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All patients with suspected CCB poisoning should undergo prompt evaluation even when the initial vital signs are normal. This urgency is due to the potential to initiate early GI decontamination and pharmacologic therapies before patients manifest severe poisoning. This is particularly important with ingestions involving sustained-release formulations. Intravenous access should be obtained and initial treatment should be directed toward aggressive GI decontamination of patients with large recent ingestions. All patients who become hypotensive should receive a fluid bolus of 10 to 20 mL/kg of crystalloid which should be repeated as needed. Caution is required, as aggressive fluid resuscitation should not be given to patients with congestive heart failure, evidence of ARDS, or chronic kidney disease (CKD).
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Pharmacotherapy should focus on maintenance or improvement of both cardiac output and peripheral vascular tone. Although atropine, calcium, insulin, glucagon, isoproterenol, dopamine, epinephrine, norepinephrine, and phosphodiesterase inhibitors have been used with reported success in CCB-poisoned patients, no single intervention has consistently demonstrated efficacy. It is also important to be aware that certain treatment such as vasopressors may be detrimental with long-term use, so these should be avoided when there are more effective and safer treatment options.
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Although therapy for hypotension and bradycardia should begin with crystalloids and atropine, most critically poisoned patients will not respond to these initial efforts and will require further pharmacotherapy. While it would be ideal to initiate each therapy individually and monitor the patient’s hemodynamic response, in the most critically ill patients, multiple therapies should be administered simultaneously. A reasonable treatment sequence based on existing data and clinical experience should initially consist of isotonic fluids, atropine, glucagon, and calcium. If the patient does not respond to these initial treatments, hyperinsulinemia-euglycemic therapy should be initiated. In cases of refractory shock or in cardiac arrest, the use of 20% intravenous fat emulsion should be considered. The use of vasopressors such as norepinephrine or dopamine can result in tissue ischemia with long-term use and thus should be avoided. Phosphodiesterase inhibitors such as inamrinone, milrinone, and enoximone have been used to treat CCB poisoning.54,82,103 These xenobiotics inhibit the breakdown of cAMP by phosphodiesterase, thereby increasing intracellular cAMP concentrations, resulting in increased cardiac output. Despite some reported success, phosphodiesterase inhibitors are not readily available, and there are other xenobiotics that are more effective and easier to utilize (Fig. 61–2).
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Gastrointestinal Decontamination
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Because CCB poisoning is a leading cause of poisoning fatality, attempts to prevent absorption from the GI tract should be strongly considered, assuming there are no contraindications for the described techniques below. This is particularly important if sustained-release CCBs are suspected. Patients who present early with minimal or no symptoms can have delayed cardiovascular toxicity, which can be profound and refractory to conventional treatment, making early GI decontamination a cornerstone in CCB management.
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Induced emesis is contraindicated because CCB-poisoned patients can rapidly deteriorate. Orogastric lavage should be considered for all patients who present early (1–2 hours postingestion) after large ingestions and for those who are critically ill and require immediate endotracheal intubation. Although the effects of orogastric lavage following overdose of a sustained-release CCB have not been specifically studied, given the toxicity of CCB poisoning, orogastric lavage should still be strongly considered. When performing orogastric lavage in a CCB-poisoned patient, it is important to remember that lavage may increase vagal tone and potentially exacerbate any bradydysrhythmias.94 Pretreatment with a therapeutic dose of atropine may therefore be desirable.
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All patients with CCB ingestions should receive 1 g/kg of activated charcoal orally or via nasogastric tube as long as the airway is stable or protected. Multiple-dose activated charcoal (MDAC) (0.5 g/kg every 4–6 hours) without a cathartic should be administered for nearly all patients with either sustained-release pill ingestions or signs of continuing absorption. Although data are limited, there is no evidence that MDAC increases CCB clearance from the serum.79 Rather, its efficacy may be a result of the continuous presence of activated charcoal throughout the GI tract, which adsorbs any active xenobiotic from its slow-release formulation. MDAC should not be administered to a patient with inadequate GI function (eg, hypotension, diminished peristaltism sounds (Antidotes in Depth: A1).
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WBI with polyethylene glycol solution (1–2 L/h orally or via nasogastric tube in adults, up to 500 mL/h in children) should be initiated for patients who ingest sustained-release products and for whom there are no contraindications.15 Administration should be continued until the rectal effluent is clear (Antidotes in Depth: A2).
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Atropine is often first-line medication for patients with symptomatic bradycardia from xenobiotic poisoning such as organic phosphorus compounds, β-adrenergic antagonists, and calcium channel blockers. While the use of atropine improved both heart rate and cardiac output in an early dog model of verapamil poisoning and a few patients with bradycardia from CCB poisoning,30,77 reports of patients with severe CCB poisoning demonstrate atropine to be largely ineffective.45,74,89 The decreased effectiveness may be largely due to the negative inotropic effects and/or peripheral vasodilation of CCBs. Given its availability, familiarity, efficacy in mild poisonings, and safety profile, atropine should be considered as initial therapy in patients with symptomatic bradycardia.
