Disease-a-Month 60 (2014) 509–524

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Disease-a-Month journal homepage: www.elsevier.com/locate/disamonth

The general approach to the poisoned patient Trevonne M. Thompson, MD, FACEP, FACMT, Jillian Theobald, MD, PhD, Jenny Lu, MD, MS, Timothy B. Erickson, MD, FACEP, FACMT, FAACT

Introduction In 2012, the most recent year for which data are available, there were 2,275,141 human exposures reported to the poison control centers in the United States.1 Poisoning became the number one cause of accidental death in the United States in 2008, exceeding motor vehicle collision deaths for the first time since 1980.2 The poisoning death rate increased by 90% in the decade between 1999 and 2008.2 Knowledge surrounding the approach to the poisoned or potentially poisoned patient is important for all healthcare professionals. This centers on recognition of the poisoning, anticipation of poisoning effects, and the prevention or treatment of those effects. Medical toxicology is a subspecialty whose practitioners have expertise in the diagnosis, management, and prevention of all manners of poisoning, including adverse effects from medications, environmental and occupational exposures, and biologic agents.3,4 Medical toxicology is a small specialty. The American Board of Emergency Medicine (ABEM) is the administrative sponsoring board for certifying medical toxicologists. Since recognition in 1992 by the American Board of Medical Specialties as a sub-board of ABEM, only several hundred diplomates have certified in medical toxicology.5 While the number is small, access to these providers is not limited. Institutions without medical toxicologists have access to accredited poison control centers. The American Association of Poison Control Centers (AAPCC) provides accreditation for poison centers in the US. There are many criteria for accreditation.6 Among the requirements is the availability of appropriately trained staff 24 hours per day. Specialists in poison information (colloquially called SPIs or “spies”) are the trained nurses or pharmacists (occasionally physicians) who actively provide much of the poison center services and must pass a national certification examination every seven years. Poison centers undergo a review by the AAPCC every five years. To obtain and maintain accreditation, there must be at least one board-certified medical toxicologist available for consultation at all times. In the United States, one phone number (1-800-222-1222) provides the caller—healthcare worker or general public—with 24-hour access to a specialist in poison information and/or medical toxicologist within their region. Poison centers reduce healthcare costs.7,8 One way this http://dx.doi.org/10.1016/j.disamonth.2014.10.002 0011-5029/& 2014 Mosby, Inc. All rights reserved.

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is accomplished is by reducing unnecessary healthcare facility visits by civilian callers.8 Poison centers also serve as vehicles for toxicosurveillance, recognizing poisoning trends earlier in their development than may have otherwise been recognized.9

Toxicokinetics and toxicodynamics Xenobiotics are substances, natural or synthetic, that are foreign to the human body. Toxicokinetics refers to the absorption, distribution, metabolism, and excretion of a xenobiotic under toxicologic conditions. Similarly, toxicodynamics refers to the toxic concentrations of xenobiotics and their clinical effect. Toxicokinetics and toxicodynamics are related to pharmacokinetics and pharmacodynamics, respectively. Healthcare practitioners should understand that pharmacokinetic and pharmacodynamic data may not necessarily apply in the poison or overdose situation. Additionally, the common notion of a substance being classified as toxic or non-toxic does not apply to the practice of medical toxicology. The Renaissance physician Paracelsus described this principle as such: “What is it that is not a poison? All things are poison and nothing is without poison. Solely, the dose determines that a thing is not a poison.”10

The general approach to the poisoned patient Having an organized and consistent approach to the management of poisoned or potentially poisoned patients is paramount, focusing on both diagnosis and treatment.11 Figure 1 represents such an approach. When presented with a poisoned or potentially poisoned patient, considerations for both diagnosis and treatment may occur sequentially or simultaneously, depending on the clinical situation and severity of illness. The diagnostic arm consists of taking an appropriate toxicologic history and performing a physical examination with attention to

Obtain poisoning history Perform physical examination Diagnosis

Toxidrome recognition Diagnostic testing

Poisoned Patient

ABCs of emergency care Decontamination Treatment Enhanced elimination Focused therapy/antidotal therapy

Consult toxicologist/regional poison center Fig. 1. The two-pronged approach to the poisoned patient.

