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Pulmonary CPC Taylor Pruett, MD January 11, 2008 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. 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. 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 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 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 Laboratory Data 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 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 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. 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 Objectives Discussion of pre-transplant diagnosis Discussion of post-transplant diagnosis Desired diagnostic testing Problem List (Pre-transplant) Dyspnea Hepatitis C with cirrhosis Pulmonary function abnormalities (decreased DLCO) Severe hypoxemia Intrapulmonary shunt 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 <60 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 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 (>7 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) 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 IPVDs 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 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 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 nonventilated 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 IPVDs 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 <80 mmHG and A-a gradient >20 mmHG) 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 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. 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 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 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 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. 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 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) 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 >25 mmHg at rest or 30 mmHg with exercise -Pulmonary capillary wedge pressure PCWP <15 mmHG -Pulmonary vascular resistance >120 dynes/sec/cm5 -Transpulmonary gradient >10 mmHg (difference between mean PAP and PCWP 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 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 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 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 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 (Ortner’s 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 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 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 Dshaped septum with paradoxical bulging during diastole; tricuspid regurgitation secondary to right ventricular dilatation 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 Dshaped septum with paradoxical bulging during diastole; tricuspid regurgitation secondary to right ventricular dilatation 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 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 Dshaped septum with paradoxical bulging during diastole; tricuspid regurgitation secondary to right ventricular dilatation 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. 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 Patients with pulmonary hypertension but without resulting Class I 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 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 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 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 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 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) 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 procedurerelated mortality risk. Transplantation – both lung and heart-lung transplant have been successful in IPAH Liver transplant has been successful in patients with PPHTN 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 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 Summary Pre-transplant diagnosis: Hepatopulmonary Syndrome Post-transplant diagnosis: Pulmonary Hypertension Diagnostic procedure needed: Right heart catheterization Thanks! Dr. William Petersen Dr. Karen Brust Dr. Esther Fields Dr. Geoff Fillmore Dr. Heather Henderson Dr. Jonathan Mock References Murray and Nadel’s Textbook of Respiratory Medicine, 4th ed. (2005) Current Diagnosis and Treatment in Cardiology, 2nd ed. (2003) UpToDate Prognosis of Pulmonary Arterial Hypertension. Chest 2004; 126:1 Diagnosis and Treatment of Pulmonary Hypertension. American Family Physician 2001; 63:9 www.lib.mcg.edu www.rfumsphysiology.pbwiki.com