Johnell Diwan, RN, BSN Pulmonary Hypertension Clinic Coordinator Legacy Medical Group, Pulmonary & Sleep Medicine

Nursing Considerations For Prostacyclin Therapy In The

Treatment Of PAH Johnell Diwan, RN, BSN

Pulmonary Hypertension Clinic CoordinatorLegacy Medical Group, Pulmonary & Sleep Medicine

Background and definition Clinical classification Pathophysiology/Natural history Signs and symptoms/diagnosis Treatment of PAH Emergency Considerations

Presentation Outline

PAH Background

Rare disease (orphan designation) of the pulmonary microvasculature affecting 15 to 50 people per million inhabitants in the Western world1

Affects all races

Affects all ages; however, most prevalent in 4th and 5th decades of life

Higher prevalence in females

Global burden of PAH may be underestimated because of:1,2

Underdiagnosis (eg, nondescript symptoms)

Misdiagnosis (eg, asthma, left-heart disease)

Increasing risk factors (eg, HIV infection, schistosomiasis)

HIV, human immunodeficiency virus.

1. Humbert. Eur Respir J. 2007;30:1-2. 2. Humbert et al. Chest. 2007;132:365-367.

PAH is a Devastating Disease

1. McLaughlin. J Am Coll Cardiol. 2009. 2. Humbert. Am J Resp Crit Care Med. 2006.

2. 3. Humbert. Eur Resp Rev. 2012. 4. Armstrong. bmjopen.bmj.com. 2012. 5. Champion. Circulation. 2009.

3. 6. Badesch. Chest. 2010

Seven-year survival from time of diagnostic right-sided heart catheterization for full REVEAL Registry cohort,using left truncation methods. ■ = estimated survival estimate ± SE at each particular time point

7-year Survival in PAH from REVEAL

REVEAL, Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management

Benza et al Chest 2012;142 (2):448-456

CO, cardiac output; mPAP, mean pulmonary arterial pressure; PAWP, pulmonary arterial wedge pressure; PVR, pulmonary vascular resistance; WU, Wood units.

1. Kaluski et al. Heart Drug. 2003;2:225-235. 2. Rubin. Chest. 1993;104:236-250. 3. McLaughlin and McGoon. Circulation. 2006;114:1417-1431. 4. McLaughlin et al. Circulation. 2009;119:2250-2294.

mPAP ≥25 mm Hg

Diagnostic Criteria For PAH1-4

mPAP, ≥25

mm Hg

≤15 mm Hg

PAWP ≤15 mm Hg

PVR >3 WU PVR >3 WU

1

2

3

PAH Differentiation From PH (5th World Symposium)

LVEDP, left ventricular end-diastolic pressure; PAP, pulmonary arterial pressure; PAWP, pulmonary artery wedge pressure;

PH, pulmonary hypertension.

Hoeper M, et al. J Am Coll Cardiol. 2013;62(25):42-50.

PAH PH

Mean PAP ≥25 mm Hg

Mean PAP ≥25 mm Hg +

PAWP/LVEDP ≤15 mm Hg+

PVR > 3 Woods units

PH-Nice Classification, 2013

CTEPH, chronic thromboembolic pulmonary hypertension; COPD, chronic obstructive pulmonary disease; ILD, interstitial lung disease; HIV, human immunodeficiency virus; PH, pulmonary hypertension; WHO, World Health Organization. Simonneau G et al. J Am Coll Cardiol. 2013;62:D34-D41.

● Idiopathic (IPAH)● Heritable● Drug- and toxin-

induced● Associated with

other conditions (APAH)– Connective tissue

disease – HIV infection – Portal

hypertension – Congenital heart

disease (repaired)– Schistosomiasis WHO Group 1′

● Pulmonary veno-occlusive disease

● Pulmonary capillary hemangiomatosis

● WHO Group 1″ Persistent PH of the newborn

● Systolic dysfunction

● Diastolic dysfunction

● Valvular disease

• Congenital/acquired left heart inflow/outflow tract obstruction and congenital cardiomyopathies