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toxidrome recognition. A toxidrome, or toxicologic syndrome, is a constellation of symptoms and signs that lead to a certain class of poisons. Depending on the specific situation, certain diagnostic tests may provide useful information regarding the poisoning event and case management. The treatment arm involves the ABCs of emergency care—airway, breathing, and circulation. In a critical situation, the basic tenets of advanced cardiac life support should be followed. Decontamination refers to preventing or reducing absorption of a substance. There are various methods of decontamination. The clinical scenario will determine which method, if any, should be used. After absorption has occurred, certain xenobiotics are amenable to an enhanced elimination procedure. Both decontamination and enhanced elimination are further discussed in separate sections of this article. Many cases of poisoning have nuances or challenges best identified and managed with the assistance of a regional poison center and/or medical toxicologist. A healthcare practitioner should consider the early involvement of poison center staff or a medical toxicologist in any case of poisoning or in situations where there is concern for a possible poisoning.

The toxicologic history When obtaining a toxicologic history, it is important for the practitioner to understand the FIVE Ws as outlined in Table 1. The first W represents who: who is the patient? Is the patient, for example, an infant or bedridden nursing home patient with dementia? These two examples illustrate important points. An infant cannot intentionally overdose. A bedridden nursing home patient with dementia should not have independent access to their medications. Understanding who the patient is imparts important information when gathering the history. Additional pieces of information include the patient’s occupation, hobbies, and other contextual circumstances. An industrial lab worker or hobbyist may have access to substances that a typical patient may not. The next W represents whose: to whose medication or product was the patient exposed? A healthy patient who overdoses on his/her roommate’s pills may have a different course than a patient who overdoses on the medication he/she uses chronically. The next W represents what product. Besides knowing the name or class of a substance, the precise formulation can impact care. There are, for example, many forms of the various pharmaceutical agents—immediaterelease pills, sustained-release pills, transdermal patches, rectal and vaginal suppositories, suspensions, and elixirs. Similarly, the route of the exposure is important. It should not be Table 1 The toxicologic history: The 5 Ws. Who is the patient? e.g., infant, adolescent, or bedridden nursing home patient occupation and hobbies Whose medication or substance? took own medication or took someone else’s pills acute exposure, chronic exposure, or acute-on-chronic exposure What product? identify the substance and preparation ascertain route of exposure When did the exposure occur? was it a single exposure or chronic exposure Why did the exposure occur? suicide attempt or therapeutic misadventure accidental or mind-altering experience

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assumed that a transdermal patch was used in the prescribed manner. In the abuse situation, for example, fentanyl patches have been used on scrotal skin, orally, and rectally.12,13 The penultimate W represents when. The timing of the exposure is important to ascertain and can have implications on the predicted onset of effects and clinical course. The final W pertains to why: why did the patient have the exposure? Was the exposure a suicide attempt, medication administration error, accidental, or an attempt to achieve a mind-altering experience? Each of these have different risk patterns for the various exposures. When a patient cannot speak for him- or herself, the healthcare provider should use any available resource to obtain information. Paramedics, police, friends, and family can provide information about the prehospital scene or time of last known patient contact. This is particularly important in patients with altered mental status, who are psychotic, who are under the influence of recreational drugs, or who have attempted suicide, as they may be unreliable historians.14–16 The practitioner should inquire about suicide notes, text messages, or social media postings in patients where there is concern for self harm. Important information can be obtained using modern technology.17–19 The practitioner should inquire about all medication that may have been used, including herbal preparations, vitamins, and home remedies. Empty pill bills bottles do not necessarily mean those pills were ingested but could still provide useful information. Similarly, if presented with pill bottles, a practitioner should not rely on the information printed on the bottle. Instead, visual inspection of the pills and confirmation via pill imprint is best. People can easily put various pills into any pill bottle or container. Calling the patient’s pharmacy to obtain an up-to-date medication list can also prove helpful in sorting through an ingestion history. In the case of an occupational or industrial exposure, a practitioner should obtain information regarding the conditions at the site of the exposure and the material safety data sheets (MSDS) for all chemicals or substances involved.

The toxicologic physical examination When a patient presents with a possible toxic exposure, the physical exam should initially focus on a few critical areas, followed by a more comprehensive exam when the patient is stabilized. Evaluation should begin with assessment of airway patency, rate and depth of ventilation, circulatory status, and mental status. After these areas are addressed, a more thorough physical exam should ensue. The secondary comprehensive exam should focus on areas that are toxicologically important such as vital signs, neurological findings, and skin parameters. It is imperative to perform frequent re-examinations as the physical exam is often dynamic in toxicological exposures and patients can abruptly decompensate.20,21 Also, specific exposures are often associated with classic physical exam findings. However these findings may not always be seen depending on the dose ingested, the timing of the ingestion, co-ingestants, and the preexisting medical condition of the patient. History may often be limited or deceptive in poisoned patients; therefore, treating the patient and the physical manifestations of their exposure can be more important than focusing on historical details in certain cases. Toxic vital signs A complete set of vital signs must be obtained in every poisoned patient. A core temperature is essential as both drugs of abuse and therapeutic drugs can cause alterations in temperature. A finding of hyperthermia is typically a bad prognostic factor, especially for temperatures above 40.51C as it can lead to irreversible neuron damage.22,23 On the other hand, intoxicated patients may be hypothermic as their intoxication can lead to an environmentally induced hypothermia. Even medications at therapeutic doses can cause hypothermia.24 A bedside capillary glucose is also important to obtain and should be considered a vital sign. Combinations of vital signs not usually seen together can also be helpful in determining a possible exposure and directing treatment. For example, a patient who is hypotensive and bradycardic was likely exposed to a

