1. vet. Pharmacol. Therap. 1 7 , 21 1-2 1 7, 1994.

Effects of hypertonic saline on myocardial contractility in anaesthetized

P. W. HELLYER &
R. E. MEYER
Department of Anatomy, Physiological
Sciences and Radiology. North Carolina
State University, College of Veterinary Medicine,
4700 Hillsborough Street, Raleigh.
N C 2 7 6 0 6 , USA
Hellyer, P.W., Meyer, R.E. Effects of hypertonic saline on myocordial contracti-
lity in anaesthetized pigs. 1. vet. Pharmacol. Therap. 1 7 , 211-2 17.
The cardiac effects of hypertonic saline (HS, 7.5% NaCl) were evaluated using a
number of indices derived from the left ventricular (LV) pressurevolume rela-
tionship. Left ventricular end-systolicelastance (elastance), the slope of the end-
systolic pressure-volume relationship, end-systolic elastance normalized for
enddiastolic volume (elastance(,,,,), the rate of rise of LV pressure (dPldt,,,),
and dP/dt,,/end-diastolic volume were used to assess myocardial contractility.
Pigs were anaesthetized with isoflurane and instrumented for haemodynamic
measurements, LV pressure, and volume (conductance catheter) determina-
tions. Elastance was determined during transient (8-10 s) caudal vena caval
balloon occlusion. Following instrumentation, the end-tidal isoflurane concen-
tration was reduced and maintained at 1 minimum alveolar concentration
(1.5%).Pigs were randomly administered either 0.9%NaCl (n = 7) or HS (n =
9) at a dose of 4 ml/kg, over 3 min into the right atrium. There were no signifi-
cant differences in LV or haemodynamic measurements between isotonic saline
and HS treated pigs a t any time point. Elastance, elastance(,,,,, and
dP/dt,,,/end-diastolic volume did not change in either treatment group. In con-
trast, dPldt,, increased significantly (P < 0.015) at 5 min compared to base-
line after treatment with HS. End-diastolic volume increased significantly from
5 to 30 min following treatment with HS. Left ventricular end-diastolic pres-
sure increased significantly at 5 and 60 min in HS treated pigs. Central venous
and pulmonary arterial wedge pressures, and cardiac index increased signifi-
cantly at 5 min after treatment with HS. Total peripheral resistance decreased
significantly at 5 min, followed by a return to baseline in the HS group. These
results suggest that HS is not a positive inotrope in the anaesthetized pig and
that increases in cardiac index are primarily due to an increased preload.
(Paper received 14 January 1993; accepted for publication 3 June 1993)
Peter W. Hellyer, DVM, MS, Department of Anatomy, Physiological Sciences and
Radiology, North Carolina State University, College of Veterinary Medicine, 4700
Hillsborough Street, Raleigh, NC 27606, USA

INTRODUCTION al., 1986), increased adrenergic activity secondary to cate-

Hypertonic saline (HS 7.5% sodium chloride solution) at a rate of
4-5 ml/kg intravenously (i.v.) increases cardiac output and
mean arterial pressure to a greater degree than a n equivalent
volume of isotonic saline in cats (Bitterman et al.. 1987; Muir &
Sally, 1989),dogs (Velasco et al., 1980), swine (Traverso et al..
1987; Wade et al.. 1989). horses (Schmall et al., 1990), and
sheep (Nakayama et a!., 1984) with hypovolaemic hypotension.
The mechanism(s) responsible for the beneficial haemodynamic
effects of HS are not completely understood, but increased venous
return secondary to an increased plasma volume (Schertel et al.,
1990),decreased peripheral vascular resistance (Rocha-e-Silva et
cholamine release (Liang & Hood, 1978), activation of a pul-
monary vagal reflex (Younes et al.. 1 9 8 5 ) , and increased
myocardial Contractility (Kien et al.. 1991a. b) have been postu-
lated to play important roles.
Although it has been proposed that hypertonic solutions
increase cardiac contractility, conflicting evidence suggests that
hyperosmotic, ionic solutions are negative inotropes.
Intracoronary injections of hyperosmolar solutions of glucose
and mannitol, with osmolality from 300 to 1800 milliosmols
(rn0sm) increased cardiac contractility in anesthetized dogs
whereas hyperosmolar NaCl (900 m0sm) caused marked
decreases in contractility (Newell et al.. 1980). Hyperosmolar

