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AARC Clinical Practice Guideline

Evidence-Based Clinical Practice Guideline:Inhaled Nitric Oxide for Neonates

With Acute Hypoxic Respiratory Failure

Robert M DiBlasi RRT-NPS FAARC, Timothy R Myers RRT-NPS,and Dean R Hess PhD RRT FAARC

Inhaled nitric oxide (INO) is a colorless, odorless gas that is also a potent pulmonary vasodilator.When given via the inhaled route it is a selective pulmonary vasodilator. INO is approved by theUnited States Food and Drug Administration (FDA) for the treatment of term and near-termneonates with hypoxemic respiratory failure associated with clinical or echocardiographic evidenceof pulmonary arterial hypertension. A systematic review of the literature was conducted with theintention of making recommendations related to the clinical use of INO for its FDA-approvedindication. Specifically, we wrote these evidence-based clinical practice guidelines to address thefollowing questions: (1) What is the evidence for labeled use? (2) What are the specific indicationsfor INO for neonates with acute hypoxemic respiratory failure? (3) Does the use of INO impactoxygenation, mortality, or utilization of extracorporeal membrane oxygenation (ECMO)? (4) DoesINO affect long-term outcomes? (5) Is INO cost-effective therapy? (6) How is the appropriatedosing regimen and dose response to INO established? (7) How is the dose of INO titrated andweaned? (8) Which INO delivery system should be used? (9) How should INO be implemented withdifferent respiratory support devices? (10) What adverse effects of INO should be monitored, andat what frequency? (11) What physiologic parameters should be monitored during INO? (12) Isscavenging of gases necessary to protect the caregivers? Using the Grading of RecommendationsAssessment, Development, and Evaluation (GRADE) scoring system, 22 recommendations are de-veloped for the use of INO in newborns. Key words: inhaled nitric oxide; mechanical ventilation;neonate; persistent pulmonary hypertension of the newborn; hypoxemia. [Respir Care 2010;55(12):1717–1745. © 2010 Daedalus Enterprises]

Introduction

Inhaled nitric oxide (INO) is a colorless, odorless gasthat is also a potent pulmonary vasodilator. When given

via inhalation, NO rapidly diffuses across the alveolar-capillary membrane and is bound to hemoglobin, and thushas little effect on the systemic circulation.1,2 This results

Robert M DiBlasi RRT-NPS FAARC is affiliated with the RespiratoryCare Department, Seattle Children’s Hospital and Center for Develop-mental Therapeutics, Seattle Children’s Research Institute, Seattle, Wash-ington. Timothy R Myers RRT-NPS is affiliated with Women’s andChildren’s Respiratory and Procedural Services, and the Pediatric HeartCenter, Rainbow Babies and Children’s Hospital, and with the Departmentof Pediatrics, Case Western Reserve University; Cleveland, Ohio. Dean RHess PhD RRT FAARC is affiliated with Respiratory Care Services, Mas-sachusetts General Hospital, and with the Department of Anesthesia, Har-vard Medical School, Boston, Massachusetts.

Preparation of this clinical practice guideline was supported by the AmericanRespiratory Care Foundation through an unrestricted grant from Ikaria. Ikariawas not involved in creating the questions, doing the literature search,

writing the review, or drafting the recommendations. Full editorial controlrests with the authors and the American Association for Respiratory CareClinical Practice Guidelines Committee.

Mr DiBlasi has disclosed relationships with GE Healthcare and MonaghanMedical. Mr Myers has disclosed relationships with Cardinal and DiscoveryLabs. Dr Hess is an employee of the Massachusetts General Hospital, whichreceives royalties on patents licensed to Ikaria. He has also disclosed rela-tionships with Philips Respironics, Covidien, Impact, Pari, and Novartis.

Correspondence: Robert M DiBlasi RRT-NPS FAARC, Respiratory CareDepartment, Seattle Children’s Hospital and Center for DevelopmentalTherapeutics, Seattle Children’s Research Institute, 1900 Ninth Avenue,Seattle WA 98101. E-mail: [email protected].

RESPIRATORY CARE • DECEMBER 2010 VOL 55 NO 12 1717

in limiting the effect of INO to the lungs, making it aselective pulmonary vasodilator. There are several physi-ologic effects that make INO an appealing therapy forinfants with pulmonary hypertension. INO can decreasepulmonary vascular resistance, improve ventilation-perfu-sion inequalities, and reduce right-to-left intra-cardiacshunting of blood through the foramen ovale and ductusarteriosus,3 all of which can contribute to improved arte-rial oxygenation and hemodynamic stability.

Neonatal hypoxic respiratory failure may be caused bypersistent pulmonary hypertension of the newborn (PPHN)and other diseases that contribute to pulmonary arterialhypertension. These diseases include respiratory distresssyndrome, meconium aspiration syndrome, pneumonia,sepsis, congenital diaphragmatic hernia, and some congen-ital cardiac anomalies. In the early 1990s, several casestudies and case series reported the use of INO for thetreatment of PPHN. This was followed by several multi-center randomized controlled double-blinded studies ofINO for PPHN. On December 23, 1999, the United StatesFood and Drug Administration (FDA) approved the use ofINO for the treatment of term and near-term (� 34 wk)neonates with hypoxic respiratory failure associated withpulmonary hypertension.

The only FDA-approved formulation of INO is INO-max, marketed by Ikaria, Clinton, New Jersey. The tradename for INOmax and the specific labeled indication is

INOmax, in conjunction with ventilatory supportand other appropriate agents, is indicated for thetreatment of term and near-term (� 34 wk) neo-nates with hypoxic respiratory failure associatedwith clinical or echocardiographic evidence of pul-monary hypertension, where it improves oxygen-ation and reduces the need for extracorporeal mem-brane oxygenation.

On September 23, 2005, the Therapeutic Products Di-rectorate of Health Canada issued a Notice of Compliancefor INOmax, NO for inhalation, in essence approving Ikariato market NO for infants � 34 weeks in Canada.

INO is commonly used as a front-line therapy in neo-nates with hypoxic respiratory failure associated with pul-monary hypertension. However, many practical questionsremain related to its appropriate clinical use for its labeledindication. The cost of the drug has been a concern sinceits release. Its cost has a substantial impact on the operat-ing costs of many hospitals. It appears that much of theincrease in the use of the drug has been for indications thatare off-label. The use of INO is increasingly used withpremature infants, pediatric patients, and adults with hy-poxemic respiratory failure. However, for the purpose ofthis evidence-based review and clinical practice guideline,we will focus only on the evidence related to the FDA

labeled indications in neonates with hypoxic respiratoryfailure associated with pulmonary hypertension.

Accordingly, a systematic review of the literature wasconducted with the intention of making recommendationsrelated to the clinical use of INO for its FDA-approved in-dication. Specifically, we wrote these evidence-based clinicalpractice guidelines to address the following questions:

1. What is the evidence for labeled use?2. What are the specific indications for INO for neo-

nates with acute hypoxemic respiratory failure?3. Does the use of INO impact oxygenation, mortality,

or utilization of extracorporeal membrane oxygenation(ECMO)?

4. Does INO affect long-term outcomes?5. Is INO cost-effective?6. How is the appropriate dosing regimen and dose re-

sponse to INO established?7. How is the dose of INO titrated and weaned?8. Which INO delivery systems should be used?9. How should INO be implemented with different re-

spiratory support devices?10. What adverse effects of INO should be monitored,

and at what frequency?11. What physiologic parameters should be monitored

during INO?12. Is scavenging of gases necessary to protect the care-

givers?

Methods

To identify the evidence addressing these questions, aPubMed (MEDLINE) search was conducted using the fol-lowing search terms:

“Inhaled nitric oxide” with limits of English language,human studies, all child (0–18 y)

“Nitric oxide and neonate” with limits of English lan-guage, human studies, all child (0–18 y)

“Nitric oxide therapy” with limits of English language,human studies, all child (0–18 y)

“Nitric oxide administration” with limits of English lan-guage, human studies, all ages

“Nitric oxide delivery” with limits of English language,human studies, all ages

“Nitric oxide and monitoring” with limits of Englishlanguage, human studies, all ages

The search timeframe included published papers indexedbetween January 1, 1990, and December 31, 2009. Refer-ences and abstracts were retrieved into reference-manage-ment software (EndNote, ISI, Berkeley, California) forfurther analysis.

By inspection of their titles, references having no pos-sible relevance to the study questions were eliminated. Forthe titles that remained, the abstracts were reviewed andassessed for relevance, and additional references were elim-

INHALED NITRIC OXIDE FOR NEONATES WITH ACUTE HYPOXIC RESPIRATORY FAILURE

1718 RESPIRATORY CARE • DECEMBER 2010 VOL 55 NO 12

inated as appropriate. This process was conducted inde-pendently by 3 individuals, after which their reference listswere merged to provide the reference base for further anal-ysis. Throughout the process of developing these guidelines,the authors surveyed cross-references to identify additionalreferences to be added to the reference base for analysis.Results of the searches and inclusion and exclusion criteriaresulted in the inclusion of 131 relevant articles (Fig. 1).

Data were extracted from the selected references usinga standardized critique form. To validate this form and toestablish the reliability of the review process, several ref-erences were initially evaluated by members of the com-mittee during a face-to-face meeting. All references werethen independently examined by at least two of the au-thors. The critiques were compared and differences wereresolved using an iterative process.

Recommendations were based on a modification of theGrading of Recommendations Assessment, Development, andEvaluation (GRADE) scoring system.4 The strength of therecommendation is given a level of 1 when the benefits clearlyoutweigh the risks and burdens (or vice versa) for nearly allpatients. A level of 2 is weaker and given when risks andbenefits are more closely balanced or are more uncertain. Thequality of the evidence is given a grade of A, B, C, or D forhigh, moderate, low, and very low, respectively.

The draft document was peer-reviewed by experts onthe subject of INO therapy in newborns. Each of the re-viewer’s comments was carefully assessed and the docu-ment was further revised as appropriate.

What Is the Evidence for the Labeled Indication?

The most comprehensive systematic review and meta-analysis of the use INO therapy in term or near-term in-fants comes from the Cochrane Collaboration.5 Only ran-domized trials were included in that review, resulting in 12studies that were analyzed. The overall quality of the stud-ies was variable. The highest quality studies were fullyblinded, adequately powered, multi-center randomized con-trolled trials with external data-monitoring groups that ex-amined clinically important outcomes.6,7 Some studies wereof intermediate quality, because they had variable degreesof blinding and examined primarily oxygenation out-come.8-10 A third group of studies were single (or few)center studies that were unblinded, had very small samplesizes, and/or investigated short-term oxygenation respons-es.11-15 Following this systematic review, the results of oneadditional prospective randomized controlled and un-blinded multi-center trial was reported.16

What Are the Specific Indications for INO forInfants With Acute Hypoxemic Respiratory Failure?

This is a practical question facing the clinician at thebedside caring for a newborn with acute hypoxemic respi-

ratory failure. It can be addressed by careful examinationof the evidence from randomized controlled trials (Ta-ble 1)7-22 and observational studies (Table 2).23-45 The ran-domized controlled trials enrolled term or near-term new-borns born at � 34 weeks gestation. Although the criteriafor post-partum age differed among those studied, patientswere generally � 5 days old and were treated for a max-imum of 14 days.

All studies included some criteria for the severity oflung function and the degree of shunt. Although the oxy-genation criteria differed to some extent among the stud-ies, most were consistent with PaO2

� 100 mm Hg on FIO2

Fig. 1. Literature review process.



Tab

le1.

Cri

teri

afo

rIn

itiat

ing

INO

,Fr

omR

ando

miz

edC

ontr

olle

dT

rial

s

Firs

tA

utho

rSt

udy

Des

ign

Subj

ects

P aO

2O

xyge

natio

nIn

dex

Exc

lusi

ons

Bar

efie

ld14

1996

Sing

le-c

ente

rR

CT

8co

ntro

l9

INO

Ech

oev

iden

ceof

PPH

N

P aO

2�

100

mm

Hg

onF I

O2

1.0

Not

stat

ed�

35w

k,w

eigh

t�

2kg

,m

ajor

cong

enita

lan

omal

y,co

ngen

ital

diap

hrag

mat

iche

rnia

,pr

ofou

ndas

phyx

ia,

subs

tant

ial

blee

ding

NIN

OS7

1997

Mul

ti-ce

nter

RC

T12

1co

ntro

l11

4IN

ON

otst

ated

�25

2at

leas

t15

min

apar

t�

34w

kge

stat

ion,

�14

dof

life,

CH

D

NIN

OS17

1997

Mul

ti-ce

nter

RC

T28

cont

rol

25IN

OA

llw

ithC

DH

Not

stat

ed�

252

atle

ast

15m

inap

art

�34

wk

gest

atio

n,�

14d

oflif

e

Rob

erts

819

97M

ulti-

cent

erR

CT

28co

ntro

l30

INO

Ech

oev

iden

ceof

PPH

N

�55

mm

Hg

onF I

O2

1.0

on2

cons

ecut

ive

dete

rmin

atio

ns30

min

apar

t

Not

stat

ed�

37w

kge

stat

ion,

prev

ious

EC

MO

orhi

gh-f

requ

ency

vent

ilatio

n,C

DH

,sus

pect

edlu

nghy

popl

asia

,CH

D,u

ncor

rect

edhy

pote

nsio

n,po

lycy

them

ia,p

neum

otho

rax,

leth

alch

rom

osom

alab

norm

ality

Kin

sella

1819

97M

ulti-

cent

erR

CT

107

INO

98H

FOV

Ech

oev

iden

ceof

PPH

N

P aO

2�

80m

mH

gon

F IO

21.

