1. Use of Dialysis and Hemoperfusion in Treatment of Poisoning 報告者 : R2 楊世正 日期 : 2009-02-13

2. Management of drug overdose and poisoning a.Cardiorespiratory support b.Early gastric lavage c.Administration of multiple-dose activated charcoal (MDAC) d.Specific antidotes e.Hemodialysis, hemoperfusion, and peritoneal dialysis

3. 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 small Vd, low protein bindingUseful if small Vd, low protein binding Clinical benefit unprovenClinical benefit unproven

4. 1995 American Association of Poison Control Centers (AAPCC) data - 2 million poisonings: 1995 American Association of Poison Control Centers (AAPCC) data - 2 million poisonings: MDAC, alkalinization treatment > > Hemodialysis > Hemoperfusion

5. I. Dialysis and hemoperfusion II. Management of poisoning with selected agents

7. A. Indications Who needs it? What’s the best technique? Will it work?

8. Who needs it? Critically ill despite supportive careCritically ill despite supportive care –eg, phenobarb OD with intractable shock Known lethal doseKnown lethal dose –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 with level of 200

9. Criteria for consideration of dialysis or hemoperfusion in poisoning (I) 1.Progressive deterioration despite intensive supportive therapy 2.Severe intoxication with depression of midbrain function leading to hypoventilation, hypothermia, and hypotension 3.Development of complications, such as pneumonia or septicemia, coma

10. Criteria for consideration of dialysis or hemoperfusion in poisoning (II) 4.Impairment of normal drug excretory function in the presence of hepatic, cardiac, or renal insufficiency 5.Intoxication with agents with metabolic and/or delayed effects (e.g., methanol, ethylene glycol, and paraquat) 6.Intoxication with an extractable drug or poison, which can be removed at a rate exceeding endogenous elimination by liver or kidney

11. B. Choice of therapy

12. What ’ s the best technique? Peritoneal dialysisPeritoneal dialysis HemodialysisHemodialysis HemoperfusionHemoperfusion Continuous hemofiltration & hemoperfusionContinuous hemofiltration & hemoperfusion Urinary pH manipulationUrinary pH manipulation Mulitple dose activated charcoalMulitple dose activated charcoal

13. Serum concentration DrugMg/dlMcmol/l Method of choice Phenobarbital100430 HP, HD Glutethimide40180HP Methaqualone40160HP Salicylates800 4.4 mmol/L HD Theophylline40220 HP, HD Paraquat0.10.4 HP > HD Methanol500 16 mmol/L HD Meprobamate100460HP

14. 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

15. Peritoneal dialysis (PD) 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 Not very effective, being 1/8 to 1/4 as efficient as hemodialysisNot very effective, being 1/8 to 1/4 as efficient as hemodialysis

16. Peritoneal dialysis Rarely performed unless - It’s the only available method - It’s the only available method - Hemodialysis is difficult to institute quickly, such as in small children - Hemodialysis is difficult to institute quickly, such as in small children - Hypothermic poisoned patient, to help in core rewarming - Hypothermic poisoned patient, to help in core rewarming

18. Hemodialysis Best if drug is: –water-soluble –low molecular weight –not highly protein bound ethanol, ethylene glycol, lithium, methanol, and salicylates Not very useful in :Not very useful in : –lipid-soluble –large volumes of distribution –extensive protein binding

19. Hemodialysis Amphotericin B [9,241], vancomycin [1,500] Water-soluble, high molecular weights diffuse across dialyzer membranes slowly; removal rate is accelerated by use of high- flux membranes and hemodiafiltrationWater-soluble, high molecular weights diffuse across dialyzer membranes slowly; removal rate is accelerated by use of high- flux membranes and hemodiafiltration

20. Hemoperfusion Blood is passed through a device containing adsorbent particles, ex: activated charcoal, resin...Blood is passed through a device containing adsorbent particles, ex: activated charcoal, resin...

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

22. Hemoperfusion More effective than HD in Protein-bound drugsProtein-bound drugs Lipid-soluble drugsLipid-soluble drugs If a drug is equally well removed by HD and HP, hemodialysis is preferred 1. Potential problems of cartridge saturation 1. Potential problems of cartridge saturation 2. Treat coexisting acid–base disturbances 2. Treat coexisting acid–base disturbances

23. Continuous hemodiafiltration, hemoperfusion

24. Potentially useful in drugs with moderately large volumes of distribution (V D ) and slow inter-compartmental transfer times to prevent post-therapy rebound of plasma drug levelsPotentially useful in drugs with moderately large volumes of distribution (V D ) and slow inter-compartmental transfer times to prevent post-therapy rebound of plasma drug levels Continuous hemoperfusion has been used in meprobamate, theophylline, and phenobarbital toxicityContinuous hemoperfusion has been used in meprobamate, theophylline, and phenobarbital toxicity Continuous hemodiafiltration has been used in ethylene glycol and lithium toxicityContinuous hemodiafiltration has been used in ethylene glycol and lithium toxicity Continuous treatment VS repeated conventional treatment ??

