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Key Clinical Questions
How do you manage drug-induced prolongation of the QTc interval and torsades de points?
What is the initial evaluation and management of suspected overdose of sedatives, analgesics, stimulants, and other drugs of abuse?
When should you suspect a withdrawal syndrome and how do you prevent withdrawal in patients at risk?
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This chapter will review common overdoses and withdrawal syndromes encountered in the hospital setting following admission from the Emergency Department. According to American Association of Poison Control Centers (AAPCC), the top four substances most frequently involved in adult exposure are prescription medications. Analgesics, sedatives, antipsychotics, antidepressants, and cardiovascular medications accounted for over 150,000 exposures in 2013 (23% of all substances). The top three substance category associated with the most fatalities included prescription sedatives or hypnotics, cardiovascular medications, and opioids. For further prescribing information (see Chapter 73 [Patient Safety and Quality Improvement in Post-Acute Care, section on polypharmacy], Chapter 48 [Perioperative Pain Management], Chapter 99 [Pain], Chapter 216 [Palliation of Common Symptoms], and Chapter 223 [Mood and Anxiety Disorders]).
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INITIAL APPROACH TO SUSPECTED OVERDOSE
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The general initial evaluation for most overdoses occurs in the emergency department (ED). The assessment and management of a suspected overdose always begin with the stabilization (Airway, Breathing, Circulation [ABCs]). Emergency physicians quickly establish if a patient has stable vital signs, evaluate the need for respiratory support or intubation for airway protection, and provide fluid resuscitation. Admitting hospitalists should determine what was done in the emergency department, initial impressions of the ED staff, pending tests, red flags that might alter triage plans, and next best steps. Clinicians should also have a low threshold to consult with poison control. The use of gastrointestinal decontamination and renal replacement therapies for overdoses are covered in Chapter 100 (Suspected Intoxication and Overdose).
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PRACTICE POINT
All local poison control centers may be reached through the American Association of Poison Control Centers (AAPCC) centralized phone number (800-222-1222). A medical toxicologist can provide emergent consultation, including recommendations for testing, treatment, and monitoring.
The World Health Organization’s list of international poison centers may be accessed online.
www.who.int/gho/phe/chemical_safety/poisons_centres/en/index.html
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If the patient is willing and able, it is important to ascertain what substance(s) were ingested, including dosages and timing. If such information cannot be obtained from the patient, collateral sources for second-hand accounts should be sought, including family and friends, EMS reports, outpatient health care providers and pharmacies. If self-harm is suspected, institute suicide precautions and obtain appropriate psychiatric evaluation to determine a safe disposition. With an unintentional intoxication, counsel the patient regarding medication dosing in order to avoid repeat events.
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Complete blood count (CBC), coagulation tests, comprehensive metabolic profile (CMP), serum osmolality and osmolar gap, acetaminophen and salicylate levels, and electrocardiogram (ECG) are routinely performed. Additional blood work may include arterial blood gas analysis, troponin, creatine kinase (CK), serum ethanol levels, drug levels, and an additional red top tube on hold. Urine studies should include a pregnancy test in women if appropriate. Urine toxicology studies are frequently ordered. However, these screens have significant limitations that may mislead the ordering clinician:
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False-positive screens occur for many commonly tested drugs such as amphetamines due to the presence of many other drugs (including ephedrine, pseudoephedrine, ranitidine, trazodone, and chlorpromazine).
A positive initial screening test may not identify the drug responsible for acute intoxication due to drug detection at levels that produce no clinical effects or due to the persistence of detectable levels following ingestion during the previous days to weeks.
False-negative screens result from an inability to detect certain drugs such as “designer” amphetamines available over the internet, benzodiazepine metabolites, and phencyclidine (PCP) congeners.
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Detection of a particular drug, however, may alter medical management if a positive screen alerts the clinician to:
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Initiate measures to reduce toxicity as in acetaminophen overdose.
Avoid certain medications such as β-blockers in patients with a positive cocaine screen.
Consider stimulant-induced psychosis for a patient presenting for the first time with psychosis and a positive drug screen for cocaine or amphetamine.
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Clinicians should always consider the possibility of multiple drug toxicity, especially salicylates, acetaminophen, antidepressants, alcohol, and illicit substances. A concise summary of the evaluation and management of these drugs is outlined in Table 250-1.
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MEDICATIONS THAT PROLONG THE QT INTERVAL
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The QT interval (the start of the Q wave and the end of the T wave on the ECG) represents the electrical depolarization and repolarization of the ventricles. Measuring the QT should be performed from leads II, V5, or V6 using the longest measurement for highest sensitivity. The heart rate (R-R cycle length) influences the duration of the QT interval (ie, the slower the heart rate, the longer the R-R interval and QT interval). Analysis of the duration of repolarization requires correction of the heart rate. A QTc >450 ms in men and >470 ms in women is considered prolonged. See Chapter 108 (The Resting ECG). Online calculators are available that use a variety of popular methodologies) (http://www.mdcalc.com/corrected-qt-interval-qtc/, http://reference.medscape.com/calculator/qt-interval-correction-ekg, or http://www.medical-calculator.nl/calculator/QTc/).
