SESSION

Inhaling Nitric Oxide: A Selective Pulmonary Vasodilator and Bronchodilator*

Warren William
Jesse

M. Zapol,

M.D.,

F.C.C.P.;

Konrad

J. Falke,

M.D.;

E. Hurford, M.D., D. Roberts, Jr., M.D. of animal

of human established

F.C.C.P.;

and

n a number
diseases firmly

models
subjects, as

and
inhaled

clinical
nitric pulmonary

pulmonary
oxide (NO) vasodi-

tent
we

pulmonary required

an

hypertension of the newborn (PPHN), animal model of this condition. We

is now

a selective

lator.
SE[.ECTIVE

chose to study the near-termim sheep fetus, since its birth weight (3.5 to 4.5 kg) approximates the hiumnan, and pulmonary hesnodynamimics can he readily momiitored. We sought to learn

PULMONARY examined the

VASODILATION

IN

LAMBS

if inhaled arterial time fetus the lungs, produced

NO by cesarean occluded pulmonary

could

dilate of the section, the umvasocon0.1). perin the

We

first

effect

of

inhaled

NO

on

the

the fetal bilical

muscularized lamb, We

pulmonary delivered ventilated and

circulation

normal pulmonary with a previously 80 parts pulmonary systemic resistance

effects of

circulation implanted (ppm) pressure pressure Therefore,

inhalation

heft NO

of time awake 40 kg lamb atrial cathieter. Inhaling did not alter the normal cardiac output (CO), or systemic vascular
proceeded the to study

mechanically

per

million

circulation,

artery arterial (SVR).

NO

(PAP), (SAP),
we upon

striction by inhaling \Ve anesthetized the

fornied a thioracotomy,

a hypoxic gas mixture (Flo, fetus with potent narcotics, and measured pressure atriumn, and flowmeter

the the

pharmacologically

constricted pulmonary U466i9, of NO 02 were inhaled

pulmonary circulation. vessels we continuously a thromboxane analog. continuously mixed with measured by NO dose-pulmonary

To stably infused

constrict intravenously

pulmonary measured

artery,
with

left ultrasonic

aorta. Flow was probes placed

Sheep breathed low levels of NO.

mixtures NO amid the was

34 32 30

chemiluminescence. vasodilator

First, response

examined. As can vascular resistance 6 mm of inhaling inhalation

promptly

be observed in Figure 1, the pulmonary (PVR) and PAP decreased during the each NO mixture, and each time NO ceased
The

was
increased.

for
SAP

mm,
and

the
SVR

PAP
were

and
unchanged.

PVR

It

is important

to

note

that

the

pulmimonary

vasodilator

effect occurred at low that potent vasodilation

inhaled NO (65 percent

levels (Ic, 5 ppm) and of maximal vasodilais less than (25 ppm). 80 The amid NO PAP ppmim NO inhalawithout Once vasoconnot not

tion) occurred at 20 ppm inhaled NO which the NIOSH standard for 8-h working exposures We for tion up then examined the lowered effect the of inhaling infusion, PVR to 1 h during a U46619

I
020
10 9 6

40

60

60

100

120

continuously

a-I

t _

evidence of tolerance to this pulmonary again, there was a rapid return of striction Tolerance occur
require

vasodilator. pulmonary

within to since
metabolism

mninutes after NO pulmonary NO

to
PULMONARY

ceasing NO vasodilation nitroglycerine)

vasodilator active

administration, should does

molecule.
IN TUE TERM

inhaled

(unlike
the

SELECTIVE

VASODILATION LAMB

:
2

NEWBORN

Next sheep lieved *From

we fetus.2

examined Since

inhalation pulmonary component

of NO of the

by

the

near-term is be020 40

vasoconstriction syndrome Harvard

to be a key the Department

of persisMedical School FIGuRE

infusion

60

ido

ic

Tim.

