Management of Poisonings and Intoxications

Abstract

Poisoning occurs after exposure to any of a number of substances, including medicines, which can result in severe toxicity including death. The nephrologist may be involved in poisonings that cause kidney disease and for targeted treatments. The overall approach to the poisoned patient involves the initial acute resuscitation and performing a risk assessment, whereby the exposure is considered in terms of the anticipated severity and in the context of the patient's status and treatments that may be required. Time-critical interventions such as gastrointestinal decontamination (e.g., activated charcoal) and antidotes are administered when indicated. The nephrologist is usually involved when elimination enhancement techniques are required, such as urine alkalinization or extracorporeal treatments. There is increasing data to guide decision making for the use of extracorporeal treatments in the poisoned patient. Principles to consider are clinical indications such as whether severe toxicity is present, anticipated, and/or will persist and whether the poison will be significantly removed by the extracorporeal treatment. Extracorporeal clearance is maximized for low–molecular weight drugs that are water soluble with minimal protein binding (<80%) and low endogenous clearance and volume of distribution. The dosage of some antidotes (e.g., N-acetylcysteine, ethanol, fomepizole) should be increased to maintain therapeutic concentrations once the extracorporeal treatment is initiated. To maximize the effect of an extracorporeal treatment, blood and effluent flows should be optimized, the filter with the largest surface area selected, and duration tailored to remove enough poison to reduce toxicity. Intermittent hemodialysis is recommended in most cases when an extracorporeal treatment is required because it is the most efficient, and continuous kidney replacement therapy is prescribed in some circumstances, particularly if intermittent hemodialysis is not readily available.

Introduction

Poisonings are a major cause of morbidity and mortality worldwide. Poisoning can occur from diverse exposures including medicines, chemicals (e.g., household, industrial, pesticides), or natural toxins from animals (e.g., snakes, spiders) or plants. Furthermore, poisoning can be intentional or accidental (including occupational) following acute, chronic, or acute-on-chronic exposures. Each scenario potentially manifests differently, which in turn prompts different approaches to management.

In 2020, there were over 2 million toxic exposures reported to US poison control centers,¹ with an estimated 100,000 fatalities from drug overdose, representing the leading cause of death in young adults.² Although poisonings are usually managed by critical care physicians and clinical/medical toxicologists, the nephrologist also has a crucial role for selected cases. This relates to kidney disease being a risk factor for some poisonings and/or the utilization of elimination enhancement techniques in toxicological management.

Rapid initiation of appropriate management reduces the severity and duration of poisoning. The general approach to the poisoned patient necessitates prompt resuscitation and stabilization and clinical and laboratory evaluation. When appropriate, time-critical treatments include antidotes, gastrointestinal decontamination, and enhanced elimination techniques. These decisions are largely made on a case-by-case basis, depending on the exposure, the patient, and the manifestations. The evidence supporting specific treatments are often based on limited data such as case reports or theoretical rationale. Fortunately, clinical recommendations on the basis of data and expert consensus are increasingly available to support decision making.

Resuscitation and Supportive Care

All poisonings, especially those that are acute and intentional, which can progress quickly, should be considered serious. Management commences with a detailed assessment of the airway, breathing, circulation, and neurological function. Initial interventions are applied according to standard indications, including endotracheal intubation, ventilatory support, and administration of fluids, inotropes, or vasopressors. Volume repletion is an important part of management to correct volume depletion because it improves hemodynamics and optimizes kidney function and elimination of some drugs (e.g., lithium, dabigatran, baclofen, digoxin). Seizures and agitation are treated with titrated doses of benzodiazepines.

Severe poisoning commonly prompts admission to the intensive care unit and continuous cardiac monitoring. This is indicated until peak effects are anticipated (which may be problematic to ascertain if there is ongoing absorption of the poison) and until recovery. In the absence of clinical toxicity, medical clearance of the patient may be considered after a minimum observation period. Intentional poisonings often require mental health input.

Risk Assessment

The toxicological risk assessment is a cognitive process performed by the clinician to predict the clinical course for a specific exposure. It guides the triaging of patients and initiation of therapy and is conducted concurrently with resuscitation and supportive care.³ Components of the risk assessment include identifying the poison (what?), the exposure (how much?), the duration (how long?), patient factors (who?), and timing (when?). Some poisonings manifest with shared clinical characteristics, referred to as a toxidrome (e.g., serotonin toxicity, sympathomimetic, cholinergic, opioid, and anticholinergic), and may help identify a poison when clinical information is lacking.⁴ Investigations are essential to the toxicological risk assessment, in particular an electrocardiogram, blood gas, routine blood chemistry including kidney function, and drug assays, as appropriate.

