Association between furosemide administration and outcomes in patients undergoing cardiac surgery

doi:10.21203/rs.3.rs-1903852/v1

Background: Furosemide is widely used during the perioperative period of cardiac surgery. But the influence of furosemide on outcomes after cardiac surgery remains uncertain. We aim to investigate the relationship between furosemide usage and clinical outcomes among cardiac surgery patients.

Methods: Patients who underwent cardiac surgery were identified from MIMIC‑III database. In order to fully and comprehensively assess the influence of furosemide, we transform the total dosage of furosemide into four new variables (total dose of furosemide≥200mg, total dose of furosemide/weight, average daily dose of furosemide, and average daily dose of furosemide≥20mg/d) for further analysis. Cox and logistic regression analysis were used to evaluate the associations between five furosemide related variables and clinical outcomes of cardiac surgery accordingly.

Results: A total of 6,752 cardiac surgery patients were included in this analysis. 84.0% patients have used furosemide after cardiac surgery. In the cox regression after adjusted all confounding factors, average daily dose of furosemide (HR 1.07; 95% CI 1.003-1.011; P=0.001), average daily dose of furosemide≥20mg/d (HR 2.099; 95% CI 1.221-3.606; P=0.007) and total dose of furosemide≥200mg (HR1.975; 95% CI 1.095-3.562; P=0.024) were associated with increased risk of in-hospital mortality. Total dose of furosemide (HR 1.00; 95% CI 1.000-1.001; P=0.023) and average daily dose of furosemide (HR 1.003; 95% CI 1.001-1.006; P=0.016) were associated with increased risk of one-year mortality. In the logistic regression after adjusted all confounding factors, all five variables of furosemide usage were significantly increased the risk of length of ICU stay≥3d and mechanical ventilation≥48h; total dosage of furosemide, total dose of furosemide ≥200mg, total dose of furosemide/weight were associated with a higher risk of length of hospital stay≥14d.

Conclusions: We demonstrated that high dose of furosemide was associated with increased mortality and adverse outcomes among cardiac surgery patients. It suggests that high-dose furosemide should be cautiously used in cardiac surgery patients.

Furosemide

Cardiac surgery

Mortality

Cardiac surgery is often accompanied with volume overload, heart function and renal function damage(1–3). Diuretics represent the mainstay of treatment for reduce fluid retention and volume load, increase urine volume, improve hemodynamic stability and organ function in the circumstances of acute and chronic heart failure(4). Furosemide is the most commonly used loop diuretic and is widely administrated during the perioperative period of cardiac surgery. A survey of 38 centers of the European Workgroup of Cardiothoracic Intensivists shown that 34 centers would routinely use furosemide to increase urine output when urine volume decreased to 0.5 ml/kg per hour(5).

Several studies have reported that furosemide might relieve the severity of acute kidney injury (AKI) and reduce the probability of hemodialysis after cardiac surgery(6, 7). But the effect of furosemide on mortality and prognosis in patients undergoing cardiovascular surgery remains unclear. Some observational studies have reported a significant association between high dose furosemide administration and detrimental effects on survival in heart failure patients(8, 9). Chris J et al. recently reported furosemide dose increase was associated with worse one-year mortality in heart failure patients(10). A recent clinical study about furosemide using and outcomes of transcatheter aortic valve implantation (TAVI) suggested a mean dose of 51.1 mg furosemide is associated with an increased 1-year death rate in TAVI patients(11). It was hypothesized that higher doses of furosemide may reflect the severity of diseases rather than a true risk factor. We designed this retrospective observational study to assess the association between furosemide use and outcomes in cardiac surgery patients from MIMIC-III database.

2.1. Sources of data

All data of present observational study were based on a large critical care database: Medical Information Mart for Intensive Care III version 1.4(MIMIC-III v1.4) database. The MIMIC-III contains the clinical information of more than 60,000 critically ill patients from Beth Israel Deaconess Medical Center (BIDMC) (Boston, USA) between 2001 and 2012. Our study was consistent with the Strengthening the Reporting of Observational studies in Epidemiology (STROBE) statement. The institutional review boards (IRB) of Beth Israel Deaconess Medical Center (BIDMC) and Massachusetts Institute of Technology (MIT) approved the project and informed consents were exempted due to all patients’ data were anonymized before the data were obtained. To obtain access to the MIMIC-III database, a web-based course “Protecting Human Research Participants” from the National Institutes of Health have been completed (Record ID 37938207). All methods were carried out in accordance with relevant guidelines and regulations.

