MEDiaL
J
U R N A L
A d h e m a r M o n te iro P a c h e c o J r., R a u l S e rg io M a rtin s C o im b ra , U w e K re im e ie r, L o re n z F re y , K o n ra d M e s s m e r
H y p e rto n ic v o lu m e th e ra p y : fe a sib ility in th e p re v e n tio n a n d
tre a tm e n t o f m u ltip le o rg a n fa ilu re a n d se p sis
Department
of Surgery, Santa Casa School of Medicine, Institute for Anesthesiology,
University of Munich,
Germany
S m a ll-vo lu m e re su scita tio n b y m e a n s o f b o lu s in fu sio n o f h yp e rto n ic sa lin e so lu tio n s w a s first a p p lie d fo r th e p rim a ry tre a tm e n t o f se ve re h e m o rrh a g ic a n d tra u m a tic sh o ck a n d p ro m p tly re sto re d ce n tra l h e m o d yn a m ics a n d re g io n a l o rg a n b lo o d flo w . M e ch a n ism s o f a ctio n a re d ive rse -
i.
m a in te n a n ce o f h ig h ca rd ia c o u tp u t (d ire ct m yo ca rd ia l stim u la tio n ; in cre a se in in tra va scu la r vo lu m e ); ii. m a in te n a n ce o f p e rip h e ra l a rte ria l va so d ila tio n (e ffe ct o f h yp e ro sm o la lity; p la sm a vo lu m e e ffe ct) a n d iii. re d u ctio n o f tissu e e d e m a (sh iftin g o f tissu e w a te r a lo n g th e o sm o tic g ra d ie n t). T h e se m e ch a n ism s p ro m o te th e re sto ra tio n o f th e se ve re ly im p a ire d m icro circu -la tio n fre q u e n tly se e n a lso in se p sis. H yp e rto n ic vo lu m e th e ra p y h a s b e e n th e o b je ct o f se ve ra l e xp e rim e n ta l stu d ie s o f a cu te h yp e rd yn a m ic e n d o to xe m ia , h o w e ve r, a g re a te r n u m b e r o f clin ica l stu d ie s h a ve to b e d e ve lo p e d fo r th e b e tte r u n d e rsta n d in g o f th e p o sitive , a n d p e rh a p s h a za rd o u s, e ffe cts o f sm a ll-vo lu m e re su scita tio n in se p sis a n d m u ltip le o rg a n fa ilu re . T h e a im o f th is p a p e r is to re vie w th e co n ce p ts in vo lvin g su ch so lu tio n s, a n d th e ir p o te n tia l u se in tre a tm e n t o f p ro fo u n d h yp o vo le m ia a n d m icro circu la to ry d e te rio ra tio n a sso cia te d w ith se p sis a n d e n d o to xic sh o ck.U N IT E R M S : S e p sis. M u ltip le o rg a n fa ilu re . H yp e rto n ic so lu tio n . S h o ck.
IN T R O D U C T IO N
I
in b o thn ju r yis th e le a d in gm a le s a n d f e m a le sc a u s e o f m o r b id ityu n d e r 4 5 y e a r sa n d m o r ta lityo f a g e a n d th e th ir d c a u s e in th e g e n e r a l p o p u la tio n , p r e c e d e d o n ly b y c a r d io v a s c u la r d is e a s e s a n d c a n c e r ( 2 , 4 2 ) . E f f o r ts to " r e d u c e tr a u m a d e a th s f o c u s o n th e im p r o v e m e n t o f p r e-A d d re s s fo r c o rre s p o n d e n c e :
A d h e m a r M . P a c h e c o J r. R . M a rtin ic o P ra d o , 9 0 / A p . 1 3 3 S a o P a u lo /S P - B ra s il- C E P 0 1 2 2 4 -0 1 0
h o s p ita l c a r e b y r a p id r e s u s c ita tio n f r o m h y p o v o le m ia a n d s y s te m ic h y p o te n s io n . B e s id e s v e n tila to r y a s s is ta n c e , p r im a r y r e s u s c ita tio n f r o m s e v e r e tr a u m a a n d s h o c k a im s a t c a r d io c ir c u la to r y s u p p o r t b y v ig o r o u s v o lu m e th e r a p y a n d e v e n tu a lly v a s o a c tiv e d r u g s to e n s u r e p e r ip h e r a l o x y g e n d e liv e r y .
S e v e r e h y p o v o le m ia a n d tr a u m a tic s h o c k c a u s e a s ig n if ic a n t r e d u c tio n in s p la n c h n ic b lo o d f lo w a n d is c h e m ic in ju r y o f th e in te s tin a l m u c o s a ( 1 6 , 3 2 ) . S h o c k a n d h y p o p e r f u s io n , c a u s e m u c o s a l in ju r y , a n d r e s u lt in th e s u b s e q u e n t tr a n s lo c a tio n o f b a c te r ia a n d to x in s f r o m th e g u t lu m e n in to th e s y s te m ic c ir c u la tio n ( 3 ) . T h e c o n c e p t o f th e r e p e r f u s io n le s io n b y g e n e r a tio n o f o x y g e n f r e e r a d ic a ls v ia th e e n z y m e x a n th in e o x id a s e , w h ic h h a s its h ig h e s t c o n c e n tr a tio n in th e v illo u s tip o f th e in te s tin a l m u c o s a , h a s b e e n id e n tif ie d a s th e k e y d e te r m in a n t in th e p r o c e s s o f b a c te r ia l a n d e n d o to x in tr a n s lo c a tio n ( 1 6 ,
1 9 ).
T h e
re c o g n itio n
th a t g u t fa ilu re
a n d th a t o f d ista n t
o rg a n s
m a y
b e c a u sa lly
re la te d
h a s le d to h e ra ld in g
th e
g u t a s th e
"m o to r"
o f m u ltip le
sy ste m
o rg a n
fa ilu re
(8 ,
1 3 ). S y ste m ic
se p sis a n d la te m u ltip le
sy ste m o rg a n fa ilu re
a re th e
m o st
fre q u e n t,
a n d o fte n
fa ta l
c o m p lic a tio n s
o f
tra u m a
a n d m a jo r
su rg e ry
(7 , 1 2 , 5 1 ).
