Enhanced elimination of poisons

INTRODUCTION — Management of the poisoned patient begins with a thorough evaluation, recognition that poisoning has occurred, identification of the agent(s) involved, assessment of severity, and prediction of toxicity. Therapy involves the provision of supportive care, prevention of poison absorption, and, when appropriate, the use of antidotes and other interventions to enhance elimination of the poison.

Methods to enhance the rate of elimination of poisons following a toxic ingestion are reviewed here. General issues regarding the management of toxic ingestions, specific issues related to gastrointestinal decontamination and gastric emptying, and the diagnosis and management of specific poisonings are discussed separately:

●General poisoning (see "General approach to drug poisoning in adults" and "Initial management of the critically ill adult with an unknown overdose" and "Approach to the child with occult toxic exposure")

●Gastrointestinal decontamination (see "Gastrointestinal decontamination of the poisoned patient")

●Select poisonings (see "Acetaminophen (paracetamol) poisoning: Management in adults and children" and "Salicylate (aspirin) poisoning: Clinical manifestations and evaluation" and "Methanol and ethylene glycol poisoning: Management" and "Lithium poisoning" and "Carbamazepine poisoning" and "Valproic acid poisoning" and "Gabapentinoid poisoning and withdrawal" and "GABA-B agonist (baclofen, phenibut) poisoning and withdrawal" and "Barbiturate (phenobarbital) poisoning")

GENERAL INDICATIONS AND CONTRAINDICATIONS — Enhanced elimination techniques can accelerate removal of a toxin, but few studies have investigated whether they actually shorten the duration of clinical toxicity and/or improve clinical outcomes. The main methods of enhancing the elimination of toxins are listed in the table (table 1).

General indications for enhanced elimination techniques include:

●Ingestion of a poison whose elimination can be enhanced.

●Failure of a patient to respond to maximal supportive care.

●The clinical course is predicted to be complicated based on the nature and/or concentration of the toxin, impaired clearance of the toxin, comorbid illness, concomitant severe electrolyte or other laboratory derangements that can be corrected with enhanced elimination, or some combination of these elements.

In all cases, the expected benefits of the use of an enhanced elimination technique must be carefully weighed against the risk of potential complications associated with the technique.

MULTIPLE-DOSE ACTIVATED CHARCOAL — Multiple-dose activated charcoal (MDAC) is a commonly used method for enhancing the elimination of toxins and may play an important role in specific poisonings. MDAC and other methods for gastrointestinal decontamination are discussed in detail separately. (See "Gastrointestinal decontamination of the poisoned patient", section on 'Multidose activated charcoal'.)

URINARY ALKALINIZATION

General concepts and mechanism — The urinary excretion of some drugs can be enhanced by altering the urine pH [1,2]. Altering the pH converts a lipid-soluble intact acid (HA) or base (BOH) in the tubular lumen into the charged salt (A- or B+):

The charged particle is lipid-insoluble and cannot easily move back across the renal epithelium. This leads to a marked increase in drug excretion.

Raising the urine pH to 7.5 to 8.0 in patients poisoned with weak acids (such as salicylates and phenobarbital) will drive the first reaction to the right, producing the desired increase in concentration of the charged salt (A-). Importantly, phenobarbital is the only barbiturate for which alkalinization is indicated, as short-acting barbiturates are metabolized in the liver, not eliminated via the kidney [3,4].

Urinary acidification (urine pH below 5.5) with ammonium chloride or ascorbic acid was used in the past to treat intoxications with weak bases such as amphetamines, quinidine, or phencyclidine. However, this practice has been abandoned, as efficacy has not been established and iatrogenic toxicity (from severe acidemia) can occur.