2.2. Data collection and definitions

PostgreSQL tool (version 9.6) was used for data collection. The following data were collected or calculated: age, identification number of patients, body mass index (BMI), gender, arterial blood gas on the first day of ICU admission (PH, PaO2, BE, anion gap, bicarbonate, lactate), comorbidities (included diabetes, hypertension, solid tumor, chronic pulmonary diseases, liver disease, chronic renal disease and congestive heart failure), vital sign on the first day of ICU admission (including heart rate, respiratory rate, MAP, temperature, CVP and SPO2), laboratory parameters on the first day of ICU admission (including WBC, hemoglobin, platelet, bun, creatinine, glucose, potassium, chloride, sodium, PT and APTT), blood transfusion, vasopressors use, type of cardiac surgery, the day of death, and the length of hospital and ICU stays and length of mechanical ventilation.

The primary outcomes were in hospital mortality and one year mortality after cardiac surgery. Secondary outcomes were length of hospital stay ≥ 14d, length of ICU stay ≥ 3d and mechanical ventilation ≥ 48h.

The total dose of furosemide administration of each patient was extracted, and we transform the total dosage of furosemide into four new variables:1) total dose of furosemide ≥ 200mg; 2) total dose of furosemide/weight; 3) average daily dose of furosemide; 4) average daily dose of furosemide ≥ 20mg/d.

2.3. Population selection criteria

Patients with valvular surgery or coronary artery bypass grafting surgery were selected. The exclusion criteria were that: age < 18 years old, no weight data, data missing > 5%.

2.4. Statistical methods

Continuous variables were presented as mean ± standard deviation and the differences between two groups were compared using the Mann-Whitney U-test for non-normal distribution. Categorical variables were presented as frequency and percentage and the differences between two groups were compared using χ2 test or Fisher exact test.

To investigate the relationship between furosemide usage and outcomes among cardiac surgery patients, we divided the study cohort into two groups according to the average daily dose of furosemide, patients with average daily dose of furosemide < 20mg present low furosemide dose group and patients with average daily dose of furosemide ≥ 20mg present high furosemide dose group.

Both univariable and multivariable cox regression were performed to estimate the relationship between furosemide and the in-hospital mortality and one year mortality post cardiac surgery. We choose the following variates as potential confounders for adjusting in the multivariable cox proportional hazards model: cardiac surgery type, age, gender, BMI, arterial blood gas, comorbidities, laboratory tests, vital signs, blood transfusion and vasopressors usage. The hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated. Multivariable logistic regression analysis was performed to investigate the association between furosemide administration and secondary outcomes with the following variates as potential confounders for adjusting: cardiac surgery type, age, gender, BMI, arterial blood gas, comorbidities, laboratory tests, vital signs, blood transfusion and vasopressors usage. The odds ratios (ORs) with 95% confidence intervals (CIs) were calculated.

Subgroup analysis was performed to estimate the relationship between furosemide and the in-hospital mortality by using multivariable cox regression. We distinguished subgroups according to the following criteria: age ≥ 60 or age < 60; female or male; BMI ≥ 28 kg/m2 or BMI < 28 kg/m2; vasopressors use or non-vasopressors use; blood transfusion or non-blood transfusion; renal failure or non-renal failure; congestive heart failure or non-congestive heart failure. The hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated.

The factors related to higher dosage of furosemide administration (including average daily dose of furosemide ≥ 20mg/d and total dose of furosemide ≥ 200mg) were analyzed by multivariable logistic regression. The odds ratios (ORs) with 95% confidence intervals (CIs) were calculated.

We use SPSS version 26.0 (IBM, Armonk, NY) for statistical analysis. P value < 0.05 was considered statistically significant.

3.1. Subject characteristics

A total of 6752 patients underwent cardiac surgery were selected. The criteria of data exclusion and procedure of data selection was presented in Figure.1. 84.0% patients used furosemide after cardiac surgery.

Baseline characteristics of the subjects are shown in Table 1. Compared with cardiac surgery patients with average daily dose of furosemide < 20mg(N = 6033), cardiac surgery patients with average daily dose of furosemide ≥ 20mg(N = 719) have significant higher level of total dose of furosemide (62.7 ± 73.4 vs 509.8 ± 625.9), total dose of furosemide/weight (0.8 ± 1.0 vs 6.3 ± 8.6), average daily dose of furosemide (7.1 ± 5.3 vs 40.8 ± 38.4), total dose of furosemide ≥ 200mg (3.1% vs 62.4%) (Table.1).

Patients with high furosemide dosage tend to be older and have higher BMI, higher rate of diabetes, chronic pulmonary diseases, heart failure, renal failure, blood transfusion, vasopressors use and valvular surgery, higher value of WBC counts, bun, creatinine, glucose, PT, APTT, anion gap and lactate. Cardiac surgery patients with average daily dose of furosemide ≥ 20mg also have significant increased length of vasopressors use and length of ventilation. The average daily dose of furosemide ≥ 20mg group have significantly increased risk of in hospital mortality (1.2% vs 6.7%), length of hospital stays ≥ 14d (14.9% vs 27.3%), length of ICU stays ≥ 3d (32.4% vs 74.2%), and mechanical ventilation ≥ 48h (7.3% vs 33.9%) (Table.1).

