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4/18/2018
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PEDIATRIC PULMONARY HYPERTENSION PHARMACOTHERAPY
Angelica J. Ng, PharmD, BCPS, BCPPSPediatric Clinical Pharmacist UCSF Benioff Children’s Hospital
11th International Conference Neonatal & Childhood Pulmonary Vascular Disease ・April 19, 2018
Pediatric Pulmonary Hypertension Pharmacotherapy2
DISCLOSURE (AND DISCLAIMER)
I have no conflicts of interests to disclose
Unless otherwise noted, all medications to be discussed are off-label
Pediatric Pulmonary Hypertension Pharmacotherapy3
OVERVIEW
Brief overview of pulmonary hypertension as a disease state
Pharmacologic management of pulmonary hypertension – targeted therapies
- Medication safety and regulatory considerations
Pharmacotherapeutic considerations in the perioperative management of pediatric pulmonary hypertension
Pediatric Pulmonary Hypertension Pharmacotherapy4
UCSF BENIOFF CHILDREN’S HOSPITAL 183-bed quaternary care teaching hospital
- 24 pediatric cardiac ICU/ TCU beds, 32 PICU/TCU beds and 58 NICU beds
Nationally ranked in pediatric cardiology and pulmonology (US News & World Report
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Pediatric Pulmonary Hypertension Pharmacotherapy5
UCSF PEDIATRIC PULMONARY HYPERTENSION PROGRAM
Established 2011
1st PHA-Accredited Pediatric Center for Comprehensive Care on the west coast
149 – 200 patients being actively managed
- Most commonly associated diagnoses: congenital heart disease, congenital diaphragmatic hernia, idiopathic, bronchopulmonary dysplasia
20 – 29 patients on IV/SQ prostacyclin therapy
https://phassociation.org/phcarecenters/peds/ucsf/. Accessed March 29, 2018
Pediatric Pulmonary Hypertension Pharmacotherapy6
PULMONARY HYPERTENSION
Defined as an increase in mean pulmonary arterial pressure ≥25 mmHg at rest as assessed by right heart catheterization
Pediatrics:
- Same definition, (slightly) different etiologies
- Catch-22: worse outcomes if left untreated but lack of data for pediatric-specific therapeutic strategies
Pediatric Pulmonary Hypertension Pharmacotherapy7
GOALS OF THERAPY
selective pulmonary vasodilation, restoration of
normal endothelial function, and reversal of remodeling of the
pulmonary vasculature
reduce right ventricular afterload and prevent right ventricular
failure
Ultimately, improved survival and allowance of normal activities of childhood without the need to self-limit
Pediatric Pulmonary Hypertension Pharmacotherapy8
FDA APPROVAL TIMELINE
1995 2001 2002 2004 2005 2007 2008 2009 2012 2013 2015 2017
Epoprostenol(Flolan®)
Bosentan(Traceleer®)
Treprostinil(Remoudlin®)
Iloprost(Ventavis®)
Sildenafil (Revatio®)
Letairis(Ambrisentan®)
Epoprostenol(Veletri®)
Treprostinil(Tyvaso®)
Tadalafil(Adcirca®)
Sildenafil suspension (Revatio®)
Treprostinil(Orenitram®)
Riociguat(Adempas®)
Macitentan(Opsumit®)
Selexipag(Uptravi®)
Bosentan tablet for oral
suspension (Tracleer®)
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Pediatric Pulmonary Hypertension Pharmacotherapy9
ENDOTHELIAL PATHWAYS
https://www.researchgate.net/figure/Key-pathways-involved-in-the-pathophysiology-of-pulmonary-hypertension-Three-main_fig1_49646627. Accessed March 26, 2018
Pediatric Pulmonary Hypertension Pharmacotherapy10
ENDOTHELIN PATHWAY
Endothelin 1 is a potent vasoconstrictor- ET-1 + ETA → vasoconstriction
Endothelin Receptor Antagonists- Bosentan (Tracleer®) – non-selective- Ambrisentan (Letairis®) – selective for ETA- Macitentan (Opsumit®) – non-selective
Biology of ET-1 and ET receptors is complex- Is “selectivity” better?