1. vet. Phannacol. Therap. 1 7 , 211-2 17. 1994 211

2 12 P.W. Hellyer 6 R. E. Meyer
solutions of sucrose or urea (osmolality > 400-450 mosm)
administered to dogs had a negative inotropic effect, resulting in
cardiac failure (Wildenthal et al., 1969a). This is in contrast to
solutions that had an osmolality less than 400 mosm, in which
contractility was increased. Isolated rat hearts infused with 7.5%
NaCl had depressed ventricular function: however, the infusion
of equimolar sucrose (2400 mOsm) had a positive inotropic effect
(Brown et al., 1990). Thus, excess concentrations of Na' may
attenuate the positive inotropic effects of hyperosmolar solutions.
In addition to the direct effects of hyperosmolar solutions on con-
tractility, hypertonic NaCl may act through an increase in
plasma catecholamine concentrations in anaesthetied dogs
(Liang & Hood, 1978). PAdrenergic receptor blockade with
practolol abolished the positive haemodynamic effects of hyper-
tonic NaCl, indicating the importance of catecholamines in. the
haemodynamic effects of hypertonic NaCl.
Changes in preload and afterload induced by the rapid admin-
istration of HS confound the evaluation of myocardial contractil-
ity. Ideally, evaluation of left ventricular (LV) contractility should
utilize indices that are sensitive to changes in inotropic state, are
independent of changes in preload and afterload, and are insensi-
tive to changes in heart rate (Kass & Maughan, 1988).
Isovolemic contraction phase indices, such as dP/dt,,. are sensi-
tive and relatively specific for changes in inotropic state provided
that preload does not change (Kass et al., 1987). Left ventricular
end-systolic elastance (elastance), the slope of the maximal end-
systolic pressure-volume relationship, is a relatively load-inde-
pendent and sensitive index of myocardial contractile state
(Kass et d.,1987). In this study, we tested the hypothesis that
the rapid administration (over 3 min) of a small volume (4
rnl/kg) of 7.5% NaCl would increase cardiac contractility, as
measured by elastance, in isoflurane-anaesthetied. normo-
volaemic pigs.
MATERIALS AND METHODS
Animal preparation
Sixteen domestic pigs, weighing 23.0 f 0.4 kg (mean f SEM),
derived from a specific-pathogen free source, were the subjects of
this study. All pigs were treated humanely in accordance with
National Institute of Health guidelines for the use of experimental
animals and with approval of the Institutional Animal Care and
Use Committee at North Carolina State University. Food, but not
water, was withheld for 12 h prior to the induction of anesthesia.
Pigs were anaesthetized with isoflurane in 0,by facemask, oro-
tracheally intubated, and ventilated at a constant tidal volume.
Ventilation was controlled to maintain arterial CO, tensions at
approximately 40 mmHg and end-tidal CO, at approximately
5%. End-tidal CO, was measured continuously with a Hewlett-
Packard infrared gas analyzer; The concentration of isoflurane
was adjusted to maintain a surgical plane of anesthesia during
the instrumentation period. Expired anaesthetic concentra-
tions were measured continuously with an anaesthetic agent
monitor (Biochem 8100).Lactated Ringers solution was admin-
