Portopulmonary Hypertension and the Liver Transplant Candidate

Abstract

The management of the liver transplant (OLT) candidate with portopulmonary hypertension (PPHTN) has dramatically changed in the past 3 years. Careful preoperative evaluation with functional characterization of right ventricular function plays a critical role. The pulmonary vascular response to epoprostenol infusion serves as a deciding factor for OLT candidacy. Careful perioperative attention to avoid right ventricular failure from acutely elevated pulmonary artery pressures or sudden increases in right ventricular preload is a key physiologic tenet of management. With increased surgical expertise, anesthetic sophistication, and availability of epoprostenol, PPHTN is no longer considered an absolute contraindication for OLT.

Full text

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0041-1337/99/6708-1087/0
TRANSPLANTATION
Copyright © 1999 by Lippincott Williams & Wilkins, Inc.
Vol. 67, 1087–1093, No. 8, April 27, 1999
Printed in U.S.A.
Transplantation?
OVERVIEW
PORTOPULMONARY HYPERTENSION AND THE LIVER
TRANSPLANT CANDIDATE
PAUL C. KUO,1JEFFREY S. PLOTKIN,2SEAN GAINE,3REBECCA A. SCHROEDER,2VINOD K. RUSTGI,1
LEWIS J. RUBIN,3AND LYNT B. JOHNSON1
Departments of Surgery and Anesthesia, Georgetown University Medical Center, Washington, DC 20007, and
Department of Medicine, University of Maryland, Baltimore, MD 21201
The management of the liver transplant (OLT) can-
didate with portopulmonary hypertension (PPHTN)
has dramatically changed in the past 3 years. Careful
preoperative evaluation with functional characteriza-
tion of right ventricular function plays a critical role.
The pulmonary vascular response to epoprostenol in-
fusion serves as a deciding factor for OLT candidacy.
Careful perioperative attention to avoid right ventric-
ular failure from acutely elevated pulmonary artery
pressures or sudden increases in right ventricular
preload is a key physiologic tenet of management.
With increased surgical expertise, anesthetic sophisti-
cation, and availability of epoprostenol, PPHTN is
no longer considered an absolute contraindication
for OLT.
Portopulmonary hypertension (PPHTN*) is a recognized
complication of end-stage liver disease that adversely affects
the outcome of orthotopic liver transplantation (OLT). Based
on anecdotal case reports, PPHTN had been considered an
absolute contraindication to liver transplantation. However,
this contraindication has been re-examined as a result of
accumulated experience with the surgical techniques of OLT,
improved anesthetic and critical care, advances in pharma-
cologic treatment for primary pulmonary hypertension, and
increased understanding of PPHTN. Now, certain subcatego-
ries of PPHTN patients have successfully undergone OLT
with modifications in surgical technique and adjunctive
pharmacologic therapy (1–4). We summarize the current
PPHTN literature and suggest a management strategy,
based on use of epoprostenol, for the OLT candidate with
PPHTN.
This management algorithm has been used at our institu-
tion for preoperative evaluation of 11 PPHTN patients, of
whom 3 have successfully undergone OLT. Given the current
lack of complete outcome data regarding OLT and PPHTN,
we present this algorithm as a starting point for further
thought and discussion. Certainly, this strategy is far from
ideal and will evolve with greater accumulated experience
with this difficult patient population. The ideal management
strategy can evolve only with outcome analysis of larger
numbers of patients in a central database format, as sug-
gested by Mandall and Krowka (5).
DEFINITION
PPHTN can be loosely characterized as pulmonary hyper-
tension in the setting of portal hypertension. Although
PPHTN does not carry a precise, universally accepted defi-
nition, most investigators have applied the following criteria
of the NIH Patient Registry for the Characterization of Pri-
mary Pulmonary Hypertension to patients being considered
for OLT: a) mean pulmonary artery pressure (MPAP) ? 25
mm Hg, and 2) pulmonary capillary wedge pressure (PCWP)
? 15 mm Hg (6). The presence of portal hypertension is
generally inferred by a history of variceal bleeding, charac-
teristic physical stigmata such as caput medusae, or imaging
studies demonstrating hepatic cirrhosis, varices, or extrahe-
patic portal venous obstruction. This definition assumes the
absence of secondary processes as the cause of pulmonary
hypertension, such as cardiac valvular disease, pulmonary
emboli, collagen vascular disease, schistosomiasis, or inges-
tion of certain toxins or appetite suppressants. Based on
previous reviews and case reports documenting PPHTN in
the presence of extrahepatic portal venous thrombosis with-
out cirrhosis, the presence of portal hypertension is con-
sidered the essential antecedent to the development of
PPHTN (7).
