Pulmonary CPC

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Pulmonary CPC

• Taylor Pruett, MD
• January 11, 2008

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CC Weakness

• HPI 54 year old Caucasian female with chief
  complaint of weakness. She has a history of
  cirrhosis secondary to Hepatitis C. Extensive
  rheumatologic evaluation at the time of diagnosis
  was negative.
• The patient was referred to the pulmonary
  department 2 years prior to the current
  presentation for dyspnea. Several tests were
  performed in evaluation of this. Spirometry was
  normal the DLco was 49 predicted. Shunt study
  X 2 was 11. Oxygen requirements to maintain
  oxygen saturations over 92 was 4-6 LPM.
  Echocardiogram with agitated saline was normal
  except for the late appearance of bubbles in the
  pulmonary veins suggestive of intrapulmonary
  shunting. Pulmonary arteriograms and CT of the
  chest were normal.

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• Due to the persistent hypoxemia, the patient was
  listed high for transplant.
• Liver transplant was performed eight months prior
  to this admission. The patient reported that she
  no longer required oxygen by two months
  post-transplant.
• Four months prior to this admission the patient
  had a mild course of rejection, and one month
  prior to admission she was diagnosed with hepatic
  encephalopathy. Liver biopsy was performed at
  that time and revealed Grade 3, stage 2 Hepatitis
  C without rejection. Lactulose was initiated,
  but since then the patient has had increasing
  weakness, dyspnea, and mild lower extremity
  edema.
• Her BP post-transplant was in the 120s/70s and
  her creatinine ranged from 1.4-1.9. Her
  transaminases were 2X the upper limit of normal.

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History

• Past Medical History as above, plus iron
  deficiency anemia and allergic rhinitis
• Past Surgical History liver transplant, cesarean
  section 20 years ago, tonsillectomy remotely
• Social The patient currently stays at home. She
  denies alcohol, tobacco, or illicit drug use.
  She and her husband live in Waco
• Allergies Erythromycin, Zosyn, Vicodin

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Medications

• Prograf 1 mg po daily
• Myfortic 360 mg po nightly
• Prevacid 30 mg po BID
• Bumex 1 mg po daily
• Centrum daily
• Caltrate-D daily
• Actigall 300 mg po QID
• Reglan 10 mg po TID

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Physical Exam

• Vital Signs Afebrile, BP 115/77, P 84, O2 sat
  93 on RA
• General Fatigued, Oriented X3
• HEENT PERRLA, mild icterus, oral mucosa moist
• Neck no adenopathy JVP with a variable degree
  of elevation by multiple examiners
• Lungs no rales
• Cardiovascular regular rhythm with questionable
  murmur and ventricular lift
• Abdomen soft, no rebound tenderness, no
  hepatomegaly or evidence of ascites
• Extremities edema to the lower calves that is
  symmetric

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Laboratory Data

• TBili 4.7
• Alk phos 119
• AST 88
• ALT 32
• TP 6.0
• Alb 3.7
• INR 1.5
• PT 17.4
• PTT 43
• BNP 1792

• WBC 4.9, normal diff
• Hb 17.1
• Platelets 106
• Troponin 0.14
• CK 48
• CKMB 7.5
• Na 140
• K 5.5
• Cl 107
• carbon dioxide 22
• BUN 21
• Cr 1.9

8
Studies

• EKG revealed normal sinus rhythm with right axis
  deviation, right ventricular hypertrophy, and an
  incomplete right bundle branch block. There was
  evidence of left atrial enlargement and
  anteroseptal infarction, age undetermined.
• Chest Xray hazy opacification at the loft lower
  thorax with blunting of the costophrenic angles
  bilaterally consistent with pleural fluid or
  thickening. Cardiac silhouette remains prominent
  and there is slight fullness at the hilar region.
• Limited echocardiogram at the bedside in the
  Emergency room revealed a large pericardial
  effusion.

