inhaled!prostacyclins!in! pediatric!patients

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INHALED!PROSTACYCLINS!IN!

PEDIATRIC!PATIENTS:!!!!!!!!!!!!!!!!!!!!!!!

THE!NEW!NITRIC!OXIDE?!!

!

September!11th

,!2015!

University!of!Texas!at!Austin!!

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! !

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Molly!McNaull,!PharmD!

PGYO1!Pharmacy!Resident!

Seton!Healthcare!Family!!

!!

!

9/11/15%

1%

Inhaled Prostacyclins in Pediatric Patients: The New Nitric Oxide?

September%11th,%2015%%University%of%Texas%at%Aus>n%% Molly%McNaull,%PharmD%PGYG1%Pharmacy%Resident%Seton%Healthcare%Family%%

Conflict of Interest

• No%conflicts%of%interest%to%disclose%%

2%

Objectives

•  Review disease states in which inhaled nitric oxide and inhaled prostacyclins are commonly used

•  Compare and contrast inhaled nitric oxide with

prostacyclin therapies

•  Evaluate the literature available on inhaled nitric oxide and prostacyclin use in pediatric patients

•  Determine if inhaled epoprostenol may be used in place of inhaled nitric oxide

3%

Pulmonary Hypertension (PH)

4%

PH Definition

•  Eleva>on%of%mean%pulmonary%artery%pressure%(PAPm)%▫  PAPm%≥%25%mmHg%

•  Due%to%various%causes%%▫  Pulmonary%arterial%hypertension%%▫  Persistent%pulmonary%hypertension%of%the%newborn%▫  Acute%lung%injury%▫  Acute%respiratory%distress%syndrome%

Galiè%N%et%al.%Eur$Heart$J.%2015;%pii:%ehv317.$

5%

Pulmonary Arterial Hypertension (PAH)

6%

9/11/15%

2%

PAH Background •  Vascular%prolifera>on%and%remodeling%of%pulmonary%arterioles%!%pulmonary%vascular%resistance%(PVR)%%

•  Defini>on%▫  PAPm%≥%25%mmHg%▫  PVR%>%3%Wood%units%▫  PAWP%≤%15%mmHg%

• Median%survival%for%idiopathic%PAH%%▫  Prior%to%synthe>c%prostacyclin:%%2.8%years%%▫  Now:%%>%7%years%%

Galiè%N%et%al.%Eur$Heart$J.%2015;%pii:%ehv317.%Benza%RL%et%al.%Chest.%2012;142(2):448G56.%

7%

PAH Pathophysiology

hep://circresearch.com/gallery/tag/pulmonaryGhypertension/%

8%

Types of PAH •  Idiopathic%or%familial%(IPAH%or%FPAH)%%•  Common%comorbidi>es%▫  Congenital%heart%disease%(CHD)%%▫  Chronic%lung%disease%▫  Connec>ve%>ssue%disease%▫  Liver%disease%

Ivy%et%al.%J$Am$Coll$Cardiol.2013;D117G26.%%

9%

Persistent Pulmonary Hypertension of the Newborn (PPHN)

10%

PPHN Background

•  Failure%of%PVR%to%decrease%aher%birth%

•  Presenta>on%%▫  Within%12%hours%of%birth%%▫  Cyanosis%▫  Acidosis%▫  Hypotension%%

• Mortality%rate%of%10%%%

% Bendapudi%P%et%al.%Paediatr$Respir$Rev.%2015;16(3):157G61.$

11%

Normal Fetal Circulation •  Low%SVR%

•  Elevated%PVR%

•  Presence%of%shunts%▫  Ductus%arteriousus%%▫  Foramen%ovale%

•  Vasoconstric>on%

•  Low%produc>on%of%vasodilators%▫  Nitric%oxide%%▫  Prostacyclin%%

Steinhorn%%RH.%Pediatr$Crit$Care$Med.%2010;11(2S):79G84.%TeixeiraGMendonca%C%and%HenriquesGCoelho%T.%Rev$Port$Cardiol.$2013;32(12):1005G12.%

12%

9/11/15%

3%

Holloway%B%et%al.$URMC$Health$Encyclopedia%2015.%

13%

Normal Cardiopulmonary Transition at Birth

•  Fetal%prepara>on%▫  Increased%expression%of%nitric%oxide%synthases%▫  Prostacyclin%pathway%