istered at a rate of approximately 10 ml/kg/h during instrumen-
tation.
Instrumentation
The left and right carotid arteries, the left jugular vein, and the
left and right femoral veins were surgically exposed and isolated.
A flow-directed,thermistor-tipped Swan-Ganz catheter (Edwards
Labs,) was inserted in the right femoral vein and passed retro-
grade with the distal port in the pulmonary artery and the proxi-
mal port in the right atrium. Pulmonary arterial and right atrial
pressures were measured using balanced and calibrated trans-
ducers (Statham P23 ID). The zero reference measurement was
considered to be at the level of the right atrium. Polyethylene
tubing was inserted in the jugular vein for the administration of
drugs and i.v. fluids. A balloon-occlusion catheter (Medi-Tech
Inc.) was inserted in the left femoral vein and passed to the cau-
dal vena cava. A dual-tipped, high fidelity micromanometer
catheter (Millar Instruments) was inserted in the left carotid
artery and positioned with the distal transducer in the left ventri-
cle and the proximal transducer in the aorta to measure pres-
sures. Placement of catheters was confirmed by observation of
characteristic pressures and waveforms.
A 7 French, multielectrode. conductance volume catheter
(Webster Laboratories) was inserted in the right carotid artery
and positioned in the left ventricle along the ventricular long
axis. The conductance catheter consisted of 11 equally spaced
electrodes (0.85 cm apart) at the distal end of the catheter. The
distal electrode was positioned within the apex of the left ventri-
cle and the most proximal electrode(s) was positioned just above
the aortic valve. A constant 2 0 kHz current, with a n amplitude
of 30 PA RMS, was applied between electrodes 1 and 11. Five
independent voltage differences were measured between five
adjacent pairs of electrodes and converted to left ventricular vol-
ume by a conditioning amplifier (Sigma-5, Leycom). Proper posi-
tioning of the conductance catheter in the left ventricle was con-
firmed by observation of the segmental volume signals generated
from the conductance catheter in relation to the QRS complex of
the ECG. The segmental volume signal decreases immediately
after the R wave associated with ventricular ejection. Therefore,
coupling of the electrical and mechanical activities of the heart
was used to ensure proper positioning of the conductance
catheter. The catheter was adjusted until at least four of the five
volume segments were correctly placed in the left ventricle. Total
ventricular volume was derived from the sum of the individual
volume segments with a small adjustment for the apical seg-
ments (Baan et al., 1981, 1984). Once positioned, the conduc-
tance catheter was not moved for the remainder of the experi-
ment.
The time-varying LV volume was determined from the sum of
the segmental conductances, the specific conductivity of the
blood, the interelectrode distance, and the conductance of struc-
tures surrounding the ventricular cavity (parallel conductance).
The conductance catheter cardiac output was calibrated by com-
paring it to the cardiac output measured by thermodilution
1. vet. Pharmacol. Therap. 17,211-217,1994

