Download Dialysis? Hemoperfusion? Enhanced elimination of drugs

Lithium Poisoning: when is
hemodialysis indicated?
Kent R. Olson, MD
Medical Director - SF Division
California Poison Control System
Case
• A 32 year old woman
ingested 20 lithium carbonate 300 mg
tablets in a suicide attempt
• She is drowsy and her speech is
slurred
• Her serum Li = 6 mEq/L
• Hemodialysis needed?
Lithium
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Alkali metal (like Na, K)
Widely used for bipolar disorder
Therapeutic range 0.6-1.2 mEq/L
Toxicity = mainly CNS
– Tremor, slurred speech, muscle twitching
– Confusion, delirium, seizures, coma
– Recovery may take weeks
• Toxicity may occur as a result of
acute overdose or chronic use
Pharmacokinetics
• Completely absorbed orally
– Volume of distribution approx 0.8 L/kg
– Slow entry into CNS
– Initial serum levels do NOT reflect brain levels
• Eliminated entirely by the kidneys
– Half-life 14-20 hours
– Prolonged in patients with renal insufficiency
– Promoting saline excretion hastens Li removal
Li Case, continued
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Na = 140
K = 4.0
Cl = 110
HCO3 = 26
BUN = 8
Cr = 1.0
Glucose = 98
EtOH = 0.16 gm% U Tox (+) benzo’s
Enhanced drug elimination:
• Who needs it?
• Will it work?
• What’s the best technique?
Who needs it?
• Critically ill despite supportive care
– eg, phenobarbital OD w/ intractable shock
• Known lethal dose or blood level
– eg, salicylate; methanol / ethylene glycol
• Usual route of elimination impaired
– eg, lithium OD in oliguric patient
• Risk of prolonged coma
– eg, phenobarbital OD w/ level of 250
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?
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:
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camphor
antidepressants
digoxin
opioids
phencyclidine
phenothiazines
Small Vd:
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alcohols
lithium
phenobarbital
phenytoin
salicylate
valproic acid
“But they reported the CLEARANCE
was really good - - - 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
Which method?
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Urinary pH manipulation
Peritoneal dialysis
Hemodialysis
Hemoperfusion
Multiple 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:
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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
Salicylate poisoning
• Indications for dialysis:
– severe metabolic acidosis
– serum level > 100 mg/dL (acute OD)
– level > 60 mg/dL (elderly, chronic OD)
• Note:
– alkalinize serum and urine
– dialysis preferred: can correct electrolyte and fluid
abnormalities
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
Lithium case, cont . . .
• The Poison Control Center was
consulted about hemodialysis
• The toxicologist advised:
• IV saline at a rate of 150 cc/hr
• Recheck serum Li in 4 hours
Li case, cont . . .
• After 4 hrs, the Li was 2.2 mEq/L
• A 3rd level 4 hrs later was 1.1
• The patient gradually recovered from
her alcohol and benzodiazepine
intoxication
What happened?
“Two-compartment”
Model
Lithium
Another Lithium Case
• A 42 year old man brought from a
board and care with mumbling,
tremor, has a seizure in the ED
• Chronic Li use, no other meds
• BUN = 44 Cr = 2.6
Na = 148
• Li = 3.8 mEq/L
• Repeat Li 4 hours later = 3.6 mEq/L
Acute vs Chronic Li
• Acute:
– High level, drops rapidly
– Absent symptoms
• Chronic:
– Often associated w/ renal insufficiency, DI
– Occurs gradually
– Symptoms more severe, even with lower
levels (eg, 2 - 2.5 and above)
Lithium and dialysis
• Indications for dialysis:
– serum level > 6? 8? 10? (acute OD)
– level > 4 ? (chronic)
– level 2.5-4 with severe Sx?
Lithium and dialysis
• 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
– Not very good at removing intracellular Li
CVVH (a.k.a. CRRT)
• 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
Lithium: summary
• 2-compartment model
– Early levels misleadingly high
– By the way --- don’t use a green-top tube!
• Acute vs chronic intoxication
• Dialysis is not rapidly effective
– Li is slow to leave intracellular compartment
• IV fluids often the best bet