Renal Failure

ISSN: 0886-022X (Print) 1525-6049 (Online) Journal homepage: http://www.tandfonline.com/loi/irnf20

Renal Function After Cardiac Surgery: Adverse

Effect of Furosemide

Raúl Lombardi, Alejandro Ferreiro & Cristina Servetto

To cite this article: Raúl Lombardi, Alejandro Ferreiro & Cristina Servetto (2003) Renal Function
After Cardiac Surgery: Adverse Effect of Furosemide, Renal Failure, 25:5, 775-786, DOI: 10.1081/
JDI-120024293

To link to this article: https://doi.org/10.1081/JDI-120024293

Published online: 07 Jul 2009.

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RENAL FAILURE
Vol. 25, No. 5, pp. 775–786, 2003

CLINICAL STUDY

Renal Function After Cardiac Surgery: Adverse

Effect of Furosemide

Raúl Lombardi, M.D.,1,* Alejandro Ferreiro, M.D.,3

and Cristina Servetto, Pharm.D.2
1
Department of Critical Care Medicine, and 2Biochemistry
Laboratory, IMPASA, Montevideo, Uruguay
3
National Institute for Cardiac Surgery, Montevideo, Uruguay

ABSTRACT

Renal failure is a frequent event after cardiopulmonary by-pass. Hemodynamic

alterations that occur during surgery, as well as factors depending on the host,
are the main risk factors for renal dysfunction. To evaluate the frequency and
risk factors for renal dysfunction in this setting, a cohort of fifty patients with
preoperative serum creatinine under 1.5 mg/dL, submitted to cardiac surgery with
cardiopulmonary by-pass was analyzed. Variables related to preoperative patient
condition, intraoperative and postoperative periods were recorded. Renal
function was assessed by clearances of creatinine, urea and free water, also by
fractional excretion of sodium (FENa), at baseline, at anesthetic induction and
during postoperative period. Patients were arbitrarily divided in two groups,
according to the serum creatinine (SCr) value at the end of the postoperative
period: Group I: SCr <2 mg/dL (n ¼ 44 patients (88.5%)) and Group II: SCr
>2 mg/dL (n ¼ 6 patients (11.5%)). A decrease of renal function was observed

*Correspondence: Raúl Lombardi, M.D., Department of Critical Care Medicine, IMPASA,

L.A. de Herrera 2275, 11600, Montevideo, Uruguay; Fax: (598 2) 307-0281; E-mail:
rlombard@mednet.org.uy.

775

DOI: 10.1081/JDI-120024293 0886-022X (Print); 1525-6049 (Online)

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776 Lombardi, Ferreiro, and Servetto

in all patients: creatinemia raised from 1.04
0.2 to 1.55
0.4 mg/dL (33%),
associated with a rise in FENa. Differences between group I and group II using
univariate analysis were: baseline serum creatinine (1.01
0.23 mg/dL vs.
1.26
0.19 mg/dL, p ¼ 0.03), FENa (0.99
0.8 vs. 2.2
2.1, p ¼ 0.04), furosemide
dose during surgery normalized to body surface area (93.2
23 mg/1.73 m2 BSA
vs. 135
38 mg/1.73 m2 BSA, p<0.001), and hemodilution index (17.3
4.3% vs.
22.8
3.2%, p<0.01). In the multiple regression model, baseline creatinemia and
furosemide dose were associated to renal dysfunction.

Key Words: Acute renal failure; Cardiopulmonary by-pass; Open-heart surgery;

Furosemide.

