Download Relation of Extracellular Fluid Volume to Saluresis

Relation of Extracellular Fluid Volume
Arterial Pressure during Drug-Induced
Saluresis
to
By MICHAEL DAvIDOV, M.D., LILLIAN GAVRILOVICH, M.D.,
WILLIAM MROCZEK, M.D.,
AND
FRANK A. FINNERTY, JR., M.D.
SUMMARY
The immediate fall in arterial
pressure following furosemide in the 17 hypertensive
asociated with a decrease in plasma volume, cardiac output, and
extracellular fluid volume, and an increase in urinary sodium excretion. A glucose infusion
administered at the trough of hypotension in an amount exceeding the urinary output
resulted in the return of arterial pressure to control levels in each patient. Although an
increase in plasma volume was noted in each patient, it was significantly below control
levels. The central venous pressure, cardiac output, and state of negative sodium balance
following the glucose infusion remained unchanged, but the extracellular fluid volume
had re-expanded. It would seem that the changes in arterial pressure either after furosemide or during the glucose infusion were related to changes in extracellular fluid.
The fact that a decreased pressor response to norepinephrine following furosemide was
associated with a decrease in extracellular fluid and the fact that expansion of extracellular fluid with glucose restored the pressor response to normal further document the
importance of the extracellular fluid in the regulation of arterial pressure.
patients studied
was
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Additional Indexing Words:
Pressor response
Plasma volume
Chloride space
Norepinephrine
Furosemide
Extracellular fluid
Hypotension
Hypertension
administration of dextran with the diuretic
agents prevent the fall in arterial pressure. On
the other hand, in hypertensive patients in the
sodium-depleted state there seemed to be a
direct relation between arterial pressure and
sodium balance. Thus, the fall in arterial
pressure after diuretic therapy could immediately be corrected by administration of
hypertonic saline in an amount sufficient to
produce positive sodium balance. Similarly,
the fall in arterial pressure, which usually
accompanied the diuretics, could be prevented
by the concomitant administration of hypertonic saline. It was concluded that in the
hypertensive patient in the sodium-depleted
state a direct relation existed between arterial
pressure and sodium balance; a positive
sodium balance was associated with a rise in
arterial pressure, whereas a negative sodium
pREVIOUS studies from this laboratory
have established that the immediate fall in
arterial pressure during drug-induced saluresis
was more related to the production of
negative sodium balance than the reduction in
plasma volume.' The replacement of plasma
volume with dextran at the peak of hypotension during diuresis did not increase the
arterial pressure nor did the concomitant
From the Department of Medicine, Georgetown
University School of Medicine and the Georgetown
University Medical Division, District of Columbia
General Hospital, Washington, D. C.
This work was done during Dr. Davidov's tenure of
a Postdoctoral Research Fellowship of the Washington Heart Association.
Investigation was supported in part by Research
Grants HE-10294 and HE-11713 from the National
Heart Institute, National Institutes of Health, U. S.
Public Health Service, Bethesda, Maryland.
Circulation, Volume XL, September 1969
349
DAVIDOV ET AL.
350
balance
associated with
fall in arterial
vein and advanced into the thorax until the
Several parameters that might have influenced this relation were not measured. Infusions of hypertonic saline, particularly in the
hypertensive patient, might have increased the
central venous pressure and altered the
cardiac output, thus affecting the arterial
pressure. The increase in arterial pressure
after the administration of hypertonic saline
could have been due to a direct effect of the
sodium ion on the arterial wall or secondary to
the expansion of extracellular fluid volume.
Although the effect of sodium on the vessel
wall cannot readily be detennined in vivo,
changes in the central venous pressure,
cardiac output, and extracellular fluid volume
can be determined. When data from these
previous experiments were analyzed, it was
found that the amount of sodium retained
during the infusion of hypertonic saline was
not reflected by a comparable increase in
serum sodium concentration. When the
changes in extracellular fluid volume were
calculated, it was found that the extracellular
fluid volume (chloride space) increased after
the infusion of hypertonic saline, which
suggested the possibility that it was the
expansion of the extracellular fluid volume
and not simply sodium balance that influenced
the arterial pressure. To exclude the influence
of sodium balance on the arterial pressure it
seemed essential, therefore, to expand the
extracellular space by a non-sodium containing infusion. The experiments previously
reported were therefore repeated, substituting
infusions of glucose for hypertonic saline.
with intrathoracic respiracould be recorded. The catheter
was connected to a Statham P23G strain-gauge
transducer* and leveled 5 cm below the sternal
angle. A brachial or radial artery was cannulated
percutaneously with an 18-gauge needle and was
connected to a Statham P23b strain-gauge
transducer,* fixed at heart level. The arterial
pressure, central venous pressure, and electrocardiogram were recorded simultaneously and continuously on a Sanborn 560 multichannel recorder.t Calibration of the pressure transducer
was performed at the end of each experiment by
applying static pressures from 0 to 200 mm Hg.
