In order for a patient to benefit from extracorporeal methods of elimination, the toxin must satisfy several conditions.
1. The apparent volume of distribution of the toxin should be limited(ideally no more than 1 l/kg body weight). Toxins with apparent volumes of distribution above 60 l/kg cannot be effectively removed by these methods, and those with intermediate values require prolonged therapy.
2. Protein binding should be limited.
3. There should be a positive relationship between plasma concentration and toxicity.
4. Elimination should follow a single-compartment model.
The choice of technique is based on equipment availability, patient characteristics (hemodynamic stability and renal function), and relative efficiency of the method. The mnemonic I STUMBLE (T§ble7) can be used to recall some agents for which extracorporeal elimination is of potential benefit. In the case of attendant renal failure, the choice is clearly in favor of hemodialysis. Hemoperfusion, using a coated charcoal filter, is superior to dialysis for phenobarbital and theophylline intoxication.
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table 7 A useful mnemonic for drugs susceptible to elimination by extracorporeal methods
In assessing hemoperfusion and/or hemodialysis from a biological standpoint, plasma or blood concentrations are often used as an indication of the efficiency of the process. Like clinical parameters, these may be misleading, as plasma and blood concentrations are frequently poorly representative of the total body burden of the toxin. Furthermore, the simple observation of evolving plasma concentrations fails to consider an often large (up to 80 per cent) concomitant hepatic clearance of the compound and the role of continuing absorption of the compound from the gastrointestinal tract.
Figure 1 illustrates how surveillance of blood or plasma concentrations may be misleading. Likewise, clearance data may be misleading. The meaning of plasma clearance in a specific intoxication is dependent on the apparent volume of distribution of the toxin, the protein binding, and alternative routes of elimination (other than kidney). For example, in intoxication by cyclic antidepressants, even though efficient plasma clearance may be obtained, the net result is minimal owing to their large apparent volumes of distribution which indicate a wide diffusion of the substance in the body. In addition, even with identical clearance over two equal periods of time, the portion of toxin cleared by extracorporeal elimination may vary tremendously depending on the contribution of extrarenal elimination (e.g. hepatic metabolism) of the product.
Fig. 1 Schematic representation of plasma drug concentrations after ingestion. The plasma concentrations of an ingested toxin are the sum of many factors, including absorption, distribution, metabolism, and excretion. Thus evaluation of efficacy of elimination methods by plasma concentrations is impractical. In time period A of this schematic curve, the concentration is strongly influenced by continued gastrointestinal absorption. Results obtained during this period may be erroneously interpreted as inadequacy of extracorporeal elimination. In time period B, the combination of ongoing absorption, distribution into various tissue compartments, and elimination results in a plateau effect. Results obtained during this period may be erroneously interpreted in either direction. In time period C, the elimination and metabolism of the drug predominate and plasma concentrations fall at a faster rate. Results obtained during this period may be erroneously attributed to efficacy of extracorporeal elimination.
A better approach to evaluating extracorporeal methods is measurement of the toxic agent in the dialysate (hemodialysis), or measurements of the concentration on the arterial and venous sides of the hemoperfusion filter multiplied by the blood flow across the system. In this way, a ratio of eliminated toxin to ingested dose can be calculated to assess efficiency. If the blood flow through the extracorporeal system is unknown, the toxicokinetics of the product can be compared with its spontaneous pharmacokinetics.
Hepatic clearance of drugs for which plasma and urine concentrations are available and reliable may be calculated, based on the formula for apparent volume of distribution (Fig 2).
Fig. 2 Calculation of hepatic clearance. The relationship of drug quantity in the body to to its blood concentration is
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