BLOOD VOLUME IN ACUTE PULMONARY EDEMA/Figueras, Weil 349
5. Sandler H, Dodge HT, Hay RE, et al: Quantitation of valvular in- 13. Olesen KH: The natural history of 271 patients with mitral stenosis under
sufficiency in man by angiocardiography. Am Heart J 65: 501, 1963
6. Gorlin R, Gorlin SG: Hydraulic formulae for calculation of the area of
the stenotic mitral valve, other cardiac valves, and central circulatory
shunts. I. Am Heart J 41: 1, 1951
7. Berkson J, Gage RP: Calculation of survival rates for cancer. Proc Staff
Meetings Mayo Clin 25: 270, 1950
8. Mantel N: Evaluation of survival data and two new rank order statistics
arising in its consideration. Cancer Chemother Rep 50: 163, 1966
9. Cox DR: Regression models and life tables. J Roy Statist Soc 34: 187,
1972
10. Kirklin JW, Pacifico AD: Surgery for acquired valvular heart disease. N
EngI J Med 288: 133, 1973
11. Munoz S, Gallardo J, Diaz-Gorrin JR, White PD: Influence of surgery
on the natural history of rheumatic mitral and aortic valve disease. Am J
Cardiol 35: 234, 1975
12. Roy SB, Gopinath N: Mitral stenosis. Circulation 38(suppl 5):V-68, 1968
Blood Volume Prior to and Following Treatment
of Acute Cardiogenic Pulmonary Edema
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JAIME FIGUERAS, M.D., AND
SUMMARY Following onset of acute cardiogenic pulmonary
edema in 21 patients, increases in hematocrit, plasma protein concen-
tration, and colloid osmotic pressure were associated with decreases
in plasma volume. Accordingly, there was a loss of hypo-oncotic fluid
into the extravascular spaces. Following treatment with oxygen,
furosemide, and morphine sulfate and reversal of clinical and radio-
graphic signs of pulmonary edema, declines in hematocrit, plasma
protein concentration, and colloid osmotic pressure were associated
DURING HEART FAILURE in which there is a rise in
left ventricular filling pressure and secondarily in mean left
atrial and pulmonary artery pressures and pulmonary blood
volume, hydrostatic forces account for increased pulmonary
capillary filtration with extravasation of fluid into the inter-
stitium and subsequently into the alveoli of the lung. At the
same time, renal and endocrine mechanisms account for salt
and water retention. Acute cardiogenic pulmonary edema
(PE) has been attributed, at least in part, to retention of
fluid, increases in plasma volume, and consequently in-
creases in the preload on the heart.''3 However, acute car-
diogenic pulmonary edema is associated more often with in-
creases than decreases in hematocrit and plasma protein
concentration.4' The changes would be more consistent
with a decrease rather than an increase in plasma volume. In
From the Institute of Critical Care Medicine, University of Southern
California School of Medicine, the Los Angeles County/USC Medical
Center, and the Center for the Critically Ill, Hollywood Presbyterian Medical
Center, Los Angeles, California.
Supported by USPHS research grants GM-16464 from the National
Institute of General Medical Sciences, ROt HS 01474 from Health Resources
Administration, by the Parker B. Francis Foundation of Kansas City,
Missouri, and by the Cardiopulmonary Laboratory Research Foundation of
Los Angeles, California.
Dr. Figueras is presently a Clinical Fellow in the Department of Car-
diology, Cedars-Sinai Medical Center, Los Angeles, California.
Address for reprints: Max Harry Weil, M.D., Ph.D., Center for the
Critically Ill, University of Southern California School of Medicine, 1300 N.
Vermont Avenue, Los Angeles, California 90027.
Received August 8, 1977; revision accepted September 20, 1977.
medical treatment. Br Med J 2: 349, 1962
14. Rowe JC, Bland EF, Sprague HB et al: The course of mitral stenosis
without surgery: Ten and twenty year perspectives. Ann Intern Med 52:
741, 1960
15. Breslow N: Contribution to the discussion on the paper by DR Cox. J
Roy Statist Soc (B) 34: 216, 1972
16. Breslow N: Analysis of survival data under the proportional hazards
model. Internat Stat Review 43: 45, 1975
17. Cox, DR: Partial likelihood. Biometrika 63: 269, 1975
18. Breslow N, Crowley J: A large sample study of the life table and product
limit estimates under random censorship. Ann Statist 2: 437, 1974
19. Cox DR, Hinkley DV: Theoretical Statistics. London, Chapman and
Hall, 1974, pp 344-350
20. Hample FR: The infiuence curve and its role in robust estimation. J Am
Statist Assoc 69: 383, 1974
21. Miller, RG: The Jackknife - a review. Biometrika 61: 1, 1974
MAX HARRY WEIL, M.D., PH.D.
with increases in plasma volume. Hypo-oncotic edema fluid was
therefore reabsorbed into the vascular compartment.