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beta-blocker, calcium channel blocker, digoxin, guanfacine, or clonidine. Few other medications or drugs cause simultaneous hypotension and bradycardia. Neurologic exam The neurologic exam of a poisoned patient is one of the most important and useful parts of the physical exam and should begin with an assessment of global mental status. Alterations in mental status are common and not only include depressed mental status but also agitation, delirium, and psychosis.25 Whether someone is awake enough to respond or follow commands can dictate the treatment intervention chosen. For instance, a patient’s mental status may be so severely depressed they require intubation while another patient may not require intubation but is too drowsy to receive activated charcoal. Another important physical exam component is the eye exam, specifically the pupil size and eye movements. Mydriasis can be seen in sympathomimetic and anticholinergic toxidromes; miosis is found in the cholinergic and opiate toxidromes. Abnormal eye movements such as nystagmus could be due to medications and drugs of abuse such as sedatives, antiepileptic drugs, and phencyclidine/ketamine.26 The extremities of the patient should be assessed for muscle tone, tremor, and clonus. Rigidity can be indicative of neuroleptic malignant syndrome, whereas clonus is typically seen in the setting of serotonin syndrome.20,27 Both drug intoxication and drug withdrawal can produce tremor.28 Seizures can occur in overdose, withdrawal, and with medications at therapeutic doses that lower the seizure threshold.29 Skin exam Examination of the skin of a poisoned patient can be helpful in determining the etiology of a poisoning. Patients should be undressed and parameters such as color, temperature, dryness, and the presence and characteristics of any lesions should be noted. Undressing the patient is essential, especially to look for medication patches that could be hidden in inconspicuous places such as the scrotum in cases of opioid transdermal patch abuse.30 Red skin can indicate carbon monoxide, cyanide, niacin, scromboid, or boric acid exposures. Blue discoloration of the skin could be due to cyanosis or methemoglobinemia. Yellow skin is often due to liver failure or hemolysis, both of which can be drug induced. The moisture of the skin is important to help differentiate an anticholinergic-mediated poisoning from a sympathomimetic poisoning as an anticholinergic-poisoned patient will have dry skin. Skin lesions are also important to evaluate and can indicate prolonged down time or exposure to a specific toxin. Ecchymosis or bulla over dependent areas of the body may indicate a prolonged down time from any sedative hypnotic (“coma blisters”). Odors Olfactory clues aiding in diagnosis have long been considered important from the timehonored diagnosis of pediatric inborn errors of metabolism to the present day diagnosis of infection via electronic noses.31,32 Blood, serum, or urine concentrations of some substances can be obtained to help guide management; however, the results may not be known immediately. In such cases, bedside clinical findings such as odors can guide diagnosis and therapy. Amitraz poisoning is an example. Amitraz is an insecticide, and poisoning can mimic that of an organophosphate. Odors can help to differentiate the two and guide management.33 Classically, specific odors have been associated with certain toxins, as summarized in Table 2. Toxidromes A toxidrome is a constellation of signs and symptoms associated with a specific poison.34 As outlined in Table 3, there are many toxidromes.35,36 Identifying a toxidrome while examining a

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Table 2 Odors that suggest a particular toxin or diagnosis. Odor

Possible source

Bitter almonds Carrots Freshly mown hay Fruity Garlic Gasoline Mothballs Peanuts Pears Peppery Minty Rotten eggs

Cyanide Cicutoxin (water hemlock) Phosgene Ketosis (diabetic ketoacidosis or isopropanolol) Organophosphates, arsenic, DMSO, or selenium Hydrocarbons Naphthalene, camphor, or amitraz Vacor (PNU) Chloral hydrate o-Chlorobenzylidenemalonitrile (tear gas) Methylsalicylate Hydrogen sulfide, sulfur dioxide, or N-acetylcysteine

patient can help narrow the differential diagnosis of potential causative agents and also direct therapy. It is important to keep in mind that patients may not manifest all characteristics of a toxidrome at any given time point. This is another reason frequent re-examinations are vital.

