Effects of Albumin/Furosemide Mixtures on Responses to Furosemide in Hypoalbuminemic Patients
NAGA CHALASANI*,
J. CHRISTOPHER GORSKI,
JOHN C. HORLANDER, SR.*,
REBECCA CRAVEN,
HELENA HOEN,
JUAN MAYA and
D. CRAIG BRATER
*Division of Gastroenterology, Department of Medicine, Indiana University
School of Medicine, Indianapolis, Indiana. Division of Clinical Pharmacology, Department of Medicine, Indiana
University School of Medicine, Indianapolis, Indiana. Division of Biostatistics, Department of Medicine, Indiana University
School of Medicine, Indianapolis, Indiana.
Correspondence to Dr. D. Craig Brater, Indiana University School of Medicine,
1120 South Drive, Fesler Hall 302, Indianapolis, IN 46202-5114. Phone:
317-274-8157; Fax: 317-274-8439; E-mail:
dbrater{at}iupui.edu
Abstract. Hypoalbuminemic patients often have sufficient fluid
accumulationto mandate diuretic therapy but are often resistant to diuresis.
Studieshave suggested that hypoalbuminemia itself impairs deliveryof
effective amounts of diuretic agent into the urine, the siteof action.
Therefore, administration of mixtures of albuminand loop diuretics may
enhance responses. Thirteen patientswith biopsy-proven cirrhosis and ascites
(age, 51.2 ±8.1 yr; Child-Pugh score, 8.5 ± 1.0; serum albumin
concentration,3.0 ± 0.6 g/dl) were studied in this randomized
crossoverstudy. Sodium balance was maintained throughout the study witha
metabolic diet. All patients received spironolactone, butadministration of
all other diuretic agents was discontinued.Each patient received all of the
following four treatments intravenously:(1) 40 mg of furosemide,
(2) 25 g of albumin, (3) 40 mg of furosemideand 25 g of
albumin premixed ex vivo, and (4) 40 mg of furosemideand 25
g of albumin infused simultaneously into different arms.Responses were
assessed by measuring urinary sodium excretionand relating the urinary
furosemide excretion rate to the sodiumexcretion rate. Additionally, the
pharmacokinetics of furosemidewere assessed. Furosemide pharmacokinetics were
similar forall treatment arms. Albumin alone had negligible diuretic effects.
Neitheralbumin regimen increased the response to furosemide. Moreover,the
relationship between the urinary furosemide excretion rateand the sodium
excretion rate was unaffected by albumin. Inconclusion, albumin failed to
enhance the diuretic effects offurosemide in cirrhotic patients with ascites.
Therefore, thecoadministration of albumin and furosemide for the treatmentof
cirrhosis, and likely other hypoalbuminemic conditions, shouldnot be used
clinically.
Different strategies have been used to alleviate diuretic resistancein
hypoalbuminemic patients. Infusions of albumin itself havebeen used. Such
trials have demonstrated negligible if any benefit
(1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16).
Specificto this study, recent reports suggest that albumin/diuretic
coadministrationresults in enhanced diuresis in patients with cirrhosis or
nephroticsyndrome
(17,18,19,20).
This strategy was derived from a studyin analbuminemic rats
(18). Those animals exhibited
a 10-foldhigher volume of distribution of furosemide than did normalanimals,
because there was no albumin to bind furosemide andretain it in the plasma.
As a result of this large volume ofdistribution, insufficient concentrations
of the diuretic reachedsecretory sites in proximal nephrons, with
concomitantly littledrug secreted into the urine. Therefore, negligible
diureticresponse ensued. When these animals were treated with a mixtureof
albumin and furosemide, the volume of distribution decreased,the drug was
trapped in plasma and delivered to the urine, anddiuresis was restored
(18).
Clinical trials assessing this strategy are conflicting, andmost have not
been rigorously performed (13,
17,18,19,20).
