|Year : 2012 | Volume
| Issue : 1 | Page : 1-7
|Extracorporeal management of poisonings
Satish Mendonca1, Sanjay Gupta1, Ankur Gupta2
1 Department of Nephrology, All India Institute of Medical Sciences, India
2 Department of Nephrology, University of Ottawa, Ontario, Canada
Click here for correspondence address and email
|Date of Web Publication||3-Jan-2012|
| Abstract|| |
Extracorporeal methods have been an integral part in the management of poisonings. The elimination of a drug or toxin by extracorporeal techniques (ECT) is governed by the properties of the toxin and the chosen extracorporeal therapy. The various ECT include hemodialysis, hemoperfusion, hemofiltration, continuous renal replacement therapy and peritoneal dialysis, all of which have been used some time or another for the management of poisonings. This review highlights the concepts forming the basis for selecting one modality over the others.
|How to cite this article:|
Mendonca S, Gupta S, Gupta A. Extracorporeal management of poisonings. Saudi J Kidney Dis Transpl 2012;23:1-7
| Introduction|| |
Poisoning is an art practiced since time immemorial, though, in recent times, intentional and accidental episodes are more common. This contrasts the management, which has evolved slowly over time, and has picked up only in the last century.
Development of extracorporeal management of poisons evolved in 1950 when Doolan  demonstrated that substantial quantity of Salicylate can be removed with dialysis and thereafter Jorgensen published a paper on dialyzable poisons. 
Till date, there are 142 dialyzable poisons as maintained in the poison manual. 
This review will focus on the modalities of the extracorporeal methods available and the principles and indications for the removal by these techniques, as there is a paucity of knowledge and experience in this aspect of medicine, in spite of a continuous trickle of cases in the emergency and a dilemma for the physician as to when and how to use extracorporeal techniques for poisoning.
| Modalities of Extracorporeal Techniques (ECT)|| |
- Hemodialysis + hemoperfusion
- Continuous renal replacement therapy (CRRT)
- Sustained low-efficiency dialysis (SLED)
- Peritoneal dialysis
| Kinetics of Toxin Removal by ECT|| |
The elimination of a drug or toxin by ECT is governed by the properties of the toxin and the extracorporeal therapy chosen; hence, understanding the kinetics of toxin removal is essential.
1. Molecular weight (MW)
Toxin removal during hemodialysis occurs primarily by diffusion into the toxin-free dialysate across a semi-permeable membrane. The relationship between molecular weight and toxin extraction is inversely proportional, i.e. as the MW increases, the removal decreases. Low-MW solutes [<500 daltons (D)] diffuse easily through the pores of even low-flux dialysis membranes such that their clearance is primarily dependent on membrane surface area, blood-to-dialysate concentration gradient and blood and dialysate flow rates. Larger solutes (>1000 D in the case of low-flux membranes) have limited membrane permeability and are removed through convective clearance ("solute drag" from ultrafiltration) rather than diffusion. Most toxins are less than 500 D and hence are easily removed by hemodialysis. With the advent of high-flux and high-efficiency dialyzers, even larger MW substances can now be dialyzed.
2. Protein binding
The quantity of toxin that is bound to plasma or tissue proteins is another determinant of drug removal. The diffusive removal of a drug by hemodialysis requires unbound drug to cross the dialysis membrane, because the larger size of the drug-protein complex limits its dialysis membrane permeability. Convective removal by hemofiltration also does not occur to any significant degree because the drug is bound to non-ultrafilterable plasma proteins and the complex is very large to cross the pores of the membrane.
Hemoperfusion, however, may be more effective in these cases as the adsorbent (e.g., activated carbon) competes with plasma proteins for binding the toxin. The degree of protein binding can be influenced by many factors, including alterations in plasma protein concentration and the presence of different pathologic states.  For example, hypoalbuminemia results in less protein available for binding, and uremic organic acid accumulation leads to a reduction in binding sites for acidic drugs (e.g., salicylates, warfarin and phenytoin). These alterations increase the fraction of unbound, biologically active drug; as a result, it is possible that therapeutic efficacy (or toxicity) may occur at a lower total drug concentration than observed in the normal state.  However, because hepatic enzymes metabolize unbound drug, it is possible that these alterations in protein binding may actually enhance drug clearance. Drug levels become invaluable when dealing with such complex pharmacokinetic situations.
Highly protein-bound drugs include arsenic, calcium channel blockers, diazepam, phenytoin, salicylate and other non-steroidal anti-inflammatory drugs (NSAIDs), thyroxine and tricyclic antidepressants (TCAs). Compounds with minimal protein binding include the alcohols (methanol, ethylene glycol, isopropanol, ethanol), aminoglycosides and lithium. Alterations in protein binding are clinically relevant for drugs that exhibit a narrow therapeutic index (e.g., lithium, digoxin). 