Ommkm)

of Anesthesia,

at Massachusetts Anaesthesiologie,

This

study

was
and

HL-42397 139/1-3/2-3.

General Hospital, Boston; and Khimiik fur Freie Universitat, Berlin, Germany. supported by US Public Health Service grant Deutsche Forschungsgemeinschaft grant Fa

1. Plots
of (5-80

of mean

oxide mixture
mean

at
SEM).

U46619. ppm) at F1o2 0.6

PAP amid PVR dluring a contimmuous Lambs breathed various levels of nitric F1o2 0.6 for 6 mm, then breathed a gas for 6 mm without nitric oxide (n = 8,

(Reprinted
/ 105

with

permission.)
1994 / Supplement

CHEST

/ 3 / MARCH,

87S

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about
pulmonary

the rapid

ductus
artery.

arteriosus,
Hypoxic

descending
breathing (10 with

aorta,
percent

and

levels

of cGMP

were

increased

threefold.
IN GUINEA PIGS

caused
hypertension

pulmonary

vasoconstriction

pulmonary Since nary tissue

BRONCIIODILATION

NO tion

and right-to-left despite continued hypoxia of pulmonary vascular of the There direction was no of

ductal shunting. Breathing produced a rapid reducresistance and PAP, with shunting of
via

inhaled

NO

can

diffuse

through pulmonary

gas

and

pulmosmooth that Howalveoli

to reach

upstream

artery

reversal arteriosus.

the

ductus arterial hysheep

change

systemic

muscle cells inhaled NO ever, airways and sion highly ous a mucus of NO. lipid solubility

causing them to dilate, this suggested might also dilate constricted airways. have a thicker epithehium than the coating, Thus, soluble (about we

pressure during NO breathing. This study that inhaled NO promptly and selectively poxic fetus. Two First, additional findings of this the concomitant presence pulmonary vasoconstriction in the

demonstrated reversed near-term

and both should impede the diffuwere not confident that even a like that of NO with a low would aquereach to model with a within half oxygen)

substance3

study are of severe

important. respiratory pH (pHa) ability of pulmoin the oxygen elevated monophosNO should

airway smooth muscle in a sufficient concentration effectively reduce airway tone, We chose for our the anesthetized tracheostomy. a constant measurements tidal We volume stably These open small chest animals guinea can be pig placed

acidosis (PaCO2 79 15 mm 714 0.06, mean SD) did inhaled nary newborn may
with

Hg and arterial not reduce the the hypoxic with by states of asphyxia breathing markedly

NO circulation.

to selectively Thus, are often

vasodilate clinical combined reversed we measured

temperature piethysmograph, of breath-to-breath airway can constricted be obtained the using airways a computer of the

and accurate pressure and monitor. pig oxide gas.

tone

which

hypercapnia

be more effectively added NO. Second,

guinea Nitric inhaled

with at

lung phate activate contains reasoned and tor. ppm

and plasma levels of cyclic guanosine (cGMP) during NO breathing. Since its receptor a ferrous that tissue we the inhaling levels learned fetal lung

an intravenous methachohine various concentrations was

We noted that a stable

infusion. added to the

state of increased

airway

molecule, guanylate cyclase, (which heme ring) to produce cGMP, we NO of this that should important within tissue and elevate 4 mm the secondary of breathing plasma circulating circulating media80

could
tance

be
(RL)

produced
and

by a reduced ppm the

infusing

methachohine. increase of pulmonary compliance a rapid Cdyn.

This

was resis-

characterized Adding related ppm NO 80 70 5 to reduction

by a threefold 300 NO increased

dynamic produced increased

(Cdyn). and Inhaling dose15 Thus,

lung Indeed, NO,

of Ri. and

reduced

RL by 50 percent.

