Inhaled Pulmonary Vasodilators: Are There Indications...

Inhaled Pulmonary Vasodilators: Are There Indications Within thePediatric ICU?

Bradley A Kuch MHA RRT-NPS FAARC, Alvin L Saville RRT, Joan Sanchez De Toledo MD,and Shekhar T Venkataraman MD

IntroductionLiterature SearchInhaled Nitric Oxide

Pediatric Acute Respiratory FailureCongenital and Acquired Cardiac Disease/Post-Cardiac SurgeryShould Inhaled Nitric Oxide Be Used Outside of the Neonatal Period?

Inhaled Aerosolized Pulmonary VasodilatorsPharmacodynamics and DosingEpoprostenol SodiumIloprostTreprostinil

Safety Considerations During the Delivery of Inhaled Pulmonary VasodilatorsSummary

Inhaled nitric oxide (INO) is only FDA-cleared for neonates (> 34 weeks gestation) with hypoxicrespiratory failure-associated pulmonary hypertension. Off-label use of INO is common in thepediatric population despite a lack of evidence regarding survival benefit, questioning whether thetherapy should be considered outside the neonatal period. A lack of definitive evidence combinedwith increasing health-care costs has led to the use of less costly inhaled prostacyclin as an alter-native to INO, presenting unique patient safety concerns. We evaluate the current evidence andpatient safety considerations regarding inhaled pulmonary vasodilators in the pediatric population.Key words: pediatrics; nitric oxide; prostacyclin; pulmonary hypertension. [Respir Care2017;62(6):678–698. © 2017 Daedalus Enterprises]

Introduction

All pediatric uses of inhaled pulmonary vasoactive agentsare off-label and controversial regarding their safety and

efficacy. Commonly used agents include inhaled nitric ox-ide (INO), aerosolized epoprostenol sodium, iloprost, andtreprostinil. Evidence supporting inhalational administra-

Mr Kuch, Mr Saville, and Dr Venkataraman are affiliated with the De-partment of Respiratory Care Services, and Mr Kuch is also affiliatedwith the Transport Team, Children’s Hospital of Pittsburgh of Universityof Pittsburgh Medical Center, Pittsburgh, Pennsylvania. Drs Sanchez DeToledo and Venkataraman are affiliated with the Departments of CriticalCare Medicine and Pediatrics, University of Pittsburgh School of Med-icine, Pittsburgh, Pennsylvania.

The authors have disclosed no conflicts of interest.

Mr Kuch presented a version of this work at the 55th RESPIRATORY CARE

Journal Conference, “Pediatric Respiratory Care,” held June 10-11, 2016,in St Petersburg, Florida.

Correspondence: Bradley A Kuch MHA RRT-NPS FAARC, Children’sHospital of Pittsburgh of UPMC, 4401 Penn Avenue, Suite 5465, Pitts-burgh, Pennsylvania 15224. E-mail: [email protected].

DOI: 10.4187/respcare.05360

678 RESPIRATORY CARE • JUNE 2017 VOL 62 NO 6

tion of these medications in the pediatric population islimited and inconclusive. The health-care transition fromvolume-based to value-based reimbursement models hasincreased administrative scrutiny concerning health-carecost and outcome. A lack of supportive evidence, directdelivery costs, and patient safety concerns continue to fuelthe debate over the following questions. (1) Should in-haled pulmonary vasodilators be used outside the neonatalperiod? (2) What duration of INO therapy should be usedbefore considering an alternative pulmonary vasodilator?(3) Is INO associated with improved survival outcomes inchildren? (4) Is INO useful outside of its indicated use? (5)What other pulmonary vasodilators can be considered inthe pediatric population? (6) What complications are as-sociated with inhaled pulmonary vasodilator administra-tion?

Literature Search

To identify potentially relevant literature addressing theabove-mentioned questions, a PubMed (MEDLINE) searchwas conducted using the following search terms and cri-teria. Each search term was limited to English language,human studies, and children (1 month to 18 y of age):“inhaled pulmonary vasodilators,”; “inhaled nitric oxide,”;“inhaled prostacyclin,”; “inhaled iloprost,”; “inhaledepoprostenol,”; and “inhaled treprostinil,” (Fig. 1). Theselected time frame included papers published betweenJanuary 1, 1990, and June 1, 2016. References and ab-stracts were retrieved and reviewed by the authors foradditional analysis.

Through inspection of reference titles, references withno relevance to this review’s questions were eliminated.The remaining references’ abstracts were reviewed for rel-evance and eliminated as deemed appropriate. The remain-

ing references’ cross-references were evaluated to identifyadditional literature to be added as they relate to the focusof the review questions. Subsequently, 73 relevant articleswere included in this review.

Inhaled Nitric Oxide

Nitric oxide is a potent pulmonary vasodilator synthe-sized in the vascular endothelium. Generated in vivo fromL-arginine in the presence of nitric oxide synthase, NOactivates soluble guanylate cyclase, increasing intracellu-lar cyclic guanosine monophosphate, inhibiting the entryof calcium into the cell.1 The second pathway is activationof K� channels, leading to hyperpolarization and vasculardilatation. The final component is stimulation of cyclicguanosine monophosphate-dependent protein kinase,which activates myosin light chain phosphatase, leading todephosphorylation and further smooth muscle relaxation.1

When delivered via the respiratory tract, the principal ef-fect occurs in adequately ventilated areas of the lung, pro-ducing localized short-term pulmonary vasodilatation withlittle systemic effect. Nitric oxide has also been found todown-regulate leukocyte response, decrease platelet ag-gregation, facilitate neurotransmission, reduce apoptosis,augment bronchodilation, and attenuate inflammatory re-sponses from cellular injury after cellular ischemia and/ortissue reperfusion.1

In 1999, the FDA cleared inhaled nitric oxide for neo-natal patients (� 34 weeks gestation) with hypoxic respi-ratory failure associated with clinical or echocardiographicevidence of pulmonary hypertension.2 The clearance andcommercial availability of a reliable delivery system fa-cilitated INO therapy’s crossover into other theoretical clin-ical applications. Currently, the agent’s effectiveness andrelatively safe therapeutic profile makes INO a commontherapeutic approach for treatment of neonatal acute hy-poxic respiratory failure with and without elevated pulmo-nary pressures, isolated pulmonary hypertension, cardiacand lung transplantation, severe ARDS, and pediatric acutehypoxemic respiratory failure.

Increasing health-care costs and decreasing reimburse-ment have led to administrative scrutiny regarding the useof INO, as direct-delivery costs of INO administrationimpact operating margins of all health-care organizations.It has been reported that direct cost of INO delivery was$100/h for an annual cost of $1.8 million institution-widein a single pediatric tertiary care center.3 These projectionsare conservative, since other cost estimates approach $125/hwith large academic tertiary pediatric centers assuming$1–4 million annually in INO cost.4 Moreover, the pro-jected United States health-care inflation rate is estimatedat 2.6% for 2016, adding additional annual fiscal outlays(Bureau of Labor Statistics, http://data.bls.gov/timeseries/CUUR0000SAM?output_view�pct_12mths, Accessed

Fig. 1. Literature review flow chart. Search parameters were Eng-lish language, human studies, children (1 month to 18 y of age),and publication date between January 1, 1990, and June 1, 2016.Search terms were: inhaled pulmonary vasodilators, inhaled nitricoxide, inhaled prostacyclin, inhaled iloprost, inhaled epoprostenol,and inhaled treprostinil.

INHALED PULMONARY VASODILATORS IN THE PICU

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http://data.bls.gov/timeseries/CUUR0000SAM?output_view=pct_12mths

http://data.bls.gov/timeseries/CUUR0000SAM?output_view=pct_12mths

March 9, 2016). These considerations have renewed theeffort to reduce practice variation, improve quality, andmore efficiently utilize the expensive therapy of INO. Ithas been demonstrated that implementation of standard-ized INO initiation and weaning guidelines/protocols areeffective in decreasing practice variation and direct INOcost without impacting mortality.3 It is difficult to supportthe use of clinical guidelines regarding INO at this time,because no conclusive evidence exists supporting survivalbenefit associated with INO delivery in the pediatric pop-ulation.

Pediatric Acute Respiratory Failure

INO for treatment of pediatric acute respiratory failureremains debatable, with outcome benefit from varying eti-ologies being unfounded. INO is thought to reverse ven-tilation/perfusion mismatch by selectively mediating pul-monary vasomotor tone in well-ventilated regions of thelung, reducing pulmonary vascular resistance, pulmonaryhypertension, and right heart work load.5 Acute clinicalresponse to INO has been reported in small case series,demonstrating immediate improvement in oxygenation atlow concentrations (Table 1).6-8 Abman et al6 describedthe use of INO in 17 children with severe hypoxic respi-ratory failure from non-homogeneous etiologies. Diagno-sis included ARDS (n � 10), bronchopulmonary dysplasia(n � 6), and acute pneumonitis (n � 1).6 Compared werePaO2

and hemodynamics before and during INO therapy,with measurements collected 30 min after the initiation oftherapy.6 They demonstrated immediate improvement inoxygenation (mean PaO2

� 58 � 13 mm Hg vs86 � 25 mm Hg, P � .01), lower mean pulmonary arterypressure (42 � 6 mm Hg vs 31 � 6 mm Hg, P � .01),decreased intrapulmonary shunt (39 � 7% vs 32 � 7%,P � .01), and an increase in cardiac index by 14% (P � .01).6

Abman et al6 concluded that INO acutely improved oxy-genation and decreased pulmonary vascular resistance with-out adverse hemodynamic consequences in children withsevere acute hypoxemic respiratory failure. The study wasnot powered to identify mortality benefit. Okamoto et al7

reported similar findings in small series of 7 children withpediatric ARDS. The American-European Consensus Con-ference definition of ARDS was used to identify potentialsubjects.12 Etiologies of ARDS included both direct andindirect origins. The study protocol incorporated 2 phases.Phase 1 included baseline (1 h of steady-state pressurecontrol ventilation) and post-INO initiation (30 min afterstart of nitric oxide inhalation) measurements.7 Phase 2evaluated INO dose response on the following day on thesame ventilator setting as phase 1, including the discon-tinuation of the therapy and evaluation of respiratory andhemodynamic measures at INO concentrations of 0.13,0.25, 0.5, 1, 2, 4, 8, and 16 parts ppm.7 Results demon-

strated that 16 ppm of INO produced improvement inPaO2

/FIO2(68 � 10 vs 136 � 37, P � .02) and SpO2

(93 � 1%vs 99 � 1%, P � .05), with a significant correlation be-tween the INO-induced PaO2

/FIO2increase from baseline

PaO2/FIO2

measures (r � 0.93, P � .01).7 The alveolar-arterial oxygen difference also decreased from 594 � 11to 529 � 38 mm Hg (P � .02).7 Hemodynamics increasedslightly during nitric oxide inhalation; increases includedsystolic arterial blood pressure (95 � 10 mm Hg vs100 � 10 mm Hg, P � .05), Mean arterial blood pressure(67 � 7 mm Hg vs 72 � 8 mm Hg, P � .05), and diastolicarterial blood pressure (52 � 6 mm Hg vs 56 � 7 mm Hg,P � .05), respectively.7 Dose-response tests have shownthe optimal concentration of INO to be � 4 ppm, withimprovements observed at concentrations as low as � 1ppm.7 The group concluded that INO frequently improvedoxygenation in children with ARDS with improvementsobserved at concentrations � 1 ppm, a dose that decreasesthe risk of toxic reactions.7

Sheridan et al8 sought to assess the effect of INO onintrapulmonary shunt in 11 children with ARDS second-ary to inhalational and burn injury. Intrapulmonary shuntwas measured by PaO2

