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Cases from the Pulmonary Hypertension Service
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 Roxana
Sulica, MD Director, Pulmonary Hypertension
Program
Assistant Professor of Medicine
Mount Sinai School of Medicine
New York, New York
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 Ramona
Doyle, MD
Associate Professor of Medicine
Medical Director, Lung and Heart-Lung Transplantation
Co-Director, Vera M. Wall Center for Pulmonary Vascular
Disease
Stanford University Medical Center
Stanford, California
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CASE 1:
A 42-year-old woman with HIV-related pulmonary arterial
hypertension (WHO class II) presented to the emergency
room with a 2-day history of fever, dysuria, lightheadedness,
and increased abdominal girth. Her medications at home
included continuous intravenous epoprostenol at a rate of
25 ng/kg/min, furosemide 80 mg po qd, and co-trimoxazole
for PCP prophylaxis. Her heart rate (HR) was 140/min regular,
blood pressure (BP) was 72/45 mmHg, she had an oxygen
saturation of 95% on 3L/min nasal cannula and a temperature
of 38 Celsius degrees. Her mucous membranes
were moist; she had elevated jugular venous pressure and
evidence of ascites. Cardiac examination revealed a right
ventricular heave, loud P2, murmur of tricuspid regurgitation,
and right-sided gallop. Lungs were clear to auscultation
bilaterally, the liver was slightly enlarged, and she had
suprapubic tenderness. Hickman line insertion site had no
evidence of erythema or discharge. Electrocardiographic
examination showed sinus tachycardia at a rate of 138/min,
right axis deviation, and incomplete right bundle branch
block. Chest radiography demonstrated cardiomegaly, but
neither lung parenchymal infiltrates nor pleural effusions.
Total white blood cell count was 14.5 x 1000/dL with 95%
polymorhphonuclear cells, and urinalysis showed numerous
white blood cells, positive leukocyte esterase and nitrite.
Blood urea nitrogen (BUN) was 32 mg/dL and serum creatinine
(Cr) 1.8 mg/dL (baseline BUN/Cr = 16/0.9). Blood and
urine cultures were collected. She was immediately given
one liter of crystalloid infusion over 90 minutes, followed by
a continuous infusion of normal saline at 100 mL/h and one
dose of intravenous Piperacillin-Tazobactam. HR remained
elevated at 135/min and BP remained low at 70/45 mmHg;
she had minimal urine output and complained of worsening
shortness of breath. Her pulmonary hypertension physician
was called, the patient was transferred to the CCU, and
intravenous fluids were discontinued. Repeat BUN at 4
hours was 38 mg/dL and Cr was 2.2 mg/dL. Urine Na was
25 mEq/L, with a fractional excretion of sodium of 0.22.
Bedside echocardiogram showed right ventricular dilatation
and severe dysfunction, enlarged right atrium, and a small
pericardial effusion without tamponade physiology. She
received 80 mg of furosemide intravenously and continuous
infusion of dopamine at 2 mcg/kg/min and dobutamine at 3
mcg/kg/min. After 2 hours, BP increased to 85/55 mmHg,
and she urinated 250 cc of urine. Dobutamine was
increased in 1 mcg/kg/min increments to 5 mcg/kg/min over
3 hours and the patient was initiated on standing dose of
intravenous furosemide 80 mg intravenously every 12 hours.
Upon urine culture results that showed growth of Klebsiella
pneumoniae sensitive to fluoroquinolones, the patient was
transitioned to oral ciprofloxacin, after receiving 48 hours of
intravenous antibiotics. Blood cultures were negative. Over
the next 3 days, her BP remained stable at 95-100
mmHg/50-60 mmHg, HR of 95-110/min (sinus tachycardia),
she was afebrile, and her respiratory status improved.
She had good urine output, her oxygen supplementation
requirement decreased and renal function returned to normal.
Dopamine and dobutamine were tapered to off, intravenous
furosemide converted to oral form, and she was discharged
home on oral antibiotics after a 7-day hospital stay.
Discussion:
This case provides an example of acute right heart failure
precipitated by an intercurrent urinary tract infection in a
patient with pulmonary arterial hypertension who was relatively
well controlled with intravenous epoprostenol. Patients
with pulmonary arterial hypertension have little tolerance for
any comorbidity, which can easily precipitate acutely
decompensated right heart failure (ADRVF), particularly in
cases with significant baseline right ventricular dysfunction.
