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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
Raul Lombardi, M.D.,1,* Alejandro Ferreiro, M.D.,2
and Cristina Servetto, Pharm.D.3
1Department of Critical Care Medicine, IMPASA,
Montevideo, Uruguay2National Institute for Cardiac Surgery, Montevideo, Uruguay3Biochemistry Laboratory, IMPASA, 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 1.5mg/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 <2mg/dL (n¼ 44 patients (88.5%)) and Group II: SCr
>2mg/dL (n¼ 6 patients (11.5%)). A decrease of renal function was observed
*Correspondence: Raul Lombardi, M.D., Department of Critical Care Medicine, IMPASA,
L.A. de Herrera 2275, 11600, Montevideo, Uruguay; Fax: (598 2) 307-0281; E-mail:
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120024293_JDI25_05_R1_070303
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DOI: 10.1081/JDI-120024293 0886-022X (Print); 1525-6049 (Online)
Copyright & 2003 by Marcel Dekker, Inc. www.dekker.com
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in all patients: creatinemia raised from 1.04� 0.2 to 1.55� 0.4mg/dL (33%),
associated with a rise in FENa. Differences between group I and group II using
univariate analysis were: baseline serum creatinine (1.01� 0.23mg/dL vs.
1.26� 0.19mg/dL, p¼ 0.03), FENa (0.99� 0.8 vs. 2.2� 2.1, p¼ 0.04), furosemide
dose during surgery normalized to body surface area (93.2� 23mg/1.73m2 BSA
vs. 135� 38mg/1.73m2 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 renalfailure (ARF).[1–3]
Open-heart surgery adds supplementary risk because of the severe hemodynamicalterations that occur during cardiopulmonary by-pass (CPB).[4] Frequency of ARFin this setting is variable, ranging from 1.1–5% for severe forms requiring renalreplacement therapy,[4,5] up to 21% in less severe forms.[2] Moreover, according tosome investigators, a transient decline in renal function is a regular consequence ofextracorporeal 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 mildforms, to 10–20%.[2] In addition to mortality, ARF adds morbidity[2] and increasethe length of stay and hospital charges.[8–10]
Renal injury depends mainly on hemodynamic alterations that may occur alongsurgery and the postoperative period. Among these alterations the following factorsare included: non pulsatile flux during the CPB, low mean arterial pressure (MAP)usually below the renal autoregulation level,[11] bio-incompatibility mediated by theextracorporeal perfusion system,[12] hemolysis, hypothermia and low cardiac outputsecondary to myocardial depression,[13] potentially deleterious effects of vasoactiveand inotropic drugs and the use of nephrotoxic drugs, as well as the existence ofprevious nephropathy or chronic renal failure.
This study describes the changes that occur in renal function after cardiac surgerywith cardiopulmonary by-pass and establishes risk factors for the development ofARF in patients with preoperative normal renal function.
METHODS
Fifty adult patients submitted to cardiac surgery with total cardiopulmonaryby-pass, in Instituto Nacional de Cirugıa Cardıaca—IMPASA between 1st March to31st May 1998 with preoperative serum creatinine (SCr) level less or equal to1.50mg/dL were included.
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Anesthetic and Surgical Technique
Anesthesia was performed as usual (diazepam 0.3mg/kg and morphine 0.5mg/kgat induction continued by isoflurane 1–2% inhalator anesthetics on maintenance);pancuronium was employed for curarization. Mechanical ventilation during surgerywas performed with a volumetric respirator (Engstrom�). EKG was continuouslymonitored in DII derivation. Systolic, diastolic, and mean arterial pressures wereregistered through radial artery cannulation. The central venous pressure (CVP)was monitored through subclavian or internal jugular vein catheterization. A bladdercatheter was placed for diuresis control and to collect urine along the study period.
Sodium heparin was used for anticoagulation at an initial dose of 300UI/kg,supplementary doses were administered to allow an activated coagulation timehigher than 480 sec. At surgery end, protamine sulfate was administered in a dosesufficient to reach an activated coagulation time between 90 and 120 s.