/FIO2immediately before and 1 h

after INO initiation. The mean age of the cohort was8.3 � 4.8 y, with a mean burn size of 64 � 22% of totalbody surface area and a mean Murray lung score of 3.1 � 0.5at study entry. Initial concentration of nitric oxide was5.8 � 1.9 ppm, and maintenance was 6.7 � 2.4 ppm. Find-ings from this small study demonstrated that low-doseINO improved PaO2

/FIO2from baseline (94.9 � 50 mm Hg

vs 190 � 74 mm Hg, P value not provided). PaO2/FIO2

increased by an average of 162 � 214%.8 Non-survivorshad significantly less of a response when compared withsurvivors (7.3 � 6.4% vs 213 � 226%, P � .03). Theauthors concluded that INO can be safely administered totreat ARDS in children with burns and appears to aidventilator management. In addition to their conclusions,they hypothesize that immediate improvement in oxygen-ation with the delivery of nitric oxide may be associatedwith survival.8

Larger studies demonstrated similar findings in pediat-ric ARDS. Fioretto et al9 conducted a prospective histor-ically controlled observational study evaluating the acuteand sustained effect of INO compared with conventionaltherapy. Pediatric ARDS was defined according to theAmerican European Consensus Conferences definitionpublished in 1994.9 The primary aim of this study was toevaluate the early administration of INO as it relates toimprovement in oxygenation measures and reduction inventilator parameters, ICU stay, and mortality. Oxygen-ation assessment included PaO2

/FIO2and oxygenation index

(OI) at baseline, 30 min, and 4 h in the INO group.9

Inhaled nitric oxide therapy was initiated at a median of1.5 h (range 1–96 h) following the diagnosis of ARDS.9



Tab

le1.

Pedi

atri

c-Sp

ecif

icSt

udie

sE

valu

atin

gIn

hale

dN

itric

Oxi

dean

dIt

sE

ffec

ton

Oxy

gena

tion

Mea

sure

sD

urin

gth

eT

reat

men

tof

Hyp

oxic

Res

pira

tory

Failu

rean

dPe

diat

ric

AR

DS

Stud

ySu

bjec

tsan

dSt

udy

Des

crip

tion

Star

ting

Dos

e(p

pm)

Inte

rven

tion

and

Mea

sure

sFi

ndin

gsan

dC

oncl

usio

nC

omm

ents

Abm

anet

al6

N�

17;

seve

rehy

poxi

cre

spir

ator

yfa

ilure

20G

asex

chan

gean

dhe

mod

ynam

ics

befo

rean

daf

ter

30m

inof

INO

deliv

ery.

INO

impr

oved

oxyg

enat

ion

and

low

ered

pulm

onar

yva

scul

arre

sist

ance

with

out

nega

tive

hem

odyn

amic

effe

ctin

pedi

atri

cac

ute

hypo

xic

resp

irat

ory

failu

re.

Oxy

gena

tion

impr

oved

in15

of17

subj

ects

;50

%A

RD

Ssu

rviv

al;

100%

non-

AR

DS

surv

ival

.

Oka

mot

oet

al7

N�

7;pe

diat

ric

AR

DS,

age

rang

e2

mon

ths

to17

y16

P aO

2/FIO

2an

dP (

A-a

)O2

resp

onse

toin

itiat

ion

ofIN

O;

mea

sure

ofdo

se/r

espo

nse

toid

entif

yop

timal

conc

entr

atio

n.

INO

prod

uced

impr

ovem

ent

inP a

O2/F

IO2

from

base

line

inal

lsu

bjec

ts.

P (A

-a)O

2de

crea

sed

sign

ific

antly

.O

ptim

aldo

sew

as�

4pp

m,

with

som

ere

spon

seat

�1

ppm

NO

.

All

subj

ects

dem

onst

rate

dim

prov

emen

tin

oxyg

enat

ion;

43%

coho

rtsu

rviv

alra

te.

Sher

idan

etal

8N

�11

;pe

diat

ric

burn

subj

ects

with

seve

reA

RD

S,ag

era

nge

11m

onth

sto

14y

5–10

Intr

apul

mon

ary

shun

ting

mea

sure

dby

P aO

2/FIO

2;ev

alua

ted

resp

onse

toIN

Osu

rviv

ors

vsno

n-su

rviv

ors.

INO

impr

oved

P aO

2/FIO

2fr

omba

selin

e.N

on-s

urvi

vors

had

sign

ific

antly

less

ofa

resp

onse

whe

nco

mpa

red

with

surv

ivor

s.

73%

surv

ival

rate

.Im

med

iate

resp

onse

may

beas

soci

ated

with

surv

ival

.

Fior

etto

etal

9N

�39

;pe

diat

ric

AR

DS,

INO

vhi

stor

ical

cont

rol

20E

arly

adm

inis

trat

ion

ofIN

O;

acut

eim

prov

emen

tin

P aO

2/FIO

2

and

OI.

P aO

2/FIO

2w

aslo

wer

(P�

.001

)an

dO

Ihi

gher

(P�

.001

)in

the

INO

grou

p,le

adin

gto

decr

ease

sin

F IO

2an

dve

ntila

tor

setti

ngs.

INO

grou

pm

orta

lity

was

low

ervs

cont

rol

(P�

.001

);no

diff

eren

cein

LO

S.

Dem

irak

caet

al10

N�

17ne

onat

alan

dpe

diat

ric

subj

ects

with

AR

DS

20(n

eona

tal)

,10

(ped

iatr

ic)

Intr

apul

mon

ary

shun

ting

mea

sure

dby

OI;

P (A

-a)O

2;sy

stem

icar

teri

alpr

essu

re.

Sign

ific

ant

impr

ovem

ent

with

in24

hin

OI

(P�

.001

),P (

A-a

)O2

(P�

.001

),an

dsy

stem

icar

teri

alpr

essu

re(P

�.0

03).

Prol

onge

dde

liver

yof

INO

asso

ciat

edw

ithox

ygen

atio

nim

prov

emen

t.

Bro

nick

iet

al11

N�

55;

pedi

atri

cA

RD

S,IN

Ovs

plac

ebo

5M

ean

OI

at4,

12,

and

24h;

days

aliv

ean

dve

ntila

tor-

free

atda

y28

;ra

teof

EC

MO

-fre

esu

rviv

al.

Sign

ific

ant

impr

ovem

ent

inO

Iat

12h

with

INO

;IN

Oas

soci

ated

with

redu

ctio

nof

dura

tion

ofm

echa

nica

lve

ntila

tion

and

grea

ter

rate

ofE

CM

O-f

ree

surv

ival

.

No

diff

eren

cein

28-d

mor

talit

ybe

twee

ngr

oups

(P�

.07)

.

Sign

ific

ant

inco

nsis

tenc

yex

ists

rega

rdin

gox

ygen

atio

nm

easu

res

thro

ugho

utth

elit

erat

ure.

INO

�in

hale

dni

tric

oxid

eP (

A-a

)O2

�al

veol

ar-t

o-ar

teri

algr

adie

ntL

OS

�le

ngth

ofst

ayO

I�

oxyg

enin

dex

EC

MO

�ex

trac

orpo

real

mem

bran

eox

ygen

atio

n



Administration of INO improved oxygenation, as mea-sured by both the PaO2

/FIO2and OI at 30 min and 4 h after

initiation.9 Comparative analysis revealed that FIO2and

peak inspiratory pressure could be quickly reduced.9 Thegroup also found a lower mortality rate in the INO group(16.5% vs 47.6%, P � .001), which is particularly inter-esting, given the fact that the INO group had significantlylower PaO2

/FIO2values and higher OI that may indicate a

greater severity of lung injury.9 No difference in ICU stayor duration of mechanical ventilation was found.9 Fiorettoet al9 concluded that early initiation of INO resulted inacute and sustained improvement in oxygenation and areduction in ventilator settings, which may contribute to areduction in mortality rate in pediatric ARDS. The studyhad several limitations. The statistical power and overalllevel of this evidence is limited as a result of its nonran-domized design and small number of subjects. Further-more, the historical controls and co-interventional vari-ance over the 4-y period may have contributed to theoutcome. Case in point: The INO group had a higher meanairway pressure, PEEP, and PaCO2

levels at the time ofenrollment, which leads to the question of whether theoutcome benefit was associated with INO or the lung-protective ventilation strategy.

More recently, Bronicki et al11 conducted a multi-centerrandomized controlled blinded trial comparing low-dose(5-ppm) inhaled nitric oxide with a placebo (nitrogen) inchildren with ARDS. Fifty-five children were randomizedfrom 5 centers between 2003 and 2005.12 Study subjectsremained on the assigned study drug until death, separa-tion from mechanical ventilation, or day 28 after the ini-tiation of therapy.11 Oxygenation was measured using theOI, with assessment made at 4, 12, and 24 h followingstudy initiation.11 Outcome measures included days aliveand ventilator-free at day 28, survival, and rate of extra-corporeal membrane oxygenation (ECMO)-free survival.11

The group reported a trend in OI at hour 4, which becamestatistically significant at hour 12. They found no differ-ence between groups at the 24-h time point.11 The INOgroup had a significantly greater number of days alive andventilator-free (14.2 � 8.1 d vs 9.1 � 9.5 d, P � .05) andrate of ECMO-free survival (92% vs 52%, P � .01). Bron-icki et al11 concluded that low-dose INO was associatedwith a reduction in duration of mechanical ventilation anda greater rate of ECMO-free survival. This study was thefirst to evaluate the outcome of pediatric ARDS withoutcrossover, identifying the impact of INO on outcome. Themechanisms responsible for improved outcomes of thisstudy are unknown, and, given the short duration of oxy-genation improvement, it does not appear to be related toa sustained enhanced oxygenation.11 A potential mecha-nism for which INO may improve outcome in pediatricARDS may be related to its modulation of coagulation andinflammation, since both play a prominent role in patho-

genesis of the disease.13-18 Limiting the risk of thrombo-occlusion while reducing inflammatory-mediated alve-olar damage, in theory, should improve outcome.However, this benefit has not been demonstrated as itrelates to mortality outcomes. There were several lim-itations with this study. The sample size was small fora study that included 9 North American centers. Also,the subjects were enrolled over 10 y ago, a time whenventilation strategies were inconsistent and evolving.The authors also note that “guidelines on the manage-ment of mechanical ventilation were established by theinvestigators; however, the study lacked an explicit pro-tocol.”11 The absence of a definitive mechanical venti-lation protocol creates a potential for practice variation,which could potentially lead to an underestimate of thetreatment benefit of INO.

The most recent meta-analysis from the CochraneCollaboration conducted by Afshari et al19 evaluated 14randomized controlled trials that included 1,303 sub-jects. All included studies compared INO with no in-tervention or placebo controls. The subject populationincluded both children and adults with ARDS or acutelung injury, and the primary outcome measure was all-cause mortality. Additional outcomes included improve-ment of oxygenation, duration of mechanical ventila-tion, ventilator-free days, and ICU and hospital stay.19

The authors reported a statistically significant improve-ment in PaO2

/FIO2and OI in the first 24 h of adminis-

tration.19 However, limited data demonstrated an insig-nificant effect of INO on duration of mechanicalventilation, ventilator-free days, and stay in the ICU andhospital.19 The authors found no mortality differencebetween groups with little variation in the pooled stud-ies, as indicated by an I2 value of 0 (40.2% vs 38.6%,relative risk 1.06, 95% CI 0.93–1.22, I2 � 0).19 Therewas an apparent increased risk of renal impairmentamong the adult population that was not seen in chil-dren.19 From these data, it was concluded that INO re-sults in a transient improvement in oxygenation; how-ever, INO cannot be recommended for patients withacute hypoxic respiratory failure.19 These findings val-idate the finding of the prior Cochrane Collaborationreview conducted by Sokol et al,20 who concluded thatINO transiently improved oxygenation but did not pos-itively affect mortality. Both of these meta-analyses hadlimitations, which included the use of data sets that hadboth adult and pediatric populations. It is well under-stood that the pathology and response to ARDS differgreatly between adults and children.21,22 Case in point:The most common etiology for ARDS in adults is sepsis(indirect), whereas in children, it is pneumonia (di-rect).23,24 Furthermore, children’s comorbidities differgreatly from those of the adult population. Limitationssuch as these indicate the need for more comprehensive



studies evaluating the effect of INO on outcome onmore homogeneous data sets with well-defined second-ary outcomes.