Less commonly used criteria of pulmonary hypertension
include a pulmonary vascular resistance (PVR) ? 120 dyne/
sec/cm?5, transpulmonary gradient (TPG) ? 10 mm Hg, or
MPAP ? 30 mm Hg during exercise (8). PPHTN has also
been subjectively subcategorized as mild, moderate, and se-
vere (1, 2, 9). These definitions have been based on MPAP or
systolic pulmonary artery (PA) pressure and vary from au-
thor to author. In general, use of this subcategorization
should be avoided because it does not reflect the anatomy or
functional capacity of the right heart. In the primary pulmo-
1087
1Address correspondence to: Paul C. Kuo, MD, Department of
Surgery, 4 PHC, 3800 Reservoir Rd. NW, Washington, DC 20007.
E-mail: kuop@gunet.georgetown.edu.
2Departments of Surgery and Anesthesia, Georgetown University
Medical Center.
3Department of Medicine, Unversity of Maryland.
*Abbreviations used: HPS, hepatopulmonary syndrome; MPAP,
mean pulmonary artery pressure; NYHA, New York Heart Associa-
tion; OLT, orthotopic liver transplant; PA, pulmonary artery; PCWP,
pulmonary capillary wedge pressure; PPHTN, portopulmonary hy-
pertension; PVR, pulmonary vascular resistance.

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nary hypertension population, the New York Heart Associa-
tion (NYHA) classification I-IV is also used to convey func-
tional information. However, in patients with PPHTN,
fatigue or dyspnea may reflect the severity of liver disease
rather than pulmonary dysfunction. Therefore, if a patient
carries the diagnosis of PPHTN, the clinical decision algo-
rithm should be based on anatomic, functional, and hemody-
namic data rather than stratification alone.
The relationship between PPHTN and another pulmonary
syndrome associated with end-stage liver disease, hepatop-
ulmonary syndrome (HPS), remains largely unknown. HPS
is defined as the presence of intrapulmonary vasodilatation
with hypoxemia (arterial oxygen tension less than 70 mm Hg
on an FiO2?0.21) (10). Although HPS and PPHTN were
originally thought to be distinct entities, case reports are now
emerging which document the co-existence of both disease
states (10). The relevance of HPS in the setting of PPHTN to
a patient being considered for OLT is unknown. Given the
evolving understanding of this relationship, we concentrate
on PPHTN as an isolated entity in this review.
PREVALENCE OF PPHTN
PPHTN was first described in 1951 by Mantz and Craige in
an article entitled, “Portal axis thrombosis with spontaneous
portocaval shunt and resultant cor pulmonale.” In 1983, Mc-
Donnell and colleagues reviewed a single institution’s au-
topsy files of 17,901 patients older than 1 year. They found
that the prevalence of primary pulmonary hypertension was
0.13%. In contrast, the prevalence of pulmonary hyperten-
sion in those with cirrhosis was almost 6-fold greater at
0.73%. In an accompanying clinical series of 2459 patients
with biopsy-proven cirrhosis, the prevalence of concomitant
pulmonary hypertension was 0.61% (11). Hadengue and col-
leagues examined a series of 507 patients with portal hyper-
tension who underwent prospective right heart catheteriza-
tion and found the prevalence of pulmonary hypertension to
be 2% (12). Based on these studies, the prevalence of PPHTN
in patients with portal hypertension or cirrhosis is approxi-
mately 1–2%. Although these data indicate that PPHTN may
be an issue of academic interest only, subsequent clinical
studies from liver transplant centers suggest that the prev-
alence of PPHTN is higher in patients with end-stage liver
disease being evaluated for transplantation. Four centers
have retrospectively analyzed the incidence of PPHTN in
their patients who have undergone OLT (1–3, 9). The earliest
study was conducted in 1993 by Plevak and colleagues, who
found that 33 of 263 (12.5%) patients who underwent OLT at
the Mayo Clinic between 1985 and 1991 had PPHTN, as
defined by a PVR ? 120 dyne/sec/cm?5(9). Subsequent stud-
ies by Taura et al. and Castro et al. found that the prevalence
of PPHTN, as defined by MPAP ? 25 mm Hg, in patients
undergoing OLT was 3.5% and 4.0%, respectively (1, 3). Fi-
nally, Ramsay and co-workers found the prevalence of
PPHTN to be 8.5% in 1205 patients undergoing OLT at
Baylor University Medical Center (9). Given that these stud-
ies included only patients undergoing OLT, the prevalence of
PPHTN in patients presenting for OLT evaluation is un-
doubtedly higher. Patients with excessive levels of pulmo-
nary hypertension were viewed as having a contraindication
for OLT and, as a result, were not included in these retro-
spective analyses of OLT patients. A reasonable estimate of
the prevalence of PPHTN in patients presenting for OLT
evaluation is 5–10%.
