Albumin infusion in humans does not model exercise induced hypervolaemia after 24 hours

Albumin infusion in humans does not model exercise

induced hypervolaemia after 24 hours

A . H A S K E L L , C . M . G I L L E N , G . W . M A C K a n d E . R . N A D E L

The John. B. Pierce Laboratory and Departments of Cellular & Molecular Physiology and Epidemiology & Public Health, The Yale

University School of Medicine, New Haven, CT, USA

ABSTRACT

We rapidly infused 234 � 3 mL of 5% human serum albumin in eight men while measuring

haematocrit, haemoglobin concentration, plasma volume (PV), albumin concentration, total protein

concentration, osmolality, sodium concentration, renin activity, aldosterone concentration, and atrial

natriuretic peptide concentration to test the hypotheses that plasma volume expansion and plasma

albumin content expansion will not persist for 24 h. Plasma volume and albumin content were

expanded for the first 6 h after infusion (44.3 � 1.9±47.2 � 2.0 mL kg)1 and 1.9 � 0.1±

2.1 � 0.1 g kg)1 at pre-infusion and 1 h, respectively, P < 0.05), but by 24 h plasma volume and

albumin content decreased signi®cantly from 1 h post-infusion and were not different from pre-

infusion (44.8 � 1.9 mL kg)1 and 1.9 � 0.1 g kg)1, respectively). Plasma aldosterone concentration

showed a signi®cant effect of time over the 24 h after infusion (P < 0.05), and showed a trend to

decrease at 2 h after infusion (167.6 � 32.5)1 06.2 � 13.4 pg mL)1, P � 0.07). These data

demonstrate that a 6.8% expansion of plasma volume and 10.5% expansion of plasma albumin

content by infusion does not remain in the vascular space for 24 h and suggest a redistribution occurs

between the intravascular space and interstitial ¯uid space.

Keywords aldosterone, atrial natriuretic peptide, Evan's blue dye, plasma albumin content, plasma

volume, renin.

Received 6 June 1997, accepted 22 June 1998

Plasma volume (PV) expansion is a well-demonstrated

consequence of endurance exercise training in humans

(Kjellberg et al. 1949, Oscai et al. 1968, Senay 1972,

Convertino et al. 1980a, 1980b, 1991, Coyle et al. 1986,

Gillen et al. 1991). Albumin content expansion has been

associated with 86±100% of PV expansion after exer-

cise (Convertino et al. 1980a, Gillen et al. 1991). A

single 90-minute intense exercise session expands PV

by 10% after 24 h, and lasts up to 44 h (Gillen et al.

1991, 1994). After this exercise protocol, plasma albu-

min content rises within 1 h, prior to PV expansion, to

the level it maintains throughout the subsequent 24 h

(Gillen et al. 1991). Mechanisms resulting in a rapid

autoinfusion of albumin and ¯uid after exercise likely

include a short-term increase in lymphatic return

(Olszewski et al. 1977).

Albumin's role as the single largest contributor to

plasma colloid osmotic pressure (Berne & Levy 1990)

puts it in a unique position to potentially regulate PV,

and raises the possibility that the rapid rise and plateau

of plasma albumin content after exercise contributes to

the maintenance of PV expansion through 24 h. Al-

bumin infusion has been used to model acute changes

in plasma volume and plasma albumin content, al-

though these studies have not characterized the effects

of albumin infusion over 24 h (Parving et al. 1974,

Lamke & Liljedahl 1976, Fortney et al. 1981, Hubbard

et al. 1984, Mack et al. 1991, Loon et al. 1992, Renkin

et al. 1992, Riddez et al. 1997). Clinically, albumin is

used as an acute volume expander for cardiovascular

resuscitation (Jelenko et al. 1979, Lucas et al. 1980,

Rackow et al. 1989, GineÁs et al. 1991). While clinical

experience shows the effects of albumin infusion in

critically ill patients to be short lived, these data may not

be applicable to healthy subjects because of the dif-

ferent transcapillary ®ltration properties and interstitial-

lymphatic dynamics in this population (Parving 1972,

Feldt-Rasmussen 1986, Lundvall & LaÈnne 1989,

Rackow et al. 1989, Aukland & Reed 1993, Jaap et al.

