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1270 SECTION 15: Toxicology dose ingested or a steady-state serum digoxin level (Table 193-3). In an acute poisoning, each vial of digoxin-Fab reverses approximately 0.5 milligram of ingested digoxin. In hemodynamically stable patients, half the calculated total neutralizing dose is infused initially, and the other half is given if an adequate clinical response is not seen in 1 to 2 hours. 28 Observational studies report that a total of 200 to 480 mil ligrams of digoxin-Fab (5 to 12 vials) were required to effectively treat severely digoxin-toxic patients. 27 When the ingested dose is unknown and serum level is unavailable, 10 vials are recommended as initial treatment in life-threatening situations. Digoxin-Fab is administered IV through a 0.22-mm filter over 30 minutes, except in cardiac arrest, when the dose is given as an IV bolus. Calculations of a full neutralizing dose may overestimate the amount of digoxin-Fab necessary, and smaller doses may adequately eliminate digoxin from the central compartment. 29 In chronic toxicity, an acceptable approach in the hemodynamically stable patient without clear lifethreatening arrhythmias is to administer half of the dose calculated by level. If instability develops, the remainder of the full calculated dose can be administered. One to three vials (40 to 120 milligrams) of digoxin- Fab are often adequate in reversing chronic toxicity. Total serum digoxin levels obtained following digoxin-Fab administration have little correlation with clinical toxicity. Because most laboratory assays do not distinguish between antibody-bound and unbound digoxin, total serum levels obtained following digoxin-Fab administration may increase 10- to 20-fold. 27 However, because the Fab-digoxin complex is not pharmacologically active, this increased level does not correlate with clinical toxicity. In the presence of renal failure, the Fab-digoxin complex may persist in the circulation for prolonged periods. 30 Recurrent toxicity can occur up to 10 days after digoxin-Fab administration in patients with renal failure as the complex degrades. Due to the large molecular weight of the Fab-digoxin complex (45,000 to 50,000 Da), hemodialysis does not enhance its elimination, although plasma exchange may be of benefit. 31,32 New liver support devices incorporating albumin-based dialysis and plasma filtration may be expected to be able to clear the Fabdigoxin complex based on molecular weight alone; some devices have been reported to clear substances up to 100 kDa. 33 However, there is no experience using this technique with digoxin-poisoned patients.  DISPOSITION AND FOLLOW-UP Extended observation with serial digoxin and potassium levels is recommended for anyone with a confirmed acute ingestion. Asymptomatic patients should be observed until the serum digoxin level is decreasing on serial measurements and the potassium level has remained normal. Patients with signs of toxicity should be admitted to a monitored unit. Consultation with a medical toxicologist or the regional poison control center is recommended. Patients receiving digoxin-Fab require intensive care unit observation for 6 to 12 hours. 28 Patients in renal failure who receive digoxin-Fab may be at risk of delayed toxicity, as the Fab-digoxin complex can dissociate several days later. Finally, patients with suspected suicidality should undergo behavioral health or psychiatric evaluation before discharge.

ensive care unit observation for 6 to 12 hours. 28 Patients in renal failure who receive digoxin-Fab may be at risk of delayed toxicity, as the Fab-digoxin complex can dissociate several days later. Finally, patients with suspected suicidality should undergo behavioral health or psychiatric evaluation before discharge. REFERENCES The complete reference list is available online at www.TintinalliEM.com. TABLE 193-3 Calculation of Digoxin-Specific Antibody Fragment (Fab) Full Neutralizing Dose Based on suspected amount ingested Digoxin body load (milligrams) = 0.8 × suspected ingested amount (milligrams) Digoxin body load (milligrams) = serum digoxin concentration (nanograms/mL) × 5.6 L/kg × weight (kg)/1000 One vial (about 40 milligrams) of digoxin-Fab neutralizes 0.5 milligram of digoxin ingested Based on total serum digoxin concentration Number of vials = serum concentration (nanograms/mL) × patient weight (kg)/100 Beta-Blockers Matthew K. Riddle Christian Tomaszewski INTRODUCTION β-Adrenergic receptor antagonists (β-blockers) are medications used in the treatment of various cardiovascular, neurologic, endocrine, ophthalmologic, and psychiatric disorders. Among all drug-related fatalities reported to poison control centers nationwide in 2016, β-blockers were involved in 8% of all cases and were responsible for 2% of single-agent fatal exposures. PHARMACOLOGY The β-adrenergic receptors are membrane glycoproteins present as three subtypes in various tissues (Table 194-1). These receptors play a critical role in cardiovascular physiology by modulating cardiac activity and vascular tone. During times of stress (i.e., catecholamine release), β-adrenergic receptor stimulation increases myocardial and vascular smooth muscle cell activity through a sequence of intracellular events (Figure 194-1). 