http://lan.sagepub.com/Laboratory Animals

http://lan.sagepub.com/content/42/3/265The online version of this article can be found at:

 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

  

Published by:

http://www.sagepublications.com

On behalf of: 

  Laboratory Animals LtdLaboratory Animals Ltd

can be found at:Laboratory AnimalsAdditional services and information for    

  http://lan.sagepub.com/cgi/alertsEmail Alerts:

 

http://lan.sagepub.com/subscriptionsSubscriptions:  

http://www.sagepub.com/journalsReprints.navReprints:  

http://www.sagepub.com/journalsPermissions.navPermissions:  

What is This? 

- Jul 1, 2008Version of Record >>

by guest on October 11, 2013lan.sagepub.comDownloaded from by guest on October 11, 2013lan.sagepub.comDownloaded from by guest on October 11, 2013lan.sagepub.comDownloaded from by guest on October 11, 2013lan.sagepub.comDownloaded from by guest on October 11, 2013lan.sagepub.comDownloaded from by guest on October 11, 2013lan.sagepub.comDownloaded from by guest on October 11, 2013lan.sagepub.comDownloaded from by guest on October 11, 2013lan.sagepub.comDownloaded from by guest on October 11, 2013lan.sagepub.comDownloaded from by guest on October 11, 2013lan.sagepub.comDownloaded from by guest on October 11, 2013lan.sagepub.comDownloaded from by guest on October 11, 2013lan.sagepub.comDownloaded from by guest on October 11, 2013lan.sagepub.comDownloaded from

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

270 D Papadimitriou et al.

Laboratory Animals (2008) 42

(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

Mice and rats as cardiopulmonary resuscitation models 271

Laboratory Animals (2008) 42

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

272 D Papadimitriou et al.

Laboratory Animals (2008) 42

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.

References

Akulinin VA, Stepanov SS, Semchenko VV,Belichenko PV (1997) Dendritic changes of thepyramidal neurons in layer V of sensory-motorcortex of the rat brain during the postresuscitationperiod. Resuscitation 35, 157–64

Anderson RH, Webb S, Brown NA (1998) The mousewith trisomy 16 as a model of human hearts withcommon atrioventricular junction. CardiovascularResearch 39, 155–64

Bache RJ (1978) Effect of nitroglycerin and arterialhypertension on myocardial blood flow followingacute coronary occlusion in the dog. Circulation 57,557–62

Bottiger BW, Krumnikl JJ, Gass P, Schmitz B, MotschJ, Martin E (1997) The cerebral ‘no-reflow’phenomenon after cardiac arrest in rats – influenceof low-flow perfusion. Resuscitation 34, 79–87

Bottiger BW, Teschendorf P, Krumnikl JJ, et al. (1999)Global cerebral ischemia due to cardiocirculatoryarrest in mice causes neuronal degeneration andearly induction of transcription factor genes in thehippocampus. Brain Research. Molecular BrainResearch 65, 135–42

Brazzamono S, Mays AE, Rembert JC, et al. (1984)Increase in collateral blood flow following repeatedcoronary artery occlusion and nitroglycerinadministration. Circulation Research 54, 204–7

Brazzamono S, Rembert JC, Greenfield JC (1988)Effect of nitroglycerin on myocardial collateralconductance in awake dogs. American Journal ofPhysiology 254, 751–5

Colley PS, Sivarajan M (1984) Regional blood flow indogs during halothane anesthesia and controlledhypotension produced by nitroprusside or nitrogly-cerin. Anesthesia Analgesia 63, 503–10

Corbett D, Nurse S (1998) The problem of assessingeffective neuroprotection in experimental cerebralischemia. Progress in Neurobiology 54, 531–48

Damiano RJ, Asano T, Smith PK, Cox JL (1990)Effect of the right ventricular isolation procedureon ventricular vulnerability to fibrillation.Journal of the American College of Cardiology

15, 730–6Davidson CJ, Bonow RO (2001) Cardiac catheteriza-

tion. In: Heart Disease (Braunwald E, Zipes D,Libby P, eds). Philadelphia: WB Saunders, 359–86

