“A Best Practices Approach to Treating Pulmonary Hypertension for

the ED and Acute Care Provider”

Sean M. Studer, MD, MScChief, Pulmonary & Critical Care

Director, Pulmonary Hypertension& Lung Transplantation

Newark Beth Israel Medical Center

Disclosures

• Promotional speaker: Actelion, Gilead, United Therapeutics/Lung Rx

• Research funding: Actelion, Gilead, United Therapeutics/Lung Rx

• No off label discussion of medications

Lecture Goals: PAH

• Summarize diagnosis/classification of PAH• Describe lower v. higher risk patients• Review current medication therapies • Analyze approaches to managing

emergencies in PAH

Pulmonary Arterial Hypertension:Definition

• Mean PA pressure > 25 mmHg with PCW <15 mmHg– (NIH Registry on PPH, 1987)

• PVR = 3 Units

• ??Exercise mean PA pressure > 30 mmHg

PVR = TPG/CO

TPG = PAM-PCW

World Conference on Pulmonary Hypertension Revised Nomenclature and ClassificationDana Point 2008

I PAH • iPAH• Heritable PAH• Collagen vascular disease• Congenital L to R shunts• Portal pulmonary HTN• HIV• Drugs (e.g. anorexigens)• PPHN

II Pulmonary venous HTN• Left heart disease

III PH assoc with hypoxia• COPD• Interstitial lung disease (IPF)• Sleep disordered breathing• High altitude

IV ThromboembolicV Multifactorial (e.g. sarcoid)

PAH Pulmonary hypertension

At Risk Populations for PAH: WHO Gr. I

Impact of PAH

• Annual incidence: 15/million pop.; 6/mil iPAH• Orphan disease by US Food & Drug Admin. • Demographics of affected patients:

– More common in women– Mean age at diagnosis 36 years; All ages affected

(Ann Int Med 1987;107:216-23, Chest 2007;131:5-6)

Idiopathic PAH: Survival Without Treatment

adapted from D’Alonzo GE, et al. Ann Int Med 1991;115:343-49

Est. Median survival: 2.8 yrs(95% CI, 1.9 to 3.7 years)

68%

48%34%

0

20

40

60

80

100

0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 5

Years of follow up

Su

rviv

al (

%)

Assessment of PAH:History I: Signs and Symptoms

– Initial signs and symptoms• Dyspnea – Fatigue• Syncope – Edema• Dizziness – Angina

– Non-specific nature of complaint can lead to:• Confusion with other conditions• Delayed diagnosis (~18-36 months)

(Galie N, et al. Lancet 2008; 371:2093-2100)

Assessment of PAH:Physical Examination

• RV lift /heave• Increased P2• TR, PI murmurs• Signs of congestion• Right-sided extra heart sounds

VC RA RV PAPC

PV LA LV Ao

HTN

DCM HCM

MS Myxoma Cor triatriatum

Anomalous PV PVOD

COPD IPF

PE PPS

PHTN: Where’s the Lesion?

PAH-a pre-capillaryarteriopathy

Findings on Electrocardiogram

• RVH, RAE, RAD, RV strain, [RBBB]-typical

• Arrhythmias not typical- may need ED attn

Chest X-Ray in PAH

RV, right ventricular.McLaughlin VV et al. J Am Coll Cardiol. 2009;53:1573-1619.

Prominent CentralPulmonary Artery

PeripheralHypovascularity

Right DecendingPulmonary Artery

RV Enlargement

Assessment of PAH:Echocardiography

• RV size and function• Right atrial size• Tricuspid regurgitation?• Estimated RV systolic pressure• Dilation, flow reversal of IVC?• Pericardial effusion?• Lack of left sided chamber and valve

abnormalities

Echocardiogram-Severe iPAH

Pericardial Effusion in PAH• Small- moderate effusions are sign of

higher risk due to elevated underlying pressures. No emergent intervention generally…

• Tamponade is not uncommon and ECG/echo may be helpful in confirming--drainage of effusion may be warranted.

PAH: Diagnostic Evaluation

H&P, ECG, CXR ? PH

Echo

PH; left heart dz, congenital R to L shunt

No evidence of PH

Serologies CVD, HIV

V/Q, chest CT, PFT, sleep study Thromboembolism, intrinsic lung dz

RHCIPAH FPAH 6MWT

Pulmonary Arterial Hypertension:Goals of Medication Therapy

• Improve functional class/QOL

• Improve exercise capacity

• Prevent clinical worsening

• Improve survival

• Improve hemodynamics (?)