T h e
p rim a ry
fa c to r
re n d e rin g
p a tie n ts
a t risk
fo r
d e v e lo p in g
m u ltip le
sy ste m
o rg a n fa ilu re
a fte r sh o c k a n d
tra u m a
is th e
p e rsiste n c e
o f im p a ire d
m ic ro -c irc u la tio n
w ith
its se q u e la e
fo r c e llu la r
a n d o rg a n
fu n c tio n
(6 , 4 2 ).
A s a c o n se q u e n c e
o f p ro lo n g e d
lo w flo w sta te , a sso c ia te d
w ith
m a ssiv e
b lo o d
lo ss
a n d
tissu e
tra u m a ,
n u tritio n a l
b lo o d flo w a n d o x y g e n
d e liv e ry
a re c o m p ro m ise d
(2 9 , 3 0 ).
T h e c a p illa rie s'
lu m e n b e c o m e s
n a rro w e d
d u e to sw e llin g
o f
e n d o th e lia l
c e ll's
a n d
th e
a d h e sio n
o f
a c tiv a te d
p o ly m o rp h o n u c le a r
le u k o c y te s
(P M N L )
to
th e
e n d o th e liu m
a re p h e n o m e n a
th a t m a y c o m p le te ly
a b o lish
lo c a l flo w .
In a d d itio n ,
th e in te ra c tio n
o f P M N L
w ith th e
v e n u la r
e n d o th e liu m
is e n h a n c e d
b y th e lib e ra tio n
o f to x ic
o x y g e n
sp e c ie s
(2 0 )
a n d
fo llo w e d
b y
th e
re le a se
o f
v a so a c ti v e m e d ia to rs
(2 6 ), p ro m o tin g
fu rth e r re d istrib u tio n
o f tissu e p e rfu sio n
a n d im p e d im e n t
o f n u tritio n a l
flo w (6 ,
4 2 ).
M ic ro c irc u la to ry
fa ilu re
p re se n t
d u rin g
e sta b lish e d
se p sis
is d e v e lo p e d
a n d su sta in e d
b y th e d ire c t
a c tio n
o f
e n d o to x in
a n d th e re le a se
o f v a so a c tiv e
m e d ia to rs
(2 1 ).
C y to k in e s
su c h
a s in te rle u k in -l
a n d
in te rle u k in -6
a n d
tu m o r n e c ro sis
fa c to r a re a b le to e lic it m a n y o f th e sy ste m ic
e ffe c ts c h a ra c te ristic a lly
se e n d u rin g e n d o to x e m ia
(1 7 ,4 3 ).
T h e se
c y to k in e s
h a v e
a lso re c e n tly
b e e n
sh o w n
to o c c u r
in th e b lo o d stre a m
a s a re sp o n se
to h e m o rrh a g e
a n d tissu e
tra u m a
(1 4 ).
T h e e n su in g
a c tiv a tio n
o f c a sc a d e
sy ste m s
a n d
P M N L -e n d o th e lia l
in te ra c tio n
fa v o r
a sig n ific a n t
re d istrib u tio n
o f
c a p illa ry
p e rfu sio n
w ith in
th e
m ic ro v a sc u la r
n e tw o rk ,
re su ltin g
in a c ritic a l
o v e ra ll
re d u c tio n
in
n u tritio n a l
b lo o d
flo w
(9 ,
4 2 ,
5 0 ).
M ic ro c irc u la to ry
fa ilu re is th u s re g a rd e d
a s a p re d o m in a n t
m e c h a n ism
fo r
in a d e q u a te
o x y g e n
e x tra c tio n ,
w h ic h
d e v e lo p s
a s e a rly
a s th e
in itia l
h y p e rd y n a m ic
p h a se
o f
se p tic
sh o c k
(5 , 4 2 , 4 8 ).
"T h e
h y p e rto n ic
sm a ll-v o lu m e
tre a tm e n t
w ith
h y p e rto n ic
sa lin e
so lu tio n s
h a s b e e n v a lid a te d
in v a rio u s
e x p e rim e n ta l
m o d e ls
o f se v e re
h e m o rrh a g ic
sh o c k a n d in
p re -h o sp ita l
a n d
e m e rg e n c y
ro o m
c a re
tria ls
o f tra u m a
p a tie n ts.
D a ta
fro m
th e se
p a p e rs
h a v e d e m o n stra te d
th e
e ffic a c y
o f h y p e rto n ic
v o lu m e
th e ra p y
in re sto rin g
c e n tra l
h e m o d y n a m ic s
a n d
in
n o rm a liz in g
th e
a ffe c te d
m ic ro c irc u la tio n .
H e n c e ,
p re v e n tio n
o f e a rly
d e a th s
a n d
la te
c o m p lic a tio n s,
su c h
a s se p sis
a n d
m u ltip le
sy ste m
o rg a n
fa ilu re ,
h a s
stim u la te d
th e
in v e stig a tio n
o f th e
fe a sib ility
o f
th is
n e w
c o n c e p t
in v o lv in g
v o lu m e
re p la c e m e n t
in se p sis
a n d e n d o to x ic
sh o c k .
C O N C E P T O F " S M A L L - V O L U M E
R E S U S C I T A T I O N "
E x p e rim e n ta l
d a ta o n sm a ll-v o lu m e
re su sc ita tio n
o f
d o g s su b je c te d
to se v e re
h e m o rrh a g ic
sh o c k ,
w h ic h
w a s
le th a l
in
a n im a ls
tre a te d
w ith
iso to n ic
sa lin e ,
w e re "
p u b lish e d
in 1 9 8 0 .
