Pulmonary Hypertension: Intravenous, Subcutaneous, Inhaled, or Oral

1
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

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

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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, lt 3 after 2000
• Improvement in surgery and post op care
• PH crisis 0.75 mortality 20
• Causes
• CPB (endothelial dysfunction), hypoxia, stress

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Therapeutic approach
ENCOURAGE AVOID
Anatomic investigations Residual anatomic disease
Opportunities fro right to left shunt as pop off Intact atrial septum in right heart failure
Sedation/Anesthesia Agitation/ pain
Moderate hyperventilation Respiratory acidosis
Moderate alkalosis Metabolic acidosis
Adequate inspired oxygen Alveolar hypoxia
Normal lung volumes Atelectasis or overdistention
Optimal hematocrit Excessive hematocrit
Inotropic support Low output and low coronary perfusion
Vasodilators Vasoconstrictors/increased afterload
Wessel D. Beghetti (editor) Elsevier 2006
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Vasodilators Inhaled versus Intravenous
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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

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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

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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

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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

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Failure to Respond to iNO

• Inadequate lung recruitment
• Lung hypoplasia
• Severe plexiform arteriopathy
• ACD
• SPB deficiency / ACBA3 gene
• Impaired Vasoreactivity
• LV systolic/diastolic dysfunction
• Discrete pulmonary vein stenosis

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Inhaled NO RCT Double Blind
Miller, et al. Lancet. 2000356(9240)1464-9
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Inhaled NO RCT Double Blind
Time to criteria met weaning and time on study
gas
Miller, et al. Lancet. 2000356(9240)1464-9
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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 37CD005055
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Inhaled NO use CHCO
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Inhaled NO
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Therapy of acute right heart failure
SAP
PAP
RV function
Volume-Preload Hb gt 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
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Post Op CHD IV Sildenafil
N 17
4
Fraisse, et al. Intensive Care Med (2011)
37502509
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Sildenafil iNO rebound
Namachivayam, et al. Am J Respir Crit Care Med
2006174(9)1042-7
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Effects of Inhaled Iloprost in Postoperative CHD
1.25-5 µg/dose Q 2 hours
Vorhies EE et al Pediatr Cardiol. 2014
Dec35(8)1337-43
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Effects of Inhaled Epoprostenol in PPHN after iNO
50-100 ng/kg/min
Kelly, et al. J Pediatr 2002141 830
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Inhaled Treprostinil
3-6 breaths (18-36 mcg)
Takatsuki et al Pediatr Cardiol (2013)
3410061012
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Therapy Targets for PAH
Humbert M, Sitbon O, Simonneau G. N Engl J Med
20043511425-36
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PAH Treatments
Inhaled treprostinil
IV treprostinil
CCB, anticoagulation, digitalis, diuretics
Sildenafil
SC treprostinil
Tadalafil
Ambrisentan
Epoprostenol
Iloprost
Bosentan
lt1995
2008
2009
2005
2013
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2006
2007
Riociguat Macitentan Oral Treprostinil
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PAH-specific Treatment Options for Adults Failing
Acute Vasoreactivity Testing
Oral Therapy Oral Therapy Oral Therapy Oral Therapy Inhaled Therapy Continuous Parenteral Therapy
ERAs PDE5 Inhibitors sGC Stimulator Prostacyclin Prostacyclins Prostacyclins
Ambrisentan Sildenafil Riociguat Treprostinil Iloprost Epoprostenol
Bosentan Tadalafil Treprostinil RTS epoprostenol
Macitentan Treprostinil (SC or IV)
Note No PAH-specific medication is FDA approved
for use in pediatric populations. All PAH
specific medication use in pediatrics represents
off-label use.
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WSPH 2013 - Consensus Pediatric IPAH/HPAH
Treatment AlgorithmHigher risk vs. Lower Risk
Factors
LOWER RISK DETERMINANTS OF RISK HIGHER RISK
No Clinical evidence of RV failure Yes
No Progression of Symptoms Yes
No Syncope Yes
Growth Failure to thrive
I,II WHO Functional Class III,IV
Minimally elevated SBNP / NTproBNP Significantly elevated Rising level
Echocardiography Severe RV enlargement/dysfunction Pericardial Effusion
Systemic CI gt 3.0 L/min/m2 mPAP/mSAP lt 0.75 Acute Vasoreactivity Hemodynamics Systemic CI lt 2.5 L/min/m2 mPAP/mSAP gt 0.75 RAP gt 10mmHg PVRI gt 20 WUm2
Ivy, et al. J Am Coll Cardiol. 201362D117-26
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WSPH -2013 Consensus Pediatric IPAH/HPAH
Treatment Algorithm
Expert Referral
General Consider Diuretics, Oxygen,
Anticoagulation, Digoxin
Acute Vasoreactivity Testing
Positive gt 1 y.o.
Negative
Oral CCB
Lower Risk
Higher Risk
ERA or PDE-5i (oral) Iloprost (inhaled) Treprostin
il (inhaled)
Epoprostenol or Treprostinil (IV/SQ) Consider
Early Combination ERA or PDE-5i (oral)
No
- Improved - Sustained reactivity
Reassess considerearly combo-therapy
Yes
Lung transplant
Atrial septostomy
Continue CCB
Ambrisentan (IIaC), Bosentan (IB), CCB (IC),
Epoprostenol (IB), Iloprost (IIbC), Sildenafil
(IBUSA?), 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.
2009531573-1619.
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Kaplan-Meier Estimated Survival From Start of
Sildenafil Treatment in STARTS-1 and -2
Barst RJ, et al. Circulation in press
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SQ Treprostinil
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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 201413(2)68-75
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• 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. doi10.1371/journal.
pone.0042180
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Oral Treprostinil
Laser Drilled Hole
Semi-permeable Membrane

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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

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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 gt7 days