No evidence of alinearity or hysteresis was
found.
Mean pressures were obtained by electronic
filtering. The intravenous catheters were kept
patent by intermittent administration of a small
amount of a dilute heparin solution. An indwelling catheter was placed in the urinary bladder,
and urine was collected at timed intervals during
the entire study.
After the arterial pressure and heart rate were
stable for 1 hour, control determinations of
plasma volume and cardiac output were made.
The indicator for plasma volume determination
was 1311-RISA (Abbott radioiodinated serum
albumin). After collection of a blank sample, 5 ,uc
of the indicator was injected during a period of 3
seconds into the vena cava from an in vitro
calibrated syringe. Samples were obtained from
the antecubital vein of the opposite arm in tubes
containing dried heparin, at 20, 25, 30, 35, and
40 minutes after administration of the indicator.
The radioactivity of the samples was determined
in a scintillation well counter.t The plasma
volume was calculated by extrapolating the
radioactivity to the time of injection. Appropriate
corrections for background radioactivity were
made continually. Counts per second per milliliter
were plotted on the ordinate and the time in
minutes on the abscissa on semilogarithmic
was
pressure.
a
central
venous pressure
tory variation
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paper.
Methods
Seventeen patients, seven male and 10 female,
were selected from the hypertensive clinic of the
District of Columbia General Hospital. In
addition to the elevated arterial pressure, each of
the patients had objective evidence of vascular
disease. None of these patients was in congestive
heart failure or had received any antihypertensive
or diuretic therapy for 1 month before and during
the entire study. No one was uremic.
The patients arrived in the cardiovascular
laboratory in the fasting state. A 36-inch
polyethylene catheter was placed percutaneously
through a 14-gauge needle into an antecubital
Serial relative changes in cardiac output were
determined by the dye-dilution method with
indocyanine green as an indicator, a photoelectric
earpiece, and a Mark II Cambridge dye recorder
with a high resistance input circuit. The integral
of the indicator-dilution curves was determined
according to the method of Lillienfield and
Kovach.2 The cardiac output was expressed in
*Stathba Instrument Inc., Hato Rey, Puerto Rico.
tHewlett Packard Company, Waltham, Massachusetts.
*Nuclear Instrument and Chemical Corporation,
Chicago, Illinois.
Circulation, Volume XL, September 1969
351
DRUG-INDUCED SALURESIS
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arbitrary units derived from the reciprocal of the
area under the recorded curve.
At the end of the control period, each patient
received 100 to 200 mg of furosemide intravenously. Furosemide was supplied in 2-ml
ampules with a concentration of 10 mg/ml and
was administered undiluted. The plasma volume
and cardiac output determinations were repeated
at the peak of hypotension. Following these
determinations, an infusion of 5% glucose in
water was started. The glucose infusion was
administered rapidly (25 to 65 minutes) in an
amount equal to or exceeding the urinary output.
The total amount of glucose solution needed to
increase the arterial pressure to control levels was
recorded, and the determinations of cardiac
output and plasma volume were again repeated.
The amount and location of the fluid retained
during the glucose infusion were determined as
follows: the amount of fluid administered minus
the urinary output equals the amount of fluid
retained. The total amount of fluid retained minus
the change in plasma volume (before and after
infusion) represents the amount of fluid retained
extravascularly.
Serial changes in extracellular fluid volume
were calculated from the changes in concentration of chloride in extracellular water ([CI]E),
the chloride balance (bcl), and the initial extracellular fluid volume (El) was measured by inulin
space, according to the formula3:
(E1 [GCIEI) -bc1
E
The
serum
determined by the method of Cotlove and
associates4 on a Buchler-Cotlove chloridometer.
Serum protein was determined by the Biuret
method.5
The sensitivity of the arterial pressure to
norepinephrine was determined in 10 patients.
Levarterenol bitartrate was administered as an
intravenous infusion in a concentration of 4
,ug/ml of 5% glucose in water with an infusion
withdrawal pump.* The rate of infusion was
regulated according to the increase in arterial
pressure and varied between 4 and 24 ,ug/min.