T h e a u th o rs
d e m o n stra te d
th a t 7 .5 %
sa lin e in fu se d
in a v o lu m e
e q u iv a le n t
to o n ly
1 0 % o f th e
sh e d
b lo o d
v o lu m e
ra p id ly
in c re a se d
sy ste m ic
p re ssu re
a n d re sto re d
c a rd ia c
o u tp u t,
th u s a llo w e d
1 0 0 % lo n g -te rm
su rv iv a l
o f d o g s (5 2 ).
D e F e lip p e
e t a I., d e sc rib e d
th e
h y p e rto n ic
sm a
ll-v o lu m e
th e ra p y
o n
1 2
in te n siv e
c a re
p a tie n ts
in
h y p o v o le m ic
sh o c k
re fra c to ry
to c o n v e n tio n a l
tre a tm e n t.
In
th e se
p a tie n ts,
th e
sh o c k
sta te
w a s
re se rv e d
a fte r
in tra v e n o u s
in je c tio n s
o f
1 0 0 -4 0 0
m l o f 7 .5 %
so d iu m
c h lo rid e
- g iv e n
5 0 m l a t a tim e
- b y
a rise
in a rte ria l
p re ssu re ,
im p ro v e m e n t
o f u rin e
flo w
a n d
re c o v e ry
o f
c o n sc io u sn e ss
(1 5 ).
In
th e
p a st
fe w
y e a rs,
v a rio u s
re se a rc h
g ro u p s
d e v e lo p e d
th e n o v e l
c o n c e p t
o f p rim a ry
re su sc ita tio n
b y
m e a n s
o f h y p e rto n ic
sa lin e
so lu tio n s
a n d
d e m o n stra te d
th a t, e v e n in th e p re se n c e
o f a 5 0 %
b lo o d
lo ss, a v o lu m e
a s sm a ll
a s 4 m llk g
b o d y
w e ig h t
o f 7 .2 % -7 .5 %
so d iu m
c h lo rid e is e n o u g h to in sta n ta n e o u sly
re sto re c a rd ia c o u tp u t
a n d to sig n ific a n tly
in c re a se
sy ste m ic
p re ssu re
(2 7 , 3 0 ).
D u rin g
sm a ll-v o lu m e
re su sc ita tio n
th e h y p e rto n ic
sa lin e
so lu tio n
is g iv e n
fo r 2 -5 m in th ro u g h
a p e rip h e ra l
v e in ;
th is
m o d e
o f
a d m in istra tio n
re su lts
in
a ra p id
a n d
p ro n o u n c e d
in c re a se
in th e p la sm a
so d iu m
c o n c e n tra tio n
a n d th e re b y
in itia te s
a ste e p
tra n sm e m b ra n e o u s
o sm o tic
g ra d ie n t.
T h e
m o st
im p o rta n t
m e c h a n ism
o f a c tio n
o f
h y p e rto n ic
so lu tio n s
is th e in sta n ta n e o u s
m o b iliz a tio n
o f
e n d o g e n o u s
flu id
a lo n g
th e
o sm o tic
g ra d ie n t
w ith
a n
in c re a se
in tra v a sc u la r
v o lu m e
(2 7 , 3 8 ); in a d d itio n ,
d ire c t
m y o c a rd ia l
stim u la tio n ,
c e n tra l
n e rv o u s
sy ste m
(C N S )
stim u la tio n ,
n e u ro g e n ic
re fle x
m e c h a n ism s,
e n h a n c e d
sy m p a th e tic
d i"sc h a rg e , h o rm o n e
re le a se ,
im p ro v e m e n t
o f
b lo o d flu id ity ,
re -e sta b lish m e n t
o f sp o n ta n e o u s
a rte rio la r
v a so m o tio n ,
a n d
p e rip h e ra l
a rte ria l
v a so d ila tio n
a re
in v o lv e d
(2 7 ).
M o st re c e n t stu d ie s
su g g e st
th a t th e ra p id
c a rd io v a sc u la r
re sp o n se
to h y p e rto n ic
so lu tio n s
m ig h t b e
p a rtly
m e d ia te d
b y th e re le a se
o f e ic o sa n o id s
(3 6 ).
In se v e re
h y p o v o le m ia ,
b o lu s
in fu sio n
o f 4 m llk g
b o d y
w e ig h t
7 .2 % -7 .5 %
sa lin e
so lu tio n
h a s b e e n
sh o w n
to le a d to a n in c re a se
in p la sm a
v o lu m e
b y 8 -1 2
m l/k g
b o d y w e ig h t (4 5 ,4 9 ).
M a z z o n i
e t a I., h a v e c a lc u la te d
th a t,
a fte r a 2 0 %
b lo o d
lo ss, 7 .5 %
sa lin e
so lu tio n
g iv e n
o v e r
1 0 se c in a n a m o u n t e q u iv a le n t
to o n e -se v e n th
o f th e a c tu a l
b lo o d lo ss, re -e sta b lish e s
n o rm a l b lo o d v o lu m e
w ith in o n e
S a o P a u lo M e d ic a l J o u r n a l/ R P M 1 1 3 ( 6 ) : 1 0 5 3 - 1 0 6 0 , 1 9 9 5 P A C H E C O J r . , A . M . ; C O I M B R A , R . S . M . ; K R E I M E I E R , U . ; F R E Y , L . & M E S S M E R , K . - H y p e r t o n ic
1 0 5 5
m in (3 8 ).
T h ese au th o rs
ascrib e th e in stan tan eo u s
v o lu m e
effect to th e rap ip in flu x
o f flu id fro m
th e m icro v ascu lar
en d o th eliu m ,
red b lo o d
cells, an d th e in terstitiu m .
H Y P E R T O N I C
S A L I N E / D E X T R A N
R E S U S C I T A T I O N
S ev eral
au th o rs
h av e rep o rted
th e tran sien t
resp o n se
o f
th e
card io v ascu lar
sy stem
after
sm all-v o lu m e
resu scitatio n
u sin g ex clu siv ely
h y p erto n ic
so d iu m ch lo rid e
(2 7 ).