Ditchey RV, Lindenfeld J (1988) Failure of epinephrineto improve the balance between myocardial oxygensupply and demand during closed-chest resuscita-tion in dogs. Circulation 78, 382–9

Ditchey RV, Perez RA, Slinker BK (1994)Beta-adrenergic blockade reduces myocardial injuryduring experimental cardiopulmonary resuscita-tion. Journal of the American College ofCardiology 24, 804–12

Ditchey RV, Winkler JV, Rhodes CA (1982) Relativelack of coronary blood flow during closed-chestresuscitation in dogs. Circulation 66, 297–302

Dowden J, Corbett D (1999) Ischemic preconditioningin 18- to 20-month-old gerbils: long-term survivalwith functional outcome measures. Stroke 30,1240–6

Ericsson BF (1971) Hemodynamic effects of vaso-pressin. An experimental study in normovolemicand hypovolemic anesthetized dogs. Acta

Chirurgica Scandinavica. Supplement 414, 1–29Fiala JC, Spacek J, Harris KM (2002) Dendritic spine

pathology: cause or consequence of neurologicaldisorders? Brain Research. Brain Research Reviews39, 29–54

Fujii M, Hara H, Meng W, Vonsattel JP, Huang Z,Moskowitz MA (1997) Strain-related differences in

Mice and rats as cardiopulmonary resuscitation models 273

Laboratory Animals (2008) 42

susceptibility to transient forebrain ischemia inSV-129 and C57black/6 mice. Stroke 28, 1805–11

Garrey W (1914) The nature of fibrillary contraction ofthe heart: its relation to tissue mass and form.American Journal of Physiology 33, 397–414

Gazmuri RJ, Weil MH, Bisera J, Tang W, Fukui M,McKee D (1996) Myocardial dysfunction aftersuccessful resuscitation from cardiac arrest.Critical Care Medicine 24, 992–1000

Ginsberg MD, Busto R (1989) Rodent models ofcerebral ischemia. Stroke 20, 1627–42

Groszmann R, Kravetz D, Bosch J, et al. (1982)Nitroglycerin improves the hemodynamic responseto vasopressin in portal hypertension. Hepatology

2, 757–62Grubb NR, Fox KA, Smith K, et al. (2000) Memory

impairment in out-of-hospital cardiac arrest survi-vors is associated with global reduction in brainvolume, not focal hippocampal injury. Stroke 31,1509–14

Gudipati CV, Weil MH, Bisera J, Deshmukh HG,Rackow EC (1988) Expired carbon dioxide: a non-invasive monitor of cardiopulmonary resuscitation.Circulation 77, 234–9

Halperin HR, Guerci AD (1990) Vasoconstrictorsduring CPR. Are they used optimally? Chest 97,787–9

Halperin AY, Tsitlik JE, Guerci AD, et al. (1986)Determinants of blood flow to vital organs duringcardiopulmonary resuscitation in dogs. Circulation73, 539–50

Handley AJ, Koster R, Monsieurs K, Perkins GD,Davies S, Bossaert L (2005) European ResuscitationCouncil Guidelines for Resuscitation 2005 Section2. Adult basic life support and use of automatedexternal defibrillators. Resuscitation 67, S7–23

Himori N, Watanabe H, Akaike N, Kurasawa M, ItohJ, Tanaka Y (1990) Cerebral ischemia model withconscious mice. Journal of Pharmacology Methods

23, 311–27Hori N, Carpenter DO (1994) Functional and mor-

phological changes induced by transient in vivo

ischemia. Experimental Neurology 129, 279–89Huang L, Weil MH, Cammarata G, Sun S, Tang W

(2004) Nonselective [beta]-blocking agent improvesthe outcome of cardiopulmonary resuscitation in arat model. Critical Care Medicine 32 (suppl.),378–80

Hypothermia after Cardiac Arrest Study Group (2002)Mild therapeutic hypothermia to improve theneurologic outcome after cardiac arrest. NewEngland Journal of Medicine 346, 549–56

Iwao T, Toyonaga A, Oho K, et al. (1996) Effect ofvasopressin on esophageal varices blood flow inpatients with cirrhosis: comparisons with theeffects on portal vein and superior mesentericartery blood flow. Journal of Hepatology 25, 491–7

