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DOI: 10.1258/la.2007.006035
2008 42: 265Lab AnimD Papadimitriou, T Xanthos, I Dontas, P Lelovas and D Perrea
researchThe use of mice and rats as animal models for cardiopulmonary resuscitation
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REVIEW ARTICLE
The use of mice and rats as animal models forcardiopulmonary resuscitation research
D Papadimitriou, T Xanthos, I Dontas, P Lelovas and D PerreaDepartment of Experimental Surgery and Surgical Research, University of Athens Medical School,15B Agiou Thoma Street, 11527 Athens, Greece
Summary
Cardiopulmonary resuscitation (CPR) after the induction of cardiac arrest (CA) hasbeen studied in mice and rats. The anatomical and physiological parameters of thecardiopulmonary system of these two species have been defined during experimental studiesand are comparable with those of humans. Moreover, these animal models are more ethical toestablish and are easier to manipulate, when compared with larger experimental animals.Accordingly, the effects of successful CPR on the function of vital organs, such as the brain,have been investigated because damage to these vital organs is of concern in CA survivors.Furthermore, the efficacy of several drugs, such as adrenaline (epinephrine), vasopressin andnitroglycerin, has been evaluated for use in CA in these small animal models. The purpose ofthese studies is not only to increase the rate of survival of CA victims, but also to improvetheir quality of life by reducing damage to their vital organs after CA and during CPR.
Keywords Mice; rats; animal model; cardiopulmonary resuscitation
Experimental studies on the mechanismsand therapies of cardiac arrest (CA) have beenconfined generally to large experimentalanimals, such as dogs and pigs (Kette et al.1991, Tang et al. 1997). The amount ofresources devoted for research on the mech-anisms and therapies has been very limited(Weil et al. 2001). The fact that 700,000individuals suffer from CA in Europe (Sanset al. 1997), and ,5% of out-of-hospitalvictims of CA survive (Nolan 2005), justifiesthe need for augmenting the current researcheffort (Kaluski et al. 2005).
Despite extensive research, the contem-porary therapeutic modalities are not effica-cious in the treatment of CA. The use ofelectrical defibrillation and the combinationof chest compressions with rescue breathingand intravenous adrenaline (epinephrine) arethe only currently recommended therapeuticmodalities for treating CA (Handley et al.
2005). Needless to say, successful resuscita-tion is not only represented by the return ofspontaneous circulation (ROSC), but shouldalso incorporate cerebral resuscitation. Basedon the results from clinical and animalstudies, only mild hypothermia has beenproven thus far to provide cerebral protectionduring and after CA that is caused by ven-tricular fibrillation (VF) (Hypothermia afterCardiac Arrest Study Group 2002).
Mice and rats have been establishedas experimental models for conductingresearch into the mechanisms of CA and theeffects of cardiopulmonary resuscitation(CPR), not only because of their low cost butbecause the clinical situations can be accurat-ely reproduced in these species. Moreover,the haemodynamic measurements duringCPR of mice and rats are confirmatory of thoseestablished in humans and other mammals,such as swine (Song et al. 2002). Furthermore,these rodent models have the advantage ofbeing subjected to a standardized insult andthe resultant haemodynamic and respiratorymeasurements are pertinent to outcome.
Correspondence: T Xanthos.Email: theodorosxanthos@yahoo.com
Accepted 4 September 2007
# Laboratory Animals Ltd DOI: 10.1258/la.2007.006035. Laboratory Animals (2008) 42, 265–276
However, small animal resuscitationmodels are very sensitive to minimal diffe-rences in experimental protocols, wheredelays between the cessation of precordialchest compression and defibrillation can befatal (Sato et al. 1997).