● COPD● ILD● Other pulmonary

diseases with mixed restrictive and obstructive pattern

● Sleep-disordered breathing

● Alveolar hypoventilation disorders

● Chronic exposure to high altitude

● Developmental lung diseases

Chronic thromboembolic

pulmonary hypertension

Unclear multifactorial mechanisms

• Hematologic disorders

• Systemic disorders

• Metabolic disorders

• Others

WHO GROUP 1

PAH

WHO GROUP 2Left-heart

related

WHO GROUP 3

Lung/hypoxia related

WHO GROUP 4

CTEPH

WHO GROUP 5

Other

Pulmonary Hypertension

Pathophysiology/Natural History

Vascular Changes and Disease Progression in PAH

14

Right Ventricle Pulmonary Arteries

Thin RV wallHealthy PA EndotheliumThin walled relaxed PAsLarge capillary network

Normal CO/PVR and perfusion

Hypertrophied RVAbnormal PA endothelium

Constricted stiff PAsLoss of microvessels

Normal CO, mild increase in PVR, moderate decrease in perfusion

Dilated RVCell proliferation in the PA wall

Obliterative PA remodelingSevere decrease in CO and perfusion

with severe increase in PVR

Progression of Pulmonary Vascular Disease

Champion H, et al. Comprehensive invasive and noninvasive approach to the RV. Circulation. 2009;120:992-1007


CO, cardiac output; LV, left ventricle; PA, pulmonary artery; PVR, pulmonary vascular resistance; RV right ventricle.

Figure adapted from Champion et al. Circulation. 2009;120:992-1007. With permission.

14












Thin RV wall Healthy PA endotheliumThin-walled relaxed PAsLarge capillary network




Normal CO, mild ↑ PVR, moderate ↓ in perfusion

Dilated RVCell proliferation in PA wallObliterative PA remodelingSevere ↓ CO and perfusion,

with severe ↑ PVR

Right Ventricle

Pulmonary Arteries

Failu

reC

om

pen

sati

on

Norm

al

14












Signs and Symptoms/Diagnosis

Early Symptoms of PAH

McLaughlin et al. J Am Coll Cardiol. 2009;53:1573-1619.

Shortness of breath (dyspnea)

Swollen ankles and legs (edema)

Dizziness

Feeling tired or

worn out (fatigue)

Rapid or irregular heart beats (Tachycardia)

Late Symptoms of PAH


Shortness of breath (dyspnea)Chest pain (angina)

Fainting (syncope)

Swollen abdomen (ascites)

Low blood pressure

Jugular Venous Distention

Hepatomegaly

Diagnosis of PAHa

Diagnostic Outcomes

History and physicalb Evaluate signs and symptoms, family history, associated diseases, ANA

Chest x-rayb Assess for RV enlargement, peripheral hypovascularity (pruning), and prominent pulmonary arteries

Echocardiogram Assess for RV and RA enlargement, RV dysfunction, TR velocity to measure RVSP

Electrocardiogram Evaluate for right heart enlargement and strain, cardiac rhythm

Cardiac catheterizationb

Evaluate for CHD; measure wedge pressure or LVEDP; establish severity and prognosis; test vasodilator therapy

PFTs with DLCO Assess obstructive and restrictive airway disease

VQ scan Rule out thromboembolic disease

ANA, antinuclear antibody; CHD, congenital heart disease; DLCO, diffusing capacity of the lung for carbon monoxide; HIV, human immunodeficiency virus; LVEDP, left ventricular end-diastolic pressure; PFT, pulmonary function test; RA, right atrial; RV, right ventricular; RVSP, right ventricular systolic pressure; TR, tricuspid regurgitation; VQ, ventilation-perfusion.a Additional tests may be ordered to rule out possible causes of PAH (pulmonary arteriography, blood tests [HIV, hepatic disease, scleroderma], polysomnography [sleep-disordered breathing]). b Required for referral.

McLaughlin and McGoon. Circulation. 2006;114:1417-1431.

WHO Functional Classification

WHO, World Health Organization.

Rubin. Chest. 2004;126(suppl 1):7S-10S.

WHO Definition

Class I Patients with PAH but without resulting limitation of physical activity. Ordinary physical activity does not cause undue dyspnea or fatigue, chest pain, or near syncope

Class II Patients with PAH 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 PAH resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary physical activity causes undue dyspnea or fatigue, chest pain, or near syncope

Class IV Patients with PAH with inability to carry out any physical activity without symptoms. These patients manifest signs of right heart failure. Dyspnea or fatigue may even be present at rest. Discomfort is increased by any physical activity

US/DS/MAR11/001

Echocardiographic Characterization of PAH Disease Progression

Images and video courtesy of Paul Forfia, MD, Hospital of the University of Pennsylvania Heart and Vascular Center.

