CONTENTS
Specific diuretics
General approach to diuresis in acute care medicine
Managing problems that arise during diuresis
[1] acetazolamide: dosing
⚠️ Diuretic tolerance often arises when acetazolamide is used for >48 hours. (37675009)
adjunctive diuresis in heart failure
- ADVOR trial: (36027559)
- Patients admitted with heart failure were randomized to adjunctive 500 mg IV acetazolamide daily for up to three days (with all patients receiving furosemide).
- Patients were previously on furosemide.
- Acetazolamide improved decongestion and especially natriuresis.
- Acetazolamide didn't appear to benefit patients on >60 mg/day of furosemide prior to admission, suggesting that it may not be helpful among patients with chronic diuretic resistance (such patients often develop hypertrophy of the distal nephron, so they might benefit more from thiazides or amiloride). (38589570)
- Acetazolamide did increase the likelihood of a creatinine increase by >0.3 mg/dL (40% vs. 20%).
- Patients on SGLT2-inhibitors were excluded. Since acetazolamide and SGLT2-inhibitors both increase sodium excretion in the proximal convoluted tubule, it's unclear how beneficial acetazolamide would be among patients on SGLT2-inhibitors. (38300391)
- ⚠️ Patients in this trial did receive daily magnesium infusions – so if acetazolamide is utilized, care should be directed towards magnesium monitoring and repletion.
metabolic alkalosis
- Typical dose: 500-1000 mg IV, q12-q24. The dose depends on the severity of the alkalosis and how briskly the patient is being diuresed (since ongoing diuresis will usually exacerbate the alkalosis).
- For management of established metabolic alkalosis, the following regimen is aggressive, yet proven to be safe among ICU patients in the DIABOLO trial: (26836730)
- In patients receiving simultaneous loop diuretics: 1,000 mg IV acetazolamide q12hr.
- In patients not receiving simultaneous loop diuretics: 500 mg IV acetazolamide q12hr.
- For prevention of metabolic alkalosis in the context of ongoing diuresis, lower doses may be appropriate.
hyperkalemia
- 500-1,000 mg IV x1 may be reasonable for life-threatening hyperkalemia. 📖
elevated ICP (intracranial pressure)
- For acute ICP elevation in the context of critical illness, 1000 mg IV may be followed by 250-1000 mg IV q12 hours.(36122055, 32503897) Acetazolamide may cause NAGMA (non-anion gap metabolic acidosis) and hypokalemia, so electrolytes should be followed and corrected (e.g., with exogenous bicarbonate and potassium supplementation).
[2] acetazolamide: contraindications & cautions
- Hypokalemia.
- Metabolic acidosis.
- Stable, chronic metabolic alkalosis compensatory for chronic respiratory failure (avoid reduction of bicarbonate to below the patient's chronic baseline level).
- Advanced liver disease (may increase the risk of encephalopathy). (37675009)
[3] acetazolamide: indications & use
- Hyperkalemia (acetazolamide promotes renal loss of potassium, in conjunction with loop and thiazide diuretics).
- This is a component of the nephron bomb for treatment of hyperkalemia. 📖
- Metabolic alkalosis (e.g. contraction alkalosis, which often arises during large-volume diuresis).
- Elevated intracranial pressure: Acetazolamide reduces CSF secretion. This may be useful as a therapy for communicating (non-obstructive) hydrocephalus.
[4] acetazolamide: pharmacology
- Oral bioavailability is ~100% (but may decrease with higher doses).
- Time to onset following IV administration: 15-60 minutes.
- Half-life is ~10 hours.
- Duration of effect may be ~12 hours. (37675009)
[5] acetazolamide: mechanism of action & physiological effects
effects on electrolytes
- Reduces bicarbonate level.
- Strongly reduces potassium level.
- Reduces calcium level.
- Reduces magnesium level.
physiology
- Acetazolamide is a carbonic anhydrase inhibitor, which prevents reabsorption of sodium bicarbonate in the proximal tubule. Consequences include:
- (1) Stimulates secretion of sodium bicarbonate.
- (2) Causes potassium wasting and hypokalemia.
- (3) Increased delivery of sodium to the macula densa, which may induce tubuloglomerular feedback, thereby reducing the renal blood flow and the glomerular filtration rate (GFR).
- Acetazolamide has intrinsic renal vasodilatory effects, which might protect the nephron against ischemia-reperfusion injury. (37675009)
[1] SGLT2i: dosing & considerations when starting therapy
🛑 down-titration of other antihyperglycemic therapies
- Hypoglycemia may result from the addition of an SGLT-2 inhibitor to a insulin, sulfonylureas, or glinides (e.g., repaglinide).
- Risk factors for hypoglycemia include:
- GFR >45 ml/min (such patients will excrete more glucose).
- HgA1c <7.5%
- History of hypoglycemic episodes.
- Patients whose baseline glucose levels are in a low/normal range.
- Measure to avoid hypoglycemia:
- Consider dose-reduction of other agents when adding SGLT-2 inhibitor.
- Follow glucose levels more carefully. (34979145)
empagliflozin
- 10 mg/day is the usual dose for heart failure or chronic kidney disease.
- 25 mg/day:
- [1] Acute heart failure: EMPAG-HF trial used 25 mg/day for five days among patients with acute heart failure and volume overload, to augment diuresis. 📄
- [2] Diabetes: 25 mg/day may be used in patients with insufficient response to 10 mg/day. However, this dose shouldn't be used in patients with GFR <45 ml/min.
dapagliflozin
- Dapagliflozin: 10 mg/day.
- Severe hepatic impairment: 5 mg/day initial dose.