The concept that acute heart failure with pulmonary edema is
associated with an increase in intravascular volume is therefore not
supported. To the contrary, there is a reduction of blood volume dur-
ing acute pulmonary edema. During reversal of acute pulmonary
edema with diuresis, there was re-expansion rather than contraction
of blood volume.
the present study, intravascular volumes were measured dur-
ing cardiogenic pulmonary edema to quantitate plasma and
total blood volumes following onset of acute pulmonary
edema.
Loop diuretics have been remarkably effective for im-
mediate management of cardiogenic pulmonary edema.6 7
However, the mechanisms by which the diuretic agents
produce their favorable effects are not securely established.
The most widely held concept has been that potent diuretics
like furosemide re-establish cardiac competence by decreas-
ing intravascular volume during the course of diuresis.8' 9
Preload would therefore be decreased and the effective
workload on the heart would be reduced. However, in the
present studies, measurements of intravascular volume after
treatment with oxygen, morphine, and furosemide
demonstrated an expansion rather than contraction of the
intravascular volume.
Methods
Patients
Studies were performed in 21 patients, 11 men and 10
women, ranging from 44 to 83 (median 67) years in age. In
16 of the patients, PE was observed at the time of admission
to the Center for the Critically Ill and in five patients, PE
appeared during the course of in-patient care. Each patient
presented with acute onset of respiratory distress,
orthopnea, and unequivocal evidence of myocardial disease.
 350 CI RCULATION VOL 57, No 2, FEBRUARY 1978

Bilateral moist rales and radiographic signs of grade 3 or 4
pulmonary edema, according to the criteria of Turner, Lau,
and Jacobson,"0 were documented in each instance. In 11
patients, there was expectoration of frothy fluid. Patients
who had evidence of bleeding, clinical signs of shock, or
patients who had either colloid infusions or blood
transfusions were excluded.
Previous history of acute pulmonary edema was elicited in
nine of the 21 patients; 11 patients had been treated with
diuretics prior to the occurrence of acute pulmonary edema;
and six patients had evidence of peripheral edema on admis-
sion. In two instances acute myocardial infarction was sub-
sequently demonstrated by electrocardiographic and enzyme
changes. Clinical data are summarized in table 1.
The initial set of measurements were obtained im-
mediately after referral to the Center for the Critically Ill
from either the emergency department or general medical
services following onset of acute PE. Oxygen was the only
agent administered prior to the initial set of measurements.
A second set of measurements was obtained between 4 and
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furosemide during the initial 24 hours of management
ranged from 40-160 (mean 71.4) mg.
Thirteen healthy volunteer physicians, nurses, or
technicians in whom plasma volume was measured after at
least 3 hours of bed rest, constituted a reference (group 1)
for comparison of intravascular volume. The volunteers, 10
men and 3 women, ranged from 19 to 34 (median 25) years
in age.
Fifty additional patients, 24 men and 26 women ranging
from 22 to 86 (median 62) years in age served as a second
reference group (group 2). These patients were referred to
our Center for the Critically Ill for emergency care and ad-
mitted for observation because of chest pain. None had
clinical or radiographic evidence of heart failure or PE.
Acute myocardial infarction was subsequently excluded in
each patient on the basis of sequential electrocardiographic
and enzyme studies. There were no complicating illnesses or
deaths prior to hospital discharge.
Methods

12 hours after admission in each of the patients. A third set Arterial blood pressure was directly measured following
of measurements was obtained between the 12th and 36th catheterization of the femoral artery by percutaneous
hour in a subgroup of ten of the patients. Except for one methods previously described" in four patients, or indirectly
patient who succumbed within 30 hours following initial by sphygmomanometer in 17 patients. Samples of arterial
measurements, all patients responded favorably to treat- blood were obtained by percutaneous puncture of the
ment and were discharged from the hospital.