Early stage PAH Moderate severity PAH Severe PAH

Echocardiography provides estimated RV systolic pressure and morphologic cardiac abnormalities

RVLV

RV LVRV

LV

Triad of right heart findings1,2

RV enlargement (98% of patients)2

Septal flattening (systolic [interventricular]; 90% of patients)2

RV systolic dysfunction (qualitative; 76% of patients)2

Other features2

RA enlargement (92% of patients)“Grade I” diastolic dysfunction (peak E < peak A; 70% of patients)Normal LV function (all patients)>Mild mitral regurgitation (<2% of patients)

IPAH, idiopathic pulmonary arterial hypertension; LV, left ventricular; RA, right atrial; RV, right ventricular .

1. Forfia and Vachiéry. Am J Cardiol. 2012;110(6)(suppl):16S-24S. 2. Bossone et al. J Am Soc Echocardiogr. 1999;12(8):655-662.

Echocardiographic Features of IPAH

Right Heart Catheterization Confirms PAH Diagnosis

Confirm diagnosisa

◦ Gold standard

Evaluate severity of PAH

Assess congenital heart defects

Exclude left-sided heart disease

Assess response to vasodilator challenge

Assess key hemodynamic parameters

Required for every patient with suspected pulmonary hypertension

1. McLaughlin et al. Circulation. 2009;119:2250-2294. 2. Tolle et al. Circulation. 2008;118:2183-2189.

Vasodilator Testing During RHC1,2

Measurement of pulmonary vasoreactivity is important in PAH diagnosis and treatment selection

Must be done cautiously in patients with PAH, especially in those with signs of overt right heart failurea or hemodynamic instability

Positive response defined by ≥10 mm Hg in mPAP, with mPAP ≤40 mm Hg and without CO

Approximately 13% of patients with IPAH have a positive responseOnly 6.8% had a favorable clinical response to chronic CCB therapy at 1

year

Other PAH treatments should be evaluated if patient does not improve to FC I or II

CCB, calcium channel blocker; IPAH, idiopathic pulmonary arterial hypertension; RHC, right heart catheterization.

1. McLaughlin et al. J Am Coll Cardiol. 2009;53:1573-619.

2. Oudiz and Langleben. Adv Pulmonary Hypertension. 2005;4:15-25.

Acute right heart failure with shock is considered a contraindication to vasodilator testing.

Hemodynamic Progression of PAH

CO, cardiac output; PAP, pulmonary arterial pressure; PVR, pulmonary

vascular resistance; RAP, right atrial pressure.

Time

PAPPVRRAP

CO

Pre-symptomatic/ Compensated

Symptomatic/ Decompensating

Symptom Threshold

Right Heart Dysfunction

Declining/ Decompensated

Symptoms

Treatment of PAH

Management Priniciples

Protect the Right Side of the Heart, Improve Right Ventricular Function

♥ Digoxin♥ Oxygen ♥ Control Volume status with diuretics and fluid restriction

♥ DRY IS GOOD!!!♥ Anti-coagulants

Considerations in Treatment Choice

◦ Responsiveness to acute vasodilators

◦ Functional class

◦ Rate of progression

◦ Prior or concomitant drug therapy (therapeutic

pathway)

◦ Pulmonary hemodynamics, RV function

◦ Comorbidities (liver, heart disease, immunity)

◦ Psychosocial/financial

◦ Patient/clinician preference

Important Risk Factors

BNP, B-type natriuretic peptide; CI, cardiac index; CPET, cardiopulmonary exercise test; 6MWD, 6-minute walk distance; RAP, right atrial pressure; RV, right ventricular; VO2, volume of oxygen consumption; WHO, World Health Organization.


Determinants of risk Lower risk Higher risk

Clinical evidence of RV failure No Yes

Progression Gradual Rapid

WHO functional class II, III IV

6MWD Longer (>400 m) Shorter (<300 m)

CPET Peak VO2 >10.4 mL/kg/min Peak VO2 <10.4 mL/kg/min

Echocardiographic findings Minimal RV dysfunction

Pericardial effusion, significant

RV enlargement/dysfunction, right atrial enlargement

Hemodynamics RAP <10 mm Hg CI >2.5 L/min/m2

RAP >20 mm Hg CI <2.0 L/min/m2

BNP Minimally elevated Significantly elevated

Treatment Outcomes Used To Determine Response To Therapy And Prognosis

Functional class I or IIEchocardiography/CMR

Normal/near-normal RV size and function

HemodynamicsNormalization of RV function (RAP <8 mm Hg and CI >2.5 to 3.0 l/min/m2)

6-min walk distance>380 to 440 m; may not be aggressive enough in young individuals

Cardiopulmonary exercise testingPeak VO2 >15 ml/min/kg and EqCO2 <45 l/min/l/min

B-type natriuretic peptide levelNormal

FC, functional class; CMR, cardiac Magnetic resonance; RV, right ventricle; RAP, right atrial pressure;

CI, cardiac index; 6MWD, 6-minute walk distance.

