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 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 6  |  Issue : 3  |  Page : 273-281

Furosemide stress test, a novel assessment tool for tubular function in critically ill patients with acute kidney injury: potential therapeutic and prognostic values


1 Department of Critical Care Medicine, Beni Suef University, Beni Suef, Egypt
2 Department of Critical Care Medicine, Cairo University, Egypt
3 Department of Critical Care, Nasser Institute Hospital, Cairo, Egypt

Date of Submission20-Jun-2018
Date of Acceptance29-Nov-2018
Date of Web Publication29-Aug-2019

Correspondence Address:
MD Hamdy M Saber
Department of Critical Care Medicine, Beni Suef University, Beni Suef
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/roaic.roaic_30_18

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  Abstract 

Introduction Acute kidney injury (AKI) is well recognized for its effect on the outcome of patients admitted to ICU. The pursuit of improved biomarkers for the early diagnosis of AKI and its outcomes is an area of intense contemporary research; studies demonstrated the utility of furosemide stress test (FST) for predicting the severity of AKI, and a possibility of administration as a treatment for acute kidney injury network (AKIN) I and II.
Patients and methods A total of 80 patients in ICU of Nasser Institute Hospital (July 2014–2015) were recruited, including 40 patients who received FST and 40 patients who received standard management. Patients included were those who developed AKI grades Ι–Π according to AKIN criteria. They were assessed clinically and followed through the duration of the study by hourly central venous pressure measurement (CVP) and urine output for 6 h, besides daily kidney function tests and estimated glomerular filtration rate for 3 days.
Results In the first 6 h, there was a significant increase in urine output in group I after first and second hours (P=0.026, 0.008, respectively), as well as cumulative UOP over 6 h (P=0.003), as compared with group II. The cutoff point regarding UOP for detection of progress to AKIN III and dialysis was found to be 325 ml in both groups, with sensitivity of 86.7% and specificity of 68% in group I and sensitivity of 95% and specificity of 95% in group II. There was a highly significant difference between the two groups concerning hypotension, which occurred in 11 patients in group I versus none in group II, with P value of 0.001, whereas there was no significant difference between both the groups concerning progression to AKIN III and dialysis, with P value of 0.260; ICU stay, with P value of 0.621; and mortality, with P value of 0.201. Our results in group I patients who did not show worsening of AKIN class had significantly higher urine output as compared with those whose AKIN class worsened, with P value of 0.001.
Conclusion FST is a good predictor of severity of tubular damage in early stages of AKI, with no additional privilege over standard management in the treatment of AKI. Moreover, it carries more risk of hemodynamic compromise.

Keywords: acute kidney injury, dialysis, furosemide


How to cite this article:
Saber HM, Mahmoud WF, Khaled H, Awad MA. Furosemide stress test, a novel assessment tool for tubular function in critically ill patients with acute kidney injury: potential therapeutic and prognostic values. Res Opin Anesth Intensive Care 2019;6:273-81

How to cite this URL:
Saber HM, Mahmoud WF, Khaled H, Awad MA. Furosemide stress test, a novel assessment tool for tubular function in critically ill patients with acute kidney injury: potential therapeutic and prognostic values. Res Opin Anesth Intensive Care [serial online] 2019 [cited 2019 Oct 19];6:273-81. Available from: http://www.roaic.eg.net/text.asp?2019/6/3/273/265715


  Introduction Top


Acute kidney injury (AKI) is a common complication of critical illness. Overall, 7–10% of ICU patients develop AKI during their ICU stay [1], and 45–60% of them are associated with high mortality [2]. An early detection of adult patients with AKI may provide the opportunity to promptly treat and prevent the deterioration of kidney injury [1].

Patients who develop AKI often require renal replacement therapy; however, clinicians often disagree about the optimal timing of the initiation of renal replacement therapy [3].

Because AKI biomarker levels change over time depending on the timing and severity of injury [4], a functional assessment of renal function might enhance biomarker performance. Furosemide has an appealing pharmacokinetic property, being actively secreted directly into the renal tubules. As most common form(s) of intrinsic AKI involve acute tubular injury, furosemide stress test (FST) was proposed for the assessment of renal tubular function.

Aim of work

The aim of our study is to evaluate the value of FST as a predictor of severity of AKI and its possible therapeutic and prognostic implications.


