8.2 Continuous Renal Replacement Therapy (CRRT) vs Intermittent Hemodialysis

Physical Principles of Extracorporeal Clearance

Renal replacement therapy relies on three distinct physical transport mechanisms across a semipermeable synthetic membrane to restore fluid, electrolyte, and acid-base homeostasis:

Loading diagram...

1. Diffusion (Dialysis)

Diffusion represents the passive movement of solute molecules down a concentration gradient governed by Fick's law of diffusion. In a dialysis circuit, blood flows through hollow capillary fibers while sterile dialysate fluid flows in the opposite direction (counter-current) outside the fibers. The rate of diffusive transport ($J_d$) is proportional to the concentration difference across the membrane, the membrane surface area ($A$), the solute diffusion coefficient ($D$), and inversely proportional to membrane thickness ($x$):

$J_d = -D \cdot A \cdot \frac{\Delta C}{x}$

Diffusion is highly efficient for small, unbound water-soluble molecules ($< 500\text{ Da}$), such as urea ($60\text{ Da}$), potassium ($39\text{ Da}$), sodium ($23\text{ Da}$), and creatinine ($113\text{ Da}$). However, diffusive clearance declines logarithmically as molecular weight increases, offering minimal clearance for middle molecules ($> 1,000\text{ Da}$).

2. Convection (Hemofiltration)

Convection refers to the bulk transport of solute driven across a semipermeable membrane alongside plasma water in response to a hydrostatic pressure gradient—a physical phenomenon termed solvent drag. A high transmembrane pressure (TMP) forces large volumes of plasma water across the membrane into the effluent compartment as ultrafiltrate. Solutes small enough to pass through the membrane pores are swept along in the solvent stream. The convective clearance ($K_c$) is determined by the ultrafiltration rate ($Q_{\text{uf}}$) and the sieving coefficient ($S$) of the molecule:

$K_c = Q_{\text{uf}} \times S$

The sieving coefficient ranges from 0 (completely rejected by the membrane, such as albumin, molecular weight $66.5\text{ kDa}$) to 1.0 (freely permeable, identical concentration in plasma water and ultrafiltrate, such as urea). Convective clearance is remarkably effective for both small molecules and middle-to-large molecules ($500\text{ to }50,000\text{ Da}$), such as $\beta_2$-microglobulin ($11.8\text{ kDa}$), circulating pro- and anti-inflammatory cytokines ($8\text{ to }30\text{ kDa}$), myoglobin ($17\text{ kDa}$), and vancomycin ($1.4\text{ kDa}$).

3. Ultrafiltration

Ultrafiltration represents the net convective movement of plasma water across the membrane driven by transmembrane pressure, used therapeutically to achieve net negative fluid balance and resolve hypervolemia.

---

Continuous Modalities: SCUF, CVVH, CVVHD, and CVVHDF

Continuous renal replacement therapies (CRRT) operate 24 hours a day to provide gradual, continuous clearance and fluid control. Modalities differ based on the fluid streams employed:

Loading diagram...

1. Slow Continuous Ultrafiltration (SCUF)

• Mechanics: Blood is pumped through the circuit without dialysate ($Q_d = 0$) and without replacement fluid ($Q_{\text{rf}} = 0$). Ultrafiltrate is generated at low rates ($100\text{ to }300\text{ mL/h}$) solely to remove fluid.
• Indications: Isolated volume overload refractory to diuretics in patients who are hemodynamically precarious, where uremia, hyperkalemia, and acid-base derangements are absent.
• Limitations: Minimal solute clearance; will not treat uremia or severe acidosis.

2. Continuous Veno-Venous Hemofiltration (CVVH)

• Mechanics: Solute clearance occurs entirely by convection. Massive ultrafiltrate volumes ($20\text{ to }35\text{ mL/kg/h}$) are generated and discarded. To prevent rapid hypovolemic exsanguination, physiological electrolyte replacement fluid is infused into the blood circuit.
• Pre-dilution vs. Post-dilution Replacement:
  • Pre-dilution: Replacement fluid is infused into the circuit prior to the filter. This dilutes the blood entering the capillary fibers, lowering the circuit hematocrit and solute concentration. Pre-dilution decreases hemoconcentration within hollow fibers, reduces membrane protein fouling, lowers transmembrane pressure, and substantially prolongs filter lifespan. However, because it dilutes the plasma entering the filter, solute clearance efficiency per liter of effluent is reduced by $15\text{ to }20\%$, requiring a proportionally higher prescribed effluent flow rate.
  • Post-dilution: Replacement fluid is infused into the venous bubble trap after the filter. Because undiluted blood enters the filter, convective solute clearance is $100\%$ efficient. However, as ultrafiltrate is extracted along the length of the capillary fibers, the intra-luminal blood becomes progressively hemoconcentrated. This increases the filtration fraction ($FF$), elevating blood viscosity and circuit thrombosis risk.
  • Filtration Fraction Formula:

$FF = \frac{Q_{\text{uf}}}{Q_p} \times 100\% = \frac{Q_{\text{uf}}}{Q_b \times (1 - \text{Hct})} \times 100\%$

3. Continuous Veno-Venous Hemodialysis (CVVHD)

• Mechanics: Solute clearance occurs entirely by diffusion. Counter-current dialysate fluid runs through the outer dialysate compartment ($Q_d = 20\text{ to }30\text{ mL/kg/h}$) while blood flows through the inner hollow fibers. Ultrafiltration is added independently to achieve the desired net negative fluid balance.
• Advantages: Eliminates the high transmembrane pressures and hemoconcentration seen in pure convection, reducing circuit clotting while providing outstanding small-solute (urea, potassium) clearance.

4. Continuous Veno-Venous Hemodiafiltration (CVVHDF)

• Mechanics: Combines convective and diffusive clearance. Both counter-current dialysate fluid ($Q_d$) and convective replacement fluid ($Q_{\text{rf}}$) are infused simultaneously.
• Advantages: Maximizes simultaneous clearance of small molecules (via diffusion) and middle-to-large molecules (via convection) while keeping the filtration fraction well within safe operating limits ($< 20\%$).

Modalities Comparison Table

---

CRRT vs. Intermittent Hemodialysis (IHD): Clinical Indications

Randomized trials (such as the Hemodiafe and SHARF trials) and meta-analyses show similar survival with CRRT and IHD across broad ICU cohorts, and KDIGO considers them complementary. KDIGO suggests CRRT rather than IHD (grade 2B) for hemodynamically unstable patients and for patients with acute brain injury or raised intracranial pressure, for the reasons below:

1. Hemodynamic Instability and Septic Shock

Intermittent hemodialysis removes solutes and fluid rapidly over a contracted 3- to 4-hour window, requiring high blood flow rates ($300\text{ to }450\text{ mL/min}$) and ultrafiltration rates frequently exceeding $1,000\text{ to }1,500\text{ mL/h}$. This rapid volume extraction outpaces the physiological plasma refilling rate from the interstitial space, precipitating intradialytic hypotension in up to 40% of critically ill patients.

Intradialytic hypotension induces transient myocardial stunning, compromises mesenteric and coronary perfusion, and critically causes recurrent ischemic renal insults, transforming recovering tubular epithelium back into necrotic tissue and significantly prolonging time to renal recovery. Conversely, CRRT extracts fluid slowly ($50\text{ to }200\text{ mL/h}$) over 24 hours, preserving mean arterial pressure, coronary perfusion, and promoting renal recovery.

2. Acute Brain Injury, Cerebral Edema, and Acute Liver Failure

In patients with acute intracranial pathology—including acute liver failure (ALF) with hyperammonemia, severe traumatic brain injury (TBI), large hemispheric ischemic stroke, or intracranial hemorrhage—conventional intermittent hemodialysis should be avoided (KDIGO suggests CRRT) because rapid solute removal can precipitate cerebral edema and herniation via dialysis disequilibrium syndrome:

Loading diagram...

Because CRRT clears urea continuously and slowly, plasma osmolality remains stable, preventing osmotic gradients between the intravascular space and brain tissue. In acute liver failure, CRRT also continuously removes neurotoxic circulating ammonia, reducing cerebral glutamine synthesis and astrocytic swelling.

---

Vascular Access and Circuit Anatomy

Reliable vascular access is the lifeline of CRRT. Access failure accounts for $> 30\%$ of unplanned circuit downtime, causing circuit clotting, blood loss, and inadequate dialytic delivery.