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Hospital Course

• The patient was admitted for further evaluation
• She underwent pericardiocentesis with removal of
  175 ml of serous fluid
• Blood pressure subsequently declined with fall in
  urine output
• EKG was unchanged
• Creatinine increased from 1.9 on admission to 2.7
  then 3.8 the following day
• A diagnostic procedure was performed, and the
  patient ultimately expired

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Objectives

• Discussion of pre-transplant diagnosis
• Discussion of post-transplant diagnosis
• Desired diagnostic testing

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Problem List (Pre-transplant)

• Dyspnea
• Hepatitis C with cirrhosis
• Pulmonary function abnormalities (decreased DLCO)
• Severe hypoxemia
• Intrapulmonary shunt

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Hepatopulmonary Syndrome

• Hepatopulmonary syndrome consists of a triad of
  advanced chronic liver disease, arterial
  oxygenation defect, and widespread intrapulmonary
  vascular dilations (IPVDs)
• Estimated to occur in 4 47 of patients with
  chronic liver disease
• Mild to moderate hypoxemia is common in chronic
  liver disease
• Severe hypoxemia with PaO2 lt60 mmHg should
  suggest HPS (in the absence of other
  cardiopulmonary disease)
• Can be associated with any form of chronic liver
  disease as well as some forms of acute liver
  disease

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Clinical Manifestations

• 80 of patients have signs of chronic liver
  disease as their initial presentation. 20
  present with dyspnea.
• The presence of abundant spider angiomata has
  been suggested as a marker for the severity of
  HPS
• Frequently associated with hyperdynamic
  circulation manifested as elevated cardiac output
  (gt7 L/min), decreased systemic and pulmonary
  vascular resistance, and narrowed arterial
  mixed venous oxygen content difference
• Pulmonary findings include platypnea (increase in
  dyspnea in the upright position) and orthodexia
  (decrease O2 sat in the upright position)

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Intrapulmonary Vascular Dilations

• IPVDs are the hallmark of hepatopulmonary
  syndrome
• They are widespread vascular dilations which
  result in decreased resistance and increased
  blood flow through the pulmonary vasculature.
• Unclear what causes IPVDs. Suggested causes
  include failure of the damaged liver to
  metabolize circulating vasodilators, production
  of a vasodilator by the liver, and inhibition of
  circulating vasoconstrictor by the damaged liver
• Nitric oxide and the persistent induction of
  nitric oxide synthase are presumed to play a role
  in the development of IPVDs

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IPVDs
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• Diffuse dilatation of the pulmonary circulation
  results in a right-to-left shunt, orthodexia,
  loss of hypoxia induced vasoconstriction, and
  over-perfusion of low ventilation areas
• Orthodexia thought to be secondary to perfusion
  of IPVDs in the lung bases in the upright
  position

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Hypoxemia in HPS

• Three components to gas exchange abnormalities
  
• -ventilation - perfusion mismatch
• -intrapulmonary shunting
• -impaired oxygen diffusion
• All of these mechanisms are a direct result of
  IPVDs
• When HPS is mild, the predominant mechanism of
  hypoxemia is V/Q mismatch. This is due to the
  presence of areas in which ventilation is
  preserved, but perfusion is profoundly increased
  due to massive dilation of the vessels
• When HPS is severe, the primary mechanism of
  hypoxemia is intrapulmonary right-to-left
  shunting

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Right-to-Left Shunting

• Anatomic shunt exists when the alveoli are
  bypassed. This occurs in intracardiac shunts,
  pulmonary AVMs, and hepatopulmonary syndrome
• Physiologic shunts occur when there is perfusion
  of non-ventilated areas such as in atelectasis,
  pneumonia, and ARDS
• IPVDs do not function as true anatomic shunts
• Oxygen molecules are unable to diffuse to the
  center of the blood vessel due to the degree of
  dilation and the large diameter of the vessel.
• Oxygenation typically improves as supplemental
  oxygen is provided

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IPVDs
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Diagnosis

• Echocardiogram (contrast-enhanced) gold
  standard for diagnosis
• Nuclear Scanning (Scans show uptake over the
  kidneys of Technetium-labeled macroaggregated
  albumin which should normally be trapped by the
  pulmonary bed)
• Pulmonary angiography (used to exclude other
  causes of hypoxemia)
• Chest Xray (usually relatively normal)
• Pulmonary function tests
• -Spirometry (usually normal unless there is
  coexisting obstructive or restrictive lung
  disease)
• -Diffusion capacity (mildly to severely
  impaired)
• -Shunt fraction
• -ABG (PaO2 lt80 mmHG and A-a gradient gt20
  mmHG)

