Inhaled nitric oxide and high concentrations of oxygen in pediatrics patients with congenital cardiopathy and pulmonary hypertension: report of five cases

W e r th e r B r u n o w d e C a r v a ln o , A n r o n lO c ;a r lo s C a m a r g o C a r v a lh o , G is e le L im o n g e li G u r g u e ir a , A n g e la M it y o Ik e d a , J u n e H o L e e , D ir c e u R o d r ig u e s A lm e id a

Inhaled nitric oxide and high concentrations of oxygen in

pediatrics patients with congenital cardiopathy and pulmonary

hypertension: Report of five cases

Departments

of Pediatrics and Cardiology, Escola Paulista de Medicina,

Universidade Federal de Sao Paulo - Sao Paulo, Brazil

Five patients w ith ages ranging from 6 m onths to 3 years w ere analyzed. All received inhaled nitric oxide (N O - 20 parts per m illion (ppm ) ) and oxygen (0

2 - at a concentration of 90-95% ) by m eans of an oxygen hood. M ean Pulm onary Artery Pressure (M PAP), M ean Aortic Pressure (M AoP), Pulm onary Vascular R esistance (PVR ) and System ic Vascular R esistance (SVR ) w ere m easured and the calculation of their relationship to pulm onary/system ic flow (O p/O s) w as perform ed by the catheterization' of the fem oral artery vein. Three patients presented reduction in PVR and increase in O p/O s. There w ere no system ic alterations or any side effect from using N O .

U N ITER M S: N itric O xide - Pulm onary H ypertension- C ongenital C ardiopathy.

IN TR O D U C TIO N

P

neonatal persistent pulm onary hypertension, acute

respiratory discom fort syndrom e, in patients w ith chronic

obstructi ve pulm onary disease, and especially in the

im m ediate postoperative period after surgical correction

of congenital cardiopathies w hich are accom panied by

A d d r e s s fo r c o r r e s p o n d e n c e : W e r th e r B r u n o w d e C a r v a lh o R u a S a o P a u lo A n tig o , 145 1 2h

flo o r S a o P a u lo /S P .- B r a s il- C E P 0 5 6 8 4 - 0 1 0

PH (I). Pulm onary hypertension contributes to the

w orsening of hypoxem ia and overload of the right

ventricle. T hese cardiopathies lead to hypertrophy and

hyperplasia of the vascular m usculature and consequent

vasoconstriction. C onventional treatm ent after, surgery

consists of using hyperventilation, alkalization, increase

in the inhaled oxygen fraction, inotropics and vasodilators.

T he great advantage in using inhaled nitric oxide

(N O ) is that, contrary to system ic vasodilators, it only

reaches the ventilated alveoli, thereby causing selective

pulm onary vasodilation (2,3) w ith deviation of the flow

to these areas, thus im proving oxygenation and

intrapulm onary shunt, in a m anner sim ilar to w hat occurs

w ith the use of high oxygen concentrations in the

evaluation prior to surgery, during catheterization.

1 6 0 3

T a b le I

D ia g n o s is o f c a r d io p a th ie s a n d a g e r a n g e o f 5 p a tie n ts s u b m itte d to in h a le d N O a n d o x y g e n a t h ig h

c o n c e n tr a tio n s .

O u r m ain o b jectiv e w as to v erify w h eth er in h aled N O is a safe p ro ced u re fo r p atien ts w ith co n g en ital card io p ath ies an d fo r th e p ro fessio n al g ro u p in v o lv ed in its ap p licatio n . A s a seco n d ary o b jectiv e, w e co m p ared in h aled N O w ith th e ad m in istratio n o f o x y g en co n cen tratio n s clo se to 1 0 0 % , o b serv in g alteratio n s in th e m ean p u lm o n ary artery p ressu re (M P A P ), m ean ao rtic p ressu re (M A o P ), p u lm o n ary v ascu lar resistan ce (P V R ), sy stem ic v ascu lar resistan ce (S V R ) an d th e relatio n sh ip o f p u lm o n ary /sy stem ic flo w (Q p /Q s) d u rin g th e p reo p erativ e p h ase, fo r p ed iatric p atien ts w ith co n g en ital card io p ath y an d P H .

C a s e

2 3 4 5

A g e

2 y e a r s

2 y e a r s

1 y e a r

3 y e a r s

6 m o n th s

C a r d io p a th y

In te r v e n tr ic u la r c o m m u n ic a tio n ,

A o r tic in s u ffic ie n c y .

