DARU Journal of Pharmaceutical Sciences (2020) 28:263–269

https://doi.org/10.1007/s40199-020-00339-8

RESEARCH ARTICLE

Efficacy of furosemide-albumin compared with furosemide

in critically ill hypoalbuminemia patients admitted to intensive care
unit: a prospective randomized clinical trial
Ata Mahmoodpoor 1 & Sahra Zahedi 2 & Arezou Pourakbar 3 & Hamed Hamishehkar 4 & Kamran Shadvar 1 &
Parina Asgharian 5 & Farnaz Shahabi 1 & Hadi Hamishehkar 4

Received: 30 August 2019 / Accepted: 24 March 2020 / Published online: 14 April 2020
# Springer Nature Switzerland AG 2020

Abstract
Background Some physicians co-administer albumin with loop diuretics to overcome diuretic resistance in critically ill hypoal-
buminemia patients, though previous studies have reported conflicting results on this matter.
Objective The effects of adding albumin to furosemide to enhance its efficacy in critically ill hypoalbuminemia patients are
evaluated.
Methods This was a non-blinded randomized trial. 49 adult critically ill patients with hypoalbuminemia and generalized edema
who received randomly furosemide and furosemide/albumin complex were enrolled. The patients’ urine was collected at
intervals of 2, 4, 6 and 8 h after initiation of the furosemide treatment, and the urine output and urinary excretion of furosemide
and sodium were measured. The urinary excretion of furosemide was considered an indicator of drug efficacy.
Results The amount of sodium and furosemide excreted in urine showed no significant differences between the two groups;
however, the mean of the urinary excretion of furosemide in the first 2 h after drug infusion was significantly higher (p = 0.03) in
the furosemide/albumin group. No significant correlation between APACHE II scores and serum albumin levels and the urinary
excretion of furosemide was seen.
Conclusion The results indicated that there is not statistically significant differences between groups with furosemide alone and
combined with albumin in urinary furosemide excretion. It seems that adding albumin for furosemide pharmacotherapy regime is
not recommended as an intervention to increase furosemide efficacy in critically ill hypoalbuminemia patients.
Trial registration IRCT with the registration number IRCT201412132582N12 in 23 February 2015; https://en.irct.ir/trial/2356

