Pulmonary

Arterial
Hypertension
(PAH)
Emily Johnson
April 19, 2023
 Objectives

Review characteristics and pathophysiology of pulmonary arterial hypertension (PAH)

Explain management strategies for critically ill patients with PAH

Evaluate clinical trial evidence for the treatment of pulmonary arterial hypertension

2
 Background on
Pulmonary
Hypertension

3
 Classification of Pulmonary Hypertension

4 Ruopp NF et al. JAMA. 2022;327(14):1379-91.

 Pulmonary Arterial Hypertension (PAH)

▪ Definition: a subtype of pulmonary hypertension that is characterized by a mean pulmonary artery

pressure greater than 20 mmHg and a pulmonary artery wedge pressure of 15 mmHg or lower
▪ PAH is further divided into subgroups based on etiology
▪ Epidemiology: 25 persons per 1 million population in Western countries
▪ Annual incidence: 2 to 5 cases per million
▪ If left untreated, PAH progresses to right heart failure and death
▪ With PAH-specific therapies, 5-year survival has improved from 34% in 1991 to more than 60% in 2015

5 Ruopp NF et al. JAMA. 2022;327(14):1379-91.

 Subtypes of PAH
▪ Idiopathic
▪ Meets hemodynamic criteria for PAH but is not associated with another disease process
▪ Heritable
▪ Variants in the bone morphogenetic protein receptor 2 gene (BMPR2) account for approx. 75% of heritable
PAH
▪ Drug- and toxin-associated
▪ Pulmonary veno-occlusive disease
▪ Pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis
▪ PAH in long-term responders to calcium channel blockers
▪ PAH associated with other medical conditions including connective tissue disease, HIV, and congenital heart
disease
▪ Most commonly patients with scleroderma, although it also occurs with systemic lupus erythematosus,
mixed connective tissue disease, rheumatoid arthritis, and Sjogren syndrome

6 Ruopp NF et al. JAMA. 2022;327(14):1379-91.

 Drugs and Toxins Associated with PAH
Definite Association Possible Association
• Aminorex • Alkylating agents (cyclophosphamide,
• Benfluorex mitomycin C)
• Dasatinib • Amphetamines
• Dexfenfluramine • Bosutinib
• Fenfluramine • Cocaine
• Methamphetamines • Diazoxide
• Toxic rapeseed oil • Sofosbuvir
• Indirubin (Chinese herb Qing-Dai)
• Interferon alpha and beta
• Leflunomide
• L-tryptophan
• Phenylpropanolamine
• Ponatinib
• Carfilzomib
• Trichloroethylene
• St. John’s Wort

7 Ruopp NF et al. JAMA. 2022;327(14):1379-91.

 Pathophysiology

8 Ruopp NF et al. JAMA. 2022;327(14):1379-91.

 Right Ventricular (RV) Heart Failure in PAH

▪ Vascular remodeling (thickening of the vascular wall

via hypertrophy) results
▪ Contributes to increased pulmonary vascular
resistance and an increase in mean pulmonary
artery pressure
▪ These changes make it difficult for the right
ventricle to pump blood through the pulmonary
arteries and into the lungs due to the increased
pressure
⎻ The right ventricle undergoes hypertrophy to
adapt to an increasing afterload

9 Ruopp NF et al. JAMA. 2022;327(14):1379-91.

 Clinical Presentation

Exertional dyspnea Fatigue

Chest pain Fluid retention

10 Ruopp NF et al. JAMA. 2022;327(14):1379-91.

 World Health Organization (WHO) Classification of Functional Status of
Patients with Pulmonary Hypertension (PH)

