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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
Progression of Pulmonary Vascular Disease
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
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
Thin RV wall Healthy PA endotheliumThin-walled relaxed PAsLarge capillary network
Normal CO/PVR and perfusion
Hypertrophied RVAbnormal PA endothelium
Constricted stiff PAsLoss of microvessels
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
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
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
McLaughlin et al. J Am Coll Cardiol. 2009;53:1573-1619.
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.
McLaughlin et al. J Am Coll Cardiol. 2009;53:1573-1619.
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