under steady state conditions, according to the methods
described by Kass (Kass et al., 1988). The gain for the segmental
volume signals was adjusted until the conductance cardiac out-
put equalled the thermodilution cardiac output. A correction
term for the parallel conductance was calculated following the
administration of 5 ml of HS into the right atrium (Baan et al.,
1984). The correction term was determined at least twice, the
results averaged, and the values entered into the computer for
the remainder of the experiment.
Steady-state LV pressure and volume signals were obtained
over an 8 s period at end-expiration with the ventilator turned
off. Once the end-tidal CO, and systolic arterial pressure returned
to their previous values (generally I 1 min), the ventilator was
turned off again at end-expiration and LV pressure and volume
signals obtained during transient (8-10 s) caudal vena caval bal-
loon occlusion.
Experimentalprotocol
Following instrumentation, sodium heparin (5000 USP units,
i.v.) was administered to maintain patency of catheters. The
isoflurane concentration was reduced to maintain a constant
end-tidal anaesthetic concentration (1 minimum alveolar con-
centration, 1.5%) (Eisele et al.. 1985). Neuromuscular blockade
was induced by administering pancuronium bromide (0.1
mg/kg, i.v.) and repeated as needed to prevent reflex muscular
movement. Baseline LV and haemodynamic measurements (t =
0) were taken 30 min after reaching a stable end-tidal anaes-
thetic concentration. Pigs were randomly administered either
7.5%NaCl (HS, n = 9),or 0.9% NaCl (control, n = 7) at a dose of
4 ml/kg over 3 min into the right atrium. Left ventricular and
haemodynamic measurements were obtained at time = 5, 15.
30. 45, and 60 min. Since a large bolus of HS will change the
resistance properties of the blood, the specific conductivity of the
blood was measured immediately before each determination of
LV volume and the conductance signal adjusted accordingly.
Packed cell volume and total plasma proteins were measured at
30 and 60 min. The pigs were killed at the end of the experimen-
tal protocol, while still anaesthetized, with a bolus of KCl in the
left ventricle.
Analysis
Left ventricular, aortic, and pulmonary arterial pressures, and
the ECG were recorded with a multichannel physiograph
(Honeywell, VR12). Each analog signal from the physiograph
was digitized at 200 Hz and stored on a microcomputer using the
Codas data acquisition program (Dataq Instruments). Digitized
data were analyzed following the end of the experiment.
Pulmonary arterial wedge and central venous pressures were dis-
played on the physiograph and recorded manually. The rate of
rise of LV pressure (dPldt,,) was determined by analysis of the
digitized data, using a waveform oriented analysis package
(Dataq Instruments). Cardiac output was determined by ther-
modilution, using 5 ml of 5% dextrose (OOC), with the mean of
three determinations accepted as the experimental value for each
1. vet. Pharmacol. Therap. 17,211-2 17, 1994
Hypertonic saline and myocardial contractility 2 13
time period. Cardiac output was normalized for body weight and
expressed as cardiac index (CI. ml/s/kg). Pulmonary vascular
resistance (mmHg/ml/s/kg) was calculated as: PVR = (P, -
Ppaw)/CI, where P, = mean pulmonary arterial pressure and PWw
= pulmonary arterial wedge pressure. Total peripheral resistance
(mmHg/ml/s/kg) was calculated as: TPR = (Pma- CVP)/CI. where
P,, = mean aortic pressure and CW = central venous pressure.
Elastance was calculated from the end-systolic points from
each pressurevolume loop during caudal vena caval occlusion
(Conduct PC, Leycom). Only those pressurevolume loops, in
which the end-systolic pressure was greater than 65 mmHg were
used in the calculation of elastance. Premature beats and the
subsequent beat were not used in the calculation of elastance.
The absolute value of elastance is somewhat dependent upon
heart size, making comparisons between animals dif6cult.
Therefore, normalized elastance (mmHg) was calculated as: elas-
tance,,,,, = elastance x V,, where V, = steady-state LV end-
diastolic volume (Berko et al., 1987). The slope of the dP/dt,, -
V, relationship was used to minimize the effects of preload on
dPldt,,. Only those slopes in which the correlation coefficient
was greater than 0.5 were used for further statistical analysis.
Statistical analysis
Data are expressed as mean & SEM. Statistical analysis was done
using an univariate split plot analysis with time as the split plot
factor. Means were compared between treatment groups at each
level of time using an independent t-test and were considered sig-
nificantly different at P < 0.05. Means were compared between
t i e s within a treatment group by use of a paired t-test. Since
there were six time measurements. a total of 15 t-tests were per-
formed in each group. A t-test was considered significantly differ-
ent at P < 0.001 to give an overall alpha level < 0.01 5 (15 x
0.001 = 0.015). Blood for measurement of packed cell volume
and total plasma proteins was collected at only three time points
(t = 0, 30, and 60 min). Therefore, differences over time within
each group were considered significant at P < 0.01 to give an
overall alpha level < 0.03 ( 3 x 0.01 = 0.03).
RESULTS
Left ventricular measurements
There were no significant differences in LV measurements
between isotonic saline and HS treated pigs at any time point.
Myocardial contractility, as assessed by elastance, elastance,,,,,,
or dPldt,,/V, did not change with the administration of either
HS or isotonic saline (Table 1).The rate of rise of LV pressure
increased significantly at 5 min compared to baseline, but had
returned towards baseline by 15 min in the HS group (Table 1).
End-diastolic volume increased significantly from 5 to 30 min fol-
lowing treatment with HS. whereas -end-diastolic pressure
increased significantly at 5 and 60 min in HS pigs (Table 1).
Haemodynamic and blood constituent measurements
There were no significant differences in haemodynamic or blood
2 14 P. W.Hellyer b R. E. Meyer