ENDOTHELIN PATHWAY
ET-1 – Endothelin 1ETA – Endothelin Receptor AETB – Endothelin Receptor B
Pediatric Pulmonary Hypertension Pharmacotherapy11
ENDOTHELIN RECEPTOR ANTAGONISTS
Bosentan (Tracleer ®)Ambrisentan(Letairis ®)
Macitentan(Opsumit®)
Pediatric Data or FDA Approval
FDA approved 2017Phase III trial suspended*
Phase III trial recruiting
Dosing Frequency Twice daily Once daily Once daily
Teratogenic Yes Yes Yes
REMS program Yes Yes Yes
Adverse EffectsAnemiaElevated LFTsEdema
++++
+/--
++
+--
*as of March 30, 2018
Pediatric Pulmonary Hypertension Pharmacotherapy12
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Pediatric Pulmonary Hypertension Pharmacotherapy13
REMSRisk Evaluation and Mitigation Strategy
FDA requirement for manufacturers; ensures that benefit of a medication outweigh its risks
Provider must be enrolled in REMS program; restricted distribution
In a nutshell:Bosentan Ambrisentan, Macitentan
Patient enrollment Male and female patients enrolled Female patients enrolled
Liver ToxicityCounsel patients on risk of liver toxicity
LFTs on initiation then monthlyN/A
TeratogenicityCounsel on teratogenicity
Pregnancy test before initiation and monthly thereafter (and 1 month after discontinuation); yearly pregnancy status update
BOSENTANTHE BASICS
Non-selective endothelin receptor antagonist Administration: oral/enteral Pharmacokinetic and pharmacodynamic considerations:
- Bioavailability: ~50%- Metabolism: Hepatically via CYP2C9 and CYP3A4 (active metabolite)- Drug Interactions: Induces CYP2C9 (weak) and CYP3A4 (moderate)
Adverse Reactions: hepatic dysfunction, anemia, edema Access: only available through specialty pharmacies
Pediatric Pulmonary Hypertension Pharmacotherapy14
BOSENTANDOSING
Dosing is no longer straightforward!
Historically (UCSF Practice):
- Initial: 1 mg/kg/dose BID, maintenance: 2 mg/kg/dose BID
FUTURE-1 study: Bosentan plasma concentrations achieved in children are lower than those in adults (even at 4 mg/kg/dose BID)
FUTURE-3 study: can dose Bosentan up to three times daily
Pediatric Pulmonary Hypertension Pharmacotherapy15
BOSENTANDOSING
New labeling:
Initial (4 weeks) Maintenance
Patients >12 years of age and >40 kg 62.5 mg twice daily 125 mg twice daily
Patients >12 years of age and <40 kg 62.5 mg twice daily 62.5 mg twice daily
Patients ≤12 years of age ≥4-8 kg˃8-16 kg ˃16-24 kg ˃24-40 kg
16 mg twice daily 32 mg twice daily 48 mg twice daily 64 mg twice daily
16 mg twice daily 32 mg twice daily 48 mg twice daily 64 mg twice daily
http://www.tracleer.com/assets/PDFs/Tracleer_Full_Prescribing_Information.pdf. Accessed March 27, 2018.
Pediatric Pulmonary Hypertension Pharmacotherapy16
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Conundrum: ”hazardous” medication that needs
to be compounded AND needs to be provided by a specialty pharmacy
↓
cannot prescribe as a suspension (since outpatient pharmacy only
able to provide tablets)
BOSENTANDOSAGE FORMS & MED SAFETY
https://www.uspharmacist.com/article/bosentan-625-mg-ml-oral-suspension. Accessed March 27, 2018.
Lack of pediatric-friendly dosage form until very very recently!
Pediatric Pulmonary Hypertension Pharmacotherapy17
BOSENTANDOSAGE FORMS & MED SAFETY
To split or not to split tablets?
Patient education sheet developed by UCSF Pediatric Pulmonary Hypertension Program
Required constant vigilance at transitions of care to make sure correct dose/instructions ordered
Pediatric Pulmonary Hypertension Pharmacotherapy18
Tablet for oral suspension
accompanied pediatric labeling September 2017
BOSENTANDOSAGE FORMS & MED SAFETY
http://www.tracleer.com/px/about-tracleer. Accessed March 27, 2018.