Despitethe uncertainty of efficacy, many physicians administer
furosemide/albuminmixtures to enhance diuresis in hypoalbuminemic patients,
particularlythose with nephrotic syndrome or cirrhosis
(13). Examinationof this
issue among patients with nephrotic syndrome is confoundedby the proteinuria
of such patients, which can lead to urinarybinding of diuretic agents
(21). Hypoalbuminemic patients
withcirrhosis thus represent a better model to study this issue.We therefore
conducted a randomized crossover study to determinethe effects of
albumin/furosemide mixtures on the response tofurosemide in cirrhotic
subjects with ascites.
Patients
After institutional review board approval, 13 patients withbiopsyproven
cirrhosis of varying causes gave written informedconsent for participation in
this study. Patient characteristicsare listed in
Table 1. All participants were
in stable clinicalcondition, without evidence of active infection,
gastrointestinalhemorrhage, or other acute illnesses (e.g.,
congestive heartfailure or untreated endocrinopathies) that would affect the
responseto a diuretic agent. All subjects were awaiting liver transplantation
andhad Child-Pugh class B or C cirrhosis. Patients with alcoholabstinence of
<12 mo, serum creatinine concentrations of>2 mg/dl, 24-h urine protein
excretion of >100 mg, orportasystemic shunts were ineligible.
Table 1. Patient demographics and clinical characteristicsa
Protocol
Two weeks before admission, patients who were not receivingspironolactone
began to be treated with a dose of 50 mg twicedaily. This strategy was
selected in preference to discontinuingspironolactone treatment for all
patients because of uncertaintyregarding the length of spironolactone
treatment cessation neededto allow all effects to dissipate. Participants
were admittedto the General Clinical Research Center at Indiana University
MedicalCenter, where they remained until completion of the study. Atthe time
of admission, they were placed on a metabolic dietcontaining 30 mEq of sodium
and 60 to 80 mEq of potassium, with3 L/d of dietary fluids. Administration of
all other diureticagents was discontinued at the time of admission. This
sodiumrestriction allowed safe discontinuation of these diuretic agents
withoutweight gain throughout the study. Full chemistry panel and complete
bloodcount analyses, urinalysis, and baseline weight assessmentswere
performed for each subject at the time of admission. Thereafter,individuals
were weighed and serum electrolyte and creatinineconcentrations were measured
each morning. In addition, 24-hurine samples were collected each day for
measurement of electrolytesand creatinine. Patients were equilibrated on the
metabolicdiet until they attained sodium balance, as defined by two
consecutive24-h urinary sodium excretion values that varied 20% and no
changein two consecutive daily weights of >0.5 kg. After sodiumbalance
was attained, participants underwent one of the fourphases of the study, in
random order, as follows: (1) 25 g ofalbumin alone administered
intravenously in 30 min, (2) 40 mgof furosemide alone administered
intravenously in 30 min, (3)albumin (25 g) and furosemide (40 mg)
premixed ex vivo for 10min and infused intravenously in 30 min,
which duplicated themethod used by Inoue et al.
(18), or (4) albumin
(25 g) andfurosemide (40 mg) infused intravenously, into opposite forearms
simultaneously,in 30 min.
Patients fasted, except for distilled water, from midnight until4 h after
administration of the study medication. A 10 ml/kgdistilled water load was
administered orally before the startof the 30-min infusion of furosemide
and/or albumin, to ensurethe ability to produce frequent urine samples. Urine
and serumsamples were collected before the dose and 0.5, 1, 1.5, 2, 2.5,3,
4, 6, 8, and 24 h after the dose. Urine losses were replacedfor 8 h with
equal volumes of one-half normal saline solutionadministered intravenously,
to prevent volume depletion andthe development of acute diuretic tolerance.
The concentrationof urinary sodium elicited by loop diuretics is reasonably
wellapproximated by 0.45% normal saline solution; therefore, thismethod
maintained volume status in each subject.
After finishing the first phase of the protocol, subjects continuedto
receive the metabolic diet until they reached sodium balance,as previously
defined. The second phase of the protocol wasthen performed in a manner
identical to the first. Similarly,the third and fourth phases of the protocol
were conducted aftereach volunteer attained sodium balance. At least 48 h
separatedeach phase. This design allowed individual subjects to achieve
comparablestates of sodium balance before each phase of the study, sothat
they could serve as their own control subjects.
