Tricyclic Antidepressants

1
Extracorporeal Techniques in the Treatment of
Poisoned Patients
2
Techniques commonly used for extracorporeal drug
removal

• 1. Haemodialyis
• 2. Haemoperfusion
• 3. Continuous haemofiltration
• 4. Continuous haemodiafiltration

3
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)

4
When should extracorporeal techniques be
considered?

• 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

Poisoning with a drug that is removed by one of
the techniques AND
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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)

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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

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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 (gt 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
8
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

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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
  ICUs can be used to operate the system, the only
  special equipment required is the perfusion column

10
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

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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

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Indications for Haemoperfusion 1

• Characteristics of compounds that make them
  amenable to removal by HPF

• - Adsorbed by charcoal
• - Low volume of distribution (lt 1 L/kg)
• - Single compartment kinetics
• - Low endogenous clearance (lt 4mL/kg/min)
• Protein binding, water solubility molecular
  size are not such limiting factors because the
  drug is in direct contact with the adsorbent

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Indications for Haemoperfusion 2

• Carbamazepine
• Phenobarbitone
• Theophylline
• (Meprobomate)
• (Phenytoin Kawasaki 2000)
• (Na Valproate)
• (Salicylates)

Drugs for which haemoperfusion may be used in
clinical toxicology practice
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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)

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Half-life clearance of carbamazepine in
overdose

• 1. Controls T1/2 19-32 hrs Clearance 59-90
  ml/min (Hundt HKL 1983, Vreeth 1986,
  Cutler RE 1984)
• 2. MDAC T1/2 8.6-9.5 hrs Clearance 105-113
  ml/min
• (Wason S 1992, Boldy DAR 1987,
  Monty-Cabrera 1996)
• 3. HPF T1/2 8.6-10.7 hrs Clearance 80-129
  ml/min
• (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

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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 gt 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

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Half-life and clearance of phenobarbitone in
overdose

• 1. Controls T1/2 80-120 hrs Clearance 4-27
  ml/min (Hardman JG 1996, Vale JA 1987)
• 2. MDAC T1/2 12-36 hrs Clearance 84 ml/min
• (Boldy DAR 1986, Pond SM 1984)
• 3. HDx T1/2 no data Clearance 22-49 ml/min
• (Verbooten GA 1980, Cutler RE 1987)
• 4. HPF T1/2 7.2-11 hrs Clearance 77-140
  ml/min
• (Cutler RE 1987, Jacobsen D 1984)

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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

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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)

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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)

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Problems with haemodialysis in poisoned patients

• 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

Only available in a limited number of centres

• 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

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Indications for Haemodialysis 1

• Characteristics of compounds that make them
  amenable to removal by HDx

• - Molecular weight lt 500D
• - Water soluble
• - Poorly bound to plasma protein
• - Low volume of distribution (lt 1 L/kg)
• - Single compartment kinetics
• - Low endogenous clearance (lt 4mL/kg/min)

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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)

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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

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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
• (Vree TB 1994, Prescott LF 1982)
• 3. HDx T1/2 1.9 hrs Clearance 80 - 86 ml/min
• (Pond SM 1984, Jacobsen D 1988)
• 4. HPF 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)

UA Urinary Alkalinisation to pH 8.5
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Salicylate poisoning HDx or HPF?

• HPF achieves marginally better clearance but
  cant 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

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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 lt 7.2 (increased CNS transit
  of salicylate)
• Salicylate concentration gt 700-800mg/l
  (50-58mmol/l)
• no data as to whether HDx in this group alters
  outcome, but salicylate level gt 900mg/l
  associated with 5 mortality
  (Chapman BJ 1989)
• children (lt12yr) elderly (gt65yr) more
  susceptible to CNS toxicity, therefore lower
  threshold for HDx (Krause DS 1992) Low
  er thresholds in chronic salicylate poisoning

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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 (1500-4200
  ml/hr)
• Synthetic membranes have a cut-off limit of up to
  10 - 40,000 D

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Haemofiltration haemodiafiltration(CVVHF) (CV
VHDF)

• 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

CVVHDF
CVVHF

• HDF allows greater removal of smaller molecules
  (lt500D) and also better control of hyperkalaemia
  and other metabolic disturbances
• (CUPID combination of CVVHF and intermittent
  HDx)

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Haemofiltration
Characteristics of drugs that make them amenable
to HF molecular size - mass lt 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 / (AV)

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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

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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 (lt 500D) ... this includes most drugs

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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

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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 (lt15
  excreted unchanged)
• T1/2 19-34hrs in overdose (8hrs therapeutically)

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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

36
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
• gt 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)
• gt 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
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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

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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

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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

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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

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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

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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 its 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 ...