Anatomical and physiologicalsimilarities and differences betweenthe cardiopulmonary systems ofhumans, mice and rats
It is becoming more and more obvious thatit is crucial to have extensive knowledgeof the specific anatomical differences andphysiological parameters in rodent models ofCA for the proper extrapolation of theexperimental findings to humans (Webbet al. 1996, Anderson et al. 1998, Waller et al.2000). Although mice and rats have a four-chamber heart that consists of ventricles andatria and is therefore similar to the humanheart, significant differences to the humanheart do exist. The heart rate of an adulthuman is about 60–70 beats/min (Wessels &Sedmera 2003), whereas the rates in themouse and the rat are higher, namelybetween 500 and 600 beats/min in mice andbetween 260 and 450 beats/min in rats(Orr 2002). In addition, several cardiopul-monary variables have been defined in miceand rats and are comparable with thosemeasured in humans. Specifically, for anaes-thetized mice, the mean aortic pressureranges between 80 and 100 mmHg, the dias-tolic aortic pressure ranges between 72 and90 mmHg, the right atrial pressure rangesbetween 22 and 8 mmHg, the coronary per-fusion pressure (CPP), which is the differencebetween the minimal aortic diastolicpressure and the right atrial diastolicpressure, is about 83–85 mmHg and the end-tidal pressure of carbon dioxide (PETCO2)is between 23 and 35 mmHg (Song et al.2002, Neigh et al. 2004). For anaesthetizedrats, the values are similar to those in theanaesthetized mouse: mean aortic pressure71– PETCO2 93 mmHg; right atrial pressure22 to 8 mmHg; CPP 80–85 mmHg;PETCO2 33–40 mmHg (Popp et al. 2007).In humans, the value for the mean aortic
pressure is between 70 and 90 mmHg, theright atrial pressure is between 2 and7 mmHg and the PETCO2 is between 25 and35 mmHg (Davidson & Bonow 2001).
Furthermore, the PETCO2 in all speciesdecreases to almost zero during CA andreaches between 30 and 40% of normalbaseline values during precordial com-pressions. ROSC is heralded by a prominentand progressive increase in end-tidal pCO2,which is coincident with the reappearance ofarterial pulsations and a rise in arterialpressure (Gudipati et al. 1988). These obser-vations of the changes in PETCO2 duringCPR are indistinguishable from thosemeasured in swine. In addition, the CPP,which is produced by precordial compressionwhen doing CPR, has been shown to be acritical determinant of resuscitability inhumans, swine, mice and rats (Ditchey et al.1982, Halperin et al. 1986, Paradis et al.1990, Xanthos et al. 2007). The thresholdCPP value for successful resuscitation usingCPR in the rat and the mouse has beendetermined to be 20 mmHg (von Planta et al.1988) and between 16 and 30 mmHg (Songet al. 2002), respectively, whereas inhumans it is between 15 and 20 mmHg(Zhong & Dorian 2005). Prolonged failureof myocardial perfusion during CAis followed by global myocardial ischaemicinjury and post-resuscitation myocardialdysfunction, both of which account forthe fatal progression after successfulresuscitation in humans, mice and rats(Tang et al. 1995, Gazmuri et al. 1996,Sun et al. 1999).
Because the mouse has a high resting heartrate, the refractory period is correspondinglyshort (Manoach 1984, Damiano et al. 1990).Therefore, it is difficult to secure re-entrantrhythms with which to sustain VF.Consequently, VF reverts spontaneously tonormal sinus rhythm during the initial 1.5min of electrically-induced CA (Garrey 1914,Wiggers 1940, Winfree 1994), a finding thathas not been confirmed in swine and dogs.Therefore, the continuous delivery of a low-intensity electric current is necessary tomaintain VF. Moreover, in the setting of VF,the ultimate effect is a failure of the heart tomaintain forward blood flow, which includes
266 D Papadimitriou et al.
Laboratory Animals (2008) 42
coronary, systemic and pulmonary bloodflows.
Despite the numerous differences in theseparameters from those of humans, the physio-logical parameters and haemodynamicmeasurements obtained from mice and rats arewell defined during CA and CPR, renderingthem useful models to study CA.
Experimental studies in mice and rats
The description of the experimental studiesin mouse and rat models of CA and theirresults are summarized in Tables 1 and 2.
Vital organ damage in experimentally-induced CA
Global cerebral ischaemia following CAis a major concern for human CA victimsbecause it results in neuronal death thatoccurs predominantly in ‘watershed’ regionsof the brain. The hippocampus is one of themain regions of the brain that is damagedpredominantly during CA (Bottiger et al.1999, Sadowski et al. 1999, Kofler et al.2004). However, a decrease in the hippo-campal volume is not significantly correlatedwith memory impairment in human CAsurvivors (Grubb et al. 2000). The poorneurological outcome of CA in humans,demonstrated by moderate to severe cogni-tive deficits, learning difficulties, changesin emotional and social behaviours anddepression (Nunes et al. 2003, Reich et al.1983), is probably due to the use ofnon-efficacious drugs at the time of CA. Atthe time of writing, we are not aware of anyknown pharmacological agent that has beenshown to improve the neurological outcomein human CA survivors, despite promisingresults from animal studies (Jastremski et al.1989, Roine et al. 1993).