Keywords Hypoalbuminemia . Furosemide . Edema . Critical ill

Introduction

Volume overload is a common problem in critically ill pa-

* Hadi Hamishehkar
tients, and it is an independent risk factor for mortality [1].
hamishehkar@gmail.com
Fluid overload is typically treated with volume restriction
1
Department of Anesthesiology, Tabriz University of Medical and diuretic usage. However, furosemide resistance can oc-
Sciences, Tabriz, Iran cur in critically ill patients despite alterations in the method
2
Iranian Evidence Based Medicine Center of Excellence, Tabriz of administration, dosing or patient conditions that hinder
University of Medical Sciences, Tabriz, Iran reaching the targeted fluid status [2]. Different mechanisms
3
Student Research Committee, Tabriz University of Medical Sciences, can lead to diuretic resistance in patients, such as reduced
Tabriz, Iran renal circulation and, consequently, a decrease in the
4
Drug Applied Research Center, Tabriz University of Medical a m o u n t o f d r u g t r a n s f e r r e d t o t h e t a rg e t s i t e [ -
Sciences, Tabriz, Iran 3];hypoalbuminemia, which leads to reduced furosemide
5
Faculty of Pharmacy, Tabriz University of Medical Sciences, secretion to tubular lumen [4–6];and the accumulation of
Tabriz, Iran organic acids, which may compete with furosemide in the
264
secretion into the tubular lumen by anionic carriers in the
proximal tubule [7]. Previous studies have shown that furo-
semide efficacy is dependent on plasma albumin concentra-
tion, and more than 95% of its molecules are bound to albu-
min. This albumin furosemide complex reaches the proxi-
mal tubular cells to interact with an anion transporter and be
translocated to the tubular lumen to show the action in the
ascending limb of the loop of Henle [5]. In hypoalbumin-
emia patients, the amount of albumin-furosemide complex
in the proximal tubule is reduced; thus, the administration of
albumin with furosemide can be considered as a solution to
overcome resistance to furosemide in critically ill hypoal-
buminemia patients [5]. Although the clinical efficacy of
the albumin-furosemide combination has not been proven,
this combination is used by physicians in intensive care
units. Clearly, albumin has some limitations, like increased
risk of infection, allergic reactions and high cost, which
make it inappropriate for use in situations with uncertainty
[8]. A recently published review reported that the use of the
albumin-furosemide combination remains a controversial
pharmacotherapy for edema management in patients with
nephrotic syndrome [9].
Some studies have shown the beneficial effects of the
combination of albumin and furosemide compared with
furosemide alone in the treatment of nephrotic syndrome
[10–14], cirrhosis and ascites [15], chronic kidney disease
[16], and acute lung injury [17]. These effects can be
attributed to the effect of albumin on improving furose-
mide delivery to the site as well as the pharmacokinetic
changes of furosemide and subsequently increased diuret-
ic effects.
On the other hand, some studies have rejected any signifi-
cant effects of the furosemide-albumin combination. They
have shown that this combination does not enhance diuresis
or natriuresis in hypoalbuminemia patients and that it has no
effect on the pharmacodynamics and pharmacokinetics of fu-
rosemide [2, 10, 18].
Considering the conflicting results, the large amount of
albumin used in clinical practice, and the cost-effectiveness
of albumin, the current study evaluated the efficacy of
furosemide-albumin compared with furosemide alone in crit-
ically ill hypoalbuminemia patients with generalized edema
admitted to an intensive care unit.
Methods
This study was approved by the Ethics Committee of Tabriz
University of Medical Sciences with the registration number
IR.TBZMED.REC93118 in 11 November 2014 and regis-
tered in IRCT with the registration number
IRCT201412132582N12 in 23 February 2015.
DARU J Pharm Sci (2020) 28:263–269
Patients
After obtaining ethical approval for this study, 49 adult pa-
tients in two closed-format adult ICUs of two tertiary
university-affiliated hospitals (Shohada Hospital, a 300-bed
trauma center; Imam Reza Hospital, a 700-bed general hospi-
tal) in northwestern Iran were enrolled in this prospective ran-
domized trial conducted from December 2014 to January
2017.
Informed consent was obtained from patients or their next
of kin before enrollment. Inclusion criteria were patients aged
18 years or older, plasma albumin level lower than 4 g/dl,
generalized edema in need of diuretic therapy, and admitted
to the ICU. Exclusion criteria were having received diuretics
within 24 h prior to the study, lack of furosemide indication,
contraindication to furosemide (e.g., a history of hypersensi-
tivity, hypovolemia, or dehydration) or albumin and kidney
dysfunction (Clcr less than 30 ml/min). From 49 patients, 38
had serum albumin levels lower than 3 g/dl and were assigned
into two groups in order to examine the efficacy of albumin
added to furosemide therapy. The 11 remaining patients had
generalized edema and plasma albumin levels higher than 3 g/
dl, but less than 4 g/dl, and received randomly furosemide and
furosemide/albumin complex in order to evaluate the correla-
tion between albumin level and urinary furosemide excretion
rate in all 49 patients. For evaluation of correlation between
plasma albumin level and urinary furosemide excretion (as
indicator of furosemide efficacy), we need vast range of plas-
ma albumin level.
Study design
This was a non-blinded randomized trial.. Thirty-eight pa-
tients were randomly allocated to one of two interventions
with computer-generated random numbers list which was pre-
pared by our statistics consultant not involved in the study.