3.2. Association between furosemide administration and mortality after cardiac surgery.

In univariate cox regression, total dose of furosemide, total dose of furosemide/weight, average daily dose of furosemide, average daily dose of furosemide ≥ 20mg/d and total dose of furosemide ≥ 200mg were all associated with increased risk of in-hospital and one-year mortality (Table.2).

In multivariate cox regression after adjusted all confounding factors, the results shown average daily dose of furosemide (HR 1.07; 95% CI 1.003–1.011; P = 0.001), average daily dose of furosemide ≥ 20mg/d (HR 2.099; 95% CI 1.221–3.606; P = 0.007) and total dose of furosemide ≥ 200mg (HR1.975; 95% CI 1.095–3.562; P = 0.024) were associated with increased risk of in-hospital mortality; total dose of furosemide (HR 1.00; 95% CI 1.000-1.001; P = 0.023) and average daily dose of furosemide (HR 1.003; 95% CI 1.001–1.006; P = 0.016) were associated with increased risk of one-year mortality (Table.2).

3.3 The relationship between furosemide using and second outcomes of cardiac surgery.

In multivariate logistics regression after adjusted all confounding factors, the results shown total dose of furosemide (OR 1.003; 95% CI 1.002–1.003; P < 0.001), total dose of furosemide/weight (OR 1.242; 95% CI 1.187–1.299; P < 0.001), total dose of furosemide ≥ 200mg (OR 5.153; 95% CI 3.846–6.905; P < 0.001) were significantly increase the risk of length of hospital stays ≥ 14d after cardiac surgery (Table.3).

Total dose of furosemide (OR 1.017; 95% CI 1.015–1.019; P < 0.001), total dose of furosemide/weight (OR 3.623; 95% CI 3.078–4.264; P < 0.001), average daily dose of furosemide (OR 1.035; 95% CI 1.025–1.044; P < 0.001), average daily dose of furosemide ≥ 20mg/d (OR 4.062; 95% CI 3.109–5.307; P < 0.001), total dose of furosemide ≥ 200mg (OR 29.350; 95% CI 16.72–51.51; P < 0.001) were significantly increase the risk of length of ICU stays ≥ 3d in multivariate logistics regression after adjusted all confounding factors after cardiac surgery (Table.3).

Total dose of furosemide (OR 1.004; 95% CI 1.003–1.005; P < 0.001), total dose of furosemide/weight (OR 1.379; 95% CI 1.305–1.457; P < 0.001), average daily dose of furosemide (OR 1.013; 95% CI 1.006–1.019; P < 0.001), average daily dose of furosemide ≥ 20mg/d (OR 3.048; 95% CI 2.259–4.114; P < 0.001), total dose of furosemide ≥ 200mg (OR 10.987; 95% CI 7.896–15.290; P < 0.001) were significantly increase the risk of mechanical ventilation ≥ 48h in multivariate logistics regression after adjusted all confounding factors after cardiac surgery (Table.3).

3.4 Subgroup analysis of furosemide administration and in-hospital mortality.

In the subgroup analysis, we have revealed that average daily dose of furosemide ≥ 20mg/d would significantly increase the risk of in-hospital mortality after cardiac surgery in the following subgroups: age < 60 (HR 1.018; 95% CI 1.007–1.029; P = 0.001), BMI ≥ 28 kg/m2 (HR 1.019; 95% CI 1.012–1.026; P < 0.001), vasopressors use (HR 1.004; 95% CI 1.001–1.008; P = 0.022), blood transfusion (HR 1.005; 95% CI 1.002–1.009; P = 0.003), renal failure (HR 1.093; 95% CI 1.026–1.164; P = 0.006) and non-congestive heart failure (HR 1.016; 95% CI 1.004–1.028; P = 0.01) after adjusted all confounding factors. (Table.4).

3.5 Factors related to high dosage of furosemide administration.

The results shown that female, BMI ≥ 28 kg/m2, bicarbonate, BUN, chronic pulmonary diseases, congestive heart failure, blood transfusion, vasopressors use and lactate level were positive factors correlated with high dosage of furosemide administration (average daily dose of furosemide ≥ 20mg/d and total dose of furosemide ≥ 200mg). Platelet level was negative factor correlated with high dosage of furosemide administration (average daily dose of furosemide ≥ 20mg/d and total dose of furosemide ≥ 200mg) (Table.5).