0N

otst

ated

Neo

nate

s�

34w

kge

stat

ion,

urge

ntne

edfo

rE

CM

O,

leth

alco

ngen

ital

anom

aly

Day

1119

97Si

ngle

-cen

ter

RC

T11

cont

rol

39IN

OE

cho

evid

ence

ofPP

HN

Not

stat

ed�

25C

onge

nita

lhe

art

dise

ase

Wes

sel12

1997

Sing

le-c

ente

rR

CT

23co

ntro

l26

INO

Ech

oev

iden

ceof

PPH

N

P aO

2�

100

mm

Hg

onF I

O2

1.0

Not

stat

ed�

34w

k,co

ngen

ital

hear

tdi

seas

e,co

ngen

ital

diap

hrag

mat

iche

rnia

Dav

idso

n1019

98M

ulti-

cent

erR

CT

41co

ntro

l11

4IN

OE

cho

evid

ence

ofPP

HN

P aO

240

–100

mm

Hg

onF I

O2

1.0,

mea

nai

rway

pres

sure

�10

cmH

2ON

otst

ated

�37

wk

gest

atio

n,�

72h

oflif

e,lu

nghy

popl

asia

synd

rom

es,c

onge

nita

lhe

art

dise

ase,

�gr

ade

2in

trac

rani

alhe

mor

rhag

e,un

corr

ecte

dpo

lycy

them

ia,m

ean

syst

emic

arte

rial

pres

sure

�35

mm

Hg,

leth

alsy

ndro

me,

chro

mos

omal

abno

rmal

ity,u

seof

intr

aven

ous

vaso

dila

tors

afte

ren

try

crite

ria

wer

em

etat

stud

ysi

te,u

ncon

trol

labl

eco

agul

opat

hyC

ornf

ield

1319

99M

ulti-

cent

erR

CT

23co

ntro

l15

INO

Ech

oev

iden

ceof

PPH

N

P aO

2�

100

mm

Hg

on2

bloo

dga

ses

60m

inap

art

�25

on2

sepa

rate

bloo

dga

ses

60m

inap

art

Neo

nate

s�

34w

kge

stat

ion,

infa

nts

�7

dol

d,co

ngen

ital

anom

aly,

intr

aven

tric

ular

hem

orrh

age

ofgr

ade

3or

4,em

erge

ncy

need

for

EC

MO

,C

HD

Fran

co-B

elgi

anIN

OT

rial

Gro

up19

1999

Mul

ti-ce

nter

RC

T52

cont

rol

55IN

ON

otst

ated

15–4

0L

etha

lco

ngen

ital

anom

aly,

CH

D,

CD

H,

pulm

onar

yhy

popl

asia

;re

frac

tory

sept

icsh

ock;

abno

rmal

neur

olog

ical

stat

usdu

eto

seve

rebi

rth

asph

yxia

orgr

ade

3or

4in

trac

rani

alhe

mor

rhag

eC

lark

620

00M

ulti-

cent

erR

CT

122

cont

rol

126

INO

Ech

oev

iden

ceof

PPH

N

Not

stat

ed�

25�

34w

kge

stat

ion,

�4

dof

life,

urge

ntne

edfo

rE

CM

O,r

efra

ctor

yhy

pote

nsio

n(m

ean

arte

rial

pres

sure

�35

mm

Hg)

,pro

foun

dhy

poxe

mia

(PaO

2�

30m

mH

g),l

etha

lco

ngen

ital

anom

aly,

subs

tant

ial

blee

ding

diat

hesi

s,ac

tive

seiz

ures

,and

hist

ory

ofse

vere

asph

yxia

Chr

isto

u1520

00Si

ngle

-cen

ter

RC

T20

cont

rol

21IN

OE

cho

evid

ence

ofPP

HN

P aO

2�

100

mm

Hg

onF I

O2

1.0

Not

stat

edM

ajor

cong

enita

lan

omal

y;ge

stat

iona

lag

e�

34w

k

Fine

r2020

01Si

ngle

-cen

ter

RC

Tof

2IN

Odo

ses

15at

1–2

ppm

21at

10–2

0pp

mP a

O2

�10

0m

mH

gon

2bl

ood

gase

sta

ken

atle

ast

30m

inap

art

with

ina

2-h

peri

od

�10

�34

wk

gest

atio

n,�

30d

old,

CD

H,C

HD

,int

rave

ntri

cula

rhe

mor

rhag

egr

ade

2or

wor

se,

plat

elet

s�

100,

000,

deci

sion

mad

eno

tto

prov

ide

full

med

ical

trea

tmen

t

Sadi

q2120

03M

ulti-

cent

erR

CT

42C

ontr

ol43

INO

Ech

oev

iden

ceof

PPH

N

P (A

-a)O

250

0–60

0m

mH

gon

2co

nsec

utiv

ebl

ood

gase

sat

leas

t1

hap

art

onF I

O2

1.0

Not

stat

ed�

2kg

,le

thal

mal

form

atio

n,no

surf

acta

nt

Kon

duri

2220

04M

ulti-

cent

erR

CT

149

cont

rol

150

INO

Ech

oev

iden

ceof

PPH

N

Not

stat

ed15

–24

onF I

O2

�0.

80on

any

2ar

teri

albl

ood

gase

sat

leas

t15

min

and

�12

hap

art

�34

wk

gest

atio

n,�

14d

old,

life-

thre

aten

ing

cong

enita

lm

alfo

rmat

ions

,C

HD

othe

rth

anpa

tent

duct

usar

teri

osus

orpa

tent

fora

men

oval

e,C

DH

,pr

evio

usIN

Oth

erap

y,hi

gh-f

requ

ency

jet

vent

ilatio

n

INO

�in

hale

dni

tric

oxid

eR

CT

�ra

ndom

ized

cont

rolle

dtr

ial

CH

D�

cong

enita

lhe

art

dise

ase

PPH

N�

pers

iste

ntpu

lmon

ary

hype

rten

sion

ofth

ene

wbo

rnE

CM

O�

extr

acor

pore

alm

embr

ane

oxyg

enat

ion

HFV

�hi

gh-f

requ

ency

vent

ilatio

nH

FOV

�hi

gh-f

requ

ency

osci

llato

ryve

ntila

tion

P (A

-a)O

2�

alve

olar

-art

eria

lox

ygen

diff

eren

ceC

DH

�co

ngen

ital

diap

hrag

mat

iche

rnia



Tab

le2.

Cri

teri

afo

rIn

itiat

ing

INO

,Fr

omO

bser

vatio

nal

Stud

ies

Firs

tA

utho

rSt

udy

Des

ign

Subj

ects

P aO

2/Oxy

gena

tion

Oxy

gena

tion

Inde

xE

xclu

sion

s

Rob

erts

2319

92Pr

ospe

ctiv

eca

sese

ries

6 Clin

ical

evid

ence

ofPP

HN

Not

stat

edN

otst

ated

Non

est

ated

Kin

sella

2419

92Pr

ospe

ctiv

eca

sese

ries

9 Ech

oev

iden

ceof

PPH

NP a

O2

�40

mm

Hg

�40

Non

est

ated

Kin

sella

2519

93Pr

ospe

ctiv

eca

sese

ries

9 Ech

oev

iden

ceof

PPH

NP a

O2

�40

mm

Hg

�40

Ges

tatio

nal

age

�34

wk

Kin

sella

2619

94Pr

ospe

ctiv

eca

sese

ries

15 PPH

NE

CM

Ocr

iteri

aE

CM

Ocr

iteri

aN

one

stat

ed

Fine

r2719

94Pr

ospe

ctiv

eca

sese

ries

23 Ech

oev

iden

ceof

PPH

NF I

O2

1.0

�20

afte

rsu

rfac

tant

�35

wk

gest

atio

n,le

thal

mal

form

atio

ns,s

truc

tura

lca

rdia

cdi

seas

e,IV

HB

uhre

r2819

95Pr

ospe

ctiv

eca

sese

ries

10 Hyp

oxem

icre

spir

ator

yfa

ilure

F IO

2�

0.8

for

�16

h,or

�0.

9fo

r�

8h

P aO

2no

tst

ated

Not

repo

rted

�14

dol

d,bi

rth

wei

ght

�1,

500

g,C

HD

,IV

H,e

xces

sive

hype

rbili

rubi

nem

ia,s

yste

mic

hypo

tens

ion,

seve

rebi

late

ral

lung

hypo

plas

iaT

urbo

w29

1995

Pros

pect

ive

case

seri

es13 E

cho

evid

ence

ofPP

HN

P (A

-a)O

2�

610

mm

Hg

�35

–40

Ges

tatio

nal

age

�36

wk

Mul

ler30

1996

Pros

pect

ive

case

seri

es10 PP

HN

P aO

2�

40m

mH

gfo

r�

2h

or�

50m

mH

g�

4h

�40

�35

wk

gest

atio

nal

age,

CH

D,

IVH

,fa

mily

hist

ory

ofre

dbl

ood

cell

dise

ase

Stra

nak31

1996

Ret

rosp

ectiv

eca

sese

ries

15 Ech

oev

iden

ceof

PPH

NP (

A-a

)O2

�55

0m

mH

gon

F IO

21.

0�

25�

35w

kge

stat

ion,

seve

reC

DH

,sev

ere

IVH

,irr

ever

sibl

elu

ngin

jury

,le

thal

chro

mos

omal

abno

rmal

ities

,pro

long

edm

etab

olic

acid

osis

,se

vere

circ

ulat

ory

failu

re,p

rolo

nged

blee

ding

time

orco

agul

opat

hy,

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nt�

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1.0 and an oxygenation index (OI) � 25. Echocardio-graphic evidence of PPHN was used in some studies, butnot all.

INO does not benefit newborns with congenital dia-phragmatic hernia, and its use is not indicated in thosepatients.7 In addition, there are concerns that outcomesmay be worse in infants with congenital diaphragmatichernia who received INO, compared to controls. Data areavailable from 2 studies related to the use of INO withcongenital diaphragmatic hernia.7,17 The incidence of deathor requiring ECMO was 40/46 in controls and 36/38 withINO (relative risk 1.09, 95% CI 0.95–1.26). Mortality wasnot affected by use of INO (18/46 controls, compared with18/38 with INO, relative risk of death 1.20, 95% CI 0.74–1.96). There were no significant differences in oxygen-ation outcomes between the 2 groups 30 min followingstudy gas initiation.7 Moreover, there was a significantincrease (P � .04) in the requirement for ECMO in thegroup receiving INO (31/46 controls, compared with 32/38with INO, relative risk 1.27, 95% CI 1.00–1.62).

The use of INO therapy has been described for thepreoperative and postoperative management of hypoxicinfants with pulmonary hypertension related to congenitalheart disease. In the preoperative cases, pulmonary hyper-tension can arise from increased pulmonary blood flowand consequent remodeling of the pulmonary vascular bed.Cardiac catheterization studies have demonstrated that pul-monary vascular resistance and pulmonary arterial pres-sure are lower in infants with congenital heart diseasetreated with INO therapy (20 ppm) than with FIO2

1.0(P � .02).46

Cardiopulmonary bypass during repair of congenitalheart disease has been associated with severe lung inflam-mation and increases in pulmonary hypertension in theimmediate postoperative period.47 These postoperative hy-pertensive crises occur in approximately 7% of patientswith congenital heart disease, with an associated mortalityof about 29%.48 In these infants, INO therapy administeredin the postoperative period was shown to decrease pulmo-nary arterial pressure49 and increase cardiac output.50

In a Cochrane review, Bizzarro and Gross51 evaluatedoutcomes related to the use of INO therapy for the post-operative management of patients with congenital heartdisease necessitating repair. Based on a low enrollment ofindividual studies, the authors concluded that postopera-tive use of INO does not result in a significant reduction inmortality and the number of pulmonary hypertensive cri-ses, nor does its use appear to significantly alter hemody-namics or result in any improvement in other clinicallyrelevant outcomes such as arterial oxygenation. This anal-ysis consisted of 4 randomized controlled trials in patientswho ranged in age from 1 day to 20 years of age. How-ever, it is unclear how many of the infants included inthese studies met the FDA label claim. Thus, there are

insufficient data to support the routine use of INO therapyin postoperative management of hypoxic term or near-term infants with congenital heart disease.

Although it has not been studied, strong physiologicrationale supports the contraindication of using INO innewborns with congenital heart disease dependent on right-to-left shunt. Although also not studied, strong ethical ra-tionale supports the contraindication of using INO in new-borns with lethal congenital anomalies and congestive heartfailure.

Does the Use of INO Impact Oxygenation,Mortality, or ECMO Utilization?

A major question surrounding the use of INO therapy iswhether it alters the clinical course of critically ill, hypox-emic infants who have not responded to conventional meth-ods of respiratory support. As mentioned previously, acomprehensive Cochrane review and meta-analysis, sum-marized by Finer and Barrington,5 was designed to deter-mine whether INO therapy in the term or near-term hy-poxemic infant improves oxygenation and reducesmortality and ECMO utilization.

The 2 indices of oxygenation typically reported in theliterature related to INO are the OI and PaO2

. OI is calcu-lated as:

OI � [(FIO2� P� aw)/PaO2

] � 100

where P� aw is mean airway pressure. OI at 30–60 min afterinitiation of INO was reported in 6 studies.7-9,11,12,15 Allbut one trial15 reported a significant improvement in OIfollowing INO therapy. The meta-analysis by Finer andBarrington,5 showed that OI within 30–60 min of startingINO is significantly lower (weighted mean difference�9.59, 95% CI 12.50 to �6.68). PaO2

30–60 min aftertreatment was evaluated in 6 studies.7-9,11,12,15 All studiesexcept one15 reported a significant benefit of INO. Themeta-analysis5 shows that PaO2

30–60 min after treatmentwas significantly higher in the INO group (weighted meandifference 45.5 mm Hg, 95% CI 34.7–56.3).