PATHOLOGY AND PATHOPHYSIOLOGY OF PPHTN
The pulmonary pathology of PPHTN is similar to that of
primary pulmonary hypertension (13). The muscular pulmo-
nary arteries exhibit medial hypertrophy and intimal fibrosis
in a concentric laminar configuration. The smaller muscular
pulmonary arteries frequently demonstrate plexiform lesions
typified by a circumscribed dilatation of a pulmonary artery
at its origin or bifurcation with thinning of the media, loss of
smooth muscle cells, and disappearance of the internal elas-
tic lamina. In addition, a plexus of narrow slit-like channels
are present within the lumen of the dilated segment. The
distal portion of the plexiform lesion then drains into a di-
lated, thin-walled vessel terminating in the alveolar capillar-
ies. In their autopsy study of pulmonary hypertension and
cirrhosis, McDonnell and colleagues found the pulmonary
vascular changes to be identical to those in hypertensive
pulmonary vascular disease without evidence for veno-occlu-
sive disease or recurrent thromboembolism (11). These au-
thors graded the pulmonary pathologic changes and found
that all PPHTN patients exhibited plexiform lesions with
dilation of postglomoid precapillary vessels and/or vascular
necrosis. However, it should be noted that the pathologic
changes occur in a patchy fashion within the lung and cor-
relate very poorly with cardiopulmonary hemodynamic func-
tion (14). Matsubara and colleagues performed a histometric
study comparing pulmonary vasculature with portal venous
vasculature in 21 autopsy cases of hepatic cirrhosis (15).
When compared with controls, those with cirrhosis exhibited
significantly increased mean wall thickness in the small pul-
monary arteries. In addition, the authors found an increased
ratio of wall thickness to radius in the small pulmonary
arteries of patients with cirrhosis, suggesting increased re-
sistance to flow.
The pathophysiology of PPHTN and its associated clinical
signs and symptoms have not been extensively studied until
recently. In a retrospective study of 26 patients with docu-
mented PPHTN, Hadengue and co-workers found that car-
diac index varied inversely with the mean pulmonary artery
pressure and was significantly lower in five patients who
died from pulmonary hypertension (1.52?0.14 L/min-m2)
when compared with five who died from liver failure
(3.69?1.88 L/min-m2). In addition, those who died from pul-
monary hypertension had lower Childs-Pugh scores and he-
patic venous pressure gradients and had higher MPAP and
PVR (12). To further characterize the hemodynamic profile of
PPHTN, we compared 30 PPHTN patients with 30 patients
with cirrhosis and 30 patients with primary pulmonary hy-
pertension alone. All patients underwent right heart cathe-
terization, transthoracic echocardiography, pulmonary func-
tion tests, ventilation-perfusion scanning, and arterial blood
gas measurements. Patients with PPHTN exhibited hemody-
namic features of both primary pulmonary hypertension and
cirrhosis. In addition to increased MPAP and PVR, those
with PPHTN also had an elevated cardiac index and de-
pressed systemic vascular resistance. The PPHTN patients
also had an accentuation of the chronic respiratory alkalosis
typically seen in primary pulmonary hypertension and an
increased alveolar-arterial gradient in comparison with those
patients with liver disease alone (7). These data indicate that
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PPHTN represents a clinical entity with some features spe-
cific to pulmonary hypertension and others specific to cirrho-
sis.