Clinical testing Extensive laboratory testing by healthcare providers is often performed when treating poisoned patients, especially in those with unknown intoxications. Consultation with a poison control center or medical toxicologist can aid in the judicious selection of clinically helpful tests. Routine tests Commonplace tests, such as blood chemistry, may add important diagnostic clues in the symptomatic overdose patient. Hypoglycemia might suggest sulfonylureas or insulin overdose. New renal failure might suggest nephrotoxic agents. A urine pregnancy test should be performed in women of childbearing age, as a positive result could potentially necessitate a Table 3 Common toxidromes, their clinical presentation, and causative agents. Toxidrome

Characteristic findings

Potential vital sign abnormalities

Common agents

Anticholinergic

Agitation/delirium Mydriasis Dry skin Miosis Diarrhea Vomiting Bronchorrhea Diaphoresis Agitation Mydriasis Diaphoresis Sedation Miosis Decreased bowel sounds Stupor Coma Slurred speech Sedation Slurred Speech

Tachycardia

Antihistamines Cyclic antidepressants

Bradycardia

Ogranophosphates

Tachycardia Hypertension Hyperthermia Bradypnea Bradycardia

Cocaine Amphetamine Caffeine Hydrocodone Heroin

Hypothermia Bradypnea

Benzodiazepines Barbiturates

Tachycardia Hypotension

Quetiapine Aripiprazole

Cholinergic

Sympathomimetic

Opioid

Sedative hypnotic

Atypical antipsychotic

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Table 4 Diagnostic tests and their usefulness in poisoned patients. Blood gas analysis Complete blood count Liver profile Lactate Creatinine kinase Ammonia Acetaminophen concentration Prothrombin time (INR) Ketones Urinalysis Electrocardiogram

Salicylates and acid–base disturbances Methotrexate and colchicine Hepatotoxins (aminita phalloides and acetaminophen) Metformin, seizures, cyanide, and propylene glycol Rhabdomyolysis Valproic acid and liver failure Symptoms of overdose may appear in delayed fashion Coumadin and superwarfarins Isopropanol and acetone pH can guide urinary alkalinization therapy QRS and QT intervals and cardiac rhythm in cardiotoxic agents

modification in treatment. Table 4 lists other diagnostic tests to consider and the usefulness of these tests in the poisoned patient. Quantitative blood tests should be ordered for those drugs or toxins in which blood or serum concentrations will help confirm exposure, predict toxicity, or guide specific therapy. The healthcare practioner should follow serial concentrations of drugs that have erratic absorption kinetics such as salicylates and valproic acid. Measurable drug/toxin levels usually available in clinically relevant time frames include acetaminophen, salicylates, ethanol, theophylline, lithium, iron, carboxyhemoglobin, methemoglobin, lead, digoxin, and certain anticonvulsants (e.g., valproic acid, phenytoin, carbamazepine, and phenobarbital). Toxic alcohol analyses, including ethylene glycol and methanol, are often sent to reference laboratories and are not done in many local hospitals. In such cases, the practitioner should know the hospital or healthcare facility’s procedure for sending specimens to reference laboratories to have the samples processed rapidly. Even in this case, a period of hours may transpire before results are known. Treatment for toxic alcohol poisoning should be started empirically in such cases where there is suspicion. Other drug concentrations (e.g., antipsychotics) are measurable in reference laboratories but frequently take several days to return. These concentrations may help confirm an exposure after the fact but may not be available in a clinically relevant time frame. After obtaining routine labs and learning that a patient has a metabolic acidosis, the practitioner has to determine whether a widened anion gap is present. To assess for a widened anion gap metabolic acidosis, calculate the anion gap using this formula: Na-(Cl þ HCO3). The mnemonic CAT MUDPILES lists common causes of an elevated anion gap (average normal ¼ 8– 12 mEq/L) (Table 5). The evaluation of an unexplained metabolic acidosis often involves ordering a serum osmolality measurement and then calculating the osmolal gap. The practitioner should understand that interpretation of the osmolal gap could be challenging. The osmolal gap is the difference between the measured serum osmolality (most accurately determined by freezing

Table 5 Causes of a widened anion gap: CAT MUDPILES. Cyanide or carbon monoxide Acetaminophen (massive), aspirin, or alcoholic ketoacidosis Toluene Methanol, metformin, or massive overdoses Uremia Diabetic ketoacidosis Paraldehyde or propylene glycol Iron, isoniazid, or ibuprofen (massive) Lactic acidosis Ethylene glycol Salicylates