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Medication-induced long QT syndrome (LQTS) increases the risk of the potentially lethal arrhythmia known as torsades de pointes (TdP). Between 1983 and 1999, 761 cases of TdP were reported, causing oversight from the FDA to remove medications from the market that could potentially cause QT prolongation. Antiarrhythmics that prolong the QT interval include amiodarone, disopyramide, dofetilide, ibutilide, mibefradil, procainamide, quinidine, sematilide, and sotalol. Entire classes of medications are well known to prolong QT and have been implicated in acquired LTQS and are still in common use in the United States (Table 250-2). TdP is usually self-limiting; however, it may develop into ventricular fibrillation and sudden cardiac death.
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Patients should be stratified on the basis of risk factors; patients at increased risk for prolonged QT and TdP include female gender, advanced age, prolonged baseline QTc, electrolyte abnormalities (hypokalemia and hypomagnesemia), a history of heart disease (CHF/CAD), hepatic and/or renal dysfunction, and bradycardia. Polypharmacy with multiple medications associated with increased QT interval further increases risk. Initial evaluation should be medication review, ECG and comprehensive metabolic profile.
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Once a patient develops TdP, ICU level care is warranted. If TdP does not self-terminate, immediate electrical cardioversion is indicated for all unstable ventricular arrhythmias. In stable patients, the goal is electrolyte stabilization with magnesium and potassium. For refractory cases, induction of tachycardia via chronotropes or direct pacing is sometimes used to shorten the QT interval. After removing all offending agents, the mainstay of management is:
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IV magnesium
IV potassium (goal 4.5-5.0 mEq/L)
For refractory cases, direct transvenous overdrive pacing and/or isoproterenol for heart rate goal 90 to 110 beats/min
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For patients who develop drug-induced prolonged QT syndrome and TdP, a family history should also be obtained to identify congenital LQTS. This might require ECGs of first-degree relatives and possibly genetic testing (see Chapter 134 [Ventricular Arrhythmias]).
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CARDIOVASCULAR MEDICATIONS
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The pleotropic effects of BBs in hypertension, heart failure, coronary artery disease, migraines, and anxiety have increased prescription patterns of these medications, and consequently increased the potential for overdose in the general population despite the increase of safety of newer selective BBs. BBs inhibit either one or a combination of the three types of β-receptors. β-1 is located on mostly cardiac tissue and has chronotropic and ionotropic effect with some effect on juxtaglomerular cells causes release of renin. β-2 receptors regulate smooth muscle tone and are well known to influence bronchial smooth muscle relaxation with some effect on pancreatic islet cells causing release of insulin. BBs affect the β-receptor by preventing G proteins from converting adenosine triphosphate (ATP) to cyclic-adenosine monophosphate (cAMP). Consequently, there is less intracellular calcium available for muscular contraction.
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Although BBs have been well studied for effects on each receptor at therapeutic dose, receptor selectivity is lost at overdose plasma levels. Lipid solubility is an important consideration in some BBs as this is associated with more side effects due to crossing the blood-brain barrier and untoward CNS involvement. Some BBs cause quinidine-like sodium channel blockade (ie, acebutolol, propanolol, oxprenolol, and betaxolol), which is exacerbated at toxic doses.
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The most typical presentation of patient with BB overdose is bradycardia, first-degree heart block, and hypotension. The standard evaluation for suspected BB overdose includes blood pressure measurement, a 12 lead ECG, CMP for evaluation of end-organ damage or hypoperfusion, serum lactate, finger stick blood sugars, and complete neurological assessment. Propranolol overdose may be associated with QRS prolongation, seizures, and coma. Pindolol, a partial agonist, may cause tachycardia in high doses. Sotolol, a class III antiarrhythmic, may cause QT prolongation, ventricular fibrillation, ventricular tachycardia, or torsades. Some BBs have an increased lipophilic profile with additional CNS effects such as CNS depression and somnolence. Additional unselective beta receptor antagonism can cause bronchospasm and decreased inotropy. A chest x-ray may be indicated to assess for pulmonary edema. Additional symptoms include syncope, chest pain, and seizures. Mild hypoglycemia and hyperkalemia may be seen due to the effect of β-receptor activity on the kidneys and pancreas. At high doses, inadvertent inhibition of the sodium receptor leads to QRS prolongation and an increased susceptibility for arrhythmias.
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Treatment of acute BB toxicity is dependent on the severity of the ingestion. Initially, the patient will need supportive care with close cardiac, blood pressure, and electrolyte monitoring. Hypotension and bradycardia require fluid resuscitation; failure to respond may require several agents similar to calcium channel blockers (Table 250-3). More severe cases will require vasopressors with β-1 agonist properties such as dopamine or norepinephrine. Refractory symptomatic bradycardia may require direct cardiac pacing, mechanical intra-aortic balloon pump and cardiology consultation. Dialysis may remove poorly protein bound BBs that are excreted by the kidneys (atenonol, sotalol, nadolol) (see Chapter 133 [Bradycardia]).