In addition to the studies on global cerebralischaemia, the results of many investigationsof focal ischaemia in which various vessel-occlusion techniques, such as bilateralcommon carotid artery occlusion and/orthree or four vessel occlusion in the absenceor presence of systemic hypotension, havebeen described in mice (Ginsberg & Busto1989, Traystman 2003). In contrast to global
cerebral ischaemia models, which producebehavioural deficits, in which there are his-topathological signs of injury, and whichtherefore reflect the clinical situation, thesevessel occlusion techniques do not accu-rately reflect the clinical situation inhumans. More specifically, vessel occlusiondoes not cause a complete cessation ofcirculation, due to the presence of collateralarteries. The often-observed asymmetricalinjury and the strain-related differences inthese models (Fujii et al. 1997) are caused bydifferent degrees of hypoplasia of the pos-terior collateral artery. Furthermore, bloodflow to hindbrain regions, such as the brain-stem and cerebellum, is maintained in thesevascular occlusion models (Sheng et al.1999). Another disadvantage of vessel occlu-sion techniques is that compressing thechest during CPR and impaired post-ischaemic cardiac function create a period oflow blood flow that in itself is capable ofcausing more neuronal damage by aggravat-ing the no-reflow phenomenon (Bottigeret al. 1997). The resultant brain ischaemia is,thus, isolated in vessel occlusion techniques,whereas the whole body is affected in humanCA. Thus, the clinical situation is muchmore complex than most global ischaemiaocclusion models reflect. Furthermore, themany intra- and post-ischaemic factors thatmight influence neurological outcome, aswell as the efficacy of various therapeuticmodalities, have been overlooked whenusing the focal ischaemia models.
To study the neurological effects of globalcerebral ischaemia, the most widely usedrodents are gerbils, mice and rats (Ginsberg &Busto 1989, Traystman 2003, Popp et al.2007). In a global cerebral ischaemia mousemodel, Kofler and colleagues proved that theseverity of the brain injury was dependentupon the duration of CA and theintra-ischaemic brain temperature (Kofleret al. 2004). In order to increase survival, itwas found that reducing body temperature to278C, to cause intra-ischaemic whole-bodyhypothermia, improved neurologicalrecovery from CA. In addition, induction ofpost-ischaemic mild hypothermia (targettemperature 32–348C measured in thehuman urinary bladder) has been shown
Mice and rats as cardiopulmonary resuscitation models 267
Laboratory Animals (2008) 42
Tab
le1
Exp
eri
men
tal
stu
die
so
fch
an
ges
invit
al
org
an
saft
er
card
iac
arr
est
Aim
of
the
stu
dy
An
imal
mo
del
Meth
od
of
card
iac
arr
est
Tim
eo
fb
asi
clife
sup
po
rtTi
me
of
dru
gs
ad
min
istr
ati
on
Co
ncl
usi
on
s
(1)
Tost
ud
yw
heth
er
the
haem
od
ynam
ican
dre
spir
ato
rych
an
ges
du
rin
gca
rdio
pu
lmo
nary
resu
scit
ati
on
(CPR
)in
mic
eare
com
para
ble
wit
hth
ose
of
larg
em
am
mals
(So
ng
et
al.
2002)
Mic
eA
ltern
ati
ng
curr
en
tA
fter
4m
ino
fu
ntr
eate
dca
rdia
carr
est
Inco
ntr
ast
toth
ere
sult
sfo
un
din
larg
em
am
mals
,ca
rdia
carr
est
inb
oth
the
rat
an
dth
em
ou
seis
,th
ere
fore
,m
ore
oft
en
ass
oci
ate
dw
ith
pu
lsele
ssele
ctri
cal
act
ivit
yo
fth
eh
eart
or
asy
sto
le
(2)
Toch
ara
cteri
zesp
ati
al
learn
ing
an
dm
em
ory
defi
cits
elici
ted
by
card
iac
arr
est
(CA
)w
ith
CPR
(CA
/CPR
)in
mic
e(N
eig
het
al.