•  Rapid%fall%in%PVR%and%PAP%

•  10Gfold%rise%in%pulmonary%blood%flow%

•  Signals%for%transi>on%▫  Mechanical%distension%of%the%lung%▫  Decrease%in%CO2%tension%in%lungs%▫  Increase%in%O2%tension%in%lungs%

Steinhorn%%RH.%Pediatr$Crit$Care$Med.%2010;11(2S):79G84.%

14%

Causes of PPHN • Maladapta>on%of%pulmonary%vascular%bed%▫  Idiopathic%PPHN%

•  Hypoplas>c%vasculature%▫  Congenital%diaphragma>c%hernia%%

•  Constricted%pulmonary%vasculature%▫ Meconium%aspira>on%syndrome%▫  Pneumonia%%▫  Respiratory%distress%syndrome%%

%Steinhorn%%RH.%Pediatr$Crit$Care$Med.%2010;11(2S):79G84.%

15%

Acute Lung Injury (ALI)

16%

ALI and ARDS Definition •  ALI%▫  Acute%hypoxia%%▫  PaO2/FiO2≤%300%mmHg%

•  ARDS%%▫  Severe%hypoxemic%respiratory%failure%%!  PaO2/FiO2≤%200%mmHg%on%PEEP%≥%5cm%H2O%▫  Bilateral%infiltra>on%on%chest%imaging%%▫  Inflammatory%injury%to%alveolar%capillary%barrier%

Han%S%and%Mallampalli%RK.%%J$Immunol.%2015;194:855G60.%

17%

ALI Risk Factors

Ware%LB%and%Maehay%MA.%N$Engl$J$Med.%2000;342(18):1334G49.%

Primary'Lung'Injury' Secondary'Lung'Injury''

Pneumonia% Sepsis%

Aspira>on% Mul>ple%trauma%

Pulmonary%contusion% Cardiopulmonary%bypass%

Fat,%amnio>c%fluid%or%air%emboli%

Drug%overdose%%

NearGdrowning%or%inhala>on%injury%

Acute%pancrea>>s%

Reperfusion%pulmonary%edema%

Transfusion%of%blood%products%%

18%

9/11/15%

4%

ARDS Pathophysiology

Han%S%and%Mallampalli%RK.%J$Immunol.%2015;194:855G60.%

19%


Han%S%and%Mallampalli%RK.%J$Immunol.%2015;194:855G60.%

20%


hep://samadimd.com/yourGcare/acuteGrespiratoryGdistressGsyndrome%

21%

PH Treatment Strategies

•  Reverse%underlying%cause%%

•  Suppor>ve%therapy%%▫ Mechanical%ven>la>on%%▫  Prone%posi>oning%%▫  Inhaled%nitric%oxide%(iNO)%%▫  Surfactant%replacement%for%neonates%

•  Extracorporeal%membrane%oxygena>on%(ECMO)%

Curr$Probl$Pediatr$Adolesc$Health$Care$2013;%43:278G284%

22%

Pharmacotherapy

23%

Inhaled Nitric Oxide (iNO) Product' INOmax'gas'for'inhala;on'

Mechanism%of%ac>on%

Vascular%smooth%muscle%relaxa>on%!%pulmonary%vasodila>on%!%increase%in%PaO2%

Pediatric%dosing%% 1G40%ppm%

Adverse%events% Hypotension,%methemoglobinemia,%pulmonary%edema,%hypoxemia%

Cost% $100G200%per%hour%%

Ichinose%F%et%al.%CirculaAon.%2004;%109:%3106G11.%%Pierce%CM%et%al.%BMJ.$2002;325(7359):336.%Torbic%H%et%al.%J$Crit$Care.$2013;28:844G8.%

INOmax%[package%insert]%INO%Therapeu>cs.%2013.%%%

24%

9/11/15%

5%

iNO Mechanism

Berne%RM.%Berne$&$Levy$Physiology.$2008.$Philadelphia,%PA:%Mosby/Elsvier.%%

25%

iNO Adverse Effects

BinGNun%A%and%Schreiber%MD.%J$Perinatol.$2008;%28:S84G92.%

26%

Why Not iNO? •  Cost%%•  Toxicity%and%adverse%events%•  Inconsistent%pa>ent%response%•  Lack%of%postopera>ve%mortality%benefit%for%children%with%PH%and%CHD%