Table 1.Left ventricular measurements from control and HS treated pigst

Time (minl

Parameter Treatment 0 5 15 30 45 60

Elastance
(mmHglml) Control 2.1 f 0.6 2.0 f 0.5 2.1 f 0.7 2.4 f 0.9 2.3 f 0.9 2.2 f 0.7
HS 1.7 f 0.2 1,5 f 0.2 1.5 f 0.2 1.4 f 0.2 1.4 f 0.2 1.4 f 0.1
Hastance,,,,,
( m g ) Control 95 f 18 89 f 14 93 f 18 98 f 20 95 f 19 95f16
HS 105 f 15 89f11 9 0 f 11 85f9 8 7 f 10 85f10
dP/dt,,
(mmHg/s) Control 1725 f 189 1728 f 173 1708 f 159 1708 f 157 1551 f 136 1664 f 156
Hs 1593 f 95 1881 f 95' 1685 f 74 1739 f 154 1 6 4 0 f 111 1591 f 98
dPldt,,lV,
(mmHg/s/ml) Control 20 f 9.8 37 i 16.0 32 f 12.8 28 f 16.4 25 f 7.6 29 f 13.4
HS 18 f 5.4 12 f 1.0 11 f 0 . 4 14 f 2.4 12 f 3.2 12 f 1.8
End-diastolic
volume (ml) Control 58f11 61 f 11 59 f 11 59 f 11 5 7 f 12 5 8 f 11
HS 64f8 77 f 8* 75 f 8' 76 f 9* 68 f 10 64f8
Enddiastolic
pressure (mmHg) Control 8.0 f 1.7 11 f 1.4 10 f 1.3 9.0 f 1.7 9.0 f 2.2 9.0 f 1.8
HS 7.0 f 1.4 11 f 1.4' 9.0 f 1.4 9.0 f 1.5 9.0 f 1.5 10 f l.6*

*Significantlydifferent(P < 0.015) from 0 min value: tFollowing baseline measurements (t = 0),pigs were administered either 0.9% NaCl (Control) or
7.5%)NaCl (HS) at a dose of 4 mllkg over 3 min. Results are mean f SEM.
constituent measurements between isotonic saline and HS sure did not change in either treatment group. Pulmonary vas-
treated pigs at any time point. Hypertonic saline produced a sig- cular resistance tended to decrease at 5 min following HS: how-
nificant, but transient, increase in cardiac index compared to ever, the differences were not significant (Table 2 ) . Packed cell
baseline that peaked at 5 min (Fig. 1).This was accompanied by volume decreased significantly at 30 and 6 0 min in the HS
a significant decrease in total peripheral resistance compared to group, whereas total plasma proteins decreased in both groups at
baseline at 5 min. followed by a return towards baseline, in the 30 and 60 min (Table 3).
HS group (Fig. 2 ) . Systolic and mean aortic pressures, and heart
rate did not change in either treatment group (Table 2). Central
venous pressure and pulmonary arterial wedge pressure tran- DISCUSSION
siently increased at 5 min and returned towards baseline by 1 5
min in HS treated pigs (Table 2 ) . Mean pulmonary arterial pres- The aim of this study was to determine if changes in myocardial
2.9 o 0.9% N a C l
A 7.5% N a C l
o 0.9% NaCl
2.6 A 7.5% NaCl