2,3 The β-receptor is coupled to a stimulatory Gs protein. This Gs protein stimulates adenylate cyclase, which in turn catalyzes the formation of cyclic adenosine monophosphate (cAMP), the so-called intracellular second messenger. Increased cAMP ultimately phosphorylates the L-type calcium channel, which leads to channel opening and calcium entry into the cell. This increase in cytosolic calcium acts at the ryanodine receptor, a calcium channel on the sarcoplasmic reticulum, causing it to release its stored calcium into the cytosol. This process is termed calcium-induced calcium release. Stored calcium becomes available to participate in mechanical contraction via the actin and myosin complex. Like the cardiac myocyte, the vascular smooth muscle uses L-type calcium channels to regulate intracellular calcium and subsequently coordinate vascular tone. Phosphodiesterase breaks down cAMP to adenosine 5’-monophosphate, which removes the stimulus for calcium channel opening, and the contractile process ceases. The β-blockers modulate the activity of cardiac myocytes and vas cular smooth muscle contraction by decreasing calcium entry into the cell. 2,3 Therapeutically, β-blockade lessens the work performed by diseased or injured myocardium and lowers elevated blood pressure. In toxicity, excessive β-blockade may lead to bradycardia, decreased con tractility, hypotension, and ultimately cardiogenic shock. CHAPTER TABLE 194-1 Location and Activity of β-Adrenergic Receptors β-Receptor Type Location Agonism Antagonism 1 Myocardium Increases inotropy Increases chronotropy Decreases inotropy Decreases chronotropy Kidney Eye Stimulates renin release Stimulates aqueous humor production Inhibits renin release Inhibits aqueous humor production 2 Bronchial smooth muscle Causes bronchodilation Causes bronchospasm Visceral smooth muscle Relaxes uterus Causes ileus — Skeletal muscle Increases force of contraction Stimulates glycogenolysis — Liver

Stimulates renin release Stimulates aqueous humor production Inhibits renin release Inhibits aqueous humor production 2 Bronchial smooth muscle Causes bronchodilation Causes bronchospasm Visceral smooth muscle Relaxes uterus Causes ileus — Skeletal muscle Increases force of contraction Stimulates glycogenolysis — Liver Vascular Stimulates glycogenolysis and gluconeogenesis Vasodilation Inhibits glycogenolysis and gluconeogenesis Minimal vasoconstriction 3 Adipose tissue Skeletal muscle Stimulates lipolysis Stimulates thermogenesis Inhibits lipolysis Inhibits thermogenesis Tintinalli_Sec15_p1187-1332.indd 1270 8/2/19 8:40 PM

Stimulates renin release Stimulates aqueous humor production Inhibits renin release Inhibits aqueous humor production 2 Bronchial smooth muscle Causes bronchodilation Causes bronchospasm Visceral smooth muscle Relaxes uterus Causes ileus — Skeletal muscle Increases force of contraction Stimulates glycogenolysis — Liver Vascular Stimulates glycogenolysis and gluconeogenesis Vasodilation Inhibits glycogenolysis and gluconeogenesis Minimal vasoconstriction 3 Adipose tissue Skeletal muscle Stimulates lipolysis Stimulates thermogenesis Inhibits lipolysis Inhibits thermogenesis Tintinalli_Sec15_p1187-1332.indd 1270 8/2/19 8:40 PM CHAPTER 194: Beta-Blockers 1271 The pharmacologic properties of various β-blockers influence their spectrum of action, adverse drug reactions, and toxicity (Table 194-2).4,5 These properties include receptor selectivity, sodium channel blockade (also known as membrane-stabilizing activity), lipid solubility, protein binding, and partial agonist activity (also known as intrinsic sympa thomimetic activity). For example, highly lipid-soluble agents (such as propranolol) readily cross the blood–brain barrier and achieve high concentrations in brain tissue. 2,3 This may contribute to the more severe CNS manifestations of mental status depression, seizures, and coma seen after an overdose of such agents. 2,3 In addition to β-antagonism, several β-blockers also inhibit myocardial sodium channels (similar to quinidine and cyclic antidepressants), rendering these drugs potentially more cardiodepressant following overdose. 3 However, in massive over doses, all β-blockers can be severely cardiodepressive. 6 Although β 1 cardioselective medications have less risk of unwanted β2 effects, such as bronchospasm, selectivity is often lost following large overdoses.3 Several β-blockers, such as pindolol, have partial agonist activity, causing weak stimulation of the β-receptor, with a lesser tendency for bradycardia during therapeutic use. 4 Some β-blockers, such as labetalol and carvedilol, are also antagonists at α 1-adrenergic receptors, which can result in exaggerated hypotension during therapeutic use. Sotalol is unique among β-blockers in its action as a Vaughan-Williams class III agent, causing blockade of inward rectifier potassium channels involved in cardiac repolarization. 