate
concentration of 6.4 mEq/l, indicative of severe tissue anoxia. Phentolamine was administered by a constant infusion at a dose varying between 5 and 20 mg/h. The response
was rapid, characterized by the disappearance of pulmonary edema, the
normalization of arterial blood and
central venous pressures and the
complete correction of lactic acidosis in a few hours. The series was extended to include finally a total of
15 patients with the same clinical
and metabolic response [3]. All patients survived.
These results attested to an important improvement in tissue perfusion after vasodilator administration
and were attributed to a decreased
systolic load due to the fall in systemic resistance combined with better distribution of peripheral perfusion following the relief of excessive
adrenergic vasoconstriction.
As a matter of fact, Taylor et al.
[4] had already investigated the circulatory effects of the acute intravenous injection of phentolamine in
normal subjects and in patients with
hypertensive disease. The intravenous administration of 5 mg of the
drug was shown to produce a prompt
reduction in systemic vascular resistance. This resulted in a rapid fall in
systemic blood pressure associated
with a significant increase in heart
rate and cardiac output without large
or consistent changes in stroke volume. The response was essentially
the same in both groups of subjects,
although the time course of their response was different, being significantly slower in the hypertensive
group. It was concluded that the predominant vascular activity of phentolamine was to cause a direct relaxation of vascular smooth muscle on
the resistance vessels of the systemic
circulation. The drug also developed
a moderate antagonism to circulating
catecholamines with a weak sympathetic blocking activity.
Considering the circulatory effects of phentolamine observed in
normal subjects, it could be assumed
that such a vasodilation in patients
with acute left ventricular failure
would be of particular benefit. It had
been previously shown that the onset
of pump failure was associated with
two “compensatory” mechanisms: a
reflex vasoconstriction in systemic
vessels causing an increase in left
ventricular workload and myocardial
oxygen demand and a redistribution
of blood volume towards the heart
and the lungs. It could then be assumed that pharmacological vasodilation would improve ventricular
ejection and possibly produce a shift
of blood from the lungs to the periphery by reducing venous tone.
These hypotheses were fully confirmed by Majid, Sharma and Taylor
in an article published in the Lancet
[5] a few months after our initial
presentation. In a series of 12 patients with severe acute or subacute
left ventricular failure due to ischemic heart disease, phentolamine
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was administered by intravenous
infusion. The initial dose was
5 mg/min for 1 min followed by a
dose adjusted in each subject to
reduce the supine mean systemic
arterial pressure by approximately
25 mmHg. The fall in blood pressure
produced rapid relief of dyspnea associated with a progressive clearing
in pulmonary edema and a significant reduction of heart size, as we
had described. But most interesting
was the hemodynamic response observed in the group of patients with
severe heart failure: phentolamine
infusion produced a rapid and substantial reduction in left ventricular
end-diastolic and pulmonary-artery
mean pressures associated with an
increase in stroke volume and cardiac output. These benefits in ventricular performance were attributed essentially to two mechanisms: the reduction in cardiac pressure load obtained by lowering the raised vascular resistance and an increase in the
capacity of the peripheral vessels,
particularly the veins, which reduced
the volume of blood in the dilated
heart. A reflex increase in sympathetic activity secondary to the fall in
systemic blood pressure could not be
definitively discarded. But the absence of significant change in heart
rate made an increase in inotropic
activity unlikely.
This study was the first to use
sophisticated left and right catheterization techniques to measure the response of cardiac output and filling
pressures to peripheral vasodilation.
It demonstrated the therapeutic value
of reducing systemic vascular resistance in patients with severe left
ventricular failure. It showed that relief of the workload of a failing heart
could provide significant clinical
benefit with apparently no hazard to
the cerebral and coronary circulations.
During the early 1970s, several
studies demonstrated that the incidence and severity of left ventricular
failure complicating acute myocardial
infarction were directly related to the
extent of ventricular mass necrosis.
Consequently the ideal therapy would
minimize myocardial oxygen demand
and raise oxygen delivery to the
ischemic area. On a theoretical basis,
one could expect that phentolamine,
as well as other vasodilators, might
improve heart pump function without
interfering adversely with the myocardial oxygen metabolism.
In 1973, Kelly et al. [6] used
phentolamine to decrease arterial
blood pressure in 11 hypertensive
patients with acute myocardial infarction and left ventricular dysfunction. Six had a history of chronic
hypertension confirmed by ophthalmoscopy and electrocardiographic
signs of left ventricular hypertrophy.
The remaining five had no previous
history of hypertension. The hemodynamic response to low doses of
phentolamine was similar to those
previously described with a significant decline in arterial and pulmonary capillary wedge pressures and
a concomitant increase in cardiac
index. Interestingly, as stroke work
index and heart rate were unchanged,
the rate-pressure time product
thought to be a reasonable index of
myocardial oxygen consumption decreased significantly in the group
with acute hypertension. The conclusion was that, in such conditions of
acute hypertension, reduction of left
ventricular afterload might offer advantages over current therapy for left
ventricular dysfunction.