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

26. Will it work? Volume of distribution:Volume of distribution: –is the drug accessible? –how big a volume to clear? Clearance (CL):Clearance (CL): CL = flow rate x extraction ratioCL = flow rate x extraction ratio –does the method efficiently cleanse the blood?

27. C. Importance of volume of distribution

28. Importance of volume of distribution The volume of distribution (V D ) is the theoretical volume into which a drug is distributedThe volume of distribution (V D ) is the theoretical volume into which a drug is distributed Some drugs will have V D values exceeding the volume of total body water (0.6 L/kg) because they are extensively bound to, or stored in, tissue sitesSome drugs will have V D values exceeding the volume of total body water (0.6 L/kg) because they are extensively bound to, or stored in, tissue sites

29. 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 = 0.6 L/kgTotal body water = 0.6 L/kg ECF = 0.25 L/kgECF = 0.25 L/kg Blood or plasma = 0.07 L/kgBlood or plasma = 0.07 L/kg

30. A high V D, the amount of drug present in the blood represents only a small fraction of the total body loadA high V D, the amount of drug present in the blood represents only a small fraction of the total body load Additional drug will enter the blood from tissue stores, sometimes causing a “rebound” of the toxic manifestationsAdditional drug will enter the blood from tissue stores, sometimes causing a “rebound” of the toxic manifestations

31. Vd for some common drugs Large Vd: CamphorCamphor TricyclicsTricyclics DigoxinDigoxin OpioidsOpioids PhencyclidinePhencyclidine PhenothiazinesPhenothiazines GlutethimideGlutethimide Small Vd: AlcoholsAlcohols LithiumLithium PhenobarbitalPhenobarbital PhenytoinPhenytoin SalicylateSalicylate Valproic acidValproic acid

32. D. Technical points

33. 1.Vascular access 2.Choice of hemodialyzer. High-flux, high-efficiency dialyzers with high urea clearances should generally be used High-flux, high-efficiency dialyzers with high urea clearances should generally be used 3.Choice of a hemoperfusion cartridge. Typical sorbents are activated carbons (charcoals), ion exchange resins, or nonionic exchange macroporous resins Typical sorbents are activated carbons (charcoals), ion exchange resins, or nonionic exchange macroporous resins

34. 4.The hemoperfusion circuit similar to a hemodialysis circuit, and includes an air detector and a venous air trap similar to a hemodialysis circuit, and includes an air detector and a venous air trap 5.Priming the hemoperfusion circuit 6.Heparinization during hemoperfusion Heparin should be given in amounts sufficient to maintain the patient's activated clotting time or partial thromboplastin time at about twice the normal value Heparin should be given in amounts sufficient to maintain the patient's activated clotting time or partial thromboplastin time at about twice the normal value

35. 7.Duration of hemoperfusion A single 3-hour treatment will substantially lower the blood levels of most poisons A single 3-hour treatment will substantially lower the blood levels of most poisons More prolonged use of a hemoperfusion cartridge is inefficient, because the charcoal tends to become saturated More prolonged use of a hemoperfusion cartridge is inefficient, because the charcoal tends to become saturated

36. E. Complications

37. HemodialysisHemodialysis a)Hypophosphatemia. - P is not present in standard dialysis solutions - Respiratory insufficiency and other complications - Can be avoided by supplementing the dialysis solution with b)Alkalemia. - Unphysiologically high concentrations of bicarbonate c)Disequilibrium syndrome in acutely uremic patients

38. E. Complications HemoperfusionHemoperfusion  Mild transient thrombocytopenia and leukopenia can occur but levels usually return to normal within 24 to 48 hours  Adsorption or activation of coagulation factors: may be clinically significant in patients with liver failure Continuous therapyContinuous therapy  Fluid and electrolyte imbalances may be potential problems  Prolonged anticoagulation may predispose to bleeding