Even with another obvious source of infection (in this case,
a urinary tract infection) patients receiving continuous intravenous
prostacyclin through a central catheter who present
with fever should have blood cultures done and receive
empiric coverage for gram-positive organisms. Patients with
ADRVF are usually hypotensive and tachycardic and in a low
flow state. Any further increase in the right ventricular preload
(such as with intravenous fluid administration) may
exacerbate right ventricular dysfunction, as it did in this
case. The systemic hypotension that follows is due to
decreased left ventricular filling from interventricular septal
shift and decreased right ventricular output. Intravenous
fluid administration should be done with great caution in
patients with pulmonary hypertension and requires clear evidence
of true intravascular fluid depletion, such as a history
of recent fluid loss, dry mucous membranes, or drenching
sweats with large insensible fluid loss. Patients who present
in septic shock, particularly if it is complicated by cardiogenic
shock, may be extremely difficult to manage and likely
will require pulmonary artery catheterization to guide
management. Decreased urinary output and evidence of prerenal
azotemia can be due to low cardiac output and cannot
be considered evidence enough to begin intravenous fluid
administration, as was the case in our patient.
The goal of BP support is to decrease the right ventricular
dilatation and to directly improve the right ventricular
contractility. Right ventricular dilatation is primarily
decreased by administration of intravenous loop diuretics.
Because of bowel edema, orally administered diuretics may
be ineffective. By decreasing the right atrial size and pressure
diuretics improve right ventricular filling and contractility,
and in some cases, may be the only intervention
required to improve systemic hemodynamics. Most patients,
however, will benefit from direct right ventricular inotropic
support and vasopressors, as in this case where low-dose
dopamine and dobutamine were used. In patients with right
ventricular failure dobutamine is the inotropic agent of
choice, despite some potential direct pulmonary hypertensive
effect. Milrinone may be more beneficial as a pulmonary
vasodilator, but the pronounced systemic hypotension
induced by this agent has the potential to decrease
venous return to the already insufficient right heart, worsening
the right ventricular failure. All vasopressors may have a
direct pulmonary vasoconstrictor effect, but low-dose
dopamine, phenylephrine, norepinephrine, or vasopressin
may be used to sustain the systemic blood pressure.
Improved systemic hemodynamics are usually translated in
improved renal function, increased diuresis, and further
increased right ventricular contractility. In conclusion the
mainstay of therapy in cases of hypotension from right ventricular
failure in pulmonary arterial hypertension is not
intravenous fluid administration, but rather inotropic support,
diuretics, and vasopressors.
CASE 2:
A 58-year-old man with hepatitis C-cirrhosis (MELD = 32,
refractory ascites, recurrent variceal bleeds, episodes of
hepatic encephalopathy, and hepato-renal syndrome) and
porto-pulmonary hypertension was called for cadaveric
orthotopic liver transplantation (OLT). He had been deemed
an appropriate candidate for OLT after 9 months of therapy
with subcutaneous treprostinil. His initial cardiac catheterization
at the time of diagnosis of porto-pulmonary hypertension
revealed the following hemodynamics: mean pulmonary
artery pressure (mPAP) of 55 mmHg, pulmonary artery
occlusion pressure (PAOP) of 10 mmHg, cardiac output (CO)
of 6 L/min and pulmonary vascular resistance (PVR) of 600
dynes x s x cm-5. He lived alone, was mildly encephalopathic,
and his wife, who had multiple sclerosis, resided in
a nursing home. With hemodynamics that posed a prohibitive
operative risk for OLT, and an inappropriate social situation
for intravenous epoprostenol therapy, treatment was
initiated with subcutaneous treprostinil. Six months after
initiation a follow-up right heart catheterization on 36
ng/kg/min of treprostinil showed the following hemodynamics:
mPAP of 33 mmHg, PAOP of 15 mmHg, CO of 8.7
L/min, and PVR of 166 dynes x s x cm-5. On the basis of
these numbers he was listed for liver transplantation and
because of rapidly progressing liver disease he received a
graft after 3 months.
Preoperatively his mPAP was 40 mmHg, his central
venous pressure (CVP) was 18 mmHg, PAWP was 20 mmHg,
and CO was 8.5 L/min, with a PVR of 188 dynes x s x cm-5.
