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Charcoal Haemoperfusion: Does it still have a role in the management of the poisoned patient?

Charcoal Haemoperfusion: Does it still have a role in the management of the poisoned patient?. Dr Paul Dargan Consultant Physician & Clinical Toxicologist Guy’s & St Thomas’ Poisons Unit London, UK. Haemoperfusion (HPF): History.

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Charcoal Haemoperfusion: Does it still have a role in the management of the poisoned patient?

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  1. Charcoal Haemoperfusion: Does it still have a role in the management of the poisoned patient? Dr Paul Dargan Consultant Physician & Clinical Toxicologist Guy’s & St Thomas’ Poisons Unit London, UK

  2. Haemoperfusion (HPF): History • HPF was first used in toxicology in the 1960’s for barbiturate poisoning • Initially with uncoated charcoal columns, subsequently (1970’s) with coated charcoal (Yatzidis H1964, Vale JA 1975) • Since these initial reports HPF has been attempted in the treatment of a number of other poisonings • e.g. carbamazepine, theophylline, salicylates, meprobomate, phenytoin, sodium valproate, paraquat, thallium, dichlorvos, digoxin, tricyclic antidepressants etc…

  3. Haemoperfusion: Technique • Blood is pumped (150 - 250 mL/min) through a column containing an adsorbent, usually activated charcoal, coated with a biocompatible ultrathin® membrane

  4. HPF: ‘Non-charcoal’ adsorbents • Other adsorbents have been used in the past • e.g. resins (D6W1X-2), amberlite (XAD-2/4) • There is very little literature on their clinical use • In vitro data suggests resins may have  adsorptive capacity for lipophilic compounds (Rosenbaum J 1971) • But they are less biocompatible  cytokine activation & greater hypocalcaemia/thrombocytopenia (Pond SM 1991, Rosenbaum J 2000, Franssen EJ1999) • Non-charcoal HPF columns are not widely available • This talk will concentrate on Charcoal HPF (cHPF)

  5. Haemoperfusion: Technique • A standard haemofiltration / haemodialysis pump can be used (Milonovich LM 2001) • The only special equipment required is the perfusion column • Anticoagulation (heparin or prostacyclin) is required • HPF does not correct electrolyte / acid-base disturbances or uraemia

  6. Haemoperfusion: Technique • Adsorptive capacity  over time: • deposition of drug, cellular debris & proteins • maximum capacity of each column ~ 4 hours • Inotropes & other IV drugs should be infused distal to the device to minimise HPF removal (Webb D1993, Ehlers S 1978, Blye E 1984) • Cost: • cHPF column ~ € 120 (US$ 150) • high-flux HDx/HF membrane ~ € 60 - 80 (US$ 75 - 100) … but don’t need dialysate / replacement fluid

  7. Characteristics of compounds that are removed by cHPF (1): • Low volume of distribution (Vd < 1 L/kg) -cHPFonlyclearssubstancesfromthevascularcompartment - looking at HPF clearance in isolation can be misleading and it must be interpreted in the context of Vd e.g. Amitriptyline: cHPF clearance of 110 mL/min but <0.2% of ingested dose removed by cHPF because Vd 16 L/kg (Diaz-Buxo J 1978, Gram L 1972) • Adsorbed by charcoal

  8. Characteristics of compounds that are removed by cHPF (2): • Low endogenous clearance (< 4mL/kg/min) • Protein binding, water solubility & molecular size are not such limiting factors as with haemodialysis: • Membrane on cHPF columns is ~ 1-5mm (compared to the 30-50mm with HDx membranes) and so doesn’t present a significant barrier to solute diffusion (Ludwig S 1987, Chang T 1975, Webb D 1993) • Strong affinity of many substances for AC can help overcome protein binding (Bressolle F 1994, Blye E 1984)

  9. Complications of Haemoperfusion • Commontoallextracorporealtechniques: • Hypotension: particularly during the first 15 mins • minimised by priming the circuit & gradually  blood flow to overcome internal resistance (~25mmHg) • can be difficult hypotensive patients, but inotropes can be used (Rommes J 1992) • Nosocomial infection • Rare: bleeding/thrombosis at the access site • Rare: systemic bleeding due to anticoagulation (and potentially thombocytopenia)

  10. Complications of Haemoperfusion 2 Complications specific to HPF: i) Leucopenia, hypocalcaemia & cytokine activation: - significant with earlier devices, clinically insignificant with modern ultrathin® coated columns (KolthammerJ’76, SangsterB’81, RommesJ ’83 & ’92, Vanholder R ’99, Singh S ’04 ) ii) Charcoal embolisation: - prevented by the ultrathin® membrane & a filter in the venous line

  11. Complications of Haemoperfusion 2 Complications specific to HPF: iii) Thrombocytopenia • Up to 50-75% with uncoated adsorbents • Only 10-25 % with ultrathin® coated adsorbents • Greatest with cellulose nitrate, lowest with heparin hydrogel and cellulose acetate membranes (Hampel C 1978, Rommes J 1992, Chang T 1977, Pond S 1979) • Clinically significant bleeding is reported but is rare, particularly with newer columns (even in combination with anticoagulation) (Rommes J 1992, Singh S 2004)

