Clinical trial NCT04919564
Conditions: Chronic Kidney Disease Cardiac Disease
Keywords: Furosemide Kidney Dysfunction Glomerular Filtration Rate
Sponsor: National Cardiovascular Center Harapan Kita Hospital Indonesia
Start date: 2021-05-27; Completion date: 2022-02-28
Enrollment: 90 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Chronic kidney disease is an independent risk factor for cardiovascular disease associated with increased mortality rate during cardiac surgery in proportion to the kidney function. Chronic kidney disease is defined by decreased glomerular filtration rate (GFR) as classified by Kidney Disease: Improving Global Outcome (KDIGO). Deterioration of kidney function has a complex and multifactorial pathophysiologic derangement. In order to counter kidney injury associated with cardiac surgery, several pharmacologic and non-pharmacologic interventions have been studied to prevent perioperative deterioration of kidney function. Diuretics as pharmacologic measure are often used post-cardiac surgery to treat fluid overload and managing patient with acute kidney injury by preventing anuria. Loop diuretics (furosemide) may improve renal blood flow, decrease reabsorption in renal tubules, decrease oxygen demand and energy consumption (blocking potassium/sodium/2cloride co-transport in loop of Henle), and prevent hypoxic injury of renal medulla. Low dose continuous furosemide hypothetically has a protective effect on cardiac surgery patients with kidney dysfunction, measured improved glomerular filtration rate, decreased indication for therapeutic furosemide infusion, and decreased need of renal replacement therapy. On the other hand, administration of furosemide is rather harmful in severe kidney dysfunction. Therefore, the objective of this study is to determine the protective effect of low-dose continuous furosemide perioperative in cardiac surgery patients with mild to moderate kidney dysfunction.

Detailed description:
The study was a double-blind randomized controlled trial to determine the protective effect of low-dose continuous furosemide perioperative in cardiac surgery patients with mild to moderate kidney dysfunction. Ethical clearance for the study was approved by Institutional Review Board of National Cardiovascular Center Harapan Kita. Patients eligible for the study was recruited and written informed consent was obtained after clear explanation of the study. Allocation of furosemide and control group was done using simple computer randomization by staff who was not involved in the study. Furosemide infusion and normal saline was prepared by independent pharmacist blinded to the study. Furosemide solution was prepared to contain 40 mg of furosemide diluted with normal saline to a total volume of 40 cc (1 mg / 1 cc) and control solution was prepared to contain only 40 cc of normal saline. Both solution was packaged in 50-cc syringe and prepared in similar fashion. The solution was administered after induction of anesthesia with rate of 2 cc per hour for 12 hours.

Baseline participant were collected before surgery. All cardiac surgery procedure was done in concordance to hospital standard operating procedure. The primary outcomes of the study were glomerular filtration rate, need of diuretic infusion dose after intervention, need of renal replacement therapy and the secondary outcomes were ICU length of stay and in hospital mortality. The calculated sample size estimated was 41 participants per group, accounting for drop-out rate, expected sample size was 45 participants per group (90 participants in total).

Arms: arm 1: Continuous furosemide 2 mg/hour for a period of 12 hours begins since anesthetic induction arm 2: Continuous NaCl 0.9% 2 cc/hour for a period of 12 hours begins since anesthetic induction
Interventions: intervention 1: Furosemide in 0.9 % NaCl 100 Mg/100 mL (1 mg/mL) intervention 2: NaCl 0.9%
Intervention descriptions: intervention 1: Furosemide 2 mg/hour infusion for 12 hours since induction intervention 2: NaCl 0.9% 2 cc/hour for a period of 12 hours since anesthetic induction

Protocol documents:
Prot_SAP_000.pdf: 
Institutional Review Board (IRB)/ 
Komite Etik Penelitian 
RS. Jantung dan Pembuluh Darah Harapan Kita 
POB/     / 
Berlaku mulai:  
 
 15 Mei 2015 
  
Hal 1 dari 6 
 
LAMPIRAN 3 
FL/03-010/01.0 
 
 
http://www.pjnhk.go.id/ 
Study Protocol  
 
Study Protocol Summary 
Title 
Main Researcher 
dr. Prieta Adriane, SpAn., M.Kes.,KAKV 
RS Jantung dan Pembuluh Darah Harapan Kita, Jakarta 
Sponsor 
none 
Aims  
1. 1. to Analyze trends in estimated glomerular filtration rate parameters from administration of 
low-dose furosemide continuous infusion in patients with mild-moderate renal dysfunction 
undergoing cardiac surgery. 
2. 2. To analyze the need for a therapeutic dose of intravenous diuretic after low-dose continuous 
furosemide in patients with mild to moderate renal dysfunction undergoing cardiac surgery. 
3. 3. To analyze the need to use renal replacement therapy as a marker of worsening renal 
function leading to acute renal failure after continuous administration of low-dose furosemide in 
patients with renal dysfunction undergoing cardiac surgery. 
Ethical Issue(s) of the Protocol 
1. Administration of fluids or drugs to patients that can affect patient outcomes 
2. Taking blood samples from patients for laboratory examination 
3. Evaluating the effects of drug administration 
4. Patient condition follow up in study period 
5. Inconvenience of patient or family for additional information needed in research involvement 
 
