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DIALYSIS? HEMOPERFUSION? What’s up with enhanced elimination of drugs? Kent R. Olson, MD Medical Director - SF Division California Poison Control System.

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Presentation on theme: "DIALYSIS? HEMOPERFUSION? What’s up with enhanced elimination of drugs? Kent R. Olson, MD Medical Director - SF Division California Poison Control System."— Presentation transcript:

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2 DIALYSIS? HEMOPERFUSION? What’s up with enhanced elimination of drugs? Kent R. Olson, MD Medical Director - SF Division California Poison Control System

3 Case study: Case study: A 30 year old man accidentally drank 3 ounces of CAMPHORATED OIL, mistaking it for castor oil.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.He vomited and later developed seizures and hypotension. After 2 hours of hemoperfusion he began to awaken, and he subsequently recovered fully.After 2 hours of hemoperfusion he began to awaken, and he subsequently recovered fully.

4 Hemoperfusion Uses hemodialysis machine - but runs blood directly through a charcoal- or sorbent-containing filter Blood from patient ARTERY or VEIN Return to patient

5 Case, continued... The plasma camphor level before hemoperfusion was 1.7 mcg/mLThe plasma camphor level before hemoperfusion was 1.7 mcg/mL Extraction of camphor by the machine was ~ 99%Extraction of camphor by the machine was ~ 99% However, no measurement of the total amount of camphor removed:However, no measurement of the total amount of camphor removed: Probably less than 1% of the 18 gram dose was removed !!Probably less than 1% of the 18 gram dose was removed !!

6 What happened? Triumph of the anecdotal case:Triumph of the anecdotal case: –I did “such and so” –the patient got better –it must have been the “SUCH and SO!” But:But: –the volume of distribution of camphor is HUGE –and, the patient would likely have gotten better anyway, despite the hemoperfusion

7 Enhanced drug elimination: Who needs it?Who needs it? Will it work?Will it work? What’s the best technique?What’s the best technique?

8 It’s not used very often: 1995 AAPCC data - 2 million poisonings: 1995 AAPCC data - 2 million poisonings: Urine alkalinization: used in 0.35%Urine alkalinization: used in 0.35% Hemodialysis: used in 0.04%Hemodialysis: used in 0.04% Hemoperfusion: used in 0.0003%Hemoperfusion: used in 0.0003%

9 Who needs it? Critically ill despite supportive careCritically ill despite supportive care –eg, phenobarb OD w/ intractable shock Known lethal dose or blood levelKnown lethal dose or blood level –eg, salicylate; methanol / ethylene glycol; theophylline; paraquat? Usual route of elimination impairedUsual route of elimination impaired –eg, lithium OD in oliguric patient Risk of prolonged comaRisk of prolonged coma –eg, phenobarbital OD w/ level of 200

10 Will it work? Volume of distribution:Volume of distribution: –is the drug accessible? –how big a volume to clear? Clearance (CL):Clearance (CL): –does the method efficiently cleanse the blood? –what is the intrinsic clearance?

11 Volume of distribution (Vd) A calculated number - not real = amt. of drug / plasma conc. = mg/kg / mg/L = L/kgA calculated number - not real = amt. of drug / plasma conc. = mg/kg / mg/L = L/kg Total body water = 0.7 L/kg or ~ 50 LTotal body water = 0.7 L/kg or ~ 50 L ECF = 0.25 L/kg or about 15 L in adultECF = 0.25 L/kg or about 15 L in adult Blood or plasma = 0.07 L/kg or ~ 5 LBlood or plasma = 0.07 L/kg or ~ 5 L

12 Vd for some common drugs Large Vd: camphorcamphor antidepressantsantidepressants digoxindigoxin opioidsopioids phencyclidinephencyclidine phenothiazinesphenothiazines Small Vd: alcoholsalcohols lithiumlithium phenobarbitalphenobarbital phenytoinphenytoin salicylatesalicylate valproic acidvalproic acid

13 “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/minCL = 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/dayBut Cl is expressed in mL/min... NOT mg/min or gm/hr or tons/day Total drug elimination depends on drug concentration:Total drug elimination depends on drug concentration: mcg/mL x mL/min = mg/min

14 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

15 Two drugs with the same CL Dialysis CL VdFraction eliminated in 60 min of dialysis Dialysis CL VdFraction eliminated in 60 min of dialysis 200 mL/min 500 L 1% 200 mL/min 500 L 1% 200 mL/min 50 L 17% 200 mL/min 50 L 17% T½ = 0.693 Vd / CL

