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transcript
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: robert.diblasi@seattlechildrens.org.
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.
INHALED NITRIC OXIDE FOR NEONATES WITH ACUTE HYPOXIC RESPIRATORY FAILURE
RESPIRATORY CARE • DECEMBER 2010 VOL 55 NO 12 1719
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
INHALED NITRIC OXIDE FOR NEONATES WITH ACUTE HYPOXIC RESPIRATORY FAILURE
1720 RESPIRATORY CARE • DECEMBER 2010 VOL 55 NO 12
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
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mos
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rmal
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etab
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1996
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pect
ive
case
seri
es17 E
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evid
ence
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1997
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pect
ive
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ries
26 Ech
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ceof
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ase,
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es32 PP
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ries
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tal
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ital
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seas
e
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�in
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dni
tric
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rsis
tent
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INHALED NITRIC OXIDE FOR NEONATES WITH ACUTE HYPOXIC RESPIRATORY FAILURE
RESPIRATORY CARE • DECEMBER 2010 VOL 55 NO 12 1721
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-
INHALED NITRIC OXIDE FOR NEONATES WITH ACUTE HYPOXIC RESPIRATORY FAILURE
1722 RESPIRATORY CARE • DECEMBER 2010 VOL 55 NO 12
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.)
INHALED NITRIC OXIDE FOR NEONATES WITH ACUTE HYPOXIC RESPIRATORY FAILURE
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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.)
INHALED NITRIC OXIDE FOR NEONATES WITH ACUTE HYPOXIC RESPIRATORY FAILURE
1724 RESPIRATORY CARE • DECEMBER 2010 VOL 55 NO 12
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.)
INHALED NITRIC OXIDE FOR NEONATES WITH ACUTE HYPOXIC RESPIRATORY FAILURE
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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.
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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-
INHALED NITRIC OXIDE FOR NEONATES WITH ACUTE HYPOXIC RESPIRATORY FAILURE
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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)
INHALED NITRIC OXIDE FOR NEONATES WITH ACUTE HYPOXIC RESPIRATORY FAILURE
1728 RESPIRATORY CARE • DECEMBER 2010 VOL 55 NO 12
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)
INHALED NITRIC OXIDE FOR NEONATES WITH ACUTE HYPOXIC RESPIRATORY FAILURE
RESPIRATORY CARE • DECEMBER 2010 VOL 55 NO 12 1729
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
INHALED NITRIC OXIDE FOR NEONATES WITH ACUTE HYPOXIC RESPIRATORY FAILURE
1730 RESPIRATORY CARE • DECEMBER 2010 VOL 55 NO 12
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)
INHALED NITRIC OXIDE FOR NEONATES WITH ACUTE HYPOXIC RESPIRATORY FAILURE
RESPIRATORY CARE • DECEMBER 2010 VOL 55 NO 12 1731
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
30m
inun
tilbe
nefi
cial
resp
onse
achi
eved
.If
nobe
nefi
cial
resp
onse
with
in2
h,IN
Odi
scon
tinue
d
INO
decr
ease
dby
5pp
mev
ery
30m
into
the
low
est
dose
that
mai
ntai
ned
the
bene
fici
alre
spon
se,
orun
til1
ppm
was
reac
hed
Dai
lyIN
Odi
scon
tinua
tion
atte
mpt
.IN
Ono
tre
star
ted
ifth
ere
was
a�
25%
chan
gein
P aO
2,oxy
gen
satu
ratio
n,ox
ygen
atio
nin
dex,
P (A
-a)O
2,or
virt
ual
shun
taf
ter
INO
disc
ontin
ued
—
Lau
bsch
er36
1997
1020
%de
crea
sein
oxyg
enat
ion
inde
xIf
nore
spon
seto
10pp
m,
tria
lsof
20an
d40
ppm
.IN
Odi
scon
tinue
din
non-
resp
onde
rs
Not
stat
edN
otst
ated
—
Bib
an37
1998
10P a
O2
orP (
A-a
)O2
INO
incr
ease
dby
step
sof
10pp
m,
upto
max
imum
40pp
m
Not
stat
edN
otst
ated
—
Kos
sel4
020
0010
P aO
2IN
Oin
crea
sed
from
10pp
mto
80pp
m,
in10
-ppm
step
sN
otst
ated
Not
stat
ed—
Tw
oret
zky4
120
015,
20,
or40
,ra
ndom
lyap
plie
d
P aO
2an
dpu
lmon
ary-
to-
syst
emic
arte
rial
pres
sure
ratio
Not
stat
edN
otst
ated
Not
stat
edIn
itial
INO
dose
of20
ppm
optim
um
Gup
ta42
2002
25O
2sa
tura
tion
incr
ease
to�
80%
(pre
fera
bly
�90
%)
EC
MO
Whe
nF I
O2
�0.
