Extracorporeal drugs overdose & toxin removal

1. Extracorporeal Toxin
removal
(ECT)
Definition /
It is a removal of drugs & toxins from blood via an artificial
methods.
In 1950 >>> Doolan demonstrated Salicylate can be removed
with dialysis
Thereafter, Jorgensen published a paper on dialyzable poisons.
Up to date, there are 142 dialyzable toxins

2. A Common case scenario
22 years old F arrived unconscious to ER , her mother
found an empty bottle of Tegretol table (200mg )
beside her.
after being urgently resuscitated ,she shifted to ICU for
further management .

3. Qs need to be answered…
 IS IT INDICATED TO DO DIALYSIS ?
 IS THIS DRUG DIALYSABLE ?
 WHAT IS THE BEST MOOD OF REMOVAL ?
 WHAT IS THE BEST PRESCRIPTION ( RATE , PUMP , FILTE TYPE )?
 WHAT SHOULD WE MONITOR and WHEN TO STOP ?
?

4. 1st) Indications of ECT
There are no clear guidelines
for ECT starting .
However, there are certain
situations where it is absolutely
& urgently indicated.

5. Progressive clinical deterioration (in spite of intensive therapy )
Hemodynamic instability (including depression of mid-brain
function)
Prolonged coma grades III and IV,
prolonged assisted ventilation for more than 48h.
Acute renal failure caused by sever nephrotoxic overdose.
Impairment of natural excretion of the toxin (hepatic, cardiac or
renal failure)
Intoxication with agents with metabolic and/or delayed effects, such
as methanol, ethylene glycol and paraquat.
highly toxic (potentially lethal) dose (best determined after gastric
decontamination).

6. 2nd) Is it dialyzable ?
>>Dailyzability
It is the capacity of drugs or toxins to be
removed by a dialysis membrane
 Affected by drug/toxin kinetics & extracorporeal
related factors

7. drug/toxin kinetics
 Molecular Weight
 Volume distribution
 protein binding
 endogenous clearance
 Rebound phenomena
ECTR-Related Factors
 Dialysis membrane
 Flow rate
 Dialysate rate
 Ultrafiltration rate
 Cartidge saturation
Dialyzibility

8. Drug/toxin kinetics :
1. Molecular weight (MW)
[<500 daltons D] solutés diffuse easily
[>1000 D] in the case of low-flux membranes) diffuse difficulty.
Most toxins are less than 500 D so easily removed by hemodialysis.
With the advent of high-flux and high-efficiency dialyzers,even
larger MW substances can now be dialyzed (< 15,000 Da)
New high-cutoff and middle-cutoff membranes remoev poisons
up to 50,000 Da,( availability restricted)
As the MW increases, the removal decreases.

9. 2.Protein binding
 Highly protein-bound drugs include:
Drugs with minimal protein binding include :
Calcium channel blockers, phenytoin,
salicylate and (NSAIDs),
thyroxine
antidepressants (TCAs).
Arsenic,
Alcohols (methanol,ethylene glycol,isopropanol, ethanol),
Aminoglycosides
Lithium.
toxins & drugs with high PB are difficult to dialysate

10. 3. Volume of distribution (Vd)
dose of the drug in the body
VD = ------------------------------------------
serum level of drug
 a large VD (>2 L/kg), overall removal by ECTR will be low.
Widely distributed drugs& toxins are difficultly to collect

11.  Toxins with a large Vd are not ideally suitable for removal by ECT,
 Drugs with a large Vd include
digoxin easily crosses the dialyzer; however, because of its high VD (5–7 L/kg),
Less than 5 % of total body of digoxin will be removed in a 6-h dialysis session
Drugs with a small Vd are ‘
Digoxin
CCB
ß-blockers .
TCAs
barbiturates,
chloroquine,
colchicines,
quinidine,,
phenothiazines
Alcohols
lithium
salicylates,
paracetamol,
aminoglycosides

12. Rebound phenomenon
 Drugs with a large Vd are liable for rebound phenomenon.
because ECTR will only remove the toxin from the intravascular compartment
due to which the levels fall, causing a diffusion of the drug back into the
intravascular compartment from the extravascular compartmen causing more
toxicity.
IVC INTERSTATIAL
toxin
ECTR
toxin

13. Endogenous Clearance
Removal of toxin via natural ways eg.kidney liver
Endogenous
clearance
kidney ,liver
Exogenous
clearance
like ECTR
No
ECTR
because the hepatic clearance of lidocaine (>1,000 mL/min) greatly exceeds the
clearance with dialysis (150 mL/min), ECTR of lidocaine is never indicated.
Thisis also true of many street drugs.
Any impairment in endogenous metabolic and elimination route wil lower the
decisional threshold to initiate dialysis,