39. I. Dialysis and hemoperfusion II. Management of poisoning with selected agents

40. A. Acetaminophen (MW 151) Activated charcoal should be given within 4 hours after ingestion.Activated charcoal should be given within 4 hours after ingestion. Serum levels should be measured (Rumack-Matthew nomogram) to establish the risk for hepatotoxicity and requirement for N-acetyl cysteine (NAC) therapy.Serum levels should be measured (Rumack-Matthew nomogram) to establish the risk for hepatotoxicity and requirement for N-acetyl cysteine (NAC) therapy. If serum levels are > 150 mg/L (1.0 mmol/L) at 4 hours, the likelihood of toxicity is high and NAC (PO or IV) should be given.If serum levels are > 150 mg/L (1.0 mmol/L) at 4 hours, the likelihood of toxicity is high and NAC (PO or IV) should be given. Liver toxicity may be found at lower serum levels when combined with ingestion of alcohol

41. Acetaminophen poisoning Moderately water soluble, minimally protein bound -> removed by dialysis or hemoperfusionModerately water soluble, minimally protein bound -> removed by dialysis or hemoperfusion Note:Note: –check serum level and give Activated charcoal within 4 hours –NAC remains the treatment of choice (150 mg/L at 4 hours)

42. B. Aspirin (MW 180) In adults: metabolic acidosis with respiratory alkalosisIn adults: metabolic acidosis with respiratory alkalosis In children: isolated metabolic acidosisIn children: isolated metabolic acidosis The appearance of CNS symptoms is a sign of severe poisoningThe appearance of CNS symptoms is a sign of severe poisoning

43. B. Aspirin (MW 180) Symptoms are present and serum salicylate levels are > 50 mg/dL (2.8 mmol/L) TX: MDAC, alkaline diuresisSymptoms are present and serum salicylate levels are > 50 mg/dL (2.8 mmol/L) TX: MDAC, alkaline diuresis Serum level > 80 mg/dL (4.4 mmol/L) or the condition of the patient warrants aggressive management: HemodialysisSerum level > 80 mg/dL (4.4 mmol/L) or the condition of the patient warrants aggressive management: Hemodialysis V D of only 0.15 L/kg 50% protein bound. aspirin is well removed by hemodialysisV D of only 0.15 L/kg ; 50% protein bound. aspirin is well removed by hemodialysis

44. Salicylate poisoning Indications for dialysis:Indications for dialysis: –severe metabolic acidosis –serum level > 80 mg/dL –condition of the patient warrants aggressive management Note:Note: –check serum level (units!! mg/dL) –alkalinize serum and urine –dialysis preferred: can correct electrolyte and fluid abnormalities

45. C. Barbiturates Phenobarbital (MW 232)  Toxic : > 3 mg/dL (130 mcmol/L)  Coma : > 6 mg/dL (260 mcmol/L) MDAC: first-line therapyMDAC: first-line therapy Alkalinization of the urineAlkalinization of the urine 50% protein bound, V D is only 0.5 L/kg; the drug is well removed by either hemodialysis or hemoperfusion50% protein bound, V D is only 0.5 L/kg; the drug is well removed by either hemodialysis or hemoperfusion

46. Phenobarbital Indications for dialysis:Indications for dialysis: –level > 6 mg/dL (coma prolonged) –failure of supportive care (ie, intractable hypotension) –complications such as pneumonia Notes:Notes: –MDAC is first-line therapy –HP > HD no evidence that HD will improve overall survival

47. D. Digoxin (MW 781) Digoxin-induced arrhythmiasDigoxin-induced arrhythmias 50% at serum levels of 2.5 ng/mL 50% at serum levels of 2.5 ng/mL (3.2nmol/L) 90% at serum levels of 3.3 ng/mL 90% at serum levels of 3.3 ng/mL (4.2nmol/L) Treatment:Treatment: 1. correction of hypoK, hypoMg and alkalosis 1. correction of hypoK, hypoMg and alkalosis 2. oral activated charcoal 2. oral activated charcoal The V D of digoxin is large (8 L/kg in normal patients, 4.2 L/kg in dialysis patients)The V D of digoxin is large (8 L/kg in normal patients, 4.2 L/kg in dialysis patients) 25% protein bound25% protein bound Only 5% of body load will be removed by 4-hour HD

48. D. Digoxin (MW 781) Hemoperfusion: more effective, improve symptoms, not routinely recommended (large V D, total body clearance is limited)Hemoperfusion: more effective, improve symptoms, not routinely recommended (large V D, total body clearance is limited) Indicated for Digoxin-specific antibody fragments (Fab fragments)Indicated for Digoxin-specific antibody fragments (Fab fragments)  massive ingestions  profound intoxication  hyperK, life-threatening arrhythmia