This information is interpreted with knowledge of the poisoning being treated. For example, the onset of poisoning is usually rapid (e.g., within 2–4 hours) after acute intentional poisoning, but there are exceptions including ingestion of a sustained-release xenobiotic or one that is metabolized to a more toxic compound (e.g., acetaminophen, methanol) or cellular poisons (e.g., bromoxynil, salicylate, 2,4-dinitrophenol). Certain acute exposures are associated with more severe outcomes. Here, risk may be predicted on the basis of the dose (e.g., >400 mg/kg valproic acid⁵), symptoms (e.g., coma in carbamazepine poisoning⁶), blood or plasma concentration (e.g., salicylate concentration >100 mg/dl or >7.2 mmol/L⁷), or other laboratory tests (e.g., lactate concentration >15 mmol/L in metformin poisoning⁸).

Chronic poisoning (e.g., over weeks) may be associated with persistent toxicity, due to intercurrent illness with AKI or drug-drug interactions, which cause accumulation of a therapeutic drug over time. Here, clinical toxicity may be severe (e.g., neurotoxicity including confusion and seizures from lithium or complete heart block from digoxin) despite relatively lower plasma concentrations than are observed after acute poisoning.

The risk assessment is adjusted according to new information from history and/or investigations and clinical progression. Advice by a clinical/medical toxicologist or Poison Control Center is invaluable and recommended in most cases.

Gastrointestinal Decontamination

Gastrointestinal decontamination is a time-critical intervention that has the potential to reduce the severity and duration of poisoning by decreasing the amount of the poison that is absorbed. Activated charcoal is most commonly used for gastrointestinal decontamination, at a usual dose of 50 g in adults. Activated charcoal should be initiated within approximately 2 hours of ingestion, but there are notable exceptions including extended-release medications (e.g., diltiazem, theophylline) and enteric-coated medicines (e.g., valproic acid). A second dose of activated charcoal may be given 2–4 hours later in the case of large exposures, in particular when the drug concentration is seen to increase after the first dose (e.g., acetaminophen, valproic acid, salicylates). Activated charcoal is not effective for acids or alkali, alcohols (including ethylene glycol and methanol), ions, or metals such as lithium and iron.

Whole bowel irrigation involves the enteral administration of a large volume (1 L/h) of an isotonic solution such as polyethylene glycol (macrogol) until the rectal effluent is clear. Indications include exposures that are nonresponsive to activated charcoal, extended-release formulations, “body packers,” or a highly toxic exposure.

Care is required when giving gastrointestinal decontamination to patients at risk of aspiration, including due to vomiting, depressed conscious state, or seizures. In such cases, once the patient has been intubated for airway protection, decontamination is usually administered using a nasogastric or orogastric tube. Other forms or gastrointestinal decontamination such as gastric lavage and forced emesis are almost never recommended, as they are of low efficacy given that most patients present many hours after poisoning and poorly tolerated. Lavage requires a large bore orogastric tube, thereby requiring intubation. Electrolyte and water imbalances have been reported and both delay the time to administration of the more effective activated charcoal.

Antidotes

Antidotes are direct or indirect agonists or antagonists to the effect of a poison, including through actions at a receptor (e.g., naloxone for opioids), inhibitors of metabolism (e.g., fomepizole for methanol), and binding for inactivation (e.g., chelators, antivenoms). Indications vary depending on the specific poison, but they are usually administered in the context of demonstrated toxicity and/or a confirmed high drug concentration (e.g., N-acetylcysteine for acetaminophen). The antidote dosage varies depending on the poisoning exposure and is titrated to clinical response or the results of investigations. A list of the more commonly used antidotes is provided in Table 1.

Table 1.

Examples of poisons for which antidotes are recommended

Poison	Antidote
Acetaminophen (paracetamol)	N-acetylcysteinea
Anticholinergic drugs	Physostigmine for significant delirium
Anticholinesterase insecticides	Atropine and possibly pralidoxime or obidoxime
Benzodiazepines	Flumazenil (rarely required)
β-adrenergic antagonists	Adrenaline, insulin-dextrose infusion
Calcium channel blockers	Calcium, insulin-dextrose infusion
Carbon monoxide	Oxygen
Cyanide	Hydroxocobalamin and/or thiosulfate
Dabigatran	Idarucizumab
Digoxin	Digoxin Fab antitoxin, atropine
Envenomation (e.g., snake, spider)	Antivenom
Ethylene glycol/methanol	Ethanol or fomepizolea
Iron	Deferoxamine
Isoniazid	Pyridoxinea
Lead	Ca,Na2-EDTA or succimer (DMSA)
Methotrexate	Folinic acid, glucarpidase
Opioids	Naloxone
Poison-induced methemoglobinemia (e.g., dapsone, alkyl nitrite)	Methylene blue
Salicylates	Bicarbonate
Sulfonylureas	Octreotide, glucose
Tricyclic antidepressants	Bicarbonate
Valproic acid	L-carnitinea
Warfarin	Vitamin K

DMSA, dimercaptosuccinic acid.