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The dosing of atropine for xenobiotic induced bradycardia is similar to the dose used for Advanced Cardiac Life Support. Dosing should begin with 0.5 to 1.0 mg (minimum of 0.1 mg; 0.02 mg/kg in children) intravenously every 2 or 3 minutes up to a maximum dose of 3 mg in all patients with symptomatic bradycardia. However, treatment failures should be anticipated in severely poisoned patients. In patients in whom whole-bowel irrigation (WBI) or MDAC will be used, the use of atropine must be carefully considered, weighing the potential benefits of improved heart rate, and thus cardiac output, against the anticholinergic effects with potential decreased GI motility.
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Ca2+ is another treatment often utilized for CCB poisoning to increase in extracellular Ca2+ concentration with an increase in transmembrane concentration gradient. Pretreatment with intravenous Ca2+ prevents hypotension without diminishing the antidysrhythmic efficacy prior to therapeutic verapamil use in reentrant supraventricular tachydysrhythmias.22,88 This also is observed with CCB poisoning where Ca2+ tends to improve blood pressure more than heart rate. Experimental models have also demonstrated the utility of Ca2+ salts with CCB poisoning. In verapamil-poisoned dogs, improvement in inotropy and blood pressure was demonstrated after increasing the serum Ca2+ concentration by 2 mEq/L with an intravenous infusion of 10% calcium chloride (CaCl2) at 3 mg/kg/min.30,36
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Clinical experience demonstrates that Ca2+ reverses the negative inotropy, impaired conduction, and hypotension in many humans poisoned by CCBs.56,60,79 Unfortunately, this effect is often short lived, and more severely poisoned patients may not improve significantly with Ca2+ administration alone.18,45,83 Although some authors believe that these failures might represent inadequate dosing, optimal effective dosing of Ca2+ is unclear and they recommend repeat doses of Ca2+ to markedly increase the serum ionized Ca2+ concentrations.42,56 The excessive use of Ca2+ can result in significant complications, particularly if a Ca2+ infusion is used.87 Caution should be exercised in the administration of Ca2+ in patients who may have suspected acute cardioactive steroid poisoning as a cause of their bradycardia.14 The use of Ca2+ in the setting of cardioactive steroid poisoning may result in cardiac complications such as asystole (Chap. 65).
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Recommendations for poisoned adults include an initial intravenous infusion of approximately 13 to 25 mEq of Ca2+ (10–20 mL of 10% CaCl2 or 30–60 mL of 10% Ca2+ gluconate) followed by either repeat boluses every 15 to 20 minutes up to three to four doses or a continuous infusion of 0.5 mEq/kg/h of Ca2+ (0.2–0.4 mL/kg/h of 10% CaCl2 chloride or 0.6–1.2 mL/kg/h of 10% Ca2+ gluconate) (Antidotes in Depth: A29). Careful selection and attention to the type of Ca2+ used is critical for dosing. Although there is no difference in efficacy of CaCl2 or calcium gluconate, 1 g of CaCl2 contains 13.4 mEq of Ca2+, which is about three times the 4.65 mEq found in 1 g of calcium gluconate. Thus, in order to administer equal doses of Ca2+, three times the volume of calcium gluconate compared with that of CaCl2 is required. The main limitation of using CaCl2, however, is that it has significant potential for causing tissue injury if extravasated, so administration should ideally be via central venous access. Adverse effects of intravenous Ca2+ include nausea, vomiting, flushing, constipation, confusion, hypercalcemia, and hypophosphatemia.
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Glucagon is an endogenous polypeptide hormone secreted by the pancreatic alpha-cells in response to hypoglycemia and catecholamines. In addition, it has significant inotropic and chronotropic effects (Antidotes in Depth: A18).17,92,108 Glucagon is a therapy of choice for β-adrenergic antagonist poisoning (Chap. 62) because of its ability to bypass the β-adrenergic receptor and activate adenylate cyclase via a Gs protein in the myocardium.105 Thus, glucagon is unique in that it is functionally a “pure” β1 agonist, with no peripheral vasodilatory effects (Fig. 61–2). There are reports of both successes and failures of glucagon in CCB-poisoned patients who failed to respond to fluids, Ca2+, or dopamine and dobutamine.19,23,37,45
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Dosing for glucagon is not well established.6 An initial dose of 3 to 5 mg IV, slowly over 1 to 2 minutes, is reasonable in adults, and if there is no hemodynamic improvement within 5 minutes, retreatment with a dose of 4 to 10 mg may be effective. The initial pediatric dose is 50 μg/kg. Because of the short half-life of glucagon, repeat doses may be useful. A maintenance infusion should be initiated once a desired effect is achieved. Adverse effects include vomiting and hyperglycemia, particularly in diabetics or during continuous infusion. In addition, patients who receive repeat administration develop tachyphylaxis, which is an acute decrease in response to a drug after repeated administration.
