Pulmonary CPC Taylor Pruett, MD January 11, 2008.

Pulmonary CPCPulmonary CPC

Taylor Pruett, MDTaylor Pruett, MD

January 11, 2008January 11, 2008

CC: WeaknessCC: Weakness HPI: 54 year old Caucasian female with chief HPI: 54 year old Caucasian female with chief

complaint of weakness. She has a history of complaint of weakness. She has a history of cirrhosis secondary to Hepatitis C. Extensive cirrhosis secondary to Hepatitis C. Extensive rheumatologic evaluation at the time of diagnosis rheumatologic evaluation at the time of diagnosis was negative. was negative.

The patient was referred to the pulmonary The patient was referred to the pulmonary department 2 years prior to the current presentation department 2 years prior to the current presentation for dyspnea. Several tests were performed in for dyspnea. Several tests were performed in evaluation of this. Spirometry was normal; the DLco evaluation of this. Spirometry was normal; the DLco was 49% predicted. Shunt study X 2 was 11%. was 49% predicted. Shunt study X 2 was 11%. Oxygen requirements to maintain oxygen saturations Oxygen requirements to maintain oxygen saturations over 92% was 4-6 LPM. Echocardiogram with over 92% was 4-6 LPM. Echocardiogram with agitated saline was normal except for the late agitated saline was normal except for the late appearance of bubbles in the pulmonary veins appearance of bubbles in the pulmonary veins suggestive of intrapulmonary shunting. Pulmonary suggestive of intrapulmonary shunting. Pulmonary arteriograms and CT of the chest were normal.arteriograms and CT of the chest were normal.

Due to the persistent hypoxemia, the patient was Due to the persistent hypoxemia, the patient was listed high for transplant.listed high for transplant.

Liver transplant was performed eight months prior to Liver transplant was performed eight months prior to this admission. The patient reported that she no this admission. The patient reported that she no longer required oxygen by two months post-longer required oxygen by two months post-transplant.transplant.

Four months prior to this admission the patient had a Four months prior to this admission the patient had a mild course of rejection, and one month prior to mild course of rejection, and one month prior to admission she was diagnosed with hepatic admission she was diagnosed with hepatic encephalopathy. Liver biopsy was performed at that encephalopathy. Liver biopsy was performed at that time and revealed Grade 3, stage 2 Hepatitis C time and revealed Grade 3, stage 2 Hepatitis C without rejection. Lactulose was initiated, but since without rejection. Lactulose was initiated, but since then the patient has had increasing weakness, then the patient has had increasing weakness, dyspnea, and mild lower extremity edema.dyspnea, and mild lower extremity edema.

Her BP post-transplant was in the 120s/70s and her Her BP post-transplant was in the 120s/70s and her creatinine ranged from 1.4-1.9. Her transaminases creatinine ranged from 1.4-1.9. Her transaminases were 2X the upper limit of normal. were 2X the upper limit of normal.

HistoryHistory Past Medical History: as above, plus iron deficiency Past Medical History: as above, plus iron deficiency

anemia and allergic rhinitisanemia and allergic rhinitis Past Surgical History: liver transplant, cesarean Past Surgical History: liver transplant, cesarean

section 20 years ago, tonsillectomy remotelysection 20 years ago, tonsillectomy remotely Social: The patient currently stays at home. She Social: The patient currently stays at home. She

denies alcohol, tobacco, or illicit drug use. She and denies alcohol, tobacco, or illicit drug use. She and her husband live in Wacoher husband live in Waco

Allergies: Erythromycin, Zosyn, VicodinAllergies: Erythromycin, Zosyn, Vicodin

MedicationsMedications Prograf 1 mg po dailyPrograf 1 mg po daily Myfortic 360 mg po nightlyMyfortic 360 mg po nightly Prevacid 30 mg po BIDPrevacid 30 mg po BID Bumex 1 mg po dailyBumex 1 mg po daily Centrum dailyCentrum daily Caltrate-D dailyCaltrate-D daily Actigall 300 mg po QIDActigall 300 mg po QID Reglan 10 mg po TIDReglan 10 mg po TID

Physical ExamPhysical Exam Vital Signs: Afebrile, BP 115/77, P 84, O2 sat 93% Vital Signs: Afebrile, BP 115/77, P 84, O2 sat 93%

on RAon RA General: Fatigued, Oriented X3General: Fatigued, Oriented X3 HEENT: PERRLA, mild icterus, oral mucosa moistHEENT: PERRLA, mild icterus, oral mucosa moist Neck: no adenopathy; JVP with a variable degree Neck: no adenopathy; JVP with a variable degree

of elevation by multiple examinersof elevation by multiple examiners Lungs: no ralesLungs: no rales Cardiovascular: regular rhythm with questionable Cardiovascular: regular rhythm with questionable

murmur and ventricular liftmurmur and ventricular lift Abdomen: soft, no rebound tenderness, no Abdomen: soft, no rebound tenderness, no

hepatomegaly or evidence of asciteshepatomegaly or evidence of ascites Extremities: edema to the lower calves that is Extremities: edema to the lower calves that is

symmetricsymmetric

Laboratory DataLaboratory Data

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

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

StudiesStudies EKG revealed normal sinus rhythm with right axis EKG revealed normal sinus rhythm with right axis

deviation, right ventricular hypertrophy, and an deviation, right ventricular hypertrophy, and an incomplete right bundle branch block. There was incomplete right bundle branch block. There was evidence of left atrial enlargement and anteroseptal evidence of left atrial enlargement and anteroseptal infarction, age undetermined.infarction, age undetermined.