The individual allocation which was closed in sequentially
numbered opaque envelopes, was opened at enrollment; pa-
tient data were recorded on the envelopes. Furosemide was
added into albumin 10 min before infusion. During the study,
patient blood pressure levels were monitored intensively. In
the case of SBP < 90 mmHg or a decrease greater than 30% of
the pre-intervention blood pressure, the infusion was
discontinued and treatment (e.g., intravenous fluid or vaso-
pressor) was administered as needed. In such cases, the patient
was excluded from the study. Furosemide was used for 38
hypoalbuminemia patients as follows: 100 ml half saline plus
20 mg furosemide (group 1: n = 20) or 100 ml of 20% human
albumin plus 20 mg furosemide (group 2: n = 18). The re-
maining 11 patients received furosemide randomly with and
without albumin (4 patient with and 6 patients without albu-
min). At intervals of 2,4,6, and 8 h after initiation of the furo-
semide infusion, the patients’ urine was collected in matte
DARU J Pharm Sci (2020) 28:263–269
microtubes (to prevent photodegradation of the furosemide in
the urine samples) and then stored in a freezer at −80 °C.
Urinary sodium levels were measured at times 2 and 4 after
starting the furosemide infusion. Data related to the underly-
ing diseases of the patients was recorded. The severity of
illness was calculated using the Acute Physiology and
Chronic Health (APACHE II) scoring system. The
Cockcroft-Gault Equation was used to calculate Clcr.
Urinary analysis of sodium and furosemide
An Auto-analyzer Faith 1000 (Laola) was used in order to
measure urine sodium. Besides that High Performance
Liquid Chromatography (HPLC) was used to measure the
concentration of total furosemide in urine. This HPLC system
made up of a pump, a UV detector, an integrator and an injec-
tor. The analytic column was a 5 μm-particle-sized Nova-pak
C18 column, 4.6 × 25 cm (Knauer, German) and the mobile
phase of 0.1 M formic acid and methanol (50:50) was deliv-
ered at a flow rate of 1 ml/min and the pH set on 3.4. UV
detection was performed in 273 nm and the injection volume
of sample was 20 μl, so for preparing the sample, 100 μl urine
samples were mixed with 900 μl water and then samples cen-
trifuged at 3500 RPM for 5 min.
Statistical analysis
Continuous and categorical data were compared between two
groups with Student’s t test and Chi-square test, respectively.
Repeated measures analysis of variance was used to detect
significant changes in urinary excreted of furosemide during
8 h after infusion between two groups during sequential mea-
sured times. Pearson correlation coefficient was used to eval-
uate correlation between parameters. A two-sided P value less
than 0.05 was considered significant. All statistical analyses
were performed with the SPSS software (Statistical Package
for the Social Sciences, version 16.0, SPSS Inc., Chicago, Ill,
USA).
Results
The demographic characteristics of all patients are shown in
Table 1. Approximately 65% of patients were male, and 70%
of patients were under mechanical ventilation. All patients
were critically ill with APACHE II scores of around 18.
Furosemide or furosemide/albumin complex was infused over
25 min.
The patient recruitment and randomization process is sum-
marized in Fig. 1 (CONSORT Diagram). The diagnoses of the
enrolled patients are presented in Table 2. Three main diagno-
ses for patients upon entry to the study were malignancy
265
Table 1 Demographic characteristics of patients
Characteristic Mean ± SD (n = 49)
Age (year) 71.1 ± 14.6
Weight (Kg) 70.9 ± 5.7
Gender (male/female) 32/17
Serum Alb (g/dl) 2.6 ± 0.5
Clcr (ml/min) 73.2 ± 31.9
APACHE II 18 ± 5.8
Infusion time (min) 24.2 ± 7.97
Urine output 6 h before (ml) 766.8 ± 384.4
Urine output 8 h after (ml) 2366.9 ± 922.6
Alb: Albumin; Clcr: Clearance Creatinine; APACHE II: Acute
Physiology and Chronic Health Evaluation; Na2: Sodium after 2 h; Na4:
Sodium after 4 h
(30.6%), cardiovascular disorders (28.6%), and cerebrovascu-
lar disorders (14.3%).
The comparison of demographic characteristics (Table 3)
showed no significant differences between the groups in terms
of age, weight, gender, albumin serum level, kidney function,
illness severity, furosemide infusion time, fluid balance during
6 h before intervention, and urine output 8 h after intervention.
A comparison of the urinary excretion of furosemide and
sodium in both groups is presented in Table 4. Urinary excret-
ed sodium 4 h after drug infusion (p = 0.94) as well as at
intervals of 2 and 4 h after infusion (p = 0.92 and p = 0.50,
respectively) did not differ significantly between the groups.
The mean urinary furosemide excretion rate in the first 2 h
after drug infusion in Group 2 was 1.87 ± 0.27 mg, while it
was 1.11 ± 0.20 mg in Group 1 (p = 0.03), but at intervals of 4,
6, and 8 h after infusion had no significant difference between
the two groups. The urinary furosemide excretion rate at 6 h
and 8 h after drug infusion did not differ between the groups
(p = 0.33, p = 0.38, respectively). Moreover, a repeated mea-
sures ANOVA showed no significant difference between the
two groups in the urinary excretion of furosemide at intervals
of 2 h up to 8 h (p = 0.19; Fig. 2).
To discovery any correlation between illness severity and
serum albumin level and the urinary excretion of furosemide,
data on the 49 study patients was analyzed (Table 5). No
correlations were observed between APACHE II score and
serum albumin level with the urinary excretion of furosemide
during 6 and 8 h (Table 5).
Discussion
The present study investigated the effect of furosemide com-
bined with albumin on the furosemide response of hypoalbu-
minemia patients admitted to intensive care units and exam-
ined the relationship between disease severity in these patients
266 DARU J Pharm Sci (2020) 28:263–269

