Chapter 59. Poisonings & Intoxications

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.

In a drug intoxicated hypotensive patient who requires pressor agents to maintain an adequate blood pressure, if pressors are administered through the dialysis blood lines they should be placed distal to the drug-removing device since they are readily removed through the hemodialysis membrane or sorbent. Pressor requirements may need to be increased during the procedure even if pressors are administered in a completely separate line for the same reason.

If dialysate regeneration systems using a sorbent system (the REDY system) are used in the treatment of patients who have been poisoned, there is the theoretical risk of sorbent saturation, and drug removal rates may decrease over time.

Sorbent Hemoperfusion

Hemoperfusion was quite popular for the treatment of poisoning in the 1970s and 1980s. Currently in the United States activated charcoal hemoperfusion devices, but not resin hemoperfusion devices, are available for clinical use.

Certain resins have been shown to be most effective for removal of lipid-soluble drugs, with drug clearance rates from blood often exceeding those achieved by charcoal hemoperfusion; these are available in Europe. A partial list of the available hemoperfusion devices is given in Table 59–5. Hemoperfusion relies on the physical process of adsorption. For many drugs clearance was better than with hemodialysis. The hemoperfusion circuit for treatment of drug intoxication can but need not be combined with dialysis in certain situations (particularly when there is a serious acidosis shown to be corrected by bicarbonate dialysate). The manufacturers Instructions for Use should be followed since some devices come “dry” and others need to be flushed with saline, and heparinization protocols differ. The most efficient drug removal is achieved with blood flow rates of approximately 300 mL/minute. Even in the hypotensive patient lower blood flow rates achieve significant drug removal.

Removal of lipid-soluble drugs, such as glutethimide and methaqualone, was far more efficient with XAD-4 resin hemoperfusion than with activated charcoal. Modern dialyzers with high permeability may be of greater efficiency than those used in the 1970s and 1980s, and a reappraisal of dialysis versus charcoal hemoperfusion in poisoning may be called for (see Case 3 below). However, the spectrum of drugs taken in overdose situations in the twenty-first century is quite different from that used in the late twentieth century, and studies to reexamine drugs that are obsolete may never be done.

Complications of Hemoperfusion

The principal side effect of hemoperfusion with charcoal or resin preparations is platelet depletion of about 30% or greater, which may or may not give rise to clinical bleeding problems. Reductions in serum calcium and serum glucose and transient decreases in white blood cell counts, usually mild, may be seen. A mild reduction of 1–2°F in body temperature is expected, due to no rewarming in the extracorporeal circuit, and frequent body temperatures should be taken in deeply comatose patients. The decreases in platelet concentration usually return to normal within 24–48 hours following a single hemoperfusion.

Criteria for Hemodialysis in Poisoning

The prime consideration in the decision to employ extracorporeal techniques to remove poisons is based on the clinical features of poisoning, particularly if the patient's condition deteriorates progressively despite intensive supportive therapy.

Suggested clinical criteria are outlined in Table 59–6. These criteria should be used along with the plasma concentrations of common drugs (Table 59–7), above which hemodialysis or hemoperfusion should be considered. Table 59–8 lists the reported dialyzable drugs; many of these reports are single case reports, since it has been difficult to undertake controlled studies. In addition, it cannot be overstated that a large number of these reports are anecdotal, but critical review of drug removal rates indicates that those drugs not enclosed in parentheses are most efficiently removed. For further information see Aronoff et al (1999).

Hemoperfusion & Hemodialysis with Chelating Agents

In patients on dialysis, aluminum and iron intoxication can be treated with deferoxamine in conjunction with dialysis (continuous ambulatory peritoneal dialysis or hemodialysis) or hemoperfusion for removal of the deferoxamine–aluminum or deferoxamine–iron complex. Clinical improvement in the osteomalacia component of renal osteodystrophy is seen after aluminum is removed. Encephalopathy, iron overload, and anemia also improve.

Heavy metals and their salts are not removed efficiently by dialysis or hemoperfusion alone. During hemodialysis, metal removal may be enhanced with chelating agents, such as N-acetylcysteine or cysteine. On the other hand, removal of mercury and thallium by hemoperfusion appears modest at best.

Digoxin antibodies, specifically the Fab fragments, neutralize digoxin and reduce any toxicity. Recrudescence of digoxin poisoning has been reported 24–48 hours after administration of Fab antibodies in renal failure patients. In a kinetic analysis of elderly and renally impaired patients with digoxin and digitoxin poisoning, it was suggested that the dose of Fab antibodies should be the same as for young patients or those with normal renal function. In digoxin poisoning the elimination halftime of digoxin in anephric patients can be substantially reduced with the addition of hemoperfusion.

Case 1: Methanol Intoxication

A 32-year-old male with no significant past history drank a bottle of windshield washer fluid as he was being arrested in an attempt to avoid going straight to jail. He was promptly brought to the emergency department where he was evaluated. His only symptom at the time was nausea without vomiting. He denied chest pain, dyspnea, headache, diaphoresis, and visual disturbances. His blood pressure (BP) was 146/86 mm Hg, temperature (T) 98.7°C, pulse (P) 106 and regular, and respiration (R) 14 rpm. Examination of the head, eyes (including fundi), neck, lungs, heart, chest, abdomen, nervous system, and extremities was entirely normal.