14. Low MW
Low VD
Low protein binding
Low lipid soluble
Low rebound
Easy dialyzable
High MW
High VD
High protein binding
High lipid soluble
High rebound
Difficult / non dialyzable

15. ECTR-Related Factors
 dialysis membrane (i.e., material, surface area,
porosity),
 the concentration gradient
 the blood flow rate ,
 the dialysate/ultrafiltrate flow rates.
 hemoperfusion cartridges saturaturation

16. • Hemodialysis
• Hemoperfusion
• Hemofiltration
• Hemodialysis + hemoperfusion
• Continuous renal replacement therapy(CRRT)
• Sustained low-efficiency dialysis (SLED)
• Plasmapheresis
• Peritoneal dialysis
ECTR Modilties

17.  principle
 Diffusion of the toxin through semi-permeable
membrane into the dialysate.
 The removal is directly proportional to the surface
area of the dialyzer used, the porosity and the dialysate
and blood flow rate
 complications
 most common acute complications of hemodialysis are
systemic hypotension, between 15% and 30%
 risk of rebound toxicity
 practical solutions for hypotension during HD.
sodium modeling, ultrafiltration modeling,
 lowering dialysate temperature to 35°C,
 increasing dialysate calcium concentration,
α1-adrenergic agonist midodrine)
 Notes
 Drugs with a low MW, low protein binding, small Vd and low lipid solubility are
easily dialyzed.
 Such drugs include salicylates, methanol, ethylene glycol and theophylline
 the high flux membrane have the capacity for removal of larger molecules and highly
protein-bound poisons such as carbamazepine and phenytoin which was
exclusively removed by hemoperfusion
Hemodialysis

18. Hemoperfusion
The principle
 the adsorption of the drug to the
adsorbent, which is usually activated
charcoal or an ion exchange resin.
 Adsorption means the binding of the
toxin by hydrogen bonds to the
adsorbent.
 Activated charcoal is the most common
adsorbent used.
Hemoperfusion, >> more effective in case of high protin pinding toxins
( activated carbon) competes with plasma proteins for binding the toxin.

20. Teqhnique (priming)
flow of anti-coagulated blood through the cartridge at a flow
rate of 150–200 mL/min.not > 340 ml/m. to avoid the risk of hemolysis.
 The anti-coagulation is maintained with heparin
 Adsorba 300c advocates priming with 500cc dextrose to
reduced incidence of hypoglycemia.
 followed by heparinized (c2500 iu heparin) in 1000c n/s to
prevent hemolysis.
 For termination of HP session start with inversion of cartridge
up side down then follow usual steps of standard termination
protocol .

21. CRTT&HD TMC TEAM

22. Complication
 Hypersensitivity duo to complement system activation
 newer devices with charcoal that is coated with an ultrathin film are
available .
 limited experience with most centers.
 SATURATION The hemoperfusion cartridge usually gets saturated after
3–4 h, more thane one cartridge has to be inserted if the patient requires
prolonged hemoperfusion
 does not correct the acid–base disturbances, electrolyte imbalance
and fluid status .
 1. Thrombocytopenia (30%)
 2. Leucopenia (10%)
 3. Hypocalcemia
 4. Hypoglycemia
 5. Reduction of fibrinogen
 6. Hypothermia

23. Hemodialysis vs. hemoperfusion
in a case where hemoperfusion and
hemodialysis are indicated, hemodialysis is
usually preferred because
There are certain case reports where both the
dialyzer and the hemoperfusion device are
used together in this case, the blood should
first pass through the dialyzer and thereafter
the hemoperfusion cartridge so that there is
minimal saturation of the cartridge that
increases its life span which used in
cases of sever phenobarbitol and tegertol
posing associated with acid base balance
abnormality..wich
it is cheaper,
corrects acid–base abnormalities
fluid and electrolyte imbalances
easily available

24. A frequently asked question is whether HD or HP is
superior for treatment of poisoning?
Early clinical experience with HP suggested that it was more
effective than HD or PD for poison removal.
recent studies have shown comparable results with the
newer high-flux, high-efficiency dialyzers .
HP is preferred when the toxin is lipid-soluble or
significantly protein-bound
poisons with a large Vd are not likely to be efficiently
removed by HP.
HP is associated with more frequent complications and
higher cost, particularly since the cartridges need to be
replaced regularly because of saturation.