[2] SGLT2i: contraindications & concerns
contraindications & cautions
- ⚠️ GFR <20-30 ml/min.
- Diabetes: Empagliflozin is contraindicated for GFR <30 ml/min.
- Heart failure or CKD: Empagliflozin is contraindicated for GFR <20 ml/min (EMPEROR-Reduced and EMPEROR-Preserved used a cutoff of GFR>20 ml/min as calculated using CKD-EPI formula). (37125324)
- ⚠️ Any history of DKA (diabetic ketoacidosis).
- ⚠️ No carbohydrate intake (e.g., NPO): SGLT-2 inhibitors should be held temporarily.
- ⚠️ Type-1 diabetes.
- ⚠️ Type-2 diabetes being treated with a sulfonylureas, insulin, and/or meglitinide (e.g., repaglinide).
- This is only a relative contraindication.
- Addition of an SGLT-2 inhibitor may increase the risk of hypoglycemia.
- Down-titration of these agents should be considered, depending on the level of glycemic control (discussed further below). (37125324)
- ⚠️ Uncontrolled hypernatremia. (37194077)
- ⚠️ Hypovolemia.
- ⚠️ History of recurrent genital or urinary tract infections (especially among patients with diabetes).
- ⚠️ Pregnancy.
concerns regarding: risk of diabetic ketoacidosis among inpatients
- Key concepts:
- [1] SGLT2-inhibitors should be avoided in patients with type-1 diabetes, any history of DKA, or no carbohydrate intake.
- [2] Among non-diabetic patients, the risk of diabetic ketoacidosis is exceedingly low. (36455120, 35678922, 35801339)
- [3] Among patients with type-2 diabetes, SGLT2-inhibitors are generally safe as long as the patient is eating.
- Evidentiary basis includes:
- EMPULSE trial: among 265 inpatients with heart failure, there were no episodes of ketoacidosis. Patients treated with SGLT2i had numerically lower rates of kidney injury or urinary tract infection. (35228754)
- Khunti et al: among inpatients with COVID, treatment with SGLTi was associated with a trend towards reduced likelihood of developing diabetic ketoacidosis. (36074663)
- DARE-19 trial: RCT evaluating dapagliflozin among hospitalized patients with COVID-19. 2/613 patients treated with dapagliflozin did develop DKA, which was non-severe. (34302745)
- RECOVERY RCT involved 2113 patient with COVID who were treated with empagliflozin. The risk of ketoacidosis was 0.2% among patients treated with empagliflozin versus 0.1% in the control group (not a statistically significant difference).
concerns regarding genitourinary tract infections
- Infection risk is predominantly problematic among patients with diabetes (who will spill the most glucose in their urine). (34979145)
- SGLT-2 inhibitors increase the risk of vulvovaginal candidiasis or balanitis by ~2-4 fold.
- SGLT-2 inhibitors may cause a small increase in the risk of bacterial urinary tract infections.
concerns regarding acute kidney injury
- SGLT-2 inhibitors may occasionally cause a reduction in GFR due to decreased glomerular filtration pressure. This reflects a reduction in GFR without actual harm to the kidney. If GFR falls by >30%, then a dose reduction or other intervention may be needed. (34979145)
- SGLT2-inhibitors are well established to improve long-term renal outcomes. Furthermore, meta-analysis of RCTs involving outpatients found that SGLT-2 inhibitors reduced the risk of acute kidney injury by 37%. (36351458)
- Some RCTs involving initiation of SGLT2-inhibitors among hospitalized patients have found reduced rates of acute kidney injury and the need for dialysis among patients started on SGLT2 inhibitors (e.g., DARE-19, DEFENDER, EMPAG-HF).
[3] SGLT2i: indications & use
heart failure (including both HFrEF & HFpEF)
- Basics:
- Indicated for any patient with symptomatic heart failure (effectiveness is unrelated to ejection fraction).
- SGLT2-inhibitors may promote synergistic natriuresis when combined with loop diuretics.
- SGLT2-inhibitors also preserve renal function, a relevant benefit since many patients with HFpEF also have chronic kidney disease.
- Evidentiary basis includes:
- DAPA-HF trial: Dapagliflozin in symptomatic patients with EF<40%. SGLT2i caused a reduction in the composite of worsening heart failure or cardiovascular death.
- Emperor-Reduced trial: Empagliflozin in symptomatic patients with EF <40%. SGLT2i caused a reduction in the composite outcome of heart failure hospitalization or death.
- EMPEROR-Preserved trial: empagliflozin reduced the composite of mortality and heart failure hospitalization in patients with HFpEF, regardless of diabetes status.
- PRESERVED-HF trial: Dapagliflozin improved heart failure symptoms, functional status, and exercise capacity (regardless of diabetes status).
- EMPULSE trial: acute heart failure patients randomized to placebo vs. empagliflozin. Empagliflozin improved cardiovascular endpoints. The rate of acute renal failure was lower in the empagliflozin group. 📄
- EMPAG-HF: acute heart failure patients with volume overload were randomized to placebo vs. 25 mg/day empagliflozin shortly after admission (<12 hours). Empagliflozin increased the urine output over five days by 25% (2 liters). Patients in the empagliflozin group received less furosemide, indicating greater furosemide sensitivity. Worsening renal function (creatinine increase by 0.3 mg/dL) was three times as frequent in the placebo group (32% vs. 12%). 📄
- Benefits revealed in meta-analysis:
- Reduced risk of cardiovascular death (HR 0.87).
- Reduced risk of hospitalization for heart failure (HR 0.72).