WHO
Functional Description
Class (FC)
FC I Ordinary physical activity does not cause excessive dyspnea, fatigue,
chest pain, or near syncope
FC II Ordinary physical activity causes excessive dyspnea, fatigue, chest
pain, or near syncope, but these patients are comfortable at rest
FC III Less than ordinary activity causes excessive dyspnea, fatigue, chest
pain, or near syncope, but these patients are comfortable at rest
FC IV Patients who are unable to carry out any physical activity without
symptoms. These patients have signs of right heart failure. Dyspnea
and/or fatigue may be present at rest. Discomfort is increase by any
physical activity
11 Klinger JR et al. Chest. 2019;155(3):565-586.
 Diagnosis

Clinical Presentation

Physical Exam

Right heart catheterization is required to confirm

diagnosis

• Assessment of pulmonary hemodynamics and cardiac output to

calculate pulmonary vascular resistance

12 Ruopp NF et al. JAMA. 2022;327(14):1379-91.

 Management in
Intensive Care Unit
2022 European Society of
Cardiology (ESC)/European
Respiratory Society (ERS)
Guidelines for the diagnosis and
treatment of pulmonary
hypertension

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 Volume Status and Oxygen Support
▪ Assessment and management of volume status
▪ Hypovolemia and hypervolemia can negatively impact blood pressure and cardiac function
▪ Majority of cases of RV failure involve volume overload
▪ Diuretics or hemodialysis to remove excess fluid

▪ Adequate oxygenation is vital since alveolar and arterial hypoxia, acidosis, and hypercapnia can all cause
pulmonary vasoconstriction
▪ Maintain oxygen saturation >90-92%
▪ Intubation and invasive mechanical ventilation should be avoided if possible in patients with advanced RV
failure
⎻ Associated with increased in-hospital mortality

14 Nowroozpoor A et al. Tanaffos. 2019;18(3):180-207.

 Targeted Pulmonary Vasodilator Therapy

▪ Reduction of increased RV afterload is an important aspect of treatment for RV failure

▪ Prostacyclins, inhaled nitric oxide, endothelin receptor antagonists (ERAs), and PDE5 inhibitors are
available options, although there is a lack of clinical trials regarding the use of these options in critical care
settings
▪ Intravenous prostacyclin analogues are the treatment of choice patients with severe RV dysfunction
▪ Intravenous infusion of epoprostenol or treprostinil is generally used as initial treatment

15 Nowroozpoor A et al. Tanaffos. 2019;18(3):180-207.

 Prostacyclin Analogues: Treprostinil and Epoprostenol
Mechanism 1. Target vasoconstriction by directly dilating pulmonary and systemic arterial
of Action vascular beds
2. Target platelet aggregation by inhibiting platelet aggregation
3. Inhibit smooth muscle cell proliferation
Dosing Epoprostenol
• IV infusion
• Initial dose: 2 ng/kg/minute (a lower initial dose may be used if patient
is intolerant of starting dose. Increase dose in increments of 1 to 2
ng/kg/minute at intervals of >15 minutes until dose-limiting side effects
occur or further increase is not clinically necessary
• Usual dose when used as monotherapy: 25 to 40 ng/kg/minute
Treprostinil
• SQ or IV continuous infusion
• Initial dose if new to prostacyclin therapy: 1.25 ng/kg/minute
• If dose cannot be tolerated, reduced to 0.625 ng/kg/min
Adverse • Systemic vasodilation (hypotension, flushing, headache, dizziness), diarrhea,
Effects jaw pain, musculoskeletal pain
Contraindic • Epoprostenol: heart failure with decreased left ventricular ejection fraction
ations • Treprostinil (oral): severe hepatic impairment
Clinical • Epoprostenol is the only prostacyclin to demonstrate mortality benefit in a
Evidence clinical trial of 82 patients (mortality rate, 0% vs. 5%; P=0.003)
• Treprostinil increases time to clinical worsening and improves symptoms and
6-minute walk distance
16
United Therapeutics. Treptostinil Mechanism of Action. Accessed April 12, 2023. https://www.unitedbyph.com/treprostinil
 Epoprostenol Continuous Infusion PowerPlan