A few months later another clinical investigation was published in
the same journal by Chatterjee et al.
[7] from the group of Cedars-Sinai
Medical Center in Los Angeles, describing the hemodynamic and metabolic responses to vasodilator therapy in patients with acute myocardial
infarction. Thirty-eight patients were
examined and were divided in three
groups according to the severity of
left ventricular failure estimated on
the initial level of pulmonary capillary wedge pressure and stroke work
index. In group III (15 patients) all
had clinical evidence of left ventricular failure, 14 had frank pulmonary
edema and 8 had clinical features of
shock. In 11 patients, phentolamine
was used: 5 mg were administered
intravenously in the first minute then
at a rate of 0.1–0.2 mg/min. In the
remaining 27 patients, sodium nitroprusside was infused at a rate of
16–200 µg/min. The infusion of the
vasodilator was gradually increased
until the mean arterial blood pressure
decreased by not more than
20 mmHg or when there was a significant decrease in pulmonary capillary wedge pressure. Pressures and
cardiac output were measured with a
balloon-tip triple lumen catheter using the thermodilution technique.
Coronary sinus flow was determined
by the constant infusion technique.
The myocardial extraction ratio for
lactate was calculated from arterial
and coronary sinus blood samples.
The study showed that the hemodynamic response to phentolamine or
nitroprusside was identical to that reported previously. But it also demonstrated that the benefit in heart performance was greater in those patients
with the most severely depressed cardiac function. The functional improvement was obtained without any
increase in metabolic cost. Myocardial oxygen demand either remained
unchanged or even, in some cases,
fell and myocardial lactate extraction
did not decrease. Therefore, it appeared that vasodilator therapy might
well play an important role in the
treatment of pump failure following
myocardial infarction.
These expectations were confirmed in another hemodynamic
study performed in a series of
15 patients with acute myocardial infarction [8]. It was shown that with a
dose of 10 mg/h, phentolamine could
be used in normotensive patients
without adverse effects; the fall of
mean arterial blood pressure was less
than 15 mmHg and was associated
with a significant increase in cardiac
output and a substantial reduction in
right and left filling pressures. The
overall clinical course appeared surprisingly good with a mortality rate
of 13% in a group of high-risk patients.
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In conclusion, for years the therapy of congestive heart failure had
focused on trying to influence the
factors which at that time were recognized as the determinants of myocardial function, such as reducing
the diastolic filling of the ventricle
with diuretics or increasing its contractility with inotropic drugs. In the
early 1960s, several studies demonstrated that the diseased left ventricle
was highly dependent on peripheral
vascular factors, which had been
hitherto relatively neglected. In the
normal heart, an increased impedance to ventricular ejection was well
tolerated and did not change stroke
volume. In the presence of left ventricular dysfunction, an enhanced
impedance could lead to a decrease
in cardiac output with an increase in
ventricular volume and pressure.
This abnormal response appeared of
particular importance when it was
shown that heart failure itself produced an arteriolar vasoconstriction
and different alterations in vascular
wall structure, which increased impedance to ventricular outflow and
thus further deteriorated ventricular
performance. The pharmacological
reduction of impedance with the use
of vasodilator drugs led to a new approach. It has proved to be a most
important adjunction in the management of both acute and chronic heart
failure [9].
References
1. Ross J, Braunwald E (1964) The study
of left ventricular function in man by
increasing resistance to ventricular ejection with angiotensin. Circulation
29:739–749
2. Enrico JF, Poli S, Grandjean T,
Perret C (1971) Utilité de la phentolamine dans le traitement de l’oedème
pulmonaire aigu. Schweiz Med
Wochenschr 9:325–328
3. Enrico JF, Poli S, Perret C (1971)
La phentolamine dans le traitement de
l’oedème aigu “réfractaire”. Bull
Physio-Path Respir 7:1319–1340
4. Taylor SH, Sutherland GR, MacKenzie
GJ, Staunton HP, Donald KW (1965)
The circulatory effects of intravenous
phentolamine in man. Circulation
31:741–754
5. Majid PA, Sharma B, Taylor SH (1971)
Phentolamine for vasodilator treatment
of severe heart failure. Lancet
2:719–724
6. Kelly DT, Delgado CE, Taylor DR,
Pitt B, Ross RS (1973) Use of phentolamine in acute myocardial infarction associated with hypertension and left ventricular failure. Circulation 47:729–735
7. Chatterjee K, Parmley WW, Ganz W,
Forrester J, Walinsky P, Crexells C,
Swan HJC (1973) Hemodynamic and
metabolic responses to vasodilator therapy in acute myocardial infarction. Circulation 48:1183–1193
8. Perret C, Gardaz JP, Reynaert M,
Grimbert F, Enrico JF (1975) Phentolamine for vasodilator therapy in left
ventricular failure complicating acute
myocardial infarction. Haemodynamic
study. Br Heart J 37:640–646
9. ACC/AHA Guidelines for the evaluation and management of chronic heart
failure in the adult: executive summary
(2001). Circulation 104:2996–3007