diuretic therapy

diuresis

Modern strategy has shifted from ‘escalating monotherapy’ to early sequential nephron blockade and natriuresis-guided titration (Mullens Protocol).

Decongestion reduces morbidity (readmission), but loop diuretics themselves do not improve survival (TRANSFORM-HF).

summary: mullens protocol

Based on Mullens W, et al. Eur J Heart Fail. 2019.

Step	Time	Trigger / Check	Action
1. Initial Therapy	T+0	Fluid Overload	IV Loop Diuretic (2.5x Home Dose)
2. Response Check	T+2	$U_{Na}<50$ mmol/L	Double the Dose
		$U_{Na}>50$ but low vol	Increase Frequency (e.g. q6h)
3. Volume Check	T+6	Urine Output $<150$ mL/h	Repeat Bolus / Start Infusion
4. Efficiency Check	T+24	Efficiency $<0.4$ kg/40mg	Add Thiazide (Metolazone) or Acetazolamide
5. Refractory	Any	Hypochloraemia ($C{l}^{-}<96$)	Hypertonic Saline (SALT-HF Protocol)

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core concepts: the mortality paradox

1. the ‘neurohormonal brake’

Loop diuretics inhibit $N{a}^{+}$ at the macula densa (NKCC2).

• Physiology: The kidney interprets this as ‘hypovolaemia’ $\to$ massive Renin release.
• Result: Upregulation of RAAS (Angiotensin II/Aldosterone) $\to$ vasoconstriction and cardiac fibrosis.
• Trade-off: Haemodynamic improvement (decongestion) comes at the cost of neurohormonal activation.

2. mortality vs. morbidity

• Loops: Remove the fluid (symptom control).
• GDMT (BB/ACEi/MRA): Block the RAAS surge caused by the loops (mortality control).
• If patient is euvolemic but hypotensive/azotemic, wean the loop first to preserve the GDMT.

Drug Class	Target	Decongestion	Mortality Benefit?
Loops	Haemodynamics (Preload)	+++	Neutral (TRANSFORM-HF)
ACE Inhibitors/ARNI	Neurohormonal (RAAS)	+	YES (Remodelling)
Beta Blockers	Neurohormonal (SNS)	- (Worsens acute)	YES (Arrhythmia/Remodelling)
Spironolactone (MRA)	Neurohormonal (Aldo)	+/- (Weak diuretic)	YES (Antifibrotic - RALES)
SGLT2 Inhibitors	Metabolic/Osmotic	++	YES (Pleiotropic - EMPEROR)
Low Sodium Diet	Volume Load	+/-	Neutral (QoL only - SODIUM-HF)

step 1: the loop foundation (DOSE-AHF)

Mechanism: Inhibits NKCC2 ($N{a}^{+}-K^{+}-2C{l}^{-}$) in the Thick Ascending Limb (25% of Na reabsorption).

dosing & evidence

Based on DOSE-AHF

• Start: IV Bolus $\ge$ 2.5x Home Total Daily Dose.
• Intensity: High dose strategy is superior to low dose for dyspnoea relief and fluid loss.
• Mode: No difference between continuous infusion and bolus for initial therapy.

why switch loops?

Furosemide has erratic oral absorption ($10\text{–}100\%$), which is often worsened by gut oedema.

Agent	Bioavailability	Potency ($F{E}_{Na}$)	Clinical Role
Furosemide	10–100% (Erratic)	20–25%	Standard first-line.
Bumetanide	80–100% (Stable)	20–25%	Use if Furosemide fails (gut oedema).
Torsemide	80–100%	20–25%	Longer half-life prevents rebound.
Metolazone	~65%	5–8%	‘Booster’ to overcome distal hypertrophy.

monitoring: the mullens protocol

Natriuresis-guided therapy prevents ‘clinical inertia’.

T+2 hours (the ‘quality’ check): is the kidney responding?