Other investigators have found patients with PPHTN to
exhibit evidence on the electrocardiogram (ECG) of right
ventricular hypertrophy (79%), right axis deviation (79%),
and right bundle branch block (59%).However, only 4% of
PPHTN patients had a normal ECG. On CXR, this group of
PPHTN patients had prominent pulmonary arteries (78%)
and cardiomegaly (74%) (16). The corresponding signs and
symptoms of PPHTN have been tabulated by Robalino and
Moodie in their retrospective multicenter study of 78 patients
with PPHTN (16). The most common complaints were: dys-
pnea on exertion (81%), syncope (24%), and chest pain (24%).
The parallel physical findings were a loud P2heart sound
(82%), systolic murmur (69%), edema (35%), and right heart
failure (34%). Unfortunately, in the setting of portal hyper-
tension and cirrhosis, many signs and symptoms such as
dyspnea, edema, or ascites (representative of right heart
failure) may be masked or attributed purely to liver dysfunc-
tion.
The natural history of PPHTN was examined by Robalino
and Moodie in 1991 (16). In the absence of any pharmacologic
interventions, the prognosis with this syndrome is poor, with
a mean survival period after diagnosis of 15 months and a
6-month mortality of 50%. The causes of death in 66% were
right heart failure and infection. Despite this grim picture,
the recent introduction of epoprostenol and alternative sur-
gical techniques for OLT have significantly altered the prog-
nosis for selected PPHTN patients.
PPHTN AND OLT
The original designation of PPHTN as an absolute contra-
indication to OLT was based on clinical “lore” and case re-
ports demonstrating excessive perioperative mortality with
PPHTN in OLT. DeWolf and colleagues quoted an 80% peri-
operative mortality for PPHTN patients undergoing OLT
based on their experience with five patients with “severe”
PPHTN (17). Subsequent retrospective studies by Castro,
Taura, Plevak, and Ramsay have further defined the role of
PPHTN in perioperative mortality after OLT (1–3, 8). In
1993, Plevak retrospectively reviewed the Mayo Clinic expe-
rience with 307 consecutive OLTs. There were 33 (12.5%)
who had PPHTN as defined by PVR ? 120 dyne-sec-cm?5
(range 121–277); no perioperative deaths were found, and
there were no long term deaths related to PPHTN. These
authors conclude that “mild to moderate” PPHTN is not a
contraindication to OLT (2). Similarly, Taura found 8 cases of
PPHTN from a retrospective study of 226 patients undergo-
ing OLT and found no adverse outcomes associated with
“mild to moderate” pulmonary hypertension. These patients
had MPAP in the range of 28–38 mm Hg (1). In a retrospec-
tive review of 1205 consecutive OLTs, Ramsay and colleagues
found that mild (n?81; systolic PAP 30–44 mm Hg) and
moderate (n?14; systolic PAP 45–59 mm Hg) PPHTN did not
influence the outcome after OLT. In contrast, severe PPHTN
(n?7; systolic PAP ? 60 mm Hg) was associated with pro-
gressive right heart failure after OLT, 42% mortality at 9
months after OLT, and 71% mortality at 36 months after
OLT (9). To date, there have been no reports that attempt to
stratify OLT outcome in this population based on right atrial
and ventricular pressures, right atrial and ventricular anat-
omy, overall cardiac performance, or functional NYHA sta-
tus. In total, these studies indicate that mild-to-moderate
PPHTN does not alter outcome after OLT, although severe
PPHTN remains problematic. However, these studies lack
conformity to a specific definition of PPHTN and the mild-
moderate-severe subcategories. As a result of their retrospec-
tive nature, these studies are biased, because the recipients
were preselected and the diagnosis and categorization of
PPHTN were determined in the operating room after place-
ment of the pulmonary artery catheter. Ideally, the diagnosis
of PPHTN is made preoperatively during evaluation for can-
didacy and pharmacologic intervention instituted before
transplantation.