  Patients and methods Top


Our study was a prospective cohort observational study that was conducted on 80 consecutive patients in the general ICU of Nasser Institute Hospital in the period from November 2014 until April 2015. The protocol was approved by the ethical committee and written consent was signed by patients.

The study population was divided into two groups:
  1. Group I (patients group): 40 consecutive patients who received FST upon inclusions in the study followed by furosemide infusion after 6 h.
  2. Group II (control group): 40 consecutive patients who received standard management with optimizing volume status, bolus diuretics up to infusion, and avoiding nephrotoxic agents.


AKI was diagnosed according to acute kidney injury network (AKIN) criteria in oliguric patients [5],[6].

We included in this study any ICU patient with age greater than 18 years having AKI, with AKIN stage I [6 h of oliguria (<0.5 ml/kg/h) or 0.3 mg/dl rise in serum creatinine, or, increase in 1.5–2 folds above baseline serum creatinine] or AKIN stage II [12 h of oliguria (<0.5 ml/kg/h) or increase >2–3 folds above baseline serum creatinine], whereas we excluded patients with baseline glomerular filtration rate (GFR) less than 30 ml/min, patients with known hypersensitivity to loop diuretics, those with AKIN stage III, and those having evidence of volume depletion or obstructive uropathy.

Data collected included demographic data, comorbidities, clinical and laboratory parameters, adverse effects related to furosemide usage, and outcome parameters (length of stay in ICU, progression to AKIN III with a need for dialysis and in-hospital mortality).

FST in group 1:
  1. Patients who are loop diuretic naive will receive 1.0 mg/kg of intravenous furosemide as a bolus dose.
  2. Patients who were previously treated with loop diuretics within the previous 7 days will receive 1.5 mg/kg of intravenous furosemide as a bolus dose.


To minimize the risk of hypovolemia, urine output will be replaced milliliter for milliliter each hour for 6 h after the FST. The treating team could elect not to replace the volume if net volume loss is considered clinically desirable. Urine output will be measured hourly for 6 h and in total for 24 h, and positive response to FST dose is attained if the patient has urine output more than 0.5 ml/kg/h within first 6 h. Patients after 6 h will receive furosemide infusion titrated to response heralded by improvement of kidney function and urine output.

In group II

  1. Patients will receive standard management with optimizing volume status, bolus diuretics up to infusion, and avoiding nephrotoxic agents.


Follow-up of patients was performed up to ICU discharge, improvement of kidney function, or death whichever occurred first.

Statistical analysis

Data were coded and entered using the statistical package for the social science, version 22 (SPSS Inc., Chicago, Illinois, USA), version 17 for Microsoft Windows. Data were summarized using mean, SD, median, minimum, and maximum for quantitative variables and frequencies (number of cases) and relative frequencies (percentages) for categorical variables. Comparisons between groups were done using the nonparametric Mann–Whitney test. For comparing categorical data, χ2 test was performed. The exact test was used instead when the expected frequency is less than 5. Receiver operating characteristic curve for detection of progress using total urine output was constructed, and area under curve analysis was performed to get the best cutoff value. P values less than 0.05 were considered as statistically significant.


  Results Top


Demographic data

The mean age in group I was 55.8±12.63 years, with no significant difference from group II (mean: 55.28±15.89 years) (P=0.946). Regarding comorbidities (hypertension–diabetes mellitus–ischemic heart disease), there was no statistically significant difference between the two groups ([Figure 1]).
Figure 1 Comorbidities in both groups.

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Clinical parameters

The mean arterial pressure in group I over first 6 h was 84.86±11.49 mmHg, which did not significantly differ from group II (mean, 83.64±10.34; P=0.657). There was a tendency of higher central venous pressure (CVP) in group I (11.15 cmH2O) than group II (9.58), but it did not reach statistically significant difference (P=0.062).

Regarding urine output (first 6 h) (ml) in the first 6 h, there was a statistically significant increase in urine output (UOP) in group I after first and second hours (P=0.026, 0.008, respectively), as well as cumulative UOP over 6h (P=0.003), as compared with group II ([Figure 2] and [Figure 3]).
Figure 2 Cutoff points of urine output: to predict progress to AKIN III and dialysis. AKIN, acute kidney injury network.

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Figure 3 Cutoff points of urine output in group I to predict progress to AKIN III and dialysis. AKIN, acute kidney injury network.