In o rd er to p reserv e
th e in trav ascu lar
v o lu m e
g ain ,
7 .2 % -7 .5 %
salin e
so lu tio n
h as
b een
co m b in ed
w ith
co llo id s,
i.e., d ex tran
6 0 /7 0 o r h y d ro x y eth y lstarch ,
to elicit
a sy n erg istic
effect
b y in creasin g
p lasm a
o sm o lality
an d
p ro v id in g
h ig h p lasm a o n co tic p ressu re (8 , 2 4 , 2 7 ). A n im al
stu d ies
h av e
rev ealed
th at,
co m p ared
w ith
h y p erto n ic
so d iu m
ch lo rid e
alo n e,
h y p erto n ic
salin e
6 % d ex tran
7 0
cau ses
o n ly
a slig h tly
b etter
in itial
resp o n se,
b u t clearly
lead s
to a m o re
su stain ed
circu lato ry
resp o n se
an d
an
in creased
su rv iv al
(2 5 , 3 4 ,4 9 ,5 3 ).
B ased o n o rig in al w o rk
p u b lish ed
b y S m ith
et al. (4 9 ), K ram er
an d co -w o rk ers
recen tly
rep o rted
th at h y p erto n ic
so d iu m
ch lo rid e
m ix ed
w ith 6 % d ex tran
7 0 g iv en
after sev ere
h em o rrh ag e
o v er
tw o
h o u rs
resto red
card iac
o u tp u t
fo r at least
1 8 0 m in ,
w h ich
w as
sig n ifican tly
lo n g er
th an
h y p erto n ic
salin e
so lu tio n
alo n e o r 6 % d ex tran
7 0 in iso to n ic
salin e (2 5 ).
T h e co n cep t o f ap p ly in g
sm all v o lu m es o f h y p erto n ic
salin e/d ex tran
so lu tio n
fo r p rim ary
resu scitatio n
fro m
sev ere
h y p o v o lem ia
h as
p ro v en
to b e effectiv e
in a
p ro sp ectiv ely
ran d o m ized
stu d y
o f trau m a
p atien ts.
A s
co m p ared
to R in g er's
lactate,
b o lu s
in fu sio n
o f 2 5 0
m l
7 .5 % N aC I
4 .2 % d ex tran
7 0 at th e
site
o f th e
accid en t
resu lted
in a h ig h er
sy stem ic
p ressu re
(4 9 m m H g
v s 1 9
m m H g )
an d
h ig h er
su rv i v al rate
(8 /1 0 p atien ts
v s 3 /1 0
p atien ts)
(2 2 ).
In an ex ten sio n
o f th eir first stu d y , in 1 9 8 9
H o lcro ft
et aI., rep o rted
a stu d y
in v o lv in g
6 0 trau m a
p atien ts
in a
ran d o m ized ,
p ro sp ectiv e
d o u b le-b lin d
trial.
T h e
ad m in istratio n
o f 7 .5 %
salin e/d ex tran
resu lted
in
h ig h er
b lo o d
p ressu re
w h en
th e
p atien ts
reach ed
th e
em erg en cy
ro o m
as co m p ared
to R in g er's
lactate g iv en in
th e sam e am o u n t
(2 5 0 m l), an d fo llo w ed
b y co n v en tio n al
flu id th erap y .
T h e 3 0 -d ay -su rv iv al
rate w as sig n ifican tly
h ig h er
after sm all-v o lu m e
resu scitatio n
u sin g
h y p erto n ic
salin e/d ex tran
(2 3 ).
M atto x
et aI., in 1 9 9 1 , an aly zed
3 5 9 p atien ts
w ith a
m ean In ju ry S ev erity S co re (IS S ) o f 1 9 , w h o receiv ed eith er
2 5 0 m l 7 .5 %
salin e
in 6 % d ex tran
7 0 o r R in g er's
lactate,
fo llo w ed
b y co n v en tio n al
th erap y . T h ere w as n o d ifferen ce
in o v erall
su rv iv al
w ith in
th e first 2 4 h o u rs;
h o w ev er,
in
th e su b g ro u p
o f p atien ts
req u irin g
su rg ery
an d th o se w ith
a p en etratin g
in ju ry ,
h y p erto n ic
salin e/d ex tran
in fu sio n
p ro v ed
to b e su p erio r
to R in g er's
lactate
(p
<0 .0 2 an d p
<0 .0 1 ,
resp ecti
v ely ).
In
ad d itio n ,
th ere
w ere
few er
co m p licatio n s
(acu te resp irato ry
d istress
sy n d ro m e,
ren al
failu re, co ag u lo p ath y )
th an in th e stan d ard
treatm en t
g ro u p
(3 7 ).
T h e u se o f h y p erto n ic
salin e/d ex tran
so lu tio n s
h as
p ro v en
to b e safe
in p atien ts,
as H o lcro ft
et al. (2 3 ),
M an in g as
et al.
(3 5 ),
an d
M atto x
et
al.
in th e
U S A
m u lticen ter
trial (3 7 ), d id n o t en co u n ter
an y ad v erse effects.
In p articu lar,
n o an ap h y lacto id
reactio n s
o r d ex tran -related
co ag u lo p ath ies
w ere o b serv ed .
E F F E C T O F S M A L L - V O L U M E
R E S U S C I T A T I O N
O N T H E
M I C R O C I R C U L A T I O N
I N T R A U M A
A N D
S H O C K
M icro circu lato ry
im p airm en t,
w ith
its
seq u elae
affectin g cellu lar an d o rg an fu n ctio n ,
is a ch allen g in g
facto r
after
p rim ary
resu scitatio n
fro m
sev ere
trau m a.
T h e
p ersisten ce
o f th is
co n d itio n
m ay
trig g er
a sy stem ic
in flam m ato ry
resp o n se
an d m u ltip le
sy stem
o rg an failu re.
