Because of modern medical approaches mortality from poisoning is low. However, severe poisoning in certain groups of patients is associated with a high mortality: poisons with toxic metabolites (eg, methanol, ethylene glycol, and acetaminophen), poisons inducing metabolic changes (eg, salicylates), and poisons that produce deep coma (eg, phenobarbital). This chapter will discuss the role of forced diuresis and modern dialysis techniques used to treat poisoning, and will give the clinician guidance in the appropriate use of these treatments applied to drug or chemical intoxication. We will use real case reports to illustrate these points.

The cumulative American Association of Poison Control Center (AAPCC) database now contains 33.8 million human poison exposures. During 2003, 2,395,582 human exposures were reported by 64 participating poison centers, reflecting an increase of 0.7% compared to the 2002 AAPCC report, and an increase of 10.5% over the exposures reported in 2000. Although the majority of cases were managed at home, in 2003, 525,710 cases required treatment in a health care setting and 1106 patients died; 134,619 patients were treated with single dose activated charcoal, 7875 were treated by alkalinization, 1509 received hemodialysis, and 27 received hemoperfusion.

One method of removing toxins from the body is the administration of multiple doses of activated charcoal. Charcoal given acutely decreases the absorption of toxins from the gastrointestinal tract, but has also been recommended in repeated doses in the hope of trapping toxic substances from the enterohepatic recirculation. However, although there is some experimental evidence that this mode of therapy can decrease the half-life of many xenobiotics, there are only a few toxic substances for which multidose charcoal administration has been shown to be effective. According to the American Academy of Clinical Toxicology, these include carbamazepine, dapsone, phenobarbital, quinine, and theophylline. One recent study in volunteers suggests that repeated doses of superactivated charcoal may have some detoxification benefit up to 3 hours after acetaminophen ingestion. However, two other volunteer studies conclude that multidose activated charcoal may not be effective more than 1 hour after acetaminophen overdose. Multidose activated charcoal has also been reported to reduce death and serious arrhythmias in yellow oleander poisoning (Table 59–1).

Many substances are eliminated by the kidneys if they are filtered and not reabsorbed or if they are actively secreted by the tubules into the urine. Filtration occurs freely for smaller molecules (<5000 Da) that are not highly bound to plasma proteins such as albumin. Phenobarbital is such a substance. For such substances to be excreted effectively, they must remain largely in the tubular fluid as they traverse the nephron.

If a substance is cleared by filtration and kidney function is good, it is important to maintain that level of function in order to continue elimination of that substance. It is therefore crucial to support the patient’s extracellular fluid volume by giving appropriate intravenous saline, ie, to maintain a good diuresis. However, the concept of overhydrating a patient to “force” a diuresis has not been shown to be of benefit in poisoning and risks overloading the left ventricle. Repletion and maintenance of extracellular volume are always indicated, especially in salicylate poisoning, where there is usually a loss of about 2 L in the adult. The patient should be monitored for signs of volume overload or depletion.

The natural ability of the kidneys to clear the blood of many substances is also enhanced by the kidneys’ secretion of substances into the urine. The tubules take up many xenobiotics that circulate in plasma, even if they are bound to proteins, and move them into the lumen to be excreted. There are separate transport pathways for anions (such as penicillin) and cations (such as gentamicin).

Renal excretion of a particular xenobiotic can be increased if there is a form of the substance that is less readily reabsorbed back into the blood from the tubular lumen. Many drugs and toxins are weak acids or bases that diffuse back into tubular cells in their neutral form but are poorly absorbed as anions or cations. For this reason, if the pH of the urine can be maintained such that the nonreabsorbable ionized form is favored, there will be greater net excretion of that substance (Table 59–2). In general, anionic substances (such as salicylate) are best excreted at a higher urine pH (above 7), whereas cationic drugs (such as phencyclidine) are best excreted at a low urine pH (below 5.5). This phenomenon is called “diffusion trapping.” It is seen in the case of urinary ammonium, which is the main route of renal hydrogen ion excretion. Ammonia freely diffuses from the tubular lumen into the cells and the blood. However, in the relatively acid urine pH, most of the ammonia takes up hydrogen ions, and the resultant ammonium ion is trapped in the tubular lumen to be readily excreted.