Death or requirement for ECMO was reported in 8 tri-als. In 6 studies,7-9,11,13,16 crossover use of INO in controlswho did not respond to initial treatment was not allowed,while in the remaining 2 studies10,15 crossover use of INOin controls was permitted. Analysis7-9 of the 6 stud-ies6,8,10,12,15,17 that did not allow crossover use of INO incontrols found a statistically significant reduction in thecombined outcome of death and requirement for ECMO(relative risk 0.65, 95% CI 0.55–0.76, risk difference �0.20,95% CI �0.27 to �0.13) (Fig. 2). None of the studies thatreported mortality found a significant effect on this outcomealone (relative risk 0.91, 95% CI 0.60–1.37) (Fig. 3). Re-quirement for ECMO was reported in 8 studies, and the meta-



analysis showed a significant reduction in requirement forECMO (relative risk 0.63, 95% CI 0.54–0.75, risk differ-ence �0.19, 95% CI �0.26 to �0.12). The number-needed-to-treat with INO to prevent one infant from requiring ECMOis 5.3 (95% CI 3.8–8.3) (Fig. 4).

The majority of infants described in the Cochrane meta-analysis by Finer and Barrington5 were described as beingextremely ill when INO therapy was initiated. A numberof studies explored whether outcomes are better when INOtherapy is instituted earlier in the disease course.

Konduri et al22 reported that INO improves oxygenationbut does not reduce the combined incidence of ECMO/mortality when initiated at an OI of 15–25, compared withinitiation at OI � 25, suggesting no benefit in terms ofoutcome with initiation of INO earlier in the disease pro-

cess. The Franco-Belgian Collaborative NO trial group19

evaluated outcomes in mechanically ventilated pre-term(� 33 wk) and near-term infants (� 33 wk) treated withearly (OI 12.5–30) and later (OI 15–40) INO therapy at10 ppm. In the near-term infants, low-dose INO therapyinstituted early in the course of respiratory failure signif-icantly improved oxygenation, and shortened the durationof mechanical ventilation and stay in the intensive careunit.

Gonzalez et al16 evaluated whether early treatment withINO therapy in newborns with moderate respiratory fail-ure improves oxygenation and attenuates the developmentof severe hypoxemic respiratory failure. Mechanically ven-tilated infants were randomized to receive INO therapy as:(1) an early method of therapy (with OI between 10 and

Fig. 2. Analysis of studies of inhaled nitric oxide (INO) that used the outcomes of survival or requirement for extracorporeal membraneoxygenation (ECMO) with and without backup use of INO in controls. M-H � Mantel-Haenszel risk ratio. NINOS � Neonatal Inhaled NitricOxide Study Group. (Adapted from Reference 5, with permission.)



30), or (2) when infants, being managed with FIO21.0 had

OI � 40. In the early-INO group (n � 28), mean OIdecreased significantly at 4 hours (P � .05) and remainedlower over 48 hours. In the control group (n � 28), OIincreased and remained significantly higher over the sub-sequent 48 hours (P � .001) following administration ofINO. The median requirement for oxygen therapy wassignificantly less in the early INO group than in the controlgroup (P � .003). The findings of that study suggest thatthere may be some clinical benefit to initiating INO ther-apy earlier in the disease process.

Does INO Therapy Affect Long-Term Outcomes?

Long-term outcomes were evaluated in 8 studies of dif-ferent designs and methodological validity (Table 3).52-59

For survivors of the 1997 Neonatal Inhaled Nitric OxideStudy Group (NINOS) study,8 there was no significantdifference in the occurrence of neurodevelopmental se-quelae between the INO and control infants.57 There wereno differences in the occurrence of hearing impairment orin infant development scoring systems. The occurrence ofseizures was less in the INO infants (4/85 INO infants,compared with 13/87 controls, P � .046). There were nodifferences in requirement for later hospital readmission,use of home medications, apnea monitors, home oxygen,use of gastrostomy tubes, or requirement for speech ther-apy. Survivors with congenital diaphragmatic hernia hadcomparable neurodevelopmental outcomes at follow-up.

Rosenberg et al52 conducted a prospective observationallongitudinal medical and neurodevelopmental follow-upof 51 infants treated as neonates for PPHN with INO. The

Fig. 3. Analysis of studies of inhaled nitric oxide (INO) that used the outcome of survival with and without backup use of INO in controls.M-H � Mantel-Haenszel risk ratio. NINOS � Neonatal Inhaled Nitric Oxide Study Group. (Adapted from Reference 5, with permission.)



original number of treated infants was 87, of whom 62survived, 51 were seen at 1 year of age, and 33 completeda 2-year evaluation. The 1-year and 2-year follow-up ofthe INO infants found 11.8% (1-year) and 12.1% (2-year)rates of severe neurodevelopmental disability. Rosenberget al concluded that medical and neurodevelopmental out-comes were similar to those reported in non-treated PPHNneonatal patients.

Dobyns et al53 investigated whether the use of INO forsevere PPHN causes impaired lung function during in-fancy. It was a prospective study of lung function in 22infants who received (n � 15) or did not receive (n � 7)INO, and were compared to healthy control infants (n � 18).Passive respiratory mechanics and functional residual ca-pacity were measured. No differences were found in lungfunction between treatment groups and healthy control in-fants of the same age. Dobyns et al concluded that INO for

Table 3. Studies of Long-Term Outcomes in Patients Who ReceivedINO at Birth

FirstAuthor

Year Study Design Subjects

Rosenberg52 1997 Observationalcohort

51

Dobyns53 1999 Observationalcohort

22

Lipkin54 2002 Multi-center RCT 155 (41 control, 114 INO)Clark55 2003 Multi-center RCT 201 (total control and INO)Ichiba56 2003 Observational

cohort18

NINOS57 2000 Multi-center RCT 173 (88 control, 85 INO)Ellington58 2001 Multi-center RCT 60 (25 control, 35 INO)Konduri59 2007 Multi-center RCT 199 (149 control, 150 INO)

INO � inhaled nitric oxideRCT � randomized controlled trial

Fig. 4. Analysis of studies of inhaled nitric oxide (INO) that used the outcome of requirement for extracorporeal membrane oxygenation(ECMO) with and without backup use of INO in controls. M-H � Mantel-Haenszel risk ratio. NINOS � Neonatal Inhaled Nitric Oxide StudyGroup. (Adapted from Reference 5, with permission.)



the treatment of severe PPHN does not alter lung functionduring early infancy.

Lipkin et al54 evaluated the medical and neurodevelop-mental outcomes of children with moderately severe PPHNtreated with or without INO. This was a follow-up at 1 yearof patients enrolled in the Davidson et al study.10 From aninitial enrollment of 155 subjects, there was follow-up for133 of the 144 children who survived. No significant dif-ferences between the placebo and INO groups were seenfor any long-term outcomes. Re-hospitalization occurredin 22%, and growth did not differ. The composite neuro-development and audiologic outcome showed impairmentin 46% of the infants. There were major neurologic ab-normalities in 13%, cognitive delays in 30%, and hearingloss in 19% of the infants. Adverse outcomes were thesame in INO and control groups.

Clark et al55 reported the 1-year follow-up of patientsenrolled in their randomized controlled trial of INO.7 Therewas no difference in 1-year mortality between infants whoreceived INO and controls. There were no inter-group dif-ferences in the numbers of patients who required medica-tions for pulmonary disease or supplemental oxygen. Thenumber of neonates reported to have an abnormal neuro-logical examination or developmental delay was also sim-ilar in both groups. Clark et al concluded that use of low-dose INO reduces the use of ECMO without increasing theincidence of adverse outcomes at 1 year of age.

Ellington et al58 assessed 60 of 83 survivors of a ran-domized controlled trial of INO.13 No differences werefound in pulmonary, neurologic, cognitive, behavioral, orneurosensory outcomes; hospital readmission rates; or pa-rental ratings of child’s health. The overall neurologic hand-icap rate was 15%, and the rate of hearing deficit was 7%.The rate of important behavioral problems was 26%. Lev-els of satisfaction expressed were high for each group. Nodifferences in parental ratings were found between groups.The authors concluded that no adverse health or neurode-velopmental outcomes were observed among infants treatedwith INO therapy. Enrollment in either arm of this ran-domized controlled trial did not seem to affect parentalsatisfaction with the hospital care that their child received.

Ichiba et al56 described the outcomes at 3 years in 18term and near-term infants treated with INO. None of theinfants had substantial sensorial hearing loss at 3 years. Athird of the infants had reactive airways disease at18 months, but 3 infants showed spontaneous resolutionby 3 years. One infant was diagnosed with mild neurode-velopmental disability.

Konduri et al59 performed a neurodevelopmental fol-low-up in survivors at 18–24 months, who were supportedwith early INO (OI 15–25) or a standard approach(OI � 25).19 There were no differences in neurodevelop-mental impairment or hearing loss between the 2 groups.

Is INO Therapy Cost-Effective?

A concern related to the use of INO is its expense. Thecost-effectiveness of this therapy has been explored inseveral studies. Lonnqvist et al39 reported that the cost ofINO compares favorably to ECMO. However, that analy-sis is dated and does not apply to the current costs of INO.Truog et al60 calculated the charges for INO therapy andfor ECMO for each patient, and concluded that INO canreduce costs by avoiding ECMO. Neither of those studiesused sophisticated cost-effective analysis strategies.

Jacobs et al61 conducted a cost-effectiveness analysisbased on 123 subjects enrolled in the Canadian arm of 2parallel randomized controlled trials of INO for hypox-emic respiratory failure. It was conducted from the per-spective of the provider and included cost until hospitaldischarge. Costs were estimated from the resources used ata single center. For babies without congenital diaphrag-matic hernia, Jacobs et al found that patients receivingINO therapy had mean costs of $2,404 United States dol-lars more than patients receiving placebo, but that differ-ence was not statistically significant. (P � .25). There wasno statistically significant difference in reported mortality.In a follow-up study,62 Jacobs et al incorporated 18–24-month follow-up cost and outcome data on the 96 babieswithout congenital diaphragmatic hernia, 68 of whom com-pleted follow-up (20 died). There were no statistically sig-nificant differences in costs between treated and non-treatedinfants reported.

Lorch et al63 created a decision model using outcomesdata from 6 published randomized controlled trials of INOin hypoxemic newborns and from a cohort of 123 babieswith PPHN treated at a single hospital over an 11-yearperiod. Costs were estimated from the resources used bythe single-center cohort. They conducted their analysisfrom the United States societal perspective. In the study,INO increased the cost of care by $1,141 per infant, witha cost-effectiveness of $33,234 per life saved and $19,022per Quality-Adjusted Life Year (QALY) gained (with costanalysis from intervention to 1 year post-discharge). Ex-tending the time for cost analysis to lifetime improved theratio to $976 per QALY.

Angus et al64 used a decision model to assess the cost-effectiveness of INO, using the outcome data from the 2largest randomized controlled trials. Several sources wereused to convert resources to costs, including an analysis ofthe detailed hospital bills of 260 babies referred to 1 of 4ECMO centers for possible ECMO treatment. Their anal-ysis was conducted from the United States societal per-spective. They reported that if INO is used only in ECMOcenters it is both more effective and cheaper than placebo(cost savings of $1,880 per case, 95% CI $7,420 cheaperto $3,550 more expensive). The cost savings was predom-inantly due to decreased need for ECMO in the INO group.



The cost-effectiveness was $62,666 saved per QALY. Therelatively small sample sizes of the 2 trials on which theanalyses are based led to considerable uncertainty aroundthe point estimates of cost-effectiveness. It should be notedthat these cost-effectiveness studies were based on theassumption of on-label use, and the time horizon was re-stricted to the first year of life, conservatively assumingthat all costs and effects of INO have disappeared at 1 year.

How Is the Appropriate Dosing Regimenand Dose Response to INO Established?

Starting doses of 5–20 ppm were used in randomizedcontrolled trials (Table 4) and observational trials (Ta-ble 5) of INO in newborns. Evidence is lacking for benefitof doses � 20 ppm. In the NINOS study,8 infants withsevere hypoxemia were randomized to receive an FIO2

of1.0 (placebo control gas) or INO (experimental gas). Forinfants who did not respond to 20 ppm INO or placebo,similar proportions of the INO group and the control grouphad at least partial responses to 80 ppm INO or placebo aswell. However, infants who had complete responses at20 ppm did not have a similar response when INO wasincreased to 80 ppm. In the Davidson et al study10 therewere no dose-dependent differences between the 5, 20,and 80 ppm and its ability to produce a sustained improve-ment in oxygenation. In that study, methemoglobinemia(defined as � 7%) occurred only in the 80 ppm group. Ina study by Cornfield et al,13 INO at 2 ppm did not acutelyimprove oxygenation or prevent clinical deterioration, butdid attenuate the rate of clinical deterioration. Infants whoreceived 20 ppm had an acute improvement in oxygen-ation only if they were not previously treated with 2 ppm.Cornfield et al concluded that initial treatment with a sub-therapeutic dose of INO may diminish the clinical responseto 20 ppm. Finer et al20 reported that INO at doses as lowas 1–2 ppm was as efficacious as 10 or 20 ppm. An initialdose of 1–2 ppm did not differ significantly from an initialdose of 10–20 ppm in terms of improving PaO2

, OI, orresponse rate. The length of time that infants required INOdid not differ by the initial dose, but more infants in thelow-dose group required dose escalation, compared withthe high-starting-dose group. The authors of the CochraneReview5 concluded that, on the basis of the evidence pres-ently available, it appears reasonable to use INO with aninitial concentration of 20 ppm for term and near-terminfants with hypoxic respiratory failure who do not have adiaphragmatic hernia.

