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Exposures to toxic substances, whether accidental or intentional, remain a significant contributor to morbidity and mortality in the U.S. Approximately 10,830 calls are placed to the Poison Control hotline daily, while The American Association of Poison Control Centers (AAPCC) reported over 2.3 million human exposure calls in 2011, most commonly due to analgesics (12.9%), sedatives and antipsychotics (11%), and antidepressants (6.4%).
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The American Academy of Clinical Toxicology (AACT) and the European Association of Poisons Centres and Clinical Toxicologists (EAPCCT) provide detailed guidance regarding overdose, poisoning and withdrawal. In addition assistance should always be obtained from regional poison control centers.
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The American Association of Poison Control Centers (AAPCC) can be contacted by the following means: www.aapcc.org or 1-800-222-1222.
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Clinicians must follow a systematic and consistent approach throughout evaluation and management. A basic history and physical exam, followed by a more focused poison-specific exam, is vital, from which point management is directed toward the provision of acute stabilization, supportive care, prevention of absorption and, when applicable, the use of antidotes and enhanced elimination techniques.
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Due to depressed mentation or reluctance to cooperate useful information may be obtainable from a patient's associates (family, friends, and coworkers), or from first responders and bystanders. Environmental clues such as suicide notes, drug paraphernalia and empty pill bottles can provide valuable information. Once the patient is identified, reviewing prior hospital records may reveal a history of recent prescriptions, previous overdoses and any psychiatric history.
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Specificity regarding the type of drug or toxin (including; prescription, illicit, over the counter and herbal medications), the dosage, route of exposure, time of exposure or ingestion and intent requires close attention. Unknown pills or chemicals require identification by consultation with a regional poison control center, computerized drug database, or product manufacturers.
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Toxidromes are specific symptoms and physical signs that correlate with the manifestations of a drug class on a particular set of neuroreceptors.
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Performed quickly while resuscitative measures are being instituted, a toxidrome-oriented exam should include vital signs, a focused neurological exam centered on level of consciousness, pupillary and motor reaction, broad examination of the skin noting moisture, cyanosis, rashes, and puncture marks, focused evaluation of the respiratory system, and assessment of bowel sounds. See Table 58–1 Toxidromes-oriented physical exam and Table 58–2: Toxidrome clinical findings.
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Bedside serum glucose testing is a requirement for any patient with altered mentation, after which immediate empiric dextrose administration is recommended in cases where measurement result is low, or not available. Thiamine should also be replaced in patients suspected to be deficient, to prevent precipitation of Wernicke encephalopathy (chronic alcoholics). However, it is not recommended to delay glucose administration while thiamine is administered.
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Salicylates, acetaminophen, and alcohol are all easily available and commonly used agents, therefore may be co-ingested in addition to other medications in deliberate overdose attempts. Acetaminophen and salicylates are also found in numerous combination preparations of prescription drugs and over-the-counter medications. These agents therefore may worsen outcomes or complicate presenting symptoms and signs in an overdose. Because these agents are so commonly used and potentially treatable, it is recommended to routinely check these blood levels in all overdose patients.
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Additional basic investigations should include, complete blood count (CBC), serum electrolytes, blood urea nitrogen, serum creatinine, coagulation profile, liver function tests (LFTs), creatine kinase (CK), arterial blood gas (ABG), serum osmolality, calculated osmolar gap, and a urine analysis (crystals, myo- or hemoglobinuria).
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Specific scenarios may necessitate additional testing including specific drug levels, or testing for methemoglobin and carboxyhemoglobin. Serum concentrations may be of utility in the management of salicylate, acetaminophen, barbiturates, digoxin, ethanol, iron, lithium, and theophylline overdose as these serum assays provide rapid result and are widely available.
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Urine toxicology screen does not necessarily reflect current intoxication, and may serve in some cases as a distracter rather than a diagnostic aid in patients with change in mental status.
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An electrocardiogram may assist in the evaluation for the presence and severity of specific ingestions, or may demonstrate drug-related cardiotoxicity. Serially, the electrocardiogram (EKG) can facilitate the monitoring of progression of specified toxicities. Performed in all subjects with suspected drug ingestion, the key features to note include heart rate, dysrhythmia, axes, and intervals (QRS and QTc).