- Reduction in all-cause mortality (HR 0.92; CI 0.86-0.99). (37125324)
chronic kidney disease
- Chronic kidney disease, especially with albuminuria.
type II diabetes
- SGLT-2 inhibitors are not front-line therapy for isolated diabetes, but they may be useful for patients with renal and/or cardiac comorbidities.
- Indications include patients who aren't reaching glycemic targets with:
- Overt atherosclerotic coronary disease (e.g., prior myocardial infarction).
- Heart failure.
- Chronic renal insufficiency.
- High cardiovascular risk (e.g., hypertension, obstructive sleep apnea). (34654997)
[4] SGLT2i: pharmacology
empagliflozin
- Peak plasma time: 1.5 hours after administration.
- Half-life is ~12 hours.
- Some hepatic metabolism occurs, but empagliflozin is primarily excreted as unchanged drug (mostly in the urine, but also in the feces).
[5] SGLT2i: mechanism of action & physiological effects
- Metabolic effects:
- Reduction in insulin levels.
- Reduction in hemoglobin A1C of ~0.5-1%.
- Weight loss may occur.
- SGLT-2 inhibitors promote excretion of sodium and glucose:
- In the proximal tubule, SGLT2 is located close to the Na/H exchanger 3 (NHE3). The two transporters act together, such that SGLT2 inhibition can promote natriuresis. (34654997) However, the predominant effect seems to be osmotic diuresis, since SGLT-2 inhibitors increase sodium levels. (37194077)
- SGLT2-inhibitors bring more sodium to the macula densa, reducing the afferent vessel vasodilation and intraglomerular pressure. This decreases albuminuria and kidney damage over time. (34654997)
- Effect on other electrolytes:
[1] loop diuretics: dosing & agent selection
how to dose IV furosemide
- [a] Determine an effective dose (20-240 mg IV):
- Initial IV dose:
- Patients on chronic oral furosemide: use 2.5 times the patient's outpatient furosemide dose (e.g., 40 mg PO furosemide –> 100 mg IV furosemide). (DOSE trial 21366472, 35190215) For PO torsemide multiply by 10, for PO bumetanide multiply by ~200.
- Otherwise: ~40-80 mg IV (depending on renal function and disease severity). Higher doses are generally required in renal failure.
- Furosemide stress test: if a furosemide dose of 1 mg/kg is used (for patients naive to loop diuretics) or 1.5 mg/kg (for patients previously exposed to loop diuretics), then the volume of urine produced within two hours provides prognostic information about the likelihood of developing renal failure: 📖
- The key is empiric dose titration. If there is no result in an hour, keep doubling the dose until the patient responds (or until you reach a maximal dose, as discussed below). This rapid dose-titration should empirically define an effective furosemide dose.
- The target urine output following an effective dose is >100-150 ml/hour. (30600580)
- Initial IV dose:
- [b] Determine the proper dosing interval:
- Furosemide will typically cause diuresis for <6 hours (“LASIX” was so named because it LAsts SIX hours – but this is based on oral pharmacokinetics; IV administration may only cause diuresis for ~2 hours).(37675009) After the furosemide wears off, the kidney generally retains sodium. So, giving IV furosemide once daily will often achieve relatively little (~2 hours of diuresis, ~22 hours of sodium retention).
- More effective diuresis generally depends on giving furosemide more frequently (rather than necessarily in higher doses). Depending on the clinical scenario, this may involve giving the furosemide q6hr, q8hr, or q12hr.
- Co-administration of a long-acting thiazide (e.g. indapamide or metolazone) may help prevent sodium retention when the furosemide wears off, thereby facilitating effective diuresis.
- Maximal furosemide dose?
- The maximal dose for a single IV furosemide bolus is usually quoted as being 250 or 300 mg. (29141174, 32164892)
- The maximal cumulative daily furosemide dose might be between 600-1,500 mg. (35614905, 32164892)
- High doses of furosemide may increase the risk of ototoxicity, with argues for the use of combination diuretic regimens.
IV bumetanide
- There is no evidence that bumetanide is superior or inferior to furosemide.
- 1 mg IV bumetanide is roughly equivalent to 40 mg IV furosemide. In renal failure, the half-life of furosemide increases, making furosemide last longer (so 1 mg IV bumetanide might be roughly equivalent to 20 mg IV furosemide).
- The longer half-life of furosemide could theoretically make furosemide superior for intermittent dosing.
- The shorter half-life of bumetanide could theoretically make this superior for administration as a continuous infusion.
- Doses of IV bumetanide:
- Bolus 0.5 – 10 mg.
- Continuous infusion ~0.5-1 mg/hr.
continuous infusion of loop diuretic: discussed below ⚡️
roughly equivalent doses of various agents:
- 40 mg IV furosemide.
- 80 mg oral furosemide (roughly; oral bioavailability is variable)
- 1 mg bumetanide PO/IV.
- 20 mg torsemide PO (Torsemide is Twice as potent as IV furosemide).
[2] loop diuretics: contraindications & cautions
- Hypokalemia.
- (Note: Patients with an allergy to sulfa antibiotics can safely receive loop diuretics.) (14573734)
[3] loop diuretics: indications & use
- Loop diuretics are the most potent class of diuretics.
- PRN dosing of bolus loop diuretics is usually the cornerstone of any diuretic regimen.
[4] loop diuretics: pharmacology
time to onset
- Following an intravenous dose, peak action occurs after 30 minutes (for both furosemide and bumetanide).
- Following oral administration, peak drug concentrations are reached within 0.5-2 hours (30936153).
half-life & metabolism
- Furosemide:
- Half-life is 1.5-2 hours.
- Heart failure, hepatic dysfunction, or renal dysfunction: ~2.5-2.8 hours.