1993). Hubbard et al. (1984) studied the effect of

Correspondence: Ethan R Nadel, PhD, The John B. Pierce Laboratory, 290 Congress Ave., New Haven, CT 06519, USA.

Acta Physiol Scand 1998, 164, 277±284

Ó 1998 Scandinavian Physiological Society 277

infusing 25±50 g of albumin in a 25% albumin solution

under varying conditions, demonstrating a plasma vol-

ume expansion which does not persist for 24 h.

However, this study does not directly compare to the

post-exercise state: the infused albumin mass is ap-

proximately twice that of the albumin expansion after

exercise, and the infusate concentration is hyperonco-

tic, relying on reabsorption of up to 440 mL saline

(»13% of plasma volume) from the interstitial ¯uid

compartment for restitution of an isoncotic solution

(Lamke & Liljedahl 1976).

The purpose of this study was to test the assertion

that the immediate post-exercise plasma volume and

plasma albumin content expansion is not suf®cient to

maintain hypervolemia for 24 h. We tested this hy-

pothesis by infusing an isotonic albumin solution of

similar volume to that seen after exercise and subse-

quently measuring plasma volume and plasma constit-

uents for 24 h.

METHODS

Subjects

Eight healthy men (age 26.4 � 1.8 year, body weight

73.5 � 1.9 kg, _V O2max 49.6 � 2.1 mL kg)1 min)1)

gave informed consent for participation in this proto-

col, which was approved by the Yale University Human

Investigation Committee. The subjects had no history

of heart or kidney disease and were not taking medi-

cation. Each subject was familiarized with the equip-

ment, test chamber, and study protocol at least 1 day

prior to testing. A ®xed diet (dinner, 1400 kcal, 1.8 g

Na+; breakfast, 380 kcal, 0.2 g Na+; lunch, 940 kcal,

1.8 g Na+) was provided starting the evening before

testing including 1 L of water to drink the night before

each test day. Additional water intake at home was al-

lowed ad libitum. Subjects were asked to refrain from

exercising and consuming alcohol or caffeine on the

day preceding testing and on both test days. Compli-

ance was veri®ed via written questionnaire each

morning of testing.

Protocol

A number of steps were taken to insure a similar

baseline state of volume homeostasis including regu-

lating ambient temperature, posture, and pre-data col-

lection hydration. Aggressive pre-testing hydration

prevents subjects from starting testing at different levels

of dehydration. Subjects drank 10 mL kg)1 water in

14 � 3 min and rested for 90 min, after which they

voided. Body weight was unchanged from pre-hydra-

tion to post-void (73.76 � 1.96±73.70 � 1.95 kg), and

urine osmolality was 61 � 12 mosmol kg H2O, dem-

onstrating the subjects' well-hydrated state. Similarly,

regulation of ambient temperature (27 � 0.1 °C) be-

tween subjects and across testing days prevents the

effects of temperature regulating mechanisms within

the body from confounding the response to infusion.

Finally, upright seated posture was chosen for this ex-

periment. Although using this posture may result in

¯uid shifts between the intravascular and interstitial

¯uid compartments (Sejrsen et al. 1981, Noddeland

1982, Parazynski et al. 1991, Lundvall & Bjerkhoel

1994), in order to mimic the post-exercise state used by

Gillen et al. (1991) a similar postures must be used to

prevent the effects of postural compensatory mecha-

nisms from confounding the response to infusion.

