Diuretic Therapy in Critically Ill
Source: Saengngammongkhol P. Ramathibodi Hospital 2025 + KDIGO AKI 2026 + ESC HF 2021 + ESICM Fluid Therapy 2025 (ICM 2025;51:1749–1763)
🪴 Part 1: Basic Renal Physiology — Sodium Handling
| Segment | Na reabsorb | Transporter | กลไก |
|---|---|---|---|
| PCT | 60–70% | NHE3, SGLT2, NaHCO₃ cotransporter | Paracellular + glucose/AA cotransport; volume-status dependent |
| TALH | 25–30% | NKCC2 | ROMK recycles K⁺ → lumen+ → paracellular Ca²⁺/Mg²⁺ (claudin-16/19) |
| DCT | 10% | NCC | ↑Ca²⁺ reabsorption (thiazide-sensitive) |
| Collecting duct | 10% | ENaC • Na⁺/K⁺-ATPase | Aldosterone-dependent; ADH → AQP2 (free water) |
PCT reabsorption เพิ่มขึ้นใน edematous states (HF, cirrhosis) → ให้ diuretic ที่ออกฤทธิ์ downstream มีประสิทธิภาพลดลง — เหตุผลหลักของ diuretic resistance
💊 Part 2: Diuretic Classification & Pharmacology
แบ่ง 3 กลุ่ม:
- Natriuretics: ลด Na⁺ reabsorption ที่ different tubular sites — Carbonic anhydrase inhibitor, Loop diuretic, Thiazide, K-sparing
- Aquaretics: ยับยั้ง vasopressin receptor → ลด free water reabsorption (ไม่ใช่ natriuresis)
- Osmotic diuretics: สร้าง osmotic force ใน tubule
2.1 Carbonic Anhydrase Inhibitor (Acetazolamide)
ยับยั้ง CA II (cytoplasm, 95%) และ CA IV (luminal border) → ขัดขวาง bicarbonate reclamation → HCO₃⁻ คั่งใน lumen → alkaline diuresis + Na⁺/K⁺ excretion
- Dose: Oral 250–375 mg; IV 500 mg (ไม่มีในไทย); FENa ~4%
| Clinical Indication | Adverse Effect |
|---|---|
| Idiopathic intracranial hypertension | Abnormal taste, GI distress |
| Glaucoma | Hypokalemia (ถ้าใช้นาน เสริม NaHCO₃) |
| Mountain sickness | Proximal RTA (type 2) |
| Prophylaxis hypokalemic periodic paralysis type I | Poor efficacy long-term: Braking phenomenon — Ca II absorb HCO₃⁻ 1/3, Na⁺ still reabsorb distally, metabolic acidosis → ↓filtered HCO₃⁻, TGF activation |
| Metabolic alkalosis จาก loop diuretic (ICU use) | — |
2.2 Loop Diuretics
OOK ฤทธิ์โดย inhibit NKCC2 ที่ TALH (reabsorb 25–30% filtered Na⁺) → Natriuresis; ↓lumen+ potential → calciuresis/magnesiuresis; disrupts countercurrent multiplication → ↓medullary osmotic gradient → dilute urine (loss Na + free water) → risk of hyponatremia ต่ำกว่า thiazide
Loop diuretics ต้อง deliver ผ่าน OAT1/3 ที่ PCT-S2:
- Competitors: Probenecid, Beta-lactam, Uremic organic anions
- Hypoalbuminemia: ↑Vd, ↓diuretic delivery, albuminuria → ↓free drug ใน lumen
- NSAIDs: ↓PGE2 → ลด loop diuretic action ที่ TALH
| Furosemide | Bumetanide | Torsemide | |
|---|---|---|---|
| Oral bioavailability | 64% (variable) | 80–100% | 80–100% |
| Onset IV | ~5 min | ~5 min | ~5 min |
| T½ | 2h | 1–1.5h | 3–6h |
| FENa% | 20–25% |
Ceiling Doses Loop Diuretics:
| Condition | Furosemide IV | Furosemide PO | Bumetanide | Torsemide |
|---|---|---|---|---|