Jastremski M, Sutton-Tyrrell K, Vaagenes P,Abramson N, Heiselman D, Safar P (1989)

Glucocorticoid treatment does not improve neuro-logical recovery following cardiac arrest. BrainResuscitation Clinical Trial I Study Group. Journal

of the American Medical Association 262, 3427–30Kaluski E, Uriel N, Milo O, Cotter G (2005)

Management of cardiac arrest in 2005: an update.Israel Medical Association Journal 7, 589–94

Kette F, Weil MH, Gazmuri RJ (1991) Buffer solutionsmay compromise cardiac resuscitation by reducingcoronary perfusion pressure. Journal of theAmerican Medical Association 266, 2121–6

Kofler J, Hattori K, Sawada M, et al. (2004)Histopathological and behavioural characterizationof a novel model of cardiac arrest and cardiopul-monary resuscitation in mice. Journal ofNeuroscience Methods 136, 33–44

Kono S, Bito H, Suzuki A, et al. (2002a) Vasopressinand epinephrine are equally effective for CPR in arat asphyxia model. Resuscitation 52, 215–19

Kono S, Suzuki A, Obata Y, Igarashi H, Bito H, Sato S(2002b) Vasopressin with delayed combination ofnitroglycerin increases survival rate in asphyxia ratmodel. Resuscitation 54, 297–301

Liard JF (1989) Vasopressin reduces oxygen uptake inintact dogs but not in sinoaortic-denervated dogs.American Journal of Physiology 257, 1–9

Lindner KH, Dirks B, Strohmenger HU, Prengel AW,Lindner IM, Lurie KG (1997) Randomised com-parison of adrenaline/epinephrine and vasopressinin patients with out-of-hospital ventricular fibril-lation. Lancet 349, 535–7

Lindner KH, Prengel AW, Brinkmann A, StrohmengerHU, Lindner IM, Lurie KG (1996) Vasopressinadministration in refractory cardiac arrest. Annals

of Internal Medicine 124, 1061–4Lindner KH, Prengel AW, Pfenninger EG, et al. (1995)

Vasopressin improves vital organ blood flow duringclosed-chest cardiopulmonary resuscitation in pigs.Circulation 91, 215–21

Livesay JJ, Follette DML, Fey KH, et al. (1978)Optimizing myocardial supply/demand balancewith alpha-adrenergic drugs during cardiopulmon-ary resuscitation. Journal of Thoracic andCardiovascular Surgery 76, 244–51

Lurie KG, Voelckel GW, Iskos DN, et al. (2002)Combination drug therapy with vasopressin, adre-naline (epinephrine) and nitroglycerin improvesvital organ blood flow in a porcine model of ven-tricular fibrillation. Resuscitation 54, 187–94

Manoach M (1984) Factors influencing maintenanceand spontaneous termination of ventricular fibril-lation. International Journal of Cardiology 5,398–402

Martinez MC, Vila JM, Aldasoro M, Medina P, Flor B,Lluch S (1994) Relaxation of human isolatedmesenteric arteries by vasopressin and desmopres-sin. British Journal of Pharmacology 113, 419–24

Mayr VD, Wenzel V, Voelckel WG, et al. (2001)Developing a vasopressor combination in a pig

274 D Papadimitriou et al.

Laboratory Animals (2008) 42

model of adult asphyxial cardiac arrest. Circulation

104, 1651–6Michael JR, Guerci AD, Koehler RC, et al. (1984)

Mechanisms by which epinephrine augmentscerebral and myocardial perfusion during cardio-pulmonary resuscitation in dogs. Circulation 69,822–35

Miller R (2000) Anesthesia for thoracic surgery. In:Anesthesia. 5th edn. Philadelphia: ChurchillLivingstone, 1706–9

Miller RR, Awan NA, DeMaria AN, et al. (1977)Importance of maintaining systemic blood pressureduring nitroglycerin administration for reducingischemic injury in patients with coronary disease.American Journal of Cardiology 40, 504–8

Neigh GN, Glasper ER, Kofler J, et al. (2004)Cardiac arrest with cardiopulmonary resuscitationreduces dendritic spine density in CA1 pyramidalcells and selectively alters acquisition of spatialmemory. European Journal of Neuroscience 20,1865–72