Pediatric Pulmonary Hypertension Pharmacotherapy19
BOSENTANDOSAGE FORMS & MED SAFETY
Availability of 32 mg soluble tablet and dosing recommendations based on age and weight categories promote “cleaner” inpatient orders and
outpatient prescriptions (so far…)
Pediatric Pulmonary Hypertension Pharmacotherapy20
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NITRIC OXIDE-cGMP PATHWAY
Pediatric Pulmonary Hypertension Pharmacotherapy21
Increasing cGMP production stimulates vasodilation and antiproliferation
Achieved by:
- Stimulating cGMP production (inhaled NO, SGC stimulator)
- Preventing cGMP breakdown by PDE-5 (PDE-5 Inhibitors)
NITRIC OXIDE-cGMP PATHWAY
Soluble Guanylate Cyclase Stimulator
+
NO – Nitric Oxide PDE – PhosphodiesteraseSGC – Soluble Guanylate Cyclase
Pediatric Pulmonary Hypertension Pharmacotherapy22
NITRIC OXIDE-cGMP MEDICATIONS
Sildenafil (Revatio®) Tadalafil (Adcirca®) Riociguat (Adempas®)
Class PDE-5 Inhibitor PDE-5 Inhibitor SGC stimulator
Pediatric Data or FDA Approval
Phase III trials completed
Phase III trials in progress
Phase III trial in progress
Dosing Frequency Three times daily (usually)
Once daily N/A
Adverse Effects headache, nausea, myalgia, nasal
congestion, flushing
headache, nausea, myalgia, nasal
congestion, flushingN/A
Pediatric Pulmonary Hypertension Pharmacotherapy23
SILDENAFILTHE BASICS
Phosphodiesterase-5 Inhibitor
Administration: oral/enteral (IV in some cases)
Pharmacokinetic and pharmacodynamic considerations:
- Bioavailability: ~40% (tablets and suspension are bioequivalent)
- Metabolism: Hepatically via CYP2C9 and CYP3A4
- Drug Interactions: weak inhibitor of CYP2C9; major substrate of CYP3A4 (remember bosentan?)
Pediatric Pulmonary Hypertension Pharmacotherapy24
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SILDENAFILTHE BASICS
Adverse Reactions:
- headache, nausea, myalgia, nasal congestion, flushing
- Hypotension? Reflux? Vision changes?
Access: available through community pharmacies
Pediatric Pulmonary Hypertension Pharmacotherapy25
SILDENAFILDOSING
Not straightforward either!
Generally: 1 mg/kg/dose TID
Titrate based on “tolerability” (ex. decrease to 0.75 mg/kg/dose Q6H)
Children and adolescents < 18 years oldWeight Dose
8 to 20 kg 10 mg three times daily
>20 kg to 45 kg 20 mg three times daily
>45 kg 40 mg three times daily
Pediatric Pulmonary Hypertension Pharmacotherapy26
Pediatric Pulmonary Hypertension Pharmacotherapy27
SILDENAFILSTARTS-1 AND STARTS-2 TRIALS ““In summary, although children randomized to [high sildenafil] had an
unexplained increased mortality compared to [lower sildenafil], multiple analyses raised uncertainty about the survival/dose relationship; all dose groups displayed favorable survival for children with PAH. STARTS-1 efficacy results and the long-term survival rates favor use of lower sildenafil doses.”