25.  A double-lumen central catheter is required
 A temporary femoral catheter is preferred,
 To maximize efficacy, the largest surface area dialyzer should be used.
 Heparinization of the circuit is favored to prevent clotting.
 The blood flow and dialysate/effluent flow should be maximized for
optimal clearance .
 Adjustment of the dialysate concentration of calcium, phosphate,
magnesium, potassium, and/or bicarbonate is essential.
 A single 6-h extracorporeal treatment will usually sufficient to lower blood
levels of most toxins .
 (hemoperfusion cartridges may need to be replaced because of saturation
in cases of sever toxicity which need prolonged session ).

26. 3. Hemofiltration
Principle
removes toxins by convection across a membrane
techinque
Water-like substances move out from the plasma
through the membrane, and this fluid is replaced
with isotonic fluids.
The rate of removal of the toxin is influenced by
The hemofiltration efficiently removes high MW
toxins up to 40,000 D.
methotrexate
 vancomycin, methanol,
 procainamide, thallium, lithium
the degree of protein binding .
the ultrafiltration (UF)
the sieving coefficient, which is the ability of the
solute to cross a membrane by convection

27. 4. Continuous renal replacement therapy
(CRRT)
 The role of continuous therapies in poisoning is not well
established.
 Principle (convective transport , filtration) or both.
 CRRT has a distinct advantage in hemodynamically unstable
patients.
 CRRT also be effective for the slow, continuous removal of
substances with
 tight tissue binding
 large volumes of distribution,
 slow “rebound phenomenon” (e.g., lithium, procainamide
and methotrexate).
 Continuous methods are useful for intoxicants such as
paraquat, lithium, thallium, methotrexate, procainamide
and methanol.
 They are useful even if the treatment is initiated many hours
or days after exposure.

28. HD HP HF+CRTT
PRINCIPLE DIFFUSION ADSORBTION Convectiotion+/filtration
ADVANTAGES Less cost
Easier
Correct other metabolic
electrolyte imbalance
Suitable for most drugs
over dose
More effective
especially in case
of toxin with high
protein bindings
Lipid soluble.
More suitable in
hemodynamic unstable
patients
Poisons with prolong
metabolic effect
(methanol) Large
MW>40000 Da
DISADVANTAGES Heamodynamic
unstability
less effective inDrugs
with high protin binding
large vd
Cost effective
Need expert
Thrombocytopenia
Cost effective
Full time staff
Common
examples
Salicylate
Alcholol methanol&ethnel
glycol
Lithium
Valproate
Thiophyline
Phenobaribtol
Thiophyline
Gluthemide
crbimazine
Methotroxate
Ethylen glycol
Lithim
valproate
Metformin
paracetamol

29. 5. Slow low efficiency dialysis
(SLED)
 It is a new technique that is described as an alternative to
IHD and CRRT.
 SLED combines the advantages of both IHD and CRRT by
using conventional hemodialysis machines at
 slower blood flow rates of 200mL/min,
 slower dialysate flow rates of 300–350 mL/min
 prolonged periods of 8–12 h on a daily basis.
 In hemodynamiccally unstable, critically ill patients, SLED
is better tolerated, results in high solute clearance and fluid
removal and does not entail the same level of complexity or
costs associated with continuous therapies.

30. 6 Plasmapheresis and plasma exchange
 The role of plasma exchange is not well defined in acute
poisoning but has been used for toxins that are highly protein
bound (>80%) withlow volumes of distribution (< 0.2 L/kg body
weight)
 Poisonings complicated by massive hemolysis(e.g., hemolytic
anemia from sodium chloratepoisoning) or
methemoglobinuria
 Large MW > 50,000 D eg cisplatin other chemotherapy
 Adverse outcomes from plasma exchange involve
 vascular access placementcomplications
 , bleeding and hypersensitivity

31. 7. Peritoneal dialysis (PD)
 The role of PD is limited in poisoning as it is not an effctive
method for ECTR
 PD can be useful in situations such as pediatric
poisoning.