^aThe dose of the antidote must be adjusted during extracorporeal treatment.

There are specific considerations relevant to nephrologists when prescribing antidotes. These include antidote removal by extracorporeal treatments, which prompts dose up-titration (e.g., ethanol or fomepizole), antidote accumulation in patients with advanced kidney disease, which prompts dose down-titration (e.g., EDTA), and persistent or recurrent toxicity in patients with advanced kidney disease requiring repeated doses of antidotes (e.g., dabigatran,⁹ digoxin¹⁰).

Enhanced Elimination

Elimination enhancement modalities can be divided between corporeal treatments, which augment physiological process, and extracorporeal treatments, which require an artificial device located outside the body.¹¹ Extracorporeal treatments and urine alkalinization are increasingly used (Figure 1). Nephrologists are frequently consulted for input at this stage.

Figure 1.

Trends in the use of elimination enhancement techniques in the United States.

Corporeal Treatments

Urine Alkalinization

Increasing urine pH can either increase solubility of the poison or the proportion of a weak acid that is ionized. Ionized poisons are less easily reabsorbed through kidney tubules and more readily eliminated in urine. The efficacy of urine alkalinization depends on the relative contribution of kidney clearance to the total body clearance of the poison; e.g., if <1% of the ingested poison is excreted unchanged in the urine, even a ten-fold increase in kidney elimination will have no clinically significant effect.¹² Criteria that determine whether a poison is amenable to urine alkalinization are (1) it is eliminated unchanged by the kidneys, (2) smaller volume of distribution (V_D) (see below), (3) lower protein binding, and (4) a weak acid (pK_a between 3 and 7). Urine alkalinization is most often used to enhance the excretion of salicylates but can also be used for chlorpropamide, phenobarbital, herbicides (e.g., 2,4-dichlorophenoxyacetic acid [2,4-D], 4-chloro-2-methylphenoxyacetic acid, mecoprop), fluoride, and methotrexate (Table 2).¹²

Table 2.

Poisons whose elimination may be enhanced by corporeal techniques

Urine Alkalinization	Multiple-Dose Activated Charcoal	Sodium Polystyrene Sulfonate	Prussian Blue
Chlorophenoxy herbicides	Carbamazepine	Lithium	Radiocesium
(2,4-D, MCPA, MCPP)	Colchicine	Potassium	Thallium
Chlorpropamide	Dapsone
Diflusinal	Digoxin
Fluoride	Phenobarbital
Methotrexate	Phenytoin
Phenobarbital	Quinine
Salicylates	Salicylates
	Theophylline
	Yellow oleander
	Amanita phalloides

2,4-D, 2,4-dichlorophenoxyacetic acid; MCPA, 4-chloro-2-methylphenoxyacetic acid; MCPP, methylchlorophenoxypropionic acid (Mecoprop).

Target urine pH should be 7.5–8.5 while maintaining a blood pH ≤7.55. Sodium bicarbonate (100 mmol) is administered as a bolus, followed by 100–150 mmol/L in 5% dextrose in water at a rate of up to 200 ml/h. Serum potassium should be ≥4 mmol/L before buffer administration. In the setting of hypokalemia, potassium is reabsorbed in the collecting duct in exchange for a proton, so urine cannot be readily alkalinized. Furthermore, alkalinization induces kaliuresis, which may lead to dangerous hypokalemia and subsequent dysrhythmias. Serum potassium and ionized calcium must be closely monitored and corrected accordingly. Other potential complications include hypernatremia, pulmonary, and cerebral edema. Carbonic anhydrase inhibitors are contraindicated for urine alkalinization of poisons as they can worsen metabolic acidemia and exacerbate toxicity, as in the case, for example, of a salicylate poisoning where acidemia can accelerate salicylate entry in the central nervous system.

