DIALYSIS? HEMOPERFUSION? What’s up with enhanced elimination of drugs? Kent R. Olson, MD Medical Director - SF Division California Poison Control System

Case study: A 30 year old man accidentally drank 3 ounces of CAMPHORATED OIL, mistaking it for castor oil. He vomited and later developed seizures and hypotension. After 2 hours of hemoperfusion he began to awaken, and he subsequently recovered fully.

Hemoperfusion ARTERY or VEIN VEIN Blood from patient Return to patient Uses hemodialysis machine - but runs blood directly through a charcoal- or sorbent-containing filter

Case, continued . . . The plasma camphor level before hemoperfusion was 1.7 mcg/mL Extraction of camphor by the machine was ~ 99% However, no measurement of the total amount of camphor removed: Probably less than 1% of the 18 gram dose was removed !!

What happened? Triumph of the anecdotal case: But: I did “such and so” the patient got better it must have been the “SUCH and SO!” But: the volume of distribution of camphor is HUGE and, the patient would likely have gotten better anyway, despite the hemoperfusion

Enhanced drug elimination: Who needs it? Will it work? What’s the best technique?

It’s not used very often: 1995 AAPCC data - 2 million poisonings: Urine alkalinization: used in 0.35% Hemodialysis: used in 0.04% Hemoperfusion: used in 0.0003%

Who needs it? Critically ill despite supportive care eg, phenobarb OD w/ intractable shock Known lethal dose or blood level eg, salicylate; methanol / ethylene glycol; theophylline; paraquat? Usual route of elimination impaired eg, lithium OD in oliguric patient Risk of prolonged coma eg, phenobarbital OD w/ level of 200

Will it work? Volume of distribution: Clearance (CL): is the drug accessible? how big a volume to clear? Clearance (CL): does the method efficiently cleanse the blood? what is the intrinsic clearance?

Volume of distribution (Vd) A calculated number - not real = amt. of drug / plasma conc. = mg/kg / mg/L = L/kg Total body water = 0.7 L/kg or ~ 50 L ECF = 0.25 L/kg or about 15 L in adult Blood or plasma = 0.07 L/kg or ~ 5 L

Vd for some common drugs Large Vd: camphor antidepressants digoxin opioids phencyclidine phenothiazines Small Vd: alcohols lithium phenobarbital phenytoin salicylate valproic acid

mcg/mL x mL/min = mg/min “But they reported the CLEARANCE was really good - - - 200 mL/min . . .” CL = flow rate x extraction ratio eg, dialysis rate 250 mL/min; if extraction is 80%, Cl = 200 mL/min But Cl is expressed in mL/min . . . NOT mg/min or gm/hr or tons/day Total drug elimination depends on drug concentration: mcg/mL x mL/min = mg/min

Example: amitriptyline OD 60 kg man ingests 100 x 25 mg Elavil tabs Vd = 40 L/kg or 2400 L Est. Cp = 2500 mg / 2400 L ~ 1 mcg/mL Hemoperfusion with CL of 200 mL/min Drug removal = 200 mL/min x 1 mcg/mL = 200 mcg/min or 0.2 mg/min or 0.5% per hour

Two drugs with the same CL Dialysis CL Vd Fraction eliminated in 60 min of dialysis 200 mL/min 500 L 1% 200 mL/min 50 L 17% T½ = 0.693 Vd / CL

What is the intrinsic CL? If intrinsic (or endogenous) CL is large, an enhanced removal method may not add much to total CL examples of HIGH endogenous CL: lidocaine, opioids, TCAs, many beta-blockers examples of LOW endogenous CL: alcohols, atenolol, lithium, salicylate, phenytoin, theophylline General rule: method should increase total CL by at least 30%

Summary of desired kinetics Small volume of distribution Vd less than 1 L/kg Low endogenous CL less than 4 mL/min/kg Single-compartment kinetics rapid equilibration between blood and tissues avoid problem of rebound in blood levels

