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Michael Ramsay, MD, FRCA
Chairman, Department of Anesthesiology and Pain Management
Baylor University Medical Center
Clinical Professor, Department of Anesthesiology and Pain
Management
University of Texas Southwestern Medical Center
Dallas, Texas
The perioperative management of patients presenting
for orthotopic liver transplantation who have associated
pulmonary hypertension still presents a challenge to the
operative team. As a result of the limited amount of accurate
data available, and because the conclusions reported are
often conflicting, it has not been easy to develop an
evidence-based strategy for the safe management of these
patients through liver transplantation. 1-13
This failure to reach a consensus opinion may be a result
of the fact that patients have very different pathological
presentations. When there are various associated comorbidities
coupled with a lack of complete hemodynamic and echocardiographic
data, it is difficult to make a precise comparative evaluation
between transplant candidates.
Typically, patients with advanced liver disease experience
a hyperdynamic circulatory state, with increased cardiac
output and decreased systemic vascular resistance.14
In addition, some patients with pulmonary hypertension
associated with liver disease have increased venous blood
volume due to systemic volume overload, or they may have
left, right, or biventricular cardiac dysfunction. Patients
with portal hypertension have true portopulmonary hypertension
when the measured pulmonary hypertension is accompanied
by an increased resistance to pulmonary blood flow, as
demonstrated by a calculated (pulmonary vascular resistance
is a calculation based on the other measurements) increase
in pulmonary vascular resistance, in the presence of a
normal pulmonary capillary occlusion pressure or left
ventricular end-diastolic pressure.
It is essential, therefore, to accurately characterize
the pulmonary hemodynamics in these patients. The required
hemodynamic data must be determined from right heart catheterization
and must include the following values: mean pulmonary
artery pressure (mPAP), cardiac output, pulmonary artery
occlusion pressure, and calculated pulmonary vascular
resistance, in the stable, resting state. Cardiac output
is typically high in this patient group. If a normal or
low value is obtained, volume depletion is usually present;
however the diagnosis of cardiomyopathy should be considered.
If the patient is volume depleted, the volume replenishment
needed to restore homeostasis may lead to the demonstration
of an even higher mean pulmonary artery pressure than
initially measured, although the pulmonary vascular resistance
is unlikely to change.
Pulmonary hypertension may be found in up to 20% of
patients with cirrhosis of the liver. However, according
to some studies, true portopulmonary hypertension has
a prevalence of about 5% in patients presenting for orthotopic
liver transplantation. 9,1
High cardiac output, cardiac failure, cardiomyopathy,
and volume overload account for a number of non-portopulmonary
hypertension presentations, and the management of these
patients is very different from those with true portopulmonary
hypertension. In fact, some degree of cardiomyopathy (downregulation
of beta receptors) has been reported to occur in all cirrhotic
patients, thereby blurring the lines between true portopulmonary
hypertension and pulmonary hypertension secondary to other
causes.15
Portopulmonary hypertension is defined as the existence
of portal hypertension with a resting mPAP >25 mm Hg,
a pulmonary artery occlusion pressure <15 mm Hg, and
pulmonary vascular resistance > 240 dynes.s.cm-5.
Essential hemodynamic measurements are calculated as
follows: mPAP (mm Hg) = pulmonary artery systolic pressure
+ [(pulmonary artery systolic pressure – pulmonary
artery diastolic pressure) / 3]; pulmonary vascular resistance
(dynes.s.cm-5) = (mPAP – pulmonary artery occlusion
pressure) x 80 / cardiac output. Cardiac index (cardiac
output/body surface area) and pulmonary vascular resistance
index allow body surface area to be taken into account
so that true comparative measurements may be made. However,
rarely does the portopulmonary hypertension literature
provide this complete information.