2004)
Mic
eK
Cl
7m
in45
sin
toth
earr
est
peri
od
,th
em
ou
sew
as
ven
tila
ted
on
100%
oxy
gen
At
8m
info
llo
win
gin
ject
ion
of
KC
l,8m
go
fad
ren
alin
ein
0.5
mL
salin
e
CA
an
dC
PR
ina
mo
use
mo
del
resu
lts
inse
lect
ive
mem
ory
imp
air
men
tsu
chth
at
acq
uis
itio
n,b
ut
no
tre
ten
tio
n,o
fa
spati
al
task
isin
hib
ited
(3)
Toch
ara
cteri
zeh
isto
path
olo
gic
al
an
db
eh
avi
ou
ral
featu
res
of
CA
(Ko
fler
et
al.
2004)
Mic
eK
Cl
10,
12
or
14
min
aft
er
ind
uct
ion
of
CA
10,
12,
or
14
min
aft
er
ind
uct
ion
of
CA
Ad
isso
ciati
on
betw
een
fun
ctio
nal
an
dh
isto
log
ical
ou
tco
me
was
fou
nd
,em
ph
asi
zin
gth
eim
po
rtan
ceo
fco
mb
inin
gb
oth
ou
tco
me
measu
res
for
eva
luati
on
of
neu
rop
rote
ctiv
est
rate
gie
s(4
)To
stan
dard
ize
am
eth
od
of
CPR
inra
ts(v
on
Pla
nta
et
al.
1988)
Rats
Alt
ern
ati
ng
curr
en
tA
fter
4m
ino
fve
ntr
icu
lar
fib
rillati
on
Th
ism
od
el
of
CPR
dem
on
stra
ted
larg
eve
no
art
eri
al
an
dp
CO
2
gra
die
nts
ass
oci
ate
dw
ith
red
uce
dp
ulm
on
ary
exc
reti
on
of
CO
2d
uri
ng
the
low
-flo
wst
ate
.M
ean
ao
rtic
pre
ssu
re,
coro
nary
perf
usi
on
pre
ssu
re,an
den
d-t
idal
CO
2d
uri
ng
chest
com
pre
ssio
nw
ere
pre
dic
tive
of
succ
ess
ful
resu
scit
ati
on
268 D Papadimitriou et al.
Laboratory Animals (2008) 42
Tab
le2
Exp
eri
men
tal
stu
die
so
fd
rug
s
Aim
of
the
stu
dy
An
imal
mo
del
Meth
od
of
card
iac
arr
est
Tim
eo
fb
asi
clife
sup
po
rt(B
LS)
Tim
eo
fd
rug
sad
min
istr
ati
on
Co
ncl
usi
on
s
(1)
Toexa
min
eth
eeff
ect
iven
ess
of
the
dela
yed
com
bin
ati
on
of
nit
rog
lyce
rin
wit
hva
sop
ress
inin
card
iop
ulm
on
ary
resu
scit
ati
on
(CPR
)in
a6
min
asp
hyx
iara
tm
od
el
(Ko
no
et
al.
2002b
)
Rats
Suff
oca
tio
n,
ind
uce
db
yo
bst
ruct
ing
the
trach
eal
tub
e
6m
inaft
er
suff
oca
tio
nV
aso
pre
ssin
start
ed
just
befo
reB
LS(V
-Gr)
an
dn
itro
gly
ceri
n(V
N-G
r)w
as
ad
min
iste
red
45
saft
er
vaso
pre
ssin
Th
ed
ela
yed
com
bin
ati
on
of
nit
rog
lyce
rin
aft
er
the
ad
min
istr
ati
on
of
vaso
pre
ssin
was
mo
reeff
ect
ive
than
vaso
pre
ssin
alo
ne
(in
crease
dsu
rviv
al
rate
)
(2)
Toco
mp
are
the
eff
ect
so
fva
sop
ress
inan
dad
ren
alin
ew
ith
mese
nte
ric
isch
aem
ia,
as
dete
rmin
ed
by
inte
stin
al
mu
cosa
lto
no
mete
rp
CO
2d
uri
ng
the
po
st-r
esu
scit
ati
on
peri
od
(Stu
der
et
al.