Catheter Selection and Anatomical Sites

Acute CRRT utilizes large-bore, dual-lumen non-tunneled catheters (typically 12 to 14 French in caliber) placed under real-time ultrasound guidance:

1. Right Internal Jugular (RIJ) Vein: The first-choice, preferred anatomical site. The RIJ provides a direct, straight vertical course into the superior vena cava and cavoatrial junction. It exhibits the lowest rates of vascular recirculation, lowest risk of catheter kinking, and preserves the thoracic vasculature. Recommended catheter length: about $15\text{ cm}$ (about $20\text{ cm}$ for the left internal jugular vein).
2. Femoral Vein: The second-choice site. Excellent in emergency situations, agitated patients, severe cervical trauma, or patients with profound coagulopathy where non-compressible arterial puncture in the neck is perilous. However, femoral catheters require longer designs ($20\text{ to }25\text{ cm}$) to ensure the tip reaches the large-caliber inferior vena cava. Short femoral catheters terminate in the common iliac vein, predisposing to high recirculation rates ($> 20\%$) and flow obstruction.
3. Left Internal Jugular Vein: Third choice; its tortuous course through the brachiocephalic vein increases catheter dysfunction and recirculation.
4. Subclavian Vein: Last choice for temporary dialysis access (KDIGO; preferably on the dominant-hand side if it must be used). Subclavian dialysis catheters carry a high incidence of central vein stenosis (reported in up to 40-50%). Fibrotic stenosis of the subclavian vein permanently destroys the ipsilateral upper extremity for future arteriovenous fistula (AVF) or graft (AVG) creation should the patient progress to end-stage kidney disease.

---

Circuit Anticoagulation: Regional Citrate vs. Systemic Heparin

Extracorporeal blood contact with foreign synthetic plastic tubing and membrane hollow fibers rapidly activates the intrinsic and contact coagulation cascades, causing circuit thrombosis. Modalities of anticoagulation include:

1. Regional Citrate Anticoagulation (RCA)

KDIGO suggests (2B) regional citrate anticoagulation rather than heparin for CRRT in patients without contraindications. RCA provides potent, complete anticoagulation confined exclusively to the extracorporeal circuit, completely eliminating the systemic bleeding risks associated with heparin.

Loading diagram...

• Mechanism: Trisodium citrate ($Na_3\text{Citrate}$) is infused pre-filter into the arterial blood line. Citrate chelates free ionized calcium ($\text{Ca}^{2+}$) into soluble calcium-citrate complexes. Because ionized calcium is an obligate co-factor for the tenase and prothrombinase complexes and platelet activation, driving circuit ionized calcium down to $0.25\text{ to }0.35\text{ mmol/L}$ completely paralyzes the coagulation cascade inside the filter.
• Systemic Neutralization: As blood returns to the patient through the venous line, an infusion of calcium chloride ($CaCl_2$) or calcium gluconate is administered to replenish systemic calcium stores and maintain systemic ionized calcium strictly between $1.10\text{ and }1.30\text{ mmol/L}$.
• Systemic Metabolism: In the patient's liver, skeletal muscle, and renal cortex, the absorbed citrate enters the mitochondrial tricarboxylic acid (Krebs) cycle, where each molecule of citrate is oxidized to yield three molecules of bicarbonate ($\text{HCO}_3^-$).

Citrate Toxicity / Accumulation ("Citrate Lock")

When systemic metabolism of citrate is severely impaired—characteristically in acute liver failure, decompensated cirrhosis, or profound shock states with severe tissue hypoperfusion and lactic acidosis (mitochondrial failure)—citrate cannot enter the Krebs cycle and accumulates in the circulation.

The Diagnostic Triad of Citrate Toxicity

1. Elevated Total-to-Ionized Calcium Ratio: Unmetabolized circulating citrate binds systemic calcium, expanding the chelated fraction. Total serum calcium appears elevated or normal, while physiologically active ionized calcium drops. A ratio of:

$\frac{\text{Total Calcium (mmol/L)}}{\text{Systemic Ionized Calcium (mmol/L)}} > 2.5$

(Both values must be in the same units; convert total calcium from mg/dL to mmol/L by dividing by 4.0.) A ratio above 2.5 strongly suggests citrate accumulation. 2. Escalating Calcium Infusion Requirements: The infusion pump must continually increase calcium delivery to maintain a stable systemic ionized calcium level. 3. Worsening Metabolic Acidosis with an Elevated Anion Gap: Because citrate is an unmeasured circulating organic tri-anion, its accumulation expands the serum anion gap ($[\text{Na}^+] - [\text{Cl}^-] - [\text{HCO}_3^-]$) while failing to yield bicarbonate.

2. Systemic Unfractionated Heparin

Historically the most common anticoagulant, infused pre-filter and titrated to a systemic activated partial thromboplastin time (aPTT) of 45 to 65 seconds or circuit anti-Xa activity of $0.25\text{ to }0.35\text{ IU/mL}$.

• Major Disadvantages: Carries a $10\text{ to }25\%$ incidence of major systemic hemorrhage, induces heparin-induced thrombocytopenia (HIT Type II), and demonstrates unpredictable resistance in septic patients due to acquired antithrombin III deficiency.