PHARMACOLOGIC INTERVENTION FOR PPHTN
A right heart catheterization and vasodilator trial should
be considered before empirical vasodilator therapy is initi-
ated in patients with pulmonary hypertension or PPHTN
(18). Baseline hemodynamic assessment will help determine
the degree of pulmonary hypertension, reveal characteristic
hemodynamic parameters, and exclude left heart filling prob-
lems (7, 19). At the time of catheterization, a vasodilator trial
using short acting agents such as inhaled nitric oxide or
epoprostenol provides a guide to therapy (20). Some 20–30%
of patients with primary pulmonary hypertension have a
decrease in mean pulmonary artery pressure and an increase
in cardiac output in response to a vasodilator trial. This
positive response predicts sustained hemodynamic improve-
ment and prolonged survival with chronic vasodilator ther-
apy (21, 22). We have applied this management paradigm to
other forms of intrinsic pulmonary vascular disease, such as
PPHTN.
Inhaled nitric oxide is a specific pulmonary vasodilator;
however, proper use of nitric oxide in the treatment of
PPHTN remains unclear (23). Nitric oxide may be useful
perioperatively in patients with milder pulmonary hyperten-
sion who develop significant hypertension with hepatic allo-
graft reperfusion (24). However, this approach is less likely to
be successful in patients with more severe baseline pulmo-
nary hypertension or in patients with a more complicated
perioperative course. As a result, attention is focused on
chronic treatment of the pulmonary hypertension to achieve
optimal conditions at the time of transplantation (4).
There have been no trials of oral vasodilators in the chronic
treatment of PPHTN. However, in studies of primary pulmo-
nary hypertension, patients with a favorable response to an
acute vasodilator trial during right heart catheterization
demonstrated improved survival and regression of right ven-
tricular hypertrophy with calcium channel blockers (21, 22).
Indiscriminate use of oral vasodilator therapy in pulmonary
hypertension without first determining an individual’s re-
sponse during a initial vasodilator trial may result in wors-
ening gas exchange, hypotension, or death (25, 26). However,
abrupt discontinuation can lead to fatal rebound pulmonary
hypertension (22). Amblodipine (2.5–20 mg/day), nifedipine
(30–240 mg/day) and diltiazem (120–900 mg/day) are the
most commonly used agents. Verapamil is generally avoided
because of its negative inotropic effects and lack of activity in
the pulmonary circulation. Although the role of calcium
channel blockers in chronic therapy of PPHTN is unknown,
consideration may be given to their use in isolated instances,
KUO ET AL.
April 27, 1999
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such as lack of availability of epoprostenol for chronic infu-
sion.
Epoprostenol is a potent vasodilator with a short half-life
(3–5 min) that requires delivery through a permanent in-
dwelling catheter by a continuous infusion pump. In a ran-
domized trial in primary pulmonary hypertension, epopro-
stenol improved hemodynamics and exercise tolerance and
prolonged survival in patients with severe primary pulmo-
nary hypertension (NYHA III-IV) who did not have a favor-
able response during acute vasodilator testing and were
therefore not candidates for calcium channel blocker therapy
(27–29). Whereas epoprostenol is currently only approved for
treatment of primary pulmonary hypertension, it has dem-
onstrated efficacy in patients with other forms of intrinsic
pulmonary vascular disease, including PPHTN, scleroderma,
and systemic lupus erythematosus (30). However, epoproste-
nol should be avoided in postcapillary pulmonary hyperten-
sion because of the risk of acute pulmonary edema (27). To
preempt the recurrence of symptoms, regular dose adjust-
ments of epoprostenol are required during the first year of
therapy. It is speculated that the reason for the increased
dose requirement may be either enhanced drug degradation
or an increase in vasoconstrictive mediators such as throm-
boxane. Epoprostenol is also effective long-term in patients
with severe primary pulmonary hypertension who do not
demonstrate an acute vasodilator response at the time of
initial catheterization, suggesting chronic non-vasodilator
modes of action, such as vascular remodeling and antiplate-
let or antiproliferative properties (29, 31, 32). Beneficial ef-
fects of epoprostenol in PPHTN have also been reported (30).
Four patients with PPHTN who received epoprostenol over a
period of 6–14 months had a 29–46% decrease in mean
pulmonary artery pressure and a 22–71% decrease in
PVR (30).
Experience with epoprostenol has directed research toward
alternative approaches to reversing the pathologic vascular
lesions that were previously considered to be irreversible
(32). Agents currently under consideration include specific
phosphodiesterase inhibitors, endothelin receptor antago-
nists, and prostacyclin analogs. Inhaled iloprost, a stable
prostacyclin analogue, is undergoing prospective study in
Europe. Chronic inhaled nitric oxide or oral nitric oxide do-
nors continue to have potential benefit.