Recently, Gupta et al25 conducted a retrospective pro-pensity score-matched study using linked data from 2 na-tional registries evaluating the effect of inhaled nitric ox-ide on outcome in children with acute lung injury. Linkeddata were from the Virtual Pediatric System LLC databaseand the Pediatric Health Information System focusing onthe most recent 6 y (2009–2014). Initial analysis included20,106 children (� 18 y of age) from 9 hospitals who weremechanically ventilated for acute lung injury. Propensityscore development identified 1,042 subjects matched one-to-one and separated into 2 groups: Group 1 (n � 521)received INO for � 24 h, and Group 2 (n � 521) did notreceive INO during their hospital course.25 Variables wereincluded from the following categories: baseline demo-graphics, ICU admission, clinical data, procedural, diag-nostic, and outcome measures.25 The group evaluated bothunadjusted (before matching) and propensity-matched out-comes. Unadjusted outcomes revealed that children re-ceiving INO were younger, with more comorbidities,greater severity of illness, increased incidence of cardio-pulmonary resuscitation, greater resource utilization, andhigher mortality rate.25 Propensity score matching demon-strated no difference in mortality. However, other out-comes, including ventilator-free days, duration of mechan-ical ventilation, ICU and hospital stay, and hospital costs,were significantly worse in the group treated with nitricoxide.25 Gupta et al25 concluded that INO is not associatedwith improved mortality rates; rather, it is associatedwith increased hospital utilization and cost. The find-ings of this study are significant because the study uti-lized the most up-to-date data available, reflecting cur-rent treatment strategies, including lung-protectiveventilation, prone positioning, use of ECMO, and renalreplacement therapy. In addition, the observational com-parative effectiveness study design using propensitymatching represents real-life practice without the limi-tation of study protocols.25 The design also removes thepotential for biased patient selection regarding treat-ment while addressing effectiveness and outcome. How-ever, the study had several potential limitations. First,propensity matching only occurs on observed variables,making it possible that unmeasured factor(s) may havehad an effect on outcome. Second, the data were ob-tained from multi-center registries, which calls into ques-tion data integrity, compliance, and validation. Further-more, there is the potential for coding errors withinlarge data sets. Finally, the study lacked information onkey variables, such as oxygenation measures, acute lunginjury etiologies, and mechanical ventilation data.

Congenital and Acquired CardiacDisease/Post-Cardiac Surgery

Pulmonary vascular endothelial dysfunction resultingin pulmonary hypertension has been a long-acceptedcomplication following the repair of congenital cardiaclesions, often exacerbated by cardiopulmonary by-pass.26,27 One of the first known clinical studies of INOto treat postoperative pulmonary hypertension was con-ducted by Wessel et al,28 who investigated the etiologyof pulmonary vascular endothelial dysfunction beforeand after cardiac lesion repair requiring cardiopulmo-nary bypass. They characterized pulmonary vascular dys-function via a decreased response to acetylcholine post-bypass.28 It was found that the vascular dysfunction wasassociated with an increased response to INO when com-pared with pre-bypass measures.28 The group also re-ported a 3-fold increase in plasma level of cyclic guanos-ine monophosphate during delivery of INO.28 Thefindings of this study led to additional small trials eval-uating the administration of INO in treating refractorypulmonary hypertension that suggested a potentially life-saving role of INO.29,30

Early small studies evaluated the effect of INO forthe treatment of pulmonary hypertension for surgicalrepair of congenital heart disease (Table 2). Russellet al32 used a randomized controlled double-blind studyto compare 40 children undergoing cardiopulmonary by-pass for repair of congenital cardiac lesions. Pulmonaryhypertension was defined as a mean pulmonary arterypressure � 50% of the mean systemic arterial pressure.32

Thirteen subjects (36%) were separated from cardiopul-monary bypass with pulmonary hypertension.32 All sub-jects with pulmonary hypertension responded to INOwith an average reduction of 19% in mean pulmonaryartery pressure at 20 min.32 No difference between groupswas found when comparing mean systemic arterial pres-sure, heart rate, and arterial pressure following initia-tion of INO.32 The authors concluded that INO selec-tively decreases mean pulmonary artery pressure inchildren with pulmonary hypertension following cardio-pulmonary bypass surgery.32 Limitations of this studyhave created some questions regarding the author’s find-ings. Pulmonary vascular resistance was not directlymeasured, which leads to the question whether the de-crease in mean pulmonary artery pressure was an effectof INO or a decreased cardiac output. The fact that therewas no documented decrease in mean systemic arterialpressure leads to the conclusion that the decrease inpulmonary pressure probably occurred from a decreasein pulmonary vascular resistance. However, a decreasein cardiac output cannot be ruled out. Furthermore, thesmall (19%) reduction in mean pulmonary artery pres-sure witnessed in this study may suggest that hyperven-



Tab

le2.

Pedi

atri

cSt

udie

sE

valu

atin

gIn

hale

dN

itric

Oxi

deT

hera

pyan

dIt

sE

ffec

ton

Hem

odyn

amic

san

dO

xyge

natio

nM

easu

res

inC

hild

ren

With

Con

geni

tal

and/

orA

cqui

red

Hea

rtD

isea

se

Ref

eren

cean

dSt

udy

Typ

eSu

bjec

tsan

dSt

udy

Des

crip

tion

Star

ting

Dos

e(p

pm)

Find

ings

and

Res

ults

Con

clus

ion

Day

etal

31

rand

omiz

edco

ntro

lled

tria

lN

�40

,sy

stol

icpu

lmon

ary

arte

rial

pres

sure

�50

%sy

stol

icsy

stem

icar

teri

alpr

essu

reea

rly

post

-op

follo

win

gre

pair

ofC

HD

;n

�20

rece

ived

20-p

pmIN

O;

n�

20re

ceiv

edco

nven

tiona

ltr

eatm

ent

20IN

Oim

prov

edfr

omba

selin

e;H

R,

syst

olic

pulm

onar

yar

teri

alpr

essu

re,

LA

P,pH

,P a

CO

2,P a

O2/F

IO2

(P�

.05)

;2

syst

olic

pulm

onar

yar

teri

alpr

essu

re:

syst

olic

syst

emic

arte

rial

pres

sure

(P�

.01)

;no

diff

eren

cebe

twee

ngr

oups

at1

h.

INO

did

not

impr

ove

pulm

onar

yhe

mod

ynam

ics

and

gas

exch

ange

imm

edia

tely

follo

win

gC

HD

repa

ir.

Rus

sell

etal

32

rand

omiz

edco

ntro

lled,

doub

le-b

lind

N�

40,

follo

win

gsu

rgic

alco

rrec

tion

ofC

HD

;pu

lmon

ary

hype

rten

sion

�m

ean

pulm

onar

yar

teri

alpr

essu

re�

50%

mea

nsy

stem

icar

teri

alpr

essu

re;

n�

13:

INO

(n�

5)vs

nitr

ogen

(n�

8)

8036

%(n

�13

)se

para

ted

from

bypa

ssw

ithm

ean

pulm

onar

yar

teri

alpr

essu

re�

50%

;IN

Ore

duce

dm

ean

pulm

onar

yar

teri

alpr

essu

reby

19%

(P�

.008

).

INO

sele

ctiv

ely2

mea

npu

lmon

ary

arte

rial

pres

sure

inC

PBsu

bjec

tsw

ithpu

lmon

ary

hype

rten

sion

and

had

noef

fect

onth

ose

with

out

it.

Mor

ris

etal

33

pros

pect

ive

rand

omiz

edcr

osso

ver

N�

12;

mea

npu

lmon

ary

arte

rial

pres

sure

�25

mm

Hg,

norm

alpH

;IN

Ovs

hype

rven

tilat

ion

(�7.

50)

5–10

Hyp

erve

ntila

tion

alte

red

pulm

onar

yar

teri

alpr

essu

re,

PVR

,ce

ntra

lve

nous

pres

sure

,ca

rdia

cou

tput

,an

d1

SVR

;IN

Ose

lect

ivel

y2

pulm

onar

yar

teri

alpr

essu

rean

dPV

R;

PVR

re-e

duca

tion

was

com

para

ble

betw

een

grou

ps;

com

bine

dre

sulte

din

smal

lre

duct

ion

inPV

R.

INO

and

hype

rven

tilat

ion

effe

ctiv

ely

2pu

lmon

ary

arte

rial

pres

sure

and

PVR

inch

ildre

nw

ithpu

lmon

ary

hype

rten

sion

post

-CPB

.IN

Oha

dbe

nefi

tov

erhy

perv

entil

atio

nse

cond

ary

tone

gativ

eef

fect

onca

rdia

cou

tput

and

SVR

.M

iller

etal

30

rand

omiz

edco

ntro

lled,

doub

le-b

lind

N�

124;

INO

(n�

63)

vspl

aceb

o(n

�61

);in

cide

nce

ofPH

TC

;du

ratio

nof

mec

hani

cal

vent

ilatio

n

10IN

Ofe

wPH

TC

:R

R0.

66;

P�

.001

;sh

orte

rdu

ratio

nof

mec

hani

cal

vent

ilatio

n:P

�.0

2;no

adve

rse

toxi

cev

ents

.

INO

less

ened

the

risk

ofPH

TC

and

shor

tene

dth

edu

ratio

nof

mec

hani

cal

vent

ilatio

nw

ithou

tto

xic

effe

ct.

Wes

sel

etal

28

pros

pect

ive

inte

rven

tiona

lN

�34

child

ren

with

CH

Dbe

fore

(n�

12)

and

afte

rsu

rgic

alre

pair

onca

rdio

pulm

onar

yby

pass

(n�

22);

com

pare

dac

etyl

chol

ine

vsIN

O;

PVR

;cG

MP

leve

ls

80IN

Ode

crea

sed

PVR

whe

nco

mpa

red

with

acet

ylch

olin

e(P

�.0

01);

min

imal

effe

cton

syst

emic

circ

ulat

ion;

3-fo

ldin

crea

sein

cGM

Ple

vels

whe

nco

mpa

red

with

acet

ylch

olin

e(P

�.0

01).

