Extracorporeal Techniques in the Treatment of Poisoned Patients

1. Extracorporeal Techniques in the Treatment of Poisoned Patients

2. Techniques commonly used for extracorporeal drug removal: 1. Haemodialyis 2. Haemoperfusion 3. Continuous haemofiltration 4. Continuous haemodiafiltration

3. Other techniques that are available: 1. Peritoneal Dialysis - much poorer drug clearance than haemodialysis & so very rarely used (Blye E 1984, Shannon M 1990) 2. Plasmapheresis • available in a very limited number of centres • high rate of complications • 3 published case reports: thyroxine & theophylline OD (Binemilis J 1987, Jones JS 1986, Laussen P 1991) 3. Exchange transfusion • rebound increase in drug concentration • case reports: e.g. chloral hydrate, iron, theophylline, quinine, methaemoglobinaemia (Mowry JB 1983, Burrows A 1972, Berlin G 1985, Shannon MW 1992)

4. When should extracorporeal techniques be considered? Poisoning with a drug that is removed by one of the techniques AND Severe clinical features or markers of severe toxicity and failure to respond to full supportive care or Significantly raised blood concentration for a toxin with good correlation between blood concentration and clinical effect Impairment of the normal route of elimination of the compound

5. Two main factors influence drug removal by extracorporeal techniques 1. Kinetics of the drug: - need to consider toxicokinetics and not just pharmacokinetics - the ‘ideal’ drug kinetics differ for each technique 2. Mechanism of removal for each technique Intervention is only worthwhile if total body clearance is increased by at least 30% (Cherskov M 1982)

6. Drug Kinetics and Extracorporeal Techniques (1) 1. Molecular size - not just molecular mass, also steric hindrance & polarity 2. Volume of distribution - the larger the Vd the less drug is available in the blood compartment for presentation to the extracorporeal device 3. Protein binding - generally only free drug is cleared, this is particularly important for haemodialysis

7. Drug Kinetics and Extracorporeal Techniques (2) 4. Rate of endogenous clearance - the contribution of extracorporeal removal is greater for drugs with low endogenous clearance - if endogenous clearance is high (> 4ml/kg/min), it is unlikely that further techniques to increase elimination will alter outcome (Pond SM 1991) 5. Rate of redistribution: often difficult to predict - if slow redistribution from a secondary compartment, after stopping the technique there is likely to be a rebound in concentration of the drug

8. Limited Data on drug clearance by the techniques in the literature • Data largely based on isolated case reports • It is not possible to extrapolate from one extracorporeal system to the other • Have to rely on: • knowledge of the principles of the methods and kinetics of the drug involved • data from previous reports in which the removal kinetics have been studied before, during and after elimination

9. Haemoperfusion(HPF) • First reported use in poisoning was for barbiturates(Yatzidis 1964) • Blood is pumped through a column containing an adsorbent, usually activated charcoal - otheradsorbentshavebeenusedinthepaste.g. resin, amberlite and haemacol - theadsorbentiscoatedwithabiocompatible, ultrathin® membrane • A standard haemofiltration pump present on most ICU’s can be used to operate the system, the only special equipment required is the perfusion column

10. Haemoperfusion 2 • Performed for 4-6hrs at flow rates of 150-250ml/min • Resistance of 25-30mmHg within filter (Webb DJ 1993) • Can be difficult or impossible in hypotensive patients: low flow rates and/or clotting of the lines will force abandonment of the procedure • Anticoagulationwithheparin(PTT 2.0-2.5)orprostacyclinis required, to reduce risk of clotting of the circuit • The adsorptive capacity decreases over time because of deposition of cellular debris and proteins (Ehlers SM 1978) • HPF does not correct electrolyte disturbances, metabolic acidosis or uraemia

11. Complications of Haemoperfusion 1. Complicationscommontoallextracorporealtechniques - e.g. hypotension, bleeding/thrombosis at the access site, systemic bleeding due to anticoagulation, nosocomial infection 2. Complications specific to HPF: i) Thrombocytopenia - 30-50% with uncoated adsorbents (Hampel 1978) - 10-30 % with ultrathin® coated adsorbents (Chang 1977) ii) Leucopenia - minimal with ultrathin® coated adsorbents iii) Hypocalcaemia - rarely clinically significant (Pond SM 1979) iv) Charcoal embolisation - filter in the venous line prevents charcoal emboli