O s tio a tr iu m - v e n tr ic u la r is c o m u n is

In te r v e n tr ic u la r c o m m u n ic a tio n

In te r v e n tr ic u la r c o m m u n ic a tio n ,

P e r s is te n c e o f th e a r te r ia l c a n a l

In te r v e n tr ic u la r a n d in te r a tr ia l

c o m m u n ic a tio n

P A T IE N T S A N D M E T H O D S

R E S U L T S

F ig u r e 1 - A lte r a tio n s in p u lm o n a r y v a s c u la r r e s is ta n c e ( P V R )

d u r in g in h a la tio n o f N O ( 2 0 p p m ) a n d o x y g e n a t h ig h c o n c e n tr a tio n s .

In th is stu d y w e co u ld o b serv e, as sh o w n in F ig u re 1 , th at p atien ts 1 , 2 an d 5 p resen ted a d ecrease in p u lm o n ary v ascu lar resistan ce u sin g N O at 2 0 p p m sim ilar to th e resu lt

- - X - -c a s e 1

~ c :a s e 2

- - - '- c a s e 3

- - .- - . c a s e 4

- " " '- c a s e 5

N O ( 2 0 p p m )

O x y g e n

1 4 1 2 1 0 8 6 4 2 o B A S A L ~

.c

"

D u rin g N O in h alatio n , th e in h aled o x y g en fractio n w as m ain tain ed at a lev el o f 4 0 % to 5 0 % . M o n ito rin g o f N O an d n itro g en d io x id e (N 0

2) w as p erfo rm ed w ith a B ed fo n t

E C 9 0 m o n ito r (B ed fo n t S cien tific L td ); m o n ito rin g o f th e in h aled fractio n o f o x y g en w as p erfo rm ed th ro u g h a M in iO X III m o n ito r (C ataly st R esearch ), p laced clo se to th e p atien t's n o stril.

T h is stu d y w as carried o u t w ith th e ap p ro v al o f th e M ed ical E th ics C o m m ittee o f th e S ao P au lo H o sp ital. C riteria fo r p articip atio n in th is stu d y w ere ch ild ren b elo w 1 3 y ears w ith co n g en ital card io p ath y an d w h o p resen ted p u lm o n ary h y p erten sio n w ith M P A P >2 5 m m H g , b efo re su rg ical co rrectio n . T h e sam p le co n sisted o f 5 p atien ts p resen tin g sev eral ty p es o f card io p ath ies an d ag es ran g in g fro m 6 m o n th s to 3 y ears, as sh o w n in T ab le 1 . A ll p atien ts p resen ted p u lm o n ary h y p erten sio n b y in tracard iac sh u n t.

T h e ch ild ren w ere su b m itted to cath eterizatio n th ro u g h can n u latio n o f th e fem o ral artery . H em o d y n am ic m easu rem en ts o f th e ao rtic'p ressu re (m m H g ), p u lm o n ary artery (m m H g ) an d rig h t atriu m (m m H g ), an d m easu rem en ts o f p u lm o n ary an d sy stem ic v ascu lar resistan ces (W o o d u n its), an d p u lm o n ary (Q p ) an d sy stem ic (Q s) flo w s, w ere o b tain ed b y a stan d ard fo rm u la, w h ere th e flo w is th e ratio b etw een th e o x y g en co n su m p tio n an d th e d ifferen ce in th e arterial an d v en o u s o x y g en co n ten t (Q = V 0

2 /C a02 -C v 02, w h ere V 02 =

o x y g en co n su m p tio n ; C a0

2

=

C v 0

2 = V en o u s o x y g en co n ten t). T h ese m easu rem en ts

w ere o b tain ed in . th ree p h ases: b asal, w ith 1 0 m in u tes o f o x y g e~ , in h alatio n , an d 5 m in u tes o f N O in h alatio n at a co n cen tratio n o f 2 0 p arts p er m illio n (p p m ).

D u rin g th e p ro ced u re, th e p atien ts w ere sed ated w ith m id azo lam , in trav en o u s (IV ) at a d o sag e o f 0 .1 m g /k g , . an d b reath ed ro o m air sp o n tan eo u sly . F o r in h alatio n , an o x y g en h o o d w ith a 1 5 L /m in o x y g en flo w reach in g co n cen tratio n s b etw een 9 0 % to 9 5 % w as u sed fo r 1 0 m in u tes. N O w as ap p lied u sin g a cy lin d er w ith a m ix tu re o f n itric o x id e an d n itro g en (N O /N

2) o f 1 0 0 0 p p m . T h e

g as en tered th e circu it an d m ix ed w ith o x y g en at a flo w o f 5 1 /m in ju st b efo re ~ h e en tran ce o f th e h o o d (F ig . 1 ).

