Journal of the American College of Cardiology Vol. 38, No.

4, 2001
© 2001 by the American College of Cardiology ISSN 0735-1097/01/$20.00
Published by Elsevier Science Inc. PII S0735-1097(01)01486-3

REVIEW ARTICLE

The Evolving Management of Acute Right-Sided

Heart Failure in Cardiac Transplant Recipients
Bozena Stobierska-Dzierzek, MD, Hamdy Awad, MD, Robert E. Michler, MD, FACC, FACS
Columbus, Ohio
Avoidance of the clinical syndrome of acute right-sided heart failure after heart transplan-
tation is, unfortunately, not possible. Clinical experience and the literature certainly suggest
that a significant factor in the successful management of right ventricular (RV) failure is
recipient selection. Moreover, threshold hemodynamic values beyond which RV failure is
certain to occur and heart transplantation is contraindicated do not exist. Nor are there values
below which RV failure is always avoidable. Acute RV failure will remain a difficult and
ever-present clinical syndrome in the transplant recipient. Goals in the treatment of this
clinical problem include:
1. Preserving coronary perfusion through maintenance of systemic blood pressure.
2. Optimizing RV preload.
3. Reducing RV afterload by decreasing pulmonary vascular resistance (PVR).
4. Limiting pulmonary vasoconstriction through ventilation with high inspired oxygen
concentrations (100% FiO2), increased tidal volume and optimal positive end expiratory
pressure ventilation.
Inhaled nitric oxide is recommended before leaving the operating room in cases where the
initial therapies have had little impact. Intra-aortic balloon counterpulsation is employed in
patients with impaired left ventricular (LV) function and may be of benefit in patients with
RV dysfunction resulting from ischemia, preservation injury or reperfusion injury. Optimal
LV function reduces RV afterload and PVR. A proactive decision regarding RV assist device
implantation is made before leaving the operating room and is highly dependent upon overall
hemodynamics, size and function of the ventricles as seen on transesophageal echocardiog-
raphy, renal function and surgical bleeding. Only through careful preoperative planning can
this life-threatening condition be managed in the postoperative period. (J Am Coll Cardiol
2001;38:923–31) © 2001 by the American College of Cardiology