32. GUIDE LINE

33. Common drugs toxicity
Acetaminophen. although it is not efficiently extracted by.ECTR but it is dialyzable .
Early and prolonged use of N-acetylcysteine (NAC) remains the therapy of choice .
ECTR is recommended only in patients with excessively large overdoses with features of
mitochondrial dysfunction manifested by early development of altered mental status and
severe metabolic acidosis prior to the onset of hepatic failure.
IHD is the preferred ECTR modality in acetaminophen poisoning .
 Narcotics and “street” drugs. A common cause of overdose and death,
 narcotics and other street drugs are not amenable to extraction by ECTR
 antagonists and supportive therapy are the mainstays of treatment.
 Nonbarbiturate hypnotics, sedatives, and tranquilizers.
 they have high apparent Vd and lipid solubility and therefore are not removed well by ECTR
Other miscellaneous toxins. This group includes paraquat, amanita mushroom toxin, there is little
evidence that ECTR are clinically effective for the t their reatment
paraquat and procainamide are tightly tissue bound and released slowly,
CRRT may be efficacious .
the effectiveness of other ECTR modilities remains debatable
Organophsophorus poisoning is common . no wide agreement about the ECTR modality of choice but
many expertise recommend HP in cases of lethal OP poisoning.

34. Sever methanol poisoning
1 coma
2 seizures
3 new vision deficit
Sever metabolic acidosis
IHD Is the ECTR Of choice
CRTT Is an alternative mode especially in case of late presentation .
HD is indicated in the patient intoxicated with long-acting
barbiturates and who have poor renal function.
four key recommendations.
(a) ECTR should be restricted to cases of severe long-acting barbiturate
poisoning.(phenoparb)
(b) The indications for ECTR are the presence of prolonged coma, respiratory
depression necessitating mechanical ventilation, shock, persistent toxicity,
or increasing or persistently elevated serum barbiturate concentrations
despite treatment with MDAC.
(c) Intermittent HD is the preferred mode of ECTR, and MDAC treatment should be
continued during ECTR.
(d) Cessation of ECTR is indicated when clinical improvement is apparent ).

35. clinically non dialyzable drugs
Tricyclic antidepressants&.digoxin
 have a high Vd .high lipid solubility.
 The fraction of drug available for extraction from the circulation is
minuscule.
 The EXTRIP workgroup concluded that TCAs are not dialyzable
and stated that ECTR is not recommended in severe TCA
poisoning because poisoned patients with TCAs are not likely to
have a clinical benefit from extracorporeal removal .
Barbiturates. The short-acting barbiturates are highly lipid-
bound and poorly dialyzable.
 On the other hand, longer acting barbiturates, especially phenobarbital, are more water-soluble

36. The Future
The future lies in hemoperfusion devices coated
with drug-specific antibodies or the antidote of
the toxin instead of activated

37. Our reference
EXTRIP group is an international collaboration among recognized
experts from nephrology, clinical toxicology, critical care,
pharmacology and supported by over 30 professional societies
A group of experts in 2010 met to discuss the reference to develop
guidelines on the use of ECTR in severe poisoning based on systematic
reviews of the literature combined with multidisciplinary expert consensus

38. Important EXTRIP recommendation
 Recommendations for salicylates, lithium, theophylline, valproate, or thallium
provide indications for ECTR based on specific cutoff plasma concentrations
irrespective of the signs or symptoms.
 ECTR mainly reduces the overall cost of antidote therapy and length of
hospital stay in the case of early methanol poisoning prior to the development
of acidosis.
 The workgroup also provided criteria for ECTR cessation, which usually
noticeable clinical improvement of toxic symptoms,
 targets of surrogate parameters of toxicity (e.g., pH or lactate),
 or a specific poison concentration below which toxicity is no longer expected.
 recommendations include the preferred type of ECTR for every reviewed poison
(favoring intermittent HD in all circumstances)
 specific recommendations regarding anticoagulation, special populations, and
antidotal dose.
 For tricyclic antidepressants and digoxin, the adverse effects of ECTR outweigh
any potential benefit of ECTR, and thus the recommendations are not to perform
ECTR.

39. The executive summaries of all EXTRIP recommendations are published
at http://www.extrip-
workgroup.org/recommendations

41. Our recent experience

42. 26 years old women presented with palpitation after
intentionally ingested 180 tablet (36 g ) of caffeine
in a suicide attempt .
her HR 160 bpm . BP 80/60 during initial evaluation
she has seizures and develops a wide complex
tachycardia which degenerates into multiple
pulseless cardiac arrest. In between she retained
sinus tachy cardiac rhythm 180 she received
isopronalol infusion she circulatory support without
any beneficent
Real case

43. ECTR modality of choice
IHD
IHD started and tachycardia resolved
bp restored and weaned from MV discharged to home.
Dialyzable
Kinetics of caffeine revealed to MW 340d low
protein binding and low vd

44. Thank you .