- Excreted by the kidney (with ~1/3 metabolized by the kidney into furosemide glucuronide).
- Bumetanide:
- Torsemide:
oral bioavailability
- Furosemide: 10-100%.
- Bumetanide: 80-100%.
- Torsemide: 70-100%. (35190215)
- Bumetanide has a 1:1 conversion of IV:PO.
- Furosemide has a roughly 1:2 conversion of IV:PO, but oral bioavailability is variable to this is a very rough conversion.
albumin binding & tubular entry
- Loop diuretics have high albumin binding (>90%), so they aren't freely filtered into the tubule. In order to enter the nephron lumen, they must be actively secreted in the proximal tubule:
- Entry through the basolateral membrane via organic anion transporters 1 and 3 (OAT 1 and 3).
- Entry through the apical membrane via multidrug resistance-associated protein 4 (MRAP4). (38240883)
- Secretion is impaired in uremia due to competition for organic anion transporters with other organic anions which accumulate in renal failure. Additionally, metabolic acidosis impairs tubular secretion.
[5] loop diuretics: mechanism of action & physiological effects
effect on various electrolytes
- Increases bicarbonate (“contraction alkalosis”) and hypochloremia.
- Hypochloremia may contribute to loop diuretic resistance. (38240883)
- Increases sodium (causes dehydration, with excessive loss of water).
- Reduces potassium.
- Reduces magnesium.
- Reduces calcium.
physiology
- The primary effect is blockade of the Na/K/Cl channel, which is located predominantly on the thick ascending loop of Henle. Consequences include:
- (1) Increased magnesium, and calcium wasting.
- Mg and Ca are reabsorbed between cells in the thick ascending loop of Henle, driven by a lumen-positive electrochemical gradient. Loop diuretics reduce this electrochemical gradient.
- Furosemide was once used as a treatment for hypercalcemia, but this has largely fallen out of favor.
- (2) Contraction alkalosis.
- (3) Blockade of NaCl entry into the macula densa (which normally occurs via the NKCC2 channel). Consequences of this are:
- [i] Blockage of tubuloglomerular feedback. This ultimately leads to renal vasodilation, which is potentially beneficial (via increases in prostaglandin E2).
- [ii] Increased renin production:
- This increases Angiotensin II levels (which may increase blood pressure and potentially defend the glomerular perfusion).
- This also increases aldosterone levels (which may increase sodium retention by the distal nephron, potentially impairing further diuresis).
[6] loop diuretics: continuous infusion
general concepts
- One pitfall of loop diuretics is that they last for a finite period of time (<6 hours for furosemide, less for bumetanide). In between diuretic doses, the kidney will retain sodium. If diuretic doses are spaced too far apart, this may defeat the effectiveness of diuresis.
- Multiple RCTs have compared the efficacy of intermittent boluses versus continuous infusions of loop diuretic. There is no definitive evidence that either strategy is superior.
- The primary advantage of a diuretic infusion is that it may be titrated continuously by the nurse at the bedside. This may lead to a greater amount of attention to the amount of urine output (ensuring that the patient truly meets their diuretic goals).
- Diuretic infusions are useful only in patients who have responded to a bolus of roughly ≦2 mg IV bumetanide or ≦100 mg IV furosemide (if the patient is refractory to bolus doses, they will similarly be refractory to an infusion; further discussion of pharmacokinetics below).
selection of furosemide vs. bumetanide
- Furosemide has a half-life of 1.5-3 hours, whereas bumetanide has a half-life of 1-1.5 hours (with longer half-lives in the context of renal dysfunction or heart failure).
- Pharmacokinetically, it makes more sense to use continuous infusions for medications with a short half-life. Therefore, it could make sense to choose a bumetanide infusion over a furosemide infusion (if both are available).
nuts & bolts of a continuous diuretic infusion:
[1] consider the addition of adjunctive diuretics
- Continuous diuretic infusions are generally capped at moderate doses (e.g., maximal infusion rate of 1 mg/hr bumetanide or 40 mg/hour furosemide).
- To achieve an adequate response at low-to-moderate doses of loop diuretic, additional diuretics should be considered (especially metolazone; discussed further below: ⚡️).
[2] dosing: start with a loading bolus
- A loading bolus achieves two objectives:
- (a) Rapidly establishes a therapeutic drug level.
- (b) Empirically determines a dose that is effective (e.g., if the initial bolus is ineffective, then a higher loading bolus may be needed).
- ⚠️ For patients who require a loading bolus of >2 mg bumetanide or >100 mg furosemide, it may be pharmacokinetically impossible to achieve target drug levels with a continuous infusion that is capped at 1 mg/hr bumetanide or 40 mg/hour furosemide (respectively). Such patients may be best treated with a multi-agent diuretic strategy including intermittent boluses of loop diuretic. Intermittent boluses doses will achieve higher peak serum levels, which may be required to pierce the minimum threshold of diuretic efficacy in patients with high-level loop diuretic resistance. For example, a 250 mg furosemide IV bolus achieves a therapeutic level of furosemide that is impossible to pharmacokinetically achieve with a continuous infusion.
[3] dosing: continuous infusion
- Dose range:
- Furosemide 5-40 mg/hour continuous infusion.
- Bumetanide 0.25-1 mg/hour continuous infusion.
- Titrate for a urine output of >150 ml/hour.
- The initial infusion rate may be calculated using the following equation:
- Infusion rate = (0.7 x loading dose)/(half life).
- If we estimate the half-life of bumetanide as ~1.25 hours and furosemide as ~2 hours, then the infusion rate may be approximated as follows:
- Bumetanide: infusion rate ~ 0.5 times loading dose.