Registry data from the International Society of Heart and
Lung Transplantation show that, despite advances in peri-
operative management, right ventricular (RV) dysfunction
accounts for 50% of all cardiac complications and 19% of all
early deaths in patients after heart transplantation (1).
Right ventricular dysfunction and pulmonary hyperten-
sion have long been considered vexing problems in cardiac
surgery. As early as the 1950s, Guyton et al. (2) conducted
experiments in an animal model of pulmonary hypertension.
They demonstrated that, when the normal RV was exposed
to increased pulmonary artery pressure, it would suffer acute
failure, resulting in circulatory collapse of the animal.
In the 1960s at Stanford, several early post-transplantation
deaths were due to acute right-sided heart failure (HF). It
occurred in patients with pulmonary hypertension, reviving the
idea that the normal (donor) right ventricle is unable to bear a
sharp increase in its external workload. This led to a refinement
in recipient inclusion criteria by excluding patients with severe
pulmonary hypertension (2).
In 1971, Griepp et al. (3) first reported the relationship
between elevated preoperative pulmonary vascular resistance
(PVR) and the risk of death from acute RV failure after
From the Division of Cardiothoracic Surgery, Ohio State University, Columbus,
Ohio.
Manuscript received September 11, 2000; revised manuscript received May 24,
2001, accepted June 14, 2001.
heart transplantation. Numerous other studies confirmed
this association (4 – 6).
Subsequent analyses of larger numbers of patients con-
firmed PVR as an incremental risk factor for early death
after heart transplantation. Indeed, preoperative pulmonary
hypertension and increased PVR have not only been asso-
ciated with post-transplant morbidity from acute RV failure
and all-cause perioperative mortality, but they have also has
been associated with other causes of postoperative morbid-
ity, including post-transplant infections and arrhythmias
(7,8).
Pulmonary hypertension, like arterial hypertension, is a
phenomenon of diverse causes that include both increases in
flow and in resistance across the pulmonary vascular bed.
Patients with chronic HF may develop pulmonary hyper-
tension for several reasons, including direct backward trans-
mission to the lungs of increased left ventricular (LV)
pressure resulting in a “reactive” increase in pulmonary
pressure due to pulmonary vasoconstriction (9). This reac-
tive pulmonary vasoconstriction may eventually lead to
irreversible elevation of PVR. The exact time course for the
development of pulmonary hypertension varies by HF
etiology but usually will take years to develop.
Pulmonary hypertension and increased PVR are often
used interchangeably. They are, however, two distinct phys-
iologic events with important respective hemodynamic con-
924 Stobierska-Dzierzek et al.
Management of Acute Right Heart Failure in Transplant Recipients
Abbreviations and Acronyms
cAMP ⫽ cyclic adenosine 3⬘5⬘ monophosphate
CVVHD ⫽ continuous venous-venous hemofiltration
and dialysis
GMP ⫽ guanosine monophosphate
HF ⫽ heart failure
LV ⫽ left ventricle, left ventricular
PVR ⫽ pulmonary vascular resistance
PVRI ⫽ pulmonary vascular resistance index
RV ⫽ right ventricle, right ventricular
SPAP ⫽ systolic pulmonary artery pressure
TPG ⫽ transpulmonary gradient
sequences for the patient. The recognition that pulmonary
hypertension may occur with or without reversible elevation
of PVR is of key importance in predicting the success or
failure of the transplanted heart.
THE ANATOMY AND PHYSIOLOGY OF THE RV
Anatomically, the RV can be divided into an inflow and
outflow region. The crista supraventricularis is a muscular
region that separates the inflow and outflow portions of the
RV and is continuous with the tricuspid valve anterior
leaflet, the interventricular septum and the RV free wall.
The crista supraventricularis functionally integrates me-
chanical events during systole to narrow the orifice of the
tricuspid valve and to cause the RV free wall to move toward
the septum propelling blood into the lungs. The pattern and
timing of contraction is different for the inflow and outflow
portions. Contraction of the RV inflow region occurs before
that of the outflow region, resulting in a peristaltic action.
The earlier contraction of the inflow region may occur
because of the presence of more Purkinje fibers. Contraction
of the outflow region is of longer duration than the inflow
region (10).
Herdt et al. (11) demonstrated that not only do these
regions differ in embryological structure, but they also differ
in response to inotropes. The outflow tract arises from the
bulbus cordis, whereas the inflow tract arises from the
ventricular portion of the primitive cardiac tube (11). The
inotropic response of the outflow tract is greater than that of
the inflow tract, perhaps as a mechanism to protect the
pulmonary vasculature from high pressure (11).
The shape of the RV in cross-section is that of a crescent.
The thin RV free wall embraces the interventricular septum
along with the LV during contraction. The interventricular
septum is pulled toward the LV with subsequent RV free
wall flattening. While contraction of the LV involves radial
constriction and longitudinal shortening, RV contraction
involves free wall shortening and flattening (10). The
smaller mass and lower systolic and diastolic pressures of the
RV result in coronary blood flow during both systole and
diastole.
The thin walls and crescent shape result in a highly
compliant RV chamber, which is able to accommodate large
JACC Vol. 38, No. 4, 2001
October 2001:923–31
increases in volume. However, the adaptive mechanisms of
the RV are not well suited to large increases in pressure. The
normal pulmonary vasculature provides a low-pressure sys-
tem that can respond to great fluctuations in blood flow
without a great change in pressure by the recruitment of
underperfused pulmonary blood vessels along with further
dilation of already perfused pulmonary blood vessels.
Formerly, the RV was viewed as a passive conduit
connecting the venous circulation to the pulmonary circu-
lation. As such, the RV was not considered to be as
important as the LV in the maintenance of normal hemo-
dynamics. It is now recognized that the RV and LV are
interdependent and have similar vitally important functions.
The ventricles share a common blood supply through the
interventricular septum. The interventricular septal config-
uration may be altered during diastole if there is acute
distention of either ventricle. Acute ventricular dilation will
result in alterations to the opposing ventricle. These alter-
ations will include changes in compliance, geometry and
blood flow. For example, with acute failure of the RV from
any cause, the RV will dilate, increase its wall tension and
become ischemic and less compliant; and the interventric-
ular septum will shift toward the LV, leading to a smaller
underfilled LV (9,10).
PULMONARY HYPERTENSION AS A RISK
FACTOR FOR HEART TRANSPLANT PATIENTS
Once a diagnosis of preoperative pulmonary hypertension
has been defined by cardiac catheterization, it is important
for patients to be subdivided further into those with “fixed”
or “irreversible” PVR and those with “reactive” or “revers-
ible” PVR. Reactive PVR may be discerned by measuring
baseline hemodynamics followed by provocative therapy