Laboratory data showed serum osmolality 390 mOsm/kg, Na 138 mEq/L, K 6.3 mEq/L, Cl 99 mEq/L, CO2 23 mEq/L, blood urea nitrogen (BUN) 11 mg/dL, creatinine 0.8 mg/dL, and glucose 96 mg/dL. Urinalysis was normal; the methanol level was 227 mg/dL.

The patient was begun promptly on intravenous ethanol and subsequently given fomepizole. The following day he had pH 7.376, Pco2 44.2, Po2 86.9, and HCO3 25.3. His ethanol level was 159.9 mg/dL. Hemodialysis was performed and the methanol level fell to 59 mg/dL. By the following day it had rebounded to 90 mg/dL and a second hemodialysis was performed on day 3, with the methanol level falling to 28 mg/dL. At no time during the hospitalization was the patient significantly acidotic, and his ophthalmologic examination remained normal. He was discharged asymptomatic to jail on the fifth hospital day. This case illustrates that prompt inhibition of alcohol dehydrogenase can entirely prevent both the life-threatening acidosis and the ocular complications. The use of fomepizole eliminates the need for continual monitoring of the patient's ethanol level, which was formerly necessary when ethanol was the only available alcohol dehydrogenase blocker; however, giving fomepizole does not obviate the use of hemodialysis. The course of hospitalization can be considerably shortened by dialyzing out the methanol, even if a second procedure is necessary. Furthermore, if acidosis has set in, dialysis quickly corrects it. In cases of severe methanol intoxication, as in this case, dialysis may avoid the need to give a second dose of fomepizole.

Case 2: Ethylene Glycol Poisoning

A previously healthy 28-year-old man was hospitalized 3 hours after drinking 280 mL of antifreeze containing 95% ethylene glycol. He was tremulous and agitated but not obviously intoxicated. His BP was 137/88 mm Hg, T 98.8°F, P 88 bpm, and R 24 rpm. His head, eyes, neck, lungs, heart, abdomen, neurologic system, and extremities were all normal.

Laboratory data showed serum osmolality 362 mOsm/kg, Na 146, K 4.5, Cl 110, and CO2 11. BUN was 10 mg/dL and creatinine 1.1 mg/dL. Arterial pH was 7.17, Pco2 26, and Po2 105. The serum ethylene glycol level was 303 mg/dL. The urine had no protein, glucose, or cells, but contained numerous envelope- and needle-shaped crystals. The patient was loaded with saline and ethanol and was subsequently hemodialyzed. At no time did the patient show any decrease in renal function. Timed collections of blood and urine for ethylene glycol were performed before and after hemodialysis. Endogenous renal clearance of ethylene glycol was 27.5 mL/minute, while hemodialysis clearance of ethylene glycol was 136.6 mL/minute. By 30 hours after ingestion the patient's ethylene glycol level was zero. The patient was discharged after 72 hours with no target organ damage from the ingestion. This case illustrates that prompt administration of an alcohol dehydrogenase blocker (ethanol or fomepizole) can prevent injury to the kidneys, heart, and brain; hemodialysis clearance of ethylene glycol is about five times greater than the endogenous clearance of the toxin; and because it is so much more efficient, hemodialysis is an important means of rapidly reducing the amount of ethylene glycol and its metabolites in the body and can substantially shorten the hospital stay.

Case 3: Aluminum Intoxication

A 75-year-old female was admitted from another hospital 8 days following irrigation of the bladder with a 1% alum solution (aluminum potassium sulfate) for intractable hemorrhagic cystitis. Her mental status had been impaired from postirrigation day 3 and a serum Al drawn on day 3 was reported 5 days later to be 423 μg/L. Six hours after a 500 mg infusion of deferoxamine she was dialyzed for 4 hours using a 2 M2 high-flux dialyzer for 4 hours. Because of past reports that charcoal hemoperfusion was superior to hemodialysis, she was treated on day 2 with a 4 hour hemoperfusion 6 hours after the same dose of deferoxamine. Total (chelated and nonchelated) Al extraction by the devices was calculated. Although starting at a lower extraction ratio than hemoperfusion (20% versus 38%), hemodialysis had an average extraction ratio of 24% versus an average of 16% because of saturation of the hemoperfusion device (extraction was only 5% at 2 and 4 hours). In addition, the patient had no changes in platelets during hemodialysis, but profound thrombocytopenia after hemoperfusion. The patient was subsequently treated with chelation and hemodialysis alone. This illustrates the need to reappraise older literature in light of improvements in dialysis.

Case 4: Salicylate Poisoning

A 22-year-old college student was found wandering in the residence hall. She was examined at the student health center where she was found to be irritable, confused, tachypneic, and mildly hypotensive. Her roommate called the student health center to report that the patient had just broken up with her boyfriend, and that she had found some pills lying on the bathroom floor and an empty aspirin container. This prompted transfer of the patient to a tertiary care center where she was found to be acidemic (pH 7.24) and hypokalemic, with a salicylate concentration of 75 mg/dL. Shortly after admission it was noticed that she was somnolent. This prompted admission to the medical intensive care unit where hemodialysis was performed via a femoral vein catheter. Within 2 hours her acidosis had improved (pH 7.34) and the salicylate concentration was 35 mg/dL and by 4 hours her pH was 7.4 and the salicylate concentration was 20 mg/dL. Dialysis was discontinued. This case illustrates that central nervous system (CNS) changes in the presence of acidemia reflect CNS trapping of salicylate and an urgency to correct the pH with bicarbonate dialysate and that salicylate is an ideally dialyzable drug (although protein binding is high, the bond is weak and the molecule traverses dialysis membranes easily).