• Test: Spot Urine Sodium ($U_{Na}$).
• Target: $>50\text{–}70\text{ mmol/L}$.
• Action: If below target $\to$ Double the dose.

T+6 hours (the ‘quantity’ check): is the volume actually leaving?

• Test: Cumulative Urine Output.
• Target: $>150\text{ mL/hr}$ (approx 1000 mL total at 6h).
• Action: If below target $\to$ Repeat the bolus (or start infusion).

T+24 hours (the ‘efficiency’ check): what is the cost?

• Formula: $\frac{\text{Kg Weight Loss}}{\text{Total Daily Dose (in 40mg units)}}$.
• Target: $>0.4\text{ kg}$ per 40mg equivalent.
• Action: Poor efficiency $\to$ Add Sequential Blockade (Thiazide/Acetazolamide) for the next day.

sulfa allergy

True cross-reactivity between antibiotic sulfonamides and non-antibiotic sulfonamides (diuretics) is rare/theoretical. HOWEVER, if history of SJS/TEN or Anaphylaxis to Furosemide/Thiazides:

• All Sulfonamides (Loops, Thiazides, Acetazolamide) are contraindicated.
• Ethacrynic Acid a non-sulfa loop may be used.
  • Dose: 50mg IV $\approx$ 40mg Furosemide.
  • Warning: High risk of Ototoxicity.

step 2: optimization (infusion)

If boluses fail to achieve target $U_{Na}$ despite dose escalation:

• Continuous Infusion: Consider switching (e.g., 10–40 mg/hr). Maintains constant tubular concentration above the natriuretic threshold, preventing ‘post-diuretic salt retention’ (rebound) that occurs between boluses.

step 3: mechanisms of resistance

If ceiling dose loop (e.g., Furosemide 400-600mg IV) fails, resistance mechanisms are active.

1. Braking Phenomenon: Acute restoration of sodium balance (rebound retention) once the drug wears off.
2. Distal Hypertrophy: Chronic loop blockade $\to$ DCT cell hypertrophy $\to$ avid $N{a}^{+}$ uptake downstream.
3. Chloride Depletion Syndrome: (Key Driver)

   Loops waste $C{l}^{-}$. Low distal $C{l}^{-}$ delivery triggers Macula Densa $\to$ Renin Release (tubuloglomerular feedback). The kidney avidly holds sodium because chloride is low (hypochloraemic metabolic alkalosis). Fix: Aggressive KCl repletion, Hypertonic Saline, or Acetazolamide.

step 4: sequential nephron blockade

Synergism is achieved by blocking $N{a}^{+}$ reabsorption at multiple sites.

1. proximal blockade (acetazolamide)

• Site: Proximal Convoluted Tubule (Carbonic Anhydrase inhibitor).
• Evidence: ADVOR Trial (2022).
  • Findings: 500mg IV Daily + Loop vs Placebo + Loop. Improved decongestion (42% vs 31%).
  • Predictor of Response: Benefit is magnified when baseline Bicarbonate is elevated ($HC{O}_3^{-}\ge 27$ mmol/L).
• Role: Efficiency. Increases natriuresis per mg of Loop. Corrects metabolic alkalosis.

2. distal blockade (thiazides)

• Site: Distal Convoluted Tubule (inhibits NCC).
• Role: Potency. Overcomes distal hypertrophy.
• Evidence: Weak. Unlike the large ADVOR/CLOROTIC trials, evidence for Metolazone relies on small studies/observational data ($n<250$ total).
• Metolazone Pearls:
  • Give 30+ mins BEFORE the Loop.
  • Long half-life (14–24h); daily dosing is sufficient.
  • Costs: IV Chlorothiazide is equally effective but costly.
  • Caution: Massive electrolyte wasting ($K^{+}$, $N{a}^{+}$).