Treatment included oxygen administered by rebreathing femoral artery or from the arterial catheter. Duplicate
measurements of the pH of arterial blood (pHa), arterial
mask, ventimask, or nasal prongs in oxygen concentrations oxygen tension (PaO,), arterial carbon dioxide tension
ranging from 28 to 60 (mean 40) %. After an initial set of (PaCO2), oxygen saturation (SaO,) hematocrit, total plasma
measurements had been obtained, morphine sulfate was in- protein concentration, plasma colloid osmotic pressure,
jected intravenously in bolus doses ranging from 2 to 5 mg plasma osmolality, plasma sodium, plasma potassium and
with total dose ranging from 5 to 15 mg until acute anxiety arterial blood lactate (lactate,) were obtained on a single
was relieved. Furosemide was administered by intravenous
bolus injection in amounts of 40 or 80 mg. Additional doses sample of 6 ml of heparinized blood.
of 40 or 80 mg of furosemide were administered after 1 hour Arterial blood gases were measured by standard electrode
in the absence of a diuretic response. The total dose of technique utilizing a Radiometer Model pH M 27 System.
Oxygen saturation was measured with an Instrumentation
TABLE 1. Clinical Data on 21 Patients with Acute Pulmonary Laboratory Cooximeter Model 182. Hematocrit was
Edema measured by microhematocrit technique. Total protein con-
Radiographic centration was estimated by refractometry (Americal Op-
pulmonary tical Refractometer TS meter Model 10400). Plasma colloid
Pt/Age/Sex Etiology Complications edemat
osmotic pressure was measured with a transducer-mem-
1/S.H./70/M ASHD 4+ brane system by methods previously described." Plasma os-
2/M.K./59/F ASHD DM 4+
3/N.A./69/M CM 4+ molality was determined by freezing point depression utiliz-
4/F.K./75/M ASHD CLD 4+ ing an Advanced Digimatic Osmometer Model 3D. Plasma
5/I.S./83/F ASHD 4+ sodium and potassium were measured with an IL Flame
6/G.M./67/M CM DM 4+ Photometer Model 143. Arterial blood lactate was analyzed
7/T.A./69/M HHD 4+ by an automated technique developed in our laboratory."3
8/E.W./81/F ASHD 3+
9/L.Z./67/F HHD 3+ Plasma volume (PV) was measured in each case using
10/D.W./55/F ASHD 4+ radio-iodinated human serum albumin (RI"12SA). Red cell
ll/T.C./78/F ASHD 4+ mass was measured on 15 occasions in 14 patients using "Cr
12/F.H./67/M HHD 3+ labeled autologous red blood cells. Isotope activity was
13/R.S./44/M ASHD 3+ determined at intervals of 15, 25, 35, and 45 min after injec-
14/J.C.*/67/M ASHD CLD 4+
15/J.H./72/F ASHD 4+ tion of the tracer with subsequent extrapolation of the radio-
16/M.J./65/F ASHD 4+ active counts to zero time by methods previously reported.'4
17/P.V./81/F ASHD 4+ Total blood volume (TBV) was estimated from the
18/F.B./57/F ASHD DM 3+ plasma volume and hematocrit with appropriate correc-
19/D.C./53/M CM 3+ tions15 as follows:
20/M.D./59/M ASHD 4+
21/J.H./50/M HHD 4+
* = Nonsurvivor. TBV = PV X 100 (1)
tAccording to criteria of Turner et al.10 100 - (Hct X 0.87)
Abbreviations: ASHD = arteriosclerotic heart disease; HD = hyper-
tensive heart disease; CM = myocardiopathy; DM = diabetes mellitus;
CLD = chronic lung disease. in which 0.87 represents the combined correction factor for
 BLOOD VOLUME IN ACUTE PULMONARY EDEMA/Figueras, Weil 351

"trapped" plasma (0.96) and the ratio of peripheral to cen- PLASMA VOLUME, MEASURED ml/kg
tral hematocrit (0.91). Hematocrit was measured in 80-
duplicate and in no instance was the difference between
duplicate measurements greater than one percent. The 60- 0
plasma volume was measured on 34 occasions in the 21
patients. Because of the relatively prolonged periods of time 0/
required for intravascular equilibration of the radioactive 40
tracer following intravenous injection, blood volume was 0
0

measured prior to treatment in only six of the 21 patients. In r: 0.95

20L,
the remaining 15 patients, blood volumes were computed
from subsequent measurements on the basis of changes in
L>'L-/14 I I
hematocrit. Adjustments were made for the volumes of 30 50 70 90 110
blood which had been removed for laboratory testing. The PLASMA VOLUME,COMPUTED mi/kg
following formula was derived for this purpose: PV1= FIGURE 1. Relationship between measured plasma volume and
computed plasma volume in six patients with acute pulmonary
PV2 edema.
