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Pulmonary Hypertension: Intravenous, Subcutaneous, Inhaled, or Oral – What to Choose and Why

Pulmonary Hypertension: Intravenous, Subcutaneous, Inhaled, or Oral – What to Choose and Why. John Kim MD, Julia McSweeney RN, CPNP, Joanne Lee PharmD , Dunbar Ivy MD. Disclosures. Steering Committee: Gilead/GSK, Actelion

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Pulmonary Hypertension: Intravenous, Subcutaneous, Inhaled, or Oral – What to Choose and Why

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  1. Pulmonary Hypertension: Intravenous, Subcutaneous, Inhaled, or Oral – What to Choose and Why John Kim MD, Julia McSweeneyRN, CPNP, Joanne Lee PharmD, Dunbar Ivy MD

  2. Disclosures • Steering Committee: Gilead/GSK, Actelion • The University of Colorado SOM contracts with Actelion, Gilead, Pfizer, United Therapeutics for Dr Ivy to be a consultant

  3. Outline • Background / General Approach • Inhaled Nitric Oxide • Alternative / Supplementary Therapy • Outpatient Therapy • Newer Therapies

  4. Postoperative PH Mortality • Immediately after surgery or in the first 48 hours • Mortality • 30% in 80-84, 6.8 % 90-94, < 3% after 2000 • Improvement in surgery and post op care • PH crisis 0.75%; mortality 20% • Causes • CPB (endothelial dysfunction), hypoxia, stress

  5. Therapeutic approach Wessel D. Beghetti (editor) Elsevier 2006

  6. Inhaled NO A B v PAP PVR RVEF CO Shunt PAO2 DO2 ( ) MAP SVR PAP PVR RVEF CO Shunt PAO2 DO2 ( ) MAP SVR v v v v v v v v v v 0 v v v v v v v v v 0 Nitroprusside 0 Vasodilators: Inhaled versus Intravenous

  7. Inhaled Nitric Oxide • Indication: Hypoxemic respiratory failure in term neonates • Use of iNO in CHD is off-label • Mechanism of action • Stimulates production of cGMP • Microselective effect • Macroselective effect

  8. INO in Post-Operative CHD • Neonate • TAPVR / Truncus Arteriosus / Scimitar Syndrome / D-TGA with PPHN / OHT • Infant • VSD / AVSD / DORV / AP Window / • MS / AS / • Other

  9. iNO Benefits • Selective Pulmonary vasodilator with essentially no systemic effects • Deactivated when combines with hemoglobin • Decreases PVR without effecting SVR • NO has a dramatic effect on decreasing PA pressures acutely in pts with PH. • Quick acting and short half life • Decreases V/Q mismatch • Decreases intrapulmonary shunt • Increases PaO2

  10. iNO Risks • Methemoglobin • Decreased O2 carrying capacity of Hb • Nitrogen Dioxide formation • Acute lung injury • NO unstable, converts to NO2 in presence O2 • NO ppm, O2 level, and time effect NO2 Prod. • Rebound Pulmonary Hypertension • Exogenous delivery may decrease endogenous production • Slow recovery from effects of CPB • Residual pulmonary vascular disease

  11. “Failure to Respond” to iNO • Inadequate lung recruitment • Lung hypoplasia • Severe plexiformarteriopathy • ACD • SPB deficiency / ACBA3 gene • Impaired Vasoreactivity • LV systolic/diastolic dysfunction • Discrete pulmonary vein stenosis

  12. Inhaled NO: RCT Double Blind Miller, et al. Lancet. 2000;356(9240):1464-9

  13. Inhaled NO: RCT Double Blind Time to criteria met weaning and time on study gas Miller, et al. Lancet. 2000;356(9240):1464-9

  14. Inhaled NO: Cochrane Database Bizzarro, et al. Cochrane Database Syst Rev. 2005 Oct 19;(4):CD005055 Bizarro, et al. Cochrane Database Syst Rev. 2014 Jul 3;7:CD005055

  15. Inhaled NO use CHCO

  16. Inhaled NO

  17. Therapy of acute right heart failure SAP PAP RV function Volume-Preload Hb > 12 – (14g%) - Nor-epinephrine iLA (AJRCCM 2004) “Terlipressin/Vasopressin” • - PDE-3-Inhibitor • Epinephrine low dose • Dobutamine • Vasopressin • - Levosimendan • RV-assist /ECMO • Increase FiO2 • Inhaled NO • Sildenafil i.v. /p.o. • PGI2 i.v. / inhaled • ETRA?? • “Levosimendan” - Fenestration / BAS Adapted from Prof Schranz, Giessen