Niemann JT, Haynes KS, Garner D, Renni CJ III,Jagels G, Stormo O (1986) Post-countershockpulseless rhythms: response to CPR, artificialcardiac pacing, and adrenergic agonists. Annals ofEmergency Medicine 15, 112–20

Nolan J (2005) European Resuscitation CouncilGuidelines for Resuscitation 2005. Section1. Introduction. Resuscitation 67, 1–4

Nunes B, Pais J, Garcia R, Magalhaes Z, Granja C,Silva MC (2003) Cardiac arrest: long-term cognitiveand imaging analysis. Resuscitation 57, 287–97

Orr HE (2002) Rats and mice. In: BSAVA Manual ofExotic Pets (Meredith A, Redrobe S, eds). 4th edn.Barcelona, Spain: Grafos, 14

Otto CW, Yakaitis RW (1984) The role of epinephrinein CPR: a reappraisal. Annals of Emergency

Medicine 13, 840–3Paradis NA, Martin GB, Rivers EP, et al. (1990)

Coronary perfusion pressure and the return ofspontaneous circulation in human cardiopulmon-ary resuscitation. Journal of the American Medical

Association 263, 1106–13Popp E, Vogel P, Teschendorf P, Bottiger BW (2007)

Vasopressors are essential during cardiopulmonaryresuscitation in rats: is vasopressin superior toadrenaline? Resuscitation 72, 137–44

Prengel AW, Lindner KH, Keller A, Lurie KG (1996)Cardiovascular function during the postresuscita-tion phase after cardiac arrest in pigs: a comparisonof epinephrine versus vasopressin. Critical CareMedicine 24, 2014–19

Reich P, Regestein QR, Murawski BJ, DeSilva RA,Lown B (1983) Unrecognized organic mental dis-orders in survivors of cardiac arrest. American

Journal of Psychiatry 140, 1194–7Reilly PM, Bulkley GB (1993) Vasoactive mediators

and splanchnic perfusion. Critical Care Medicine21, 55–68

Reilly PM, MacGowan S, Miyachi M, Schiller HJ,Vickers S, Bulkley GB (1992) Mesenteric vaso-constriction in cardiogenic shock in pigs.Gastroenterology 102, 1968–79

Robinson LA, Brown CG, Jenkins J, et al. (1989) Theeffect of norepinephrine versus epinephrine onmyocardial hemodynamics during CPR. Annals ofEmergency Medicine 18, 336–40

Roine RO, Kajaste S, Kaste M (1993)Neuropsychological sequelae of cardiac arrest.Journal of the American Medical Association 269,237–42

Ruskin A (1947) Pitressin test of coronary insuffi-ciency. American Heart Journal 34, 569–79

Sadowski M, Wisniewski HM, Jakubowska-SadowskaK, Tarnawski M, Lazarewicz JW, Mossakowski MJ(1999) Pattern of neuronal loss in the rat hippo-campus following experimental cardiac arrest-induced ischemia. Journal of Neurological Science

168, 13–20Sanders AB (2006) Therapeutic hypothermia after

cardiac arrest. Current Opinion in Critical Care 3,213–17

Sans S, Kesteloot H, Kromhout D (1997) The burdenof cardiovascular diseases mortality in Europe. Taskforce of cardiology on cardiovascular mortality andmorbidity statistics in Europe. European HeartJournal 18, 1231–48

Sato Y, Weil MH, Sun S, et al. (1997) Adverse effects ofinterrupting precordial compression during cardio-pulmonary resuscitation. Critical Care Medicine25, 733–6

Sheng H, Laskowitz DT, Pearlstein RD, Warner DS(1999) Characterization of a recovery global cerebralischemia model in the mouse. Journal ofNeuroscience Methods 88, 103–9

Sirinek KR, Adcock DK, Levine BA (1989)Simultaneous infusion of nitroglycerin and nitro-prusside to offset adverse effects of vasopressinduring portosystemic shunting. American Journalof Surgery 157, 33–7