In this large retrospective case-control study involving 6752 cardiovascular surgery patients, we found that the use of the diuretic furosemide was very common in patients undergoing cardiovascular surgery (84.0% patients had used furosemide after cardiovascular surgery). The use of high dose furosemide was significantly associated with an increased risk of death in patients after cardiovascular surgery.

Volume overload is very common after cardiopulmonary bypass surgery due to hemodynamic instability, capillary leak and acute renal function injury(12, 13). Volume overload is related with adverse outcomes in both adult and infant cardiac surgery patients(14, 15). Volume overload is also considered to be an effective predictor of renal and heart dysfunction. Urgent intervention and treatments are necessary to reduce volume overload post cardiac surgery. Diuretics and blood ultrafiltration are the most important ways to reduce excessive volume load and improve organ function after cardiovascular surgery. Furosemide is the most commonly used diuretic and is widely administrated during the perioperative period of cardiac surgery. In our report, 84.0% of patients had used furosemide, this means the use of furosemide was very routine after cardiac surgery.

Moderate use of furosemide may help to improve the damaged cardiopulmonary function, but high-dose use of furosemide may have adverse effects (6–8, 10). In this study, the results shown average daily dose of furosemide (HR 1.07; 95% CI 1.003–1.011; P = 0.001), average daily dose of furosemide ≥ 20mg/d (HR 2.099; 95% CI 1.221–3.606; P = 0.007) and total dose of furosemide ≥ 200mg (HR1.975; 95% CI 1.095–3.562; P = 0.024) were associated with increased risk of in-hospital mortality. Total dose of furosemide (HR 1.00; 95% CI 1.000-1.001; P = 0.023) and average daily dose of furosemide (HR 1.003; 95% CI 1.001–1.006; P = 0.016) were associated with increased risk of one-year mortality. Our study also found that the use of high-dose furosemide was significantly correlated with the increase of hospitalization time and mechanical ventilation time. This result suggested that high-dose use of furosemide have adverse effects in cardiac surgery patients. Similar results were reported from Cantey E. et al that a mean dose of 51.1 mg furosemide was associated with an increased 1-year death rate in TAVI patients(11). In chronic heart failure, high-dose of diuretic usage was an independent factor related to adverse long-term outcome within 2 years(9). In critically ill patients, high-dose of furosemide usage was also significantly increase mortality(16).

We further analyzed the factors of using high-dose furosemide in patients after cardiac surgery. The findings of our study revealed that female, BMI ≥ 28 kg/m2, chronic pulmonary diseases, congestive heart failure, blood transfusion, vasopressors use, high level of bicarbonate, BUN and lactate were positive factors correlated with high dosage of furosemide administration. It means patients who need high-dose diuretics are often accompanied by more severe cardiopulmonary function damage, hemodynamic disorder, renal injure and volume overload. It was hypothesized that higher doses of furosemide may reflect the severity of diseases rather than a true risk factor(17).

In the subgroup analysis, furosemide administration (average daily dose of furosemide ≥ 20mg/d) would significantly increase the risk of in-hospital mortality after cardiac surgery in the following subgroups: age < 60, BMI ≥ 28 kg/m2, vasopressors use, blood transfusion, renal failure and non-congestive heart failure patients. The results suggest that the use of high-dose furosemide in these populations may have more serious adverse outcomes.

Our results strongly confirm the adverse effects of high-dose furosemide on patients after cardiac surgery. Therefore, how to reduce the use of furosemide is important to the prognosis of patients after cardiac surgery. Cardiopulmonary bypass(CPB) have adverse effects on patients' renal and cardiac function, and would lead to serious fluid overload(1). This adverse effect increased with the duration of CPB. We believe that reducing the time of CPB can effectively protect cardiac function and has a significant impact on reducing the use of diuretics after operation. Off pump technology and mini-CPB can decrease the system inflammation, reduce bleeding and transfusion requirements, and reduce renal function damage(18, 19), these technologies would help to reduce the use of furosemide after operation. For patients with circulatory instability and severe renal dysfunction, it is important to use continuous renal replacement therapy (CRRT) as soon as possible instead of using high-dose diuretics. Delaying the timing of CRRT may cause serious adverse events to patients(20, 21). Transthoracic echocardiography can accurately evaluate the volume status and effectively guide liquid therapy in critical ill patients. Studies have confirmed that using echocardiography to assess volume status can reduce the mortality of critically ill patients (22). We believe that the use of echocardiography can effectively reduce the use of furosemide.

This retrospective study revealed the correlation between furosemide administration and postoperative mortality and adverse events in cardiac surgery patients. It indicated that high doses of furosemide administration may reflect the severity of diseases. We need to carefully evaluate and adjust the patient's volume status to reduce the use of furosemide in order to reduce adverse events caused by furosemide in cardiac surgery patients.