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Insulin-Euglycemia Therapy
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Insulin-euglycemia or high-dose insulin-euglycemia (HIE) therapy has become the treatment of choice for patients who are severely poisoned by CCBs. Healthy myocardial tissue relies predominantly on free fatty acids for its metabolic needs, and CCB poisoning forces it to become more carbohydrate dependent.49,50,52,53 At the same time, CCBs inhibit Ca2+-mediated insulin secretion from the β-islet cells in the pancreas, making glucose uptake in myocardial cells dependent on passive diffusion down a concentration gradient rather than insulin-mediated active transport.20 In addition, there is evidence that the CCB-poisoned myocardium also becomes insulin resistant, possibly by dysregulation of the phosphatidylinositol 3 kinase pathway (Antidotes in Depth: A17). This may prevent normal recruitment of insulin-responsive glucose transporter proteins. The combination of inhibited insulin secretion and impaired glucose utilization may explain why severe CCB toxicity often produces significant hyperglycemia.51,52
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Many CCB-poisoned patients have been successfully treated with HIE therapy as demonstrated by improved hemodynamic function, mainly resulting from improved contractility, with little effect on heart rate. There are also reports of the failure of this treatment, but this may represent initiation of therapy in terminally ill patients with multiple organ failure.28,45
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Although the dose of insulin is not definitively established, therapy typically begins with a bolus of 1 unit/kg of regular human insulin along with 0.5 g/kg of dextrose. If blood glucose is greater than 300 mg/dL (16.65 mmol/L), the dextrose bolus is unnecessary. An infusion of regular insulin should follow the bolus starting at 1.0 units/kg/h titrated up to 2 units/kg/h if no improvement after 30 minutes. Some authors advocate the use of even higher doses (10 units/kg) of insulin.25 A continuous dextrose infusion, beginning at 0.5 g/kg/h, should also be started. Glucose should be monitored every 30 minutes for the first 4 hours and titrated to maintain euglycemia. The response to insulin is typically delayed for 15 to 60 minutes, so the use of HIE should be considered very early in the patient’s course if severe CCB poisoning is suspected. Primary complications of HIE include hypoglycemia and hypokalemia from intracellular shifting of potassium. It is essential to note that the development of hypoglycemia is an indication to increase glucose delivery rather than decrease the insulin infusion rate.
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Intravenous Fat Emulsion
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Intravenous fat emulsion (IFE) has been used as a source of parenteral nutrition and as a diluent for intravenous drug delivery of highly lipophilic medications such as propofol and liposomal amphotericin.24 The use of IFE as an antidote is most extensively studied for the treatment of local anesthetic toxicity, specifically from bupivacaine, but has been utilized in overdoses from other lipophilic drugs such as psychiatric medication, calcium channel blockers, and β-adrenergic antagonists.
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IFE is a white, milky liquid composed of two types of lipids, triglycerides and phospholipids. It is sterile and nonpyrogenic with a pH of about 8 (range, 6–9). IFEs are isotonic solutions (260–310 mOsm/L) and are available in 5%, 10%, 20%, and 30% solutions.97 There are three proposed mechanisms of action for IFE: activation of ion channels (calcium); enhancement of intracellular metabolism95; and acting as a lipid sink to sequester lipid-soluble drugs. The latter mechanism is the most likely explanation based on existing literature.
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An important property of medications that may determine the effectiveness of IFE is lipophilicity. Lipophilicity means the tendency of a drug to partition between lipophilic organic phase and the polar aqueous phase, and value of lipophilicity most commonly refers to logarithm of partition coefficient P (logP) between these two phases. For ionizable compounds, the partition is changed as a function of pH; this relationship is called a distribution constant (logD) or sometimes also as an apparent partition coefficient. Drugs that are highly lipophilic may benefit more from the use of IFE in severe poisoning. Table 61–3 lists major CCBs with their logD and logP values.
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Existing experimental evidence supports that IFE decreases the toxicity of a few lipid-soluble drugs, most notably bupivacaine.100,101 Pretreatment with IFE also increased the dose of certain medications to cause toxicity.102 Other models suggest that IFE is an effective therapy for CCB-poisoned patients. In a controlled study of rodents that were poisoned with verapamil, the use of IFE resulted in both increased survival and heart rate when compared to the control groups.9,70,93 IFE was also used on a patient with severe verapamil poisoning who failed Ca2+ and HIE but when given IFE showed improvement and survival. Serum verapamil concentrations were measured before and after IFE treatment. There was a decrease in verapamil after IFE administration once the lipid was removed from the samples, which demonstrate sequestration of verapamil28 (Antidotes in Depth: A20).