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Echocardiogram

• Contrast-enhanced echo is the preferred
  diagnostic modality for detecting IPVDs
• Intravenous indocyanine dye or agitated saline
  can differentiate between intracardiac and
  intrapulmonary shunts. These are normally
  filtered by the pulmonary bed and do not enter
  the left heart.
• In an intracardiac shunt, dye will appear in the
  left heart within 3 heartbeats
• In an intrapulmonary shunt, dye will appear in
  the left heart later, within 3-6 heartbeats
• TEE can directly visualize microbubbles in the
  pulmonary veins as they enter the left atrium

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Treatment

• Multiple attempts have been made to improve
  oxygenation in HPS. There has been no
  improvement associated with attempts to
  physically occlude IPVDs, oppose vasodilators,
  and treatment of the underlying liver disease.
• A few case reports have documented improvement
  with transjugular intrahepatic portosystemic
  shunt placement (TIPS), but this has been
  inconsistent and its use is not recommended.
• One report on a single patient successfully
  treated with inhaled N(G)-nitro-L-arginine
  methyl ester (L-NAME) which is an inhibitor of
  nitric oxide synthesis. Treatment resulted in an
  increase of PaO2 from 52 to 70 mmHg and an
  increase in the 6 minute walk distance.

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Liver Transplant

• To date, liver transplant offers the most benefit
  for patients with severe and refractory
  hypoxemia.
• Significant improvements in oxygenation and
  reversal of shunting have been documented after
  transplantation.
• No randomized trials have been performed in this
  area, however, multiple observational studies
  show significant survival benefit

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Back to our patient

• Met criteria for HPS (severe hypoxemia, chronic
  liver disease, IPVDs)
• Underwent liver transplant 8 months ago.
  Significant improvement in oxygenation (she no
  longer required supplemental O2 after 2 months)
• Unfortunately, the patient has now developed
  signs of chronic liver disease including hepatic
  encephalopathy.
• Biopsy of the transplanted liver reveals advanced
  hepatitis C

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Current Problem List

• Weakness, Dyspnea, Edema
• Active hepatitis C in transplanted liver
• Immunocompromised
• Evidence of right-sided heart failure
  (demonstrated by EKG, elevated BNP, and physical
  exam)
• Pericardial effusion

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Pulmonary Hypertension

• Pathologic state characterized by consistently
  elevated pulmonary arterial pressure and
  secondary right ventricular failure.
• Defined as a mean pulmonary artery pressure
  greater than 25 mmHg at rest or 30 mmHg with
  exercise (as measured with right heart cath)
• Elevation of the pressure inside the normally low
  pressure pulmonary vascular bed results in
  increased vascular resistance and decreased
  cardiac output.
• Results from reduction in the caliber of the
  pulmonary vessels, an increase in pulmonary blood
  flow, or both.

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Classification

• Pulmonary hypertension was previously classified
  as either Idiopathic pulmonary arterial
  hypertension (IPAH also called Primary
  pulmonary hypertension) or secondary pulmonary
  hypertension
• Some forms of secondary PH very closely resemble
  IPAH in their histopathologic features, history,
  and response to treatment.
• The World Health Organization has now
  reclassified pulmonary hypertension into five
  groups

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WHO Classifications

• Group 1 PH Pulmonary Arterial Hypertension
• Group 2 PH Pulmonary venous hypertension PH
  due to left-sided heart disease (atrial,
  ventricular, or valvular)
• Group 3 PH PH associated with disorders or the
  respiratory system or hypoxemia includes
  interstitial lung disease, COPD, obstructive
  sleep apnea, alveolar hypoventilation disorders,
  and other causes of hypoxemia
• Group 4 PH PH caused by chronic thromboembolic
  disease includes chronic thrombotic occlusion
  of the vasculature as well as non thrombotic PE
  (eg, schistosomiasis)
• Group 5 PH caused by inflammation, mechanical
  obstruction, or extrinsic compression of the
  pulmonary vasculature (sarcoidosis,
  histiocytosis, fibrosing mediastinitis)