Table 2demonstrates that the
participants were in comparable clinicalconditions before each phase of the
study.
Table 2. Documentation of sodium balance before each phase of the
studya
Analyses
Serum and urine samples were assayed for sodium, furosemide,and creatinine
using techniques described in detail elsewhere
(22,23,24,25).
Becausecreatinine clearance values did not change during the study,those
data are not reported. Responses were analyzed in severalways. First, total
sodium excretion was compared for differenttreatments. Second, the
sensitivity of the nephron to furosemidewas determined, as described
previously, by relating the urinaryfurosemide excretion rate to the sodium
excretion rate
(22,23,24,25).
Third,the pharmacokinetics of furosemide were examined, because ofthe
potential of albumin to alter these parameters. Standardmodel-independent
methods were used to determine the pharmacokineticparameters of interest
(Win-Nonlin version 1.1; Scientific Consulting,Apex, NC). The terminal
elimination rate constant (ß)was determined by linear regression. The
elimination half-lifewas determined as t1/2 = 0.693/ß. The area
under theserum concentration versus time curve
(AUC0) was determinedby a combination of linear
and logarithmic trapezoidal methods,with extrapolation to infinity from the
last measured serumconcentration, using the terminal elimination rate
constant.The clearance of furosemide was calculated as
dose/AUC0.
Statistical Analyses
Statistical analyses were performed using SAS software (SAS,Inc. Cary,
NC). Univariate repeated-measures ANOVA models fora crossover design were
used to analyze the urine excretionmeasures. Treatment effects were tested in
the primary analysismodel with control for the period of study
(i.e., the time thesubject had been in the study). The inclusion of
the periodmain effect accounted for the effects of metabolic diet durationon
the treatment response. Person was treated in the model asa random effect, to
account for the four repeated measurementsobtained for each person (one with
each treatment). Separatemodels were used for 6- and 24-h urine measurements.
Becausediuretic responses returned to baseline levels within 6 h (seebelow)
and because 24-h results did not differ from 6-h findings,the 6-h data are
reported. When an overall treatment effectwas significant, pairwise
comparisons between the treatmentswere tested with P adjustment
using Sidak's multiple-comparisonprocedure. The effects of the baseline serum
albumin concentrationon the response to different treatments were tested by
addingserum albumin level-treatment interaction to the primary analysis
model.Albumin was tested as a continuous variable as well as a categorical
variable,i.e., <3 g/dl (n = 7) versus >3
g/dl (n = 6). Carryovereffect was tested by adding the treatment
from the previousperiod to the primary analysis model. P values of
0.05 wereconsidered statistically significant.
Response to Furosemide
The effects of albumin on the response to furosemide were assessedin three
ways. First, Table 3 presents
the total amounts ofurine, sodium, and furosemide excreted in 6 h. Albumin
alonehad no effect; similarly, it had no effect on the diuretic and
natriureticeffects of furosemide (Table
3 and Figure 1). It
can be notedfrom Figure 1 that
the response returned to baseline valuesby 6 h. Second, previous studies
demonstrated that the timecourse of delivery of a loop diuretic to its
urinary site ofaction is an independent determinant of the overall response
(25).
Figure 2depicts the time
course of furosemide delivery into the urine,wherein albumin had no effect.
Finally, we and others have demonstratedthat the most precise way to assess
the pharmacodynamics ofa loop diuretic is to relate the urinary excretion
rate of thediuretic, which reflects the amount reaching the site of action,
tothe response as the urinary sodium excretion rate
(22,23,24,25).
Figure 3demonstrates that this
relationship was not affected by eithermethod of concomitant albumin
infusion. Overall, albumin infusionhad no effect either on the delivery of
furosemide to its siteof action (Table
3 and Figure 1) or
on the sensitivity of thenephron to furosemide
(Table 3 and
Figure 3).
Figure 3. Relationship between the urinary furosemide excretion rate and the sodium
excretion rate, with and without albumin.