Indications and efficacy — Drugs that are likely to respond to urinary alkalinization usually meet four criteria [4,5]:

●They are predominantly eliminated unchanged by the kidney

●They are distributed primarily in the extracellular fluid compartment

●They are minimally protein-bound

●They are weak acids with pKa ranging from 3.0 to 7.5

Urinary alkalinization may be useful for helping to eliminate drugs listed in the following table (table 2). Diuresis with an isotonic fluid may enhance elimination of drugs listed here: (table 3)

The clinical course of phenobarbital-poisoned patients may be improved by the use of urinary alkalinization [2,6]. One study of 16 phenobarbital-poisoned patients found that the concomitant use of both urinary alkalinization and MDAC doubled the rate of elimination and shortened the period of unconsciousness by up to 50 percent compared with patients receiving supportive care alone [2]. No comparable data exist showing improved clinical outcomes with the use of urinary alkalinization in other types of poisoning [5].

Urinary alkalinization is the most effective single method short of hemodialysis to enhance salicylate excretion, producing a mean elimination half-life of 5 hours versus half-lives of 8 and 19 hours in patients treated with isotonic saline solution diuresis or standard supportive care, respectively [7]. (See "Salicylate (aspirin) poisoning: Management", section on 'Serum and urine alkalinization'.)

Technique — The goal of urinary alkalinization is to achieve a urine pH of 7.5 or higher while maintaining a serum pH no higher than 7.55 to 7.6. This is generally done by administering an intravenous (IV) bolus of 1 to 2 mEq/kg of 8.4 percent sodium bicarbonate, followed by continuous infusion of sodium bicarbonate. The fluid for continuous infusion is mixed by diluting 150 mEq of sodium bicarbonate into one liter of 5 percent dextrose in water (D5W). Prior to the initiation of therapy, baseline measurements of electrolytes, blood urea nitrogen, serum creatinine, glucose, systemic pH, urinary pH, and serum drug concentrations should be performed. Placement of a Foley catheter is recommended to accurately measure urine output.

Some hospitals have experienced shortages of sodium bicarbonate. In such cases, sodium acetate may be used as a substitute [8]. Boluses of sodium acetate are potentially dangerous and should not be given. For use in poisoned patients, sodium acetate 1 mEq/kg body weight is administered IV over 15 to 20 minutes, followed by an infusion at twice the maintenance rate. As with sodium bicarbonate, the fluid for continuous infusion is mixed by diluting 150 mEq of sodium acetate into 1 liter of D5W. All other baseline laboratory measurements and precautions should be observed as above.

Adults — After initial fluid resuscitation with isotonic 0.9% saline or Lactated Ringer solution and intravenous bolus of sodium bicarbonate, the sodium bicarbonate continuous infusion should be administered at approximately 200 to 250 mL/hour. The rate should be titrated based on the urinary and systemic pH, which should be monitored throughout treatment. Intravenous fluid should be adjusted to maintain a urine pH ≥7.5 and serum pH <7.60.

Children — After initial fluid resuscitation with isotonic 0.9% saline or Lactated Ringer solution and intravenous bolus of sodium bicarbonate, the sodium bicarbonate continuous infusion should be administered at approximately 1.5 times maintenance fluids. The rate should be titrated to maintain a urine pH ≥7.5. Increases in serum pH up to 7.60 are well tolerated in patients with normal renal function. Subsequent fluid administration should be based on urine output and ongoing losses. (See "Maintenance intravenous fluid therapy in children".)

Acetazolamide should not be used to alkalinize the urine. Acetazolamide raises urine pH and lowers systemic pH, which may cause clinical deterioration in some cases. Close monitoring of blood and urine pH, electrolytes, respiratory status, and urine output is important when diuresis and urinary alkalinization procedures are performed. (See "Salicylate (aspirin) poisoning: Clinical manifestations and evaluation", section on 'Pediatrics' and "Salicylate (aspirin) poisoning: Management".)

Contraindications — Urine alkalinization is contraindicated in patients with established or incipient kidney failure, pulmonary edema, and cerebral edema. In addition, volume overload may complicate therapy in patients with preexisting cardiac disease [4].

