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 the 18 gram dose was removed !!

5. 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

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 %

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: 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?

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

12. mcg/mL x mL/min = mg/min
“But they reported the CLEARANCE was really good 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

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 L 1%
200 mL/min L %
T½ = 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: 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

31. Theophylline poisoning
Indications for dialysis:
serum level > 100 mg/L (acute OD)
level > 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 > 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: 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

34. Lithium Indications for dialysis: Notes:
serum level > 6? 8? 10? (acute OD)
level > 4 ? (chronic)
level 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 mL/min
But only for 3-4 hours at a time
Rebound between dialysis sessions
CVVH adds mL/min
But can be provided continuously
Volume cleared ~ 50L/day vs 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