- Hct2 * 0.87
between initial measurements and measurements after
-PV2 + B * Hct1 * 0.96 (1 - Hct1 * 0.87) (2) reversal of pulmonary edema on the 21 patients were
analyzed by the Student's t-test for paired observations.
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Hct1* 0.87
in which PV, represents the initial plasma volume in ml/kg.
PV2 represents measured plasma volume on a subsequent
occasion in ml/kg. Hct1 and Hct2 represent corresponding
values of measured hematocrit expressed as decimals. B
represents total volume of blood withdrawn for laboratory
testing in the time interval between measurements 1 and 2
(averaging 95 ml). Since the largest volume withdrawn was
in close time proximity to the initial measurement of
hematocrit, Hct1 was used for adjustment of effects of blood
removal. The correction factor of 0.87 represents adjust-
ment for the combined effects of trapped plasma and the
ratio between peripheral and central hematocrit.'5 16 Total
blood volume was then computed with formula (1). In four
instances, PV2 was computed from PV1 in an analogous
manner:
PV1
PV I - Hct1- 0.87
- PV1 - B' Hct1 * 0.96(1- Hct2 0.87)
-
(3)
Hct2 * 0.87
The applicability of these computations was empirically
tested as part of the investigation. In six patients
measurements of plasma volume were available on two con-
secutive occasions, immediately after admission and on a
second occasion after an interval of 4 to 10 hours. The
differences between measured plasma volume and the
plasma volume computed from changes in hematocrit with
formula (2) were compared for purposes of this validation.
The estimate of total blood volume based on measure-
ment of plasma volume and hematocrit was separately
validated. The total blood volume representing the sum of
the measured plasma volume, and red cell mass was com-
pared to the total blood volume derived from measurement
of plasma volume and hematocrit by formula (1) on 15 oc-
casions.
Statistical analysis of differences between the measure-
ments on 21 patients and the two control groups was by
Student's t-test for unpaired observations. Differences
Results
Comparison of Measured and Computed Values of Plasma and
Blood Volume
In the six patients in whom plasma volume was measured
consecutively within an interval of 4 to 10 hours, the
measured plasma volume on the first occasion was
41.0 ± 4.7 ml/kg (mean + SEM) and the volume computed
by formula (2) was 39.6 ± 2.9 ml/kg (fig. 1). The correla-
tion between measured plasma volume and plasma volume
estimates computed from the changes in hematocrit was
r = 0.95. These observations provide evidence that changes
in hematocrit may be utilized for calculation of changes in
plasma volume in this context.
The total blood volume computed as the sum of 15
separate measurements of plasma volume and red cell mass
averaged 62.4 ± 2.7 ml/kg. Total blood volume computed
from plasma volume and hematocrit formula (1) averaged
61.9 ± 2.8 ml/kg. These differences were not statistically
significant (fig. 2). The correlation coefficient between
measured and computed blood volume was r = 0.90. These
TOTAL BLOOD VOLUME, MEASURED ml/kg
90 -
0
o 0
70- 0/
0 So
50- 0
r: 0.90
30- /
I,/,30 . I I I
50 70 90 110
TOTAL BLOOD VOLUME, ESTIMATED ml/kg
FIGURE 2. Relationship between total blood volume representing
the sum of measured plasma volume and red cell mass and the total
blood volume computed from plasma volume and hematocrit in 15
patients with acute pulmonary edema.
 352 CIRCULATION VOL 57, No 2, FEBRUARY 1978

TABLE 2. Initial Plasma and Total Blood Volumes (mean TABLE 4. Effects of Therapy in 21 Patients with Acute Pul-
SEM) monary Edema (mean - SEM)
Plasma vol. Total blood vol. Prior Following P
No. (ml/kg) (ml/kg) Hct. %
Heart rate, beats/min 111 3.5 95 4.6 <0.02
Normal Systolic blood pressure,
subjects mm Hg 146 - 9.8 135 6.5 NS
(group 1) 13 44.6 1.4 73.3 2.3 42.9 0.9 Diastolic blood pressure,
Acute mm Hg 83 - 6.3 74 3.2 NS
FI02 0.38 - 0.01 0.39 0.01 NS
pulmonary PaO2, mm Hg 74.9 - 8.2 88.5 i7.4 NS
edema 21 36.6 1.7* 60.6 -
2.6* 45.1 1.7
85.2 i 2.6
SaO2, %' 95.2 1.0 <0.005
*P <0.005, control vs PE. PaCO2, mm Hg 46.4 2.9 40.9 2.6 <0.05
pHa, units 7.27 0.03 7.38 0.02 <0.002
observations support the methodology of the present study Lactatea, mM/L 3.2 0.5 1.7 0.2 <0.005
in which estimates of total blood volume are derived from Plasma sodium, mEq/L 137 1.1 138 az 0.8 NS
Plasma potassium,
measurements of plasma volume and hematocrit. Since red mEq/L 4.5 - 0.2 4.2 = 0.2 NS
cell mass was measured in only a minority of occasions, es- Plasma osmolality,
timates of total blood volume for purposes of this study were mOsm/kg 306 - 3.1 297 - 3.2 <0.005
therefore computed from measurements of plasma volume
and hematocrit.