K ram er
et aI.,
d em o n strated
an
in crease
in
o x y g en
co n su m p tio n
in
u n an esth etized
ad u lt
sh eep
resu scitated
fro m
sev ere
h em o rrh ag e
b y 7 .5 % salin e
6 % d ex tran
7 0 in
a d o se eq u iv alen t
to 1 0 % o f b lo o d
lo ss (2 4 ).
In ad d itio n ,
N ak ay am a
et aI.,
d escrib ed
th e
rev ersal
o f
cellu lar
ab n o rm alities
after h em o rrh ag ic
sh o ck in rats (4 6 ).
T h ese
lab o rato ry
fin d in g s
co n firm
th e p o sitiv e
resu lts
fro m
th e
ab o v e cited p re-clin ical
trials, an d h av e receiv ed
su b stan tial
su p p o rt
fro m recen t ex p erim en tal
stu d ies
o n th e effect o f
sm all-v o lu m e
resu scitatio n
w ith
h y p erto n ic
so lu tio n s
o n
o rg an
an d n u tritio n al
b lo o d
flo w
(2 9 , 3 0 , 3 3 , 4 7 ).
O u r
ex p erim en tal
d ata p rev io u sly
p u b lish ed ,
b ased
o n stu d ies
em p lo y in g
rad io activ e
m icro sp h eres
in
p ro tracted
trau m atic-h em o rrh ag ic
sh o ck w ith a 5 0 % b lo o d lo ss, h av e
d em o n strated
th at
n u tritio n al
b lo o d
flo w
sig n ifican tly
in creases
w ith in 5 m in o f i.v . b o lu s in fu sio n
'o f o n ly 4 m il
k g b o d y
w eig h t
7 .2 %
salin e,
w h ile
th e p erip h eral
sh u n t
flo w rem ain s
far b elo w
p re-h em o rrh ag e
lev els
(2 9 ).
T h e
ad d itio n
o f h y p ero n co tic
(l 0 % )
d ex tran
6 0
n o t
o n ly
p ro lo n g s
b u t
also
sig n ifican tly
en h an ces
th e
m icro circu lato ry
effect
o f 7 .2 %
salin e
alo n e
(T ab le
1
)-in fu sio n
o f 4 m llk g
b o d y
w eig h t
o f
1 0 %
d ex tran
6 0 in
7 .2 %
salin e
so lu tio n
in o u r
ex p erim en ts
co m p letely
resto red
n u tritio n al
b lo o d flo w in k id n ey ,
g astric
m u co sa,
'TABLE 1
Com parative evaluation of the m echanism s involved in sm all-volum e
resuscitation
using 7.2% -7.5% saline and 6% -12% dextran
60nO
solution
1. Restoration of plasma volume
2. Vasodilation
3. Myocardial stimulation
4. Hemodilution with improvement in blood fluidity
5. Restoration of spontaneous arteriolarvasomotion
6. Reduction of leukocyte/endothelial
interaction
7.2% -7.5% NaCI
+++
++
++
++
++
o
6% -12% Dextran 60/70
++
+
+
+++
+
++
s m a ll in te s tin e , c o lo n a n d p a n c re a s . D e s p ite s im ila r
c h a n g e s o f th e c e n tra l h e m o d y n a m ic p a ra m e te rs (s y s te m ic
p re s s u re , c a rd ia c o u tp u t), b lo o d flo w to th e s e o rg a n s
re m a in e d s ig n ific a n tly lo w e r a fte r h y p e rto n ic s a lin e
re s u s c ita tio n w ith o u t d e x tra n (2 9 ).
O n e re a s o n fo r th e s u p e rio rity o f th e h y p e rto n ic
-h y p e ro n c o tic s a lin e /d e x tra n s o lu tio n a p p e a rs to b e th e h ig h
o n c o tic p o w e r a n d w a te r b in d in g c a p a c ity o f c o n c e n tra te d
d e x tra n s o lu tio n - th e 2 5 g d e x tra n in fu s e d w ith , e .g . 2 5 0
m l 1 0 % d e x tra n 6 0 , w ill h a v e th e a b ility to k e e p 5 0 0 -6 2 5
m l w a te r in th e in tra v a s c u la r s p a c e . T h is m a in ta in s th e
c irc u la to ry e ffe c t e lic ite d b y th e h y p e rto n ic s a lin e s o lu tio n ,
a s c o m p a re d to th e a d d itio n o f a le s s c o n c e n tra te d s o lu tio n ,
i.e ., 6 % d e x tra n 6 0 , (w a te r b in d in g c a p a c ity 3 0 0 -3 7 5 m Il
2 5 0 m 1 6 % d e x tra n s o lu tio n ). F u rth ~ rm o re , B a y e r a n d c o
-w o rk e rs h a v e re c e n tly p re s e n te d th e ir d a ta o n th e
m ic ro c irc u la to ry e ffe c ts o f h y p e rto n ic -h y p e ro n c o tic
d e x t~ a n s o lu tio n a fte r is c h e m ia /re p e rfu s io n in ju ry in th e
h a m s te r d o rs a l s k in fo ld m o d e l (4 ). T h e s e a u th o rs
d e m o n s tra te d th a t u p o n 4 h is c h e m ia a n d re p e rfu s io n o f
s tria te d m u s c le , th e n u m b e r o f le u k o c y te s a d h e rin g to th e
Table 2
Effects of sm all-volum e resuscitation
using 7.2% -7.5% saline/dextran solution
Systemic pressure
Cardiac output
Vascular resistance
Nutritional blood flow
Urinary output
Survival rate
e n d o th e liu m o f p o s tc a p illa ry v e n u le s w a s s ig n ific a n tly
re d u c e d o v e r 2 4 h p o s tre p e rfu s io n a fte r b o lu s in fu s io n o f
h y p e rto n ic s a lin e /d e x tra n s o lu tio n , w h e re a s th e h y p e rto n ic
s a lin e a lo n e d id n o t e x h ib it a s ig n ific a n tly p ro te c tiv e e ffe c t
o n p o s tis c h e m ic le u k o c y te /e n d o th e lia l in te ra c tio n . B a s e d
o n la b o ra to ry in v e s tig a tio n o n u n c o n tro lle d h e m o rrh a g e
in a n e s th e tiz e d ra b b its , h y p e rto n ic s a lin e /d e x tra n h a s b e e n
s u g g e s te d to in c re a s e " in trin s ic " m ic ro v a s c u la r re a c tiv ity ,
a n d th u s le a d to m o re e ffic ie n t c a rd io d y n a m ic
im p ro v e m e n t th a n c o n v e n tio n a l re s u s c ita tio n w ith R in g e r's
la c ta te g iv e n e v e n a t 8 .5 tim e s th e in fu s io n v o lu m e o f
h y p e rto n ic s a lin e /d e x tra n (1 1 ).