CPB

may

resu

ltin

pulm

onar

ydy

sfun

ctio

npo

stop

erat

ivel

y;IN

Om

aypl

ayan

impo

rtan

tdi

agno

stic

role

and

ther

apeu

ticro

lein

child

ren

with

card

iac

dise

ase.

ppm

�pa

rts

per

mill

ion

CH

D�

cong

enita

lhe

art

dise

ase

INO

�in

hale

dni

tric

oxid

eH

R�

hear

tra

teL

AP

�le

ft-a

tria

lpr

essu

rePV

R�

pulm

onar

yva

scul

arre

sist

ance

SVR

�sy

stem

icva

scul

arre

sist

ance

CPB

�ca

rdio

pulm

onar

yby

pass

PHT

C�

pulm

onar

yhy

pert

ensi

vecr

isis

RR

�re

lativ

eri

skcG

MP

�cy

clic

guan

osin

em

onop

hosp

hate



tilation and 100% oxygen administration could have thesame effect.32 That being said, hyperventilation and100% oxygen delivery are not without risk. This prac-tice may decrease cardiac output via increased meanairway pressure and systemic vascular resistance whileincreasing the risk of hyperoxic lung injury.33,34

The effect of conventional hyperventilation comparedwith INO has been evaluated in a prospective randomizedcrossover study in children (n � 12) with pulmonary hy-pertension (pulmonary artery pressure � 25 mm Hg) fol-lowing repair of congenital heart disease.33 Measurementsincluded cardiac output derived from hemodynamic pa-rameters in subjects assigned to either INO or hyperven-tilation. Therapeutic hyperventilation was achieved with-out change in mean airway pressure.33 Morris et al33

reported that hyperventilation was as effective in decreas-ing pulmonary artery pressure and pulmonary vascular re-sistance as INO. However, hyperventilation resulted in adecrease in cardiac output and an increase in systemicvascular resistance.33 They concluded that INO and hy-perventilation are both effective at lowering pulmonaryartery pressure and pulmonary vascular resistance; INOselective action on the pulmonary circulation offers ad-vantages over hyperventilation.33 The study, albeit small,suggests that the use of INO in children with pulmonaryhypertension undergoing cardiopulmonary bypass for re-pair of congenital heart disease may aid in the reduction ofright heart work load.

Two randomized control trials have addressed the ef-fectiveness of INO for the treatment of postoperative pul-monary hypertension following repair of congenital heartdisease. Day et al31 randomized children with pulmonaryhypertension to receive either 20 ppm INO (n � 20) orconventional therapy (n � 20), evaluating the incidence ofpulmonary hypertensive crisis per group. Pulmonary hy-pertension was defined as a systolic pulmonary pressure� 50% of systemic arterial pressure, reported as the ratioof systolic pulmonary to systolic systemic arterial pres-sure.31 Results demonstrated a small but significant de-crease in systolic pulmonary arterial pressure/systolic sys-temic arterial pressure 1-hour after INO initiation in thestudy group (P � .01).31 No difference between subjectgroups was observed at baseline or 1 h (P � .066).31 Threesubjects in the INO group and 4 in the control groupexperienced life-threating pulmonary hypertensive crisis.31

A power analysis revealed that � 2,000 subjects would beneeded to determine if INO decreases the incidence ofpulmonary hypertensive crisis.31 It was concluded that INO“did not substantially improve hemodynamics and gasexchange” immediately following congenital cardiac sur-gery and “failed to decrease the incidence of pulmonaryhypertensive crisis.”31 These data suggest limited valueof INO in this patient population. Weighing the qualityof this evidence comes with caution, since the authors

point out that no treatment protocols were followed dur-ing the study period, creating significant risk of biasregarding subject selection and use of pharmacologicadjuncts.31

The second study is the largest randomized placebo con-trolled trial investigating the use of INO to limit pulmo-nary hypertensive crisis following congenital cardiac sur-gery. This study compared 124 infants randomly assignedto either low-dose (10 ppm) INO (n � 61) or a placebo(n � 63), evaluating the number of pulmonary hyperten-sive crises, time receiving the study gas, and ICU stay.30

Subjects who received INO had 30% fewer pulmonaryhypertensive crises and had a shorter median time to ex-tubation readiness.30 The study was underpowered to es-timate mortality outcome benefit, which is a common prob-lem in developing randomized controlled trials in thisspecific patient population.

Limitations of these studies are well outlined in aCochrane review conducted by Bizzarro et al,35 whoconcluded that no difference was found with the use ofINO in mortality, number of pulmonary hypertensivecrises, change in mean pulmonary artery pressure, heartrate, or PaO2

/FIO2. The review only included 4 random-

ized trials, which included 210 participants.35 They noteda significant lack of measured clinical outcomes thatincluded long-term mortality, stay, and neurodevelop-mental outcomes.35 More importantly, the authors stated,“it was difficult to draw valid conclusions given con-cerns regarding methodological quality, sample size, andheterogeneity.”35

Given these data and their limitations, it is difficult todraw any conclusion regarding INO therapy following re-pair of congenital heart disease. Use of INO in childrenwith congenital heart disease appears to decrease pulmo-nary pressure during diagnostic evaluation, as well as pre-and post-surgical repair. Reduction of pulmonary vascularresistance appears to affect oxygenation in a small numberof well-designed ICU-based studies. However, these stud-ies are not powered to show mortality benefit. Compound-ing the issue of mortality as an outcome measure is thatunderlying anatomic anomalies may limit the effective-ness of INO. Furthermore, congenital heart disease is oftencomplicated by accompanying congenital anomalies thatmay result in morbidity and mortality unrelated to lungvasoactivity. For these reasons, additional study is neededto better understand the effect of INO on mortality. At thistime, it is difficult to draw any conclusions surrounding itsrole as a therapy to decrease pulmonary vascular resis-tance in children with either acquired or congenital heartdisease, and it should be considered as an adjunctive res-cue therapy in the presence of documented pulmonaryhypertension.



Should Inhaled Nitric Oxide Be Used Outside of theNeonatal Period?

Inhaled nitric oxide is only cleared for neonatal patients(� 34 weeks gestation) with hypoxic respiratory failureassociated with clinical or echocardiographic evidence ofpulmonary hypertension, and all pediatric applications re-main off-label. Despite this, its application continues togrow in the pediatric ICU. Definitive conclusions regard-ing the use and benefit of the therapy outside the neonatalperiod remain controversial. Inhaled NO seems to acutelyimprove oxygenation in children with acute hypoxemicrespiratory failure in the first 24–96 h of therapy; how-ever, there is no evidence demonstrating outcome benefitassociated with its use.6-8,9,11 The lack of evidence regard-ing mortality should be considered, because therapies aimedat modifying lung disease have little effect outcome, sincesystemic inflammation, multi-organ dysfunction, and im-munosuppression are significant contributors to the patho-genesis of pediatric ARDS and its outcome.5,36-38 More-over, INO has been associated with greater ECMO-freesurvival and may decrease the need for extracorporeal sup-port in children.

Significant disagreement exists regarding the benefit ofINO administration during ECMO in the pediatric popu-lation. Recent evidence from a large post hoc analysis ofdata from an administrative database calls into questionthe benefit of the therapy among pediatric patients receiv-ing extracorporeal life support for respiratory or cardiacetiologies. Tadphale et al39 compared subjects receivingINO during ECMO (INO group) with ECMO subjects notreceiving the therapy at any point during their hospital stay(no INO group). They reported no survival benefit asso-ciated with the use of INO during ECMO support. Rather,the group demonstrated increased morbidity, longer dura-tion of mechanical ventilation, longer length of hospitalstay, and higher hospital costs. These results should bereviewed with caution, because bias may exist regardingcase mix between groups, lack of information regardingtype of ECMO support (ie, venoarterial or venovenous),and the inability to control for severity of illness. For thisreason, the authors suggest that their findings be inter-preted as exploratory.39 That being said, these data doseem to suggest that INO therapy during ECMO may notaffect outcome in both severe respiratory and cardiacfailure.

The use of goal-directed treatment guidelines has beenadvocated to decrease cost associated with administrationof inhaled nitric oxide. Although single-center reports sug-gest that protocols may decrease direct INO delivery costs,it is difficult to support their use at this time, becausecurrently no evidence exists supporting a survival benefitin the pediatric population.3 More study is needed regard-ing the incorporation of INO into goal-directed protocols;

using evidence-based lung-protective strategies optimiz-ing mechanical ventilation and reversing hypoxemia untilfurther critical care intervention can occur may benefitpatient outcomes. Although the most recent evidence sug-gest no mortality benefit associated with the use of INO, itdoes not address the benefit associated with the use ofgoal-directed therapies, which include inclusion criterion,definition of responders, and weaning strategies for thenon-responder population. Long-term administration ofINO and its effect on inflammatory modulation during theacute phase of acute lung injury/pediatric ARDS cannot beruled out.10,40 Additional study is needed to discern thebenefit of INO as it relates to its anti-inflammatory effecton long-term measures, such as pulmonary function, homeoxygen requirements, and quality of life measures. Untilmore definitive evidence is reported, INO should only beconsidered as a recue therapy in severe acute respiratoryfailure or documented right-sided heart dysfunction andcannot be recommended for the routine treatment of acutehypoxic respiratory failure in children.

Inhaled Aerosolized Pulmonary Vasodilators

Some authors have proposed the use of more cost-ef-fective inhaled pulmonary vasodilators to defray growingINO costs. Literature has suggested that aerosolized epopro-stenol, milrone, iloprost, and treprostinil may be effectivealternatives to INO for acute and/or chronic pulmonaryhypertension. Inhaled prostacyclin has been proven to actas a selective pulmonary vasodilator in adult ARDS andfollowing repair of congenital heart disease (Table 3).47-51

Evidence suggests these agents may improve oxygenationand right-ventricle afterload and are equally effective as arescue therapy in infants and children with pulmonary hy-pertension as INO; nevertheless, significant safety con-cerns exist regarding the lack of backup delivery systemsand delivery alarms and negative effects on mechanicalventilators. Aerosolized pulmonary vasodilators have thetheoretical potential to improve oxygenation through de-creasing ventilation-perfusion mismatching, lowering pul-monary vascular resistance, and decreasing right-ventricleafterload and may affect the outcome of children withpulmonary hypertension associated with ARDS/acute lunginjury and congenital heart disease.41,42 Most evidence re-garding aerosolized selective pulmonary vasodilators fo-cuses on the use of epoprostenol, which has been shownhave similar efficacy, lower potential for systemic adverseeffects, and lower cost than nitric oxide.41,42,52 These at-tributes have propagated the use of inhaled prostacyclindespite the lack of high-level clinical evidence evaluatingmortality as a primary outcome.

The topic of aerosolized pulmonary vasodilators remainscontroversial; thus, examining the topic requires an under-standing of the each agent’s pharmacodynamics, dosing,



Tab

le3.

Inha

led

Nitr

icO

xide

Ver

sus

Pros

tacy

clin

The

rapy

inA

dult

and

Pedi

atri

cA

cute

Hyp

oxic

Res

pira

tory

Failu

re:

Out

com

eV

aria

bles

Incl

ude

Hem

odyn

amic

and

Oxy

gena

tion

Mea

sure

men

ts

Ref

eren

cean

dSt

udy

Typ

eSu

bjec

tsan

dSt

udy

Des

crip

tion

Mea

sure

men

tsFi

ndin

gsan

dR

esul

tsC

oncl

usio

n

Zw

issl

eret

al41

Cro

ssov

erN

�8

adul

tsw

ithse

vere

AR

DS;

INO

vsep

oIm

prov

emen

tin

:P a

O2,

pulm

onar

yar

teri

alpr

essu

re,

and

dose

resp

onse

epo

and

INO2

pulm

onar

yar

teri

alpr

essu

re;

epo

20%2

pulm

onar

yar

teri

alpr

essu

reat

10ng

/kg/

min

;ep

ono

�in

QS/Q

T;

INO

2Q

S/Q

T(a

lldo

ses)

Bot

hin

hale

dPG

I 2an

dN

Om

ayin

duce

sele

ctiv

epu

lmon

ary

vaso

dila

tatio

nan

din

crea

seP a

O2

inse

vere

AR

DS.

