Abstract
B
Clinical Context
Although thiazide diuretics (e.g., hydrochlorothiazide, chlorthalidone, or metolazone) and potassium sparing diuretics (e.g., spironolactone) are established therapies for chronic HF, loop diuretics such as furosemide or bumetanide are the mainstay for acute or severe HF.2,3 Loop diuretics work through two mechanisms: an immediate venodilator effect as well as diuresis of fluid and electrolytes. 2 Some HF patients enrolled in hospice develop refractory dyspnea, and swelling with resultant anxiety despite the use of opioids or benzodiazepines.4–6 SC furosemide, which is more easily administered at home than IV, has been proposed to help these patients.
Pharmacology
Bumetanide has not been established as safe and/or effective subcutaneously, thus furosemide is the preferred SC diuretic. Typically, the IV furosemide formulation is given through an SC clysis line for continuous subcutaneous infusions (CSCI) or a SC butterfly needle for intermittent dosing. Hence, SC and IV costs are essentially equivalent. For patients with an indwelling IV catheter, there is little rationale to utilize SC over IV. Furosemide formulations come in 20 to 50 mL syringes with concentrations of 10 mg/mL. Current daily dose limits are based on available commercial syringes and are ∼200–300 mg daily. This may change as the market for SC medications changes. 7
Onset of diuresis is 1–1.5 hours for oral; 30 minutes for SC; 5 minutes for IV furosemide. Therefore, if there is minimal urine output one to two hours after oral administration of furosemide, it is reasonable to consider a dose of parenteral furosemide in the setting of symptomatic dyspnea from HF. 8
Diuretic effect is six to eight hours for oral; four hours for SC; two hours for IV furosemide. 9
For intermittent SC dosing, many experts recommend starting with an equivalent oral dose. For CSCI dosing, calculate the initial hourly dose from the previous daily oral dose.10,11 For example, someone receiving 100 mg/day of oral furosemide should receive 100 mg SC in 24 hours or 4 mg/hour CSCI.
Outcomes
A human, preclinical, placebo-controlled trial demonstrated that furosemide has diuretic activity when administered subcutaneously. 9 The clinical evidence for SC furosemide otherwise is in a handful of case reports and series. In a series of 43 consecutive end-stage HF patients prescribed CSCI by palliative care or hospice clinicians, CSCI was associated with a median weight loss of 5.6 kg and most patients avoided hospital admission and terminal breathlessness. 10 A case series of HF patients who received intermittent SC furosemide demonstrated a prompt resolution of weight gain, breathlessness, and peripheral edema. 4
Side Effects and Safety
Diuretics can cause intravascular volume depletion and kidney injury. Furosemide promotes diuresis of sodium, potassium, magnesium, and chloride that can lead to significant electrolyte abnormalities and subsequent risk for cardiac arrhythmia. 7 Furosemide infusions have been associated with ototoxicity when used at doses >1600 mg daily or when used concurrently with a medication associated with ototoxicity (e.g., vancomycin).7,12 Self-resolving dermatologic site reactions involving stinging/burning at the site of injection may occur in up to 23% receiving CSCI. 9
Controversies
Clinicians should be cognizant of several unresolved clinical questions regarding the appropriate use of SC furosemide. 11
In general, the data supporting the efficacy of SC furosemide are less robust than other SC palliative-based medications, for example, SC use of opioids. 11
Clinical debate remains regarding the need for serum monitoring of renal function and electrolyte abnormalities for dying HF patients receiving SC furosemide to prevent sentinel iatrogenic events such as renal failure or cardiac arrhythmias. When prognosis is anticipated to be less than a month and goals of care are comfort, the rationale for serum laboratory monitoring may be less compelling.
For patients who can still safely swallow oral medications, adjuvant oral diuretics such as chlorthalidone and metolazone may augment the effectiveness of SC furosemide.5,13
Although empiric oral potassium supplementation has been associated with prolonged survival in those initiating furosemide use, 14 there is no current literature supporting or arguing against the use of oral potassium in standard end-of-life diuretic use and supplementation may depend on goals of care.
It remains unclear whether the optimal approach to utilizing SC is as a rescue therapy when clear signs of acute HF are apparent—for example, breathlessness and peripheral edema—versus a preventative approach wherein intermittent SC furosemide doses are given in response to weight gain.
Conclusion
In the setting of end-of-life HF management, there appears to be a role for the use of SC furosemide when oral treatment fails. Although further research is needed, small clinical investigations have demonstrated effective diuresis and prevention of hospital admissions and hospice de-enrollment without significant adverse effects from SC furosemide.