Frusemide is the most frequently used diuretic in critically ill patients . It exerts its action by selectively blocking the Na+/K+/2Cl− co-transporter in the luminal membrane of the thick ascending limb of the loop of Henle (Supplementary Fig. S1). To reach the site of action, it is first taken up by the proximal cells via organic anion transporters and then secreted into the luminal space from where it is transported to the distal tubule. Frusemide generates greater loss of water than sodium loss, resulting in the production of hypotonic urine. Diuretic resistance is not uncommon in patients receiving prolonged therapy with loop diuretics. Furthermore, concern has been raised that diuretic use may be associated with harmful effects, including acute kidney injury (AKI). This has led to uncertainty among clinicians about when and how to use frusemide safely and effectively in critically ill patients with and without AKI . Here, we address ten common myths about frusemide and its application in critically ill patients (Fig. 1).
Frusemide causes AKI.
No, it does not.
Frusemide promotes diuresis and is particularly useful in patients with fluid overload. However, it is a common conception that diuretics may cause AKI. In fact, few studies have identified diuretic use as a risk factor for AKI . However, most reports did not distinguish between different aetiologies of AKI and included patients with AKI due to hypovolaemia. It is very likely that inappropriate use of diuretics in this patient population contributes to the development of AKI. However, when used appropriately in patients with fluid overload, frusemide may actually resolve AKI, presumably due to resolution of intrarenal congestion and reduction of renal oxygen consumption [3, 4].
Frusemide and fluids together can prevent AKI in high-risk patients.
There is a common belief that the co-administration of frusemide and fluids increases diuresis without causing hypovolaemia. In fact, automated matched hydration systems using diuretics and fluids together exist for the prevention of contrast-associated AKI (CA-AKI). While some authors found a reduction in the incidence of CA-AKI , studies in patients with AKI did not demonstrate a beneficial effect on progression of AKI . In general, fluids should be considered as therapy for patients with intravascular hypovolaemia and diuretics should be reserved for patients with intravascular hypervolaemia.
Frusemide is contraindicated in AKI.
No, it is not.
Frusemide is indicated in patients with fluid overload, including those with AKI. However, higher doses may be needed in AKI, especially in severe AKI where the risk of diuretic resistance is higher, too. Frusemide also has a role in the management of hyperkalaemia . Finally, frusemide can be used as a diagnostic tool in AKI when assessing tubular function and risk of progression to higher stages of AKI (i.e. frusemide stress test) .
Frusemide can kick-start kidney function.
No, this is not the case.
Frusemide may lead to significant diuresis in patients with AKI. However, this has to be regarded as an indication of functioning tubular cells, rather than a direct beneficial effect of frusemide on renal function . Repeated doses of frusemide, especially in high doses and in anuric patients, may lead to a significant increase in side effects, in particular ototoxicity . In patients with fluid overload, who are not diuretic-responsive, there is no role for repeated frusemide application . In this situation, extracorporeal fluid removal should be considered.
Frusemide works better if given together with albumin.
In plasma, frusemide is highly protein-bound, and severe hypoalbuminaemia is associated with impaired frusemide secretion into the tubular lumen. The evidence supporting the combined use of albumin and frusemide is sparse. In a study including patients with liver cirrhosis and ascites, the administration of premixed loop diuretic and albumin (40 mg frusemide and 25 g albumin) did not enhance the natriuretic response . In contrast, a randomized controlled cross-over study in 24 patients with chronic kidney disease (CKD) and hypoalbuminaemia showed a significant increase in urine volume with frusemide and albumin . However, at 24 h, there were no longer any significant differences. A meta-analysis including 10 studies demonstrated better control of fluid balance with co-administration of frusemide and albumin in hypoalbuminaemic patients . Studies in patients with normal blood protein levels are inconclusive, pointing to no direct benefit of combined infusion in these patients.
Frusemide infusion is more effective than frusemide boluses.
No, it is not.
Several randomized controlled trials (RCTs) and meta-analyses showed that sustained diuresis is easier to achieve with continuous frusemide infusion compared to intermittent bolus therapy , but there is no evidence of better outcomes, including mortality, length of hospital stay, effect on renal function or electrolyte disturbances.
Frusemide can prevent renal replacement therapy (RRT).
No, it can’t.
Frusemide has a role in inducing diuresis in patients with fluid overload. If diuretic responsive, the administration of frusemide may buy time before RRT can be initiated. A meta-analysis reported that the administration of loop diuretics was associated with shorter duration of RRT . However, frusemide has no direct effect on chances of renal recovery. A pilot trial (the SPARK study) compared low-dose frusemide versus placebo in patients with early AKI and found no difference in the rate of worsening AKI or need for RRT .
Frusemide helps to wean anuric patients from RRT.
No, it does not.
In patients treated with RRT, increasing diuresis is a common reason for discontinuing RRT, and diuretics are frequently used for this purpose. However, there is no evidence that diuretics are effective at improving creatinine clearance or inducing renal recovery [12, 13]. However, it should be noted that frusemide was also associated with a higher incidence of ototoxicity, a risk that may be particularly relevant to anuric patients at increased risk of frusemide accumulation .
Frusemide-induced diuresis after AKI implies full renal recovery.
No, it does not.