The end-point of the infusion was taken as a rise
in mean arterial pressure in excess of 25% above
control levels or a 15 mm Hg rise in the diastolic
pressure for 10 minutes. The same speed of
infusion was repeated at the peak of hypotension
following furosemide and after the arterial
pressure was restored with the glucose infusion.
were
Results
The trough of the hypotension following
furosemide occurred in 2 to 3 hours. The
average reduction in mean arterial pressure
was 17 + 7% (from an average of 139 + 16 to
an average of 115 + 16 mm Hg; table 1). The
average urinary output during furosemide
diuresis was 1920 610 ml. At the time of
greatest hypotension there was a 16 + 8% (530
-+ 268 ml) decrease in the plasma volume.
[C1]E2
and urinary chloride concentrations
*Harvard Apparatus Co. Inc., Dover, Massachusetts.
Table 1
Effect of Furosemide and Glucose Infusions on Arterial Pressure, Plasma Volume, and Urinary Output
Mean arterial pressure
(mm Hg)
Case
Control
1
2
3
4
5
6
7
8
9
10
Av.
S.D.
120
160
123
150
140
125
120
130
155
130
135
+15
*
Furosemide Glucose
95
135
110
135
130
105
100
95
125
115
114
+16
120
160
125
160
150
120
120
125
150
140
137
±17
Plasma volume
(ml)
Control
2483
3062
2970
2990
2983
4647
4076
3254
3091
3341
3290
±623
Furosemide
Glucose
(net chgs)
Urine
-135
-270
-170
-150
-198
-633
-226
-442
-291
-221
-274
±85
1147
1025
2575
3052
1166
1460
2000
1430
1090
2690
1763
±758
-290
-1090
-670
-339
-324
-867
-606
-969
-557
-445
-616
±282
Glucose adminstered (increase in plasma volume plus urinary output).
Circulation, Volume XL, September 1969
(ml)
Rise in PV Fluid
Total amount following retained
of glucose
glucose
extraadministered infusion vascularly*
(ml)
(ml)
(ml)
14-80
1800
3849
4570
2623
2885
2702
2500
2000
3380
2779
±948
155
820
500
189
126
234
380
527
266
224
342
±217
178
255
774
1329
1331
1191
322
543
644
466
703
±439
352
DAVIDOV ET AL.
Effect of Furosemide and Glucose
on
Table 2
Arterial Pressure, Plasma Volume, Urinary Output, and Extracellular
Fluid
Mean arterial pressure
(mm Hg)
Case Control Furosemide Glucose
11
12
13
14
15
16
17
Av.
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S.D.
140
135
170
152
155
120
150
146
±16
135
130
165
150
155
120
150
144
±16
95
105
130
135
135
105
120
117
±=17
Plasma volume
(ml)
Control Furosemide
Glucose
(net chgs)
Urine
(ml)
-533
-272
-368
-306
-233
-820
2431
1810
2100
2200
2100
3168
2171
2283
±940
3486
3176
2581
3406
2425
3360
4401
3262
±652
-311
-406
i206
The glucose infusion was administered in 25
to 65 minutes. The mean arterial pressure
returned to control or near control levels in 10
of 17 patients when the amount of glucose
administered was equivalent to the urinary
output (table 1). Thus, in these 10 patients
after the administration of glucose there was a
20+ 6% average increase in arterial pressure.
Although the glucose infusion was associated with an increase in plasma volume in
every patient, it should be noted that the
-345
-106
-182
-177
-217
-532
-289
-264
±142
Rise in
Chloride space
(L)
following Glucose
glucose needed to
infusion restore AP Control Furosemide Glucose
(ml)
(ml)
2100
1650
1870
2000
1600
2450
2000
1953
4=93
188
70
186
129
16
288
22
128
±100
21.4
18.5
16.0
20.9
24.3
20.2
19.5
16.8
14.9
18.6
23.6
18.7
21.0
18.2
15.9
19.3
25.2
19.9
plasma volume did not return to control levels.
The average increase in plasma volume in
these patients was 342 + 217 ml. The average
amount of glucose administered was 2,779 +
948 ml. The average urinary output was 1,763
+ 758 ml, which left 703 + 439 ml of fluid
unaccounted for. It was postulated that the
excess fluid was extravascular and probably
extracellular.