Wal

mra

thet

al42

rand

omiz

edcr

osso

ver

N�

16ad

ults

with

AR

DS;

INO

vsep

oIm

prov

emen

tin

:P a

O2/F

IO2,

pulm

onar

yar

teri

alpr

essu

re,

and

dose

resp

onse

epo

and

INO1

P aO

2/FIO

2;ep

o2

pulm

onar

yar

teri

alpr

essu

re(P

�.0

5);

INO

noch

ange

;ep

ono

�in

SVR

orm

ean

arte

rial

pres

sure

Res

pons

edo

se:

INO

17.8

�2.

7pp

m;

epo

7.5

ng/k

g/m

in;1

oxyg

enat

ion.

Van

Hee

rden

etal

43

pros

pect

ive

nonr

ando

miz

edin

terv

entio

nal

N�

9ad

ults

with

seve

reA

RD

S;do

sera

nge

0–50

ng/k

g/m

inIm

prov

emen

tin

:P a

O2/F

IO2,

P (A

-a)O

2,an

ddo

sere

spon

se1

P aO

2/FIO

2(P�

.003

);1

P (A

-a)O

2

(P�

.01)

;�

at0–

10ng

/kg/

min

Dos

e-re

late

def

fect

betw

een

vary

ing

dose

sof

epo;

noef

fect

onsy

stem

icor

pulm

onar

yar

teri

alpr

essu

re.

Dun

kley

etal

44

retr

ospe

ctiv

eob

serv

atio

nal

N�

16ad

ults

with

AR

DS

Impr

ovem

ent

in:

%�

P aO

2/FIO

2,do

sere

spon

se,

and

med

icat

ion

erro

rs

62.5

%re

spon

seat

30ng

/kg/

min

;1

44.5

%in

P aO

2/FIO

2;25

%m

edic

atio

ner

ror

Gre

ater

resp

onse

inP a

O2/F

IO2

may

bere

late

dto

high

erdo

se;

hypo

tens

ion

obse

rved

in18

.8%

ofsu

bjec

ts.

Dom

enig

hetti

etal

45

pros

pect

ive

nonr

ando

miz

edin

terv

entio

nal

N�

15ad

ults

;pr

imar

yvs

seco

ndar

yA

RD

S;ep

oIm

prov

emen

tin

:P a

O2

and

%�

P aO

2/FIO

2

53.3

%(8

/15)

resp

onde

dw

itha

�10

%�

inP a

O2/F

IO2;

dose

:32

�1

ng/k

g/m

inep

oim

prov

edox

ygen

atio

nin

seco

ndar

yA

RD

S;a

high

erdo

sem

aybe

need

ed.

Deh

lem

etal

46

doub

le-b

lind,

rand

omiz

edpl

aceb

o-co

ntro

lled

tria

l

N�

14ch

ildre

nw

ithac

ute

lung

inju

ry;

step

wis

edo

sing

ofep

o(1

0,20

,30

,40

,an

d50

ng/k

g/m

in)

vspl

aceb

o

Art

eria

lbl

ood

gase

s;he

mod

ynam

ics;

�in

OI;

dose

resp

onse

26%

incr

ease

inO

I(I

R3–

35%

)at

30ng

/kg/

min

;8/

14(5

7%)

resp

onde

rs;

num

ber

need

edto

trea

t�1.

8(9

5%C

I1.

2–3.

2)

Aer

osol

ized

pros

tacy

clin

impr

oved

oxyg

enat

ion

inch

ildre

nw

ithac

ute

lung

inju

ry.

INO

�in

hale

dni

tric

oxid

eep

o�

inha

led

epop

rost

enol

P (A

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2�

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olar

-to-

arte

rial

grad

ient

QS/

QT

�sh

unt

frac

tion

PGI 2

�pr

osta

cycl

inSV

R�

syst

emic

vasc

ular

resi

stan

ceO

I�

oxyg

enin

dex



evidence base, and safety profile. For the purpose of thisreview, each area will be discussed with emphasis on pe-diatric populations.

Pharmacodynamics and Dosing

Prostacyclin is a naturally occurring prostaglandin pro-duced primarily by endothelial cells of the vascular intimaand is a known antiregulatory and potent vasodilator.53

Epoprostenol, iloprost, and treprostinil increase the con-centration of cyclic adenosine monophosphate in smoothmuscle cells of the vascular endothelium.54 In contrast,INO modulates vasodilatation through stimulation of sol-uble guanylate cyclase, producing cyclic guanosine mono-phosphate.54 Other clinical characteristics include inhibi-tion of platelet activation, inhibition of leukocyte activation,adhesion, and antiproliferation.54 These effects provide the-oretical benefits in the treatment of pediatric ARDS. Pros-tacyclin preferentially enhances the cyclic guanosine mono-phosphate axis activity, increasing endogenous surfactantproduction, a characteristic not found with INO.55,56 Patho-genesis of ARDS results in worsening pulmonary compli-ance and oxygenation from increasing lung water.38 Pro-tein-rich exudate contained in the alveolus inactivatessurfactant proteins, worsening lung compliance, leading toatelectasis and intrapulmonary shunting.38 Increasing sur-factant production may decrease the need for toxic venti-lator settings, thus limiting the risk of barotrauma, atelec-trauma, and volutrauma. Additionally, prostacyclin havebeen found to suppress the synthesis of tumor necrosisfactor � in activated monocytes, a cytokine implicated inthe pro-inflammatory state in ARDS.56,57 The significantexpression of interleukin-6, -1, and -10 and tumor necrosisfactor �-associated ARDS may result in the suppression ofprostacyclin release, which calls into question whether sup-plementation of prostacyclin may be beneficial during themanagement of pediatric ARDS.57

Epoprostenol Sodium

The FDA cleared epoprostenol sodium in 1995 for long-term intravenous management of primary pulmonary hy-pertension in New York Heart Association Class III andClass IV patients not responding to conventional therapy(http://www.accessdata.fda.gov/drugsatfda_docs/nda/2000/20–444S003_Flolan_Corres.pdf, Accessed March 3,2017). Intravenous administration of epoprostenol has beenassociated with worsening ventilation/perfusion mismatch,tachycardia, hypotension, inhibition of platelet aggrega-tion, and taxiphylaxsis.58 Some have postulated that thecontinuous nebulization of the medication may minimizeor even eliminate these adverse events.53,54 Epoprostenolwas never intended for inhalational applications and isonly available in an intravenous preparation. The high pH

of epoprostenol is potentially caustic to the airways andmay result in direct lung injury. For this reason, nebuliza-tion of prostacyclin analogs approved and available in in-halational preparations should only be considered for thisapplication. Moreover, continuous aerosolized administra-tion of epoprostenol creates potential technical and phys-iologic patient safety risks.

Several small studies have evaluated the hemodynamiceffect of continuous inhalation of epoprostenol in children.Dahlem et al,46 in a small prospective trial, failed to dem-onstrate any adverse effects in children (� 18 y of age)receiving inhaled epoprostenol. Conversely, Brown et al59

retrospectively reviewed the use of epoprostenol for thetreatment of acute pulmonary hypertension. In this cohort,30% of subjects experienced at least one adverse effect,with the most common event being a decrease in systolicblood pressure requiring fluid boluses or vasoactiveagents.59 Of the 6 subjects, 5 were neonates, which led theauthors to conclude that there is a greater incidence ofadverse events in infants younger than 30 d.59 These find-ings may be related to volume distribution, surface area/bodymass ratios, and the absorption kinetics found in pediatriccompared with neonatal populations. Therefore, the use ofaerosolized epoprostenol in neonates necessitates more ag-gressive critical care monitoring.59

Ideal dosing of inhaled epoprostenol in the pediatricpopulation remains unclear, with the highest quality evi-dence being obtained from the only prospective random-ized controlled trial by Dahlem et al.46 That group evalu-ated the change in oxygenation measured by OI after dosesof 10, 20, 30, 40, and 50 ng/kg/min, compared with aplacebo.46 They demonstrated a significant improvementin OI at 30 ng/kg/min.46 Moreover, there was a trend to-ward significance at doses of 20, 40, and 50 ng/kg/min.46

The group also demonstrated a bell-shaped response curveregarding oxygenation improvement, which may help toidentify peak dosing in the pediatric ARDS population.

Aerosolized prostacyclin has been shown to be effectivein improving oxygenation and lower pulmonary vascularresistance in children with acute hypoxic respiratory fail-ure and congenital heart disease.19,46,57,59-62 Dahlem et al46

reported a 26% improvement in OI compared with theplacebo group. In terms of response, the group calculatedthe number needed to treat to observe a 20% increase in OIis one.46 This point is interesting because INO possesses asignificant rate of non-response in this patient population,which may result from an inability to achieve optimalventilation, complicated by lung water, atelectasis, andlobular consolidation, contributing to a need for additionalcritical care intervention over 24–48 h to achieve optimalventilation status. Limitations of the study included a smalldata set, non-homogeneous lung injury etiologies, insuffi-cient power to assess mortality outcomes, and a lack of



secondary outcomes, such as duration of mechanical ven-tilation or hospital costs.46

Brown et al59 retrospectively evaluated the efficacy ofinhaled epoprostenol for the management of acute pulmo-nary hypertension in 20 subjects (13 neonates and 7 pedi-atrics) � 18 y of age. The authors reported a significantimprovement in OI in the neonatal group (25.6 � 16.3 vs14.5 � 13.6, P � .02).59 However, improvement was notobserved in children � 30 d of age (29.6 � 15.3 vs25.6 � 17.8, P � .56).59 The group concluded that neo-nates may benefit more consistently from inhaled prosta-cyclin than older children.59 They further recommendedthat more intensive monitoring is warranted when deliv-ering aerosolized prostacyclin therapy. Designed as a pilotstudy, limitations consistent with the retrospective natureof the study do exist. For example, the study lacked com-plete data regarding echocardiographic evaluation; sub-jects did not receive consistent drug administration, withthe first subject receiving epoprostenol every 2 h and theremaining cohort being administered continuous nebuliza-tion; and the cohort consisted of a non-homogeneous pa-tient population, including neonates and children older than30 d.59 For these reasons, the results should be interpretedwith caution, which further supports the need for largeprospective controlled studies addressing the effectivenessof prostacyclin in pediatric acute hypoxic respiratoryfailure.

