key: cord-265848-afkeuwup
authors: nan
title: Chapter 2 Emergency Management of Poisoning
date: 2007-12-31
journal: Haddad and Winchester's Clinical Management of Poisoning and Drug Overdose
DOI: 10.1016/b978-0-7216-0693-4.50007-4
sha: 
doc_id: 265848
cord_uid: afkeuwup

nan

Medical toxicology is one of the most important and dynamic fields in medicine today, since the practicing physician is continually faced with the management of poisoning, drug overdose, and adverse drug effects. The abuse of both prescription and illicit drugs in the United States continues unabated. Because the process of drug approval is more rapid, it is often not until the agent has been in use for some time, during the postmarketing period, before its toxicity is fully appreciated.

Defining the incidence of human poisoning is not easy. There are multiple sources of data on drug overdose and substance abuse. The Toxic Exposure Surveillance System (TESS) of the American Association of Poison Control Centers tabulates referrals for human poisoning called into the nation's poison centers. In 2004, it recorded 2,395,582 exposures, with 1106 deaths; analgesics were the most common cause of a fatal outcome. 1 The National Institute of Drug Abuse surveys emergency department visits through its Drug Abuse Warning Network (DAWN), and in 2002 reported that a total of 4427 deaths resulted from drug abuse, with cocaine being the most commonly implicated agent. 1, 2 However, these sources vastly underestimate the number of toxic events in humans. For example, reports of intoxicated patients who die from trauma, drowning, and fires are not consistently included in any national data set, nor are those of patients with medical complications from therapy, such as chemotherapy or anesthetics. Morbidity that results from chronic abuse (e.g., heart disease from cocaine or nicotine abuse and cirrhosis from alcohol abuse) or industrial exposures, and the long-term effects of environmental hazards, is not rigorously compiled and is probably impossible to quantify.

The most common causes of poisoning-related death in the United States have been carbon monoxide poisoning, cocaine use, and tricyclic antidepressant overdose. 1 Poisoning with analgesics, aspirin, and acetaminophen also remains a leading cause of death. Calcium channel blocker overdose has surpassed digitalis overdose as the most common cause of cardiovascular drug-related death.

To poison means to injure or kill with a substance that is known or discovered to be harmful. Thus, the term poisoning connotes clinical symptomatology. It also implies that the toxic exposure is unintentional (e.g., in the case of an elderly patient who misreads a drug label). In contrast, the term overdose implies intentional toxic exposure, either in the form of a suicide attempt or as inadvertent harm secondary to purposeful drug abuse. The terms poisoning and drug overdose often are used interchangeably, especially when prescription drugs are the agents, even though by definition a drug overdose does not produce poisoning unless it causes clinical symptoms.

Poisoning has a bimodal incidence, occurring most commonly in children who are 1 to 5 years of age and in the elderly. Overdose, whether motivated by suicidal intent or the result of abuse, occurs through adulthood. Toxic exposure in those between the ages of 6 and 12 years is uncommon; when it occurs, the patient must be assessed carefully to ensure that psychiatric follow-up is provided when indicated. 1

The general approach to the poisoned patient can be divided into six phases: (1) stabilization; (2) laboratory assessment; (3) decontamination of the gastrointestinal tract, skin, or eyes; (4) administration of an antidote; (5) elimination enhancement of the toxin; and (6) observation and disposition.

Because overdose patients are often clinically unstable when discovered, resuscitation with establishment of the airway, adequate support of ventilation and perfusion, and maintenance of all vital signs (including temperature) must be accomplished first. Continuous cardiac and pulse oximetry monitoring is essential. Rapid-sequence intubation (RSI) may be indicated in patients with an airway in jeopardy. Naloxone, 2 mg intravenously (IV); thiamine, 100 mg intravenously (IV); and 50% dextrose, 50 mL IV (if patients are shown on Dextrostix testing to be hypoglycemic) are generally given to all adults in coma, once an IV line has been established and appropriate blood studies have been performed. 3, 4 Maintenance of blood pressure and tissue perfusion may require the provision of volume, correction of acid-base disturbance, administration of pressor agents, and antidotal therapy. only for reversal of pure initial dose not to exceed 1 mg benzodiazepine sedation β blockers Glucagon Adult: 5-10 mg (IV) initially Stimulates cAMP synthesis, increasing Child: 50-150 ug/kg (IV) initially myocardial contractility Continuous infusion as needed Calcium channel Calcium chloride 10% 1 g (10 mL) (IV) over 5 min as initial Avoid extravasation; tissue destructive blockers dose; repeat as necessary in critical patients; doses up to 10 g may be necessary to restore blood pressure Insulin/glucose 0.5-1.0 U/kg initially then Monitor serum potassium and glucose 0.5-1.0 U/kg/hr as needed to maintain systolic blood pressure Therefore, this task requires a thorough understanding of advanced airway management principles and of their application in a manner that prevents worsening of the clinical situation. RSI is a method of rapidly obtaining airway control with minimal physiologic disturbance. The process of RSI involves a patterned sequence of preparation, drug administration, intubation, and postintubation management. [5] [6] [7] In the emergency department, RSI has historically had its greatest role in the patient with severe head trauma in whom intubation could exacerbate already increased intracranial pressure. However, because it is designed to blunt or prevent all adverse responses associated with endotracheal intubation, RSI is the ideal method of intubation in the poisoned patient. With the use of drugs having a short duration of action, RSI also is advantageous because it is a measure that permits temporary airway control for the patient with mildly compromised airway reflexes who requires gastrointestinal decontamination (lavage followed by activated charcoal administration) but who does not require prolonged intubation. RSI requires several essential steps that include the use of pharmacologic agents (Table 2A-2) . To be performed safely, RSI must occur in the following sequence.

The clinician must first evaluate the patient's airway to determine the necessary equipment and the best technique for safe intubation. Particular attention should be directed to abnormalities in the cervical spine and temporomandibular joint because these will significantly impede rapid and uncomplicated intubation. If there is any question about the stability of the cervical spine, immobilization must be maintained. The oral cavity should be closely examined for the presence of foreign bodies.

In addition to basic airway management, many victims of poisoning require advanced management that includes endotracheal intubation. Clinical situations in which endotracheal intubation may be necessary in poisoned patients are numerous (Box 2A-1). Intubation offers the advantages of complete airway control, protection from aspiration of gastric contents, provision of a route for suctioning of secretions, and a means of optimizing both oxygenation and ventilation. However, the process of intubating an awake patient is difficult and is associated with potential adverse effects, including coughing, gagging, vomiting, tachycardia or bradycardia, hypertension, hypoxia, and increased intracranial pressure. Moreover, emergency intubation can be challenged by vocal cords that are obscured by secretions, unusual airway anatomy, a full stomach, or active vomiting.

Before intubation, all necessary equipment must be present so that serious delays or unforeseen complications can be prevented. An IV line should be established and the patient connected to a cardiac monitor and pulse oximeter. The equipment necessary for endotracheal intubation is outlined in Box 2A-2. The proper functioning of all equipment should be ensured before it is used. Appropriate endotracheal tube size also should be determined (Table 2A-3) . Unanticipated difficulties with intubation are common; "difficult airway" equipment (e.g., illuminated or fiberoptic-directed endotracheal tubes) should be kept close at hand.

Oxygen should be administered for 2 to 3 minutes before intubation; this produces a washout of nitrogen from the lungs, replacing this gas with an oxygen reservoir. The oxygen reservoir allows several minutes of apnea during which intubation can be performed without the risk of producing hypoxia. Assisted ventilation with bag-valve-mask apparatus should only be provided if the patient's own respiratory efforts are inadequate because it risks inflation of the stomach, which increases the likelihood of vomiting. Patients who are breathing spontaneously should be given 100% oxygen by face mask for several minutes before intubation.

Pretreatment involves the administration of pharmacologic agents that prevent adverse physiologic changes that may occur during intubation. Agents included in this category are lidocaine and atropine.

IV administration of the anesthetic lidocaine appears to blunt the increase in intracranial pressure that 16 CONCEPTS IN MEDICAL TOXICOLOGY anesthetics, ketamine can produce significant elevations in pulse, blood pressure, intracranial pressure, and myocardial oxygen consumption, and such an increase in any of these could worsen the patient's clinical condition. Because ketamine has a potent bronchodilating effect, it retains its important role as an induction agent in the patient with severe bronchospasm. [11] [12] [13] After administration of a sedative/anesthetic, skeletal muscle relaxation is performed. Skeletal muscle relaxants, all of which interrupt acetylcholine function at the myoneural junction, are typically divided into depolarizing and nondepolarizing categories. Depolarizing agents, of which succinylcholine is the model drug, produce muscle depolarization before paralysis; this results in initial generalized muscle fasciculation. Nondepolarizing relaxants produce paralysis without initial depolarization. The nondepolarizing skeletal muscle relaxants include pancuronium, vecuronium, atracurium, and rocuronium.

Succinylcholine is the most popular muscle relaxant because it has several desirable properties, including a rapid onset of action (less than 1 minute) and an extremely short duration of action. Customary paralyzing doses of succinylcholine are 1 to 2 mg/kg IV.

Despite its efficacy and popularity, succinylcholine can produce several adverse effects. These include hyperkalemia, prolonged paralysis, malignant hyperthermia, and hemodynamic changes. Hyperkalemia, which can be severe, has been most commonly associated with administration of succinylcholine to those with burns, crush injuries, select neuropathies (e.g., Guillain-Barré syndrome), and myopathies (e.g., childhood muscular dystrophies). Prolonged paralysis can occur in those who have a genetic deficiency in serum cholinesterase, the enzyme that inactivates the drug. Prolonged paralysis may also occur in patients with liver disease, the elderly, and those who have ingested anticholinesterase insecticides (carbamates or organophosphates). Malignant hyperthermia is a syndrome characterized by muscle rigidity, hyperthermia, autonomic disturbances, acidosis, rhabdomyolysis, myoglobinuria, renal failure, and coagulopathy. Occurring in genetically predisposed individuals, malignant hyperthermia may appear without warning in those who are given inhalation anesthetics or succinylcholine. The mortality rate associated with this syndrome is approximately 5% to 10%. A malignant hyperthermia-like picture can also occur in children with skeletal muscular disorders (e.g., muscular dystrophy) who are given succinylcholine. Finally, succinylcholineinduced muscle depolarization can lead to transient increases in intracranial and intra-abdominal pressure, with accompanying changes in cardiac output. 14 Because of these potential adverse effects, nondepolarizing muscle relaxants are often recommended as adjuncts to or substitutes for succinylcholine use. As adjuncts, nondepolarizing agents, when given before succinylcholine, can prevent muscle fasciculation and its attendant physiologic effects. The so-called "defasciculating dose" of a nondepolarizing agent is approximately one tenth the full dose of that agent. For example, pancuronium can be given in a dose of 0.01 mg/kg IV before the accompanies intubation. Although scientific proof of lidocaine's efficacy is sparse, it is appropriateparticularly in the patient with suspected intracranial hypertension-to administer lidocaine, 1.0 to 2.0 mg/kg IV, 3 to 4 minutes before intubation. [8] [9] [10] Bradycardia can accompany RSI in two circumstances. In young children, both posterior pharyngeal stimulation and administration of succinylcholine can result in severe bradycardia. Therefore, in children younger than 5 years, atropine should be administered before induction. The dose of atropine is 0.01 to 0.02 mg/kg (maximum, 1.0 mg). No less than 0.1 mg of atropine should be administered because smaller doses can produce paradoxical bradycardia.

Severe bradycardia can also occur in patients of any age who have been exposed to medications or toxins with negative chronotropic actions. For example, in patients who have ingested β antagonists (e.g., propranolol), calcium channel blockers, and digoxin, RSI can produce an abrupt decrease in heart rate or frank cardiac arrest. Therefore, in patients who are undergoing RSI after exposure to these agents, atropine should either be administered prophylactically or kept immediately available should emergency administration become necessary.

Induction consists of two components: administration of a sedative/anesthetic agent to produce unconsciousness, and the subsequent administration of an agent that produces complete skeletal muscle relaxation (paralysis); both actions facilitate intubation. Because administration of these drugs leads to apnea and paralysis, it is essential that induction proceed quickly and efficiently; this underscores the importance of having all intubation equipment immediately available and in working order.

A number of medications of different pharmacologic classes are used to produce sedation before skeletal muscle relaxation (see Table 2A -2). These drugs include benzodiazepines, opioids, barbiturates, propofol, etomidate, and ketamine. Among the benzodiazepines, midazolam, when given in a dose of 0.1 mg/kg IV (up to a range of 5 to 6 mg in an adult), is ideal because its effects are rapid in onset and short in duration. The drug also offers the advantage of producing muscle relaxation and amnesia. Opioids are another class of drugs that can be used; however, many opioids, such as morphine, may prompt histamine release, with resultant hemodynamic changes. Fentanyl in a dose of 2 to 5 μg/kg is highly effective at producing rapid sedation and relaxation with minimal cardiovascular change. Several barbiturates can produce rapid sedation and relaxation. The most popular of these is sodium thiopental (dose 3 to 5 mg/kg). Equally effective but with a shorter duration of action are methohexital, propofol, and etomidate. Finally, ketamine is a dissociative anesthetic that can produce rapid onset of a state in which the patient is insensitive to pain but maintains an awake appearance and continues to have protective airway reflexes. The typical IV induction dose of ketamine is 1 to 2 mg/kg. Unlike other sedatives/ administration of succinylcholine to prevent fasciculation. Nondepolarizing agents can also be used solely for skeletal muscle relaxation. However, they generally have a much slower onset of action (as long as 3 to 5 minutes) and produce a longer duration of paralysis. Also, many nondepolarizing agents stimulate histamine release, producing significant hemodynamic changes. Therefore, they are not ideal agents for RSI. Rocuronium appears to have the most rapid onset of all nondepolarizing agents, approaching that of succinylcholine with regard to time to complete muscle relaxation in the less than ideal conditions generally found during emergency intubation. 15 Significant warnings to succinylcholine use in the pediatric population have been recently added, based on the possibility of life-threatening cardiac arrhythmias. According to these new warnings, children with undiagnosed myopathies (e.g., a muscular dystrophy) could develop hyperkalemia sufficient to produce a cardiac disturbance. 16 Intubation Suction must be immediately available when intubation is performed. The patient undergoing emergency intubation often has a full stomach; the risk for vomiting and aspiration is therefore significant. This risk is minimized both by the RSI technique and by the direct application of pressure on the cricoid cartilage (Sellick's maneuver), which occludes the esophagus. Adequate preoxygenation and limiting the duration of the intubation attempt to less than 20 to 30 seconds should prevent significant hypoxia.

The differences between the airway of the child and that of the adult have important implications for endotracheal intubation.

1. The child has a relatively large tongue; this makes direct visualization of the larynx difficult. 2. The child has larger tonsils, which also obscure visualization. 3. The infant's larynx is located more cephalad than that of the adult. As a result, the angle between the tongue and the glottis is more acute, and visualization of the larynx is impaired. 4. The subglottic area of the infant is the narrowest part of the larynx and may impede the passage of an endotracheal tube passed through the vocal cords.

Immediately after successful endotracheal intubation, placement of the endotracheal tube must be confirmed by detection of bilateral equal breath sounds on chest auscultation, end-tidal carbon dioxide monitoring, or chest radiography; of these, chest auscultation is the least sensitive method and should never be used in isolation to confirm endotracheal tube placement. After confirmation, the tube should be secured either with a strap or with benzoin and adhesive tape. Inflation of the endotracheal tube cuff should be performed to minimize aspiration of gastric contents (although aspiration of activated charcoal around cuffed endotracheal tubes is a frequent occurrence). Until recently, because the airway of the young child has an area of narrowing ("physiologic cuffing"), cuffed endotracheal tubes were not used in the pediatric patient. Pediatric cuffed tubes are now available; their use is encouraged in most circumstances. If long-term intubation is necessary, sedatives/anesthetics and nondepolarizing muscle relaxants should continue to be administered.

In unskilled or unprepared hands, emergency endotracheal intubation can have disastrous consequences. Even when performed by the most experienced hands, this complex procedure can have complications that should be anticipated so that they can be quickly recognized and treated. These complications include: 

Poisoned patients often present to the emergency department with hypotension or frank shock. Provision of circulatory support through interventions that may include volume expansion, vasopressor therapy, antidote administration, and correction of electrolyte and acidbase disturbances is essential in initial management.

Many medications and toxins produce hypotension (Box 2A-3). Depending on the ingested substance, the low blood pressure may have a number of causes. For example, blood pressure depressions may occur from direct depression of myocardial contractility (e.g., quinidine), disturbances of central nervous system cardiorespiratory centers (e.g., clonidine), severe gastrointestinal fluid losses (e.g., acetaminophen, iron, arsenic, ricin, mushrooms), peripheral vasodilation (e.g., angiotensin-converting enzyme inhibitors), or a combination of these effects (e.g., theophylline, calcium channel blockers, tricyclic antidepressants). Hypotension also can result from the secondary effects of toxins (e.g., cocaineinduced myocardial infarction). Finally, blood pressure disturbances in the poisoned patient may represent accompanying trauma (e.g., severe spinal cord injury or internal hemorrhage). With the multitude of possible causes, the clinician, on the basis of the known pathophysiology of a particular drug and after having performed a thorough physical assessment, should determine, if at is mechanistically the source of intravascular volume loss, the use of colloid solutions may be preferred. Whole blood is most valuable in situations in which there is frank blood loss. With severe hemolysis (e.g., after arsine or stibine exposure), exchange transfusion with whole blood may be necessary.

Usually, the adequacy of volume expansion is determined clinically by an increase in blood pressure. Other clinical signs of improved cardiac output include resolution of cyanosis and normalization of capillary refill time. Central venous pressure and Swan-Ganz catheter monitoring, although invasive, provide the best evidence of appropriate intravascular volume.

Fluid overload is a potential complication of volume expansion. This is most likely to occur in patients who receive excess fluids over a short period of time. Also, after an overdose of a myocardial depressant such as tricyclic antidepressants or quinidine, a fluid bolus that could be tolerated by a healthy individual can produce pulmonary edema in the overdose patient. Therefore, administration of modest boluses of fluid is generally recommended; if cardiac output remains inadequate after fluids have been given, vasopressor therapy should be initiated.

In the patient with severe hypotension, vasopressor therapy is necessary if blood pressure is not satisfactorily improved after volume expansion. Vasopressors are drugs that can be administered to maintain cardiac output. These agents have specific effects on the heart or blood vessels, augmenting myocardial function or increasing vasomotor tone, or both. With rare exception, vasopressors used in the acute management of hypotension are short-acting drugs that must be given by continuous IV infusion. 17 Vasopressors generally act at adrenergic (α and β), D (dopamine), or glucagon receptors (Table 2A-4 ). The adrenergic system has been further defined with the recognition of two major α-adrenergic receptor subtypes (α 1 and α 2 ) and three β-adrenergic receptor subtypes (β 1 , β 2 , and β 3 ). Coupled with intracellular G proteins, these membrane-bound receptors effect an intracellular chain of events that includes changes in the activity of adenylate cyclase. This action goes on to modulate the level of intracellular cyclic adenosine monophosphate (cAMP), which in turn alters phospholipase activity or opens gated calcium channels. Although the cellular mechanisms of this system have become much better defined, the general principles of vasopressor action remain unchanged. For example, α-adrenergic receptor agonists produce vascular smooth muscle contraction. β 1 -Adrenergic receptor agonists produce increased heart rate and contractility, whereas β 2 -adrenergic receptor agonists promote generalized smooth muscle relaxation (including bronchial and vascular). Vasopressor therapy is designed to improve cardiac output through manipulation of the specific receptor most appropriate for the clinical situation. A number of vasopressors can be used to provide blood pressure support (see Table 2A -4) . The all possible, the probable cause of hypotension if he or she is to provide a specific intervention.

