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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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Complications of Haemoperfusion
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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2Complications specific to HPF:
iii) Thrombocytopenia
Complications of Haemoperfusion
- 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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Complications of Haemoperfusion
2Complications 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
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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
cHPF for Carbamazepine Poisoning
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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cHPF for Carbamazepine Poisoning
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
Theophylline Poisoning: HDx or cHPF?
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
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)
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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
Theophylline Poisoning: HDx or cHPF?
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