SUGGESTIONS FOR DETECTION AND
MANAGEMENT OF PPHTN
Preoperative diagnosis of PPHTN is essential because of
the increased morbidity and mortality associated with trans-
plantation. The proven efficacy of chronic epoprostenol ther-
apy for pulmonary hypertension, with its capacity to induce
right ventricular remodeling and improve function, makes
preoperative identification of PPHTN crucial. The ideal di-
agnostic screening test must be sensitive and specific in
detecting altered pulmonary vascular reactivity and right
ventricular dysfunction. It must assess pulmonary and car-
diac responses to rapid changes in preload and afterload.
Finally, it must be cost-effective and entail minimal risk to
the patient.
Although right heart catheterization remains the “gold
standard,” various noninvasive studies are used as screening
tools. Of these, transthoracic echocardiography is most
widely used. Findings of a dilated or hypertrophied right
ventricle or atrium, pulmonary valvular insufficiency, or
shifting of the interventricular septum into the left ventricle
raise suspicion of pulmonary hypertension. Pulmonary sys-
tolic pressures can be estimated in the presence of a tricuspid
regurgitant jet. At our institution, the room air arterial blood
gas is used as an adjunctive screening tool. We have shown
that patients with PPHTN demonstrate an exaggerated re-
spiratory alkalosis, more profound even than that character-
istic of patients with either primary pulmonary hypertension
or end-stage liver disease alone (7). The combination of a
suspicious blood gas result with an abnormal echocardio-
gram has been a successful screening regimen to identify
patients with PPHTN (Fig. 1). In our recent series of OLT
performed from 1994 to 1998, this regimen was associated
with a positive predictive value of 96% and a negative pre-
dictive value of 100%.
If PPHTN is suspected, right heart catheterization is indi-
cated to confirm and quantify pulmonary hypertension.
There is consensus that patients with “mild to moderate”
PPHTN may have transplantation risk similar to patients
without pulmonary hypertension, although the definition of
“mild to moderate” varies among institutions (1, 2). It is also
thought that those with “moderate to severe” disease are an
unacceptable risk (8, 17). As an alternative to stratification,
we designate an MPAP ? 40 mm Hg as the level at which
OLT can be performed safely. Those patients with a MPAP ?
40 mm Hg are treated with chronic intravenous epoprostenol
and followed at 3–6 month intervals with right heart cathe-
FIGURE 1. Decision algorithm for diagnosis and treatment of
PPHTN before OLT. (Abbreviations: RA-ABG, room air arterial
blood gas; DSE, dobutamine stress echo; LV, left ventricle; RV, right
ventricle; NO, nitric oxide)
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terization. The goal of treatment is lowering the MPAP to ?
40 mm Hg. In combination with initial right heart catheter-
ization, it is also necessary to determine the state of left
ventricular function. Dobutamine stress echocardiography
has proven itself invaluable in this role. Its sensitivity and
specificity in diagnosing coronary artery disease is important
because those patients with coexistent coronary artery dis-
ease may be ruled out as potential transplant candidates.
Finally, pulmonary function testing and ventilation-perfu-
sion scanning are also necessary to rule out alternative eti-
ologies of pulmonary hypertension, such as chronic pulmo-
nary emboli or chronic hypoxia.
Once the MPAP is ? 40 mm Hg and left ventricular func-
tion is deemed adequate, we proceed to assess the right
ventricular response to rapid volume infusion. Although
right heart catheterization identifies patients with static pul-
monary hypertension, the effect of volume-mediated pulmo-
nary hypertension is an additional consideration that could
be lethal at the time of allograft reperfusion. In patients with
end-stage liver disease, the pulmonary vasculature reacts in
an aberrant fashion to rapid volume infusion. We have shown
that these patients will develop significantly elevated MPAP
and PCWP after rapid infusion of one liter of crystalloid
solution compared with normal patients (19). Consequently,
we have added a fluid challenge to the standard DSE protocol
to evaluate the dynamic function of the right ventricle and
pulmonary vasculature. When the maximum dose of dobut-
amine has been achieved (40–50 ?g/kg/min), 1 liter of normal
saline is infused over 10 min in the presence of a pulmonary
artery catheter. Pulmonary hemodynamic and right ventric-
ular responses are noted and pressure changes measured. If
mean pulmonary pressures do not exceed 40 mm Hg, we feel
that the right ventricle demonstrates adequate functional
reserve, and the patient is allowed to undergo transplanta-
tion. However, if the MPAP increases to ? 40 mm Hg or the
right ventricle develops significant dysfunction, chronic infu-
sion of epoprostenol is continued, and the process repeated in
3–6 months. Even in those patients who exhibit acceptable
hemodynamic profiles, epoprostenol should be continued
while awaiting OLT. It has been shown that right ventricular
remodeling can occur in these patients and, theoretically,
further improvement may occur in the interim.