with pulmonary vasodilators and repeat hemodynamic mea-
surements. Agents such as sodium nitroprusside, adenosine,
prostacyclin and inhaled nitric oxide have been used for this
purpose (11–14). Pulmonary vascular resistance, PVR index
(PVRI), peak systolic pulmonary artery pressure (SPAP)
and transpulmonary gradient (TPG) are hemodynamic
measurements that should be evaluated carefully before
transplantation. No one test can accurately predict outcome,
but together, these evaluations are useful for risk stratifica-
tion. Clearly, patients with reversible components to their
pulmonary vasculature have a better prognosis than patients
with fixed or irreversible pulmonary hypertension.
Michler et al. (15) have reported an approximately
fourfold higher transplant mortality among patients with
fixed pulmonary hypertension when compared with patients
without pulmonary hypertension. Of particular importance,
the transplant mortality for patients with reactive pulmonary
hypertension remains high and does not fall to the level seen
in patients without pulmonary hypertension (15,16).
At the Ohio State University, it is our practice to define
“fixed” pulmonary hypertension (patients considered to be at
high risk for transplantation) as those patients who, after
JACC Vol. 38, No. 4, 2001
October 2001:923–31 Management of Acute Right Heart Failure in Transplant Recipients
provocative vasodilator therapy, have either a PVR ⱖ4 WU,
a PVRI ⱖ6 WU/m2 (particularly useful in the pediatric and
small size patient population), an SPAP ⱖ60 mm Hg or a
TPG ⱖ15 mm Hg (17–19). The patients who present the
most cause for concern are those for whom several param-
eters are elevated. Importantly, each of these hemodynamic
parameters may act independently. For example, a PVR ⫽
4 WU may be seen in a patient with an SPAP ⫽ 40 mm Hg
and a TPG ⫽ 12. Distinguishing whether a patient such as
this can be successfully transplanted requires experience,
careful preoperative therapy and monitoring, intuition and a
measure of good luck.
Over the years, we have learned that there exists a group
of patients who at first evaluation may be thought to have
irreversible pulmonary hypertension, but who may be con-
verted into the reactive category through vasodilator condi-
tioning. “Vasodilator conditioning” is an aggressive se-
quence of long-term inotropic support (e.g., dobutamine or
milrinone) followed by provocative testing, followed by the
addition of a second inotrope, followed by provocative
testing, all performed in an attempt to condition the
pulmonary vasculature into a maximally dilated state. If the
conditioning is successful, these patients may be considered
for transplantation and, if accepted, should be maintained
on this regimen until transplantation. These patients require
intensive management after transplantation and remain at
significant risk for acute RV failure.
The expectation is that a patient’s elevated pulmonary
artery pressure and resistance will fall after transplantation.
The time course for this appears to vary in the literature. For
example, Bhatia et al. (20) evaluated post-transplant reso-
lution of pulmonary hypertension and reported a continual
decrease in hemodynamic indexes throughout the first year,
with 80% of patients demonstrating normal PVR at one
year.
The remarkable results seen with prostacyclin in the
management of patients with primary pulmonary hyperten-
sion have prompted interest in using this agent in the
preoperative conditioning of patients with secondary pul-
monary hypertension stemming from chronic HF. Our
team and others have seen dramatic clinical improvement in
patients with congenital heart disease and Eisenmenger’s
syndrome referred for heart-lung transplantation. These
patients have exhibited subjective clinical improvement,
elimination of cyanosis, improved RV function and in-
creased exercise performance. Whether this improvement
can be expected to be long lasting and whether these
findings should prompt surgical correction of the cardiac
defect combined with lung transplantation remain contro-
versial. It should be recognized that long-term prostacyclin
therapy is an extremely expensive therapy that should be
reserved for situations in which other therapies have proved
unsuccessful.
Unfortunately, normal preoperative PVR does not rule
out the potential for increased PVR and acute RV failure
after heart transplantation. Organ preservation and cardio-
Stobierska-Dzierzek et al. 925
pulmonary bypass have deleterious effects upon ventricular
function, and it has been shown that cardiopulmonary
bypass may result in an increase in PVR (21).
TREATMENT OF RV FAILURE
Right ventricular failure in heart transplant recipients is of
multifactorial etiology. Most commonly, it results from
coupling a donor heart not adapted to elevated pulmonary
artery pressure and resistance to the increased afterload of
pulmonary hypertension and increased pulmonary resistance
in the recipient. Additionally, adaptation by the donor heart
may be impaired by ischemia and reperfusion injury associ-
ated with organ preservation.
Right ventricular failure results in dilation, ischemia and
decreased contractility. Decreased pulmonary blood flow
and leftward septal shift subsequently leads to lower LV
filling and reduced systemic cardiac output.
In order to optimize RV hemodynamics, one must consider
the following manipulations. These include maximizing coro-
nary perfusion through maintenance of aortic pressure, reduc-
ing preload to a distended and ischemic RV, decreasing RV
afterload by reducing PVR, optimizing myocardial oxygen
delivery and limiting ventricular oxygen consumption. Ar-
rhythmias and atrioventricular conduction disturbances should
be appropriately treated to maintain stroke volume of the right
and left ventricles. Prevention of low cardiac output is manda-
tory. Effective therapy for RV failure remains very challenging.
Although numerous therapeutic options have been sug-
gested, there is no single best approach to the treatment of
RV failure. Key elements include judicious fluid infusion,
inotropic support and high-inspired oxygen concentrations
(100% FiO2) to encourage pulmonary dilation. Optimizing
RV preload should be considered if central venous pressure
is ⬍10 mm Hg, which would be unlikely. The administra-
tion of intravenous fluids, resulting in an increase in right
atrial pressure without a concomitant increase in cardiac
output, would suggest that no further volume replacement is
necessary.
Isoproterenol and dobutamine are frequently used to
increase contractility and reduce RV afterload. They are
often inadequate to reverse RV failure, and they may
induce arrhythmias as well as increase myocardial oxygen
consumption. Various modes of pharmacological vaso-
dilation have been described, including prostaglandins,
beta-sympathomimetics, phosphorylase III inhibitors (mil-
rinone), nitrocompounds (nitroglycerin, sodium nitroprus-
side), alpha-adrenolitics (tolazoline, hydralazine), adenosine
and inhaled nitric oxide. These vasodilators have all been
used with variable degrees of success (Table 1). Vasodilator
treatment is often complicated by hypotension, which may
compromise RV coronary blood flow and, additionally,
worsen RV failure (22–27). This is often why alpha-
adrenergic agonists such as levarterenol are instituted as
complementary therapy.
The goal in the treatment of RV failure is to dilate