25
20 15

LVSWITX

60 __,50

10 5

E
RVSWI 0

0 120

150
-

*N

100
80-

120
C

90 60

60

PaCc

30

Hyp
0

oxi

00

40

[minI

20

40

[mm]

FIGURE 2. Nitric oxide (NO) 40 ppm was inhaled during hypoxia by 9 normal volunteers. This figure illustrates the effects on mean PAP and wedge (PCWP) pressures, PVR, PaO2, and PaCO,, as well as right (RVSWI) and heft (LVSWI) ventricular stroke work indexes. All data mean SEM. Asterisk = p<O.Ol, value differs from first control breathing air. (Reprinted with permission.6)

88S

36th

Annual

Aspen

Lung

Conference

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we

discovered

that

inhaled

NO pig and

could given the

promptly methachohine. inhaled NO examined

reduce Our dosethe

mm Hg

airway initial effect infusion inhaling ing but after have striction leukotriene NO

tone in the guinea studies characterized response, of

PAP
6050403020 10
-

bronchodilator

we thereafter

breathing NO for 1 h during a continuous of methachohine. Analogous to our studies of NO to produce pulmonary vasodilation, breath1 h stably minutes reduced of recurred, methachohine inhaled pigs effects due of histamine, NO vasodilation the ceasing and increase NO of airway inhalation, tone, the ceased

for

within

bronchoconstriction stopping the demonstrated in guinea D4,

subsequently

infusion. Additional studies NO can reverse bronchoconto an intravenous or are neurokinin produced or hypotension infusion A.5 locally, due of The and to

0-

bronchodilator

BASELINE

NO
l8ppm

NO
36ppm

BASELINE

there was no systemic inhaling NO.

CLINICAL

STUDIES

OF

NO

INHALATION

Pa02
mm Hg

I PlO2

Adult

Human

Hypoxic our NO, NO. could

Pulmonary circulatory

Vasoconstriction studies normal in sheep of to

Following with humans inhaled to

pulmonary we First examined we

350 300250

short-term

exposures volunteers pulmonary monitored and a pulse at by

Pa02

studied

learn if NO vasoconstriction.6 with oximeter. 0.12, the

oximetry

reverse human hypoxic Nine healthy subjects were catheter, the arterial subjects saturation
to 86

#{149}

#{163}

200 l50 100#{149} 50 0

BASELINE
#{149}

8
.I
... .

a Swan-Ganz

line,

By allowing mean oxygen

(SpO2) was

to breathe measured
percent, and

FIo2 pulse
was

I.
V

reduced

near 50 mm Hg. Hypoxia Breathing 40 ppm NO the PVR and PAP to before hypoxia ppm NO during vasoconstriction. blood globin breathing slow return constriction. Adult We nary of ing regions the Respiratory reasoned circulation, hung in flow. and not selectively in that the Distress pressure levels during (Fig 2). hypoxia There or remained hypoxia of a minor

elevated both the PVR for 10 mm immediately the baseline values

and PAP. reduced air

breathing

NO
l8ppmn

NO BASELINE J#{244}ppmn

In two volunteers, breathing 10 completely reversed pulmonary was no change in the systemic resistance, 1 percent. 10 mm of hypoxic was for level and Cessation followed pulmonary methemoof NO by the vasobelow

vascular

60U

50
Syndrome selectively locally dilate respiratory vascular occur or fluid might collapsed dilated ventilated distress tone only filled and in the pulmoregions syndrome augmentventilated hung areas NO artery obtain as

#{149}

4030-

a v.
A

.
.0A
#{163}
..-

if NO adult reducing

it might

20hO 0-

(ARDS), blood

This

contributing to the venous blood shunt. Inhaled should then cause a steal or diversion of pulmonary blood flow towards well ventilated lung. We could evidence tion of such a salutary vascular NO effect by noting and PAP, of pulmonary resistance

BASELINE

NO I8ppm

NO J6ppnm

BASELINE

a reducas well shuntin marked of a or PA

an increase PaO2 due to reduced intrapuimonary ing of venous blood. Such an effect would be contrast conventional prostacychin, pressure, they augment to the effects of intravenous (such as intravenous to nonventilated administration vasodilator PGI2). These however, blood flow