Appropriate cardiac output relies on the adequacy of intravascular volume. After poisoning, intravascular volume may decrease abruptly. This decrease can be absolute, occurring as a result of a direct loss of intravascular volume (e.g., pulmonary edema, gastrointestinal pooling), or relative, resulting from severe peripheral vasodilation (e.g., angiotensin-converting enzyme inhibitor or α-antagonist overdose). In either case, hypotension should first be treated with the administration of volumeexpanding agents. 17 Many fluids are acceptable for emergency volume expansion. Normal saline and lactated Ringer's solution are generally the most readily available isotonic agents. Adults should receive up to 500-to 1000-mL boluses of isotonic fluid while blood pressure is monitored; children should be given 10 to 40 mL/kg. After the administration of each bolus, the patient should be reassessed for improvements in cardiac output.

Alternative fluids that can be used for volume expansion in the poisoned patient include albumin and whole blood. Each of these fluids has a role that is best determined by the pathophysiologic mechanism responsible for the hypotension. Being colloid rather than crystalloid in nature, these fluids in theory maintain intravascular volume better than saline solutions do. In clinical situations in which a "leaky capillary syndrome" BOX 2A-3 Ricin indications for the use of these drugs vary slightly, depending on the clinical circumstance.

Epinephrine elevates blood pressure primarily through its α-adrenergic-stimulating properties. This effect also is valuable in improving myocardial and cerebral blood flow. Because it also has prominent β-adrenergic agonist effects, epinephrine is variably effective at producing marked increases in blood pressure. Epinephrine therapy is initiated at a dose of 0.1 to 0.5 μg/kg/min. Epinephrine is particularly effective in intoxications associated with hypotension and bronchospasm (e.g., Hymenoptera envenomation and anaphylactic reactions).

Norepinephrine stimulates both αand β-adrenergic receptors, with slightly greater stimulation of α-adrenergic receptors. The effect is improved vasomotor tone in conjunction with increased myocardial chronotropy and inotropy. Norepinephrine infusions are typically initiated in a dose of 0.1 to 0.5 μg/kg/min.

Dopamine is a precursor of norepinephrine. The most popular of vasopressors, dopamine appears to have at least three mechanisms of action: (1) promotion of norepinephrine synthesis, (2) a tyramine-like effect that stimulates release of preformed norepinephrine, and (3) direct stimulation of vascular dopamine receptors.

The cardiovascular effects of dopamine are variable, depending on the infusion rate. At relatively low doses (1 to 2 μg/kg/min), the drug dilates renal and mesenteric vessels without marked increases in heart rate or blood pressure. At doses of 2 to 10 μg/kg/min, β-adrenergic receptor stimulation predominates, producing significant increases in cardiac output. Finally, at doses greater than 10 μg/kg/min, α-adrenergic receptor stimulation is the primary action, resulting in marked peripheral vasoconstriction. The general dose range for dopamine infusion is 2 to 20 μg/kg/min.

Dopamine is safe and effective for any type of druginduced hypotension. In the past, there have been theoretic concerns that dopamine's β-adrenergic effect in the face of phenothiazine or tricyclic antidepressant intoxication would increase the peripheral vasodilatation associated with overdose, exacerbating hypotension. However, experimental data and clinical experience have failed to confirm this adverse effect from dopamine use. Also, with hypotension after monoamine oxidase inhibitor overdose, dopamine's effects are somewhat unpredictable; it may be relatively ineffective (owing to the lack of preformed norepinephrine), or it can produce an exaggerated response (because of its tyramine-like action).

Dobutamine is a synthetic catecholamine with almost exclusive β-adrenergic receptor-stimulating effects. Its primary mechanism of blood pressure improvement is direct myocardial inotropy; thus, reflex peripheral vasodilation may occur with its use. Unlike dopamine, dobutamine does not release preformed norepinephrine. The usual dosage range for dobutamine is 2 to 20 μg/kg/min, although doses as high as 40 μg/kg/min have been used. High-dose infusions often increase myocardial oxygen demands, which, if unmet, can result in myocardial ischemia. Nonetheless, dobutamine is extremely effective in syndromes of heart failure.

Phenylephrine has both αand β-adrenergic receptorstimulating properties, although its α-adrenergic receptor actions predominate. Phenylephrine is a potent stimulator of vasomotor tone; it is therefore very effective in patients in hypotensive states resulting from severe peripheral vasodilation (e.g., following overdose with an α-adrenergic antagonist, such as prazocin or a phenothiazine neuroleptic, e.g., chlorpromazine). Phenylephrine centrations of extracellular calcium, particularly in the face of channel blockade (e.g., after overdose of calciumchannel blockers), sometimes improve contractility. Administration of IV calcium chloride is indicated in the management of hypotension resulting from calcium channel blocker overdose (see Table 2A -1), hyperkalemia, and hypocalcemia.

A thorough history taking and physical examination are essential to the diagnosis of the toxic patient. Poisoning should be suspected in any patient who presents with multisystem disturbance until proven otherwise.

Although the initial manifestations of poisoning are myriad, a patient with acute poisoning often presents with coma, cardiac arrhythmia, seizures, metabolic acidosis, or gastrointestinal disturbance, either together as symptom complexes or as isolated events. Symptom complexes, or toxidromes (Table 2A- 5) , may give clues to an unknown poisoning. For example, a patient with a history of depression who presents with coma, seizures, a widened QRS complex or evidence of dysrhythmia on electrocardiography, and dilated pupils has likely taken a tricyclic antidepressant. Hepatic, renal, respiratory, and hematologic disturbances are generally delayed manifestations of poisoning.

The clinical evaluation, in addition to the history taking and physical examination, includes an assessment of major signs of toxicity presented by the patient and evaluation of the laboratory data.

When one suspects poisoning or drug overdose, the primary goal of history taking is identification of the toxic agent. Sometimes diagnosis is easy, as in the case of the toddler who ingests iron tablets in the mother's presence. Sometimes it is difficult, as in the case of the patient who is hiding a history of drug abuse and passes out at work or who has an unexpected seizure. Prior medical or psychiatric history, current medications, and allergies should be obtained from family or friends if the patient is unable to relate the information. The following questions may be revealing:

What other medicines are in the house? What was the patient doing that day? Does the patient live alone, did he or she just lose a job, or have there been recent emotionally traumatic events? Is the patient eating a special diet or taking a new health food, alternative medication, or performance enhancer? Could the patient inadvertently have taken too much of a prescribed medication? If it can be identified, is the substance nontoxic? (See Box 2A-4.)

The physical examination can help in determining the extent of poisoning and may reveal the presence of a infusions are given in a typical dose range of 0.1 to 0.5 μg/kg/min.

Amrinone is a novel, nonadrenergic cardiac stimulant that improves myocardial contractility while inducing vasodilation. Its mechanism of action appears to be direct inhibition of phosphodiesterase; the result of this is increased intracellular cAMP activity, an action that increases transmembrane calcium flux, potentiating cardiac chronotropy and inotropy. Amrinone's effects have been compared with those of dobutamine and nitroprusside combination therapy. Amrinone may be particularly valuable in the treatment of calcium channel blocker intoxication; its inhibition of cAMP breakdown results in greater phosphorylation of L-type calcium channels, potentially increasing their permeability. Experimental data support its role in this specific poisoning. 18 Amrinone can be used to treat syndromes of left ventricular failure but should not be administered in the presence of myocardial ischemia; like dobutamine, it may increase myocardial demands, resulting in infarction. Because of its potent vasodilating action, amrinone may cause a hypotensive response in those with low intravascular volume. The usual dosage range for this agent is 5 to 15 μg/kg/min; the total daily dose should not exceed 10 mg/kg per day.

Glucagon is a single-chain pancreatic polypeptide that is an effective inotropic and chronotropic agent. Its mechanism of action is direct stimulation of myocardial glucagon receptors; these receptors, when stimulated, increase the formation of myocardial cAMP. The resultant effect is positive inotropy and, to a lesser degree, positive chronotropy. Glucagon is theoretically most effective after β blocker overdose, in which decreased β-adrenergic receptor activation leads to diminished cAMP production. The hormone may also provide therapeutic benefit in hypotension after calcium channel blocker overdose. 18 Glucagon is given in an initial dose of 1 to 10 mg (50 to 150 μg/kg in children). If effective in augmenting blood pressure, it can be given as a continuous infusion of 5 to 10 mg/hr (100 μg/kg/hr in children). Some preparations of glucagon are marketed as a lyophilized compound with a 0.2% phenol-based diluent for reconstitution. While single doses of such a product can be given after standard reconstitution, glucagon for continuous infusion should be reconstituted with saline to prevent phenol toxicity. Adverse effects from glucagon include hyperglycemia, nausea, vomiting, and ileus.

Calcium plays a key role in regulating cardiac inotropy through its binding to troponin C, an action that permits interaction between actin and myosin. Although most of the calcium that produces this change resides in an intracellular calcium pool, extracellular calcium does diffuse into cells and contributes to increased contractility. Although diffusion of calcium into the myocardium is "gated"-that is, it is tightly controlled-high con- hypoxia or prolonged pressure and are seen after sedativehypnotic overdoses (especially barbiturate overdose), carbon monoxide poisoning, and thermal burns. Bullae may also follow rattlesnake envenomation. Bullous lesions or soft tissue swelling should prompt evaluation for rhabdomyolysis, an occasional finding in patients following prolonged coma or severe hyperthermia, such as in cocaine abuse.

It is important to smell the patient's breath. Alcohol is the most common odor detected on the breath of an intoxicated patient in the emergency department. The accurate identification of other odors varies greatly among physicians. A fruity odor may be detectable in the patient with diabetic ketoacidosis. Cyanide poisoning can be associated with the smell of almonds. The smell of cleaning fluid suggests carbon tetrachloride poisoning. Gasoline, camphor, hydrogen sulfide, ether, turpentine, methyl salicylate, paraldehyde, phenol, and organophosphate insecticides all have characteristic odors. Arsenic and tellurium intoxication is associated with the odor of garlic.

A nasal examination may reveal chronic insufflation of cocaine. An edematous, often elongated uvula may be seen with marijuana use or exposure to corrosive agents.

Auscultation of the lungs may provide diagnostic clues. In narcotic or tricyclic antidepressant overdose, pulmonary edema may be a complication, leading to the appearance of adventitious noises. In all overdose patients, aspiration pneumonitis, the result of a depressed gag reflex, is a possibility. Inhalation of toxic gases may produce wheezing and pulmonary compromise. Pneumothorax may be detected in patients who smoke cocaine, methamphetamine, or any other heated, impure substance. Mediastinal emphysema from marijuana or crack cocaine smoking also may be detected by auscultation.

Examination of the heart may reveal a new murmur, which in an intravenous drug abuser suggests endocarditis. Bradycardia is common after the overdose of four classes of cardiac agents: calcium channel blocker, β blocking agents, digitalis preparations, and central α 2 antagonists (e.g., clonidine or guanfacine). A ventricular arrhythmia on electrocardiography in a young patient suggests cocaine toxicity. An irregularly irregular heartbeat that is new in a patient on an alcoholic binge suggests atrial fibrillation-the so-called "holiday heart" syndrome.

A boardlike abdomen in a patient with a history of spider bite is characteristic of black widow envenomation. Examination of the abdomen in an overdose patient often reveals an adynamic ileus. In patients with abdominal pain, a surgical abdomen must be ruled toxic syndrome, of any underlying disease, or concomitant trauma. Repeated assessment, especially of vital signs and of cardiac, pulmonary, and neurologic status, is critical to proper management of the toxicologic patient. The physical examination also can provide valuable clues as to the particular toxin involved (Table 2A-6) .

As part of the initial evaluation, complete determination of vital signs, including measurement of body temperature initially and throughout the emergency department assessment, is mandatory. Obtaining a core body temperature measurement may be necessary. Hyperthermia can occur with a number of ingestions and in infectious illness, but it is characteristic of poisoning with salicylates, anticholinergics, monoamine oxidase inhibitors, and dinitrophenol; it is occasionally also seen after intoxication with phencyclidine, LSD, or cocaine, especially following seizures. Life-threatening malignant hyperthermia following drug overdose may occur. Hypothermia is common and may occur because of exposure to cold, hypoglycemia, or overdose of a number of sedatives, especially barbiturates, ethanol, carbamazepine, narcotics, and phenothiazines. Bradycardia can be seen with overdose of digitalis, cholinergic agents, β blockers, and calcium channel blockers, but it also may be seen with hypothermia or spinal cord trauma. Hypertension is characteristic of intoxication with cocaine, amphetamines, phencyclidine, and sympathomimetics.

The skin should be examined for needle tracks, burns, bruises, or lacerations. Needle tracks may be confined to the groin or other areas that are not readily visible. A "boiled lobster" appearance suggests ingestion of a boric acid-containing roach powder insecticide. Generalized flushing suggests an allergic reaction, niacin overdose, anticholinergic poisoning, scombroid fish poisoning, or an alcohol-disulfiram reaction.

Diaphoresis suggests hypoglycemia, salicylate or organophosphate poisoning, hyperthyroidism, drug or alcohol withdrawal, or shock from cardiac or other etiology. Jaundice may follow overdose of acetaminophen, aspirin, iron, carbon tetrachloride, mushrooms, copper, or phosphorus. Petechiae and ecchymoses suggest coumadin overdose. Bullae may be secondary to skin out. Hepatomegaly suggests liver congestion (e.g., with pyrrolizidine toxicity).

All patients should undergo a careful neurologic examination. Issues of major concern are concomitant head trauma and spinal cord trauma in comatose patients. Serial neurologic examinations are key to proper assessment (see discussion of coma in section on Level of Consciousness).

The extremities should be evaluated to detect thrombophlebitis, fracture or dislocation, or vascular insufficiency. Rhabdomyolysis and the compartment syndrome are definite concerns in overdose patients, especially in those with prolonged coma or underlying trauma.

The toxicologic patient presenting in the acute setting often exhibits the following, either alone or in combination: coma, cardiac arrhythmia, metabolic acidosis, gastrointestinal disturbance, and seizures.

Consciousness is defined as an awareness of self and the environment. Coma is unarousable unresponsiveness. Wakefulness implies the ability to be aroused. These three functional states are mediated by the ascending reticular activating system, a tract that courses through the diencephalon, midbrain, and pons. Diseases produce coma either by diffusely affecting the brain or by encroaching upon the brainstem. Coma may be produced by (1) a supratentorial mass lesion, such as a subdural hematoma; (2) a brainstem lesion (uncommon); or (3) metabolic disorders that widely depress or interrupt brain function.

One of the most common manifestations of acute poisoning is coma. The principles of coma management are relatively straightforward. Patients in coma must be stabilized initially by establishment of an airway, proper oxygenation with continuous pulse oximetry, insertion of an IV line with normal saline, and resuscitation, if necessary (see earlier section on Emergency Management). The clinical evaluation of the comatose patient is invaluable not only in determining the depth of coma and assessing for trauma, but also in providing a baseline for repeated clinical assessment. Coma can be assessed either using the simple AVPU (Alert, responsive only to Verbal stimuli, responsive only to Painful stimuli, Unresponsive) or Glascow coma scales.

The major causes of coma in patients seen in the emergency department include poisoning (e.g., carbon monoxide poisoning), drug overdose, head trauma, cerebrovascular accident, anoxia, infection (e.g., meningitis), and diabetes and other systemic disorders such as renal failure, hepatic coma, and cardiac arrhythmia. The physician must rule out each condition before establishing the diagnosis of poisoning.

Supratentorial structural lesions are suggested by a rapid progression of signs, including changes in respiratory pattern, disconjugate gaze, lateralizing signs, or loss of doll's eyes movements.

A metabolic cause of coma may be indicated by the persistence of the pupillary light reflex; a depression of respiration and consciousness more pronounced than other neurologic signs; preceding altered mental states; asterixis or fasciculations, or both; the presence of a ciliospinal reflex; and extracranial signs, such as jaundice. Repeated assessment of the comatose patient is critical to proper management of poisoning.

Evaluation of the patient's pupils is most helpful. Midpoint fixed pupils or a unilateral dilated pupil suggests a structural lesion. Pinpoint pupils suggest overdose of opiates, clonidine, organophosphate insecticides, nerve agents (e.g., sarin), chloral hydrate, phenothiazines, or nicotine. Dilated pupils are nonspecific.

A disturbance of ocular movements (e.g., loss of doll's eyes movements) suggests a structural lesion. Nystagmus suggests intoxication with phenytoin, phencyclidine, carbamazepine, and, occasionally, ethanol.

It is important to note abnormal patterns of breathing. Posthyperventilation apnea, Cheyne-Stokes respirations, and apneustic breathing strongly suggest that a structural lesion is the cause of the patient's coma. Central neurogenic hyperventilation is a classic presentation of brainstem injury. Kussmaul breathing can occur after salicylate or dinitrophenol poisoning. Compensatory hyperventilation may accompany methanol or ethylene glycol poisoning or other toxin-producing metabolic acidosis. Respiratory arrest is a common presentation in the patient who has taken a central nervous system depressant and may lead to multisystemic dysfunction resulting from severe hypoxic injury.

Decorticate and decerebrate posturing suggests a structural lesion. It is important to realize that patients with poisoning or drug overdose (e.g., tetrodotoxin intoxication) may appear brain dead; have fixed, dilated pupils; be in an unresponsive coma; and lack the cold caloric response, yet recover fully in time.

A 12-lead electrocardiogram and continuous cardiac monitoring are essential for any patient with significant poisoning. Evidence of an arrhythmia or other important diagnostic clues may be present on electrocardiography, such as a widened QRS complex in cyclic antidepressant overdose or a prolonged QT interval in trazadone or arsenic poisoning overdose. Box 2A-5 lists common toxic causes of cardiac arrhythmia.

The patient with life-threatening cardiac arrhythmia or cardiac arrest should be managed on the basis of the general principles of resuscitation and the American Heart Association's advanced cardiac life support

Causes of a high-anion gap metabolic acidosis are listed in Box 2A-6. The assessment of metabolic acidosis includes not only arterial (or, less ideally, venous) blood gas analysis, but also studies of serum sodium, potassium, chloride, carbon dioxide, blood urea nitrogen (BUN), creatinine, glucose, acetone, serum osmolality, and urine pH, as well as urinalysis. Determination of the anion gap is helpful in the diagnosis and management of poisoning.

The clinician can measure serum osmolality either directly by determining the freezing point (osmometry) or by calculation. The formula for calculating osmolality is Serum osmolality = 2 × Na + (mEq/L) + BUN (mg/dL)/2.8 + Glucose (mg/dL)/18

When laboratory data are expressed in international (SI) units, the formula for calculation of serum osmolality simply equals 2 × Na + BUN + glucose. The normal serum osmolality is 280 to 295 mOsm/L. An osmometer measurement indicating a serum osmolality that is more than 10 mOsm/L greater than the calculated osmolality is termed an osmolar gap; it suggests the presence of an osmotically active substance that is not accounted for by the calculated osmolality. Causes of an osmolar gap are listed in Box 2A-7. The most common cause of an osmolar gap is consumption of an alcohol. The osmolar gap can be used to estimate the serum concentration of an alcohol, based on that alcohol's molecular weight (Table 2A-7) . A substance contributes to osmolality only if it achieves relatively high blood levels and has a low molecular weight. Most drugs or intoxicants cannot be detected with use of the osmolar gap.