Table 1. Pharmacotherapy for Pulmonary Hypertension and Right Ventricular Failure After Heart Transplantation
Author
Williams et al. (1995) (55)
Auler et al. (1996) (42)
Kieler-Jensen et al. (1995) (26)
Kieler-Nielsen et al. (1993) (25)
Pascual et al. (1990) (27)
Bauer et al. (1997) (19)
Agent Studied and Dosage
Inhaled NO up to 70 ppm
Inhaled NO 20 ppm
Inhaled NO 5, 10, 20 ppm
Prostacyclin 16 ⫾ 2 ng/kg/min
Prostaglandin E1 202 ⫾ 27 ng/kg/min
Sodium nitroprusside 1.0 ⫾ 0.2 ␮g/kg/min
Prostacyclin 12.4 ⫾ 1.7 ng/kg/min
Sodium nitroprusside 3.3 ⫾ 1.7 ␮g/kg/min
Nitroglycerin 6.6 ⫾ 1.8 ␮g/kg/min
Prostacyclin 0.5 up to 5.0 ng/kg/min
Prostaglandin E1
No. of Patients Response
5 Inhaled NO was used in patients with right ventricular
failure after failed treatment with prostacyclin and
sodium nitroprusside. All patients survived and were
discharged from the hospital.
10 Significant decrease in SVRI (p ⫽ 0.01), PVRI (p ⬍
0.05), PVRI/SVRI (p ⫽ 0.0025), TPG (p ⫽ 0.05)
and an increase in CI (p ⫽ 0.0007). No changes in
MPAP, SAP, PWP, RAP.
13 CO, SV, RVEDV, CVP were the highest with
prostacyclin compared with both prostaglandin E1
and sodium nitroprusside. SVR and PVR were
lowest with prostacyclin. PVR was highest with
sodium nitroprusside. MPAP, TPG, CVP decreased
with all treatments, but most pronounced effect was
noted with inhaled NO 20 ppm.
9 CO, SV, RVEDV, CVP were higher for prostacyclin
than for nitroglycerin or sodium nitroprusside. PVR
was lower for prostacyclin than for sodium
nitroprusside. SVR was lowest for prostacyclin.
PVR/SVR ratio did not differ for these three
vasodilators.
9 Preop Postop Late
RAP 9⫾6 7⫾6 12 ⫾ 5
PAP 38 ⫾ 10 32 ⫾ 8 24 ⫾ 6
CI 1.6 ⫾ 0.4 2.2 ⫾ 0.7 3.7 ⫾ 1.2
PVR 466 ⫾ 91 421 ⫾ 368 122 ⫾ 42
SVR 2,089 ⫾ 290 1,318 ⫾ 263 870 ⫾ 263
13 (Gr 1) ⫹ 19 (Gr2) Gr 1 (treated only if symptoms of right ventricular
failure developed)—7 of 13 patients survived, 6
deaths within 60 postoperative days.
Gr 2 (preventive therapy with prostaglandin E1 plus
inotropic support started during weaning from
cardiopulmonary bypass. Three of 19 patients died.
Prostaglandin E1 initial dose was 50 ng/kg/min.
Max dose 200 ng/kg/min used if PAP rose to a
value higher then half of systemic pressure.
Treatment was continued up to 48 h.
926
Comment
When 70 ppm NO and FiO2 of
ⱖ0.6 were used safety appeared
confirmed.
Selective action of inhaled NO on
pulmonary circulation
confirmed.
Stobierska-Dzierzek et al.
Prostacyclin was the best choice
for i.v. vasodilatatory treatment
in patients after heart
transplantation. Inhaled NO is
the only selective pulmonary
vasodilator. Useful in cases of
severe right ventricular failure
associated with hypotension.
Prostacyclin was a less efficient
venodilator and a more efficient
dilator of systemic resistance
vessels. Prostacyclin was not
more selective to the pulmonary
circulation than nitroglycerin or
Management of Acute Right Heart Failure in Transplant Recipients
sodium nitroprusside.
The use of prostacyclin enabled
weaning from other drugs
within 48 h. No side effects, no
worsening of hemodynamics
after discontinuation of
prostacyclin.
Prophylactic therapy of pulmonary
hypertension with vasodilators
in infants and children after
heart transplantation was safe
and effective in preventing right
ventricular failure in the
postoperative period.
JACC Vol. 38, No. 4, 2001
October 2001:923–31
JACC Vol. 38, No. 4, 2001 Stobierska-Dzierzek et al. 927
October 2001:923–31 Management of Acute Right Heart Failure in Transplant Recipients