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Group 1 PAH

• Referred to as Pulmonary Arterial Hypertension
  (PAH)
• Includes sporadic and familial IPAH, as well as
  PAH secondary to diseases which localize to the
  small pulmonary arterioles (Collagen vascular
  diseases, congenital heart disease with
  systemic-to-pulmonary shunts, portal
  hypertension, HIV, and anorexigens)
• Hemodynamic parameters of PAH
• -mean PAP gt25 mmHg at rest or 30 mmHg with
  exercise
• -Pulmonary capillary wedge pressure PCWP lt15
  mmHG
• -Pulmonary vascular resistance gt120
  dynes/sec/cm5
• -Transpulmonary gradient gt10 mmHg
  (difference between mean PAP and PCWP

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• Idiopathic pulmonary arterial hypertension exists
  when another cause cannot be identified. There
  may be a role of an abnormal bone morphogenic
  protein receptor type II (up to 25 of sporadic
  IPAH have abnormal BMPR2)
• Possibly autosomal dominant with incomplete
  penetrance of BMPR2 in familial IPAH
• Collagen vascular diseases such as scleroderma
  cause obliteration of alveolar capillaries and
  narrowing of small arteries and arterioles due to
  pulmonary vascular disease and interstitial
  fibrosis. There is an association with the
  presence of Raynaud phenomenon and those who
  develop PAH.
• Intracardiac shunts result in pulmonary blood
  volume overload, resulting in PAH
• Anorexigens, stimulants, HIV can all result in
  PAH
• Portopulmonary Hypertension

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Portopulmonary Hypertension

• PPHTN refers to pulmonary arterial hypertension
  which is associated with portal hypertension and
  there is no other identifiable cause of the PAH.
• PPHTN is demonstrated by right heart cath. The
  parameters for diagnosis are the same as PAH.
• The prevalence of PPHTN is highest in patients
  undergoing evaluation for liver transplant (3.5
  to 16.1)
• Chronic liver disease without portal hypertension
  does not cause PPHTN.
• Causes of portal hypertension which have been
  associated with PPHTN include cirrhosis, portal
  vein thrombosis, hepatic vein sclerosis,
  congenital portal circulation abnormalities, and
  periportal fibrosis

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Pathogenesis of PPHTN

• The cause of PPHTN is not known.
• The most accepted theory is that a humoral
  substance which would normally be metabolized by
  the liver is able to reach the pulmonary
  circulation. Proposed substances include
  serotonin, IL-1, endothelin-1, glucagon,
  secretin, thromboxane B2, and vasoactive
  intestinal peptide.
• Increased levels of all of these substances have
  been detected in patients with portal
  hypertension
• May be a genetic predisposition (abnormal BMPR2)
• Thromboembolism from the portal system
• Hyperdynamic circulation in patients with liver
  disease may cause PPHTN due to increased blood
  flow and increased sheer stress on the pulmonary
  vasculature

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Pathology

• The findings in PPHTN are identical to those seen
  in IPAH.
• Findings include vasoconstriction, remodeling of
  the muscular pulmonary arterial walls, and in
  situ thrombosis
• 2 subtypes of pulmonary arteriopathy in PPHTN
• -Plexogenic pulmonary arteriopathy medial
  hypertrophy, intimal fibrosis, and lesions which
  involve the entire wall of the vessel.
• -Thrombotic pulmonary arteriopathy
  characterized by medial hypertrophy, thrombosis,
  and eccentric, nonlaminar intimal fibrosis.
• Plexogenic lesions generally indicate that PH is
  irreversible.
• Medial hypertrophy is an early and potentially
  reversible form of the disease

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Clinical Presentation

• Patients typically present with exertional
  dyspnea, lethargy, and fatigue. These symptoms
  are due to inability of the cardiac output to
  increase with exercise.
• Exertional chest pain, syncope, and edema may
  develop as right ventricular failure develops.
• Anorexia and abdominal pain may result from
  passive hepatic congestion
• Cough, hemoptysis, and hoarseness (Ortners
  syndrome) may develop due to compression of the
  laryngeal nerve by a dilated pulmonary artery.
• In PPHTN, manifestations of portal hypertension
  typically precede those of PAH. These symptoms
  typically appear from 2-15 years before PAH is
  documented

