Management of CCB Overdoses

GI Decontamination

In cases of severe overdose, patients may present with lethargy from hypotension and poor cerebral flow, and the risk for aspiration and pneumonitis should be strongly considered in these patients if GI decontamination is considered. GI decontamination is best in cases where the patient is hemodynamically stable and presents early to the emergency department (ED), preferably within 2 hours[7, 9]; early use might decrease drug absorption and enterohepatic circulation, thus lowering the drug levels.[16] However, in cases in which the drug consumed was an extended‐release preparation, GI decontamination is beneficial even when the patient presents late to the ED.[17] GI decontamination is typically achieved using activated charcoal (1 g/kg body weight) or by performing whole bowel irrigation (WBI) with polyethylene glycol.[9] However, there is very little evidence that either approach changes the overall outcome, and WBI can be potentially harmful for patients with hemodynamic instability.[18] Therefore, airway and circulation maintenance is preferable to this approach.

Catecholamines

Catecholamines, such as dopamine, dobutamine, and norepinephrine, appear to be obvious choices in the management of cases of CCB overdose, because most patients present with hypotension and bradyarrhythmias.[19] However, there is no evidence to show the superiority of 1 agent over another in the management of CCB drug toxicity. Catecholamines increase the heart rate and blood pressure and increase systemic vascular resistance, which can potentially decrease the cardiac output by increasing the afterload.

Calcium Salts

In cases of severe overdose, the initial measures are typically not sufficient for stabilizing the patient. Intravenous (IV) calcium salts have been evaluated in animal models[20, 21] and, anecdotally, in human case reports.[22, 23, 24] However, the response to treatment has been mixed, with improvement in hemodynamic parameters in some cases and treatment failures in other cases. Moreover, the effects of these treatments are typically short lived, and repeated dosing might be required. Calcium salts are typically administered with the theoretical scheme of reversing antagonism with a higher calcium load and increasing cardiac inotropy. Calcium gluconate and calcium chloride are 2 frequently used agents, although no clear guidelines exist regarding this approach and the required dosage.[22] There are also published case reports in which refractory hypotension was treated with continuous calcium infusion in an attempt to reach predefined serum calcium levels.[24] However, the fear of iatrogenic hypercalcemia and its consequences is constant.[25] Calcium chloride contains 3 times the calcium for the identical volume compared to calcium gluconate and is more corrosive to the blood vessels; therefore, it is best administered through a central intravenous access. Although the evidence is limited to a few case reports, continuous calcium infusion appears effective and safe as an adjunctive therapy for patients with severe hypotension resulting from CCB overdose.[21, 22, 23, 24, 26]

Glucagon

Although insulin and glucagon are physiologically counter‐regulatory, they have a similar effect on heart stimulation. In animal models, the positive inotropic and chronotropic effects of glucagon have been clearly demonstrated.[27] Glucagon increases intracellular cyclic adenosine monophosphate (AMP) by stimulating adenylyl cyclase, a mechanism by which glucagon possibly exerts its inotropic effect.[7] Most studies conducted on the use of glucagon in the treatment of CCB overdose originated in an era in which bovine or porcine glucagon was used, and these animal glucagon products contained insulin.[9] Glucagon is typically initiated at 50 to 150 g/kg as bolus dosing, with a repeat dosing after 3 to 5 minutes.[9] A continuous IV infusion can then be administered following the initial treatment, because glucagon has a very short half‐life and works rapidly.[7, 9] However, there is no established maximum infusion dose of glucagon, and it should be titrated to the desired clinical outcome. IV glucagon therapy also carries a risk for nausea and vomiting,[7, 28] which in combination with lethargy may increase the risk for aspiration pneumonitis. The evidence for the use of glucagon in cases of CCB overdose is predominantly based on animal models[27]; evidence in human subjects is limited to case reports.[11, 28, 29] Some cases have demonstrated an improvement in hemodynamics with glucagon, whereas in a few cases, glucagon failed to result in such improvement.[30] In cases in which the ingestion history is unclear or there is polysubstance ingestion, as with ‐blockers and CCBs, glucagon is an ideal treatment agent[9]; in contrast, in single CCB overdose, glucagon might not be as helpful as more recent treatment modalities.