49. D. Digoxin (MW 781) Digoxin may be released from the Fab– digoxin complex, leading to a rebound in toxicityDigoxin may be released from the Fab– digoxin complex, leading to a rebound in toxicity Ujhelyi et al., 1993 Ujhelyi et al., 1993 Plasmapheresis performed soon after Fab fragment administration promotes removal of the Fab–digoxin complexesPlasmapheresis performed soon after Fab fragment administration promotes removal of the Fab–digoxin complexes Zdunek, 2000

50. E. Toxic alcohols Nontoxic toxic metabolites Nontoxic toxic metabolites MethanolMethanol Ethylene glycol.Ethylene glycol. antifreeze solutions, deicing solutions, hydraulic brake fluid, foam stabilizers, chemical solvents windshield washing fluids, paints, solvents, copier fluids, and illegally manufactured (wood) alcohol alcohol dehydrogenase Formic acid glycolic acid Ethylene glycol and methanol are the commonest causes of fatal toxic alcohol poisoning metabolized to oxalate, cause renal failure

51. E. Toxic alcohols Unexplained metabolic acidosis + increases in anion gaps & osmolal gapsUnexplained metabolic acidosis + increases in anion gaps & osmolal gaps However, an elevated AG and OG are rarely concomitantly present early or very late after ingestion of toxic alcoholsHowever, an elevated AG and OG are rarely concomitantly present early or very late after ingestion of toxic alcohols Toxic alcohol not been metabolized -> only osmolal gap increased Toxic alcohol has undergone metabolism -> only anion gap increased

52. E. Toxic alcohols Alcohols are rapidly absorbed and have the same V D as waterAlcohols are rapidly absorbed and have the same V D as water MDAC or gastric lavage has a limited roleMDAC or gastric lavage has a limited role Competitive inhibition: ethanol or fomepizole (4-methylpyrazole) for the affinity of enzyme alcohol dehydrogenase in the liverCompetitive inhibition: ethanol or fomepizole (4-methylpyrazole) for the affinity of enzyme alcohol dehydrogenase in the liver affinity for alcohol dehydrogenase : Fomepizole > ethanol

53. E. Toxic alcohols Either ethanol or fomepizole should be given as soon as possible  Delay the conversion to toxic metabolites  Allow time for the disposal of the parent drug and its toxic metabolites through the urinary, metabolic, and dialytic routes

54. E. Toxic alcohols Insufficient data to define the relative roles of fomepizole and ethanol in the treatment of toxic alcohol poisoningInsufficient data to define the relative roles of fomepizole and ethanol in the treatment of toxic alcohol poisoning Advantages of Ethanol : clinical experience, lower cost (1:100)Advantages of Ethanol : clinical experience, lower cost (1:100) Advantages of Fomepizole: validated efficacy, predictable pharmacokinetics, ease of administration, and fewer adverse effects. Probably safer in children and pregnant womenAdvantages of Fomepizole: validated efficacy, predictable pharmacokinetics, ease of administration, and fewer adverse effects. Probably safer in children and pregnant women Ethanol can cause CNS depression, phlebitis, hypoglycemia, and respiratory depression

55. E. Toxic alcohols Mild intoxications, adequate renal function: ethanol or fomepizoleMild intoxications, adequate renal function: ethanol or fomepizole Toxic alcohols’ breakdown with resultant metabolic acidosis, poor renal function: hemodialysisToxic alcohols’ breakdown with resultant metabolic acidosis, poor renal function: hemodialysis Hemodialysis is highly effective in rapidly removing both toxic alcohols and their metabolites and in correcting metabolic abnormalitiesHemodialysis is highly effective in rapidly removing both toxic alcohols and their metabolites and in correcting metabolic abnormalities

56. E. Toxic alcohols Overall, prognosis correlates better with the severity of acidosis and toxic metabolite concentrations rather than the parent alcohol concentrationsOverall, prognosis correlates better with the severity of acidosis and toxic metabolite concentrations rather than the parent alcohol concentrations

57. Ethylene glycol (MW 62) Toxicity : The first phase occurs <1 hour: --- CNS depression similar to ethanol intoxication. In severe poisoning, can result in coma and seizures and can last 12 hoursThe first phase occurs <1 hour: --- CNS depression similar to ethanol intoxication. In severe poisoning, can result in coma and seizures and can last 12 hours The second phase (toxic effects of glycolic acid) : cardiac and respiratory failure 12 hours after ingestionThe second phase (toxic effects of glycolic acid) : cardiac and respiratory failure 12 hours after ingestion --- Severe metabolic acidosis, renal failure ( result of oxalate precipitation) --- Severe metabolic acidosis, renal failure ( result of oxalate precipitation) flank pain, hypocalcemia, and acute tubular necrosis accompanied by oxalate crystals in the urine