40 consecuve paents with Alb> 3 g/dl and 115 hypoalbuminemic (Alb<3 g/dl) paents with
generalized edema evaluated for eligibility generalized edema evaluated for eligibility

Excluded (N=25) Excluded (N=71)

Receiving diurec past 24 h N=10 Receiving diurec pass 24h N=30
Dehydraon of hypotension N=2 Dehydraon or hypotension N=22
Severe illness N=12
Severe illness N=7
Others N=7
Others N=6

44 paents
randomized
15 paents received
furosemide/furosemide
with albumin

Incomplete sampling N=3

Severe hypotension need to Group 1 N=22 Group 2 N=22
stop infusion N=1 Furosemide Furosemide with albumin

Incomplete sampling N=3

Incomplete sampling N=2
Severe hypotension
need to stop infusion N=1

Analyzed N=20 Analyzed N=18

Analyzed N=11

Fig. 1 A CONSORT diagram

and hypoalbuminemia and patient response to the drug. The affecting diuresis and natriuresis 8 h after the infusion. The
results showed that there was no significant difference be- diuretic response of furosemide is determined and correlated
tween furosemide with albumin and furosemide alone in by the amount of drug reaching the renal tubule, not by the
quantity present in the plasma [19]. So the urinary excretion of
Table 2 Diagnosis at entry furosemide was considered an indicator of drug efficacy, and
it was not significantly different between groups. As with all
Diagnosis Frequency Percent previous studies, total part of furosemide (not free fraction)
was analyzed in urine.
Cardiovascular disorders:
Based on a search of the literature, this study was the first to
MI 2 4
compare the efficacy of a combination of albumin and furose-
Pulmonary Edema 6 12.3
mide with furosemide alone in edematous states of critically ill
Pulmonary embolism 6 12.3
patients. Also, the correlation of hypoalbuminemia and sever-
Malignancy:
ity of disease was evaluated.
Gastrointestinal Cancer 7 14.3
Fliser et al. observed an improvement in response to an
Urinary tract Cancer 5 10.2
infusion of furosemide with albumin in nine patients with
Respiratory tract Cancer 3 6.1
nephrotic syndrome. They stated that the effect of albumin
Cerebral disorders:
was due to hemodynamic changes in the kidney and unrelated
ICH 4 8.2
to the rate of furosemide secretion (independent of changes in
SAH 3 6.1 the pharmacokinetic parameters of furosemide) [14]. In their
Infection disease: study on analbuminemic rats, Inoue et al. observed positive
Pneumonia 4 8.1 effects of albumin on the development of furosemide diuretic
Sepsis 2 4.1 responses and suggested that the resistance mechanism in hy-
Trauma 4 8.2 poalbuminemia patients may be due to poor drug delivery to
GI Bleeding 2 4.1 renal tubular due to serum albumin deficiency [5]. In the study
Unknown 1 2 on 24 patients with CKD with a mean serum albumin level of
2.9 ± 0.3, Phakdeekitchareon and Boonyawat revealed a sig-
ICH intracerebral hemorrhage, GI Gastrointestinal, MI Myocardial
Infarction, SAH subarachnoid hemorrhage nificant difference in urine output and urinary sodium and
potassium excretion in 6 h with an infusion of combined
DARU J Pharm Sci (2020) 28:263–269 267