Despite a wide range of serum albumin concentrations (2.1 to4.3 g/dl), we
also failed to detect any interaction betweenserum albumin concentrations and
the response to furosemide,whether the albumin concentration was analyzed as
a continuousvariable or as a categorical variable (P > 0.05).
Furosemide Pharmacokinetics Figure 4 demonstrates serum
furosemide concentrations versustime, and
Table 4 lists the estimated
pharmacokinetic parameters.Albumin infusion would be predicted to potentially
have twoeffects on the pharmacokinetics of furosemide. First, its bindingof
furosemide might result in increased AUC and decreased clearanceand volume of
distribution values. This did not occur in ourstudy. Second, albumin might
enhance urinary furosemide excretion,as occurred in the animal study of Inoue
et al. (18).
Table 3demonstrates a lack of
effect of albumin on the total amountof furosemide excreted into urine;
Figure 2 demonstrates that
albumininfusion had no effect on the time course of furosemide excretion.
The volume status of hypoalbuminemic patients, including thosewith
cirrhosis and ascites, can sometimes be difficult to manage,because even
large doses of potent diuretics have diminishedefficacy and result in
complications (e.g., electrolyte andacid base disturbances or renal
failure) (26). Several
potentialmechanisms for such diuretic resistance have been suggestedand
include hypoalbuminemia, diminished GFR, altered pharmacokineticsand
pharmacodynamics of loop diuretics, and simultaneous administrationof
nonsteroidal anti-inflammatory drugs
(18,
27,28,29,30,31).
Wespecifically examined the potential role of hypoalbuminemiain affecting
the pharmacokinetics and/or pharmacodynamics offurosemide. We observed no
beneficial effect of albumin, arguingthat this therapeutic strategy should
not be used.
There has long been interest in the use of intravenously administered
albuminto enhance diuresis in hypoalbuminemic patients. After salt-poorhuman
albumin became available in 1944, several anecdotal reportssuggested that
albumin infusions could enhance diuresis in cirrhoticpatients
(4,5,6,7,8).
In contrast, a randomized study publishedin 1962 demonstrated that repeated
albumin infusions failedto decrease the diuretic needs of cirrhotic subjects
with refractoryascites (9).
Similar studies of patients with nephrotic syndromehave demonstrated no
utility of albumin alone in the treatmentof this disorder
(13,14,15,16).
Moreover, data from this studyindicate no diuretic effect of albumin alone
(Table 3 and
Figure 1).More recently,
however, Gentilini et al.
(17) demonstratedthat albumin
infusion produced a 26% increase in sodium excretioncaused by furosemide in
hospitalized cirrhotic patients withascites. That study did not characterize
the pharmacokineticsor pharmacodynamics of furosemide and therefore did not
offerany mechanistic clues regarding why albumin would enhance theefficacy
of furosemide. It did reinforce the uncertainty regardingthe utility of
albumin in enhancing diuretic responses.
Studies of patients with nephrotic syndrome have been similarly
conflicting.The seminal study by Inoue et al.
(18) in analbuminemic rats
alsoreported the effects of an ex vivo mixture of furosemide and
albuminin four patients with nephrotic syndrome. All patients exhibitedan
increase in urine volume, compared with furosemide alone.No information was
provided with respect to the design of thisclinical component of their study
or the results in terms ofsodium excretion. Akicek et al.
(19) studied the effects of
albuminalone, furosemide alone, and the combination in eight hypoalbuminemic
patientswith nephrotic syndrome. Each patient received each treatment,in
random order, but there was no re-equilibration between phasesof the study.
Albumin alone had negligible natriuretic effects(13 ± 8 mEq/4 h) and
had no effect on the response tofurosemide. Fliser et al.
(20) also studied nine
patients withnephrotic syndrome. Their study included dietary equilibration,
andthey measured the amount of furosemide that reached the urinarysite of
action. There was no effect on urinary furosemide levels.Albumin increased
the response to furosemide by 20%. The mechanismseemed to involve an increase
in renal blood flow. Those authorsconcluded that the effects were
statistically significant butlikely not clinically relevant.