HYPERTONIC SOLUTIONS IN SEPSIS AND
ENDOTOXIN SHOCK
A fte r th e in itia l e x p e rim e n ta l w o rk b y V e la s c o a n d
c o -w o rk e rs (5 2 ) a n d th e c lin ic a l o b s e rv a tio n s o f D e F e lip p e
e t a l. o n in te n s iv e c a re p a tie n ts (1 5 ), v a rio u s re s e a rc h
g ro u p s s ta rte d to in v e s tig a te th e c irc u la to ry e ffe c t o f
h y p e rto n ic s o lu tio n s in s ta n d a rd iz e d a n im a l m o d e ls o f
h e m o rrh a g ic s h o c k , w h e re a s d a ta o n its e ffe c t o n
e x p e rim e n ta l m o d e ls o f s e p s is a n d e n d o to x in s h o c k h a v e
re m a in e d s c a rc e .
T h e in fu s io n o f h y p e rto n ic s o lu tio n s w ith a n
o s m o la lity o f 2 4 0 0 m o s m o l/k g c o n ta in in g 5 0 % g lu c o s e ,
in s u lin a n d p o ta s s iu m
(G IK ),
is k n o w n to im p ro v e m y o c a rd ia l p e rfo rm a n c e in s e p tic s h o c k in d o g s (1 0 ).M u llin s a n d H u d g e n s re p o rte d th a t a s m a ll v o lu m e o f
h y p e rto n ic s a lin e -1 .2 m llk g o f 1 0 8 0 m m o l s o d iu m /l (6 .3 %
N a C l s o lu tio n ) g iv e n o v e r 9 0 m in . re s u s c ita te d d o g s in
e n d o to x in s h o c k to th e s a m e e x te n t a s th e id e n tic a l a m o u n t
o f s o d iu m g iv e n a s is o to n ic R in g e r's la c ta te (4 4 ).
1057
T re a tm e n t w ith h y p e rto n ic sa lin e w a s a sso c ia te d w ith a
sm a lle r in c re a se in sk in a n d su b c u ta n e o u s tissu e ly m p h
flo w , in d ic a tin g le ss in te rstitia l e d e m a fo rm a tio n . R e c e n tly ,
A rm iste a d e t a I., c o m p a re d th e e ffe c t o f 1 0 m l/k g b o d y
w e ig h t h y d ro x y e th y lsta rc h (H E S 4 5 0 /0 .7 ) in 0 .9 % N a C I
w ith h y d ro x y e th y lsta rc h in 7 .5 % N a C I g iv e n o v e r 3 0 m in
fo r in itia l flu id re su sc ita tio n in se p tic sh o c k in d o g s (1 ).
A rte ria l p re ssu re , c a rd ia c fillin g p re ssu re s, c a rd ia c o u tp u t,
stro k e v o lu m e , o x y g e n d e liv e ry a n d o x y g e n c o n su m p tio n
re a c h e d h ig h e r v a lu e s a fte r th e a d m in istra tio n o f th e
h y p e rto n ic sa lin e /h y d ro x y e th y lsta rc h a s c o m p a re d to
iso to n ic h y d ro x y e th y l sta rc h ; h o w e v e r, th e flu id
re q u ire m e n ts d u rin g th e su b se q u e n t 3 h w e re n o t
sig n ific a n tly d iffe re n t b e tw e e n th e tw o g ro u p s.
B a se d o n th e fa v o ra b le re su lts o b ta in e d in o u r
p re v io u s stu d ie s o n sm a ll-v o lu m e re su sc ita tio n fro m
h e m o rrh a g ic (3 0 ) a s w e ll a s tra u m a tic -h e m o rrh a g ic
h y p o te n sio n (2 9 ), w e h a v e a n a ly z e d th e e ffic a c y o f
h y p e rto n ic -h y p e ro n c o tic so lu tio n in a sta n d a rd iz e d m o d e l
o f a c u te p o rc in e e n d o to x e m ia . O u r m o d e l is c h a ra c te riz e d
b y a h ig h c a rd ia c o u tp u t/lo w p e rip h e ra l re sista n c e
c irc u la to ry sta te d u rin g su sta in e d i.v . in fu sio n o f e n d o to x in ,
w ith v ig o ro u s v o lu m e su p p o rt in o rd e r to m a in ta in th e
n o rm a l le ft v e n tric u la r fillin g p re ssu re (2 8 ). In th e se
e x p e rim e n ts, 4 m l/k g b o d y w e ig h t o f h y p e rto n ic (7 .2 % )
sa lin e c o m b in e d w ith h y p e ro n c o tic (1 0 % ) d e x tra n 6 0
so lu tio n w e re g iv e n a s b o lu s in fu sio n o v e r 2 m in a fte r 3 0
m in o f h y p e rd y n a m ic e n d o to x e m ia (3 1 ). S m a ll-v o lu m e
re su sc ita tio n w ith h y p e rto n ic sa lin e /d e x tra n so lu tio n le d
to a sig n ific a n tly in c re a se in c a rd ia c in d e x w ith in le ss th a n
5 m in , w h ile sy ste m ic p re ssu re re m a in e d u n a ffe c te d . T h e
h y p e rd y n a m ic c irc u la to ry sta te w a s m a in ta in e d th ro u g h o u t
th e e n su in g 3 h o b se rv a tio n p e rio d , d u rin g w h ic h o n ly a
fra c tio n o f th e a m o u n t o f c o n v e n tio n a l 6 % d e x tra n 6 0 h a d
to b e su b stitu te d a s c o m p a re d to a c o n tro l g ro u p w ith o u t
p re in je c tio n o f h y p e rto n ic sa lin e /d e x tra n . S y ste m ic o x y g e n
d e liv e ry , a s w e ll a s b lo o d flo w to h e a rt, k id n e y s, a n d
sp la n c h n ic o rg a n s, re m a in e d h ig h (3 1 ).
