DIALYSIS? HEMOPERFUSION? What’s up with enhanced elimination of drugs?

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

2. 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.

3. 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

4. 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 the18 gram dose was removed !!

5. What happened? • Triumph of the anecdotal case: • 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

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

7. 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%

8. 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

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

10. 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

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

12. “But they reported the CLEARANCE was really good - - - 200 mL/min . . .” • CL = flow rate x extraction ratioeg, 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

13. 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

14. 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

15. 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%

16. 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

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

19. 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

20. 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

22. 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

23. 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

25. 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

26. 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

28. 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

29. 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

30. Salicylate poisoning • Indications for dialysis: • 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

31. 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

32. 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

33. Phenobarbital • Indications for dialysis: • 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

34. Lithium • Indications for dialysis: • 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

35. Lithium

36. 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/dayvs 36 L/day w/ 4 hours of HD • No rebound

37. 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