2-4 cAMP 5’AMP ATP Sarcoplasmic reticulum Cell membrane Myosin Actin/tropomyosin-troponin Sarcomere Ca2+ Sequestered Ca2+ RyR RyR Ca2+ Glucagon β-agonist L-VDDC Ca2+ + + + + + PKA active PDE B1 FIGURE 194-1. Cardiac myocyte β 1-receptor and calcium signaling. Following myocyte depolarization, extracellular calcium (Ca 2+) enters the cell via the L-type or voltage-gated calcium channel (L-VDCC) and binds to the ryanodine receptor (RyR) in the sarcoplasmic reticulum, causing an efflux of sequestered Ca 2+ out of the sarcoplasmic reticulum into the cytosol. Free Ca 2+ binds to troponin that allows the myosin and actin interaction, resulting in contraction of the cardiac myocyte. Binding of a β-agonist to the β 1-adrenergic receptor (B1) on the cell surface activates the Gs protein. The Gs protein then activates adenylate cyclase (AC), which converts adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP). The increased cAMP activates protein kinase A (PKA). Activated PKA serves as further stimulus for the L-VDCC opening. Glucagon independently activates adenylate cyclase. cAMP is metabolized by phosphodiesterase (PDE) into inactive adenosine 5’-monophosphate (5’AMP). In addition to cardiopulmonary effects, β-blockers alter metabolism in the liver, skeletal muscle, and adipose tissue. Under normal conditions, the heart uses free fatty acids as its primary energy source, but during times of stress, it switches to carbohydrate metabolism. The inhibition of glycogenolysis and gluconeogenesis in β-blocker overdose reduces the availability of carbohydrates for use by metabolically active cells. Although hypoglycemia can occur as a consequence of β-blocker toxicity, it is actually uncommon.

but during times of stress, it switches to carbohydrate metabolism. The inhibition of glycogenolysis and gluconeogenesis in β-blocker overdose reduces the availability of carbohydrates for use by metabolically active cells. Although hypoglycemia can occur as a consequence of β-blocker toxicity, it is actually uncommon. 2 In the presence of adequate glucose stores, euglycemia and even hyperglycemia are more common than hypoglycemia. Clinically relevant pharmacokinetic characteristics include drug for mulation (regular or extended release), rate of drug absorption, protein binding, lipid solubility, elimination (mostly by hepatic metabolism), and volume of distribution. These properties determine onset of symp toms, duration of symptoms, target organ toxicity, and potential treat ment modalities. CLINICAL FEATURES Toxicity due to β-blockers can produce a spectrum of clinical symptoms (Table 194-3). 2,3,7 The timing of symptom appearance depends upon the formulation. Absorption of regular-release β-blockers occurs rapidly, often with peak effects within 1 to 4 hours. However, delays of up to 6 hours following acute ingestion have occurred. 8 Experience is limited regarding onset of symptoms with poisoning following an ingestion of sustained-release β-blocker formulations, but based on other sustainedrelease cardiac drugs, it is assumed that symptoms may be delayed for >6 hours after ingestion. 2,3 Co-ingestants that alter gut function, such as opioids and antimuscarinic drugs, may affect absorption of β-blockers and subsequent onset of symptoms. The primary target of β-blocker toxicity is the cardiovascular sys tem, and the hallmark of severe toxicity is bradycardia with shock. 2,3,7,9 Bradycardia due to sinus node suppression or conduction abnormali ties occurs in virtually all significant β-blocker intoxications, although ingestion of β-blockers with partial agonist activity may initially present with hypertension and tachycardia. 9 The β-blockers with sodium chan nel antagonism can cause conduction abnormalities, leading to a widecomplex bradycardia that can worsen hypotension and shock (especially when the QRS interval is >100 milliseconds). The cardiotoxic profile of sotalol is different from that of other β-blockers due to its blockade of potassium channels, causing QT prolongation. 3 Thus, sotalol is more often associated with ventricular dysrhythmias, including premature ventricular contractions, bigeminy, ventricular tachycardia, ventricular fibrillation, and torsades de pointes. β-Blockers also affect the CNS and pulmonary system. Neurologic manifestations include depressed mental status, coma, and seizures. 2 These symptoms most likely occur due to a combination of hypoxia secondary to poor perfusion, sodium channel antagonism, and direct neuronal toxicity. 2 More lipophilic β-blockers, such as propranolol, cause greater neurologic toxicity than the less lipophilic agents.9 Seizures are generally brief, and status epilepticus is rare. 2 Antagonism of the β2-receptor in bronchial smooth muscle can cause bronchospasm, both in the setting of nonselective β-blockers and in large ingestions of cardioselective β-blockers, where β 1 selectivity may be lost. DIAGNOSIS The diagnosis of β-blocker toxicity is primarily made on clinical grounds, including patient history, physical examination findings, and results of basic diagnostic testing. Patients commonly present with a history of intentional overdose or therapeutic misadventure. The diagnosis may be more challenging in cases of polypharmacy, multidrug overdose, or chronic drug toxicity. In addition to β-blockers, multiple other drugs and toxins can present with bradycardia and hypotension; however, there are several features that can help to differentiate these exposures (Table 194-4).

