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CHAPTER 195: Calcium Channel Blockers 1275  PHOSPHODIESTERASE INHIBITORS Phosphodiesterase inhibitors such as milrinone have been used to treat β-blocker toxicity. These agents inhibit the breakdown of cAMP , thereby sustaining intracellular calcium levels (Figure 194-1). 2,3 In animal models, phosphodiesterase inhibitors produce positive inotropic effects without increasing myocardial oxygen demand but have no appreciable effect on heart rate. Compared with glucagon, phosphodi esterase inhibitors do not provide any additional benefit and therefore have no advantage over glucagon. However, if glucagon is not available or pharmacy stores have been exhausted, a phosphodiesterase inhibi tor is a reasonable alternative. In the setting of a β-blocker overdose, milrinone is administered as a continuous IV infusion, starting with a 50 micrograms/kg IV bolus, followed by an IV infusion of 0.375 to 0.75 microgram/kg per minute for milrinone.  SODIUM BICARBONATE Sodium bicarbonate is used to treat severe acidosis and wide QRS interval dysrhythmias secondary to sodium channel blockade. β-Blockers with sodium channel antagonism (e.g., propranolol; Table 194-2) can interfere with ventricular depolarization, predisposing to cardiac dysrhythmias. When the QRS interval is longer than 120 milliseconds, it is reasonable to administer sodium bicarbonate. 2 The suggested dose is a rapid bolus of 2 to 3 mEq/kg over 1 to 2 min.2,3,6 Thus, a 70-kg adult receives a bolus of 140 to 210 mEq of sodium bicarbonate, or three to four ampules (50 mL each) of 8.4% sodium bicarbonate. Repeat boluses or an infusion may be required to maintain the QRS interval at <120 milliseconds.  CARDIAC PACING Internal or external pacing may be considered to treat bradycardia in the setting of β-blocker toxicity. 2,3 Electrical capture and restoration of blood pressure are not always successful, potentially due to the lack of intra cellular calcium needed for contraction. 2,3 Cardiac pacing may be most beneficial in treating torsades de pointes associated with sotalol toxicity.  EXTRACORPOREAL ELIMINATION (HEMODIALYSIS) The high degree of protein binding and lipid solubility of β-blockers, as well as their large volume of distribution, renders extracorporeal drug removal useless for most drugs in this class. Acebutolol, atenolol, nadolol, and sotalol may be amenable to removal through hemodialysis owing to their lower protein binding, water solubility, and lower volume of distribution.  EXTRACORPOREAL CIRCULATION Occasionally, extreme means of resuscitation, including extracorporeal circulation (extracorporeal membrane oxygenation) and intra-aortic balloon pumps, have been successful when pharmacologic measures have failed to reverse cardiogenic shock. 42,43 DISPOSITION AND FOLLOW-UP Patients who develop altered mental status, bradycardia, conduction delays, or hypotension should be managed in an intensive care unit. A patient who ingests a sustained-released β-blocker product warrants admission and monitoring for the development of delayed toxicity. 2,3,9 Patients ingesting an overdose of immediate-release β-blocker tablets who remain asymptomatic and have normal vital signs at 6 hours after time of ingestion can be deemed medically safe for discharge or admis sion to a psychiatric facility. REFERENCES The complete reference list is available online at www.TintinalliEM.com. Calcium Channel Blockers Clifford P.

