Effects of hypertonic saline on myocardial blood flow in a porcinemodel of prolonged cardiac arrest

Matthias Fischer a,*, Alfred Dahmen a, Jens Standop b, Andreas Hagendorff c,Andreas Hoeft a, Henning Krep a

a Department of Anaesthesiology and Intensive Care Medicine, University of Bonn, Sigmund Freud Street 25, D-53105 Bonn, Germanyb Department of Surgery, University of Bonn, Bonn, Germany

c Department of Cardiology, University of Leipzig, Leipzig, Germany

Received 18 February 2002; accepted 7 May 2002

Abstract

Objective: To evaluate the effects of hypertonic saline (HS) on myocardial reperfusion pressure (MPP) and blood flow (MBF),

and cardiac index (CI) during and after cardiopulmonary resuscitation (CPR). Methods: In 21 domestic swine (16�/23 kg) open

chest cardiac massage was initiated after 10 min of ventricular fibrillation. With the onset of CPR animals randomly received HS

(7.2%; 2 ml/kg per 10 min or 4 ml/kg per 20 min) or normal saline ((NS); 2 ml/kg per 10 min). Haemodynamic variables were

monitored continuously, and coloured microspheres were used to measure MBF and CI before cardiac arrest (CA), during CPR and

5, 30 and 120 min after the return of spontaneous circulation. Results: During CPR HS significantly increased MPP, MBF, and CI

in comparison to NS (P B/0.05, resp., MANOVA). Doubling the volume of HS did not improve the haemodynamic effects seen

after application of 2 ml/kg per 10 min. HS-infusion significantly increased the survival rate at 120 min, 6/7 and 5/7 animals receiving

2 ml/kg per 10 min or 4 ml/kg per 20 min versus 2/7 after NS-infusion (P B/0.05, x2-test). Conclusions: HS applied during open chest

cardiac massage enhanced MBF and CI, and significantly increased resuscitation success and survival rate. The positive effects of

this promising new approach need to be confirmed in clinical studies. # 2002 Elsevier Science Ireland Ltd. All rights reserved.

Keywords: Cardiac arrest; Cardiopulmonary resuscitation; Fluid therapy; Hypertonic saline; Myocardial blood flow; Cardiac output; Post-

resuscitation period

Resumo

Objectivo : Avaliar os efeitos do soro salino hipertonico (SH) na pressao de reperfusao miocardica (PRM), no debito sanguıneo

(DS) e no ındice cardıaco (IC) durante e apos reanimacao cardio-pulmonar (RCP). Metodos: Iniciou-se massagem cardıaca aberta

em 21 porcos domesticos (16�/23 kg) apos 10 min de fibrilhacao ventricular. Com o inıcio da RCP, os animais receberam de forma

randomizada SH (7.2%; 2 ml/kg durante 10 min ou 4 ml/kg durante 20 min) ou soro fisiologico (SF); 2 ml/kg durante 10 min). Os

parametros hemodinamicos foram monitorizados continuamente e foram utilizadas microesferas coloridas para a determinacao do

DS e IC, antes da paragem cardıaca (PC), durante a RCP e 5, 30 e 120 min apos o retorno da circulacao espontanea. Resultados :

Durante a RCP o SH aumentou significativamente a PRM, o DS e o IC em comparacao com o SF (P B/0.05, resp., MANOVA). A

duplicacao do volume de SH nao melhorou o efeito hemodinamico observado depois da administracao de 2 ml/kg durante 10 min.

A perfusao de SH aumentou significativamente a taxa de sobrevivencia aos 120 min: 6/7 e 5/7 dos animais que receberam 2 ml/kg

durante 10 min ou 4 ml/kg durante 20 min contra 2/7 apos a infusao de SF (P B/0.05, teste do x2). Conclusoes: A aplicacao de SH

durante massagem cardıaca aberta melhorou o DS e o IC, e aumentou significativamente o sucesso da reanimacao e a taxa de

sobrevivencia. O efeito positivo desta nova abordagem promissora deve ser confirmado em estudos clınicos. # 2002 Elsevier

Science Ireland Ltd. All rights reserved.

Palavras chave: Paragem cardıaca; Ressuscitacao cardio-pulmonar; Fluidoterapia; Soro salino hipertonico; Debito sanguıneo miocardico; Debito

cardıaco; Perıodo pos-reanimacao

* Corresponding author. Tel.: �/49-228-287-4114; fax: �/49-221-287-4125

E-mail address: matthias.fischer@ukb.uni-bonn.de (M. Fischer).

Resuscitation 54 (2002) 269�/280

www.elsevier.com/locate/resuscitation

0300-9572/02/$ - see front matter # 2002 Elsevier Science Ireland Ltd. All rights reserved.

PII: S 0 3 0 0 - 9 5 7 2 ( 0 2 ) 0 0 1 5 1 - X

Resumen

Objetivo : Evaluar los efectos de la solucion salina hipertonica (HS) en la presion de repercusion miocardica (MPP) y el flujo

sanguıneo (MBF), y en el ındice cardıaco (CI) durante y despues de la reanimacion cardiopulmonar (CPR). Metodos : En 21 cerdos

domesticos (16-23 kgs) se inicio masaje cardıaco abierto despues de 10 minutos de fibrilacion ventricular. Junto con la RCP los

animales recibieron randomizadamente HS (7.2%; 2 ml/kg por 10 min o 4ml/kg por 20 min) o salino normal ((NS) 2ml/kg por 10

min). Se monitorearon continuamente los parametros hemodinamicas, y se usaros microesferas coloreadas para medir MBF y CI

antes del paro cardıaco (CA), durante la RCP y 5, 30 y 120 minutos despues del retorno a circulacion espontanea. Resultados :

Durante la RCP el HS aumento significativamente MPP, MBF, y CI en comparacion con el NS (P B/0.05, resp., MANOVA). El

duplicar el volumen de HS no mejoro los efectos hemodinamicas vistos despues de la aplicacion de 2ml/kg por 10 minutos. La

infusion de HS aumento significativamente la tasa de sobreviva a los 120 minutos, 6/7 y 5/7 animales que recibieron 2 ml/kg por 10

min o 4 ml/kg por 20 min versus 2/7 despues de la infusion de NS (P B/ 0.05, x2-test). Conclusiones : El HS aplicado durante masaje

cardıaco abierto aumento el MBF y CI, y aumento significativamente el exito de la resucitacion y tasa de sobreviva. El efecto

positivo de este nuevo promisorio acceso (aproximacion) necesita ser confirmada en estudios clınicos. # 2002 Elsevier Science

Ireland Ltd. All rights reserved.