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Physical exam

• Increased intensity of the pulmonic component of
  the second heart sound (may be palpable).
  Splitting of the second heart sound widens with
  right ventricular failure or right bundle branch
  block
• Systolic ejection murmur, increased with
  inspiration
• Right ventricular failure results in systemic
  venous hypertension, which can lead to elevated
  jugular venous pressure, RV third heart sound,
  tricuspid murmur if regurgitation is present,
  hepatomegaly, pulsatile liver, peripheral edema,
  and ascites

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Diagnostic Evaluation

• Chest Xray classic findings include enlargement
  of pulmonary arteries with distal pruning. This
  may not be seen until late in the course of the
  disease
• Electrocardiogram evidence of right ventricular
  hypertrophy, right axis deviation, right bundle
  branch block, right atrial enlargement
• Pulmonary function tests look for evidence of
  underlying lung disease
• Echocardiogram estimate pulmonary artery
  systolic pressure and assess right ventricular
  size and function may show D-shaped septum with
  paradoxical bulging during diastole tricuspid
  regurgitation secondary to right ventricular
  dilatation

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Diagnostic Evaluation

• Chest Xray classic findings include enlargement
  of pulmonary arteries with distal pruning. This
  may not be seen until late in the course of the
  disease
• Electrocardiogram evidence of right ventricular
  hypertrophy, right axis deviation, right bundle
  branch block, right atrial enlargement
• Pulmonary function tests look for evidence of
  underlying lung disease
• Echocardiogram estimate pulmonary artery
  systolic pressure and assess right ventricular
  size and function may show D-shaped septum with
  paradoxical bulging during diastole tricuspid
  regurgitation secondary to right ventricular
  dilatation

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Electrocardiogram demonstrating the changes of
right ventricular hypertrophy (long arrow) with
strain in a patient with primary pulmonary
hypertension. Right axis deviation (short arrow),
increased P-wave amplitude in lead II (black
arrowhead), and incomplete right bundle branch
block (white arrowhead) are highly specific but
lack sensitivity for the detection of right
ventricular hypertrophy.12
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Diagnostic Evaluation

• Chest Xray classic findings include enlargement
  of pulmonary arteries with distal pruning. This
  may not be seen until late in the course of the
  disease
• Electrocardiogram evidence of right ventricular
  hypertrophy, right axis deviation, right bundle
  branch block, right atrial enlargement
• Pulmonary function tests look for evidence of
  underlying lung disease
• Echocardiogram estimate pulmonary artery
  systolic pressure and assess right ventricular
  size and function may show D-shaped septum with
  paradoxical bulging during diastole tricuspid
  regurgitation secondary to right ventricular
  dilatation

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The four chamber view shows severe dilation of
the right ventricle (RV) and right atrium (RA)
with evidence of high right sided filling
pressure the interventricular septum (red arrow)
and the interatrial septum (white arrows) bulge
into the left ventricle (LV) and left atrium (LA)
respectively.
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Diagnosis

• Overnight oximetry nocturnal desaturation is
  common in PH. However, polysomnography is the
  gold standard for diagnosis of obstructive sleep
  apnea
• V/Q scan evaluate for thromboembolic disease
• Labs HIV, LFTs, ANA, RF, ANCA, BNP
• Exercise testing determine NYHA class and
  establish a baseline for determining response to
  treatment
• Right heart catheterization - needed to confirm
  the diagnosis by measuring PA pressures

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Primary Therapy

• For secondary forms of pulmonary hypertension,
  the primary therapy is aimed at the underlying
  cause.
• There is no primary therapy for Group 1 PAH, and
  advanced therapy is often required.
• There are several therapies which should be
  considered for all groups including-Diuretics
  to decrease hepatic congestion and peripheral
  edema
• -Oxygen therapy for anyone with hypoxemia
• -Anticoagulation due to the risk of
  intrapulmonary thrombosis and thromboembolism
  from sluggish pulmonary flow, dilated right
  heart, and venous stasis
• -Digoxin to improve left ventricular
  function and control heart rate in patients with
  SVT associated with right heart dysfunction
  