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Table 6 Causes of an elevated osmolal gap: ME DIE. Methanol Ethylene glycol Diuretics (mannitol) or diabetic ketoacidosis (acetone) Isopropyl alcohol Ethanol

point depression method) and the calculated serum osmolarity. The most commonly used formula is as follows: 2Na þ Glucose=18 þ BUN=2:8 þ Ethanol=4:6 An increased osmolal gap suggests the presence of an osmotically active substance in the serum. Table 6 lists agents that increase the osmolar gap. An osmolal gap of 10 has been arbitrarily defined as normal. In actuality, the range of normal is approximately  15 to þ10.37 Patients with a “normal” gap of 10 may actually have an increased gap if their baseline is  15. Patients presenting late in a toxic alcohol intoxication, for example, may not have a significant osmol gap due to metabolism of the osmotically active parent compound into their acid metabolites. The osmol gap may be “normal” and the anion gap high. In early presenters, there may be a high osmol gap and low anion gap, if the parent compound has not yet significantly metabolized.38 Figure 2 illustrates this principle. Toxicology screens Although commonly ordered in a “shotgun” fashion for all patients presenting with a toxicological problem, urine toxicology screens have limited usefulness in the adult patient. They may be helpful, however, in the altered patient or in the pediatric patient who cannot communicate or who has been intentionally poisoned. Here are some important concepts concerning urine drug screens:

 

Negative screens do not rule out the possibility of poisonings. Numerous dangerous poisons including pharmaceutical drugs or industrial agents are not included. Additionally, a negative result may have little clinical correlation if specimens are collected too early or too late. Drugs screened typically include abused drugs such as cocaine, benzodiazepines,

Osmolar load

Anion gap

(osmolal gap)

(metabolic acidosis)

Time since ingestion Fig. 2. Schematic demonstrating the relationship between osmolal gap and anion gap in toxic alcohol poisoning. (Adapted with permission from Mycyk and Aks.38)

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Table 7 Duration of drugs of abuse detected in urine39 (actual drugs detected vary by immunoassay used). Alcohol (7–12 hours) Amphetamine (48 hours) Methamphetamine (48 hours) Barbiturate Short-acting (e.g., pentobarbital) (24 hours) Long-acting (e.g., phenobarbital) (24 hours) Benzodiazepine Short-acting (e.g., lorazepam) (3 days) Long-acting (e.g., diazepam) (30 days) Cocaine metabolites (2–4 days) Marijuana Single use (3 days) Daily use (10–15 days) Long-term (4 30 days) Opioids Codeine (48 hours) Heroin (morphine) (48 hours) Hydromorphone (2–4 days) Methadone (3 days) Morphine (48–72 hours) Oxycodone (2–4 days) Propoxyphene (6–48 hours) Phencyclidine (8 days)

 



amphetamines, phenobarbital, marijuana, phencyclidine, and opioids/opiates. Detected drug metabolites may remain positive in the urine for several days after an exposure, and even when positive the implicated drugs may be contributing no clinical symptoms. Table 7 demonstrates the duration of drug detection in the urine drug screen.39 Depending on the immunoassay used, there are many false-positives and false-negatives. Many amphetamine-related drugs can cause the amphetamine test to be positive, even if amphetamines are not present. The benzodiazepine screen frequently only detects benzodiazepines that are metabolized to oxazepam (e.g., diazepam). Depending on the immunoassay used for opioids, some screens will not detect synthetic opioids such as meperidine and propoxyphene. Specific qualitative positive results may require quantitative confirmation through gas chromatography/mass spectrometry if necessary. This is not typically performed in hospital laboratories.

Urine testing Urine analysis is frequently performed, although the history and clinical presentation may preclude additional usefulness of the test. Calcium oxalate crystals may indicate ethylene glycol poisoning if the clinical symptoms and signs are suggestive, although crystals are often absent. The use of the Wood’s lamp to detect urine fluorescence following ethylene glycol poisoning lacks specificity.40,41 Occult urinary blood without red blood cells indicates rhabdomyolysis. The urinary pH is often used to monitor urinary bicarbonate therapy for salicylate overdose. Selected radiologic studies Abdominal films A plain abdominal radiograph (KUB) may reveal selected radiopaque pills, drug-filled packets, or leaded objects such as paint chips. A negative exam does not exclude a toxic ingestion or exposure as many drugs and poisons are not radiopaque. Drugs or toxins that may be visible on films are listed by the mnemonic PICS (Table 8).