Song L, Weil MH, Tang W, Sun S, Pellis T (2002)Cardiopulmonary resuscitation in the mouse.Journal of Applied Physiology 93, 1222–6

Stiell IG, Hebert PC, Wells GA, et al. (2001)Vasopressin versus adrenaline/epinephrine forinhospital cardiac arrest: a randomised controlledtrial. Lancet 358, 105–9

Studer W, Wu X, Siegemund M, Seeberger M (2002)Resuscitation from cardiac arrest with adrenaline/epinephrine or vasopressin: effects on intestinalmucosal tonometer pCO2 during the postresuscitation period in rats. Resuscitation53, 201–7

Sun SJ, Weil MH, Tang W, Povoas HP (1999) Thecombined effects of buffer and adrenergic agents onpost resuscitation myocardial function. Journal of

Pharmacology and Experimental Therapeutics 291,773–7

Mice and rats as cardiopulmonary resuscitation models 275

Laboratory Animals (2008) 42

Suzuki S, Takeshita A, Imaizumi T, et al. (1989)Biphasic forearm vascular responses to intraarterialarginine vasopressin. Journal of Clinical

Investigation 84, 427–34Tang W, Weil MH, Schock RB, et al. (1997) Phased

chest and abdominal compression-decompression:a new option for cardiopulmonary resuscitation.Circulation 95, 1335–40

Tang W, Weil MH, Sun S, Noc M, Yang L, Gazmuri RJ(1995) Epinephrine increases the severity of postre-suscitation myocardial dysfunction. Circulation 92,3089–93

Traystman RJ (2003) Animal models of focal andglobal cerebral ischemia. Institute of Laboratory

Animal Resources Journal 44, 85–5von Planta I, Weil MH, von Planta M, et al. (1988)

Cardiopulmonary resuscitation in the rat. Journalof Applied Physiology 65, 2641–7

Waller BR, McQuinn T, Phelps AL, et al. (2000)Conotruncal anomalies in the trisomy 16 mouse:an immunohistochemical analysis with emphasison the involvement of the neural crest. AnatomicalRecord 260, 279–93

Webb S, Brown NA, Anderson RH (1996) The struc-ture of the mouse heart in late fetal stages.Anatomy Embryology 194, 37–47

Weil MH, Becker L, Budinger T, et al. (2001)Workshop executive summary report: postresusci-tative and initial utility in life saving efforts(PULSE). Circulation 103, 1182–4

Welsh FA, Harris VA (1991) Postischemic hypother-mia fails to reduce ischemic injury in gerbil

hippocampus. Journal of Cerebral Blood Flow and

Metabolism 11, 617–20Wenzel V, Lindner KH, Mayer H, et al. (1998)

Vasopressin combined with nitroglycerin increasesendocardial perfusion during cardiopulmonaryresuscitation in pigs. Resuscitation 38, 13–17

Wessels A, Sedmera D (2003) Developmentalanatomy of the heart: a tale of mice and man.Physiological Genomics 15, 165–76

Wiggers CJ (1940) The mechanisms and nature ofventricular fibrillation. American Heart Journal 20,399–412

Winfree AT (1994) Electrical turbulence in three-dimensional heart muscle. Science 266, 1003–6

Wright M, Heath RB, Wingfield WE (1986) Effects ofxylazine and ketamine on epinephrine-inducedarrhythmia in the dog. Veterinary Surgery 16,398–403

Xanthos T, Lelovas P, Vlachos I, et al. (2007)Cardiopulmonary arrest and resuscitation inLandrace/Large White swine: a research model.Laboratory Animals 41, 353–62

Youngberg A (2000) Low cardiac output status. In:Cardiac, Vascular and Thoracic Anesthesia. 1stedn. Philadelphia: Churchill Livingstone, 450–4

Zhong J, Dorian P (2005) Epinephrine and vasopressinduring cardiopulmonary resuscitation.Resuscitation 66, 263–9

Zito RA, Diez AR, Groszmann RJ (1985) Comparativeeffect of nitroglycerin and nitroprusside onvasopressin-induced cardiac dysfunction in the dog.Journal of Cardiovascular Pharmacology 5, 586–91

276 D Papadimitriou et al.

Laboratory Animals (2008) 42