•  Transient%benefits%seen%in%ARDS%in%adults%▫  Poor%methodology%in%pediatric%studies%

•  Lack%of%data%for%preterm%neonates%%

Bizzarro%M%et%al.%Cochrane$Database$Syst$Rev.$2014;7:CD005055%Adhikari%NK%et%al.%BMJ.2007;334:779.%

Bronicki%RA%et%al.%J$Pediatr.2015;166:365G9.%

27%

iNO Literature Cita;on' Pa;ent'

Popula;on'Interven;on' Findings''

Miller%OI%et%al.%Lancet.%2000;356%(9240):1464G69.%

Infants%(n=124)%%!%correc>ve%surgery%for%CHD%

iNO%10ppm%or%Placebo%

•  Fewer%PHTC%•  Shorter%>me%to%extuba>on%•  No%toxic%effects%•  No%difference%in%mortality%

Bronicki%RA%et%al.%%J$Pediatr.2015;%166:365G9.%

Children%with%ARDS%(n=55)%%

iNO%5ppm%%or%%Placebo%%

•  Improved%OI%at%12%h,%no%longer%at%24%h%

•  Reduced%mechanical%ven>la>on%%•  ECMOGfree%survival%%•  No%difference%in%mortality%

Roberts%JD%Jr%et%al.%N$Engl$J$Med.%1997;336(9):605G10.%$

FullGterm%infants%with%severe%hypoxemia%and%PPHN%(n=58)%

iNO%80ppm%or%Placebo%

•  Doubled%systemic%oxygena>on%in%53%%of%iNO%group%

•  ECMOGfree%survival%•  No%difference%in%mortality%or%AE%

28%

Prostacyclins

29%

Prostacyclin (PGI2) Mechanism •  Ac>va>on%of%adenylate%cyclase%▫  Vasodila>on%of%vascular%beds%

•  Decreased%thrombogenesis%and%platelet%aggrega>on%▫  ARDS%%

Berne%RM.%Berne$&$Levy$Physiology.$2008.$Philadelphia,%PA:%Mosby/Elsvier.%%

30%

9/11/15%

6%

Generic' Dosing'' Adverse'Events' HalfElife' Cost*'

Iloprost' Inh:$2.5G7.5%mcg/dose%5G9%>mes/day%%

Cough,%flushing,%headache,%nausea,%hypotension,%bleeding,%bronchospasm%%

20G30%minutes%

$80G433%

Trepros;nil' Inh:$$3%to%9%breaths%(6%mcg/%breath)%4%>mes/%day%IV/subcut:$$50G70ng/kg/min%

Inh:$hypotension,%bleeding,%cough,%headache,%nausea,%flushing,%syncope%%IV/subcut:$infusion%site%reac>on,%diarrhea,%jaw%pain%

4%hours% Inh:$$$24G73%$IV/subcut:$$$64%%

Epoprostenol'' IV:$2%ng/kg/min,%>trate%q30%min%by%2ng/kg/min%%(max=%120ng/kg/min)%$

Infusion%site%reac>on,%flushing,%headache,%hypotension,%agita>on,%chest%pain,%tachycardia,%dizziness,%arthralgia%

6%minutes%

$10G20%

%Ventavis®%[prescribing%informa>on].%Actellion%Pharmaceu>cals%US,%Inc.%2013.%Remodulin®%[prescribing%informa>on].%United%Therapeu>cs%Corp.%2014.%

Flolan®%[prescribing%informa>on]%GlaxoSmithKline.%2015.%

*Es>mated%cost%per%day%for%a%10%kg%pa>ent%

PGI2 Medications

31%

Why Inhaled Prostacyclins?

