The effect of low-dose furosemide in critically ill patients with early acute kidney injury

Bagshaw. J Crit Care 2017;epublished July 12th. doi:

Clinical Question

• In critically ill patients, with mild renal failure, does furosemide infusion compared to placebo worsen kidney function?

Background

• Furosemide is commonly used in ICU patients with 60-70% of patients with AKI receiving diuretics
• The rationale for using diuretics includes prevention of tubular obstruction, reduction in medullary oxygen consumption and increase in renal blood flow as well as reducing fluid overload and venous congestion
• There is controversy as to whether this is helpful of harmful in this setting with trials providing conflicting results
• Four RCTs in patients with established renal failure have not shown improvement in clinically meaningful endpoints and there are risks of harm including hearing loss
• Studies in patients with RISK RIFLE AKI are lacking and of poor quality
• There is also variation in practice between centres and between individual clinicians
• A positive fluid balance is associated with a worse outcome in the ICU patient
• It is not known if furosemide can change this risk.

Design

• Pilot, randomized, blinded, placebo-controlled trial
• Phase 2 trial – testing effectiveness and safety
• Multicentre (3 ICUs)
• Randomization 1:1, blocks of variable size (4-8), stratified for site and presence of sepsis
• Blinding of study investigators and treating clinicians
• Study infusion bags of furosemide and placebo appeared identical
• A sample size of 214 patients was required to provide 80% power of detecting a 20% absolute reduction in the proportion who progress from RIFLE RISK class
  • Only 73 patients were recruited prior to early termination due to:
    • Study staff seconded to assist with pandemic influenza 2009
    • Drug shortages
• Statistical analysis was by intention to treat

Setting

• 3 University affiliated hospitals: Canada (1) and Australia (2)
• Study conducted between September 2009 and June 2014

Population

• Inclusion:
  • RISK RIFLE category AKI (Creatinine x1.5 baseline or UO < 0.5ml/kg/hr for 6 hours)
  • Peripheral or central catheter + urinary catheter
  • >/= 2 Systemic Inflammatory Response Syndrome (SIRS) criteria
  • Immediate resuscitation goals met; fluid resuscitated or vasoactive agents commenced
• Exclusion:
  • Age <18 years
  • Pregnancy (confirmed/suspected)
  • Obstructive etiology of AKI
  • ESKD on dialysis or transplant
  • Recent RRT
  • Recovering AKI (25% decrease in Cr)
  • Acute pulmonary oedema requiring urgent furosemide
  • Patient already on furosemide infusion
  • Moribund/expected to die within 24 hours or limits of medical therapy
  • Prior enrolment
• Baseline demographics were similar between groups although those in the furosemide group had more exposure to vancomycin (67.6% vs 38.9%).

Intervention

• 2000mg of furosemide was put in 500ml of normal saline. A loading dose of 0.4mg/kg followed by an infusion of 0.05mg/kg/h. The infusion was titrated to achieve a urine output of 1-2ml/kg/hr (maximum 0.4mg/kg/hr)
  • The infusion ran for 24 hours at a minimum to 7 days maximum
  • The infusion was discontinued if kidney recovery occurred, RRT was commenced, death, adverse reaction attributable to study drug, ICU discharge

Control

• An identical bag of 500ml normal saline was hung and run with the titration to urine output as above

Management common to both groups

• Other aspects of patient management were left to the discretion of the treating clinicians

Outcome

• Primary outcome: worsening of AKI as defined by progression of RIFLE category from RISK to a more severe category (INJURY, FAILURE, RRT) in the 7 days after randomization
  • There was no difference in the primary endpoint of worsening AKI between furosemide and placebo groups
    • Furosemide 43.2% vs Placebo 37.1%
    • Odds Ratio (as reported in paper) 1.52 (95% CI 0.61 to 3.83, P = 0.48)
    • Absolute Risk Increase 7.13% (95% CI -15.25% to +29.52%, P = 0.63)
  • There was no difference in the subgroup with sepsis or when a multivariate analysis was performed taking into account vancomycin exposure, APACHE II score, pre-randomization furosemide or oliguria.
• Secondary outcome: cumulative fluid balance, serum K+/Mg++, acid-base status, rates of RRT, rates of renal recovery, hospital mortality
  • There was no statistical difference across secondary endpoints, although patients who received furosemide had 1081ml less in cumulative fluid balance

Authors’ Conclusions

• A furosemide infusion compared to placebo did not change the incidence of progression to a worse degree of kidney injury

Strengths

• RCT, multicenter, allocation concealment, double blinding
• Complete data for primary endpoint
• Intention to treat analysis
• An important clinical question based on a sound pharmacological mechanism

Weaknesses

• Underpowered
• Early termination increasing the chance of a Type I error
• 30.6% of patients in the placebo arm received supplementary furosemide (compared to 10.8% in the treatment group)
• The study is limited to those with RISK category RIFLE AKI and may not apply to those with other degrees of renal dysfunction
• The use of furosemide may benefit some types of renal failure, eg ATN vs renal hypoperfusion but this trial was not large enough to explore this

The Bottom Line

• This trial does little to add to my clinical approach to using furosemide in patients with acute kidney injury
• The small size and methodological flaws make conclusions difficult to reach
• The impact of furosemide therapy on fluid balance is likely the most important consideration and I will continue to give a test bolus dose of furosemide to patients like this and be encouraged to use further diuretics if they have a good diuresis after the test dose

External Links

• [article] The SPARK study: The effect of low-dose furosemide in critically ill patients with early acute kidney injury: A pilot randomized blinded controlled trial
• [further reading] Development and standardization of a furosemide stress test to predict the severity of acute kidney injury
• [further reading] Acute Kidney Injury: life in the fastlane

Metadata

Summary author: Celia Bradford
Summary date: 2 August 2017
Peer-review editor: Duncan Chambler