Question 7

Potential indications
1.    Use as a diuretic for fluid overload
-Acute treatment of Fluid overload/LVF for first line therapy.
Primary respiratory failure i.e. ARDS, inc non-cardiogenic pulmonary oedema. TACO,
 
Secondary to other organ failures e.g. CCF (peripheral and pulmonary oedema), CRF (peripheral and pulmonary oedema), CLD (oedema or ascites)
+/-
-Chronic/maintenance therapy for CCF, CRF, CLD, Use in high altitude sickness. HACE. HAPE.
 

2.    Use as a diuretic as a forced diuresis
In pathologies such as rhabdomyolysis, barbiturate poisoning.

3.    Electrolyte manipulation
Use in hypercalcaemia (with fluid as a forced diuresis)
Use in urgent hyperkalaemia control as adjunct with salbutamol for compartment shift Use in hypernatremia 2’ to water intoxication.
E.g., TURP syndrome, psychogenic polydipsia, SIADH (with or without fluid restriction)

4.    As one of First line therapies in chronic hypertension control. OR acute hypertensive emergencies.

5.    Paediatric bronchopulmonary dysplasia management
 

Proposed Benefits
•    Reduction of preload and afterload in CCF and RHF- Venodilation and diuresis causing reduction in RAP and PCWP
•    Changes renal failure from oliguric to non-oliguric and this may reduce duration of AKI (controversial- limited or poor evidence for this)
•    May reduce need for renal replacement therapy in terms of fluid balance requirements however shown no benefits in RCTs
•    First line treatment of volume overload and electrolyte homeostasis
•    Frusemide is a Loop diuretic which Increases Tubular flow but there seems to be no clinical benefit for this only theoretical.

Adverse effects –
•    Worsening renal function -particularly if diuretic therapy is not accompanied by adequate hydration.
•    Increased electrolyte abnormalities- hypokalaemia, hypomagnesaemia, Hypernatraemia
•    Metabolic alkalosis
•    Hearing loss, vertigo and nystagmus in toxic doses
•    Sulpha cross reactivity but this is very rare
•    Worsening of gout as reduction of clearance of uric acid Drug interactions
Additive with aminoglycosides for ototoxicity
Reduction in lithium renal clearance given increased Li toxicity risk
 

The Evidence
DOSE   trial   (2011)   bolus   high   dose   frusemide   (2.5x  daily  dose)    reduced mortality in decompensated heart failure patients over low dose or infusion.

Cochrane review 2013- no clear benefit for any AKI sparing strategies including frusemide. Cochrane review 2015- no benefit from routine use of frusemide in transfusions to avoid TACO.
A recent meta-analysis published 2018 by Bove et al that concluded that there was no difference in mortality or length of hospital stay in patients given frusemide boluses in established renal failure which is consistent with others, but there was a survival benefit in the subgroup receiving Frusemide as a preventative measure. The conclusion was that there is no evidence at present to unequivocally support the use of Frusemide in acute kidney injury in the intensive care unit in unselected patients.

A number of other meta-analysis have consistently found higher urine output, decreased use of RRT and duration of RRT but no improvement in outcome.

SPARK study (2017) confirmed the above findings but also noted that there was an increased rate of electrolyte abnormalities with frusemide.

The European society of Intensive care consensus statement 2017 advised against the use of Loop diuretics in unselected patients with AKI due to lack of evidence for benefit in use and increased risk of adverse effects.

In summary, from the evidence available – the use of frusemide is not without adverse effects but may reduce the use of RRT in some patients. At present there is insufficient evidence to unequivocally support its use in unselected patients with established renal failure in ICU. However, in this setting, it may be beneficial in some patients in preventing the use of RRT and in those patients with fluid overload

Examiners Comments:

This question was generally poorly answered. A number of candidates lacked knowledge about proposed benefits of frusemide use and adverse effects. Rather than a summary statement of the evidence, many candidates chose to describe their own practice, not answering the question asked.

Discussion

The college answer, though overabundant with Inappropriately Capitalised Words, is an excellent piece of work, and difficult to improve upon in terms of raw content. All one can do is rearrange the points and dress them with some references.

In terms of answering, the question sounds a lot like "describe all the possible uses of frusemide you can think of". The college answer, however, seems to be very focused on the use of frusemide in renal failure. 