McLaughlin V, et al. JACC. 2013;62(25) Supp D.

Nitric oxidedeficiency

Endothelinoverexpression

Prostacyclin

deficiency

ERAsBlock the binding of ET-1 to its receptors, preventing vasoconstrictor effects of ET-13

PDE-5 inhibitorsBlock the activity of PDE-5, restoring vasodilation through an increase in cGMP1

ProstacyclinSupplement the deficiency in PGI2, resulting in vasodilation and inhibition of platelet aggregation2

THERAPIES

ABNORMALITIES

Vasoactive Mediators Involved In PAH

cGMP, cyclic guanosine monophosphate; ERA, endothelin receptor antagonist; ET-1, endothelin; PDE-5, phosphodiesterase type 5; PGI2, prostacyclin.

1. Humbert et al. J Am Coll Cardiol. 2004;43(suppl S):13S-24S. 2. Humbert et al. N Engl J Med. 2004;351:1425-1436. 3. Galiè et al. Eur Heart J. 2004;25:2243-2278.

Prostacyclins

Humbert M, Sitbon O, Simonneau G. Drug Therapy: Treatment of Pulmonary Arterial Hypertension. New England Journal of Medicine. 2004;351:1425-36.

Flolan® Remodulin® Ventavis®

Epoprostenol sodium Tyvaso®

Veletri ®

• Relax smooth muscle by increasingintracellular cAMP

• Inhibit platelet aggregation

• Inhibit smooth muscle cell proliferation

• Inhibit pulmonary vascular remodeling

Prostacyclins act to:

Attributes

• Must be initiated in a hospital or controlled setting• Dosed in ng per kg per minute• Usually initiated at 2ng per kg per minute • Increased by 2ng per kg per minute until dose-limiting • effects warrant reduction

Clinical considerations

Epoprostenol Sodium (Flolan® / Veletri ® )

• Half-life 3-5 minutes • Requires continuous IV administration • Potential rebound effect • Requires dedicated central tunneled catheter for chronic use, can

use peripheral or PICC for acute use• Stable for 24 hours on pump with icepacks, stable for 48 hours

refrigerated, stable for 8 hours at room temperature• Ice packs required• Generic equivalent is AP rated (final formulation only)

Other considerations:

DO NOT stop pump under any circumstancesDO NOT draw blood or flush (dedicated line)

• Not compatible with any medications or fluids • Risk of central line infection and sepsis• Insert peripheral IV for central line complications

Flolan® (epoprostenol sodium) [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2011.Epoprostenol sodium for injection [package insert]. Irvine, CA: TEVA; 2009.

Goal: to improve exercise capacity in patients with WHO group I PAH

Expected/Excess

Epoprostenol SodiumDose-limiting considerations:

• Flushing

• Jaw pain

• Diarrhea

• Nausea

• Vomiting

• Hypotension

• Rash

• Headache

• Foot pain

• Warm extremities

Insufficient

• Short of breath at rest

• Pallor

• Cough

• Cool extremities

• Chest pain

• Cyanosis

Flolan® (epoprostenol sodium) [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2008.Epoprostenol sodium for injection [package insert]. Irvine, CA: TEVA; 2009.

Patient Supplies Flolan® Epoprostenol sodium

Veletri®

Photo Source: Internal Accredo Photo

Remodulin (treprostinil)

Attributes

Clinical Considerations

• Half-life = 4.5 hours • Dosed in ng per kg per min• Dose is increased based on clinical response

(increments of 1.25 ng/kg/min for 4 weeks and later at 2.5 ng/kg/min per week)

• Remodulin IV—initiated in a hospital setting• No reconstitution necessary – dilute to volume

appropriate for pump being used (normal saline, sterile water, sterile glycine diluent for Flolan)

• Stable at room temperature, no ice packs needed

• Risk of central line infection and sepsis• DO NOT stop Remodulin IV under any

circumstance

Remodulin ® (treprostinil) Injection [package insert]. Research Triangle Park, NC: United Therapeutics Corp.; 2014.