3. Volume of distribution (Vd)
It is the apparent volume of the drug distributed in the body. It is calculated by dividing the dose of the drug in the body by the serum level. Toxins with a large Vd are not ideally suitable for removal by ECT, as they are extensively distributed in the body and ECT will remove only a fraction of the drug due to which there is a tendency of the drug to diffuse back into the intravascular compartment and cause toxicity.
Drugs with a large Vd include digoxin, calcium channel blockers, barbiturates, ß-blockers, chloroquine, colchicines, quinidine, strychnine, TCAs and phenothiazines.
Drugs with a small Vd are alcohols, lithium, salicylates, paracetamol, aminoglycosides and theophyllines.
4. Rebound phenomenon
Drugs with a large Vd are liable for rebound phenomenon. This is because ECT will only remove the toxin that is there in the intravascular compartment due to which the levels fall, causing a diffusion of the drug back into the intravascular compartment from the extravascular compartment.
Type of ECT influencing toxin removal
This involves the diffusion of the toxin through a 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.  The most common acute complications of hemodialysis are systemic hypotension, which ranges between 15% and 30%. Although there are several strategies that may be employed to improve hemodynamic stability during hemodialysis (e.g., sodium modeling, ultrafiltration modeling, lowering dialysate temperature to 35°C, increasing dialysate calcium concentration, use of the α1 -adrenergic agonist midodrine), hypotension remains the principle drawback that limits the efficacy of drug removal during this procedure. Drugs with a low MW, low protein binding, small Vd and low lipid solubility are easily dialyzed.
Such drugs include salicylates, methanol, lithium, ethylene glycol and theophylline.
The principle is 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 or Vanderwal's forces to the adsorbent. Activated charcoal is the most common adsorbent used. However, ion exchange resins that contain XAD 4 amberlite are also available. Charcoal hemoperfusion results in irreversible binding, whereas resin hemoperfusion reversibly binds the toxin.  Activated charcoal is carbon that undergoes processing by treatment with steam at high temperatures so that the pores open up and increase the surface area for adsorption.
The earlier hemoperfusion cartridges contained charcoal that caused a lot of hypersensitivity reactions due to activation of the complement system when the blood came into contact with the charcoal, and there was a high incidence of charcoal embolization. To prevent this, newer devices with charcoal that is coated with an ultrathin film are available. Hemoperfusion involves the flow of anti-coagulated blood through the cartridge at a flow rate of 150-200 mL/min. The anti-coagulation is maintained with heparin and the aim is to maintain the activated clotting time to twice normal. The normal dose of heparin is about 2000-3000 units. However, due to adsorption of heparin, about 10,000 units may be required. The requirement is of a blood pump, which is available in an ordinary hemodialysis machine. The hemoperfusion cartridge is first primed with 2-3 L of normal saline; however, most cartridges have their own instructions on priming, such as Clarke's hemoperfusion cartridge advocates priming with dextrose initially so that there is a reduced incidence of hypoglycemia.
Another problem with the hemoperfusion device is that there is limited experience with most centers, leading to an inherent inertia in using it. Besides, it is also costly and has a short shelf life and hence they are available at short notice in a very few centers. Hemoperfusion also does not correct the acid-base disturbances, electrolyte imbalance and fluid status in patients with poisoning.
The hemoperfusion cartridge usually gets saturated after 3-4 h, and a new cartridge has to be inserted if the patient requires prolonged hemoperfusion. The MW, protein binding or lipid solubility do not influence hemoperfusion.
The various hemoperfusion devices that are available are listed in [Table 1]. Complications of hemoperfusion:
The decision to initiate hemoperfusion is taken with caution because of the side-effects and the cost and expertise involved, and it lies purely with the treating physician as there are no definite guidelines for initiation. However, in a case where hemoperfusion and hemodialysis are indicated, hemodialysis is usually preferred because it is cheaper, corrects various acid-base abnormalities and fluid and electrolyte imbalances and is easily available.
- Thrombocytopenia (30%)
- Leucopenia (10%)
- Reduction of fibrinogen
There are certain case reports where both the dialyzer and the hemoperfusion device are used together and arranged in series. ,,,, In such a 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.
The process of hemofiltration removes toxins by convection across a membrane; it does not involve the flow of dialysate. 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 degree of protein binding and the ultrafiltration (UF) and the sieving coefficient, which is the ability of the solute to cross a membrane by convection.
The convective transport of hemofiltration efficiently removes high MW toxins up to 40,000 D.
The toxins amenable are vancomycin, methanol, procainamide, hirudin, thallium, lithium and methotrexate.