enture. The diagnosis may be more challenging in cases of polypharmacy, multidrug overdose, or chronic drug toxicity. In addition to β-blockers, multiple other drugs and toxins can present with bradycardia and hypotension; however, there are several features that can help to differentiate these exposures (Table 194-4). Laboratory testing is recommended to assess renal function, glucose level, oxygenation, and acid-base status. Although specific β-blocker drug levels might be of value for later confirmation of an ingestion, these levels are not helpful initially because they do not correlate with the degree of toxicity and are generally not available in a timely fashion to affect acute management. 2,3,7 False-positive amphetamine results can Tintinalli_Sec15_p1187-1332.indd 1271 8/2/19 8:40 PM

value for later confirmation of an ingestion, these levels are not helpful initially because they do not correlate with the degree of toxicity and are generally not available in a timely fashion to affect acute management. 2,3,7 False-positive amphetamine results can Tintinalli_Sec15_p1187-1332.indd 1271 8/2/19 8:40 PM 1272 SECTION 15: Toxicology TABLE 194-2 β-Blocker Pharmacologic Profiles Agent β 1 Selectivity Lipophilicity Partial Agonism Protein Binding (%) Sodium Channel Blockade Half-Life (h) Maximum Recommended Adult Daily Dose (milligrams) Acebutolol + Moderate + 25 + 3–4 1200 (800 in elderly) Atenolol + Weak 0 6–16 0 6–9 100 (HTN) 200 (angina) Betaxolol + High 0 55 ± 14–22 40 Bisoprolol ++ Moderate 0 30–40 0 9–12 20 (HTN) 10 (HFrEF) Carvedilol 0 Moderate 0 >95 ± 7–10 50 (IR) 80 (ER) Esmolol + Weak 0 55 ± 9 min NA Labetalol + Weak 0 50 ± 3–4 2400 Metoprolol ++ Moderate 0 12 ± 3–4 450 (HTN) 400 (angina) Nadolol 0 Weak 0 30 0 12–24 320 (HTN) 240 (angina) Nebivolol +++ Moderate 0 98 0 8–27 40 Oxprenolol 0 Moderate ++ 80 + 1–2 Pindolol 0 High ++ 40–60 ± 3–4 60 (HTN) 40 (angina) Penbutolol 0 High + 80–98 0 5–20 80 Propranolol 0 High 0 >90 ++ 3–4 640 (HTN) 320 (angina) Sotalol 0 Weak 0 Minimal 0 12 640 Timolol 0 High ± 10–60 0 4–5 60 Abbreviations: + = some activity; ++ = strong activity; ± = possible activity; 0 = no activity; ER = extended-release form; HTN = hypertension; HFrEF = heart failure with reduced ejection fraction; IR = immediaterelease form; NA = not applicable. be seen on urine drug screens from labetalol, because one of its metabolites is structurally similar to amphetamine. 10 Cardiac function may be evaluated with a 12-lead ECG, rhythm monitor, and bedside cardiac US. 11 A drug-induced Brugada pattern has been reported in propranolol overdose, a β-blocker that also blocks cardiac sodium channels. 12 TREATMENT  GENERAL MANAGEMENT Patients with suspected β-blocker overdose should be evaluated in a critical care area of the ED with appropriate monitoring because they may experience abrupt cardiovascular collapse or neurologic depression. If orotracheal intubation is performed, the drugs used for sedation and paralysis may worsen hypotension in the setting of an already depressed myocardium (see Chapter 29A, “Tracheal Intubation”). 2,3,7 No one particular treatment is consistently effective in the manage ment of β-blocker toxicity, and multiple simultaneous treatment mea sures may be required to resuscitate the critically ill patient. Therapy should be tailored to each individual case based on exposure history, ECG, bedside cardiac US, and/or central hemodynamic monitoring. The goal of resuscitation is to improve hemodynamics and organ per fusion. Specific end points of therapy may include a cardiac ejection fraction of 50% or greater, a reduction of the QRS interval to <120 mil liseconds, a heart rate of >50 to 60 beats/min, a systolic blood pressure of >90 to 100 mm Hg (12.0 to 13.3 kPa) in an adult, urine output of 1 to 2 mL/kg per hour, and improved mentation.