pulmonary vessels and reduce PVR while maintaining

artery pressure; NO ⫽ nitric oxide; PAP ⫽ pulmonary artery pressure; PVR ⫽ pulmonary vascular resistance; PVRI ⫽ pulmonary vascular resistance index; PWP ⫽ pulmonary wedge pressure; RAP ⫽ right atrial pressure; RVEDV ⫽
CI ⫽ cardiac index; CO ⫽ cardiac output; CVP ⫽ central venous pressure; DPAP ⫽ diastolic pulmonary artery pressure; ICU ⫽ intensive care unit; i.v. ⫽ intravenous; LVSW ⫽ left ventricular stroke work; MPAP ⫽ mean pulmonary

right ventricular end-diastolic volume; SAP ⫽ systolic arterial pressure; SI ⫽ stroke index; SPAP ⫽ systolic pulmonary artery pressure; SV ⫽ stroke volume; SVR ⫽ systemic vascular resistance; SVRI ⫽ systemic vascular resistance index;
in the management of patients
usefulness of prostaglandin E1

with pulmonary hypertension

systemic blood pressure and coronary perfusion. Except for

after heart transplantation.

The study demonstrated the
inhaled nitric oxide, all other drugs currently used to treat
pulmonary hypertension and increased PVR are nonselec-
Comment

tive vasodilators and may lead to systemic hypotension.

End stage therapies include RV assist devices, extracor-
poreal membrane oxygenation and, of historical interest,
pulmonary arterial counterpulsation.

GUIDELINES TO SPECIFIC DRUG THERAPIES

Isoproterenol. Isoproterenol, a nonselective beta-agonist,
MPAP and PVR, increase in CI, SI and LVSW.

is a positive inotropic and chronotropic agent, and in

Sixty minutes after arrival in the ICU, MPAP was

Three of 18 patients died. Significant decrease in

therapeutic doses it increases cardiac output (28). However,

in contradistinction to other inotropic drugs, isoproterenol
42.5 ⫾ 42.5

produces pulmonary and peripheral vasodilation (28,29). As

After CPB

21.8 ⫾ 6.7
30.6 ⫾ 8.3

a pulmonary vasodilator, isoproterenol is one of the pre-

Response

ferred inotropic agents in heart transplantation patients with

elevated PVR. The dosage of isoproterenol should be
reduced gradually because PVR may return quickly to
54.4 ⫾ 11.9
40.9 ⫾ 9.04
Before CPB

29.1 ⫾ 5.5

elevated baseline levels after discontinuation of this drug.

Dobutamine. Dobutamine is primarily a beta-agonist with
almost normal.

only minimal alpha-receptor agonist activity. This agent is,

therefore, useful when further vasoconstriction is undesir-
MPAP

able. At higher doses, dobutamine may induce tachycardia

DPAP
SPAP

and atrial arrhythmias and increase oxygen demands. It is

useful as an inotrope in patients with HF and elevated
pulmonary artery pressures. The mechanism of action is
No. of Patients

through the cyclic adenosine 3⬘5⬘ monophosphate (cAMP)-

mediated intracellular pathway for inotropic stimulation.
18

Milrinone. Milrinone belongs to the class of drugs known

as bipiridine phosphodiesterase III inhibitors. Their positive
inotropic action is combined with a vascular smooth
muscle-relaxing effect. The pharmacologic action of milri-
operation and was continued for up to 7

none is mediated via the cAMP pathway; thus, it is

independent of adrenoreceptor activity or increased cate-
Prostaglandin E1 30–120 ng/kg/min,
Agent Studied and Dosage

infusion started within 24 h after

cholamine levels. Application of phosphodiesterase III in-

hibitors avoids stimulation of downregulated or desensitized
beta-receptors, which may be seen commonly in HF pa-
tients managed with long-term dobutamine therapy before
transplant. Unlike dobutamine, milrinone does not increase
oxygen demand, presumably because milrinone reduces
arterial afterload. Beta-agonists can be combined with
phosphodiesterase inhibitors to produce synergistic hemo-
days.

dynamic effects as well as increasing cAMP levels via two

separate, and possibly synergistic, mechanisms (30,31).
In an animal model of heart transplantation with pulmo-
nary hypertension, it was demonstrated that intravenous
TPG ⫽ transpulmonary gradient.

administration of milrinone increased RV preload re-

Vincent et al. (1992) (56)

cruitable stroke work and decreased mean pulmonary artery

Table 1. (continued)