te-release β-blocker tablets who remain asymptomatic and have normal vital signs at 6 hours after time of ingestion can be deemed medically safe for discharge or admis sion to a psychiatric facility. REFERENCES The complete reference list is available online at www.TintinalliEM.com. Calcium Channel Blockers Clifford P. Masom Christian Tomaszewski INTRODUCTION Calcium channel blockers (CCBs) are commonly used for the treatment of hypertension and angina pectoris and for ventricular rate control in supraventricular dysrhythmias. Less common uses include migraine prophylaxis and treatment of esophageal spasm, pulmonary hyperten sion, or arterial vasospasm due to Raynaud’s disease. PHARMACOLOGY Understanding the physiology of calcium in the cardiovascular system is crucial to understanding the effects of CCBs. Influx of calcium is regu lated by L-type calcium channels, which are found predominantly in the heart, vascular smooth muscle, and pancreatic β islet cells. Intracellular calcium facilitates sinoatrial node depolarization and propagation of the electrical signal through the atrioventricular node. Additionally, myocytes rely on L-type channels to allow intracellular calcium influx during the plateau phase (phase 2) of the action potential, which signals the release of stored calcium from the sarcoplasmic reticulum, allowing myocardial contraction. Calcium influx is also necessary for the release of insulin. Therefore, CCBs have multiple effects by blocking the entry of calcium required for normal pacemaker activity, atrioventricular nodal conduction, myocardial contraction, and insulin release. At therapeutic concentrations, CCBs bind to the α 1 subunit of the L-type calcium channel, causing the channel to favor the closed state and thereby decreasing calcium entry. At very high concentrations, some CCBs (notably verapamil) may occupy the channel canal and completely block calcium entry. The results are profound smooth muscle relaxation, weakened cardiac contraction, blunted cardiac automaticity, and intracardiac conduction delay. 1 Clinically, these effects produce hypotension and bradycardia. Animal data suggest that verapamil overdose also impairs myocardial carbohydrate intake, which contributes to the negative cardiac inotropy. 3 All CCBs undergo hepatic metabolism through CYP3A4. The three main pharmacologic classes of CCBs are phenylalkyl amines, benzothiazepines, and dihydropyridines (which is the class that includes most newer CCB agents) ( Table 195-1). It is easiest to think of CCBs as dihydropyridines (all CCBs with generic names ending in “pine”) and nondihydropyridines. All CCBs relax vascular smooth muscle, reduce pacemaker activ ity, and decrease cardiac contractility. However, these effects occur at different dose ranges for each drug. All three CCB classes increase coronary blood flow in a dose-dependent fashion. 4 Each group binds a different region of the calcium channel and has different affinities for calcium channels in various tissues. Verapamil is the most potent negative inotrope of all CCBs. At any concentration, it causes at least as much depression of heart contraction as it does vascular smooth muscle dilatation. 5 The combined cardiovascular effect may be one reason that verapamil overdose causes more deaths than all other CCBs combined.6 Dihydropyridines bind more selectively to vascular smooth muscle calcium channels than to cardiac calcium channels and therefore relax smooth muscle at concentrations producing almost no negative inotropy. The difference in the effects of these agents is the reason for preferential use of specific agents in particular clinical situations.

d more selectively to vascular smooth muscle calcium channels than to cardiac calcium channels and therefore relax smooth muscle at concentrations producing almost no negative inotropy. The difference in the effects of these agents is the reason for preferential use of specific agents in particular clinical situations. 7 The nondihydropyridines, verapamil and diltiazem, are used to manage hypertension, achieve rate control in atrial flutter and atrial fibrillation, and abolish supraventricular reentrant tachycardias. Dihydropyridines are typically used to treat diseases with increased peripheral vascular tone, such as hypertension, Prinzmetal’s angina, and vasospasm after subarachnoid hemorrhage. The original three CCBs—verapamil, nifedipine, and diltiazem—all have relatively short serum half-lives (Table 195-1). Consequently, CHAPTER Tintinalli_Sec15_p1187-1332.indd 1275 8/2/19 8:40 PM