Chest Xray: hazy opacification at the loft lower Chest Xray: hazy opacification at the loft lower thorax with blunting of the costophrenic angles thorax with blunting of the costophrenic angles bilaterally consistent with pleural fluid or thickening. bilaterally consistent with pleural fluid or thickening. Cardiac silhouette remains prominent and there is Cardiac silhouette remains prominent and there is slight fullness at the hilar region.slight fullness at the hilar region.

Limited echocardiogram at the bedside in the Limited echocardiogram at the bedside in the Emergency room revealed a large pericardial Emergency room revealed a large pericardial effusion.effusion.

Hospital CourseHospital Course The patient was admitted for further evaluationThe patient was admitted for further evaluation She underwent pericardiocentesis with removal of She underwent pericardiocentesis with removal of

175 ml of serous fluid175 ml of serous fluid Blood pressure subsequently declined with fall in Blood pressure subsequently declined with fall in

urine outputurine output EKG was unchangedEKG was unchanged Creatinine increased from 1.9 on admission to 2.7 Creatinine increased from 1.9 on admission to 2.7

then 3.8 the following daythen 3.8 the following day A diagnostic procedure was performed, and the A diagnostic procedure was performed, and the

patient ultimately expiredpatient ultimately expired

ObjectivesObjectives

Discussion of pre-transplant Discussion of pre-transplant diagnosisdiagnosis

Discussion of post-transplant Discussion of post-transplant diagnosisdiagnosis

Desired diagnostic testing Desired diagnostic testing

Problem List (Pre-Problem List (Pre-transplant)transplant)

DyspneaDyspnea Hepatitis C with cirrhosisHepatitis C with cirrhosis Pulmonary function abnormalities (decreased Pulmonary function abnormalities (decreased

DLDLCOCO)) Severe hypoxemiaSevere hypoxemia Intrapulmonary shuntIntrapulmonary shunt

Hepatopulmonary Hepatopulmonary SyndromeSyndrome

Hepatopulmonary syndrome consists of a triad of Hepatopulmonary syndrome consists of a triad of advanced chronic liver disease, arterial advanced chronic liver disease, arterial oxygenation defect, and widespread oxygenation defect, and widespread intrapulmonary vascular dilations (IPVDs)intrapulmonary vascular dilations (IPVDs)

Estimated to occur in 4 – 47% of patients with Estimated to occur in 4 – 47% of patients with chronic liver diseasechronic liver disease

Mild to moderate hypoxemia is common in chronic Mild to moderate hypoxemia is common in chronic liver diseaseliver disease

Severe hypoxemia with PaO2 <60 mmHg should Severe hypoxemia with PaO2 <60 mmHg should suggest HPS (in the absence of other suggest HPS (in the absence of other cardiopulmonary disease)cardiopulmonary disease)

Can be associated with any form of chronic liver Can be associated with any form of chronic liver disease as well as some forms of acute liver diseasedisease as well as some forms of acute liver disease

Clinical Manifestations Clinical Manifestations 80% of patients have signs of chronic liver 80% of patients have signs of chronic liver

disease as their initial presentation. 20% disease as their initial presentation. 20% present with dyspnea.present with dyspnea.

The presence of abundant spider angiomata has The presence of abundant spider angiomata has been suggested as a marker for the severity of been suggested as a marker for the severity of HPSHPS

Frequently associated with hyperdynamic Frequently associated with hyperdynamic circulation manifested as elevated cardiac output circulation manifested as elevated cardiac output (>7 L/min), decreased systemic and pulmonary (>7 L/min), decreased systemic and pulmonary vascular resistance, and narrowed arterial – vascular resistance, and narrowed arterial – mixed venous oxygen content differencemixed venous oxygen content difference

Pulmonary findings include platypnea (increase Pulmonary findings include platypnea (increase in dyspnea in the upright position) and in dyspnea in the upright position) and orthodexia (decrease O2 sat in the upright orthodexia (decrease O2 sat in the upright position)position)

Intrapulmonary Vascular Intrapulmonary Vascular DilationsDilations

IPVDs are the hallmark of hepatopulmonary IPVDs are the hallmark of hepatopulmonary syndromesyndrome

They are widespread vascular dilations which They are widespread vascular dilations which result in decreased resistance and increased result in decreased resistance and increased blood flow through the pulmonary vasculature.blood flow through the pulmonary vasculature.