  
  

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Advanced Therapy

• Refers to the administration of agents with
  complex mechanisms of action including
  vasodilation, vascular growth, and remodeling
• Most well established in patients with Group 1
  PAH
• May be applicable in all groups if they remain
  NYHA class III or IV after primary therapy
• Patients should undergo vasoreactivity testing
  prior to initiation of advanced therapy

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Vasoreactivity test

• Involves administration of a short-acting
  vasodilator and then measurement of hemodynamic
  response with right heart catheterization.
• Commonly used vasodilators include epoprostenol,
  adenosine, and inhaled nitric oxide
• The vasoreactivity test is positive if the mean
  pulmonary artery pressure decreases by at least
  10 mmHg or to a level less than 40 mmHg, with an
  increased or unchanged cardiac output and
  minimally reduced or unchanged systemic blood
  pressure

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Calcium Channel Blockers

• Patients with a positive vasoreactivity test
  should be tried on a calcium channel blocker.
  Those with a negative test have not been shown to
  benefit from CCB therapy
• The goal of CCB therapy is to decrease pulmonary
  artery pressure and decrease the right
  ventricular afterload
• A positive response to treatment is referred to
  as patients being in functional class I or II
  with near normal hemodynamics after several
  months of therapy
• Patients with PPHTN should not undergo
  vasoreactivity testing because they are rarely
  vasoreactive and they have high risk of adverse
  effects from pure vasodilator therapy

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Advanced Therapy

• Patients with a negative vasoreactivity test,
  those who failed a 6 month CCB trial, and
  patients with PPHTN should be considered for
  alternative therapy
• Advanced therapy includes Prostanoids, Endothelin
  receptor antagonists, or Phosphodiesterase
  inhibitors
• Prostanoids Epoprostenol (Flolan), Treprostinol
  (Remodulin), and Iloprost (Ventavis)
• Endothelin receptor antagonists Bosentan
  (Tracleer)
• Phosphodiesterase inhibitors Sildenafil
  (Viagra, Revatio)

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Refractory Pulmonary Hypertension

• Atrial septostomy creates a right-to-left shunt
  in order to increase systemic blood flow and
  bypass the pulmonary vascular obstruction. In
  some patients this increases cardiac output and
  improves systemic oxygen delivery. There is a
  high procedure-related mortality risk.
• Transplantation both lung and heart-lung
  transplant have been successful in IPAH
• Liver transplant has been successful in patients
  with PPHTN

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Prognosis

• Survival in untreated IPAH is approximately 3
  years. If there is severe PAH or right
  ventricular failure, survival is usually less
  than one year.
• Prognosis in PPHTN is extremely poor with high
  six month mortality (50). Death is usually from
  infection or right heart failure

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Poor prognostic factors

• Age greater than 35 at presentation
• NYHA class III or IV with failure to improve to a
  lower class during treatment
• Pericardial effusion
• large right atrial size
• elevated right atrial pressure
• septal shift during diastole
• increased BNP
• hypocapnea

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Summary

• Pre-transplant diagnosis Hepatopulmonary
  Syndrome
• Post-transplant diagnosis Pulmonary Hypertension
• Diagnostic procedure needed Right heart
  catheterization

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Thanks!

• Dr. William Petersen
• Dr. Karen Brust
• Dr. Esther Fields
• Dr. Geoff Fillmore
• Dr. Heather Henderson
• Dr. Jonathan Mock

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References

• Murray and Nadels Textbook of Respiratory
  Medicine, 4th ed. (2005)
• Current Diagnosis and Treatment in Cardiology,
  2nd ed. (2003)
• UpToDate
• Prognosis of Pulmonary Arterial Hypertension.
  Chest 2004 1261
• Diagnosis and Treatment of Pulmonary
  Hypertension. American Family Physician 2001
  639
• www.lib.mcg.edu
• www.rfumsphysiology.pbwiki.com