Palabras clave: Paro cardıaco; Reanimacion cardiopulmonar; Terapia de fluidos; Salino Hipertonico; Flujo sanguıneo miocardico; Gasto cardıaco;

Perıodo postresucitacion

1. Introduction

The success of resuscitation after sudden cardiac

arrest depends crucially on myocardial reperfusion

pressure (MPP), myocardial blood flow (MBF), and

caval blood flow to the heart [1,2], which are severely

reduced by systemic ischaemic vasoparalysis. Vasocon-

strictors are known to increase MBF [3,4], and adrena-

line (epinephrine) and vasopressin are the drugs of

choice in cardiopulmonary resuscitation (CPR) [5].

However, the effectiveness of cardiac massage is im-

paired additionally by a plasma shift from the intra- to

the extravascular compartment leading to intravascular

hypovolaemia and haemoconcentration [6�/8]. This

plasma loss amounts to 20 ml/kg after 1 h of cardiac

arrest (CA) [9]. Based on these findings the influence of

volume loading on resuscitation success was investigated

by several groups. Grundler et al. reported that expan-

sion of blood volume before induction of cardiac arrest

increased resuscitation success rate [10]. In contrast, the

infusion of large volumes of blood or isotonic solutions

during CPR decreased myocardial perfusion pressure

and blood flow [11�/13]. These effects may abolish

resuscitation success. However, it has not been estab-

lished which infusion, a crystalloid or oncotic solution,

and the volume of that solution giving during CPR, will

provide the best resuscitation success and longterm

survival.

An established approach for increasing blood volume

and improving haemodynamics during haemorragic

shock is to administer a small volume of a hypertonic

solution, the so-called ‘small volume resuscitation’ [14].

After severe haemorrhage, an infusion of 4�/6 ml/kg

hypertonic saline (HS) (7.2�/7.5%) has been shown to

improve blood pressure and intravascular volume in

experimental studies [14�/19] and in clinical trials [20�/

22]. Furthermore, improvement in systemic haemody-

namic variables after hypertonic fluid resuscitation has

been associated with an increase in organ microcircula-

tion [23�/31]. These data suggest that a small volume of

a hypertonic solution given during CPR could reducemacro- and microcirculatory disorders interfering with

successful resuscitation and longterm survival. In fact,

recently it was demonstrated that early volume expan-

sion during cardiac massage using a small volume of a

hypertonic isooncotic solution improved postischaemic

systemic haemodynamics and reduced the cerebral no-

reflow phenomenon [7]. However, no quantitative data

of organ blood flow after small volume resuscitationduring CPR have been established to date. We, there-

fore, studied the effects of an infusion of HS

on MBF and systemic haemodynamic variables during

and after CPR in pigs. Hypertonic saline was applied at

two different volumes using identical infusion rates, 2

ml/kg per 10 min or 4 ml/kg per 20 min, in order to

investigate whether increasing volumes of HS would

enhance resuscitation success and haemodynamic vari-ables.

2. Material and methods

2.1. Animal preparation and recording of physiological

variables

All experiments were carried out in accordance with

the German legislation on animal care, and approved by

the local authorities. After premedication with 50 mg/kg

ketamine hydrochloride intramuscularly and cannula-

tion of an ear vein, anaesthesia was induced in 21

domestic pigs (14�/23 kg) with midazolam 0.1 mg/kg andfentanyl 0.01 mg/kg intravenously. After tracheal in-

tubation the animals were paralysed (pancuronium

bromide 0.2 mg/kg per h) and ventilated mechanically

M. Fischer et al. / Resuscitation 54 (2002) 269�/280270

(Narkosespiromat 656, Drager AG, Lubeck, Germany).

Tidal volume was set to 15 ml/kg and ventilation rate

was adjusted to maintain an arterial carbon dioxide

pressure of 40�/45 mmHg. Anaesthesia was maintained

by i.v. administration of midazolam 0.4 mg/kg per h and

fentanyl 0.015 mg/kg per h. Additionally, animals

received an infusion of lactated Ringer’s solution of 4

ml/kg per h.

Rectal temperature was measured with a thermistor

probe and kept constant at 38 8C using a heating pad.

Following introduction of anaesthesia surgical vascular

cutdowns were performed on both femoral vessels. The

left femoral vessels were cannulated with 3 F micro-

manometer-tipped catheters (PCB 307, transducer TCB

100, Millar Inst. Inc., Houston, TX, USA) for the

measurement of central venous and arterial pressures. A

7 F triple lumen catheter and a 3 F catheter (Cavafix,

Braun Medical AA, Melsungen, Germany) were in-

serted into the right femoral vein and artery for drug

and fluid administration, and blood sampling. A

sternotomy was performed and the left ventricle of the

heart was cannulated anterograde through the atrium

with a micromanometer tipped 3 F catheter (PCB 307,

transducer TCB 100, Millar Inst. Inc., Houston, TX,

USA). This catheter was used for the measurement of

left ventricular pressures and calculation of left ventri-

cular contractility variables (dp /dtmax). MBF and car-

diac output (CO) were determined using the coloured

microsphere technique [32]. For application of coloured

microspheres a 3 F catheter was placed into the left

atrium. An electrocardiogram was recorded from three

needle electrodes using a 8-channel monitor (CM 112,

Honeywell, Eindhoven, Netherlands).