INTRODUCTION

Major surgery is a well-established risk factor for development of acute renal

failure (ARF).[1–3]
Open-heart surgery adds supplementary risk because of the severe hemodynamic
alterations that occur during cardiopulmonary by-pass (CPB).[4] Frequency of ARF
in this setting is variable, ranging from 1.1–5% for severe forms requiring renal
replacement therapy,[4,5] up to 21% in less severe forms.[2] Moreover, according to
some investigators, a transient decline in renal function is a regular consequence of
extracorporeal circulation.[6]
ARF after cardiac surgery is associated with a dramatic rise in mortality rate.
In cases of severe renal insufficiency, fatality reaches to 31–90%[7,8] and in mild
forms, to 10–20%.[2] In addition to mortality, ARF adds morbidity[2] and increase
the length of stay and hospital charges.[8–10]
Renal injury depends mainly on hemodynamic alterations that may occur along
surgery and the postoperative period. Among these alterations the following factors
are included: non pulsatile flux during the CPB, low mean arterial pressure (MAP)
usually below the renal autoregulation level,[11] bio-incompatibility mediated by the
extracorporeal perfusion system,[12] hemolysis, hypothermia and low cardiac output
secondary to myocardial depression,[13] potentially deleterious effects of vasoactive
and inotropic drugs and the use of nephrotoxic drugs, as well as the existence of
previous nephropathy or chronic renal failure.
This study describes the changes that occur in renal function after cardiac surgery
with cardiopulmonary by-pass and establishes risk factors for the development of
ARF in patients with preoperative normal renal function.

METHODS

Fifty adult patients submitted to cardiac surgery with total cardiopulmonary

by-pass, in Instituto Nacional de Cirugı́a Cardı́aca—IMPASA between 1st March to
31st May 1998 with preoperative serum creatinine (SCr) level less or equal to
1.50 mg/dL were included.
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Renal Function After Cardiac Surgery 777

Anesthetic and Surgical Technique

Anesthesia was performed as usual (diazepam 0.3 mg/kg and morphine 0.5 mg/kg
at induction continued by isoflurane 1–2% inhalator anesthetics on maintenance);
pancuronium was employed for curarization. Mechanical ventilation during surgery
was performed with a volumetric respirator (EngströmÕ ). EKG was continuously
monitored in DII derivation. Systolic, diastolic, and mean arterial pressures were
registered through radial artery cannulation. The central venous pressure (CVP)
was monitored through subclavian or internal jugular vein catheterization. A bladder
catheter was placed for diuresis control and to collect urine along the study period.
Sodium heparin was used for anticoagulation at an initial dose of 300 UI/kg,
supplementary doses were administered to allow an activated coagulation time
higher than 480 sec. At surgery end, protamine sulfate was administered in a dose
sufficient to reach an activated coagulation time between 90 and 120 s.
Cardiopulmonary by-pass was performed in all cases, with a non-pulsatile regimen.
The system was primed with crystalloid solution, plus sodium bicarbonate and
mannitol 20%. The systemic flux during CPB was maintained close to 2.2 L/min/m2
body surface area and MAP nearby 60
10 mmHg. Membrane oxygenators were
used in all cases. All patients were operated in mild systemic hypothermia
(31–34 C). Mannitol and furosemide were used at 3 mL/kg and 1 mg/kg respectively,
at the beginning of the CPB. Supplementary doses of furosemide were administered
if diuresis on surgery was inappropriate to volume status or hemodilution.
Cefuroxime was used for antibiotic prophylaxis.
The following variables were prospectively recorded:

(1) Demographics and preoperative variables. Age, gender, height,

weight, body surface area, comorbidities (diabetes, hypertension, nephro-
pathy), underlying cardiac disease, drug exposure (radiocontrast,
nonsteroids anti-inflammatory drugs, b-blockers, calcium antagonists,
angiotensin-converting enzyme inhibitors, nephrotoxic antibiotics).
(2) Intraoperative variables. Type of surgery (aortocoronary by-pass, valve
surgery, combined surgery, aortic artery surgery, other), cardiopulmonary
by-pass time (CPBT), aortic cross-clamping time (ACT), MAP on
perfusion time and aortic cross-clamping time, diuresis, furosemide dose,
mannitol dose, hemodilution index (preoperative Hct—Hct on CPB),[7]
autotransfusion volume, inotropic drugs, intra-aortic counterpulsation
balloon use. A low cardiac output was considered when more than
8 mg/kg/min dopamine or dobutamine, and/or adrenaline, noradrenaline
or isoproterenol at any dose were needed to stabilize hemodynamic
status.[8] Intra-aortic counterpulsation balloon was placed when drugs
failed.
(3) Postoperative variables. MAP, CVP, average MAP and CVP six hours
previous to the maximum SCr level reached, diuresis, inotropic drugs use,
ICU length stay, complications other than ARF, in-hospital mortality.
(4) Assessment of renal function. Urine and serum levels of urea, creatinine,
sodium, potassium, chloride, and osmolality were measured. Blood and
urine samples were taken at anesthetic induction (T0) and during the
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778 Lombardi, Ferreiro, and Servetto

postoperative period at the first hour (T1), 6 h (T2), 12 h (T3), and 24 h (T4).
Urine output was measured at the same periods. Creatinine, urea, osmolar
and free water clearances, fractional excretion of sodium, potassium and
chloride, and trans tubular potassium gradient were then calculated.