Therapeutic Targets for PAH

Humbert M, Sitbon O, Simonneau G. N Engl J Med 2004;351:1425-36

Phosphodiesterase type 5 inhibitor

Exogenous nitric oxide

Endothelinreceptor antagonists

Prostacyclin derivatives

Endothelinreceptor A

Endothelin 1Nitric oxide

Prostacyclin (prostaglandin I2)

Endothelinreceptor B

Vasodilation and antiproliferation

Vasodilation and antiproliferation

Vasodilation and antiproliferation

cGMP

cAMP

Pre-proendothelinà Proendothelin

L-arginineà L-citrulline

Arachidonic acid à Prostaglandin I2

++

Phosphodiesterase type 5

Smooth muscle cells

Endothelincells

Vessel lumenNitric oxide pathway

Endothelin pathway Prostacyclin pathway

PAH Determinants of Risk

McLaughlin and McGoon. Circulation 2006;114:1417-31

Lower Risk Determinants of Risk Higher Risk

No Clinical evidence ofRV failure Yes

Gradual Progression Rapid

II, III WHO class IV

Longer (>400 m) 6MW distance Shorter (<300 m)

Minimally elevated BNP Very elevated

Minimal RV dysfunction

Echocardiographicfindings

Pericardial effusion,significant RV dysfunction

Normal/near normalRAP and CI Hemodynamics High RAP, low CI

Emergency issues on therapy:General considerations

• Involve specialty pharmacy early- if infusion drug pump will usually be labeled with toll-free phone #

• Contact PAH program for more information re: patient

• Emergency issues not well studied-patients use support group rec’s; we’ll review by type of therapy

Endothelin is a KeyPathogenic Mediator *

Clozel. Ann Med. 2003: 35; 1-5.

Proliferationvascular smooth musclefibroblasts

Fibrosisfibroblast proliferationá extracellular matrix proteins↓ collagenase production

Inflammationá vascular permeabilityneutrophil / mast cell activation promotes cellular adhesioná cytokine production

Hypertrophycardiac/vascular

Vasoconstrictiondirect or via facilitation of other vasoconstrictor systems (reninangiotensin system, sympathetic)

ET

* Based on animal, in-vitro, and human hemodyamic models

Endothelin Receptor Antagonists• Bosentan (Tracleer)

• Improves walk distance and functional class

• FDA approved for class II-IV PAH

• LFTs, pregnancy concerns

• Ambrisentan (Letairis)

• Once daily dosing, Class II-IV PAH

• Improves six minute walk distance

• LFTs, pregnancy concerns

Emergency Issues-ERAs• Liver enzyme abnormalities (AST/ALT)-few

cases of unexplained hepatic failure

• Lower extremity edema- usually not an emergency but can be misinterpreted as sign of another condition

• Worsening of disease can present as low cardiac output; may need more therapy

PDE 5 inhibitors

• Sildenafil (Viagra, Revatio)• FDA approved for class II-IV PAH• Oral, well-tolerated• Usual PDE 5 inhibitor concerns

• Tadalafil (Cialis, Adcirca)– Oral, once daily dosing– FDA approved for class II-IV PAH

Emergency issues: PDE-5i

• Priapism• Visual changes- often reversible with

drug cessation• Hypotension with nitrate therapy• Worsening of PAH may present with

reduced cardiac output

Epoprostenol (Flolan® & generic) and RTS- Epoprostenol

• Continuous IV Rx, half life of minutes

•Expensive, Requires ice packs unless RTS-epoutilized

• Significant adverse effects-GI, Musc-skel.

AutoCadd Legacy Pump

Room temp. stable epoprostenol(Veletri)

• Does not require ice packs at room temp (77 degrees F)

• Reconstituted with saline or sterile H2O• For NYHA Class III-IV patients• Same half life of minutes

Treprostinil (Remodulin®)

•Stable at room temperature; longer half-life•Continuous IV or SQ •Smaller pump (SQ) •Limiting factor traditionally was site pain•Typical prostacyclin side effects

Emergency issues: Infusion Prostacyclin Therapy

• Deliver system complications:– Catheter-related blood stream infection– Catheter-related thrombosis, bleeding, etc

• Abrupt cessation may result in rebound PAH-always try to continue infusion- peripheral IV is OK

• GI adverse effects may lead to volume depletion; High output cardiac state not uncommon

Iloprost Inhalation Solution: Dosage and Administration

• 6-9 inhalations daily during waking hours– No more than once every two

hours-Most patients ~5 x daily• Dose: 2.5 or 5 mcg delivered• Dosed via prodose AAD system

• Adverse effects (with rate >5% placebo subtracted) include flushing, cough, headache, trismus, insomnia, hypotension, vomiting, increased alkaline phosphatase

Optineb-ir Device Overviewfor inhaled treprostinil

• “Tyvaso inhalation system”

• Inhaled tre. dosing – 4x daily (~2-3 minutes

per treatment)

• “Repetitive-breath”system– Patient must manually

time each inhalation

Inhaled Rx: Emergency Issues

• Abrupt withdrawl is not a consideration• In absence of delivery device usually

not advisable to use alternative nebulizer device

• Ask family/friends to get patient’s device or consider alternative treatment option

Summary: Emergencies in PAH on Medication Therapy

#1. Obtain current treatment to identify risks; e.g. no nitrates with PDE-5 Rx

#2. Infusions are almost never abruptly discontinued and require special handling- contact specialty pharmacy and patient’s PAH prescriber

#3. Acute risks include pericardial effusion and low cardiac output- echocardiography often essential

Conclusions: Best practices for PAH

• Proper diagnosis and classification of PAH is critical to best practice

• Titrate approach for high vs. low risk pts • Understanding current therapies will improve

emergency response• Focused testing, involving specialty

pharmacy /PAH program quickly will add information and promote best decisions

Thanks for your attention!

Newark Beth Israel Medical Center Pulmonary Hypertension & Lung Transplant

888-NJ-LUNG-1www.LungTransplantNJ.com