ecific end points of therapy may include a cardiac ejection fraction of 50% or greater, a reduction of the QRS interval to <120 mil liseconds, a heart rate of >50 to 60 beats/min, a systolic blood pressure of >90 to 100 mm Hg (12.0 to 13.3 kPa) in an adult, urine output of 1 to 2 mL/kg per hour, and improved mentation. TABLE 194-3 Common Findings With β-Blocker Toxicity Cardiovascular Hypotension Bradycardia Conduction delays and blocks (first-degree atrioventricular block) Ventricular dysrhythmias (sotalol) Asystole Decreased contractility CNS Depressed mental status Coma Psychosis Seizures Respiratory arrest Pulmonary Bronchospasm Electrolytes Hypoglycemia (uncommon) Hyperkalemia TABLE 194-4 Toxicologic Causes of Bradycardia and Hypotension Cause Differentiating Features Calcium channel blockers Elevated lactate level and possible hyperglycemia Naturally occurring cardioactive steroids (oleander, foxglove, lily of the valley, rhododendron, and Bufo toads) Ventricular ectopy May cross-react with digoxin immunoassay Class IC antiarrhythmic drugs (propafenone) Wide-complex bradycardia Clonidine Opioid-like manifestations: coma, miosis, decreased respirations Cyanide Profound metabolic acidosis and elevated lactate level Digoxin (acute) Hyperkalemia Elevated level on digoxin immunoassay Organophosphates Cholinergic toxidrome Tintinalli_Sec15_p1187-1332.indd 1272 8/2/19 8:40 PM

ide-complex bradycardia Clonidine Opioid-like manifestations: coma, miosis, decreased respirations Cyanide Profound metabolic acidosis and elevated lactate level Digoxin (acute) Hyperkalemia Elevated level on digoxin immunoassay Organophosphates Cholinergic toxidrome Tintinalli_Sec15_p1187-1332.indd 1272 8/2/19 8:40 PM CHAPTER 194: Beta-Blockers 1273  GI DECONTAMINATION Although there is little evidence to support routine GI decontamina tion following overdose of most substances, ingestion of a significant quantity of β-blockers with the risk of severe toxicity is a circumstance in which early decontamination should be considered. 13 Activated charcoal may be of benefit if it can be given within 1 hour after ingestion in a patient without airway compromise. 14,15 There may be an additional window of opportunity for activated charcoal therapy following ingestion of extended-release β-blockers. After airway protection, consider gastric lavage in recent, large ingestion. Ipecac syrup and cathartic agents are not recommended. 16 Gastric lavage is not recommended.13 Whole-bowel irrigation may be beneficial and should be considered after a large ingestion of an extended-release product.  PHARMACOLOGIC TREATMENT Specific pharmacologic therapies are directed at restoring perfusion to critical organ systems by improving myocardial contractility, increas ing heart rate, or both. 2,3,7 This is done through fluid resuscitation and administration of glucagon, adrenergic agonists, high-dose insulin, calcium, and phosphodiesterase inhibitors ( Figure 194-2). Individual pharmacologic therapies have variable effectiveness and are often used simultaneously. 7 Aggressive measures such as hemodialysis, hemoper fusion, cardiac pacing, placement of intra-aortic balloon pumps, and extracorporeal circulatory support have also been used when patients are refractory to pharmacologic therapy. Treatment of sotalol toxicity may require the use of additional pharmacologic measures due to its potassium channel effects. In addition to the therapies discussed earlier, magnesium supplementation, lidocaine, and cardiac overdrive pacing may be of specific benefit if there is QT prolongation or torsades de pointes.  GLUCAGON Glucagon is a first-line agent in the treatment of acute β-blocker– induced bradycardia and hypotension. 2,19 Glucagon, produced in the pancreatic α-cells from proglucagon, independently activates myocar dial adenylate cyclase, bypassing the impaired β-receptor and increasing intracellular cAMP (Figure 194-1). Glucagon has demonstrated positive inotropic and chronotropic effects in both animal models and human studies. 20 Effects from an IV bolus of glucagon are seen within 1 to 2 minutes, reach a peak in 5 to 7 minutes, and have a duration of action of 10 to 15 minutes. 2,3 Due to the short duration of effect, a continuous infusion is often necessary after bolus administration. The initial bolus dose of glucagon is 3 to 10 milligrams (30 to 150 micrograms/kg in children), and if no response is seen within 15 minutes, a repeat bolus can be given. If a beneficial effect is seen from the glucagon bolus, a continuous infusion of 1 to 5 milligrams/h (20 to 70 micrograms/kg per hour in children) can be used to maintain this effect. Titrate the glucagon infusion to achieve adequate hemodynamic response. There is no identified maximum therapeutic dose or duration of treatment. The amount of glucagon required to treat a significant β-blocker overdose may exceed the total amount available at any given hospital. 19 The positive inotropic and chronotropic effects of glucagon may not be maintained for a prolonged period due to tachyphylaxis.