The pathological changes in the microvasculature of
the lungs of patients with portopulmonary hypertension
include plexogenic arteriopathy, medial hyperplasia, thrombosis,
and eventually fibrosis, quite similar to those findings
found in idiopathic pulmonary arterial hypertension. Concomitant
with these changes, vascular dilations and shunt formation
may occur, such as that seen in patients with hepatopulmonary
syndrome. 21 This observation
suggests that these changes may to balance the physiological
outcome until one predominates.22
The pulmonary vascular abnormalities may progress, even
after orthotopic liver transplantation, unless long-term
pulmonary vasodilator therapy is instituted.1,
23 The shunt formations do resolve after transplantation,
however, and this may reveal the underlying pulmonary
hypertension. Therefore, transplantation may be considered
an effective therapy for hepatopulmonary syndrome, in
contrast to portopulmonary hypertension.
A calculated pulmonary vascular resistance >240 dynes.s.cm-5
is generally considered pathological, although some authorities16,17
have defined pulmonary hypertension by a value >120
dynes.s.cm-5. Portopulmonary hypertension is further graded
hemodynamically into mild (mPAP 25 to 35 mm Hg) moderate
(mPAP >35 to 45 mm Hg) and severe (mPAP> 45 mm Hg).
Management of the patient with portopulmonary hypertension
>35 mm Hg depends on the causative factors. Volume
overload may be treated with diuresis or, if renal function
is severely impaired, by utilizing continuous venovenous
hemodialysis. If this treatment is effective and ventricular
function is good, then transplantation may continue without
extra risk. If cardiac function is poor as the result
of a cardiomyopathy and filling pressures remain elevated,
then the patient is at significant risk if transplantation
is undertaken, unless significant improvement in cardiac
function is achieved with inotropic agents. In most of
the liver failure patients presenting for transplantation,
pulmonary vascular resistance is low and left ventricular
function appears enhanced, such that it takes experience
in this group of patients to diagnose even moderate degrees
of ventricular dysfunction. If reduced left ventricular
function is noticed on echocardiography, it is likely
that a severe cardiomyopathy exists and the transplantation
should be deferred for further evaluation.
Reactive pulmonary hypertension may respond to anesthesia,
adequate ventilation, and pulmonary vasodilators. Patients
with fulminant liver disease who also have associated
metabolic and respiratory acidosis may well have pulmonary
hypertension that will respond to correction of the acidosis
and adequate ventilation. Patients diagnosed with portopulmonary
hypertension just prior to liver transplantation may respond
to acute pulmonary vasodilator therapy. Inhaled nitric
oxide (iNO), the prostacyclin analogue iloprost, intravenous
milrinone, epoprostenol, and oral sildenafil have all
been administered to reduce mPAP with varied responses.18,19
If the mPAP is lowered to 35 mm Hg or less, the pulmonary
vascular resistance is< 240 dynes.s.cm-5, and right
ventricular function is good, there is no reported increased
risk to proceeding with transplantation. 17
If the mPAP and pulmonary vascular resistance remain
elevated, whether the patient will survive liver transplantation
may depend on right ventricular function and the added
stressors applied to it during the perioperative period.
There are reports of successful transplantation in patients
with an mPAP of 53 mm Hg and pulmonary vascular resistance
as high as 639 dynes.s.cm -5. However, other reports demonstrate
100% mortality in patients with an initial mPAP >50
mm Hg.12,20
Moderate and severe portopulmonary hypertension places
the liver transplantation patient at increased risk of
perioperative morbidity and mortality.17, 20 The data
available to date indicate a perioperative mortality of
greater than 70% if liver transplantation were carried
out with an mPAP of 45 mm Hg or higher and up to 100%
if the mean pressure were >50 mm Hg. There is no increase
in mortality risk if the mPAP is 35 mm Hg or less.20 A
multicenter, national liver transplant database reported
an overall mortality perioperatively of 36% for patients
with portopulmonary hypertension undergoing transplantation.
17
Despite the realization that pulmonary hypertension
may increase the morbidity and mortality of patients undergoing
orthotopic liver transplantation, and the close attention
to the cardiopulmonary system during the patient’s
pretransplant assessment, it is not uncommon for patients
to be diagnsed on the operating table at the induction
of anesthesia.24 This is because the symptoms of end-stage
liver disease are similar to those of severe pulmonary
hypertension, and the time course for development of pulmonary
hypertension is unknown. The risk to the patient with
portopulmonary hypertension is based on two major outcomes
that are very dependent on right ventricular function.