Complications — Complications of alkalinization include hypokalemia, excessive alkalemia, and ionized hypocalcemia, which results from increased protein binding of calcium. The administration of 20 to 40 meq/L (mmol/L) potassium chloride may be required if the plasma potassium concentration falls during urinary alkalinization. Monitoring and repletion of ionized calcium is recommended to prevent a deterioration in cardiac function.

EXTRACORPOREAL REMOVAL — Extracorporeal treatment (ECTR) of poisonings entails the use of a heterogenous group of modalities to promote removal of a toxicant and to support or temporarily replace the function of a vital organ. ECTR modalities include hemodialysis, hemoperfusion, hemofiltration, hemodiafiltration, therapeutic plasma exchange, exchange transfusion, and peritoneal dialysis. ECTR modalities are used in only 0.1 percent of poisonings [9,10].

Since 2012, expert and evidence-based consensus recommendations for ECTR for a number of poisons have been published by the Extracorporeal Treatments in Poisoning (EXTRIP) workgroup. This group of international experts principally recommend hemodialysis as the preferred ECTR for severe poisoning from long-acting barbiturates, ethylene glycol, methanol, lithium, metformin, salicylate, theophylline, thallium, and valproic acid; and recommend against ECTR for poisoning from cyclic antidepressants, calcium channel blockers, digoxin, methotrexate, propranolol, chloroquine, hydroxychloroquine, and quinine [11-28]. Per this workgroup, ECTR is suggested for select cases of severe acetaminophen, carbamazepine, and isoniazid poisoning and may be reasonable for severe phenytoin toxicity [15,21,23,25,29]. As of 2021, this workgroup has added recommendations for ECTR for patients with severe toxicity from gabapentinoids (eg, gabapentin, pregabalin), sotalol, atenolol, and baclofen who also have concurrent kidney impairment [30-32]. Details about ECTR and other aspects of management for these toxicants are found in the UpToDate topics devoted to the poisoning in question.

Hemodialysis and hemoperfusion — Although rarely necessary for the care of poisoned patients, hemodialysis is used in greater than 95 percent of patients in whom extracorporeal treatment (ECTR) is employed to enhance poison elimination [33-35]. During hemodialysis, up to 400 mL of blood per minute passes through an extracorporeal circuit in which toxic compounds in blood diffuse through a semipermeable membrane down a concentration gradient into a dialysate. Electrolyte disturbances and metabolic acidosis induced by certain drugs also can be readily corrected with this intervention. (See "Kidney replacement therapy (dialysis) in acute kidney injury: Metabolic and hemodynamic considerations".)

Hemoperfusion refers to the circulation of blood through an extracorporeal circuit containing an adsorbent such as activated charcoal or polystyrene resin. In contrast to hemodialysis circuits, hemoperfusion devices contain thin, highly porous membranes and adsorbents that provide a large surface area to directly bind toxins [36]. Clearance rates are higher with hemoperfusion than hemodialysis if the adsorbent binds the ingested toxin; the extraction ratio for hemoperfusion approximates 1.0 for some poisons, and drug clearance rates approach the rate of blood flow through the hemoperfusion circuit. The use of hemodialysis or hemoperfusion for the treatment of specific poisonings is discussed in the topics devoted to those toxins.

Intermittent hemodialysis remains the first choice ECTR, rather than continuous renal replacement therapy (CRRT), due to its greater speed removing toxin in the early stages of treatment, when minimizing toxin exposure and distribution is critically important. In addition, hemodialysis is still more widely available worldwide and less costly than CRRT [34,37,38]. The use of CRRT is discussed separately. (See 'Continuous renal replacement therapy (hemofiltration)' below.)

Peritoneal dialysis is much less effective than hemodialysis or hemoperfusion, and is rarely, if ever, indicated in the care of poisoned patients.

