Transcript Dialysis? Hemoperfusion? Enhanced elimination of drugs

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
Blood
from
patient
VEIN
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:
– 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:
– 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
“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 venovenous (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
Carbamazepine
Ethylene glycol
Lithium
Methanol
Methotrexate
Phenobarbital
Procainamide
Salicylate
Theophylline
Valproic acid
Preferred Method
HP
HD
HD
HD
HF
HP
HF
HD or HP
HP or HD
HD or HP
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
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:
– 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:
– 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