  18. Post Op CHD: IV Sildenafil N = 17 4 Fraisse, et al. Intensive Care Med (2011) 37:502–509

  19. Sildenafil iNO rebound Namachivayam, et al. Am J Respir Crit Care Med 2006;174(9):1042-7

  20. Effects of Inhaled Iloprost in Postoperative CHD 1.25-5 μg/dose Q 2 hours Vorhies EE et al Pediatr Cardiol. 2014 Dec;35(8):1337-43

  21. Effects of Inhaled Epoprostenol in PPHN after iNO 50-100 ng/kg/min Kelly, et al. J Pediatr 2002;141: 830

  22. Inhaled Treprostinil 3-6 breaths (18-36 mcg) Takatsuki et al Pediatr Cardiol (2013) 34:1006–1012

  23. Therapy Targets for PAH Humbert M, Sitbon O, Simonneau G. N Engl J Med 2004;351:1425-36

  24. PAH Treatments Inhaled treprostinil IV treprostinil CCB, anticoagulation, digitalis, diuretics Sildenafil SC treprostinil Tadalafil Ambrisentan Epoprostenol Iloprost Bosentan <1995 2005 2008 2009 2013 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2006 2007 Riociguat Macitentan Oral Treprostinil

  25. PAH-specific Treatment Options for Adults Failing Acute Vasoreactivity Testing Note: No PAH-specific medication is FDA approved for use in pediatric populations. All PAH –specific medication use in pediatrics represents off-label use.

  26. WSPH 2013 - Consensus Pediatric IPAH/HPAH Treatment AlgorithmHigher risk vs. Lower Risk Factors Ivy, et al. J Am Coll Cardiol. 2013;62:D117-26

  27. WSPH -2013 Consensus Pediatric IPAH/HPAH Treatment Algorithm * Expert Referral General: Consider Diuretics, Oxygen, Anticoagulation, Digoxin Acute Vasoreactivity Testing Positive + > 1 y.o. Negative Oral CCB Lower Risk Higher Risk ERA or PDE-5i (oral) Iloprost (inhaled) Treprostinil (inhaled) Epoprostenol or Treprostinil (IV/SQ) Consider Early Combination ERA or PDE-5i (oral) No - Improved - Sustained reactivity Reassess considerearly combo-therapy Yes Atrial septostomy Lung transplant Continue CCB Ambrisentan (IIaC), Bosentan (IB), CCB (IC), Epoprostenol (IB), Iloprost (IIbC), Sildenafil (IB**USA?), Tadalafil (IIaC), Treprostinil SQ/IV (IIbC/IIaC), Treprostinil Inh (IIbC), atrial septostomy (IIaC) *Use of all agents is considered off label in children aside from sildenafil in EU **Dosing recommendations per EU approved dosing for children Modified from J Am Coll Cardiol. 2009;53:1573-1619.

  28. Kaplan-Meier Estimated Survival From Start of Sildenafil Treatment in STARTS-1 and -2 Barst RJ, et al. Circulation in press

  29. SQ Treprostinil

  30. New PH Therapies Riociguat (Bay 63-2521) • sGC stimulator • Independent of NO • Enhances sensitivity of sGC to NO • Phase II/II trials PAH Caccamo, et al. Advances in Pulmonary Hypertension 2014;13(2):68-75

  31. Overexpression of cGMP in 8 week old rats leads to Bone Hyperostosis Miura K, Namba N, Fujiwara M, Ohata Y, et al. (2012) PLoS ONE 7(8): e42180. doi:10.1371/journal.pone.0042180

  32. Oral Treprostinil Laser Drilled Hole Semi-permeable Membrane

  33. Summary • Postoperative PH less common than previous • Most patients respond to preventive management and RV support (milrinone) • iNO first line but expensive • I.V. sildenafil and inhaled prostacyclin beneficial • Newer therapies challenging to use in CICU

  34. Guidelines for iNO usage at CHCO in an effort to optimize utilization of INO • Improve patient selection • Stricter criteria for initiation and discontinuation • Lowest tolerable dose • More aggressive weaning based on literature and present findings AHRF 3-4 days of utilization PPHN 3-7 days CHD 2-4 days • Pulmonary hypertension consult for patients with difficulty weaning off iNO >7 days

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