Unclear what causes IPVDs. Suggested Unclear what causes IPVDs. Suggested causes include failure of the damaged liver to causes include failure of the damaged liver to metabolize circulating vasodilators, production metabolize circulating vasodilators, production of a vasodilator by the liver, and inhibition of of a vasodilator by the liver, and inhibition of circulating vasoconstrictor by the damaged circulating vasoconstrictor by the damaged liverliver

Nitric oxide and the persistent induction of Nitric oxide and the persistent induction of nitric oxide synthase are presumed to play a nitric oxide synthase are presumed to play a role in the development of IPVDs role in the development of IPVDs

IPVDsIPVDs

Diffuse dilatation of the pulmonary Diffuse dilatation of the pulmonary circulation results in a right-to-left shunt, circulation results in a right-to-left shunt, orthodexia, loss of hypoxia induced orthodexia, loss of hypoxia induced vasoconstriction, and over-perfusion of vasoconstriction, and over-perfusion of low ventilation areaslow ventilation areas

Orthodexia thought to be secondary to Orthodexia thought to be secondary to perfusion of IPVDs in the lung bases in perfusion of IPVDs in the lung bases in the upright positionthe upright position

Hypoxemia in HPSHypoxemia in HPS Three components to gas exchange Three components to gas exchange

abnormalities: abnormalities: -ventilation - perfusion mismatch-ventilation - perfusion mismatch -intrapulmonary shunting-intrapulmonary shunting -impaired oxygen diffusion-impaired oxygen diffusion All of these mechanisms are a direct result of All of these mechanisms are a direct result of

IPVDsIPVDs When HPS is mild, the predominant When HPS is mild, the predominant

mechanism of hypoxemia is V/Q mismatch. mechanism of hypoxemia is V/Q mismatch. This is due to the presence of areas in which This is due to the presence of areas in which ventilation is preserved, but perfusion is ventilation is preserved, but perfusion is profoundly increased due to massive dilation profoundly increased due to massive dilation of the vesselsof the vessels

When HPS is severe, the primary mechanism When HPS is severe, the primary mechanism of hypoxemia is intrapulmonary right-to-left of hypoxemia is intrapulmonary right-to-left shuntingshunting

Right-to-Left ShuntingRight-to-Left Shunting Anatomic shunt exists when the alveoli are Anatomic shunt exists when the alveoli are

bypassed. This occurs in intracardiac shunts, bypassed. This occurs in intracardiac shunts, pulmonary AVMs, and hepatopulmonary pulmonary AVMs, and hepatopulmonary syndromesyndrome

Physiologic shunts occur when there is Physiologic shunts occur when there is perfusion of non-ventilated areas such as in perfusion of non-ventilated areas such as in atelectasis, pneumonia, and ARDSatelectasis, pneumonia, and ARDS

IPVDs do not function as true anatomic shuntsIPVDs do not function as true anatomic shunts Oxygen molecules are unable to diffuse to the Oxygen molecules are unable to diffuse to the

center of the blood vessel due to the degree of center of the blood vessel due to the degree of dilation and the large diameter of the vessel.dilation and the large diameter of the vessel.

Oxygenation typically improves as Oxygenation typically improves as supplemental oxygen is providedsupplemental oxygen is provided

IPVDsIPVDs

DiagnosisDiagnosis Echocardiogram (contrast-enhanced) – gold standard for Echocardiogram (contrast-enhanced) – gold standard for

diagnosisdiagnosis Nuclear Scanning (Scans show uptake over the kidneys of Nuclear Scanning (Scans show uptake over the kidneys of

Technetium-labeled macroaggregated albumin which Technetium-labeled macroaggregated albumin which should normally be trapped by the pulmonary bed) should normally be trapped by the pulmonary bed)

Pulmonary angiography (used to exclude other causes of Pulmonary angiography (used to exclude other causes of hypoxemia)hypoxemia)

Chest Xray (usually relatively normal)Chest Xray (usually relatively normal) Pulmonary function tests Pulmonary function tests -Spirometry (usually normal unless there is coexisting -Spirometry (usually normal unless there is coexisting

obstructive or restrictive lung disease)obstructive or restrictive lung disease) -Diffusion capacity (mildly to severely impaired)-Diffusion capacity (mildly to severely impaired) -Shunt fraction -Shunt fraction -ABG (PaO2 <80 mmHG and A-a gradient >20 mmHG)-ABG (PaO2 <80 mmHG and A-a gradient >20 mmHG)

EchocardiogramEchocardiogram Contrast-enhanced echo is the preferred Contrast-enhanced echo is the preferred

diagnostic modality for detecting IPVDsdiagnostic modality for detecting IPVDs Intravenous indocyanine dye or agitated saline Intravenous indocyanine dye or agitated saline

can differentiate between intracardiac and can differentiate between intracardiac and intrapulmonary shunts. These are normally intrapulmonary shunts. These are normally filtered by the pulmonary bed and do not enter filtered by the pulmonary bed and do not enter the left heart. the left heart.

In an intracardiac shunt, dye will appear in the In an intracardiac shunt, dye will appear in the left heart within 3 heartbeatsleft heart within 3 heartbeats

In an intrapulmonary shunt, dye will appear in In an intrapulmonary shunt, dye will appear in the left heart later, within 3-6 heartbeatsthe left heart later, within 3-6 heartbeats

TEE can directly visualize microbubbles in the TEE can directly visualize microbubbles in the pulmonary veins as they enter the left atriumpulmonary veins as they enter the left atrium

TreatmentTreatment Multiple attempts have been made to improve Multiple attempts have been made to improve

oxygenation in HPS. There has been no oxygenation in HPS. There has been no improvement associated with attempts to improvement associated with attempts to physically occlude IPVDs, oppose vasodilators, physically occlude IPVDs, oppose vasodilators, and treatment of the underlying liver disease.and treatment of the underlying liver disease.