pressure (31).
Author

Thyroxine and glucagon may also increase adenyl cyclase

activity, increasing cAMP and producing a similar effect on
RV function (32–34). We have used both tri-iodothyronine
(the active metabolite) and L-thyroxine in cases of severe
RV failure, with anecdotal improvement in rare cases.
928 Stobierska-Dzierzek et al.
Management of Acute Right Heart Failure in Transplant Recipients
Prostaglandin E1 and prostacyclin. Prostaglandin E1 and
prostacyclin are naturally occurring substances, with similar
structures and short half-lives in the circulation. They are
potent pulmonary vasodilators. Both agents are effective in
the treatment of increased PVR and RV failure in patients
after heart transplantation and in patients who receive RV
assist devices (35–37). After intravenous infusion, prosta-
glandin E1 is almost completely cleared from the circulation
during its first pass through the lungs. Prostacyclin also has
a short half-life, but it is metabolized in the liver.
It has been demonstrated that prostaglandin E1 is at least
as effective as nitroglycerin or nitroprusside in reversing
pulmonary hypertension. In several reports, patients who
responded to prostaglandin E1 treatment had postoperative
mortality rates approaching patients without pulmonary
hypertension (38 – 40).
In pediatric patients, Bauer et al. (18) demonstrated that
the early administration of prostaglandin E1 had an advan-
tage over delayed treatment of clinically evident RV failure.
Early vasodilator therapy with prostaglandin E1 and the
phosphodiesterase III inhibitor enoximone was introduced
immediately before weaning from cardiopulmonary bypass,
limiting pulmonary hypertension and RV failure.
A similar therapeutic profile has been observed with
prostacyclin. When used in doses between 0.5 ng/kg per
min to 5.0 ng/kg per min, prostacyclin had few side effects.
Importantly, hemodynamic conditions were stable after the
discontinuation of prostacyclin. The addition of prostacyclin
in patients with pulmonary hypertension has been credited
with the ability to wean other vasodilatory drugs within a
short period of time.
Kieler-Jensen et al. (26) compared the hemodynamic
profile of prostacyclin with sodium nitroprusside and nitro-
glycerin showing that postoperative vasodilation with pros-
tacyclin was associated with a higher stroke volume and
cardiac output compared with nitroprusside and nitroglyc-
erin. Prostacyclin infusion also resulted in pronounced
systemic vasodilation without lowering central filling pres-
sures. In a second study by Kieler-Jensen et al. (26), they
demonstrated that the pulmonary vasodilatory effect of
prostacyclin was more pronounced than that seen with
nitroglycerin but was comparable to the effect seen with
nitroprusside. However, the systemic vasodilation caused by
prostacyclin was more pronounced than that seen with
either sodium nitroprusside or nitroglycerin. In essence,
prostacyclin was no more selective for the pulmonary
circulation than nitroprusside but was a significantly more
effective systemic vasodilator than either nitroglycerin or
sodium nitroprusside.
When the hemodynamic effects of prostaglandin E1,
nitric oxide and nitroprusside were compared, it was dem-
onstrated that both systemic and PVR were lowest, while
stroke volume and cardiac output were highest with pros-
tacyclin. On the other hand, nitric oxide was the only
selective pulmonary vasodilator and, therefore, the only
JACC Vol. 38, No. 4, 2001
October 2001:923–31
agent not associated with the addition of an alpha agonist to
support systemic blood pressure.
Adenosine. Adenosine is a pulmonary vasodilator with a
very short half-life. It is primarily used as a provocative
agent in the preoperative evaluation of patients with pul-
monary hypertension. The vasodilating action of adenosine
is mediated through membrane A2 receptors on pulmonary
vascular smooth muscle cells with subsequent activation of
adenyl cyclase and release of cAMP. Adenosine is cleared
from the circulation by adenosine deaminase after a single
pass through the lungs. The selective action of adenosine on
the pulmonary circulation results from its very short plasma
half-life (⬍10 s), limiting the amount of adenosine that
reaches the systemic circulation.
Adenosine is a suitable diagnostic agent to determine
reversibility of pulmonary hypertension in patients awaiting
heart transplantation. Adenosine lowers the transpulmonary
gradient and PVR, but its clinical application for long-term
therapy is limited due to its effect of increasing pulmonary
capillary wedge pressure and the risk of inducing pulmonary
edema. Therefore, it is rarely used in the management of
acute RV failure resulting from pulmonary hypertension.
Interestingly, Fullerton et al. (41) used 50 ␮g/kg per min of
adenosine to treat pulmonary hypertension in a group of
patients after valve replacement and coronary bypass surgery
without inducing systemic hypotension. However, others have
shown that, when adenosine is infused in higher doses
(70 mg/kg per min to 100 mg/kg per min), systemic vasodi-
lation has been shown to occur (42– 44).
Inhaled nitric oxide. Nitric oxide is a gaseous biological
mediator released by the vascular endothelium. It is a
potent, rapidly acting and selective pulmonary vasodilator.
Inhaled nitric oxide decreases PVR and pulmonary pressure
without effecting systemic vascular resistance (45,46).
Nitric oxide exerts its vasorelaxation action by stimulating
cyclic guanosine monophosphate (GMP) release in smooth
muscle cells. Because the half-life of cyclic GMP is ⬍1 min,
the vasodilation action of nitric oxide essentially ends when
inhaled nitric oxide is withdrawn. Nitric oxide is quickly
inactivated by hemoglobin, forming methemoglobin, nitrate
and nitrite ions (47). The fact that nitric oxide is inactivated
directly in the lumen of the vessel limits its effect to the