Barst RJ et alon behalf of the STARTS-2 investigators
Pediatric Pulmonary Hypertension Pharmacotherapy28
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SILDENAFILSTARTS-1 AND STARTS-2 – THE FALLOUT
August 2012 October 2012 March 2014
Pediatric Pulmonary Hypertension Pharmacotherapy29
SILDENAFILDOSAGE FORMS & MED SAFETY (& ECONOMICS)
10 mg/mL (112 mL): $9,883.76 (~$8/mg)Generic Sildenafil tablets 25 mg (30): $1,993.91 (~$2.60/mg)
Discard 60 days after reconstitution
Pediatric Pulmonary Hypertension Pharmacotherapy30
TADALAFILTHE BASICS
Phosphodiesterase-5 Inhibitor
Administration: oral/enteral
Pharmacokinetic and pharmacodynamics considerations:
- Half-life: 15 – 17.5 hours
- Metabolism: Hepatically via CYP3A4
Pediatric Pulmonary Hypertension Pharmacotherapy31
TADALAFILTHE BASICS
Adverse Reactions:
- headache, nausea, myalgia, nasal congestion, flushing
Access: available through community pharmacies
Dosing: 1 mg/kg/dose once daily Tadalafil tablets 20 mg (60): $4,809.60 (~$4/mg)
Pediatric Pulmonary Hypertension Pharmacotherapy32
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PROSTACYCLIN PATHWAY
Pediatric Pulmonary Hypertension Pharmacotherapy33
Endogenous prostacyclin synthesized from arachidonic acid → increased cAMP → vasodilation (but also inhibits platelet activity and smooth muscle cell growth)
PROSTACYCLIN PATHWAY
PROSTACYCLIN THERAPY
PROSTACYCLIN ANALOGUES
PARENTERAL
Epoprostenol
Treprostinil
INHALED
Iloprost
Treprostinil
ORAL
Treprostinil
PROSTACYCLIN RECEPTOR AGONIST
Selexipag
Prostacyclin receptor agonist
Pediatric Pulmonary Hypertension Pharmacotherapy34
PROSTACYCLIN MEDICATIONS
Epoprostenol(Flolan®, Veletri®)
Treprostinil(Remodulin®,
Tyvaso®, Orenitram®)
Iloprost(Ventavis®)
Selexipag(Uptravi®)
ClassProstacyclin
analogueProstacyclin
analogueProstacyclin
analogueProstayclin IP
Receptor Agonist
Pediatric Data or FDA Approval Clinical
data/experience
Clinical data/experience for inhaled/parenteral
routesPhase II trial for PO
Clinical data/experience
Minimal clinical data/experience
Routes IV (inhaled?) IV, SQ, inhaled, PO Inhaled PO
Pediatric Pulmonary Hypertension Pharmacotherapy35
INHALED PROSTACYCLINS
Pediatric Pulmonary Hypertension Pharmacotherapy36
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EPOPROSTENOLFLOLAN®, VELETRI® – THE BASICS
Synthetic prostacyclin
Administration: continuous IV infusion (requires central access)
Pharmacokinetic and pharmacodynamic considerations:
- Metabolism: rapidly hydrolyzed
- Half-life: ≤ 6 mins → abrupt withdrawal or sudden large dose reductions can cause severe rebound pulmonary hypertension; possible death
Pediatric Pulmonary Hypertension Pharmacotherapy37
EPOPROSTENOLFLOLAN®, VELETRI® – THE BASICS
Initiate at 2 ng/kg/min and titrate upwards as tolerated
Dose-limiting side effects: nausea, diarrhea, vomiting, hypotension, headache, jaw pain
Access: only available through specialty pharmacies
Pediatric Pulmonary Hypertension Pharmacotherapy38
EPOPROSTENOLFLOLAN®, VELETRI® – LOGISTICS
Central access → increased risk of infection
Flolan® only stable for 8 hours at room temperature (needs ice packs for 24-hour administration)
Flolan® only compatible with Flolan®-specific diluent
Veletri® is room-temperature stable but limited data in pediatrics
Very short half-life → need back ups of everything! (i.e. medication, IV access, pump and associated supplies)
Pediatric Pulmonary Hypertension Pharmacotherapy39
TREPROSTINILREMODULIN® – THE BASICS
Synthetic prostacyclin analogue
Administration: IV, SQ
Pharmacokinetic and pharmacodynamic considerations:
- Metabolism: hepatically via CYP2C8
- Half-life: ~4 hours
Pediatric Pulmonary Hypertension Pharmacotherapy40
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TREPROSTINILREMODULIN® – THE BASICS
Initial infusion rates vary (typically 1.25 ng/kg/min); pediatric patients may require higher starting rates (2-4 ng/kg/min)
Titrate upwards as tolerated
