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Daniela Brady, RNResearch Nurse ClinicianPulmonary Hypertension CenterColumbia University Medical Center
Disclosures� United Therapeutics, Speaker’s Bureau
Prostacyclin (PGI2)� Naturally occuring prostaglandin metabolite of arachidonic
acid (PGI2)� Continuously produced by the vascular endothelium by
prostacyclin synthase � A relative deficiency of prostacyclin may contribute to the
pathogenesis of PAH
Prostacyclin pathway
Arachidonic acid Prostaglandin I 2
Prostacyclin (PGI 2)
cAMP
Vasodilation and antiproliferation
Smooth muscle cells
Prostacyclin derivatives
+
Pulmonary artery in
patient with PAH
PGI2 and its derivatives have potent vasodilatory, antiproliferative and antithrombotic effects on vascular smooth muscl e cells.
PGI2: Mechanism of Action
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Main Properties of Prostacyclin� Systemic and pulmonary vasodilation via relaxation of vascular
smooth muscle cells
� Inhibition of platelet aggregation
� Inhibition of vascular cell migration and proliferation
� Cytoprotective effect: prevention of ischemic cell injury
� Improvement in pulmonary clearance of endothelin-1
� Possible inotropic effect
Prostanoids� Developed to mimic the favorable characteristics of
prostacyclin (PGI2) but offer alternate modes of delivery� Longer half-life or other features (e.g.
thermostability) to improve risk-benefit ratio and/or quality of life issues associated with epoprostenol delivery
Intravenous Epoprostenol (PGI2)� Rapidly hydrolyzed in circulation (t1/2 = 3 min)� Unstable at room temperature – requires ice packs � thermo-stable formulation FDA approved; not tested in children
� Many potential side effects� Requires continuous IV infusion for sustained effect
� PGI2 was first used as an acute vasodilator in 1980 in a child with IPAH
FDA approved 1995; FC III/IV PAH
Epoprostenol vs. Conventional TherapyChange from Baseline in 6-Minute Walk Test
Epoprostenol (11; 41) Conventional Therapy (14; 40)
-60
-40
-20
0
20
40
60
80
Met
ers
Week 1 Weeks 8 and 12 (Mean)
Rubin, et al. Ann Intern Med, 1990; Barst, et al. NEJM, 1996
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Barst, RJ. et al. Circulation 1999
K-M survival curves comparing survival of nonrespon ders (n=24) treated with long-term PGI2 with survival of nonresponders (n=22 ) for whom PGI2 was indicated but unavailable
Epoprostenol and Survival in Children
Yung, D. et al. Circulation 2004;110:660-665
Kaplan-Meier curves for survival and treatment succ ess in patients in more recent medical era (n=44)
Pediatric PAH Survival and Treatment success in “Epo Era”
Epoprostenol (Flolan)Epoprostenol –thermostable (Veletri)
Epoprostenol delivery system (CADD pump) IV/SQ Prostanoid Side Effects
� Flushing�Headache�Diarrhea �Nausea/emesis� Jaw pain� Leg pain
�Hypotension�Dizziness� Syncope�Delivery complications� Site pain� Site reaction
Vary according to drug and route of delivery
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Epoprostenol Delivery System Complications �Local site infection �Catheter related bloodstream infections�CADD pump malfunction� bolus effect� cessation phenomenon – due to short half life
of epoprostenol
Epoprostenol� Prostacyclin is effective in treating group 1 PAH� improve pulmonary hemodynamics� prolong survival� improve symptoms� extend exercise tolerance
� Caution� numerous side effects� inconvenience and risks with continuous infusion
Pediatric PAH Indications for IV epoprostenol: general guidelines�WHO FC III or IV patient (presence of right heart
failure)� Non-responsive to AVT� Very young patients (<7yrs); maximize benefit
during rapid lung development� Syncope (particularly if already on oral tx)� Failed oral trial (how long do you wait?)� Consider a lower threshold knowing the natural
history in children is worse than adults, untreated
Treprostinil (remodulin)� Longer acting prostacyclin analogue� (t ½= 4 hours)
� Stable at room temperature� No ice packs or refrigeration required� Mixed cassettes last 48 hours
� SQ or IV form
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Treprostinil Delivery Systems� CADD Legacy� Chrono 5� Minimed 407 C (IV/SQ)
IV/SC Bioequivalence Study
Laliberte et al. J Cardiovasc Pharmacol. 2004.