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 Epoprostenol Continuous Infusion PowerPlan (Continued)

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19
 Targeted Pulmonary Vasodilator Therapy (Continued)

▪ Inhaled Nitric oxide (NO) or inhaled epoprostenol

▪ An option for patients with RV failure who cannot tolerate intravenous therapy with vasodilator due to
systemic hypotension
▪ Mechanism of action: relaxes vascular smooth muscle and improves oxygenation
▪ Adverse effects:
⎻ Increased pulmonary artery pressure (with abrupt discontinuation)
⎻ Methemoglobinemia
⎻ Inhaled nitric oxide may increase the risk of renal injury
▪ Dosing for right ventricular dysfunction:
⎻ Inhalation: 20 ppm via mechanical ventilation circuit (dosage range: 5 to 20 ppm)

20 Aryal S et al. Curr Opin Pulm Med. 2020;26(5):414-21.

 Phosphodiesterase 5 Inhibitors: Sildenafil and Tadalafil

Mechanism of • Inhibit phosphodiesterase 5-based degradation of cyclic

Action guanosine monophosphate, causing vasodilation, particularly in
the pulmonary vasculature

Adverse Effects • Headache, flushing, hypotension

Contraindications • Concurrent therapy with riociguat (due to similar mechanism of

action)
• Not recommended in pulmonary veno-occlusive disease
Clinical Evidence • In a randomized clinical trial of patients with PAH (n=278),
sildenafil (vs. placebo) improved 6-minute walk distance by 45 m
to 50 m, WHO functional class by at least 1 class in 28% to 42% of
patients, and mean pulmonary artery pressure by 2.1 mmHg to 4.7
mmHg
• In a randomized clinical trial (n=405), tadalafil improved 6-minute
walk distance by 31 m compared with placebo

21 Ruopp NF et al. JAMA. 2022;327(14):1379-91.

 Inotropic and Vasopressor Support

▪ In right ventricular failure, consider agents to improve contractility

▪ Dobutamine: beta-1 agonist that improves myocardial contractility and reduces right ventricular afterload
▪ Milrinone: phosphodiesterase-3 inhibitor that increases contractility via direct inotropic effect as well as
indirectly by decreasing afterload
⎻ Associated with systemic hypotension that may necessitate vasopressor therapy

▪ Hypotension
▪ Vasopressors should be used cautiously as they increase right ventricular afterload
⎻ Epinephrine
⎻ Norepinephrine

22 Aryal S et al. Curr Opin Pulm Med. 2020;26(5):414-21.

 Mechanical Circulatory Support

▪ Veno-arterial extracorporeal membrane oxygenation (ECMO) is a widely used approach to manage RV failure
▪ Bridge patients to transplantation if irreversible right HF
▪ May be used as a bridge to recovery in patients with potentially reversible RV failure
▪ No general recommendations for the use of ECMO (consider patient factors and local resources)

23 Aryal S et al. Curr Opin Pulm Med. 2020;26(5):414-21.

 Other PAH
Medications

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 Endothelin Receptor Antagonists: Bosentan and Ambrisentan

Mechanism of • Endothelin 1 (a potent endogenous vasoconstrictor) is

Action overexpressed in the pulmonary vasculature of patients with
PAH
• These block the activity of endothelin 1, resulting in
vasodilation
Adverse Effects • Bosentan: increased hepatic transaminases (black box warning
for hepatoxicity), edema, respiratory tract infections
• Ambrisentan: peripheral edema, abnormal liver function tests,
cough
Contraindications • Ambrisentan: idiopathic pulmonary fibrosis
• Bosentan and ambrisentan: discontinue in pulmonary veno-
occlusive disease
Clinical Evidence • Based on two randomized clinical trials (n=32 and n=213) →
Bosentan (vs. placebo) improved 6-minute walk distance by 44
m to 70 m and WHO functional class in approximately 42% to
43% of patients
• Ambrisentan (n=500) demonstrated improvement in time to
clinical worsening and 6-minute walk distance