During abdominal preparation the subcutaneous treprostinil
administration was discontinued. Systemic blood pressure
was 85/55 mmHg before induction of general anesthesia
and decreased to 70/35 mmHg after induction. This fall in
blood pressure responded to a phenylephrine bolus of 0.2
mg. Approximately half an hour after treprostinil discontinuation
a continuous intravenous epoprostenol infusion was
started at 2 ng/kg/min and adjusted to keep mPAP = 30-40
mmHg, with up-titration in 1-2 ng/kg/min increments every
30 to 60 minutes. Cardiac output was constantly monitored
and remained at 6.5-8.5 L/min. Inhaled nitric oxide (NO)
was kept on stand-by for potential rebound pulmonary
hypertensive episodes, but was not used. After removal of
ascites, mPAP, PAOP, and CVP decreased by 10 mmHg.
Intermittent boluses of phenylephrine (0.2 mg) and vasopressin
(2-4 U) were used to maintain the mean systolic BP
above 45-50 mmHg. During the procedure the patient
received a total of 6 L crystalloid infusion, 10 U of fresh
frozen plasma, and 5 units of packed red blood and he was
placed on continuous veno-venous hemofiltration (CVVH).
He remained stable hemodynamically throughout the transplant,
including during the anhepatic phase. Upon graft
revascularization during a 2 minute hypotensive episode
(with a decrease in the mean systemic BP to 30 mmHg and
a rebound mPAP to 45 mmHg) he received 4 U of vasopressin
and this increased the mean systemic BP to 50
mmHg, without significant change in mPAP. On completion
of the transplant operation he was receiving 15 ng/kg/min of
continuous intravenous epoprostenol. He was transferred to
the surgical intensive care unit, where he remained hemodynamically
stable. The next day subcutaneous treprostinil
was reinitiated and up-titrated in 3-4 ng/kg/min increments,
with simultaneous down-titration of intravenous
epoprostenol in 1-2 ng/kg/min decrements, until a dose of
30 ng/kg/min of treprostinil were reached. Prior to discontinuation
of the pulmonary artery catheter the mPAP was 32
mmHg, the CO was 7.5 L/min, the PAOP was 12 mmHg, and
the calculated PVR was 213 dynes.
Discussion:
This case illustrates the strategy that may be employed for
the perioperative hemodynamic management of patients
with porto-pulmonary hypertension who require OLT. Portopulmonary hypertension is a type of pulmonary arterial
hypertension that develops in patients with end-stage liver
disease, characterized by the presence of a true pulmonary
arteriopathy (elevated PVR) and (potential for) right ventricular
dysfunction. Perioperative mortality is significantly
increased in the presence of moderate to severe pulmonary
hypertension. These patients require chronic therapy for pulmonary
hypertension for hemodynamic optimization prior to
OLT, and case series in the literature support the use of continuous
intravenous epoprostenol in these circumstances.
This patient was treated with subcutaneous treprostinil
instead because of the lack of social support and his own
inability to manage the complexities of intravenous
epoprostenol therapy. With the advent of alternative therapeutic
options for pulmonary arterial hypertension, it is likely
that physicians will use other forms of chronic prostacyclin
therapy, ideally in the setting of organized clinical trials.
This patient had a good hemodynamic response to treprostinil,
rendering him an OLT candidate, but the particular
challenge in his case was the timing of transition from subcutaneous
to intravenous prostacyclin during the surgical
procedure. Given the relative unpredictability of the time of
OLT, it is not possible to transition these patients in
advance. Liver transplantation surgery is associated with
hemodynamic instability, rebound pulmonary hypertension,
and precipitation of right ventricular failure, particularly
after induction of general anesthesia, after graft revascularization,
and during the first postoperative days. Transitioning
from one to another form of prostacyclin therapy during OLT
may increase the risk of hemodynamic instability. In this
case, transition from subcutaneous treprostinil to prostacyclin
infusion was successfully achieved with guidance from
pulmonary artery catheterization.
As a general rule, prostacyclin deficiency may be associated with rebound pulmonary
hypertension and prostacyclin excess with systemic hypotension.
There is a difference in half-lives between epoprostenol
and treprostinil (2 to 3 minutes and 2 to 4 hours, respectively)
and anecdotal evidence suggests that approximately two
to three times more treprostinil (in nanograms) is required
for an equivalent effect. Inhaled NO may be used for the
pulmonary vasodilator effect, particularly in cases with
systemic hypotension, because of its selectivity for the
pulmonary vasculature. Inotropic agents and vasopressors,
as well as volume replacement or volume removal, may be
used as needed for the hemodynamic management during liver
transplantation.
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