The causes of toxic gastrointestinal disturbance are many. The patient with iron, arsenic, or ricin poisoning has severe, repeated episodes of vomiting and may develop gastrointestinal hemorrhage. Theophylline overdose also causes persistent retching. Acute lithium and arsenic poisoning characteristically produce massive diarrhea. Patients with acute mercury poisoning have a mucous-type diarrhea, with the subsequent development (ACLS) guidelines. If cyclic antidepressant overdose is suspected, administration of IV sodium bicarbonate is indicated for correction of ventricular arrhythmia or conduction disturbances. Sodium bicarbonate may also be effective in the treatment of other overdose by other agents associated with prolongation of the QRS interval, including diphenhydramine and cocaine. Administration of IV calcium chloride is the primary therapeutic measure for calcium channel blocker overdose. Use of digoxin antibody fragments is indicated for digitalis poisoning, and glucagon for β blocker overdose (see Table 2A -1). In referred patients who have already been hospitalized elsewhere, ventricular arrhythmia may be due to hyperkalemia because renal failure may have ensued; in such patients, IV sodium bicarbonate, glucose/insulin, and, if necessary, calcium chloride administration may be warranted. Magnesium has a singular role in the treatment of drug-induced prolongation of the QT interval, a conduction disturbance that is often the prelude to torsades de pointes and other lifethreatening disturbances. 19 In all intoxicated patients, correction of hypoxia, metabolic acidosis, and fluid and electrolyte disturbance serves to reduce the incidence of cardiac arrhythmias.

Digoxin and other digitalis compounds Lithium of hemorrhagic colitis. One of the most striking presentations is caused by phosphorus poisoning, which produces luminescent vomitus and flatus. The early presentation of organophosphate or nerve agent exposure is similar to that of acute gastroenteritis and is characterized by abdominal cramps, vomiting, and diarrhea, with subsequent development of neurologic signs. Poisoning from mushrooms (see Chapter 23), toxic marine life (see Chapter 25), botulism, and food (see Chapter 26) should be included in the differential diagnosis. Chemotherapeutic agents (see Chapter 56) are well-known causes of toxic gastroenteritis. The management of gastrointestinal disturbance in the toxic patient includes following the general principles of blood, fluid, and electrolyte resuscitation, when indicated; judicious use of parenteral antiemetics to control persistent vomiting; specific measures such as antidotal therapy (e.g., in iron or organophosphate poisoning); or interventional therapy, such as charcoal hemoperfusion (in theophylline overdose) or hemodialysis (in lithium overdose), when indicated.

Common agents that cause seizures are listed in Box 2A-8. Almost any drug or toxin is capable of producing a seizure. Delayed seizures occurring during a recovery period may be a sign of sedative-hypnotic or alcohol withdrawal.

Seizures should be managed first with establishment of an airway and oxygenation. Patients with a simple isolated seizure may require only observation and supportive care, whereas repetitive seizures or status epilepticus, which can be life threatening, must be managed aggressively. Some seizures are particularly difficult to control, such as those seen with theophylline or cocaine overdose.

The standard regimen for seizure control in overdose of an unknown agent is use of the full therapeutic dosages of benzodiazepines (e.g., diazepam or lorazepam), followed by administration of phenytoin or a barbiturate (e.g., phenobarbital or pentobarbital). In patients with status epilepticus, RSI may be necessary and the use of thiopental is indicated, with electroencephalographic monitoring to ensure control of electrical seizure activity; the use of additional paralytics, such as pancuronium bromide, may be warranted.

Specific measures to control seizures may be indicated, such as administration of pyridoxine for isoniazidinduced seizures.

Box 2A-9 lists specific blood studies whose results may be used for diagnosis and to direct therapy of the overdose patient. In every significant poisoning, routine studies include a complete blood count; determination of serum electrolytes, glucose, BUN, creatinine, and calcium; urinalysis; prothrombin time; pulse oximetry; end-tidal CO 2 monitoring, and 12-lead electrocardiography. Arterial blood gas analysis is necessary for evaluating respiratory status and acid-base abnormalities, particularly in the comatose or seizure patient. The measurement of serum salicylate and acetaminophen levels is generally added in the case of the patient with overdose of an unknown substance, because these agents are often co-ingestants or are contained in combination drugs. Measurement of hepatic enzymes is important in the evaluation of acetaminophen toxicity. The advantage of a toxicologic drug screen in initial management is equivocal. Box 2A-10 gives a partial list of drugs and toxins not commonly pH monitoring is helpful in the management of salicylate overdose. Urine is the best specimen to use for "drug screening" purposes. A urinalysis is also useful in the early identification of acute renal failure or rhabdomyolysis with myoglobinuria. The intravenous drug abuser requires special blood testing, such as evaluation for human immunodeficiency virus, a hepatitis profile, a blood culture to identify bacteremia, and evaluation for rhabdomyolysis.

Chest radiography is an aid for diagnosing aspiration pneumonia or pulmonary edema. Box 2A-11 lists agents that are radiopaque on plain film radiography of the abdomen. Computed tomography may be useful if underlying trauma is suspected. Finally, lumbar puncture may be indicated for ruling out meningitis in a patient with fever and coma.

OCULAR DECONTAMINATION See Chapter 15.

Being the largest and most superficial organ in the body, the skin is often subject to exposure to toxins and is affected in 7.9% of reported cases. At least 50% of occupational illnesses involve the skin. The effects of these exposures can be local or systemic (Box 2A-12) .

The skin provides many barriers to the absorption of toxins. The stratum corneum forms an important first barrier and is highly effective when it is completely intact. However, when skin wounds are present, when the wounds are wet, and when exposure is to certain highly lipophilic substances (e.g., organophosphate insecticides), significant absorption of toxin through the skin can occur. The skin of infants is notable for being more permeable than that of adults to substances of all classes. detected with routine drug screening. Further laboratory blood studies are tailored to assess the individual diagnostic and therapeutic needs of the patient. It is extremely important to remember to "treat the patient, not the lab." One should never withhold therapy while waiting for a confirmatory drug level in a critical patient, such as a patient with tricyclic antidepressant overdose who is exhibiting a widened QRS complex. In contrast, performing hemodialysis on a completely asymptomatic patient with lithium overdose on the basis of one test result indicating an elevated serum lithium concentration would be equally unwise.

Serial blood level determinations are often helpful in guiding therapy in patients undergoing hemodialysis; in patients in whom concretions have formed, such as those with barbiturate, iron, salicylates, or meprobamate intoxication; or in patients receiving antidotal therapy (e.g., serial measurement of lead level is useful in patients receiving IV CaNa 2 EDTA for management of lead poisoning).

A urinalysis is necessary. Performing a urine pregnancy test is wise in all women of childbearing age. Urine The range of dermal toxins is broad. Most of these substances are corrosive agents capable of producing burns that may become full thickness (i.e., third degree). Other types of agents are irritants, sensitizers (including photosensitizers), allergens, vesicants, and exfoliants.

As with ocular exposures, the general principles of management after exposure to dermal toxins are many. As soon as a toxic dermal exposure is recognized, decontamination efforts should begin. If the victim is immersed in a toxic fluid, the first step in management is his or her extrication without injury to the assistant. The victim should disrobe him-or herself at the scene. If the victim requires assistance, undressing should be done as safely as possible. Protective gear should be donned before assistance with decontamination is rendered. Unless the agent is highly reactive (e.g., elemental sodium), it is appropriate to wash the victim thoroughly with water, preferably in a nearby decontamination shower. Generally speaking, water should not be used to decontaminate skin in exposures to sodium, phosphorus, calcium oxide, chlorosulphonic acid, and titanium tetrachloride. When emergency medical personnel arrive to the scene, they should continue skin decontamination. Again, if the agent is known to have significant dermal absorption, emergency medical personnel should provide themselves every available level of self-protection. Certain toxins such as organophosphates can contaminate the air within the ambulance and produce ill effects among personnel if prehospital decontamination efforts are inadequate.

Upon arrival at a health care facility, the victim may require quarantine, depending on the nature of the agent. Skin decontamination in a decontamination shower should continue. Particular caution should be exercised in the decontamination of victims of organophosphate insecticide or organophosphate-based nerve gas exposure; health care personnel have been overcome secondarily by contaminants on victims when they assisted in their care without donning proper protective gear.

Water is the most commonly used skin decontaminant and is highly effective for most dermal exposures. In select cases, specific agents should be used to assist in management (Table 2A-8) .

Without exception, toxin-induced skin burns should be treated according to existing burn management guidelines. These include wound débridement and dressing, monitoring for infection, fluid management, and surgical consultation when appropriate.

After the ingestion of a toxic substance, with the exception of agents that have a direct toxic effect on the gastrointestinal tract (e.g., iron or corrosives), that substance must be systemically absorbed and circulated before it reaches a target organ and exerts clinical toxicity. Preventing the absorption of toxin is therefore the foundation of treatment after ingestion of a toxin has occurred. The term gastrointestinal decontamination (GID) has been coined to describe those interventions that are useful in preventing toxin absorption. With the exception of rare interventions such as gastroscopy, GID is considered to have only three components: (1) gastric evacuation, (2) administration of adsorbent, and (3) catharsis. Gastric evacuation is accomplished through gastric lavage. Syrup of ipecac, once used as an emetic for treatment of toxic ingestions, is no longer routinely recommended for this purpose. There are several agents that can adsorb toxic substances, reducing their systemic absorption and subsequent toxicity (Table 2A-9) . Of these, activated charcoal is the most important adsorbent; there are few substances that activated charcoal will not adsorb (Box 2A-13). Catharsis, once an integral part of management, also has a diminishing role in the treatment of poisoned patients.

Gastrointestinal decontamination is discussed in greater detail in Chapter 2B.

With the development of sophisticated new antidotes and the changing spectrum of clinical poisoning, the use of emergency antidotes is assuming an increasing role in clinical toxicology. However, antidotes are useful in only a fraction of poisonings. 1 Table 2A -1 lists the common emergency antidotes. In poisoning with a known substance, early antidote use is indicated for emergency stabilization, often within the first hour. (4) urine alkalinization. Potential roles for these interventions are found in Table 2A-10 and Box 2A-14. Further discussion of elimination of a substance that has already been absorbed is provided in Chapter 2C.

Observation and supportive care are the mainstays of therapy for the poisoned patient. Indiscriminate use of gastric lavage, antidotes, and drugs should be avoided. All too often, the toxic agent is unknown, multiple drugs have been taken, or the patient is too unstable to undergo an aggressive therapy such as hemodialysis. Monitoring of vital signs, cardiac telemetry, and oxygen saturation is mandatory.

Hospitalization in an intensive care unit is generally indicated for the patient with serious poisoning. Multisystem monitoring with blood studies and assessment of other parameters are indicated, and upon detection of any specific system disturbance, appropriate subspecialty consultation is warranted.

Some agents such as iron, mercury, acetaminophen, paraquat, carbon tetrachloride, and Amanita phalloides toxin have a latent phase, in which the patient appears to recover from the initial insult, only to decompensate 24 to 72 hours postingestion. Patients with overdose of sustained-release capsules, such as calcium channel blocker or theophylline preparations, also may have delayed manifestation of poisoning. Rarely, the tricyclic antidepressants have been known to cause fatal arrhythmia up to 3 days following ingestion. Some effects are not seen until later, such as hypertension following phencyclidine ingestion, hemorrhagic colitis following mercury ingestion, and disseminated intravascular coagulation following snakebite. One must also watch for the delayed pulmonary (see Chapter 9), hepatic (see Chapter 11), renal (see Chapter 12) , and hematologic (see Chapter 14) manifestations of poisoning.

Hyperbaric oxygen can provide oxygen at pressures greater than normal atmospheric pressure, which is given as 1 atmosphere (atm) or 760 mm Hg. Three atmospheres is the maximal pressure humans can tolerate over a reasonable period of time; hyperbaric units generally do not exceed 2.5 to 2.8 atm. The use of hyperbaric oxygenation is becoming standard therapy for patients with significant carbon monoxide poisoning, and it is becoming more available (see Chapter 87) for carbon tetrachloride poisoning, and possibly for cyanide and hydrogen sulfide poisoning.

Admission to an intensive care unit following antidotal therapy for further management and observation is generally indicated. Further discussion of each antidote and its use is provided in the chapter on the specific poison. Patients may require observation because of an underlying disease that may be exacerbated because of the overdose, such as diabetes, congestive heart failure, cardiac rhythm disturbances, or chronic lung disease. Observation may be necessary to evaluate or treat complications, such as in a patient with an overdose who fell and sustained trauma or in a patient who develops aspiration pneumonitis or interstitial pulmonary edema.

The IV use of illicit drugs is associated with multiple complications; observation is especially indicated for patients experiencing these complications, which include bacterial endocarditis, rhabdomyolysis, and neurologic sequelae.

The disposition of the patient with intoxication may involve medical and psychiatric care as well as social follow-up. All patients admitted to the hospital with intentional overdose warrant close observation and the institution of suicide precautions. These patients may need appropriate restraint or observation if further injury or additional overdose attempts are to be prevented. Overt or subtle attempts or gestures indicate the need for psychiatric evaluation. Often, outpatient follow-up is necessary; for example, a child with kerosene ingestion may require further examination and chest radiography, and a child who has ingested anticoagulant rat poison may require serial outpatient monitoring of prothrombin times. The issue of child abuse or neglect may need consideration whenever a pediatric patient is treated. Finally, long-term follow-up may be indicated; for example, hepatitis and HIV testing may be needed in the IV drug abuser. CONCEPTS is very difficult in a single center or even multiple centers. Confirmation of exposure by laboratory studies is often unavailable, requiring the clinician to depend on the history (which may be inaccurate) and physical findings (which may be nonspecific) in arriving at the diagnosis of poisoning. There are likewise problems with randomization schemes, 5 and basic inclusion and exclusion criteria.

In addition, there are problems with the process of evidence-based reviews themselves. Language bias occurs in some evidence-based reviews, 6 such that non-English language publications, potentially of good quality, are often excluded from consideration. In addition, the premises on which the evidence review is based may not be universally applicable. The conclusions reached, based on studies performed in urban tertiary care centers where hospitals are capable of providing state-ofthe-art intensive care, may not apply equally to a remote hospital in a rural area, or even less so to a clinic in a developing country. Thus, while careful consideration should be given to position papers and consensus conference proceedings, individual judgment will necessarily enter into the decision to employ any decontamination method for a given case of exposure. Unfortunately, an unintended consequence of the publication of position papers is that they may in fact squelch further research. 5

A number of methods of decontamination exist and may be employed depending on the circumstances of exposure. Decontamination of the skin and eyes, as well as the gastrointestinal tract, will be discussed. Extracorporeal methods of purification (hemodialysis, charcoal filtration, etc.) are covered in Chapter 2C.

Decontamination of the skin and eyes is employed to reduce local tissue injury (chemical burns or irritation) and/or absorption that may result in systemic consequences. The decision to perform skin and eye decontamination is often based on the presence of symptoms, such as burning or itching. This is an insensitive evaluation method; thus, decontamination of these organs should primarily depend on careful consideration of the circumstances of exposure and the physical and toxicologic properties of the compound. Protection of personnel during eye and skin decontamination is important to avoid secondary contamination of health care providers. The choice of personal protective equipment is beyond the scope of this chapter. The reader is referred to Chapter 103 and to the recent Occupational Safety and Healthy Administration (OSHA) best practices document. 7

In almost all cases, clothing, jewelry, and shoes should be rapidly and completely removed prior to washing. It has been suggested in studies of radionuclide contamination that this process alone can remove the majority of a contaminant. This will, of course, depend on the physical properties of the toxicant but is a logical first step. Solids and dust should be gently brushed away before decontamination with a solution. In this way, the heat generated from water reactive compounds can be diminished, as is caking of solids.

In some cases, water or other decontamination solutions may be unavailable or in short supply. In such cases, dry decontamination, using an absorbent material (charcoal, flour, earth) followed by brushing or wiping may be attempted.

The selection of skin decontamination solutions has historically been a choice between water for polar (watersoluble) compounds and water plus a mild soap or detergent for nonpolar compounds. Water alone is typically employed for initial eye decontamination. Physiologic saline and other saline-based eye washes are often employed for eye decontamination in health care and industrial settings. The use of these solutions has been largely empiric and practical, based on widespread availability rather than on critical evaluation of their efficacy. Yano and colleagues studied water irrigation of burns involving 1 mol/L HCl in rats, measuring subcutaneous pH as a measure of penetration of the acid and efficacy of decontamination. These investigators found that maximal subcutaneous pH depression had occurred by 7 minutes following application of the acid. Animals undergoing water irrigation at 1 or 3 minutes postexposure demonstrated some benefit; however, animals irrigated at 10 minutes had no appreciable improvement in pH, compared with control. 8 These investigators had previously demonstrated lack of efficacy of water irrigation after 10 minutes in a 2N NaOH burn model. 9 Clearly time is of the essence in irrigation of corrosive exposures. With regard to eye exposures, Kuckelkorn and colleagues 10 pointed out that water is hypotonic to corneal stroma, allowing edema and increased penetration by chemicals. They recommend use of amphoteric solutions to avoid these problems.

In recent years, a number of novel decontamination solutions have come to market. Diphoterine (Prevor Laboratories, Moulin de Verville, France), an amphoteric solution has been proposed for use in both acid and alkali exposures of eyes and skin, with emphasis on immediate irrigation (at the scene of the incident) rather than for hospital treatment. A recent article 11 that compared Diphoterine to physiological saline in alkaline eye burns demonstrated more rapid healing of grade 1 and 2 burns with Diphoterine than with saline. The study suffers from a number of deficiencies, including lack of randomization and significant delays and variability in initial irrigation (in the field) and secondary irrigation in hospital (with either Diphoterine or saline). Nonetheless, the time to corneal reepithelialization was approximately six times as long after saline for grade 1 burns and almost twice as long for grade 2 burns, compared with Diphoterine-treated eyes. There were an insufficient number of grade 3 burns to detect any significant difference between groups. Despite its shortcomings, this study suggests the potential for improved healing using Diphoterine in alkaline eye burns and warrants further investigation. The same study group had previously shown in a study of ammonia burns in New Zealand albino rabbit eyes that early application (within 10 minutes) of Diphoterine rapidly corrected pH, whereas saline irrigation did not. Furthermore, saline-treated eyes had stromal edema, whereas Diphoterine-treated eyes did not. 12 The need for early irrigation is emphasized by this experimental study; however, the cited clinical study demonstrates some benefit even with delayed treatment (mean 4.7 hours). 11 Cavallini and Casati studied Diphoterine in experimental skin burns in rats involving 52% hydrochloric acid. Skin flushing with Diphoterine reduced substance P release during the first 48 hours after burn and was associated with better wound healing and higher concentrations of β-endorphin 7 days later when compared with normal saline or 10% calcium gluconate. 13 Hall and colleagues 14 Most authors recommend against neutralization of acid and base burns due to the risk for exothermic reaction leading to thermal burns. Simple dilution with water or milk after oral ingestion of corrosives is uncommon in Europe, but the norm after ingestions in the United States. Penner demonstrated in an ingestion model that dilution of concentrated sulfuric acid with an equivalent volume of water results in a temperature elevation of approximately 80°C. Neutralization results in even greater heat production. He suggested that vigorous gastric aspiration (likewise considered controversial given the risk for esophageal or gastric perforation) prior to cold fluid lavage is the treatment of choice in patients treated immediately following acid ingestion. 15 A recent experimental study involving irrigation of rat skin exposed to 2N NaOH with 5% acetic acid suggests that neutralization may not always be contraindicated. The investigators demonstrated more rapid correction of pH, no difference in peak temperatures, and improved outcomes in animals treated with 5% acetic acid rather than water. These findings cannot inundated with contaminated casualties. Decontamination protocols that are not deployable within minutes (preferably 5 to 10 minutes) after an incident may serve little purpose in protecting the facility and health care providers from contamination. Serious consideration should be given to the complexity of the setup process, one that typically will not be employed frequently. One example of a locally developed immediate deployment sheltered outdoor decontamination unit is shown in Figure 2B -4. This unit can be deployed in less than 2 minutes and provides for decontamination of both ambulatory and stretcher patients.