6an
din
fant
stab
le,
atte
mpt
edIN
Ow
eani
ngin
5-pp
mde
crem
ents
ever
y2–
4h,
asto
lera
ted,
dow
nto
5pp
m
Onc
est
able
onIN
Oof
5pp
m,
INO
disc
ontin
ued
whi
leke
epin
gF I
O2
cons
tant
.If
O2
satu
ratio
ndr
oppe
d10
%or
to�
85%
,th
isw
asco
nsid
ered
wea
ning
failu
rean
dIN
Ow
asre
star
ted
at5
ppm
.A
fter
the
infa
ntre
cove
red,
F IO
2
was
incr
ease
dby
0.4
and
ase
cond
INO
wea
ning
atte
mpt
was
mad
e.
—
(con
tinue
d)
INHALED NITRIC OXIDE FOR NEONATES WITH ACUTE HYPOXIC RESPIRATORY FAILURE
1732 RESPIRATORY CARE • DECEMBER 2010 VOL 55 NO 12
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
Hw
ang4
320
045–
10Pr
e/po
st-d
ucta
lox
ygen
satu
ratio
ndi
ffer
ence
Not
stat
edIN
Ode
crem
ent
of5
ppm
atte
mpt
edev
ery
4–9
hIN
Ode
crea
sed
from
5pp
mto
off.
INO
rest
arte
dif
S pO
2de
crea
sed
by10
%or
to�
85%
—
Gut
hrie
44
2004
Low
dose
:�
18M
id-d
ose:
18–2
2H
igh
dose
:�
22
P aO
2/FIO
2N
otst
ated
Not
stat
edN
otst
ated
Low
-dos
eIN
O(�
18pp
m)
appe
ars
tobe
asef
fica
ciou
sas
high
-dos
eIN
O(�
22pp
m)
Faki
oglu
45
2005
80�
20%
incr
ease
inox
ygen
atio
nin
dex
orP (
A-a
)O2
afte
r1
hof
INO
—1
haf
ter
star
ting
INO
,do
sere
duce
dto
40pp
man
dm
aint
aine
dfo
rat
leas
t12
h.IN
Oth
enre
duce
dto
20,
10,
and
5pp
m,
at15
-min
inte
rval
s.Pa
tient
rece
ived
low
est
dose
that
kept
P aO
2�
60m
mH
gor
oxyg
ensa
tura
tion
�90
%
Wea
ned
from
INO
at5
ppm
ifF I
O2
�0.
6.W
eani
ngvi
a1-
ppm
INO
decr
emen
tsov
erse
vera
lho
urs.
Ifpa
tient
faile
dto
mai
ntai
nac
cept
able
oxyg
enat
ion,
INO
was
resu
med
.
—
INO
�in
hale
dni
tric
oxid
eP (
A-a
)O2
�al
veol
ar-a
rter
ial
oxyg
endi
ffer
ence
EC
MO
�ex
trac
orpo
real
mem
bran
eox
ygen
atio
nN
A�
not
appl
icab
leN
D�
noda
ta
INHALED NITRIC OXIDE FOR NEONATES WITH ACUTE HYPOXIC RESPIRATORY FAILURE
RESPIRATORY CARE • DECEMBER 2010 VOL 55 NO 12 1733
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
INHALED NITRIC OXIDE FOR NEONATES WITH ACUTE HYPOXIC RESPIRATORY FAILURE
1734 RESPIRATORY CARE • DECEMBER 2010 VOL 55 NO 12
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
INHALED NITRIC OXIDE FOR NEONATES WITH ACUTE HYPOXIC RESPIRATORY FAILURE
RESPIRATORY CARE • DECEMBER 2010 VOL 55 NO 12 1735
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
INHALED NITRIC OXIDE FOR NEONATES WITH ACUTE HYPOXIC RESPIRATORY FAILURE
1736 RESPIRATORY CARE • DECEMBER 2010 VOL 55 NO 12
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
INHALED NITRIC OXIDE FOR NEONATES WITH ACUTE HYPOXIC RESPIRATORY FAILURE
RESPIRATORY CARE • DECEMBER 2010 VOL 55 NO 12 1737
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
INHALED NITRIC OXIDE FOR NEONATES WITH ACUTE HYPOXIC RESPIRATORY FAILURE
1738 RESPIRATORY CARE • DECEMBER 2010 VOL 55 NO 12
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
INHALED NITRIC OXIDE FOR NEONATES WITH ACUTE HYPOXIC RESPIRATORY FAILURE
RESPIRATORY CARE • DECEMBER 2010 VOL 55 NO 12 1739
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-
INHALED NITRIC OXIDE FOR NEONATES WITH ACUTE HYPOXIC RESPIRATORY FAILURE
1740 RESPIRATORY CARE • DECEMBER 2010 VOL 55 NO 12
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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INHALED NITRIC OXIDE FOR NEONATES WITH ACUTE HYPOXIC RESPIRATORY FAILURE
RESPIRATORY CARE • DECEMBER 2010 VOL 55 NO 12 1745