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Receiver operating characteristic curve was plotted for detection of worsening of kidney function using total urine output in the first 6 h in group I; it yielded a cutoff value of 575 ml with sensitivity of 84% and specificity of 93.3% (P=0.001), where patients who failed to achieve this value progressed to AKIN III and dialysis ([Figure 1]).

However, in group II, patients who achieved 450 ml of urine in the first 6 h showed improvement, whereas patients who failed to achieve this value progressed to AKIN III and needed dialysis, with sensitivity of 100% and specificity of 95% (P=0.001) ([Figure 4]).
Figure 4 Cutoff points of urine output in group II to predict progress to AKIN III and dialysis. AKIN, acute kidney injury network.

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Laboratory measurements

Serum creatinine

Regarding serum creatinine on admission, there was no statistically significant difference between both the groups (P=0.052). On day 1, there was a statistically significant lower creatinine level in group I as compared with group II (P=0.031); however, there was A nonsignificant difference on days 2 and 3 between the two groups (P=0.145 and 0.242, respectively) ([Table 1]).
Table 1 Serum creatinine follow-up in both groups

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Glomerular filtration rate

Regarding calculated GFR, there was a highly significant difference between the two groups on day 1, being higher in group I (P=0.019), but there was no significant difference between both groups in the second or third days. Moreover, it was noticed that GFR was increasing progressively by time in both groups. The delta GFR (difference between GFR on admission and on the third day) in group I improved from 15.78 to 24.37 ml/min/1.73 m2, whereas in group II, it increased from 11.17 to 20.50 ml/min/1.73 m2, but there was no significant difference (P=0.939) ([Figure 5]).
Figure 5 Comparing GFR between both groups over follow-up days. GFR, glomerular filtration rate.

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Adverse effects

Hypotension within first 6 h

Regarding hypotension as an adverse effect in group I, 11 patients had hypotension in group I, representing 27.5%, whereas no patients in group II had this adverse effect, which was statistically significant (P=0.001) ([Figure 6]).
Figure 6 Comparing hypotension in both groups.

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Electrolytes imbalance

Collectively, there was no statistically significant difference between both groups concerning hypokalemia, hypomagnesemia, and hypophosphatemia, whereas hyponatremia did not occur in any patient in both groups ([Table 2]).
Table 2 Comparing the incidence of electrolyte imbalance during the follow-up days

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Outcome parameters

Progression to acute kidney injury network III and need for dialysis

Regarding progression in group I, 15 (37.5%) patients progressed to AKIN III, whereas in group II, 20 (50%) patients progressed to AKIN III, representing approximately 50%. However, there was no statistically significant difference between the two groups (P=0.260).

Correlation between progression to acute kidney injury network III and need for dialysis with urine output within first 6 h

Patients who did not progress to AKIN III showed a nonsignificant higher urine output (848±298.78 ml) in group I versus (752.50±171.28 ml) in group II, with P value of 0.24.

However, patients who progressed to AKIN III showed a significantly lower urine output (285±84.85 ml) in group II versus in group I (376.67±157.96 ml), with P value of 0.026.

Upon comparing patients who exhibited worsening of AKIN class with those who did not worsen in group one, we found higher UOP in the former group, with high statistical significance (P=0.001), which reflects the capability of FST dose as a predictor of progression to AKIN III and dialysis ([Table 3]).
Table 3 Urine output in response to furosemide stress test in progression group

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Length of stay in ICU

Regarding the length of ICU stay in group I, the mean length of stay was 4.81±1.85 days, with range from 3 to 10 days, whereas in group II, the mean was 4.8±2.38 days, with range from 3 to 14 days. There was no statistically significant difference between both groups (P=0.621).

Mortality

Regarding mortality in group I, there were five (12.5%) patients who died, whereas in group II, there was only one (2.5%) patient who died, but still there was no statistically significant difference between the two groups (P=0.201).


  Discussion Top


AKI is a well-recognized major health problem in ICU patients all over the world. It is well established that early diagnosis and prompt management may prevent progression to more severe renal injury and need of more invasive, lengthy, and hence costly treatment [1].

Recent studies have demonstrated the utility of FST as a functional test for predicting the severity of AKI [4].