58. Ethylene glycol (MW 62) Early aggressive management of acidosis with sodium bicarbonate is essentialEarly aggressive management of acidosis with sodium bicarbonate is essential An ethylene glycol level above 50 mg/dL (8.1 mmol/L) is an indication for dialysisAn ethylene glycol level above 50 mg/dL (8.1 mmol/L) is an indication for dialysis

59. Indications for treatment of ethylene glycol or methanol poisoning with ethanol or fomepizole 1.Documented plasma ethylene glycol or methanol concentrations >20 mg/dL or 2.Documented recent (hours) history of ingestion of toxic amounts of ethylene glycol or methanol and osmolal gap >10 mmol/kg or 3.History or strong clinical suspicion of ethylene glycol or methanol poisoning and at least two of the following criteria : a. a.Arterial pH <7.3 b. b.Serum bicarbonate <20 mmol/L c. c.Osmolal gap >10 mmol/kg d. d.Urinary oxalate crystals (in the case of ethylene glycol) or visual signs or symptoms (in the case of methanol) present

60. Indications for hemodialysis in patients with severe ethylene glycol or methanol poisoning 1.Severe metabolic acidosis (pH <7.25–7.30) 2.Renal failure 3.Visual symptoms/signs 4.Deteriorating vital signs despite intensive supportive care 5.Ethylene glycol or methanol levels >50 mg/dL 5.Ethylene glycol or methanol levels >50 mg/dL (unless fomepizole is being administered and patient is asymptomatic with a normal pH)

61. Ethylene glycol (MW 62) Hemodialysis should be performed until acidosis has resolved and the ethylene glycol levels are <20 mg/dL (3.2 mmol/L)Hemodialysis should be performed until acidosis has resolved and the ethylene glycol levels are <20 mg/dL (3.2 mmol/L) If ethylene glycol levels are unavailable, dialysis should be performed forat least 8 hoursIf ethylene glycol levels are unavailable, dialysis should be performed for at least 8 hours

62. Ethylene glycol (MW 62) Redistribution of ethylene glycol may result in rebound elevation of ethylene glycol levels within 12 hours after cessation of dialysis and repeat dialysis may be necessaryRedistribution of ethylene glycol may result in rebound elevation of ethylene glycol levels within 12 hours after cessation of dialysis and repeat dialysis may be necessary Serum osmolality, electrolytes, and acid–base status should be monitored closely within 24 hours after dialysisSerum osmolality, electrolytes, and acid–base status should be monitored closely within 24 hours after dialysis

63. Ethylene glycol (MW 62) Pyridoxine (500 mg IM four times daily) and thiamine (100 mg IM four times daily) should be considered to increase the metabolism of glyoxylate ( 乙醛酸 )Pyridoxine (500 mg IM four times daily) and thiamine (100 mg IM four times daily) should be considered to increase the metabolism of glyoxylate ( 乙醛酸 ) In addition, judicious intravenous fluids should be given to prevent calcium oxalate crystal deposition in the kidneys and acute renal failureIn addition, judicious intravenous fluids should be given to prevent calcium oxalate crystal deposition in the kidneys and acute renal failure Chow et al., 1998 Chow et al., 1998 Chow et al., 1998 Chow et al., 1998

64. Guidelines for use of ethanol in toxic alcohol poisonings (1) 1)Loading dose: 0.6 g/kg [10% ethanol in D5W (7.6 mL/kg) or 43% oral solution or 86’ undiluted liquor (34 g ethanol/dL) 1.8 mL/kg] 2)Maintenance dose: a. In alcoholic patients 154 mg/kg per hour a. In alcoholic patients 154 mg/kg per hour b. In nonalcoholic patients 66 mg/kg per hour b. In nonalcoholic patients 66 mg/kg per hour c. Double dose during hemodialysis or enrich dialysatewith 100 mg/dL ethanol a c. Double dose during hemodialysis or enrich dialysatewith 100 mg/dL ethanol a a d. Double dose if given orally with charcoal d. Double dose if given orally with charcoal

65. Guidelines for use of ethanol in toxic alcohol poisonings (2) 3)Monitor serum ethanol concentrations every 1–2 hours and adjust infusion rate to maintain serum ethanol level of 100– 150 mg/dL. Thereafter, monitor ethanol levels every 2–4 hours 4)Continue until methanol or ethylene glycol concentrationsare <20 mg/dL and patient is asymptomatic with normal arterial pH