On the basis of the aforementioned data for analbuminemic ratsand the data
presented above for patients with hypoalbuminemia,it was unclear whether the
hypothesis constructed from the animaldata could be extrapolated to
hypoalbuminemic patients, leadingto the motivation for our study. We think
that patients withcirrhosis represent the best clinical model for examination
ofthe principles underlying the potential utility of albumin/furosemide
mixtures.In nephrotic syndrome, results are likely confounded by therapid
excretion of administered albumin into the urine and theability of albumin to
bind loop diuretics in the urine
(21).Our data convincingly
demonstrated that coadministration ofalbumin did not enhance the diuretic
response to furosemide.Correspondingly, the pharmacokinetics and
pharmacodynamics offurosemide were not altered by concomitant albumin
administration(Tables 3 and
4 and Figures
2 and
4). This lack of effect has
severalpossible explanations. First, the dose of albumin infused maynot have
been sufficient. We doubt that this is a reasonableexplanation, because the
dose of albumin used in our study wastwice the amount used by Gentilini
et al. (17) and was
the sameas that used by Inoue et al.
(18). Moreover, the use of
largerdoses of albumin would not be practical and would be expensive.Second,
it may be necessary to administer repeated doses ofalbumin to produce
benefits. This issue was not addressed byour study, but previous studies with
repeated doses of albuminyielded mixed results
(4,5,6,7,8,9).
Third, it is possible thatthe baseline serum albumin concentration in our
study populationwas not low enough to yield a benefit from albumin infusion.
However,we consider this possibility to be unlikely, because similaralbumin
concentrations were observed in the patients describedby Gentilini et
al. (17) and in our
patients (3.0 ± 0.7and 3.0 ± 0.6 g/dl, respectively). The range
of albuminconcentrations for our patients was 2.1 to 4.3 g/dl. Therefore,we
included patients with substantial hypoalbuminemia. In addition,we tested for
a relationship between diuretic response and serumalbumin concentrations and
found none. Fourth, the sample sizemay not have been sufficient for detection
of a significanteffect. We observed a mean difference in the 6-h urinary
sodiumexcretion produced by furosemide with and without albumin of9.7 mEq,
with a SD of 81.7 mEq. On the basis of these data,we would need to study 563
patients to demonstrate a differencewith 80% power at the 5% significance
level. Even if we proveda significant effect with such a sample size, it is
apparentthat the magnitude of that effect would not be clinically
relevant.
Although our crossover design decreased interindividual variability,the
design presents a potential risk of carryover effects. Weminimized such
effects by including a washout period and byattaining sodium balance before
each phase of the study. Moreover,the statistical absence of any effect of
previous treatmentargues against carryover effects.
In conclusion, albumin administered in an ex vivo mixture with
furosemideor administered simultaneously with furosemide did not enhance
diureticeffects in patients with cirrhosis and ascites. In addition,the
administration of albumin did not alter the pharmacokineticsor
pharmacodynamics of furosemide. These data argue againstthe clinical use of
this therapeutic strategy. It is likelythat these results can be extrapolated
to other hypoalbuminemicdisorders, such as nephrotic syndrome.
Acknowledgments
This study was supported by National Institutes of Health GrantsAG07631,
DK37994, DK56012-01, and RR00750 (to the General ClinicalResearch
Center).
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Received for publication August 8, 2000.
Accepted for publication October 11, 2000.
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Top
Abstract
Introduction
20% and no
change in two consecutive daily weights of >0.5 kg. After sodium balance
was attained, participants underwent one of the four phases of the study, in
random order, as follows: (1) 25 g of albumin alone administered
intravenously in 30 min, (2) 40 mg of furosemide alone administered
intravenously in 30 min, (3) albumin (25 g) and furosemide (40 mg)
premixed ex vivo for 10 min and infused intravenously in 30 min,
which duplicated the method used by Inoue et al.
(18), or (4) albumin
(25 g) and furosemide (40 mg) infused intravenously, into opposite forearms
simultaneously, in 30 min. 
) was determined by a combination of linear
and logarithmic trapezoidal methods, with extrapolation to infinity from the
last measured serum concentration, using the terminal elimination rate
constant. The clearance of furosemide was calculated as
dose/AUC0