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CALCIUM CHANNEL OVERDOSE
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CCBs inhibit transmembrane flow of calcium ions through voltage-gated L-type channels. These medications cause vascular smooth muscle relaxation leading to vasodilation which lowers blood pressure and have negative inotropic and chronotropic myocardial effects. CCBs also restrict pancreatic beta cell insulin secretion causing hyperglycemia. There are two major categories, the dihydropyridines (preferentially inhibit channels in the vasculature) and the nondihydropyridines (selectively block channels in the myocardium and delay atrioventricular conduction and sinus node function). For example, amlodipine, felodipine, nicardipine, and nifedipine are categorized as dihydropyridines, while verapamil and diltiazem belong to the nondihydropyridine category. There are numerous CCBs in both immediate and extended release preparations with widely variable half-lives from 1 to 50 hours. Bioavailability depends on first pass metabolism and all are metabolized by P-450 enzymes (CYP3A). High serum concentrations due to overdose overwhelm first-pass metabolism leading to increased circulating drug concentrations with even longer half-lives. CCB toxicity can be seen with ingestions of more than five times the usual dose.
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Typically, dihydropyridine overdose leads to vasodilation with hypotension and reflex tachycardia, whereas nondihydropyridine overdose leads to decreased cardiac contractility and bradycardia. With higher drug concentrations, however, the L-type channel selectivity is often lost so that bradycardia, hypotension, and decreased cardiac contractility may occur due to overdoses from either CCB category. Negative inotropic effects may be associated with heart failure. Ventricular dysrhythmias and mental status changes are usually not seen; however, CNS depression with confusion may be progressing to coma in isolated cases or in patients with refractory hypotension. β-blocker (BB), clonidine and digoxin ingestions may present similarly and should be considered in the differential diagnosis. Unlike CCB, clonidine tends to cause miosis and sinus bradycardia rather than high-degree AV block. BBs may cause hypoglycemia whereas CCB may cause hyperglycemia.
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Basic laboratory data testing begins with the ECG, CBC, CMP, calcium, and cardiac enzymes to exclude cardiac ischemia as a possible etiology of the hypotension or arrhythmia. ECG may reveal bradycardia, PR prolongation, or escape rhythms with advanced AV blocks. Chest x-ray may be obtained to evaluate for pulmonary edema. Digoxin levels should be obtained if concomitant ingestion is suspected. CCB assays are not routinely available and not be part of standard evaluation.
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Asymptomatic, stable patients require monitoring for hypotension, bradycardia, and hyperglycemia as these patients may quickly decompensate. Depending on whether the ingested formulation was immediate-release, standard-release or extended release, a recommended length of observation is 6, 6 to 12, and 24 to 36 hours, respectively. When hypotension does not respond to aggressive fluid resuscitation, a combination of IV calcium, glucagon, high dose insulin, vasopressors, and IV lipid emulsions should be administered. Atropine and glucagon may be administered for symptomatic bradycardia. In patients with mild symptoms, these treatments may be implemented sequentially (every 15 minutes with interval reassessment) whereas multiple therapies should be implemented simultaneously in hemodynamically unstable patients (Table 250-3). Calcium chloride administration requires a central line.
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More aggressive and invasive therapies are needed, including transvenous pacemaker, intra-aortic balloon pump, cardiopulmonary bypass, and extracorporeal membrane oxygenation (ECMO) if the patient remains hemodynamically unstable despite the aforementioned therapies. Hemodialysis is not effective since CCBs have large distribution volumes and are highly protein bound.
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ANTIDEPRESSANTS AND ANTIPSYCHOTICS
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Despite its narrow therapeutic window, lithium remains widely utilized; in 2010 the AAPCC was notified of over 6000 cases of lithium toxicity. Lithium is rapidly and completely absorbed from the digestive tract, with a half-life of 18 to 36 hours. Time to peak concentration varies based on the formulation, ranging from 0.5 to 3 hours for immediate release to 2 to 6 hours for extended release. Lithium is nearly exclusively eliminated by the kidneys so renal compromise readily lends itself to toxicity.
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Clinically, lithium intoxication presents differently depending on whether it is acute, acute on chronic, or chronic. Acute or acute on chronic lithium toxicity typically presents with gastrointestinal complaints including nausea, vomiting, and diarrhea. Later in the course of acute poisoning, patients develop neurologic complaints including sluggishness, ataxia, confusion/agitation, and neuromuscular excitability (myoclonic jerks, coarse tremor or seizure). Acute kidney injury may be the cause or the result of acute lithium toxicity. Chronic toxicity will often present as nephrogenic diabetes insipidus with accompanying hypernatremia, polyuria, and polydipsia. Chronic toxicity can demonstrate the same neurologic effects as acute toxicity. Chronic toxicity may also present with a spectrum of pathology including hypothyroidism, hyperparathyroidism with accompanying hypercalcemia. Lithium overdose should be differentiated from neuroleptic malignant syndrome, the latter is more likely to cause rigidity. Laboratory evaluation should include serum lithium level, basic metabolic profile to address renal function, sodium and calcium levels, and ECG. Lithium levels do not accurately predict toxicity due to slow absorption into the central nervous system. A slight elevation in levels may be associated with lithium toxicity, especially in chronic users.