3. Mean PAP, arterial oxygenation efficiency (PaO F1o2). and intrapuimonaiy shunting QS/cT in nine patients wit ARDS during inhalation of nitric oxide, Solid symbols represent patients treated with extracorporeal membrane oxygenation. (Reprinted with permission.7)
FIGURE

nitroprusside agents lower lung areas, regions increas-

ing shunting We first ppm trasted NO in these

of venous examined nine results

blood
the patients with

and thereby
effects with an of severe infusion
1994

reducing

the 18

inhaling ARDS of

Pa02. and 36 con-

by vasodilating

shunting

and

prostacychin.7

CHEST

/ 105 / 3 / MARCH,

/ Supplement

89S

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P.10

.?_0fl

off

off

oft
*

off 400

of

off

off

off

off

of

50*

40 I

* *

300
I

I E E

3L

200

a. a.

24

100 0 U.O#{149}#{149} 0 a.
-

10
0

I o J.

-100 -200

#{182}
*

I
* *

12

75

9
C

I
ji

TI

50 6 0 3
C

E
-I

i
25

0
0

0>
A A A

-3

dayl

dayl

FIGURE 4. Hemodynamic function and gas exchange before, durimig, amid after l)rief interruptions (arrows) of nitric oxide inhalation (bars) dmmring the first 6 days of treatment in seven patients with ARDS. Values are means SE (solid symbols); also shown (open symbols) are the means SE of the individual differences between the values for the effect of treatment and the mneans of tile values determined before and after interrupting NO therapy. The standard errors for the treatment effects were small, indicating that the effects of withdrawal of nitric oxide were clear and precisely estimated.

Each asterisk interrupting

denotes a significant NO therapy. (Reprinted

difference with as well

from

the meami of the values

determined

before

and after

permission.7)

The level

NO

inhalation
(s/QT),

rapidhly

reduced

the with

PAP the

as the

Blood

levels

of miiethemoglobin

always

remained

below

of shumit

measured

multiple

inert

1.3 percent.
Congenital Since Heart children Disease with congemiitai heart disease (CHD)

gas technique, while tients. This contrasted reduced the PAP but There was no change Since these results promising, tients Several we

increasing the PaQ in these pawith a prostacyclin infusion which markedly increased
QS/QT

(Fig

3). so

of SVR or SAP during NO inhalation. of inhaling NO in ARDS were to treat seven severely periods with lung disease, membrane severe ARDS eventually

can develop studied the

NO, and

severe pulmonary oxygen.

We

pulmonary artery helnodynamic

these effects with

hypertension, we effects of inhaling

those produced by

proceeded

ill pa-

compared

with ARDS for hong patients had severe

NO inhalation. and they were oxygenation imihaled 5 to seven from

breathing
to 6.5 years

studied heart

ten defects.5

children Each 10 mm
inhaling

from

3 months
due to

with

chromiic

plslmonary

hypertension

also treated with extracorporeal (ECMO). Seven patients with 20 ppm

patiemits

diverse breathed
catheterization.
promrlpt

congenital
We
reduction

spontaneously during NO
without

20 to 80 ppm
found
of

NO PAP The NO was

for
that

a cardiac produced
causing

NO

for periods and The day, were was

NO

of 3 to 53 days, were

six of these discharged

a PVR NO CHD

survived

amid reduction greater

PVR of than

the hospital. period each and drawn,

QT

NO inhalatiomm and the changes recorded a prompt PaO/FIo,

was once again

was stopped in QS/QT, 4). When of PAP, ratio, and reduce

Qs/QT administered,

for a brief PaO,, PAP, NO PVR, the was and opposite

Believing

systemic produced

vasodilation. by inhaling

PAP that

and

produced

PVR there with

when

(Fig increase

withQsI

by breathing 100 percent further reduced the PAP who lator were for
NO

oxygen. and PVR Q a selective

CHD,

Indeed, breathing of children with pulmonary during when surgery

a reduced reduction formnation,

breathing NO may period

production

90 percent provide
with

effect

Inhaled permoperative of
for enous

vasodithe endog-

that edema

the

of PAP and since

would the

help decreased

pulmonary allowed each

improved.