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In some cases, a plain abdominal film may demonstrate radiopaque medications such as iron tablets, and enteric-coated preparations, while indirect visualization of drug packets (body packers and stuffers) may be demonstrated by the alteration of bowel gas patterns. Additionally, visualized radiographic evidence of non-cardiogenic pulmonary edema and/or Adult Respiratory Distress Syndrome on an anterior posterior (AP) chest film, can suggest the exposure to specific toxic agents.
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A non-contrast head Computerized Tomography (CT) should be considered in anyone with a change in mental status to exclude non-toxicological causes. In addition significant hypertension and change in mental status, in the setting of overdose with agents with stimulant properties, may be secondary to intracranial complications such as hemorrhage, stroke or encephalopathy.
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Initial Hospital Care
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“Treat the patient, not the poison” is the adage summating the guiding principle of medical toxicology, and the treatment of this certain population of patients. Still, the methods are generally similar to those utilized frequently in the care of critically ill patients.
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In the majority of cases, general supportive care is paramount and frequently sufficient to affect complete recovery, yet initial therapeutic measures will depend on the toxin ingested, severity of illness, and time elapsed between exposure and presentation. Assistance should always be obtained from regional poison control centers.
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Acute respiratory failure and severe acid-base disturbances demand endotracheal intubation and mechanical ventilation. Intubation for the purpose of airway protection should be undertaken early in the poisoned patient with depressed mental status unless a rapidly reversible cause is known given high risk of aspiration, which is increased at times when gastric decontamination must be performed.
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Abnormal hemodynamics such as blood pressure, heart rate, and temperature should be treated in the standard way as per hospital guidelines. An appropriate volume of isotonic intravenous crystalloids should be used to treat hypotension. Refractory hypotension and shock should be treated with direct-acting vasopressors (norepinephrine, epinephrine, or vasopressin) however this may be ineffective in cases of calcium channel overdose (see calcium channel overdose).
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Hypertension as sequelae of agitation, or arising directly from ingestion of agents with stimulant properties, can be treated initially with sedatives such as benzodiazepines. Should hypertension require specific therapy due to associated end-organ dysfunction (hypertensive emergency), dihydropyridine subclass calcium-channel blockers are preferable given a profile of potent vasodilatation and few negative effects on cardiac conduction and contractility.
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Hyperthermia should be very closely monitored. When the temperature exceeds 39 degrees Celsius urgent cooling is required. Numerous techniques exist and initially should include the use of fans, antipyretic medications (unless contra-indicated), cold IV fluids and ice baths. More specialized methods include the use of intravenous cooling catheters and cooling pads applied to the skin. Those with excessive agitation, recurrent seizures or increased muscular tone may require sedation and paralysis to prevent excessive heat production.
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Seizures resulting from poisoning or withdrawal are best initially treated with benzodiazepines from which escalation to antiepileptic drugs may be necessitated by persistence of seizures, noting that phenytoin is not recommended in the poisoned patient. In case of refractory seizure, general anesthesia and paralytic agents may be required, and treatment should be monitored with serial or continuous electroencephalography (EEG).
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Altered Mental State-Agitation or Coma
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Drug associated agitated behavior is best treated with benzodiazepine administration, complimented by high-potency antipsychotics as indicated. Antipsychotics should however be used with caution as they can lower seizure threshold and worsen hyperthermia and arrhythmias (prolong QT) in certain cases of poisoning. Coma or depressed mental state management should focus on protection of the airway. In those patients with a depressed mental status with no compromise in airway, empiric treatments with naloxone, glucose and thiamine can be administered. The routine use of flumazenil, in the obtunded patient, for potential benzodiazepine overdose is not recommended due to the numerous adverse reactions associated.
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Rhabdomyolysis is a clinical condition characterized by myocyte injury and leakage of intracellular contents into the extracellular space. The most serious complication is renal failure and it is estimated that 8%-15% of all cases of acute renal failure (ARF) are caused by rhabdomyolysis. There are numerous triggers of rhabdomyolysis, however the final common pathway is depletion of muscle ATP stores causing loss of myocte integrity causing dysfunction and release of intracellular contents.
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Myocyte injury leads to release and increased levels of creatine kinase (CK), myoglobin, potassium, phosphorous, and uric acid. Calcium levels may be low. Myoglobin is excreted in the urine, which becomes a red/brown color. Heme pigment casts cause renal tubular injury and renal failure, which may worsen electrolyte abnormalities and produce an anion gap metabolic acidosis. Other serious complications include cardiac arrhythmias and arrest, compartment syndrome and disseminated intra-vascular coagulation (DIC). Patients usually report muscle pain, weakness and dark urine. Diagnosis is made by detecting markedly elevated levels of CK (usually greater than 5000 IU/L) with evidence of myoglobinuria on urine dipstick and microscopy.