For the studies that evaluated the initial response to INOtherapy, oxygenation criteria were evaluated. In those stud-ies, INO therapy was typically discontinued if a responsecould not be demonstrated. Due to the rapid onset of actionof INO, a response, if present, can be seen quickly (within1 hour). Evidence is lacking for benefit of continuing INO

therapy in patients who do not demonstrate a response interms of improved oxygenation. Due to the costs associ-ated with INO therapy, its continued use when an im-provement in oxygenation has not been demonstrated can-not be supported by the available evidence.

It is possible that non-response to INO is related to alack of adequate ventilation and/or lung recruitment (eg,the gas does not reach all portions of the lung). Thus, whenINO is initiated, the clinician should ensure (as much aspossible) that the lungs are adequately inflated and thatsufficient mean airway pressure is being applied to main-tain end-expiratory lung volume.65,66

How Is the Dose of INO Titrated and Weaned?

An issue of practical importance is rebound hypoxemiaand pulmonary hypertension when INO is discontinued.67-71

In a retrospective review, Sokol et al72 reported a 30 mm Hgdecline in PaO2

when INO was discontinued from a dose of1 ppm. Secondary analysis of a multi-center prospectiverandomized double-blind study,11 reported that decreasesin the PaO2

were observed only at the final step of with-drawal (ie, when the INO was discontinued). The weaningprocess began when respiratory status appreciably im-proved (OI � 10). A reduction in INO to 1 ppm beforediscontinuation of the drug minimized the decrease in PaO2

when INO was discontinued. By assessing the decrease inPaO2

, when INO was discontinued from a dose of 1 ppm,they suggested that a rebound decrease in PaO2

could beprevented with a 20% increase in FIO2

. In a retrospectivestudy, Carriedo and Rhine73 reported that withdrawing INOin non-responders did not result in rebound when NO ex-posure was limited to 30 min; this supports prompt dis-continuation of INO following a short trial in non-responders. Aly et al67 also reported that reboundhypoxemia can be ameliorated by an increase in FIO2

be-fore discontinuation of INO. Case studies and case serieshave reported benefit from use of phosphodiesterase in-hibitors to attenuate rebound hypoxemia when INO is dis-continued.74-79

Which INO Delivery System Should Be Used?

Prior to the late 1990s, the majority of mechanicallyventilated infants receiving INO therapy were supportedusing time-cycled, pressure-limited, continuous-flow ven-tilators. Customized INO gas delivery systems consistingof separate NO and N2 gas cylinders, gas blenders, flowmeters, stand-alone NO/NO2 gas monitors, and improvisedscavenging systems were commonly implemented. NO wascontinuously titrated into the inspiratory limb of the ven-tilator, using a flow meter, and the mean delivered INOconcentration was estimated using a theoretical calcula-tion, or was measured using a combined NO/NO2 analyz-



Tab

le4.

INO

Dos

ean

dR

espo

nse

Cri

teri

a,Fr

omR

ando

miz

edC

ontr

olle

dT

rial

s

Firs

tA

utho

rSt

artin

gD

ose

(ppm

)R

espo

nse

Cri

teri

aA

ppro

ach

toN

on-r

espo

nder

sIN

OD

osin

gT

itrat

ion

INO

Dis

cont

inua

tion

Cri

teri

aC

omm

ents

Bar

efie

ld14

1996

20–8

0P a

O2

�80

mm

Hg

for

�1

hIf

P aO

2�

40m

mH

g,IN

Oin

itiat

edat

40pp

mor

incr

ease

dby

40pp

m.I

fP a

O2

40–9

9m

mH

g,IN

Oin

itiat

edat

20pp

mor

incr

ease

dby

20pp

m.I

fP a

O2

�10

0m

mH

g,IN

Om

aint

aine

dat

that

dose

.

IfP a

O2

�15

0m

mH

g,IN

Ore

duce

dby

5pp

mun

til20

ppm

;F I

O2

then

redu

ced

until

�0.

7,th

enIN

Ore

duce

dby

5-pp

mde

crem

ents

to5

ppm

.

Red

uced

from

5pp

mto

zero

ppm

byde

crem

ents

of1–

2pp

m—

NIN

OS7

1997

20In

crea

sein

P aO

2af

ter

30m

inof

INO

Com

plet

ere

spon

se:

�20

mm

Hg

Part

ial

resp

onse

:10

–20

mm

Hg

No

resp

onse

:�

10m

mH

g

INO

disc

ontin

ued

ifno

resp

onse

at20

ppm

or80

ppm

With

com

plet

ere

spon

se,

cont

inue

dat

20pp

m.

With

less

than

com

plet

ere

spon

se,

80pp

m.

With

part

ial

resp

onse

,co

ntin

ued

atth

elo

wes

tIN

Odo

seth

atpr

oduc

edat

leas

ta

part

ial

resp

onse

.

Alg

orith

ms

for

wea

ning

INO

,es

cala

ting

INO

dose

afte

rcl

inic

alde

teri

orat

ion,

and

rest

artin

gIN

Oaf

ter

unsu

cces

sful

wea

ning

not

repo

rted

.IN

Oco

uld

cont

inue

for

acu

mul

ativ

em

axim

umof

14d.

No

clea

rbe

nefi

tfr

omin

crea

sing

INO

from

20pp

mto

80pp

m

Rob

erts

819

9780

INO

cons

ider

edsu

cces

sful

ifP a

O2

�55

mm

Hg

orox

ygen

atio

nin

dex

�40

INO

imm

edia

tely

disc

ontin

ued

inpa

tient

sw

ithno

initi

alre

spon

se

Red

uced

by10

ppm

afte

r20

min

and

twic

ea

day,

ifP a

O2

�55

mm

Hg.

IfP a

O2

decr

ease

dby

15%

orto

�55

mm

Hg

with

in10

min

afte

rth

ech

ange

,th

enIN

Ora

ised

toth

epr

evio

usly

acce

ptab

lele

vel.

INO

redu

ced

afte

r20

-min

stud

ype

riod

and

twic

ea

day

ther

eaft

er.

IfP a

O2

�55

mm

Hg,

INO

decr

ease

dby

10pp

m.

IfP a

O2

decr

ease

dby

15%

orto

�55

mm

Hg

10m

inaf

ter

chan

ge,

INO

retu

rned

topr

evio

usle

vel.

Oth

erw

ise,

INO

decr

ease

dto

zero

ppm

orm

axim

umof

40pp

m.

Hal

fth

ein

fant

sne

eded

�2

dof

INO

.L

onge

stIN

Otr

eatm

ent

8.5

dM

edia

nIN

Odo

sera

pidl

yde

crea

sed

to�

20pp

mby

2d

Day

11

1997

20N

otev

alua

ted

INO

cont

inue

dun

tilF I

O2

�0.

5or

patie

ntre

ceiv

edE

CM

ON

otde

scri

bed

Not

desc

ribe

d—

Wes

sel1

219

9780

Not

eval

uate

d—

Wea

ning

per

pres

etpr

otoc

olth

atlo

wer

edth

edo

sefr

om80

ppm

to40

ppm

afte

r1

h.If

tole

rate

d,th

atdo

sew

asco

ntin

ued

upto

12h

and

dose

redu

ctio

nsto

5pp

mw

ere

atte

mpt

edea

chda

y.

INO

disc

ontin

ued

whe

ndo

seco

uld

bere

duce

dto

5pp

mfo

rat

leas

t12

hw

hile

P aO

2�

60m

mH

gan

dF I

O2

�0.

5.

—

Kin

sella

18

1997

20P a

O2

�60

mm

Hg

onF I

O2

1.0

for

2h

Non

-res

pond

ers

trea

ted

with

INO

and

HFO

V.N

opa

tient

inw

hom

20pp

mIN

Ofa

iled

had

asu

stai

ned

resp

onse

to40

ppm

.

20pp

mfo

r4

han

dth

ende

crea

sed

to6

ppm

.If

P aO

2�

60m

mH

gw

asno

tsu

stai

ned

with

20pp

m,

atr

ial

of40

ppm

was

allo

wed

.

At

24h,

INO

disc

ontin

ued.

Ifad

equa

teox

ygen

atio

nno

tsu

stai

ned

afte

rdi

scon

tinui

ngIN

O,

INO

rest

arte

dfo

ran

othe

r24

h.T

reat

men

tco

ntin

ued

until

INO

with

draw

alw

asno

tas

soci

ated

with

ade

crea

sein

oxyg

enat

ion.

With

seve

relu

ngdi

seas

e,re

spon

seto

HFO

Vpl

usIN

Ow

asbe

tter

than

toH

FOV

alon

eor

INO

with

conv

entio

nal

vent

ilatio

n.W

ithou

tsu

bsta

ntia

llu

ngdi

seas

e,bo

thIN

Oan

dH

FOV

plus

INO

wer

em

ore

effe

ctiv

eth

anH

FOV

alon

e(c

ontin

ued)



Tab

le4.

INO

Dos

ean

dR

espo

nse

Cri

teri

a,Fr

omR

ando

miz

edC

ontr

olle

dT

rial

s(c

ontin

ued)

Firs

tA

utho

rSt

artin

gD

ose

(ppm

)R

espo

nse

Cri

teri

aA

ppro

ach

toN

on-r

espo

nder

sIN

OD

osin

gT

itrat

ion

INO

Dis

cont

inua

tion

Cri

teri

aC

omm

ents

Dav

idso

n10

1998

5,20

,or

80IN

Osu

cces

s:im

prov

edP a

O2

�60

mm

Hg

onF I

O2

�0.

6an

dm

ean

airw

aypr

essu

re�

10cm

H2O

INO

failu

re:

P aO

2�

40m

mH

gfo

r30

min

NA

Sequ

entia

l20

%IN

Ode

crem

ents

ata

min

imum

of30

min

and

am

axim

umof

4h

Dis

cont

inue

dw

hen

20%

ofin

itial

dose

was

reac

hed.

—

Cor

nfie

ld13

1999

2O

xyge

natio

nin

dex

�35

for

1h

afte

rIN

ON

on-r

espo

nder

sto

2pp

mre

ceiv

ed20

ppm

Not

desc

ribe

dN

otde

scri

bed

Sub-

ther

apeu

ticIN

Odo

sem

ayad

vers

ely

affe

ctcl

inic

alre

spon

seto

ath

erap

eutic

INO

dose

Fran

co-B

elgi

anIN

OT

rial

Gro

up19

1999

10O

xyge

natio

nin

dex

at2

hU

ncle

ar.T

hera

pyde

cisi

ons

left

topr

imar

y-ca

reph

ysic

ian

Dec

reas

edto

5pp

man

dsl

owly

tape

red

Not

desc

ribe

d—

Cla

rk6

2000

20N

otev

alua

ted

NA

Dec

reas

edto

5pp

mat

4h

ifst

able

,PaO

2�

60m

mH

g,an

dpH

�7.

55;

othe

rwis

e,ev

alua

ted

ever

y4

hfo

rIN

Ode

crea

se.

Dur

ing

the

firs

t24

h,IN

Oco

uld

bere

turn

edto

20pp

mif

P aO

2�

60m

mH

gan

dF I

O2

was

1.0.

Aft

er24

h,IN

O5

ppm

.

INO

cont

inue

dat

5pp

mun

tilF I

O2

�0.

7,th

ene

onat

eha

dbe

entr

eate

dfo

r96

h,or

the

neon

ate

was

7d

old,

whi

chev

erca

me

firs

t.

—

Chr

isto

u15

2000

40N

otev

alua

ted

Not

eval

uate

dD

ecre

ased

to20

ppm

afte

r1

h.If

oxyg

enat

ion

did

not

dete

rior

ate,

the

low

est

acce

ptab

leIN

Odo

sew

asde

term

ined

daily

.

Not

desc

ribe

d—

Fine

r20

2001

1–2

or10

–20

(ran

dom

lyde

term

ined

)

�20

%in

crea

sein

P aO

2

and

�20

%de

crea

sein

oxyg

enat

ion

inde

x

Dou

blin

gof

INO

with

inth

epr

otoc

oldo

sera

nge

(low

-dos

egr

oup

1,2,

4,an

d8

ppm

;hi

gh-d

ose

grou

p10

,20,

40,a

nd80

ppm

).If

alo

w-d

ose-

grou

ppa

tient

at8

ppm

did

not

have

afu

llre

spon

seaf

ter

1h,

trie

d20

ppm

and

incr

ease

dpe

rth

ehi

gh-d

ose

prot

ocol

.IN

Odi

scon

tinue

din

non-

resp

onde

rs.

Atte

mpt

ever

y12

hto

decr

ease

INO

by50

%D

isco

ntin

uatio

nw

aspe

rfor

med

from

dose

sof

0.5–

1pp

m

—

(con

tinue

d)



Tab

le4.