The Institutional Review Board approved the protocol.

STATISTICAL ANALYSIS

Data are expressed as mean
SD, or median and range. For univariate analysis,
Student’s ‘‘t’’ test, ANOVA, Mann-Whitney or Wilcoxon rank tests were used for
continuous variables. Chi-square test or exact Fisher test for qualitative variables.
Multiple regression analysis and bivariate logistic regression model were used to
identify independent risk factors for renal dysfunction. Longitudinal data were ana-
lyzed with repeated measures ANOVA or Kruskall-Wallys test. A probability less
than 5% for the null hypothesis was considered of statistic significance. All tests were
two-tailed. Statistical package SPSS 9.0 (SPSS Inc., Chicago, Illinois) was used for
data processing and statistical analysis.

RESULTS

All 50 patients stayed along the study period. Thirty-two (64%) were male and
eighteen (36%) female. Mean age was 61.4
9.9 y (30–80 y). Forty-six patients had
comorbidities: hypertension (36), diabetes (12), and nephropathy (2). Underlying
cardiac disease was ischemic in the majority of cases (38) and valvular disease
(10). Thirty-two patients were treated with antiplatelet drugs prior to surgery,
twenty-three received b-blockers, fifteen ACEI, and fourteen, calcium antagonist.
In patients exposed to radiocontrast agents, the median time between exposition and
surgery was 1 day (range: 1–15 days). Tables 1 and 2 summarize intraoperative

Table 1. Intraoperative variables.

Type of surgery

Coronary by-pass 36
Valve replacement 10
By-pass and valve replacement 2
Other 2
CPB timea (min) 77.7±34
Aortic cross clamping time (min) 42.9±19.8
Furosemide dose (mg) 101.5±28
Mannitol dose (g) 61.5±21.3
Hemodilution index 18±4.6
Autotransfusion volume (mL) 591.7±570
a
Cardiopulmonary by-pass time.
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Renal Function After Cardiac Surgery 779

Table 2. Values of MAPa during surgery.

Intraoperatory Minimum MAP Early 12 h Late 12 h

MAP during surgery postoperatory time postoperatory time

MAP (mmHg) 53.4
9.8 41.1
12.5 77.3
57 74.7
53.5

Range 33–77 0–62 57–99 53–99
a
Mean arterial pressure.

1,8 90
1,6 80
1,4 70

CCr (ml(min)
SCr (mg/dl)

1,2 60
1 50
0,8 40
0,6 30
0,4 20
0,2 10
0 0
BAS AL TO T1 T2 T3 T4

SCr (mg/ml) CCr (ml/min)

Figure 1. Serum creatinine (SCr) (mg/dl), and creatinine clearance (CCr) (mL/min) through
the observation period.

variables. Aorto-coronary by-pass was the predominant type of surgery. Mean

CPBT was 77.7
34 min (median: 71.5 min; range: 22–215 min), ACT was
42.9
19.8 min (median: 37.5 min; range: 8–101 min). Mean mannitol dose
61.5
21.3 g and mean furosemide dose was 101.5
28 mg. MAP values during
intraoperative and postoperative period are shown in Table 2.
Figure 1 provides information on SCr and creatinine clearance. There was an
early decline of renal function after open-heart cardiac surgery, but in none of the
patients renal failure was mild or severe. Serun creatinine increased from baseline
normal values in all patients in the first 6 h PO (1.03
0.28–1.53
0.4 mg/dL), with a
progressive decline to 1.46
0.48 mg/dL at 24 h PO. Creatinine clearance showed a
marked decline from preoperative values in all patients, with a mean percentage
reduction of 28.2
16.5% ( p<0.001) at 24 h PO. There was a frank polyuria in
the first hour PO (1240 mL/h), with a progressive decline of urine output to
normal values after 12 h PO (71 mL/h) (Fig. 2). Diuresis was not correlated with
SCr, CCr, or furosemide dose.
For the analysis of risk factor for ARF, patients were arbitrarily divided into
two groups according to SCr at the end of the observation period (T4): group I:
SCr <2 mg/dL, (46 patients (88.5%)); group II: SCr 2 mg/dL (six cases (11.5%)).
None of the patients required renal replacement therapies.
Figure 3 shows SCr evolution in Group I and Group II patients. Group I patients
had a rise in SCr with a concomitant decline in CCr in the first 6 h PO, with partial
recovery at 24 h PO. Serum creatinine in Group II continued to rise at 24 h PO.
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780 Lombardi, Ferreiro, and Servetto