On two consecutive days, subjects reported to the

laboratory at 7:00 AM. They sat for 1.25 h prior to in-

fusion, during which time a 20-gauge indwelling venous

catheter was placed in a forearm vein and a 21-gauge

butter¯y needle was placed in a forearm vein distal to

the catheter. Blood samples were taken from the

forearm venous catheter at heart level without stasis at

the times indicated in Fig 1, and were replaced with an

equal volume of 0.9% NaCl solution.

Subjects were infused with a 5 g dL)1 solution of

human serum albumin in 0.9 g dL)1 NaCl (Baxter)

through the forearm catheter at a rate of 500 mL h)1

using an infusion pump (3 M). In order to maximize PV

expansion, we infused as much of a 250 mL bottle as

possible resulting in a mean infusion volume of

234 � 3 mL. The upstream butter¯y needle was used

for sampling during the infusion and was removed

shortly after infusion. Subjects remained seated for 6 h

from the start of infusion.

The next day, subjects underwent the same hydra-

tion routine as on the previous day and were seated for

1.25 h, during which time a 21-gauge butter¯y needle

was placed in a cutaneous forearm vein. Blood samples

were taken as indicated in Fig 1, including a blood

volume determination by Evan's blue dye dilution. This

Figure 1 Experimental protocol. Eight subjects completed day 1 and

day 2 on subsequent days. Subjects hydrated with 10 mL kg)1 body

wt water. Large arrows represent 20 mL blood samples, small open

arrows represent 4 mL blood samples, and small closed arrows rep-

resent 10 mL blood samples. U and W represent voiding and body

weight measurements. Dye represents injection of Evan's blue dye.

Albumin infusion in humans � A Haskell et al. Acta Physiol Scand 1998, 164, 277±284

278 Ó 1998 Scandinavian Physiological Society

involved the intravenous injection of »3 mL of Evan's

blue dye (David Bull Laboratories). Exact injection

volume was calculated from the change in syringe

weight to �0.0001 g (Mettler). Three blood samples

were taken at 10-minute intervals following the dye

injection. Subjects returned to the lab at least 1 week

after experimentation for determination of _V O2max

using a standard upright bicycle ergometer protocol.

Analyses

A small aliquot of each blood sample was used for

determination, in quadruplicate, of haematocrit by

microhaematocrit (� 0.2%), haemoglobin concentra-

tion by cyanomethaemoglobin (� 0.1 g dL)1, Boeh-

ringer Mannheim Diagnostics, Inc.), and total protein

concentration by plasma refractometry (� 0.1 g dL)1).

The rest of the 4 mL blood samples were placed into

heparinized tubes (Vacutainer), while the 20 mL sam-

ples were divided: 10 mL into heparinized tubes, 5 mL

into sodium EDTA tubes (Vacutainer) and 5 mL into

potassium EDTA tubes (Vacutainer). These tubes were

centrifuged for 15 min at 1500 ´ g, 4 °C and a portion

of the plasma was refrigerated for determination, the

same day, of plasma albumin concentration colorimet-

rically by the bromcresol purple reaction (� 0.1 g dL)1,

Sigma), and osmolality by freezing point depression

(� 1 mosmol Kg H2O, Advanced Instruments). The

remaining plasma was divided: half frozen at ) 20 °C

for later analysis of sodium concentration by ¯ame

photometry (� 0.1 meq L)1, Instrumentation Labora-

tory), and the rest frozen at ) 70 °C for later deter-

mination of PRA by radio-immunoassay of generated

angiotensin I (CV 1.3% for midrange samples, Incstar),

aldosterone by radio-immunoassay (CV 1.9% for mid-

range samples, Diagnostic Products Corporation), and

atrial natriuretic peptide (ANP) by radio-immunoassay

(CV 3.9% for midrange samples, Incstar). A sample of

the infusate was tested for albumin and sodium con-

centrations.