children

especially

after
is

cardiac

a 10 to 15 percent reduction these patients with low

prolonged periods, until

of FIo2, levels of
their lung

we
NO injury

treated
inhalation had

the effects of prolonged be examimied to learn

probably reduced. In addition, periods of NO breathing should if NO prevents pulmonary vascular

36th Annual Aspen Lung Conference

90s

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muscularization pulmonary Persistent Based clear

hator

and hypertension.

vascular

obliteration

in children

with

4.

Will

NO

be

a useful

human

bronchodihator?

REFERENCES

Pulmonary upon studies

NO

Hypertension of near-term a selective pulmonary

of the fetal

Newborn sheep, it was vasodiWe brief augment pulmosince pulwe

In

1 Frostell oxide: pulmonary 2 Roberts reverses acidotic 3 Shaw and 4 AW,

C,

Fratacci vasoconstriction. Chen T-Y, lamb. AJ.

M-D, pulmonary Kawai Circ

Vain

JC.

et

al.

Inhaled

miitric hiypoxic

a selective JD,

vasodilator Circuhatiomm N, et al. Res 1993; of nitric Soc JM, in guinea et

reversiimg 1991; Inhaled in the oxide 72:246-54

that
of

inhaled the ovine treated of NO

was perinatal

pulmonary circulation.2 PPHN would measure

iii

83:2038-47 nitric oxide hvpoxic and

therefore periods their nary the

not of

seven inhalation chose of ductal

patients to learn not

with if NO

with

pulmonary newborn Vosper

vasoconstriction Solubility j Cheni Drazan oxide Kim in

in aqIIeOUs Trans 1977;

PaO2.9
persistence

We

to invasively critically shunting makes to interpret,

nonaqueous PM, of Shore

solvents. SA, nitric SA, oxide A constricted

Faraday al. pigs.

hemodynamics hemodynamics
to delay

in these difficult
a possibly

newborns newborn and and

73:1239-44 Duptmy action 5 1992; Dupuy inhaled neurokinin 6 Respir Frostell nitric Bromichodilator inhaled

monary
wish

did
each

J Chin

Invest of aimd

lifesaving

treatment.

the

seven

newborns,

there SpO, while

was

a prompt

signifian NO. and in

90:421-28 PM, Shore nitric

K, et al. histamine, guinea

Bronchodilator leukotriene pigs [abstract]. C, hypoxic et al.

action D4,

cant increase of preductal increased postductal PaO2 The one ing tion babies and h with mained The
NO

and in five infants, breathing 80 ppm breathing NO,

Ammi Rev Inhaled Anoxide Med nitric 87:447-53 nitric oxide for 1993; oxide

increased infant, ceased.

PaO2

persisted

while

Dis 1993; 147:A286 CC, Blomqvist H, oxide selectively without 1993; R, Falke respiratory JD. JD, Lang heart Polaner psmlmonary SB, 78:427-35 KJ, Lopez distress P. Bigatello disease. DM,

Hedebstierna humnan systemic Inhaled

the PaO2 remained The six others et aP#{176} reported NO treated clinical after the is presently in PPHN

elevated after NO breathwere treated with ECMO. nine babies NO inhaled The of NO studied muiticenter Hypertension with inhalaof up to 24 h. All nine during 6 ppm inhalation, NO PaO2 inhalation. in a blinded trials.
10 9

reverses causing

pulmonary

vasoconstriction esthesiology 7 Rossaint the 8 adult 328:399-405 Roberts Roberts in persistent

vasodilation. nitric

Kinsella

treating for periods with

of 10 to 20 ppm improved six infants sustained improved inhalation fashion their were

F, et al. syndrome. LM, Circulation Lang

09 exchange

N Engh et al. Inhaled 1993: of the

for 24 re-

improvement. withdrawal being by Pulmonary

two

in comigenital

P. et al. Inhaled

randomized NO and Inhalation COPD Pepke-Zaba

hypertension Shiaffer 1992; as a E, et

newhormm.