Hyperinsulinemia‐Euglycemia Therapy

In recent years, increasing evidence from multiple case reports and case series has shown the superiority of high‐dose insulin therapy over other treatment modalities (Table 3). Insulin acts as a potent inotrope[31, 32] and vasodilator. In their prospective observational series of 7 patients, Greene et al. report the successful use of hyperinsulinemia‐euglycemia therapy (HIET) with no significant adverse events when combined with conventional measures in a critical‐care setting.[33] Similarly, more than 50 cases have been reported in which HIET was used successfully in the management of CCB overdoses.[34]

Although there is wide variation in the insulin dosing regimens in published case reports, hyperinsulinemia therapy is typically initiated with a 0.5 IU/kg to 1 IU/kg bolus, followed by a continuous drip of 0.5 UI/kg per hour to 1 IU/kg per hour. This dose is titrated every 15 to 20 minutes until satisfactory hemodynamic and clinical stability is noted. Titrations are usually avoided for a shorter time interval because insulin must enter cells and initiate intracellular signaling and metabolic activation. However, the response to HIET might be delayed, and other therapeutic modalities could be required simultaneously until the clinical effects of insulin are observed.

Euglycemia should be maintained by checking the blood glucose levels every 30 minutes and using a dextrose solution to maintain the blood glucose within the upper limits of normal.[35] Hyperglycemia noted in CCB overdose cases indicates the degree of insulin resistance and serves as a marker of the severity of the overdose.[14, 15] In particular, patients who are hyperglycemic at presentation may not require supplemental dextrose infusion despite the high‐dose insulin therapy. The blood glucose level should be checked every 30 minutes for the first 4 hours and then hourly to avoid overlooking hypoglycemia during the treatment regimen, especially in intubated and sedated patients. Fluids containing dextrose may be initiated at 0.5 to 1 g/kg per hour and titrated to maintain euglycemia.[9, 11]

However, there is no consensus as to how long the infusion should be continued once initiated. Although insulin has not been shown to induce tachyphylaxis in experimental animal models, many clinicians prefer to discontinue the infusion once hemodynamic stability has been achieved. There is also no evidence indicating whether a weaning protocol would make any difference over abrupt discontinuation.[36] The physiological effects of insulin persist for hours after the discontinuation of the infusion and will gradually taper down with time. Therefore, theoretically, an abrupt cessation should seldom cause any deleterious effects.[11] Dextrose supplementation may be required to maintain euglycemia for up to 24 hours following discontinuation of the insulin drip due to the elevated insulin levels.[11, 36]

Insulin is a potent vasodilator in the coronary and pulmonary vasculature but does not increase the requirement for myocardial oxygen. Instead, insulin facilitates endothelial nitric oxide activity through the phosphoinositide 3‐kinase (PI3K) pathway, which translates into vasodilatation of the capillary microvasculature and better perfusion at the capillary junction. As a result, insulin corrects the capillary dysfunction that is the major pathology in cardiogenic shock and the ultimate presentation in severe CCB overdose.

Gradinac et al. reported that patients with cardiogenic shock, in the postoperative period of coronary artery bypass grafting, showed a better cardiac index with the use of IV insulin therapy.[37] In an experiment on explanted human myocardium, von Lewinski et al. demonstrated the positive inotropic effect of insulin through calcium‐dependent pathways as well as PI3K pathways.[38] Moreover, Hsu et al. demonstrated with human myocardial cells that this inotropic property of insulin was dose dependent, with better responses observed after the use of higher doses of insulin; in addition, this effect was rapid (ie, as fast as 5 minutes after the infusion) and was sustained throughout the duration of insulin treatment.[39] The best clinical translation of this finding was demonstrated by Yuan et al.[11] in their case series of 5 patients with severe cardiogenic shock secondary to CCB overdoses.