Fecal Elimination Enhancement

Multiple doses of activated charcoal (MDAC) enhance the elimination of certain poisons by interrupting their enterohepatic circulation or by promoting passive back diffusion from the intestinal capillaries to the gut lumen, a process often referred to as gut dialysis. Typical dosage is 25 g of activated charcoal every 2 hours until clinical or biochemical end points are achieved. Present guidelines recommend MDAC for poisoning due to carbamazepine, dapsone, phenobarbital, quinine, and theophylline.^13,14 In addition, MDAC may be of benefit in poisonings due to colchicine, Amanita phalloides, salicylates, cardiac glycosides,¹⁵ or phenytoin.¹⁶ Ion exchange resins may adsorb poisons from the gut capillaries into the lumen. For example, sodium polystyrene sulfonate, historically used for treating hyperkalemia, can also reduce the lithium half-life.¹⁷ Prussian blue binds radiocesium and thallium in the bowel lumen and enhances their fecal elimination (Table 2).¹⁸

Forced Diuresis

Administration of large volumes of isotonic fluids with or without loop diuretics is rarely used today to enhance elimination of poisons due to low efficacy and the risk of complications, including pulmonary edema and electrolyte abnormalities.

Extracorporeal Treatments

Recommendations

Over the past decade, evidence-based consensus recommendations for the use of extracorporeal treatments for managing poisoning have been published by the EXtracorporeal TReatments In Poisoning (EXTRIP) workgroup, a large multinational multidisciplinary group (Table 3, http://www.extrip-workgroup.org/).^6,7,19–35 These guidelines are based on principles described in this article and were derived from systematic reviews of the literature, using accepted, robust, and reproducible methodology. The goal of the guidelines was to standardize management of specific complex poisonings and propose directions for future research.³⁶

Table 3.

EXtracorporeal TReatments In Poisoning recommendations

Poison	Indications		Choice of Extracorporeal Treatment	Cessation of Extracorporeal Treatment	Other Considerations
	Clinical and Laboratory	Poison Concentration
Acetaminophen (paracetamol)	Metabolic acidemia, coma	>1000 mg/L (6620 μmol/L)	HD>CKRT	Clinical improvement	Dose of NAC should be at least doubled during HD
Baclofen	Coma requiring mechanical ventilation AND impaired kidney function	Not specified	HD	Clinical improvement	Not recommended if normal kidney function
Barbiturates (long acting)	Coma, mechanical ventilation, shock	Increasing or persisting (not specified)	HD>HP/CKRT	Clinical improvement	Coadminister MDAC
ß-Adrenergic antagonists	Atenolol and sotalol only: refractory bradycardia with hypotension AND impaired kidney function	Not specified	HD	Clinical improvement
Calcium channel blockers	Not indicated
Carbamazepine	Refractory seizures, life-threatening dysrhythmias, prolonged coma, respiratory depression requiring mechanical ventilation, despite MDAC	Increasing or persistently elevated (not specified)	HD>CKRT/HP	Clinical improvement OR [carbamazepine] <10 mg/L (42 µmol/L)	Coadminister MDAC
Chloroquine/hydroxychloroquine/quinine	Not indicated
Ethylene glycol	Shock, coma, seizures, anion gap >23 mmol/L,a impaired kidney function	>310 mg/dl (50 mmol/L) if antidote used >62 mg/dl (10 mmol/L) if no antidote used	HD>CKRT	Anion gap <18 mmol/L, normalization of acid-base parameters, [ethylene glycol] <25 mg/dl (10 mmol/L)	ECTR may not be required if normal kidney function and fomepizole used The dose of ethanol and fomepizole must be adjusted during ECTR
Gabapentin/pregabalin	Coma requiring mechanical ventilation AND impaired kidney function	Not specified	HD	Clinical improvement	Not recommended if normal kidney function
Isoniazid	If standard dose pyridoxine cannot be administered, if there are refractory seizures	Not specified	HD
Lithium	Decreased LOC, seizures, dysrhythmias, impaired kidney function	>5.0 mEq/Lb Expected time to reduce the [Li] to <1.0 mEq/L >36 h	HD>CKRT	Clinical improvement OR [Li] <1.0 mEq/L	Consider CKRT after HD because of rebound concentrations post-HD
Metformin	Shock, failure of standard supportive measures, decreased LOC, [lactate] >20 mmol/L, pH <7.0	Not specified	HD>CKRT	[Lactate] <3 mmol/L AND pH >7.35	Repeat sessions using HD or CKRT Closely monitor lactate and pH for additional ECTR courses
Methanol	Coma, seizures, new vision deficits, pH ≤7.15, anion gap >24 mmol/La	>70 mg/dl (21.8 mmol/L) if fomepizole used >60 mg/dl (18.7 mmol/L) if ethanol used	HD>CKRT	Clinical improvement AND [methanol] <20 mg/dl (6.2 mmol/L)	ECTR may not be required if normal kidney function and fomepizole used The dose of ethanol and fomepizole must be adjusted during ECTR Folic acid should be continued during ECTR
Phenytoin	Severe poisoning, such as prolonged coma or ataxia	Not specified	HD>HP	Clinical improvement	Listed indications are suggestions only; effectiveness of ECTR is uncertain
Methotrexate	Not indicated; possible (rare) exception is rapid initiation immediately after a large intravenous exposure (e.g., dosing error), when there is still a large burden in blood, before it has fully distributed to tissues
Salicylates	Altered mental status, ARDS, impaired kidney function, pH ≤7.20	>100 mg/dl (7.2 mmol/L)	HD>HP>CKRT	Clinical improvement AND [salicylate] <20 mg/dl (1.4 mmol/L)	ET may be used in children, coadminister MDAC
Thallium	Significant exposure, severe poisoning	>1 mg/L (4.6 µmol/L)	HD>HP or CKRT	[Thallium] <0.1 mg/L (0.5 µmol/L)
Theophylline	Seizures, life-threatening dysrhythmias, shock, clinical deterioration despite optimal care, GI decontamination cannot be administered	>100 mg/L (555 mmol/L) in acute exposure) >60 mg/L (333 mmol/L) in chronic poisoning	HD>HP>CKRT	Clinical improvement OR [theophylline] <15 mg/L (83 mmol/L)	Coadminister MDAC
Tricyclic antidepressants	Not indicated
Valproic acid	Cerebral edema, coma, shock, acute hyperammonemia, pH ≤7.10, respiratory depression	>1300 mg/L (9000 μmol/L)	HD>CKRT/HP	Clinical improvement OR [valproic acid] <100 mg/L (700 μmol/L)	Consider another dose of activated charcoal if valproate concentrations continue to rise after the first dose