INO

Dos

ean

dR

espo

nse

Cri

teri

a,Fr

omR

ando

miz

edC

ontr

olle

dT

rial

s(c

ontin

ued)

Firs

tA

utho

rSt

artin

gD

ose

(ppm

)R

espo

nse

Cri

teri

aA

ppro

ach

toN

on-r

espo

nder

sIN

OD

osin

gT

itrat

ion

INO

Dis

cont

inua

tion

Cri

teri

aC

omm

ents

Sadi

q21

2003

10–8

0�

20%

impr

ovem

ent

inP (

A-a

)O2

orox

ygen

atio

nin

dex

INO

disc

ontin

ued

inno

n-re

spon

ders

Star

ted

at10

ppm

,fo

llow

edby

incr

ease

sof

10–2

0pp

mev

ery

30m

inun

tilno

furt

her

P aO

2in

crea

seor

until

80pp

mw

asre

ache

d.

Wea

ning

ofIN

Oal

low

edon

lyw

hen

min

imal

vent

ilato

rse

tting

san

dF I

O2

0.3–

0.5

achi

eved

,or

ifm

ethe

mog

lobi

n�

5%.

—

Kon

duri

22

2004

5�

20m

mH

gin

crea

sein

P aO

2

All

wer

eco

ntin

ued

onIN

O,

rega

rdle

ssof

initi

alre

spon

se,

until

they

wea

ned

off

Star

ted

at5

ppm

;20

ppm

if�

20m

mH

gP a

O2

incr

ease

on5

ppm

.K

ept

at20

ppm

if�

10m

mH

gP a

O2

incr

ease

.If

�10

mm

Hg

P aO

2

incr

ease

at20

ppm

,re

turn

edto

5pp

m

Wea

ning

at12

-hin

terv

als,

per

the

prot

ocol

’sal

gori

thm

.IN

Odo

sew

eane

dto

0.5

ppm

befo

redi

scon

tinui

ng.

—

INO

�in

hale

dni

tric

oxid

eH

FOV

�hi

gh-f

requ

ency

osci

llato

ryve

ntila

tion

NA

�no

tap

plic

able

P (A

-a)O

2�

alve

olar

-art

eria

lox

ygen

diff

eren

ce



Tab

le5.

INO

Dos

ean

dR

espo

nse

Cri

teri

a,Fr

omO

bser

vatio

nal

Stud

ies

Firs

tA

utho

rSt

artin

gD

ose

(ppm

)R

espo

nse

Cri

teri

aA

ppro

ach

toN

on-r

espo

nder

sD

osin

gT

itrat

ion

Dis

cont

inua

tion

Cri

teri

aC

omm

ents

Rob

erts

23

1992

80Im

prov

edpo

st-d

ucta

lS p

O2

NA

NA

Shor

t-te

rmst

udy.

INO

disc

ontin

ued

inal

lsu

bjec

tsaf

ter

30m

in—

Kin

sella

24

1992

10–2

0P a

O2

INO

sequ

entia

llyad

min

iste

red

at10

and

20pp

mN

DIN

Odi

scon

tinue

daf

ter

4h

or24

h,pe

rst

udy

prot

ocol

—

Kin

sella

25

1993

20P a

O2,

P (A

-a)O

2,ox

ygen

atio

nin

dex

All

infa

nts

rece

ived

INO

for

24h

Aft

er4

hat

20pp

m,

INO

decr

ease

dto

6pp

mfo

r20

h

INO

disc

ontin

ued

at24

h.R

esta

rted

for

12–2

4h

ifox

ygen

atio

nco

uld

not

bem

aint

aine

d

—

Kin

sella

26

1994

20P a

O2,

P (A

-a)O

2,ox

ygen

atio

nin

dex

All

infa

nts

rece

ived

INO

for

24h

20pp

mfo

r4

h,th

endo

sede

crea

sed

to6

ppm

for

the

follo

win

g20

h

INO

disc

ontin

ued

at24

h.If

adeq

uate

oxyg

enat

ion

(art

eria

l/alv

eola

rox

ygen

ratio

�0.

10)

not

sust

aine

d,IN

Ore

star

ted

for

anot

her

24h

—

Fine

r27

1994

5,10

,20

,30

,40

,60

,or

80

Incr

ease

of10

mm

Hg

inP a

O2

or10

%in

O2

satu

ratio

n

Dos

e-re

spon

sest

udy.

Dos

esad

min

iste

red

inra

ndom

orde

r

Res

pond

ers

rece

ived

low

est

dose

that

gene

rate

da

resp

onse

for

24h.

The

ndo

sede

crea

sed

5pp

mev

ery

15m

in.

IfP a

O2

decr

ease

d10

mm

Hg,

INO

incr

ease

dto

prev

ious

dose

INO

disc

ontin

ued

ifox

ygen

atio

nin

dex

�10

No

P (A

-a)O

2di

ffer

ence

betw

een

any

ofth

edo

ses

Buh

rer2

819

958

P aO

2in

crea

se�

10m

mH

gD

oubl

edat

10-m

inin

terv

als

(up

to80

ppm

)un

tilpo

sitiv

ere

spon

seob

serv

ed

Dos

edo

uble

dor

halv

edto

achi

eve

sust

aine

dP a

O2

impr

ovem

ent

Dis

cont

inue

dw

hen

INO

ceas

edto

impr

ove

P aO

2or

whe

nP a

O2

�50

mm

Hg

coul

dbe

achi

eved

onF I

O2

�0.

5w

ithou

tIN

O

—

Tur

bow

29

1995

20D

ecre

ase

of20

%in

P (A

-a)O

2or

40%

inox

ygen

atio

nin

dex

Infa

nts

trea

ted

with

EC

MO

Dec

reas

edto

6pp

mat

4–12

hN

otst

ated

—

Mul

ler3

019

9620

P aO

2in

crea

seof

10m

mH

gD

ose

incr

ease

din

10-p

pmin

crem

ents

,up

to80

ppm

INO

disc

ontin

ued

inno

n-re

spon

ders

INO

with

draw

alte

sted

ever

y12

h—

Stra

nak3

119

9620

P aO

2,P (

A-a

)O2,

oxyg

enat

ion

inde

xN

otst

ated

20pp

mfo

r6

h,de

crea

sed

to15

ppm

,th

ento

3pp

m,

asqu

ickl

yas

poss

ible

INO

wea

ned

whe

nF I

O2

�0.

6,un

less

inte

rrup

tion

caus

edde

teri

orat

ion

ofca

rdio

pulm

onar

yst

abili

ty.

Tem

pora

ryF I

O2

incr

ease

tom

aint

ain

P aO

2af

ter

INO

wea

ning

—

Dem

irak

ça32

1996

20P a

O2

Dos

etit

ratio

nw

ith1,

5,10

,20

,40

,an

d80

ppm

INO

;15

min

for

each

step

Aft

erdo

se-r

espo

nse

test

ing,

used

the

dose

that

achi

eved

the

best

P aO

2

Dai

lyIN

Odi

scon

tinua

tion

atte

mpt

with

PEE

P�

6cm

H2O

and

F IO

2

�0.

8.IN

Odi

scon

tinue

dif

P aO

2

rem

aine

dst

able

afte

rIN

Ow

ithdr

awal

and

requ

ired

F IO

2

incr

ease

�20

%

Eff

ectiv

edo

sew

as20

ppm

(con

tinue

d)



Tab

le5.

INO

Dos

ean

dR

espo

nse

Cri

teri

a,Fr

omO

bser

vatio

nal

Stud

ies

(con

tinue

d)

Firs

tA

utho

rSt

artin

gD

ose

(ppm

)R

espo

nse

Cri

teri

aA

ppro

ach

toN

on-r

espo

nder

sD

osin

gT

itrat

ion

Dis

cont

inua

tion

Cri

teri

aC

omm

ents

Gol

dman

33

1996

20�

20%

impr

ovem

ent

inP a

O2

INO

tria

lat

70pp

mIN

Ore

duce

dby

1–2

ppm

ever

y15

–30

min

whi

leke

epin

gve

ntila

tor

setti

ngs

unch

ange

d.T

helo

wes

tIN

Odo

sene

eded

toke

epth

epo

st-d

ucta

lO

2

satu

ratio

nbe

twee

n88

%an

d95

%w

asde

term

ined

.

Whe

nIN

Ow

asdi

scon

tinue

d,a

0.1

F IO

2in

crea

sew

asal

low

edto

mai

ntai

nO

2sa

tura

tion

�88

%.I

fre

quir

edF I

O2

incr

ease

was

�0.

1,lo

w-d

ose

INO

(�5

ppm

)w

asus

ed.

—

Lön

nqvi

st34

1997

3�

25%

decr

ease

inox

ygen

atio

nin

dex

Step

wis

eIN

Oin

crea

se:

10m

inat

3,10

,30

,60

,an

d10

0pp

m

Dos

e-re

spon

sest

udy

Not

stat

edIN

Odo

ses

�30

ppm

wer

esu

ffic

ient

tode

crea

seth

eox

ygen

atio

nin

dex

by�

25%

inth

eva

stm

ajor

ityof

resp

ondi

ngpa

tient

sH

offm

an35

1997

2525

%in

crea

sein

eith

erP a

O2

orO

2sa

tura

tion,

or25

%de

crea

sein

oxyg

enat

ion

inde

x,P (

A-a

)O2,

orvi

rtua

lsh

unt

Dos

ein

crea

sed

by10

ppm

(up

to50

ppm

)ev

ery

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er.80,81 In order to maintain consistent INO delivery to thepatient, the clinician was required to manually adjust theINO gas flow, using a flow meter, following changes inventilator settings or with changes in the patient’s inspira-tory flow and minute ventilation requirements.82 Adequategas mixing and a relatively stable INO level could beobtained when continuous-flow INO delivery systems wereused in earlier-generation infant ventilators.83 Cliniciansapplied continuous-flow INO delivery systems to newer-generation microprocessor ventilators that provided phasic(or intermittent) gas flow profiles during the respiratorycycle, which results in greater fluctuations and underesti-mation of INO gas delivery to the patient.84-86 Moreover,continuous INO gas delivered to the circuit during exha-lation had the potential for accumulation of a large andpotentially toxic bolus of NO/NO2 gas to be delivered tothe patient with the onset of the next ventilator breath.81,86,87

In addition to the wide variability of delivered INO, con-tinuous-flow INO delivery systems have also been identi-fied with patient-safety issues during mechanical ventila-tion, including tidal volume augmentation, ventilator triggercompromise, and ventilator failure.88 Based on these fac-tors, systems that use a constant flow titration of INO gasmay not provide an accurate and reliable INO level, maypose major patient-safety issues, and are not be recom-mended to deliver INO therapy.

Following FDA approval in 1996, the first universalINO delivery system with an integrated gas injector mod-ule, hot-film flow sensor, fast-response gas monitoring/alarm system, and back-up delivery system was designedfor use with most forms of mechanical ventilation.89 ThisINO delivery system measures flow within the ventilatorsystem, using a hot-film anemometer, and injects NO intothe inspiratory limb, using mass flow controls, at a ratethat is proportional to the measured ventilator flow to de-liver the desired INO level (aka proportional-flow sys-tem).90 Compared with earlier-generation INO delivery sys-tems (constant flow titration method), proportional-flowINO delivery systems have been shown to provide moreconsistent and accurate delivery of INO gas concentra-tion89,90 without having to independently adjust the NOflow following changes in the ventilator settings.91

According to the FDA, INO therapy should only beadministered using an approved delivery system.92 Thissystem is composed of a gas injector module that is capa-ble of maintaining a constant INO concentration duringthe inspiratory flow, regardless of variation in flow ratewithin the respiratory cycle. The delivery system shouldalso minimize the amount of time that INO is mixed withoxygen, to avoid potentially toxic gases from forming. Inaddition, this system should include the following compo-nents: (1) INO gas analyzer with high/low alarms, (2) NO2

gas analyzer with high alarms, and (3) oxygen analyzerwith high/low alarms. Continuous monitoring of gas levels

and alarms can warn the clinician of changes in the deliv-ered INO and FIO2

concentrations, accumulation of NO2,and disruption in the gas supply (ie, catastrophic emptyingof gas cylinders and unintended disconnections). Cylindergauges that monitor the gas pressure are also helpful indetermining the level of gas supply. Back-up gas cylindersand a manifold system that provides uninterrupted gassupply to the patient are useful in providing seamless de-livery of INO therapy when exchanging gas cylinders. Inthe event that the INO system becomes inoperable, a sec-ondary or back-up INO delivery system (ie, manual ven-tilation) should also be included to minimize disruption ofgas delivery and potential patient decompensation. Thesesystems should also have a back-up battery in the event ofa power failure.

Current INO delivery systems use a single aluminumgas or drug canister with pharmaceutical grade NO(800 ppm) mixed with N2 as the inert gas (INOmax). Thecylinder contains 1,936 L of NO/N2 at 2,000 PSI andweighs 44 lbs when full. The gas is also certified to con-tain less than 5 ppm of nitrogen dioxide (NO2). All INOdrug mixtures must be handled and stored in compliancewith federal, state, and local regulations.

Currently there are 3 FDA-approved commercially avail-able delivery devices for the administration of INO. Theyare the INOvent (Datex-Ohmeda), INOmax DS (Ikaria),and AeroNOx (International Biomedical). The INOvent isthe most widely used system, and is most commonly em-ployed with conventional and high-frequency ventilators.This device is being phased out as a delivery system by thegas manufacturer and replaced with the INOmax DS. TheAeroNOx system can also be used with mechanical ven-tilators, but is only capable of stable INO delivery duringperiods of constant flow. This device is most frequentlyused for INO therapy during patient transport. A briefdescription of the operational principles of these devices islisted in Table 6. Each has a safety feature that shuts downdelivery when the monitoring system measures an NOconcentration of � 100 ppm.