T h e fo llo w in g m e c h a n ism s a re re sp o n sib le fo r th e
e ffe c ts o f h y p e rto n ic v o lu m e th e ra p y in h y p e rd y n a m ic
se p sis a n d e n d o to x in sh o c k - i. m a in te n a n c e o f h ig h c a rd ia c
o u tp u t (d ire c t m y o c a rd ia l stim u la tio n ; in c re a se in p re lo a d );
ii. m a in te n a n c e o f p e rip h e ra l v a so d ila ta tio n (d ire c t e ffe c t
o fh y p e ro sm o la lity ; v o lu m e e ffe c t); iii. re d u c tio n o f tissu e
e d e m a (sh iftin g tissu e w a te r). T h e se th re e m e c h a n ism s
p ro m o te th e re sto ra tio n o f th e se v e re ly im p a ire d
m ic ro c irc u la tio n .
F u rth e rm o re , sm a ll-v o lu m e re su sc ita tio n re d u c e s
b lo o d v isc o sity d u e to th e c o n c u rre n t h e m o d ilu tio n , th e re b y
im p ro v in g th e flu id ity o f b lo o d th ro u g h th e c a p illa rie s, a n
e ffe c t th a t is e v e n m o re p ro n o u n c e d w h e n h y p e rto n ic sa lin e
is c o m b in e d w ith a c o llo id w h ic h itse lf e x h ib its p o sitiv e
rh e o lo g ic p ro p e rtie s. T h e sp e c ific a c tio n o f h y p e rto n ic
sa lin e re su sc ita tio n a t th e m ic ro c irc u la to ry le v e l h a s b e e n
e m p h a siz e d b y M a z z o n i a n d c o -w o rk e rs (3 8 ), w h o
c o n c lu d e d fro m th e ir m o d e l a n a ly sis o n b lo o d v o lu m e
re sto ra tio n a fte r h e m o rrh a g e , th a t m o b iliz a tio n o f flu id o u t
o f th e e n d o th e liu m is m o st p ro n o u n c e d in th o se c a p illa rie s
w ith sw o lle n e n d o th e liu m , a c o n d itio n th a t is fre q u e n tly
o b se rv e d a fte r su sta in e d p e rio d s o f e v e n fo c a l isc h e m ia .
T h is sh ift o f flu id fro m th e e n d o th e liu m in c re a se s th e
lu m in a l d ia m e te r, a n d th u s re d u c e s th e h y d ra u lic re sista n c e
o f c a p illa rie s. T h e sa m e a u th o rs d e m o n stra te d th e
re o p e n in g o f sh o c k -n a rro w e d c a p illa rie s u p o n in fu sio n o f
7 .5 % N a C I 6 % d e x tra n 7 0 in th e te n u issim u s m u sc le o f
ra b b its in h e m o rrh a g ic sh o c k (3 9 ).
C L I N I C A L A P P L I C A T I O N
O F S M A L L
-V O L U M E
R E S U S C I T A T I O N
T h e p ro m isin g re p o rts fro m p re -c lin ic a l stu d ie s a b o u t
th e e ffic a c y o f sm a ll-v o lu m e re su sc ita tio n u sin g h y p e rto n ic
sa lin e /d e x tra n so lu tio n s fo r p rim a ry tre a tm e n t o f se v e re
tra u m a a n d h e m o rrh a g e (2 2 , 2 3 , 3 5 ), a n d th e p o te n tia lly
fa v o ra b le o p e ra tio n a l m e c h a n ism s, p a rtic u la rly a t th e le v e l
o f th e m ic ro c irc u la tio n , h a v e in itia te d c lin ic a l
in v e stig a tio n s in in te n siv e c a re p a tie n ts (2 7 ). R e c e n tly ,
H a n n e m a n n a n d c o -w o rk e rs re p o rte d o n p re lim in a ry d a ta
o b ta in e d fro m c ritic a lly ill p a tie n ts w ith se p sis o r a c u te
re sp ira to ry d istre ss sy n d ro m e . T h e a u th o rs d e m o n stra te d
th e e ffic a c y o f 2 -4 m l/k g b o d y w e ig h t o f7 .5 % h y p e rto n ic
sa lin e c o m b in e d w ith 6 % h y d ro x y e th y lsta rc h o n c e n tra l
h e m o d y n a m ic s a n d o x y g e n m e ta b o lism (1 8 ); a t th e e n d
o f th e 1 5 m in in fu sio n p e rio d , th e c a rd ia c in d e x h a d
in c re a se d , a s h a d p u lm o n a ry c a p illa ry w e d g e p re ssu re ,
m e a n p u lm o n a ry a rte ry p re ssu re , o x y g e n d e liv e ry a n d
o x y g e n c o n su m p tio n , w h ile p e rip h e ra l re sista n c e w a s
fo u n d to h a v e d e c re a se d .
C O M M E N T S
T h e n o v e l c o n c e p t o f sm a ll-v o lu m e re su sc ita tio n
u sin g h y p e rto n ic so lu tio n s h a s b e e n v a lid a te d in v a rio u s
e x p e rim e n ta l m o d e ls o f se v e re h y p o v o le m ia a n d sh o c k .