2002)
Rats
Alt
ern
ati
ng
curr
en
t4
min
aft
er
ven
tric
ula
rfi
bri
llati
on
9m
inaft
er
ven
tric
ula
rfi
bri
llati
on
Th
ead
min
istr
ati
on
of
vaso
pre
ssin
inst
ead
of
ad
ren
alin
efo
rC
PR
ten
ds
tob
eass
oci
ate
dw
ith
low
er
resu
scit
ati
on
succ
ess
,b
ut
less
mese
nte
ric
isch
aem
ia
(3)
Toexa
min
eif
an
on
-sele
ctiv
e[b
eta
]-ad
ren
oce
pto
ran
ata
go
nis
tag
en
tim
pro
ves
the
ou
tco
me
of
CPR
,in
com
pari
son
wit
had
ren
alin
e(H
uan
get
al.
2004)
Rats
Th
e[b
eta
]-ad
ren
erg
iceff
ect
of
ad
ren
alin
esi
gn
ifica
ntl
yin
crease
dth
ese
veri
tyo
fp
ost
-resu
scit
ati
on
myo
card
ial
dys
fun
ctio
n
(4)
Toexa
min
ew
heth
er
the
ß-a
dre
nerg
iceff
ect
so
fad
ren
alin
e,
wh
en
ad
min
iste
red
du
rin
gC
PR
,ad
vers
ely
aff
ect
po
st-r
esu
scit
ati
on
myo
card
ial
fun
ctio
nw
hen
com
pare
dw
ith
tho
seo
fa
sele
ctiv
ea
-ad
ren
oce
pto
rag
on
ist,
ph
en
ylep
hri
ne,
an
dw
hen
ad
ren
alin
ew
as
com
bin
ed
wit
ha
sho
rt-a
ctin
gß
1-a
dre
no
cep
tor
an
tag
on
ist
(Tan
get
al.
1995)
Rats
Cu
rren
t4
(gro
up
1)
an
d8
(gro
up
2)
min
aft
er
ven
tric
ula
rfi
bri
llati
on
4m
inaft
er
BLS
Ad
ren
alin
e,
wh
en
ad
min
iste
red
du
rin
gC
PR
un
der
the
exp
eri
men
tal
con
dit
ion
s,si
gn
ifica
ntl
yin
crease
sth
ese
veri
tyo
fp
ost
-resu
scit
ati
on
myo
card
ial
dys
fun
ctio
nin
con
seq
uen
ceo
fit
sß
1-a
dre
nerg
icact
ion
s
(5)
Toass
ess
po
ssib
leb
en
efi
tsre
gard
ing
neu
rolo
gic
al
reco
very
,in
aca
rdia
carr
est
mo
del
inra
ts,
wh
ere
vaso
pre
ssin
vers
us
ad
ren
alin
ean
dth
eco
mb
inati
on
of
bo
thd
rug
sw
as
test
ed
ag
ain
sta
pla
ceb
o(P
op
pet
al.
2007)
Rats
Ele
ctri
cal
fib
rillati
on
wit
halt
ern
ati
ng
curr
en
t
Aft
er
7m
ino
fg
lob
al
isch
aem
iaA
dm
inis
trati
on
of
vaso
pre
ssin
du
rin
gC
PR
do
es
no
tim
pro
veb
eh
avi
ou
ral
an
dce
reb
ral
his
top
ath
olo
gic
al
ou
tco
me,co
mp
are
dw
ith
the
use
of
ad
ren
alin
eo
rth
eco
mb
inati
on
of
bo
thva
sop
ress
ors
,aft
er
card
iac
arr
est
inth
isca
rdia
carr
est
rat
mo
del
Mice and rats as cardiopulmonary resuscitation models 269
Laboratory Animals (2008) 42
to reduce the extent of brain damage afterglobal ischaemia (Hypothermia after CardiacArrest Study Group 2002, Sanders 2006).There is also experimental evidence thatdemonstrates that hypothermia must bemaintained for at least 1 or 2 h to be effective(Welsh & Harris 1991). These researchersshowed that a brief period of hypothermia,of ,30 min, was unlikely to exert aneuroprotective effect.