| GFR 20–50 | 80–160 mg | 160 mg | 6 mg | 50 mg |
| GFR <20 | 200 mg | 240 mg | 10 mg | 100 mg |
| Nephrotic (normal GFR) | 120 mg | 240 mg | 3 mg | 50 mg |
| Cirrhosis | 40–80 mg | 80–160 mg | 1 mg | 20 mg |
| Heart failure | 40–80 mg | 80–160 mg | 1 mg | 20 mg |
2.3 Thiazide and Thiazide-like Diuretics
Inhibit NCC ที่ DCT → Natriuresis; ต่างจาก loop diuretics: ↑Ca²⁺ reabsorption (hypercalcemia); ↓Ca²⁺ excretion
HTCZ eGFR adjusted dose:
- eGFR >50: 25 mg; eGFR 20–50: 50 mg; eGFR <20: 100 mg (เพิ่ม dose ตาม renal impairment)
ADR: Volume depletion/azotemia, Hypokalemia, Hypomagnesemia, Metabolic alkalosis, Hypercalcemia, Hyperuricemia, Hyperglycemia, Hyperlipidemia
Thiazide-induced Hyponatremia mechanisms:
- Reduced distal filtrate delivery (↓GFR, ↑PT reabsorption)
- Inhibition of NCC → impairs maximal dilution
- ↑Collecting duct water permeability: ADH-dependent (volume depletion → ↑ADH) + ADH-independent (↑luminal PGE2 จาก ↓PGT activity; SLCO2A1 variant)
Risk: Female, old age, low body mass, SLCO2A1 variant, excessive water intake
2.4 K-sparing Diuretics
Inhibit ENaC ที่ late distal tubule/collecting duct — 2 กลุ่ม:
- ENaC inhibitors: Amiloride, Triamterene (direct channel block)
- MRA: Spironolactone, Eplerenone, Finerenone (nonsteroidal MRA)
Block ENaC → ↓lumen negative potential → ↓K⁺ secretion (ROMK) + ↓H⁺ secretion (H⁺-ATPase) → Hyperkalemia + Type 4 RTA
| Drug | Dose | T½ | Indication |
|---|---|---|---|
| Spironolactone | 25–50 mg PO | 16.5h | Cirrhotic ascites + loop (ratio 100:40), HFrEF, Resistant HTN |
| Eplerenone | 25–50 mg | 3–6h | HFrEF (ลด gynecomastia) |
| Finerenone | Nonsteroidal MRA | — | Diabetic nephropathy (ลด CV events, CKD progression) |
ADR: Hyperkalemia (major), Gynecomastia (spironolactone>>eplerenone)
2.5 Vasopressin Receptor Antagonist (Aquaretics/Vaptans)
Inhibit V2 receptor ที่ cortical collecting duct → block vasopressin-stimulated AQP2 insertion → ↓free water reabsorption → electrolyte-free water excretion (ไม่เพิ่ม Na⁺ excretion — จึงเป็น aquaretic ไม่ใช่ natriuretic)
- Indications: SIAD, Hypervolemic hyponatremia (ADHF, Cirrhosis, ใช้เฉพาะ Na <135), ADPKD
- ADR: Hypernatremia (ถ้า monitor ไม่ดี), Transaminitis (tolvaptan)
2.6 Osmotic Diuretics
Free filtrated แต่ poorly reabsorbed → osmotic force ตลอดทั้ง nephron → ↓passive reabsorption
- Drugs: Mannitol, Sorbitol, Glycerol
- Indications: Cerebral edema (hepatic encephalopathy, severe head injury), Dialysis disequilibrium syndrome
- ADR: Hypertonic hyponatremia (translocation) → hypernatremic dehydration; AKI (renal vasoconstriction); Osmotic nephrosis (tubular necrosis)
2.7 Pharmacology Comparison (ESC Heart Fail 2019)
| Acetazolamide | Loop | Thiazide-like | MRA | Amiloride | |
|---|---|---|---|---|---|
