The Effects of Furosemide usage on Organ System Failure Status based on Modified Sequential Organ Failure Assessment Score in Critically ill Patient

INTRODUCTION

Intravenous fluid administration has been one of the most common therapies used for a critically ill patient in intensive care. However, 86% of patients got positive-balanced fluid accumulation, which led to fluid overload problems in 35% of patients in ICU in 2009–2012.^[1] Moreover, some observational researches prove the correlation between fluid accumulation increment with multi-system organ dysfunction.^[1-6] It is said that every 1% fluid volume increment in fluid overload case leads to 3% chance of mortality.^[3] Furosemide is one of the most potent first-line pharmacological therapy for fluid overload cases.^[2-7] Diuretic has been proven to lower intra-abdominal pressure, which is one of the early pathophysiologies of fluid overload leading to multi-organ dysfunction.^[8,9] The effort to excrete fluid solves the physiology problems but do not solve the main disease.^[2,3,10] There is not any research proving the diuretic benefit, while organ hypoperfusion persists. Moreover, furosemide usage as the strongest diuretic has some adverse effects to the patient, including hyperuricemia, hyponatremia, hypokalemia, hypomagnesemia, hypotension, and dehydration. Hence, this research aims to analyze the correlation of organ dysfunctions status changes, shown by modified sequential organ failure assessment (MSOFA) score, with the furosemide administration on ICU patients with fluid overload.

MATERIAL AND METHODS

A retrospective cohort was conducted by analyzing secondary data from patients’ medical records. The sampling method was consecutive sampling (nonprobability sampling). This research protocol had been approved by the local Institutional Review Board of Medical Faculty. This research was held in the Intensive Care Unit of a National General Hospital for 12 months.

The research samples included all of the accessible population which fulfilled inclusion criteria (17 years and above ICU patients who used fluid resuscitation therapy was having fluid overload condition based on positive fluid balance status, was using furosemide diuretic therapy for no more than 72 h, and fluid overload patients who did not use any diuretic therapy) and not suitable to exclusion criteria (patients with not complete medical record data and fluid overload patients who were indicated to use mechanic therapy). The sample size was calculated to be 194 patients for demographic descriptive data and categorical comparative hypothesis testing, divided into 97 fluid overload patients with diuretic usage and 97 fluid overload patients without diuretic usage. MSOFA score was recorded on the 1^st day and the 3^rd day of fluid overload diagnosis on the patients.

Dependent variable of this research is furosemide usage status on the patients, while the independent variable is MSOFA score changes after the diuretic therapy (categorized into two categories: “good” if MSOFA score decreases and “bad” if MSOFA score increases or persists).

Data were shown as frequencies and percentage for qualitative variables and mean ± standard deviation or medians for quantitative variables. To check the normality of the distribution of the data, we used the Kolmogorov– Smirnov test. Comparisons for clinical and demographic data were performed using Chi-square test, non-paired t-test, and Mann–Whitney U-test. Thereafter, comparative hypothesis testing to dichotomy nominal variables was conducting using Chi-square testing in SPSS Application version 20.0. P < 0.05 were regarded to be statistically significant.

RESULTS

Of 781 subjects of ICU patients who were eligible to the inclusion criteria of this study, 587 subjects were excluded due to not complete data and indication of mechanical therapy for fluid overload management. Hence, 194 subjects were analyzed in this study.

Clinical and sociodemographic data of the fluid overload patients are reported in Table 1. Significant factors on furosemide usage (P < 0.05) included total fluid changes, total fluid after therapy, organ system dysfunctions before therapy (including the respiratory and central nervous system), organ system dysfunction after therapy (cardiovascular), and MSOFA score before therapy. Very significant factors (P < 0.001) include total fluid before therapy, organ system dysfunction after therapy (central nervous system), and MSOFA score after therapy.

Furthermore, the association between MSOFA score changes and furosemide usage is shown in Table 2 as a 2 × 2 table. Both groups resulted in a higher percentage of patients with bad organ failure development, depicted by worsening MSOFA score changes. However, there were better MSOFA score changes in patients with no furosemide usage, compared to those with furosemide administration. Based on the Chi-square test, there was a significant association between diuretic usage and MSOFA score changes (P < 0.05). The relative risk value was 1.271 (95% CI 1.108–1.458).