  12. Complications of Haemoperfusion 2 Complications specific to HPF: iii) Thrombocytopenia & prostacyclin • In vitro studies have shown prostacyclin (cf heparin) results in a less marked fall in platelet count (Woods HF 1980, Rommes J 1983) • There have been a number of case reports/series describing its successful use clinically (Rommes JH 1992, Kennedy HJ 1985 Langenecker K 1999) • But no (controlled) clinical studies comparing it with heparin

  13. Indications for cHPF 3 essential questions to ask when considering cHPF: • Will cHPF effectively remove a clinically significant proportion of the toxin from the body ?? • Is cHPF likely to have a positive effect on morbidity (& potentially mortality) ?? • This needs to be balanced against potential complications (& merits of alternative treatments e.g. MDAC, HDx) cHPF should only be considered in a small minority of cases of clinically severe poisoning

  14. HPF: No Controlled Data • NO prospective controlled studies looking at the effect of HPF on outcome in poisoned patients • Therefore no data to be able to answer criteria 2 • Two retrospective series suggest  mortality in those treated with HPF, possibly due to selection of more severely poisoned patients (Bismuth C 1979, Hampel G 1987) • However, a number of other series (with similar selection bias) show similar or improved survival (e.g. Woo O 1984, Traford J 1977, Shannon M 1993)

  15. HPF: What evidence is available? • Most of the data on HPF in poisoning comes from: • in vitro /animalwork • case-reports/series studying drug kinetics before, during & after the procedure • Direct comparison between the reports can be difficult as many of them involve: • multiple ingestions • and/or different treatment regimes • and/or different HPF columns / blood flow rates

  16. How frequently is HPF used? • There continue to be a number of reports describing the use of HPF in poisoned patients (Cameron R ’02, Graudins A’02, Singh S ’04, Peng A ’04) • The only epidemiological data comes from TESS:

  17. cHPF Clinical Indications • cHPF has been used in many different poisonings • It is most commonly used for: • carbamazepine & theophylline poisoning • The rest of this talk will focus on these agents & the relative role of cHPF compared to multi-dose activated charcoal (MDAC) and HDx • Recent improvements in dialysis technology make some of the older HPF - HDx comparisons less valid (Palmer BF 2000)

  18. cHPF for Carbamazepine Poisoning • Causes significant and prolonged toxicity (T1/219-32 hrs) (Weaver DF 1988, Hundt HK 1983, Luke DR 1985) • Low Vd (1.4L/kg) & endogenous clearance (1.3 mL/kg/min) • Binds activated charcoal • Protein binding ~ 74% and low water solubility • therefore no significant ‘conventional’ HDx clearance (Cutler RE 1987) • 3 recent reports of ‘high-flux’ HDx with moderate removal /clearance (53-64 mL/min) of carbamazepine (Tapolyai M 2002 Kielstein J 2002 Schuerer DJE 2000)

  19. cHPF for Carbamazepine Poisoning • Recent report: 31yr ingested 60g SR carbamazepine - developed severe clinical features: coma, seizures, ileus - Ileus limited treatment with WBI / MDAC & so treated with HPF at 77hrs post-ingestion • After 1 hr of cHPF: • Rousable with no further seizures •  carbamazepine concentration 176- 106mmol/L • T½: during HPF 0.17hr … post HPF: 6.2 hrs Graudins A et al Emerg Med 2002

  20. cHPF for Carbamazepine Poisoning • MDAC& HPFcarbamazepineclearancetosimilarextent (Hundt HK ’83, Vreeth ’86, Cutler RE 1’84) (Wason S ’92, Boldy D ’87, Monty-Cabrera ’96) (Chan K ’81, Leslie P ’83, De Groot G ’84, Nilsson ’84)

  21. MDAC or cHPF for severe carbamazepine poisoning? • MDAC& HPFcarbamazepineclearancetosimilarextent • No studies have shown an impact on outcome with either method • Administration of MDAC in CBZ poisoning is often limited by ileus (de Zeeuw R 1979, Sethna M 1989, Spiller H 1990) • HPF should generally be reserved for: - life-threatening toxicity (e.g. cardiotoxicity, status epilepticus) - particularly cases with poor gut motility or those that are deteriorating despite MDAC

  22. Theophylline Poisoning: HDx or cHPF? • Both acute & chronic theophylline poisoning can cause significant morbidity and mortality • Theophylline poisoning is less common than 10 years ago, but still occurs: • NPIS(L) 2002: 34 cases requiring ICU admission • Theophylline kinetics: • Low Vd 0.5 L/kg & endogenous clearance (0.7mL/kg/min) • 40 - 50 % protein bound • binds AC • T1/2 19 - 34hrs in overdose