2000

Diuresis (ml/hr)
1500 1240

1000 76 8
364
500 122 71
0
CPB 1 hr 2-6 hr 7-12 hr 13-24hr
Period

Figure 2. Diuresis along the study period (mL/hr).

19

SCr PreOp (mg/dl)

2
SCr 1 hr PO (mg/dl)

SCr 6 hr PO (mg/dl)
20
1 SCr 12 hr PO (mg/dl)

SCr 24 hr PO (mg/dl)
33

0 FeNa T4 (%)
Group I Group II

Figure 3. Evolution of serum creatinine (SCr) along the observation period in patients with
SCr at T4 less or equal to 2 mg/dl (Group I), or above 2 mg/dl (Group II). It is also shown
FENa at the end of the study (T4).

FeNa was within normal values at 24 h PO in Group I while continued elevated in

Group II patients (1.3
0.3% vs. 2.4
0.4%; p<0.05) (Fig. 3). In 20 cases (40%),
SCr remained above 1.5 mg/dL at the end of the observation period (Fig. 4). All
but six patients (88%) continued with a depressed creatinine clearance despite of
‘‘normal’’ creatinine values at 24 h postoperative.
In Tables 3 and 4 are showed results of univariate and multivariate
analysis, respectively. There were no differences between preoperative or intra-
operative hemodynamic variables between groups. Also, there were no differences
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Renal Function After Cardiac Surgery 781

Table 3. Results of univariate analysis. Only baseline SCr, FENa at T4,

frusemide dose and hemodilution were statistically associated with groups.

Group I Group II p value

Baseline SCr (mg/dl) 1.01±0.23 1.26±0.19 0.030

FENa T4 0.99±0.8 2.2±2.1 0.040
Frusemide dose (mg) 96.5±20 140±49 0.001
Hemodilution index 17.3±4.3 22.8±3.2 0.004

Table 4. In multivariate analysis, only baseline Scr and

furosemide dose reached statistical significance.

Variable b t P

Baseline Cr 0.707 6.167 0.000

Furosemide dose 0.474 4.927 0.000

2
SCr (mg/dl)

PreOp SCr (mg/dl)

1
SCr PO 1 hr (mg/dl)

SCr PO 6 hr (mg/dl)

SCr PO 12 hr (mg/dl)

SCr PO 24 hr (mg/dl)

0 FENA T4 (%)

Scr T4 < 1.5 mg/d1 Scr T4 > 1.5 mg/d1

Figure 4. Evolution of serum creatinine (SCr) along the observation period in patients with
SCr at T4 less or equal to 1.5 mg/dL, or above 1.5 mg/dL. It is also shown FENa at the end of
the study (T4).
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782 Lombardi, Ferreiro, and Servetto

3, 0

SCr Predicted Value (mg/dl) 2, 5

2, 0

1, 5

1, 0

,5
,5 1, 0 1, 5 2, 0 2, 5 3, 0 3, 5

SCr at 24 hs PO (mg/dl)

Figure 5. Multiple regression model shows association of furosemide dose and baseline
creatininemia with SCr at 24 h. There is a high correlation between observed and calculated
SCr at 24 h (r ¼ 0.836).

between group in urea, osmolar and free water clearance, potassium, chloride, and
transtubular potassium gradient.
In univariate analysis baseline SCr, FENa at T4, furosemide dose, and hemodi-
lution index were significantly different between groups (Table 3). In multivariate
logistic regression analysis only baseline SCr (GI: 1.01
0.23 mg/dL, GII: 1.26

