Plasmapheresis in Acute Intoxication and Poisoning

Mechanisms of Action

The therapeutic benefit of plasmapheresis in acute poisoning and drug overdose is based on the rapid removal of drugs or toxins that cannot be eliminated adequately by usual therapeutic interventions. Plasmapheresis can remove rapidly toxins of all sizes, including protein- and lipid-bound toxins with a low volume of distribution. As for any extracorporeal technique, plasmapheresis only removes substances located in the vascular compartment. As the volume of distribution increases, the usefulness of any extracorporeal treatments (ECTR) decreases substantially. The tissue stores of a poison will remain unaffected except for reequilibration with decreasing plasma concentrations. Other possible benefits of plasmapheresis in the treatment of poisoning and drug overdose are the effects on toxins-induced complications such as hemolysis or thrombotic thrombocytopenic purpura. For instance, in cases of drug-induced hemolysis, plasmapheresis has the potential for removing red blood cell destruction products and hemoglobin. In addition, infusion of normal plasma may have beneficial effects, independent of removal of toxic circulating compounds. For example, plasmapheresis with autologous plasma as replacement fluid provides an opportunity to administer active cholinesterase in organophosphate poisonings.

Technical Overview

Plasmapheresis involves withdrawal of venous blood, separation of plasma from blood cells, and reinfusion of cells with autologous plasma or another replacement solution. Plasma and blood cells are separated by centrifugation or membrane filtration. Usually, the equivalent of 1 to 1.5 plasma volumes (or 2.5 to 4.0 L) is removed during a session. To maintain plasma volume, the removed plasma is replenished with an equal amount of replacement fluids. The typical replacement fluids are fresh-frozen plasma, 5% albumin or other plasma derivatives (e.g., cryosupernatant), and crystalloids (e.g., 0.9% saline, Ringer's lactate). The choice of fluid affects oncotic pressure, coagulation, efficacy of the procedure, and potential side effects. Albumin usually is preferred to plasma because of the risk of hypersensitivity reactions and transmission of viral infections with the latter. For some indications for which infusion of normal plasma may be beneficial (e.g., organophosphate poisoning), fresh frozen plasma is the preferred replacement solution. With poisons tightly bound to albumin, removal by plasmapheresis without replacement of albumin theoretically could increase its free fraction and may cause a transient resurgence of clinical toxicity. Similarly, in drugs that are highly bound to alpha-1-acid glycoprotein, such as quinidine, the combination of 5% albumin and fresh frozen plasma could be considered, although alpha-1-acid glycoprotein has a low binding capacity and there are no studies to confirm the clinical efficacy of this approach.

Comparisons With Other Extracorporeal Detoxification Methods

There are some advantages of plasmapheresis over other extracorporeal detoxification methods, such as hemodialysis and hemoperfusion. The removal of toxins by plasmapheresis is not dependent on the size of the molecule as is the case for hemodialysis. Plasmapheresis can remove a number of substances that are not removed effectively by either hemodialysis or hemoperfusion (e.g., protein-bound compounds), because it can clear albumin-poison complexes. Plasmapheresis also can remove active metabolites as well as unchanged drugs. Liver support devices have similar clearance properties as plasmapheresis ; however, it is not as frequently available and more expensive than plasmapheresis. Intoxications with substances with lower percentages of protein binding are best treated with hemodialysis (e.g., methanol, ethylene glycol) because the clearance attainable by hemodialysis is clearly superior. In addition, certain drugs that induce metabolic complications in poisoned patients are treated more appropriately with hemodialysis, which also corrects acid-base and electrolyte abnormalities associated with these poisons (e.g., aspirin). Therefore the choice of the extracorporeal detoxification modality clearly depends on the characteristics of the drugs or toxins implicated. Box 100.1 shows the characteristics of poisons/drugs that must be considered in the choice of the detoxification method, with specific indications for plasmapheresis.

Pharmacokinetic Considerations

As for any extracorporeal therapy used in poisoning, plasmapheresis should be considered only for drugs or toxins that have a prolonged half-life. For substances that are metabolized rapidly (i.e., have a high endogenous clearance), plasmapheresis is unlikely to accelerate the removal rate significantly (see Box 100.1 ). Furthermore, the additional clearance provided by plasmapheresis may be insufficient to induce clinical benefit.

The elimination of drugs or toxins by plasmapheresis is governed by several factors. The extracorporeal elimination efficiency of plasmapheresis for a given substance depends on the volume of distribution, protein binding, intercompartment equilibration, and exchange plasma volume. In addition, the time interval between ingestion and plasmapheresis initiation seems to be a crucial factor affecting its elimination. The ideal drug for removal by plasmapheresis is one that is highly protein bound, without restriction to molecular weight (MW), and a small volume of distribution. A large proportion of poisons have a MW in the 100 to 1000 Da range and are removable by other extracorporeal therapies. Some advocate that plasmapheresis is useful only when the plasma protein binding is greater than 80% to 95% and the volume of distribution is lower than 0.2 L/kg body weight. Examples include rituximab (MW = 145,000) and immunoglobulins such as IgM (MW = 925,000). Other examples include cisplatin, vincristine, and L-thyroxine. Liver support devices are available in some centers around the world and share similar clearance capacities (e.g., high level of protein binding) compared with plasmapheresis. The molecular adsorbent recirculating system (MARS) and single-pass albumin dialysis (SPAD) can clear molecules up to 60,000 Da, whereas the Prometheus system has a cutoff of approximately 200,000 Da. However, evidence supporting the efficacy of albumin dialysis in removing highly protein-bound poisons is even more limited.

Limitations of Published Reports

Several limitations complicate the interpretation of published reports that evaluated the efficacy of plasmapheresis in acute intoxication and poisoning. First, no randomized controlled trial has been carried out to determine the range of indications, potential benefits, and cost effectiveness of plasmapheresis in acute intoxication and poisoning. Most reports evaluating plasmapheresis efficacy are case reports or case series. Second, in most studies, patients were treated concurrently with hemodialysis and/or specific antidotes, rendering it difficult to evaluate the effect of plasmapheresis. Third, the majority of published studies failed to report important pharmacokinetic data to evaluate the efficacy of plasmapheresis to eliminate the drugs or toxins. For instance, most reports failed to report the total amount of the drug or toxin in the discarded plasma and the procedure's contribution to total drug clearance. The amount of drug removed in the discarded plasma is the best parameter evaluating drug removal, because plasma concentrations can be misleading. Therefore treatment recommendations on the use of plasmapheresis in acute poisoning and drug overdose are limited.

Efficacy of Plasmapheresis in Specific Intoxications

The treatment of poisoning with plasmapheresis has been reported for a number of agents ( Table 100.1 ).