66. Guidelines for use of fomepizole in the treatment of ethylene glycol and methanol poisoning 1.Loading dose: 15 mg/kg IV in 100 mL 0.9% saline over30 minutes to 1 hour 2.Maintenance dose: 10 mg/kg every 12 hours for four doses, then 15 mg/kg every 12 hours 3.Dose adjustments during hemodialysis: 15 mg/kg every 4 hours or 1–1.5 mg/kg per hour infusion during dialysis 4.Continue until methanol or ethylene glycol concentrations are <20 mg/dL and patient is asymptomatic with normal arterial pH

67. Methanol (MW 32) Methanol poisoning:Methanol poisoning: -> Early temporary CNS depression -> Early temporary CNS depression -> a latent period lasting 6–24 hours -> a latent period lasting 6–24 hours -> development of metabolic acidosis and visual symptoms (blurred vision, decreased visual acuity, photophobia, visual field defects to complete blindness, due to formic acid accumulation) -> development of metabolic acidosis and visual symptoms (blurred vision, decreased visual acuity, photophobia, visual field defects to complete blindness, due to formic acid accumulation) Early signs include optic disc hyperemia and decreased pupillary reflexes to lightEarly signs include optic disc hyperemia and decreased pupillary reflexes to light

68. Methanol (MW 32) Initial management is similar to that for ethylene glycol toxicity, including the correction of acidosis with intravenous sodium bicarbonate to pH 7.35–7.4Initial management is similar to that for ethylene glycol toxicity, including the correction of acidosis with intravenous sodium bicarbonate to pH 7.35–7.4 Ethanol or fomepizole should be administered to prevent formation of formic acidEthanol or fomepizole should be administered to prevent formation of formic acid

69. Methanol (MW 32) Indication for hemodialysis : Significant metabolic acidosis (pH <7.25–7.3)Significant metabolic acidosis (pH <7.25–7.3) abnormalities of visionabnormalities of vision Deteriorating vital signsDeteriorating vital signs Renal failureRenal failure Electrolyte abnormalities unresponsive to conventional therapyElectrolyte abnormalities unresponsive to conventional therapy Serum methanol concentration >50 mg/dL (15.6 mmol/L)Serum methanol concentration >50 mg/dL (15.6 mmol/L) Ophthalmologic abnormalities may persist transiently or permanently and should not be considered an indication to continue dialysis

70. Methanol (MW 32) Hemodialysis should be continued until acidosis is corrected and serum methanol levels are <20 mg/dL (6.3 mmol/L)Hemodialysis should be continued until acidosis is corrected and serum methanol levels are <20 mg/dL (6.3 mmol/L) When methanol concentrations are very high, dialysis of 18–21 hours may be requiredWhen methanol concentrations are very high, dialysis of 18–21 hours may be required

71. Methanol (MW 32) Redistribution of methanol may result in elevation of methanol concentrations after dialysis ceases, and repeat dialysis may be necessaryRedistribution of methanol may result in elevation of methanol concentrations after dialysis ceases, and repeat dialysis may be necessary Serum osmolality and acid–base status should be monitored frequently for the first 24–36 hours after hemodialysis ceasesSerum osmolality and acid–base status should be monitored frequently for the first 24–36 hours after hemodialysis ceases

72. Isopropanol 異丙醇 (MW 60) Found in rubbing alcohol, antifreeze, and frost removerFound in rubbing alcohol, antifreeze, and frost remover Common cause of poisoning, only occasionally fatalCommon cause of poisoning, only occasionally fatal Oxidized by alcohol dehydrogenase to acetoneOxidized by alcohol dehydrogenase to acetone Unlike ethylene glycol and methanol, isopropanol intoxication are due to the parent compoundUnlike ethylene glycol and methanol, isopropanol intoxication are due to the parent compound

73. Isopropanol (MW 60) Gastrointestinal and CNS symptoms, including confusion, ataxia, and coma, occur in 1 hourGastrointestinal and CNS symptoms, including confusion, ataxia, and coma, occur in 1 hour Hypotension due to cardiac depression and vasodilation can occur in severe intoxicationHypotension due to cardiac depression and vasodilation can occur in severe intoxication High serum osmolal gap without acidosis + increased urinary or serum acetone level -> highly suggestive of isopropanol poisoningHigh serum osmolal gap without acidosis + increased urinary or serum acetone level -> highly suggestive of isopropanol poisoning

74. Isopropanol (MW 60) Supportive treatmentSupportive treatment Inhibition of alcohol dehydrogenase is not warranted because acetone is less toxic than the parent compoundInhibition of alcohol dehydrogenase is not warranted because acetone is less toxic than the parent compound Indcation for Hemodialysis:Indcation for Hemodialysis: - isopropanol levels are >400 mg/dL (67 mmol/L) - isopropanol levels are >400 mg/dL (67 mmol/L) - significant CNS suppression - significant CNS suppression - renal failure - renal failure - hypotension - hypotension