 
 
 
Low Dose Continuous Furosemide Effect on Cardiac Surgery Patients With Kidney 
Dysfunction 


Institutional Review Board (IRB)/ 
Komite Etik Penelitian 
RS. Jantung dan Pembuluh Darah Harapan Kita 
POB/     / 
Berlaku mulai:  
 
 15 Mei 2015 
  
Hal 2 dari 6 
 
LAMPIRAN 3 
FL/03-010/01.0 
 
 
http://www.pjnhk.go.id/ 
Study Protocol  
 
Study Design  
Clinical Study : double blinded randomized controlled study 
Anticipated Outcome 
Perioperative administration of low dose continuous furosemide infusion can gives protective effect 
in cardiac surgery patients with mild to moderate kidney, Measured by the improvement of post 
operative eGFR 
Inclusion and exclusion criteria 
Inclusion criteria: 
1) 18-65 years old  
2) Undergo elective heart surgery, types of surgery: coronary bypass (coronary artery bypass 
graft/CABG), single heart valve replacement surgery, one or two heart valve repair surgery, 
coronary bypass surgery with single heart valve repair/replacement. 
3) Using cardiopulmonary bypass machine in surgical procedures  
4) Patients with ejection fraction >40% 
5) Patients with mild to moderate impaired renal function (eGFR 30-89 mL/min/1.73 m2 and 
have never had renal replacement therapy  
Exclusion criteria: 
1) Heart disease patients with ejection fraction < 40% 
 
2) Patients with preoperative acute renal failure of any cause 
 
3) Patients with stage 4-5 chronic renal failure and/or who require previous renal replacement 
therapy 
 
4) Patients with emergency surgery or undergo redo operation heart surgery 
 
5) Patients with complex heart disease, for example those requiring IABP insertion, replacement 
of more than 2 heart valves, coronary heart disease with severe valve abnormalities, patients 
with suspected severe pulmonary hypertension. 
 
6) Congenital heart disease patients 
 


Institutional Review Board (IRB)/ 
Komite Etik Penelitian 
RS. Jantung dan Pembuluh Darah Harapan Kita 
POB/     / 
Berlaku mulai:  
 
 15 Mei 2015 
  
Hal 3 dari 6 
 
LAMPIRAN 3 
FL/03-010/01.0 
 
 
http://www.pjnhk.go.id/ 
Study Protocol  
 
7) Patients with major blood vessel (aorta) disorders and/or those affecting the renal artery 
supply directly 
 
8) Patients who are following other studies that affect drug administration 
 
9) Patients with hemodynamic compromise caused by bleeding, sepsis, anaphylactic or 
cardiogenic shock 
 
10) Patients who refuse to be involved in the study 
 
Withdrawal or discontinuation Criteria 
Kriteria withdrawal: 
1) Hemodynamically unstable patient (with persistent hypotension, taking > 2 inotropic drugs/ > 
2 vasoactive drugs, patient with IABP, patient with ECMO)  
2) Patients in cardiogenic shock  
3) Patients with long use of cardiopulmonary bypass machine (>140 minutes) 
4) Patients with pulmonary hypertension crisis or severe pulmonary hypertension  
5) Patients who have to undergo redo surgery for any reasons 
6) Patients with postoperative bleeding requiring large amounts of transfusion 
7) Patients given extra bolus furosemide or mannitol outside the established protocol 
8) Patients with anaphylactic shock of any cause 
Interventions 
Ethical clearance for the study was approved by Institutional Review Board of National 
Cardiovascular Center Harapan Kita. Patients eligible for the study was recruited and written 
informed consent was obtained after clear explanation of the study. Allocation of furosemide and 
control group was done using simple computer randomization by staff who was not involved in 
the study. Furosemide infusion and normal saline was prepared by independent pharmacist 
blinded to the study. Furosemide solution was prepared to contain 40 mg of furosemide diluted 
with normal saline to a total volume of 40 cc (1 mg / 1 cc) and control solution was prepared to 
contain only 40 cc of normal saline. Both solution was packaged in 50-cc syringe and prepared 
in similar fashion. The solution was administered after induction of anesthesia with rate of 2 cc 


Institutional Review Board (IRB)/ 
Komite Etik Penelitian 
RS. Jantung dan Pembuluh Darah Harapan Kita 
POB/     / 
Berlaku mulai:  
 
 15 Mei 2015 
  
Hal 4 dari 6 
 
LAMPIRAN 3 
FL/03-010/01.0 
 
 
http://www.pjnhk.go.id/ 
Study Protocol  
 
per hour for 12 hours.  
 