In seven of 17 patients the arterial pressure
returned to control levels before an infusion of
glucose was completed (table 2). The average
Table 3
The Effect of Furosemnide and Glucose Infusion on Central Venous Pressure, Cardiac Output,
and Total Peripheral Resistance
Central venous pressure
(mm Hg)
Case
Control
Furosemide
Glucose
1
4
5
5.0
4.0
2.0
1.5
4.5
2.0
-7
+8
7
8
9
10
8.5
5.0
11
4.0
12
13
2.0
3.0
7.0
2.5
9.0
5.5
14
15
16
17
Cardiac output
(% chgs)
Furosemide
Glucose
4.5
2.0
2.0
1.5
2.5
5.0
2.5
6.5
3.0
7.0
4.5
3.0
2.5
2.5
7.o
3.5
9.5
5.0
Total peripheral resistance
(% chgs)
Furosemide
Glucose
-5
0
+6
+13
0
-23
-15
-14
-26
+11
+1
+19
0
+12
-39
-11
-10
-10
-16
-3
-11
+14
-19
0
-15
-12
-1
-14
-6
0
_6
-4
+3
0
Circulation, Volume XL, September 1969
DRUG-INDUCED SALURESIS
353
Table 4
Effect of Furosemide and Glucose Infusion on
Arterial Pressure During Norepinephrine Infusion
Per cent change in mean arterial pressure
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Case
Control
Furosemide
Glucose
1
3
6
+28
+29
+31
+15
+11
+10
+27
7
+28
+14
+31
8
10
+25
+29
+12
+11
+29
+31
11
+25
+15
+23
12
14
15
16
17
+26
+26
+19
+19
+20
+13
+8
+9
+3
+11
+25
+28
+21
+22
+22
Av.
S.D.
25
i4
11
±3
27
i4
+30
+35
uxinary output in these patients was 2,283 +
940 ml. The average amount of glucose needed
to restore the arterial pressure was 1,953 + 93
ml. In five of these patients the relative
changes in extracellular fluid were calculated
from the changes in concentration of serum
chloride. At the peak of hypotension after
furosemide the chloride space was decreased
an average of 1.5 L (table 2). When the
arterial pressure returned to control levels
during the glucose infusion, the chloride space
was re-expanded.
The changes in central venous pressure,
cardiac output, and calculated total peripheral
resistance during the experiment are tabulated
in table 3. Although central venous pressure,
cardiac output, and total peripheral resistance
decreased after furosemide and returned to
control or near control values during the
glucose infusion, none of -these changes was
considered significant (P, 0.2).
During the control period, norepinephrine
produced a 25 ± 4% average increase in mean
arterial pressure in the 12 patients studied
(table 4). At the trough of hypotension
following furosemide the same rate of infusion
of norepinephrine produced an 11 ± 3% average increase in mean arterial pressure.
After the arterial pressure was restored with
glucose, the same rate of norepinephrine
infusion produced a 27 + 4% average increase
Circalation, Volume XL, September 1969
in mean arterial pressure. The serial changes
in mean arterial pressure, extracellular fluid,
response of arterial pressure to norepinephrine, plasma volume and sodium balance
after furosemide, and glucose in patients 17
are plotted in figure 1.
Discussion
The fall in arterial pressure after furosemide
in the 17 hypertensive patients studied was
associated with a decrease in plasma volume,
central venous pressure, and cardiac output
FUROSEMI DE
,ONTROL
GLUCOSi
150
MEAN ARTERIAL
PRESSURE
(mm Hg)
140
130
120
25
EXTRACELLULAR
FLU I D
( LITERS )
24
23
RESPONSE TO
NOREPI NEPHR I NE
(% RISE IN AP)
20
10
3400
PLASMA VOLUME
( ml )
3000
2800
0
SODIUM BALANCE -50
( mEq )
- 100
Figure 1
Note the direct relation between the change in
arterial pressure, pressor response to norepinephrine,
extracellular fluid volume, and plasma volume, and
the lack of relation of arterial pressure to changes in
sodium balance.
DAVIDOV ET AL.
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and an increase in urinary sodium excretion.
The administration of glucose resulted in the
return of arterial pressure to control levels in
each patient. Although an increase in plasma
volume was noted in each patient when the
arterial pressure returned to control levels, the
plasma volume was still 270 ± 145 ml below
control values. In this regard, it should be
noted that previous experiments in this
laboratory demonstrated that the replacement
of plasma volume with dextran solution at the
peak of hypotension following diuretic therapy had no effect on the reduced arterial
pressure.'
The administration of glucose that resulted
in return of arterial pressure to control values
did not alter the negative sodium balance.
This observation seems to be in conflict with
the data previously reported from this laboratory. It was noted then that in the hypertensive patient in the sodium depleted state there
was a direct relation between arterial pressure
and sodium balance. The fall in arterial
pressure during saluresis was attributed to the
production of negative sodium balance, and
the increase in arterial pressure that followed
administration of hypertonic saline was attributed to the production of positive sodium
balance. The ability of glucose infusion to
restore the arterial pressure reported here
casts doubt on the importance of sodium
balance in the previous experiments.