was significantly increased, and the total protein concentra-
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Initial Measurements tion and colloid osmotic pressure were significantly

The values of the initial total blood volume (TBV) and
plasma volume (PV) in patients with acute PE were com-
pared to those of reference group 1 (table 2). Differences
between the two groups were highly significant. In 17 of the
21 patients the TBV was less than 70 ml/kg and in 16
patients the plasma volume was less than 38 ml/kg, indicat-
ing a significantly lower vascular volume. There were no
significant differences in the parameters measured or
calculated between nine patients with prior history of acute
pulmonary edema and the 12 patients in whom pulmonary
edema occurred for the first time. There were also no signifi-
cant differences in these parameters between the 11 patients
who had been previously treated with diuretics and the
remaining ten patients. The reduction in total blood and
plasma volumes was associated with an increase in total pro-
tein concentration of plasma and in the plasma colloid os-
motic pressure which were significantly larger than reference
group 2 (table 3).
Effects of Therapy
Following treatment, heart rate declined significantly but
a concurrent decrease in arterial pressure was not
statistically significant. Reversal of clinical signs of
pulmonary edema was paralleled by increases in arterial
oxygen saturation to normal values and a significant reduc-
tion in PaCO2 and arterial blood lactate with reversal of
acidemia (table 4). Although urine output exceeded fluid in-
take by 1053 ± 143 ml, hematocrit declined, plasma volume
decreased (fig. 3 and table 5). Weak associations between
changes in plasma volume and changes in total protein
(r =- 0.460), changes in COP (r = - 0.644), and changes
in hematocrit (r = - 0.440) were observed. A decline in
plasma osmolality was observed between the initial and sec-
ond measurement (306 ± 3.1 vs 297 ± 3.2 mOsm/kg,
P < 0.005), but plasma sodium and potassium were not
significantly changed (table 4).
In the ten patients in whom a third set of measurements
was available, an additional increase in plasma volume and a
further reduction in total protein and colloid osmotic
pressure were observed. However, only the differences
between the initial and third measurements were statistically
significant (table 6). The relationships between plasma
volume, colloid osmotic pressure, and hematocrit during re-
versal of pulmonary edema in these ten cases are graphical-
ly shown in figure 4.
Discussion
In patients with chronic heart failure and especially in the
presence of generalized edema, prior investigations have
demonstrated either increases in intravascular volume'17-1 or
no consistent changes.20 During acute cardiogenic
pulmonary edema, however, blood volume is more fre-
quently reduced. In 16 of the 21 patients herein reported, the
PLASMA VOL. ml/kg TOTAL PROT. gm/dI PLASMA ONCOTIC PRESS.
0 0 mm Hg
60- -8 9.5

o 10 0 el
TABLE 3. Initial Colloid Osmotic Pressure (COP), Total
Protein (TP) and Hematocrit (Hct) (mean- SEM) 40
COP TP
N (mm Hg) (g/dl) Hct % i o X0 o

Chest pain 20
C Itx i- . 0
16 pz ooi
(group 2) 50 23.5 0.4 7.1 0.1 41.7 0.8
CN~ l"Rx C Rx
Acute
pulmonary FIGURE 3. Comparison of plasma volume, total protein, and
edema 21 26.7 0.7** 8.1 0.2** 45.1 1.7* plasma oncotic (colloid osmotic) pressure in reference groups (C)
**P <0.001, control vs PE.
and in patients with acute cardiogenic pulmonary edema before (I)
*P <0.005, control vs PE. and following (Rx) treatment.