HD, hemodialysis; CKRT, continuous KRT; NAC, N-acetylcysteine; HP, hemoperfusion; MDAC, multiple doses of activated charcoal; ECTR, extracorporeal treatment; LOC, level of consciousness; ARDS, acute respiratory distress syndrome; ET, exchange transfusion; GI, gastrointestinal.

^aThe anion gap is calculated by (Na⁺ + K⁺) − (Cl⁻ + HCO₃⁻)

^bThe lithium concentration frequently exceeds this value for acute poisonings, with favorable outcomes without extracorporeal treatment in the context of normal kidney function, in particular if the patient is naive to lithium.

Decision Making in the Absence of Recommendations

Clinical decision making for extracorporeal treatments in the context of poisonings for which EXTRIP recommendations are not available is informed by understanding the risk assessment (see above), clinical effects and time course of the poisoning, other treatments available, expected risk versus benefit of extracorporeal treatments, the poison's physicochemical characteristics and pharmacokinetics, and available extracorporeal treatments, as summarized in Figure 2. In each case, decision making occurs on a case-by-case basis. For example, AKI may be an indication for extracorporeal treatments in some poisonings (e.g., metformin, baclofen), but not others.

1. Clinical toxicology of the poison

   The risk assessment should first predict that the poisoning is severe (see above). Extracorporeal treatments are less likely to be needed if less invasive treatments, such as antidotes (Table 1) or corporeal treatments for enhanced elimination (Table 2), are available. If toxicity is expected to be prolonged despite these treatments, an extracorporeal treatment can be considered.

2. Expected clinical impact of extracorporeal treatments

   The clinician must anticipate which benefits are expected from the extracorporeal treatment and weigh these benefits against its risks and costs. For example, hemodialysis (HD) will reduce the likelihood of mortality after a massive ingestion of salicylates or methanol. The advantages of extracorporeal treatments in those circumstances would largely outweigh costs and complications of the procedure. In contrast, HD may only marginally reduce the duration of mechanical ventilation in baclofen poisoning while potentially increasing the risk of withdrawal.³⁰ Risks of extracorporeal treatments include those associated with catheter insertion and bleeding from anticoagulation and antidote removal (e.g., N-acetylcysteine, ethanol, fomepizole, and pyridoxine). Costs of a single dialysis, including equipment and nursing/physician fees, are usually minor compared with the cost of a day in the intensive care unit and can reduce the duration over which costly antidotes are needed (e.g., fomepizole for methanol poisoning).³⁷

3. Characteristics of poisons that influence their removal by extracorporeal treatments

Figure 2.

Schematic approach to extracorporeal treatment. ECTR, extracorporeal treatment; HCO, high cutoff filter; MCO, middle cutoff filter.