Results from the measurements of the variables were

recorded continuously on a 6-channel polygraph (Poly-

physiograph, Schwarzer GmbH, Munchen, Germany)

and processed using a personal computer and the

DasyLab data acquisition software (DataLog, Mon-

chengladbach, Germany). Traces of 30 s duration were

recorded with a sampling rate of 125 Hz, processed and

written to a database. For each trace period arterial and

central venous pressures were averaged. The diastolic

and systolic aortic, central venous, and left ventricular

pressures were defined as the minimum or maximum

values of each trace, respectively. Myocardial perfusion

pressure was calculated from the difference between

aortic diastolic and the higher value of either left

ventricular diastolic or central venous diastolic pressure.

To estimate postischaemic left ventricular diastolic and

systolic function, dp /dtmax was calculated before and

after CA. The data obtained during CPR are the average

values of the haemodynamic measurements determined

from the first 10 traces (�/5 min) after starting cardiac

massage.

2.2. Myocardial blood flow and cardiac index

MBF and CO were measured with coloured poly-

styrene microspheres of 15 mm diameter with a densityof 1.09 g/ml (DYE-TRAK#, Triton Technologies Inc.,

San Diego, CA, USA) [32,33]. About 900 000 micro-

spheres were dissolved in 5 ml saline containing 0.02%

Tween 80 in a Hamilton syringe (type 1002, Hamilton,

Bonaduz, Switzerland). White-, yellow-, red-, blue-, and

violet-coloured microspheres were randomly assigned to

the measurements and were slowly and continuously

injected into the left atrium through the 3F catheterbefore CA, during CPR, and 5, 30, and 120 min after

return of spontaneus circulation (ROSC). During CPR,

the injection was started at 90 s after the beginning of

internal heart massage. Systemic haemodynamic values

remained unchanged during injection at all time points.

The reference flow was withdrawn starting 30 s before

and then during, and for 3 min after the microsphere

injection at a rate of 2.75 ml/min (withdrawal pump:Braun AA, Melsungen, Germany). At the end of the

experiments, the animals were sacrificed and the hearts

were removed. To determine the average MBF, the

hearts were cut into 42 defined samples of left ventricle

including septum. Subsequently, the tissue samples were

further divided into samples of subendomyocardial and

subepimyocardial layers and weighed (BP 310 S, Sartor-

ius, Germany). Then, the coloured microspheres werequantified by their dye content. After digestion of the

tissue samples with 4 M KOH and of the blood samples

with 16 M KOH, the microspheres were filtered through

a polyester filter (Nucleopore: pore size 8 mm; diameter

25 mm; Costar, Bodenheim, Germany). A special high-

grade steel vacuum filtration chamber was constructed

to avoid loss of microspheres during the filtering

process. The dye was recovered from the microspheresby adding 100 ml dimethylformamide. Then, the dye

solution was transferred into 0.3 ml glass tubes and

separated from additional particles and microspheres by

centrifugation at 2000�/g (Abofuge 1, Heraeus Christ,

Dusseldorf, Germany). Spectrophotometric analysis of

the dye solutions was performed using a UV/visible

spectrophotometer (model DU64, Beckmann, Dussel-

dorf, Germany; wave length range: 300�/820 nm with 1nm optical band width). Since microspheres with five

different colours were used for multiple measurements

of MBF and CO in each animal, the total spectrum was

measured. The spectra were transferred to a personal

computer using the Data-Leader Software (Beckmann),

and the composite spectrum of each dye solution was

resolved into spectra of single constituents by a matrix

inversion technique using the DYE-TRAK-MISS softwarepackage (Triton Technologies, Inc.). From the spectro-

photometric data, average MBF, left ventricular sub-

endomyocardial subepimyocardial MBF-ratio (R ), and

CO were calculated using the following equations:

M. Fischer et al. / Resuscitation 54 (2002) 269�/280 271

MBF (ml=g per min)�AS�Vref �A�1ref �W�1

s

(AS, absorption of tissue sample; Vref, reference flow

(ml/min); Aref, absorption of reference flow; Ws, weight

of tissue sample);

R�MBFendo

MBFepi

(MBFendo, regional blood flow of the left ventricularsubendomyocardial layers; MBFepi, regional blood flow

of the left ventricular subepimyocardial layers);

CO (ml=min)�CMinj�Vref �CMref�1

(CMinj, count of injected coloured microspheres; Vref,reference flow (ml/min); CMref, count of coloured

microspheres in reference blood sample).

From the results of the CO measurements and the

body weight of each individual animal a modified

cardiac index (CI�/CO/kg bw) was calculated for each

time point. Later, the modified CI was used to calculate

the systemic vascular resistance index (SVRI) as follows:

SVRI (dyne=s cm5 per kg)

��

MAP � CVP

CI� [80]

�(kg body weight)

(MAP, mean arterial blood pressure; CVP, central

venous pressure).

2.3. Cardiac arrest and cardiopulmonary resuscitation

Cardiac arrest of 10 min duration was induced at

normothermia by internal electrical stimulation with a 9

V DC current shock. During CA, mechanical ventila-

tion, anaesthesia, and infusions were interrupted and the

heating system was switched off. In all experiments CPR

was performed by the same investigator (J.S.), who wasblinded to the fluid administered during resuscitation.

CPR was started with open chest cardiac massage

using a compression rate of approximately 70/min. The

heart was compressed under blood pressure control to

maximize diastolic aortic pressure. With the onset of

open chest heart massage, 0.03 mg/kg adrenaline was

injected intravenously and artificial ventilation was

resumed with 100% O2 at a rate 40% above baseline.At the same time, infusion of either isotonic saline or HS

was initiated as described in detail below. After 5 min of

cardiac massage, the first DC-countershock (25 J;

Theracard 361D; Siemens AG, Erlangen, Germany)

was carried out using internal defibrillator electrodes.