25 Ruopp NF et al. JAMA. 2022;327(14):1379-91.

 Soluble guanylate cyclase stimulator: Riociguat

Mechanism • Enhances cyclic guanosine monophosphate

of Action production, causing vasodilation

Adverse • Hypotension, headache, dizziness

Effects
Contraindic • Use with caution in patients with hepatic
ations impairment
• Not recommended for PAH due to pulmonary
veno-occlusive disease
Clinical • In a randomized clinical trial (n=444), riociguat
Evidence (vs. placebo) improved WHO functional class
(21% vs. 14%; P=0.003) and improved 6-
minute walk distance by 30 m (P <0.001)

26 Ruopp NF et al. JAMA. 2022;327(14):1379-91.

 Maintenance Regimen

27 Ruopp NF et al. JAMA. 2022;327(14):1379-91.

 Clinical Evidence

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 In-vitro and in-vivo comparisons of high versus low concentrations of
inhaled epoprostenol to adult intubated patients

Objective To compare high (n=84) and low concentration (n=80) iEPO

delivery specific to adult mechanical ventilation
Study design Retrospective

Patient population • Average age: 55

• 43% male
• Indication to use iEPO:
• Hypoxemia: 70%
• Pulmonary hypertension: 34%
• Right heart failure: 21%
Methods • iEPO was initiated at a dose of 50 ng/kg/min and maintained
for a minimum of 24 h after initiation
• iEPO weaning was determined by the treating physician(s)
and titrated down by 10 ng/kg/min every 30–60 min if the
patient’s status remained stable

29 Li J et al. Respir Res. 2021;22(1):231.

 In-vitro and in-vivo comparisons of high versus low concentrations of
inhaled epoprostenol to adult intubated patients

Primary Outcome • In patients with pulmonary hypertension and/or right heart

failure, incremental changes in mPAP were compared between
the two groups.
• Positive response to iEPO was defined as mPAP decreased by
10%
Results • After 30–120 min of iEPO administration, both delivery
strategies significantly improved oxygenation in hypoxemic
patients and reduced mean pulmonary arterial pressure
(mPAP) for patients with pulmonary hypertension. However, no
significant differences of the incremental changes were found
between two delivery groups.
• Compared to the low concentration group, the high
concentration delivery group had a shorter duration of invasive
ventilation (6 vs. 9 days, p=0.028)
• Intensive care unit length of stay and mortality were similar
between the two groups

30 Li J et al. Respir Res. 2021;22(1):231.

 References
▪ Humbert M, Kovacs G, Hoeper M, et al. 2022 ESC/ERS guidelines for the diagnosis and treatment of
pulmonary hypertension. Eur Respir J. 2023;61(1):2200879.
▪ Ruopp NF, Cockrill BA. Diagnosis and treatment of pulmonary arterial hypertension: a review. JAMA.
2022;327(14):1379-91.
▪ Aryal S, King CS. Critical care of patients with pulmonary arterial hypertension. Curr Opin Pulm Med.
2020;26(5):414-21.
▪ Hassoun PM. Pulmonary arterial hypertension. N Engl J Med. 2021;385(25):2361-76.
▪ Li J, Augustynovich AE, Gurnani PK, et al. In-vitro and in-vivo comparisons of high versus low concentrations
of inhaled epoprostenol to adult intubated patients. Respir Res. 2021;22(1):231.
▪ Nowroozpoor A, Malekmohammad M, Seyyedi SR, et al. Pulmonary hypertension in intensive care units: an
updated review. Tanaffos. 2019;18(3):180-207.
▪ Klinger JR, Elliott CG, Levine DJ, et al. Therapy for pulmonary arterial hypertension in adults: update of the
CHEST guideline and expert panel report. Chest. 2019;155(3):565-586.

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 Questions?

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