First an acute increase in pulmonary vascular resistance
during transplantation may result in right ventricular
dysfunction, which results in an elevation of right heart
pressures, causing congestion and failure of the new liver
graft. Second, a profound increase in pulmonary vascular
resistance, as may be seen following reperfusion of the
new liver graft, may cause the right ventricle to fail
acutely, with resulting serious morbidity or mortality.
Right ventricular function should be assessed by echocardiography,
whether the diagnosis of portopulmonary hypertension is
made preoperatively or on the operating room table. Preoperatively,
right ventricular systolic pressures >50 mm Hg and/or
abnormal right ventricular chamber size, wall motion,
or septal movement toward the left ventricle, require
further analysis of hemodynamic data by right heart catheterization.
The pulmonary vascular resistance that is calculated from
the right heart catheter is very dependent on cardiac
output. Typically elevated in cirrhotic patients, cardiac
output is found to increase in most patients following
reperfusion of the new liver graft. In a majority of patients,
this increase in cardiac output is in the range of 5%
to 10%. However, the increase is unpredictable and may
reach 300% or greater in a small number of patients (3.8%).24
This massive unpredictable increase may stress a marginal
right ventricle. Therefore, the key to survival in this
patient population is good right ventricular function,
and this must be assessed carefully before transplantation
and during the procedure.
How rapidly portopulmonary hypertension can develop
is uncertain, as reports vary from 3 weeks to 5 years.24,25
Pulmonary thromboembolism may be the cause of an acute
presentation of portopulmonary hypertension. As mentioned
above, routine transthoracic contrast-enhanced echocardiography
(CE-TTE) should be performed as part of the pretransplantation
work-up. The symptoms of portopulmonary hypertension are
too similar to those of end-stage liver disease to be
able to differentiate without CE-TTE.
Echocardiographic findings of abnormal right ventricular
function provide an indication for right heart catheterization,
it can be used to monitor the effectiveness of pulmonary
vascular therapy, and it can be used as an assessment
tool for determining the ability of the right ventricle
to compensate for the increased pulmonary vascular resistance.26,27
If the right ventricle can adjust to the increased afterload
over time by hypertrophying, this may provide a better
chance of decreasing morbidity and mortality during transplantation.
Perioperative risk to the patient is not only related
to the absolute value of the mPAP and pulmonary vascular
resistance but is also a function of the condition of
the right ventricle. Once portopulmonary hypertension
has been diagnosed, follow-up screening by CE-TTE to assess
effectiveness of therapy and right ventricular function
should occur at least every 6 months.
Right heart catheterization is the gold standard for
the diagnosis of pulmonary hypertension, including portopulmonary
hypertension.28 It not only
provides accurate assessment of portopulmonary hypertension,
pulmonary hypertension, and ventricular function, it can
help sort out the differential diagnosis of hyperdynamic
circulation, volume overload, and increased afterload.
It also allows an evaluation of acute vasoreactivity and
can be used to monitor the effectiveness of therapeutic
interventions.
Up to 60% of patients with portopulmonary hypertension
may not have their condition detected until reaching the
operating room, undergoing the induction of anesthesia
prior to liver transplantation.24
If diagnosed for the first time in the operating room,
once an accurate diagnosis has been made and right ventricular
function has been assessed by transesophageal echocardiography
(TEE), a decision has to be made whether to proceed with
surgery or delay transplantation to a future date after
effective vasodilator therapy. Acute vasodilator testing
should be considered when a diagnosis of moderate portopulmonary
hypertension (mPAP >35 to 45 mm Hg) has been made.
