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

12/3/17 1

MANAGEMENT OF PULMONARY HYPERTENSION IN THE ICU

RAMONA DOYLE MD CLINICAL PROFESSOR OF MEDICINE UCSF

DISCLOSURES

• I am a full-time employee of Blade Therapeutics. Blade Therapeutics is a small, private

biopharmaceutical company advancing novel anti-fibrotic therapies to meet important patient needs.

• 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.

LEARNING OBJECTIVES

• 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

MANAGING PH IN THE ICU

“Don’t just do something, stand there…”

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CLASSIFICATION OF PH

Group 1. Pulmonary arterial hypertension (PAH)

• Idiopathic (IPAH)
• Heritable (HPAH)
• bone morphogenetic protein receptor type 2 (BMPR2)
• activin receptor-like kinase 1 gene (ALK1), endoglin

(with or without haemorrhagic telangiectasia)

• unknown
• Drug- and toxin-induced
• Associated with (APAH):
• connective tissue diseases
• Human immunodeficiency virus (HIV) infection
• portal hypertension
• congenital heart disease (CHD)
• schistosomiasis
• chronic haemolytic anaemia
• Persistent pulmonary hypertension of the newborn (PPHN)

Group 2. Pulmonary hypertension due to left heart disease

• Systolic dysfunction
• Diastolic dysfunction
• Valvular disease

Group 3. Pulmonary hypertension due to lung diseases and/or hypoxemia

• Chronic obstructive pulmonary disease (COPD)
• Interstitial lung disease (ILD)
• Other pulmonary diseases with mixed restrictive and obstructive pattern
• Sleep-disordered breathing
• Alveolar hypoventilation disorders
• Chronic exposure to high altitude
• Developmental abnormalities

Group 4. Chronic thromboembolic pulmonary hypertension (CTEPH) Group 5. PH with unclear multifactorial mechanisms

• Haematological disorders: myeloproliferative disorders, splenectomy
• Systemic disorders: sarcoidosis, pulmonary Langerhans cell histiocytosis,

lymphangioleiomyomatosis, neurofibromatosis, vasculitis

• Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid

disorders

• Others: tumoural obstruction, fibrosing mediastinitis, chronic renal failure
• n dialysis

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

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CLASSIFICATION OF PH DIAGNOSIS OF PH: ECHOCARDIOGRAM DIAGNOSIS OF PH IN THE ICU

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DIAGNOSIS OF PH IN THE ICU ACUTE PULMONARY EMBOLISM IN THE ICU

• Patients in ICU by definition at higher risk for pulmonary embolism
• RV dysfunction is key determinant of prognosis in acute PE
• RV dysfunction or persistent hypotension at presentation = acute high risk PE
• Acute high risk PE is trigger for thrombolysis – catheter directed vs systemic
• Intermediate risk PE and some high risk - anticoagulation only

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

valvular corrective surgery

• SIOVAC study
• A RDBPCT study of 200 adult patients with residual PH following corrective valvular heart surgery
• Primary endpoint was HF composite score (mortality, hospital admission for HF, worse exercise tolerance and

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

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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

PATHOPHYSIOLOGY OF DECOMPENSATED RV FAILURE

SUPPORTING RV failure IN PAH

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EXTRACORPOREAL MEMBRANE OXYGENATION

• ECMO- devIce which pumps blood out of body through an oxygenator and then back into the body
• Takes oxygen-poor blood and converts it to oxygen-rich blood
• Acts as a pump to improve circulation
• 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

ATRIAL SEPTOSTOMY

• Used as bridge in patients with severe PAH awaiting transplant
• Allows decompression of RV expense at the expenses of oxygen content
• Used to be all-or-none, now can gradually dilate to preferred shunt level
• Newer devices removable

PAH: FDA APPROVED THERAPIES

Prostacyclin — Epoprostenol

(IV infusion) — Treprostinil (SC or IV infusion, inhaled, or oral) — Iloprost (inhaled) — Selexipag/Uptravi

ERAs

• Bosentan (oral)
• Ambrisentan (oral)
• Macitentan (oral)

sCG stimulator Riociguat (oral) PDE-5 inhibitors — Sildenafil (oral) — Tadalafil (oral)

ERA = endothelin receptor antagonist PDE = phosphodiesterase sCG = soluble guanylate cyclase

1 3 2

• Approved drugs act

predominantly via vasodilation and anti- proliferation effects

CAUSES OF ACUTE DECOMPENSATON IN PAH

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PROGNOSIS IN PAH WITH RHF PROGNOSIS IN PAH WITH RHF PROGNOSIS IN PAH WITH RHF PROGNOSIS IN PAH WITH RHF

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PROGNOSIS IN PAH WITH RHF LUNG TRANSPLANTATION IN PAH

• Lung transplant is a viable option in PAH to improve life expectancy and quality of life
• Double lung transplant is preferred
• Improved outcomes when compared to single lung transplant recipients
• Risk of reperfusion injury after single lung transplant
• Some patients require heart-lung transplantation when they have LV failure or anatomical

abnormalities

• Transplant in the era of new PAH therapies
• FROM 2004-2015 there were 32,237 lung transplants worldwide (897 of them were IPAH)
• In same time period ther were 812 combined heart-lung transplants (222 IPAH)
• 4.1% of all lung or heart-lung transplant recipients have PH as primary diagnosis

PERIOPERATIVE MANAGEMENT OF THE PATIENT WITH PAH

• Patients with PAH are susceptible to hypotension and cardiac arrest during surgery
• Anesthetic drugs reduce sympathetic tone
• Positive pressure ventilation alters venous return
• Risk factors for hemodynamic compromise
• History of syncope, NYHA Class IV, low 6MWD, RV failure
• Induction is high risk for hemodynamic compromise
• Venodilation by anesthesia
• Reduced venous return by positive pressure ventilation
• Reduced RV stroke volume by paralysis

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CLASSIFICATION OF PH

Group 1. Pulmonary arterial hypertension (PAH)

• Idiopathic (IPAH)
• Heritable (HPAH)
• bone morphogenetic protein receptor type 2 (BMPR2)
• activin receptor-like kinase 1 gene (ALK1), endoglin

(with or without haemorrhagic telangiectasia)

• unknown
• Drug- and toxin-induced
• Associated with (APAH):
• connective tissue diseases
• Human immunodeficiency virus (HIV) infection
• portal hypertension
• congenital heart disease (CHD)
• schistosomiasis
• chronic haemolytic anaemia
• Persistent pulmonary hypertension of the newborn (PPHN)

Group 2. Pulmonary hypertension due to left heart disease

• Systolic dysfunction
• Diastolic dysfunction
• Valvular disease

Group 3. Pulmonary hypertension due to lung diseases and/or hypoxemia

• Chronic obstructive pulmonary disease (COPD)
• Interstitial lung disease (ILD)
• Other pulmonary diseases with mixed restrictive and obstructive pattern
• Sleep-disordered breathing
• Alveolar hypoventilation disorders
• Chronic exposure to high altitude
• Developmental abnormalities

Group 4. Chronic thromboembolic pulmonary hypertension (CTEPH) Group 5. PH with unclear multifactorial mechanisms

• Haematological disorders: myeloproliferative disorders, splenectomy
• Systemic disorders: sarcoidosis, pulmonary Langerhans cell histiocytosis,

lymphangioleiomyomatosis, neurofibromatosis, vasculitis

• Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid

disorders

• Others: tumoural obstruction, fibrosing mediastinitis, chronic renal failure
• n dialysis

33

Simonneau G et al. J Am Coll Cardiol 2009

PAH AND RV FAILURE