Complica;ons'of'Parenteral'

•  Hypotension%%•  Nausea%%•  Dizziness%•  Myalgias%%•  FluGlike%syndrome%•  Bleeding%%

•  Direct%administra>on%allows%for%selec>vity%%

•  Decreased%rates%of%adverse%events%%

Benefits'of'Inhaled''

Flolan®%[prescribing%informa>on]%GlaxoSmithKline.%2015.%Torbic%H%et%al.%J$Crit$Care.$2013;28:844G8.%

Dahlem%P%et%al.%Crit$Care$Med.$2004;32(4):1055G60.%

32%

Evidence for Inhaled Iloprost

%%%

Vorhies%EE.%Pediatr%Cardiol.%2014;%35(8):%1337G43.%%Ivy%DD%et%al.%%J$Am$Coll$Cardiol.$2008;51:161G9.%

Limsuwan%A%et%al.%%Int%J$Cardiol.$2008;129(3):333G8.%

Ivy%

• Transi>on%from%IV%prostanoids%%• Sustained%func>onal%improvement%in%PAH%

Vorhies%• Alterna>ve%to%iNO%for%postopera>ve%PH%in%CHD%%%

AE%• Lower%airway%reac>vity%

33%

Evidence for Inhaled Treprostinil

Takatsuki%et%al.,%Pediatr$Cardiol.$2013;%34:%1006G12.%Krishnan%U%et%al.,%Am$J$Cardiol.$2012;%110:%1704G9.%

McIntyre%CM%et%al.%Pulm$Circ.2013;3(4):862G9.%

Takatsuki%• Studied%for%use%in%AVT%

Krishnan%

• WHO%func>onal%class%improvement%• Exercise%capacity%improvement%%

AE%

• Well%tolerated%in%infants%• Cough,%hypotension%%

34%

Epoprostenol: The Other Inhaled Prostacyclin

•  Con>nuous%infusion%via%nebulizer%%▫  Recons>tute%and%dilute%IV%solu>on%%

•  Pediatric%dosing:%%%▫  Ini>al:%10G50%ng/kg/min%%!  Titrate%by%10%ng/kg/min%q30%min%%! Max:%100G150%ng/kg/min%

Torbic%H%et%al.%J$Crit$Care.$2013;28:844G8.%

35%

Inhaled Epoprostenol (iEPO) in Adult Patients

$Preston%IR%et%al.%Pulm$Circ$2013;%3(1):%68G73.%

De%Wet%CJ%et%al.%J$Thorac$Cardiovasc$Surg$2004;127(4):1058G67.$

Preston%•  Vasodilator%effects%in%PH%comparable%to%iNO%

De%Wet%•  PH,%RV%dysfunc>on,%refractory%hypoxemia%•  Decreased%PAPm%compared%to%baseline%%

AE%•  No%significant%AE%

36%

9/11/15%

7%

Could inhaled epoprostenol replace inhaled nitric

oxide in the pediatric population with pulmonary

hypertension?

CLINICAL QUESTION

37%

CHD%

Adult%ALI%

ALI%PPHN%

Literature Review

38%

Carroll'CL'et'al.'J"Card"Surg.'2005;20:436E9.'Title' Inhaled$prostacyclin$following$surgical$repair$of$congenital$heart$

disease$–$a$pilot$study$

Objec;ve'' To%examine%the%effect%of%iEPO%in%the%immediate%postopera>ve%period%in%children%with%congenital%heart%disease%

Popula;on' Children%with%CHD%undergoing%intracardiac%surgery%with%preopera>ve%PH%(n=6)%%

Methods' Prospec>ve,%preliminary%pilot%study%%iEPO%administered%postopera>vely%%Hemodynamics%at%baseline,%aher%iEPO,%and%aher%discon>nua>on%

Results' •  Reduced%PAPm%from%25%mmHg%to%21%mmHg%(p%<%0.01)%•  ImprovedPaO2/FiO2%ra>o%from%275%to%433%(p=0.01)%%•  No%change%in%PVR/SVR%%

Conclusions' iEPO%reduced%PAP%and%improved%oxygena>on%Children%with%CHD%and%PH%may%benefit%from%iEPO%Further%inves>ga>on%in%a%large%group%is%warranted%%

39%

Torbic H, Szumita PM, Anger KE et al. Inhaled epoprostenol vs inhaled nitric oxide for hypoxemia in critically ill patients. J Crit Care 2013;28:844-8.