If three defibrillations failed to induce ROCS, an

additional dose of 0.03 mg/kg adrenaline was injected

and heart massage was continued for another 3 minuntil the next defibrillation was performed. If this cycle

had to be repeated more than 10 times without ROSC,

the resuscitation was considered unsuccessful. After

ROSC, Ringer’s solution and pancuronium infusions

were resumed and the heating system was switched on.

During the ensuing 120 min period of spontaneous

recirculation neither catecholamines to stabilize cardiacaction, nor buffers to adjust arterial base excess to

normal, were infused.

2.4. Study protocol

A randomisation list was generated with a random

generator (Microsoft† Excel 97 SR-1). From this list the

animals were assigned to one of the following resuscita-tion protocols: (1) CPR in combination with volume

expansion by i.v. infusion of 2 ml/kg HS (HS; 7.2%

NaCl) in 10 min; (2) CPR in combination with volume

expansion by i.v. infusion of 4 ml/kg HS (HS; 7.2%

NaCl) in 20 min; (3) CPR in combination with i.v.

infusion of 2 ml/kg normal saline (NS; 0.9% NaCl) in 10

min. The animals given the infusion of NS served as the

reference to detect the effects of an early volumeexpansion with HS at different volumes. Seven animals

were assigned to each resuscitation protocol. Infusions

were started at the onset of open chest cardiac massage

and lasted for 10 or 20 min, respectively, in order to

keep the infusion rates identical between the experi-

mental groups.

2.5. Blood analyses

Arterial blood samples were withdrawn at defined

time points for the assessment of following parameters:

blood gases and pH (ABL 505, Radiometer, Kopenha-

gen, Denmark), plasma concentrations of electrolytes

(LX 7, Beckmann, Munchen, Germany), glucose (Epos,

Eppendorf, Hamburg, Germany) and lactate (Vidros250, Johnson & Johnson, Strasbourg, France), serum

osmolality (Vapour Pressure Osmometer, Knauer, Ber-

lin, Germany) and haematocrit (Celldyn 3500, Abbott,

Wiesbaden, Germany).

2.6. Statistical analysis

All data are expressed as means9/standard deviation

(S.D.). Differences in the time courses of haemodynamic

variables, MBF and CI, and blood analyses were

analyzed for statistical significance using a multivariant

analysis of variance (MANOVA) with a repeated

measures factor and a between group factor for treat-

ment (STATISTICA for Windows; StatSoft, Tulsa, OK,

USA). For post-hoc analysis the Tukey’s HSD test wasemployed. The x2-test was used for survival rate

analysis. Statistical significance was assumed for P B/

0.05.

M. Fischer et al. / Resuscitation 54 (2002) 269�/280272

3. Results

3.1. Resuscitation success and survival rate

Ventricular fibrillation leading to immediate circula-

tory arrest could be induced in all animals (Fig. 1.).

Return of spontaneous circulation could be achieved in

6/7 animals receiving 2 ml/kg per 10 min HS, in 5/7

animals receiving 4 ml/kg per 20 min HS, and in 3/7animals receiving NS. Shortly after successful resuscita-

tion, one animal from the reference group developed

cardiac failure and died 45 min after ROSC. Therefore,

only in two animals of the reference group recirculation

could be monitored for 2 h after resuscitation. The 120

min survival rate in animals receiving 2 ml/kg per 10 min

HS was significantly higher in comparison to animals

receiving NS (P�/0.03, x2-test), but an increase of theHS-infusion to 4 ml/kg per 20 min did not improve post-

resuscitation survival further (Fig. 2.). Overall, small

volume resuscitation during CPR at both volumes

increased resuscitation success and survival rate signifi-

cantly (P�/0.02 vs. reference, x2-test; Fig. 2.).

Among the animals that were successfully resusci-

tated, no differences were found for the duration of

cardiac massage (NS: 6.29/2.4 min; HS 2 ml/kg per 10min: 6.19/2.1 min; HS 4 ml/kg per 20 min: 5.79/1.5

min), the amount of adrenaline required during CPR

(NS: 0.059/0.03 mg/kg; HS 2 ml/kg per 10 min: 0.049/

0.01 mg/kg; HS 4 ml/kg per 20 min: 0.039/0.01 mg/kg),

and the number of defibrillations to induce ROSC (NS:

1.49/0.8; HS 2 ml/kg per 10 min: 1.59/1.0; HS 4 ml/kg

per 20 min: 2.09/1.8) between the experimental groups.

Fig. 1. Cardiopulmonary resuscitation after 10 min of cardiac arrest in a pig treated with 2 ml/kg per 10 min 7.2% NaCl. In this experiment, CO was

continuously measured using an electromagnetic flow probe (EP 455 R, Carolina Medical Inc., Durham, NC, USA) attached to the ascending aorta.

The polygraphic traces demonstrate instantaneous cessation of blood flow after induction of ventricular fibrillation, and return of spontaneous

circulation after 5 min of internal heart massage and a single electrical counter shock (25 J). ECG: electrocardiogram; AP: systemic arterial pressure;

LVP: left ventricular pressure; CO: cardiac output.

Fig. 2. Survival rate of pigs receiving either normal saline (NS) or

7.2% hypertonic saline (HS) during internal heart massage. N�/7 in

each group; ‘HS total’ summarizes all animals receiving 7.2% NaCl.

M. Fischer et al. / Resuscitation 54 (2002) 269�/280 273

3.2. Haemodynamic variables, myocardial blood flow and

cardiac index during CPR

Before induction of ventricular fibrillation, haemody-

namic variables were in the physiological range in all

animals (Table 1). During resuscitation, the rate of

cardiac compressions was identical in the groups (Table

1). Cardiac massage induced a significant increase of

mean and diastolic central venous (CVP/DCVP) and of

left ventricular diastolic pressure (LVDP) compared

with prearrest conditions in all animals (P B/0.05).