th increased peripheral vascular tone, such as hypertension, Prinzmetal’s angina, and vasospasm after subarachnoid hemorrhage. The original three CCBs—verapamil, nifedipine, and diltiazem—all have relatively short serum half-lives (Table 195-1). Consequently, CHAPTER Tintinalli_Sec15_p1187-1332.indd 1275 8/2/19 8:40 PM 1276 SECTION 15: Toxicology extended-release (ER) formulations have been developed for all three. Because ER formulations prolong drug absorption, onset of effect may be delayed and toxicity may be prolonged following overdose. 8,9 Several of the newer dihydropyridines have prolonged duration of action and, therefore, are generally not formulated as ER products. Because newer formulations are released frequently, it is helpful to consult with the ED pharmacist or contact a regional poison control center for help in determining if a given product ingested in an overdose is formulated as an immediate-release (IR) or ER preparation. CLINICAL FEATURES The most prominent and life-threatening effects are an extension of the therapeutic effects on the cardiovascular system, particularly decreased cardiac output and peripheral vasodilation. Hypotension is the most common physiologic abnormality after overdose. 10,11 Patients with moderate verapamil or diltiazem (nondihydropyridines) poison ing often have sinus bradycardia, varying degrees of atrioventricular block, and hypotension. Atrioventricular block occurs more often with verapamil than with diltiazem or nifedipine. 12 Mild or moderate dihydropyridine overdoses usually cause peripheral vasodilatation with resultant hypotension and reflex tachycardia. 12 Like all CCBs, dihydropyridines lose their selectivity in large overdoses and may present with sinus bradycardia or normal rate in severe toxicity. All CCBs may cause complete heart block, depressed myocardial contractility, and vasodila tation that ultimately results in cardiovascular collapse. Pulmonary and CNS effects are generally secondary to decreased myocardial function and impaired organ perfusion. Cardiogenic pul monary edema is sometimes observed in severe overdoses, especially if large volumes of crystalloid are infused during resuscitation. Acute lung injury (noncardiogenic pulmonary edema) has also been reported. 13,14 Seizures, delirium, stroke, and coma have been described and are presumed to be secondary to cerebral hypoperfusion. Alteration in consciousness in the absence of hypotension should not be attributed to CCB toxicity; in such a scenario, evaluate for other causes of mental status alteration. Nausea and vomiting are common. 15 Life-threatening GI complications include bowel necrosis and ischemia, even without hypotension. ER products can cause development of bezoars. TABLE 195-1 Oral Calcium Channel Blockers Class Standard Preparation (IR) Half-Life (h) Maximum Adult Daily Dose (milligrams) Comments Nondihydropyridines     More cardioselective Phenylalkylamines Verapamil 2–5 480 for IR and ER Most potent negative inotrope of all CCBs Benzothiazepines Diltiazem 3–5 480 for IR and 540 for ER

5-1 Oral Calcium Channel Blockers Class Standard Preparation (IR) Half-Life (h) Maximum Adult Daily Dose (milligrams) Comments Nondihydropyridines     More cardioselective Phenylalkylamines Verapamil 2–5 480 for IR and ER Most potent negative inotrope of all CCBs Benzothiazepines Diltiazem 3–5 480 for IR and 540 for ER Dihydropyridines (most newer calcium channel blockers fall into this class) More selective for vasculature Nifedipine 2 180 for IR and 90 for ER

5-1 Oral Calcium Channel Blockers Class Standard Preparation (IR) Half-Life (h) Maximum Adult Daily Dose (milligrams) Comments Nondihydropyridines     More cardioselective Phenylalkylamines Verapamil 2–5 480 for IR and ER Most potent negative inotrope of all CCBs Benzothiazepines Diltiazem 3–5 480 for IR and 540 for ER Dihydropyridines (most newer calcium channel blockers fall into this class) More selective for vasculature Nifedipine 2 180 for IR and 90 for ER Amlodipine 30–50 10 Nicardipine 8–14 120 for IR and ER Felodipine 8 10 Isradipine   10 Nimodipine Early: 1–2; terminal: 8–9 Nisoldipine 7–12 34 Abbreviations: ER = extended release; IR = immediate release. TABLE 195-2 Differential Diagnosis of Bradycardia, Atrioventricular Block, and Hypotension •   Hypothermia •   Acute coronary syndrome •   Hyperkalemia •   Hypothyroidism •   Cardiac glycoside toxicity •   β-Blocker toxicity •   Antiarrhythmic drugs class IA and IC toxicity •   Central α2-adrenergic agonist (clonidine or tetrahydrozoline) toxicity •   Large overdoses of sedative-hypnotics and muscle relaxants DIAGNOSIS  POTENTIAL TOXICITY Adults receiving long-term therapy with CCBs can develop hypotension, bradycardia, or cardiac conduction abnormalities if they ingest as little as twice their regular daily dose. 16 It is hypothesized that patients receiving long-term CCB therapy have comorbidities and may be taking additional medications, such as other antihypertensives, that render these patients sensitive to adverse effects from relatively small increases over their usual CCB regimen. Children may be sensitive to CCB toxicity, and deaths have been reported after even single-tablet ingestion. 6,17 Therefore, all pediatric CCB ingestions should be referred for medical attention and observation. ER preparations complicate overdose management by delaying the onset of toxicity. IR CCBs generally display toxicity within 1 to 2 hours and up to 6 hours after ingenstion. 12 ER preparation may delay toxicity to 6 to 12 hours after ingestion, with reports up to 16 hours after ingestion. 