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Table 8 Substances that are potentially visible on plain abdominal radiography (mnemonic PICS). Packets—cocaine or opioid packers/stuffers Iron and other metals (lead, arsenic, and mercury) Chloral hydrate Sustained-release or enteric-coated substances

Illicit drug packets may or may not be visible. In some cases, the vehicle in which the drug is contained (enteric coating or latex) may be more radiopaque than the drug itself. Visibility may also depend on time of ingestion. In practice, the KUB may be most useful for identifying radiopaque foreign bodies or in monitoring the progress of gastrointestinal decontamination in poisonings such as pediatric lead ingestions. Computed tomography (CT) Performing a CT scan of the brain in the undifferentiated patient with altered mental status patient should be done routinely. Abdominal CT scans for poisoned patients may be indicated when it is necessary to further investigate radiopaque foreign bodies. Ingested drug packets have also been detected by CT. Compared to plain radiographs and ultrasound, a CT scan generally has higher diagnostic sensitivity for identifying drug packets, although a negative test does not absolutely exclude an ingestion.42,43 The clinical scenario would determine whether an abdominal CT is necessary in such cases. Consultation with a medical toxicologist or regional poison control center would also be prudent. Ultrasound Sporadic case reports and a few small studies have addressed ultrasound in detecting toxic ingestions of echogenic material such as pills or drug packets.44–46 As a diagnostic bedside tool in the poisoned patient, however, ultrasound remains under investigation. Its utility is limited by factors including the operator’s skill, the patient’s body habitus, characteristics of the substance (s) ingested, and the timing and circumstances surrounding a potential ingestion.

Treatment The management of a poisoned or potentially poisoned patient begins with comprehensive supportive measures. Most poisoned patients will do well when supportive measures are provided and when any derangements are addressed. The first priority of any patient presenting in an urgent situation is to maintain the principles of advanced cardiac life support.47 The ABCs of advanced cardiac life support should be followed in the poisoning situation. The early consultation of a medical toxicologist or regional poison center should be considered and can help the practitioner anticipate the course of a poisoning case. Patients who are poisoned may present with a range of mental status abnormalities, from normal to status epilepticus. The mental status of a poisoned patient can change rapidly, necessitating frequent repeat examinations. The hemodynamic status of a poisoned patient can similarly span the range from normal to unstable and can change rapidly. When it is necessary to endotracheally intubate a patient, rapid sequence induction is typically preferred as is the use of short-acting paralytic agents. The concern when using longer-acting paralytics is that they may mask convulsions in a patient at risk for seizures. When hyperkalemia is a concern or in the case of cholinesterase inhibitor poisoning, non-depolarizing paralytic agents should be used. A patient’s oxygenation status can be monitored with a bedside pulse oximeter. There are two important issues to consider with pulse oximetry. The first is that certain toxins can demonstrate a normal pulse oximeter reading despite severe poisoning. This is particularly the case with carbon monoxide poisoning.48 The second consideration is that the pulse oximeter should not be a substitute for arterial/venous blood gas measurement or other measure of

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acid–base status. A poisoned patient can have severe metabolic derangements despite a normal pulse oximeter reading. Capnography can also be used to assess and monitor ventilation in patients with depressed mental status.49,50 Intravenous access should be seriously considered in any poisoned or potentially poisoned patient. This is the case even in a patient who seems to be asymptomatic. As previously stated, a poisoned patient’s mental status and hemodynamic status can change rapidly. The sudden onset of convulsions or rapid development of severe hypotension could make vein cannulation difficult if not previously performed. Until the exact nature of a poisoning is known and specific treatment performed when indicated, the poisoned or potentially poisoned patient should be closely observed with specific attention to the mental status, oxygenation and ventilation, and hemodynamic status. There are situations where delayed gastrointestinal absorption of a toxin is possible or the overdose or poisoning involved a drug with delayed onset of symptoms and signs. A 12-lead electrocardiogram and continuous cardiac monitoring should be considered for any drug or toxin with potential cardiac toxicity. An electrocardiogram and cardiac monitoring should also be considered in polysubstance ingestions and in situations of unknown ingestion. There are many agents that cause seizures in the overdose situation (Table 9). Toxin-induced seizures are different from seizures in patients with epilepsy or those who have structural lesions.51 Toxin-induced seizures are the result of global central nervous system processes; they typically do not start with a single focus.51 Benzodiazepines, barbiturates, and valproic acid should be considered the first-, second-, and third-line therapies for toxin-induced seizures as these drugs act globally.51 The “coma cocktail” refers to a combination of medications that is given empirically to a poisoned or potentially poisoned patient who presents with CNS depression or coma. The approach to the poisoned patient should be deliberate, and empiric medication administration should be considered cautiously. While there is no standard “coma cocktail,” a typical cocktail may include dextrose, naloxone, and thiamine. Flumazenil and physostigmine are sometimes included. The dextrose component is used to treat hypoglycemia as a cause of CNS depression or coma. The availability of point-of-care capillary glucose testing obviates the need to empirically treat for hypoglycemia. Naloxone is used to treat opioid toxicity as a cause of the CNS depression or coma. Naloxone is an opioid receptor antagonist that is effective in reversing opioid toxicity. If opioid toxicity is a consideration, a dose of 0.4–2 mg may be given intravenously or intranasally.52,53 There are some important issues to consider with naloxone. Opioid tolerant patients may rapidly enter opioid withdrawal. This is an unpleasant but not life-threatening condition. Certain drugs, such as fentanyl, may require naloxone doses in excess of the typical dosing range.52 The duration of effect for naloxone is shorter than the duration of effect for many opioids, and repeated administration may be necessary. In certain cases naloxone can be administered by infusion or by nebulization.2,54 If naloxone is not available, intubation is appropriate to manage the respiratory depression in opioid overdose. Thiamine use should be reserved for malnourished patients at risk for Wernicke’s encephalopathy.55 It is unnecessary to give thiamine empirically to patients who present with depressed mental status or coma.