Calculations

Plasma Evan's blue dye concentration was calculated

colorimetrically at 620 nm and standardized to an Ev-

an's blue control prepared in subject plasma. PV was

calculated from the average plasma concentration of

Evan's blue dye and the mass of dye injected. The

percentage change in PV was calculated using ha-

ematocrit and haemoglobin, and converted to absolute

PV using the Evan's blue PV measurement. Blood

volume was calculated from PV and haematocrit.

Plasma albumin content and total protein content were

calculated by multiplying the respective concentration

by PV. PV, blood volume, plasma albumin content, and

plasma total protein content are reported as the value

divided by the subject's pre-infusion body weight.

Statistics

The effect of time was tested using analysis of variance

for repeated measures for haematocrit, haemoglobin

concentration, plasma osmolality, plasma total protein

concentration and content, plasma albumin concen-

tration and content, PV, blood volume, plasma sodium

concentration, PRA, plasma aldosterone concentration,

and plasma ANP concentration. Comparisons were

made between the 1 and 24 h data, and multiple post hoc

comparisons were made between the pre-infusion and

the 45 min, 1, 2, 4, 6 and 24 h data for haematocrit,

haemoglobin concentration, plasma total protein con-

centration and content, plasma albumin concentration

and content, PV, and blood volume. Plasma aldoste-

rone concentration was analysed using multiple post

hoc comparisons between the pre-infusion and the

45 min, 2, and 24 h data. Comparisons were considered

signi®cantly different with a con®dence level of

P < 0.05. The con®dence level for multiple compari-

sons was adjusted using a Bonferroni correction, such

that the cut-off for signi®cance was P < 0.001 for

blood constituents and P < 0.0167 for aldosterone

data. Values are reported as mean � SE.

RESULTS

A volume of 3.19 � 0.09 mL kg body wt)1 of albumin

solution was infused. The infusate composition in-

cluded albumin (5.41 � 0.05 g dL)1) and a Na+

(140.8 � 1.4 meq L)1). This resulted in infusion of

0.173 � 0.006 g albumin kg)1 (12.6 � 0.2 g albumin)

and 0.449 � 0.015 meq Na+ kg)1.

Volume expansion was isotonic, such that plasma

osmolality and plasma Na+ concentration did not

change over the course of the experiment (Table 1). PV

expansion of 6.1% at 1 h and 4.9% at 2 h was associ-

ated with decreased haematocrit and haemoglobin

concentration (Table 1, Fig. 2). Twenty-four hours af-

ter infusion, PV was signi®cantly decreased from 1 h

after infusion, and PV, haematocrit, and haemoglobin

concentration were not different from pre-infusion.

Blood volume trends were similar to those of PV.

Plasma albumin concentration increased from pre-in-

fusion by 4.0% at 1 h and 5.2% at 2 h but was not

different from pre-infusion at 24 h (Table 1). Plasma

total protein concentration was decreased from pre-

infusion at 1 h, although it was not different from pre-

infusion at 2 or 24 h. Albumin content was signi®cantly

elevated from pre-infusion by 10.6% at both 1 h and at


Acta Physiol Scand 1998, 164, 277±284 A Haskell et al. � Albumin infusion in humans

2 h, but was not different from pre-infusion at 24 h

(Table 1, Fig. 2). Total protein content followed a

similar trend.

There was a signi®cant effect of time on plasma

aldosterone concentration, but not on PRA or ANP

(Fig 3). Plasma aldosterone concentration showed a

trend to decrease from pre-infusion at 2 h (P � 0.07).

Plasma aldosterone concentration was 167.6 � 32.5,

124.8 � 16.4, 106.2 � 13.4 and 185.3 � 39.6 pg mL)1,

plasma ANP concentration was 31.2 � 1.2, 31.8 � 2.2,

31.1 � 1.8 and 28.3 � 3.5 pg mL)1 and PRA was

1.68 � 0.26, 1.27 � 0.30, 1.64 � 0.41 and

1.79 � 0.53 ng A1 mL)1 h)1 at pre-infusion, 45 min, 2

and 24 h post-infusion, respectively.