CPB, Cardiopulmonary bypass; CRRT, Continuous renal replacement therapy; HR, Hazard ratios; CI, Confidence intervals; OR, Odds ratios.

Acknowledgements

Not applicable.

Author contributions

CLZ wrote the main manuscript text; JHL, XFW, ZLC and XS completed data collation and validation; CLZ and JHL revised the final draft and supervised it. All authors reviewed the manuscript. All authors read and approved the final manuscript.

Funding

This work was supported by grants from the National Natural Science Foundation of China (No.81900529), China Postdoctoral Science Foundation (No.2021M691649) and Jiangsu Postdoctoral Science Foundation (No.2021K524C).

Availability of data and materials

We performed a retrospective study involving ICU patients from MIMIC-III database with patients undergoing cardiac surgery. The datasets generated during the current study are available in database (https://mimic.mit.edu/).

Ethics approval and consent to participate

The institutional review boards (IRB) of Beth Israel Deaconess Medical Center (BIDMC) and Massachusetts Institute of Technology (MIT) approved the project and informed consents were exempted due to all patients’ data were anonymized before the data were obtained. Our study was consistent with the Strengthening the Reporting of Observational studies in Epidemiology (STROBE) statement . All methods were also carried out in accordance with relevant guidelines and regulations.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Declaration of conflict of interest

None to declare.

Lannemyr L, Bragadottir G, Krumbholz V, Redfors B, Sellgren J, Ricksten S. Effects of Cardiopulmonary Bypass on Renal Perfusion, Filtration, and Oxygenation in Patients Undergoing Cardiac Surgery. Anesthesiology. 2017;126(2):205–13.
Busse L, Barker N, Petersen C. Vasoplegic syndrome following cardiothoracic surgery-review of pathophysiology and update of treatment options. Critical care (London, England). 2020;24(1):36.
Millar J, Fanning J, McDonald C, McAuley D, Fraser J. The inflammatory response to extracorporeal membrane oxygenation (ECMO): a review of the pathophysiology. Critical care (London, England). 2016;20(1):387.
Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. European journal of heart failure. 2016;18(8):891–975.
Lassnigg A, Donner E, Grubhofer G, Presterl E, Druml W, Hiesmayr M. Lack of renoprotective effects of dopamine and furosemide during cardiac surgery. Journal of the American Society of Nephrology: JASN. 2000;11(1):97–104.
Kunt AT, Akgün S, Atalan N, Bitir N, Arsan S. Furosemide infusion prevents the requirement of renal replacement therapy after cardiac surgery. Anadolu kardiyoloji dergisi: AKD = the Anatolian journal of cardiology. 2009;9(6):499–504.
Fakhari S, Bavil FM, Bilehjani E, Abolhasani S, Mirinazhad M, Naghipour B. Prophylactic furosemide infusion decreasing early major postoperative renal dysfunction in on-pump adult cardiac surgery: a randomized clinical trial. Research and reports in urology. 2017;9:5–13.
Kapelios CJ, Kaldara E, Ntalianis A, Sousonis V, Repasos E, Sfakianaki T, et al. High furosemide dose has detrimental effects on survival of patients with stable heart failure. Hellenic journal of cardiology: HJC = Hellenike kardiologike epitheorese. 2015;56(2):154–9.