A few case reports have documented improvement A few case reports have documented improvement with transjugular intrahepatic portosystemic with transjugular intrahepatic portosystemic shunt placement (TIPS), but this has been shunt placement (TIPS), but this has been inconsistent and its use is not recommended.inconsistent and its use is not recommended.

One report on a single patient successfully treated One report on a single patient successfully treated with inhaled N(G)-nitro-L-arginine methyl ester with inhaled N(G)-nitro-L-arginine methyl ester (L-NAME) which is an inhibitor of nitric oxide (L-NAME) which is an inhibitor of nitric oxide synthesis. Treatment resulted in an increase of synthesis. Treatment resulted in an increase of PaO2 from 52 to 70 mmHg and an increase in the PaO2 from 52 to 70 mmHg and an increase in the 6 minute walk distance.6 minute walk distance.

Liver TransplantLiver Transplant To date, liver transplant offers the most benefit for To date, liver transplant offers the most benefit for

patients with severe and refractory hypoxemia.patients with severe and refractory hypoxemia. Significant improvements in oxygenation and reversal Significant improvements in oxygenation and reversal

of shunting have been documented after of shunting have been documented after transplantation.transplantation.

No randomized trials have been performed in this No randomized trials have been performed in this area, however, multiple observational studies show area, however, multiple observational studies show significant survival benefitsignificant survival benefit

Back to our patient…Back to our patient… Met criteria for HPS (severe hypoxemia, chronic liver Met criteria for HPS (severe hypoxemia, chronic liver

disease, IPVDs)disease, IPVDs) Underwent liver transplant 8 months ago. Significant Underwent liver transplant 8 months ago. Significant

improvement in oxygenation (she no longer required improvement in oxygenation (she no longer required supplemental O2 after 2 months)supplemental O2 after 2 months)

Unfortunately, the patient has now developed signs of Unfortunately, the patient has now developed signs of chronic liver disease including hepatic chronic liver disease including hepatic encephalopathy.encephalopathy.

Biopsy of the transplanted liver reveals advanced Biopsy of the transplanted liver reveals advanced hepatitis Chepatitis C

Current Problem ListCurrent Problem List Weakness, Dyspnea, EdemaWeakness, Dyspnea, Edema Active hepatitis C in transplanted liverActive hepatitis C in transplanted liver ImmunocompromisedImmunocompromised Evidence of right-sided heart failure (demonstrated Evidence of right-sided heart failure (demonstrated

by EKG, elevated BNP, and physical exam)by EKG, elevated BNP, and physical exam) Pericardial effusionPericardial effusion

Pulmonary HypertensionPulmonary Hypertension Pathologic state characterized by consistently Pathologic state characterized by consistently

elevated pulmonary arterial pressure and elevated pulmonary arterial pressure and secondary right ventricular failure.secondary right ventricular failure.

Defined as a mean pulmonary artery pressure Defined as a mean pulmonary artery pressure greater than 25 mmHg at rest or 30 mmHg with greater than 25 mmHg at rest or 30 mmHg with exercise (as measured with right heart cath)exercise (as measured with right heart cath)

Elevation of the pressure inside the normally low Elevation of the pressure inside the normally low pressure pulmonary vascular bed results in pressure pulmonary vascular bed results in increased vascular resistance and decreased increased vascular resistance and decreased cardiac output.cardiac output.

Results from reduction in the caliber of the Results from reduction in the caliber of the pulmonary vessels, an increase in pulmonary pulmonary vessels, an increase in pulmonary blood flow, or both.blood flow, or both.

ClassificationClassification Pulmonary hypertension was previously classified as Pulmonary hypertension was previously classified as

either Idiopathic pulmonary arterial hypertension either Idiopathic pulmonary arterial hypertension (IPAH – also called Primary pulmonary hypertension) (IPAH – also called Primary pulmonary hypertension) or secondary pulmonary hypertensionor secondary pulmonary hypertension

Some forms of secondary PH very closely resemble Some forms of secondary PH very closely resemble IPAH in their histopathologic features, history, and IPAH in their histopathologic features, history, and response to treatment.response to treatment.

The World Health Organization has now reclassified The World Health Organization has now reclassified pulmonary hypertension into five groupspulmonary hypertension into five groups

WHO ClassificationsWHO Classifications Group 1 PH – “Pulmonary Arterial Hypertension”Group 1 PH – “Pulmonary Arterial Hypertension” Group 2 PH – “Pulmonary venous hypertension” – Group 2 PH – “Pulmonary venous hypertension” –

PH due to left-sided heart disease (atrial, PH due to left-sided heart disease (atrial, ventricular, or valvular)ventricular, or valvular)

Group 3 PH – “PH associated with disorders or Group 3 PH – “PH associated with disorders or the respiratory system or hypoxemia” – includes the respiratory system or hypoxemia” – includes interstitial lung disease, COPD, obstructive sleep interstitial lung disease, COPD, obstructive sleep apnea, alveolar hypoventilation disorders, and apnea, alveolar hypoventilation disorders, and other causes of hypoxemiaother causes of hypoxemia