40%

Torbic'H'et'al.'J"Crit"Care."2013;28:844E8."Objec;ve''

•  To%compare%efficacy,%safety,%and%cost%outcomes%in%pa>ents%who%have%received%either%iEPO%or%iNO%for%hypoxic%respiratory%failure%

Popula;on'

•  ADULTS%(n=105)%mechanically%ven>lated%and%receiving%iEPO%or%iNO%for%improvement%in%oxygena>on%

Study'Design'

•  Retrospec>ve,%singleGcenter%analysis%%

Methods'

•  Aher%failing%maximal%conven>onal%therapy,%pa>ents%were%started%on%pulmonary%vasodilator%

•  Dosing%•  iNO:%1G80%ppm%%•  iEPO:%10G50%ng/kg/min%

41%

Torbic'H'et'al.'J"Crit"Care."2013;28:844E8."Results'

42%

See%Appendix,%page%2%

9/11/15%

8%

Torbic'H'et'al.'J"Crit"Care."2013;28:844E8."Primary'Outcome''

•  Change%in%PaO2/FiO2%ra>o%aher%1%hour%of%vasodilator%therapy%%

Secondary'Outcomes'

•  ICU%length%of%stay%•  Hospital%length%of%stay%•  Dura>on%of%therapy%•  Dura>on%of%mechanical%ven>la>on%•  Incidence%of%adverse%events%•  Cost%

43%


Primary%Outcome%%

Change%in%PaO2/FiO2%ra>o%aher%1%hour:%%no%difference%(p=0.36)%•  iNO%increase%by%%%%%%%%%%%%%%%%%%%%%%%%%%20.58%±%91.54%•  iEPO%increase%by%%%%%%%%%%%%%%%%%%%%%%%%33.04%±%36.19%

44%



45%


Torbic'H'et'al.'J"Crit"Care."2013;28:844E8."Conclusions'

•  No%detectable%differences%between%iNO%and%iEPO%%•  PaO2/FiO2%•  Clinical%outcomes%%•  Adverse%events%

•  iNO%is%associated%with%greater%drug%expenditure%

Limita;ons'

•  Retrospec>ve%study%%•  Single%academic%medical%center%•  Several%indica>ons%for%use%%•  Differences%in%baseline%characteris>cs%between%groups%

•  Weight%%•  Baseline%PaO2/FiO2%

Applica;on'

In$adults$with$ARDS$•  iEPO$appears$to$be$as$safe$and$effecAve$as$iNO$at$a$substanAally$lower$cost$$…Does$this$hold$true$for$pediatric$paAents?$$$

46%

Dahlem P, van Aalderen WM, de Neef M et al. Randomized controlled trial of aerosolized prostacyclin therapy in children with acute lung injury. Crit Care Med 2004;32:1055-60.

47%

Dahlem'et'al.'Crit"Care"Med."2004;32(4):1055E60.'Objec;ve''

To%inves>gate%whether%iEPO%improves%oxygena>on%in%children%with%ALI%

Popula;on'

Children%(n=14)%with%acute%lung%injury%requiring%mechanical%ven>la>on%%•  PaO2/FiO2%ra>o%≤%300%torr%•  Bilateral%infiltrates%on%chest%radiograph%%Exclusion:%%%•  Thrombocytopenia%%•  aPTT%>%43%seconds%•  Intracranial%hemorrhage%%•  CHD%

Study'Design'

•  DoubleGblind,%placeboGcontrolled%%

48%

9/11/15%

9%

Dahlem'P'et'al.'Crit"Care"Med."2004;32(4):1055E60.'Methods'

•  Crossover%randomiza>on%•  Group%1:%'iEPO,%then%normal%saline%•  Group%2:''normal%saline,%then%iEPO%

•  Prostacyclin%dosing%•  Stepwise%increments%(10,%20,%30,%40%and%50%ng/kg/min)%%

•  Data%collec>on%•  HR,%MAP,%ABG,%and%required%ven>lator%sezngs%%•  Flow/volume%(F/V)%curves%in%9%of%14%pa>ents%

•  Primary%outcome%•  Oxygena>on%index%(OI)%

49%

Dahlem'P'et'al.'Crit"Care"Med."2004;32(4):1055E60.'Results'

50%



Significant%improvement%in%OI%with%iEPO%at%30%ng/kg/min%compare%to%placebo%•  Median%extent%of%improvement:%%26%%%

51%



52%



53%



Adverse%effects%%•  No%difference%seen%in%HR,%MAP,%or%FiO2%•  No%bleeding%events%%•  In%those%with%F/V%curves,%no%airway%hyperreac>vity%

54%


9/11/15%

10%

Dahlem'P'et'al.'Crit"Care"Med."2004;32(4):1055E60.'Conclusions'