Which method? Urinary pH manipulation Peritoneal dialysis Hemodialysis Hemoperfusion Mulitple dose activated charcoal Continuous hemofiltration

Urinary pH manipulation Alkaline diuresis traps weak acids in alkaline urine useful for salicylates, phenobarbital, chlorpropamide risk of fluid overload Acid diuresis traps weak bases may enhance elimination of amphetamines TOO RISKY - may worsen myoglobinuric RF

Peritoneal dialysis Theoretically useful if drug is: water soluble small (MW <500) not highly protein bound not so bad you don’t mind waiting . . . TOO SLOW Rarely performed unless it’s the only available method

Hemodialysis Can be arteriovenous or veno-venous (double-lumen catheter) Requires anticoagulation Best if drug is: water-soluble small (MW <500) not highly protein bound Also good for correcting fluid & electrolyte abnormalities

Hemodialysis, continued . . . Newer machines have higher flow rates, better extraction ratios Note: DON’T use the REDY system - these portable HD units have very limited volume dialysate which is recycled, and CL may be very poor

Charcoal hemoperfusion Uses same vascular access and dialysis pumps Greater anticoagulation required Saturation of charcoal limits duration But, it is not dependent on drug size, water solubility or protein binding - as long as drug binds to charcoal Can be used in series with dialysis

Multiple dose oral charcoal - “gut dialysis” Charcoal slurry along the entire intestinal tract Large surface area for adsorption of drug diffusing across intestinal epithelium from capillaries Useful if drug likes AC, small Vd, low protein binding Clinical benefit unproven

Continuous hemofiltration Plasma moves across semipermeable membrane under hydrostatic pressure No dialysate Solutes follow the plasma water - size up to MW ~ 10,000-40,000 CL lower than HD or HP, but it can be performed 24 hrs/day

Drug Preferred Method Carbamazepine HP Ethylene glycol HD Lithium HD Methanol HD Methotrexate HF Phenobarbital HP Procainamide HF Salicylate HD or HP Theophylline HP or HD Valproic acid HD or HP

Salicylate poisoning Indications for dialysis: Note: severe metabolic acidosis serum level > 100 mg/dL (acute OD) level > 60 mg/dL (elderly, chronic OD) Note: check units!! (mg/dL vs mg/L) alkalinize serum and urine dialysis preferred: can correct electrolyte and fluid abnormalities

Theophylline poisoning Indications for dialysis: serum level > 100 mg/L (acute OD) level > 60-80 mg/L? (chronic) seizures Notes: HP or high-flux HD Control Sz w/ phenobarbital Rx hypotension w/ beta blockers

Methanol, Ethylene Glycol Indications for dialysis: elevated level > 50 mg/dL severe acidosis increased osmolal gap > 10-15 mmol/L Notes: HD only - not adsorbed to AC give blocking drug (EtOH, 4-MP) - Note: need to increase dosing during dialysis

Phenobarbital Indications for dialysis: Notes: level > 190-200 mg/L failure of supportive care (ie, intractable hypotension) Notes: rarely seen anymore HP > HD repeated dose AC shortens half-life but not length of coma

Lithium Indications for dialysis: Notes: serum level > 6? 8? 10? (acute OD) level > 4 ? (chronic) level 2.5-4 with severe Sx? Notes: 2-compartment model, very slow redistribution from tissues patients rarely get quick improvement difficult to evaluate need and benefit IV saline “diuresis” may be nearly as effective

Lithium

Estimate for Lithium Usual renal Cl 25-35 mL/min Hemodialysis adds 100-150 mL/min But only for 3-4 hours at a time Rebound between dialysis sessions CVVH adds 20-35 mL/min But can be provided continuously Volume cleared ~ 50L/day vs 36 L/day w/ 4 hours of HD No rebound

Remember: Consider pharmacokinetics and known behavior of the drug What clinical evidence is there for benefit with enhanced removal? Most patients will get better anyway