| Site | Proximal | TALH | Early DCT | Late distal/CD | Late distal/CD |
| Onset PO | 1h | 0.5–1h | 1–2.5h | 48–72h | 2h |
| FENa% | 4% | 20–25% | 5–8% | 2% | 2% |
| Oral bioavailability | Dose-dependent | Furosemide 64% | 65–75% | ~90% | 30–90% |
🔄 Part 3: Ultrafiltration (UF)
Principles
Convection ขับเคลื่อนด้วย transmembrane pressure (TMP) → solutes ถูก “dragged” ไปพร้อม water (solvent drag) เหมาะสำหรับ middle molecules (cytokines, β2-microglobulin); ต่างจาก diffusion ที่ขึ้นกับ concentration gradient (small solutes)
Modalities
| Modality | Blood flow (mL/min) | Fluid removal (mL/h) | Notes |
|---|---|---|---|
| Intermittent UF | 250–400 | 0–2000 | Widely available; hemodynamic instability risk |
| Continuous UF (SCUF/CVVH) | 50–100 | 0–300 | Hemodynamically stable; CVVH allows Na/water dissociation |
| Peritoneal dialysis | N/A | 0–500 | No venous access; hemostable; paediatrics |
| HD intermittent | 250–400 | 0–2000 | Adds solute clearance |
| HD continuous | 50–100 | 0–300 | Hemostable + solute clearance |
UF Rate in CKRT
U-shaped relationship ระหว่าง UF rate กับ mortality (Nat Rev Nephrol 2021):
- UF rate ต่ำเกินไป → organ oedema
- UF rate สูงเกินไป → organ ischaemia
- “Zone of safe UF”: 1–1.75 mL/kg/h = lowest mortality risk
Loop Diuretic vs Isolated UF
| Loop Diuretics | Isolated UF | |
|---|---|---|
| Neurohormonal | Direct RAAS/SNS activation | No neurohormonal activation |
| Urine | Hypotonic | Isotonic plasma water removal |
| Na/water control | Unpredictable | Precise |
| Resistance | Develops with time | Restores diuretic responsiveness |
| Electrolytes | ↓K⁺, ↓Mg²⁺ | No effect |
| Anticoagulation | ไม่ต้องการ | ต้องการ |
UF Trials (ESICM 2025)
ESICM 2025: Suggest AGAINST routine UF/extracorporeal fluid removal หลัง acute resuscitation phase without other RRT indication (Conditional, low certainty)
| Trial | n | Key Finding |
|---|---|---|
| RAPID-CHF | 40 | NS; trend toward higher weight loss ใน UF |
| UNLOAD | 200 | UF>DT weight loss; NS renal function |
| CARRESS-HF | 188 | Sig ↑SCr ใน UF arm; Higher SAEs |
| CUORE | 56 | Sig ↑SCr ใน DT at 6mo |
| AVOID-HF | 224 | Higher SAEs in UF arm |
🚧 Part 4: Diuretic Resistance
Definition
Inadequate clearance of edema despite adequate doses — ก่อน label ว่า resistant: exclude incorrect diagnosis, poor compliance, high sodium intake
Adaptation Mechanisms
Humoral/neuronal changes: ↑RAAS, ↑Sympathetic, ↑ADH, ↓PGE2 (PGE2 ปกติ inhibit NKCC2)
Short-term: Post-diuresis salt retention — ↓volume → ↑RAAS/SNS → enhanced Na⁺ reabsorption inter-dose (Braking Phenomenon graph)
Long-term — Nephron Remodeling:
- DCT: ↑NCC expression
- Principal cell: ↑ENaC expression
- Intercalated cell: ↑Pendrin → ↑Na⁺/Cl⁻ reabsorption
Mechanisms of Diuretic Resistance
| กลุ่ม | กลไก |
|---|---|