Laoinlmalaof et

in Primary

cet 1992; 340:818-19 Kinsella JP, Neish tional the nitric newborn. j, nitric in M-D, of with hypertension. oxide Lancet oxide

al.

Low-dose hypertension A-T, Lancet

imi persistent Higenbottam pulmonary

pulmnonarv 340:819-2(1 TW, cause Dinh-XIIan of

selective

et al

reported

a study
in

of

10-mm

imihalawith paPVR et in and They PVR

11

Pepke-Zaba Inhaled vasodilation 338:1173-74

al.

tion periods of 40 ppm NO in air primary pulmonary hypertension. tients gas, was
aP2

eight Apparently They or CO.

patients these bags noted Fratacci

pulmonary 1991: to in

hypertension. C, Andrivet amid inhalation lung 1)is

breathed

from

previously

prepared

of mixed
12

and NO2 levels were reduced but did not have recently with that
and slightly

not reported. report PAP the 40 ppm

the

Fratacci infusion patients nary

Defouihloy acetylchohine chronic Am Rev

P. et al. Responses of disease 1992: nitric oxide

reported and

results NO
PaO2.

of inhaled hypertension. reduced the

NO

obstructive Respir

ammd pulmmio145:A722

patients reported
PAP

COPD breathing

pulmonary

increased

THE

FUTURE

OF

NO

Inhaled pulmonary clinical be learned. main to be

1. To

NO

is

now

vasodilator pulmonary In our studied:

the

firmly established as a selective in a number of animal models and of humans. several

of inhaled

Nitric Oxide lnhalation* Effects on the Ovine Neonatal Pulmonary and Systemic Circulations
Vincent Tanir M. hese esis DeMarco, Ellis,

diseases opinion,
toxicity

Much important
NO. For

remains areas
how

to relong

Ph.D.;
Ph.D.; and

Jeffrey Sidney were nitric causes

Ski

nu,Iing.

Casxin, designed

M.D.; Ph.D.
to test an the hypoth-

T
derived arterial

experiments that relaxing pressure inhaled factor, and and (N

=

define

oxide

(NO), a decrease vascular ovine

endothehiumin pulmonary (PVR) pulmonary

and safe lem?

2. diseases

it safe

at what levels is it safe for humnans to breathe NO? for the newborn to breathe NO? Is NO breathing for
If

Is

pulmonary constricted 7; age

=

resistance neonatal

the
NO can

acutely
breathing NO cost

injured
is safe,

lung?
then

Is genotoxicity
in which

a probrespiratory ben-

in the
circulation 5.7

normal

13.9

SD
were

3.3;
placed

mass
in the

SD Using

0.8
aseptic

kg).
surgery, catheters

effectively

produce

important

efits? 3.
of

PPHN? If proven lung Chronic

CHD? ARDS? safe, will prolonged injury or even

vascular

NO save hives
diseases

breathing in the
such as

prevent treatment
CHD?

*Fromn

the

Department

of

Physiology.

University froni AHA (S

of

Florida,

additional
chronic

pulmonary

COPD?

pulmonary

hypertension?

Gainesville. This study was supported in part by a grant Heart Association, Florida Affiliate, aim Fellowship (V.D.), and NIH grant HLLOS34

the American Postdoctoral

CHEST

/ 105 / 3 / MARCH,

1994

/ Supplement

91S

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