75. Other alcohols Propylene glycol (MW 76) Propylene glycol 丙二醇 (MW 76) Toxicity: lactic acidosis and an elevated osmolal gapToxicity: lactic acidosis and an elevated osmolal gap 2-butoxyethanol (MW 118) Toxicity: metabolic acidosis, hepatic injury, and respiratory distressToxicity: metabolic acidosis, hepatic injury, and respiratory distress Hemodialysis is effective in removing these alcohols and may be indicated in severe intoxications

76. Methanol, Ethylene Glycol Indications for dialysis:Indications for dialysis: –elevated level > 50 mg/dL –severe acidosis –Renal failure –Visual symptoms/signs –Deteriorating vital signs despite intensive supportive care Notes:Notes: –HD only - not adsorbed to AC –give blocking drug (EtOH, 4-MP) –need to increase dosing during dialysis

77. F. Lithium carbonate Most intoxications result from chronic accumulation, renal failure, diuretic use and dehydration, and interactions with ACEI and NSAIDsMost intoxications result from chronic accumulation, renal failure, diuretic use and dehydration, and interactions with ACEI and NSAIDs lithium toxicity (MW for Li = 7) Mild (serum Li 1.5–2.5 mmol/L), moderate (serum Li 2.5– 3.5 mmol/L) : neuromuscular irritability, nausea, and diarrheaMild (serum Li 1.5–2.5 mmol/L), moderate (serum Li 2.5– 3.5 mmol/L) : neuromuscular irritability, nausea, and diarrhea Severe toxicity (serum Li >3.5 mmol/L) : seizures, stupor, and permanent neurologic deficiSevere toxicity (serum Li >3.5 mmol/L) : seizures, stupor, and permanent neurologic defici

78. F. Lithium carbonate Stop diuretics, give half normal saline to rehydrate the patientStop diuretics, give half normal saline to rehydrate the patient As lithium is 0% protein bound with a V D of 0.8 L/kg, it is removed very well by dialysisAs lithium is 0% protein bound with a V D of 0.8 L/kg, it is removed very well by dialysis

79. F. Lithium carbonate Indication for Hemodialysis: (a) serum Li >3.5 mmol/L (b) serum Li >2.5 mmol/L with appreciable symptoms or with renal insufficiency (c) when serum Li is 2.5 ~ 3.5 mmol/L in asymptomatic patients but when levels are expected to rise or are not expected to fall below 0.8 mmol/L in the next 36 hours

80. F. Lithium carbonate Repeated dialysis may be necessary until serum Li levels remain below 1.0 mmol/L for 6–8 hours after dialysisRepeated dialysis may be necessary until serum Li levels remain below 1.0 mmol/L for 6–8 hours after dialysis Prolonged continuous hemodiafiltration may reduce the rebound of lithium levels post treatmentProlonged continuous hemodiafiltration may reduce the rebound of lithium levels post treatment Leblanc et al., 1996 Leblanc et al., 1996

81. Lithium Indications for dialysis:Indications for dialysis: –serum Li >3.5 mmol/L –serum Li >2.5 mmol/L with appreciable symptoms or with renal insufficiency Notes:Notes: –2-compartment model, very slow redistribution from tissues –patients rarely get quick improvement –IV saline “diuresis” may be nearly as effective

82. G. Mushroom poisoning Initially with severe gastrointestinal symptoms followed by hepatic insufficiency and cardiovascular collapseInitially with severe gastrointestinal symptoms followed by hepatic insufficiency and cardiovascular collapse Early referral to a liver transplantation unitEarly referral to a liver transplantation unit PlasmapheresisPlasmapheresis

83. G. Mushroom poisoning Paraquat (MW 257) Ingestion of more than 10 mL of paraquat concentrate: Pulmonary fibrosis and renal, multiorgan failure Survival is dependent on the amount ingested and the plasma levels with respect to time of ingestion Plasma levels > 3 mg/L (12 mcmol/L): usually fatal

84. G. Mushroom poisoning Initial management includes gastric lavage with administration of activated charcoal or Fuller Earth with cathartic Hemoperfusion is effective in drug removal: plasma level > 0.1 mg/L (0.4 mcmol/L) Paraquat has a large V D and a slow intercompartmental transfer rate: Repeated or continuous hemoperfusion for several days to maintain plasma levels below 0.1 mg/L

85. H. Phenothiazines and tricyclic antidepressants Highly protein bound, extremely large volumes of distribution (14–21 L/kg) Hemoperfusion can be useful in temporarily lowering the plasma drug level and reducing acute toxicity Treatment of intoxication with these agents is largely supportive, including correction of acidosis with bicarbonate