There was no change in mean subject weight over

the hydration period on either day 1 or day 2, indicating

that subjects expelled a volume equal to what they

drank. Subject weights were not signi®cantly different

on day 2 compared with day 1 (Table 1), indicating

similar hydration states on each of these days. The

mean body weight at the end of day 1 was decreased by

0.7 kg indicating a loss of total body water over the 6-h

post-infusion period.

DISCUSSION

This experiment demonstrates that the intravenous in-

fusion of an isotonic albumin solution, in quantities

suf®cient to produce PV expansion similar to that ex-

hibited during exercise induced hypervolaemia, will not

remain in the vascular space for 24 h. Similarly, plasma

albumin content following infusion rose approximatelyTab

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Figure 2 Change in plasma volume (áPV) and change in plasma

albumin content (áAlbumin content) during the 24 h after the start

of infusion. Each subject is represented by a unique symbol.

Mean � SE is represented by a closed circle with error bars. Data

during infusion are indicated. *Different from pre-infusion

(P < 0.05). Different from 1 h (P < 0.05)



according to the changes seen during exercise recovery

(Gillen et al. 1991), but was not maintained throughout

the 24 h recovery period (Fig 4).

A balance between synthesis and degradation and a

balance between capillary ef¯ux and lymphatic return

maintain plasma albumin content. Perturbations to this

equilibrium result in protein and ¯uid shifts which tend

to restore pre-perturbation ratios of ¯uid and protein

between the vascular space and the interstitial ¯uid

space. Albumin infusion creates such an imbalance, and

indeed, at 24 h after infusion, »20% of the volume

expansion and 33% of the albumin content expansion

remain in the vascular space (Fig. 5). The mechanisms,

which restore this ratio, can be explained by changes in

Starling forces, which drive transcapillary ¯uid and

protein movement, and indirectly determine lymphatic

return. Infusion, and subsequent hypervolaemia, creates

an increased hydrostatic pressure gradient across the

capillary wall (Reed 1988, Renkin et al. 1988, Wolf et al.

Figure 3 Plasma atrial natriuretic peptide concentration (ANP),

plasma renin activity (PRA) and plasma aldosterone concentration

(Aldosterone) at pre-infusion, and 45 min, 2 and 24 h after the start

of infusion. Data displayed are mean � SE for eight subjects. *Sig-

ni®cant effect of time (P < 0.05). Trend to differ from pre-infusion

(P � 0.07).

Figure 4 Comparison of percentage change in albumin content

(%áAlbumin content) and plasma volume (%áPV) following infu-

sion and exercise. Exercise data from Gillen et al. (1991). *Different

from pre-infusion or pre-exercise, respectively (P < 0.05). Different

from respective 1 h data (P < 0.05).



1989, Convertino et al. 1991, Rippe & Haraldsson

1994), resulting in an increase in transcapillary albumin

escape predominantly across large pores secondary to

convective ¯ow (Rippe & Haraldsson 1994). While

lymph ¯ow may transiently increase in response to in-

creased interstitial ¯uid pressure (Aukland & Reed

1993), lymphatic return of albumin would likely lag

behind the increase in transcapillary ¯ux because in-

terstitial albumin concentration is diminished secondary

to dilution (Olszewski et al. 1977). Following similarly

reasoning, the plasma albumin content expansion re-

ported by Gillen et al. (1991) 1 h after exercise creates

an imbalance of albumin content. During exercise, in-

creased capillary hydrostatic pressure results in a large

¯uid and protein movement from the intravascular

space into the interstitial ¯uid space (Mohsenin &

Gonzalez 1984, Harrison 1985). Immediately after ex-

ercise the direction of ¯uid and protein movement are

reversed as capillary hydrostatic pressure returns to

baseline and plasma oncotic pressure and interstitial

¯uid hydrostatic pressure remain elevated (Mohsenin &

Gonzalez 1984). Finally, ¯uid translocates from the

interstitial space via the lymphatics in contracting

muscle, leading to protein intravascularization (Engeset

et al. 1977, Olszewski et al. 1977, Morimoto et al. 1979).