It is common practice to utilize physicians, nurses, and other critical emergency department (ED) staff to do decontamination. This is probably not advisable for a number of reasons. First, decontamination does not require great technical skill, and very little stabilization be generalized, but indicate the need to readdress current dogma regarding neutralization. 16 

The ideal duration of eye and skin decontamination is yet to be determined. Recommendations for copious irrigation are common, without further precision. Fifteen minutes is probably the most commonly recommended duration for eye irrigation. Kuckelkorn and colleagues have recommended a minimum of 30 minutes for eye irrigation after chemical exposures. 17 One retrospective study of 172 eye burn victims suggested that outcomes were better among those who had prolonged (1 to 2 hours) irrigation. 18 Irrigating to a relatively neutral pH is often attempted. If this is employed, it is helpful to remember that the pH of saline for intravenous injection (often employed for eye irrigation) is appreciably acidic (approximately 4.5) so that one should wait a few minutes after irrigation to measure the pH in order to allow the patient's own tears to replace the saline irrigation fluid in the conjunctival sac.

The appropriate temperature for decontamination fluids has also been poorly studied. While increasing temperature of decontamination liquids reduces the likelihood of hypothermia in inclement climes and improves water solubility, heat also dilates skin pores and blood vessels, which may lead to increased absorption. If excessive, it may aggravate chemical or thermal burns. OSHA's recently published Best Practices Guide for First Receivers 7 recommends a 5-minute wash with tepid water, based on recommendations from the U.S. Army for chemical decontamination. 19 Mcintyre and colleagues recommend "warm, but not excessively warm" water for decontamination. 20 Eye irrigation should be performed with room temperature solutions. Careful thought should be given to environmental conditions and risk for exposure when decontamination must be done out of doors.

The duration and type of skin and eye decontamination performed in mass casualty situations may vary from that in cases involving single patients based on triage considerations. Management of mass casualties is covered in Chapter 103.

A great number of options have been developed in recent years for skin decontamination, due to the increased interest in hazardous materials and chemical terrorism issues. Examples of decontamination stretchers and facilities are shown in Figures 2B-1 to 2B-3. Many others exist. One of the overriding considerations in determining the kind of decontamination facilities and equipment to purchase should be their capacity for rapid deployment. The experience with the sarin terrorist attack in Tokyo revealed that hospitals may be rapidly can be performed during the decontamination process. Furthermore, if there are problems and decontaminating personnel are unable to continue, such a practice results in incapacitation of primary emergency care providers. Neither should security personnel, in general, be tasked with this responsibility, since a mass casualty situation will require their services for security itself. A number of alternatives have been suggested. Some hospitals train housekeeping staff to perform decontamination. Others have nurses from other units (burn units have extensive experience in wound care and cleaning) don protective clothing and prepare for decontamination while the ED staff prepares the decontamination facility and the ED proper to receive casualties.

Decontamination of radionuclides from the skin may be performed in a manner analogous to chemical exposures. Uranium hexafluoride exposures should be treated in a manner analogous to that for hydrofluoric acid burns. Wounds heavily contaminated with radionuclides may require surgical débridement and should be covered after initial decontamination. See Chapter 104 regarding radiation emergency management for further information.

Hydrogen fluoride, ammonium biflouride, and other soluble fluorides may pose a unique case in terms of decontamination. While an initial quick flush with water is appropriate, the patient may benefit from rapid decontamination with a substance that can bind the fluoride. Hexafluorine has been reported to prevent significant skin burns in both humans and experimental animals when applied immediately after exposure. 21, 22 Two randomized studies in rats found, however, that Hexafluorine was no better than water in preventing electrolyte disturbances caused by fluoride 23, 24 and perhaps less effective than water or water plus calcium gluconate in reducing burn injury. 24 Thus, Hexafluorine's efficacy in fluoride injury remains controversial. 25 Researchers in hydrogen fluoride manufacturing facilities frequently recommend skin irrigation with benzalkonium chloride solution based on studies performed in pigs. 26, 27 Calcium gluconate irrigation of skin 28 and eyes 29 has also been recommended to bind fluoride and prevent further injury. Other investigators have found calcium gluconate to be no more effective than water or saline and perhaps detrimental in eye irrigation. 30, 31 In summary, the ideal decontamination of hydrogen fluoride burns to skin and eyes remains to be determined.

Phenol is unique in its capacity to cause nonpainful burns and systemic toxicity. Water irrigation may increase phenol absorption. 32 Generally accepted skin irrigation therapy consists of isopropanol 32, 33 or polyethylene glycol solutions. 32,34

White phosphorus is pyrophoric (i.e., it burns in the presence of air). It is thus indispensable to provide adequate copious irrigation with water. The application of copper sulfate has been recommended, 35 but an experimental study in rats demonstrated increased lethality in animals receiving topical treatment with 1% copper sulfate. 36 Eldad and colleagues have evaluated various phosphorus burn treatment recommendations and have concluded that copious water irrigation is superior to other treatments. 37

High-pressure injection injuries should be mentioned here due to their requirement for special care and high 

All eye and skin exposures resulting in violation of the epithelium should prompt consideration of the need for tetanus toxoid administration.

The only emetic currently recommended for use in humans is syrup of ipecac. Previously employed emetics continue to be responsible for significant pathology, however. The administration of table salt has long been condemned in the literature 40 ; nonetheless, recent reports illustrate that its use has not been completely abandoned and that it remains potentially lethal. 41, 42 Liu reported that copper sulfate continues to be used in China for emetic purposes and has resulted in multiple fatalities in recent years. 43 The dose of ipecac is 5 to 10 mL in children 6 to 12 months of age or 15 mL in children 1 to 12 years of age. This should be followed by 10 to 20 mL water per kg body weight. Older children and adults should receive 30 mL ipecac followed by 200 to 300 mL of water. Ipecac is contraindicated in the following situations:

Ingestion of petroleum distillates Ingestion of strong acids or bases Ingestion of strychnine or other proconvulsants Unconsciousness or absence of gag reflex Ipecac has a number of potential adverse effects, including lethargy, cramps, and diarrhea. When taken chronically, it may induce muscle cramps and both skeletal 44 and cardiac myopathy. 45 It is subject to frequent abuse by patients with eating disorders, a factor that led to a review of the product's safety by the FDA in 2003.

The American Academy of Clinical Toxicology (AACT) and the European Association of Poisons Centres and Clinical Toxicologists (EAPCCT) reviewed the medical literature regarding the use of ipecac in 1997. 46 This combined task force more recently examined their previous findings and literature that had appeared since their earlier review. In brief, they concluded that syrup of ipecac should not be administered routinely in the management of poisoned patients. They pointed out that in experimental studies the amount of marker removed by ipecac was highly variable and diminished with time. Furthermore they concluded that there is no evidence from clinical studies that ipecac improves the outcome of poisoned patients and recommended that its routine administration in the ED be abandoned. Finally, they signaled the absence of data to support or exclude ipecac administration soon after poison ingestion, the administration of ipecac potentially reducing the effectiveness of activated charcoal, oral antidotes, and whole bowel irrigation (WBI). 47 There are indications that the use of syrup of ipecac has dramatically declined in recent years, and it is likely that this trend will continue. 48, 49 Bond examined the evolving use of ipecac in U.S. poison centers, comparing rates of referral to the ED and moderate or greater outcomes in patients younger than 6 years with unintentional ingestions. This comparison was carried out according to the frequency with which centers recommended use of ipecac. Overall, use of ipecac was extremely rare (1.8%) and significant adverse outcomes even lower (0.6%). Comparing the two groups of 32 centers each, there were no significant differences in referral rates or adverse outcomes. Bond concluded that there was no reduction in resource utilization (ED referral) or improvement in patient outcome from the use of syrup of ipecac at home and that while the data could not exclude a benefit in a very limited set of poisonings, such a benefit remained to be proven. Shannon, in an editorial in the same issue, sounded the demise of ipecac on the basis of lack of proven efficacy, changing patterns in poison center approaches to the management of pediatric ingestions (including preference for activated charcoal when decontamination is indicated), and the move by the FDA to rescind ipecac's over-the-counter status. 50 This prediction was prescient, since the American Academy of Pediatrics, based on Bond's article and the factors cited by Shannon, revised its position statement on ipecac use, calling for abandonment of the regular stocking of it in the home. 51 More recently, a U.S. government-convened review panel of experts published their conclusions regarding ipecac use. 52 The panel concluded that the use of ipecac syrup might have an acceptable benefit-to-risk ratio when:

There is no contraindication to the use of ipecac syrup. There is substantial risk of serious toxicity to the victim. There is no alternative therapy available or effective to decrease gastrointestinal absorption (e.g., activated charcoal). There will be a delay of more than 1 hour before the patient will arrive at an emergency medical facility. Ipecac syrup can be administered within 30 to 90 minutes of the ingestion. Ipecac syrup administration will not adversely affect more definitive treatment that might be provided at a hospital.

Given these restrictions, rural residents might consider keeping ipecac on hand for home use under poison center direction. Otherwise, these recommendations sharply limit the applicability of the drug and, thus, the induction of vomiting in general. are many unknowns in any clinical trial, the most significant of these being the time between ingestion and treatment and the amount of toxicant ingested. It is fair to say that the evidence for efficacy is currently deficient, but that lack of efficacy has not been proven either.

The use of endoscopy in the diagnosis of caustic injuries is addressed in Chapter 98. Its use in the retrieval of foreign objects, such as batteries, 59 firearm cartridges, 60 and various pill fragments [61] [62] [63] [64] [65] [66] has been reported in humans and studied in animals, 67 but has not been systematically addressed in humans. Faigel and colleagues report that endoscopic use of the Roth net was most effective in removal of button batteries. 67 Like other forms of decontamination, endoscopy to retrieve tablet fragments has been associated with significant complications; thus, the decision to perform endoscopy in these circumstances should be carefully weighed against the risks. 62

Surgical gastrointestinal decontamination has been employed for button battery ingestions, 68-70 cocaine and narcotic drug packets, [71] [72] [73] [74] [75] [76] [77] and bezoars of iron 78 and theophylline, 79 among others. Batteries passing the esophagus usually are expelled in the feces and are generally believed to require no intervention, although recent reports of early battery leakage have called the "wait and see" approach into question. 80, 81 Button batteries, when impacted in the esophagus, should generally be removed by endoscopy unless perforation is suspected. 59, 67, 82 The trend toward use of smaller batteries by manufacturers has decreased the incidence of this problem. In the case of cocaine and heroin bodypackers/stuffers, many cases can be managed conservatively with WBI or other purgatives. Most researchers agree, however, that acute toxicity (drug leakage) and bowel obstruction are indications for immediate laparotomy. 71, 73, 75 

Charcoal binds to diverse substances, rendering them less available for systemic absorption from the gastrointestinal tract. It is obtained as a product of pyrolysis of numerous organic compounds (petroleum, wood, peat) and "activated" by heating it to 600º F to 900º F, in the presence of steam, carbon dioxide, or air. This gives the product a small particle size and large surface area. While charcoal adheres to many substances, a significant number of compounds and classes of compounds are poorly absorbed by charcoal. These include metals (lithium, sodium, iron, potassium) and alcohols. Thallium appears to be an exception, being relatively well absorbed by charcoal. 83 

The employment of gastric lavage is controversial and varies markedly depending on geographic area and the background and training of the practitioner. Gastric lavage involves blind placement of a large-bore gastric tube into the stomach, in a patient who can either protect his or her own airway or in whom the airway has been protected by an endotracheal tube, with the goal of removing toxicant remaining in the stomach through a combination of instillation of water or physiological saline, followed by suction or gravity-induced drainage. This cycle of instillation/drainage is repeated until the effluent is clear or until several liters of water/saline have been passed through the tube. This procedure has been widely popular in the past and continues to be employed in many EDs around the world. It is, however, a largely unproven therapy.

The indications for gastric lavage are recent ingestion (generally less than 1 hour, unless the ingestion involves agents that decrease gastric motility, such as anticholinergics) of a substance of sufficient quantity to be likely to cause serious harm in the absence of removal. The procedure should be given greater consideration in ingestions for which inadequate treatment modalities exist (paraquat) or in cases where delivery of proven effective therapy (antidotes or extracorporeal removal) is likely to be delayed.

Ingestion of low-viscosity petroleum products, corrosives (acids and alkalis) and inability to protect the airway (unless tracheal intubation has been performed beforehand) are contraindications to gastric lavage.

Serious adverse effects of gastric lavage are relatively rare but may be significant. The procedure may induce hypoxia, 53 perforation of the gastrointestinal tract or pharynx, 54,55 fluid and electrolyte abnormalities, 56 inadvertent tracheal intubation, as well as aspiration pneumonitis. 57 Tracheal intubation is not completely protective against aspiration.

The AACT/EAPCCT recently reviewed the animal and clinical literature regarding gastric lavage and published a position statement, 58 which states in part that gastric lavage should not be employed routinely, if ever, in the management of poisoned patients. The study group pointed out that in experimental studies, the amount of marker removed by gastric lavage is highly variable and diminishes with time and that few clinical studies have demonstrated a beneficial effect on outcome.

The quality of the gastric lavage literature is, for the most part, lacking. Few studies have the power to detect significant differences in outcome for a single toxicant, and it seems unscientific to compare outcomes after ingestion of widely varying products. Furthermore, there 38 

Activated charcoal products containing sorbitol should be avoided where possible because (1) the efficacy of cathartics is lacking (see below); (2) sorbitol is emetogenic and can increase the risk for vomiting the charcoal; and (3) sorbitol administration in infants is associated with dehydration and other life-threatening events.

Activated charcoal is administered as a slurry, either in water or sorbitol, orally or via a nasogastric tube. Dose recommendations vary, but generally a larger dose is considered better, to assure that binding capacity exceeds the amount of toxicant present. The recommended dose is 0.5 to 1 g/kg in children or 25 to 100 g in adults.

In general, to be maximally effective, charcoal should be administered as soon as possible after ingestion of the toxicant, preferably within 1 hour. Green and colleagues studied this issue in healthy volunteers in a randomized crossover study. After giving 4 g (the equivalent of eight extra-strength tablets) of acetaminophen to patients, then giving charcoal at 1, 2, or 3 hours after ingestion, they found no differences in the area under the curve of plasma acetaminophen. The investigators stated that "data do not support the administration of activated charcoal as a gastrointestinal decontamination strategy beyond 1 hour after drug overdose." 84 While there are obvious problems in extrapolating toxicokinetic results from a study involving a nontoxic dose to all overdoses, the results do suggest that benefit clearly decreases over time.

As for most decontamination measures, the indications for single dose activated charcoal are controversial. The recently released revision of the Single-dose Activated Charcoal Position Statement of the AACT/ EAPCCT states that single-dose activated charcoal should not be administered routinely in the management of poisoned patients, but that it may be considered if a patient has ingested a potentially toxic amount of a poison (which is known to be adsorbed to charcoal) up to 1 hour previously. The researchers state that the potential for benefit after 1 hour cannot be excluded. Finally, they emphasize that there is no evidence that the administration of activated charcoal improves clinical outcome. 85 

Charcoal administration is generally considered contraindicated in ingestions of caustics, since it is probably ineffective in reducing their potential for harm and furthermore makes endoscopy difficult. Charcoal generally should not be administered when there is a high risk for gastrointestinal hemorrhage or perforation. Charcoal is likewise contraindicated in any patient in whom the airway protection is not assured. It should not be administered in the presence of hydrocarbons with high aspiration potential. Charcoal should not be administered in the case of ileus or mechanical bowel obstruction.

One of the most common adverse events associated with charcoal administration is vomiting, which occurs in approximately 7% to 15% of patients. Abdominal bloating is also quite common. Both diarrhea and constipation may occur. Complications have been described, including pulmonary aspiration and direct administration into the lungs via misplaced nasogastric tube. Aspiration appears to be relatively rare, but may have serious consequences. 57, [86] [87] [88] [89] 

Multiple-dose activated charcoal (MDAC) has been proposed for use in the case of drugs that undergo extensive enterohepatic or enteroenteric circulation. Drugs with small volumes of distribution are particularly susceptible to removal by adsorption to charcoal in the gut, which has sometimes been referred to as "gastrointestinal dialysis." Although experimental and volunteer studies have demonstrated that MDAC increased elimination of a number of compounds, there is little proof of clinical benefit.

The AACT/EAPCCT has concluded that although many studies in animal and volunteer studies have demonstrated MDAC increases drug elimination significantly, there are no controlled studies in poisoned patients that demonstrate MDAC reduces morbidity and mortality. Pending further evidence of direct benefits, the study group recommended that MDAC be considered only if a patient has ingested a life-threatening amount of carbamazepine, dapsone, phenobarbital, quinine, or theophylline. 90

The contraindications for MDAC are essentially those of single-dose activated charcoal. The admonition for use in intestinal obstruction is of even greater import in the case of MDAC. The presence of decreased peristalsis (often associated with anticholinergic drugs and opiates) should provoke extreme caution in the administration of MDAC.

Prussian blue is an effective absorbent for the management of thallium and cesium intoxications. See Chapters 75 and 104 for further information.

Fuller's earth is often recommended for gastrointestinal decontamination of paraquat (see Chapter 78) . Although effective for this purpose, this substance is found in few hospitals. Activated charcoal is an effective absorbent of paraquat and should be employed when Fuller's earth is not available. 91 hypermagnesemia may result in cardiac dysrhythmias. Elderly patients and those with renal dysfunction are at particular risk. [93] [94] [95] Massive doses of cathartics may result in cardiopulmonary arrest. 93

WBI involves the administration, by mouth or nasogastric tube, of large amounts of an iso-osmotic polyethylene glycol electrolyte solution (Go-Lytely [Braintree Laboratories, Braintree, MA], Co-Lyte [Schwarz Pharma, Mequon, WI], and others) with the goal of removing unabsorbed toxicant from the gastrointestinal tract as rapidly as possible by rectal expulsion. One rationale for its use includes the fact that some compounds are poorly absorbed by charcoal, particularly iron and lithium. WBI may be of particular interest in the case of sustainedrelease or enteric-coated compounds and in the case of drug packets (body packers). The AACT/EAPCCT's consensus panel concluded that WBI should not be used routinely and that there is no conclusive evidence that it improves the outcome of poisoned patients. Based on evidence from volunteer studies, the group recommended that WBI be considered for potentially toxic ingestions of sustained-release or enteric-coated drugs, particularly in those patients who present more than 2 hours after drug ingestion. They more strongly endorsed WBI for patients who have ingested substantial amounts of iron because the morbidity is high and there are no other effective options for gastrointestinal decontamination. Another potential indication cited for the use of WBI is expulsion of ingested packets of illicit drugs. 96 

Polyethylene glycol electrolyte solution (e.g., Go-Lytely, Co-Lyte, NuLytely [Braintree Laboratories, Braintree, MA]) is administered by mouth or nasogastric tube at 25 to 40 mL/kg/hr until the rectal effluent is clear or until the desired effect is otherwise demonstrated (e.g., passage of drug packets demonstrated by imaging studies). Computed tomography (CT) with contrast has often been used to identify retained packets, but a recent case report demonstrated incomplete sensitivity of CT to detect all unexpelled drug packets. 72

WBI is contraindicated in the presence of mechanical or functional (ileus) bowel obstruction or perforation and in the presence of significant gastrointestinal hemorrhage. It should likewise be avoided if the patient is hemodynamically unstable.