Table 3 Demographic
characteristics of patients in 2 Characteristic With Alb (n = 18) Without Alb (n = 20) P value
groups
Age (year) 70.7 ± 15 67.6 ± 13.8 0.51
Weight (Kg) 70 ± 5.1 70.5 ± 5.1 0.77
Gender 12 (66.7%) 13 (65%) 0.90
Serum Alb (g/dl) 2.4 ± 0.3 2.5 ± 0.3 0.60
Clcr 75.5 ± 32.2 77.3 ± 34.6 0.88
APACHE II 20 ± 4.7 17 ± 6.4 0.11
Mean Arterial Pressure 95.4 ± 1.3 96.3 ± 1.1 0.13
Infusion time (min) 22.6 ± 8.4 25.2 ± 7 0.30
Urine output 6 h before (ml) 705.6 ± 263.4 708.8 ± 429 0.98
Urine output 8 h after (ml) 2396.1 ± 992.2 2072.5 ± 844 0.29

Data for gender is presented as male, n (%); Data is presented as Mean ± SD; Student’s t test and Chi-square test
were used for analysis

albumin and furosemide compared with furosemide alone
[16]. In their randomized, cross-over study on 11 patients aged
3 to 18 years with nephrotic syndrome, Dharmanej et al. re-
vealed results that showed a better response to diuresis, natri-
uresis, and weight loss with the furosemide-albumin complex
compared with furosemide alone. It is noteworthy that this
increase in diuresis was transient, and the natriuretic effects
returned to their previous state after 48 h due to the
catabolization of the albumin. Also, free water clearance was
not significantly different between the two groups. In spite of
these results, it is suggested that a higher dose of furosemide
should be used to overcome diuretic resistance in patients with
nephrotic syndrome before albumin is added to the furose-
mide regime [20].
In contrast, the results of other studies indicate that albumin
does not affect furosemide responsiveness. In a study by
Doungngern et al. on 31 hypoalbuminemia patients hospital-
ized in the intensive care unit (with a mean serum albumin of
2.1 ± 0.5), urine output and volume loss in the two groups at 6,
24, and 48 h after infusion showed no significant difference
[2]. In a blinded randomized pilot study, Oczkowski et al.
showed that edematous patients received furosemide with
100 ml 25% albumin did not have significant differences in
the fluid balance and urine output comparing with patients
received furosemide and 100 ml normal saline as placebo.,
but it should be considered that this study was underpowered
to address all evaluated clinical outcomes [21].
Studies on patients with ascites have also had controver-
sial results. In a study of 126 patients with ascites associ-
ated with cirrhosis by Genitilini et al., the effects of an
infusion of albumin-furosemide (with a mean serum albu-
min of 3.07 ± 0.5) were compared with the effects of a
single diuretic (with a mean serum albumin of 3.17 ± 0.5)
on ascites treatment, duration of hospitalization, recurrence
of ascites, and hospitalization. The results showed a posi-
tive effect of albumin added to the furosemide infusion in
ascites; the duration of hospitalization was reduced, and the
recurrence of ascites was prevented. It was argued that this
effect of albumin is due to increased intravascular volume,
increased oncotic pressure, and improved transmission of
furosemide to the kidney [15]. In contrast, another study on
13 patients found no significant differences in urine output,

Table 4 Urinary excretion of

furosemide and sodium Characteristic With Alb (n = 18) Without Alb (n = 20) P value

A2mg (%) 1.87 ± 0.27 (9.36%) 1.11 ± 0.20 (5.56%) 0.03

A4mg (%) 0.81 ± 0.22 (4.05%) 0.91 ± 0.19 (4.57%) 0.73
A6mg (%) 0.65 ± 0.21 (3.23%) 0.58 ± 0.14 (2.89%) 0.79
A8mg (%) 0.38 ± 0.11 (1.88%) 0.42 ± 0.12 (2.10%) 0.80
Excreted furosemide 6 h (mg) 3.33 ± 0.59 2.60 ± 0.42 0.33
Excreted furosemide 8 h (mg) 3.56 ± 0.73 2.76 ± 0.54 0.38
Na2 (mEq/lit) 86.42 ± 8.25 87.08 ± 7.17 0.95
Na4 (mEq/lit) 77.90 ± 8.51 86.63 ± 9.54 0.50
Excreted Na 4 h (mEq) 152.98 ± 18.27 155.26 ± 25.26 0.94