12. Indications for Haemoperfusion 1 • Characteristics of compounds that make them amenable to removal by HPF: - Adsorbed by charcoal - Low volume of distribution (< 1 L/kg) - Single compartment kinetics - Low endogenous clearance (< 4mL/kg/min) • Protein binding, water solubility & molecular size are not such limiting factors because the drug is in direct contact with the adsorbent

13. Indications for Haemoperfusion 2 Drugs for which haemoperfusion may be used in clinical toxicology practice: • Carbamazepine • Phenobarbitone • Theophylline • (Meprobomate) • (Phenytoin[Kawasaki 2000]) • (Na Valproate) • (Salicylates)

14. Haemoperfusion for carbamazepine poisoning • Significant morbidity (arrhythmias, coma, convulsions) and mortality with large ingestions (Jones AL 1998, Weaver DF 1988) • T1/2 in overdose 19-32 hrs (8-13hrs therapeutically) and so causes prolonged toxicity (Hundt HKL 1983, Luke DR 1985) • Low Vd (1.4 L/kg)& endogenous clearance (1.3 ml/kg/min), binds activated charcoal • Protein binding 74% and not water soluble • therefore no significant HDx clearance(Cutler RE 1987) • recent report of the use of ‘high-efficiency’ dialysis for carbamazepine, however no data on clearance given (Schuerer DJE 2000)

15. Half-life & clearance of carbamazepine in overdose: 1. Controls: T1/2 19-32 hrs Clearance 59-90 ml/min (Hundt HKL 1983, Vreeth 1986, Cutler RE 1984) 2. MDAC: T1/2 8.6-9.5 hrs Clearance 105-113 ml/min (Wason S 1992, Boldy DAR 1987, Monty-Cabrera 1996) 3. HPF: T1/2 8.6-10.7 hrs Clearance 80-129 ml/min (Leslie PJ 1983, De Groot G 1984, Nilsson 1984) • MDAC and HPF increase carbamazepine clearance to a similar extent • HPF should be reserved for: - life-threatening toxicity (e.g. cardiotoxicity, status epilepticus) - particularly cases with poor gut motility or renal impairment

16. Haemoperfusion for phenobarbitone poisoning • Barbiturate poisoning is now rare in the UK, but large ingestions can cause significant: • morbidity (coma and cardiorespiratory depression) • mortality~ 1-10% with ingestion of > 6g (Goldfrank LR 1986) • T1/2 in overdose 80-120 hrs(10-16 hrs therapeutically)& so causes prolonged toxicity(Vale JA 1987) • Phenobarbitone: low Vd (0.6-1.2 L/kg) & endogenous clearance (0.06 ml/kg/min), binds activated charcoal, protein binding 25-51%, not water soluble

17. Half-life and clearance of phenobarbitone in overdose: 1. Controls: T1/2 80-120 hrs Clearance 4-27 ml/min (Hardman JG 1996, Vale JA 1987) 2. MDAC: T1/2 12-36 hrs Clearance 84 ml/min (Boldy DAR 1986, Pond SM 1984) 3. HDx: T1/2 no data Clearance 22-49 ml/min (Verbooten GA 1980, Cutler RE 1987) 4. HPF: T1/2 7.2-11 hrs Clearance 77-140 ml/min (Cutler RE 1987, Jacobsen D 1984)

18. Haemoperfusion for phenobarbitone poisoning • Both MDAC and HPF increase phenobarbitone clearance, HPF to a greater extent • Most cases respond to full supportive care together with use of MDAC (Jacobsen D 1984,Goldfrank LR 1986) • HPF should be reserved for:(Jacobsen D 1984, De Groot G 1982) • life-threatening toxicity & deterioration despite full supportive care (coma & cardiorespiratory depression) • particularly patients with poor gut motility or renal impairment