The contrasting results following albumin infusion

and exercise suggest that, for up to 40 h after exercise,

mechanisms must compensate for the forces, which

tend to restore plasma albumin content to pre-exercise

levels. These mechanisms are not well de®ned,

although a number of modi®cations to albumin equi-

librium could impede the restoration of plasma albumin

content after exercise. They include increased albumin

synthesis, decreased albumin degradation, sustained

increase in lymphatic return, and decreased transcapil-

lary escape rate for albumin. This study cannot shed any

light on the possible roles of protein translocation or

the synthesis to degradation ratio on post-exercise PV

expansion. However, a recent study from our labora-

tory indicates that PV expansion following exercise is

associated with decreased transcapillary escape rate for

albumin (Haskell et al. 1997), and preliminary work

suggests that albumin synthesis may be increased during

the 24-h period after exercise.

Total body water decreased by 700 mL over 6 h

following infusion, including urinary and evaporative

losses. Despite this loss, neither the albumin content

nor the plasma volume signi®cantly decrease from its

respective post-infusion level over this time period. The

infused albumin may retain ¯uid in the vascular space at

the expense of interstitial ¯uid volume owing to its

colloid osmotic properties. However, the subjects' up-

right posture complicates this analysis. Blood sampling

while the subject is in the upright position may un-

derestimate the haemoconcentration occurring in de-

pendent body parts, thus overestimating plasma volume

(Lundvall & Bjerkhoel 1994). In addition, intravascular

¯uid may be lost to the interstitial ¯uid compartment of

dependent body parts, although these losses are mini-

mized by a posture dependent veno-arteriolar re¯ex

(Sejrsen et al. 1981).

While plasma renin activity and ANP were un-

changed from pre-infusion at 45 min and 2 h post-

infusion, aldosterone concentration showed a signi®-

cant effect of time as well as a trend for 37% reduction

at 2 h. However, we cannot be sure that the changes in

aldosterone seen after infusion were accompanied by a

corresponding increase in urine output or urine Na+

excretion rate. The lack or response in PRA and ANP

contradicts similar data after infusion (Loon et al. 1992),

although the latter study infused over twice the volume

of 5% albumin solution in the same time period.

Figure 5 Comparison of actual and predicted changes in plasma

volume (áPV) and albumin content (áAlbumin content). Predicted

values represent 20% of áPV and 33% of áAlbumin content at 1 h

and signify the distribution, at 24 h, of infusate throughout the ex-

tracellular ¯uid space according to baseline ratios between the intra-

vascular space and the interstitial ¯uid space.



Subjects in this latter study were similarly well hydrated,

but they were supine during testing. This may indicate

the threshold for ANP and PRA response lies between

the volumes infused in these two studies, or that pos-

tural effects outweigh a volume stimulus of the size we

infused. We did not measure arginine vasopressin as it

has been shown to respond to changes in osmolality of

plasma rather than PV changes of this size (Kimura

et al. 1976).

In summary, we have shown that the body is able to

restore PV and plasma albumin content to pre-infusion

values 24 h after the addition of an albumin load to the

vascular space equal to that seen after intense exercise.

However, as albumin content expansion is maintained in

the vascular space following exercise for over 24 h, we

conclude that the translocation of albumin into the vas-

cular space 1 h after intense exercise is not suf®cient, and

compensatory mechanisms are required, to maintain

hypervolemia for 24 h after an intense exercise bout.

We would like to thank Cheryl Kokoszka and Tamara S. Morocco for

technical support. This work was supported by National Heart, Lung,

and Blood Institute Grants HL 20634 and HL39818 and NASA grant

NAGW-4056.

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Albumin infusion in humans does not model exercise induced hypervolaemia after 24 hours