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IVFs (typically normal saline) should be administered, up to a 2 L bolus followed by 200 mL/h as tolerated. Patients should be monitored for the development of hypernatremia due to diabetes insipidus. Avoid using phenytoin for seizure treatment as it can decrease renal clearance of lithium. Hemodialysis effectively removes lithium from the serum and therefore is the primary treatment for significant toxicity. However, serial dialysis may be required due to inability to remove intracellular lithium; in some cases lithium levels may increase despite effective dialysis. Most experts recommend hemodialysis for serum lithium levels > 2.5 mEq/L with serious manifestations (eg, seizure or altered mental status) or levels > 4 mEq/L regardless of clinical status. Therapeutic goal is to reduce levels to < 1 mEq/L. Lithium levels should be monitored for 8 to 12 hours after dialysis to exclude rebound of lithium reentering the serum from the intracellular space. Additionally, dialysis may be considered for patients that cannot tolerate fluid resuscitation (renal compromise, volume overload, heart failure). Nephrogenic diabetes insipidus may respond to indomethacin (more effective in inhibiting renal prostaglandin synthesis than other nonsteroidal drugs and works within a few hours), thiazide diuretics (acting by mild volume depletion), and amiloride (enhances action of thiazide natriuresis and partially blocks potassium elimination from concurrent thiazide administration).
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NONCYCLIC ANTIDEPRESSANT OVERDOSE
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Noncyclic antidepressants include:
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These medications are widely prescribed for depression and anxiety disorders. Bupropion is also prescribed for smoking cessation. In general, they are safe and well-tolerated, especially when compared to TCAs and monoamine oxidase inhibitors (MAOIs). Despite more than 46,000 SSRI overdoses reported in 2011, only two deaths resulted.
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Unlike tricyclics none of these drugs have significant anticholinergic effects. Most drugs cause central nervous system depression. Bupropion, a stimulant, may cause seizures due to inhibition or reuptake of norepinephrine and dopamine. Trazodone and mirtazapine can cause hypotension due to peripheral α-adrenergic blockade. SSRI intoxication may lead to seizures and/or serotonin syndrome. SSRIs are well absorbed in the gastrointestinal tract and reach peak levels in 1 to 8 hours. SSRIs inhibit neurotransmitter-specific pumps that transfer serotonin from the synapse (where they have their activity) into the cytoplasm of the afferent neuron. They are eliminated by the liver. The half-life for the majority of the SSRIs is in the range of 20 to 30 hours, with exceptions being fluoxetine (24-72 hours) and fluvoxamine (15 hours). A significant number of substances effect serotonergic pathways and can precipitate serotonin syndrome in a patient taking SSRIs (eg, tramadol, cocaine, carbamazepine, St. John’s wort, linezolid, MAOIs, meperidine). This syndrome may develop during hospitalization so must be considered both for newly presenting patients and as a complication arising during the treatment of another disorder.
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Diagnosis is based on clinical criteria. In order to meet Hunter criteria, the patient must have a history of ingestion of a serotonergic drug and one of the following: spontaneous clonus; inducible clonus or ocular clonus and diaphoresis or agitation; tremor and hyperreflexia; hypertonia and temperature greater than 38°C and ocular clonus or inducible clonus.
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Laboratory evaluation should include CBC, CMP, and CK. An ECG should be obtained to look for QTc prolongation (fluoxetine, citalopram, escitalopram, venlafaxine). SSRI drug levels are not recommended. There are also many false positives in urine assays.
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INPATIENT MANAGEMENT OF THE SEROTONIN SYNDROME
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Benzodiazepines are the mainstay of therapy to ease agitation and address mild hypertension and tachycardia. A typical starting dose is diazepam 5 to 10 mg IV with titration to effect; patients may require repeat dosing q10min. Supportive therapy is aimed at normalizing vital signs. Patients may exhibit severe hypertension or tachycardia, which should be treated with short acting agents (eg, esmolol, nitroprusside). Hyperthermia should be aggressively treated according to the severity. Physical restraints and butyraphones (haloperidol) are not recommended given concern for worsening hyperthermia. Additional supportive care should include IVFs, oxygen and cardiac monitoring. The antihistamine, cyproheptadine, also has serotonergic antagonism although quality evidence is lacking for its efficacy.
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See Chapter 92 (Hyperthermia and Fever).
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TRICYCLIC ANTIDEPRESSANT OVERDOSE
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Though tricyclic antidepressants (TCAs) remain the 12th most common substance associated with fatalities from ingestion despite having been largely supplanted by SSRI’s in the treatment of depression. The therapeutic window is narrow, and TCAs have a half-life ranging from 7 to 58 hours. The drug is rapidly absorbed in the gastrointestinal tract at therapeutic doses and undergoes conversion in the liver to the active metabolite, nortriptyline. Peak levels in the serum for amitriptyline at normal doses are observed at 2 to 5 hours. In the setting of overdose, however, anticholinergic effects may slow gastrointestinal absorption and delay peak levels. TCAs have wide ranging effects including: antagonism of cardiac fast sodium channels, anticholinergic and antiadrenergic effects, antagonism of histamine-1 receptors, and antagonism of central nervous system GABA-A receptors.