However, LVDP increased significantly after infusion

of HS 4 ml/kg per 20 min compared with of NS or HS at

2 ml/kg per 10 min, but remained in the physiological

range as did the CVP and DCVP (Table 1). Myocardial

perfusion pressure (MPP) during CPR was significantly

reduced compared with prearrest conditions in all

groups but was higher after infusion of HS at both

dosages compared to the NS group (Table 1). However,

the improvement in MPP compared with the reference

group reached statistical significance only in animals

treated with the lower volume of HS (2 ml/kg per 10

min; P B/0.05; Fig. 3.). This observation was mainly due

to the difference in the DCVP, but also in part to the

difference in the diastolic arterial pressure during CPR,

which reached the level of prearrest conditions only in

animals treated with the lower volume of HS (Table 1).

MBF rose during internal heart massage in all

animals, but the 4-fold increase in animals receiving

HS was significantly higher than the 2-fold increase in

the reference group (P B/0.05; Fig. 4.). Furthermore, the

left-ventricular subendomyocardial-subepimyocardial

MBF ratio increased in the HS-treated groups from

1.019/0.28 (2 ml/kg per 10 min) and 1.069/0.24 (4 ml/kg

per 20 min) to 1.429/0.54 and 1.389/0.70 (P B/0.05,

respectively), whereas it remained unchanged during

NS-infusion (0.969/0.28 and 1.029/0.48). The CI during

CPR was significantly reduced compared with thephysiological conditions before induction of CA in all

animals (P B/0.05; Fig. 5). In fact, open chest heart

massage with NS induced a CI of 179/10% of baseline,

whereas HS-treatment during CPR increased CI to 269/

14% and 339/13% (P B/0.05 vs. reference; Fig. 5.) of

baseline, respectively. The SVRI before CA was in the

same range in all groups (NS: 2159/120; HS 2 ml/kg per

10 min: 1919/88; HS 4 ml/kg per 20 min: 2299/62 dyne/scm5 per kg, respectively) and equally increased 2�/3 fold

during CPR (NS: 5829/192; HS 2 ml/kg per 10 min:

7529/795; HS 4 ml/kg per 20 min: 5559/297 dyne/s cm5

per kg, respectively).

3.3. Haemodynamic variables, myocardial blood flow and

cardiac index during recirculation

Ten minutes after ROSC tachycardia and arterial

hypertension following adrenaline administration dur-

ing CPR was present in all groups (Table 2). Whereas

tachycardia was sustained during the 120 min recircula-

tion period the mean aortic blood pressure decreased tothe prearrest level within 20 min. Initially after ROSC,

CVP was significantly lower in HS treated animals, but

CVP continuously increased in these animals during the

observation period. At the measurement end points the

CVP was increased significantly compared with the

prearrest level in all groups but remained in the

physiological range (Table 2). No difference was detect-

able in MPP during recirculation among the groups.After ROSC MPP initially increased but soon became

Table 1

Haemodynamic variables before CA and during CPR

NS (2 ml/kg per 10 min) HS (2 ml/kg per 10 min) HS (4 ml/kg per 20 min)

Before CA

HR (bpm) 113925 107917 102922

CVP (mmHg) 6.892.2 5.493.1 5.292.3

DCVP (mmHg) 4.792.8 493.3 3.691.8

LVDP (mmHg) 3.393.4 3.694 4.897.1

MPP (mmHg) 53.297.3 50.698.3 52.9917.6

SAP (mmHg) 8896 89915 95925

DAP (mmHg) 5897 56910 60918

During CPR

HR (bpm) 719128 76968 689118CVP (mmHg) 13.992.98 13.1938 11.992.78DCVP (mmHg) 8.492.78 7.393.88 7.391.58LVDP (mmHg) 9.296.38 7.993.98 13.797.18*§MPP (mmHg) 20.996.38 34.8914.28* 30.9913.38SAP (mmHg) 629108 83923* 84927*

DAP (mmHg) 3396.28 45912.8 43.39178

Means9S.D.; n�7 in each group; HR�heart rate; HR?�cardiac compressions; CVP/DCVP�mean/diastolic central venous pressure;

MPP�myocardial perfusion pressure; LVDP�diastolic left ventricular pressure; DAP/SAP�diastolic/systolic arterial pressure; 8P B0.05 vs.

prearrest conditions; *P B0.05 vs. reference (NS); §P B0.05 vs. HS 2 ml/kg per 10 min.

M. Fischer et al. / Resuscitation 54 (2002) 269�/280274

normal. Finally, left ventricular contractility as deter-

mined by calculation of the maximal rate of

pressure increase (dp /dtmax) was increased almost iden-

tically in the early recirculation period (10 min past

ROSC) in the experimental groups. Twenty minutes

after ROSC dp /dtmax significantly decreased in the

reference group compared with the baseline and to HS

treated animals (P B/0.05, respectively, Table 2). How-

ever, no additional signs of postischaemic left ventricu-

lar dysfunction were detectable and dp /dtmax was not

different among the groups with different fluid admin-

istration.

Myocardial postischaemic hyperaemia was present in

all animals during the early recirculation period. Five

minutes after ROSC the increase in the MBF was

approximately 7�/11-fold (Table 3). Whereas MBF

decreased to near baseline values in the HS treated

animals at 30 min after ROSC, postischaemic hyper-

Fig. 3. Myocardial perfusion pressure (MPP) before and during CPR. MPP was significantly reduced during CPR in all groups, but attenuation was

less dramatic after infusion of hypertonic saline than of normal saline. 8P B/0.05 vs. baseline before CA; *P B/0.05 vs. reference group (NS).

Fig. 4. Myocardial blood flow raised during open chest heart massage in all groups, but a significant increase was detectable only after small volume

resuscitation. 8P B/0.05 vs. baseline before cardiac arrest; *P B/0.05 vs. reference group (NS).