A subcategory of PPHTN patients merits special mention.
Patients with elevated right atrial and ventricular pressures
may exhibit normal or only mild elevations in pulmonary
artery pressure. This occurs as a result of significantly de-
pressed right ventricular function in the face of long-standing
elevations in pulmonary artery pressures. Decompensation
of right sided pump function in these cases suggests a poor
overall outcome. If OLT candidacy remains an issue, we
believe volume challenge in these patients should be per-
formed with great caution. In addition, although right ven-
tricular remodeling has been documented after chronic
epoprostenol infusion therapy, it is unknown whether this
specific subcategory of patients will also respond.
Other pulmonary vasodilating agents, such as inhaled ni-
tric oxide, have not been shown to be of any value during the
perioperative management of these patients (6, 33). As a
result, it is unknown what role inhaled nitric oxide should
have in the initial preoperative evaluation. Certainly, if a
specific patient demonstrates a response to inhaled nitric
oxide, then it may serve as an additional therapeutic option
for use in the operating room or the intensive care unit.
SUGGESTIONS FOR PERIOPERATIVE
MANAGEMENT OF PPHTN
Perioperative communication and cooperation between the
anesthesiology and surgery teams are imperative to a suc-
cessful outcome. Maintenance of good right ventricular func-
tion and low pulmonary arterial pressures are foremost
among the management goals. Using the “piggy-back” tech-
nique results in a short anhepatic period and decreases the
magnitude of hemodynamic changes associated with reper-
fusion. Alternatively, use of a veno-venous bypass, including
use of a portal venous cannula, also minimizes the conse-
quences of vena caval clamping and unclamping.
Intraoperative monitoring should include peripheral and
pulmonary arterial catheters and transesophageal echocar-
diography (TEE), in addition to standard noninvasive moni-
tors. Hemodynamic parameters should be maintained in a
fairly narrow range: MAP?70 mmHg, cardiac index ?3.0
l/min/m2, and PCWP 10–14 mmHg. TEE is useful in confirm-
ing adequate preload in settings in which central venous
pressure and PCWP may be unreliable and in assessing right
ventricular function. The patient should be kept warm, espe-
cially in light of the detrimental effect of hypothermia on
pulmonary vascular resistance. Unfortunately, physiologic
changes known to exacerbate pulmonary hypertension are
exactly those routinely seen on allograft reperfusion, that is,
hypercarbia, hypothermia, and acidosis. Several steps are
taken before reperfusion to decrease the physiologic effects of
the combination of caval unclamping and washout of the
newly perfused allograft. These include hyperventilating
with 100% oxygen and correcting metabolic parameters as
much as possible, especially acidosis, hypocalcemia, and hy-
perkalemia. Also, adequate depth of anesthesia is important,
and, should hypoxia and hypercarbia occur, they should be
treated immediately. The upper caval clamp should be re-
moved slowly and may need to be replaced should the acute
volume load prove be in excess of the functional reserve of the
right ventricle. Pulmonary vasodilators, including epoproste-
nol, inhaled nitric oxide, nitroglycerin, and sodium nitroprus-
side, should be available if pressures become excessive, al-
thoughhypoxia resulting
systemic hypotension, and general lack of efficacy, limit their
usefulness. We preferentially use epoprostenol titrated from
2 to 10 ng/kg/min as a specific pulmonary vasodilator, al-
though systemic hypotension may ensue.