- Furosemide: infusion rate ~ 0.35 times loading dose.
[1] thiazides: dosing & agent selection
IV chlorothiazide
- Dose range: 500-1,000 mg IV q12.
- Indications to choose chlorothiazide:
- [1] Patient unable to take PO medications.
- [2] Rapid onset required.
- Limitations of IV chlorothiazide:
- More expensive (with equivalent efficacy as compared to 5 mg metolazone BID in the 3T trial).
- Relatively short half-life (~2 hours).
indapamide
- Dose range: 2.5-10 mg PO daily.
- Indications/benefits:
metolazone
- Dose range: 5 mg PO daily to 10 mg PO BID.
- Indications/benefits:
- Longer half-life (~12 hours) may promote ongoing diuretic pressure that prevents sodium retention.
- Metolazone is supported by more evidence in acute decompensated heart failure (5 mg PO daily or BID is a classic dose used in the AVOID-HF trial, CARESS-HF, and the 3T trial). (26519995, 23131078, 23131078)
- The high efficacy of metolazone in patients with reduced GFR may relate to its additional effect on blocking the proximal tubule carbonic anhydrase and thus reducing sodium and chloride reabsorption in the proximal convoluted tubules. (36630939, 35190215)
hydrochlorothiazide (HCTZ)
- Dose range: 25 mg daily to 100 mg PO BID.
- Hydrochlorothiazide blocks both the distal tubule sodium/chloride cotransporter (NCC) and also the proximal tubule Na/H exchanger. (35190215)
- CLOROTIC trial:
- RCT investigating adjunctive hydrochlorothiazide among patients with acute heart failure who previously were on 80-240 mg/day furosemide. Hydrochlorothiazide improved fluid output, but did increase the number of patients who experienced a 0.3 mg/dL rise in creatinine (46% vs. 17%).
- Hydrochlorothiazide was dosed based on GFR:
- GFR >50 ml/min: 25 mg/day.
- GFR 20-50 ml/min: 50 mg/day.
- GFR <20 ml/min: 100 mg/day.
- One small RCT found that 25 mg/day hydrochlorothiazide had no effect on ICU-acquired hypernatremia. (27984823) This may simply be too low of a dose to have any effect.
roughly equivalent doses:
- 2.5 mg indapamide.
- 5 mg metolazone.
- 500 mg chlorothiazide.
- 50 mg hydrochlorothiazide.
- 25 mg of chlorthalidone. (35190215)
[2] thiazides: contraindications & cautions
- Hypokalemia.
- Hyponatremia.
- Metabolic alkalosis.
[3] thiazides: indications & use
benefits of using a thiazide diuretic (in combination with a loop diuretic)
- [1] Avoiding hypernatremia: Loop diuretic therapy by itself tends to promote excretion of dilute, hypotonic urine. This frequently leads to hypernatremia, which eventually must be treated by administering free water (which largely eliminates the volume loss). Addition of a thiazide diuretic to a loop diuretic promotes excretion of sodium (natriuresis), leading to more effective volume loss. 🌊
- [2] Improved responsiveness to furosemide: Addition of a thiazide diuretic may prevent or reverse resistance to loop diuretics.
- Chronic furosemide use leads to up-regulation of sodium reabsorption in the distal convoluted tubule – which impairs furosemide's effectiveness. Administration of a thiazide may restore responsiveness to furosemide.
[4] thiazides: pharmacology
- Time to onset:
- IV chlorothiazide: 30 minutes.
- Oral thiazide: ~1-2.5 hours.
- Oral bioavailability:
- Indapamide ~93%.
- Metolazone ~70%.
- Hydrochlorothiazide ~70%.
- Half-life:
- Indapamide: 14-24 hours.
- Metolazone: 8-14 hours.
- Chlorothiazide: ~2 hours.
- Hydrochlorothiazide: 6-15 hours.
- Albumin binding:
- Like loop diuretics, thiazides are bound to albumin and secreted into the tubule via organic anion transporters.
- Secretion into the tubule is delayed in renal failure, reducing diuretic efficacy.
[5] thiazides: mechanism of action & physiological effects
effect on various electrolytes
- Increases bicarbonate.
- Reduces sodium (due to increases in sodium excretion and reduction in the excretion of water).
- Reduces potassium (due to stimulation of aldosterone & increased distal tubule flow).
- Effect on magnesium:
- Acute use: increases magnesium.
- Chronic use: decreases magnesium.
- Effect on calcium:
- Acute effects are variable.
- Chronic use: increases calcium.
mechanism of action
- Thiazides inhibit sodium reabsorption in the distal convoluted tubule.
- Thiazide monotherapy has a relatively weak diuretic effect (because not much sodium is generally reabsorbed in the distal convoluted tubule).
- Patients being treated with loop diuretics will tend to reabsorb more sodium in the distal convoluted tubule. Thus, adding a thiazide in combination with a loop diuretic may substantially augment the efficacy of the loop diuretic.
Amiloride and triamterene have the same mechanism of action (inhibition of passive potassium efflux out of the distal nephron via the ENaC channel). However, triamterene has a variety of unique nephrotoxic properties. Triamterene can cause nephrolithiasis, interstitial nephritis, and acute renal failure (due to effects on the prostaglandin system). (2662034, 6589647) Consequently, amiloride is the ENaC inhibitor of choice for critically ill patients.
[1] amiloride: dosing
- Diuretic in critically ill patients: ~5-20 mg daily (ideally in the morning). (37675009, 35614905)
- Chronic hypertension: 5-10 mg daily.