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TCAs cause cardiac and neurologic effects at toxic doses. Cardiac effects include sinus tachycardia, worsening cardiac dysrhythmias, and hypotension which can be difficult to control. ECG findings vary from widened QRS to QT segment prolongation and ventricular fibrillation. TCAs also may cause a range of neurologic symptoms, including seizures related to GABA-A antagonism. Anticholinergics effects may lead to delirium, urinary retention, hyperthermia, and dilated, poorly responsive pupils. Antihistaminic activity may cause decreased level of consciousness and even coma.
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Laboratory evaluation includes ECG, chemistry panel, and troponin. An ABG may be necessary to evaluate acidosis. The 12-lead ECG guides therapy and provides prognostic information. The most sensitive predictor of seizures and ventricular arrhythmias is QRS duration (>0.16 seconds). Serum and urine TCA testing does not reliably guide management or provide prognostic information. Multiple drugs cause false positive results, significant toxicity may occur at nontoxic levels, especially with chronic TCA use, and results are usually not available at the time of clinical decision-making.
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Close cardiac and neurologic monitoring should be in place for admitted patients. Telemetry and serial 12-lead ECG monitoring is recommended for patients with sinus tachycardia. ICU admission should be considered if ECG changes (including QRS prolongation, prolonged QTc, tall R waves in AVR or AVR R/S >0.7, arrhythmias), hypotension, respiratory depression, or altered mental status.
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Treatment agents should be targeted by indication (Table 250-4).
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SEDATIVE AND ALCOHOL INTOXICATION
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Sedatives constitute a diverse group of agents, including alcohol, benzodiazepines, nonbenzodiazepine hypnotic medications (so-called Z-drugs such as zolpidem [Ambien]), barbiturates, and several other compounds, including chloral hydrate and meprobamate. All sedatives dose-dependently depress neuronal function, and most of these agents can produce fatal respiratory depression.
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Both alcohol intoxication and sedative overdose present with uncoordinated motor functioning (gait ataxia, finger to nose incoordination, positive Romberg sign), nystagmus, slurred speech, and various aberrant behaviors, including behavioral disinhibition, impairment of consciousness, reduced respirations, and drowsiness or sleep. Memory disturbances and frank amnesia, frequently referred to as blackouts, are more likely with short-acting sedatives, alcohol, or a combination of the two. The history, either directly from the patient or from his or her associates, usually provides sufficient evidence to confirm intoxication with alcohol or sedatives. Laboratory testing in these patients should include a blood alcohol level (Table 250-5) obtained directly from a serum sample or indirectly by measurement of the breath alcohol content with a breathalyzer.
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A metabolic profile should be obtained to check blood glucose (malnourished patients may have hypoglycemia) and to calculate the anion gap. Other toxic alcohols (ethylene glycol [antifreeze], methanol [wood alcohol]) will cause a high anion gap acidosis and osmolar gap. Isopropyl alcohol is associated with an elevated osmolar gap but not with an elevated anion gap acidosis (see Chapter 238 [Acid Base Disorders]).
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Urine testing for benzodiazepines and barbiturates is widely available. Standard assays for benzodiazepines do not detect benzodiazepines but rather metabolites of 1,4-benzodiazepines. Therefore, they vary in their sensitivity to detect some benzodiazepines (clonazepam, lorazepam, midazolam, or alprazolam). Urine tests for other sedatives, including the Z-drugs and older sedatives (eg, meprobamate, chloral hydrate, ethchlorvynol), are not widely available, although may be requested from outside laboratories. Serum benzodiazepine levels do not correlate with clinical findings and are not readily available during emergent management.
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With alcohol intoxication, neurologic symptoms should clear within 4 hours unless due to coingestions, head trauma, or other causes. With any sedative overdose, the management is supportive and may require a period of artificial ventilation until the sedative level falls and spontaneous respiration resumes. A benzodiazepine antagonist, flumazenil, competitively binds but does not activate the gamma-aminobutyric acid (GABA) benzodiazepine receptor. The use of flumazenil may precipitate seizures in individuals who have developed physiologic dependence on benzodiazepines; therefore, this drug should only be used in consultation with a toxicologist (eg, Poison Control).
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SEDATIVE AND ALCOHOL WITHDRAWAL
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Use of a sedative or alcohol on a daily basis for more than 2 weeks may result in withdrawal upon cessation of use. The likelihood increases with longer periods and heavier use. Withdrawal can also occur with nondaily, binge pattern use (more days of the week than not). The common signs and symptoms of alcohol withdrawal are shown in Table 250-6 and delirium tremens (DTs) are shown in Table 250-7. In general, withdrawal from sedatives produces similar signs and symptoms as withdrawal from alcohol. Barbiturates and other, older sedatives may be more likely to produce seizures and/or delirium during withdrawal. The syndromes differ principally in their time course, which is directly correlated with the elimination half-life of the agent. Long-acting sedatives, such as diazepam or phenobarbital would typically present more gradually than alcohol withdrawal, and with a later onset of withdrawal seizures and peak symptoms.