| PK limitations | Gut edema → ↓absorption; Hypoalbuminemia → ↓delivery; OAT competition (CKD, probenecid, beta-lactam, uremic anions); Low CO/↑CVP → ↓renal perfusion |
| Tubular adaptation | ↑Distal NCC (DCT hypertrophy), ↑ENaC, Chloride-dependent WNK activation |
| Neurohormonal activation | Basal sodium avidity, Braking, Vasoconstriction → ↓eGFR |
Phenotype-specific Resistance
- Right HF: ↑CVP → venous congestion → ↓RV output → impaired drug delivery
- Advanced CKD: Metabolic alkalosis, chronic sodium avidity, ↓tubular secretion, ↑uremic toxins (OAT competition)
- Obesity HFpEF: Adipokines → RAAS; ↑intraabdominal pressure; RV overload
- Elderly/Frail: ↓Renal reserve, altered PK/PD, ↑AKI risk
Albumin + Furosemide ใน Hypoalbuminemia (Meta-analysis PLoS One 2021; 13 studies, n=422):
- ↑urine output MD 31.45 mL (19.30–43.59)
- Subgroup albumin <2.5 g/dL: MD 60.68 mL (24.38–96.98)
- Albumin dose ≥30 g: MD 58.77 mL (27.56–89.97)
- → พิจารณา albumin + furosemide ถ้า albumin <2.5 g/dL และมี diuretic resistance
🏥 Part 5: Clinical Application
5.1 Acute Heart Failure (AHF) — ESC 2021
IV Loop diuretics (Class I, Level C):
- Diuretic-naive: Furosemide 20–40 mg IV
- Chronic use: At least equivalent to daily oral dose
- Combination + thiazide-type for resistant oedema (Class IIa, Level B)
Diuretic Response Assessment (ESC 2021):
- Urinary spot Na⁺ ≥50–70 mEq/L หลัง 2 ชม.
- Urine output ≥100–150 mL/h หลัง 6 ชม.
- ถ้าไม่ตอบสนอง → Double dose IV → Sequential nephron blockade → ตรวจ SCr/electrolytes ทุก 24h → UF/RRT
DOSE Trial (NEJM 2011; n=308) — 2×2 factorial ADHF:
- Bolus vs Continuous: ไม่ต่างกัน VAS score หรือ SCr change
- High dose (2.5× oral): ↑↑ net fluid loss ที่ 72h (4899 vs 3575 mL, p=0.001)
- Post-hoc DOSE (J Card Fail 2016): WRF ที่ 72h → ↓ risk composite death/rehospitalization ที่ 60d — acceptable renal stress
- Cochrane 2024 (7 RCT, n=681): ไม่ต่างกัน LOS/readmission/AKI; continuous → +0.86 kg weight loss (very low certainty)
Sequential Nephron Blockade — Key Trials:
| Trial | Intervention | Outcome |
|---|---|---|
| ADVOR (NEJM 2022; n=519) | Acetazolamide 500mg IV + Furosemide | Sig decongestion 72h (RR 1.46, p<0.001); No diff mortality/rehospitalization |
| EMPULSE (Nat Med 2022; n=530) | Empagliflozin 10mg for 90d + loop | Sig composite HF outcome at 90d; early eGFR dip (<2wk), no sig at 90d |
| CLOROTIC (EHJ 2023; n=230) | Oral HCTZ (eGFR-adjusted) + Furosemide | Sig BW + dyspnea at 72h; HCTZ: more hypokalemia + renal impairment |
| SECRETs of CHF (JACC 2017; n=250) | Tolvaptan 30mg + Furosemide | No sig dyspnea; Sig BW decrease |
| ATHENA-HF (JAMA 2017; n=360) | Spironolactone 100mg/d for 96h + Furosemide | No sig NTproBNP, dyspnea, or UO |
Diuretic Strategy Algorithm (ESC 2021):
- Loop diuretic IV (naive → 20–40mg; chronic → 1–2× oral dose)