Hour0 12 24 36 48 60 72 84 96
10-3
10-2
10-1
100
Trep
rost
inil
conc
entr
atio
n, n
g/m
L
IVSC
Steady state
● IV Remodulin▲SC Remodulin
Treatment considerations: IV vs SQ� Provider/patient preferences� Financial considerations� PAH center experience� Family/care-giver support� Body image concerns� Low pain threshholds
SQ Treprostinil Site Pain Considerations
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Site Pain Management Approaches: Local/Topical options� First line remedies� Ice� Warm bath with Epsom salts� Aloe vera gel, arnica oil, capsaicin cream
� Anesthetic Agents� Lidocaine 5% patches/lidocaine cream� Caladryl lotion
� Vasoconstrictive agents� Hemorrhoid ointment
� PLO Gel compounds
Pain Management Approaches: Systemic options� Histamine H1 receptor antagonists� Loratadine, fexofenadine HCL, cetirizine HCL
� Histamine H2 receptor antagonists� Ranitidine, famotidine
� Non-opioid analgesics� Ibuprofen, acetaminophen
� GABA analogs� Gabapentin, pregabalin
� Opioid analgesics (for severe pain)� Tramadol, fentanyl patch, hydrocodone with acetaminophen
� Antidepressants� Amitriptyline
IV Epoprostenol to IV Treprostinil transition � Successful transition of 13 pediatric PAH pts
from IV epo to IV treprostinil� 2 deaths, 2 transitions to other therapies� Transitioned in hospital over 24 hours (rapid or slow)� Patients maintained their exercise capacity� Higher dose, fewer side effects� Several central line infections however, reported
before current recommendations for treprostinil line care were implemented
Ivy DD, et al. Am J Cardiol, 2007
IV Prostanoids: Minimizing risk for Catheter Related- Blood Stream Infections (CR-BSI)
� Single center experience using closed-hub system and waterproofing precautions during showering with IV prostanoids in children to minimize CR-BSI� 50 patients receiving prostanoids � Closed-hub system and maintenance of dry catheter hub
connections significantly reduced the incidence of CR-BSI (particularly infections caused by gram-negative pathogens) in patients receiving intravenous treprostinil.
Ivy DD, et al. Infection Control and Hospital Epidemiology, 2009.
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Rates of CR-BSI pre and post implementation of Closed-Hub system with protected connections
Ivy DD, et al. Infection Control and Hospital Epidemiology, 2009.
SQ Treprostinil for PH associated with CLD of infancy� Case series of 5 infants successfully treated (off-label)
with SQ treprostinil at Columbia University Medical Center� General characteristics� CLD� Former premature infants (born at 23-26 weeks)� Birth weight range 470-635 grams� 4/5 patients were under 1 year of age at the time of
initiation of therapy
SQ Treprostinil for PH associated with CLD of infancy: Results� All patients had improvement in their respiratory and
inotrope support after treprostinil initiation� There were no local reactions at SC infusion site� No evidence of pain or tenderness at infusion site� 4/5 patients are alive at present (one baby died from
suspected septic shock 2 weeks after initiation of therapy)
Transition of Pediatric PAH Patients from IV Epoprostenol to oral/inhaled agents � Retrospective review of all pediatric IPAH/FPAH
treated at Columbia (1987-2008) who transitioned off IV epo to oral/inhaled drugs� General criteria for transition off included: � FC I/II� Age > 6yrs� PAPm <35mmHg� Normal cardiac index
� Hemodynamics and clinical data were assessed on peak epoprostenol dose vs. off epoprostenol
Melnick L, et al., AJCardiol, 2010
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Transition of Pediatric PAH Patients from IV Epoprostenol to oral/inhaled agents: Results� 14/104 pediatric patients who met general criteria were
transitioned off IV epoprostenol (over several months to years; 4/03-7/08) � 13/14 remained off IV epo on oral/inhaled medications� Hemodynamics, exercise capacity (if able) and WHO
functional class remained stable off epo compared to peak epoprostenol dose. (f/u 7+6 mos); Further improvement in WHO FC was seen post epoprostenol (p<0.005)� All 13 patients are alive at present; (77% ERA, 69%
PDE-5 inhibitor, 38% CCB, 8% iloprost)
Melnick L, et al., AJCardiol, 2010
Summary: Prostanoids in Pediatric PAH� IV epoprostenol still remains the “gold standard” for the
treatment of advanced pediatric PAH� Newer agents have enabled initiation or transition to other
prostanoids and even to oral/inhaled agents in carefully selected patients� Close monitoring of side effects and diligent management are
important for patient compliance and treatment success� Caution should be applied to delay in the institution of
prostanoid therapy when using novel oral agents � As novel agents are developed so are new challenges in
decision making