0.19 mg/dL, p ¼ 0.03) and intraoperative furosemide dose (GI: 93.3
23 mg/
1.73 m2 BSA; GII 135
38.4 mg/1.73 m2 BSA, p<0.01) were independently
associated to renal dysfunction. Also, in multiple regression analysis, variables sig-
nificantly associated with SCr at 24 h. were furosemide dose (b ¼ 0.707) and baseline
creatinine (b ¼ 0.474) (Table 4). Observed and calculated SCr at 24 h showed a high
correlation (r ¼ 0.836, p<0.05). (Fig. 5).

DISCUSSION

Acute renal failure is a frequent complication in open-heart surgery. Severe ARF

requiring renal replacement therapy is seen in 2–5% of cases,[4,5,8] but less serious
forms are even more frequent.[5]
In the present study, all population showed a decrease in renal function, accord-
ing to SCr and CCr. On the other hand, FENa presented the expected changes at the
beginning of postoperative period due to diuretic use, but kept on being elevated
until the end of the observational period only in Group II. In our opinion, this
finding must be considered as an evidence of tubular injury in this subset of patients.
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Renal Function After Cardiac Surgery 783

It must be remarked that renal dysfunction was detected early, at the first hour
of postoperative period and was the greatest decline at six hour after surgery. At the
end of the 24-h period six patients (11.5%) had SCr higher than 2 mg/dL, 20 patients
(40%) had SCr higher than 1.5 mg/dL, but it must be noted that all but six patients
continued with a depressed creatinine clearance despite of ‘‘normal’’ creatinine
values at 24 h postoperative. Usually SCr is determined in cardiac surgery patients
after 24 h of surgery, so early and transient renal dysfunction can be overlooked.
Our data are in accordance with those of Wesslink et al.[6] who pointed out that renal
dysfunction is a result, almost unavoidable of extracorporeal circulation.
Cardiopulmonary by-pass determine negative effects on renal circulation, as a
consequence of nonpulsatile flux, decrease of renal perfusion pressure under the
autoregulation level and free hemoglobin toxicity secondary to hemolysis due to
extracorporeal circulation.[14,15] On the other hand, systemic inflammatory response
mediated by cytokines and other mediators, stimulated by bioincompatible
membranes, plus the effect of tissular injury due to surgery, hypothermia, aortic-
clamping, and myocardial reperfusion[12–14,16,17] lead to hemodynamic changes and
endothelial damage[18–21] which are in the base of renal injury.
We have not been able to demonstrate any association among variables related
to cardiopulmonary by-pass and renal dysfunction, as almost[6,13,22] but not all[8,11]
authors did. In a case-control study previously performed in our institution,[10] an
association between cardiopulmonary by-pass time and renal failure was found, but
it must be pointed out that CPB time in the past was longer than in the present study.
Similar considerations can be done regarding intraoperative MAP, which commonly
reached lower levels than nowadays.[11]
We have neither found association with postoperative hemodynamic
variables, nor the use of vasoactive drugs. Exposition to nephrotoxic drugs,
particularly radio-contrast media, showed no association with renal dysfunction.
In our opinion, the lack of association between hemodynamic variables and
renal dysfunction is relevant. One can hypothesize that progress in surgery and
anesthetic techniques, particularly reduction of operatory time, improvement in
cardiopulmonary by-pass equipment, use of more biocompatible membranes and
improvement on hemodynamic support during and after surgery, have reduced the
risk of renal injury. On the other hand, those factors related to the host, little or not
modifiable, could play a leading role in the pathogenesis of renal failure.
Percutaneous transluminal coronary angioplasty had selected patients leaving to
surgery the higher risk patients, according to the complexity and severity of illness.
In the present study, renal dysfunction at 24 h after surgery was clearly related
with baseline serum creatinine: SCr of Group II was higher than SCr of Group I
(1.26
0.13 mg/dL vs. 1.01
0.23 mg/dL, p ¼ 0.03). It must be pointed out that this
variable was predictive of renal dysfunction, in spite of being near normal values. This
predictive ability persists even if the arbitrary SCr value used to define groups is
reduced from 2 mg/dL to 1.5 mg/dL: 0.92
0.27 mg/dL vs 1.17
0.21 mg/dL;
p<0.01 (data not shown in results). In a retrospective study of 43,642 patients who
underwent cardiac surgery with cardiopulmonary by-pass, Chertow et al.[5] found that
a preoperative SCr higher than 1.5 mg/dL was a risk factor for the development of
renal failure. In the present group of patients, predictive SCr level was as lower as
1.26 mg/dL. A number of investigators have shown that previous renal disease
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784 Lombardi, Ferreiro, and Servetto