C A R V A L H O , W .B .; C A R V A L H O , A .C .C .; G U R G U E IR A , G .L .; IK E D A , A .M .; L E E , J .H .; A L M E ID A , D .R . - In h a le d n itr ic o x id e a n d h ig h c o n c e n tr a tio n s o f o x y g e n in p e d ia tr ic

• . . •" • .: " • . . • • . • •, • •i • .h " ro n n ,...n i+ • .•1 " •.•••n in " v ::lth \l - : : : I n nn l J lm f " 'ln ! J n lh \ ln A r t A n d n n ' ~ A n n r t n ff iv p .r.~~p.~

1 6 0 4

1 2 0

1

1 0 0 x - . - . - . - . - .x - · _ . _ . _

m

.-~ 8 0

S 6 0

...

_{.... -}

-.

1 0

9

8

7 6 5 4

Q p /Q s 3

2

1

o

BASAL

(2 0 p p m )

_ .x - ca so 1 ~ ca so 2

----ca so 3

•••. - .ca so 4

...- ca so 5

a .

o e :t ::E

4 0

20

o

BASAL

(2 0 p p m )

- - x - .ca se 1

- - - 0 - -

_ _ _ ca se 3

•••••. ca se 4

...- ca se 5

F igure 2 - A lterations in the relationship pulm onary/system ic flow (Q p/Q s) during inhalation of N O (20 ppm ) and oxygen at high concentrations.

o b ta in e d w ith o x y g e n in h a le d in h ig h c o n c e n tr a tio n s . A n

in c r e a s e in th e r e la tio n s h ip o f p u lm o n a r y to s y s te m ic f lo w

( Q p /Q s ) w a s o b s e r v e d in tw o p a tie n ts w ith 0 2 a n d o n ly

o n e w ith N O , a s s h o w n in F ig u r e 2 .

R e g a r d in g s y s te m ic a lte r a tio n s , th e r e w a s n o f a ll in

v a s c u la r r e s is ta n c e o r in a o r tic p r e s s u r e w h e n u s in g N O

( F ig u r e 3 ) .

T h e c o n c e n tr a tio n o f n itr o g e n d io x id e _{( N 0 2 ) v aried}

f r o m 0 to 0 .4 p p m in th e in te r io r o f th e o x y g e n h o o d w h ile

in th e p r o c e d u r e r o o m ( to ta l a r e a 1 2 m 2 ) th e c o n c e n tr a tio n

o f N O v a r ie d f r o m 0 to 5 p p m _{a n d N 0 2 w as n o t d etectab le.}

I n a d d itio n , w e d id n o t o b s e r v e a n y s y m p to m a to lo g y

in th e p r o f e s s io n a l w o r k e r s ( h e a d a c h e o r v o m it) r e la te d

to th e in h a le d N O .

D IS C U S S IO N

T h e r e a r e n o w s e v e r a l s tu d ie s ( 4 ,5 ) w h ic h h a v e

d e m o n s tr a te d th a t th e c lin ic a l u s e o f in h a le d N O is a s a f e

p r o c e d u r e a s lo n g a s s o m e p r e c a u tio n s a r e ta k e n : tr a in in g

o f th e p r o f e s s io n a l g r o u p r e s p o n s ib le f o r u tiliz a tio n o f th e

g a s , a n d c o n s ta n t m o n ito r in g _{o f N O /N 0 2 co n cen tratio n s}

a s w e ll a s th e le v e ls o f m e ta h e m o g lo b in e m ia . A c c o r d in g

to th e I n s titu te o f O c c u p a tio n a l S e c u r ity a n d

A d m in is tr a tio n o f H e a lth o f th e U n ite d S ta te s ( 6 ) ,th e lim it

f ix e d f o r e x p o s u r e to N O is 2 5 p p m , w h e n in h a le d f o r 8

h o u r s /d a y , a n d th a t _{o f N 0 2 is 5 p p m . In th is stu d y , th e}

f o r m a tio n _{o f N 0 2 in th e in terio r o f th e o x y g en h o o d d id}

n o t s u r p a s s 0 .4 p p m , it w a s n o t d e te c ta b le in th e p r o c e d u r e

r o o m , a n d th e c o n c e n tr a tio n o f N O in th e r o o m d id n o t

e x c e e d 5 p p m ; a ll th e s e v a lu e s a r e c o n s id e r e d h ig h ly

a c c e p ta b le .