8,12,15,18 It is therefore important to determine the exact formulation of the ingested agent to guide management decisions. If the history cannot identify the exact formulation, the clinician should assume it is ER and modify treatment conservatively. In addition to the exact formulation ingested, other important aspects in the history are the time of ingestion and the possibility of co-ingestants that may contribute to toxicity. ECG findings include sinus bradycardia, varying degrees of atrio ventricular block, and slowing of intraventricular conduction. Because dihydropyridines initially have greater effects on smooth muscle dilation then they do on myocardium, reflex tachycardia is commonly seen with low to moderate toxic ingestions of these agents. In contrast, significant overdoses of verapamil or diltiazem are frequently associated with junctional and ventricular escape rhythms. Laboratory testing and imaging are done to assess the overall metabolic state of the patient and to identify systemic complications of ingestion. Review all patient medications, and obtain digoxin levels if there is access to, or the patient is taking, digoxin. Determine if β-blockers are part of the patient’s therapy or are also ingested as part of the overdose. Hyperglycemia is often noted after CCB ingestion, which differentiates it from β-blocker ingestion, which typically results in euglycemia or sometimes hypoglycemia. CCBs inhibit calcium-mediated insulin secretion from the β islet cells in the pancreas, impeding the use of carbohydrates; CCBs also increase insulin resistance by unclear mechanisms. 19 Hyperglycemia in the setting of a CCB overdose is considered a poor prognostic indicator.20 Systemic hypoperfusion may cause a lactic acidosis with an elevated anion gap and low serum bicarbonate level. Hypokalemia may be observed in severe overdoses.

tes; CCBs also increase insulin resistance by unclear mechanisms. 19 Hyperglycemia in the setting of a CCB overdose is considered a poor prognostic indicator.20 Systemic hypoperfusion may cause a lactic acidosis with an elevated anion gap and low serum bicarbonate level. Hypokalemia may be observed in severe overdoses. Serum calcium levels are usually normal. Ionized serum calcium levels may be followed during treatment with IV calcium preparations, but the optimum serum calcium level for patients with severe CCB poisoning is unknown. CCB serum concentrations are not routinely available and are not used in management. Screen blood and urine for other potential toxins after suicidal overdose.  DIFFERENTIAL DIAGNOSIS A few conditions and other drug toxicities can produce bradycardia, atrioventricular block, and hypotension ( Table 195-2). Hypothermia should be detected during vital sign assessment. Myocardial infarction may be evident on the initial or subsequent ECG. Suspect hyperkalemia in patients with renal failure. Tintinalli_Sec15_p1187-1332.indd 1276 8/2/19 8:40 PM

s can produce bradycardia, atrioventricular block, and hypotension ( Table 195-2). Hypothermia should be detected during vital sign assessment. Myocardial infarction may be evident on the initial or subsequent ECG. Suspect hyperkalemia in patients with renal failure. Tintinalli_Sec15_p1187-1332.indd 1276 8/2/19 8:40 PM CHAPTER 195: Calcium Channel Blockers 1277 TABLE 195-3 General Treatment for Calcium Channel–Blocker Overdose * Treatment Comments Monitoring Initiate cardiopulmonary monitoring and obtain ECG. CBC; serum electrolytes and metabolic panel; magnesium, calcium, and phosphorus; VBG and serum lactate; glucose; digoxin level as indicated For all patients with potentially toxic overdose. Follow glucose levels. Naloxone If signs of opioid toxicity. Single-dose activated charcoal; protect airway If ingestion within 1 h and no vomiting or altered mental status; for children even if one tablet ingested. Multidose activated charcoal; protect airway For ER preparations. IV crystalloid for hypotension Overaggressive treatment can cause pulmonary edema. Endotracheal intubation Early intubation if altered mental status or hemody namic instability. Abbreviations: ER = extended release; VBG = venous blood gas. *See Figure 195-1 for treatment of severe toxicity. It may be difficult to distinguish CCB toxicity from cardiac glycoside toxicity; patients may be taking these drugs for the same indications and at the same time (see Chapter 193, “Digitalis Glycosides”). In general, patients with chronic digoxin poisoning have greater ventricular excitation, including rate and ectopy, than patients with CCB toxicity. In acute overdose, digoxin toxicity may be distinguished by hyperkalemia. However, because the main manifestations of acute cardiac glycoside poisoning are heart block and bradycardia, bedside differentiation may be difficult. Toxicity from β-adrenergic antagonists may be clinically indistinguishable from CCB toxicity (see Chapter 194, “Beta-Blockers”). In general, β-blocker toxicity is not as severe, and patients tend to have low to normal glucose and normal to elevated serum potassium levels. On physical exam, a patient with β-blocker toxicity may appear “cool