4. Peritoneal dialysis (PD)
The role of PD is limited in poisoning as it is not an efficient method for toxin removal. In fact, it is no more being audited by the TESS (toxic exposure surveillance systems) data for extracorporeal toxin removal in the US data registry.  However, PD can be useful in situations such as pediatric poisoning, where hemodialysis is difficult, or in certain conditions where the patient is hemodynamically unstable and hemodialysis cannot be used. Toxin removal by PD can also be enhanced by adding dextrose to the dialysis fluid that increases the convective gradient and removes larger MW drugs by UF. Furthermore, the phenomenon of ion trapping can be used to enhance toxin removal by alkalinizing or acidifying the PD fluid. Newer techniques where albumin is added to the fluid to increase the rate of highly protein-bound toxin such as barbiturates have also been documented.  In the setting of hypothermia, using pre-heated dialysate has been shown to be clinically effective in rapidly reversing hypothermia. 
5. Continuous renal replacement therapy (CRRT)
The role of continuous therapies in poisoning is not well established. Solute removal in CRRT occurs through either dialysis (diffusion-based transport) or filtration (convective transport) or both.
These continuous modalities of ECT are rarely used in the management of acute overdose because of their lower drug clearance relative to intermittent hemodialysis (IHD), cost and expertise involved. CRRT has a distinct advantage in hemodynamically unstable patients. It has also been suggested that CRRT may also be effective for the slow, continuous removal of substances that possess avid tissue binding, large volumes of distribution, slow intercompartmental transfer and are prone to "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.
6. Slow low efficiency dialysis (SLED)
It is a new technique that is described as an alternative to IHD and CRRT. IHD is often complicated by hypotension, due to which there is inadequate solute and fluid removal,  whereas CRRT is associated with higher complexity, increased nursing requirements, continuous anticoagulation and higher expenses for specialized equipment and customized solutions. 
SLED combines the advantages of both IHD and CRRT by using conventional hemodialysis machines at slower blood flow rates of 200 mL/min, reduced dialysate flow rates of 300- 350 mL/min for 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. 
7. Plasmapheresis and plasma exchange
Plasma exchange is a process in which plasma is removed from the patient and replaced with fresh frozen plasma or stored plasma.
The term plasmapheresis is used when the replacement fluids include other products (e.g., albumin) rather than plasma alone.
The role of plasma exchange is not well defined in acute poisoning but has been used for toxins that are highly protein bound (>80%) with low volumes of distribution (< 0.2 L/kg body weight). 
Poisonings complicated by massive hemolysis (e.g., hemolytic anemia from sodium chlorate poisoning) or methemoglobinuria are other indications for plasma exchange. Plasma exchange not only removes the toxin but also eliminates red cell fragments and free hemoglobin. 
Adverse outcomes from plasma exchange involve complications associated with vascular access placement, bleeding and hypersensitivity reactions to the replacement plasma proteins.
| Indications of ECT|| |
There are no clear guidelines for ECT due to paucity of randomized controlled trials and spectrum of multivariate factors involved. However, there are certain situations where it is absolutely indicated.
- Progressive clinical deterioration in spite of intensive supportive therapy and appropriate clinical management.
- Severe intoxication with abnormal vital signs, including depression of mid-brain function, resulting in hypoventilation or apnea, severe hypothermia and hypotension.
- Prolonged coma grades III and IV, and prolonged assisted ventilation for more than 48h.
- Acute renal failure caused by a (potentially) nephrotoxic intoxicant.
- Impairment of metabolism and excretion of the intoxicant in the presence of hepatic, cardiac or renal insufficiency.
- Intoxication with agents with metabolic and/or delayed effects, such as methanol, ethylene glycol and paraquat.
- Intoxication with an extractable drug or poison that can be removed at a rate exceeding endogenous elimination by liver or kidney.
- Ingestion and probable absorption of a highly toxic (potentially lethal) dose (best determined after gastric decontamination). An estimated toxic dose in the gram-range is potentially life-threatening with most drugs and almost all genuine toxins.
- A potentially fatal plasma concentration as assessed by previous experience of risk of death and severe clinical sequelae.
| The Future|| |
The future lies in hemoperfusion devices coated with drug-specific antibodies or the antidote of the toxin instead of activated charcoal.  Also, the advent of high-flux dialyzers have reduced the use of hemoperfusion devices as even large MW substances can now be dialyzed. ,
| Conclusion|| |
ECT is an important aspect of toxicology, which is often neglected because of a lack of adequate knowledge and paucity of expertise. It is life-saving in certain conditions. With the availability of newer sophisticated dialysis machines and high-flux and -efficiency dialyzers, the procedure of extracorporeal removal of toxins is quite simplified. The indications are still hazy, and it is up to the treating physicians' discretion when to employ extracorporeal methods and which form of it is most convenient.
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Department of Nephrology, University of Ottawa, Ottawa, Ontario
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