Table 9 Substances that can potentially induce seizures. Insulin and oral hypoglycemics Antidepressants e.g., cyclic antidepressants, SSRIs, and SnRIs Sympathomimetic agents Withdrawal syndromes e.g., alcohol withdrawal or benzodiazepine withdrawal Metals lead or lithium Isoniazid

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Flumazenil is a benzodiazepine antagonist that can reverse the sedative effects of benzodiazepine overdose. It can be used safely to reverse benzodiazepine sedation in acute overdoses in patients who are not habituated to the medication class; however, in patients who use benzodiazepines regularly, flumazenil use can precipitate benzodiazepine withdrawal, a potentially fatal withdrawal syndrome. As such, flumazenil should be used judiciously and only when clinically indicated. It should not be used empirically. Physostigmine is a cholinesterase inhibitor used to treat severe anticholinergic toxicity. There is no role for empiric use in an undifferentiated poisoned patient who presents with depressed mental status or coma. Decontamination Removal of the patient from the source of toxicity is the foundation of the treatment of poisoned patients. This includes removing the toxin from the body, a process called decontamination. The route of exposure will determine the route of decontamination. For dermal exposures, initial management consists of clothing removal and copious irrigation with water.56 While there are commercial irrigation agents available, it appears that time to irrigation is more important for chemical exposures that the liquid used to irrigate.57 For chemical ocular exposures, irrigation is essential. Although isotonic solutions at neutral pH are preferred, the time to irrigation is again paramount. No time should be wasted looking for a specific irrigation solution if water is readily available.58,59 As a word of caution, if the hazardous agent the patient was exposed to is an alkali metal then water should not be used for decontamination as it can ignite the highly reactive metals.60 The role of gastrointestinal decontamination has been debated. Both syrup of ipecac and gastric lavage, once common modalities of decontamination, are no longer recommended as they have not been shown to improve clinical outcome and may actually cause the patient harm.61,62 Furthermore, cathartics, especially in combination with activated charcoal, have no role in poisoning management.63 Whole bowel irrigation is another modality of decontamination that has been proposed for ingestions of sustained-release products, enteric-coated products, and toxins not adsorbed by charcoal, and drug-containing packets. Although whole bowel irrigation has been shown to decrease the serum concentration of a drug after ingestion, there are no definite studies showing it improves patient outcomes. The preferred method of gastrointestinal decontamination in awake patients with an intact airway is activated charcoal. When given orally after ingestion, activated charcoal will bind to most poisons and prevent some absorption, potentially reducing systemic toxicity. Activated charcoal does not bind lithium, heavy metals, or toxic alcohols. Charcoal is most effective if given within one hour of the time of ingestion and when given as a ratio of 10:1 (charcoal:toxin).64 However for drugs that are extended release and delay gastrointestinal transit time or have a tendency to form concretions, charcoal doses at later time points can be considered. The most common adverse effects are gastrointestinal in nature and include vomiting and constipation. The most concerning adverse effect is aspiration, although this is rare.65 Given that there is limited evidence suggesting that activated charcoal changes clinical outcome, prior to administration the treating physician should weigh both the risks and the benefits.66 Enhanced elimination Enhancing elimination is the process of removing a toxin from the body after it has been absorbed. Modalities include multiple-dose activated charcoal, urinary alkalinization, and extracorporeal elimination. Multiple-dose activated charcoal (MDAC) is the process of giving a patient multiple doses of activated charcoal over several hours in an attempt to enhance the elimination of a substance already systemically absorbed.67 This is different from the single dose of activated charcoal used for gastrointestinal decontamination. Certain drugs, such as carbamazepine and theophylline, undergo entero-entero or entero-hepatic recirculation. MDAC is thought to interrupt this

