haemo perfusion

7/27/2019 Haemo Perfusion

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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


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Since these initial reports HPF has been attemptedin

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 (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 H1964, Vale JA 1975)


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Blood is pumped (150 - 250 mL/min) through acolumn containing an adsorbent, usually activated

charcoal, coated with a biocompatible ultrathin

membrane

Haemoperfusion: Technique


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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

HPF: Non-charcoal adsorbents

In vitro data suggests resins may have adsorptivecapacity for lipophilic compounds (Rosenbaum J 1971)

Butthey 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)


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A standard haemofiltration / haemodialysis

pump can be used (Milonovich LM 2001)

The only special equipment required is theperfusion column

Anticoagulation (heparin or prostacyclin) is required

HPF does not correct electrolyte / acid-base

disturbances or uraemia

Haemoperfusion: Technique


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Inotropes & other IV drugs should be infused distal to

the device to minimise HPF removal

Haemoperfusion: Technique Adsorptive capacity over time:

- deposition of drug, cellular debris & proteins

- maximum capacity of each column ~ 4 hours

Cost:

- cHPF column ~ 120 (US$ 150)

- high-flux HDx/HF membrane ~ 60 - 80 (US$ 75 - 100)

but dont need dialysate / replacement fluid

(Webb D1993, Ehlers S 1978, Blye E 1984)


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2 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


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

Characteristics of compounds that areremoved by cHPF (2):

4 Protein binding, water solubility & molecular size are

notsuch limiting factors as with haemodialysis:- Membrane on cHPF columns is ~ 1-5mm (compared

to the 30-50mm 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)


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Complications of Haemoperfusion

1Commontoallextracorporealtechniques:- Hypotension: particularly during the first 15 mins

- minimised by priming the circuit & gradually bloodflow 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)


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i) Leucopenia, hypocalcaemia & cytokine activation:

- significant with earlier devices, clinically insignificant

with modern ultrathin coated columns(KolthammerJ76, SangsterB81, RommesJ 83 & 92, Vanholder R 99,

Singh S 04 )

ii) Charcoal embolisation:- prevented by the ultrathin membrane & a filter in the

venous line

2Complications specific to HPF:


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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)


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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


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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. Is cHPF likelyto have a positive effect on morbidity (&

potentially mortality) ??

3. 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


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NO prospective controlled studies looking at theeffect of HPF on outcome in poisoned patients

- Therefore no data to be able to answer criteria 2

HPF: No Controlled Data

Two retrospective series suggest mortality in thosetreated 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)


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Most of the data on HPF in poisoning comes from:- in vitro /animalwork

- case-reports/series studying drug kinetics before,

during & after the procedure

HPF: What evidence is available?

Direct comparison between the reports can be

difficult as many of them involve:

- multiple ingestions

- and/ordifferent treatment regimes

- and/ordifferent HPF columns / blood flow rates


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How frequently is HPF used?

There continue to be a number of reports describingthe use of HPF in poisoned patients

(Cameron R 02, Graudins A02, Singh S 04, Peng A 04)

Total

exposures

Total admitted

to critical care

Total HDx Total HPF

1992 1,864,188 - 780 1741997 2,192,088 59,211 927 48

2002 2,380,028 72,877 1400 39

The only epidemiological data comes from TESS:


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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)


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cHPF for Carbamazepine Poisoning

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)

Causes significant and prolonged toxicity (T1/2

19-32 hrs)(Weaver DF 1988, Hundt HK 1983, Luke DR 1985)

- 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)


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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 Med2002


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T (hrs)Clearance

(mL/min)

Controls 19-32 59-90

MDAC 8.6-9.5 102-113

cHPF 2.6-10.7 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& HPFcarbamazepineclearancetosimilarextent


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MDAC or cHPF for severecarbamazepine poisoning?

MDAC& HPFcarbamazepineclearancetosimilarextent No studies have shown an impact on outcome with either

method

Administration of MDAC in CBZ poisoning is oftenlimited by ileus (de Zeeuw R 1979, Sethna M 1989, Spiller H 1990)

HPF should generally be reserved for:

- life-threatening toxicity (e.g. cardiotoxicity, statusepilepticus)

- particularly cases with poor gut motility or those that are

deteriorating despite MDAC


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Both acute & chronic theophylline poisoning can

cause significant morbidity and mortality

Theophylline Poisoning: HDx or cHPF?

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


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10yr prospective observationalstudy: theophyllinepoisoning treated with cHPF (n=17) or HDx (n=39)Shannon MWAcad Emerg Med1997


HDx HPFMajor toxicity during

or after procedure

39% 28%

Clearance (mL/min) 185 294Complications NIL 1x GI bleed

1x bleed at access site


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T(hrs) Clearance (mL/min)

Controls 19-34 40-50

MDAC 2.2-8.0 120-140

HDx 2.3-6.2 83-165

cHPF 1.4-2.0 146-295


(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)


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MDAC&HDx

totalbodyclearancetoasimilarextent BUTmarginally 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 likelyto translate to a clinical impact

cHPF is generally the treatment of choice in severe

theophylline poisoning if an extracorporeal treatment

is required


Th h lli i i


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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

- ifintractable vomiting and/or ileus prevent MDAC

administration ( Shannon MW 93 & 99)


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There have been reports of clearance of a

number of other drugs with cHPF

- e.g. TCA, digoxin, paracetamol (acetaminophen),b-blockers

Agents for which cHPF is

noteffective

However, they have effective alternative

treatments &/or Vd & so cHPF has no impacton overall body burden and is notindicated

(Pond S 1979 & 1991, Blye E 1984 , Winchester J 2002)


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Barbiturates:

- cHPF totalbody clearance of phenobarbitone ~ 4x

(similar to MDAC) but not of short-medium acting

barbiturates (Jacobsen D 1984, Boldy DA 1986)

Other potential indications for cHPF

Salicylates:

- cHPF and HDx increase totalbody clearance ~ 2x

- HDx is the extracoporeal treatment of choice insevere poisoning as it also corrects acid-base and

electrolyte disturbances (Pond SM 1984, Jacobsen D 1984)


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Non-toxicological advances in HPF

There has been a recent renewed interest in HPF incritical care, hepatology and nephrology:

- Chronic renal failure: for removal of middle

molecules, b2-microglobulin etc.(Winchester JFArtif Cells 2002, Geyko FArtif 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 Biomat2004, Shoji H, Therap Dial 2003)


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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)

Conventional cHPFadsorbent

SCN sphericalpolymer carbon

Preliminary in vitro studies: SCN greater (x2)

adsorption capacity & more rapid adsorption

kinetics (x3) than conventional (Adsorba 300C)

carbons


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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)

Toxicology: Future Developments in HPF

Conventional cHPFadsorbent

SCN sphericalpolymer carbon


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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 areassociated with many fewer adverse effects

There have been no controlled studies assessing

the impact of cHPF on outcome and no studieswhich allow a direct comparison between cHPF

and either HDx or MDAC


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CONCLUSIONS

The limited data available suggests that:

- there is a continuing role for cHPF in severe

theophylline & carbamazepine poisoning

- particularly in patients who are deterioratingdespite MDAC or in those in whom MDAC use is

limited by ileus

Future developments in carbon technologies mayallow an expansion in the indications for cHPF in

toxicology & increased efficacy


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Charcoal Haemoperfusion: Does it still

have a role in the management of thepoisoned patient ?

Yes,probably, in severe theophylline andcarbamazepine poisoning

Butthe level of evidence is poor

haemo perfusion

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