 
Metode Analisa* 
The data obtained will be analyzed using the SPSS software program. Basic characteristic data will 
be displayed according to the specified variable type. Numerical variables with normal distribution will 
be displayed in the form of mean ± standard deviation or median (minimum-maximum) if the 
distribution is not normal. Categorical variables will be displayed as a percentage (amount). Data 
from the two groups were analyzed using x2 analysis (chi square) or Fisher's exact test, respectively. 
The level of statistical significance refers to the P value <0.05 
 
Evaluation Criteria (Response/Outcome) 
changes in glomerular filtration rate parameters after intervention in subjects will be evaluated, the 
need/indication for therapeutic diuretic therapy, and use of renal replacement therapy, length of stay 
in the ICU and incidence of mortality will be analyzed. 
Safety Parameters Criteria (Toxicity) 
Renal Function pre and post treatment 
Blood gas analysis 
Blood electrolyte 
 
 
 
 
 
 
 
 
 


Institutional Review Board (IRB)/ 
Komite Etik Penelitian 
RS. Jantung dan Pembuluh Darah Harapan Kita 
POB/     / 
Berlaku mulai:  
 
 15 Mei 2015 
  
Hal 5 dari 6 
 
LAMPIRAN 3 
FL/03-010/01.0 
 
 
http://www.pjnhk.go.id/ 
Study Protocol  
 
Abstract 
Background:  
Renal dysfunction is consistently an independent risk factor for the development of 
cardiovascular disease. Several studies have identified that renal dysfunction increases 
the risk of mortality in patients undergoing cardiac surgery and that the risk increases 
with the degree of renal dysfunction. Several strategies are used to prevent worsening of 
kidney function, such as the use of loop diuretics furosemide as prophylactic. Several 
recent studies have investigated the protective effect of furosemide in cardiac surgery in 
preventing worsening of renal function, but these studies mostly were conducted in 
patients with normal renal function. Patients with preoperative renal dysfunction are 
more in urgent need of effective renal protective strategies. Based on above, this study 
aimed to analyze the effect of continuous administration of low-dose furosemide on 
patients with mild to moderate renal dysfunction undergoing cardiac surgery. 
 
Methods:  
The study design was a double-blind randomized controlled trial. Subjects will be 
randomly divided into 2 groups; the furosemide group (n=43) and the control group 
(n=44). This study started since May 28, 2021; after obtaining an ethical clearance from 
the hospital ethics committee. Inclusion criteria included patients aged 18-65 years with 
left heart ejection fraction >40%, mild to moderate renal dysfunction category (eGFR 30-
89 mL/min/1.73 m2) who underwent elective cardiac surgery; such as coronary artery 
bypass graft (CABG), replacement of one heart valve, repair of one or two heart valves, 
and using cardiopulmonary bypass machine. Exclusion criteria included heart disease 
patients with stage 4-5 chronic renal failure, on renal replacement therapy, cardiac 
ejection fraction <40%, emergency or repeat surgery, complex heart disease, congenital 
heart disease, aortic vascular surgery, massive bleeding, sepsis, and currently 
participating in other research. Continuous furosemide (2 mg/hour) or 0.9% NaCl (2 
mL/hour) was given after the induction of anesthesia and continued until 12 hours of 
administration. After drug administration was completed (12 hours) the first blood sample 
was obtained to check blood urea nitrogen concentration, urea, creatinine serum and 
estimated glomerular filtration rate. Sampling was repeated again at the 24th hour, 48th 
hour and 120th hour since the drug was started. A decrease in GFR > 20% of the 
preoperative value is considered a decrease in renal function, and an increase of  >20% 
of third sample value in the fourth sample is considered an improvement of renal function. 
Deterioration of renal function to severe renal dysfunction or requiring renal replacement 
therapy is considered an event of acute renal failure. 
 
Keywords: Furosemide, Glomerulus Filtration Rate, Renal Dysfunction, Cardiac 
Surgery 
 


Institutional Review Board (IRB)/ 
Komite Etik Penelitian 
RS. Jantung dan Pembuluh Darah Harapan Kita 
POB/     / 
Berlaku mulai:  
 
 15 Mei 2015 
  
Hal 6 dari 6 
 
LAMPIRAN 3 
FL/03-010/01.0 
 
 
http://www.pjnhk.go.id/ 
Study Protocol  
 
 
Researcher, 
 
____________________________________ 
_24 Maret 2021 
dr. Prieta Adriane, SpAn, M.Kes, KAKV