Martins J, Lourenço P, Araújo JP, Mascarenhas J, Lopes R, Azevedo A, et al. Prognostic implications of diuretic dose in chronic heart failure. Journal of cardiovascular pharmacology and therapeutics. 2011;16(2):185–91.
Kapelios CJ, Laroche C, Crespo-Leiro MG, Anker SD, Coats AJS, Díaz-Molina B, et al. Association between loop diuretic dose changes and outcomes in chronic heart failure: observations from the ESC-EORP Heart Failure Long-Term Registry. European journal of heart failure. 2020.
Cantey E, Chang K, Blair J, Brummel K, Sweis R, Pham D, et al. Impact of Loop Diuretic Use on Outcomes Following Transcatheter Aortic Valve Implantation. The American journal of cardiology. 2020;131:67–73.
Romagnoli S, Rizza A, Ricci Z. Fluid Status Assessment and Management During the Perioperative Phase in Adult Cardiac Surgery Patients. Journal of cardiothoracic and vascular anesthesia. 2016;30(4):1076–84.
Haase M, Bellomo R, Story D, Letis A, Klemz K, Matalanis G, et al. Effect of mean arterial pressure, haemoglobin and blood transfusion during cardiopulmonary bypass on post-operative acute kidney injury. Nephrology, dialysis, transplantation: official publication of the European Dialysis and Transplant Association - European Renal Association. 2012;27(1):153–60.
Stein A, de Souza L, Belettini C, Menegazzo W, Viégas J, Costa Pereira E, et al. Fluid overload and changes in serum creatinine after cardiac surgery: predictors of mortality and longer intensive care stay. A prospective cohort study. Critical care (London, England). 2012;16(3):R99.
Hazle MA, Gajarski RJ, Yu S, Donohue J, Blatt NB. Fluid overload in infants following congenital heart surgery. Pediatric critical care medicine: a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies. 2013;14(1):44 – 9.
Lee SJ, Kim CW, Lee MK, Kim SH, Yong SJ, Lee WY. Effect of high-dose furosemide on the prognosis of critically ill patients. Journal of critical care. 2017;41:36–41.
De Vecchis R, Ciccarelli A, Ariano C, Cioppa C, Giasi A, Pucciarelli A, et al. In chronic heart failure with marked fluid retention, the i.v. high doses of loop diuretic are a predictor of aggravated renal dysfunction, especially in the set of heart failure with normal or only mildly impaired left ventricular systolic function. Minerva cardioangiologica. 2011;59(6):543–54.
Zhang P, Wang L, Zhai K, Huang J, Wang W, Ma Q, et al. Off-pump versus on-pump redo coronary artery bypass grafting: a systematic review and meta-analysis. Perfusion. 2020:267659120960310.
Huybregts R, Morariu A, Rakhorst G, Spiegelenberg S, Romijn H, de Vroege R, et al. Attenuated renal and intestinal injury after use of a mini-cardiopulmonary bypass system. The Annals of thoracic surgery. 2007;83(5):1760–6.
Tripathi S, Pande S, Malhotra P, Mahindru S, Thukral A, Kotwal A, et al. Optimal timing of renal replacement therapy for favourable outcome in patients of acute renal failure following cardiac surgery. Indian journal of thoracic and cardiovascular surgery. 2020;36(2):127–33.
Li S, Yang W, Chuang C. Effect of early and intensive continuous venovenous hemofiltration on patients with cardiogenic shock and acute kidney injury after cardiac surgery. The Journal of thoracic and cardiovascular surgery. 2014;148(4):1628–33.
Feng M, McSparron J, Kien D, Stone D, Roberts D, Schwartzstein R, et al. Transthoracic echocardiography and mortality in sepsis: analysis of the MIMIC-III database. Intensive care medicine. 2018;44(6):884–92.

