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Successful Liver Transplantation in a Child with Severe Portopulmonary
Hypertension Treated with Epoprostenol
INTRODUCTION
Portopulmonary hypertension (PPHTN) is a severe and potentially fatal complication of liver
disease that occurs in 5-10% of adult patients presenting for liver transplant (1). The mean
survival after diagnosis of PPHTN is approximately 15 months (2). The presence of PPHTN is
often considered a contraindication to liver transplantation due to significant perioperative
morbidity and mortality (3). Preoperative treatment with continuous intravenous epoprostenol, a
potent pulmonary vasodilator and antiproliferative agent, reduces pulmonary vascular resistance
in patients with PPHTN (4), enabling liver transplantation in some adult patients (4,5,6). There
have been very few previous reports of PPHTN in children with end stage liver disease and no
documented reports of epoprostenol infusion as a bridge to pediatric liver transplantation. We
report an 11-year-old girl with biliary atresia and severe PPHTN treated with continuous
intravenous epoprostenol before undergoing a successful orthotopic liver transplant (OLT) and
whose epoprostenol was weaned and discontinued 3 months after OLT.
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CASE REPORT
This 11-year-old African-American girl adoptee with extrahepatic biliary atresia underwent
Roux-en-Y portoenterostomy at 3 months of age at another center. She developed portal
hypertension, variceal hemorrhage, and ascites at the age of 10 years requiring treatment with
diuretics and beta-blockers and was listed for transplant. She had occasional behavior changes
with elevated ammonia levels and was treated with lactulose and a low protein diet. After
experiencing 2 syncopal episodes within a 1-week period, the diuretics and beta-blockers were
discontinued. An echocardiogram demonstrated right ventricular systolic pressure approximately
70% of systemic pressure but no right ventricular dilation or abnormality of systolic function.
Left ventricular function was normal. Cardiac catheterization confirmed severe pulmonary
hypertension with mean pulmonary artery pressure (MPAP) of 53 mmHg (Table 1). A
pulmonary artery angiogram was normal with no branch pulmonary artery stenosis (data not
shown). Administration of 100% oxygen and 80 parts per million nitric oxide both resulted in a
20% reduction of pulmonary vascular resistance. The patient was started on a continuous
infusion of intravenous epoprostenol at 0.5 ng/kg/min that was progressively increased to 12
ng/kg/min over several weeks.
Table 1
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The family subsequently relocated to California and the patient was admitted to Children's
Hospital for pretransplant evaluation. Since the initiation of epoprostenol 2 months previously,
she had no further syncopal attacks and denied chest pain, palpitations, or shortness of breath. On
admission, her medications included intravenous epoprostenol at 12 ng/kg/min, 100 mg of
spironolactone in the morning and 50 mg at night, lactulose 15 ml once a day, pantoprazole 60
mg once a day, ursodiol 300 mg twice a day, fat soluble vitamin supplements, and supplemental
oxygen at 1 l/min. Height and weight were normal for age. Physical examination revealed
hepatosplenomegaly without ascites and normal cardiopulmonary findings. She had no stigmata
of chronic liver disease. Total serum bilirubin was 0.8 mg/dl, albumin 4.2 g/dl, and prothrombin
time 13.4 seconds. Chest radiograph showed mild cardiomegaly with clear pulmonary
parenchyma. Abdominal ultrasound demonstrated a normal appearing liver and enlarged spleen
(14.2 cm in length). The gallbladder was not seen nor was a common bile duct. There was no
ascites. Doppler study showed normal flows in all the main vessels with hepatopetal portal
venous flow. Echocardiogram revealed a structurally normal heart with no evidence of elevated
pulmonary pressures. A repeat cardiac catheterization was not done.
At 11.5 years of age, 4 months after starting epoprostenol, the patient underwent orthotopic liver
transplant with a whole graft organ from a 5-year-old donor. An echocardiogram before
transplant again demonstrated good left ventricular function, normal estimated right ventricular
pressure, and no indirect signs of pulmonary hypertension. Epoprostenol infusion was
maintained at 12 ng/kg/min during transplant, and she did not require inhaled nitric oxide or
other vasodilators. The patient had no perioperative complications, remained stable
hemodynamically on the same dose of epoprostenol, and was extubated on the third
postoperative day according to the intensive unit care (ICU) protocol. She developed acute
delirium while in the ICU which resolved with risperidone. The explant liver histology showed
stage 3/4 fibrosis involving most of the liver parenchyma with foci of stage 4/4 fibrosis
(cirrhosis). There was a grade 2/4 mixed portal inflammatory infiltrate and severe bile duct
proliferation.