- Dose-limiting side effects similar to epoprostenol
Access: only available through specialty pharmacies
Pediatric Pulmonary Hypertension Pharmacotherapy41
TREPROSTINILREMODULIN ® – LOGISTICS
Longer half-life (~4 hours) and room-temperature stable
- No back-up cassette/cartridge
- Does not have to be refrigerated or hung with ice packs
Flexibility of IV or SQ administration
Benefits of SQ administration
- Less risk of infection
- May change cartridges as infrequently as Q72hours
Pediatric Pulmonary Hypertension Pharmacotherapy42
PARENTERAL PROSTACYCLINSUCSF PRACTICE
Primarily use SQ Remodulin®
- ”Soft max” rate of 0.03 mL/hr
Patients transitioned to hospital-supplied pump and medication
Requires use of order set; ordering privileges restricted to certain providers
Pediatric Pulmonary Hypertension Pharmacotherapy43
PARENTERAL PROSTACYCLINSUCSF PRACTICE
Pediatric Pulmonary Hypertension Pharmacotherapy44
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BEDSIDE RN COMPLETES SCREENING TOOL
PARENTERAL PROSTACYCLINSUCSF PRACTICE
Information obtained by nursing and pharmacy should be corroborated by orders
entered by provider
PHARMACY CONTACTS SPECIALTY PHARMACY
Pediatric Pulmonary Hypertension Pharmacotherapy45
PARENTERAL PROSTACYCLINSUCSF PRACTICE
SQ site pain commonly reported pitfall of SQ Remodulin®
Can be managed with acetaminophen, ibuprofen, and opioids as well as topical medications
Pediatric Pulmonary Hypertension Pharmacotherapy46
Pediatric Pulmonary Hypertension Pharmacotherapy47
PERIOPERATIVE MANAGEMENT
PERIOPERATIVE PULMONARY HYPERTENSIVE CRISESMedication-related Recommendations from the AHA/ATS Guidelines on Pediatric PH
Death or pulmonary hypertensive crises occur in 4.5% of pediatric pulmonary hypertension patients undergoing catheterizations and/or non-cardiac surgeries
Inciting factors: acidosis, agitation, pain, hypoxia, or tracheal suctioning
General postoperative strategies for avoiding PHC, including avoidance of hypoxia, agitation, and acidosis, should be used in children at high risk for PHCs
Class ILevel of Evidence B
Induction of alkalosis can be useful for treatment of PHCs Class IIaLevel of Evidence B
Administration of opiates, sedatives, and muscle relaxants is recommended for reducing postoperative stress response and the risk for or severity of PHCs
Class ILevel of Evidence B
In addition to conventional postoperative care, iNO and/or inhaled PGI2 should be used as the initial therapy for PHCs and failure of the right side of the heart
Class ILevel of Evidence B
Sildenafil should be prescribed to prevent rebound PH in patients who have evidence of a sustained increase in PAP on withdrawal of iNO and require reinstitution of iNO despite gradual weaning of iNO dose
Class ILevel of Evidence B
In patients with PHCs, inotropic/pressor therapy should be used to avoid RV ischemia caused by systemic hypotension
Class ILevel of Evidence B
Pediatric Pulmonary Hypertension Pharmacotherapy48
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PERIOPERATIVE PULMONARY HYPERTENSIVE CRISES
Possibility of compromised perfusion s/p cardiac surgery = decreased absorption of SQ Remodulin?
No data; UCSF practice has been to convert to IV pre-operatively
Pediatric Pulmonary Hypertension Pharmacotherapy49 Pediatric Pulmonary Hypertension Pharmacotherapy50
SUMMARY
Pediatric pulmonary hypertension is a rare disease state; requires lot of extrapolation from adult algorithms
Common pitfalls in managing pediatric pulmonary hypertension: lack of data, lack of pediatric-friendly dosage forms
Encouraging that data is coming out from individual centers but still need more robust clinical trials
Abman et al. Circulation. 2015.
REFERENCES
Abman SH. Role of Endothelin Receptor Antagonists in the Treatment of Pulmonary Arterial Hypertension. Annu Rev Med. 2009;60:13-23 Abman SH et al. Pediatric Pulmonary Hypertension: Guidelines From the American Heart Association and American Thoracic Society. Circulation.