- Check Urinary Na ±2h, UO ±6h
- ถ้าตอบสนอง → repeat similar dose q12h
- ถ้าไม่ตอบสนอง → double dose until maximum IV → Sequential blockade (CAI, HTCZ, SGLT2i, MRA, V2RA) → UF/RRT
Notes:
Hyponat → tolvaptan
Met alkalo → acetazolamide
Hypernat → thiazide
Inpatient HF → SGLT2i
5.2 Acute Kidney Injury (AKI) — KDIGO Evolution
KDIGO 2012 → 2026 — Major Shift:
| KDIGO 2012 | KDIGO 2026 | |
|---|---|---|
| Prevention | ไม่แนะนำ diuretic prevent AKI (1B) | — |
| Treatment | ไม่แนะนำ diuretic treat AKI ยกเว้น volume overload (2C) | Suggest diuretics for significant volume overload in AKI/AKD (2B) |
| UF vs Diuretic | — | Recommend initial diuretics OVER extracorporeal removal ใน AKI + volume overload ไม่มี other RRT indication (1C) |
| Role ใน ICU | — | Diuretic = marker of AKI risk prediction + marker of KRT discontinuation |
ESICM 2025 Evidence (ICM 2025;51:1749–1763): Protocolized diuretics vs usual care:
- Mortality: RR 0.90 (trend benefit)
- ICU-free days: MD +2.2 days
- Ventilator-free days: MD +2.53 days
- Need for RRT: RR 0.72 (significant)
De-Resuscitation — REDUCE Trial (Crit Care 2025; n=100):
- P: Adult circulatory shock, stabilized >12h
- Protocol: Fluid restriction + Diuretic หาก I>O 500 mL + KRT หาก I>O 1000 mL for 48h แม้ได้ diuretic
- Result: No sig 30d mortality; ↓ ICU LOS (7 vs 10d, p=0.006); ↓ Hospital LOS (16 vs 22d, p=0.006)
- 7-day cumulative fluid balance: −2353 vs +793 mL (p<0.001)
ROSE framework (R-O-S-E phases):
- Resuscitation: CLASSIC/CLOVER → no benefit of fluid restriction
- Optimization/Stabilization: → Active de-resuscitation? (REDUCE trial)
- Evacuation: Active negative fluid balance (LGFR)
5.3 KDIGO 2026 Diuretic Strategy in AKI — Escalation Pathway
| Step | Dose | Goal |
|---|---|---|
| Assessment | Furosemide 1.0 mg/kg IV (1.5 mg/kg ถ้าเคยใช้ diuretic) | UO >200 mL/2h → continue scheduled dosing |
| Escalation | Double dose (160–200 mg IV) q6–12h | Max bolus 200 mg ก่อน switch infusion |
| Synergism | Add thiazide-like (metolazone 5–10 mg PO หรือ chlorothiazide 500 mg IV) | ให้ 30–60 นาทีก่อน loop diuretic |
| Intensify | Switch continuous infusion 5–10 mg/hr | Titrate to 20 mg/hr |
| Failure | Re-evaluate for RRT | ไม่ได้ negative balance แม้ max therapy หรือ K⁺/pH deranged |
KDIGO 2026 Practice Point 3.3.1: Intermittent boluses preferred over continuous infusion เป็น initial strategy ใน AKI/AKD
5.4 Furosemide Stress Test (FST)
Dynamic test of tubular reserve — ต้องอาศัย intact renal perfusion + proximal tubular secretion + viable nephron mass
- No prior loop diuretic: Furosemide 1.0 mg/kg IV
- Prior loop diuretic: 1.5 mg/kg IV
| Response | Interpretation |
|---|---|
| UO ≥200 mL/2h | Likely reversible AKI |
| UO <200 mL/2h | High risk AKI stage 3 progression → Consider early RRT planning (ไม่ใช่ indication ทันที) |