Group 4 PH – “PH caused by chronic Group 4 PH – “PH caused by chronic thromboembolic disease” – includes chronic thromboembolic disease” – includes chronic thrombotic occlusion of the vasculature as well as thrombotic occlusion of the vasculature as well as non thrombotic PE (eg, schistosomiasis)non thrombotic PE (eg, schistosomiasis)

Group 5 PH – caused by inflammation, Group 5 PH – caused by inflammation, mechanical obstruction, or extrinsic compression mechanical obstruction, or extrinsic compression of the pulmonary vasculature (sarcoidosis, of the pulmonary vasculature (sarcoidosis, histiocytosis, fibrosing mediastinitis)histiocytosis, fibrosing mediastinitis)

Group 1 PAHGroup 1 PAH Referred to as Pulmonary Arterial Hypertension Referred to as Pulmonary Arterial Hypertension

(PAH)(PAH) Includes sporadic and familial IPAH, as well as PAH Includes sporadic and familial IPAH, as well as PAH

secondary to diseases which localize to the small secondary to diseases which localize to the small pulmonary arterioles (Collagen vascular diseases, pulmonary arterioles (Collagen vascular diseases, congenital heart disease with systemic-to-pulmonary congenital heart disease with systemic-to-pulmonary shunts, portal hypertension, HIV, and anorexigens)shunts, portal hypertension, HIV, and anorexigens)

Hemodynamic parameters of PAH:Hemodynamic parameters of PAH: -mean PAP >25 mmHg at rest or 30 mmHg with -mean PAP >25 mmHg at rest or 30 mmHg with

exerciseexercise -Pulmonary capillary wedge pressure PCWP <15 -Pulmonary capillary wedge pressure PCWP <15

mmHGmmHG -Pulmonary vascular resistance >120 dynes/sec/cm5-Pulmonary vascular resistance >120 dynes/sec/cm5 -Transpulmonary gradient >10 mmHg (difference -Transpulmonary gradient >10 mmHg (difference

between mean PAP and PCWPbetween mean PAP and PCWP

Idiopathic pulmonary arterial hypertension exists Idiopathic pulmonary arterial hypertension exists when another cause cannot be identified. There when another cause cannot be identified. There may be a role of an abnormal bone morphogenic may be a role of an abnormal bone morphogenic protein receptor type II (up to 25% of sporadic protein receptor type II (up to 25% of sporadic IPAH have abnormal BMPR2) IPAH have abnormal BMPR2)

Possibly autosomal dominant with incomplete Possibly autosomal dominant with incomplete penetrance of BMPR2 in familial IPAHpenetrance of BMPR2 in familial IPAH

Collagen vascular diseases such as scleroderma Collagen vascular diseases such as scleroderma cause obliteration of alveolar capillaries and cause obliteration of alveolar capillaries and narrowing of small arteries and arterioles due to narrowing of small arteries and arterioles due to pulmonary vascular disease and interstitial fibrosis. pulmonary vascular disease and interstitial fibrosis. There is an association with the presence of There is an association with the presence of Raynaud phenomenon and those who develop PAH.Raynaud phenomenon and those who develop PAH.

Intracardiac shunts result in pulmonary blood Intracardiac shunts result in pulmonary blood volume overload, resulting in PAHvolume overload, resulting in PAH

Anorexigens, stimulants, HIV can all result in PAHAnorexigens, stimulants, HIV can all result in PAH Portopulmonary HypertensionPortopulmonary Hypertension

Portopulmonary Portopulmonary HypertensionHypertension

PPHTN refers to pulmonary arterial hypertension PPHTN refers to pulmonary arterial hypertension which is associated with portal hypertension and which is associated with portal hypertension and there is no other identifiable cause of the PAH.there is no other identifiable cause of the PAH.

PPHTN is demonstrated by right heart cath. The PPHTN is demonstrated by right heart cath. The parameters for diagnosis are the same as PAH.parameters for diagnosis are the same as PAH.

The prevalence of PPHTN is highest in patients The prevalence of PPHTN is highest in patients undergoing evaluation for liver transplant (3.5 to undergoing evaluation for liver transplant (3.5 to 16.1%)16.1%)

Chronic liver disease without portal hypertension Chronic liver disease without portal hypertension does not cause PPHTN.does not cause PPHTN.

Causes of portal hypertension which have been Causes of portal hypertension which have been associated with PPHTN include cirrhosis, portal vein associated with PPHTN include cirrhosis, portal vein thrombosis, hepatic vein sclerosis, congenital portal thrombosis, hepatic vein sclerosis, congenital portal circulation abnormalities, and periportal fibrosiscirculation abnormalities, and periportal fibrosis

Pathogenesis of PPHTNPathogenesis of PPHTN The cause of PPHTN is not known.The cause of PPHTN is not known. The most accepted theory is that a humoral The most accepted theory is that a humoral

substance which would normally be metabolized by substance which would normally be metabolized by the liver is able to reach the pulmonary circulation. the liver is able to reach the pulmonary circulation. Proposed substances include serotonin, IL-1, Proposed substances include serotonin, IL-1, endothelin-1, glucagon, secretin, thromboxane B2, endothelin-1, glucagon, secretin, thromboxane B2, and vasoactive intestinal peptide.and vasoactive intestinal peptide.