However, the clearance of many drugs and chemicals is not substantially increased by this maneuver. Not all ionizable substances have their excretion enhanced by manipulation of urine pH. This is usually because their volume of distribution Vd is high (Table 59–3). Substances that remain exclusively (or nearly so) in total body water will have a lower Vd than those with a high affinity for lipid or protein and that appear to dissolve in a much greater quantity of water than their plasma levels indicate (digoxin is a good example). Adjusting the urine pH is effective only if the Vd is low and if an altered urine pH has actually been shown to be effective in enhancing removal of the toxin.

In the case of xenobiotics that are weak bases, such as phencyclidine, no advantage has been shown in acidifying the urine to enhance the drug’s excretion. Acidifying the blood in an attempt to accomplish this leads to metabolic acidosis, which can worsen the patient’s condition. On the other hand, renal excretion of a number of weak acids is markedly enhanced by urinary alkalinization (Table 59–4). Of these, the most important is salicylate, whose excretion can be quadrupled if the urinary pH is 7.5 or above. It is unclear, however, why this is so, since the pKa for salicylic acid is 3.0. At a urine pH of 6.0, 99.9% of the salicylate should already be ionized and therefore not reabsorbed. Mechanisms other than diffusion trapping may explain the enhanced salicylate excretion at higher urine pH.

In the past, the Done nomogram has been used to estimate the toxicokinetics of salicylate in moderate to severe overdoses. Some clinicians use this nomogram to calculate the endogenous clearance of salicylate. Unfortunately, the Done calculations were established in children and assume first-order kinetic clearance of salicylate from the body, in which the excretion of a drug is proportional to the concentration of that drug in body fluids. In fact, in severe salicylate poisoning, several elimination pathways for the drug become saturated, and the clearance becomes zero order, ie, there is a constant rate of drug removal per time, independent of concentration.

The renal excretion of two herbicides, 2,4-dichlorophenoxyacetic acid (2,4-D) and mecoprop, is also increased at a higher urine pH. Alkalinizing the urine may also help to eliminate overdoses of methotrexate. The excretion of phenobarbital and chlorpropamide is also augmented by urinary alkalinization, but this is rarely useful since the former is better eliminated by multidose activated charcoal and the latter usually responds to supportive care with glucose infusion (Table 59–2).

Many substances can be removed by hemodialysis and hemoperfusion.

Principles of Dialysis in Relationship to Drug Removal

These principles have been discussed elsewhere in this book. Factors governing drug removal are solute (or drug) size, its lipid–water partition coefficient (or lipid solubility), the degree to which it is protein bound, its volume of distribution, and the presence of a concentration gradient promoting constant removal of the drug or chemical moiety. The physical factors governing drug removal by the dialyzer are blood flow rate through the dialyzer, dialysate flow rate, dialyzer surface area, and the characteristics of the specific membrane.

For drugs (usually about 300 Da) that are diffusible across semipermeable membranes solute removal rates (clearance) increase with increasing blood flow rate. For solutes greater than 300 Da, the rate of diffusion across the membrane is less, the concentration gradients across the membrane remain high, and increasing flow rates have a decreased effect on drug clearance rates. For larger drugs, the removal rate can be increased by increasing the surface area or by choosing a high permeability membrane. The latter is the preferred method.

Clearance

Clearance of drugs and chemicals follows the same principle as that used to calculate solute clearance by the kidney. Clearance is given by the following formula: Clearance = Qb[(A − V)/A] where A is arterial or inlet concentration and V is venous or outlet concentration of the drug going through the dialyzer and Qb is the blood flow rate through the dialyzer. The ratio A − V/A is the drug extraction ratio (ER) across the dialyzer.

Hemodialysis

The procedure for hemodialysis in poisoning is identical to that used in a Stage V chronic kidney disease (CKD) patient with one or two exceptions.