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Alcohol withdrawal typically progresses through stages due to central nervous system hyperactivity:
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6 to 12 hours after last drink: tremulousness (in up to 100% of individuals) and other minor symptoms (insomnia, anxiety, gastrointestinal upset, headache)
12 to 48 hours after last drink: withdrawal seizures occurring predominantly in patients with a long history of heavy alcohol use or prior withdrawal seizures
12 to 48 hours after last drink: alcoholic visual hallucinations without mental status changes or hemodynamic instability (in up to 25% of individuals)
2 to 4 days after last drink: delirium tremens (in 4%-5% of patients)
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Other causes of symptoms suggesting DTs that do not respond to high doses of benzodiazepines or last more than a week include intoxication due to benzodiazepines, gamma hydroxybutyrate (GHB) or baclofen withdrawal.
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Laboratory evaluation should include complete blood count with differential and platelet count, coagulation tests, comprehensive metabolic profile, liver biochemical tests, amylase or lipase, ECG, urinalysis, and in selected patients cultures. The ECG should be examined to determine QTc interval (prior to initiating possible treatment with haloperidol) and to identify possible ischemia. Ethanol levels are usually low or undetectable and do not influence management. Patients may experience withdrawal signs and symptoms with an elevated blood alcohol level.
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All patients should receive thiamine before glucose administration to avoid causing Wernicke’s encephalopathy (encephalopathy, oculomotor dysfunction, gait ataxia), folate, multivitamins, intravenous hydration, correction of electrolyte disorders (especially magnesium and potassium depletion). For alcohol withdrawal, the most important element of management is prevention of seizures and DTs. Management of DTs commonly requires admission to an intensive care unit, for very close monitoring of vital signs and administration of high doses of benzodiazepines or barbiturates with or without adjunctive haloperidol. The general approach is to substitute an adequate dosage of a long-acting benzodiazepine (eg, diazepam, chlordiazepoxide, or clonazepam) to alleviate withdrawal symptoms. Some experts favor the use of lorazepam because it is not metabolized in the liver and would therefore not accumulate in patients with severe liver disease; however, metabolic function is usually well preserved until severe end-stage liver disease is present. Lorazepam’s principal advantages are that it is available as a parenteral agent, and its short half-life allows rapid titration. Administering more than one benzodiazepine will complicate management due to different half-lives and should be avoided.
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Table 250-8 provides a range of suggested doses of several common benzodiazepines and phenobarbital for use in mild to moderate alcohol withdrawal.
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A fixed dose regimen or a symptom-triggered approach is used to establish the benzodiazepine taper. The symptom-triggered approach can minimize the total dosage of benzodiazepines utilized, but may be too labor intensive to be practical in some settings. As such, a fixed-flexible dose regimen may be preferred. Clinical Institute Withdrawal Assessment for Alcohol (CIWA) is a widely used scoring system that may be used at the bedside with set protocol forms or online (http://www.reseaufranco.com/en/assessment_and_treatment_information/assessment_tools/clinical_institute_withdrawal_assessment_for_alcohol_ciwa.pdf). A score <8 supports a clinical impression that the patient has not yet developed alcohol withdrawal and withdrawal prophylaxis is appropriate. An increasing score > 8 supports withdrawal and need for intervention with an aim to achieve a score less than 8 by inducing a light sleep with benzodiazepines.
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Once stabilized, most patients can be tapered off benzodiazepines in approximately 10 days, with dosage reductions of approximately 10% of the total daily dosage each day over the course of those 10 days (which can be completed as an outpatient). Withdrawal from alcohol may also be managed very effectively with a long-acting barbiturate (phenobarbital), again with the need first to stabilize the patient’s vital signs and eliminate other withdrawal signs and symptoms, followed by a taper schedule over approximately 10 days. There is some evidence that alcohol withdrawal may also be managed with anticonvulsants (carbamazepine, gabapentin, valproic acid, and others), either in conjunction with benzodiazepines or as a standalone therapy, although the evidence thus far for anticonvulsants in alcohol withdrawal is insufficient to support their use over benzodiazepines.
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Withdrawal from sedatives is more complicated than withdrawal from alcohol. Long-term use (for more than 6 months) of benzodiazepines and Z-drugs, even at modest dosages, may be associated with a greater risk of seizures for days to weeks following cessation. As a result, many physicians recommend a sedative taper over several months under the supervision of a psychiatrist or addiction specialist. This may best be accomplished by switching a patient to phenobarbital and tapering it gradually over several months. Adjunctive use of anticonvulsants may play a role to reduce the seizure risk, but the evidence for this is limited. Withdrawal from barbiturates and other sedatives cannot safely be safely managed using benzodiazepines, because benzodiazepines do not adequately reduce the risk of seizures or withdrawal delirium. As such, phenobarbital is the agent of choice for managing withdrawal from barbiturates and other sedatives. Mixed sedative dependence syndromes, in which individuals regularly ingest multiple agents and possibly alcohol, should be managed with phenobarbital because it will safely cover withdrawal symptoms from all sedatives and alcohol.
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Acetaminophen is an analgesic drug, commonly used in combination with other drugs. The active ingredient is acetyl-para-aminophenol (APAP). The amount of acetaminophen ingested and the time to presentation are the most important prognostic indicators of hepatotoxicity. The APAP level guides therapy. The biggest benefit of N-acetylcysteine is within 12 hours of ingestion; however, treatment should be initiated for any toxic APAP level (see Chapter 100 [Suspected Intoxication and Overdose], Chapter 109 [Elevated Liver Biochemical and Function Tests], and Chapter 159 [Acute Liver Disease]).