Increased levels of all of these substances have been Increased levels of all of these substances have been detected in patients with portal hypertensiondetected in patients with portal hypertension

May be a genetic predisposition (abnormal BMPR2)May be a genetic predisposition (abnormal BMPR2) Thromboembolism from the portal systemThromboembolism from the portal system Hyperdynamic circulation in patients with liver Hyperdynamic circulation in patients with liver

disease may cause PPHTN due to increased blood disease may cause PPHTN due to increased blood flow and increased sheer stress on the pulmonary flow and increased sheer stress on the pulmonary vasculaturevasculature

PathologyPathology The findings in PPHTN are identical to those seen in IPAH.The findings in PPHTN are identical to those seen in IPAH. Findings include vasoconstriction, remodeling of the Findings include vasoconstriction, remodeling of the

muscular pulmonary arterial walls, and in situ thrombosismuscular pulmonary arterial walls, and in situ thrombosis 2 subtypes of pulmonary arteriopathy in PPHTN: 2 subtypes of pulmonary arteriopathy in PPHTN:

-Plexogenic pulmonary arteriopathy – medial hypertrophy, -Plexogenic pulmonary arteriopathy – medial hypertrophy, intimal fibrosis, and lesions which involve the entire wall of intimal fibrosis, and lesions which involve the entire wall of the vessel.the vessel.

-Thrombotic pulmonary arteriopathy – characterized by -Thrombotic pulmonary arteriopathy – characterized by medial hypertrophy, thrombosis, and eccentric, nonlaminar medial hypertrophy, thrombosis, and eccentric, nonlaminar intimal fibrosis. intimal fibrosis.

Plexogenic lesions generally indicate that PH is irreversible.Plexogenic lesions generally indicate that PH is irreversible. Medial hypertrophy is an early and potentially reversible Medial hypertrophy is an early and potentially reversible

form of the diseaseform of the disease

Clinical PresentationClinical Presentation Patients typically present with exertional dyspnea, Patients typically present with exertional dyspnea,

lethargy, and fatigue. These symptoms are due to lethargy, and fatigue. These symptoms are due to inability of the cardiac output to increase with inability of the cardiac output to increase with exercise.exercise.

Exertional chest pain, syncope, and edema may Exertional chest pain, syncope, and edema may develop as right ventricular failure develops.develop as right ventricular failure develops.

Anorexia and abdominal pain may result from Anorexia and abdominal pain may result from passive hepatic congestionpassive hepatic congestion

Cough, hemoptysis, and hoarseness (Ortner’s Cough, hemoptysis, and hoarseness (Ortner’s syndrome) may develop due to compression of the syndrome) may develop due to compression of the laryngeal nerve by a dilated pulmonary artery.laryngeal nerve by a dilated pulmonary artery.

In PPHTN, manifestations of portal hypertension In PPHTN, manifestations of portal hypertension typically precede those of PAH. These symptoms typically precede those of PAH. These symptoms typically appear from 2-15 years before PAH is typically appear from 2-15 years before PAH is documenteddocumented

Physical examPhysical exam Increased intensity of the pulmonic component of the Increased intensity of the pulmonic component of the

second heart sound (may be palpable). Splitting of second heart sound (may be palpable). Splitting of the second heart sound widens with right ventricular the second heart sound widens with right ventricular failure or right bundle branch blockfailure or right bundle branch block

Systolic ejection murmur, increased with inspirationSystolic ejection murmur, increased with inspiration Right ventricular failure results in systemic venous Right ventricular failure results in systemic venous

hypertension, which can lead to elevated jugular hypertension, which can lead to elevated jugular venous pressure, RV third heart sound, tricuspid venous pressure, RV third heart sound, tricuspid murmur if regurgitation is present, hepatomegaly, murmur if regurgitation is present, hepatomegaly, pulsatile liver, peripheral edema, and ascitespulsatile liver, peripheral edema, and ascites

Diagnostic EvaluationDiagnostic Evaluation Chest Xray – classic findings include enlargement Chest Xray – classic findings include enlargement

of pulmonary arteries with distal pruning. This may of pulmonary arteries with distal pruning. This may not be seen until late in the course of the diseasenot be seen until late in the course of the disease

Electrocardiogram – evidence of right ventricular Electrocardiogram – evidence of right ventricular hypertrophy, right axis deviation, right bundle hypertrophy, right axis deviation, right bundle branch block, right atrial enlargementbranch block, right atrial enlargement

Pulmonary function tests – look for evidence of Pulmonary function tests – look for evidence of underlying lung diseaseunderlying lung disease

Echocardiogram – estimate pulmonary artery Echocardiogram – estimate pulmonary artery systolic pressure and assess right ventricular size systolic pressure and assess right ventricular size and function; may show D-shaped septum with and function; may show D-shaped septum with paradoxical bulging during diastole; tricuspid paradoxical bulging during diastole; tricuspid regurgitation secondary to right ventricular regurgitation secondary to right ventricular dilatationdilatation

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

Diagnostic EvaluationDiagnostic Evaluation Chest Xray – classic findings include enlargement Chest Xray – classic findings include enlargement

of pulmonary arteries with distal pruning. This may of pulmonary arteries with distal pruning. This may not be seen until late in the course of the diseasenot be seen until late in the course of the disease

Electrocardiogram – evidence of right ventricular Electrocardiogram – evidence of right ventricular hypertrophy, right axis deviation, right bundle hypertrophy, right axis deviation, right bundle branch block, right atrial enlargementbranch block, right atrial enlargement

Pulmonary function tests – look for evidence of Pulmonary function tests – look for evidence of underlying lung diseaseunderlying lung disease

Echocardiogram – estimate pulmonary artery Echocardiogram – estimate pulmonary artery systolic pressure and assess right ventricular size systolic pressure and assess right ventricular size and function; may show D-shaped septum with and function; may show D-shaped septum with paradoxical bulging during diastole; tricuspid paradoxical bulging during diastole; tricuspid regurgitation secondary to right ventricular regurgitation secondary to right ventricular dilatationdilatation

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.