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process by having sufficient activated charcoal in the gastrointestinal tract to stop the reabsorption of drugs or drug metabolites that are secreted into the gastrointestinal system. There is no standard dosing regimen for MDAC. Some formulations of activated charcoal contain sorbitol. When giving MDAC, the charcoal should not contain sorbitol. The sorbitol component, when given in multiple doses, can lead to fluid and electrolyte derangements. Urinary alkalinization involves an intravenous sodium bicarbonate infusion to promote urinary elimination of substances that are weak acids. Maintaining a normal potassium concentration is essential, as appropriate alkalination cannot be achieved when hypokalemia is present. Urinary alkalinization is most commonly performed in salicylate-poisoned patients but also works in phenobarbital intoxication. Urinary acidification for weak bases, such as phencyclidine or amphetamines, is not recommended due to risk of myoglobinuria and rhabdomyolysis.68 Hemodialysis enhances removal of substances with low molecular weight, low protein binding, small volumes of distribution, and high water solubility. Hypotension may preclude its use. Alternative hemodialysis techniques such as continuous veno-venous hemofiltration (CVVH) and continuous veno-venous hemodialysis (CVVHD) have the advantages of not causing hemodynamic instability; however, the amount of drug/toxin removed may be variable or require long sessions, depending on the characteristics of the drug/toxin.69,70 Extracorporeal elimination should be considered in patients with profound acid–base disorders or electrolyte derangements, even when the causative agent is unknown. Antidotal therapy The number of effective antidotal agents are limited and are not for indiscriminate use. Table 10 lists selected antidotes and the substances for which they are indicated. As previously stated, all xenobiotics are potentially toxic. This is true for purported antidotes as well. Antidotal therapy should be used carefully and in clinical circumstances when specifically indicated. With the exception of naloxone, indiscriminant antidotal therapy use is not warranted in the patient with an unknown poisoning.71 The clinician should be familiar with the indications for use and the availability of antidotal therapy within their hospital and healthcare system.71 While administering so-called life-saving antidotes is often considered to be the sensational aspect of Table 10 Antidotes and indications. Antidote

Indication (agent)

N-acetylcysteine Fomepizole Oxygen/hyperbaric oxygen Naloxone Physostigmine Atropine/pralidoxime (2-PAM) Methylene blue Hydroxycobalamin Sodium nitrite/sodium thiosulfate Deferoxamine Dimercaprol (BAL) Succimer (DMSA) Fab fragments Glucagon Sodium bicarbonate High-dose insulin Octreotide Vitamin K and prothrombin concentrate complex Protamine sulfate Lipid emulsion therapy

Acetaminophen Methanol/ethylene glycol Carbon monoxide Opioids Anticholinergics Organophosphates Methemoglobinemia Cyanide Cyanide Iron Arsenic Lead and mercury Digoxin, colchicine, crotalids, and BW spiders Beta blockers Tricyclic antidepressants Calcium channel antagonists Sulfonylureas Warfarin Heparin Local anesthetics

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medical toxicology, antidotal therapy is used in a relatively small number of poisonings. The majority of poisoned patients are well treated with appropriate supportive care and focused attention to any anticipated or present derangements.

Disposition Most asymptomatic patients who present with a history of an intentional ingestion should be observed for at least six hours.72 Patients may be dispositioned after psychiatric consultation if they remain asymptomatic, if the substance ingested is expected to reach peak toxicity within this time frame, and the predicted toxicity is minimal. There are certain substances that will require 24 or more hours of monitoring as they have delayed peak effects, have active metabolites, are extended-release preparations, or can cause delayed toxicity.73 Specifically some of the newer antidepressants such as citalopram, bupropion, and venlafaxine have been shown to cause delayed seizures and arrhythmias. Also both carbamazepine and valproic acid can have delayed peak concentrations.74–76 These are only a few of the different substances that may require prolonged monitoring; therefore, it is important to consult with a medical toxicologist or regional poison center to determine the most appropriate time frame for which to monitor the patient.

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