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12/3/17 DISCLOSURES I am a full-time employee of Blade - PDF document

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12/3/17 DISCLOSURES I am a full-time employee of Blade Therapeutics. Blade Therapeutics is a small, private MANAGEMENT OF biopharmaceutical company advancing novel anti-fibrotic therapies to meet important patient needs. PULMONARY

  1. 12/3/17 DISCLOSURES • I am a full-time employee of Blade Therapeutics. Blade Therapeutics is a small, private MANAGEMENT OF biopharmaceutical company advancing novel anti-fibrotic therapies to meet important patient needs. PULMONARY HYPERTENSION • There is no relationship between the topic of this talk and any of the activities at Blade. • I am a Clinical Professor of Medicine at UCSF. IN THE ICU RAMONA DOYLE MD CLINICAL PROFESSOR OF MEDICINE UCSF LEARNING OBJECTIVES MANAGING PH IN THE ICU “Don’t just do something, stand there…” • Explain the pathophysiology of pulmonary hypertension • Describe the correct diagnosis of various etiologies of pulmonary hypertension in the ICU • Describe treatment modalities for pulmonary arterial hypertension 1

  2. 12/3/17 CLASSIFICATION OF PH Group 1. Pulmonary arterial hypertension (PAH) Idiopathic (IPAH) Group 3. Pulmonary hypertension due to lung • Heritable (HPAH) • diseases and/or hypoxemia • bone morphogenetic protein receptor type 2 (BMPR2) • Chronic obstructive pulmonary disease (COPD) • activin receptor-like kinase 1 gene (ALK1), endoglin (with or without haemorrhagic telangiectasia) • Interstitial lung disease (ILD) unknown • Other pulmonary diseases with mixed restrictive and obstructive pattern • Drug- and toxin-induced • Sleep-disordered breathing • • Alveolar hypoventilation disorders • Associated with (APAH): • Chronic exposure to high altitude • connective tissue diseases • Developmental abnormalities • Human immunodeficiency virus (HIV) infection Group 4. Chronic thromboembolic pulmonary • portal hypertension • congenital heart disease (CHD) hypertension (CTEPH) • schistosomiasis Group 5. PH with unclear multifactorial mechanisms • chronic haemolytic anaemia • Haematological disorders: myeloproliferative disorders, splenectomy Persistent pulmonary hypertension of the newborn (PPHN) • • Systemic disorders: sarcoidosis, pulmonary Langerhans cell histiocytosis, Group 2. Pulmonary hypertension due to left heart disease lymphangioleiomyomatosis, neurofibromatosis, vasculitis • Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid Systolic dysfunction • disorders • Diastolic dysfunction • Others: tumoural obstruction, fibrosing mediastinitis, chronic renal failure on dialysis • Valvular disease 6 Simonneau G et al. J Am Coll Cardiol 2009 COMMON CAUSES OF PH IN THE ICU PH IN THE ICU • Common causes of PH in the ICU • Acute pulmonary embolism (PE) • Perioperative PH • Post-surgical management • Hypoxemic respiratory failure • Management of pulmonary arterial hypertension (PAH) in the ICU • Management of right heart failure and PAH 2

  3. 12/3/17 CLASSIFICATION OF PH DIAGNOSIS OF PH: ECHOCARDIOGRAM DIAGNOSIS OF PH IN THE ICU 3

  4. 12/3/17 DIAGNOSIS OF PH IN THE ICU ACUTE PULMONARY EMBOLISM IN THE ICU POST-SURGICAL PH: THE SIOVAC STUDY • PH seen in almost all patients with severe mitral disease and up to 2/3 of those with aortic stenosis • Off label use of sildenafil has been promoted by some for treatment of residual PH following left heart • Patients in ICU by definition at higher risk for pulmonary embolism valvular corrective surgery RV dysfunction is key determinant of prognosis in acute PE • • SIOVAC study RV dysfunction or persistent hypotension at presentation = acute high risk PE • • A RDBPCT study of 200 adult patients with residual PH following corrective valvular heart surgery Acute high risk PE is trigger for thrombolysis – catheter directed vs systemic • • Primary endpoint was HF composite score (mortality, hospital admission for HF, worse exercise tolerance and • Intermediate risk PE and some high risk - anticoagulation only self-assessed deterioration) 33% of patients in sildenafil group worsened significantly compared with the placebo group at 14% • • Improvement was noted in only 27% of sildenafil treated patients versus 44% of controls • ESC/ERS guidelines strongly warn against use of sildenafil in post-capillary PH 4

  5. 12/3/17 CAUSES OF ACUTE RV FAILURE IN THE ICU MANAGEMENT OF ACUTE RV FAILURE IN THE ICU Preload: • Few patients will benefit from careful fluid administration • A dilated failing RV is very sensitive to volume overload; most patients benefit from diuresis even in setting of • hypotension • Afterload • Achieved through pulmonary vasodilation or relief of obstruction in pulmonary vascular bed • Reversing alveoloar hypoxia a key intervention for all patients • Inhaled pulmonary vasodilators nitric oxide and epoprostenol are agents of choice • Optimization of contractility • Dilated RV very susceptible to ischemia so adequate BP to support coronary perfusion • Role of inotropic agents less clear in RV than LV failure SUPPORTING RV failure IN PAH PATHOPHYSIOLOGY OF DECOMPENSATED RV FAILURE 5