Despite neuronal preservation, thedemonstration of dissociation between func-tional and histological outcomes confirmsthe results of numerous other studies inwhich electrophysiological or behaviouralabnormalities were described (Himori et al.1990, Hori & Carpenter 1994, Dowden &Corbett 1999). This dissociation emphasizesalso the importance of combining measuresof functional and histological outcomeswhen evaluating neuroprotective strategies(Corbett & Nurse 1998).
In addition, injuries in the hippocampushave been described in mice and rats in CAand CPR experiments. Specifically, thesemice were used to characterize the spatiallearning and memory deficits that wereelicited by CA and CPR. The results of suchinvestigations demonstrated that CA andCPR can impede with the acquisition of newspatial memory tasks without impactingupon the retention of previously learnedspatial memory tasks (Neigh et al. 2004).The mice that were subjected to CA and CPRin the current study (Neigh et al. 2004)exhibited a reduction in the total number ofdendritic spines in the pyramidal cells in theCA1 region of the hippocampus. A similarreduction in the number of dendritic spinesfollowing CA and CPR has been describedin the rat cortex (Akulinin et al. 1997). Adecrease in dendritic spine density has beenobserved also in several chronic and debili-tating human diseases that include alcoholabuse, epilepsy and Alzheimer’s disease(Fiala et al. 2002).
Pharmacological studies in experimental CA
Adrenaline (epinephrine) has been the pre-ferred biogenic amine for the treatment ofhuman CA for .30 years (Otto & Yakaitis
1984, Robinson et al. 1989) because itsa-adrenergic-mediated vasopressor actionincreases the CPP (Michael et al. 1984). Itsb-adrenergic-mediated actions, however, aredeleterious for the fibrillating myocardium(Ditchey & Lindenfeld 1988). The results ofstudies conducted in rats have establishedthat b-adrenergic-mediated positive inotropicactions provoke disproportionate increasesin myocardial oxygen consumption and,thereby, increase the severity of myocardialischaemia (Livesay et al. 1978, Niemannet al. 1986, Wright et al. 1986, Ditchey &Lindenfeld 1988, Halperin & Guerci 1990,Tang et al. 1995, Huang et al. 2004). In theseexperimental studies, it was found thatadrenaline increases also the severity of post-resuscitation myocardial dysfunction, with aconsequent reduction in the duration of post-resuscitation survival, when compared withthe results obtained following treatmentwith the selective a-adrenoceptor agonistphenylephrine, or a combination of adrena-line and a b-adrenoceptor antagonist.
Moreover, adrenaline-treated rats require alarger number of electrical countershocks toconvert VF to a cardiac rhythm that is com-patible with a pulse (Tang et al. 1995). Thisresult is consistent with those described inpreviously published reports (Niemann et al.1986, Wright et al. 1986). Furthermore,Ditchey et al. (1994) observed that pre-treating dogs with the non-selectiveb-adrenoceptor antagonist propranolol couldreduce the severity of myocardial injuryduring CPR, without compromising thelikelihood of successful defibrillation or therestoration of spontaneous circulation andthe post-resuscitation left ventricular func-tion. In their study, they also found that thenon-selective b-adrenoceptor antagonistincreased CPP during CPR. This resultsuggests that blocking of b-adrenoceptors cancause vasoconstriction by allowing unop-posed a-adrenergic stimulation of adrenergicreceptors in all resistance vessels to occur.Therefore, it may be that the use of non-selective b-adrenergic blockade improves thebalance between myocardial oxygen require-ments and oxygen demands by increasingoxygen delivery to the heart. This finding hasrecently been confirmed in a rat model of CA
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(Huang et al. 2004). It would, therefore, beappropriate to re-evaluate the use of adrena-line as the drug of first choice for CPR andthe use of b-adrenoceptor antagonists duringCPR in order to minimize post-resuscitationmyocardial dysfunction. Furthermore, it isalso appropriate to explore the efficacy ofnew therapeutic agents in the pharmaco-logical treatment of CA.