Goal: to diminish symptoms associated with exercise in patients with WHO group

I PAH

Expected/excess

Remodulin (treprostinil )

Dose-limiting considerations:

• Flushing• Nausea/vomiting• Foot/leg pain • Diarrhea• Hypotension• Rash• Warm extremities

Insufficient

• Short of breath at rest

• Fatigue• Lower extremity

edema • Syncope• Cough• Cool extremities• Pallor• Cyanosis• Chest pain

Remodulin ® (treprostinil) Injection [package insert]. Research Triangle Park, NC: United Therapeutics Corp.; 2014.

Patient SuppliesCADD-Legacy® (IV) CADD-MS® 3 (IV)

Crono Five (IV) CADD-MS® 3 (subcutaneous)

Photo Source: Internal Accredo Photo

Single Lumen CVC ONLY for prostacyclin administration.

CVC should be placed by interventional radiology or vascular surgery

If possible, anesthesia should be avoided during placemat

CVC should be tunneled under the skin

Examples of CVC’s include:◦ Broviacs◦ Hickmans◦ Groshongs

Central Venous Catheter (CVC)

CVC= Central Venous Catheter

Emergency Considerations

Adverse effects of prostacyclinIndications of pulmonary arterial hypertension

Headache Dyspnea

Jaw pain Fatigue

Nausea/Vomiting Chest pain

Diarrhea Palpitations

Extremity Pain Lower extremity edema

Flushing Ascites

Thrombocytopenia Syncope

Prostacyclin Side Effects vs PAH Symptoms

Kingman, M et al. Safety Recommendations for Administering Intravenous Prostacyclins in the Hospital . Crit Care Nurse 2013;33:32-39.

Rebound Pulmonary Arterial Hypertension

Signs and symptoms ◦ Acute respiratory decompensation◦ Tachycardia◦ Hypoxemia◦ Angina◦ Dizziness

Managing Home Infusion Pumps

If a patient is on a home infusion pump, don’t stop the pump until the Specialty Pharmacy (SP) or MD’s office has been contacted

If possible, utilize the patient as a resource for needed information such as concentration, dose, pump rate, etc

Reach out to the SP FIRST if there are questions related to dosing or the pump. They have a 24/7/365 Call Center to help with any questions or concerns you may have◦ Their number can be found on the side of the pump

Specialty Pharmacy Service Offerings

• All third-party reimbursement management– New patients– Patients transitioning from other PAH therapies

• Patient assessment and evaluation

• Teaching– Pre-teaching and ongoing support – In-home, hospital, or clinic

• Discharge planning support

• 24/7 patient hotline access

Specialty pharmacies can make initiating Remodulin therapy easier for you by providing continuous patient support with ongoing services and

resources for long-term success

Inpatient Basics Regarding Pumps

When a patient comes to the hospital, he/she should bring his/her back up pump along

If he/she does not have the back up pump, have a family member bring it from home unless you use hospital pumps for prostacyclin infusion

It is good practice to check with the hospitals’ Biomedical or Risk Management Department in advance to understand any rules or barriers to patient provided pumps in the hospital

Remodulin can be given on hospital pumps if the patient is unable to manage his/her own pump

Transitioning to a Hospital Pump

When switching to a hospital pump from a home infusion pump, consider what actions should be taken if the new concentration for Remodulin is different than the patient’s home concentration◦ Withdraw the drug from the central line before starting

the newly mixed drug (different concentration/different pump rate)

◦ Consider re-priming the line with the new concentration of drug (avoid disruption in therapy)

IV Administration – Line Issues

If patient has a central line NEVER flush the line – flushing could result in prostacyclin bolus

Do NOT interrupt the infusion A single lumen catheter (ie. Hickman) is the preferred route for

prostacyclin delivery◦ If you must give Remodulin in a double or triple lumen catheter, use the

most distal port If the patient’s central line is occluded, it is essential to place

peripheral access and utilize the peripheral line until new central access can be established ◦ Due to the risks associated with sudden infusion disruption, the patient

should have two peripheral lines placed to ensure that there is back up access if the initial peripheral access is lost

Intravenous Line Emergencies

A cracked or leaking catheter is an emergency. The patient will need to have the prostacyclin run through a peripheral line and Interventional Radiology will need to be contacted to repair the line ◦ Peripheral line is only a TEMPORARY measure

Other emergencies:◦ Catheter becomes occluded, falls out or is pulled out◦ Any interruption in the delivery of a prostanoid (IV or SC)

Urgent considerations:◦ Oozing or draining at the site◦ Fever of unknown origin

IV, intravenous; SC, subcutaneous

Questions

Documents

Johnell Diwan, RN, BSN Pulmonary Hypertension Clinic Coordinator Legacy Medical Group, Pulmonary & Sleep Medicine