Nausea and vomiting are not uncommon. Abdominal bloating and cramping may occur. Vomiting in the case of an unprotected airway may result in pulmonary aspiration.

Cathartics comprise another group of compounds recommended since ancient times for the purpose of eliminating toxicants from the gastrointestinal tract. The two most common categories of cathartics are the magnesium salts (e.g., magnesium citrate, magnesium sulfate) and nondigestible carbohydrates (e.g., sorbitol). Despite their long history of use, there is virtually no evidence of their efficacy. On the contrary, cathartics may induce significant harm in certain groups of patients, particularly children and those with renal disease.

There are no evident indications for the use of a cathartic alone in the treatment of poisoning. 92 An AACT/EAPCCT position statement concluded that experimental data are conflicting regarding the use of cathartics in combination with activated charcoal. The study group found no published clinical studies that investigated the ability of a cathartic, with or without activated charcoal, to reduce the bioavailability of drugs or to improve the outcome of poisoned patients. They went on to say that based on available data, the routine use of a cathartic in combination with activated charcoal is not endorsed and that if a cathartic is used, it should be limited to a single dose in order to minimize adverse effects of the cathartic.

The dose of sorbitol is approximately 1 to 2 g/kg. 92 When given in combination with activated charcoal for single dose-activated charcoal therapy, the dose should be determined on the basis of charcoal dosing. If multiple doses of charcoal are to be administered, repeated use of sorbitol is not recommended. For magnesium citrate, the dose is 4 to 6 mL/kg in children and 300 to 480 mL in adults.

Cathartics are contraindicated in the presence of bowel obstruction, in the absence of bowel sounds, or in the case of recent bowel surgery or intestinal perforation. They should likewise not be employed in the case of corrosive ingestions or when significant electrolyte disturbances, dehydration, or hemodynamic instability are present. Magnesium-containing cathartics must be avoided in patients with renal insufficiency and heart block. Caution should be employed in patients at extremes of age.

Cathartics frequently cause cramping, nausea, and vomiting. Significant dehydration may occur if catharsis is excessive, with resultant hypotension. Cathartic-related 40 

The decision to employ decontamination methods in an individual case must be determined based on the factors present in that individual case.

First and foremost in the decision to attempt decontamination is a determination of whether a significant exposure has occurred. This is critical for numerous reasons: (1) needless decontamination procedures may delay other definitive therapy for systemic toxicity; (2) conversely, failure to adequately decontaminate the skin may increase morbidity of contaminated patients and result in secondary contamination of health care providers and facilities; and (3) decontamination, as discussed, is not without risks. It is vital to recall Hippocrates' admonition: Primum non nocerum. Dose/ exposure assessment is extremely difficult on an acute basis due to the great number of unknowns. Young children cannot recount the quantity or quality of what they have ingested. Self-harm attempts are often accompanied by attempts to conceal or, conversely, to exaggerate the consumption of potentially toxic compounds. It is rare that contemporaneous exposure information (air concentrations or even product identification) is available after environmental exposures associated with hazardous materials releases or acts of terror. Fear associated with these events may result in psychogenic illness at times indistinguishable from that of the toxic exposure. When doubt exists, it may be safer to decontaminate, but this should be a considered decision.

Once it is established that an exposure has occurred (or if exposure cannot be excluded) and some attempt has been made to determine the magnitude of the exposure, one must examine the toxic potential of the compound(s) in question, keeping in mind that the toxicity of combined substances is not always equal to the sum of their individual toxicities. Approaches to the treatment of poisoning are deeply rooted in personal experience and colored by bias in the literature. Recent studies have reexamined the need to decontaminate victims of certain exposures that were previously approached aggressively from a therapeutic standpoint. 97, 98 

Decisions around decontamination must be individualized. A suggested approach is found in Figure 2B -5. This nonvalidated algorithm should simply be considered a pathway for considering options. There are numerous potential exceptions to the general suggestions in the figure.

One might consider gastric lavage alone in the case of presentation of poisoning within 1 hour of ingestion by a highly toxic compound that is not readily absorbed by charcoal. Lithium is one such example.

Reiterating, gastric lavage is most likely to be effective in an early-presenting, potentially lethal ingestion. Cyanide is an example of a highly toxic compound that might be removed by lavage, but is also readily absorbed by charcoal.

Yes. Illicit drug packets containing cocaine or heroin may leak. A dose of activated charcoal given prophylactically (in the absence of symptoms) could theoretically absorb eventual leakage, while WBI accelerates passage of the packets. As a reminder, clinical evidence of toxicity (leakage) is an indication for laparotomy. Similarly, charcoal followed by WBI may be indicated for ingestions of enteric coated tablets.

In cases in which ingestion of a substance known to be effectively eliminated by WBI (such as lead, zinc, or iron) is not recent (and thus not likely to benefit from gastric lavage) and when the substance is not readily absorbed by charcoal, WBI alone may be indicated.

It should be clear from the discussion that the previously common "reflex arc" of ingestion-decontamination should not apply. The decision to apply a particular procedure or combination may not be simple. For this reason, consultation with a regional poison center and/or medical toxicologist is strongly suggested in cases of uncertainty. 1. Irritants, corrosives, and substances toxic by skin absorption should be removed. Liquids with high volatility and potential for secondary contamination (organic solvents) should likewise be removed. When in doubt, decontamination is appropriate; however, life-saving interventions (ABCs) take precedence over decontamination. Personnel should wear protective garments appropriate to the hazard. 2. If the history is reliable and the ingestion is clearly nontoxic, no decontamination is required. The urge to "do something" should be weighed against the maxim to "first, do no harm." 3. Single-dose activated charcoal (SDAC) is considered most effective when administered less than 1 hour after ingestion of a toxic substance. There is insufficient evidence to support or condemn its use with toxic ingestions presenting more than 1 hour later. In general, metals (lithium, iron, but not thallium) and alcohols are poorly absorbed. 4. Multiple-dose activated charcoal (MDAC) should be considered primarily if a patient has ingested a life-threatening amount of carbamazepine, dapsone, phenobarbital, quinine, or theophylline. Multiple-dose activated charcoal increases the elimination of amitriptyline, dextropropoxyphene, digitoxin, digoxin, disopyramide, nadolol, phenylbutazone, phenytoin, piroxicam, and sotalol, but evidence is insufficient to support its use in these ingestions. 5. Whole bowel irrigation should not be performed in the presence of ileus or bowel obstruction. 6. If uncertainty exists about the need for decontamination procedures, contact the regional poison control center and/or a medical toxicologist.

effective adsorbent 1 ; it may even limit the adsorptive capacity of activated charcoal. 2

Two theories have been advanced to account for the observed acceleration of drug clearance associated with the use of MDAC after the drug's absorption from the gastrointestinal tract. One theory explains this acceleration by charcoal's interruption of the enterohepatic recirculation of hepatically metabolized drugs. The other is aptly called "gastrointestinal dialysis," a term coined by Levy in an editorial that accompanied the seminal work on this topic by Berg and colleagues. 3, 4 Using an animal model of intravenous theophylline poisoning, Kulig and colleagues measured bile theophylline concentrations and were able to demonstrate that the observed increase in theophylline clearance with MDAC was not due to interruption of enterohepatic recirculation of the drug. 5 Arimori and colleagues demonstrated in an experimental model that the exsorption rate of theophylline into the intestinal lumen increased in proportion to the administered dose of theophylline, suggesting that the gastrointestinal dialysis effect may increase with escalating dose for some toxins. 6

Given that overall mortality from overdose is low, that the efficacy of gastrointestinal decontamination techniques declines significantly with advancing time after ingestion, and that significant delay to clinical presentation occurs in the majority of ingestions, elimination enhancement techniques, including MDAC, have come under recent scrutiny. 7 Tenenbein cited case reports of complications from MDAC with a lack of proven clinical benefit in arguing that its role in the treatment of poisoning required reassessment. 8 These cautions notwithstanding, review of the available evidence suggests that MDAC can accelerate drug clearance, achieving rates comparable to more invasive techniques such as hemodialysis. Moreover, a recent study of complications associated with MDAC use found that they occurred infrequently. 9 There are also data suggesting that MDAC improves outcome in selected poisoning cases. One report describes two presentations of the same patient with phenytoin toxicity, one in which MDAC was not used and a second in which it was; the second hospitalization was 3 days shorter despite the patient having a higher serum phenytoin level. 10 A recent single-blind, randomized, placebo-controlled trial performed in Sri Lanka demonstrated a significant reduction in mortality from yellow oleander poisoning Once a drug or toxin has been absorbed, a number of means exist to enhance its elimination. Chapter 2D addresses extracorporeal techniques of toxin removal from the blood (e.g., hemodialysis and hemoperfusion), which, when performed on an emergency short-term basis such as for poisoning, are done intermittently using a large double-lumen catheter in a central vein with flow through the circuit driven by a pump. Other types of dialysis exist that also usually do not require arterial access and are more versatile in that they do not pose as great a hemodynamic stress to the patient; however, they also are generally much slower in their rates of clearance. One of these alternatives, multiple-dose activated charcoal (MDAC), involves use of the patient's own gastrointestinal mucosa as a dialyzer.

All of these techniques share in common with dialysis the underlying principle of filtering a toxin from the blood using a semipermeable membrane in order to enhance its clearance. A number of substance-related factors affect the clearance rates that can be achieved by dialysis techniques. First, a toxin must distribute primarily into the intravascular compartment-that is, have a low volume of distribution, in order to be removed by a dialysis technique at a clinically significant rate. Second, molecular size is important, with low molecular weight substances crossing the dialysis membrane from an area of high concentration (blood) to an area of low concentration (dialysate). Even higher molecular weight substances can cross and thus be removed from the blood by convection when dialysis is supplemented with ultrafiltration, which relies on a membrane with a high permeability coefficient and a high transmembrane pressure. Finally, high protein binding presents a large molecular size to the membrane (i.e., a protein-bound drug), thus limiting the rate of clearance, unless the toxin is adsorbed from the serum proteins such as with the use of a charcoal cartridge in hemoperfusion.

Delayed absorption may occur after toxic ingestion: (1) with sustained-release preparations, (2) if tablet conglomerates form in the gastrointestinal tract, (3) if the substance delays gastrointestinal motility. or, (4) if a poorly absorbed substance (e.g., phenytoin) is ingested. Multiple doses of activated charcoal have been used in these situations to enhance preabsorptive elimination. Whole bowel irrigation, the other treatment modality used to enhance preabsorptive elimination, appears to provide no additional benefit when administered to treat a drug overdose for which activated charcoal is an

CURTIS P. SNOOK, MD ■ DANIEL A. HANDEL, MD, MPH C with MDAC therapy when compared with treatment with single-dose activated charcoal. 11 Further study is needed to define the circumstances in which the benefits of MDAC appear to justify its risks. However, some predictions can be made based on available data. MDAC has been demonstrated to accelerate the clearance of a number of toxins (Box 2C-1). Chyka and colleagues found in a porcine model that MDAC enhanced elimination of acetaminophen, digoxin, and theophylline but not valproic acid. 12 Drugs with relatively lower intrinsic clearance (digoxin, theophylline) were cleared with MDAC more rapidly than were drugs with higher intrinsic clearance (acetaminophen). Interestingly, volume of distribution, half-life, and protein binding were not significantly correlated with MDAC enhancement of clearance. However, therapeutic doses were administered in this study, limiting application of these results to the overdose setting. A volunteer study of dapsone ingestion using a randomized crossover design along with data from two overdose cases showed a doubling of elimination with MDAC in healthy volunteers and a greater increase in the overdose patients, again suggesting that the effectiveness of MDAC also may be a function of dose for a given toxin. 13

Significant adverse effects with MDAC preclude its use in patients for which no significant clinical benefit is expected. There are some drugs or drug classes for which data are conflicting (Box 2C-2). For example, the available studies suggest that MDAC likely would not be beneficial in unselected cases of digoxin poisoning. However, one volunteer study of MDAC for enhancement of digoxin clearance applied kinetic predictions to suggest that greater clearance with MDAC would occur in patients with renal impairment 14 ; animal data support this assertion. 12 In a case of chronic digoxin poisoning, MDAC effectively accelerated drug clearance when digoxin antibody fragments were unavailable and hemodialysis had been unsuccessful. 15 Box 2C-3 lists the drugs investigated for which MDAC has not been shown to accelerate clearance.

MDAC often is poorly tolerated. Virtually all patients in one study complained of poor palatability and bloating with MDAC, with one patient withdrawing because of repeated vomiting. 14 Transient constipation may occur with MDAC use in susceptible patients. Protracted vomiting also has been reported to limit the usefulness of MDAC in theophylline poisoning. 16 Aspiration of charcoal is another well-recognized complication of MDAC. In one published case, an unintubated patient treated for phenobarbital and carbamazepine overdose with gastric lavage followed by MDAC vomited and aspirated 12 hours after therapy was initiated, eventually dying on hospital day 15. 17 Another reported patient with theophylline overdose was treated with ipecac followed by MDAC. He went on to develop convulsions followed by aspiration, eventuating in his death. 18 In the most sobering case, a patient aspirated activated charcoal despite airway control. 19 This patient received MDAC after intubation and gastric lavage for desipramine and thiothixene overdose. After extubation the next day, the patient vomited, aspirated charcoal, and had a cardiorespiratory arrest from which he could not be resuscitated. In a similar case, a patient who ingested thioridazine and imipramine underwent endotracheal intubation and gastric lavage after he had a seizure. He received 50 g of activated charcoal by nasogastric tube followed by 25 g and then 50 g with sorbitol every hour for 6 hours. 20 When the nasogastric tube was removed, the patient vomited, became cyanotic and had a respiratory arrest. Charcoal was suctioned from the patient's lungs until hospital day seven. Rau MDAC, multiple-dose activated charcoal. and colleagues described three deaths from charcoal aspiration among 15 patients treated with charcoal for central nervous system-depressant overdose without airway protection. Their subsequent six overdose patients were intubated prior to charcoal administration and no cases of aspiration occurred. 21 In light of this experience, any patient at risk for aspiration (i.e., one in whom diminished consciousness, depressed airway reflexes, or seizures are present or anticipated), should have a firm indication for MDAC and a protected airway before undertaking the procedure. Equally important, there appears to be a ceiling effect for charcoal adsorption such that increasing dose or frequency beyond a certain point results in no additional therapeutic benefit. 22 Overdose victims with decreased gastrointestinal motility may develop bowel obstruction with use of MDAC. A number of cases have reported MDAC resulting in small bowel obstruction, abdominal distension, constipation, rectal bleeding, and even intestinal perforation when either the overdose itself or the therapy for the overdose involved anticholinergic drugs. [23] [24] [25] [26] [27] [28] Appendicitis in association with MDAC use has been reported. 29 Another patient with chronic theophylline toxicity treated with MDAC developed small bowel obstruction and was found on laparotomy to have adhesions at the ileocecal valve secondary to a previous hysterectomy; multiple pieces of charcoal were found in the bowel at the site of obstruction measuring 4.5 × 5 × 3 cm in aggregate. 30 Cathartics are ineffective as a means of elimination enhancement after poisoning. 31 However, to avoid constipation and charcoal inspissation, cathartics often are coadministered. Sorbitol is the usual choice because of its rapid onset and palatability. Sorbitol is typically marketed in a 70% concentration with activated charcoal because it is bacteriostatic at this concen-tration. 32, 33 Using excessive or multiple doses of sorbitol with activated charcoal in poisoning is associated with significant morbidity, including hypernatremia resulting in death, and should be avoided. 34 Magnesium citrate or sulfate occasionally are used instead of sorbitol. Patients with premorbid magnesium abnormalities or those receiving excessive doses of magnesium cathartic can suffer serious morbidity, including hypermagnesemia, which can be fatal. 34

The optimal dosing for activated charcoal in MDAC is unknown. The commonly accepted dose is 1 g/kg (maximum of 50 g) of activated charcoal initially, followed by 0.5 g/kg (maximum 25 g) every 4 hours thereafter. Others have suggested a dose of 1 g/kg of activated charcoal in 4.3 mL/kg body weight of 70% sorbitol every 4 hours until the first charcoal stool appears. In children, the same weight-based dose of activated charcoal is recommended. 33 A third set of published guidelines for adults has suggested an initial dose of 50 to 100 g, with additional doses given at a rate of at least 12.5 g/hr until the patient is improving clinically and by relevant laboratory parameters. This latter set of recommendations includes lower dosing (10 to 25 g) for children younger than 5 years of age, smaller doses more frequently along with antiemetic use in vomiting patients, and no use of cathartics, particularly in young children. 7 MDAC has been used safely in infants and neonates 35, 36 ; it has even been used to treat neonatal hyperbilirubinemia. 37 Patients receiving MDAC should be intubated, ideally with a cuffed endotracheal tube, if they are obtunded or have diminished airway reflexes or seizures. The charcoal should be diluted with at least 8 mL of water per gram of charcoal. MDAC should not be administered in the presence of ileus or bowel obstruction. Coadministration of anticholinergic agents should be avoided during MDAC. Charcoal should be withheld 4 hours prior to extubation. Gastric contents should be aspirated with a nasogastric tube prior to extubation to avoid the complications previously discussed. Magnesium cathartics should be used with caution, particularly in patients with decreased renal function, and are best avoided in such patients given that safer alternatives are available. It is a common practice to give the first dose of charcoal with a cathartic, usually sorbitol, and to give subsequent doses without cathartic. The availability of only sorbitol-charcoal preparations can be problematic in hospitals with such rigid stocking patterns. 38 Electrolytes should be closely monitored if more than one dose of cathartic is administered.

Box 2C-4 summarizes the indications, contraindications, and dosing guidelines for MDAC use in poisoning. 44 Myoglobin in an animal study and in humans from drug-and exercise-induced rhabdomyolysis has been removed successfully by CVVH. [45] [46] [47] Severe lactic acidosis induced by propofol improved significantly with the use of CVVH. 48 CVVH has been shown to be safe and effective in treating radiocontrast-induced acute renal failure after percu-

Continuous veno-venous hemofiltration (CVVH) and similar modalities used for what is termed "continuous renal replacement therapy" increasingly are being used in the therapy of critically ill patients, including those suffering from poisoning. CVVH offers a number of useful advantages over traditional dialysis techniques. First, it can be used in patients with renal failure who are hemodynamically unstable and require large volumes of parenteral nutrition. In CVVH isotonic fluid is removed from the femoral vein slowly and continuously rather than in 1-to 4-L increments over a 2-to 4-hour treatment session, the typical pattern for hemodialysis (HD). Also, the diffusion clearance inherent to HD results in the return of a hypo-osmolar fluid to the intravascular space, resulting in a further loss of intravascular volume in comparison with CVVH. The latter restores volume losses with isotonic replacement fluid and fluid refilling from the overhydrated body parenchyma. 39 Second, trained nursing staff can administer CVVH, though it requires their continuous attention. Finally, the typical rebound in serum drug levels from redistribution observed after HD are not seen with continuous modalities such as CVVH.