 BLOOD VOLUME IN ACUTE PULMONARY EDEMA/Figueras, Weil 353

initial volume measured or calculated after onset of acute TABLE 6. Changes in Plasma Volume, Hematocrit (Hct),
dyspnea demonstrated a lower than normal intravascular Total Protein (TP), Colloid Osmotic Pressure (COP), and Net
volume. To this extent, volume changes during acute Fluid Loss after an Average Interval of 21.3 - 2.1 Hours of
Treatment in 10 Patients with Acute Pulmonary Edema (mean
pulmonary edema differ from those which were observed SEM)
during chronic congestive heart failure. Prior Following P
The mechanism by which volume is depleted during acute
pulmonary edema may be clarified, in part, from concurrent Plasma volume, mi/kg 37.2 -i 2.9 43.1 -- 2.3 <0.05
HCt, % 42.8 1.9 36.7 1.8 <0.001
measurements of hematocrit, total protein, and colloid os- TP, g/dl 8.2 = 0.3 6.9 i0.4 <0.001
motic pressure. Hematocrit, plasma total proteins, and COP, mm Hg 26.1 0.9 21.5 1.0 <0.002
colloid osmotic pressure were greater than those observed in Urine output-fluid intake 2823 848
the reference groups prior to reversal of pulmonary edema.
Accordingly, plasma water had been removed from the in-
travascular compartment. The evidence points to extra- protein. An increase in plasma volume was confirmed in 14
vasation of fluid from the intravascular compartment that is of the 21 patients.
low in colloid content. The likelihood that this represents, at The present observations on patients with acute heart
least in part, fluid which is extravasated into the lung is con- failure contrast to those reported by Davidov, Kakaviatos,
sistent with observations on the protein content and colloid and Finnerty9 in five patients with chronic congestive heart
osmotic pressure of pulmonary edema fluid. In a group of failure. Their patients had long-standing congestive heart
patients with frothy pulmonary edema recently studied in failure with generalized edema which had been refractory to
our center, as much as one-half liter of fluid was collected both thiazide and organomercurial diuretic agents. Plasma
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during endotracheal suction within an interval of less than
30 min. The colloid osmotic pressure of this fluid averaged
approximately one-half of the colloid osmotic pressure
plasma, a level which is consistent with values of total pro-
tein in pulmonary edema fluid previously reported by Katz
and his co-workers.21 The amounts of fluid extravasated dur-
ing pulmonary edema may exceed 2 liters in the adult.22 22
Extravasation of this fluid into the lung is traced to increases
in capillary hydrostatic pressure in excess of colloid osmotic
pressure in consequence of increases in left ventricular filling
pressure. Accordingly, the loss of substantial volumes of
hypo-oncotic fluid into the lung would explain a reduction in
volume and the increases in hematocrit and plasma protein
concentrations observed by us.
Decreases in intravascular volume may also stem from in-
creases in capillary filtration pressure in the systemic circuit
in consequence in increases in right atrial filling pressure and
increases in venous tone during heart failure.2 Muscular ex-
ercise in the struggling patient with or without heart fail-
ure,24 27 fluid losses associated with hyperventilation,28 and
the extravasation of fluid related to the secretion of large
amounts of endogenous cathecholamines29, 30 may also be
cited as additional causes for volume depletion.
Effects of Therapy
All but one patient promptly improved following treat-
volume was initially increased. After furosemide diuresis, a
decrease in plasma volume and an increase in hematocrit
were observed. Similar observations were made by Ramirez
and Abelmann in five patients with chronic heart failure.31
This differs from the present group of patients in whom
pulmonary edema appeared as an acute event.
Following administration of the diuretic agent, intravas-
cular volume was expanded over a mean period of 7.4 hours,
a time interval during which fluid excretion exceeded fluid
intake by more than 1 liter. The findings suggest that the
rate of fluid refill into the intravascular compartment ex-
ceeded the net volume of fluid excreted in the urine.
Since three agents were used for treatment, namely oxy-
gen and morphine in addition to furosemide, the role of each
individual drug is not clarified. However, recent observa-
tions by Dikshit, Vyden, Forrester et al.32 and Mond, Hunt
and Sloman33 are pertinent. These workers demonstrated
hemodynamic effects of furosemide which were not directly
related to its diuretic action. Within 15 min after ad-
ministration of furosemide, an increase in venous
capacitance was associated with a significant decrease in left
65 TOTAL BLOOD VOLml/kg a
T.B.U ~. . 2 40 P.V
55i;i-.: ~
'PLASMA VOL. ml/kg ... .....