4-
2.7

2.6

2.5
n
coo
si 2.4
;.-22

8' 2.3

2.2

2.1
1 I
2.0
0
0 15 30 45 60
Time (min) 0 15 30 45 60
Time (min)

Fig. 1. Cardiac index (mean f SEM) at baseline (t = 0) and at 5, 15. 30. Fig. 2. Total peripheral resistance (mean f SEM)at baseline ( t = 0) and
45 and 60 min following treahent with either 0.9% NaCl (control. n = at 5. 15. 30,45 and 60 mln following treatment with either 0.9% NaCl
7) or 7.5%NaCl (HS, n = 9). *Significantlydifferent (P < 0.015) from 0 (control, n = 7) or 7.5% NaCl (HS, n = 9). *Significantlydifferent (P <
min value. 0.01 5) from 0 min value.

1.vet. Pharmacol. Therup. 17.211-217. 1994

 Hypertonic saline and myocardial contractility 2 15

Table 2. Haemodynamic measurements from control and HS treated pigsf

Time (min)
_____ _____ ~

Parameter Treatment 0 5 15 30 45 60

Systolic arterial pressure

( m g ) Control 94 15.2 96 f 5.7 96 f 5.1 95 f 6.0 90 f 6.0 92 f 7.3
HS 93 1 3.0 93 f 3.0 91 f 2.7 94 f 3.4 91 f 3.1 90 f 3.0
Mean arterial pressure
(mmHg) Control 77 1 4.0 79 f 4.4 80 f 4.2 79 f 5.1 73 f 5.0 74 f 6.3
HS 79 k 2.8 78 f 2.6 76 f 2.8 80 f 3.5 77 f 3.3 76 f 2.7
Heart rate
(beatdmin) Control 122 f 11.6 118 f 9.6 120 f 10.7 119 f 12.1 111 f 7.0 111 f 8.0
HS 1 1 7 f 7.0 121 f 5.1 119 f 6.0 119 f 8.0 119 f 7.7 113 k 6.4
Central venous pressure
(mmHg) Control 5 f 1.2 6 f 1.5 6 f 1.5 6 f 1.5 5 f 1.4 5 f 1.6
HS 7 f 1.5 8 f 1.7' 7f 1.6 7 f 1.5 7 f 1.4 7 f 1.5
Pulmonary arterial wedge
pressure (mmHg) Control 8 1 1.3 9 f 1.3 9 f 1.4 8 f 1.3 8 f 1.2 9 f 1.3
HS 8 f 1.6 10 f 1.7' 9 f 1.7 8 f 1.6 8 f 1.5 8 f 1.6
Mean pulmonary
arterial pressure (mmHg) Control 17 f 1.8 18 f 1.5 17 f 1.7 17 f 1.5 17 f 1.8 17 f 1.6
HS 15 k 1.2 16 f 1.4 15 f 1.5 15 f 1.5 15 f 1.4 15 f 1.4
Pulmonary vascular
resistance (mmHg/ml/s/kg) Control 4.2 f 0.4 3.8 f 0.4 3.4 f 0.4 4.1 f 0.5 4.3 f 0.7 4.0 f 0.5
HS 3.7 f 0.2 2.7 f 0.4 3.7 f 0.5 3.6 f 0.2 3.9 f 0.5 4.0 k 0.4

*Signiilcantlydifferent ( P < 0.01 5) from 0 min value: fFollowing baseline measurements (t = O), pigs were administered either 0.9%NaCl (Control) or
7.5%NaCl (HS) at a dose of 4 ml/kg over 3 min. Results are mean f SEM.