predispose to postoperatory acute renal failure.[2,4,5,8] It is possible to hypothesize that

serum creatinine, even normal, undervalue the preoperatory renal function in this
setting (advanced age, malnutrition, hypertension, diabetes).
Group II patients received a higher dose of furosemide than Group I patients
(Group I ¼ 96.5
20.3 vs. Group II ¼ 140
49 mg, p ¼ 0.001). As mentioned above,
furosemide was routinely used during the operative time at a previously
defined bolus administered dose of 1 mg/kg, but supplementary doses
were added if needed. So, individual doses ranged between 40 and 200 mg.
There was a lack of correlation between furosemide dose and IO or PO
diuresis, so there was no dose-response correlation. Francis et al.[23] found
that administration of furosemide in bolus had vasoconstrictive effect by activation
of neuro-endocrine axis, in patients with cardiac failure. Yetman and co-workers[24]
described, in pediatric patients, that furosemide (1 mg/k body weight, i/v) led
to fall in cardiac index, rise in systemic vascular resistance and increase in ranine
and norepinephrine levels. It is conceivable that these effects of furosemide may
reinforce adverse hemodynamic consequences of cardiopulmonary by-pass, magni-
fying misdistribution of renal blood flow and sectorial renal hypoperfusion.[25,26]
Furosemide is also able to determine direct tubular toxicity, which is associated
with evidence of tubular dysfunction. A RCT performed to test the preventive
effect of furosemide in patients submitted to radiocontrast studies, demonstrated a
deleterious more than protective effect of furosemide in this setting.[27] To our
knowledge, no previous studies reported any adverse effect of furosemide in cardiac
surgery patients.
Hemodilution index was higher in Group II patients (22.8
3.2 vs. 17.3
4.3,
p ¼ 0.004). These findings are in opposition with those referred by other
investigators. Slogoff et al.[11] found that the use of crystalloids depress blood
viscosity, improving intrarenal blood flow. Myers et al.[13] arrived to similar
conclusions. On the other hand, Hardy and co-workers[28] showed that mortality
rate was higher if hemoglobin level attain 5 g/dL or less; lactacidemia was elevated
in these cases, therefore one may hypothesize that renal hypoxia could co-exist.
Preoperative renal disfunction, renal hypoperfusion and hemodilution would
be deleterious to renal function in CPB cardiac surgery, associated with
a vasoconstrictive effect of bolus intraoperative administered furosemide. In the
multivariate logistic regression analysis only preoperative serum creatinine and
intraoperative furosemide dose were significantly associated with depressed renal
function at 24 h.
In summary: the present study demonstrates an early decline of renal function
after open-heart cardiac surgery, but in none of the patients renal failure was mild
or severe. In 20 cases (40%), renal function remained abnormal at the end of the
observation period, associated with evidence of tubular impairment in those patients
with Scr higher than 2 mg/dL at 24 h from surgery. Baseline serum creatinine level, in
spite of being within normal values, was highly predictive of postoperative renal
dysfunction, which in our opinion, confirm that creatinemia underestimate renal
reserve in this setting. All but six patients (88%) continued with a depressed creatinine
clearance despite of ‘‘normal’’ creatinine values at 24 h postoperative. Intraoperative
dose of furosemide was associated with renal dysfunction, probably due to an
increase on renal vascular resistance or direct tubular nephrotoxicity induced by the
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Renal Function After Cardiac Surgery 785

diuretic. So, in the lack of evidence of the benefit of furosemide as a protector drug
in ARF, it should be avoided in cardiac surgery in the doses administered in the
present study.

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