How Should INO Be Implemented With DifferentRespiratory Support Techniques?

INO delivery devices are typically used with conven-tional, anesthesia, transport, manual, high-frequency oscil-latory, and high-frequency jet ventilators. Due to the im-proved understanding of the role of ventilators in theinitiation of lung injury93-95 and potential for increasingpulmonary vascular resistance,96 INO therapy is also ap-plied noninvasively in spontaneously breathing infants, us-ing nasal cannula, infant oxyhoods, and nasal CPAP sys-tems. It should be noted that there may be subtle differencesin system configuration when using different INO deliverysystems in conjunction with the multitude of available



respiratory support modalities. Connections to various de-livery systems are unique to each device. There are fewstudies that have been designed to test safety and efficacyof each respiratory support device during INO therapy.Where evidence-based recommendations on device safetyand efficacy are lacking, the clinician should always referto the specific manufacturer recommendations prior toimplementing INO therapy with any form of respiratorysupport.

Mechanical Ventilation

During mechanical ventilation, the stability of deliveredINO gas concentration may be affected by the respiratoryrate, inspiratory-expiratory ratio, minute volume, inspira-tory time, flow rate, mode, peak inspiratory pressure, andPEEP. The location of the gas injector module in the in-spiratory limb of the ventilator circuit is a critical factor inestablishing the appropriate dose of INO. Corrugated pa-tient tubing has been shown to provide better mixing ofINO than smooth-bore tubing, without an increase in NO2

accumulation.85 Although the vast majority of the researchhas been done using continuous-flow INO delivery sys-tems, the same principles of gas mixing and monitoringapply to proportional-flow systems during mechanical ven-tilation. Gas injection placed into the inspiratory limb closeto the patient may not allow enough time for NO andventilator system gas flow mixing to occur within the cir-cuit, resulting in an inconsistent level of INO delivery.81 Ithas been suggested that the INO gas injector module beplaced where circuit gas flow fluctuations are minimal, to

maintain the appropriate delivered NO concentrationthroughout the entire respiratory cycle. Placing the injectormodule between the ventilator gas output and the dry sideof the humidifier allows more time for gas mixing to oc-cur, and, thus, a more stable level of INO can be providedto the patient.97

INO delivery systems sample gas from the inspiratorylimb of the ventilator system to analyze INO, NO2, andFIO2

concentrations. This is most commonly achieved byplacing the sampling port in the inspiratory limb of therespiratory support device, downstream from the site ofinjection, no greater than 15 cm before the patient con-nection/interface. Additionally, the continuous gas sam-pling by the INO monitoring system may affect triggering,tidal volume delivery, and PEEP stability during mechan-ical ventilation. However, since these systems also add gasto the inspiratory limb of the ventilator, these changes areminimal. Regardless, it is necessary to continuously mon-itor the ventilation system for disparities between the setand measured ventilation parameters before and after im-plementation of INO therapy, and with changes in the INOsettings. Of equal importance, it is also necessary to adjustthe ventilator accordingly, to obtain the desired minuteventilation and mean airway pressure during INO therapy.

Manual ventilation is frequently administered in com-bination with INO delivery, using self-inflating and flow-inflating resuscitator bags.98 Most INO delivery systemsincorporate manual resuscitators as the back-up form ofventilation, and should be used during an electric or in-jector module failure. Clinicians will also use these sys-tems during periodic disconnection from mechanical ven-

Table 6. Device-Specific Details on INO Delivery Systems

INOvent, Datex-Ohmeda INOmax DS, Ikaria AeroNOx, International Biomedical

Delivery Delivers NO into the inspiratory limb.Provides a user-set, constant INOconcentration throughout theinspiration. Specifically designedinjector enables tracking of ventilatorwaveforms and delivery of asynchronized and proportional INOdose.

Delivers NO into the inspiratory limb.Provides a user-set, constant INOconcentration throughout theinspiration. Specifically designedinjector enables tracking ofventilator waveforms and deliveryof a synchronized and proportionalINO dose.

Valve controls NO flow out of the deviceand into the patient circuit. NO flowmeasured by a mass flow meter.

Monitoring Continuous online monitoring of NO,NO2, and O2 via electrochemical cells

Continuous online monitoring of NO,NO2, and O2 via electrochemicalcells

Continuous online monitoring of NO,NO2, and O2 via electrochemical cells.

Sampling rate 230 mL/min from the inspiratory limb 230 mL/min from the inspiratory limb 150 mL/min from the inspiratory limb ofthe circuit

Alarms NO, NO2, O2 NO, NO2, O2 NO, NO2, O2

Backup delivery Backup delivery fixed at 20 ppm at 15L/min

INOBlender 0–80 ppm at 5–14 L/min,or fixed at 250 mL/min bleed

AeroNOx Bagger fixed at 250 mL/min �20 ppm at 10 L/min

Battery Bedside up to 30-min. Transport head upto 3 h fully charged

Up to 6 h fully charged Up to 6 h fully charged

INO � inhaled nitric oxide



tilation and during patient transport. These systems areused only on an intermittent basis, and, thus, the reservoirsand tubing of manual resuscitators may allow NO to mixwith oxygen to form NO2. It has been suggested that usingthe smallest manual resuscitator possible to adequatelydeliver the desired tidal volume and the highest rated gasflow that is practical should reduce these effects. Further,once the flow has been turned on, the bag should be squeezed4–6 times to empty residual gas in the bag prior to usingthe system to ventilate the patient.89

Anesthesia Ventilators

INO therapy is used during and following the surgicalrepair of certain congenital cardiac lesions or during car-diac catheterization in infants with pulmonary hyperten-sion. Therefore, it is frequently necessary to safely admin-ister INO therapy in conjunction with inhaled anestheticgases using an anesthesia ventilator. The issues surround-ing the use of INO delivery systems with anesthesia ven-tilators have been described using adult test lung models.99

However, the safety and efficacy of this practice are yet tobe determined in infants.

During administration of anesthetic gas a partial re-breathing or circle system is used. This system allows thepatient to breathe a combination of fresh and exhaled gas,following CO2 elimination with an absorbing apparatus, toconserve the amount of anesthesia used. The presence ofan anesthesia bag in the circuit can promote gas mixingbut also potentially allows the formation of NO2. Whenthe INO injector module is placed within the inspiratorylimb of the ventilator, flow is measured and INO gas istitrated accordingly. However, since the monitor is alsomeasuring exhaled breath INO content, the measured INOlevel in the circuit will increase over time.

Ceccarelli et al99 evaluated the use of a proportionalINO delivery device during anesthesia ventilation, usingan adult test lung model. They found that, as long as thefresh gas supply was set higher than the patient’s minuteventilation requirement, the delivered INO level was ap-proximately within 10% of the set INO level. However,when the fresh gas supply fell below the patient’s minuteventilation, the INO delivery system measured a higherdelivered INO level than what was set. One limitation ofthat in vitro study was that Ceccarelli et al did not evaluateINO delivery using ventilator settings commonly used withneonates. As such, these adult data would be very difficultto extrapolate to neonatal ventilation. In many cases, cli-nicians resort to using conventional mechanical ventilatorsin the operating room for administration of INO therapy toneonates.

High-Frequency Ventilation

Because INO therapy may produce a more favorableresponse when using a ventilatory approach that optimizesalveolar recruitment,100 it is frequently administered dur-ing high-frequency oscillatory ventilation (HFOV) andhigh-frequency jet ventilation (HFJV). In a study by Coateset al,101 hypoxic infants with pulmonary hypertension whorequired INO had similar short-term outcomes, regardlessof whether INO therapy was delivered via HFOV or HFJV.

Fujino et al102 evaluated simulated INO delivery duringHFOV, using both continuous-flow and proportional-flowINO delivery systems. The 3100a HFOV (CareFusion,Yorba Linda, California) was configured using settingscommonly used to support neonates, and at a multitude ofINO settings. The major finding of the study was that INOtherapy was more consistent using the proportional-flowINO delivery system. In addition, placing the INO injectorbefore the humidifier (where pressure fluctuations are min-imal) resulted in appropriate mixing of INO within thecircuit, and, thus, a more stable delivered INO level. Thesefindings also suggest that analyzed NO and NO2 levelscould be accurately monitored by placing the gas samplingline in the inspiratory circuit, either close to the patientY-piece or midway through the circuit. The active exha-lation during HFOV can cause flow to travel back andforth through the injector, which may result in delivery ofINO twice that of the desired (or set) level. Therefore, ithas been suggested that a one-way valve be placed be-tween the injector and dry side of the humidifier, to pre-vent retrograde flow back into the injector.

Two studies103,104 have evaluated INO delivery duringHFJV using the Life Pulse HFJV (Bunnell, Salt Lake City,Utah). Of note, the HFJV is used in conjunction with aconventional mechanical ventilator. Mortimer et al103 con-ducted a bench study where INO was injected into thepatient circuit of the conventional ventilator only. Theyconcluded that INO delivery during HFJV is reliable usingcertain ventilator settings, but that this practice is unreli-able and should be avoided due to poor entrainment ofINO from the conventional ventilator circuit during tan-dem jet breaths.

Platt et al104 injected INO directly into the HFJV circuitusing a proportional-flow INO delivery system during sim-ulated neonatal ventilation. The effects of air entrainmentfrom the conventional ventilator circuit and mixing of NOinjected through the endotracheal tube adapter were eval-uated by measuring NO proximal as well as distal to theendotracheal tube. INO therapy was evaluated during HFJVused in conjunction with the conventional ventilator set onCPAP and intermittent positive-pressure ventilation. Theconcentration of INO measured proximal to the endotra-cheal tube was appreciably different from the level set onthe INO delivery system because of the relatively low flow



rate of gas through the HFJV circuit at the injection site,which was well below the minimum flow rate specified forthis INO delivery system. This was more evident whenusing an INO level � 20 ppm and could be remedied byadjusting the set INO level to obtain the desired levelbased on the proximal INO measurement. Fluctuations ofINO concentration, caused by entrainment of NO-free in-termittent-mandatory-ventilation breaths (5 breaths/min)from the conventional ventilator circuit, were generally� 10% of the set concentrations. The effects of air en-trainment from the ventilator circuit appeared negligiblewhen INO therapy was administered in the therapeuticrange of 10–20 ppm, where distally measured NO levelswere � 0.5 ppm from the set value. Measured NO2 was� 1.3 ppm for all ventilator settings and NO concentra-tions. Based on these findings, administering INO therapyappears to be safe and effective as long as it is injectedthrough the HFJV circuit.

Nasal Continuous Positive Airway Pressure

INO therapy has been used in combination with nasalcontinuous positive airway pressure (CPAP) systems tosupport spontaneously breathing infants with hypoxic lungdisease. Lindwall et al105,106 reported that INO can bedelivered safely and effectively using continuous-flow-titration INO delivery devices with the Infant Flow NasalCPAP system (CareFusion, Yorba Linda, California). Tre-visanuto et al evaluated the feasibility of INO therapyusing a neonatal CPAP helmet in a bench study,107 fol-lowed by a case report108 describing the successful appli-cation in the long-term treatment of an infant with pulmo-nary hypertension. INO therapy appeared feasible withthat system and was found to be an effective treatmentoption in one patient. However, those systems were stud-ied using only a continuous-flow INO titration system.

There are currently no studies that have been designedto evaluate the safety and efficacy of applying an approvedproportional-flow INO delivery device during nasal or hel-met CPAP. Additional studies are required to properlyassess the consistency of NO delivery, rate of NO2 pro-duction, and the potential effects of sampling on the de-livered CPAP level to the patient.

Oxygen Administration Devices

Ivy et al109 were the first to describe the application ofINO therapy using an oxygen hood and nasal cannula tosupport a spontaneously breathing infant with PPHN. Theinfant was supported with INO of 6–23 ppm. Methemo-globin was measured twice daily and remained � 5%throughout the treatment period. Kinsella et al110 evaluatedwhether the prolonged treatment with noninvasive INOtherapy delivered through a nasal cannula would sustain

pulmonary vasodilation in neonatal patients at risk for de-veloping PPHN following extubation from mechanical ven-tilation. Infants were supported initially using an oxygenhood, and eventually weaned to a nasal cannula. A pro-portional-flow INO delivery system was used in conjunc-tion with the nasal cannula, set at 1 L/min, using a blendedgas source, to obtain INO concentrations of 5–10 ppm.Additionally, NO was measured using an NO analyzersampling port placed into the nasopharynx. Nasopharyn-geal NO concentrations were 5.4 � 0.5 ppm and2.4 � 0.4 ppm with INO measured proximally in the de-livery device at INO set at 10 and 5 ppm, respectively. Inthis series of patients, 10 of 47 (21%) newborn infantswith protracted PPHN were treated successfully using INOtherapy administered via nasal cannula following discon-tinuation of mechanical ventilation.110

Ambalavanan et al111 evaluated INO therapy with a pro-portional-flow delivery system applied to infants withPPHN, using an infant hood. In this pilot study, 8 new-borns were randomized to receive INO therapy deliveredthrough an infant hood or oxygen delivered through anasal cannula. Two of the infants who received INO ther-apy via oxygen hood had a PaO2

� 100 mm Hg, whereasoxygenation was unchanged in the patients receiving ox-ygen via nasal cannula.

What Adverse Effects of INO Should Be Monitored?