Iloprost

Iloprost is a prostacyclin analog pharmacologically sim-ilar to epoprostenol. Compared with epoprostenol, iloprosthas lower viscosity, greater stability, more physiologic pH,and a longer half-life (20–30 min), all of which betterfacilitate nebulization.54 Iloprost inhalational solution(10 �g/mL) was cleared by the FDA in 2004 for treatmentof pulmonary arterial hypertension (World Health Organi-zation Group I) (http://www.accessdata.fda.gov/drugsatfda_docs/nda/2004/21–779_Ventavis_approv.pdf, AccessedMarch 3, 2017). Iloprost’s longer half-life has been asso-ciated with an increased risk of arterial hypotension fromsystemic spillover when compared with INO, leading tothe recommendation of intermittent delivery of iloprostrather than continuous nebulization.53,58,60,63 Currently, noevidence exists regarding the benefit of continuous nebu-lization compared with intermittent delivery of iloprostduring the treatment of acute hypoxemic respiratory fail-ure. Intermittent delivery limits the potential risks associ-ated with continuous nebulization, which include but arenot limited to inadvertent medication-line disconnectionand/or misconnection, delivery interruption, and ventilatormalfunction resulting from sticky properties of the drug.61

In contrast to epoprostenol, iloprost dosing is different,with optimal dosing remaining undefined in the pediatric

critical care setting. The recommended dose for daily man-agement of chronic pediatric pulmonary hypertension is2.5–5 �g/dose, administered 5–9 times/d up to a maxi-mum dose of 45 �g (5 �g/dose 9 times daily).53,54 In thepediatric acute care setting, iloprost doses ranged from 0.5to 2 �g/kg/dose with dose intervals between 30 min and2 h.47,64,65 Rimensberger et al47 reported that inhaled ilo-prost at a dose of 25 ng/kg/min for 10 min was equallyeffective as INO at selectively decreasing pulmonary vas-cular resistance. They further demonstrated that iloprost atthis dose increases plasma cyclic adenosine monophos-phate concentrations from baseline (P � .05) in pediatricsubjects who underwent cardiopulmonary bypass surgery.47

In a similar patient population, Loukanov et al64 demon-strated the favorable safety profile of nebulized iloprost ata dose of 0.5 �g/kg delivery every 2 h. The group did notwitness any adverse events, including bleeding complica-tions.64

Further investigation is needed to better comprehendbest-practice delivery of inhaled vasoactive agents, such asiloprost, because much variation exists in the literatureregarding delivery methodology, administration technique,and dose (Table 4). Questions remain surrounding the ideallocation for administration (ie, at the Y-piece or before thehumidifier) and evaluation of different nebulizers used toadminister these agents, in terms of particle size, aerosoloutput, and dose delivered. Diblasi et al67 evaluated thein vitro effectiveness of iloprost delivery during conven-tional and high-frequency oscillatory ventilation (HFOV)in a neonatal test-lung model. A vibrating mesh nebulizerwas placed proximal to the Y-piece (inspiratory limb) be-tween the humidifier temperature probe and the Y-piece totest conventional ventilation, between the ventilator circuitand endotracheal tube for HFOV, and between the venti-lator and the humidifier to evaluate distal nebulizer place-ment.67 Iloprost was quantified using liquid chromatogra-phy with the collection filters placed at the distal end ofthe endotracheal tube.67 The group reported greater dosedelivery with the nebulizer placed proximal to the airwayin both conventional and HFOV modes.67 Drug deliveryfrom the proximal position during HFOV was 3-fold greaterwhen compared with proximal position during conven-tional ventilation.67 The authors concluded that cliniciansshould avoid placing the nebulizer between the ventilatorand humidifier during neonatal ventilation.67 The in vitroevidence supports intermittent delivery of iloprost via avibrating mesh nebulizer during simulated neonatal me-chanical ventilation.67 Given these data, several questionsremain. First, does the increased dose delivery observed inthe HFOV model demonstrate ongoing limitations of aero-sol delivery during conventional mechanical ventilation?Should dosing be augmented to ensure that a therapeuticdose is delivered, since only 10.74% of the nominal dose(5 �g, 0.5 mL) was delivered in this mode? Second, does



Tab

le4.

Inha

led

Pros

tacy

clin

Del

iver

yD

evic

eT

ype

and

Neb

uliz

erL

ocat

ion

inth

eC

ircu

itby

Clin

ical

Tri

al

Stud

yD

rug

and

Tre

atm

ent

Reg

imen

Neb

uliz

erT

ype

Neb

uliz

erL

ocat

ion

inC

ircu

it

Zw

issl

eret

al41

Epo

pros

teno

l;15

-min

titra

ting

dose

(1,

10,

and

25ng

/kg/

min

)de

liver

yM

odif

ied

jet

nebu

lizer

:N

ebul

izer

945

(Sie

men

sE

lem

a,So

lna,

Swed

en);

8L

/min

nebu

lizer

flow

Not

spec

ifie

d

Wal

mra

thet

al42

Epo

pros

teno

l;1-

htit

ratin

gdo

seco

ntin

uous

deliv

ery

Jet

nebu

lizer

:R

aind

rop

(Pur

itan

Ben

nett,

Car

lsba

d,C

alif

orni

a);

7L

/min

nebu

lizer

flow

Insp

irat

ory

limb;

not

repo

rted

whe

ther

pre-

orpo

st-h

umid

ifie

rV

anH

eerd

enet

al43

Epo

pros

teno

l;co

ntin

uous

deliv

ery

Jet

nebu

lizer

:Si

dest

ream

(Med

ic-A

id;

Wes

tSu

ssex

,U

nite

dK

ingd

om);

syri

nge

pum

psu

pply

with

6L

/m

inne

buliz

erfl

ow

Bet

wee

nth

epa

tient

Y-p

iece

and

ET

Tw

ithth

ead

ditio

nof

tubi

ngbe

twee

nth

eE

TT

and

nebu

lizer

Dun

kley

etal

44E

popr

oste

nol;

cont

inuo

usde

liver

yA

eron

eb(A

erog

en,

Gal

way

,Ir

elan

d);

syri

nge

pum

psu

pply

Not

spec

ifie

d

Dom

enig

hetti

etal

45E

popr

oste

nol;

cont

inuo

usde

liver

yU

ltras

onic

nebu

lizer

:Se

rvo

Ultr

aN

ebul

izer

345

(Sei

men

s-E

lma

AB

,So

lna,

Swed

en)

Insp

irat

ory

limb;

not

repo

rted

whe

ther

pre-

orpo

st-h

umid

ifie

rD

ehle

met

al46

Epo

pros

teno

l;in

term

itten

tde

liver

yU

ltras

onic

nebu

lizer

:Su

n14

5(S

eim

ens-

Elm

aA

B,

Soln

a,Sw

eden

);ou

tput

�0.

1–0.

5m

L/m

inIn

spir

ator

ylim

b;no

tre

port

edpr

e-or

post

-hum

idif

ier

Bro

wn

etal

59E

popr

oste

nol;

inte

rmitt

ent

deliv

ery,

�1

hJe

t-ne

buliz

er;

Min

iHea

rtL

o-Fl

one

buliz

er(W

estm

ed,

Tuc

son,

Ari

zona

);8

L/m

inne

buliz

erfl

owIn

spir

ator

ylim

b;no

tre

port

edpr

e-or

post

-hum

idif

ier

Rim

ensb

erge

ret

al47

Ilop

rost

;in

term

itten

tde

liver

yJe

tne

buliz

er:

Res

pirg

ard

II(M

arqu

est

Med

ical

Prod

ucts

,E

ngle

woo

d,C

olor

ado)

;ou

tput

�0.

15m

L/m

in(6

L/m

in)

Insp

irat

ory

limb

orJa

ckso

n-R

ees

Bag

vent

ilatio

nci

rcui

t

Hoe

per

etal

63Il

opro

st;

inte

rmitt

ent

deliv

ery

Jet

nebu

lizer

:R

aind

rop

(Pur

itan

Ben

nett,

Car

lsba

d,C

alif

orni

a)M

outh

piec

e;sp

onta

neou

sly

brea

thin

gsu

bjec

ts

Lou

kano

vet

al64

Ilop

rost

;in

term

itten

tde

liver

yU

ltras

onic

nebu

lizer

:N

ebu-

Tec

(Kre

uzfe

drin

g,E

lsen

feld

,G

erm

any)

Dis

tal

insp

irat

ory

limb

Yilm

azet

al51

Ilop

rost

;in

term

itten

tde

liver

yJe

tne

buliz

er:

CX

3(O

mro

n,H

oofd

dorp

,N

ethe

rlan

ds)

T-p

iece

adde

dto

vent

ilato

rci

rcui

t;no

tre

port

edw

heth

erpr

e-or

post

-hum

idif

ier

Vor

hies

etal

65Il

opro

st;

inte

rmitt

ent

deliv

ery

Aer

oneb

(Aer

ogen

,G

alw

ay,

Irel

and)

Not

spec

ifie

dIv

yet

al66

Ilop

rost

;in

term

itten

tde

liver

yPr

odos

ead

aptiv

eae

roso

lde

liver

y(P

rofi

leT

hera

peut

ics,

Bog

nor

Reg

is,

Uni

ted

Kin

gdom

)or

Ineb

adap

tive

aero

sol

deliv

ery

(Res

piro

nics

,M

urry

svill

e,Pe

nnsy

lvan

ia)

Mou

thpi

ece;

spon

tane

ousl

ybr

eath

ing

subj

ects

ET

T�

endo

trac

heal

tube



large tidal breath via a larger endotracheal tube (ie, pedi-atric population) affect drug delivery? Finally, more workis needed to better understand drug delivery and particlesize in standard jet nebulizers, because their functionalproperties may greatly affect the delivery characteristics.

Pulmonary hypertension is a known complication be-fore and after repair of congenital cardiac defects. Inhala-tional administration of iloprost has been shown to im-prove oxygenation and decrease pulmonary vascularresistance in children with congenital heart disease.47,64,65,Rimensberger et al47 compared INO with iloprost for thetreatment of secondary pulmonary hypertension in chil-dren with congenital heart disease. They reported that 25ng/kg/min of iloprost was equally effective as INO at se-lectively decreasing pulmonary vascular resistance.47 Us-ing a prospective crossover design, the authors comparedsubjects either in the catheterization laboratory or immediatelyfollowing surgical repair in the ICU with documented elevatedpulmonary vascular resistance. Response was measured usingthe pulmonary vascular resistance/systemic vascular resistanceratio at baseline, 10 min after INO initiation, baseline,10 min after administration of iloprost, baseline, and 10 minfollowing delivery of combined therapy.47 It was foundthat INO (0.48 � 0.38 to 0.27 � .016, P � .001) andiloprost (0.49 � 0.38 to 0.26 � 0.11, P � .05) effectivelydecreased the pulmonary vascular resistance/systemic vas-cular resistance ratio from baseline.47 No benefit was foundduring the combined administration of the 2 therapies.47

The authors acknowledged several limitations of their study.First, iloprost was always administered after INO becauseof its longer half-life. Second, whereas the group con-firmed that hemodynamics returned to baseline, the poten-tial interaction between INO-induced and iloprost vasodi-lation effect on the epithelium cannot be ruled out.47 Finally,the group did not perform a dose-response evaluation, whichcannot rule out the dose-dependent effect on additionaldecreases in pulmonary vascular resistance/systemic vas-cular resistance ratio.47 This is important to note, becausesome have hypothesized that smaller-sized ventilator sys-tems may result in greater drug “rainout” that may limitadequate dosing in children.68

Vorhies et al65 validated the findings of Rimensbergeret al47 in a similar population. They retrospectively eval-uated the transition from INO to inhaled iloprost in 7subjects with postoperative pulmonary hypertension. Nodifferences were found in pulmonary artery pressure(P � .27) and systemic arterial pressure (P � .25) whencomparing INO and iloprost.65 Most notably, it was foundthat the pulmonary artery pressure/systemic arterial pres-sure ratio decreased following the transition to inhalediloprost (from 0.61 to 0.49, P � .03).65 No adverse eventsor complications were reported in this small data set.65 Thestudy had several limitations centered on the small samplesize and retrospective chart review design. Collected vari-

ables only included clinically relevant parameters, limitingthe assessment of potentially important characteristics. Inaddition, the small sample size presents the risk of sam-pling bias.

Treprostinil

Inhalational administration of treprostinil received FDAclearance in 2009 for patients with World Health Organi-zation Group I pulmonary arterial hypertension and func-tional class III symptoms to improve exercise capacity.62

The agent is a chemically stable prostacyclin analog sim-ilar to iloprost but with a longer elimination half-life of 4 hand more favorable administration schedule.69 Recom-mended dosing for treprostinil is 4 times/d with a targetdose of 9 breaths/treatment session, compared with themaintenance regimen for iloprost of 6–9 doses (inhala-tional)/d with a minimum of 2 h between treatments. Dos-age for pediatric patients is 3 breaths (18 �g/treatment) to9 breaths (54 �g/treatment) per treatment 4 times/d.70 Theincreased half-life and intermittent delivery regime alsolimits the potential risk of rebound pulmonary hyperten-sion resulting from the abrupt discontinuation of therapy.This has significant potential benefit when compared withepoprostenol or INO.