Our study aimed at evaluating FST as both a predictor of tubular function in AKI together with its possible therapeutic and prognostic effect on patients with AKIN (I and II) receiving FST dose upon inclusion in comparison with standard management of AKI.

In this study, we included 80 patients admitted to Nasser Institute ICU with the diagnosis of AKI (AKIN classes I and II) over the period from July 2014 till July 2015. They were divided into two groups: group I included 40 consecutive patients who received FST dose and group II included 40 consecutive patients who received standard management for AKI.

Regarding urine output, our study demonstrated that the most significant difference in urine output between group I and group II was found to be on the first and second hours after inclusion as well as cumulative UOP after 6 h, where it was higher in group I than group II. This is in concordance with Koyner et al. [7], who found that maximum diuresis was in first 2 h after providing intravenous furosemide; Lakhmir [8], who found that maximum diuresis occurred in second and third hours after receiving high-dose furosemide; and Shilliday et al. [9], who found that maximum urine flow rate was within the first 6 h after administration of furosemide.

Upon addressing serum creatinine level, our study showed that there was a gradual decline in both groups over 3 days of follow-up, but with statistical significance only demonstrated in group I versus group II on the first day; however, Shilliday et al. [9] and Grams et al. [10] stated that the significant improvement in creatinine was on second day after receiving furosemide.

Similarly GFR showed progressive improvement in our study in the follow-up period, with no significant difference between the two groups, which agreed with Heyman et al. [11] and Koyner et al. [7], who stated that GFR showed progressive improvement after receiving either high dose of furosemide versus standard management for AKI, with no significant difference as well.

Regarding adverse effects noticed in both groups, hypotension occurred only in the group receiving FST dose in contrast with Lakhmir et al. [8] where they reported no significant incidence of hypotension with the administration of high-dose furosemide [8]. No cases had hypotension in group II.

Regarding electrolytes, there was no statistically significant difference between both groups concerning hypokalemia, hypomagnesaemia, and hypophosphatemia, whereas hyponatremia did not occur in any patient in both groups.

As for progression of AKI, our study found that group II showed a higher tendency of worsening of AKIN class than group I; however, there was no statistically significant difference, which agreed with Ahmed et al. [12], who showed no significant effect of higher doses of furosemide on preventing the progression to AKIN III.

Various studies stated that UOP within 2 h of furosemide administration predicted the progression to AKIN III and need for dialysis, as Koyner et al. [7] found that UOP within 2 h was a good predictor of progression to AKIN III and need for dialysis. Ho and Sheridan [13] and Chawla and Davison [14] found that sustained urinary output response to furosemide at the early stage of AKI may be considered as a surrogate for having a mild AKI and having a lower risk of requiring dialysis. Lakhmir et al. [8] found that the total urine output in the first 2 h after the FST dose was given could predict the progression to AKIN III and dialysis with a cutoff value of 200 ml of total urine output with best sensitivity (87%) and specificity (87%). In our study, the cutoff point for detection of the worsening of AKIN class and need for dialysis was 325 ml in both groups with sensitivity 84% and specificity of 93.3% in group I, and sensitivity of 84% and specificity of 86% in group II within the first 2 h.

On the contrary, Uchino et al. [15] and Mehta et al. [16] even stated that furosemide might actually increase the risk of progression to AKIN III and need for dialysis [15],[16].

Concerning length of ICU stay, our study found that there was no statistically significant difference between the two groups in length of ICU stay, which was in concordance with Ho and Sheridan [17] and Ahmed et al. [12] who stated that there was no significant difference of administrating higher dose of furosemide in shorting the length of ICU stay versus conventional doses. However, this was discordant with Ahlstrom [18] who found that the length of stay was significantly shorter in the group who received FST dose.

In our study, we found that in group I, there were five patients who died, representing 12.5%, whereas in group II, there was only one patient who died, representing 2.5%, but there was no statistically significant difference between both groups. This was in concordance with Shilliday et al. [9], Ahmed et al. [12], and Ho and Sheridan [13], who found that there was no significant difference regarding mortality in patients who received higher doses of furosemide. However, Uchino et al. [15] and Mehta et al. [16] disagreed as they found that furosemide increased the risk of intrahospital mortality. On the contrary, Koyner et al. [7] found that FST was a good indicator of mortality.