5 5E--------.-.-.--..-.---
ment with oxygen, morphine, and furosemide. Reversal of 43
pulmonary edema was associated with highly significant ~~~~EMATOCRIT, %
37

decreases in hematocrit, colloid osmotic pressure, and total

140-- TOTAL PROTEIN,gm %o 9
24-1
PaP J -6TOT. P
TABLE 5. Changes in Plasma Volume, Hematocrit (Hct),
Total Protein (TP), Colloid Osmotic Pressure (COP), and Net 201 t:-: .PLASMA ONCOTIC PRESS. torr
ONCOTIC..SMA [3
Fluid Loss After an Average Interval of 7.4 ' 0.6 Hours of
Treatment in 21 Patients with Acute Pulmonary Edema (mean :J NE.
FUI: LSS L..
SEM)
2- -.:..-.NET FLUID LOSS, L. - -.
P r
Prior Following 0 14 21
Plasma volume, ml/kg 36.6 - 1.7 40.6 - 2.2 <0.01 HOURS
Hot, % 45.1 - 1.7 41.5 - 1.7 <0.001 FIGURE 4. Sequential changes in total blood volume, plasma
TP, g/dl 8.1 - 0.2 7.3 - 0.2 <0.001 volume, hematocrit, total protein concentration, plasma oncotic
COP, mm Hg 26.7 0.7 22.4 0.8 <0.001
Urine output-fluid intake 1053 143 (colloid osmotic) pressure and net fluid loss in ten patients with
acute cardiogenic pulmonary edema during the course of therapy.
 354 ClIRCULATION
ventricular filling pressure.32 Moreover, reversal of
pulmonary edema following administration of furosemide
may occur in the absence of diuresis.343 The fall in left ven-
tricular filling pressure may be related to increased venous
compliance, sequestration of blood in the venous
capacitance bed, and therefore a decrease in preload.
Morphine has a similar effect in that it also acts to in-
crease venous capacitance.36 Oxygen reduces pulmonary
vascular resistance stemming from hypoxia,37 and therefore
reduces the workload on the right ventricle. The effects on
venous capacitance also favor a reduction in venular and
small vein pressure and, accordingly, they account for a
reduction in capillary hydrostatic pressure. Because colloid
osmotic pressure is increased, the net hydrostatic-oncotic
gradient favors capillary refill. Experimentally, furosemide
also increases thoracic lymph flow and thereby augments in-
travascular volume.38 Since the fluid which is returned into
the intravascular compartment has a colloid content which
is only a fraction of that of plasma, concurrent reduction in
plasma total proteins, colloid osmotic pressure and
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hematocrit would be anticipated and were, in fact, found. To
this extent our results are in close agreement with the case
reported by Biagi34 in which dramatic improvement of acute
pulmonary edema after administration of furosemide was
associated with a 12% decline in the hematocrit in the
absence of diuresis.
Both physical exertion in the struggling patient during
acute pulmonary edema and bed rest following hospitaliza-
tion may affect vascular volume. In cardiac patients Iseri26
demonstrated a decrease in plasma volume during exercise
and a return to control levels after 30 min of rest. Therefore,
reduction in intravascular volume observed during acute
pulmonary edema may be accentuated by the physical
struggle and increased work of breathing. Bed rest in itself,
on the other hand, accounts for a decrease in plasma
volume39-14 following a transient initial increase. This reduc-
tion in plasma volume can already be appreciated after 6
hours of bed rest.41 The absence of such a decline in plasma
volume in the patients who are the subject of this report and
who were at bed rest lends further credence to our observa-
tions. We therefore conclude that plasma volume is more
often re-expanded rather than contracted during a 36 hour
interval of therapy during which diuresis with reversal of
acute cardiogenic pulmonary edema is documented.
Acknowledgments
The collaboration of Drs. Vinod Puri, William French, and Richard
Carlson, and Ms. Sybil Michaels in the design and execution of these studies
is gratefully acknowledged. Mr. Lawrence Portigal provided statistical con-
sultation.
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 RATE OF ATHEROSCLEROSIS CHANGE/Blankenhorn et al.
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The Rate of Atherosclerosis Change
during Treatment of Hyperlipoproteinemia
DAVID H. BLANKENHORN, M.D., SAMUEL H. BROOKS, D.SC.,
ROBERT H. SELZER, M.S., AND ROBERT BARNDT, JR., M.D.