The main disadvantage of CVVH in comparison with HD is the slower rate of toxin removal it can achieve. This disadvantage is significant if rapid toxin removal is critical to the patient's survival, which often is the case. Thus, the use of CVVH for a toxin whose elimination is enhanced by dialysis techniques should be considered only when hemodynamic instability precludes the use of HD, when HD is not available, or if the inherently slower rate of toxin removal is clinically acceptable.

CVVH does not require arterial access-a pump is used to provide the pressure gradient necessary for filtration. Anticoagulation is required to optimize the lifespan of the apparatus (which requires replacement when it becomes clotted). However, the need for anticoagulation is less than for arteriovenous techniques because of the controlled blood flow provided by the pump, particularly in smaller pediatric circuits. 40 Animal data demonstrate that CVVH can achieve adequate flow rates with pediatric-sized filters and circuits. 41 The blood is passed through a highly permeable hemofilter, forming an ultrafiltrate made up of plasma and filtered solutes. Hemodiafiltration refers to the use of a dialysate fluid on the opposite side of the filter from the blood flowing in a counter current direction. 

Box 2C-5 lists the toxins for which CVVH has been shown to speed elimination. Toxin-related factors determining clearance by CVVH include the sieving coefficient (dependent upon molecular weight and protein binding) taneous coronary interventions. 39 Hypothermia is associated with poisoning, particularly when central nervous system depressants result in excessive exposures to cold ambient temperatures. CVVH has been used with success in rewarming a patient with severe accidental hypothermia. 49

Toxins for which CVVH has not been shown to speed elimination are listed in Box 2C-6. One patient treated with a lorazepam infusion developed toxicity from the propylene glycol diluent, despite receiving CVVH with dialysis (CVVHD), suggesting that the glycol was not effectively removed. 50 Care should be exercised in choosing the replacement fluid; lactate-buffered solutions have been reported to induce hyperlactatemia. 51 Since CVVH requires systemic anticoagulation, contraindications include recent surgery and gastrointestinal or intracranial hemorrhage. However, regional heparinization can be used with those patients for whom CVVH is necessary but who cannot tolerate systemic heparinization. 40 Trisodium citrate is a useful alternative to heparin as a regional anticoagulant with CVVHD to minimize the risk of hemorrhage and thrombocytopenia. However, caution should be exercised in patients with decreased hepatic function as use of trisodium citrate in this context is associated with severe hypercalcemia. 52 A summary of the indications and contraindications for CVVH in poisoning are listed in Box 2C-7.

Though the first use of peritoneal dialysis PD dates back to 1923, 53 experiments with peritoneal lavage were carried out as early as 1877. 54 Numerous advances have been made since this early work was done, including the addition of substrates to the dialysate to enhance the elimination of certain drugs. Given the ease in most medical centers of obtaining HD, PD has fallen out of favor in most instances for the treatment of acute intoxication, although it continues to be used as a bridge when HD is not available or as an adjunct to enhance elimination. Because of its "second-tier" status, recent literature and research on its use in poisoning are sparse.

The peritoneal surface area of an adult has been estimated to be 22,000 cm 2 , 55 allowing this structure to serve as an excellent semipermeable membrane for dialysis. PD involves in principle the passive movement of drug or toxin down its concentration gradient from the intravascular space in capillaries dispersed throughout the lining of the peritoneum into the dialysis solution infused into this cavity. As with other dialysis techniques, PD is particularly effective in removing drugs with small volumes of distribution and low protein binding. 56 The intermittent method of PD involves the use of one catheter to introduce the dialysate by gravity, removing it at a later time through the same access. 54 This process also can be carried out using two catheters. 56 Two liters of fluid (1200 mL/m 2 or 50 mL/kg in children) are used per exchange, with the fluid typically left in the peritoneal cavity for 45 to 60 minutes. 55 In contrast, during continuous ambulatory peritoneal dialysis (CAPD), dialysate is left in the peritoneum for much longer periods of time. Extending this period beyond 72 hours or leaving the catheter in place between courses of PD increases the risk of infection.

Various additives, such as glucagon, albumin, prostaglandin E 2 (PGE 2 ), lipids, furosemide, streptokinase, and chelating agents, have been added to dialysis fluid in the attempt to enhance elimination with varying degrees of success. 57-59 A mildly hypo-osmolar solution is used to prevent water removal during dialysis, with electrolyte concentrations similar to that of extracellular fluid. 54 When the osmolality of the dialysate is increased, increased solute removal occurs at the expense of a negative fluid balance with each exchange. 55

Whereas PD can be a continuous process, its elimination rate is significantly less than that of HD and other more invasive methods of extracorporeal therapy. Blood flow via mesenteric circulation in PD cannot be adjusted as it can in HD, and the mechanics of instilling and draining 

In the pediatric population, PD is contraindicated when there is severe intraperitoneal hemorrhage that is sometimes seen in hemolytic-uremic syndrome with thrombocytopenia. 55 The presence of focal peritonitis, a fecal fistula or colostomy, abdominal adhesions, and recent abdominal surgery with use of a prosthetic material, a major vascular anastomosis, or an open wound, are relative contraindications for PD. 65 Box 2C-10 lists the toxins for which peritoneal dialysis has not been found effective in accelerating clearance. A summary of the indications and contraindications for peritoneal dialysis in poisoning are listed in Box 2C-11. dialysate into and from the peritoneum limit achievable clearance rates. 57 The time required to eliminate a given amount of toxin is three to six times greater with PD than with HD, depending on the properties of the agent. The elimination of small molecules that are highly membrane permeable is rate-limited by blood and dialysate flow rates, whereas the elimination rate of large molecules depends primarily on membrane surface area. 60 In severe poisoning from a dialyzable toxin, the difference in achievable clearance rates between HD and PD can have enormous clinical significance, as one case series of methanol poisoning illustrates. 61 Thus, PD should not be substituted for HD in such cases unless the latter is absolutely inaccessible. If HD is not available in one treating facility but patient transfer is possible, the patient should be transferred. PD may be used as an adjunct during the transfer to speed toxin elimination.

Similar to other methods of extracorporeal elimination enhancement, PD can produce electrolyte shifts and loss of serum proteins. Pulmonary complications, including bronchitis/pneumonia, pleural effusions, and atelectasis, also are known adverse effects. 54 Bowel perforation from catheter misplacement occurs with an incidence of 1.3% according to one report. 62 The other major complication of PD, especially CAPD, is peritonitis, which usually limits the long-term use of this technique. 55 The dialysate additive icodextrin has been reported to cause a blistering skin reaction that resolves upon cessation of the use of the substance. 63

PD can be used for toxins of up to 10,000 daltons in molecular weight and when a filtration rate of no greater than 15 mL/min is required. 64 It can be used when HD is not currently available and the patient's clinical status is critical. It can be used also when anticoagulation is contraindicated due to comorbidities. 65 PD has been more widely used in the pediatric population, especially in the contexts of acute renal failure seen in hemolyticuremic syndrome, congestive heart failure, chronic renal failure, and hyperkalemia. 55, 62 Because of the difficulties of vascular access in small children as well as the difficulty in removing excess fluid gained between courses of dialysis without causing profound hypotension, PD offers distinct advantages in this population.

The toxins for which PD hastens clearance and those for which its effects on clearance have been equivocal are listed in Boxes 2C-8 and 2C-9, respectively. Note that there are toxins listed in Box 2C-7 that are eliminated by the kidneys, such as baclofen, for which PD has been found useful in poisoning accompanied by renal failure even though PD effects on clearance are small when renal function is normal. Also, PD has proven useful in treating toxin-induced renal failure apart from effects on toxin clearance. Hypercalcemia from overadministration of vitamin D in an anephric child has been effectively BOX 2C-8 

Chapter 2C addresses the use of peritoneal dialysis, various forms of hemofiltration, and multiple-dose activated charcoal (MDAC) as so-called "gastrointestinal dialysis." This chapter discusses the more classic methods for extracorporeal removal of toxicants, namely, hemodialysis (HD) and hemoperfusion (HP). In addition, we briefly discuss a newer methodology, the molecular adsorbents recirculating system (MARS, also referred to as albumin dialysis), which was developed primarily for the treatment of fulminant liver failure (FLF), but has recently been employed in the treatment of a variety of poisonings.

As has been pointed out in previous chapters, extracorporeal methods for toxicant removal should be viewed as important adjuncts rather than as primary approaches to specific poisonings. The most effective method of removal of toxicants from the body in most cases is maintenance of properly functioning kidneys, liver, and lungs through excellent supportive care. The ultimate evaluation of efficacy of extracorporeal methods is in fact through direct comparison with spontaneous elimination by the body. 1 In the absence of careful attention to resuscitation and supportive care, these adjuncts may be of little use; they may even be dangerous. Further-more, while dozens of toxicants have been shown to be removed by HD or HP, 2 evidence-based support for significant clinical improvement from these procedures is often lacking. As will be shown, each of these procedures has benefits and risks, which must be carefully weighed against other methods of treatment.

It is difficult to ascertain the frequency with which HD and HP are employed in the treatment of poisoning. Based on the most recent Toxic Exposure Surveillance Survey, 3 it would appear that use of HD (N = 1730) largely exceeds that of HP (N = 30). Both procedures were far more commonly performed in adults older than 19 years (93% of HD cases and 90% of HP cases) than in children. Use of these extracorporeal removal techniques in children younger than 6 years was rare (seven cases of HD, one case of HP). These figures are undoubtedly underestimates of real use, since reporting to poison centers by physicians is voluntary and incomplete. Nonetheless, they suggest that extracorporeal purification therapies have a limited role in management of poisoning in the United States.

HD requires the passage of blood from the body through an external circuit, in which it is anticoagulated and placed in sustained contact with a selectively permeable membrane prior to being returned to the patient. Opposite the membrane and flowing in countercurrent direction is a heated dialysate, the composition of which can be varied according to the indications for dialysis. The variation of electrolyte concentrations, addition of buffers, and sometimes other additives allow the operator to manipulate the passage of these elements from one side of the membrane to the other. HD operates on the basis of three principles: diffusion, osmosis, and ultrafiltration. 4 Diffusion relies on concentration gradients, with solutes moving from an area of higher concentration to an area of lower concentration, ultimately resulting in equilibration. Osmotic pressure results in the movement of water from one side of a semipermeable membrane to the other, dependent on a higher concentration of solutes on the other side. Manipulation of plasma sodium concentrations (sodium profiling) during dialysis can induce a net flow of water from cells into the plasma, allowing for its ultimate removal from the plasma. Ultrafiltration involves movement of fluid across the membrane due to the presence of a pressure gradient. This principle allows control of fluid loss during dialysis and can be manipulated via varying dialysate pressure (pressure control) or by variation of dialysate flow volumes (volumetric control). Volumetric control is more common in modern dialysis machines. In the case of toxicants, diffusion into the dialysate is the primary end point, although amelioration of acid-base and electrolyte conditions is often an important additional goal.

Dialyzer specifications (blood flow rate, surface area, and membrane construction) determine, in part, the efficacy of drug or chemical removal from the blood. Pharmacodynamic and pharmacokinetic factors (molecular weight, lipid solubility, protein binding, toxicant concentration gradient, and volume of distribution [Vd] ) are equally critical factors which will be discussed in further detail below. 2

HP implies the passage of blood through a device containing absorbent particles. 2 It may be performed alone or in combination with HD and has been employed for a number of years in the management of poisonings. Resin HP with variants of Amberlite XAD (Rohm & Haas, Philadelphia, PA) was viewed as promising in the 1970s and 1980s. However, very few recent reports of resin HP have been published. [5] [6] [7] [8] [9] [10] This is likely in part due to unavailability of medical-grade resin cartridges in many geographic areas. Activated charcoal appears to be the most commonly used absorbent material based on published reports, but hospital availability of even these cartridges appears to be limited. A recent survey of New York City 911-receiving hospitals revealed that only about one third of those surveyed had charcoal hemoperfusion (CHP) cartridges readily available (only one hospital had pediatric cartridges). Just 3 of 34 responding hospitals had used CHP within the previous 5 years. Reasons cited by the authors for limited cartridge availability and use of CHP were decreasing clinical use of phenobarbital and theophylline and improved efficacy of HD. 11 CHP irreversibly binds water-and lipid-soluble drugs and chemicals in the molecular weight range of 113 to 40,000 Da, a much larger range than that for HD (<~300 Da). Plasma drug extraction ratios for HP are superior to those for HD for acetaminophen (paracetamol), digoxin, glutethimide, paraquat, phenobarbital, and theophylline. 2 However, further examination of this list may reveal, in part, why HP is seldom employed in the United States. Nacetylcysteine is effective for acetaminophen poisoning, widely available, and less invasive. Digoxin Fab fragments are far more effective than HP in binding and eliminating digitalis glycosides. Glutethimide is rarely prescribed in the United States. Paraquat poisonings are rather rare in the United States, and HP has not been shown to alter outcomes, despite of reduction of plasma concentrations. 12 As mentioned previously, phenobarbital and theophylline have largely been replaced in clinical use by other agents, and the less invasive MDAC has been shown to be effective in reducing plasma concentrations of these agents, although it has not been proven to alter outcomes. 13

The Molecular Adsorbents Recirculating System (MARS) is a relatively new method of extracorporeal decontamination, which employs dialysis across a membrane impregnated with albumin and a 20% albumin dialysate, line has a molecular weight of 299.85 Da, but is poorly removed by HD. This is due to its very large Vd. 22 The Vd is the theoretical volume into which a drug distributes in the body and is generally expressed in liters or liters/kg body weight. Substances with a small Vd (<1 L/kg) reside to a greater extent in the bloodstream and can generally be effectively removed by using extracorporeal methods. The Vd of a drug is the most important determinant of the efficacy of HP. 20 Even when extracorporeal methods are very efficient in removing toxicants from the blood, if the theoretical Vd is high, the pharmodynamic effect achieved is likely to be minimal, as the concentration at the drug target tissue may be virtually unchanged.

A third critical factor in predicting efficacy of extracorporeal methods is protein binding. HD is of limited value for substances that are highly protein bound. CHP, on the other hand, remains effective in cases of drug overdose with substances of high protein binding capacity. 20 A study conducted in 12 patients treated with HP, with drug overdoses involving 20 different drugs, showed that the efficacy of drug removal through absorption by activated charcoal was dependent on the binding affinity, which is related to the protein binding percentage. This study concluded that drugs that are protein bound at levels of up to 95% are effectively removed from the blood with HP. 20 Following HD or HP, substances with a higher Vd and high protein binding percentage tend to redistribute from storage tissues to plasma. For this reason, a single extracorporeal substance removal session may be insufficient. 21

Water solubility is also an important factor in determining dialyzability. Water-soluble substances like ethanol, methanol, ethylene glycol, salicylates, theophylline, lithium, and valproate tend to have limited distribution in adipose tissues, thus limiting their Vd. This property makes them ideal for extracorporeal drug removal.

Poisoning by a substance susceptible to extracorporeal removal is not in itself an adequate justification for the procedure. 2 In general, extracorporeal methods should be reserved for poisonings for which toxic metabolic activation is anticipated (e.g., methanol, ethylene glycol), for which blood concentrations or the amount of toxicant absorbed foretell very serious toxicity, and for patients who have not improved despite of appropriate supportive care (volume repletion, acid-base correction, use of vasopressors, ion-trapping diuresis, and administration of specific antidotes). Winchester 2 identifies six clinical considerations for HD or HP in poisoning: (1) progressive deterioration; (2) depression of midbrain function leading to hypoventilation, hypothermia, and hypotension; thus attracting highly protein-bound substances. In addition, charcoal and anion exchange resin cartridges are employed to filter the dialysate, regenerating it for continued use. 14 MARS may be of interest in the setting of poisons that have a predilection for liver toxicity, as the system is capable not only of removing certain hepatotoxins, but also reducing hyperbilirubinemia, restoring hemodynamics, diminishing hepatic encephalopathy, and improving renal function. 14 MARS has been used to maintain patients in liver failure during the peritransplant period. [15] [16] [17] [18] The existing data for MARS in general are encouraging, but the evidence base is limited. 19 This caveat is even truer in the setting of poisoning.

A number of factors determine the suitability of use of HD or HP as extracorporeal methods of removal of a given toxicant. In the case of HD, chemical and drug removal are determined by factors as blood flow rate, dialysate flow rate, dialyzer surface area, and pore structure of the chosen membrane and by pharmacodynamic and pharmacokinetic factors such as molecular size (usually <300 Da), lipid solubility, protein binding, Vd, and concentration gradient. For HP, the selection of filter material has historically been important (charcoal vs. resin cartridges). With scarce availability of resin cartridges, the choice has essentially reverted to charcoal. HP is typically reserved for drugs with a low Vd and high protein binding, 20 but as mentioned previously, compounds of larger molecular weight may be removed. HD frequently causes hypotension, whereas this is reportedly less often a problem in HP. As such, in instances where hemodynamic instability after poisoning is an issue, HP may be preferable even if less efficacious for a particular toxicant. Vasopressors such as dopamine and norepinephrine are absorbed by the cartridges and therefore should be administered in the circuit after the sorbent. A definite role for MARS therapy in poisoning has not yet been established. In general, substances that are highly bound to albumin and poorly susceptible to other forms of treatment, including HD and HP, should prompt consideration of MARS, particularly in the setting of liver failure.

In order to be effectively hemodialyzed, toxicants should ideally be of low molecular weight (<300 Da). 21 

A low molecular weight alone is not sufficient, however, to assure effective dialyzability. For example, nortripty-(3) development of, or predisposition to, complications of coma, such as pneumonia or septicemia; (4) impairment of drug excretion; (5) poisoning of substances possessing metabolic and/or delayed effects; and (6) poisons extractable at a rate exceeding endogenous elimination. These considerations could be condensed to (1) patients who are very sick or likely to become so and (2) toxicants for which HD/HP are effective in removal and known to make a clinical difference in outcome.

Blood concentrations of certain toxicants (e.g., methanol and ethylene glycol) have been proposed as indicators for HD. Historically, a plasma concentration of 50 mg/dL has been used as a threshold for the need for dialysis in both ethylene glycol 23 and methanol 24 poisonings. The availability of fomepizole, a safe and effective inhibitor of alcohol dehydrogenase, has altered the indications for HD. [25] [26] [27] [28] While HD continues to be a useful and often necessary adjunct in the treatment of toxic alcohol poisonings, an elevated blood concentration of the alcohol alone is no longer considered sufficient to require HD.