2015;132:2037-2099 Abman SH, et al. Implications of the U.S. Food and Drug Administration Warning against the Use of Sildenafil for the Treatment of Pediatric Pulmonary
Hypertension. Am J Respir Crit Care Med. March 15, 2013. Vol 187, Iss. 6, pp 572–575 Aggarwal M and Grady RM. Treatment of Pediatric Pulmonary Hypertension. Curr Treat Options Cardio Med (2018) 20: 8 Aypar E, et al. Clinical efficacy and safety oBr J Clin Pharmacol. 2009 Dec;68(6):948-55f switch from bosentan to macitentan in children and young
adults with pulmonary arterial hypertension. Cardiology in the Young (2018), 28, 542–547 Barst RJ et al. A Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Study of Oral Sildenafil Citrate in Treatment-Naive Children With
Pulmonary Arterial Hypertension. Circulation. 2012;125:324-33 Barst RJ, et al. STARTS-2: Long-Term Survival With Oral Sildenafil Monotherapy in Treatment-Naïve Pediatric Pulmonary Arterial Hypertension. Beghetti M, et al. Pharmacokinetic and clinical profile of a novel formulation of bosentan in children with pulmonary arterial hypertension: the FUTURE-1
study. Circulation. 2014 May 13;129(19):1914-23 Berger RMF, et al. FUTURE-2: Results from an open-label, long-term safety and tolerability extension study using the pediatric FormUlation of bosenTan
in pUlmonary arterial hypertension. Int J Cardiol. 2016 Jan 1;202:52-8 Berger RMF, et al. A bosentan pharmacokinetic study to investigate dosing regimens in paediatric patients with pulmonary arterial hypertension:
FUTURE-3. Br J Clin Pharmacol (2017) 83 1734–1744 Dhariwal AK and Bavdekar SB. Sildenafil in pediatric pulmonary arterial hypertension. J Postgrad Med. 2015 Jul-Sep; 61(3): 181–192
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4943407/. Accessed March 26, 2018
Pediatric Pulmonary Hypertension Pharmacotherapy51
REFERENCES
Dingemanse J, et al. Efficacy, safety and clinical pharmacology of macitentan in comparison to other endothelin receptor antagonists in the treatment of pulmonary arterial hypertension. Expert Opinion on Drug Safety, 13:3, 391-405
Gallotti R, et al. Single-Center Experience Using Selexipag in a Pediatric Population. Pediatr Cardiol (2017) 38:1405–1409 Frank BS and Dunbar I. Diagnosis, Evaluation and Treatment of Pulmonary Arterial Hypertension in Children. Children. 2018 Mar 23;5(4) Galié N, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension Ivy, Dunbar. Advances in Pediatric Pulmonary Arterial Hypertension. Curr Opin Cardiol. 2012 March ; 27(2): 70–81 Kameny RJ, Fineman J, Adatia, I. Perioperative Management of Pediatric Pulmonary Hypertension. Advances in Pulmonary Hypertension: 2016, Vol. 15,
No. 2, pp. 87-91 Lexicomp Online® , Pediatric & Neonatal Lexi-Drugs® , Hudson, Ohio: Lexi-Comp, Inc.; March 1– 30, 2018 McLaughlin VV, et al. ACCF/AHA 2009 Expert Consensus Document on Pulmonary Hypertension Circulation. 2009;119:2250-2294 Oishi P, Datar S, Fineman J. Pediatric pulmonary arterial hypertension: current and emerging therapeutic options. Expert Opinion on Pharmacotherapy,
12:12, 1845-1864 Siehr SL, et al. Hemodynamic Effects of Phenylephrine, Vasopressin, and Epinephrine in Children With Pulmonary Hypertension: A Pilot Study. Pediatr
Crit Care Med 2016; 17:428–437 Spreemann T, et al. First-in-child use of the oral soluble guanylate cyclase stimulator riociguat in pulmonary arterial hypertension. Pulmonary Circulation
2017; 8(3) 1–6 Steinhorn RH. Pharmacotherapy for Pulmonary Hypertension. Pediatr Clin N Am 59 (2012) 1129–1146 Takatsuki S and Calderbank M. Initial Experience With Tadalafil in Pediatric Pulmonary Arterial Hypertension. Pediatr Cardiol (2012) 33:683–688 Wei A, et al. Clinical Adverse Effects of Endothelin Receptor Antagonists: Insights From the Meta-Analysis of 4894 Patients From 24 Randomized
Double-Blind Placebo-Controlled Clinical Trials. J Am Heart Assoc. 2016;5: e003896
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QUESTIONS?