Table.1 Baseline and clinical characteristics of the study population

Variables	Average daily dose of furosemide＜20mg N=6033	Average daily dose of furosemide≥20mg N=719	P value
Total dose of furosemide, mg	62.7±73.4	509.8±625.9	＜0.001
Total dose of furosemide/weight, mg/kg	0.8±1.0	6.3±8.6	＜0.001
Average daily dose of furosemide, mg/d	7.1±5.3	40.8±38.4	＜0.001
Total dose of furosemide≥200mg, n (%)	190（3.1%）	449（62.4%）	＜0.001
Age	66.9±12.3	69.0±11.9	＜0.001
Age≥70, n (%)	1698（28.2%）	244（33.9%）	0.001
Gender, male, n (%)	4272（70.8%）	416（57.9%）	＜0.001
BMI, kg/m²	28.4±5.7	30.5±6.6	＜0.001
BMI≥28 kg/m², n (%)	2703（46.6%）	431（60.6%）	＜0.001
Arterial blood gas
PH	7.31±0.06	7.29±0.08	＜0.001
PaO₂, mmHg	94.5±46.2	80.3±46.5	＜0.001
BE, mmol/l	-3.2±2.8	-4.3±4.0	＜0.001
Anion gap, mmol/l	12.5±2.9	13.5±3.4	＜0.001
Bicarbonate, mmol/l	24.8±2.6	24.8±2.9	0.462
Lactate, mmol/l	2.9±1.7	3.8±2.6	0.04
Laboratory tests
WBC, 10⁹/l	14.7±5.8	15.5±7.5	0.04
Platelet, 10⁹/l	125.9±46.1	110.0±52.3	＜0.001
Hemoglobin, g/dl	12.6±1.5	12.2±1.5	＜0.001
Creatinine, mg/dl	1.4±1.2	1.8±1.1	＜0.001
Bun, mg/dl	19.2±10.4	24.2±15.2	＜0.001
Glucose, mmol/l	188.7±62.9	200.0±70.7	＜0.001
Chloride, mmol/l	109.7±4.1	109.8±4.8	0.084
Potassium, mmol/l	4.6±0.84	4.5±0.82	0.127
Sodium, mmol/l	139.7±2.7	140.2±3.3	＜0.001
APTT, S	46.6±24.8	55.9±33.7	＜0.001
PT, S	15.9±3.7	17.1±5.9	＜0.001
Vital signs
Heart rate, beats/min	84.6±9.8	85.8±10.9	0.12
MAP, mmHg	74.7±6.5	73.6±7.5	＜0.001
Respiratory rate, beats/min	17.1±2.8	17.9±3.2	＜0.001
Temperature, °C	36.9±0.5	36.8±0.6	0.416
SPO2, %	98.0±1.4	97.6±1.8	＜0.001
CVP, mmH₂O	18.9±5.2	23.4±5.2	＜0.001
Co-morbidities, n (%)
Hypertension	4253（70.5%）	519（72.2%）	0.363
Diabetes	1935（32.1%）	281（39.1%）	＜0.001
Chronic pulmonary diseases	863（14.3%）	146（20.3%）	＜0.001
Congestive heart failure	1621（26.9%）	346（48.1%）	＜0.001
Renal failure	527（8.7%）	106（14.7%）	＜0.001
Liver disease	128（2.1%）	13（1.8%）	0.679
Solid tumor	64（1.1%）	11（1.5%）	0.257
Blood transfusion, n (%)	2578（42.7%）	460（64.0%）	＜0.001
Vasopressors use, n (%)	5021（83.1%）	661（91.9%）	＜0.001
Length of vasopressors use, h	29.7±70.1	69.8±103.2	＜0.001
Length of ventilation, h	26.7±103.5	87.2±177.2	＜0.001
Classification of cardiac surgery
CABG, n (%)	3643（60.4%）	313（43.5%）	＜0.001
Valvular surgery, n (%)	1524（25.3%）	256（35.6%）	＜0.001
CABG+valvular surgery, n (%)	866（14.4%）	150（20.9%）	＜0.001
Primary outcome
In-hospital mortality, n (%)	75（1.2%）	48（6.7%）	＜0.001
One-year mortality, n (%)	259（4.3%）	84（11.7%）	＜0.001
Secondary outcomes
Length of hospital stay≥14d, n (%)	892（14.9%）	196（27.3%）	＜0.001
Length of ICU stay≥3d, n (%)	1898（32.4%）	518（74.2%）	＜0.001
Mechanical ventilation≥48h, n (%)	419（7.3%）	239（33.9%）	＜0.001

Table.2 The relationship between furosemide administration and mortality of cardiac surgery patients

	Unadjusted HR (95%CI)	P	Adjusted HR (95%CI)	P
In hospital mortality
Total dose of furosemide	1.001(1.001-1.001)	＜0.001	1.000(1.000-1.001)	0.717
Total dose of furosemide/weight	1.044(1.032-1.056)	＜0.001	1.008(0.968-1.050)	0.695
Average daily dose of furosemide	1.015(1.012-1.017)	＜0.001	1.07(1.003-1.011)	0.001
Average daily dose of furosemide≥20mg/d	5.560(3.870-7.987)	＜0.001	2.099(1.221-3.606)	0.007
Total dose of furosemide≥200mg	6.069(4.218-8.731)	＜0.001	1.975(1.095-3.562)	0.024
One-year mortality
Total dose of furosemide	1.001(1.001-1.001)	<0.001	1.000(1.000-1.001)	0.023
Total dose of furosemide/weight	1.042(1.034-1.049)	<0.001	1.027(0.998-1.057)	0.067
Average daily dose of furosemide	1.010(1.008-1.012)	<0.001	1.003(1.001-1.006)	0.016
Average daily dose of furosemide≥20mg/d	2.827(2.210-3.616)	<0.001	1.215(0.823-1.792)	0.327
Total dose of furosemide≥200mg	4.073(3.220-5.153)	<0.001	1.255(0.851-1.851)	0.252

The following variates were potential confounders: cardiac surgery type, age, gender, BMI, arterial blood gas, comorbidities, laboratory tests, vital signs, blood transfusion and vasopressors usage.