D a ta fro m th e se e x p e rim e n ts h a v e d e m o n stra te d th e
e ffic a c y o f h y p e rto n ic sa lin e /d e x tra n so lu tio n w ith re g a rd
t o t h e r e s t o r a t i o n o f c e n t r a l h e m o d y n a m i c s a n d t h e
n o r m a l i z a t i o n o f c o m p r o m i s e d m i c r o c i r c u l a t i o n . B e s i d e s
r a p i d r e s t o r a t i o n o f m a c r o h e m o d y n a m i c s a n d t h e
p r e v e n t i o n o f e a r l y d e a t h s , s m a l l - v o l u m e r e s u s c i t a t i o n
p a r t i c u l a r l y a i m s a t t h e p r e v e n t i o n o f l a t e c o m p l i c a t i o n s ,
s u c h a s s e p s i s a n d m u l t i p l e s y s t e m s o r g a n f a i l u r e , o n t h e
b a s i s o f p e r s i s t i n g m i c r o c i r c u l a t o r y d i s t u r b a n c e s .
A p r o s p e c t i v e a n d r a n d o m i z e d m u l t i c e n t e r t r i a l i n
c r i t i c a l l y i l l p a t i e n t s i n o r d e r t o a s s e s s t h e e f f i c a c y o f
h y p e r t o n i c v o l u m e t h e r a p y v e r s u s c o n v e n t i o n a l f l u i d
t r e a t m e n t i n t h e h y p e r d y n a m i c s t a t e o f s e p t i c s h o c k i s
u n d e r w a y .
T h e n o v e l t y o f h y p e r t o n i c s a l i n e / d e x t r a n
r e s u s c i t a t i o n l i e s i n i t s o p e r a t i o n a l m e c h a n i s m s a t t h e
m i c r o c i r c u l a t o r y l e v e l ; t h e s e i n c l u d e t h e m o b i l i z a t i o n o f
f l u i d p r e f e r e n t i a l l y f r o m s w o l l e n e n d o t h e l i u m , t h e
r e d u c t i o n o f p o s t i s c h e m i c l e u k o c y t e a d h e r e n c e t o t h e
e n d o t h e l i u m o f p o s t c a p i l l a r y v e n u l e s , a n d t h e r e s t o r a t i o n
o f s p o n t a n e o u s a r t e r i o l a r v a s o m o t i o n . R e o p e n i n g o f
s h o c k - n a r r o w e d c a p i l l a r i e s a n d r e s t o r a t i o n o f n u t r i t i o n a l
b l o o d f l o w i s t h u s . B e f o r e t h i s n e w c o n c e p t g a i n s e n t r a n c e
i n t o m e d i c a l t e x t b o o k s , h o w e v e r , m o r e d e t a i l e d
i n f o r m a t i o n o n t h e p o s i t i v e a n d p e r h a p s h a z a r d o u s e f f e c t s
o f s m a l l - v o l u . m e r e s u s c i t a t i o n i n p a t i e n t s h a s t o b e
a c c u m u l a t e d .
RESUMO
In tro d u 'ra o : A s s o lU 9 0 e s s a lin a s h ip e rto n ic a s e m p e q u e n o v o lu m e , a p lic a d a s e m "b o lo ", e m p re g a ra m -s e o rig in a lm e n te n o tra ta m e n to d o c h o q u e h e m o m ig ic o e tra u m a tic o g ra v e , d e m o n s tra n d o a ra p id a re s ta u ra 9 a o h e m o d in a m ic a e d o flu x o s a n g O fn e o o rg a n ic o re g io n a l. O s m e c a n is m o s d e a 9 a o s a o d iv e rs o s - 1 . m a n u te n 9 a o d o d e b ito c a rd fa c o e le v a d o (e s tfm u lo d ire to d o m io c a rd io ; a u m e n to d o v o lu m e in tra v a s c u la r); 2 . m a n u te n 9 a o d a v a s o d ila ta 9 a o a rte ria l p e rite ric a (e fe ito d a h ip e ro s m o la rid a d e ; a u m e n to d o v o lu m e p la s m a tic o ); 3 . re d u 9 a o d o e d e m a te c id u a l (flu x o d e Ifq u id o d o in te rs tfc io d e c o rre n te d o g ra d ie n te o s m 6 tic o ). E s te s e v e n to s p ro m o v e m a re c u p e ra 9 a o d a a c e n tu a d a . a lte ra 9 a o n a m ic ro c irc u la 9 a o , q u e fre q O e n te m e n te s a o ta m b e m o b s e rv a d a s n a s e p s e . M a te ria l e M e to d o s : 0 u s o d e s ta s s o lU 9 0 e s te m s id o o b je to d e v a rio s e s tu d o s e m m o d e lo s e x p e rim e n ta is d e e n d o to x e m ia h ip e rd in a m ic a a g u d a , e n tre ta n to , u m m a io r n u m e ro d e e s tu d o s c lfn ic o s s a o n e c e s s a rio s p a ra m e lh o r c o m p re e n s a o d o s e fe ito s p o s itiv o s , o u e v e n tu a lm e n te d e le te rio s , d a u tiliz a 9 a o d a s s o lU 9 0 e s c ris ta l6 id e s h ip e rto n ic a s e m p e q u e n o v o lu m e n a te ra p e u tic a d a s e p s e e fa le n c ia d e m u ltip lo s o rg a o s . O b je tiv o : 0 o b je tiv o d e s te a rtig o e a n a lis a r 0
c o n c e ito d o u s a d e s o lu 9 0 e s h ip e rto n ic a s e 0 s e u p o te n c ia l n o tra ta m e n to d a in te n s a h ip o v o le m ia e d e te rio ra 9 a o d a
m ic ro c irc u la 9 a o , q u e o c o rre n a s e p s e e n o c h o q u e e n d o t6 x ic o .
1059
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