In the absence of any clinical outcome data from extracorporeal treatment, at a minimum, enhanced elimination should be potentially significant based on properties of the poison (Table 5).

Table 5.

Factors that will enhance poison clearance during hemodialysis

Poison characteristics

Molecular weight: <10,000 Da

Protein binding: <80% at clinically relevant concentrations

Endogenous clearance: <200 ml/min

VD: <1–2 L/kg body weight

Operational characteristics of the extracorporeal treatment

Larger surface area of dialysis membrane

High blood and dialysate flows

Increased ultrafiltration rate (with replacement solution)

Increased duration of treatment

Reduced recirculation from vascular access

Two distinct extracorporeal circuits in parallel

V_D, volume of distribution.

Molecular Weight

A poison can be removed by an extracorporeal treatment only if it can pass through the pores of the membrane. Most encountered poisons have a molecular weight <2000 Da. Typically, membranes used for intermittent HD have a molecular cutoff of 10,000 Da, whereas membranes used for hemofiltration can remove poisons with a molecular weight up to 50,000 Da. Poisons with very high molecular weights (>100,000 Da, e.g., monoclonal antibodies) can only be removed by techniques such as exchange transfusion or therapeutic plasma exchange.

Protein Binding

The size of a poison-protein complex (>66,000 Da if bound to albumin) surpasses the pore size of most membranes used for HD or continuous KRT (CKRT). Generally, a poison is not considered removable by HD or hemofiltration if the protein binding is over 80%, but there are exceptions: (1) some poisons (salicylates, valproic acid) are highly protein bound at therapeutic concentrations, but at toxic concentrations, protein-binding sites are saturated, leading to a larger percentage of poison in unbound form; (2) some poisons have a high dissociation quotient (phenytoin), meaning they do not bind tightly to albumin, and once unbound poison is removed, bound poison quickly dissociates from serum proteins, replenishing the pool of removable poison; and (3) certain disease states such as hypoalbuminemia or CKD can influence the percentage of poison that is bound and/or reduce protein-binding sites.

Endogenous Clearance

An extracorporeal treatment must contribute substantially to total clearance of that poison. If liver clearance exceeds 1000 ml/min, extracorporeal clearance (which cannot realistically exceed 200 ml/min) will be inconsequential to increase total clearance. In poisons that are predominantly eliminated by kidneys, the presence of AKI will increase the relative contribution of extracorporeal clearance to total clearance, as illustrated in Figure 3. For example, the endogenous metformin clearance is 600 ml/min; assuming a clearance of metformin using CKRT of 50 ml/min, CKRT will contribute at most 10% of total clearance, whereas it will contribute almost completely to total clearance in patients with anuric AKI. By contrast, HD will contribute little to total clearance regardless of kidney function for lidocaine elimination, because of extensive liver metabolism, whereas HD will greatly contribute to overall methanol clearance once a patient receives fomepizole.

Figure 3.

Examples of the contribution of extracorporeal clearance to total clearance. Dialyzability is assessed according to alternative criteria 1 in Table 7 of the EXTRIP methods document.³⁶ CKRT, continuous KRT; HD, hemodialysis.

Volume of Distribution

The V_D of a poison is an apparent volume that quantifies the extent to which it distributes throughout the body. Extracorporeal treatments remove poisons most effectively from the intravascular space and total body water. The higher a poison's V_D, the more that it resides outside the blood compartment, so extracorporeal removal relies on redistribution kinetics, such as observed with digoxin, calcium channel blockers, or tricyclic antidepressants. In selected cases, extracorporeal treatments may be used quickly after a large exposure to a very toxic poison that has a high V_D (e.g., thallium or methotrexate), when there is still a large burden in blood, before it has fully distributed to tissues¹⁹; this timeframe is poorly defined because of pharmacokinetic and physicochemical properties of the drug but may be within approximately 4 hours postexposure.

1. D. Available extracorporeal treatments

Numerous extracorporeal treatments are available to facilitate removal of poisons. As soon as the risk assessment suggests that a patient may require an extracorporeal treatment, prompt communication with a dialysis unit, preemptive transfer, and even insertion of a dialysis catheter may be required to minimize treatment delays, even if the patient does not yet meet criteria for blood purification. Table 4 summarizes the various extracorporeal treatments available for poison removal and their differences, which impact decision-making. In each case, parameters of the extracorporeal treatment are prescribed to maximize poison clearance (see operational characteristics in Table 5). In rare cases, e.g., refractory metformin-induced lactic acidemia, two distinct extracorporeal devices may be used at the same time to increase clearance (Table 5), whereby a parallel circuit is more effective than a series circuit.