86. I. Anticonvulsants Phenytoin (MW 252) Nystagmus and ataxia occur at serum values >20 and 30 mg/mL (79 and 119 mmol/L), respectively 90% protein bound, V D of 0.64 L/kg. Removed poorly by HD, but is removed moderately well by HP

87. I. Anticonvulsants Sodium valproate (MW 166) Small V D, metabolized by liver, and has significant protein bindingSmall V D, metabolized by liver, and has significant protein binding High-flux hemodialysis with or without hemoperfusion should be considered when there is coma, severe liver dysfunction, or other organ failureHigh-flux hemodialysis with or without hemoperfusion should be considered when there is coma, severe liver dysfunction, or other organ failure

88. J. Sedatives and hypnotics Diphenhydramine An antihistamine, commonly used as an over- the-counter sedative Toxicity is usually limited to anticholinergic symptoms Treatment is supportive and directed toward anticholinergic effects Sodium bicarbonate may be beneficial if wide-complex tachycardia develops Extracorporeal treatment has a limited role

89. J. Sedatives and hypnotics Benzodiazepines (e.g., diazepam, clonazepam) Treatment is largely supportive (high degree of protein binding, high V D of some of these drugs) Flumazenil, a benzodiazepine receptor antagonist, may be considered in severe benzodiazepine poisoning

90. J. Sedatives and hypnotics Zolpidem and zaleplon Newer sedatives that act as selective benzodiazepine-1 receptor subtype agonists. Fewer side effects even in overdose. Supportive treatment is usually sufficient

91. J. Sedatives and hypnotics Meprobamate (MW 218), chloral hydrate (MW 165) Lipid soluble, moderately protein bound, and V D values of 0.7 and 1.6 L/kg, respectively Hemodialysis or hemoperfusion is indicated for patients who have been poisoned severely and not responded to standard intensive care

92. J. Sedatives and hypnotics Glutethimide (MW 217), methaqualone, methyprylon, ethchlorvynol Highly lipid soluble, large V D Poorly removed by hemodialysis and moderately well removed by hemoperfusion. Continuous hemoperfusion may be useful to prevent rebound

93. J. Sedatives and hypnotics Carbamazepine (MW 236) Hemoperfusion can be used for severe intoxications. Hemoperfusion can be used for severe intoxications. High-flux hemodialysis has been reported to give good resultsHigh-flux hemodialysis has been reported to give good results

94. K. Theophylline (MW 180) Toxic: > 25 mg/L (140 mcmol/L) (therapeutic levels being 10–20 mg/L) Seizures typically occur with levels >40 mg/L but may occur at levels as low as 25 mg/L Cardiovascular collapse is rare until levels are > 50 mg/L

95. K. Theophylline (MW 180) V D : 0.5 L/kg, 56% protein bindingV D : 0.5 L/kg, 56% protein binding Well adsorbed by charcoal, enabling efficacious removal by MDAC and hemoperfusionWell adsorbed by charcoal, enabling efficacious removal by MDAC and hemoperfusion Propranolol (1–3 mg IV) may be used to treat tachyarrhythmia, and hypokalemia should be correctedPropranolol (1–3 mg IV) may be used to treat tachyarrhythmia, and hypokalemia should be corrected

96. K. Theophylline (MW 180) Hemoperfusion/hemodialysis:Hemoperfusion/hemodialysis: - acute intoxication: >100 mg/L - acute intoxication: >100 mg/L - chronic toxicity: > 60 mg/L - chronic toxicity: > 60 mg/L - elderly or infants under 6 m/o > 40 mg/L - elderly or infants under 6 m/o > 40 mg/L Treatment should be continued until the plasma level is 25–40 mg/LTreatment should be continued until the plasma level is 25–40 mg/L

97. Theophylline poisoning Indications for dialysis:Indications for dialysis: –serum level > 100 mg/L (acute OD) –level > 60 mg/L (chronic) –Level > 40 mg/L in elderly or infants under 6 m/o Notes:Notes: –HP or high-flux HD –Treatment goal: plasma level is 25–40 mg/L –hypokalemia should be corrected

98. Take home message Cardiorespiratory support (ABC..)Cardiorespiratory support (ABC..) Consider pharmacokinetics and behavior of the drugConsider pharmacokinetics and behavior of the drug Administration of an antidote, gastric lavage, MDACAdministration of an antidote, gastric lavage, MDAC Clinical evidence for benefit with enhanced removalClinical evidence for benefit with enhanced removal

99. ~ Thanks For Your Attention ~