DiagnosisDiagnosis Overnight oximetry – nocturnal Overnight oximetry – nocturnal

desaturation is common in PH. However, desaturation is common in PH. However, polysomnography is the gold standard for polysomnography is the gold standard for diagnosis of obstructive sleep apneadiagnosis of obstructive sleep apnea

V/Q scan – evaluate for thromboembolic V/Q scan – evaluate for thromboembolic diseasedisease

Labs – HIV, LFTs, ANA, RF, ANCA, BNPLabs – HIV, LFTs, ANA, RF, ANCA, BNP Exercise testing – determine NYHA class Exercise testing – determine NYHA class

and establish a baseline for determining and establish a baseline for determining response to treatmentresponse to treatment

Right heart catheterization - needed to Right heart catheterization - needed to confirm the diagnosis by measuring PA confirm the diagnosis by measuring PA pressurespressures

Class IPatients with pulmonary hypertension but without resulting limitation of physical activity. Ordinary physical activity does not cause undue dyspnea or fatigue, chest pain, or near syncope.

Class II Patients with pulmonary hypertension resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity causes undue dyspnea or fatigue, chest pain, or near syncope.

Class III Patients with pulmonary hypertension resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary activity causes undue dyspnea or fatigue, chest pain, or near syncope.

Class IV Patients with pulmonary hypertension with inability to carry out any physical activity without symptoms. These patients manifest signs of right heart failure. Dyspnea or fatigue may be present even at rest. Discomfort is increased by any physical activity.

Primary TherapyPrimary Therapy For secondary forms of pulmonary hypertension, the For secondary forms of pulmonary hypertension, the

primary therapy is aimed at the underlying cause.primary therapy is aimed at the underlying cause. There is no primary therapy for Group 1 PAH, and There is no primary therapy for Group 1 PAH, and

advanced therapy is often required.advanced therapy is often required. There are several therapies which should be There are several therapies which should be

considered for all groups including:considered for all groups including:-Diuretics to decrease hepatic congestion and -Diuretics to decrease hepatic congestion and peripheral edemaperipheral edema

-Oxygen therapy for anyone with hypoxemia-Oxygen therapy for anyone with hypoxemia -Anticoagulation due to the risk of intrapulmonary -Anticoagulation due to the risk of intrapulmonary

thrombosis and thromboembolism from sluggish thrombosis and thromboembolism from sluggish pulmonary flow, dilated right heart, and venous stasispulmonary flow, dilated right heart, and venous stasis

-Digoxin to improve left ventricular function and -Digoxin to improve left ventricular function and control heart rate in patients with SVT associated with control heart rate in patients with SVT associated with right heart dysfunctionright heart dysfunction

Advanced TherapyAdvanced Therapy Refers to the administration of agents with complex Refers to the administration of agents with complex

mechanisms of action including vasodilation, vascular mechanisms of action including vasodilation, vascular growth, and remodelinggrowth, and remodeling

Most well established in patients with Group 1 PAHMost well established in patients with Group 1 PAH May be applicable in all groups if they remain NYHA May be applicable in all groups if they remain NYHA

class III or IV after primary therapyclass III or IV after primary therapy Patients should undergo vasoreactivity testing prior Patients should undergo vasoreactivity testing prior

to initiation of advanced therapyto initiation of advanced therapy

Vasoreactivity testVasoreactivity test Involves administration of a short-acting Involves administration of a short-acting

vasodilator and then measurement of vasodilator and then measurement of hemodynamic response with right heart hemodynamic response with right heart catheterization.catheterization.

Commonly used vasodilators include Commonly used vasodilators include epoprostenol, adenosine, and inhaled epoprostenol, adenosine, and inhaled nitric oxidenitric oxide

The vasoreactivity test is positive if the The vasoreactivity test is positive if the mean pulmonary artery pressure mean pulmonary artery pressure decreases by at least 10 mmHg or to a decreases by at least 10 mmHg or to a level less than 40 mmHg, with an level less than 40 mmHg, with an increased or unchanged cardiac output increased or unchanged cardiac output and minimally reduced or unchanged and minimally reduced or unchanged systemic blood pressuresystemic blood pressure

Calcium Channel Calcium Channel BlockersBlockers

Patients with a positive vasoreactivity test should be Patients with a positive vasoreactivity test should be tried on a calcium channel blocker. Those with a tried on a calcium channel blocker. Those with a negative test have not been shown to benefit from negative test have not been shown to benefit from CCB therapyCCB therapy