vascular smooth muscle adjacent to the alveolar unit. The
affinity of hemoglobin for nitric oxide is 3,000 times greater
than that for oxygen. Nitric oxide is a labile agent with a
half-life of 111 ms to 130 ms, which depends on the
ambient oxygen concentration.
It is the oxidation of nitric oxide to NO2 that is respon-
sible for its toxicity. The concentration of inhaled nitric
oxide should be closely monitored. The Occupational Safety
and Health Administration has established a limit of 5 ppm
per 8 h per 24-h interval as the upper limit of safe human
exposure (48).
Auler et al. (49) suggested using inhaled nitric oxide
immediately after heart transplantation to prevent RV
failure. In addition to selective pulmonary vasodilation,
JACC Vol. 38, No. 4, 2001
October 2001:923–31 Management of Acute Right Heart Failure in Transplant Recipients
inhaled nitric oxide can improve hypoxemia by improving
the ventilation perfusion relationship as a result of its
delivery as an inhalational agent. This improvement in
oxygenation is produced with lower doses of inhaled nitric
oxide than that required to induce vasodilation.
In contrast, the intravenous nonselective pulmonary va-
sodilators dilate all blood vessels of the lung. Thus, nonse-
lective pulmonary vasodilators can lead to ventilation per-
fusion mismatch and increased shunt fraction as a
consequence of vasodilation and increased pulmonary blood
flow to regions of poorly ventilated lung. Since nitric oxide
is delivered as an inhalation agent, it only reaches ventilated
regions of the lung, dilating those blood vessels and result-
ing in better ventilation perfusion matching.
Assist devices. The goal in the treatment of RV failure is
to provide adequate support of the transplanted heart
permitting time for recovery. Excellent long-term function
may be expected. Initial results with RV assist devices in the
treatment of RV failure were poor (50,51). With experience,
the midterm results with RV assist devices have been
somewhat more promising.
One important observation has been that implantation of
an RV device reduces elevated right-sided pressures in
patients who survive the removal of the device. Failure to
reduce central venous pressure was a negative predictor for
survival. In addition, the RV assist device improved organ
function (normalization of transaminase levels, urine out-
put, relieved hepatic congestion) in those who were found to
survive. Ideally, RV assist devices should be implanted early
to avoid end organ damage and should be continued for
sufficient time for the patient to show signs of recovery, that
is, a decrease in central venous pressure and diastolic
pulmonary artery pressure (52).
Our experience has confirmed the critical importance of
kidney function to outcome. It is our routine practice to
splice into the Abiomed (Danvers, Massachusetts) RV assist
device tubing, the connectors necessary for continuous
venous-venous hemofiltration and dialysis (CVVHD). This
is performed even if a patient appears to have adequate renal
function, since one must anticipate the potential for renal
dysfunction and failure. If we have chosen to insert a
Thoratec (Pleasanton, California) RV assist device, we will
insert the necessary CVVHD catheters in the femoral
vessels before leaving the operating room. The ability to
remove volume from the circulation has been a major advance
in the critical pathway for these desperately ill patients.
It is our opinion that the selection of a right-sided device
depends on three issues: 1) anticipated duration of device
implantation, 2) expectation for early endotracheal tube
extubation and mobility of the patient, and 3) cost. Both
devices are similar in terms of ease of insertion and device
management. Patients on the Thoratec device are easier to
mobilize and ambulate, and this device is better suited to
long-term implantation. Cost considerations are institu-
tionally dependent but are clearly influenced by time in use
of the device. Complications of circulatory assist devices
Stobierska-Dzierzek et al. 929
include infection, bleeding, coagulation abnormalities, mul-
tiple organ failure and neurological complications.
Of course, the most difficult question to answer is when
to insert an RV assist device. In our experience, the routine
use of nitric oxide has reduced the incidence of RV failure
requiring right-sided circulatory support. Nevertheless, this
clinical syndrome continues to occur, and the decision
regarding implantation of an RV assist device remains a
difficult one.
The lesson we have learned over the years is to begin with
a careful and stepwise review of all hemodynamic parame-
ters after the institution of maximal inotropic and vasodi-
lator support. The assessment includes a review of RV and
LV function and size by transesophageal echocardiography,
the status of mediastinal bleeding, oxygenation, presence of
arrhythmias and urinary output. This assessment invariably
takes place after several unsuccessful attempts to separate
the patient from cardiopulmonary bypass and approximately
1 h after removal of the aortic crossclamp. By this time the
surgeon and anesthesiologist generally have a “feel” for
whether or not there is any improvement in the patient’s
clinical condition. With this clinical assessment clearly in
mind, the observation of a small hyperdynamic LV, a
dilated RV, marginal urine output, atrial or ventricular
arrhythmias, or coagulopathy, should stimulate the team to
insert an RV assist device. Since a coagulopathy will require
ongoing aggressive volume resuscitation with blood prod-
ucts, one can anticipate worsening of pulmonary hyperten-
sion and pulmonary edema from the volume infusion. This
is likely to further worsen RV failure and its secondary
effects on cardiac output and end organ perfusion. We have
come to the opinion that it is safer and easier to err on the