Continuous monitoring of INO, NO2, and O2 is recom-mended during the delivery of INO. As mentioned previ-ously, this is achieved by sampling gas from the inspira-tory limb of the respiratory support device downstreamfrom the site of injection, no greater than 15 cm before thepatient connection/interface. The available approved INOdelivery devices use electro-chemical cells to measure theconcentrations of INO, NO2, and O2. NO and NO2 aremeasured in ppm and O2 is measured in percentage. Alarmpackages include high and low NO and O2, and high NO2

alarm settings.

Nitric Oxide

Inhaled NO in sufficient concentrations is considered anenvironmental pollutant, and when inhaled at extremelyhigh doses (5,000–20,000 ppm) can have direct toxic ef-fects on the lung.112 NO is a free oxygen radical that canreact with molecules to form toxic chemical compounds inthe lung, including peroxynitrite formation, which dam-ages DNA, induces lipid peroxidation, and reacts withproteins.113 INO-mediated lung injury results primarilyfrom inactivation of surfactant protein A114 and decreasedsurfactant production.115,116 Prolonged INO exposure isalso associated with a transient increase in markers ofoxidative lung injury, but this finding does not appear to



predict the development of chronic lung disease in term ornear-term newborns with hypoxic respiratory failure.117

Additionally, hypoxic newborn infants treated with INO(� 20 ppm) do not appear to be at any greater risk ofdeveloping pulmonary toxicity than are infants not treatedwith INO therapy.118

Despite the claims that INO therapy, used within thetherapeutic range, does not increase the risk for infantsdeveloping INO-mediated toxicity and consequent lunginjury, clinicians should monitor INO continuously andwean patients aggressively from INO therapy if they arenot responding, to eliminate any unnecessary exposures.Additionally, alarm limits should be set to warn cliniciansabout potential increases in INO concentration. Currently,there are no recommended guidelines for setting NO alarmsduring INO therapy.

FIO2

The delivered FIO2can be reduced as a result of dilution

with INO therapy. For example, in INO delivery devicesthat inject INO distal to the ventilator gas outlet, at an INOdose of 20 ppm (with a gas source of 800 ppm), the FIO2

will be reduced by approximately 2.5%. Therefore, it makesit difficult to near impossible to obtain an FIO2

of 1.0during INO therapy.89 The FIO2

measured by the INO de-livery system downstream from the point of NO injectionshould be used, whereas the FIO2

monitored at the venti-lator is measured prior to any gas mixing in the system.

Nitrogen Dioxide

Nitrogen dioxide (NO2) is a toxic byproduct that formswhen NO and O2 gases are allowed to mix. This chemicalreaction can take place in the gas delivery system or ven-tilator, the airway interface, and the lungs. In animal stud-ies, inhaled NO2 at approximately 2 ppm affected alveolardevelopment and surfactant production, altered the epithe-lial lining of the terminal bronchioles, and induced loss ofcilia.119,120 In human studies, inhaled NO2 at approximately2 ppm affected alveolar permeability121 and increased air-way responsiveness.122

NO2 accumulation is more likely to form when usinghigh FIO2

in combination with a high INO concentration.123

Location of the INO injection site and the type of mechan-ical ventilator used are 2 important considerations thatmay result in gas mixing differences and NO2 produc-tion.124 For instance, ventilators that apply low bias flowor no bias flow during exhalation may allow more contacttime for gases to chemically react and allow greater NO2

production than do earlier-generation ventilators that ap-ply a constant flow rate during the respiratory cycle. How-ever, these effects have not been evaluated extensivelyusing proportional-flow INO delivery systems.

There are a number of strategies that can help to avoidexcessive NO2 delivery to patients during INO therapy.Accumulation of NO2 can form in the manifolds and tub-ing of the INO delivery system, and, thus, proper purging(as recommended by the system manufacturer) of thesesystems is vital prior to instituting INO therapy. Further,systems that have been stagnant for some time period mayhave NO2 accumulation (eg, self-inflating manual resus-citator) that would benefit from being purged prior to be-ing used in a patient.

Sampling close to the patient ensures an accurate NO2

measurement because INO and O2 react very rapidly toform NO2. Sampling is done on the inspiratory limb toensure that the exhaled NO and NO2 are not measured.Although this has not been studied, the gas sampling ismost commonly performed from the inspiratory limb ofthe respiratory support device downstream from the site ofinjection, no greater than 15 cm before the patient con-nection/interface. There are no established clinical guide-lines for setting upper alarm limits on the INO deliverydevice for patients receiving INO therapy. Based on thelimited available experimental data in humans and ani-mals, it appears reasonable to set the upper NO2 alarmlimit at approximately 2 ppm, to prevent toxic gas expo-sure to the lungs.

In one study, the NO2 level was found to be less than0.5 ppm whether the neonates were treated with placebo,5 ppm INO, or 20 ppm INO over the first 48 hours. The80 ppm group had a mean peak NO2 of 2.6 ppm.11 In themajority of the randomized controlled trials evaluating INOin the therapeutic range, the reported levels have all beenwell below 2 ppm, and in infants receiving � 20 ppm,INO therapy was not discontinued but rather reduced dueto increased methemoglobin (Table 7).

Methemoglobinemia

Methemoglobinemia is a complication that results whenINO binds with heme groups within the hemoglobin. Thegreatest risk factor for methemoglobin formation is asso-ciated with the use of high INO doses. Methemoglobin canreduce the capacity of the hemoglobin molecule to bindwith O2, and consequently reduces systemic O2 delivery.In the majority of clinical trials, the maximum methemo-globin level was reached approximately 8 hours after ini-tiation of inhalation. In one study, 13 of 37 (35%) ofneonates treated with INO 80 ppm had methemoglobinexceeding 7%; whereas, lower methemoglobin levels werevirtually nonexistent at lower INO doses.11,15 In some sit-uations the methemoglobin level may peak as late as40 hours following the initiation of INO therapy. Follow-ing discontinuation or reduction of INO, the methemoglo-bin level typically returns to baseline over a period ofhours. Based on these data, severe methemoglobinemia is



Tab

le7.

Com

plic

atio

nsof

INO

,Fr

omR

ando

miz

edC

ontr

olle

dT

rial

s

Firs

tA

utho

rIn

itial

INO

Dos

eR

epor

ted

(ppm

)M

ethe

mog

lobi

nM

onito

ring

Prot

ocol

Mea

sure

dM

ethe

mog

lobi

nL

evel

sN

O2

Mon

itori

ngPr

otoc

olM

easu

red

NO

2L

evel

sB

leed

ing

Com

plic

atio

ns

Bar

efie

ld14

1996

20–8

0M

etH

bm

easu

red

befo

reIN

Oan

dev

ery

4–8

hon

INO

Mea

nM

etH

b3.

1%in

all

infa

nts.

All

Met

Hb

mea

sure

men

ts�

7%N

otm

easu

red

Not

mea

sure

dO

nein

fant

inth

eIN

Ogr

oup

died

from

ICH

duri

ngE

CM

OD

ay11

1997

20M

etH

bm

easu

red

befo

reIN

Oan

d30

–60

min

follo

win

gIN

Otr

eatm

ent

Met

Hb

1.5

�0.

1%du

ring

conv

entio

nal

vent

ilatio

n;2.

4�

0.3%

(2pa

tient

s�

4%)

duri

nghi

gh-f

requ

ency

jet

vent

ilatio

n

NO

2m

onito

red

cont

inuo

usly

Not

mea

sure

dO

nein

fant

deve

lope

dIC

H

Wes

sel12

1997

5–80

Met

Hb

mea

sure

d15

min

and

24h

follo

win

gIN

Otr

eatm

ent

Med

ian

peak

Met

Hb

1.7%

NO

2m

onito

red

cont

inuo

usly

Peak

NO

2�

1pp

min

19of

26pa

tient

s.N

opa

tient

had

conf

irm

edN

O2

�5

ppm

Ten

denc

yfo

rlo

wer

ICH

inth

eIN

Ogr

oup

NIN

OS17

1997

Met

Hb

mea

sure

dat

1,3,

6,an

d12

haf

ter

initi

atio

n,an

dsu

bseq

uent

lyat

12h

No

infa

nts

requ

ired

disc

ontin

uatio

nof

INO

rela

ted

toM

etH

bN

O2

mon

itore

dco

ntin

uous

lyan

dre

cord

edev

ery

2h

No

infa

nts

requ

ired

INO

disc

ontin

uatio

ndu

eto

NO

2

No

diff

eren

ces

inbl

eedi

ngdi

sord

ers

orne

urol

ogic

sequ

elae

NIN

OS7

1997

20–8

0M

etH

bm

easu

red

at1,

3,6,

and

12h

afte

rIN

O,

until

24h

afte

rdi

scon

tinua

tion.

INO

wea

ned

by50

%if

Met

Hb

5–10

%.

INO

disc

ontin

ued

ifM

etH

b�

10%

No

infa

nts

requ

ired

disc

ontin

uatio

nof

INO

rela

ted

toM

etH

bN

O2

mon

itore

dco

ntin

uous

ly.

INO

disc

ontin

ued

ifN

O2

�7

ppm

.IN

Ode

crea

sed

by50

%if

NO

25–

7pp

m

No

infa

nts

requ

ired

INO

disc

ontin

uatio

ndu

eto

NO

2

One

INO

infa

ntan

d2

cont

rol

infa

nts

deve

lope

dIC

H

Rob

erts

819

9720

–80

Met

Hb

mea

sure

dat

1,3,

6,an

d12

haf

ter

INO

,un

til24

haf

ter

disc

ontin

uatio

n.IN

Ow

eane

dby

50%

ifM

etH

b5–

10%

.IN

Odi

scon

tinue

dif

Met

Hb

�10

%

No

infa

nts

requ

ired

disc

ontin

uatio

nof

INO

rela

ted

toM

etH

bN

O2

mon

itore

dco

ntin

uous

lyN

oin

fant

sre

quir

edIN

Odi

scon

tinua

tion

due

toN

O2

No

diff

eren

ces

inse

veri

tyor

inci

denc

eof

ICH

betw

een

stud

ygr

oups

Kin

sella

1819

976–

20M

etH

bm

easu

red

atba

selin

e,30

min

,1,2

,4,

12,a

nd24

h,an

dev

ery

24h

for

dura

tion

ofIN

O

Met

Hb

rang

e1.

0–4.

7%ov

er24

hN

otm

easu

red

Not

mea

sure

dN

otm

easu

red

Dav

idso

n1019

985–

80M

etH

bm

easu

red

byan

unm

aske

din

vest

igat

or,

but

not

repo

rted

Not

repo

rted

NO

2m

easu

red

cont

inuo

usly

byan

unm

aske

din

vest

igat

or,

but

not

repo

rted

Not

repo

rted

Not

mea

sure

d

Cor

nfie

ld13

1999

2M

etH

bm

easu

red

ever

y6

hon

the

firs

tda

yan

dat

leas

ttw

ice

daily

for

dura

tion

ofst

udy

Met

Hb

rang

e0.

9–1.

3%ov

era

24h

peri

odN

O2

mon

itore

dco

ntin

uous

lyN

otm

easu

red

Not

mea

sure

d

Fran

co-B

elgi

anIN

OT

rial

Gro

up19

1999

10N

otm

easu

red

Not

mea

sure

dN

otm

easu

red

Not

mea

sure

dIN

Ono

tas

soci

ated

with

high

erin

cide

nce

ofIC

H

Chr

isto

u1520

0020

–40

Met

Hb

mea

sure

dda

ilyA

llM

etH

bm

easu

rem

ents

�5%

NO

2m

onito

red

cont

inuo

usly

No

abno

rmal

NO

2le

vels

Not

mea

sure

dC

lark

620

005–

20M

etH

bm

easu

red

befo

reIN

Oan

dat

4,24

,an

d96

hdu

ring

INO

.R

educ

edIN

Oby

50%

ifM

etH

b�

4%an

ddi

scon

tinue

dIN

Oif

Met

Hb

rem

aine

dhi

gh.

Onl

y2

patie

nts

had

Met

Hb

�4%

NO

2m

onito

red

cont

inuo

usly

.IN

Ore

duce

dby

50%

ifN

O2

�5

ppm

,an

ddi

scon

tinue

dif

NO

2re

mai

ned

high

No

patie

nts

had

NO

2�

5pp

mIN

Ono

tas

soci

ated

with

high

erin

cide

nce

ofIC

H

Fine

r2020

011–

80M

etH

bm

easu

red

befo

reIN

Oan

dat

6h,

and

ever

y8

hth

erea

fter

.R

educ

edIN

Oby

50%

ifM

etH

b�

5%.

Dis

cont

inue

dIN

Oif

Met

Hb

rem

aine

d�

8%

Mea

npe

akM

etH

b2.

19�

1.66

%in

high

-IN

O-d

ose

grou

p,an

d1.

36�

1.13

inlo

w-d

ose

grou

p.IN

Ono

tw

eane

dor

disc

ontin

ued

inan

yin

fant

due

toel

evat

edM

etH

b

NO

2m

onito

red

cont

inuo

usly

.IN

Ore

duce

dby

50%

ifN

O2

�3.

5pp

m,

and

disc

ontin

ued

ifN

O2

rem

aine

dhi

gh

No

infa

nts

requ

ired

INO

disc

ontin

uatio

ndu

eto

NO

2

No

infa

nts

had

ICH

Sadi

q2120

0310

–80

No

mea

sure

men

tfr

eque

ncy

men

tione

d.IN

Ow

eane

dif

Met

Hb

�5%

Mea

nM

etH

b1.

45�

0.95

%in

all

patie

nts

trea

ted.

Met

Hb

did

not

exce

ed�

5%in

any

patie

nt

NO

2m

onito

red

cont

inuo

usly

Not

mea

sure

dN

otm

easu

red

Kon

duri

2220

045–

20N

om

easu

rem

ent

freq

uenc

ym

entio

ned.