Severe metabolic acidosis accompanying methanol and ethylene glycol, as well as other toxic alcohol poisonings, is a clear indication for HD, regardless of blood concentration. In these cases, HD not only effectively removes the toxicants and their acidic metabolites, but helps in directly correcting the acid-base balance of the patient. Even when the toxicant's molecular weight, protein binding, or Vd do not conform to the criteria necessary for dialyzability, HD should be considered in the setting of severe metabolic acidosis and/or renal failure. An example of this can be found in overdoses by metformin. Metformin would be expected to be poorly dialyzable on the basis of its very large Vd. However, metformin toxicity results in severe metabolic acidosis, which may be ameliorated by application of HD techniques. 29, 30 

Both HD and HP may be performed in children, but both pose greater challenges than in adults. Vascular access is obviously more difficult in small children. For this reason, peritoneal dialysis has been historically used more often in children. However, use of peritoneal dialysis for acute renal failure in children appears to be decreasing and use of HD increasing over time. 31 As mentioned before, availability of CHP cartridges suited to use in children may be extremely limited, even in major metropolitan areas. 11 However, it appears that if antidotal therapy for ethylene glycol is administered before the onset of renal insufficiency, HD, even in children, may be safely avoided. 32 Given the long half-life of methanol, HD is still considered advisable in children after treatment with fomepizole. 33

Obviously, poisonings by substances normally eliminated by the kidneys may require HD or HP in patients with chronic renal failure. 34

Both HD and HP are associated with potential serious complications (Box 2D-1). The most serious complications associated with HD include hypotension (which by extension may lead to myocardial or brain infarction) and bleeding associated with anticoagulation. An addi- 56 CONCEPTS IN MEDICAL TOXICOLOGY BOX 2D-1 to the onset of acidosis and end-organ damage (renal failure or visual disturbances). While fomepizole is relatively expensive, a multiple-day ICU admission and HD might exceed drug costs. In other situations, HD or HP may shorten ICU or hospital stays and be cost conscious procedures. A formal cost-benefit analysis of these various treatment options would be useful.

The evaluation of efficacy of extracorporeal methods of blood purification should ultimately rest on improvement in patient outcomes. However, a good outcome after HD or HP is not equivalent to established efficacy. Indeed, the literature is replete with case reports of the "successful use" of HD and HP in cases of poisoning in which the procedure may have had little impact at all on outcome. As mentioned in the beginning, the efficacy of extracorporeal purification procedures must be compared with the efficacy of elimination of the substance in question by the kidneys, liver, and lungs. Thus, one cannot estimate the utility by simply measuring blood concentrations before and after HD/HP. 1 Rather, the amount of extracted drug should be measured directly in the dialysate or via elution from the cartridge, or alternatively, indirectly from hourly differences in simultaneously arterial (inlet)-venous (outlet) concentrations multiplied by the purification system blood flow. 1 These amounts can then be compared to the concentrations in urine (determination of spontaneous renal clearance) and to the quantity believed to have been absorbed to determine efficacy. Before and after blood concentrations give some idea of the combined efficacy of corporeal and extracorporeal elimination, but the interpretation may be clouded by ongoing intestinal absorption or redistribution of the toxicant. Elimination by other routes (pulmonary, sweat) should be likewise considered.

The list of toxic substances that have been subjected to HD and/or HP is quite long. Winchester 2 provides a list of more than 200 substances removed with dialysis and HP. As already mentioned, the ability to remove a toxic substance by HP or HD is not equivalent to an indication for these procedures. One must take into account the patient's underlying health (renal or hepatic insufficiency), the toxicity of the absorbed substance, the presence of or likelihood of advancing to severe illness, the availability of these procedures, and the availability of acceptable alternatives (good supportive care, antidotes). A list of a few substances that have frequently been subjected to extracorporeal removal follows (Table 2D-1) . The list is not comprehensive and does not necessarily imply an indication for HD/HP. The reader is referred to individual chapters for detailed indications for these and other forms of therapy. tional significant consequence is reduction of therapeutic levels of drugs, which may result in unmasking of conditions protected by these agents. Complications appear to be relatively fewer in HP, but may nonetheless be important. HP is associated with the destruction of platelets, such that significant thrombocytopenia and bleeding may occur. This complication has been reduced by coating of the sorbent particles with a polymer solution. 2 Hypocalcemia likewise may occur. 35 Rahman and colleagues recently reported on the case of a patient treated with CHP for valproate poisoning. Despite of the use of coated charcoal, the patient developed severe hemolysis, which the researchers attributed to mechanical damage to red cells by the high flow rate through the cartridge. The patient required packed red blood cells, platelets, and fibrin transfusions, developing oliguricanuric renal failure that required 23 days of HD over a period of several weeks. She ultimately regained her normal renal function. 36

Transfer HD and HP are not universally available. Thus, transfer to centers capable of performing these procedures may at times be required. The decision to transfer a patient for these therapies should rest on evaluation of several elements: (1) Is the patient stable for transport? (2) Will the patient's outcome likely be significantly better if the procedure is undertaken? (3) Are there acceptable alternatives to HD or HP? Each of these issues should be studied prior to committing a patient to prolonged and expensive or potentially hazardous transport to another facility for extracorporeal decontamination procedures.

As mentioned above, HD and HP have significant potential for complications. In certain poisonings, such as ethylene glycol and methanol intoxications, where HD was formerly routinely prescribed in the presence of high blood concentrations, recent improvements in specific antidotes have led to therapeutic alternatives. For example, if a patient with significant ethylene glycol poisoning arrives at the hospital before the onset of acidosis and renal failure, early treatment with fomepizole alone may preempt the need for HD. 25, 26, 28 Even in the case of methanol, HD may be avoided in selective cases after early treatment with fomepizole. 28 Methanol's elimination half-life is much greater than that of ethylene glycol, however, and may require prolonged antidotal treatment in the absence of HD.

Requirement for acute HD and/or HP generally implies costly intensive care unit (ICU) admission. As mentioned above, early administration of fomepizole may forego the need for HD and ICU admission in ethylene glycol and selected methanol poisonings, if administered prior

The alcohol and glycols generally have toxicity that is inversely related to molecular weight. This, along with limited protein binding, small volumes of distribution, and relatively high water solubility, makes them particularly amenable to removal by HD. Ethylene glycol (see Chapter 32B) has a molecular weight of 62 Da, it has no significant protein binding, and it distributes primarily in total body water (Vd = 0.6-0.8 L/kg), rendering it readily removable by HD. 21, 83 Additionally, glycolate, the toxic by-product of ethylene glycol responsible for acidosis, is effectively removed by HD. 59, 60 The indications for HD in ethylene glycol poisoning have been reviewed. 26, 28, 49 Pizon and Brooks have stated that an extremely high ethylene glycol level should be considered an indication for HD regardless of the patient's acid-base status or renal function due to hyperosmolarity. 78 Methanol (see Chapter 32A) is likewise small (32 Da), with minimal protein binding and a Vd of 0.6 L/kg. Formic acid, the toxic by-product of methanol responsible for acidosis and retinal toxicity, is removed by HD. 61 Hovda and colleagues have suggested that HD may be performed on an "elective" basis in selected methanol poisonings if patients are rapidly treated with bicarbonate and fomepizole. 27, 84 Several researchers have recently reviewed the indications for HD after methanol poisoning. 24, 28, 85 Isopropanol (see Chapter 32C) may also be removed by HD, although the indications for HD are limited, due to generally good outcomes with supportive care. 49, 86 HD has been proven to be effective in removing both isopropanol and acetone from the plasma. 49 Lacouture and colleagues have recommended HD in cases where the blood isopropanol concentration exceeds 400 mg/dL. 87

Salicylates (see Chapter 48) are compounds of low molecular weight. They are moderately to highly protein bound (50%-90%), with very small volumes of distribution. Although salicylates are highly protein bound at therapeutic concentrations, the fraction of unbound drug increases in the setting of overdose, rendering it amenable to removal by HD or HP. Early HD is recommended due to the high propensity of salicylates to cause serious toxicity and death. 64 The importance of concurrent alkalinization of the urine has been underscored by Higgins and colleagues. 63 Because of acid-base and electrolyte abnormalities associated with salicylate poisoning, acute HD, rather than HP, is generally preferred. 21

Theophylline (see Chapter 65) has a low molecular weight and small Vd with moderate protein binding. Shannon addressed the use of HD and HP in theophylline poisoning in a 10-year prospective, observational study. 66 The study included acute, chronic, and acute-ontherapeutic poisonings. The incidence of major toxicity was significantly greater in those undergoing HD. Shannon concluded that while HP provides a higher theophylline clearance rate than HD, the latter appears to have comparable efficacy in reducing the morbidity of severe theophylline intoxication and is associated with a lower rate of procedural complications. 66

Lithium carbonate (see Chapter 30) remains a commonly used therapeutic agent in the treatment of bipolar disorder. While its Vd is low, it concentrates in brain matter, rendering effective treatment more difficult. It has minimal protein binding and a very small molecular weight, and thus is amenable to treatment with HD. Indications for dialysis remain controversial. 88 Recently, newer forms of extracorporeal purification for lithium poisoning have been proposed 89 (see Chapter 2C) which allow slower removal of lithium without rebound levels. 58 

Annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System

Management of intentional overdose in A&E departments

Diagnosis and management of the drug overdose patient

Pediatric rapid sequence intubation: a review

Rapid sequence intubation

Rapid-sequence intubation: a safe but ill-defined procedure

Rapid sequence induction medications: an update

In patients with head injury undergoing rapid sequence intubation, does pretreatment with intravenous lignocaine/lidocaine lead to an improved neurological outcome? A review of the literature

Lidocaine and rapid sequence intubation

Acute asthma in emergency room

Does ketamine have a role in managing severe exacerbation of asthma in adults?

Emergency department use of ketamine in pediatric status asthmaticus

In patients with head injuries who undergo rapid sequence intubation using succinylcholine, does pretreatment with a competitive neuromuscular blocking agent improve outcome? A literature review

Rocuronium versus succinylcholine for rapid sequence induction intubation

Pharmacologic management of the hypotensive patient

Management of calcium channel antagonist overdose

Drug-induced prolongation of the QT interval

Single-dose oral activated charcoal in the treatment of the self-poisoned patient: a prospective, randomized, controlled trial

Prospective evaluation of gastric emptying in the self-poisoned patient

Management of acutely poisoned patients without gastric emptying

Randomized study of the treatment of phenobarbital overdose with repeated doses of activated charcoal

The revised position papers on gastric decontamination

Selecting the language of the publications included in a meta-analysis: is there a Tower of Babel bias?

Occupational Health and Safety Administration: OSHA Best Practices for Hospital-based First Receivers of Victims from Mass Casualty Incidents Involving the Release of Hazardous Substances

Effects of washing acid injuries to the skin with water: an experimental study using rats

Experimental study on alkaline skin injuries-periodic changes in subcutaneous tissue pH and the effects exerted by washing

Emergency treatment of chemical and thermal eye burns

Alkali ocular burns in Martinique (French West Indies). Evaluation of the use of an amphoteric solution as the rinsing product

Is there a delay in bathing the external eye in the treatment of ammonia eye burns? Comparison of two ophthalmic solutions: physiological serum and Diphoterine

A prospective, randomized, blind comparison between saline, calcium gluconate and diphoterine for washing skin acid injuries in rats: effects on substance P and beta-endorphin release

Diphoterine for emergent eye/skin chemical splash decontamination: a review

Acid ingestion: toxicology and treatment

The treatment of alkaline burns of the skin by neutralization

Poor prognosis of severe chemical and thermal eye burns: the need for adequate emergency care and primary prevention

Management of chemical eye injuries with prolonged irrigation

Army Center for Health Promotion and Preventive Medicine (USACHPPM): Personal Protective Equipment Guide for Military Medical Treatment Facility Personnel Handling Casualties from Weapons of Mass Destruction and Terrorism Events

Weapons of mass destruction events with contaminated casualties: effective planning for health care facilities

Hexafluorine for emergent decontamination of hydrofluoric acid eye/skin splashes

Efficacy of hexafluorine for emergent decontamination of hydrofluoric acid eye and skin splashes

Hexafluorine vs. standard decontamination to reduce systemic toxicity after dermal exposure to hydrofluoric acid

Topical treatments for hydrofluoric acid burns: a blind controlled experimental study

Topical treatments for hydrofluoric acid burns: a blind controlled experimental study

Hydrofluoric acid dermal burns. An assessment of treatment efficacy using an experimental pig model

Topical treatments for hydrofluoric acid dermal burns. Further assessment of efficacy using an experimental piq model

Comparison of topical magnesium and calcium treatment for dermal hydrofluoric acid burns

The role of calcium gluconate in the treatment of hydrofluoric acid eye burn

The efficacy of calcium gluconate in ocular hydrofluoric acid burns

Ocular hydrofluoric acid burns: animal model, mechanism of injury and therapy

Effects of isopropyl alcohol, ethanol, and polyethylene glycol/industrial methylated spirits in the treatment of acute phenol burns

Efficacy of topical phenol decontamination strategies on severity of acute phenol chemical burns and dermal absorption: in vitro and in vivo studies in pig skin

Chemical skin burns

Phosphorus burns: a practical approach to local treatment

The phosphorous burn-a preliminary comparative experimental study of various forms of treatment

Phosphorous burns: evaluation of various modalities for primary treatment

Hand injuries due to highpressure injection devices for painting in shipyards: circumstances, management, and outcome in twelve patients

High-pressure hand injection injuries caused by dry cleaning solvents: case reports, review of the literature, and treatment guidelines

Fatal hypernatremia from exogenous salt intake: report of a case and review of the literature

Fatal hypernatremia from saltwater used as an emetic

Fatal hypernatremia after using salt as an emetic-report of three autopsy cases

Death following cupric sulfate emesis

Lacomis D: Case of the month

Rapidly reversible cardiomyopathy associated with chronic ipecac ingestion

Position statement: ipecac syrup. American Academy of Clinical Toxicology; European Association of Poisons Centres and Clinical Toxicologists

Conservative management of cocaine-packet ingestion: experience in Milan, the main Italian smuggling center of South American cocaine

A massive, near-fatal cocaine intoxication in a body-stuffer. Case report and review of the literature

Heroin body packers

Cocaine-condom ingestion. Surgical treatment

The cocaine 'body packer' syndrome. Diagnosis and treatment

Surgical removal of iron tablets

Endoscopic removal of pharmacobezoar of slow release theophylline

Release of toxic metals from button batteries retained in the stomach: an in vitro study

Systemic absorption of lithium following ingestion of a lithium button battery

Button battery ingestion: an analysis of 25 cases

Comparative efficacy of thallium adsorption by activated charcoal, prussian blue, and sodium polystyrene sulfonate

How long after drug ingestion is activated charcoal still effective?

Position paper: singledose activated charcoal

Activated charcoal administration in a pediatric emergency department

The frequency of complications associated with the use of multiple-dose activated charcoal

Chronic lung disease after activated charcoal aspiration

Incidence of aspiration pneumonia in intubated patients receiving activated charcoal

American Academy of Clinical Toxicology; European Association of Poisons Centres and Clinical Toxicologists: Position statement and practice guidelines on the use of multi-dose activated charcoal in the treatment of acute poisoning

Effects of Fuller's earth and activated charcoal on oral absorption of paraquat in rabbits

Position paper: cathartics

Acute hypermagnesemia after laxative use

Hypermagnesemia induced by massive cathartic ingestion in an elderly woman without preexisting renal dysfunction

Severe hypermagnesemia due to multiple-dose cathartic therapy

Position paper: whole bowel irrigation

A prospective study of acute, unintentional, pediatric superwarfarin ingestions managed without decontamination

Acute, unintentional pediatric brodifacoum ingestions

Position paper: ipecac syrup

Home syrup of ipecac use does not reduce emergency department use or improve outcome

Ipecac syrup-induced emesis . . . no evidence of benefit

The demise of ipecac

Poison Prevention: Poison treatment in the home

Guideline on the use of ipecac syrup in the out-of-hospital management of ingested poisons

Changes in arterial oxygen tension after gastric lavage for drug overdose

Gastrointestinal tract perforation with charcoal peritoneum complicating orogastric intubation and lavage

Esophageal tear following forceful removal of an impacted oral-gastric lavage tube

Aspiration pneumonia following severe self-poisoning

Position paper: gastric lavage

Severe esophageal damage due to button battery ingestion: can it be prevented?

Bite the bullet: lead poisoning after ingestion of 206 lead bullets

Successful treatment of theophylline toxicity by upper gastrointestinal endoscopy

Radiopacity of clomipramine conglomerations and unsuccessful endoscopy: report of 4 cases

Urine sugar reagent tablet ingestion causing gastric and duodenal ulceration

Device choice and experience level in endoscopic foreign object retrieval: an in vivo study

Hazards of battery ingestion

Swallowed button batteries: is there a consensus on management?

Is surgical decontamination definitive treatment of "body-packers"?

Whole-bowel irrigation as adjunctive treatment for sustained-release theophylline overdose

Interaction between whole-bowel irrigation solution and activated charcoal: implications for the treatment of toxic ingestions

Acceleration of the body clearance of phenobarbital by oral activated charcoal

Gastrointestinal clearance of drugs with activated charcoal

Intravenous theophylline poisoning and multiple-dose charcoal in an animal model

Dose-dependency in the exsorption of theophylline and the intestinal dialysis of theophylline by oral activated charcoal in rats

European Association of Poisons Centres and Clinical Toxicologists: Position statement and practice guidelines on the use of multi-dose activated charcoal in the treatment of acute poisoning

Multiple doses of activated charcoal: time for reappraisal?

The frequency of complications associated with the use of multiple-dose activated charcoal

Use of multiple-dose activated charcoal in phenytoin toxicity

Multiple-dose activated charcoal for treatment of yellow oleander poisoning: a single-blind, randomized, placebo-controlled trial

Correlation of drug pharmacokinetics and effectiveness of multiple-dose activated charcoal therapy

Oral activated charcoal and dapsone elimination

Acceleration of digoxin clearance by activated charcoal

Digoxin toxicity in chronic renal failure: treatment by multiple dose activated charcoal intestinal dialysis

Characteristics of vomiting associated with acute sustained release theophylline poisoning: implications for management with oral activated charcoal

Fatal pulmonary aspiration of oral activated charcoal

A fatality resulting from multiple dose activated charcoal therapy (abstract)

Aspiration of activated charcoal (letter)

Pulmonary aspiration of activated charcoal: a complication of its misuse in overdose management

Fatal pulmonary aspiration of oral activated charcoal (letter)

Activated charcoal surface area and its role in multiple-dose charcoal therapy

Gastrointestinal obstruction associated with multiple-dose activated charcoal

Charcoal bezoar. small bowel obstruction secondary to amitriptyline overdose therapy

Rectal ulcer with massive hemorrhage due to activated charcoal treatment in oral organophosphate poisoning

Intestinal pseudo-obstruction following the use of enteral charcoal and sorbitol and mechanical ventilation with papaveretum sedation for theophylline poisoning

Charcoal stercolith with intestinal perforation in a patient treated for amitriptyline ingestion

Treatment with activated charcoal complicated by gastrointestinal obstruction requiring surgery

Multiple doseactivated charcoal as a cause of acute appendicitis

Small-bowel obstruction secondary to activated charcoal and adhesions

Position statement: cathartics. American Academy of Clinical Toxicology; European Association of Poisons Centres and Clinical Toxicologists

Palatability of sucrose-, sorbitol-, and saccharinsweetened activated charcoal formulations

Dosage recommendations for activated charcoal-sorbitol treatment

The genesis of the square meter-hour hypothesis

Methanol intoxication: comparison of peritoneal dialysis and hemodialysis treatment

Peritoneal dialysis in children: survey of its indications and applications

Allergic reactions to the polymeric glucose-based peritoneal dialysis fluid icodextrin in patients with renal failure

Pharmacokinetic evaluation of forced diuresis, dialysis, and hemoperfusion

Current concepts: peritoneal dialysis

Vitamin D intoxication in an anephric child

Acute digoxin overdose in a newborn with renal failure: use of digoxin immune Fab and peritoneal dialysis

Carbamazepine overdosethe effects of multiple dose activated charcoal

Carbamazepine poisoning in adolescent suicide attempters. Effectiveness of multiple-dose activated charcoal in enhancing carbamazepine elimination

Pediatric carbamazepine intoxication

Effect of oral charcoal and urine pH on dextropropoxyphene pharmacokinetics

Treatment of digitoxin overdose with oral activated charcoal

The effects of activated charcoal on digoxin and digitoxin clearance

Enhancement of phenytoin elimination by multiple-dose activated charcoal

Treatment of phenytoin toxicity with repeated doses of activated charcoal

Multiple-dose activated charcoal in management of phenytoin overdose

Multiple-dose activated charcoal compared to urinary alkalinization for the enhancement of phenobarbital elimination

Pharmacokinetics of phenobarbital during certain enhanced elimination modalities to evaluate their clinical efficacy in management of drug overdose

The effect of activated charcoal on the bioavailability of piroxicam in man

MA: Thallium and arsenic poisoning in a small midwestern town

Accelerated clearance of intravenously administered theophylline and phenobarbital by oral doses of activated charcoal in rats. A possibility of the intestinal dialysis

Effect of administration of activated charcoal and fibre on absorption, excretion and steady state blood levels of digoxin and digitoxin. Evidence for intestinal excretion of the glycosides

Multiple doses of charcoal in digoxin poisoning

Activated charcoal increases digoxin elimination in patients

Misadventures with activated charcoal and recommendations for safe use

Treatment of phenobarbital poisoning with multiple dose activated charcoal in an infant

Multiple-dose activated charcoal in an accidental vancomycin overdose

Treatment of neonatal hyperbilirubinemia with repetitive oral activated charcoal as an adjunct to phototherapy

Prevalence of sorbitol in multiple-dose activated charcoal regimens in emergency departments

Continuous venovenous hemofiltration for the treatment of contrast-induced acute renal failure after percutaneous coronary interventions

Continuous arterial-venous diahemofiltration and continuous veno-venous diahemofiltration in infants and children

Functional characteristics of pediatric veno-venous hemofiltration

Rapid removal of vancomycin by continuous veno-venous hemofiltration

Is continuous veno-venous hemofiltration for acetaminophen-induced acute liver and renal failure worthwhile?