M. Fischer et al. / Resuscitation 54 (2002) 269�/280 275

aemia was still present in the animals in the reference

group. At this time point postischaemic MBF was

significantly increased in the latter group compared

with the baseline value and to pigs receiving

HS (P B/0.05, resp.; Table 3). Two hour after ROSC,

myocardial perfusion had become normal in all groups.

Left-ventricular subendo/subepimyocardial MBF-ratio

became normal with spontaneous circulation in all

groups and did not show relevant variations during

the reperfusion period or between groups (data not

shown). Postischaemic CI immediately after

ROSC was elevated only in animals receiving HS 4 ml/

kg per 20 min (Table 4). After 30 min global re-

perfusion CI was in the normal range in all animals.

At 2 h after ROSC CI fell significantly to 50% of

baseline in the reference group, whereas it stayed on the

preischaemic baseline level in the HS treated groups

(P B/0.05, Table 4). Finally, increased vascular

resistance during CPR due to adrenaline application

decreased stepwise and at 30 min after ROSC the SVRI

reached a level close to baseline before CA in all

groups (NS: 1839/ 53; HS 2 ml/kg per 10 min: 2019/

78; HS 4 ml/kg per 20 min: 2519/53 dyne/s cm5 per kg,

respectively).

Fig. 5. Open chest cardiac massage induced a cardiac index (CI) of approximately 20�/30% of baseline values. Small volume resuscitation during

CPR raised CI in comparison to isotonic saline infusion. 8P B/0.05 vs. baseline before CA; *P B/0.05 vs. reference group (NS).

Table 2

Haemodynamic variables before CA and during recirculation

After ROSC (min)

Before CA 10 20 30 60 90 120

HR (bpm) NS (2 ml/kg per10 min) 117933 1839278 1639388 1489468 1479478 1489598 1509548HS (2 ml/kg per l0 min) 108918 1779208 1499188 1489278 1439278 1429288 1439318HS (4 ml/kg per 20 min) 90910 1679168 1479208 1469168 1389168 1339158 1369118

MAP (mmHg) NS (2 ml/kg per 10 min) 76912 109988 67929 72932 78926 74916 7099

HS (2 ml/kg per 10 min) 68912 989238 65910 62911 6596 6398 6699

HS (4 ml/kg per 20 min) 71924 106928 62911 6195 68912 66914 65914

CVP (mmHg) NS (2 ml/kg per 10 min) 4.390.1 8.697.38 7.996.48 7.4948 894.58 8.29448 8.394.68HS (2 ml/kg per 10 min) 5.193.2 6.292.3* 6.192.5 6.992.28 7.492.78 7.993.48 893.58HS (4 ml/kg per 20 min) 5.492.3 6.392.4* 6.692.3 6.692.5 6.792.2 792 7.1928

MPP (mmHg) NS (2 ml/kg per 10 min) 5897 7891 43913 52926 56921 53912 4996

HS (2 ml/kg per 10 min) 4998 75920 47910 45911 4695 4399 44911

HS (4 ml/kg per 20 min) 54921 81938 4399 4394 50911 48913 46913

dp /dtmax (mmHg) NS (2 ml/kg per 10 min) 25859375 356991377 152991028 243591693 245291301 22049798 19929500

HS (2 ml/kg per 10 min) 23009783 424997418 27369332* 21699463 21589447 20209507 20479613

HS (4 ml/kg per 20 min) 26329264 4012912068 24879890* 20059602 18569356 17459364 17069479

Means9S.D.; NS: n�2; HS 2 ml/kg per 10 min: n�6; HS 4 ml/kg per 20 min: n�5; HR�heart rate; CVP�mean central venous pressure;

MAP�mean arterial pressure; MPP�myocardial perfusion pressure; dp /dtmax�maximal rate of contractility; 8P B0.05 vs. prearrest conditions;

*P B0.05 vs. reference (NSS).

M. Fischer et al. / Resuscitation 54 (2002) 269�/280276

3.4. Blood analyses

Before the induction of ventricular fibrillation blood

variables were within the normal range in all groups

(Table 5). Ventricular fibrillation and the poor circula-

tion during CPR led to severe metabolic disturbances,

evidenced by blood lactic acidosis. However, at 30 min

after ROSC arterial pH had become almost normal.

Plasma lactate slowly decreased during reperfusion but

without reaching baseline level until the end of the

recirculation period. Although all animals received 4 ml/

kg per h lactated Ringer’s solution throughout the

experiment CA caused an increase of haematocrit in

all animals (Table 5). The application of HS during

internal heart massage diminished this increase. Due to

the sodium load of 7.2% NaCl, osmolality and plasma

sodium concentration of treated animals increased

sharply after infusion. Subsequently these values recov-

ered because of fluid shifts from the extravascular into

the intravascular compartment, but within the 120 min

recirculation period both variables became normal only

in the animals receiving the smaller volume of HS (Table

5). Ventilation with pure oxygen during resuscitation

caused an increase in PaO2 to 250�/300 mmHg in all

groups. PaO2 rose up to 30 min after CPR but then

became normal indicating that pulmonary function was

not severely disturbed. Finally, CA of 10 min and

recirculation raised plasma glucose in all groups but

no relevant differences were found (Table 5).