In the immediate preoperative setting, iNO, inhaled nitroglycerin,
or inhaled iloprost are best suited to effect an immediate
response. Intravenous vasodilators such as milrinone are
somewhat limited by the systemic vasodilation that these
agents may cause. The response to iNO is variable, with
some patients responding well and others showing no vasoreactivity
at all.18,19,29-32 Liver
cirrhosis is associated with excessive production of endogenous
nitric oxide and this may explain this unpredictable response
to iNO. 33
The goal of vasodilator testing in the portopulmonary
hypertension patient is to bring the mPAP down to 35 mmHg
or less and to reduce pulmonary vascular resistance to
<240 dynes.s.cm-5. An accurate assessment of right
ventricular function by TEE is also an essential part
of patient examination. If acute vasodilator therapy is
not effective, then surgery is postponed and long-term
vasodilator therapy such as intravenous epoprostenol or
in some centers oral bosentan is started. The use of bosentan,
a dual endothelin receptor antagonist (A and B), is generally
not recommended in portopulmonary hypertension as it may
cause a rise in hepatic enzymes, although it has a potential
advantage because it does not require long-term intravenous
access. Most pulmonary artery hypertension experts are
wary of using bosentan for portopulmonary hypertension
patients because in a
large multicenter study that excluded patients with liver
disease at least a threefold upper limit of normal elevation
of liver aminotransferases (ALT and AST) occurred in about
11% of patients, accompanied by elevated bilirubin in
a small number of cases. Epoprostenol generally produces
a greater increase in cardiac output than does iNO. It
is also a powerful systemic vasodilator that reduces systemic
as well as pulmonary vascular resistance. It can be administered
only by continuous intravenous infusion (central venous
access via portable infusion pump) since its half-life
in circulation is brief (3 to 5 min). Common adverse effects
attributable to epoprostenol include jaw pain, headache,
diarrhea, flushing, leg pain, and nausea or vomiting.
More serious complications may occur because of the delivery
system (catheter-related infections or thrombosis). Sildenafil
has been used in managing portopulmonary hypertension,
but no trials have been reported studying its efficacy
in that condition.
Those patients with portopulmonary hypertension who undergo
liver transplantation have a varied survival rate and
change in pulmonary hemodynamics. One study reported a
mortality of 71% at 36 months after transplantation in
patients with portopulmonary hypertension who did not
receive postoperative epoprostenol.1
The same group reported 100% survival in a group of patients
with portopulmonary hypertension treated acutely with
iNO followed by epoprostenol.23
Normalization of pulmonary pressures occurred in all patients,
but took between 2 days and 18 months of postoperative
epoprostenol therapy.23
Reassessment of the patient at frequent intervals by
repeat echocardiography can provide information not only
on the progress of therapy but also on the condition of
the right ventricle. With time, conditioning of the right
ventricle may
occur, and a widely dilated chamber may develop into a
hypertrophied and well-contracting ventricle. If this
occurs, then the patient may tolerate liver transplantation
with a higher mPAP.34
If pulmonary hypertension is diagnosed on the operating
room table just before starting surgery, a decision has
to be made to proceed or defer the procedure. This decision
needs to be made rapidly, as another recipient may need
to be admitted. The decision to proceed should be based
on the level of the mPAP and systemic vascular resistance,
the reversibility of the mPAP and systemic vascular resistance,
and the condition of the right ventricle, as evaluated
by TEE. It must include a careful rechecking of the hemodynamic
data to ensure its accuracy and the elimination of other
diagnoses, such as fluid overload, cardiomyopathy, and
respiratory acidosis. The reversibility of the increased
mPAP can be rapidly tested by the administration of iNO
or another pulmonary vasodilator (see above). The function
of the right ventricle may be evaluated by TEE surveillance
while a one liter fluid bolus and a dobutamine infusion
are administered. If the mPAP reduces to <35 mm Hg,
pulmonary vascular resistance falls below 240 mm Hg, and
right ventricular function is not severely impaired, a
reasonable expectation exists that surgery can proceed
safely. Inhaled nitric oxide may assist in the management
of transient acute rises in pulmonary artery pressures
associated with reperfusion of the new graft.35
An increase in cardiac output is frequently seen (5%
to 18% of patients) after reperfusion of the new graft
and is typically in the range of 5% to 10%. If there is
a significant resistance to pulmonary blood flow, then
the laws of physics dictate that the pressure must increase.