Cardiopulmonaryby-passwasperformed inall cases,withanon-pulsatile regimen.The system was primed with crystalloid solution, plus sodium bicarbonate andmannitol 20%. The systemic flux during CPB was maintained close to 2.2 L/min/m2
body surface area and MAP nearby 60� 10mmHg. Membrane oxygenators wereused in all cases. All patients were operated in mild systemic hypothermia(31–34�C). Mannitol and furosemide were used at 3mL/kg and 1mg/kg respectively,at the beginning of the CPB. Supplementary doses of furosemide were administeredif 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, valvesurgery, combined surgery, aortic artery surgery, other), cardiopulmonaryby-pass time (CPBT), aortic cross-clamping time (ACT), MAP onperfusion 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 counterpulsationballoon use. A low cardiac output was considered when more than8 mg/kg/min dopamine or dobutamine, and/or adrenaline, noradrenalineor isoproterenol at any dose were needed to stabilize hemodynamicstatus.[8] Intra-aortic counterpulsation balloon was placed when drugsfailed.
(3) Postoperative variables. MAP, CVP, average MAP and CVP six hoursprevious 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 andurine samples were taken at anesthetic induction (T0) and during the
Renal Function After Cardiac Surgery 777
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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, osmolarand free water clearances, fractional excretion of sodium, potassium andchloride, 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 forcontinuous variables. Chi-square test or exact Fisher test for qualitative variables.Multiple regression analysis and bivariate logistic regression model were used toidentify independent risk factors for renal dysfunction. Longitudinal data were ana-lyzed with repeated measures ANOVA or Kruskall-Wallys test. A probability lessthan 5% for the null hypothesis was considered of statistic significance. All tests weretwo-tailed. Statistical package SPSS 9.0 (SPSS Inc., Chicago, Illinois) was used fordata processing and statistical analysis.
RESULTS
All 50 patients stayed along the study period. Thirty-two (64%) were male andeighteen (36%) female. Mean age was 61.4� 9.9 y (30–80 y). Forty-six patients hadcomorbidities: hypertension (36), diabetes (12), and nephropathy (2). Underlyingcardiac 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 andsurgery was 1 day (range: 1–15 days). Tables 1 and 2 summarize intraoperative T1 T2
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
aCardiopulmonary by-pass time.
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variables. Aorto-coronary by-pass was the predominant type of surgery. MeanCPBT was 77.7� 34min (median: 71.5min; range: 22–215min), ACT was42.9� 19.8min (median: 37.5min; range: 8–101min). Mean mannitol dose61.5� 21.3 g and mean furosemide dose was 101.5� 28mg. MAP values duringintraoperative and postoperative period are shown in Table 2.
Figure 1 provides information on SCr and creatinine clearance. There was anearly decline of renal function after open-heart cardiac surgery, but in none of thepatients renal failure was mild or severe. Serun creatinine increased from baselinenormal values in all patients in the first 6 h PO (1.03� 0.28–1.53� 0.4mg/dL), with aprogressive decline to 1.46� 0.48mg/dL at 24 h PO. Creatinine clearance showed amarked decline from preoperative values in all patients, with a mean percentagereduction of 28.2� 16.5% ( p<0.001) at 24 h PO. There was a frank polyuria inthe first hour PO (1240mL/h), with a progressive decline of urine output tonormal values after 12 h PO (71mL/h) (Fig. 2). Diuresis was not correlated withSCr, CCr, or furosemide dose.
For the analysis of risk factor for ARF, patients were arbitrarily divided intotwo groups according to SCr at the end of the observation period (T4): group I:SCr <2mg/dL, (46 patients (88.5%)); group II: SCr �2mg/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 patientshad a rise in SCr with a concomitant decline in CCr in the first 6 h PO, with partialrecovery at 24 h PO. Serum creatinine in Group II continued to rise at 24 h PO.FeNa was within normal values at 24 h PO in Group I while continued elevated inGroup II patients (1.3� 0.3% vs. 2.4� 0.4%; p<0.05) (Fig. 3). In 20 cases (40%),
F1
F2
F3
00,20,40,60,8
11,21,41,61,8
BASAL TO T1 T2 T3 T4
SC
r (m
g/dl
)
0102030405060708090
CC
r (m
l(min
)
SCr (mg/ml) CCr (ml/min)
Figure 1. Serum creatinine (SCr) (mg/dl), and creatinine clearance (CCr) (mL/min) through
the observation period.
Table 2. Values of MAPa during surgery.
Intraoperatory
MAP
Minimum MAP
during surgery
Early 12 h
postoperatory time
Late 12 h
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
aMean arterial pressure.
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SCr remained above 1.5mg/dL at the end of the observation period (Fig. 4). Allbut 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 multivariateanalysis, respectively. There were no differences between preoperative or intra-operative hemodynamic variables between groups. Also, there were no differencesbetween group in urea, osmolar and free water clearance, potassium, chloride, andtranstubular potassium gradient.