Efficacy — Hemodialysis is most useful in removing toxins with the following characteristics:

●Low molecular weight (<500 daltons)

●Small volume of distribution (<1 L/kg)

●Low degree of protein-binding

●High water solubility

●Low endogenous clearance (<4 mL/minute per kg)

●High dialysis clearance relative to total body clearance.

The utility of hemodialysis and hemoperfusion is limited when the drug is not concentrated in the extracellular fluid because of high lipid solubility and/or tight tissue binding. These characteristics are present with tricyclic antidepressants, digoxin, and calcium channel blockers. (See "Tricyclic antidepressant poisoning" and "Digitalis (cardiac glycoside) poisoning" and "Calcium channel blocker poisoning".)

Hemodialysis removes the toxic metabolites of methanol and ethylene glycol, corrects acid-base abnormalities, and reduces end-organ sequelae and mortality associated with these poisonings [36,39-41]. Although hemodialysis clears ethylene glycol and methanol efficiently, hemodialysis is not commonly indicated when acidosis is not present, as fomepizole effectively blocks the activation of these alcohols to the toxic acidic species [42,43]. Treatment with hemodialysis early in the course of care may be prudent and cost effective for methanol-poisoned patients that present with high serum concentrations but no acidosis because endogenous clearance of methanol in those treated with fomepizole is slow. (See "Methanol and ethylene glycol poisoning: Pharmacology, clinical manifestations, and diagnosis".)

Hemodialysis substantially increases the rate of elimination of isopropanol, salicylates, theophylline, and lithium, although data regarding clinical end points are sparse [36,44-47]. A 2015 systematic review supports the use of hemodialysis to remove metformin in cases of overdose [11]. (See "Isopropyl alcohol poisoning" and "Salicylate (aspirin) poisoning: Clinical manifestations and evaluation" and "Theophylline poisoning" and "Lithium poisoning".)

Drugs adsorbed by activated charcoal can be extracted by hemoperfusion, and the rate of removal may exceed that achieved with hemodialysis. The extraction ratio of theophylline with hemodialysis, for example, is approximately 50 percent as compared with 99 percent at the beginning of hemoperfusion (before the cartridge becomes saturated). As the extraction ratio only reflects the percent removal of drug presented to the dialysis membrane or hemoperfusion cartridge; these techniques remove only a small fraction of body load of drugs with large stores. (See "Theophylline poisoning".)

High extraction ratios and clearance rates, however, do not necessarily predict improved clinical outcomes. No controlled clinical studies in poisoned patients have been performed to determine if hemoperfusion reduces morbidity or mortality as compared with supportive measures. Evidence of clinical effectiveness for hemoperfusion is based upon favorable pharmacokinetic data, animal studies, anecdotal case reports, case series, and uncontrolled retrospective studies. Three clinical studies have retrospectively compared hemoperfusion with supportive care for poisoning from a variety of drugs, but do not allow firm conclusions to be drawn regarding the relative efficacy of different management strategies [48-50].

Indications — When intoxication has occurred with a drug whose hemodialysis clearance is significantly greater than endogenous clearance, the use of hemodialysis may be necessary if the patient's condition progressively deteriorates, or when measured drug concentrations are predictive of a poor outcome without hemodialysis [36]. Practically, hemodialysis is indicated for a limited number of poisonings (table 4).

Hemoperfusion may be considered for use in severe poisoning from the toxins listed in the following table (table 5). It is significantly more effective than hemodialysis in enhancing the clearance of theophylline but is associated with a higher complication rate and is not available at most medical centers [51]. If hemoperfusion is available, it is preferred over hemodialysis in these specific agents, but hemodialysis is an acceptable alternative.

Contraindications — Hemodialysis and hemoperfusion normally require systemic anticoagulation with heparin, and patients with active hemorrhage, severe thrombocytopenia, or coagulopathy may not be candidates for these procedures. However, when appropriate, hemodialysis can be performed without anticoagulation. Hemodialysis and hemoperfusion also may not be feasible in hypotensive patients. (See "Anticoagulation for the hemodialysis procedure" and "Intradialytic hypotension in an otherwise stable patient".)