Occasionally (3.7% of patients), an increase in QT of
more than 100% of baseline may be seen (Figure).24
This massive increase in cardiac output with a fixed
pulmonary vascular resistance may cause the development
of systemic pulmonary artery pressures in patients with
preexisting pulmonary hypertension and lead to acute right
ventricular failure. Since this massive increase in cardiac
output is unpredictable, it is prudent to reduce mPAP
to a mild (>35 mm Hg) level before undertaking liver
transplantation. The increase in cardiac output is probably
the result of the removal of the obstruction to portal
blood flow by the extraction of the diseased liver, together
with the systemic vasodilatation caused by the washout
of acid metabolites and other vasodilator substances from
the new graft. Why some patients have such an increase
in cardiac output is not known, but if this occurs it
clearly adds to the risk for the patient with pulmonary
hypertension. The patient with the relatively fixed pulmonary
vascular resistance can react to the increased flow only
by an acute increase in pulmonary artery pressure and
potential right heart failure.
If an acute elevation in mPAP occurs intraoperatively,
an evaluation is made as to the etiology: increase in
volume, increase in cardiac output, and increase in pulmonary
vascular resistance or cardiac failure. Appropriate treatment
is initiated. If right heart failure occurs, the new graft
is immediately compromised, and the survival of the patient
may be in jeopardy. If conventional measures fail, atrial
septostomy and the insertion of a right ventricular assist
device may be lifesaving.
Conditioning of the right ventricle has been seen in
two of our patients who were awaiting orthotopic liver
transplantation and were being treated with epoprostenol.
The first was diagnosed on the operating room table with
an mPAP of 49 mm Hg, pulmonary vascular resistance of
384 dynes.s.cm-5, and a cardiac index of 3.6 L/m2. The
TEE revealed a markedly dilated right ventricle and atrium,
the left ventricular ejection fraction was 55% to 60%.
An iNO response test reduced mPAP to 45 mm Hg. Liver transplantation
was postponed. An epoprostenol infusion was started and
the patient tolerated a maximum dose of 8 ng/kg/min. One
year later, the patient was receiving epoprostenol at
34 ng/kg/min and mPAP was 47 mm Hg with a cardiac index
of 6.9 L/m2. At reevaluation after further therapy for
4 months, mPAP was 34 mm Hg with a cardiac index of 6.2
L/m2.
Finally, after another 8 months, the patient was admitted
for liver transplantation. The mPAP was 39 mm Hg, systemic
vascular resistance 130 dynes.s.cm-5, and cardiac index
5.1 L/m2. On TEE, the right ventricle was now noted to
be hypertrophied and contracting well; therefore transplantation
was undertaken. At reperfusion there was an increase in
cardiac output with a concomitant increase in mPAP to
a peak of 55 mm Hg but the patient’s right ventricle
tolerated this well. The patient recovered well and is
continuing treatment with epoprostenol. The experience
with the second patient was similar.34
Summary
The intraoperative management of pulmonary hypertension
in the liver transplant recipient requires an accurate
diagnosis of the etiology in order to classify the type
of pulmonary hypertension that exists, which determines
the subsequent course of action. A clear comprehension
of the hemodynamic data and cardiac function is paramount.
A TEE is essential in assessing the risk factors. Patients
with an mPAP >35 mm Hg and pulmonary vascular resistance
>240 dynes.s.cm-5 are at particular risk for orthotopic
liver transplantation, and should undergo the procedure
only after careful individual assessment of all these
parameters. The available data provide a compelling reason
to postpone transplantation when a patient is found to
have an mPAP > 35 mm Hg, and these data suggest that
attempts be made to improve hemodynamics and right ventricular
function. This may be accomplished in the operating room
prior to transplantation or may require a prolonged (and
sometimes indefinite) course of vasodilator therapy.
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