and clammy” as compared to a patient with CCB toxicity who may be warmer with flushed skin (due to arteriolar vasodilation). However, these findings are not consistent enough to have reliable diagnostic value. Fortunately, the treatment for these two poisonings is similar, with calcium, adrenergic agonists, glucagon, insulin, and pacing considered useful therapy for both. TREATMENT Begin resuscitation, obtain an ECG, and institute cardiopulmonary monitoring ( Table 195-3). Evaluate all patients, especially those with altered mental status, for hypoglycemia and opioid toxicity. Decreased level of consciousness following CCB ingestion is a result of cerebral hypoperfusion or co-ingestion. Administer oral activated charcoal if within 1 hour of ingestion of IR and ER preparations, provided patient can protect his or her airway, or intubate as needed as mental status deteriorates. Provide early airway management in patients with mental status change or hemodynamic instability. 2 Endotracheal intubation may minimize the risk of aspiration associated with GI decontamination. Vomiting is not just associated with decontamination; glucagon administration may also precipitate vomiting. Following airway management, provide cardiovascular stabilization. Give IV crystalloids for hypotension, but overaggressive fluid admin istration may produce or worsen pulmonary edema.

d with GI decontamination. Vomiting is not just associated with decontamination; glucagon administration may also precipitate vomiting. Following airway management, provide cardiovascular stabilization. Give IV crystalloids for hypotension, but overaggressive fluid admin istration may produce or worsen pulmonary edema. The goal of treat ing bradycardia is to increase end-organ perfusion rather than restore a specific heart rate; some patients with heart rates of 30 to 40 beats/ min can maintain adequate blood pressure and perfusion and therefore require only monitoring. Conversely, patients may respond to cardiac pacing with an increase in heart rate to 90 to 100 beats/min without improvement in blood pressure or perfusion; they may require addi tional therapy to improve inotropy. Therapies to increase heart rate include medications and cardiac pacing. Atropine alone is rarely effective for CCB-induced bradycardia, but administration is commonly recommended. 12 Calcium salts may improve both heart rate and blood pressure, but the response is variable. Transvenous or transcutaneous pacing is indicated for hypotensive patients with severe bradycardia (heart rate <30 beats/min), and may improve rate but may not correct hypotension. Persistent hypotension after infusion of crystalloids, administration of calcium salts, and treatment of bradycardia should be treated with adrenergic vasopressors, high-dose insulin (HDI), or both. Recommendations for HDI and additional therapies are based on animal data and human case reports or series, with the caution that case reports often document the use of multiple therapies simultaneously. 21-23 In critically ill patients, it is helpful to have early consultation with a toxicologist or the poison control center to assist with the administration of infrequently used treatments.  GI DECONTAMINATION Activated Charcoal Given the lethality of CCBs and lack of an effec tive antidote, perform GI decontamination with activated charcoal. CCBs bind well to activated charcoal, and activated charcoal should be given to adults following any potentially significant IR or ER exposure, especially if presentation is within an hour of ingestion. 24 Give activated charcoal after accidental ingestion of verapamil in children, because life-threatening toxicity has occurred from a single tablet. Give multipledose activated charcoal after ingestion of an ER preparation. Ipecac Ipecac syrup to induce emesis is not recommended.24 Gastric Lavage Routine gastric lavage is not recommended because risks outweigh benefits. Late gastric lavage is recommended by some toxicologists for a patient who presents within an hour of ingesting an amount significantly in excess of toxic exposure or for any patient who requires intubation after CCB ingestion. Whole-Bowel Irrigation Given the potential for severe toxicity, consider whole-bowel irrigation (WBI) with polyethylene glycol for patients with large ingestions of ER products. 18 A large amount of medication may be removed through WBI. Monitor closely, because complications from WBI may contribute to hemodynamic instability.  CALCIUM SALTS Exogenous calcium increases the extracellular calcium concentration and increases the transcellular gradient, driving calcium intracellularly through unblocked calcium channels. Administration of calcium salts has improved blood pressure in animal models and in human case reports of CCB toxicity. 18,26-29 However, the effects are variable, and patients with significant toxicity may not respond to calcium therapy alone. Calcium chloride (13.6 mEq per 1-gram ampule) is preferred to cal cium gluconate (4.5 mEq per 1-gram ampule) because it provides triple the amount of calcium per volume.