Technique — Hemodialysis and hemoperfusion require central venous access with a double lumen catheter. Acute vascular access for hemodialysis or hemoperfusion is best accomplished with femoral catheters, which can be rapidly and safely inserted. Subclavian catheterization can also be used; however, there is a risk of pneumothorax or hemothorax, and therapy may be delayed because of the necessity for radiographic confirmation of proper catheter placement. The duration of these procedures for poisoned patients is usually four to eight hours but should be governed by the clinical response and serum drug concentrations. (See "Central venous catheters for acute and chronic hemodialysis access and their management" and "Dialysis-related factors that may influence recovery of kidney function in acute kidney injury (acute renal failure)".)

Complications — Potential side effects of hemodialysis include hypotension, bleeding due to anticoagulation, hypothermia, air embolus, and complications that may result from obtaining central venous access (table 6). Hemoperfusion has these same complications but also poses potential risks of charcoal embolization, hypocalcemia, hypoglycemia, leukopenia (10 percent reduction), and thrombocytopenia (30 percent reduction).

Continuous renal replacement therapy (hemofiltration) — CRRT has gained acceptance as an alternative to hemodialysis and is commonplace in intensive care unit settings. CRRT includes four methods of continuous hemofiltration [52]:

●Continuous veno-venous hemofiltration (CVVH)

●Continuous veno-venous hemodiafiltration (CVVHD)

●Continuous arterio-venous hemofiltration (CAVH)

●Continuous arterio-venous hemodiafiltration (CAVHD)

To perform CRRT, blood is pumped by the patient's own arterial (CAVH) or venous (CVVH) pressure, or by a hemodialysis machine entrained in the circuit (CAVHD, CVVHD). Blood that enters the hemofiltration circuit passes through filters (sheet membrane or hollow fiber) with large pores, and an ultrafiltrate forms, which drags solutes with molecular weights up to 50,000 daltons (depending upon hemofilter pore size). Cells and solutes larger than the pore size remain in the blood and return to the circulation.

In contrast to hemodialysis or hemoperfusion, CAVH is driven by the patient's own blood pressure and so can be run continuously. The rate of fluid removal, which is equivalent to the plasma clearance of drug, can exceed 100 mL/hour; thus, fluid replacement is an essential component of the hemofiltration regimen. Hemofiltration is most often performed as CVVH or CVVHD, rather than CAVH or CAVHD.

In general, CRRT has lower clearance rates than conventional hemodialysis. The advantages of CRRT are its applicability in hemodynamically unstable patients and its ability to be set up and delivered by regular intensive care unit staff [37]. Data about drug removal using CRRT are limited [53]. Hemofiltration has been used to enhance elimination of aminoglycosides, vancomycin, and metal chelate complexes, but the technique does not remove highly protein-bound drugs effectively [54]. It may also be of benefit for intoxications with drugs that have a large volume of distribution, tight tissue binding, or slow intercompartmental transfer (such as procainamide) [37]. (See "Drug removal in continuous kidney replacement therapy".)

Complications of hemofiltration include clotting of the filter and bleeding due to the standard use of heparin (or citrate or alternative methods of anticoagulation). Fluid and electrolyte losses from the ultrafiltrate must be replaced continuously.

EXCHANGE TRANSFUSION — Exchange transfusion refers to the removal of a quantity of blood from a poisoned patient and its replacement with an identical quantity of whole blood; the process is usually repeated two to three times. Exchange transfusions are rarely indicated but may be useful in the treatment of massive hemolysis (eg, due to arsine or sodium chlorate poisoning), severe methemoglobinemia, severe sulfhemoglobinemia (eg, secondary to hydrogen sulfide exposure), or neonatal drug toxicity. Complications of the technique include transfusion reactions, ionized hypocalcemia, and hypothermia [55]. (See "Massive blood transfusion".)