In 10 patients the amount of glucose needed
to restore the arterial pressure to control levels
exceeded the urinary output by an average of
1015 + 398 ml (table 1). The average increase
in plasma volume in these patients was only
342 ± 217 ml, leaving 703 ± 439 ml of fluid
unaccounted for. This retained fluid was
extravascular, and probably extracellular. In
seven patients, however, the amount of
glucose needed to restore the arterial pressure
was less than the urinary output. In these
patients, when arterial pressure was restored
to control levels, the plasma volume was still
274+85 ml below control. From the estimation of the chloride space in five of
these patients it would seem that retained
fluid was indeed extracellular.
At the peak of hypotension following
furosemide the chloride space was decreased
an average of 1.5 L (table 2). When the
arterial pressure had returned to control
values during the infusion, the chloride space
had re-expanded. It would seem from these
data that the changes in arterial pressure
either after furosemide or during the glucose
infusion were not related to sodium balance or
plasma volume alone or due to changes in
cardiac output or central venous pressure. On
the other hand, the changes in arterial
pressure were directly related to changes in
extracellular fluid (table 2, fig. 1). These data
do not contradict the previously reported
relation between sodium balance and arterial
pressure, but suggest that this relation was
mediated through changes in extracellular
fluid. In previous studies, administration of
hypertonic saline was associated with the
production of positive sodium balance and
expansion of the chloride space. The fact that
the arterial pressure could be restored without
altering negative sodium balance in the
experiments reported here suggests that
changes in extracellular fluid significantly
influence changes in arterial pressure. It is not
possible from these data to determine whether
the increase in arterial pressure associated
with the glucose infusion was due to expansion of extracellular fluid volume and plasma
volume or due to expansion of extracellular
fluid volume alone. Freis6 has suggested that
the antihypertensive action of the diuretics is
mediated through the changes in extracellular
fluid and plasma volume. Previous data from
this laboratory have demonstrated that the
restoration of plasma volume at the trough of
hypotension following diuretics does not
restore the arterial pressure. It would seem.
therefore, that changes in arterial pressure are
more related to the changes in extracellular
fluid volume.
The changes in the pressor response to
norepinephrine after furosemide and glucose
further document the importance of the
extracellular fluid in the regulation of arterial
pressure. Thus, the decrease in extracellular
fluid after furosemide was associated with a
Circulation, Volume XL, September 1969
DRUG-INDUCED SALURESIS
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decreased pressor response that was restored
to the control by expansion of the extracellular
fluid.
Although the early fall in arterial pressure
during saluresis is associated with a decrease
in plasma volume and the production of
negative sodium balance, it seems that the
most important underlying mechanism is a
decrease in extracellular fluid. In the hypertensive patient in the sodium depleted state
there seems to be a direct relation between
arterial pressure and extracellular fluid; a
decrease in extracellular fluid is associated
with a fall in arterial pressure, whereas
expansion of extracellular fluid is associated
with a rise in arterial pressure. It is not known
whether this relation exists in hypertensive
patients in normal sodium balance or in
normotensive or hypotensive patients.
Acknowledgment
This work is done with the technical assistance of
Miss Constance Mongelli.
Circulation, Volume XL, September 1969
355
References
1. FINNERTY, F. A., JR., DAVIDOV, M., AND
KAKAVIATOS, N.: Relation of sodium balance to
arterial pressure during drug-induced saluresis.
Circulation 37: 175, 1968.
2. LILLIENFIELD, L., AND KOVACH, R.: Simplified
method of calculating mean circulation time
and downslope from indicator dilution curves.
Proc Soc Exp Biol Med 91: 595, 1956.
3. ELKINTON, J. R., AND TAFFEL, M.: Prolonged
water deprivation in the dog. J Clin Invest 21:
787, 1942.
4. COTLOVE, E., TRANTHAM, H. V., AND BowMAN,
R. L.: An instrument and method for
automatic, rapid, accurate and sensitive titration of chloride in biological samples. J Lab
Clin Med 50: 358, 1958.
5. WELCHSELBAUM, F.: Determination of protein by
biuret method. Amer J Clin Path (Tech Sect)
10: 40, 1946.
6. FREIs, E. D.: Mechanism of the antihypertensive
effects of diuretics: Possible role of salt in
hypertension. Clin Pharmacol Ther 1: 337,
1960.
Relation of Extracellular Fluid Volume to Arterial Pressure during Drug-Induced
Saluresis
MICHAEL DAVIDOV, LILLIAN GAVRILOVICH, WILLIAM MROCZEK and
FRANK A. FINNERTY, JR.
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Circulation. 1969;40:349-355
doi: 10.1161/01.CIR.40.3.349
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 1969 American Heart Association, Inc. All rights reserved.
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