Unlike other settings in which higher filling pressures are
desirable, hypervolemia should be avoided both to minimize
the detrimental effect on pulmonary pressures and to avoid
allograft engorgement seen with impaired inferior vena cava
and hepatic venous drainage. Nevertheless, volume therapy
is important in maintaining left ventricular filling to prevent
shifting of the interventricular septum into the left side. TEE
has proved especially useful in attempting to balance these
conflicting management goals. Epinephrine is our inotrope of
choice to preserve systemic perfusion pressures as well as
augment the inotropic state of the heart. Milrinone, a phos-
phodiesterase III inhibitor, is useful if a second intrope is
required. More extreme strategies have been reported to deal
with catastrophic hemodynamic changes occurring on reper-
frompulmonary shunting,
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fusion, including emergency right heart assist devices and
compression of the abdominal aorta (34).
Postoperative management of patients with PPHTN is
similar to that discussed for the intraoperative period. Any
specific pharmacologic therapy instituted in the operating
room should be continued. Mechanical ventilation will be
required for a minimum of several hours and up to several
days. Extubation may prove problematic in the face of intrin-
sic pulmonary disease, because hypoxia or hypercarbia,
which develops during the weaning process, will exacerbate
the pulmonary hypertension. Systemic hypotension and right
heart failure may then ensue and evolve into a vicious cycle
of more hypercarbia and hypoxia causing more pulmonary
hypertension. Also, the increased mobilization of fluids,
which occurs mostly on postoperative days 2 or 3 can precip-
itate right heart failure (35).
After transfer from the intensive care unit and even dis-
charge from the hospital, management differs minimally
from that of other liver transplant recipients. However,
chronic diuretic therapy is generally avoided to maintain
right-sided and left-sided preload. Epoprostenol is continued
for 6 months. At that time, the patient is weaned as toler-
ated, or oral diltiazem is substituted, guided by repeat right
heart catheterization and patient symptoms.
PPHTN AFTER OLT
Because the etiology of PPHTN is unknown, it is difficult to
determine whether PPHTN will resolve after OLT. Yoshida
and co-workers published 2 case reports comparing a lung
transplant recipient and a liver transplant recipient, both of
whom underwent transplants for PPHTN. In this instance,
PPHTN recurred in the lung recipient, but not in the liver
recipient (36). Although this suggests that hepatic dysfunc-
tion and accompanying portal hypertension are required for
development of PPHTN, OLT does not normalize pulmonary
pressures in all instances. A review of the literature shows
that seven published reports document the outcome of
PPHTN after OLT. In combination with our patient, the
cumulative data indicate that 7 of 10 PPHTN liver trans-
plant recipients demonstrated improved or normalized pul-
monary artery pressures within 6 months after the trans-
plant (17, 36–41). In addition, the retrospective reports of
Castro, Taura, Plevak, and Ramsay have further defined the
outcome of PPHTN patients after OLT (1–3, 8). Although
they do not address the issue of resolution of PPHTN, they
document that “mild-to-moderate” PPHTN does not alter
long term outcomes after OLT. In contrast, the “severe” sub-
category carries a poor outcome. Ramsay describes 5 of 7
patients with “severe” PPHTN (systolic PAP ? 60 mmHg)
with progressive right heart failure after OLT, suggesting
persistent PPHTN or decompensated right ventricular func-
tion (8). We hypothesize that PPHTN patients with a fixed
level of pulmonary vascular resistance will not exhibit re-
gression of PPHTN after OLT. In this regard, chronic admin-
istration of epoprostenol will segregate those OLT candidates
with a fixed level of pulmonary vascular resistance (Figure
1). In addition, the remodeling effects of epoprostenol have
not been addressed in these previous studies and may dra-
matically alter the outcomes.
CONCLUSION
The management of the OLT candidate with PPHTN has
dramatically changed in the past 3 years. At our institution,
careful preoperative evaluation with functional characteriza-
tion of right ventricular function plays a critical role. The
pulmonary vascular response to epoprostenol infusion serves
as a discriminating decision point in proceeding with OLT
candidacy. Careful perioperative attention to avoid right ven-
tricular failure, from acutely elevated PA pressures or sud-
den increases in right ventricular preload, is a key physio-
logic tenetto management.
expertise, anesthetic sophistication, and availability of
epoprostenol, PPHTN should no longer be considered an ab-
solute contraindication for OLT.
With increasedsurgical
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Accepted 30 December 1998.
KUO ET AL.
April 27, 1999
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