Treprostinil is administered via the Opti-Neb, a hand-held ultrasonic, single-breath nebulizer, which delivers6 �g/breath. The device is designed specifically for sub-acute settings, creating barriers to its application duringinvasive mechanical ventilation. Patel et al68 evaluated thedelivery of a standard dose of treprostinil via an in vitromodel. Using a standard jet nebulizer with 10 L/min, thegroup tested dose delivery in 2 modern ventilators. Thegroup demonstrated that the nebulizer output was linearfor 6 min, delivering a mean � SD inhaled dose of72.2 � 16.5 �g (range 47.2–98.6).68 It was concluded thatis possible to deliver aerosolized treprostinil at controlleddoses via a mechanical ventilator.68 The authors stressedthat the outlined conditions must be precisely followedbecause variation and the presence of a humidifier or in-line heat and moisture exchanger may augment dose de-livery.68 The presence of humidity may affect therapy be-cause the effect may reduce aerosol delivery.71 Theseaspects must be accounted for when considering the de-livery of treprostinil or any aerosolized medication in me-chanically ventilated patients. Additional work is neededto describe drug delivery best practices regarding nebu-lizer types, dose accuracy, breathing pattern variation, andbrand of ventilators.68

Inhaled treprostinil has been shown to be safe and ef-ficacious in adults, with a majority of evidence addressingquality-of-life- and exercise-based measures. A small bodyof evidence in the pediatric population seems to suggestsimilar findings. Krishnan et al70 describe the safety and



efficacy of inhaled treprostinil in a retrospective analysisof 29 children with documented Group 1 pulmonary arte-rial hypertension. Therapy was initiated at 3 breaths 4times/d, titrated as tolerated to a maximum of 9 breaths 4times/d.70 Treprostinil was delivered via the Opti-Neb hand-held ultrasonic nebulizer. The group reported improve-ment in World Health Organization functional class in 19of the 29 subjects; significant improvement in exercisecapacity, with 6-min walk distance increasing from455.7 � 71.5 to 498 � 70 m (P � .01); and peak oxygenconsumption increasing from 25.5 � 10.2 to 27.4 � 10mm Hg (P � .04).70 Treprostinil therapy was discontinuedin 4 subjects secondary to symptoms of cough and bron-chospasm and progression of pulmonary arterial hyperten-sion.70 Documented mild adverse effects included coughand sore throat, which did not result in discontinuation oftherapy.70 The authors concluded that treprostinil was as-sociated with improved exercise capacity and functionalclass measures and had an acceptable safety profile.70 Nopediatric-specific studies exist regarding the effect oftreprostinil on oxygenation measurement, right-heart pres-sure, or outcome in the intensive care setting.

Safety Considerations During the Delivery of InhaledPulmonary Vasodilators

Administration of INO is not without risk. A short half-life creates the risk of rebound pulmonary hypertensionresulting from the abrupt cessation of therapy. Interruptionof delivery can result from mechanical equipment failure;exhaustion of gas supply; kinking, disconnection, or ob-struction of the delivery line; and failure to connect theresuscitation bag to an INO supply. The FDA mandates abackup delivery system for continuous inhaled delivery ofpulmonary vasoactive medications. Commercially avail-able devices have such systems and alarms incorporatedinto their design; however, the risk remains. In addition,during times of high usage volume and inclement weather,a potential for limited access to delivery systems doesexist. Size of the delivery systems adds logistical chal-lenges when transferring a patient within the hospital. Mov-ing a patient for a diagnostic procedure(s) creates the needto push a device with the patient to the location of theprocedure. This increases the risk of accidental extubationand abrupt interruption of delivery.

Aerosolization of these potent medications is not with-out risk, as specific technical sources of error, adverseeffects, and physiologic deterioration have been re-ported.46,60,66 A recent independent third-party report de-scribed the potential sources of technical error during thecontinuous nebulization of epoprostenol occurring in (1)infusion pumps, (2) nebulizers, and (3) ventilators.61

Sources of technical error may result from the following.61

(1) Supplying medication to the nebulizer via an infusion

pump can lead to inadvertent misconnection and patientoverdose. Specifically, an infusion pump line that con-nects to the nebulizer can be inadvertently connected tothe patient’s intravenous line. The intravenous dose is 2ng/kg/min, where the inhalational dose may be as high as50 ng/kg/min, a 25-fold increase in dose, resulting in servehypotension and/or death. (2) There may be no alarms toalert clinicians if the therapy has been interrupted. Inter-ruption may result in physiologic deterioration from a rel-atively short pause in therapy. Electrically driven nebuliz-ers may default from continuous to intermittent deliverymodes when power is interrupted. The delivery mode mustbe assessed in the event of power loss to ensure appropri-ate administration. (3) Ventilator component malfunctionas a result of aerosolized medication can result in increasedexpiratory resistance, resulting in a failure to exhale andauto-PEEP, which may result in pneumothorax. Standardjet nebulizers add additional flow to the ventilator circuitthat may alter ventilator function.

In addition to these areas of focus, other considerationsmust be addressed regarding the safe administration ofprostacyclin. They include labeling of all infusion lines,ensuring availability of backup equipment to quickly re-establish therapy in the event of equipment failure, devel-oped policies for the proper storage and handling of themedications, and understanding of the effect of additionalgas flow on delivery monitors and associated alarms be-fore using a pneumatically driven nebulizer.61 The stickyproperties of the medication and infusion rates may alsoimpair drug delivery when it is administered via a vibrat-ing mesh nebulizer and must be considered because theymay result in fluctuations in dose delivery.

In the pediatric patient population, inhalational admin-istration of epoprostenol has been thought to cause directinjury to the lung epithelium due to being diluted in analkaline base (pH �10). Exposure to a high-pH solutionmay worsen underlying lung disease, negatively affectingpulmonary mechanics and ventilation status. Iloprost isdiluted in a neutral base, which some have hypothesizedmay be less harmful to the lung epithelium. This should beconsidered when considering administration of prostacy-clin.

Clinical deterioration and physiologic adverse effectsduring the administration of prostacyclin have been re-ported.60,72 Ivy et al66 evaluated the short- and long-termeffects of inhaled iloprost in children with chronic pulmo-nary hypertension. The group reported that the most com-mon adverse effects were headache (36%), cough (23%),and dizziness (14%), all of which improved within severaldays of the start of therapy.66 Two subjects without priorhistory of lung disease were discontinued from therapy asa result of persistent cough, dyspnea, and room air desatu-ration immediately following iloprost inhalation.66 Twoadditional subjects demonstrated lower airway obstruction



several months following the initiation of iloprost therapyas well.66 The authors concluded that inhaled iloprost mayinduce bronchoconstriction and must be considered whenadministering in children.70 Conversely, others have failedto validate these findings.46,73 Dahlem et al46 assessed theexpiratory limb flow/volume curves in 9 children random-ized to receive aerosolized epoprostenol with acute lunginjury. They reported no change in the flow/volume curveduring the study period.46 Because of limited data regard-ing the effect of prostacyclin airway sensitivity, steps mustbe taken to monitor for airway reactivity during adminis-tration of aerosolized prostacyclin and its analogs.

The vasoactive properties of prostacyclin possess thepotential to result in systemic hypotension, which is rela-tively common when administered intravenously.54 Inha-lational delivery of these agents has been found to de-crease the risk of systemic spillover and resultinghemodynamic adverse effects.54 Distance between the al-veolus and smooth muscle cell is approximately 10 �m atmost, which facilitates easy transfer of the inhaled drug.54

This results in pulmonary selectivity similar to inhalednitric oxide, with no or little effect on the systemic circu-lation.

Continuous delivery of any pulmonary vasoactive agent,whether intravenously or by inhalational administration,presents a risk of disastrous consequence in the event ofabrupt discontinuation of delivery. These include increas-ing pulmonary artery pressure and worsening oxygen-ation; both may be refractory and may require the ini-tiation of extracorporeal life support intervention. Thiswas of significant concern during the 1999 FDA clear-ance of INO.72 In January 2000, the FDA published aguidance document for nitric oxide delivery devices re-garding the need for safety and monitoring features.These features include the continuous monitoring ofNO, NO2, and O2 delivery; a backup delivery system;sensors that monitor and alarm when NO or NO2 con-centrations are out of a set range; and a backup powersupply (http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationGuidence/GuidenceDocuments/ucm073767.pdf, Accessed August 5, 2016). Current INOdelivery systems (eg, INOMAX DSir, INOmax DS, andINOvent, INO Therapeutics, Hampton, New Jersey) haveintegrated analyzers to consistently monitor NO, NO2, andO2 delivery and also have both audible and visual alarmsnotifying users of cessation of drug delivery and/or incor-rect drug concentration. They also include a backup de-livery system, backup NO cylinder (2 cylinders maintainedwith the system at all times), and internal battery in eventof a power failure. These devices are the only systems forthe continuous delivery of inhaled pulmonary vasodilatorsthat comply with all FDA delivery device requirements. Itmust be noted that nebulization of prostacyclin and itsanalogs does not affect the concentrations of NO or NO2.

Therefore, only FIO2needs to be monitored with particular

attention to gas source FIO2when using gas power nebu-

lizers. If used, these systems must have the ability to mon-itor combined FIO2

during administration.The use of inhaled vasoactive agents, such as epopros-

tenol, iloprost, and treprostinil, continues to grow as a lesscostly alternative to inhaled nitric oxide. Evidence sug-gests that these agents are equally as effective as INO atincreasing oxygenation measures and decreasing pulmo-nary vascular resistance in children with acute hypoxicfailure and cardiac disease. Epoprostenol is not approvedfor inhalational applications, and its short half-life requirescontinuous aerosol delivery. Continuous aerosol deliverysystems are often home-grown, lack alarms notifying cli-nicians of medication disconnection, have a propensity tocause ventilator malfunction, and possess a significant riskof either over- or underdosing of the medication. The morestable prostacyclin analogs iloprost and treprostinil havelonger duration of action compared with INO and epopro-stenol, allowing for intermittent treatment regimes. Inter-mittent delivery alleviates the need for continuous admin-istration but is equally effective, increasing patient safetyand possibly providing cost and work flow benefits. How-ever, nebulization of these agents is not without risk, whichmust be considered before administration to ensure accu-rate dose delivery. Future work is needed to understand theeffectiveness of both iloprost and treprostinil in pediatricARDS and pediatric cardiac disease populations.

Summary

Only FDA-cleared inhalational pulmonary vasoactiveagents should be considered for the treatment of pulmo-nary hypertension. Those currently cleared include INO(neonatal patients � 34 weeks gestation), iloprost, andtreprostinil for inhalational administration. No high-levelevidence exists supporting the routine use of INO in thepediatric population. However, INO may be considered asa rescue therapy in pediatric severe acute respiratory hy-poxic failure and right-sided heart failure. More study isneeded to ascertain the effect of INO as it relates to ho-mogeneous pathologies, its effect on long-term outcome,and cost/benefit regarding stay and morbidity.