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Salicylates are found in a number of medications, including aspirin products, bismuth subsalicylate (Pepto-Bismol) and herbal medications. Salicylate poisoning should be considered in any patient with an elevated anion gap acidosis. Serum salicylate levels may not correlate with clinical presentation due to a number of factors, including delayed absorption of enteric-coated formulations, altered absorption and elimination following overdose, and salicylate redistribution in body tissues rather than excretion by the kidneys. Available through poison control, a medical toxicologist should be consulted in any patient suspected of salicylate poisoning. Consider consultation with a nephrologist for guidance on alkalinization to promote elimination of salicylate and for recommendations and timing of possible hemodialysis.
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Opioids are now among the most commonly prescribed medications in the United States. Over 5 million people use opioids for nonmedical purposes each year, and there are over 100,000 new users of heroin each year.
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Fever, dyspnea, and acute pain are common presenting complaints of opioid-using patients. Underlying infection is often the cause of these complaints, particularly among injection drug users (IDUs). Endocarditis, skin, and soft-tissue infections, bone and joint infections, epidural abscess, and even pneumonia are more common among IDUs than in general medicine patients. When an opioid user is identified, a key part of the evaluation is to determine if the individual is physically dependent on opioids.
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The role of urine drug testing in the diagnosis of opioid use is fairly limited. Providers need to be aware of general test characteristics as well as what tests are locally available. Specific (and separate) urine radioimmunoassay screening tests can be used to screen for opiates, oxycodone, meperidine, propoxyphene, and methadone metabolites. A “negative” screening test never rules out opioid use, and a “positive” screening test can only be used to support a clinical diagnosis. Definitive testing can be performed with gas chromatography/mass spectroscopy, but such testing is expensive and results are not immediately available.
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Patients may present with symptoms of overdose (lethargy, pinpoint pupils, respiratory depression) or withdrawal (sweating, tremor, tachycardia, anxiety, pupillary dilation). Withdrawal symptoms typically begin 6 to 12 hours after the last use and will peak at 24 to 48 hours, but vary based on agent (Table 250-9).
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Overdose may occur in new opioid users, as part of a suicide attempt, when drug purity is unexpectedly high, or during induction on a long-acting opioid (eg, methadone). Injection drug users are particularly vulnerable to overdose when getting opioids from a new source where drug purity is not known and there is a mixture multiple drugs such as fentanyl and heroin. Initial treatment includes the use of the short-acting injectable opioid antagonist naloxone and supportive care. In the opioid-naïve individual, full-agonist reversal generally occurs when 0.4 mg of naloxone is given (IV/IM/SQ/ET) every 2 to 3 minutes. The intravenous route provides the most predictable response. For opioid-dependent patients, smaller doses should be used and titrated to reverse respiratory depression (giving full-reversal doses of naloxone to opioid-dependent individuals may result in a severe withdrawal syndrome); doses of 0.1 to 0.2 mg of naloxone can be used in incremental fashion to reverse respiratory depression. Patients who have overdosed with a long-acting or high-affinity agent (eg, methadone, buprenorphine) will generally need admission for oxygen, close monitoring, and an intravenous naloxone infusion.
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Management of the opioid withdrawal syndrome (OWS) should be based on patient characteristics, goals of treatment, and local resources. Always verify methodone dosage prior to administration of large doses in patients who chronically take methadone. Patient characteristics include determination of the presence or absence of pain (acute and chronic), the presence or absence of pathologic opioid use (abuse and addiction), the type and amount of opioid being used, and the cause and severity of withdrawal. The goal of treatment will be either stabilization on an opioid, or complete cessation of all opioids. For opioid-addicted patients who are not currently receiving addiction treatment, the presence or absence of pain is the primary determinant of medication selection. Patients with pain will require agonist treatment with buprenorphine, methadone, or other opioid agonists. Patients without pain (other than withdrawal pain) can be managed with clonidine or buprenorphine. Medications most commonly used for the treatment and symptom management of OWS are outlined in Table 250-10 and Table 250-11.
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There are many types of abused stimulants in the United States, including cocaine, amphetamines, ecstasy, and over-the-counter and prescription stimulants. Table 250-12 outlines the most commonly abused stimulants. Prescription stimulants include methylphenidate, methamphetamine, dextroamphetamine, mazindol, phenmetrazine, and phentermine. Prescribed stimulants may be used therapeutically for multiple conditions, including attention-deficit disorder, narcolepsy, fatigue in multiple sclerosis, and refractory depression, as well as in palliative care. Nicotine and caffeine are mild stimulants that are also in widespread use.
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Stimulant overdose usually presents with symptoms due to overstimulation of the sympathetic nervous system leading to peripheral vasoconstriction, increased heart rate, and lowered seizure threshold. Psychological effects result from stimulation of corticomesolimbic dopamine circuits in the brain, leading to desired effects (increased energy and alertness, euphoria, decreased appetite and need for sleep) as well as negative effects (anxiety, grandiosity, impaired judgment, psychosis, paranoid delusions and hallucinations, and addiction). Adrenergic poisoning syndromes have similar presentations to neuroleptic malignant syndrome, serotonin syndrome, thyroid storm, intracranial hemorrhage, and pheochromocytoma. Laboratory evaluation includes urine drug screen, CBC, CMP, creatine kinase, urinalysis, coagulation tests, liver biochemical tests, troponins, ECG, and CXR. Additional testing may include thyroid function tests and neuroimaging.