3. the ‘metabolic’ pillar (sglt2 inhibitors)

• Site: Proximal Tubule (SGLT2).
• Evidence: EMPULSE.
• Role: Standard of Care (Class I). Osmotic diuresis + renal protection. Start in hospital once stable.
• Caveat: ADVOR excluded patients on SGLT2 inhibitors. Since SGLT2i is now standard of care, the synergy is extrapolated.

4. mineralocorticoid receptor antagonists (mra)

• Evidence: ATHENA-HF.
  • Finding: High dose spironolactone (100mg) did NOT improve acute decongestion vs placebo.
  • Reason: Pharmacokinetics are too slow for acute rescue (genomic effect).
• Exception: Cirrhosis/Ascites. Secondary hyperaldosteronism is the primary driver; high dose spironolactone (up to 400mg) is effective here.

step 5: rescue therapy

1. hypertonic saline protocol

• Evidence: SALT-HF.
  • Finding: Neutral for 3h urine output overall, but improved 7-day weight loss. Safe profile. Previous inpatient meta-analyses suggested stronger acute benefit.
  • Target Population: Most effective in Hypochloraemia ($C{l}^{-}<96\text{ mmol/L}$) or Hyponatraemia.
• Mechanism: Osmotic extraction from interstitium (plasma refill) + Chloride repletion.
• Protocol (SALT-HF):
  1. Load: 150 mL of 3% NaCl IV over 30 mins.
  2. Diuretic: Give High-Dose Loop (e.g., Furosemide 250mg IV) concurrently or immediately after.
  3. Frequency: BID (Twice daily).
• Monitoring response:
  • Assess Urine Output 3–4 hours post-dose.
  • Response: If output $>500$ mL $\to$ Continue BID.
  • Failure: If output minimal $\to$ STOP infusion. (Risk of flash pulmonary oedema/hypernatraemia without excretion).
• Stop Parameters:
  • Serum $N{a}^{+}>150\text{ mmol/L}$.
  • Resolution of congestion.

2. ultrafiltration / dialysis

• Evidence: CARRESS-HF.
  • Finding: Ultrafiltration was inferior to stepped pharmacologic care (more adverse events, no benefit).
  • Why: Fixed filtration rates often exceed the patient’s plasma refill rate, leading to intravascular depletion and rising creatinine.
• Role: Last resort for uraemia/acidosis, not for ‘diuretic resistance.‘

step 6: transition & discharge

The highest risk period for readmission.

1. The ‘Stability’ Rule:
   • Ideally, observe on oral diuretics for 24–48 hours before discharge.
   • Ensure weight remains stable (no rebound accumulation).
2. Dose Conversion (IV to PO):
   • Furosemide has ~50% oral bioavailability (erratic in gut oedema).
   • Double the IV dose. (e.g., Stable on 40mg IV BID $\to$ Discharge on 80mg PO BID).
3. STRONG-HF Strategy:
   • Do not discharge solely on diuretics.
   • Rapid up-titration of GDMT (BB/ACEi/MRA/SGLT2i) before discharge reduces 180-day readmission/death.

safety & complications

permissive hypercreatinemia

If the patient is decongesting and creatinine rises: CONTINUE.

DOSE-AHF showed that while high-dose loops caused transient AKI, patients with haemoconcentration (rising Cr/Hct) had better survival. The rise is often haemodynamic (resetting).

Stop Trigger: Cr rise $>26\mu \text{mol/L}$ ($0.3\text{ mg/dL}$) without effective diuresis, or hypotension.

electrolyte wasting

Sequential blockade causes massive $K^{+}$ and $M{g}^{2+}$ loss.

• Hypokalaemia: Major risk for arrhythmia. Keep $K^{+}>4.0$. Supplement before giving Metolazone.
• Hypomagnesaemia: Prevents $K^{+}$ repletion. Keep $M{g}^{2+}>0.8$.
• Hyponatraemia:
  • Thiazides: High risk (block diluting segment). Stop if $N{a}^{+}<125$.
  • Loops: Often correct hyponatraemia (excrete hypotonic urine).