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

Dr Paul Dargan
Consultant Physician & Clinical Toxicologist Guys & St Thomas Poisons Unit London, UK

Haemoperfusion (HPF): History

HPF was first used in toxicology in the 1960s for barbiturate poisoning
Initially with uncoated charcoal columns, subsequently (1970s) with coated charcoal
(Yatzidis H 1964, 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

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

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 EJ 1999)

Non-charcoal HPF columns are not widely available

This talk will concentrate on Charcoal HPF (cHPF)

Haemoperfusion: Technique
A standard haemofiltration / haemodialysis pump can be used perfusion column Anticoagulation (heparin or prostacyclin) is required HPF does not correct electrolyte / acid-base
(Milonovich LM 2001)

The only special equipment required is the

disturbances or uraemia

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
Cost:
(Webb D 1993, Ehlers S 1978, Blye E 1984)

- cHPF column ~ 120 (US$ 150)

- high-flux HDx/HF membrane ~ 60 - 80 (US$ 75 - 100) but dont need dialysate / replacement fluid

Characteristics of compounds that are removed by cHPF (1):

1 Adsorbed by charcoal 2 Low volume of distribution (Vd < 1 L/kg)
- cHPF only clears substances from the vascular compartment
- 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)

Characteristics of compounds that are removed by cHPF (2):

3 Low endogenous clearance (< 4mL/kg/min)

4 Protein binding, water solubility & molecular size are not such limiting factors as with haemodialysis:
- Membrane on cHPF columns is ~ 1-5 mm (compared to the 30-50 mm with HDx membranes) and so doesnt 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)

Complications of Haemoperfusion
1 Common to all extracorporeal techniques:
- Hypotension: particularly during the first 15 mins
- minimised by priming the circuit & gradually blood flow to overcome internal resistance (~ 25 mmHg)

- 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)

Complications of Haemoperfusion
2 Complications specific to HPF:
i) Leucopenia, hypocalcaemia & cytokine activation:
- significant with earlier devices, clinically insignificant with modern ultrathin coated columns
(Kolthammer J 76, Sangster B 81, Rommes J 83 & 92, Vanholder R 99, Singh S 04 )

ii) Charcoal embolisation:

- prevented by the ultrathin membrane & a filter in the venous line

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)

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

Indications for cHPF

3 essential questions to ask when considering cHPF:
1. Will cHPF effectively remove a clinically significant proportion of the toxin from the body ??

2.
3.

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

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)

HPF: What evidence is available?

Most of the data on HPF in poisoning comes from:

- in vitro / animal work

- 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

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:

Total Total admitted Total HDx exposures to critical care

Total HPF 174 48 39

1992 1,864,188 1997 2,192,088 2002 2,380,028

59,211 72,877

780 927 1400

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)

cHPF for Carbamazepine Poisoning

Causes significant and prolonged toxicity (T1/2 19-32 hrs)
(Weaver DF 1988, Hundt HK 1983, Luke DR 1985)

Low Vd (1.4 L/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)

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 - 106 mmol/L - T: during HPF 0.17hr post HPF: 6.2 hrs
Graudins A et al Emerg Med 2002

cHPF for Carbamazepine Poisoning

MDAC & HPF carbamazepine clearance to similar extent
Clearance
(mL/min)

T (hrs)

Controls
MDAC cHPF

19-32
8.6-9.5 2.6-10.7

59-90
102-113 88-129

(Hundt HK 83, Vreeth 86, Cutler RE 184) (Wason S 92, Boldy D 87, Monty-Cabrera 96) (Chan K 81, Leslie P 83, De Groot G 84, Nilsson 84)

MDAC or cHPF for severe carbamazepine poisoning?

MDAC & HPF carbamazepine clearance to similar extent
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

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

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

HDx Major toxicity during 39% or after procedure Clearance (mL/min) 185 Complications NIL

HPF 28%

294
1x GI bleed 1x bleed at access site

Theophylline Poisoning: HDx or cHPF?

T (hrs) Controls MDAC HDx cHPF 19-34 2.2-8.0 2.3-6.2 1.4-2.0 Clearance (mL/min) 40-50 120-140 83-165 146-295

(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)

Theophylline Poisoning: HDx or cHPF?

MDAC & HDx total body clearance to a similar extent

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

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)

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)

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)

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)

Toxicology: Future Developments in HPF

We have recently investigated novel adsorbents in HPF columns using mesoporous polymer-based carbons based on vinylpyridine copolymers (SCN) Preliminary in vitro studies: SCN greater (x2) adsorption capacity & more rapid adsorption kinetics (x3) than conventional (Adsorba 300C) carbons
Conventional cHPF adsorbent

(Scorgie KA 2001)
SCN spherical polymer carbon

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

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

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

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