  Conclusion Top


FST can be viewed as a novel dynamic functional assessment tool of renal tubular function that appears to have good predictive capacity to identify those patients who will progress to advanced-stage AKI and need dialysis; however, FST has no additional privilege over standard management regarding therapeutic or prognostic implications. Moreover, it demonstrated a lower safety profile regarding the incidence of adverse effects.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Bellomo R, Kellum JA, Ronco C. Acute kidney injury. Lancet 2012; 380:756–766.  Back to cited text no. 1
    
2.
Coca SG, Singanamala S, Parikh CR. Chronic kidney disease after acute kidney injury: a systematic review and meta-analysis. Kidney Int 2012; 81:442–448.  Back to cited text no. 2
    
3.
Hsu RK, McCulloch CE, Dudley RA, Lo Lj, Hsu CS. Temporal changes in incidence of dialysis-requiring AKI. J Am Soc Nephrol 2013; 24:37–42.  Back to cited text no. 3
    
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Devarajan P. Emerging biomarkers of acute kidney injury. Contrib Nephrol 2007; 156:203–212.  Back to cited text no. 4
    
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Wlodzimirow KA, Abu Hanna A, Royakkers AA, Spronk PE, Hofstra LS, Kuiper MA et al. Transient versus persistent acute kidney injury and the diagnostic performance of fractional excretion of urea in critically ill patients. Nephron Clin Pract 2014; 126:8.  Back to cited text no. 5
    
6.
Bagshaw SM, George C, Bellomo R. A comparison of the RIFLE and AKIN criteria for acute kidney injury in critically ill patients. Nephrol Dial Transplant 2008; 23:1569–1574.  Back to cited text no. 6
    
7.
Koyner JL, Davidson DL, Brasha-Mitchell E, Chalikonda DM, Arthur JM, Shaw AD et al. Furosemide stress test and biomarkers for the prediction of AKI. J Am Soc Nephrol 2015; 26:2023–2031.  Back to cited text no. 7
    
8.
Lakhmir S. Diagnostic criteria for acute kidney injury. Crit Care 2013; 17:621–632.  Back to cited text no. 8
    
9.
Shilliday IR, Quinn KJ, Allison MEM. Loop diuretics in the management of acute renal failure: a prospective double-blind, placebo-controlled, randomized study. Nephrol Dial Transplant 1997; 12:2592–2596.  Back to cited text no. 9
    
10.
Grams ME, Estrella MM, Coresh J, Brower RG, Liu KD et al. Fluid balance,diuretic use and mortality in acute kidney injury. Clin J Am Soc Nephrol 2011; 6:966–973.  Back to cited text no. 10
    
11.
Heyman SN, Rosen S et al. Loop diuretics’ reduce hypoxic damage to proximal tubules of the isolated perfused rat kidney. Kid Int 1994; 45: 981–985.  Back to cited text no. 11
    
12.
Ahmed US, Iqbal HI, Akbar SR. Furosemide in acute kidney injury − a vexed issue. Austin J Nephrol Hypertens 2014; 1:1025.  Back to cited text no. 12
    
13.
Ho KM, Sheridan DJ. Meta-analysis of furosemide to prevent or treat acute renal failure. Br Med J 2006; 333:420.  Back to cited text no. 13
    
14.
Kellium JA. Diagnostic criteria for acute kidney injury: present and future. Crit Care Clin 2015; 31:621–632.  Back to cited text no. 14
    
15.
Uchino S, Doig GS, Bellomo R, Bellomo R, Morimatsu H, Morgera S et al. Beginning and ending supportive therapy for the kidney (B.E.S.T. Kidney) investigators. Diuretics and mortality in acute renal failure. Crit Care Med 2004; 32:1669–1677.  Back to cited text no. 15
    
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Mehta RL, Godin M, Bouchard J. Fluid balance in patients with acute kidney injury: emerging concepts. Nephron Clin Pract 2013; 123:238–245.  Back to cited text no. 16
    
17.
Ho KM, Sheridan DJ. Meta-analysis of furosemide to prevent or treat acute renal failure. Br Med J 2006; 333:420.  Back to cited text no. 17
    
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Ahlstrom A. Acute renal failure in critically ill patients. Helsinki, Finland: Department of Anesthesiology and Intensive Care Medicine Helsinki University; 2006. 27.  Back to cited text no. 18
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
 
 
    Tables

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