- Ascites: 15-30 mg daily (if no response, may increase to maximum dose of 40 mg/day).
- Hypokalemia due to chronic, stable potassium wasting: start at 10 mg/day, may gradually up-titrate to 40 mg/day.
- General dose-response curve: increasing efficacy is seen in a dose range from 5-40 mg, beyond which a plateau occurs. (33234024)
- ⚠️ Renal adjustment:
- GFR 10-50 ml/min: 50% dose reduction.
- GFR < 10 ml/min: contraindicated.
[2] amiloride: contraindications & cautions
contraindications
- ⚠️ Hyperkalemia.
- GFR <10 ml/min.
side effects
- Hyperuricemia (due to chronic use, with increased reabsorption in the proximal tubule).
- Side effects can also include nausea, emesis, diarrhea, and headache. (33234024)
[3] amiloride: indications & use
- Adjunctive diuretic to balance out electrolyte abnormalities (e.g., prevent hypokalemia, contraction alkalosis, and hypomagnesemia).
- Rapid onset of action makes amiloride superior to spironolactone for acute management.
[4] amiloride: pharmacology
- Oral bioavailability: ~50% (food may decrease to ~30%). (33234024)
- Time to onset: 2 hours.
- Peak effect: ~4-8 hours.
- Duration of action ~24 hours. (33234024)
- Does not undergo hepatic metabolism.
- Excreted in the urine as unchanged drug.
- Half-life:
- Normal GFR: 6-9 hours.
- GFR <50 ml/min: extends to 21-144 hours.
[5] amiloride: mechanism of action & physiological effects
effect of amiloride on various electrolytes
- Lowers bicarbonate.
- Increases potassium (“potassium-sparing diuretic”).
- Increases magnesium.
- Increases calcium.
physiology
- Amiloride reaches the nephron via glomerular filtration. (33234024)
- Amiloride acts predominantly via blocking the ENaC channel in the distal nephron.
🛑 The diuretic effect of spironolactone begins within ~2 days, so it's not generally unhelpful in critical care medicine. Sluggish onset may explain the failure of spironolactone to work in the ATHENA-HF trial.
[1] spironolactone: dosing
dosing for cirrhosis
- Current guidelines for cirrhosis suggest use with furosemide in a ratio of 100 mg spironolactone : 40 mg furosemide.
- The starting dose of spironolactone is usually 100 mg/day. (37675009) This may be up-titrated to a maximal recommended dose of spironolactone is 400 mg daily. (23463403) Guidelines recommend targeting -0.5 liter/day diuresis in patients without peripheral edema, or 1 liter/day in patients with peripheral edema. (35190215)
dosing for heart failure & relevant studies
- The dose is usually limited to 50 mg/day when used solely for heart failure.
- ATHENA-HF trial: (29141174)
- 360 patients with acute heart failure randomized to loop diuretic +/- 100 mg/day spironolactone for 96 hours.
- Spironolactone had no effect on outcomes (e.g, BNP levels, dyspnea, urine output, weight, potassium).
- An explanation for these results is that spironolactone takes so long to work (2-3 days) that it's not useful in acute heart failure or acute diuresis. It's also possible that larger doses of spironolactone may be needed. Regardless, there doesn't seem to be an evidence-based utilization for spironolactone in acute diuresis at this point in time.
[2] spironolactone: contraindications & cautions
- Hyperkalemia.
[3] spironolactone: indications & use
- Cirrhosis.
- Heart failure.
[4] spironolactone: pharmacology
- Oral bioavailability is ~90%.
- Time to onset is ~48-72 hours.
- Half-life: Biological half-life might be ~20 hours (due to the presence of active metabolites).
[5] spironolactone: mechanism of action & physiological effects
effect on various electrolytes
- Lowers bicarbonate.
- Increases potassium.
- Increases magnesium.
- Decreases calcium.
mechanism of action & physiologic effects
- Spironolactone is a mineralocorticoid inhibitor, which will impair the effects of aldosterone on the distal tubule in conditions of elevated aldosterone activity. This will tend to promote sodium excretion, potassium retention, and cause a non-anion-gap metabolic acidosis.
general properties of spironolactone
- Spironolactone will have the greatest efficacy in contexts where the renin-angiotensin-aldosterone system is highly activated (e.g. cirrhosis and heart failure). Alternatively, in situations where the basal aldosterone tone is low, spironolactone may have little clinical effect.
- Spironolactone takes 1-2 days to have maximal effect, which limits its utility in emergent situations. This also makes it difficult to perform any rapid dose-titration.
- Spironolactone is a “potassium-sparing” diuretic. In patients undergoing large-volume diuresis, addition of spironolactone may reduce hypokalemia and contraction alkalosis.
- There is increasing evidence that volume overload is detrimental to critically ill patients.
- It is common to encounter patients in the ICU who are massively volume overloaded. For example:
- Iatrogenic volume overload following 1-2 weeks of ICU care without attention to volume control.
- Volume overload due to cor pulmonale with systemic congestion.
- Simply giving furosemide is generally fine for removing a few liters in patients with normal electrolytes. However, removing larger volumes of fluid without causing electrolyte abnormalities generally requires a more sophisticated diuretic strategy.
- Electrolyte abnormalities induced by diuresis may reinforce themselves, in a vicious spiral (figure below).
This section is about a patient with gross volume overload (e.g. estimated fluid excess of several liters). The patient is diuretic-responsive, so you could probably use any diuretic(s) to eliminate fluid. The challenge here is fluid removal without causing electrolyte abnormalities or renal dysfunction.
[1] before starting
- Reduce sources of ongoing fluid intake if possible (e.g., medication infusions in normal saline).