F4
T3 T4
Group IIGroup I
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1
0
SCr PreOp (mg/dl)
SCr 1 hr PO (mg/dl)
SCr 6 hr PO (mg/dl)
SCr 12 hr PO (mg/dl)
SCr 24 hr PO (mg/dl)
FeNa T4 (%)
1
33
19
20
Figure 3. Evolution of serum creatinine (SCr) along the observation period in patients with
SCr at T4 less or equal to 2mg/dl (Group I), or above 2mg/dl (Group II). It is also shown
FENa at the end of the study (T4).
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1240
364122 71
0
500
1000
1500
2000
CPB 1 hr 2-6 hr 7-12 hr 13-24hr
Period
Diu
resi
s (m
l/hr)
Figure 2. Diuresis along the study period (mL/hr).
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Scr T4 > 1.5 mg/d1Scr T4 < 1.5 mg/d1
SC
r (m
g/dl
)
3
2
1
0
PreOp SCr (mg/dl)
SCr PO 1 hr (mg/dl)
SCr PO 6 hr (mg/dl)
SCr PO 12 hr (mg/dl)
SCr PO 24 hr (mg/dl)
FENA T4 (%)
Figure 4. Evolution of serum creatinine (SCr) along the observation period in patients with
SCr at T4 less or equal to 1.5mg/dL, or above 1.5mg/dL. It is also shown FENa at the end of
the study (T4).
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
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In univariate analysis baseline SCr, FENa at T4, furosemide dose, and hemodi-lution index were significantly different between groups (Table 3). In multivariatelogistic regression analysis only baseline SCr (GI: 1.01� 0.23mg/dL, GII: 1.26�0.19mg/dL, p¼ 0.03) and intraoperative furosemide dose (GI: 93.3� 23mg/1.73m2 BSA; GII 135� 38.4mg/1.73m2 BSA, p<0.01) were independentlyassociated to renal dysfunction. Also, in multiple regression analysis, variables sig-nificantly associated with SCr at 24 h. were furosemide dose (b¼ 0.707) and baselinecreatinine (b¼ 0.474) (Table 4). Observed and calculated SCr at 24 h showed a highcorrelation (r¼ 0.836, p<0.05). (Fig. 5).
DISCUSSION
Acute renal failure is a frequent complication in open-heart surgery. Severe ARFrequiring renal replacement therapy is seen in 2–5% of cases,[4,5,8] but less seriousforms 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 thebeginning of postoperative period due to diuretic use, but kept on being elevateduntil the end of the observational period only in Group II. In our opinion, thisfinding must be considered as an evidence of tubular injury in this subset of patients.
It must be remarked that renal dysfunction was detected early, at the first hourof postoperative period and was the greatest decline at six hour after surgery. At theend of the 24-h period six patients (11.5%) had SCr higher than 2mg/dL, 20 patients
F5
SCr at 24 hs PO (mg/dl)
3,53,02,52,01,51,0,5
SC
r P
redi
cted
Val
ue (
mg/
dl)
3,0
2,5
2,0
1,5
1,0
,5
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 (r¼ 0.836).
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(40%) had SCr higher than 1.5mg/dL, but it must be noted that all but six patientscontinued with a depressed creatinine clearance despite of ‘‘normal’’ creatininevalues at 24 h postoperative. Usually SCr is determined in cardiac surgery patientsafter 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 renaldysfunction is a result, almost unavoidable of extracorporeal circulation.
Cardiopulmonary by-pass determine negative effects on renal circulation, as aconsequence of nonpulsatile flux, decrease of renal perfusion pressure under theautoregulation level and free hemoglobin toxicity secondary to hemolysis due toextracorporeal circulation.[14,15] On the other hand, systemic inflammatory responsemediated by cytokines and other mediators, stimulated by bioincompatiblemembranes, plus the effect of tissular injury due to surgery, hypothermia, aortic-clamping, and myocardial reperfusion[12–14,16,17] lead to hemodynamic changes andendothelial damage[18–21] which are in the base of renal injury.