  6. 12/3/17 EXTRACORPOREAL MEMBRANE OXYGENATION ATRIAL SEPTOSTOMY • Used as bridge in patients with severe PAH awaiting transplant • ECMO- devIce which pumps blood out of body through an oxygenator and then back into the body Allows decompression of RV expense at the expenses of oxygen content • • Takes oxygen-poor blood and converts it to oxygen-rich blood Used to be all-or-none, now can gradually dilate to preferred shunt level • • Acts as a pump to improve circulation Newer devices removable • • Scavenges carbon dioxide • Advances in ECMO and positive results of CESAR study for ARDS due to H1N1 raised awareness/use • A powerful tool to control ventilatory needs – enhance oxygenation and CO2 removal • Likely challenging in patients with RV dysfunction PAH: FDA APPROVED THERAPIES CAUSES OF ACUTE DECOMPENSATON IN PAH 1 2 3 • Approved drugs act predominantly via vasodilation and anti- proliferation effects ERA = endothelin receptor antagonist PDE = phosphodiesterase sCG = soluble guanylate cyclase ERAs PDE-5 inhibitors Prostacyclin •Bosentan ( oral ) — Sildenafil ( oral ) — Epoprostenol ( IV infusion ) •Ambrisentan ( oral ) — Tadalafil ( oral ) — Treprostinil •Macitentan ( oral ) ( SC or IV infusion, sCG stimulator inhaled, or oral ) Riociguat ( oral ) — Iloprost ( inhaled ) — Selexipag/Uptravi 6

  7. 12/3/17 PROGNOSIS IN PAH WITH RHF PROGNOSIS IN PAH WITH RHF PROGNOSIS IN PAH WITH RHF PROGNOSIS IN PAH WITH RHF 7

  8. 12/3/17 PROGNOSIS IN PAH WITH RHF LUNG TRANSPLANTATION IN PAH PERIOPERATIVE MANAGEMENT OF THE PATIENT WITH PAH • Lung transplant is a viable option in PAH to improve life expectancy and quality of life • Double lung transplant is preferred • Patients with PAH are susceptible to hypotension and cardiac arrest during surgery • Improved outcomes when compared to single lung transplant recipients • Anesthetic drugs reduce sympathetic tone • Risk of reperfusion injury after single lung transplant • Positive pressure ventilation alters venous return • Risk factors for hemodynamic compromise • Some patients require heart-lung transplantation when they have LV failure or anatomical abnormalities • History of syncope, NYHA Class IV, low 6MWD, RV failure • Transplant in the era of new PAH therapies • Induction is high risk for hemodynamic compromise • Venodilation by anesthesia • FROM 2004-2015 there were 32,237 lung transplants worldwide (897 of them were IPAH) • Reduced venous return by positive pressure ventilation • In same time period ther were 812 combined heart-lung transplants (222 IPAH) • Reduced RV stroke volume by paralysis • 4.1% of all lung or heart-lung transplant recipients have PH as primary diagnosis 8

  9. 12/3/17 CLASSIFICATION OF PH PAH AND RV FAILURE Group 1. Pulmonary arterial hypertension (PAH) Idiopathic (IPAH) Group 3. Pulmonary hypertension due to lung • Heritable (HPAH) • diseases and/or hypoxemia • bone morphogenetic protein receptor type 2 (BMPR2) • Chronic obstructive pulmonary disease (COPD) • activin receptor-like kinase 1 gene (ALK1), endoglin (with or without haemorrhagic telangiectasia) • Interstitial lung disease (ILD) unknown • Other pulmonary diseases with mixed restrictive and obstructive pattern • Drug- and toxin-induced • Sleep-disordered breathing • • Alveolar hypoventilation disorders • Associated with (APAH): • Chronic exposure to high altitude • connective tissue diseases • Developmental abnormalities • Human immunodeficiency virus (HIV) infection Group 4. Chronic thromboembolic pulmonary • portal hypertension • congenital heart disease (CHD) hypertension (CTEPH) • schistosomiasis Group 5. PH with unclear multifactorial mechanisms • chronic haemolytic anaemia • Haematological disorders: myeloproliferative disorders, splenectomy Persistent pulmonary hypertension of the newborn (PPHN) • • Systemic disorders: sarcoidosis, pulmonary Langerhans cell histiocytosis, Group 2. Pulmonary hypertension due to left heart disease lymphangioleiomyomatosis, neurofibromatosis, vasculitis • Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid Systolic dysfunction • disorders • Diastolic dysfunction • Others: tumoural obstruction, fibrosing mediastinitis, chronic renal failure on dialysis • Valvular disease 33 Simonneau G et al. J Am Coll Cardiol 2009 9

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