SUMMARY The rate of change of femoral atherosclerosis has
been determined in 25 treated hyperlipoproteinemic patients. There
Downloaded from http://circ.ahajournals.org/ by guest on April 11, 2018
were 13 Type 11 patients and 12 Type IV patients. Serial angiograms
had been performed at an interval averaging 13 months. Film den-
sities were analyzed by digital image processing to yield a computer
estimate of atherosclerosis (CEA). Serial measurements of CEA on
each patient were used to determine atherosclerosis percent change
THIS PAPER presents information regarding rate of
change of human femoral atherosclerosis during treatment
of hyperlipoproteinemia. The estimates we report were ob-
tained by assessment of two angiograms separated by an in-
terval of approximately 13 months. Experiments of others
with hyperlipoproteinemic animals suggest that change in
fatty streaks can be detected in as short a period as eight
months after alteration of lipid levels and is followed by
change in more advanced plaques. To obtain this informa-
tion, test and control animals have been sacrificed for direct
examination of vessels at intervals after inducing or relieving
hyperlipoproteinemia.' Directly comparable experiments
are not possible in man and what is known of blood lipid
effect on atherosclerosis has been deduced from a few studies
employing angiography2-6 plus many studies where lesions
have been evaluated indirectly through atherosclerosis-
related end points.
Interpretation of lipid lowering intervention trials, such as
The Coronary Drug Project, Minnesota Coronary Survey,
and Lipid Research Clinic Primary Prevention Trial, is am-
biguous in regard to atherosclerosis change because myo-
cardial infarction is the major end point studied. Myo-
cardial infarction can occur when atherosclerosis becomes
more severe and also when thrombosis is superimposed on
unchanged atherosclerotic lesions. Myocardial infarction
can occasionally occur when coronary arteries appear nor-
From the University of Southern California School of Medicine and the
California Institute of Technology, Jet Propulsion Laboratory, Los Angeles,
California.
Supported by NHLBI Specialized Center of Research in Atherosclerosis,
Grant HL-14138; NASA Office of Life Science Program, Medical Image
Analysis Facility; and the Robert E. and May R. Wright Foundation.
Address for reprints: David H. Blankenhorn, M.D., School of Medicine,
University of Southern California, 2025 Zonal Avenue, Los Angeles, Califor-
nia 90033.
Received June 16, 1977; revision accepted August 24, 1977.
355
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volume as indicated by haemoglobin and haematocrit levels. Lancet
1: 539, 1950
43. Waterfield RL: The effects of posture on the circulating blood volume. J
Physiol 72: 110, 1931
44. Fawcet JH, Wynn V: Effects of posture on plasma volume and some
blood constituents. J Clin Pathol 13: 304, 1960
per month in that patient. CEA percent change per month was
significantly correlated with triglyceride and cholesterol level. Lower
lipid levels were associated with more rapid regression. When hyper-
lipoproteinemic types were considered separately, significant single
correlates were confined to Type IV. Triglyceride level and CEA/age
significantly predicted atherosclerosis change rate and accounted for
72% of the variability observed in Type IV patients.
mal. The occurrence of myocardial infarction implies that
vascular insufficiency has grown worse. There is no cor-
responding end point which can imply that vascular in-
sufficiency has improved. This makes intervention trials
based on myocardial infarction insensitive to changes which
might follow atherosclerosis improvement. More direct in-
formation regarding human atherosclerosis change is
desirable and now can be obtained from femoral angio-
grams. The information we report here reflects directly
measured change in lesion state with equal sensitivity to
change in either direction - regression or progression. A
limitation in interpreting the results we present is that the
relationship of femoral lesion change to long-term cardio-
vascular mortality rate is not known.
In a previous report we presented evidence that femoral
atherosclerosis as determined by angiography is common in
young patients with hyperlipoproteinemia, although they
may have few symptoms.7 We have also reported that the
visible extent of vessel wall involvement diminished in nine
of these patients among 25 treated for hyperlipopro-
teinemia and studied by serial angiography.8 In a separate
series of reports we described development of an instrumen-
tal method to assess angiograms.9-1" This method involves
converting an X-ray image recorded on film into a digital
array for computer processing using an optical image dissec-
tor. Edges of the vessel image are located by analyzing
digital data in lines perpendicular to the long axis of the
vessel. Irregularities of each vessel edge and densities of the
vessel image are analyzed further to provide assessment of
atherosclerosis through a combined measure, CEA (com-
puter estimated atherosclerosis), which has previously been
calibrated directly against atherosclerosis determined at
autopsy.9 In this report, CEA has been determined on all
films previously assessed by human readers and used to es-
timate rate of change in atherosclerotic lesions for correla-
 Blood volume prior to and following treatment of acute cardiogenic pulmonary edema.
J Figueras and M H Weil

Circulation. 1978;57:349-355
doi: 10.1161/01.CIR.57.2.349
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