- Discontinue potentially nephrotoxic medications.
- Consider discontinuing or dose-reducing antihypertensive medications (if blood pressure is borderline).
[2] for heart failure: start SGLT2-i
- SGLT2 inhibitors should be initiated for patients with heart failure if not contraindicated. ⚡️
- Reasons for early initiation of SGLT2-i include:
- (a) Early initiation increases the likelihood that therapy will be continued long-term.
- (b) Some studies suggest that SGLT2 inhibitors initiation may reduce the likelihood of acute kidney injury. (38864970, 35766022)
- (c) SGLT2 inhibitors increases sensitivity to loop diuretics. Early initiation facilitates a seamless transition to chronic maintenance therapy (avoiding the need to re-titrate loop diuretic dose later on, when SGLT2 inhibitors are started).
- (d) RCTs demonstrate that the benefits from SGLT2 inhibitors accrue early (within weeks), arguing for prompt initiation.
[3] consider 1-2 adjunctive diuretics
- Benefits of adjunctive diuretics may include:
- [1] Overcoming diuretic resistance among patients on chronic furosemide (primarily: thiazide, amiloride).
- [2] Improving natriuresis and avoiding hypernatremia/dehydration.
- [3] Preventing electrolytic shifts (with some adjunctive agents).
- [4] Reducing the risk of ototoxicity due to loop diuretics (since lower doses are required).
- Acetazolamide: ⚡️
- PRO (more useful if):
- Metabolic alkalosis (not including chronic compensatory metabolic alkalosis).
- Hyperkalemia.
- Hypochloremia. (37102974)
- CON (less useful if):
- Hypokalemia.
- Metabolic acidosis.
- Advanced liver disease (contraindicated).
- Patients on >60 mg/day furosemide prior to admission (in the ADVOR trial, patients on higher doses of furosemide didn't appear to benefit from acetazolamide).
- Patient is on an SGLT-2 inhibitor. (Acetazolamide and SGLT2-i both act in proximal convoluted tubule. It is unknown if acetazolamide adds benefit in this situation.) (38300391)
- PRO (more useful if):
- Thiazide: ⚡️
- PRO (more useful if):
- Hypernatremia.
- Chronic furosemide exposure (causes distal tubule hypertrophy). (38589570) Metolazone affects both the proximal and distal convoluted tubules, possibly making it the most powerful adjunctive agent for management of furosemide resistance.
- CON (less useful if):
- Hypokalemia.
- Hyponatremia.
- Metabolic alkalosis.
- PRO (more useful if):
- Amiloride:⚡️
- PRO (more useful if):
- Hypokalemia (especially severe or persistent).
- Metabolic alkalosis (not including chronic compensatory metabolic alkalosis).
- Hypochloremia.
- Chronic furosemide exposure (causes collecting duct hypertrophy). (38589570)
- CON (less useful if):
- Hyperkalemia.
- Metabolic acidosis.
- GFR <10 ml/min.
- PRO (more useful if):
- (Spironolactone doesn't work rapidly enough for acute diuresis.)
[4] IV loop diuretic backbone
- Use loop diuretics as needed, to achieve the target urine output.
- Typical dosing: furosemide 40-160 mg IV, as frequently as q6hr.
- Further discussion of loop diuretic dosing above: ⚡️
- If ineffective, consider additional adjunctive agents (see #3 above).
[5] follow electrolytes (including magnesium) & manage any complications
- ⚠️ Large-volume diuresis will commonly cause electrolyte abnormalities (e.g., hypernatremia, hypokalemia, contraction alkalosis). These require active management. Electrolyte abnormalities are not an indication to stop diuresis (if the patient remains fluid overloaded).
- Pre-emptive administration of KCl may be considered patients with preserved renal function (in anticipation of subsequent potassium losses).
- Management of some commonly encountered problems:
actionable causes of diuretic resistance in the ICU
- Excessive fluid & sodium intake (e.g., continuous infusions and various intravenous medications).
- Inadequate dosing/schedule of diuretics:
- Dose is below the diuretic threshold.
- Dosing interval is too long.
- Oral route is used in patients with bowel edema or dysfunction (especially with furosemide).
- Medications or substances that interfere with the diuretic:
- NSAIDs impair diuretic responsiveness.
- Some medications may compete with diuretics for entry into the renal tubule (e.g., probenecid, beta-lactams, methotrexate, urate, urea). (38695931)
- Pre-renal hemodynamics with impaired renal perfusion:
- Shock of any etiology.
- Systemic congestion (which reduces renal perfusion pressure).
- Hypovolemia (e.g., a patient with peripheral lymphedema who has already been excessively diuresed).
- Renal failure:
- Post-renal (e.g., ureter or bladder obstruction).
- Intrinsic renal failure (e.g., acute tubular necrosis).
- Foley catheter obstructed or malpositioned.
- Hypochloremia. (37675009)
evaluation of diuretic resistance
- Review the medication list for any agents that may hinder diuresis.
- Review the input/output balance (are there sources of fluid and sodium which can be curtailed?).
- POCUS including echocardiography & bladder assessment:
- [a] Is the patient truly volume overloaded and in need of further diuresis? Note that peripheral edema by itself isn't an indication for diuresis. Some patients with compensated heart failure will require somewhat elevated filling pressures (and some peripheral edema) to sustain adequate perfusion.
- [b] Evaluate the bladder and exclude a distended bladder (which would imply Foley catheter malfunction).
general approach to diuretic resistance
- Evaluate & treat for any reversible causes of diuretic resistance (as above).
- Hemodynamic optimization:
- For systemic congestion with hypotension: may consider norepinephrine (“squeeze and diurese” strategy).