These drawbacks of adrenaline have ledto the use of another vasopressor drug,vasopressin. Vasopressin is an endogenouspressor peptide whose effects have beenstudied in animal models of CA and whichhas been used successfully in CPR inhumans (Prengel A et al. 1996, Lindner et al.1997). Theoretically, vasopressin is a desir-able vasopressor for use in cases of CA and inCPR because it causes selective vasocon-striction of resistance vessels in non-vitaltissues and, at the same time it preservesblood flow to vital organs, such as the heartand brain (Mayr et al. 2001). On the otherhand, the unwanted cardiovascular effects ofvasopressin, such as transient ischaemia,transmural myocardial injury withoutinfarction, acute myocardial infarction andventricular arrhythmias including VF, havebeen described in humans since 1947(Ruskin 1947, Sirinek et al. 1989).
Vasopressin is able to increase systemicvascular resistance by direct stimulation ofthe peripheral V1 receptor (Ericsson 1971).In addition, it is better able to maintainCPP because it decreases myocardial bloodflow and is a more potent vasoconstrictorthan adrenaline. Furthermore, it has beendemonstrated in human forearm vessels(Suzuki et al. 1989) and isolated humanmesenteric arteries (Martinez et al. 1994)that vasopressin may have a biphasic action.This biphasic action is characterized by aninitial potent vasoconstriction, which ismediated by stimulation of V1 receptors andis then followed by vasodilation, which ismediated by stimulation of V2 receptors.
In clinical practice, successful resuscita-tion in refractory human CA using vaso-pressin has been reported (Lindner et al.1996). Two randomized clinical studies havedocumented higher immediate and 24 hsurvival in patients who were resuscitated
after out-of-hospital VF when vasopressinwas used instead of adrenaline (Lindner et al.1997). No differences between the effects ofvasopressin and adrenaline on the rates ofsurvival following in-hospital CA have beendocumented (Stiell et al. 2001), and thisfinding demonstrates that vasopressin is notalways more efficacious than adrenaline. Ithas been reported that the use of vasopressinor adrenaline does not affect patient survival.Despite the results from animal experimentsthat suggest improved outcomes in experi-mental CA with the use of either adrenalineor vasopressin, the results of clinical trials ofthe use of these two agents have failed toshow that either is more efficacious than theother because of their many adverse cardio-vascular effects (Zhong & Dorian 2005).
A similar conclusion to that reached in theabove-mentioned human study was obtainedfrom a study involving VF in rats (Kono et al.2002a). In this study, the investigatorsreported that vasopressin was as effective asadrenaline in the treatment of experimentalCA. Popp et al. (2007) reported recently thatthe administration of vasopressin duringCPR improved immediate survival whencompared with the use of adrenaline in CAand CPR rats. In another rat study, Studeret al. (2002) reported that successfulimmediate survival following resuscitationtended to be higher in adrenaline-treated ratswhen compared with that in vasopressin-treated rats.
In this rat study, all the resuscitated ratsshowed evidence of depressed cardiovascularfunction, as indicated by a decreased oxy-haemoglobin saturation in right atrial bloodand an increased right atrial versus arterialpCO2 gradient. Successfully resuscitatedvasopressin-treated rats differed from theadrenaline-treated rats in having a higherright atrial oxyhaemoglobin saturation,a lower intestinal tonometric pCO2,a decreased tonometric–arterial pCO2
gradient and a trend towards a smaller rightatrial–arterial pCO2 gradient, as well aslower serum lactate levels. The reason forthese differences between systemic oxygen-ation and mesenteric ischaemia is thatadrenaline (1) induces more myocardialdamage because of its a-adrenergic and
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positive inotropic actions and (2) increasesthe severity of post-resuscitation myocardialdysfunction in rats to a greater extent thanvasopressin (Tang et al. 1995). Reducedmyocardial dysfunction in the vasopressin-treated rats would have resulted in (1) ahigher pCO2, as indicated by a higher rightatrial-haemoglobin oxygen saturation, (2)reduced regional mesenteric ischaemia, asindicated by a smaller pCO2 gap and (3) lowerserum lactate levels when compared withthose measured in the adrenaline-treatedrats. Vasopressin also causes a decreasedsystemic oxygen uptake, associated with abaroreceptor reflex-mediated withdrawal ofsympathetic tone (Liard 1989).