fied maximum therapeutic dose or duration of treatment. The amount of glucagon required to treat a significant β-blocker overdose may exceed the total amount available at any given hospital. 19 The positive inotropic and chronotropic effects of glucagon may not be maintained for a prolonged period due to tachyphylaxis. Nausea and vomiting are commonly reported side effects of high-dose glu cagon therapy and may be related to esophageal sphincter relaxation. Antiemetics can be given prior to glucagon administration. Check QT interval before giving ondansetron. Intubation prior to glucagon administration may be warranted in any patient with altered mental status in order to limit the risk of aspiration. 2,3,7 Prior to 1998, glucagon was derived from porcine and bovine pan creas and contained other pancreatic compounds such as insulin and phenol as a preservative. 2 The contribution of this insulin content to the original glucagon’s overall efficacy is unclear (see discussion later in “High-Dose Insulin Therapy”). Since 1998, glucagon has been produced via recombinant technology and is devoid of insulin or phenol.  ADRENERGIC RECEPTOR AGONISTS The β-adrenergic receptor agonists—such as norepinephrine, dopa mine, epinephrine, and isoproterenol—are routinely used to treat β-blocker toxicity. 2,19 However, results have been variable even when dosages far exceed those recommended in standard guidelines for car diac resuscitation.3 The most effective adrenergic receptor agonists may be norepinephrine and epinephrine due to their chronotropic and vasopressor effects. Phenylephrine may also be beneficial as a vasopressor. Although isoproterenol may increase heart rate, it does so at the expense of vasodilation. Dobutamine has a similar downside: potential improvement in inotropy but worsening of hypotension due to vasodilation.  HIGH-DOSE INSULIN THERAPY High-dose insulin (HDI) therapy, also referred to as hyperinsulinemiaeuglycemia therapy, is an important treatment modality for β-blocker toxicity. 17,21-23 Insulin acts as an inotrope by facilitating myocardial utilization of glucose (the energy substrate employed during stress), in con trast to glucagon, epinephrine, and calcium, which promote free fatty acid utilization. 21-24 In animal models, HDI improved survival in severe β-blocker overdose compared with glucagon, epinephrine, or vasopres sin administration. 25,26 The most consistent cardiodynamic effect in these models was an increase in contractility. FIGURE 194-2. Management strategies in β-blocker toxicity. Cardiac function is evaluated using ECG, cardiac US, and/or central hemodynamic monitoring. For wide QRS interval, consider sodium bicarbonate therapy. For impaired myocardial contractility, consider glucagon, high-dose insulin, adrenergic agents, and calcium therapy. For decreased systemic vascular resistance, consider vasopressors, such as norepinephrine, epinephrine, dopamine, and phenylephrine. For bradycardia, consider glucagon, adrenergic agents, and cardiac pacing. (See text for details.) SVR = systemic vascular resistance. Evaluation (e.g., ECG, cardiac ultrasound or pulmonary artery catheter) QRS >120 ms Decreased contractility Decreased SVR Bradycardia Sodium bicarbonate Glucagon High-dose insulin Adrenergic agents Calcium salts Vasopressors Glucagon Adrenergic agents Cardiac pacing Hypotension Tintinalli_Sec15_p1187-1332.indd 1273 8/2/19 8:40 PM