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The recommended dose of IFE is a 1.5 mL/kg bolus. The bolus can be repeated several times for persistent asystole followed by an infusion of 0.25 mL/kg/min or 15 mL/kg/h to run for 30 to 60 minutes. IFE has only traditionally been given to patients in extremis from an overdose, but at this time IFE should be considered in patients who are persistently unstable despite the use of other therapies such as HIE.
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Adjunctive Pharmacologic Treatment
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Other pharmacotherapies have been studied in the setting of CCB poisoning. There are limited data with these therapies, and they should be considered only when all of the above treatments have failed. Digoxin has been experimentally evaluated in CCB poisoning since it raises the intracellular Ca2+ concentration.7,8 In a canine model of verapamil poisoning, digoxin, in conjunction with atropine or Ca2+, improved both systolic blood pressure and myocardial inotropy.7 However, because digoxin requires a significant amount of time to distribute into tissue, and because limited efficacy data and no safety data have yet been collected, more evaluation is needed before digoxin is administered to patients with CCB poisoning. Another xenobiotic that has been utilized as a treatment for CCB poisoning is levosimendan. Levosimendan is a Ca2+ sensitizer used in the management of acutely decompensated congestive heart failure. While there are reported cases of success with the use of this drug, there is also existing experimental evidence that does not support its use.2,68,96
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Most recently, methylene blue was reported in a confirmed ingestion of amlodipine poisoning in a patient that failed conventional therapy, including HIE treatment. A Swan-Ganz catheter confirmed pure vasodilatory shock, which responded to methylene blue (2 mg/kg).45 Methylene blue is also reported with success in a case of a mixed β-blocker and CCB overdose,4 and it is used in other states of refractory vasodilatory shock such as anaphylaxis and sepsis due to inhibition of methylene blue along the nitric oxide–cyclic guanosine monophosphate pathway. There is some evidence to suggest certain dihydropyridines such as amlodipine mediate its vasodilatory effects via nitric oxide, but the importance of this pathway in acute poisoning is unclear. Further investigation is required before methylene blue can routinely be recommended in patients with CCB poisoning.
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Inotropes and Vasopressors
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Catecholamines are often administered once first-line therapy such as atropine, Ca2+, glucagon, and isotonic fluids fail. There are numerous cases that describe either success or failure with various agents, including epinephrine, norepinephrine, dopamine, isoproterenol, dobutamine, and vasopressin.18,37,41,61 Based on experimental and clinical data, no single xenobiotic is consistently effective. The variability in response is from the differences of CCB involved, coingestants with other cardioactive medications, and patient response. CCB poisoning may involve the myocardium (verapamil and diltiazem) mediated by β1-adrenergic receptors, resulting in negative chronotrophy/inotrophy and/or peripheral smooth muscle relaxation (dihydropyridines) with vasodilation mediated by α1-adrenergic receptors. Despite variable success in CCB poisoning, the existing data described previously show that all vasopressors are generally inferior with significantly more adverse effects such as tissue ischemia with long-term use.
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Adjunctive Hemodynamic Support
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The most severely CCB-poisoned patients may not respond to any pharmacologic intervention. Transthoracic or intravenous cardiac pacing may be required to improve heart rate, as several case reports demonstrate.89,99 However, in a prospective cohort of CCB poisonings, two of four patients with significant bradycardia requiring electrical pacing had no electrical capture.77 In addition, even if electrical pacing is effective in increasing the heart rate, blood pressure often remains unchanged.40,41
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Intraaortic balloon counterpulsation is another invasive supportive option to be considered in CCB poisoning refractory to pharmacologic therapy.47 Intraaortic balloon counterpulsation was used successfully to improve cardiac output and blood pressure in a patient with a mixed verapamil and atenolol overdose.29
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Severely CCB-poisoned patients have also been supported for days and subsequently recovered fully with much more invasive and technologically demanding extracorporeal membrane oxygenation (ECMO) and emergent open and percutaneous cardiopulmonary bypass.40,80 The major limitation of all these technologies, however, is that they are available only at tertiary care facilities.
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Molecular adsorbents recirculating system (MARS) therapy is a specific extracorporeal albumin dialysis that is reported in the treatment of severe CCB poisoning. MARS therapy has the unique ability to selectively remove from circulation protein-bound xenobiotics that are not cleared by conventional hemodialysis. The use of MARS therapy is under current investigation with Amanita poisoning but reportedly was successfully utilized in three patients with severe nondihydropyridine CCB poisoning.72