contractility contribute to the haemodynamic response to HS.
Contractility was measured using an index, elastance, derived
from LV pressure-volume relationships, which is relatively inde-
pendent of changes in heart rate and loading conditions. The
results of this study indicate that HS does not change contractil-
ity in normovolemic, isoflurane-anaesthetized pigs.
The rapid administration of HS has been shown to increase
venous return to the heart and thereby increase preload (Schertel
et al.,1990). Increased preload was evident in the present investi-
gation by a significant increase in LV end-diastolic volume, con-
sidered to be the most appropriate measure of LV preload since
there is a close relationship between LV volume and muscle
length (Sagawa et al., 1988). Significant increases in LV end-
diastolic pressure, central venous pressure, and pulmonary arter-
ial wedge pressure further support the conclusion of an increased
preload following the administration of HS. Therefore. the signifi-
cant increase in dPldt,,, at t = 5 min in the HS group was attrib-
uted to a change in preload and not an increase in inotropic
state. This conclusion is further supported by no change in the
slope of the dPldt,, versus V, relationship.
In this study, we used several indices of contractility, elas-
tance, elastance,,,,,, and dP/dt,,/V, to evaluate myocardial
inotropic state. Virtually all indices used to evaluate myocardial
inotropic state in vivo have some degree of load dependency,
including elastance (Kass et ul., 1987). The magnitude of sensi-
tivity to changes in inotropic state detected by elastance is not as
great as with other indices: however. the advantage of elastance
is its minimal dependence upon changes in preload and afterload.
Comparison of elastance between animals is confounded by the
dependence of elastance on heart size: therefore, elastance was
normalized for baseline end-diastolic volume (Berko et al., 1987).
We also evaluated the relationship of dPldt,,, to end-diastolic
volume. which decreases the dependence of dPldt,,, on changes
in preload while maintaining its sensitivity to changes in con-

m:-- Table 3. Blood constituents from control and

1uue (llllrl)
HS treated pigst
Parameter Treatment 0 30 60

Packed cell volume (%) Control 31 f 1.1 31 f 1.4 31 f 1.0

HS 3 1 f 1.3 29 f 1.6' 29 f 1.4'
Total plasma proteins (g/dl) Control 5.4 f 0.1 5.2 f 0.1* 5.2 f 0.1*
HS 5.3 f 0.2 5.0 f 0.2* 5.0 f 0.2*
~~

*Significantlydifferent (I' < 0.03) from 0 min value: tFollowing baseline measurements (t = 0).
pigs were administered either 0.9% NaCl (Control) or 7.5% NaCl (HS) at a dose of 4 ml/kg over
3 min. Results are mean f SEM.