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Drug overdose or poisoning is a common cause of rhabdomyolysis and falls into 3 groups. 1. Trauma: Overdose victims may suffer muscle trauma from accidents or impulsive behavior leading to direct muscle injury. 2. Non-traumatic exertional: Overdose patients may develop extensive muscle activity from agitation or seizures, which can also cause extreme hyperthermia leading to myocyte injury. 3. Non-traumatic non-exertional: Certain drugs or toxins can lead to direct myocyte damage. Other drugs may induce coma leading to ischemic compression. Drug induced hyperthermia, without muscle activity, can lead to increased muscle energy demands and subsequent injury. See Table 58–3: Common drugs associated with rhabdomyolysis.
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Management of rhabdomyolysis from a poison, drug or toxin initially involves discontinuing the offending agent and using decontamination or enhanced elimination techniques to remove any drug or toxin. Aggressively control any hyperthermia, hyperactivity or agitation. Early and aggressive fluid resuscitation is the mainstay of treatment to prevent renal injury. Fluids should be started if CK levels are > 5000 IU/L. The optimal fluid and rate of repletion are unclear. Fluid repletion should be continued until plasma CK levels decrease to < 5000 IU/L and urine is dipstick negative for hematuria. A forced alkaline diuresis, raising urine pH is raised to above 6.5 with sodium bicarbonate, may diminish the renal toxicity of heme however there is no strong evidence to support this.
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Decontamination and Enhanced Elimination
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Decontamination involves removal of the toxin/poison from patient surfaces and gastrointestinal (GI) tract. In addition enhanced elimination techniques including ion tapping, chelation therapy, hemodialysis, hemoperfusion, and lipid emulsion can be used to remove poisons/toxins already absorbed.
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Surface Decontamination
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Surface decontamination involves the removal of dermal and ocular toxins by irrigation. The eye should be irrigated with an isotonic crystalloid until a physiological pH is restored.
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Gastrointestinal Decontamination
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The practice known as GI decontamination refers to the functional removal of ingested toxins from the GI tract in order to decrease absorption. No controlled clinical studies have demonstrated that the “routine” use of GI decontamination reduces morbidity and mortality in poisoned patients. However, evidence from human volunteer trials and clinical studies suggest that decontamination may reduce the absorption of toxins in the GI tract and may be helpful in select circumstances
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Many methods have faded from clinical practice due to evidence based delineation of poor efficacy, and high risks, as well as position papers compiled by AACT and EAPCCT.
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1. Ipecac—The only emetic suitable for use in humans is syrup of ipecac, and despite its unique niche, use has significantly declined due to lack of proven efficacy and risk of adverse events and therefore is not recommended.
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2. Orogastric lavage—Gastric lavage involves the insertion of a large-bore 36- to 40-French orogastric tube and the subsequent positioning of the patient in the left lateral decubitus position with the head of the bed in Trendelenburg position. The instillation of approximately 250mL of water or saline follows, with the immediate evacuation via suction applied to the distal end of the tube. This cycle is completed until the evacuated solution is free of pill fragments or particulate matter. This method is only considered to be useful in the first hour post ingestion and has been used for agents that do not bind well to activated charcoal as well as for specific life threatening poisons such as tricyclic's, theophylline and cyanide.
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Recent papers however, suggest that gastric lavage may be associated with serious complications, namely aspiration, esophageal perforation, hypothermia and death. The American Association of Poison Centers (AAPC) and the European Association of Poisons Centres and Clinical Toxicologists (EAPCCT) have issued a joint statement that gastric lavage should not be employed routinely, if ever, in the management of poisoned patients.
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3. Activated charcoal—Activated charcoal (AC) is an organic material, which adsorbs chemicals with a molecular weight range of 100-1000 Daltons, preventing gastrointestinal absorption and subsequent toxicity. The agent can be administered orally or via a nasogastric tube, in single- and multi-dose regimens depending on the toxin ingested, and is administered in a slurry in water containing 25 to 100 g initially (or for single dosing) followed by 25 to 50 g every 2 to 4 hours in adults, unless the toxin dose is known, in which case the dosing of charcoal to toxin is a 10:1 ratio.
