Presentation on theme: "DIALYSIS? HEMOPERFUSION? What’s up with enhanced elimination of drugs?"— Presentation transcript:
1DIALYSIS? HEMOPERFUSION? What’s up with enhanced elimination of drugs? Kent R. Olson, MDMedical Director - SF DivisionCalifornia Poison Control System
2Case 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.
3HemoperfusionARTERYorVEINVEINBlood from patientReturn to patientUses hemodialysis machine - but runs blood directly through a charcoal- or sorbent-containing filter
4Case, continued . . .The plasma camphor level before hemoperfusion was 1.7 mcg/mLExtraction 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 !!
5What happened? Triumph of the anecdotal case: But: I did “such and so” the patient got betterit must have been the “SUCH and SO!”But:the volume of distribution of camphor is HUGEand, the patient would likely have gotten better anyway, despite the hemoperfusion
6Enhanced drug elimination: Who needs it?Will it work?What’s the best technique?
7It’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 %
8Who needs it? Critically ill despite supportive care eg, phenobarb OD w/ intractable shockKnown lethal dose or blood leveleg, salicylate; methanol / ethylene glycol; theophylline; paraquat?Usual route of elimination impairedeg, lithium OD in oliguric patientRisk of prolonged comaeg, phenobarbital OD w/ level of 200
9Will 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?what is the intrinsic clearance?
10Volume of distribution (Vd) A calculated number - not real = amt. of drug / plasma conc. = mg/kg / mg/L = L/kgTotal body water = 0.7 L/kg or ~ 50 LECF = 0.25 L/kg or about 15 L in adultBlood or plasma = 0.07 L/kg or ~ 5 L
11Vd for some common drugs Large Vd:camphorantidepressantsdigoxinopioidsphencyclidinephenothiazinesSmall Vd:alcoholslithiumphenobarbitalphenytoinsalicylatevalproic acid
12mcg/mL x mL/min = mg/min “But they reported the CLEARANCE was really good mL/min . . .”CL = flow rate x extraction ratio eg, dialysis rate 250 mL/min; if extraction is 80%, Cl = 200 mL/minBut Cl is expressed in mL/min NOT mg/min or gm/hr or tons/dayTotal drug elimination depends on drug concentration:mcg/mL x mL/min = mg/min
13Example: amitriptyline OD 60 kg man ingests 100 x 25 mg Elavil tabsVd = 40 L/kg or 2400 LEst. Cp = 2500 mg / 2400 L ~ 1 mcg/mLHemoperfusion with CL of 200 mL/minDrug removal = 200 mL/min x 1 mcg/mL = 200 mcg/min or 0.2 mg/min or 0.5% per hour
14Two drugs with the same CL Dialysis CL Vd Fraction eliminated in 60 min of dialysis200 mL/min L 1%200 mL/min L %T½ = Vd / CL
15What is the intrinsic CL? If intrinsic (or endogenous) CL is large, an enhanced removal method may not add much to total CLexamples of HIGH endogenous CL: lidocaine, opioids, TCAs, many beta-blockersexamples of LOW endogenous CL: alcohols, atenolol, lithium, salicylate, phenytoin, theophyllineGeneral rule: method should increase total CL by at least 30%
16Summary of desired kinetics Small volume of distributionVd less than 1 L/kgLow endogenous CLless than 4 mL/min/kgSingle-compartment kineticsrapid equilibration between blood and tissuesavoid problem of rebound in blood levels
19Urinary pH manipulation Alkaline diuresistraps weak acids in alkaline urineuseful for salicylates, phenobarbital, chlorpropamiderisk of fluid overloadAcid diuresistraps weak basesmay enhance elimination of amphetaminesTOO RISKY - may worsen myoglobinuric RF
20Peritoneal dialysis Theoretically useful if drug is: water solublesmall (MW <500)not highly protein boundnot so bad you don’t mind waiting TOO SLOWRarely performed unless it’s the only available method
22HemodialysisCan be arteriovenous or veno-venous (double-lumen catheter)Requires anticoagulationBest if drug is:water-solublesmall (MW <500)not highly protein boundAlso good for correcting fluid & electrolyte abnormalities
23Hemodialysis, continued . . . Newer machines have higher flow rates, better extraction ratiosNote: DON’T use the REDY system - these portable HD units have very limited volume dialysate which is recycled, and CL may be very poor
25Charcoal hemoperfusion Uses same vascular access and dialysis pumpsGreater anticoagulation requiredSaturation of charcoal limits durationBut, it is not dependent on drug size, water solubility or protein binding - as long as drug binds to charcoalCan be used in series with dialysis
26Multiple dose oral charcoal - “gut dialysis” Charcoal slurry along the entire intestinal tractLarge surface area for adsorption of drug diffusing across intestinal epithelium from capillariesUseful if drug likes AC, small Vd, low protein bindingClinical benefit unproven
28Continuous hemofiltration Plasma moves across semipermeable membrane under hydrostatic pressureNo dialysateSolutes follow the plasma water - size up to MW ~ 10,000-40,000CL lower than HD or HP, but it can be performed 24 hrs/day
29Drug Preferred Method Carbamazepine HP Ethylene glycol HD Lithium HD Methanol HDMethotrexate HFPhenobarbital HPProcainamide HFSalicylate HD or HPTheophylline HP or HDValproic acid HD or HP
30Salicylate poisoning Indications for dialysis: Note: severe metabolic acidosisserum level > 100 mg/dL (acute OD)level > 60 mg/dL (elderly, chronic OD)Note:check units!! (mg/dL vs mg/L)alkalinize serum and urinedialysis preferred: can correct electrolyte and fluid abnormalities
32Methanol, Ethylene Glycol Indications for dialysis:elevated level > 50 mg/dLsevere acidosisincreased osmolal gap > mmol/LNotes:HD only - not adsorbed to ACgive blocking drug (EtOH, 4-MP) - Note: need to increase dosing during dialysis
33Phenobarbital Indications for dialysis: Notes: level > 190-200 mg/L failure of supportive care (ie, intractable hypotension)Notes:rarely seen anymoreHP > HDrepeated dose AC shortens half-life but not length of coma
34Lithium Indications for dialysis: Notes: serum level > 6? 8? 10? (acute OD)level > 4 ? (chronic)level with severe Sx?Notes:2-compartment model, very slow redistribution from tissuespatients rarely get quick improvementdifficult to evaluate need and benefitIV saline “diuresis” may be nearly as effective
36Estimate for Lithium Usual renal Cl 25-35 mL/min Hemodialysis adds mL/minBut only for 3-4 hours at a timeRebound between dialysis sessionsCVVH adds mL/minBut can be provided continuouslyVolume cleared ~ 50L/day vs 36 L/day w/ 4 hours of HDNo rebound
37Remember: Consider pharmacokinetics and known behavior of the drug What clinical evidence is there for benefit with enhanced removal?Most patients will get better anyway