- For normotension with low cardiac output (e.g., decompensated heart failure), may consider dobutamine.
- Avoid autoPEEP or excessive airway pressures on mechanical ventilation.
- Maximize diuretic doses & add adjunctive agents:
- [1] Loop diuretic.
- [2] Thiazide diuretic (especially: high-dose metolazone).
- [3] SGLT2-inhibitor for heart failure (may escalate 25 mg/day empagliflozin).
- [4] Amiloride.
- [5] Acetazolamide.
- Treatments of last resort:
- Hyperdiuresis (see the section below).
- Paracentesis and/or thoracentesis (if symptomatic ascites or pleural effusion).
- Dialysis.
hyperdiuresis
- Hyperdiuresis involves a combination of hypertonic saline plus a loop diuretic.
- Hyperdiuresis is a controversial technique, which may be considered in patients who don't have other therapeutic options (e.g. patients who would otherwise require dialysis).
- (Further discussion of hyperdiuresis here.)
candidate for hyperdiuresis
- Heart failure with definite volume overload, which is refractory to standard diuretic therapies (i.e. persistent congestion and inadequate urine response to diuretics).
- No acute hypertension.
- No baseline hypernatremia or hyperchloremia.
hyperdiuresis protocol
- Infuse a combination of 150 ml 3% NaCl plus a large dose of IV furosemide (e.g. ~160-250 mg) over an hour. Note that 3% saline is safe for peripheral infusion.
- If effective, may repeat this twice daily until volume goals are reached. (Alternatively, if the patient fails to respond, do not give additional doses.)
- Follow electrolytes and renal function. (If hypernatremia occurs, further doses should be withheld). (28932357)
hypernatremia
- Iatrogenic hypernatremia is common in ICU patients, particularly patients undergoing large-volume diuresis (loop diuretics cause hypernatremia).
- If the sodium starts rising, this requires aggressive therapy, which may include:
- [1] Addition of thiazide diuretics.
- [2] Aggressive administration of free water (either enteral water or intravenous D5W), based on calculation of the free water deficit.
- [3] While administering free water, the dose of furosemide may need to be increased in order to achieve a net negative fluid balance.
- Using the above approach, it is generally possible to simultaneously fix the hypernatremia while maintaining a negative fluid balance.
metabolic alkalosis
- Contraction alkalosis is common with large-volume diuresis. This can be problematic, because the metabolic alkalosis will impair the effectiveness of loop diuretics. (9616263)
- Contraction alkalosis can develop before patients have reached euvolemia. Thus, development of contraction alkalosis shouldn't be misinterpreted to mean that the patient “cannot tolerate” further diuresis.
- Contraction alkalosis requires active management, especially in patients who are continuing to be diuresed.
- ⚠️ Attempting to continue diuresis without actively managing the alkalosis will generally aggravate the alkalosis.
management of metabolic alkalosis
- [1] Hypokalemia and hypomagnesemia may contribute to metabolic alkalosis, so these should be treated aggressively if present (of course, they require treatment regardless).
- [2] For patients with persistent volume overload, add bicarbonate-wasting diuretics:
- (More on metabolic alkalosis: 📖)
hypokalemia
- Potassium wasting is caused by loop diuretics, thiazides, and acetazolamide. Thus, patients on combination diuretic regimens can easily become severely hypokalemic.
- Management:
- (a) Potassium should be aggressively repleted. This should be done orally if possible, based on the estimated potassium deficit as well as anticipated potassium losses (due to ongoing diuresis). If renal function is intact, scheduling multiple doses of enteral potassium may be a useful strategy to maintain adequate potassium levels.
- (b) Check the magnesium level and replete aggressively (discussed above).
- (c) For ongoing, problematic hypokalemia a potassium-sparing diuretic could be considered (e.g., amiloride).
- (More on hypokalemia here.)
rising creatinine
- Rising creatinine following initiation of diuresis is challenging. As with any creatinine rise in the ICU, this has a broad differential diagnosis, for example:
- (1) Diuretic-induced hypovolemic shock causing renal hypoperfusion.
- (2) Random daily fluctuations in creatinine.
- (3) Acute kidney injury due to other medications or sepsis.
- If the creatinine elevation is substantial, then it should be evaluated similarly to that of any other patient with acute kidney injury (more on this here).
- At a minimum, hemodynamic re-evaluation should occur (e.g., ultrasonography to image the heart and assess for systemic venous congestion).
- Whether or not diuretics should be held is ultimately a clinical decision, for example:
- If the patient clearly remains intravascularly congested, then continuing diuresis may be beneficial. Relief of systemic congestion should eventually cause improvement in renal function. Some patients with congestive nephropathy will have minor elevation in creatinine with diuresis, but this recovers with ongoing decongestion. Likewise, some studies of heart failure have correlated small elevations in creatinine with better outcomes (perhaps because this reflected patients who were being effectively diuresed). (20606118)
- 💡 Remember that diuretics are not intrinsically nephrotoxic (with some notable exceptions: triamterene, mannitol). Diuretics generally will only cause kidney failure if they induce hypovolemia that leads to hypoperfusion.
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- Ignoring hypernatremia or metabolic alkalosis until these are severe. Both of these issues will very predictably get worse if they aren't managed actively, so they should be treated early in an expectant fashion.
- Interpreting a metabolic alkalosis or hypernatremia to mean that the patient has been diuresed adequately, and/or that the patient cannot tolerate further diuresis. This is incorrect: these are iatrogenic complications due to a poor diuretic strategy. Often patients will develop these complications despite persistent volume overload.
- Failure to replete magnesium.
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