4. Discussion

Our data demonstrate clearly that the administration

of 7.2% HS solution during internal cardiac massage

improves myocardial haemodynamics and CI during

CPR. The improvement in systemic and myocardial

recirculation during CPR after infusion of a smallvolume of HS significantly increased resuscitation

success and survival rate. No negative side effects of

treatment with either 2 ml/kg per 10 min or 4 ml/kg per 20

min 7.2% NaCl on haemodynamic variables were

observed in the postischaemic recirculation period. Small

volume resuscitation during CPR reduced early post-

ischaemic haemoconcentration and produced a normal

haematocrit within the 2 h observation period. However,infusions of HS increased the serum osmolality and

sodium plasma concentration transiently, but these

variables became normal within the observation period

after an infusion of the smaller volume of HS. Doubling

the volume of HS at the same infusion rate did not

enhance the positive effects on haemodynamic variables

seen after application of 2 ml/kg per 10 min, but recovery

of the biochemical values was delayed and incomplete.The improvement in systemic haemodynamics and

MBF during CPR by small volume resuscitation is

based on several principles which have been evaluated

predominantly in haemorrhagic shock models. First, HS

rapidly returns circulating blood volume to normal by

shifting fluid from the endothelium, the interstitial

space, and parenchymal cells into the intravascular

space [17�/19,34�/37]. Second, osmotic dehydration leadsto cell shrinkage and reduces or even prevents endothe-

lial swelling due to hypoxic cell injury during ischaemia

and reperfusion [38,39]. Endothelial cell swelling aug-

ments postischaemic microcirculatory disorders induced

by imbalanced blood coagulation and haemoconcentra-

tion [6,8,9], and reversal of this effect may improve

nutritional organ blood flow and tissue reoxygenation.

Third, small volume resuscitation during CPR has beenshown to reduce haemoconcentration after cardiac

arrest [7], this observation was confirmed in the present

investigation. Lin first demonstrated that plasma vo-

lume shrinks after resuscitation from cardiac arrest

leading to substantial hypovolaemia and haemoconcen-

tration [9]. Since blood viscosity rises in relation to the

third power of the haematocrit [40], prevention of

haemoconcentration attenuates postischaemic microcir-culatory disturbances as confirmed by reduction in

cerebral no-reflow after cardiac arrest [7]. In our study

the haematocrit in animals receiving NS significantly

Table 3

Myocardial blood flow before CA and after ROSC

After ROSC (min)

Before CA 5 30 120

NS (2 ml/kg per

10 min)

0.8990.31 6.391.238 2.2790.598 0.7590.27

HS (2 ml/kg per

10 min)

0.7390.25 5.4892.388* 1.1690.328* 0.8790.3

HS (4 ml/kg per

20 min)

0.690.15 6.9392.58*§ 1.1190.468* 0.8890.25

Means9S.D.; CO is given in ml/g per min; NS; n�2; HS 2 ml/kg

per 10 min: n�6; HS 4 ml/kg per 20 min: n�5; 8P B0.05 vs. prearrest

conditions; *P B0.05 vs. reference (NS); §P B0.05 vs. HS 2 ml/kg per

10 min.

Table 4

Cardiac index before CA and after ROSC

After ROSC (min)

Before CA 5 30 120

NS (2 ml/kg per 10 min) 89918 99932 80959 449268HS (2 ml/kg per 10 min) 92919 96920 90933 68912*

HS (4 ml/kg per 20 min) 82910 1419188*§ 84912 82917*

Means9S.D.; CO is given in ml/kg per min; NS: n�2; HS 2 ml/kg

per 10 min n�6; HS 4 ml/kg per 20 min: n�5; 8P B0.05 vs. prearrest

conditions; *P B0.05 vs. reference (NS); §P B0.05 vs. HS 2 ml/kg per

10 min.

M. Fischer et al. / Resuscitation 54 (2002) 269�/280 277

increased from 349/1.3 to 449/2.9% at 5 min after

ROSC, whereas the rise in haematocrit was less dra-

matic in HS treated pigs (37.79/3 and 38.89/4.2%).

Although we did not measure haematocrit or blood

viscosity during CPR the amelioration of MBF during

cardiac massage was, at least in part, the result of

improved microcirculation during ischaemia. Further-

more, the observation that the haematocrit was sig-

nificantly lower at 2 h after CPR in groups receiving HS

in comparison to the reference group demonstrates that

this effect was sustained during the recirculation period.

At this time point haematocrit uniformly reached base-

line level in both groups treated with both volumes of

7.2% saline indicating that the dosage of 2 ml/kg per 10

min was effective to return the circulating blood volume

to normal within this period. Finally, small volume

resuscitation using hyperosmolar saline/dextran solu-

tions has been shown to reduce leukocyte adherence to

the endothelial wall in the striated muscle [41]. Leuko-

cyte activation increases myocardial vascular resistance

[42], and the prevention of leukocyte adhesion during

reperfusion reduces postischaemic myocardial inflam-

mation and oedema, and improves reflow and ventri-

cular function after heart transplantation [43]. However,

whether HS reduces postischaemic leukocyte plugging in

myocardial capillaries after cardiac arrest and resuscita-

tion has not been evaluated to date and also was not an

issue studied in the present investigation.

In our investigation, HS improved myocardial hae-

modynamics and blood flow mainly during CPR,

whereas only minor effects were present during recircula-

tion. The rapid onset of the effects is most likely the

explanation for this observation. Comparison of the

variables between the two groups treated with different

volumes of HS shows almost identical results for

myocardial perfusion pressure and blood flow and for

the CI during CPR. This finding was due to the

experimental protocol defining the time point of the

measurements at 5 min after induction of CPR. Since the

same infusion rates were used in both groups, identical

amounts of HS were administered at this time point.

However, once ROSC was achieved the intensity of initial

reactive myocardial hyperaemia was similar in the three

groups indicating that postischaemic vasodilation due to

the release of accumulated metabolites like lactate,

adenosine, and CO2 was not affected by the treatment

[44,45]. The fact that myocardial hyperaemia was

prolonged in the reference group, (at 30 min after

ROSC, the blood flow in these animals was about twice

as high as in HS-treated animals), may suggest that tissue

reoxygenation and systemic metabolic recovery was

delayed in these animals. The haemodynamic measure-

ments indicate that this was due to improved micro-

circulation after hypertonic infusion and not to impaired

cardiac function in animals in the reference group.