Epoprostenol should not be considered for inhalationaladministration because it is only available in and approvedfor intravenous administration and presents significant tech-nical and patient safety concerns. Both iloprost and trepro-stinil are available in inhalation preparations and should beconsidered before the use of epoprostenol. Inhalationalpreparation and intermittent treatment schedule make theseagents acceptable alternatives to aerosolized epoprostenoland potentially INO. Additional research is required re-garding aerosolized vasoactive agents and their efficacy inthe pediatric population. One area of particular interest



http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationGuidence/GuidenceDocuments/ucm073767.pdf



is the potential use of inhaled prostacyclin analogs inpatients unresponsive to INO and/or those requiring long-term nitric oxide therapy. It is critical to include accept-able time frames for cardiovascular stabilization andventilation optimization, because lung-protective strat-egies may ultimately affect therapy response and out-come in pediatric ARDS. The work may help to identifyacceptable inclusion criteria, measurable responses, ther-apeutic goals, and management strategies.

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Discussion

Fedor: I have one comment. This isgood information; I actually did a pre-sentation in my marketing class aboutswitching to other inhaled agents. Thething that we see in education on aphysician level in terms of actuallybeing able to get them to discontinuethe drug. We had a lot of problemswith the “if it ain’t broke don’t fix it”mentality, and we incur a lot of costsbased on that.

Kuch: I could not agree more, and Iassume that I am dealing with this is-sue probably as much as you are. Fromthe discussions among the group re-garding Todd Tzanetos et al,1 whichaddressed protocolization of INO:What the group did, which was reallynice, was that if they were started onINO they were automatically enrolledin the protocol. If the physician didn’twant them to be enrolled, they had towrite an order for the patient to beopted out of the protocol. In addition,they delegated the RTs [respiratorytherapists] with weaning the INO. Thesecond part was that the RTs had spe-cific criteria as to what was consid-ered a response and what was not,which is critical. I feel the successof their work was having therapistsmanage the protocol so it’s automat-ically defaulted to be enrolled andhaving good communication withphysicians as we do with ventilator-driven protocols. As long as the RTsare educated and understand who areresponders and non-responders, theywill drive that process and move itforward. That is what we are cur-rently working on, coming up with a

process. I don’t think we should limitaccess to INO, which has occurredin some areas; I think we need tohave access to nitric oxide. But wealso have to understand there are non-responders; put it in the therapists’hands, and work to wean the therapywhen there is no benefit.

Fedor: I think it requires a culturethat empowers the therapists to do suchthings. And the relationships with yourphysicians as well.

Cheifetz: In a follow-up to your priorcomments, I agree with you in con-cept regarding responders and non-re-sponders. The problem is: How to de-fine a responder? In our institution,one clinician may say that an increasein SpO2

by 5% is a responder, whileanother clinician would want to see amore significant change. We also needto consider markers of response/non-response beyond oxygenation. For ex-ample, in the post-cardiopulmonarybypass population, the issue is oftenmore right-ventricular dysfunctionthan a failure to adequately oxygen-ate. While helpful, echocardiographyis often more qualitative than quanti-tative. So, what are your thoughts andrecommendations regarding the bestapproach to objectively define an INOresponder?

Kuch: Some data suggest a 20% in-crease in PaO2

/FIO2in acute respiratory

failure. This is an area we strugglewith as well: Who is a responder andwho is a non-responder? I think itmight be institutional or an area thatcan be addressed by a group who de-fines patient-specific responses, much

like oxygenation in the neonatal pop-ulation: What is the correct saturation,given the level of lung disease? If it’ssevere lung disease, how do we defineadequate response? It may be a mov-ing target, to be honest with you. Interms of the cardiac group, obviously,the ability to monitor central venouspressure is important, and you couldassume there would be some rele-vance. So those children who comeoff bypass often have central venouspressure monitoring in place, whichmay add some value. In addition, Ithink this group is more difficult toevaluate; thus, there are only data from210 subjects, and I don’t know if wecan make any conclusions from thecurrent literature. Central venous pres-sure, cardiac output, magnitude ofshunting, and measures of that naturemay be useful in identifying respond-ers while assessing clinical benefit ofthe therapy.

Stokes: As we aerosolize these verypotent drugs–and you raised safety is-sues for patients–but do you have anyinformation on safety issues for staffand therapists? And potential environ-mental exposure that might be an is-sue?

Kuch: I did not necessarily pull andreview the environmental health andsafety literature. Anecdotally, there arereports of lightheadedness and staffbecoming flushed with nebulization ofpulmonary vasodilators. These reportsbeg the question as to how much thesymptoms experienced are directly as-sociated with the agents in question. Ithink more work needs to be done tobetter understand the effect of envi-



ronmental exposure to aerosolizedprostacyclin. However, it is interest-ing that we don’t see a significant num-ber of children becoming hypotensivewhen it’s delivered directly to the re-spiratory tract, yet there are reports ofnegative effects in exposed staff. Scav-enging of exhaled particulate or theuse of filters may be useful in limitingenvironmental exposure.

Berlinski: A comment about deliv-ery devices. We use vibrating meshnebulizers for all these studies, andthere are lots of data showing that theymight not have consistent output.Some are consistent and have goodoutput, and some are significantlydifferent. I think that’s somethingpractitioners need to keep in mind,because sometimes the lack of re-sponse may not be related to the drug,but to a device that’s not working asit should.

Kuch: That’s a great point. In fact,evidence seems to suggest the thera-peutic pediatric dose is higher thanthe adult dose. The authors hypothe-sized the need for increased dosage isrelated to the size of the pediatric air-way and resulting rainout in the en-dotracheal tube. This may be the rea-son that 30 ng/kg/min is the effectivedose being used in children, whereasin adults, the dose is lower. This isjust one theory. I did look at some ofthese studies and the devices used;there’s no consistency within the stud-ies. Some are using uniHEART nebs,others are using vibrating mesh;they’re using different devices;there’s not consistency in the liter-ature. It’s a nice area of work tofocus on, particularly through parti-cle size assessment: what particlesize is being delivered and the po-tential dose administered. There areadvanced techniques to evaluate thistopic.

Smallwood: A lot of the data youpresented highlighted the lack of evi-dence INO has for acute hypoxemic

respiratory failure or pediatric ARDS.I’m wondering if there are any furtheranalyses stratifying these subjectsbased on disease severity or sub-co-hort characteristics. Is there a smaller,sicker group that could potentially seea benefit? Do you have any insightson that?

Kuch: Yes, there was a study byDobyns et al,2 where they stratifiedsubjects by primary diagnosis into 5different groups. They included pneu-monia with chronic lung disease, pneu-monia without chronic lung disease,immunocompromised children, sep-sis, and there was another group, whichincluded trauma. Again, it was smallnumbers with a total of 108 subjectsenrolled. They demonstrated a slightbenefit in the immunocompromisedsubjects in regard to sustained im-provement in oxygenation who re-ceived INO that they did not witnessin any of the other subgroups. Smallsample size seems to be an ongoingissue, and how do we undertake a ro-bust-sized trial. That’s part of what Iwas speaking to before, if we takepneumonia or direct ARDS etiolo-gies; truly identify and define thatgroup well and evaluate outcomes;at least you would understand INO’sclinical benefit in that particulargroup.

Walsh: One question about the sec-ond point under rescue therapy: Didyou present data that showed that itdecreases the need for ECMO in apediatric population? I understand thatit does in a neonatal population, but inpediatrics?

Kuch: Yes, this was measured byECMO-free days and survival with-out ECMO, and it did seem to increasethose measures during long-term low-dose delivery of 5 ppm INO. The ben-efit was seen when compared with aplacebo of 5 ppm nitrogen. Now, thisstudy3 wasn’t specifically designed forthis outcome; I think it was a posthoc finding. However, the subjects

who received INO had longer sur-vival without ECMO. Brian, the datafrom this study are not necessarilyas convincing as the neonatal datathat demonstrated a reduction inECMO support in infants treated withINO.

Walsh: Another thing about epopro-stenol in particular that worries me isthat it was never designed for the re-spiratory tract, whereas other drugssuch as iloprost are. I’d like to see thatwe don’t consider or promote the useof pulmonary vasodilator drugs thatwere never designed for inhalationwhen there are drugs on the marketthat are. The pH of 10, it’s hypotonic;I also worry about the function of thevibrating mesh with the hypotonic so-lution as well, to Ariel’s [Berlinski]earlier point. There are multiple rea-sons we probably should not be neb-ulizing epoprostenol when we havebetter drugs on the market.

Kuch: I agree, I have more interestin iloprost because of its greater sta-bility and longer half-life, which re-sults in easier storage, and the cost isnot as prohibitive. As a therapist, Ilike the fact that you actually get aneffect for up to 2 h. If we have a con-sistent method of delivery and we cangive a treatment and then come backin 2 h and do the assessment, it’s alittle better workflow and potentiallysafer then continuous epoprostenol,where the pump could fail; there’salso risk with confusion of inhala-tional preparations with intravenouspreparations. This is a very real risk;tubing can get switched up. It’s hap-pened with feeding and intravenouslines, and it could easily happen withthese medications, and it would be ab-solutely catastrophic.

* Branson: I am sitting on the out-side of pediatrics, and I heard you sayINO doesn’t really help very much, solet’s use a cheaper probably less safeway to do something that doesn’t helpvery much. Maybe the real issue is the



orders for implementation with thiswhole class of drugs, regardless ofwhether it’s INO or some kind ofaerosolized vasodilator. If the evi-dence doesn’t support the use, don’tuse it.

Kuch: I don’t think there’s enoughevidence to say, from an outcomes per-spective, that it should be limited. Idon’t think we should limit access toINO because the patient population istenuous. A child comes in, optimizetheir ventilation, INO-stabilize thechild, and the patient does well. Myperspective on this is exactly whatyou’re saying. I think that we shouldlook at what we do when it comes toINO and other therapies for criticalillness much like we do with sepsis. Itshould be considered a goal-directedtherapy. We could easily do this withINO. A child comes in and is now, bydefinition of pediatric ARDS, a can-

didate for INO, and these are the stepswe take. At 24 h after stabilization,which could be tweaking of inotropes,optimizing ventilation, getting volumestatus corrected, continuous renal re-placement therapy; at 24 h, reassesswhether the patient has improved, andif there is no more response, then wewean the INO off. This is not evi-dence-based in any way, I’m just sug-gesting something we need to look atand build. If the child is a responder,you leave them on until a defined point,and we need to identify at which pointyou consult cardiology or bring some-one in to say, “this is ‘X’ and we needto go down another pathway.” Insteadof letting them remain on a high dollartherapy that is no longer providing clin-ical benefit. To do that, I think it needsto be RT-driven with good communi-cation with the physicians. That’s thedirection where we become more pa-tient care-centered and fiscally respon-

sible, having both the entry criteria andan exit strategy.

REFERENCES

1. Todd Tzanetos DR, Housley JJ, Barr FE,May WL, Landers CD. Implementation ofan inhaled nitric oxide protocol decreasesdirect cost associated with its use. RespirCare 2015;60(5):644-650.

2. Dobyns EL, Cornfield DN, Anas NG, Forten-berry JD, Tasker RC, Lynch A, et al. Multi-center randomized controlled trial of the ef-fects of inhaled nitric oxide therapy on gasexchange in children with acute hypoxic re-spiratory failure. J Pediatr 1999;134(4):406-412.

3. Bronicki RA, Fortenberry J, Schreiber M,Checchia PA, Anas NG. Multicenter ran-domized controlled trial of inhaled nitric ox-ide for pediatric acute respiratory distress syn-drome. J Pediatr 2015;166(2):365-369.e1.

This article is approved for Continuing Respiratory Care Educationcredit. For information and to obtain your CRCE

(free to AARC members) visitwww.rcjournal.com

* Richard D Branson MSc RRT FAARC, Dep-uty Editor, RESPIRATORY CARE.



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