(e.g., ECG, cardiac ultrasound or pulmonary artery catheter) QRS >120 ms Decreased contractility Decreased SVR Bradycardia Sodium bicarbonate Glucagon High-dose insulin Adrenergic agents Calcium salts Vasopressors Glucagon Adrenergic agents Cardiac pacing Hypotension Tintinalli_Sec15_p1187-1332.indd 1273 8/2/19 8:40 PM 1274 SECTION 15: Toxicology TABLE 194-5 Protocol for High-Dose Insulin Therapy in Severe β-Blocker Overdose •   Check serum glucose, and if <200 milligrams/dL (<11 mmol/L), administer 50 mL of 50% dextrose (0.5 gram/mL) in water IV (children 1 mL/kg of 25% dextrose). •   Administer regular insulin 1 unit/kg IV bolus. •   Begin regular  insulin  infusion  at 1.0 unit/kg  per hour along with dextrose  10% (0.1 gram/mL) in water at 200 mL/h (adult) or 5 mL/kg per hour (pediatric). •   Titrate infusion rate up to 10 units/kg per hour according to the hemodynamic goal of HR >50 beats/min and SBP >100 mm Hg (>13.3 kPa). •   Monitor serum glucose every 15–20 min. •   Titrate  dextrose  infusion  rate to maintain  serum glucose  level between  100 and 200 milligrams/dL (5.3 and 10.7 mmol/L). •   Once dextrose infusion rates have been stable for 60 min, glucose monitoring may be decreased to hourly. •   Monitor serum potassium level and start IV potassium infusion if serum potassium level is <2.8 mEq/L (<2.8 mmol/L). •   Maintain serum potassium between 2.8 and 3.2 mEq/L (2.8 and 3.2 mmol/L). Abbreviations: HR = heart rate; SBP = systolic blood pressure. HDI dosing used for treatment of β-blocker toxicity is much higher than that used for traditional glucose control in diabetes ( Table 194-5). The initial dose is regular insulin 1 unit/kg IV bolus and is followed by a continuous infusion of 1 unit/kg per hour that is titrated to the desired hemodynamic response of a heart rate at least 50 beats/min and systolic blood pressure of at least 100 mm Hg (13.3 kPa). 21-23 The maximum dose has not yet been established, although an animal model of propranolol overdose found that cardiac output increased in a dose-response man ner when the insulin dose was raised from 1 to 10 units/kg per hour, and human case reports and case series have reported doses this high.23,28 The onset of action with HDI is reported to be 15 to 45 minutes, but a delayed response of several hours has been noted. 21 HDI is con tinued until there is resolution of toxicity; the duration of HDI infu sion described in case reports ranges from 9 to 49 hours. 23 The insulin infusion can be gradually weaned or abruptly halted, and should be reinstituted if heart rate or blood pressure falls after cessation of HDI. Supplemental dextrose is needed for several hours after insulin infusion is stopped. Potential adverse effects from HDI are hypoglycemia and lowered serum potassium. Dextrose infusion is used to prevent hypoglycemia and often required during the duration of therapy. 23 Hypoglycemia tends to occur more often in the treatment of β-blocker toxicity when com pared to the treatment of calcium channel–blocker overdose. In a large case series, 41% of patients with single-agent β-blocker overdose treated with HDI developed hypoglycemia. 28 Serum potassium is monitored, and supplemental replacement is given if the level is below 2.8 mEq/L (2.8 mmol/L). 21,23 An increase in the dextrose infusion rate required to maintain serum glucose between 100 and 200 milligrams/dL (5.3 and 10.7 mmol/L), along with signs of clinical improvement, may be an indication that metabolic status is normalizing; that is, that the stress response is diminishing, the heart is reverting back to basal energy sub strates, and extra insulin is no longer needed.