19. Haemodialysis (HDx) • Most widely used for renal replacement in patients with ESRD • Only available in a limited number of centres in the UK and so often patients need to be transferred for haemodialysis • First reported use in poisoning was for barbiturates (Setter 1966)

20. Haemodialysis 2 • Blood is pumped (150-300ml/min) across a semi-permeable membrane (MW 500D) • performed for 4-8hrs at a time (intermittent) • Dialysis fluid infused countercurrenton the other side of the membrane establishing a concentration gradient • Solutes diffuse across the membrane into the dialysate • corrects uraemia and electrolyte / acid-base disturbances • Anticoagulation is required (either systemic or of the circuit)

21. Problems with haemodialysis in poisoned patients Only available in a limited number of centres • Results in rapid fluid shifts causing significant haemodynamic effects (hypoxia and hypotension) • may not be tolerated in patients with severe poisoning • Rebound in drug concentrations can occur after HDx because it is intermittent & only clears free drug in plasma • May increase elimination of drugs given therapeutically (e.g. ethanol in methanol poisoning) • Complications as for all extracorporeal techniques: • bleeding/thrombosis at the site of access or systemic bleeding due to anticoagulation, air embolism, nosocomial infection

22. Indications for Haemodialysis 1 • Characteristics of compounds that make them amenable to removal by HDx: - Molecular weight < 500D - Water soluble - Poorly bound to plasma protein - Low volume of distribution (< 1 L/kg) - Single compartment kinetics - Low endogenous clearance (< 4mL/kg/min)

23. Indications for Haemodialysis 2 • Substances for which haemodialysis may be used in clinical toxicology practice: • Salicylates (Aspirin) • Lithium • Alcohols: • ethylene glycol, methanol, ethanol, isopropanol • Theophylline • Metformin (Althoff PH 1978) • (Bromide)

24. Salicylate poisoning: HDx or HPF? • Salicylate poisoning can cause significant: • morbidity: metabolic acidosis, coma, convulsions, ARF, pulmonary oedema • mortality: up to 5% in patients with severe clinical features or metabolic acidosis (Chapman BJ 1989) • Aspirin pharmacokinetics: • Vd 0.17 - 0.21 L/kg (increased by acidaemia) • low endogenous clearance 0.88 ml/kg/min • protein binding 73 - 94 % (saturates in overdose) • molecular weight 138 D • water soluble • binds activated charcoal • T1/2 2-4.5hrs therapeutically, up to 18-36hrs in overdose

25. Salicylate poisoning: HDx or HPF? 1. Controls: T1/2 19 - 36 hrs Clearance 23 - 40 ml/min (Levy G 1965, Pond SM 1984) 2. UA*: T1/2 2.5 - 6.3 hrs Clearance 48 ml/min (Vree TB 1994, Prescott LF 1982) 3. HDx: T1/2 1.9 hrs Clearance 80 - 86 ml/min (Pond SM 1984, Jacobsen D 1988) 4. HPF: T1/2 2.4 - 6.2 hrs Clearance 57-116 ml/min (Pond SM 1984, Jacobsen D 1988) • MDAC: Probably has little impact on increasing elimination but continue MDAC until peak in salicylate level to prevent delayed absorption (Hillman RJ 1985, Proudfoot 1979) *UA=Urinary Alkalinisation to pH 8.5

26. Salicylate poisoning: HDx or HPF? • HPF achieves marginally better clearance butcan’t correct the acid-base, electrolyte and fluid balance problems that are common in patients with severe salicylate poisoning • Haemodialysis is therefore the extracorporeal method of choice for patients with severe salicylate poisoning

27. Salicylate poisoning: Indications for haemodialysis • Severe clinical features: • coma, convulsions, pulmonary oedema • acute renal failure (impairs elimination) • Metabolic acidosis resistant to correction: • particularly if pH < 7.2 (increased CNS transit of salicylate) • Salicylate concentration > 700-800mg/l (50-58mmol/l) • no data as to whether HDx in this group alters outcome, but salicylate level > 900mg/l associated with 5% mortality (Chapman BJ 1989) • children (<12yr) & elderly (>65yr) more susceptible to CNS toxicity, therefore lower threshold for HDx (Krause DS 1992)Lower thresholds in chronic salicylate poisoning