Table 4.

Summary of extracorporeal treatments and their differences

Extracorporeal Treatment	Predominant Process	Molecular Weight Cutoff (Da)	Protein Binding Cutoff	Maximal Clearance (ml/min)	Relative Cost	Complications	Advantages or Other Comments
Intermittent HD	Diffusion	<10,000 for regular dialyzersa <45,000 for middle cutoff dialyzers <60,000 for high cutoff dialyzers	<80%	240	+	+	Allows correction of uremia and acid-base and electrolyte disorders
Intermittent hemofiltration	Convection	<50,000	<80%	240	++	+	Allows correction of uremia and acid-base and electrolyte disorders
Hemoperfusion	Adsorption	<50,000 for charcoal cartridges <60,000 for Cytosorb	<95%	200	++	+++	Saturation of cartridge requires changes every 2 h
Continuous KRT	Convection and/or diffusion	<10,000–50,000	<80%	80	++	+	May include diffusion and/or convection correction of uremia and acid-base and electrolyte disorders
Therapeutic plasma exchange	Centrifugation/separation, filtration	<300,000 if filtration used	None	50	+++	+++
ELAD	Diffusion, adsorption	<250,000 for Prometheus <60,000 for MARS	<95%	50	++++	++	Liver replacement support
Peritoneal dialysis	Diffusion	<15,000	<80%–90%	20	++	++	Technically easier in neonates Does not require extracorporeal circuit
Exchange transfusion	Centrifugation/separation, filtration	None	None	10	++	++	Technically easier in neonates Correction of hemolysis

All extracorporeal treatments above are less likely to be useful for poisons that have a high volume of distribution or a high endogenous clearance (Table 5). HD, hemodialysis; ELAD, extracorporeal liver assist device; MARS, Molecular Adsorbent Recirculating System.

^aClearance of higher molecular weight solutes during hemodialysis is mainly induced by adsorption and nondiffusive solute flux with filtration and back filtration.

Hemodialysis

During HD, poison is removed from the blood by diffusion, across a semipermeable membrane, passively down a concentration gradient. Older conventional dialysis membranes had a molecular cutoff of approximately 1000 Da (larger xenobiotics could be removed from filtration/back-filtration within the dialyzer), compared with >10,000 Da for modern synthetic high-flux membranes.³⁸ This is exemplified by the increase in vancomycin (1449 Da) clearance over the years, from ≈10 ml/min with cuprophane membranes³⁹ to >100 ml/min today with polysulfone membranes.⁴⁰ In poisoning, a filter with the largest surface area and maximal blood and dialysate flow rates should be used unless a contraindication is present (e.g., concern for disequilibrium syndrome, as can be seen in severe azotemia) (Table 5).⁴¹ HD has other major advantages such as fluid removal (although rarely required in that setting), correction of metabolic abnormalities, replacement of kidney function, and highest achievable clearance among all extracorporeal treatments. Because of its prevalent use for the treatment of AKI and kidney failure, HD is the most available extracorporeal treatment and is also the least expensive and the quickest to implement.³⁷ Some care is required to the prescription of the dialysate, as poisoned patients may not share metabolic disturbances as patients with AKI. For example, phosphate may be added to the dialysate of a patient who has a low-to-normal serum phosphate concentration, and the bicarbonate concentration should be reduced in an alkalemic patient.

Hemoperfusion

During hemoperfusion, poison is removed from the blood when it passes through a charcoal or resin cartridge onto which the poison is adsorbed.⁴² Compared with diffusion, adsorption is not as limited regarding the molecular weight or protein binding of the poison. However, hemoperfusion has several disadvantages over HD: (1) The circuit requires more generous systemic anticoagulation than dialysis; (2) maximal blood flow is limited to 350 ml/min because of risk of hemolysis⁴³; (3) hemoperfusion also adsorbs platelets, white blood cells, calcium, and glucose^44,45; (4) hemoperfusion cartridges cost several-fold more than standard hemodialyzers; (5) cartridges need to be replaced every 2 hours because of saturation and loss of efficiency; (6) hemoperfusion does not correct electrolyte and acid-base disturbances and cannot remove fluid; (7) hemoperfusion cartridges are seldom available⁴⁶; and (8) hemoperfusion does not adsorb alcohols or many metals. For these reasons, HD is generally preferred in most settings where hemoperfusion is also indicated.⁴² These considerations are reflected by recent trends in the choice of extracorporeal treatment for poisonings (Figure 1).^46–48 The only hemoperfusion column available in the United States is the Gambro Adsorba 300c, a coated activated charcoal cartridge.⁴² Recently, CytoSorb, a hemoadsorption device containing polymer beads, has shown promise in removing inflammatory mediators for patients with sepsis. However, the data for removing protein-bound poisons remain unclear.⁴⁹