  23. Theophylline Poisoning: HDx or cHPF? • 10yr prospective observational study: theophylline poisoning treated with cHPF (n=17) or HDx (n=39) Shannon MW Acad Emerg Med 1997

  24. Theophylline Poisoning: HDx or cHPF? (Controls: Cutler RE 1987) (MDAC: Radowski 1986, Ohning B 1986, Sessler S 1985) (HDx: Lee C 1979, Hootkins R 1980, Shannon M 1993 & 1997, Gitomer J 2001) (cHPF: Woo OF 1985, Heath A 1987, Hootkins R 1980, Shannon M 1993 & 1997)

  25. Theophylline Poisoning: HDx or cHPF? • MDAC&HDx totalbodyclearancetoasimilarextent • BUT marginally greater  clearance with cHPF • There is no data looking at whether cHPF has an impact on outcome • however, theophylline has a small Vd (0.5L/kg) & so the  clearance is likely to translate to a clinical impact • cHPF is generally the treatment of choice in severe theophylline poisoning if an extracorporeal treatment is required

  26. Theophylline poisoning: Indications for cHPF • Grade III or IV poisoning (seizures, VT, hypotension)(Sessler CN 1990, Shannon MW 1993, Minton N 1996, Heath A 1987) • ?? ‘Prophylactically’ in a symptomatic patient with serum theophylline: • acute poisoning: >100 mg/L (600 mmol/L) • chronic poisoning: >60 mg/L (330 mmol/L), particularly in patients >60yrs of age (Olson KR ’85, Sessler CN ’90, Shannon MW ’87, ’93 & ’99) • ?? Lower threshold: • in patients with severe co-morbidity • if intractable vomiting and/or ileus prevent MDAC administration ( Shannon MW ’93 & ’99)

  27. Agents for which cHPF is not effective • There have been reports of ‘clearance’ of a number of other drugs with cHPF • e.g. TCA, digoxin, paracetamol (acetaminophen), b-blockers … • However, they have effective alternative treatments &/or Vd & so cHPF has no impact on overall body burden and is not indicated (Pond S 1979 & 1991, Blye E 1984 , Winchester J 2002)

  28. Other potential indications for cHPF • Barbiturates: • cHPF total body clearance of phenobarbitone ~ 4x (similar to MDAC) but not of short-medium acting barbiturates (Jacobsen D 1984, Boldy DA 1986) • Salicylates: • cHPF and HDx increase total body clearance ~ 2x • HDx is the extracoporeal treatment of choice in severe poisoning as it also corrects acid-base and electrolyte disturbances (Pond SM 1984, Jacobsen D 1984)

  29. Non-toxicological advances in HPF • There has been a recent renewed interest in HPF in critical care, hepatology and nephrology: • Chronic renal failure: for removal of ‘middle molecules’, b2-microglobulin etc. (Winchester JF Artif Cells 2002, Geyko F Artif Organs 2004) • Acute & acute-on-chronic liver failure (Sechser A Clin Liv Dis 2001) • Sepsis:for removal of inflammatory molecules, endo- & exo-toxins etc. (Winchester JF Bl Purif 2003, Fang H Biomat 2004, Shoji H, Therap Dial 2003)

  30. Toxicology: Future Developments in HPF • We have recently investigated novel adsorbents in HPF columns using mesoporous polymer-based carbons based on vinylpyridine copolymers (SCN) (Scorgie KA 2001) • Preliminary in vitro studies: SCN greater (x2) adsorption capacity & more rapid adsorption kinetics (x3) than conventional (Adsorba 300C) carbons Conventional cHPF adsorbent SCN spherical polymer carbon

  31. Toxicology: Future Developments in HPF Novel adsorbents: • Offer flexibility through close control of chemical purity, pore-size distribution & surface chemistry: • Potentially improved adsorption capacity & kinetics • May allow targeting of specific molecules • Highly stable and can undergo pyrolysis & high pressure steam activation making them highly biocompatible (Mikhalovsky S Perfusion 2003) Conventional cHPF adsorbent SCN spherical polymer carbon

  32. CONCLUSIONS • Extracorporeal techniques such as cHPF are indicated in only a limited number of severe cases of poisoning with selected agents • Modern coated charcoal HPF columns are associated with many fewer adverse effects • There have been no controlled studies assessing the impact of cHPF on outcome and no studies which allow a direct comparison between cHPF and either HDx or MDAC

  33. CONCLUSIONS • The limited data available suggests that: - there is a continuing role for cHPF in severe theophylline & carbamazepine poisoning • particularly in patients who are deteriorating despite MDAC or in those in whom MDAC use is limited by ileus • Future developments in carbon technologies may allow an expansion in the indications for cHPF in toxicology & increased efficacy

  34. Charcoal Haemoperfusion: Does it still have a role in the management of the poisoned patient ? • Yes, probably, in severe theophylline and carbamazepine poisoning • But the level of evidence is poor

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