Table.3 The relationship between furosemide usage and second outcomes of cardiac surgery patients

	Adjusted OR	95%CI	P
Length of hospital stays≥14d
Total dose of furosemide	1.003	1.002-1.003	＜0.001
Total dose of furosemide/weight	1.242	1.187-1.299	＜0.001
Average daily dose of furosemide	1.005	0.961-1.049	0.691
Average daily dose of furosemide≥20mg/d	0.929	0.691-1.249	0.624
Total dose of furosemide≥200mg	5.153	3.846-6.905	＜0.001
Length of ICU stays≥3d
Total dose of furosemide	1.017	1.015-1.019	＜0.001
Total dose of furosemide/weight	3.623	3.078-4.264	＜0.001
Average daily dose of furosemide	1.035	1.025-1.044	＜0.001
Average daily dose of furosemide≥20mg/d	4.062	3.109-5.307	＜0.001
Total dose of furosemide≥200mg	29.350	16.72-51.51	＜0.001
Mechanical ventilation≥48h
Total dose of furosemide	1.004	1.003-1.005	＜0.001
Total dose of furosemide/weight	1.379	1.305-1.457	＜0.001
Average daily dose of furosemide	1.013	1.006-1.019	＜0.001
Average daily dose of furosemide≥20mg/d	3.048	2.259-4.114	＜0.001
Total dose of furosemide≥200mg	10.987	7.896-15.290	＜0.001

The following variates were potential confounders: cardiac surgery type, age, gender, BMI, arterial blood gas, comorbidities, laboratory tests, vital signs, blood transfusion and vasopressors usage.

Table.4 Subgroup analysis of furosemide administration (average daily dose of furosemide≥20mg/d) and in-hospital mortality of cardiac surgery patients.

	Adjusted HR（95%CI）	P
Age≥60	1.002 (0.997-1.007)	0.406
Age＜60	1.018 (1.007-1.029)	0.001
Female	1.012 (0.996-1.028)	0.131
Male	1.001 (0.995-1.007)	0.787
BMI≥28 kg/m2	1.019 (1.012-1.026)	<0.001
BMI<28 kg/m2	1.001 (0.995-1.007)	0.788
Vasopressors use	1.004 (1.001-1.008)	0.022
Non- vasopressors use	1.294 (0.814-2.057)	0.275
Blood transfusion	1.005 (1.002-1.009)	0.003
Non- blood transfusion	0.958 (0.818-1.122)	0.593
Renal failure	1.093 (1.026-1.164)	0.006
Non-renal failure	1.002 (0.997-1.006)	0.459
Congestive heart failure	1.003 (0.998-1.008)	0.189
Non-congestive heart failure	1.016 (1.004-1.028)	0.01

The following variates were potential confounders: cardiac surgery type, age, gender, BMI, arterial blood gas, comorbidities, laboratory tests, vital signs, blood transfusion and vasopressors usage.

Table.5 Factors related to high dosage of furosemide administration of cardiac surgery patients

	Adjusted OR	95%CI	P
Average daily dose of furosemide≥20mg/d
Gender, male	0.616	0.505-0.751	<0.001
BMI≥28 kg/m2	2.00	1.643-2.434	<0.001
Bicarbonate	1.04	1.005-1.077	0.027
Platelet	0.996	0.994-0.998	<0.001
BUN	1.015	1.008-1.023	<0.001
Chronic pulmonary diseases	1.348	1.063-1.711	0.014
Congestive heart failure	1.611	1.318-1.969	<0.001
Solid tumor	2.215	1.066-4.603	0.033
Blood transfusion	1.533	1.244-1.888	<0.001
Vasopressors use	1.579	1.106-2.255	0.012
Lactate	1.148	1.098-1.201	<0.001
Total dose of furosemide≥200mg
Gender, male	0.724	0.577-0.908	0.005
BMI≥28 kg/m2	1.757	1.399-2.205	<0.001
Bicarbonate	1.068	1.028-1.110	0.001
WBC	1.028	1.013-1.043	<0.001
Platelet	0.992	0.989-0.995	<0.001
BUN	1.026	1.018-1.034	<0.001
Diabetes	1.307	1.036-1.648	0.024
Chronic pulmonary diseases	1.379	1.049-1.811	0.021
Congestive heart failure	2.414	1.927-3.024	<0.001
Blood transfusion	2.810	2.191-3.604	<0.001
Vasopressors use	1.815	1.127-2.924	0.014
Lactate	1.165	1.109-1.224	<0.001

The following variates were potential confounders: cardiac surgery type, age, gender, BMI, arterial blood gas, comorbidities, laboratory tests, vital signs, blood transfusion and vasopressors usage.

No competing interests reported.

Association between furosemide administration and outcomes in patients undergoing cardiac surgery

Status:

Version 1

Abstract

Figures

1. Introduction

2. Methods

2.1. Sources of data

2.2. Data collection and definitions

2.3. Population selection criteria

2.4. Statistical methods

3. Results

3.1. Subject characteristics

3.2. Association between furosemide administration and mortality after cardiac surgery.

3.3 The relationship between furosemide using and second outcomes of cardiac surgery.

3.4 Subgroup analysis of furosemide administration and in-hospital mortality.

3.5 Factors related to high dosage of furosemide administration.

4. Discussion

Abbreviations

Declarations

References

Tables

Additional Declarations

Status:

Version 1