KDIGO 2026 Recommendation 2.3.1 (2C adults, 2B children): Suggest FST to assess risk of progression to Stage 3 AKI/RRT ใน Stage 1–2 AKI, euvolemic/hypervolemic
Meta-analysis (11 studies, n=1366; Crit Care 2020):
- KRT prediction: Sensitivity 0.84, Specificity 0.77
- AKI progression: Sensitivity 0.81, Specificity 0.88
5.5 Discontinue KRT (KDIGO 2026)
Practice Point 5.9.3: UO >450 mL/24h without diuretics หรือ >2300 mL/24h with diuretics + 2-hour timed CrCl ≥23 mL/min → predict successful RRT discontinuation
Practice Point 5.9.4: Diuretics ก่อน/หลัง RRT discontinuation ใช้ augment UO และ fluid balance ได้ แต่ไม่ proven ว่า facilitate AKI resolution
| Trial | UO without diuretic | UO with diuretic |
|---|---|---|
| ELAIN (2016) | >400 mL/24h | >2100 mL/24h |
| AKIKI / IDEAL-ICU / AKIKI-2 | >1000 mL/24h | >2000 mL/24h |
📌 Part 6: Take-Home Messages (ICM 2024;50:1331–1334)
1. Prescription of Loop Diuretics:
- Furosemide IV 40 mg (เพิ่มถ้า reduced kidney function) หรือ infusion 2–10 mg/hr
- Bumetanide 1 mg IV bolus หรือ 0.5 mg/hr; Torsemide 20 mg IV
- T½ prolonged ใน hepatic/renal failure + heart failure
2. Managing Diuretic Resistance (Step-wise):
- ↑ dose (consider doubling) → optimize delivery
- Add Acetazolamide 250–500 mg IV daily หรือ HCTZ 50 mg/d หรือ SGLT2i (HF)
- Correct hypoalbuminemia (Albumin + Furosemide ถ้า albumin <2.5 g/dL)
- Consider RRT
3. Monitoring for Adverse Effects:
| ↓ ลง | ↑ ขึ้น |
|---|---|
| Na⁺ (thiazide) | Na⁺ (loop diuretics) |
| K⁺, PO₄⁻, Mg²⁺, Cl⁻ | pH / Metabolic alkalosis (loop + thiazide) |
| pH (acetazolamide) | Uric acid (loop diuretics) |
| Cardiac output, BP, GFR | — |
📚 Landmark Trials Summary
| Trial | Year | n | สรุป |
|---|---|---|---|
| DOSE | NEJM 2011 | 308 | Bolus = Continuous efficacy/safety; High dose → ↑fluid loss; WRF ≠ worse outcomes |
| Cochrane loop diuretic | 2024 | 681 | Bolus = Continuous clinical outcomes; continuous → slightly more weight loss |
| ADVOR | NEJM 2022 | 519 | Acetazolamide + furosemide → Sig decongestion RR 1.46; no mortality benefit |
| EMPULSE | Nat Med 2022 | 530 | Empagliflozin → Sig composite HF outcomes at 90d; early eGFR dip |
| CLOROTIC | EHJ 2023 | 230 | HCTZ + furosemide → Sig BW + dyspnea; ↑hypokalemia + renal impairment |
| ATHENA-HF | JAMA 2017 | 360 | High-dose spironolactone → No sig benefit |
| REDUCE | Crit Care 2025 | 100 | Protocolized restrictive fluid → ↓ICU LOS (7 vs 10d), ↓hospital LOS (16 vs 22d) |
| FST meta-analysis | Crit Care 2020 | 1,366 | Sensitivity 0.84/Specificity 0.77 สำหรับ KRT prediction; KDIGO 2026 (2C) |
Guidelines
- ESC HF 2021 — Eur Heart J 2021;42(36)
- KDIGO AKI 2026 — Intensive Care Med 2025;51(10):1749–1763
- ESICM Fluid Therapy Part 3 2025 — ICM 2025;51:1749–1763