While frusemide administration may lead to increased urine output (UO) in patients with AKI , frusemide-induced diuresis after AKI must not be considered a sign of full and permanent renal recovery. Even patients who experienced only a single episode of AKI and recovered excretory function remain at increased risk of CKD and increased mortality.
Frusemide should be stopped if serum creatinine is increasing, indicating worsening renal function.
No, not necessarily.
Many patients with acute heart failure have a rise in serum creatinine of 0.3 mg/dl or more during diuretic therapy . However, this must not automatically be interpreted as a sign of true worsening renal function (WRF) associated with impaired outcome. Since creatinine is measured as a concentration in serum, an isolated increase in serum creatinine in combination with a rise in haematocrit may simply be a sign of reduction in intravascular volume and effective decongestion. Importantly, it may also be associated with better outcomes. This phenomenon is termed pseudo WRF . A similar effect was observed in the FACTT trial, where restricted fluid therapy using substantial diuretic dose improved weaning from respirator but was associated with increased serum creatinine by nearly 0.3 mg/dl. Despite that, the requirement of RRT was even lower in this group .
Compliance with ethical standards
Conflicts of interest
The other authors declare having no conflict of interest related to this manuscript.
Bagshaw SM, Delaney A, Jones D, Ronco C, Bellomo R (2007) Diuretics in the management of acute kidney injury: a multinational survey. Contrib Nephrol 156:236–249CrossRefGoogle Scholar
Levi TM, Rocha MS, Almeida DN, Martins RT, Silva MG, Santana NC, Sanjuan IT, Cruz CM (2012) Furosemide is associated with acute kidney injury in critically ill patients. Braz J Med Biol Res 45:827–833CrossRefGoogle Scholar
Ho KM, Power BM (2010) Benefits and risks of furosemide in acute kidney injury. Anaesthesia 65:283–293CrossRefGoogle Scholar
Joannidis M, Druml W, Forni LG, Groeneveld ABJ, Honore PM, Hoste E, Ostermann M, Oudemans-van Straaten HM, Schetz M (2017) Prevention of acute kidney injury and protection of renal function in the intensive care unit: update 2017: expert opinion of the Working Group on Prevention, AKI section, European Society of Intensive Care Medicine. Intensive Care Med 43:730–749CrossRefGoogle Scholar
Shah R, Wood SJ, Khan SA, Chaudhry A, Rehan Khan M, Morsy MS (2017) High-volume forced diuresis with matched hydration using the RenalGuard System to prevent contrast-induced nephropathy: a meta-analysis of randomized trials. Clin Cardiol 40:1242–1246CrossRefGoogle Scholar
Bagshaw SM, Gibney RTN, Kruger P, Hassan I, McAlister FA, Bellomo R (2017) The effect of low-dose furosemide in critically ill patients with early acute kidney injury: a pilot randomized blinded controlled trial (the SPARK study). J Crit Care 42:138–146CrossRefGoogle Scholar
Chawla LS, Davison DL, Brasha-Mitchell E, Koyner JL, Arthur JM, Shaw AD, Tumlin JA, Trevino SA, Kimmel PL, Seneff MG (2013) Development and standardization of a furosemide stress test to predict the severity of acute kidney injury. Crit Care 17:R207CrossRefGoogle Scholar
Chalasani N, Gorski JC, Horlander JC Sr, Craven R, Hoen H, Maya J, Brater DC (2001) Effects of albumin/furosemide mixtures on responses to furosemide in hypoalbuminemic patients. J Am Soc Nephrol 12:1010–1016Google Scholar
Phakdeekitcharoen B, Boonyawat K (2012) The added-up albumin enhances the diuretic effect of furosemide in patients with hypoalbuminemic chronic kidney disease: a randomized controlled study. BMC Nephrol 13:92CrossRefGoogle Scholar
Kitsios GD, Mascari P, Ettunsi R, Gray AW (2014) Co-administration of furosemide with albumin for overcoming diuretic resistance in patients with hypoalbuminemia: a meta-analysis. J Crit Care 29:253–259CrossRefGoogle Scholar
Ng KT, Yap JLL (2018) Continuous infusion vs. intermittent bolus injection of furosemide in acute decompensated heart failure: systematic review and meta-analysis of randomised controlled trials. Anaesthesia 73:238–247CrossRefGoogle Scholar
Bagshaw SM, Delaney A, Haase M, Ghali WA, Bellomo R (2007) Loop diuretics in the management of acute renal failure: a systematic review and meta-analysis. Crit Care Resusc 9:60–68Google Scholar
van der Voort PH, Boerma EC, Koopmans M, Zandberg M, de Ruiter J, Gerritsen RT, Egbers PH, Kingma WP, Kuiper MA (2009) Furosemide does not improve renal recovery after hemofiltration for acute renal failure in critically ill patients: a double blind randomized controlled trial. Crit Care Med 37:533–538CrossRefGoogle Scholar
Damman K, Tang WH, Testani JM, McMurray JJ (2014) Terminology and definition of changes renal function in heart failure. Eur Heart J 35:3413–3416CrossRefGoogle Scholar
National Heart, Lung and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network, Wiedemann HP, Wheeler AP, Bernard GR, Thompson BT, Hayden D, deBoisblanc B, Connors AF Jr, Hite RD, Harabin AL (2006) Comparison of two fluid-management strategies in acute lung injury. N Engl J Med 354:2564–2575CrossRefGoogle Scholar