Hemofiltration

During hemofiltration, solute and solvent in the blood are removed by convection or solvent drag and replaced by a physiological solution. Hemofiltration has similar advantages to HD but can eliminate larger poisons, up to 50,000 Da.^41,50

Continuous Techniques

Continuous techniques, such as CKRTs, are popular in the critical care setting to manage fluid overload and AKI. They usually combine diffusion and convection, albeit at lower effluent and blood flow. Their benefit is mainly that they can be performed continuously, hence reducing the rate of net ultrafiltration, which is a concern in hemodynamically precarious patients; however, fluid removal is rarely required in poisoned patients. CKRT also reduces the rebound in poison concentration seen after HD because of redistribution from tissues to blood, although this phenomenon may not be clinically important in poisoned patients. In general, high-efficiency HD or hemofiltration is preferred to CKRT because they maximize poison clearance. However, in some centers, CKRT may be quicker to institute than HD because of staffing and patient disposition issues, in which case CKRT is a reasonable modality to trial.

Peritoneal Dialysis

Peritoneal dialysis (PD) has a limited role in acute poisoning as the maximum achievable clearance is <20 ml/min (one tenth of the clearance achievable by HD).⁵¹ An advantage of PD is that it is technically more easily feasible in resource-limited regions and in neonates.

Therapeutic Plasma Exchange

Therapeutic plasma exchange separates plasma and blood cells by filtration or centrifugation, which is then replaced by a solution that usually contains albumin or fresh frozen plasma. Poison clearance during therapeutic plasma exchange is limited to ≈50 ml/min.⁵¹ The advantage of therapeutic plasma exchange over HD is in the removal of highly protein-bound (>95%) or very large poisons over the accepted cutoffs for hemoperfusion or hemofiltration (>50,000 Da). Complications specific to therapeutic plasma exchange include hypocalcemia and hypersensitivity reactions.⁵²

Exchange Transfusion

During exchange transfusion, whole blood or red blood cells are removed by apheresis and replaced with blood products. Exchange transfusion is simpler to perform in infants because it does not require an extracorporeal circuit, although achievable poison clearance is very low (<10 ml/min).

Extracorporeal Liver Assist Devices

Extracorporeal liver assist devices, often referred as albumin dialysis, are infrequently used nowadays to support liver function in fulminant hepatitis or severe cirrhosis, often as a bridge to transplantation. There are three different major types: Single-pass albumin dialysis is a technique similar to HD on to which albumin is added to the dialysate. The Molecular Adsorbents Recirculation System is identical to single-pass albumin dialysis, but the discarded albumin-enhanced dialysate is recycled after going through a dialysis filter, a resin, and a charcoal cartridge. The Prometheus system combines albumin adsorption with HD after selective filtration of the albumin fraction through a polysulfone filter. These techniques have very limited availability, are expensive, and have not shown any benefit over therapeutic plasma exchange or hemoperfusion at removing protein-bound poisons.

If a high-efficiency extracorporeal treatment is needed, a single 6-hour session usually suffices for most poisonings, but a longer duration may be required if the molar concentration in blood is high (e.g., for toxic alcohols). After extracorporeal treatment, serial poison concentrations and clinical status should be monitored for a period long enough to account for rebound, redistribution, or ongoing absorption. The catheter should remain in place until the physician is convinced that additional sessions are unnecessary.

In conclusion, general supportive care is sufficient to manage most poisoned patients. Some patients are treated with decontamination, antidotes, and corporeal methods for enhanced elimination. In a smaller selection of cases, extracorporeal blood purification, usually consisting of HD, can help reduce the exposure of a patient to the toxic effects of a poison, which decreases the duration and/or severity of poisoning. An understanding of poison toxicokinetics can help a clinician discern what are the timely conditions and circumstances when extracorporeal treatments are most likely to be beneficial.

Disclosures

Both M. Ghannoum and D.M. Roberts are EXTRIP chairs. M. Ghannoum reports employment with Government of Quebec. D.M. Roberts's partner is employed in a business support role by a pharmaceutical company. This has no relationship to the manuscript under consideration or any of D.M. Roberts's work.

Funding

None.

Author Contributions

M. Ghannoum and D.M. Roberts conceptualized the study; were responsible for resources and investigation; wrote the original draft; and reviewed and edited the manuscript.