Data is presented as Mean ± SEM; A2: amount of furosemide in urine after 2 h; A4: amount of furosemide in urine
after 4 h; A6: amount of furosemide in urine after 6 h; A8: amount of furosemide in urine after 8 h; Student’s t test
were used for analysis
268
Fig. 2 Percent of urinary excreted of furosemide during 8 h after infusion
(20 mg). Repeated measures analysis of variance was used to detect
significant changes in urinary excreted of furosemide during 8 h after
infusion between two groups.*P < 0.05 Student’s t test in comparison
with value in control group
sodium levels, or the pharmacokinetics of furosemide over
a period of 6 h by adding albumin in response to furose-
mide [18].
In a review article, Elwell et al. concluded that the addition
of albumin to improve the efficacy of diuresis should be re-
served for hypoalbuminemia patients with refractory edema or
ascites in whom diuretic doses have been maximized [22].
Another meta-analysis showed that the addition of albumin
to furosemide can improve diuresis transiently and claimed
that future large-scale, randomized trials are needed to define
the role of this approach [23].
In the current study, no correlation was found between
albumin serum level and urinary sodium or furosemide excre-
tion. Considering that the ratio of drug to albumin binding is
constant, then the change in the amount of drug or protein
cannot affect this ratio of binding, and because the albumin/
drug ratio is too high even at 2 g/dl of albumin and the max-
imum dose of furosemide in the blood, the binding capacity of
albumin to furosemide is always unsaturated. Thus, it can be
said that from the perspective of pharmacokinetics and bio
pharmaceutics, it seems logical that hypoalbuminemia would
not have an effect on resistance to furosemide, which is con-
sistent with the current results.
The fact that the amount of furosemide secreted in the
urine at the first measurement time (2 h after initiation of
Table 5 Correlation between APACHE II score and serum Albumin
level with urinary excursion of furosemide
Furosemide 6h (n = 49) Furosemide 8h (n = 49)
APACHE II Score r = 0.09, p = 0.51 r = −0.01, p = 0.46
Serum Albumin level r = −0.14, p = 0.32 r = −0.13, p = 0.35
APACHE II: Acute Physiology and Chronic Health Evaluation; Pearson
correlation was used for analysis
DARU J Pharm Sci (2020) 28:263–269
the furosemide infusion) was significantly higher in the
albumin/furosemide combined group may imply that the
combination of furosemide with albumin may enhance the
response rate of the furosemide. However, this enhance-
ment is short and transient, and no significant difference
in response to furosemide was detected at 6 h and 8 h
follow-up.
The results of this study did not show a significant differ-
ence between the severity of illness (APACHE II score) and
the amounts of furosemide and sodium in urine. This result
may imply that the illness severity of patients admitted to the
ICU does not affect the performance of the furosemide and the
amount of drug that reaches its site of action. However, it
seems that this issue needs further evaluation in the future.
Also the lack of any correlation between plasma albumin level
and urinary excretion of furosemide may conform that hypo-
albuminemia may not decrease the efficacy of furosemide
therapy in critically ill patients.
Study limitations
The mean serum albumin level was 2.6 ± 0.5 and in the
furosemide-albumin combination and furosemide groups
was 2.4 ± 0.3 and 2.5 ± 0.3, respectively. This means that the
study population did not have severe, but rather moderate
hypoalbuminemia. Therefore, the results of this study cannot
be generalized to patients with severe hypoalbuminemia.
None of patients had diuretic resistance. Also reasons for ede-
ma varies in the general population and could be influencing
the results. The study population was heterogeneous and the
study was not blind for researchers.
Conclusion
Albumin administered with furosemide did not enhance diure-
sis in critically ill hypoalbuminemia patients. Furthermore, the
administration of albumin did not change the pharmacokinet-
ics or pharmacodynamics of furosemide. This data argues
against the routine use of this therapeutic strategy to overcome
diuretic resistance.
Acknowledgments We are grateful to ICU staffs of Imam Reza and
Shohada hospitals for their cooperation in this investigation.
Funding information This work was supported by the Drug Applied
Research Center of Tabriz University of Medical Science.
Compliance with ethical standards
Conflict of interest The authors declared no potential conflicts of inter-
est with respect to the research, authorship, and/or publication of this
article.
DARU J Pharm Sci (2020) 28:263–269
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