side of RV assist device insertion, recognizing the possibility
of early removal, as opposed to waiting until the patient
develops low output syndrome, arrhythmias, congestion and
renal dysfunction/failure.
Oversizing of the donor heart. At one time it was com-
mon practice for patients with significant preoperative
pulmonary hypertension to receive donor hearts from pa-
tients with body weights equal to or greater than that of the
recipient. It was believed that the larger the donor, the
greater the ability of the heart to adapt to a recipient’s
elevated PVR. It was also believed that oversizing helped in
the early adaptation of the donor heart and improved the
outcome of orthotopic heart transplantation in recipients
with preoperative pulmonary hypertension (53,54). How-
ever, several investigators, including Constanzo-Nordin et
al. (55) demonstrated that the outcome of recipients given
smaller hearts was similar to that of those given larger
hearts. Moreover, they demonstrated that oversizing donor
hearts did not improve the outcome of orthotopic heart
transplantation for recipients with reversible preoperative
pulmonary hypertension. In fact, they suggested that over-
sizing the donor heart in patients without pulmonary
hypertension might increase mortality. This issue remains
controversial and many investigators including Yeoh et al.
930 Stobierska-Dzierzek et al.
Management of Acute Right Heart Failure in Transplant Recipients
(56) still recommend transplanting oversized donor hearts
in patients with pulmonary hypertension.
In our opinion, this issue remains unresolved. Our expe-
rience confirms a worse outcome for undersized donor
hearts in patients with pulmonary hypertension. Interest-
ingly, some patients develop a clinical syndrome consistent
with a restrictive cardiomyopathy. It is our current practice
to transplant patients with pulmonary hypertension using a
donor weight equal to or greater than the recipient (not to
exceed 30% of the recipient weight). Personal communica-
tions with members of the transplant community continue
to demonstrate a bias toward avoiding a small donor heart in
cases of pulmonary hypertension.
Management algorithm for acute RV failure in cardiac
transplant patients. Avoidance of this clinical syndrome is,
unfortunately, not possible. Clinical experience and the
literature would suggest that a significant element in the
successful management of RV failure is recipient selection.
The literature confirms the absence of threshold hemody-
namic values beyond which RV failure is certain to occur
and heart transplantation is contraindicated. Neither are
there values below which RV failure is avoidable.
Pulmonary hemodynamic indexes represent a spectrum of
values traditionally thought to have a direct linear relation-
ship with postoperative mortality; the higher the value, it
was postulated, the more likely postoperative morbidity and
mortality. Data described herein, however, soften this no-
tion and, instead, suggest that the relationship between
elevated preoperative pulmonary hypertension/resistance
and postoperative complications and death is but an asso-
ciation— direct but not exact and by no means linear.
Therefore, it becomes the independent decision of clinicians
and their respective heart transplantation programs to es-
tablish guidelines for pulmonary hemodynamic thresholds
beyond which a patient is ineligible for transplantation, as
we have done at our institution.
Acute RV failure will remain a difficult and ever present
clinical syndrome in the transplant recipient. Goals in the
treatment of this clinical problem include:
1. Preserving coronary perfusion through maintenance of
systemic blood pressure.
2. Optimizing RV preload.
3. Reducing RV afterload by decreasing PVR.
4. Limiting pulmonary vasoconstriction through ventila-
tion with high inspired oxygen concentrations (100%
FiO2), increased tidal volume and optimal PEEP venti-
lation.
At the Ohio State University, fluid administration, milri-
none, levophed and isoproterenol are mainstays of the initial
therapy. Inhaled nitric oxide is instituted before leaving the
operating room in cases where the initial therapy has had
little impact. In patients with known significant pulmonary
hypertension, inhaled nitric oxide is begun before surgery
and after intubation and general anesthesia, with the aim of
further “conditioning” the pulmonary vascular bed before
JACC Vol. 38, No. 4, 2001
October 2001:923–31
the institution of cardioplumonary bypass and cardiac trans-
plantation. Nitric oxide is discontinued during cardiopul-
monary bypass and reinstituted once ventilation is resumed.
Leaving a patient intubated, sedated and even paralyzed for
several days is recommended in cases of severe elevation in
PVR. Vasoconstriction of pulmonary blood vessels may
occur with the simple act of awakening from anesthesia.
Intra-aortic balloon counterpulsation is employed in pa-
tients with impaired LV function and may be of benefit in
patients with RV dysfunction resulting from ischemia,
preservation injury or reperfusion injury. Optimal LV func-
tion reduces RV afterload and PVR.
A decision regarding RV assist device implantation is made
before leaving the operating room and is highly dependent
upon overall hemodynamics, size and function of the ventricles
as seen on transesophageal echocardiography, oxygenation,
renal function and surgical bleeding. Only through careful
preoperative planning can this life-threatening condition be
managed in the postoperative period.
Reprint requests and correspondence: Dr. Robert E. Michler,
Professor and Chief, Cardiothoracic Surgery and Transplantation,
Ohio State University Medical Center, 410 West 10th Avenue,
North Doan Hall, N-847, Columbus, Ohio 43201-1214. E-mail:
michler.1@osu.edu.
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