•  iEPO%improves%oxygena>on%in%children%with%ALI%•  Future%trials%are%needed%to%inves>gate%whether%this%therapy%will%improve%pa>ent%

outcomes%'

Limita;ons''

•  Study%size%%•  Designed%to%measure%surrogate%%•  Unknown%background%therapy%%

Applica;on'

•  iEPO$improves$OI$in$children$with$ALI$$•  No$AE$observed$$•  Unknown$effects$in$comparison$to$inhaled$nitric$oxide$•  Unknown$impact$on$paAent$outcomes$$

55%

Brown AT, Gillespie JV, Miquel-Verges F et al. Inhaled epoprostenol therapy for pulmonary hypertension: Improves oxygenation index more consistently in neonates than in older children. Pulm Circ 2012;2(1):61-6.

56%

Brown'AT'et'al.'Pulm"Circ.'2012;2(1):61E6.'Objec;ve''

•  To%determine%the%efficacy%of%iEPO%for%treatment%of%acute%PH%in%pediatric%pa>ents%

Popula;on'

•  Pa>ents%<%18%years%of%age%(n=20)%who%received%iEPO%for%at%least%1%hour%and%had%data%available%for%analysis%of%the%OI%before%and%during%treatment%%

Methods'

Retrospec>ve%chart%review%%•  Other%pulmonary%vasodilators%used%%•  Prepara>on:%%IV%epoprostenol%formula>on%was%recons>tuted%and%then%diluted%

for%nebuliza>on%%•  Dosing:%%

•  iEPO%at%50%ng/kg/min%nebulized%at%a%rate%of%8%ml/hr*%%%%%%%%*One%pa>ent%received%iEPO%intermieently%as%50%ng/kg%diluted%in%3%mL%of%diluent%%

57%

Brown'AT'et'al.'Pulm"Circ.'2012;2(1):61E6.'

58%


Brown'AT'et'al.'Pulm"Circ.'2012;2(1):61E6.'Primary'outcomes'

1)  Propor>on%of%pa>ents%with%improved%OI%%2)  Propor>on%of%pa>ents%whose%echocardiographic%data%(ECHO)%depicted%

improved%PAP%and/or%right%heart%mechanics%Secondary'outcomes'

•  Need%for%ECMO%%•  Deteriora>on%of%renal%or%liver%func>on%•  Significant%drop%in%SBP%%•  Worsening%respiratory%failure%%•  Death%%

59%

Brown'AT'et'al.'Pulm"Circ.'2012;2(1):61E6.'Results'

Primary%outcomes%

1)  Propor>on%of%pa>ents%with%improved%OI%%•  Significant%decrease%in%OI%from%26.4%±%15.8%to%18.6%±%16.1%

(p=0.04)%%with%the%use%of%iEPO%

60%


9/11/15%

11%

Brown'AT'et'al.'Pulm"Circ.'2012;2(1):61E6.'Subgroup'analysis''

61%



Primary%outcomes%

2)%Pa>ents%with%ECHO%before%and%during%therapy%%

20%%

35%%

5%%

10%%

30%%

RV%Func>on%

Improvement%

No%change%

Worsening%

Insufficient%data%

ECMO%

62%


Safety%endpoints%

•  AE%in%6%pa>ents%•  5%neonates%%•  Most%common%AE%

•  Hypotension%requiring%interven>on%•  Respiratory%AE%

•  Inconsistent%mean%airway%pressure%•  NebulizerGven>lator%interface%

•  Renal%func>on%•  No%change%

•  Deaths%%%•  4%(none%aeributed%to%iEPO)%

63%

Brown'AT'et'al.'Pulm"Circ.'2012;2(1):61E6.'Conclusions'

•  Further%evidence%of%good%safety%profile%with%iEPO%in%pediatric%pa>ents%•  iEPO%may%be%more%beneficial%in%neonates%than%in%older%children%•  Iden>fies%the%need%for%a%large,%randomized%control%trial%on%the%use%of%iEPO%in%the%

general%pediatric%popula>on%Limita;ons'

•  No%comparator%group%%•  Sample%size%%

•  Subgroups%%•  Majority%were%neonates%Applica;on'