DISCUSSION

This study reported significant association between diuretic usage and MSOFA score changes (P < 0.05), with a relative risk value of 1.271 (95% CI 1.108–1.458). Therefore, diuretic usage on fluid overload patient causes 1.271 times more multi-organ dysfunction than those without diuretic usages.

The inefficiency of furosemide usage in decreasing body fluid might be correlated to the theory by Shchekochikhin et al. about diuretic resistance. Diuretic resistance is caused by macula densa inhibition and negative body sodium balance which stimulates RAAS after diuretic administration.^[11] This theory also supports cardiovascular system dysfunction caused by diuretic usage in fluid overload patients. Problem shifting from respiratory system dysfunction to cardiovascular system dysfunction after therapy might be due to intra-abdominal hypertension alteration after fluid decrement.^[8] However, cardiovascular system problem after therapy caused by systemic vasoconstriction after diuretic therapy (correlated to diuretic resistance theory). There is not any research which shows a correlation between furosemide usage to central nervous system dysfunction effects, although it might be caused by hypoperfusion to central nervous system after multi-organ dysfunction.^[12]

For respiratory organ system effect from diuretics, a previous study by Libório et al., including 14,896 patients, also found that loop diuretic usage in fluid overload critically ill patients was associated with the prolonged mechanical ventilation period.^[13] This is because of a serum bicarbonate level 2 mEq/L more than others, in which metabolic alkalosis could also affect the respiratory drive and minute ventilation.^[14]

The result of this study is not supported by DOSE-AHF study that shows diuretic benefits on curing organ system dysfunction caused by fluid overload (including cerebral edema, pulmonary edema, myocardial edema, hepatic congestion, renal interstitial edema, and intestinal edema).^[8] However, previous research supports the result of the study, stating that diuretic usage causes acute kidney injury and increases the mortality of patients with 1.68 odd ratios.^[15] This is explained by apoptosis of distal tubules cells in diuretic usage. Hypokalemia induced in diuretic therapy also causes tubulointerstitial fibrosis and kidney hypertrophy. Besides, tubular necrosis is also caused by systemic vasoconstriction based on diuretic resistance theory.^[11] Hence, the patient with vein hypertension caused by mesenteric vein compression might need more fluid resuscitation for tissue perfusion than furosemide therapy. Moreover, the use of diuretics in CKD patients should be carefully evaluated due to the high risk of electrolyte imbalances.^[16]

Variation on timing and method of diuretics administration may also affect the effectiveness to cure fluid overload in critically ill patients. It is concluded from a previous study that loop diuretics should be given as early as possible which was associated with the lower mortality. For the method of administration, no difference was seen in the primary endpoint between continuous and bolus infusion.^[17]

This study is the first research of diuretic usage on fluid overload ICU patients, evaluating the multi-organ dysfunction status of the patients. This is compared to previous studies which only evaluate specific organ system in each study. However, this research has significant confounding factors, including total fluid changes, total fluid before, and total fluid and after therapy. This may lead to an imbalance of higher MSOFA score in fluid overload patients with diuretic usage. Moreover, this research does not analyze other factors, including side effects of furosemide usage, patients’ diseases, and furosemide dosage.

Furosemide therapy should be individually adjusted, especially in those who have respiration, cardiovascular, and central nervous system dysfunction. Further, the research could be conducted to analyze the right time to start diuretic therapy and the correlation between the amount of fluid change to organ dysfunction status.

CONCLUSION

From this research results, we can draw the conclusion that there is a correlation between organ dysfunction status changes and furosemide usage in intensive care patients with fluid overload condition. Furosemide usage in this research worsens organ dysfunction, especially in cardiovascular and central nervous systems. Based on relative risk result, it is proven that furosemide usage causes 1.271 times more patients with organ dysfunction worsening compared to those without any diuretics usage.