in serum glucose between 100 and 200 milligrams/dL (5.3 and 10.7 mmol/L), along with signs of clinical improvement, may be an indication that metabolic status is normalizing; that is, that the stress response is diminishing, the heart is reverting back to basal energy sub strates, and extra insulin is no longer needed.  IV LIPID EMULSION THERAPY IV lipid emulsion (ILE) therapy, also known as fat emulsion therapy or lipid rescue, is extremely effective in treating toxicity from local anesthetics and has also been used with mixed results in the treatment of toxicity from calcium channel blockers, typical and atypical antipsy chotics, cyclic and other antidepressants, and some β-blockers. 29-32 The exact mechanism is not fully understood, but the likely explanation is that lipid emulsion acts as a pharmacologic sink, sequestering lipophilic drugs into a separate lipid compartment, and the amount of free drug available to target tissues is reduced (“lipid sink” model). 33 Other potential mechanisms may include supplying the myocardium with free fatty acids and phospholipids, increasing myocardial contractility by increasing myocyte calcium concentration, and elevating blood pressure by central sympathetic activation. Animal models suggest that ILE, if effective, may be most beneficial in the treatment of toxicity from lipophilic β-blockers (Table 194-2), such as propranolol and carvedilol, rather than the more hydrophilic agents, such as metoprolol and atenolol. The dosing regimen for ILE is based on treatment of local anes thetic systemic toxicity. The standard 20% lipid emulsion is given as a 1.5 mL/kg bolus over 1 minute, followed by an infusion at 0.25 mL/kg per minute. 33 If the blood pressure remains low, an additional 1.5 mL/kg bolus may be repeated followed by an increase in the infusion rate to 0.5 mL/kg per minute. The recommended upper limit is 10 mL/kg over the initial 30 minutes. If the patient’s hemodynamic stabil ity is dependent on continued lipid infusion, the treatment may be continued beyond this level. Duration of therapy has not been fully established. If cardiac arrest occurs, a bolus dose can be given during the resuscitation. Adverse effects reported with the use of ILE for the treatment of overdose and toxicity include lipemia causing interference with laboratory analysis, hypertriglyceridemia, pancreatitis, hypersensitivity, allergic reaction, acute lung injury, acute renal failure, venous thromboembo lism, fat embolism, increased susceptibility to infection, and cardiac arrest. 35-38 Lipid emulsion may clog the hemofiltration filter, precluding renal replacement therapy and other methods of extracorporeal support during the infusion and until the lipid has been cleared from the blood. Overall, the effect of ILE in various non–local anesthetic poisonings is heterogenous, and the quality of evidence remains low to very low. Given the potential for adverse effects and the lack of strong support ing evidence for use of ILE in the treatment of β-blocker toxicity, ILE should be reserved for refractory shock after other treatment modalities have failed.  ATROPINE Atropine, a muscarinic blocker, is unlikely to be effective in the management of β-blocker–induced bradycardia and hypotension, although its use is unlikely to cause harm. 3,4,7 It may be beneficial for the treatment of other co-ingestants.  CALCIUM Canine studies and limited case reports suggest that calcium therapy may reverse depression of the myocardium via positive inotropic action, although with few chronotropic effects. 2,3 Calcium administration is not routinely recommended in β-blocker overdose, but may be considered in patients with refractory shock unresponsive to other therapies.

ase reports suggest that calcium therapy may reverse depression of the myocardium via positive inotropic action, although with few chronotropic effects. 2,3 Calcium administration is not routinely recommended in β-blocker overdose, but may be considered in patients with refractory shock unresponsive to other therapies. Calcium for IV administration is available in two forms, gluconate and chloride, both in a 10% solution. A 10-mL dose of 10% calcium chloride solution contains three times more elemental calcium, 13.6 mEq (6.8 mmol), than 10 mL of 10% calcium gluconate solution, 4.5 mEq (2.23 mmol). Thus, one 10-mL ampule of 10% calcium chloride equals three 10-mL ampules of 10% calcium gluconate. Potential adverse effects of calcium therapy include hypercalcemia, conduction blocks, worsening bradycardia, and inefficient cardiac energetics during shock (see earlier “High-Dose Insulin Therapy” section). Most patients tolerate transient increases in total calcium level without difficulty, and conduction blocks are rare. Severe soft tissue injury associated with inadvertent IV infiltration of the chloride formulation is the most concerning adverse event. Thus, calcium chloride is ideally given via central access. Calcium gluconate is only rarely associated with tissue injury and is the preferred form for peripheral administration. The optimum dose of calcium in β-blocker toxicity is unknown. Animal studies and limited human studies suggest that large amounts of calcium are needed to treat drug-induced cardiac toxicity, but these data come from experience derived from treating calcium channel–blocker toxicity. 2,3 The recommended dose of 10% calcium gluconate is 0.6 mL/kg given over 5 to 10 minutes, followed by a continuous infusion of 0.6 to 1.5 mL/kg per hour. 2,3 The equivalent dosage of 10% calcium chloride is 0.2 mL/kg given via central line over 5 to 10 minutes, followed by a continuous infusion of 0.2 to 0.5 mL/kg per hour. Ionized calcium levels should be checked every 30 minutes initially and then every 2 hours to achieve an ionized calcium level of twice the normal value. Tintinalli_Sec15_p1187-1332.indd 1274 8/2/19 8:40 PM