We have not been able to demonstrate any association among variables relatedto 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] anassociation between cardiopulmonary by-pass time and renal failure was found, butit 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 commonlyreached lower levels than nowadays.[11]
We have neither found association with postoperative hemodynamicvariables, 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 andrenal dysfunction is relevant. One can hypothesize that progress in surgery andanesthetic techniques, particularly reduction of operatory time, improvement incardiopulmonary by-pass equipment, use of more biocompatible membranes andimprovement on hemodynamic support during and after surgery, have reduced therisk of renal injury. On the other hand, those factors related to the host, little or notmodifiable, could play a leading role in the pathogenesis of renal failure.Percutaneous transluminal coronary angioplasty had selected patients leaving tosurgery 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 relatedwith baseline serum creatinine: SCr of Group II was higher than SCr of Group I(1.26� 0.13mg/dL vs. 1.01� 0.23mg/dL, p¼ 0.03). It must be pointed out that thisvariable was predictive of renal dysfunction, in spite of being near normal values. Thispredictive ability persists even if the arbitrary SCr value used to define groups isreduced from 2mg/dL to 1.5mg/dL: 0.92� 0.27mg/dL vs 1.17� 0.21mg/dL;p<0.01 (data not shown in results). In a retrospective study of 43,642 patients whounderwent cardiac surgery with cardiopulmonary by-pass, Chertow et al.[5] found thata preoperative SCr higher than 1.5mg/dL was a risk factor for the development ofrenal failure. In the present group of patients, predictive SCr level was as lower as1.26mg/dL. A number of investigators have shown that previous renal diseasepredispose to postoperatory acute renal failure.[2,4,5,8] It is possible to hypothesizethat serum creatinine, even normal, undervalue the preoperatory renal function inthis setting (advanced age, malnutrition, hypertension, diabetes).
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Group II patients received a higher dose of furosemide than Group II patients(Group I¼ 96.5� 20.3 vs. Group II¼ 140� 49mg, p¼ 0.001). As mentioned above,furosemide was routinely used during the operative time at a previouslydefined bolus administered dose of 1mg/kg, but supplementary doseswere added if needed. So, individual doses ranged between 40 and 200mg.There was a lack of correlation between furosemide dose and IO or POdiuresis, so there was no dose-response correlation. Francis et al.[23] foundthat administration of furosemide in bolus had vasoconstrictive effect by activationof neuro-endocrine axis, in patients with cardiac failure. Yetman and co-workers[24]
described, in pediatric patients, that furosemide (1mg/k body weight, i/v) ledto fall in cardiac index, rise in systemic vascular resistance and increase in ranineand norepinephrine levels. It is conceivable that these effects of furosemide mayreinforce 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 associatedwith evidence of tubular dysfunction. A RCT performed to test the preventiveeffect of furosemide in patients submitted to radiocontrast studies, demonstrated adeleterious more than protective of furosemide in this setting.[27] To our knowledge,no previous studies reported any adverse effect of furosemide in cardiac surgerypatients.
Hemodilution index was higher in Group II patients (22.8� 3.2 vs. 17.3� 4.3,p¼ 0.004). These findings are in opposition with those referred by otherinvestigators. Slogoff et al.[11] found that the use of crystalloids depress bloodviscosity, improving intrarenal blood flow. Myers et al.[13] arrived to similarconclusions. On the other hand, Hardy and co-workers[28] showed that mortalityrate was higher if hemoglobin level attain 5 g/dL or less; lactacidemia was elevatedin these cases, therefore one may hypothesize that renal hypoxia could co-exist.Preoperative renal disfunction, renal hypoperfusion and hemodilution wouldbe deleterious to renal function in CPB cardiac surgery, associated witha vasoconstrictive effect of bolus intraoperative administered furosemide. In themultivariate logistic regression analysis only preoperative serum creatinine andintraoperative furosemide dose were significantly associated with depressed renalfunction at 24 h.
In summary: the present study demonstrates an early decline of renal functionafter open-heart cardiac surgery, but in none of the patients renal failure was mildor severe. In 20 cases (40%), renal function remained abnormal at the end of theobservation period, associated with evidence of tubular impairment in those patientswith Scr higher than 2mg/dL at 24 h from surgery. Baseline serum creatinine level, inspite of being within normal values, was highly predictive of postoperative renaldysfunction, which in our opinion, confirm that creatinemia underestimate renalreserve in this setting. All but six patients (88%) continued with a depressed creatinineclearance despite of ‘‘normal’’ creatinine values at 24 h postoperative. Intraoperativedose of furosemide was associated with renal dysfunction, probably due to anincrease on renal vascular resistance or direct tubular nephrotoxicity induced by thediuretic. So, in the lack of evidence of the benefit of furosemide as a protector drugin ARF, it should be avoided in cardiac surgery in the doses administered in thepresent study.
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