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Stimulant overdose symptoms are outlined in Table 250-13.
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Treatment for acute overdose of stimulants includes stabilization of airway, breathing, and circulation, administration of activated charcoal, seizure control with benzodiazepines, aggressive management of hypertension, and management of hyperthermia. The acutely intoxicated stimulant user should be approached in a subdued manner. Specific management for cocaine-associated complications is outlined in Table 250-14.
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Designer drugs, especially MDMA (ecstasy), are stimulants with some hallucinogen-like effects, so acute physiological effects include more pronounced hypertension and hyperthermia as compared to other hallucinogens. MDMA also has serotonergic effects. Peak effects occur within 2 hours following ingestion and effects last approximately 4 to 6 hours. Ecstasy often contains adulterants. Urine drug screen will be positive for amphetamines but a negative screen does not exclusion ingestions of this drug. Hyperthermia is the main cause of death.
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Toxicity of designer drugs may be related to additives such as ketamine or LSD. There are numerous case reports of MDMA use resulting in hyperthermia, rhadomyolysis, serotonin syndrome, hyponatremia with cerebral edema, fulminant hepatic failure, and stroke. Other stimulant-derived hallucinogens may cause cardiac arrhythmias.
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The severity and duration of withdrawal from stimulants depends upon the intensity of the preceding months of chronic abuse and the presence of predisposing psychiatric disorders. In general, the “crash,” or drastic reduction in mood and energy, can start within minutes after the last use. The user experiences craving, depression, irritability, anxiety, and paranoia. The craving for stimulants decreases over several hours and is replaced by a need for sleep and food. Hypersomnolence lasts between 8 hours and 4 days. Sleep is interrupted by brief awakenings during which the user experiences hyperphagia (“the munchies”). This phase is followed by a protracted dysphoric syndrome consisting of anhedonia, boredom, anxiety, panic attacks, generalized malaise, problems with memory and concentration, and occasional suicidal ideation. This induces severe craving that may lead to resumption of stimulant use and a vicious cycle of recurrent binges. Withdrawal syndromes for stimulants require only supportive care.
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Patients may be admitted to a hospital with an overdose, intoxication, or withdrawal syndrome from drugs of abuse, including marijuana, hallucinogens, “club drugs,” and/or inhalants. Marijuana is the most frequently abused drug in the United States, with a prevalence of around 4% of the adult population. The most widely used hallucinogen is LSD, with a lifetime prevalence of use of 14% among young adults. Among club-going young adults, use of hallucinogens is up to 70%. Common “club drugs” are listed in Table 250-15.
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Indicators that would raise the suspicion of the use of these drugs are outlined in Tables 250-16 and 250-17.
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Treatment tips for the management of acute overdose of marijuana and hallucinogens are outlined in Table 250-18.
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For PCP, hypertension should be treated vigorously with intravenous antihypertensives, since it may cause hypertensive encephalopathy or intracerebral bleeding. PCP can also cause life-threatening hyperthermia with temperatures over 106°F; rapid cooling measures (ice packs, cooling blanket, etc) may be required. Psychotic behavior can be treated with haloperidol. If the patient is severely agitated and poses a potential threat to self or others, haloperidol or lorazepam is effective for control of agitation; barbiturates may be even more useful in this setting with this drug, according to some reports.
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GHB overdose may cause severe central nervous system and respiratory depression that abates over several hours. For acute GHB intoxication, supportive care includes oxygen supplementation, intravenous access, and comprehensive physiologic and cardiac monitoring. Providers should attempt to keep the patient stimulated and awake. Atropine may be used for persistent symptomatic bradycardia. Naloxone and flumazenil are ineffective, and activated charcoal is contraindicated due to the risk of aspiration and the short half-life of GHB. The most dangerous effects of GHB use often occur with the use of other drugs. Concurrent use of sedatives or alcohol may increase the risk of vomiting, aspiration, or cardiopulmonary depression; the use of GHB and stimulants may increase the risk of seizure.
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Heavy marijuana use for more than 3 weeks results in a withdrawal syndrome after abrupt cessation and consists of irritability, agitation, depression, insomnia, nausea, anorexia, and tremor that can last for weeks. Marijuana withdrawal is uncomfortable but not life threatening; treatment is entirely supportive and rarely requires adjunctive medications.
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Withdrawal from GHB is similar to withdrawal from sedatives such as benzodiazepines and alcohol; symptoms start within 6 hours of the last use, then increase in intensity over several hours to days and may persist for 2 weeks. Physiologic signs include diaphoresis, tremor, tachycardia, and hypertension. Other symptoms are nausea with vomiting, anxiety, restlessness, insomnia, and “feelings of doom.” Severe withdrawal involves agitation, delirium, and psychosis. GHB withdrawal may not respond to benzodiazepines despite very high doses. Antipsychotics or pentobarbital may have some utility in treatment of severe GHB withdrawal, although antipsychotics may lower the seizure threshold, especially when used without a sedative.
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