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

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DIALYSIS? HEMOPERFUSION?Whats up with enhanced
elimination of drugs?

• Kent R. Olson, MD
• Medical Director - SF Division
• California Poison Control System

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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.

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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
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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 !!

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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

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Enhanced drug elimination

• Who needs it?
• Will it work?
• Whats the best technique?

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Its 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

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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

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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 intrinsic clearance?

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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

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Vd for some common drugs

• Large Vd
• camphor
• antidepressants
• digoxin
• opioids
• phencyclidine
• phenothiazines

• Small Vd
• alcohols
• lithium
• phenobarbital
• phenytoin
• salicylate
• valproic acid

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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

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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

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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
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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

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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

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Which method?

• Urinary pH manipulation
• Peritoneal dialysis
• Hemodialysis
• Hemoperfusion
• Mulitple dose activated charcoal
• Continuous hemofiltration

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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

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Peritoneal dialysis

• Theoretically useful if drug is
• water soluble
• small (MW lt500)
• not highly protein bound
• not so bad you dont mind waiting . . . TOO SLOW
• Rarely performed unless its the only available
  method

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Hemodialysis

• Can be arteriovenous or veno-venous (double-lumen
  catheter)
• Requires anticoagulation
• Best if drug is
• water-soluble
• small (MW lt500)
• not highly protein bound
• Also good for correcting fluid electrolyte
  abnormalities

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Hemodialysis, continued . . .

• Newer machines have higher flow rates, better
  extraction ratios
• Note DONT use the REDY system - these portable
  HD units have very limited volume dialysate which
  is recycled, and CL may be very poor

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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

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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

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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

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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

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Salicylate poisoning

• Indications for dialysis
• severe metabolic acidosis
• serum level gt 100 mg/dL (acute OD)
• level gt 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

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Theophylline poisoning

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

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Methanol, Ethylene Glycol

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

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Phenobarbital

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

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Lithium

• Indications for dialysis
• serum level gt 6? 8? 10? (acute OD)
• level gt 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

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Lithium
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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

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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