•  iEPO$is$effecAve$in$improving$OI$in$neonates$with$PPHN$•  Efficacy$of$iEPO$in$children$with$ARDS$or$cardiac$abnormaliAes$cannot$be$

determined$$

64%

iNO Summary •  Standard%of%care%acute%exacerba>ons%of%PH%%▫  Improves%oxygena>on%%▫  Increases%ECMOGfree%survival%in%ARDS%and%PPHN%%▫  Despite%inconclusive%results%on%pa>ent%outcomes%

•  Disadvantages%of%using%iNO%▫  Cost%▫  Risk%of%toxicity%%

65%

iEPO Conclusions •  Dosing%%▫  30%ng/kg/min%nebulized%con>nuously%%

•  In%comparison%with%iNO%▫  Decreased%cost%to%pa>ent%%▫  Similar%improvements%in%PAPm%and%oxygena>on%

•  Consider%iEPO%in%pediatric%pa>ents%with%hypoxemia%refractory%to%tradi>onal%therapies%▫  PPHN%%

•  Further%research%needed%in%ARDS%and%CHD%▫  Larger%studies%▫  Mechanism%of%ac>on%!%theore>cal%benefit%%▫  Unknown%impact%on%outcomes%

66%

9/11/15%

12%

iEPO Summary •  Epoprostenol%has%been%used%to%treat%acute%exacerba>ons%of%PH%

•  Efficacy%of%iEPO%%▫  Lowers%PAP%and%improves%oxygena>on%in%CHD%postopera>vely%▫  Improves%oxygena>on%in%adults%with%ALI%▫  Improves%OI%of%neonates%with%PPHN%%

•  No%significant%differences%in%safety%or%efficacy%%seen%between%iEPO%and%iNO%in%trials%

•  Compared%to%parenteral%therapy,%iEPO%allows%for%selec>vity%▫  Minimizes%side%effects%

67%

Acknowledgements

•  Carolyn%Ragsdale,%PharmD,%BCPS%•  Lyndrick%Hamilton,%PharmD,%BCPS%•  Ronda%Machen,%PharmD,%RD%%

68%

Inhaled Prostacyclins in Pediatric Patients: The New Nitric Oxide?

September%11th,%2015%%University%of%Texas%at%Aus>n%%%Molly%McNaull,%PharmD%PYGG1%Pharmacy%Resident%%Seton%Healthcare%Family%%%

APPENDIX(

! 1!

(

Table(1.!Acronyms!!

AE( Adverse!effects! IV Intravenous! ALI( Acute!lung!injury!! MAP( Mean!arterial!pressure!ARDS( Acute!respiratory!distress!syndrome! OI( Oxygenation!index!=!!!

([mean!airway!pressure!xFiO2!x100]/PaO2)!AVT Acute!vasodilator!testing PaO2( Arterial!pressure!of!oxygen!CHD! Congenital!heart!disease!! PAPm( Mean!pulmonary!arterial!pressure!ECHO(( Echocardiography!! PAWP! Pulmonary!artery!wedge!pressure!!ECMO! Extracorporeal!membrane!oxygenation!! PEEP( Positive!end!expiratory!pressure!FiO2 Fractional!inspired!oxygen PGI2! Prostacyclin!!FPAH( Familial!pulmonary!arterial!hypertension! PH Pulmonary!hypertension F/V(curve

FlowKvolume!curve PHTC! Pulmonary!hypertensive!crisis!

HR( Heart!rate!! PPHN Persistent!pulmonary!hypertension!of!the!newborn

ICU Intensive!care!unit! PVR( Pulmonary!vascular!resistance!iEPO( Inhaled!epoprostenol!! SBP( Systolic!blood!pressure!!Inh( Inhaled! SVR( Systemic!vascular!resistance!!iNO( Inhaled!nitric!oxide! WHO( World!Health!Organization!IPAH( Idiopathic!pulmonary!arterial!hypertension! ( !

( (

APPENDIX(

! 2!

(

! !

Torbic'H'et'al.'J"Crit"Care."2013;28:844F8.

APPENDIX(

! 3!

(

!

!

Dahlem'et'al.'Crit%Care%Med.%2004;32(4):1055F60.

APPENDIX(

! 4!

!

!

APPENDIX(

! 5!

!

! !

APPENDIX(

! 6!

!

!

Brown&AT&et&al.&Pulm%Circ.!2012;2(1):61F6.(

APPENDIX(

! 7!

!

inhaled!prostacyclins!in! pediatric!patients

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