Transcript Tricyclic Antidepressants

Extracorporeal Techniques in the
Treatment of Poisoned Patients
Techniques commonly used for
extracorporeal drug removal:
1. Haemodialyis
2. Haemoperfusion
3. Continuous haemofiltration
4. Continuous haemodiafiltration
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)
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
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)
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
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
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
Haemoperfusion(HPF)
• First reported use in poisoning was for barbiturates
(Yatzidis 1964)
• Blood is pumped through a column containing an
adsorbent, usually activated charcoal
- other adsorbents have been used in the past
e.g. resin, amberlite and haemacol
- the adsorbent is coated with a biocompatible,
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
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
• Anticoagulation with heparin (PTT 2.0-2.5) or prostacyclin
is 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
Complications of Haemoperfusion
1. Complications common to all extracorporeal techniques
- 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
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
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)
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)
Half-life & clearance of carbamazepine in
overdose:
1. Controls: T1/2 19-32 hrs
2. MDAC:
Clearance 59-90 ml/min
(Hundt HKL 1983, Vreeth 1986, Cutler RE 1984)
T1/2 8.6-9.5 hrs
Clearance 105-113 ml/min
T1/2 8.6-10.7 hrs
Clearance 80-129 ml/min
(Wason S 1992, Boldy DAR 1987, Monty-Cabrera 1996)
3. HPF:
(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
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
Half-life and clearance of
phenobarbitone in overdose:
1. Controls: T1/2 80-120 hrs
Clearance 4-27 ml/min
2. MDAC:
T1/2 12-36 hrs
Clearance 84 ml/min
T1/2 no data
Clearance 22-49 ml/min
T1/2 7.2-11 hrs
Clearance 77-140 ml/min
(Hardman JG 1996, Vale JA 1987)
(Boldy DAR 1986, Pond SM 1984)
3. HDx:
(Verbooten GA 1980, Cutler RE 1987)
4. HPF:
(Cutler RE 1987, Jacobsen D 1984)
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
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)
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 countercurrent on 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)
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
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)
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)
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
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
*UA = Urinary Alkalinisation to pH 8.5
3. HDx:
4. HPF:
T1/2 1.9 hrs
(Vree TB 1994, Prescott LF 1982)
Clearance 80 - 86 ml/min
(Pond SM 1984, Jacobsen D 1988)
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)
Salicylate poisoning: HDx or HPF?
• HPF achieves marginally better clearance but
can’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
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
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 (15004200 ml/hr)
• Synthetic membranes have a cut-off limit of
up to 10 - 40,000 D
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
CVVHF
CVVHDF
• 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)
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: less important 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)]
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
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
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
Theophylline poisoning: HDx, HPF or CVVHF?
• 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)
Theophylline poisoning: HDx, HPF or CVVHF?
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
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
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
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
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
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
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
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 ...