Furthermore, the effects of vasopressinon the function of vital organs, such asthe brain, heart and intestines, but not itseffects on survival, have also been studiedin experimental animals, such as pigs(Lindner et al. 1995) and rats (Studer et al.2002, Popp et al. 2007). These resultsdemonstrate that vasopressin can be used tobring about ROSC, but can also provide vitalorgan protection.
The effects of vasopressin on mesentericfunction have also been studied during CAand CPR in rats (Studer et al. 2002). Insome animal models of CA, the use ofvasopressin caused less mesenteric ischae-mia than the use of adrenaline. This resultdiffers from that observed in humans withstable cardiovascular function, whereexogenously administered vasopressininduces splanchnic vasoconstriction (Iwaoet al. 1996). Furthermore, the absolute orrelative increases in mesenteric perfusioncan be explained by vasopressin havinga biphasic action in the vasculature. Inpatients with cardiovascular shock,vasopressin can induce an even morepronounced mesenteric vasoconstrictionbecause the vasoconstriction may bepotentiated by the action of endogenousangiotensin (Reilly et al. 1992, Reilly &Bulkley 1993). Unfortunately, the limit-ation of these animal studies is that theexperimental animals are free of anycardiovascular disease. Accordingly, it stillremains to be determined whether theobserved effects of vasopressin on
mesenteric perfusion during the post-resuscitation period can be extrapolatedto CA patients with atherosclerosis.
Due to the numerous adverse cardiovas-cular effects of vasopressin and adrenalineand their ineffectiveness in successfulCPR, their use in conjunction with thepotent vasodilator nitroglycerin has beenevaluated in CA in porcine (Lurie et al.2002) and rat models of CA (Kono et al.2002b) in an effort to reduce the incidenceof these adverse effects. Nitroglycerin isknown to increase cardiac output, while,at the same time, it maintains CPP andmean blood flow in animal models of CA(Bache 1978, Brazzamono et al. 1984,Colley & Sivarajan 1984, Zito et al. 1985,Brazzamono et al. 1988, Wenzel et al. 1998)and in humans (Miller et al. 1977,Groszmann et al. 1982). In addition, thedrug causes systemic vasodilation,especially in coronary blood vessels.A decrease in systemic vascular resistancemight reduce the CPP and mean bloodflow and could affect the outcome of CPR.It has been reported that nitroglycerinincreased mean blood flow in the ischae-mic area of the heart and decreased theresistance of the collateral vascular system(Bache 1978).
In a rat study undertaken by Kono et al.(2002b), a delay in the administrationof nitroglycerin after the administration ofvasopressin was more effective thanvasopressin alone regarding resuscitationoutcomes. The significantly greater resus-citation rates observed in this study mightbe due to the above-mentioned pharmaco-logical properties of nitroglycerin. In thisstudy, the arterial pH and bicarbonatelevels after the resuscitation phase werelow and a reduced survival rate might havebeen expected because of severe acidosis. Alow survival rate was not found, however,because nitroglycerin caused vasodilationand accelerated the washout of anaerobicmetabolites that were produced duringhypoxia. The increased resuscitation andsurvival rate was due to adequate main-tenance of the systemic circulation.Nitroglycerin can cause hypoxic pulmonaryvasoconstriction and impair pulmonary
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oxygenation of the blood (Miller 2000,Youngberg 2000). These drug-inducedaberrations were not observed in theKono study. Because no severenitroglycerin-induced side-effects, such ashypoxia or hypotension, were observedafter the resuscitation phase in this ratmodel, the combined use of nitroglycerinand vasopressin may increase the survivalrate of human CA victims when comparedwith that obtained following the adminis-tration of adrenaline alone, as has beenpreviously described in pig models (Lurieet al. 2002).
Conclusion
CA is an emergency situation and CPR isused in order to increase the survival rate ofits victims. In cases of CA, it is important touse established therapeutic modalities. Miceand rats can be used as good animal modelsof CA and for studying the effects of CPR dueto their anatomical and physiological simi-larities to humans. In addition, there are alsoethical advantages in using these animalswhen compared with the use of other animalspecies, despite their sensitivity to minimaldifferences in the experimental protocols.The efficacy of new drugs and therapeuticmodalities has been studied in these animalmodels of CA. The purpose of such studies isto increase the survival rate and quality oflife of CA victims and to evaluate new drugsand therapeutic modalities before theirintroduction into clinical practice.
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