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 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 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: Clearance (CL): 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: camphor antidepressants digoxin opioids phencyclidine phenothiazines Small Vd: alcohols lithium phenobarbital phenytoin salicylate valproic acid

mcg/mL x mL/min = mg/min “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? 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: 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 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

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: Note: 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: Chronic: 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 Acute vs chronic intoxication 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