reports of CCB toxicity. 18,26-29 However, the effects are variable, and patients with significant toxicity may not respond to calcium therapy alone. Calcium chloride (13.6 mEq per 1-gram ampule) is preferred to cal cium gluconate (4.5 mEq per 1-gram ampule) because it provides triple the amount of calcium per volume. Use a central line for infusion of calcium chloride to avoid soft tissue necrosis that can be associated with extravasation. The dose of calcium chloride is a 1-gram (10 mL of 10% solution) IV bolus over 5 minutes in adults (pediatric dose is 15 milli grams/kg or 0.15 mL/kg of the 10% solution). Calcium gluconate can be given at three times this amount. The effects of calcium administration may be transient, and repeat dosing up to every 10 to 20 minutes is commonly required. Alternatively, a continuous infusion of calcium chloride 2 to 6 grams/h may also be used in adults (pediatric dose is 10 to 40 milligrams/kg per hour). Measure ionized serum calcium levels every 30 minutes after the initial infusion is started and every 1 to 2 hours thereafter. A calcium concentration goal of approximately 1.5 to 2 times normal should be achieved. However, for patients who do not respond to other therapies, it is reasonable to continue calcium administration even when serum calcium levels are considerably elevated. An acceptable level for hypercalcemia has not been defined. Published case reports of CCB poisoning describe survival following administra tion of 30 grams of calcium chloride over 12 hours resulting in a serum calcium level of 23 milligrams/dL (5.94 mmol/L) 18 and death from iatrogenic hypercalcemia with a serum calcium level of 32.3 milligrams/dL (8.07 mmol/L). 30 A safe but effective dose of calcium salts to use in the treatment of CCB toxicity is unclear. If repeat dosing or continu ous infusions are used, hypercalcemia and/or hypophosphatemia can occur. Although monitoring of serum ionized calcium and phosphorus concentrations during repeated or prolonged calcium therapy is recommended, it is unclear if such electrolyte abnormalities have clinical Tintinalli_Sec15_p1187-1332.indd 1277 8/2/19 8:40 PM

infusions are used, hypercalcemia and/or hypophosphatemia can occur. Although monitoring of serum ionized calcium and phosphorus concentrations during repeated or prolonged calcium therapy is recommended, it is unclear if such electrolyte abnormalities have clinical Tintinalli_Sec15_p1187-1332.indd 1277 8/2/19 8:40 PM 1278 SECTION 15: Toxicology consequence or should be treated. Consultation with toxicology can assist with this management.  ADRENERGIC AGENTS Patients who do not respond to calcium administration or who require repeated doses require adrenergic agonists, typically epi nephrine or norepinephrine, titrated to a mean arterial pressure of 65 mm Hg (Figure 195-1). 21-23 No single adrenergic vasopressor is consistently effective. A response may occur with dopamine, epinephrine, norepinephrine, vasopressin, dobutamine, or isoproterenol. 31-33 Patients with decreased contractility and peripheral vasodilatation, especially in the face of relative bradycardia, may benefit from an agent with both α- and β-agonist effects, such as epinephrine or norepinephrine (Figure 195-1). Methylene blue, a nitric oxide scavenger and guanylate cyclase inhibitor used for vasople gia, and phosphodiesterase inhibitors such as amrinone, milrinone, and enoximone have been reported to improve blood pressure in animal studies and human case reports. 34-39 When standard doses are inadequate, it is reasonable to use high doses or multiple agents titrated to achieve a mean arterial blood pres sure of 65 mm Hg, although there is risk of ischemic complications. 33 Alternatively, another approach, such as HDI, glucagon, or lipid emul sion, can be considered.  