Potential indications for frusemide

• Cardiovascular indications
  • Diuresis to decrease fluid balance, which is thought to be associated with improved mortality (Shen et al, 2019)
  • Preload reduction by volume reduction and venodilation (Dikshit et al, 1973) 
  • Hyperkalemia (Mushiyakh et al, 2012) and hypercalcemia
  • Management of water excess (surely, the college meant "hyponatremia 2’ to water intoxication")
• Toxicological and endocrine indications
  • Diuresis to force urine output, eg.to prevent haemorrhagic cystitis secondary to cyclophosphamide (Droller et al, 1982)
  • Urinary acidification, for toxicological purposes (to improve clearance of weakly alkaline drugs)
• Endocrine and renal indications
  • Urinary acidification in the context of RTA (Rastogi et al, 1985)
• Other indications
  • High altitude cerebral oedema
  • High altitude pulmonary oedema

Proposed benefits of frusemide

In cardiac failure

• Decreased preload and afterload decrease LV oxygen consumption and shouldimprove symptoms from heart failure

In renal failure:

• Renal failure is typically associated with fluid overload due to oliguria, hyperkalemia and metabolic acidosis
• These derangements are also common indications for dialysis
• Frusemide may mobilise fluid, increase elimination of potassium and promote alkalinisation of the extracellular fluid
• Ergo, the use of frusemide may reduce the need for dialysis

In electrolyte disturbances

• Electrolyte depletion caused by frusemide may be beneficial where those electrolytes are present in a dangerously high concentration, and where other clearance methods are not appropriate

Adverse effects of frusemide

• Hypotension
• Worsening renal function 
• Electrolyte derangement: undesirable electrolyte depletion, hypernatremia and metabolic alkalosis.
• Urate accumulation (Kahn, 1988)
• Lithium toxicity  (Oh et al, 1977)
• Ototoxicity  (Wigand et al, 1971) including vertigo and nystagmus 
• Allergic reaction (Hansbrough et al, 1987).
• Arterial vasoconstriction (Jhund et al, 2000)
• Paralysis of mucociliary clearance (Kondo et al, 2001)
• Drug interactions can occur (Ho & Power, 2010); for example frusemide reduces clearance of cephalosporins, benzylpenicillin, gentamicin, and theophylline
• Larger doses are usually required in renal failure,  which increases toxicity
• Diuresis gives rise to decreased circulating volume and therefore may lead to the activation of the renin-angiotensin-aldosterone axis, increasing salt retention
• Increased urine output may be misinterpreted as an improvement in renal function, whereas in fact, no such improvement has taken place (and all sorts of useful diagnostic and management steps for acute renal failure would therefore be delayed)
• With frusemide, the concentration of urinary sodium becomes an unreliable discriminator between pre-renal and intra-renal causes of renal failure (not that it's particularly reliable anyway).
• Acidification of the urine may reduce the solubility of myoglobin and exacerbate free radical damage due to ionised contrast

Evidence in support of using frusemide in ICU patients

• In cardiac failure:  The 2013 AHA statement recommends loop diuretics specifically with Level 1 grade of recommendation. The DOSE trial (Felker et al, 2011)  demonstrated some improvement in secondary outcomes and self-reported symptoms when the decompensated CCF patients' regular frusemide dose was increased by 250%.
• Cardiorenal syndrome is an indication for the use of frusemide by virtue of the same mechanism as its use in heart failure (Ronco et al, 2008)
• To decrease fluid balance: there decreased mortality in shocked patients who received diuretics (Shen et al, 2019).
• Portal hypertension management:  frusemide together with other agents is probably more effective than frusemide alone (Garcia-Pagan et al ,1999).
• Acute hypercalcemia: evidence is from case cohorts only   Suki et al (1970) reported success with 100mg given every 2 hours.
• Transfusion-related circulatory overload -  "Cochrane review 2015"  which concluded "no benefit from routine use of frusemide in transfusions to avoid TACO" - that was probably Sarai et al (2015), who made those conclusions on the basis of only four studies with a total of 100 patients. 

Evidence for the use of frusemide in renal failure

• Frusemide does not prevent acute renal failure perioperatively. This was the conclusion of Zacharias et al (2013), which is probably the "Cochrane review 2013" which concluded "no clear benefit for any AKI sparing strategies including frusemide".
• Frusemide does not reduce mortality in established renal failure, according to Bove et al (2018). However, reduced duration of CRRT dependence or improved fluid balance are easier to demonstrate, and these may be interpreted as patient-centred outcomes (i.e. the patients are probably happier because they are free from the circuit for longer periods). 
• Frusemide does not prevent progression to dialysis in acute renal failure. The SPARK study (Bagshaw et al, 2017)  enrolled AKI patients and gave them frusemide, to no apparent effect beyond some undesirable electrolyte disturbances. 
• Frusemide does not improve recovery from anuric renal failure. Those kidneys will stay dead, as was confirmed by van der Voort et al (2009). The investigators infused their CRRT-dependent patients with 0.5mg/kg/hr of frusemide (that's about 40mg per hour or 960mg per day). Though urine output increased, there was no difference in the need for RRT, nor any change in survival chances.
• Frusemide may decrease mortality when used to prevent renal failure. "A trend towards a beneficial effect of intermittent furosemide administration was found when analyzing the subgroup of studies in which furosemide was administered to prevent AKI", found Bove et al (2018). However, ESICM recommend against the use of diuretics as solo agents to prevent AKI from nephrotoxic insults (Joannides et al, 2017).