Post operatively, the patient did well and the dose of epoprostenol was weaned to 4 ng/kg/min
within 8 weeks of transplant. Repeat cardiac catheterization revealed MPAP of 20 mmHg and
pulmonary vascular resistance of 2 Wood Units (Table 1). Under hemodynamic monitoring, the
epoprostenol infusion was stopped and pressure and saturation data repeated after 15 minutes.
The MPAP and pulmonary vascular resistance remained stable, and the epoprostenol was then
discontinued. The patient was observed for 24 hours in the ICU and developed no signs of
rebound pulmonary hypertension. She has restarted school and participates in physical activities
without limitation. Repeat echocardiography 7 months after discontinuation of epoprostenol was
normal.
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DISCUSSION
PPHTN is defined as pulmonary arterial hypertension (PAH) associated with portal
hypertension, with or without hepatic disease. Diagnostic criteria for PAH include a mean
pulmonary arterial pressure >25 mmHg (at rest) or >30 mmHg (during exercise), with a mean
pulmonary artery occlusion pressure (pulmonary capillary wedge pressure) of <15 mmHg (7).
PPHTN may be categorized as mild, moderate, or severe (MPAP >25 to ≤35, >35 to ≤45, and
>45 mmHg respectively) (7). Severe PPHTN is considered a contraindication to OLT as patients
with MPAP >50 mmHg have an almost 100% perioperative mortality (8).
Despite several reports on the efficacy of epoprostenol in reducing PPHTN, a recent multicenter
liver transplant database reports that the use of preoperative intravenous epoprostenol in patients
with end stage liver disease and PPHTN is not common (9). There are no pediatric patients with
liver disease and PPHTN in the database, and there are no previous reports of preoperative use of
epoprostenol in children. The only other published data on children with liver disease and
PPHTN showed successful liver transplant in 2 of 3 children without preoperative use of
vasoactive agents (10). All 3 children had moderately elevated pulmonary artery pressures at
initial diagnosis, but the 3rd child subsequently developed severe PPHTN, with a MPAP of 60
mmHg and died of perioperative complications.
Our child had severe PPHTN with only a modest reduction in pulmonary vascular resistance
during the administration of nitric oxide, indicating a modest degree of reversible
vasoconstriction. Pathological changes in pulmonary vasculature in PPHTN are similar to those
seen in idiopathic pulmonary artery hypertension and range from medial hypertrophy, indicative
of potentially reversible vasoconstriction, to plexogenic arteriopathy with more extensive
vascular remodeling (11). Kuo et al., in their decision algorithm for diagnosis and treatment of
PPHTN, suggest testing pulmonary reactivity to a vasodilator agent before OLT (1). The
American College of Chest Physicians guidelines recommend the use of a calcium-channel
blocker in children with PAH who respond significantly to acute vasodilator testing and
recommend potentially higher doses of epoprostenol than those used in adults (12). Our child had
only a moderate response to nitric oxide, but she was well controlled with relatively low doses of
epoprostenol (12 ng/kg/min). Calcium-channel blocker was not used because of her portal
hypertension. It is likely that the beneficial effects of epoprostenol therapy in our patient were
due to both the vasodilator and antiproliferative properties of this agent. Children are also more
likely to demonstrate an acute pulmonary vascular response to vasodilators than adults and have
at least as a good a response as adults on chronic vasodilator therapy (12). Of note is that she had
adequate left ventricular function, although coronary artery disease would be rare in the pediatric
population.
Acute volume challenge to assess right ventricular function before transplant and using the
piggy-back technique or veno-venous bypass during OLT to reduce the volume burden on the
right ventricle during reperfusion has been proposed (1,5). These interventions were not done in
this patient as she had demonstrated stable hemodynamics with no evidence of pulmonary
hypertension before OLT.
The optimal duration of intravenous epoprostenol therapy following OLT is unknown. However,
long-term use of intravenous epoprostenol may be associated with worsening liver function and
even death (4). This patient's epoprostenol was gradually weaned and discontinued 3 months
after the OLT. To our knowledge, this is the first report of successful discontinuation of chronic
intravenous epoprostenol after OLT as a result of complete normalization of pulmonary
hemodynamics.
In conclusion, this report contributes to the limited data on successful use of chronic intravenous
epoprostenol to optimize pulmonary hemodynamics in an 11 year old with chronic liver disease
and severe PPHTN. The significant variables include the age of the patient and the early
discontinuation of the epoprostenol after the OLT. Whether rapid reversal of PPHTN is related to
the fact that PPHTN/pulmonary arteriopathy is more amenable to therapy in children is
unknown.