Indeed, small volume resuscitation has been shown to

accelerate recovery in cardiac function [46], but our study

did not reveal major changes in systemic haemodynamics

and ventricular inotropy as determined by dp /dtmax

measurements at 10 min past ROSC. A new finding from

Table 5

Blood analyses before CA and during recirculation

After ROSC (min)

Before CA 5 30 120

pH NS (2 ml/kg per 10 min) 7.4990.1 7.2890.098 7.490.15 7.3390.1

HS (2 ml/kg per 10 min) 7.4790.06 7.2190.098* 7.3590.08 7.4590.03

HS (4 ml/kg per 20 min) 7.4690.08 7.2490.048 7.3990.03 7.4490.06

Lactate (mmol/l) NS (2 ml/kg per 10 min) 1.690.6 8.391.98 6.592.18 3.190.78HS (2 ml/kg per 10 min) 1.790.7 9.492.78 7.391.48 4.391.48HS (4 ml/kg per 20 min) 290.6 9.890.6 8 7.290.38 4.5918

Haematocrit (%) NS (2 ml/kg per 10 min) 3491.3 44.192.98 40.197.18 36.994.1

HS (2 ml/kg per 10 min) 30.895.4 37.7938* 33.192.9* 31.792.8*

HS (4 ml/kg per 20 min) 31.993.1 38.894.28* 33.593.8 31.394.2*

Osmolality (mosm/kg) NS (2 ml/kg per 10 min) 30195 30795 30991 8 30691

HS (2 ml/kg per 10 min) 30096 318948* 309968 30698

HS (4 ml/kg per 20min) 29996 326958*§ 316928*§ 314978*§Na� (mmol/l) NS (2 ml/kg per 10 min) 14393 14592 14591 14391

HS (2 ml/kg per 10 min) 14192 147938* 14492 14392

HS (4 ml/kg per 20 min) 14293 152928*§ 149918*§ 147928*§pO2 (mmHg) NS (2 ml/kg per 10 min) 17093 294944 3349398 197976

HS (2 ml/kg per 10 min) 211996 259985 2769978 199968

HS (4 ml/kg per 20 min) 199923 269960 34291028 221975

Glucose (mg%) NS (2 ml/kg per 10 min) 63921 909238 1019178 108948HS (2 ml/kg per 10 min) 91933 1359808* 1329798 1219798HS (4 ml/kg per 20 min) 78922 1289778 1099438 96948

Means9S.D.; NS: n�2; HS 2 ml/kg per 10 min: n�6; HS 4 ml/kg per 10 min: n�5;8P B0.05 vs. prearrest conditions; *P B0.05 vs. reference

(NS); §P B0.05 vs. HS 2 ml/kg per 10 min.

M. Fischer et al. / Resuscitation 54 (2002) 269�/280278

the present investigation was that the HS infusion during

heart massage induced a 40% increase of the left

ventricular subendomyocardial perfusion compared

with the subepimyocardial layer. The MBF under normalconditions is autoregulated and correlated to myocardial

function [47,48], and the perfusion of subendo- and

subepimyocardial layers is in the same range (MBFendo/

MBFepi�/1). A decrease in the ratio reflects a transmural

steal phenomenon attributed to increased compression of

subendomyocardial layers and a further vasodilation of

subepimyocardial layers during ischemia [49]. We could

not find publications describing an increase of this ratioand its possible implications on myocardial function,

and, therefore, we could only speculate whether the

observed increase of the ratio is relevant in cardiac

resuscitation or affects post-ischaemic myocardial func-

tion. However, the MBFendo/MBFepi-ratio in animals of

the reference group was in the normal range at all time

points demonstrating that the infusion of NS was not

associated with a bypass of circulation possibly inducinga transmural steal phenomenon.

Although our present data clearly supports the

beneficial effect of HS treatment on cardiac resuscita-

tion, the possibility of adverse side effects of volume

loading by small volume resuscitation during CPR

should not be dismissed. Hypertonic saline has been

shown to be deleterious in hearts with impaired con-

tractile function caused by ischemia [50�/52], however,our data did not reveal increases in central venous or

diastolic left ventricular pressure exceeding the physio-

logical range, which would indicate reduced right or left

ventricular contractility. Unchanged postischaemic ven-

tricular contractility was also confirmed by dp /dtmax-

measurements after CPR. On the other hand, this

observation could also imply that the infused 7.2%

saline solution produced a much smaller volume loadthan expected. However, the plasma volume was not

measured in our study. Another side effect of HS

described is a reduction in peripheral vascular resis-

tance, which has been seen predominantly after bolus

injection [53,54]. In the present investigation, the

calculated SVRI did not decrease during CPR and

HS-infusion. Furthermore, the observation that myo-

cardial perfusion pressure during CPR was higher afterhypertonic than after NS infusion also argues against a

relevant fall in vascular resistance induced by small

volume resuscitation during CPR in our study. We

suggest that this was apparently due to the slow

injection rate and that bolus injections should be

omitted during resuscitation procedures. Finally,

plasma sodium and serum osmolality rose after HS-

infusion resulting in an osmotic gradient. In animalsreceiving the lower volume of HS the gradient was

moderate and both variables became normal within 30

min after ROSC. In contrast, the sodium load after

infusion of 4 ml/kg per 20 min HS increased plasma

sodium and serum osmolality above the normal range,

and osmolality remained elevated during the 120 min

observation period. Since osmotic recovery was delayed

and incomplete in these animals and the haemodynamiceffects were not enhanced by the higher volume of 7.2%

saline, it was concluded that the infusion of 2 ml/kg per

10 min apparently is the appropriate dosage to achieve

beneficial haemodynamic effects without inducing rele-

vant adverse side effects in this model of CPR.

In conclusion, small volume resuscitation with 7.2%

HS during CPR improved myocardial haemodynamics

and CI, and increased resuscitation success rate andsurvival rate in a porcine model of prolonged cardiac

arrest. The infusion of 2 ml/kg per 10 min HS induced

beneficial haemodynamic effects without causing adverse

side effects, and should, therefore, be recommended for

clinical studies. Such studies should be performed in the

near future to confirm the clinical relevance of the

concept of small volume resuscitation during CPR.

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