28. Haemofiltration • Continuous technique - dissolved solute is removed by convection with plasma water when pressure is applied to one side of the membrane, cellular components and particles greater than the pore size are then passed back in to the circulation - the filtrate produced contains non-protein bound solutes up to the cut-off limit of the membrane - fluid removed in the filtrate is replaced with an appropriate (buffered) replacement fluid (given pre- or post- filter) • Blood flow rates of 125-300 ml/min generate filtrate flow rates of 25-70 ml/min(1500-4200 ml/hr) • Synthetic membranes have a cut-off limit of up to 10 - 40,000 D

29. Haemofiltration & haemodiafiltration(CVVHF) (CVVHDF) • Haemodiafiltration can be achieved by infusing dialysis fluid countercurrent to the membrane allowing diffusive solute removal by dialysis in addition to the convective removal by filtration • HDF allows greater removal of smaller molecules (<500D) and also better control of hyperkalaemia and other metabolic disturbances (CUPID = combination of CVVHF and intermittent HDx) CVVHDF CVVHF

30. Haemofiltration Characteristics of drugs that make them amenable to HF: • molecular size - mass < 10-40,000 D, steric hindrance and charge are also important (most membranes negatively charged) • single compartment kinetics • low endogenous clearance (4ml/kg/min) • low volume of distribution:lessimportant than for HDx • low protein binding: less important than for HDx Clearance (ml/min) is less appropriate for a continuous technique Sieving coefficient is the best expression of solute removal; SC of 1 indicates free passage [SC=2UF/(A+V)]

31. Haemofiltration • There is little data on the sieving coefficients of drugs • this data is ‘membrane-specific’ • the limited data available is largely for therapeutic drug concentrations: e.g. phenytoin 0.14, digoxin 0.35, cefuroxime 0.87, gentamicin 0.8, theophylline 0.5 - 0.8 • however, toxicokinetics is different to pharmacokinetics • For a drug with a sieving coefficient of 1, the concentration of drug in the filtrate will equal that in the remaining plasma (although some dilution will occur when replacement fluid is given) - therefore large volumes need to be exchanged over a prolonged period of time for a significant fall in concentration to occur

32. Haemofiltration vs. Conventional Haemodialysis • Advantages: - Availability - Less haemodynamic effects and so better tolerated by seriously poisoned patients - greater removal of high molecular weight substances e.g. aminoglycosides, iron-DFO complex - continuous technique & so rebound in drug concentration is less likely • Disadvantage: - poorer/slower clearance of low molecular weight substances (< 500D) ... this includes most drugs

33. Substances for which CVVHF / CVVHDF may be considered in poisoning • Case reports for: - Lithium (Ayuso Gatell A 1989, Bellomo R 1991, Leblanc M 1996, Hazouard E 1999) - Ethylene glycol (Christiansson LK 1995, Walder AD 1994) - Theophylline (Henderson 2001) - Vancomycin (Walczyk M 1988, Goebel J 1999, Bunchman T 1999) - N-acetylprocainamide(Domoto DT 1987) - Iron-DFO compex (Baner W 1988) • Other possible indications: - CVVHF/DF may be necessary for correction of electrolyte disturbances or lactic acidosis and for renal support - Further (in-vitro) work is required before CVVHF can be recommended for removal of other substances

34. Theophyllinepoisoning:HDx,HPForCVVHF? • Theophylline poisoning can cause significant morbidity and mortality • Theophylline pharmacokinetics: • molecular weight 180D, water soluble • Vd 0.5L/kg • low endogenous clearance (0.7ml/kg/min) • 40 - 56 % protein bound • binds activated charcoal • hepatic metabolism to inactive metabolites (<15% excreted unchanged) • T1/2 19-34hrs in overdose (8hrs therapeutically)

35. 1. Controls: T1/2 19 - 34 hrs Clearance 40 ml/min (Cutler RE 1987) 2. MDAC: T1/2 2.2 - 8.0 hrs Clearance 140 ml/min (Davis R 1985, Shannon M 1993) 3. HDx: T1/2 2.4 - 6.2 hrs Clearance 33 - 144 ml/min (Levy G 1977, Lee CS 1979, Hootkins R 1980) 4. HPF: T1/2 1.4 - 2.0hrs Clearance 96 - 276 ml/min (Woo OF 1985, Hootkins R 1980) 5. CVVHF: T1/2 5.9hrs Clearance unable to calculate (Henderson JH 2001, single case report, no AC given initially) MDAC and HDx increase clearance to a similar extent, but marginally greater increase in clearance with HPF and HPF is the treatment of choice in severe poisoning Theophyllinepoisoning:HDx,HPForCVVHF?