INO

wea

ned

ifM

etH

b�

5%.

INO

disc

ontin

ued

ifM

etH

b�

10%

.

INO

not

wea

ned

ordi

scon

tinue

din

any

infa

ntdu

eto

elev

ated

Met

Hb

NO

2m

onito

red

cont

inuo

usly

.IN

Ow

eane

dif

NO

23–

5pp

m,

and

disc

ontin

ued

if�

5pp

m

No

infa

nts

requ

ired

INO

disc

ontin

uatio

ndu

eto

NO

2

One

INO

infa

ntan

d2

cont

rol

infa

nts

had

seve

reIC

H

Gon

zále

z1620

1020

Met

Hb

mea

sure

dbe

fore

INO

and

ever

y24

hw

hile

onIN

ON

ore

port

edM

etH

bin

crea

sein

the

infa

nts

trea

ted

with

INO

NO

2m

onito

red

cont

inuo

usly

No

elev

ated

NO

2in

the

infa

nts

trea

ted

with

INO

No

high

erin

cide

nce

ofbl

eedi

ngor

coag

ulat

ion

diso

rder

inei

ther

INO

grou

p

INO

�in

hale

dni

tric

oxid

eM

etH

b�

met

hem

oglo

bin

ICH

�in

trac

rani

alhe

mor

rhag

eE

CM

O�

extr

acor

pore

alm

embr

ane

oxyg

enat

ion



not a major cause for concern if INO is delivered at thesuggested starting dose of � 20 ppm (see Table 7). Patientserum methemoglobin should be monitored approximately8 hours and 24 hours after initiation of therapy, and dailythereafter. As a general clinical rule, it has also been sug-gested that INO should be weaned or discontinued if themethemoglobin level rises above 5%.

Bleeding Disorders

INO therapy has been shown to inhibit platelet aggre-gation, adhesion, and agglutination.125 A major concern isthat there may be an increased risk of intracranial hemor-rhage in newborn infants. In a small group of infants withhypoxic lung disease, the bleeding time on INO (40 ppmfor 30 min) was prolonged significantly, when comparedwith the bleeding time performed 24 hours after the INOtherapy was discontinued (P � .05); however, no infantshad any clinical evidence of bleeding before or after thestudy was conducted.126 In all of the randomized con-trolled trials in infants, the use of INO has not been re-ported to increase the occurrence of intracranial hemor-rhage or any other bleeding-related disorders (see Table 7).Thus, the clinical risks of coagulopathy during INO ther-apy appear to be negligible. In addition, other laboratorytests may be included in the regular panel for patients atrisk for bleeding, including platelets, clotting time, hemat-ocrit, and hemoglobin. However, there are no clinical rec-ommendations suggesting that these tests are necessary forall infants receiving INO therapy. In addition, these find-ings compare well with the evidence that INO does notresult in any long-term neurodevelopmental sequelae intreated infants.

What Physiologic Parameters Should Be MonitoredDuring INO Therapy?

In addition to the gas monitoring capabilities built intoINO delivery systems, as well as clinician monitoring fortoxic effects in patients, there are certain unique physio-logic monitoring requirements for patients receiving INO.Patients on INO are nearly always in a critical care ortransport environment and thus are typically monitoredwith the customary cardio-respiratory monitoring systems.Hemodynamic monitoring may be useful to detect cardio-vascular rebound effects when weaning INO. Echocardio-graph is a useful, but expensive, method used to assess thedegree of pulmonary hypertension and response to INOtherapy. Pulmonary hypertension has been estimated ininfants via echocardiogram as the presence of either tri-cuspid regurgitation; and/or as bidirectional or right-to-leftshunting at the ductus arteriosus or foramen ovale; and/oras systolic pulmonary artery pressure � two thirds of thesystemic systolic blood pressure.18

Monitoring pre-ductal and post-ductal oxygen satura-tions may provide a useful noninvasive strategy for deter-mining the effectiveness of INO. A disparity between thepre-ductal and post-ductal saturation measurements � 5%can indicate increases in right-to-left shunting due to in-creased pulmonary vascular resistance. In patients withsevere pulmonary hypertension, a large disparity betweenpre-ductal and post-ductal saturations (approximately 30%)may be initially seen. However, post-ductal oxygen satu-ration begins to approach pre-ductal oxygen saturation inpatients who are responding to INO. Pulse oximetry pre-sents some unique challenges in this population because ofthe possibility of elevated methemoglobin, which can causepulse oximeters to read falsely low or high SpO2

.

Is Scavenging of Gases Necessary to Protect theCaregiver During INO Therapy?

Early INO systems advocated scavenging (ie, containedcollection and elimination of exhaled and unused gas) toreduce the risk of NO and NO2 exposure to healthcareproviders and patients in adjacent work areas. This wasaccomplished by exhausting gases through anesthesia fil-ters or large canisters attached to the hospital vacuumsystem. The exposure limit set by the Occupational Safetyand Health Administration (OSHA) for INO is 25 ppm asa time-weighted average throughout an 8-hour work shift.127

The exposure limit for NO2 is 5 ppm,128 which is a ceilinglimit, not to be exceeded at any time during the work shift.Studies done in intensive-care and transport settings havedemonstrated that the NO and NO2 levels in the area im-mediately adjacent to the patient receiving INO were wellbelow the OSHA safe exposure levels without gas scav-enging.

Philips et al129 evaluated employee and area exposureduring simulated conventional, manual, and high-frequencyventilation in an intensive-care room, and during initialset-up (ie, purging) and disassembly of the INO deliverysystem. Based on their observations, personal exposureswere found to be infrequent, of short duration, and wellbelow the established regulatory limits. They concludedthat the NO and NO2 were quickly diluted by mixing withroom air and by providing adequate air exchange in theroom (approximately 6 cycles per hour), so personal ex-posure is thus limited.

Lindwall et al106 evaluated caregiver exposure duringsimulated INO therapy using nasal CPAP administrationwithin an Isolette and during catastrophic release of anINOmax cylinder. They found that short-term exposureswere brief and well below the recommended workplaceexposure limits.

The standard application of INO therapy and catastrophicrelease of NO during transport raise concerns for exposinghealthcare providers and non-ventilated patients to dan-



gerously high levels of environmental NO and NO2 whileconfined to close spaces (fixed wing, helicopters, and am-bulance cabins). Portable scavenging systems have beenpreviously described in these settings.130 Kinsella et al131

evaluated the potential environmental risks for exposingcaregivers to NO/NO2 during INO therapy combined withmechanical ventilation and following simulated cata-strophic release of an INO gas cylinder (D-type cylinder).These experiments were conducted within the patient carecabins of a helicopter, fixed wing, and ground transportambulance. During INO therapy with mechanical ventila-tion, the measured NO and NO2 levels (� 0.1 ppm) werewell below the recommended healthcare giver exposurelimits. Adequacy of air exchange within ambulances andaircraft appears to render environmental toxicity unlikelyand the use of scavenging systems unnecessary duringtransport. However, important measures should be takento provide adequate air exchange is cycling through thetravel compartment at all times.

Recommendations

1. A trial of INO is recommended in newborns (� 34 wkgestation, � 14 d of age) with PaO2

� 100 mm Hg on FIO2

1.0 and/or an oxygenation index (OI) � 25 (Grade 1A).2. It is recommended that INO therapy be instituted

early in the disease course, which potentially reduces thelength of mechanical ventilation, oxygen requirement, andstay within the intensive care unit (Grade 1A).

3. It is recommended that INO should not be used rou-tinely in newborns with congenital diaphragmatic hernia(Grade 1A).

4. It is suggested that INO therapy should not be usedroutinely in newborns with cardiac anomalies dependenton right-to-left shunts, congestive heart failure, and thosewith lethal congenital anomalies (Grade 2C).

5. It is suggested that there are insufficient data to sup-port the routine use of INO therapy in postoperative man-agement of hypoxic term or near-term infants with con-genital heart disease (grade 2C).

6. The recommended starting dose for INO is 20 ppm(Grade 1A).

7. It is recommended that response to a short trial (30–60 min) of INO should be judged by an improvement inPaO2

or oxygenation index (OI); if there is no response,INO should be discontinued (Grade 1A).

8. For the newborn with parenchymal lung disease, it isrecommended that optimal alveolar recruitment be estab-lished prior to initiation of INO therapy (Grade 1A).

9. For newborns with a response to INO therapy, it isrecommended that the dose should be weaned to the low-est dose that maintains that response (Grade 1A).

10. It is recommended that INO should not be discon-tinued until there is an appreciable clinical improvement;

that the INO dose should be weaned to 1 ppm before anattempt is made to discontinue; and that the FIO2

should beincreased prior to discontinuation of INO therapy(Grade 1A).

11. It is recommended that FDA-approved INO deliverysystems should be used to assure consistent and safe gasdelivery during therapy (Grade 1C).

12. During conventional mechanical ventilation, it issuggested that the INO gas injector module should beplaced on the dry side of the humidifier (Grade 2C).

13. During conventional ventilation, it is suggested thatthe sampling port be placed in the inspiratory limb of theventilator, downstream from the site of injection, no greaterthan 15 cm proximal the patient connection/interface(Grade 2C).

14. It is suggested that the FIO2be measured down-

stream from the injection of INO into the circuit (Grade 2C).15. It is suggested that the patient/ventilator system be

continuously monitored for changes in ventilation param-eters, with adjustments to maintain desired settings duringINO therapy (Grade 2C).

16. It is suggested that the lowest effective doses of INOand O2 be used, to avoid excessive exposure to NO, NO2,and methemoglobinemia (Grade 2C).

17. It is suggested that the INO delivery system beproperly purged before use to minimize inadvertent expo-sure to NO2 (Grade 2C).

18. It is suggested that the high NO2 alarm be set at2 ppm on the delivery system to prevent toxic gas expo-sure to the lungs (Grade 2C).

19. It is suggested that methemoglobin be monitoredapproximately 8 hours and 24 hours after therapy initiationand daily thereafter.

20. It is suggested that the INO dose be weaned ordiscontinued if methemoglobin rises above 5% (Grade 2C).

21. It is suggested that continuous pulse oximetry andhemodynamic monitoring be used to assess patient re-sponse to INO therapy (Grade 2C).

22. It is suggested that scavenging of exhaled and un-used gases during INO therapy is not necessary (Grade 2C).

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2. Frostell C, Fratacci MD, Wain JC, Jones R, Zapol WM. Inhalednitric oxide: a selective pulmonary vasodilator reversing hypoxicpulmonary vasoconstriction. Circulation 1991;83(6):2038-2047. Er-ratum in: Circulation 1991;84(5):2212.

3. Bin-Nun A, Schreiber MD. Role of INO in the modulation ofpulmonary vascular resistance. J Perinatol 2008;(Suppl 3):S84-S92.

4. Restrepo RD. AARC clinical practice guidelines: from “reference-based” to “evidence-based” (editorial). Respir Care 2010;55(6):787-788.



5. Finer N, Barrington KJ. Nitric oxide for respiratory failure in in-fants born at or near term. Cochrane Database Syst Rev 2006;(4):CD000399. DOI: 10.1002/14651858.CD000399.pub2.

6. Clark RH, Kueser TJ, Walker MW, Southgate WM, Huckaby JL,Perez JA, et al. Low-dose nitric oxide therapy for persistent pul-monary hypertension of the newborn. Clinical Inhaled Nitric OxideResearch Group. N Engl J Med 2000;342(7):469-474.

7. The Neonatal Inhaled Nitric Oxide Study Group. Inhaled nitricoxide in full-term and nearly full-term infants with hypoxic respi-ratory failure. N Engl J Med 1997;336(9):597-604.

8. Roberts JD Jr, Fineman JR, Morin FC 3rd, Shaul PW, Rimar S,Schreiber MD, et al. Inhaled nitric oxide and persistent pulmonaryhypertension of the newborn. The Inhaled Nitric Oxide Study Group.N Engl J Med 1997;336(9):605-610.

9. Mercier JC, Lacaze T, Storme L, Roze JC, Dinh-Xuan AT, DehanM. Disease-related response to inhaled nitric oxide in newbornswith severe hypoxaemic respiratory failure. French Paediatric StudyGroup of Inhaled NO. Eur J Pediatr 1998;157(9):747-752.

10. Davidson D, Barefield ES, Kattwinkel J, Dudell G, Damask M,Straube R, et al. Inhaled nitric oxide for the early treatment ofpersistent pulmonary hypertension of the term newborn: a random-ized, double-masked, placebo-controlled, dose-response, multi-center study. The I-NO/PPHN Study Group. Pediatrics 1998;01(3Pt 1):325-334.

11. Day RW, Allen EM, Witte MK. A randomized, controlled study ofthe 1-hour and 24-hour effects of inhaled nitric oxide therapy inchildren with acute hypoxemic respiratory failure. Chest 1997;112(5):1324-1331.

12. Wessel DL, Adatia I, Van Marter LJ, Thompson JE, Kane JW,Stark AR, Kourembanas S. Improved oxygenation in a randomizedtrial of inhaled nitric oxide for persistent pulmonary hypertensionof the newborn. Pediatrics 1997;100(5):E7.

13. Cornfield DN, Maynard RC, deRegnier RA, Guiang SF 3rd, Bar-bato JE, Milla CE. Randomized, controlled trial of low-dose in-haled nitric oxide in the treatment of term and near-term infantswith respiratory failure and pulmonary hypertension. Pediatrics1999;104(5 Pt 1):1089-1094.

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