ALTERNATIVE METHODS — Other methods of poison treatment that function, in part, to enhance elimination of toxicants include: whole-bowel irrigation, plasmapheresis, cerebrospinal fluid removal, hyperbaric oxygen therapy, chelation therapy, specific antibody-toxin binding, enterohepatic circulatory binding of toxins, cation exchanger binding in the intestinal tract, and intravenous lipid emulsion therapy (table 1).

ADDITIONAL RESOURCES

Regional poison control centers — Regional poison control centers in the United States are available at all times for consultation on patients with known or suspected poisoning, and who may be critically ill, require admission, or have clinical pictures that are unclear (1-800-222-1222). In addition, some hospitals have medical toxicologists available for bedside consultation. Whenever available, these are invaluable resources to help in the diagnosis and management of ingestions or overdoses. Contact information for poison centers around the world is provided separately. (See "Society guideline links: Regional poison control centers".)

Society guideline links — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: General measures for acute poisoning treatment" and "Society guideline links: Treatment of acute poisoning caused by specific agents other than drugs of abuse".)

SUMMARY AND RECOMMENDATIONS

●General indications – The vast majority of patients who have ingested a poisonous substance or a toxic quantity of a drug can be managed with supportive measures. However, the severity of the ingestion and pharmacologic properties of the toxin may prompt consideration of techniques to enhance elimination of the poison in a small percentage of cases. Each technique is associated with potential complications, and the decision to use a particular technique should be based upon the drug ingested, the actual and predicted severity of poisoning, the presence of contraindications to the technique, and the effectiveness of alternative methods of treatment. (See 'General indications and contraindications' above.)

●Multiple-dose activated charcoal (MDAC) – MDAC may be useful following specific ingestions and is discussed separately. (See "Gastrointestinal decontamination of the poisoned patient", section on 'Multidose activated charcoal'.)  

●Urinary alkalinization – This may be useful for helping to eliminate drugs listed in the following table (table 2). These drugs are weak acids; the best studied are phenobarbital and salicylates. This is generally done by administering an intravenous (IV) bolus of 1 to 2 mEq/kg of 8.4 percent sodium bicarbonate followed by a continuous infusion made by diluting 150 mEq of sodium bicarbonate into one liter of 5% dextrose in water. The goal is to achieve a urine pH >7.5 and serum pH no higher than 7.55 to 7.6. (See 'Urinary alkalinization' above.)

●Isotonic fluid diuresis – This may enhance elimination of drugs that are predominantly eliminated unchanged by the kidney (table 3). (See 'Indications and efficacy' above.)

●Hemodialysis – This may be useful for patients with significant ingestion of alcohols, theophylline, lithium, salicylates, and others presented in the table (table 4). Intermittent hemodialysis remains the first choice for extracorporeal removal compared with continuous renal replacement therapy due to its greater speed removing toxin in the early stages of treatment. (See 'Hemodialysis and hemoperfusion' above.)

●Hemoperfusion – This extracorporeal removal modality refers to the circulation of blood through an extracorporeal circuit containing an adsorbent such as activated charcoal or polystyrene resin. It is not available at most medical centers, but compared with hemodialysis, may result in more rapid clearance of toxins such as theophylline, carbamazepine, valproic acid, procainamide, and others presented in the table (table 5). (See 'Hemodialysis and hemoperfusion' above.)

●Hemofiltration – Continuous renal replacement therapy has lower clearance rates than conventional hemodialysis but may be used in the management of unstable patients. (See 'Continuous renal replacement therapy (hemofiltration)' above.)

●Exchange transfusion – This refers to the removal of a quantity of blood from a poisoned patient and its replacement with an identical quantity of whole blood. It is rarely indicated but may be useful in the treatment of massive hemolysis (eg, due to arsine or sodium chlorate poisoning), severe methemoglobinemia, severe sulfhemoglobinemia (eg, secondary to hydrogen sulfide exposure), or neonatal drug toxicity. (See 'Exchange transfusion' above.)