16 What is the intrinsic CL? If intrinsic (or endogenous) CL is large, an enhanced removal method may not add much to total CLIf 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%General rule: method should increase total CL by at least 30%

17 Summary of desired kinetics Small volume of distributionSmall volume of distribution –Vd less than 1 L/kg Low endogenous CLLow endogenous CL –less than 4 mL/min/kg Single-compartment kineticsSingle-compartment kinetics –rapid equilibration between blood and tissues –avoid problem of rebound in blood levels

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19 Which method? Urinary pH manipulationUrinary pH manipulation Peritoneal dialysisPeritoneal dialysis HemodialysisHemodialysis HemoperfusionHemoperfusion Mulitple dose activated charcoalMulitple dose activated charcoal Continuous hemofiltrationContinuous hemofiltration

20 Urinary pH manipulation Alkaline diuresisAlkaline diuresis –traps weak acids in alkaline urine –useful for salicylates, phenobarbital, chlorpropamide –risk of fluid overload Acid diuresisAcid diuresis –traps weak bases –may enhance elimination of amphetamines –TOO RISKY - may worsen myoglobinuric RF

21 Peritoneal dialysis Theoretically useful if drug is: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 methodRarely performed unless it’s the only available method

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23 Hemodialysis Can be arteriovenous or veno- venous (double-lumen catheter)Can be arteriovenous or veno- venous (double-lumen catheter) Requires anticoagulationRequires anticoagulation Best if drug is:Best if drug is: –water-soluble –small (MW <500) –not highly protein bound Also good for correcting fluid & electrolyte abnormalitiesAlso good for correcting fluid & electrolyte abnormalities

24 Hemodialysis, continued... Newer machines have higher flow rates, better extraction ratiosNewer 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 poorNote: DON’T 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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26 Charcoal hemoperfusion Uses same vascular access and dialysis pumpsUses same vascular access and dialysis pumps Greater anticoagulation requiredGreater anticoagulation required Saturation of charcoal limits durationSaturation of charcoal limits duration But, it is not dependent on drug size, water solubility or protein binding - as long as drug binds to charcoalBut, 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 dialysisCan be used in series with dialysis

27 Multiple dose oral charcoal - “gut dialysis” Charcoal slurry along the entire intestinal tractCharcoal slurry along the entire intestinal tract Large surface area for adsorption of drug diffusing across intestinal epithelium from capillariesLarge surface area for adsorption of drug diffusing across intestinal epithelium from capillaries Useful if drug likes AC, small Vd, low protein bindingUseful if drug likes AC, small Vd, low protein binding Clinical benefit unprovenClinical benefit unproven

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29 Continuous hemofiltration Plasma moves across semipermeable membrane under hydrostatic pressurePlasma moves across semipermeable membrane under hydrostatic pressure No dialysateNo dialysate Solutes follow the plasma water - size up to MW ~ 10,000-40,000Solutes 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/dayCL lower than HD or HP, but it can be performed 24 hrs/day

30 DrugPreferred Method CarbamazepineHP Ethylene glycolHD LithiumHD MethanolHD MethotrexateHF PhenobarbitalHP ProcainamideHF SalicylateHD or HP TheophyllineHP or HD Valproic acidHD or HP

31 Salicylate poisoning Indications for dialysis:Indications for dialysis: –severe metabolic acidosis –serum level > 100 mg/dL (acute OD) –level > 60 mg/dL (elderly, chronic OD) Note:Note: –check units!! (mg/dL vs mg/L) –alkalinize serum and urine –dialysis preferred: can correct electrolyte and fluid abnormalities

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

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

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

35 Lithium Indications for dialysis:Indications for dialysis: –serum level > 6? 8? 10? (acute OD) –level > 4 ? (chronic) –level 2.5-4 with severe Sx? Notes: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

36 Lithium

37 Estimate for Lithium Usual renal Cl 25-35 mL/minUsual renal Cl 25-35 mL/min Hemodialysis adds 100-150 mL/minHemodialysis adds 100-150 mL/min –But only for 3-4 hours at a time –Rebound between dialysis sessions CVVH adds 20-35 mL/minCVVH 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

38 Remember: Consider pharmacokinetics and known behavior of the drugConsider pharmacokinetics and known behavior of the drug What clinical evidence is there for benefit with enhanced removal?What clinical evidence is there for benefit with enhanced removal? Most patients will get better anywayMost patients will get better anyway


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