F igure 3 - A lterations in the m ean aortic pressure (P A oP ) during

inhalation of oxygen at high concentrations and N O (20

ppm ).

I n o u r e x p e r im e n t N O p r o v e d to b e - a n e a s y - to - u s e

s u b s ta n c e a n d w e d id n o t o b s e r v e a n y im m e d ia te

c o m p lic a tio n o r a n y s id e - e f f e c t d u r in g th e p r o c e d u r e .

N o n e o f th e p r o f e s s io n a l w o r k e r s p r e s e n te d a n y

s y m p to m a to lo g y ( h e a d a c h e o r v o m it) .

D a ta in th e lite r a tu r e ( 7 ,8 ,9 ) h a v e d e m o n s tr a te d th e r o le

o f in h a le d N O f o r d e c r e a s in g P V R a n d im p r o v in g th e

o x y g e n a tio n o f p a tie n ts in th e p r e - a n d p o s to p e r a tiv e

p e r io d s o f p e d ia tr ic s u r g ic a l c o r r e c tio n . R o b e r ts e t a 1 .\5 )

o b s e r v e d a s ig n if ic a n t r e d u c tio n in p u lm o n a r y v a s c u la r

r e s is ta n c e , u s in g in h a le d N O d u r in g c a th e te r iz a tio n o r

p r e o p e r a tiv e e v a lu a tio n in c h ild r e n w ith c o n g e n ita l h e a r t

d is e a s e s a n d P H ; a n d h e d id n o t o b s e r v e s y s te m ic

h y p o te n s io n o r s ig n if ic a n t in c r e a s e s in th e le v e ls o f

m e ta h e m o g lo b in e m ia .

A lth o u g h in o u r in itia l e x p e r ie n c e w ith o n s m a ll

s a m p le o f 5 p a tie n ts , n o s ta tis tic a lly s ig n if ic a n t d if f e r e n c e s

w e r e o b s e r v e d r e g a r d in g th e f a ll o f P V R w h e n u s in g

in h a le d N O a s c o m p a r e d to b a s a l d a ta , w e o b s e r v e d th a t

th r e e o f th e s e p a tie n ts h a d a s ig n if ic a n t f a ll in P V R a n d

a n in c r e a s e in th e r e la tio n s h ip Q p /Q s , s im ila r to th a t

o b ta in e d b y u s in g o x y g e n in h ig h c o n c e n tr a tio n s ( 9 0 to

9 5 % ) . T h e s e r e s u lts in d ic a te th a t N O a t 2 0 p p m w a s a b le

to p r o v o k e d ila tio n o f th e p u lm o n a r y v a s c u la r s m o o th

m u s c u la tu r e w ith o u t c a u s in g s ig n if ic a n t s y s te m ic c h a n g e s ,

s in c e w e o b s e r v e d th a t th e v a lu e s o f S V R r e m a in e d

u n a lte r e d a n d v e r y c lo s e to th o s e m e a s u r e d d u r in g th e

b a s a l p h a s e , in a c c o r d a n c e w ith w h a t h a s b e e n r e p o r te d

in m a n y c lin ic a l s tu d ie s ( 4 ,5 ) .,O x y g e n a t h ig h c o n c e n tr a tio n s

m a y b e c o m e a h ~ g h ly to x ic g a s le a d in g to s e v e r e

p u lm o n a r y d is tu r b a n c e s s u c h a s a te le c ta s is , m u c o u s

d r y n e s s a n d e s p e c ia lly c y to to x ic le s io n s w ith p u lm o n a r y

e d e m a a n d r e s p ir a to r y in s u f f ic ie n c y (1 0 ).

S a o P a u lo M e d ica l Jo u rn a l/R P M 1 1 6 (1 ): 1 6 0 2 -1 6 0 5 , 1 9 9 8 C A R V A L H O , W .B .; C A R V A L H O , A .C .C .; G U R G U E IR A , G .L .; IK E D A , A .M .; L E E , J.H .;

1 6 0 5

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A L M E I D A , D . R . - I n h a le d n it r ic o x id e a n d h ig h c o n c e n t r a t io n s o f o x y g e n in p e d ia t r ic