HIGH-DOSE INSULIN THERAPY HDI is a promising treatment for the myocardial suppression associated with CCB poisoning. 40-47 Potential mechanisms of action include positive inotropic effects of insulin, increased calcium entry, and improved myocardial use of carbohydrates as an energy source. 19 Insulin increases intracellular transport of glucose into cardiac and skeletal muscle and has inotropic properties. 42 There are no clinical trials comparing HDI therapy directly to other treatments, but multiple human case reports show that HDI improves perfusion in CCB poisoning unresponsive to other therapies, with a therapeutic response noted within 15 to 30 minutes. 42-48 The FIGURE 195-1. Treatment algorithm for severe toxicity. After giving fluids and calcium, if inadequate response, give glucagon for hypotension. Give atropine and institute cardiac pacing for bradycardia. Consider pretreatment with an antiemetic when giving glucagon. When a patient is refractory to these treatments, high-dose insulin (HDI) and vasopressors are the next treatments recommended. HDI can be given in lieu of vasopressors; however, the recommendation is to give in concert with vasopressors because HDI response takes 15 to 30 minutes. Once there is a response, wean vasopressors first. Extracorporeal membrane oxygenation (ECMO) or lipid emulsion therapy is usually warranted if the previous modalities fail, with the authors’ preference being ECMO. If patient is to start ECMO, discuss the use of lipids with managing team before starting. If patient is not at an ECMO facility and patient cannot be transferred, lipid emulsion therapy can be started. See also Table 195-4. Crystalloids IV 20 mL/kg (may repeat) Calcium IV: calcium gluconate (30 mL 10%) or calcium chloride (10 mL 10%) (may repeat 3 times) Glucagon IV 5 milligrams if bradycardic (may repeat) May also try atropine 0.5 milligram IV and pacing Insulin 1 unit/kg followed by 1 unit/kg per hour infusion (titrate to 10 units/kg per hour).

oids IV 20 mL/kg (may repeat) Calcium IV: calcium gluconate (30 mL 10%) or calcium chloride (10 mL 10%) (may repeat 3 times) Glucagon IV 5 milligrams if bradycardic (may repeat) May also try atropine 0.5 milligram IV and pacing Insulin 1 unit/kg followed by 1 unit/kg per hour infusion (titrate to 10 units/kg per hour). Dextrose 50% 50 mL bolus (if serum glucose < 200 milligrams/dL) followed by infusion of D10W 200 mL/h Epinephrine or norepinephrine 1–5 micrograms/min (titrate to effect) Lipid emulsion 20% 1.5 mL IV bolus (may repeat) followed by 0.25 mL/kg per minute infusion Extracorporeal blood pressure support TABLE 195-4 Protocol for High-Dose Insulin Therapy in Severe Calcium Channel 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 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 insulin infusion rate up to 10 units/kg per hour according 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. main adverse effect is potential hypoglycemia, which is easily detected with point-of-care glucose testing and treated with dextrose. Hypokale mia is also seen from intracellular potassium shifts. Replace potassium if potassium falls to <2.8 mEq/L (<2.8 mmol/L). Given benefit seen in animal models and clinical reports, begin HDI for hypotensive patients, especially if they do not respond to vasopressor therapy (Figure 195-1). Doses of insulin used for HDI are greater than those for diabetic treatment (Table 195-4). 49 An initial insulin bolus is followed by a continu ous infusion along with a dextrose infusion to prevent hypoglycemia (Table 195-4). Although traditional infusion doses were started at 1 unit/kg per hour, several protocols use a higher dose of up to 10 units/kg per hour, which is considered high-dose therapy. 50,51 A recent randomized Tintinalli_Sec15_p1187-1332.indd 1278 8/2/19 8:40 PM