36. Theophylline poisoning: Indications for haemoperfusion • Grade III or IV poisoning (seizures, VT, hypotension)(Sessler CN 1990, Shannon MW 1993) • ? ‘Prophylactically’ in a patient with a serum theophylline: • > 100 mg/l (600 mmol/l) in acute poisoning - risk of seizures  50 to 35%, but uncontrolled data (Shannon MW 1987 & 1993, Olson KR 1985) • > 60 mg/l (330 mmol/l) in symptomatic chronic poisoning (Sessler CN 1990, Shannon MW 1992) • Lower threshold in patients with severe co-morbidity e.g. chronic liver disease, CCF, COPD MOST patients require MDAC & supportive care only

37. Extracorporeal treatment for lithium poisoning: • Lithium poisoning can result in significant morbidity, particularly acute on chronic overdose(Gadaleah 1988, Ferron 1995) • Vd 0.8-1.2 L/kg, molecular wt 6.9D, non-protein bound • T1/2 is 14-30hrs and so clinical effects can be prolonged in overdose

38. Indications for extracorporeal treatment in lithium poisoning: • Severe clinical effects: • coma, convulsions, respiratory failure, ARF • Consider if lithium level greater than: (Hansen HE 1978, Ellenhorn MJ 1997, Jaegar A 1993)  6 - 8 mmol/l in acute overdose  4 mmol/l in acute overdose in a patient on lithium  2.5mmol/l in symptomatic chronic accumulation • Kinetic criteria have also been proposed:(Jaegar A 1993) • e.g. amount of lithium removed by HDx in 6 hrs expected to be greater than 24 hour renal elimination • Other than the clinical indications, none of these criteria have been validated

39. Haemodialysis or CVVHF/CVVHDF for severe lithium poisoning? 1. Haemodialysis: (Jaegar A 1993, Okussa MD 1994, Scharman EJ 1997) • Controls: T1/2 14-30 hrs Clearance 10 - 40 ml/min • HDx: T1/2 3.6 - 5.7 hrs Clearance 70 - 170 ml/min • BUT rebound often occurs (Jaegar A 1985, 1993) • Lithium levels should be repeated 6-12hrs after HDx 2. CAVHDF/CVVHDF: 3 case series (9cases), 12-44hrs HF (Bellomo 1991, Leblanc 1996, Hazouard 1999) • Clinical improvement & fall in lithium concentrations • Clearance of 20.5-61.9ml/min • No significant rebound

40. Haemodialysis or CVVHF/CVVHDF for severe lithium poisoning? • Haemodialysis remains the extracorporeal method of choice in patients with severe lithium poisoning • must be aware that a rebound in lithium levels can occur after haemodialysis • If haemodialysis is not available CVVHDF may be a suitable alternative, but it will need to be performed for at least 12-18hrs

41. Conclusions 1 • For most severely poisoned patients supportive care is all that is necessary and extracorporeal techniques are indicated in only a limited number of poisonings Haemoperfusion - Carbamazepine, theophylline, phenobarbitone Haemodialysis - Salicylates, alcohols, (theophylline), lithium Haemofiltration - ?Lithium, alcohols - Correction of electrolyte disturbances or lactic acidosis and for renal support - Aminoglycosides, removal of iron-DFO in patients with ARF

42. Conclusions 2 • Haemofiltration may be used, in the future, for the treatment of selected cases of severe poisoning • However, presently, there is limited data available to guide it’s use in clinical practice • If CVVHF is being used for renal support or treatment of lactic acidosis in poisoned patients please collect blood/filtrate samples ...