The goal of CCB therapy is to decrease pulmonary The goal of CCB therapy is to decrease pulmonary artery pressure and decrease the right ventricular artery pressure and decrease the right ventricular afterloadafterload

A positive response to treatment is referred to as A positive response to treatment is referred to as patients being in functional class I or II with near patients being in functional class I or II with near normal hemodynamics after several months of therapynormal hemodynamics after several months of therapy

Patients with PPHTN should not undergo Patients with PPHTN should not undergo vasoreactivity testing because they are rarely vasoreactivity testing because they are rarely vasoreactive and they have high risk of adverse vasoreactive and they have high risk of adverse effects from pure vasodilator therapyeffects from pure vasodilator therapy

Advanced TherapyAdvanced Therapy Patients with a negative vasoreactivity test, those Patients with a negative vasoreactivity test, those

who failed a 6 month CCB trial, and patients with who failed a 6 month CCB trial, and patients with PPHTN should be considered for alternative therapyPPHTN should be considered for alternative therapy

Advanced therapy includes Prostanoids, Endothelin Advanced therapy includes Prostanoids, Endothelin receptor antagonists, or Phosphodiesterase inhibitorsreceptor antagonists, or Phosphodiesterase inhibitors

Prostanoids – Epoprostenol (Flolan), Treprostinol Prostanoids – Epoprostenol (Flolan), Treprostinol (Remodulin), and Iloprost (Ventavis)(Remodulin), and Iloprost (Ventavis)

Endothelin receptor antagonists – Bosentan Endothelin receptor antagonists – Bosentan (Tracleer)(Tracleer)

Phosphodiesterase inhibitors – Sildenafil (Viagra, Phosphodiesterase inhibitors – Sildenafil (Viagra, Revatio)Revatio)

Refractory Pulmonary Refractory Pulmonary HypertensionHypertension

Atrial septostomy – creates a right-to-left shunt Atrial septostomy – creates a right-to-left shunt in order to increase systemic blood flow and in order to increase systemic blood flow and bypass the pulmonary vascular obstruction. In bypass the pulmonary vascular obstruction. In some patients this increases cardiac output and some patients this increases cardiac output and improves systemic oxygen delivery. There is a improves systemic oxygen delivery. There is a high procedure-related mortality risk. high procedure-related mortality risk.

Transplantation – both lung and heart-lung Transplantation – both lung and heart-lung transplant have been successful in IPAHtransplant have been successful in IPAH

Liver transplant has been successful in patients Liver transplant has been successful in patients with PPHTNwith PPHTN

PrognosisPrognosis Survival in untreated IPAH is approximately Survival in untreated IPAH is approximately

3 years. If there is severe PAH or right 3 years. If there is severe PAH or right ventricular failure, survival is usually less ventricular failure, survival is usually less than one year.than one year.

Prognosis in PPHTN is extremely poor with Prognosis in PPHTN is extremely poor with high six month mortality (50%). Death is high six month mortality (50%). Death is usually from infection or right heart failureusually from infection or right heart failure

Poor prognostic factorsPoor prognostic factors

Age greater than 35 at presentationAge greater than 35 at presentation NYHA class III or IV with failure to improve NYHA class III or IV with failure to improve

to a lower class during treatmentto a lower class during treatment Pericardial effusionPericardial effusion large right atrial sizelarge right atrial size elevated right atrial pressureelevated right atrial pressure septal shift during diastoleseptal shift during diastole increased BNPincreased BNP hypocapneahypocapnea

SummarySummary

Pre-transplant diagnosis: Pre-transplant diagnosis: Hepatopulmonary SyndromeHepatopulmonary Syndrome

Post-transplant diagnosis: Post-transplant diagnosis: Pulmonary HypertensionPulmonary Hypertension

Diagnostic procedure needed: Right Diagnostic procedure needed: Right heart catheterizationheart catheterization

Thanks!Thanks!

Dr. William PetersenDr. William Petersen Dr. Karen BrustDr. Karen Brust Dr. Esther FieldsDr. Esther Fields Dr. Geoff FillmoreDr. Geoff Fillmore Dr. Heather HendersonDr. Heather Henderson Dr. Jonathan MockDr. Jonathan Mock

ReferencesReferences Murray and Nadel’s Textbook of Respiratory Medicine, 4Murray and Nadel’s Textbook of Respiratory Medicine, 4thth ed. ed.

(2005)(2005) Current Diagnosis and Treatment in Cardiology, 2Current Diagnosis and Treatment in Cardiology, 2ndnd ed. (2003) ed. (2003) UpToDate UpToDate Prognosis of Pulmonary Arterial Hypertension. Chest 2004; Prognosis of Pulmonary Arterial Hypertension. Chest 2004;

126:1126:1 Diagnosis and Treatment of Pulmonary Hypertension. Diagnosis and Treatment of Pulmonary Hypertension.

American Family Physician 2001; 63:9American Family Physician 2001; 63:9 www.lib.mcg.eduwww.lib.mcg.edu www.rfumsphysiology.pbwiki.comwww.rfumsphysiology.pbwiki.com

Pulmonary CPC Taylor Pruett, MD January 11, 2008.

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Transcript of Pulmonary CPC Taylor Pruett, MD January 11, 2008.