1. vet. Pharmacol. Therap. 17,211-2 17, 1994

216 P. W.Hellyer6 R. E. MeMer
tractility (Kass et ul., 1987). Unfortunately, dPldt,,lV, is still
dependent on changes in afterload. In the present study, elas-
tance, elastance(,,,,, and dPldt,,lV, did not change signifi-
cantly following treatment with HS. Since the primary haemody-
namic change was an increase in preload (increased 'enddias-
tolic volume) with minimal change in afterload (slight decrease
in aortic blood pressure), all of these indices should accurately
reflect any changes in inotropic state if they were present.
Therefore, we conclude that HS is not a positive inotrope in nor-
movolaemic. isoflurane-anaesthetiied pigs, even though dPldt,,
and cardiac index increased significantly at 5 min.
Determination of LV volume has been simplified by the devel-
opment of the conductance (volume) catheter (Baan et ul.,
1981). Using this catheter, LV volume can be rapidly determined
on a beat to beat basis in man and animals (Baan et al., 1984).
Volume measurements made by the conductance catheter, cou-
pled with simultaneous pressure measurements from a high-
fidelity micromanometer catheter, are used to construct beat to
beat pressure-volume loops. In this study, we measured LV pres-
sure and volume during transient (< 8 s) periods with the venti-
lator turned off at end-expiration in order to eliminate the effects
of positive pressure ventilation on the measured variables. A brief
period of load alteration is required in order to generate the end-
systolic pressure-volume points necessary for calculation of elas-
tance. Preload was reduced in this study by inflation of a balloon
catheter positioned in the caudal vena cava. Alterations in load-
ing conditions can evoke reflex sympathetic responses which
would be expected to increase the measure of contractility.
Evidence of autonomic reflexes has been demonstrated after 10 s
of sustained preload reduction: therefore, we l i i t e d the caudal
vena caval balloon occlusion to 8-10 s (Kass et al., 1986).
Our findings that HS had no effect on contractility differ from
those of Kien (Kien et al., 1991a). In that study, halothane-
anaesthetized, normovolaemic dogs were administered HS (7.5%
NaCI) at a dose of 5 mllkg, i.v., over 1 min. Elastance, derived
from the end-systolic pressurdiameter relationship, increased
significantly from 10 to 60 min following treatment with HS.
The two studies differed in many aspects, including the species
used (dog vs. pig), the anesthetic used (halothane vs. isoflurane),
and the rate of HS administration (1 min vs. 3 min). More impor-
tantly, HS was administered directly into the right atrium in our
study, whereas it was administered i.v. in Kien's study. It is possi-
ble that a bolus of HS administered i.v. would be diluted to a
greater extent than an intra-atrial injection before reaching the
coronary artery. Administering HS directly into the right atrium
may have resulted in the hyperosmolar, ionic solution exerting a
direct depressant effect upon the heart. This is supported by a
previous report in which three of Eve cats administered HS into
the aortic root died within 15 min (Muir & Sally, 1989). Thus, it
is possible that any indirect, positive inotropic effects of HS were
attenuated by a direct cardiodepressant effect of the hyperosmo-
lar solution in our pigs.
In vitro studies further support the hypothesis that ionic,
hyperosmolar solutions exert a direct, negative inotropic effect.
Rat hearts (Langendorff preparation) infused with 7.5% NaC1,
with or without dextran, had depressed ventricular developed
pressure, contractility (+dPldt), and relaxation rate (4Pldt)
(Brown et al., 1990). Similarly, increases in ionic strength by the
addition of chloride or potassium salts decreased, whereas
increases in osmolality with the addition of sucrose did not alter,
the maximum calcium-regulated force in detergent-skinned ven-
tricular muscle from guinea-pigs (Kentish, 1984). Increasing the
amount of sodium in the perfusate caused a n initial decrease in
dPldt in the vascularly perfused rabbit intraventricular septum
(Tillisch & Langer, 1974). On the other hand, increasing osmo-
lality up to that of serum (330 mOsmll) with either sucrose or
mannitol increased developed tension in cat papillary muscle
(Koch-Weser, 1963). Increases in osmolality by mannitol or
sucrose increased tension in isolated heart tissues provided the
increase in osmolality was less than or equal to 150 mOsm/l
(Wildenthal et ul., 1969b: Beyer et ul., 1986: Allen & Smith,
1987). The intracellular concentration of calcium ( [Ca2+li)also
influences the inotropic effects of non-ionic, hyperosmolar solu-
tions, such that tissues with a low [CaZ+lirespond with a positive
inotropic effect whereas a negative inotropic effect is seen in tis-
sues with a high [Caz+],(Nayler, 1961: Willerson et ul., 1974,
1978: Wildenthal et al.. 1975: Kawata et al., 1983). The evi-
dence suggests that hyperosmolar. ionic solutions exert a direct
negative inotropic effect whereas non-ionic, hyperosmolar solu-
tions exert a positive inotropic effect provided the increase in
osmolality is less than 150 m0smll and that [Ca2+Ii is low.
In summary, the administration of a small volume (4mllkg)
of HS into the right atrium resulted in a significant. but transient
increase in cardiac index. The mechanism responsible for this
increase in cardiac index is primarily an increase in preload,
demonstrated as an increase in LV end-diastolic volume.
Myocardial contractility, measured by elastance, did not
increase, indicating that HS had no positive inotropic effect.
ACKNOWLEDGMENTS
The authors thank Delta Plummer for her expert technical assis-
tance in this study. We also thank Anne Hellkamp for her assis-
tance with statistical analysis. This study was supported by the
College of Veterinary Medicine research funds.
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