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Many chemicals adsorb avidly to AC in a dose dependent fashion but certain substances particularly highly ionic compounds with low molecular weight, mineral acids, and strong bases do not bind well. AC has not been shown to adsorb ethanol, even when administered prior to ethanol ingestion. See Table 58–4: Poisons not well bound to activated charcoal.
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Those most likely to benefit from single dose activated charcoal (SDAC) must present within one hour of poison ingestion, but despite lack of evidence, potential for benefit later in the course cannot be excluded.
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Contraindications include a depressed mental status without airway protection (risk of aspiration), increased risk of severity of aspiration based on ingested toxin (eg, hydrocarbon ingestion), a need for endoscopy, ingestion of a poorly adsorbed toxin (metals including iron, lithium, alkali, mineral acids, alcohols), presence of intestinal obstruction, or concern for decreased peristalsis.
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The AACT/EAPCCT recommends multiple-dose activated charcoal (MDAC) be considered only for patients having ingested life threatening amounts of carbamazepine, dapsone, phenobarbital, quinine or theophylline. See Table 58–5: AACT/EAPCCT recommended drugs amenable to repeat dosing of activated charcoal.
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4. Bowel irrigation—Whole bowel irrigation refers to the rapid elimination of unabsorbed toxin from the GI tract through the use of iso-osmotic polyethylene glycol solution at 25 to 40 mL/kg/hr until the rectal effluent is clear. Enteric-coated and extended-release preparations, certain metals, as well as drug packets could be expelled expeditiously in this manner.
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Despite an absence of specific evidence to support improved outcomes, sizeable iron overdoses, carrying high morbidity, may benefit from this therapy noting the lack of an alternative.
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Enhanced Elimination Techniques
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Ion Trapping and Forced Diuresis
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The urinary excretion of some drugs can be enhanced by alkalization of the urine with the administration of intravenous sodium bicarbonate to produce urine with a pH >/= 7.5, exploiting the fact that the ionization of a weak acid is increased in an alkaline environment thereby making it lipid in-soluble, reducing reabsorption and enhancing elimination by trapping the toxin in the urine.
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Urine alkalization should be considered first line treatment in patients with moderate to severe salicylate poisoning that do not meet criteria for hemodialysis. See Table 58–6: Drugs with enhanced elimination by alkaline diuresis.
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Chelation therapy involves intravenous, intramuscular or oral administration of chelation agents to bind heavy metals in the blood stream promoting enhanced renal excretion. See Table 58–7: Different chelation therapies.
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Extracorporeal Techniques
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Hemodialysis (HD) can be used to remove certain toxins and correct electrolyte and acid-base disturbances induced by toxins. For HD to be effective, the toxin must reside primarily in the extracellular fluid.
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Hemoperfusion (HP) refers to the circulation of blood through an extracorporeal circuit containing an adsorbent such as activated charcoal or polystyrene resin. Drugs that are adsorbed by activated charcoal are the same drugs that are amenable to HP.
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Hemofiltration, peritoneal dialysis, plasmapheresis, and exchange transfusion can also help eliminate certain toxins. See Table 58–8: Poisons amenable to hemodialysis.
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Intravenous lipid emulsions (ILE) are the fats used in total parenteral nutrition, and ILE has been used to treat toxicity due to lipophilic medication including verapamil, beta blockers, some tricyclic antidepressants, bupivacaine and chlorpromazine.
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The proposed mechanism of action is that the ILE acts as a “lipid sink” surrounding a lipophilic drug molecule and rendering it ineffective. A second mechanism proposed is that fatty acids within the ILE provide the myocardium with a ready energy source thus improving cardiac function.
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While in the majority of poisoning cases supportive care is the key element to improving the survival, a small number of toxins are amenable to a “silver bullet” in the form of an antidote.
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By varied means, antidotes reduce or reverse the effects of a poison, but half-life of both the toxin and the antidote must be taken into account during treatment, especially regarding instances of antidotes that antagonize end-organ effects or inhibit conversion to toxic metabolites. See Table 58–9: Common antidotes/treatments.
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After the initial evaluation, treatment and observation period, patients who suffer from severe toxicity or who are at risk for complications should be admitted to the ICU. Advanced age, abnormal body temperature, and suicidal intent are associated with an increased risk of death.
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Sustained-release products, and agents with delayed onset or prolonged action may require up to 24 hrs. of observation to ensure safety.