Hyperphosphatemia in tumor lysis syndrome: the role of hemodialysis and continuous veno-venous hemofiltration

Myoglobin clearance during continuous veno-venous hemofiltration with or without dialysis

Acute rhabdomyolysis after gemfibrozil therapy in a pregnant patient complicated with acute pancreatitis and hypertriglyceridemia while receiving continuous veno-venous hemofiltration therapy

Significant myoglobin removal during continuous veno-venous haemofiltration using F80 membrane (letter)

Lactic academia and bradyarrhythmia in a child sedated with propofol

Severe accidental hypothermia: rewarming with CVVHD

Propylene glycol toxicity associated with lorazepam infusion in a patient receiving continuous veno-venous hemofiltration with dialysis

The acid-base effects of continuous hemofiltration with lactate or bicarbonate buffered replacement fluids

Profound hypercalcemia in continuous veno-venous hemofiltration dialysis with trisodium citrate anticoagulation and hepatic failure (letter)

Ueber die beseitgung giftiger stoffe aus blute durch dialyse

Peritoneal dialysis: a review

Fine RN: Peritoneal dialysis update

Pharmacokinetics of drugs during various detoxification procedures for overdose and environmental exposure

Extracorporeal therapy in the treatment of intoxication

Interactions of drugs and peritoneal dialysis

Dialysis of poisons and drugs-annual review

Evaluation of the effects of multiple-dose activated charcoal on the absorption of orally administered salicylate in a simulated toxic ingestion model

An evaluation of the effect of repeated doses of oral activated charcoal on salicylate elimination

Does multiple-dose charcoal therapy enhance salicylate excretion?

Multiple-dose charcoal and whole-bowel irrigation do not increase clearance of absorbed salicylate

Effect of multiple-dose activated charcoal on the clearance of high-dose intravenous aspirin in a porcine model

Effect of activated charcoal on absorption of nortriptyline

Effect of single and repeated doses of activated charcoal on the pharmacokinetics of doxepin

Lack of effect of oral activated charcoal on imipramine clearance

Pharmacokinetics of amitriptyline influenced by oral charcoal and urine pH

Effect of orally administered activated charcoal on vancomycin clearance

Failure of oral activated charcoal to accelerate the elimination of amiodarone and chloroquine

The effect of activated charcoal on the absorption and elimination of astemizole

Effects of charcoal, sodium bicarbonate, and ammonium chloride on chlorpropamide kinetics

Tenenbein M: Diltiazem overdose: pharmacokinetics of diltiazem and its metabolites and effect of multiple dose charcoal therapy

Effect of activated charcoal on the pharmacokinetics of pholcodine, with special reference to delayed charcoal ingestion

The effect of repeateddose activated charcoal on the pharmacokinetics of sodium valproate in healthy volunteers

Effect of oral activated charcoal on tobramycin clearance

Elimination of amrinone during continuous veno-venous haemofiltration after cardiac surgery

Acute barium intoxication and hemodiafiltration

Pharmacokinetics of ceftriaxone in patients undergoing continuous veno-venous hemofiltration

Ethylene glycol antifreeze poisoning

Pharmacokinetics of imipenem-cilastatin in critically ill patients undergoing continuous venovenous hemofiltration

Continuous venovenous haemofiltration versus continuous veno-venous haemodialysis in severe lithium self-poisoning:a toxicokinetics study in an intensive care unit

Clearance of metformin by hemofiltration in overdose

Three case reports of the use of haemodiafiltration in the treatment of salicylate overdose

Vancomycin and tobramycin clearance in an infant during continuous hemofiltration

Amikacin pharmacokinetics during continuous veno-venous hemofiltration (letter)

Acute arsenic poisoning treated by intravenous dimercaptosuccinic acid (DMSA) and combined extrarenal epuration techniques

Hemodialysis versus continuous veno-venous hemodiafiltration in the management of severe valproate overdose

Peritoneal dialysis in acute poisoning: successful treatment of a 15-month-old child ingesting 30 times the adult dose of Achrocidin

The early removal of amatoxins in the treatment of amanita phalloides poisoning (author's translation)

Management of amikacin overdose

Acute potassium dichromate poisoning: treated by peritoneal dialysis

Peritoneal dialysis for removal of copper

Role of albumin-enriched peritoneal dialysate in acute copper poisoning

Treatment of ethylene glycol poisoning with peritoneal dialysis

Intensified dialysis treatment of ethylene glycol intoxication

Treatment of glutethimide poisoning: a comparison of forced diuresis and dialysis

Peritoneal and hemodialysis for acute glutethimide

Treatment of glutethimide intoxication: an in vivo comparison of lipid, aqueous, and peritoneal dialysis with albumin

Peritoneal dialysis for isopropanol poisoning

Peritoneal dialysis for lithium poisoning

Lithium intoxication treated by peritoneal dialysis

Lithium intoxication with acute renal failure and death

Meprobamate poisoning treated by peritoneal dialysis

Meprobamate intoxication treated with peritoneal dialysis

Meprobamate poisoning: successful treatment with peritoneal dialysis

Amphetamine poisoning and peritoneal dialysis: a case report

The use of peritoneal dialysis in acute methyl alcohol poisoning

Methanol poisoning in an infant: successful treatment with peritoneal dialysis

Acute mercury poisoning by intentional ingestion of mercuric chloride

Peritoneal dialysis for severe methyprylon intoxication

Peritoneal dialysis for severe methyprylon intoxication (letter)

Propoxyphene hydrochloride poisoning: report of the first fatality

Propoxyphene hydrochloride poisoning: report of a case treated with peritoneal dialysis

Acute propoxyphene hydrochloride intoxication

Peritoneal dialysis in quinine sulfate intoxication

Peritoneal dialysis in quinine intoxication

Quinine extraction during peritoneal dialysis: the role of nonionic diffusion

Hemodialysis, peritoneal dialysis, plasmapheresis and forced diuresis for the treatment of quinine overdose

Amitriptyline hydrochloride poisoning: unsuccessful treatment by peritoneal dialysis

Fatal chloroquine poisoning in a child: experience with peritoneal dialysis

Chlorpropamide intoxication-treatment with peritoneal dialysis

Accidental poisoning with isoniazid and rifampicin in an infant: role of peritoneal dialysis

Peritoneal dialysis and haemodialysis in methaqualone (Mandrax) poisoning

Peritoneal dialysis in methaqualone overdose

Peritoneal dialysis and Lysol poisoning

Thallium ingestion with survival: ineffectiveness of peritoneal dialysis and potassium chloride diuresis

Valacyclovir neurotoxicity in a patient with end-stage renal disease treated with continuous ambulatory peritoneal dialysis

Comparison of peritoneal and hemodialysis: treatment of methanol intoxication

Peritoneal dialysis for severe salicylism: an evaluation of indications and results

Rapid correction of acute salt poisoning by peritoneal dialysis

Toxicologic and pharmacokinetic evaluation of a case of vancomycin intoxication during continuous ambulatory peritoneal dialysis

Use of peritoneal dialysis in experimental amphetamine poisoning

Baclofen neurotxicity in uremic patients: is continuous ambulatory peritoneal dialysis less effective than intermittent hemodialysis?

Peritoneal dialysis in the treatment of boric acid poisoning

Acute boric acid poisoning: report of an infant successfully treated by peritoneal dialysis

Asymptomatic boric intoxication: value of peritoneal dialysis

Ingestion of boric acid by infants

Bromate poisoning

Treatment of bromate poisoning (letter)

Near-fatal caffeine intoxication treated with peritoneal dialysis

Dialysis treatment of acute chromium intoxication and comparative efficacy of peritoneal versus hemodialysis in chromium removal

Chromic acid burns: early aggressive excision is the best method to prevent systemic toxicity

Brief clinical and laboratory observations: management of neonatal gentamicin overdosage

Removal of mercury by peritoneal dialysis

CHAPTER 2 Emergency Management of Poisoning 53

Winchester JF: Dialysis and hemoperfusion in poisoning

Annual Report of the American Association of Poison Control Centers' national poisoning and exposure database

Toltec International Inc: How hemodialysis (dialysis) works

Combined hemoperfusion and hemodialysis treatment of poisoning with cholinesterase inhibitors

Acute poisoning with bromofosmethyl (bromophos)

Use of hemoperfusion and cholinesterase in acute poisoning with organophosphate cholinesterase inhibitors-clinical analysis of 50 patients

The availability and use of charcoal hemoperfusion in the treatment of poisoned patients

Elimination of paraquat

Multiple-dose activated charcoal: a review of relevant clinical studies

The role of the Molecular Adsorbents Recirculating System (MARS) in the management of liver failure

Preconditioning by extracorporeal liver support (MARS) of patients with cirrhosis and severe liver failure evaluated for living donor liver transplantation-a pilot study

Application of MARS artificial liver support as bridging therapy before split liver retransplantation in a 15-month-old child

Application of Molecular Adsorbent Recirculating System in patients with severe liver failure after hepatic resection or transplantation: initial single-centre experiences

Experiences with MARS liver support therapy in liver failure: analysis of 176 patients of the International MARS Registry

MARS preconditioning for living donor liver transplantation: panacea or placebo?

How tightly can a drug be bound to a protein and still be removable by charcoal hemoperfusion in overdose cases?

Extracorporeal therapies for acute intoxications

Quantitative pharmacogenetics of nortriptyline: a novel approach

Fomepizole for the treatment of ethylene glycol poisoning

Fomepizole for the treatment of methanol poisoning

Fomepizole in treatment of uncomplicated ethylene glycol poisoning

Current management of ethylene glycol poisoning

REFERENCES 1. Bismuth C: Biological valuation of extra-corporeal techniques in acute poisoning

Fomepizole may change indication for hemodialysis in methanol poisoning: prospective study in seven cases

Current recommendations for treatment of severe toxic alcohol poisonings

Severe lactic acidosis treated with prolonged hemodialysis: recovery after massive overdoses of metformin

Combination of intermittent haemodialysis and highvolume continuous haemofiltration for the treatment of severe metformin-induced lactic acidosis

Acute kidney failure: a pediatric experience over 20 years

Treatment of severe pediatric ethylene glycol intoxication without hemodialysis

Childhood methanol ingestion treated with fomepizole and hemodialysis

Chronic renal disease patients with severe star fruit poisoning: hemoperfusion may be an effective alternative therapy

Extracorporeal techniques in the treatment of poisoned patients

Acute hemolysis with acute renal failure in a patient with valproic acid poisoning treated with charcoal hemoperfusion

Hemodialysis complications

Intradialytic complications during hemodialysis

High-flux hemodialysis-an effective alternative to hemoperfusion in the treatment of carbamazepine intoxication

High-efficiency dialysis for carbamazepine overdose

High-flux haemodialysis treatment as treatment for carbamazepine intoxication

Management of carbamazepine overdose

Efficacy of charcoal hemoperfusion in massive carbamazepine poisoning

Repeat charcoal hemoperfusion treatments in life threatening carbamazepine overdose

Osmol gap as a surrogate marker for serum propylene glycol concentrations in patients receiving lorazepam for sedation

Use of the osmolal gap to guide the start and duration of dialysis in methanol poisoning

Removal of propylene glycol and correction of increased osmolar gap by hemodialysis in a patient on high dose lorazepam infusion therapy

Unusual D-lactic acid acidosis from propylene glycol metabolism in overdose

Treatment of the alcohol intoxications: ethylene glycol, methanol and isopropanol

Life-threatening isopropyl alcohol intoxication: is hemodialysis really necessary?

Extracorporeal management of valproic acid toxicity: a case report and review of the literature

Acute valproate poisoning: pharmacokinetics, alteration in fatty acid metabolism, and changes during therapy

Successful use of hemodialysis in acute valproic acid intoxication

Successful treatment of valproic acid overdose with hemodialysis

High-flux hemodialysis without hemoperfusion is effective in acute valproic acid overdose

Efficiency of highflux hemodialysis in the treatment of valproic acid intoxication

Extracorporeal management of valproic acid overdose: a large regional experience

Valproic acid toxicity: overview and management

Glycolate kinetics and hemodialysis clearance in ethylene glycol poisoning. META Study Group

Glycolate causes the acidosis in ethylene glycol poisoning and is effectively removed by hemodialysis

Formate kinetics in methanol poisoning

An evidence based flowchart to guide the management of acute salicylate (aspirin) overdose

Alkalinization and hemodialysis in severe salicylate poisoning: comparison of elimination techniques in the same patient

Concepts and controversies in salicylate toxicity

Severe theophylline poisoning: charcoal haemoperfusion or haemodialysis

Comparative efficacy of hemodialysis and hemoperfusion in severe theophylline intoxication

Phosphorus-enriched hemodialysis for the treatment of patients with severe methanol intoxication

Validation of a method to predict required dialysis time for cases of methanol and ethylene glycol poisoning

Acute phenobarbital intoxication

Effectiveness of hemodialysis in the extracorporeal therapy of phenobarbital overdose

Conventional haemodialysis significantly lowers toxic levels of phenobarbital

Hemodialysis following butoxyethanol ingestion

Repeated ingestion of 2-butoxyethanol: case report and literature review

The treatment of severe drug intoxication with charcoal hemoperfusion in series with hemodialysis

Critical, acutely poisoned patients treated with continuous arteriovenous hemoperfusion in the emergency department

When should dialysis be performed in lithium poisoning? A kinetic study in 14 cases of lithium poisoning

Hemodialysis followed by continuous hemofiltration for treatment of lithium intoxication in children

Hyperosmolality: another indication for hemodialysis following acute ethylene glycol poisoning

Ethylene glycol toxicity: the role of serum glycolic acid in hemodialysis

Hemodialysis as a treatment of severe ethanol poisoning

Intravenous 4-methylpyrazole as an antidote for diethylene glycol and triethylene glycol poisoning: a case report

Successful treatment of a child with fulminant liver failure and coma caused by Amanita phalloides intoxication with albumin dialysis without liver transplantation

Molecular adsorbent recirculating system in dealing with maternal Amanita poisoning during the second pregnancy trimester: a case report

Successful use of Molecular Absorbent Regenerating System (MARS) dialysis for the treatment of fulminant hepatic failure in children accidentally poisoned by toxic mushroom ingestion

MARS: optimistic therapy method in fulminant hepatic failure secondary to cytotoxic mushroom poisoning-a case report

Phenytoin intoxication in critically ill patients

Experience with albumin dialysis in five patients with severe overdoses of paracetamol

MARS procedure as a bridge to combined liver-kidney transplantation in severe chromium-copper acute intoxication: a paediatric case report

Childhood diethylene glycol poisoning treated with alcohol dehydrogenase inhibitor fomepizole and hemodialysis

The role of continuous renal replacement therapy in the treatment of poisoning

Methanol and formate kinetics during treatment with fomepizole

Rethinking the toxic methanol level

Isopropyl alcohol intoxication: a diagnostic challenge

Acute isopropyl alcohol intoxication. Diagnosis and management

Methods used to decrease lithium absorption or enhance elimination

Treatment of lithium intoxication with continuous venovenous hemodiafiltration

Successful treatment by direct hemoperfusion of coma possibly resulting from mitochondrial dysfunction in acute valproate intoxication

Treatment of severe theophylline poisoning with the molecular adsorbent recirculating system (MARS)

Molecular adsorbent recirculating system-MARS as a bridge to liver transplantation in amanita phalloides intoxication

Successful treatment of an adult with Amanita phalloides-induced fulminant liver failure with molecular adsorbent recirculating system (MARS)

Carbamazepine has a relatively low molecular weight (236 Da), but a fairly large Vd (1-2 L/kg) and is about 80% protein bound at therapeutic levels. Its active metabolite 10,11-epoxide (CBZE), is approximately 50% protein bound. 42, 44 Because of the high protein binding, activated charcoal and CHP have generally been favored in treatment; however, high-efficiency dialysis may also be effective. 40

Valproic acid (see Chapter 40) is a low molecular weight (144 Da) anticonvulsant with a small Vd and saturable protein binding. At therapeutic concentrations, 90% to 95% of valproic acid is protein bound, but in overdose the degree of protein binding is relatively less (i.e., there is more unbound drug available for extracorporeal purification). Saturation of protein binding sites occurs at levels greater than 150 μg/mL, at which 54% to 70% of the drug is protein bound. At a level of 300 μg/mL, 35% of valproic acid is protein bound, 51,57,58 rendering it amenable to extracorporeal drug removal techniques. 55, 90 Both HP and HD, alone and in combination, have been used in cases of valproate toxicity. Valproic acid elimination has been shown to be enhanced about tenfold by the use of extracorporeal methods. 57 While the half-life of the drug is effectively diminished, the precise role of these procedures in valproate toxicity remains to be established. 58

A nonexhaustive list of substances for which MARS has been used in poisoning includes theophylline, 91 cytotoxic mushrooms, 92-97 phenytoin, 98 acetaminophen (paracetamol), 99 and a copper-chromium-containing solution. 100 MARS appears to improve liver failure from multiple causes, but further prospective studies are needed to determine the role this technique should play in patient care. 14 

In conclusion, HD and HP remain important, but secondary methods of treatment in poisoning by specific substances. These modalities cannot be substituted for excellent supportive care, and in some cases the need for them has been supplanted by effective antidotes. Both HD and HP are associated with complications and are not universally available. Careful evaluation of individual cases should guide the decision to use extracorporeal circulation. MARS or albumin dialysis may be of clinical benefit in selected poisonings.