There have also been cases of CCB overdoses in which insulin therapy has failed, which may be because the insulin protocol was initiated late as salvage therapy or because of the severity of the events.[35] Insulin therapy should be initiated early in the course of management rather than as salvage therapy.[7, 35] Agarwal et al. reported their experience in treating an patient on 3 separate occasions of CCB overdose. These authors reported rapid improvement on the third occasion, in which insulin therapy was initiated early during the course of management.[40] In recent years, HIET has been shown to be a promising approach in the management of CCB overdose. Patients with third‐degree heart blockage resulting from CCB overdose reverted to a normal sinus rhythm while on an insulin drip protocol without the intervention of a temporary pacemaker.[11]

High‐dose insulin therapy can also result in hypokalemia, which theoretically may represent a beneficial response in the management of CCB overdose, because it provides a membrane stabilizing effect by prolonging repolarization and allowing more calcium to enter the cytoplasm during cardiac systole.[11] Yuan et al. suggested a serum potassium range of 2.8 to 3.2 mEq/L during insulin‐glucose therapy.[11] Hypomagnesemia and hypophosphatemia are other electrolyte derangements reported during treatment that are similar to conditions observed in patients with diabetic ketoacidosis.[41, 42]

Intravenous Lipid Emulsion Therapy

CCBs are naturally lipophilic, and intravenous lipid emulsion (ILE) therapy has been attempted with success in cases of severe CCB overdose.[43, 44] A systematic review by Jamaty et al.[45] showed that, although the overall quality of the evidence for this modality was poor, ILE could be beneficial in the management of severe cases of CCB poisoning. ILE therapy was first described by Weinberg et al. for bupivacaine toxicity in the year 2003.[46] ILE is commonly utilized as part of total parenteral nutrition, and several case reports have shown the success of its use in the treatment of local anesthetic toxicity.[47] Although the mechanism remains to be clearly elucidated,[48] it is hypothesized that this emulsion in the circulation creates a lipid channel, which causes sequestration of lipophilic drugs, and stimulates the redistribution of lipophilic drugs from the tissues to this channel.[47] Recent data have further revealed the inotropic properties of lipid emulsion; when used for acute overdose, lipid emulsion improves ventricular contractility and diastolic relaxation, going beyond its role as a simple fuel for cardiac tissue or a lipid sink.[49] Lipid emulsion in the circulation also stimulates insulin secretion, which is beneficial in reversing the antagonism caused by CCB on the cells of the pancreas.[50] However, fat embolism, infection, and the development of acute respiratory distress syndrome have been reported as complications associated with this therapy.[51] Thus, it is prudent to involve a medical toxicologist or the regional poison center to decide whether a patient would be a candidate for this treatment approach. In most cases, this is reserved as a last resort in the management of CCB overdose. Typically, a 20% fat emulsion is used, with 1 mL/kg given as a bolus followed by a continuous infusion of 0.25 to 0.5 mL/kg per hour.[7]

Sodium Bicarbonate

Metabolic acidosis resulting from CCB overdose facilitates the binding of CCB to L‐type calcium channels; thus, correcting this acidemia might improve the hemodynamic profile. Sodium bicarbonate has been suggested as a useful adjunct because it decreases the affinity of the CCB for the calcium channel. In cases of severe toxicity, electrocardiogram (ECG) findings may show widening of the QRS complex; these ECG changes are mediated through the inhibitory action of CCB on fast sodium channels, similar to that observed in cases of overdose from tricyclic antidepressants.[9, 52]

Although the evidence is limited to a few case reports, treatment with 1 to 2 mEq/kg boluses of hypertonic sodium bicarbonate is recommended in cases in which QRS widening is noted on an ECG.[52] In cases of severe toxicity with severe acidosis, dysrhythmia, or persistent QRS widening, a sodium bicarbonate drip could be initiated, with 150 mEq of sodium bicarbonate in 1 L D₅W to run at approximately 100 to 125 mL per hour.[52]

GI Decontamination

In cases of severe overdose, patients may present with lethargy from hypotension and poor cerebral flow, and the risk for aspiration and pneumonitis should be strongly considered in these patients if GI decontamination is considered. GI decontamination is best in cases where the patient is hemodynamically stable and presents early to the emergency department (ED), preferably within 2 hours[7, 9]; early use might decrease drug absorption and enterohepatic circulation, thus lowering the drug levels.[16] However, in cases in which the drug consumed was an extended‐release preparation, GI decontamination is beneficial even when the patient presents late to the ED.[17] GI decontamination is typically achieved using activated charcoal (1 g/kg body weight) or by performing whole bowel irrigation (WBI) with polyethylene glycol.[9] However, there is very little evidence that either approach changes the overall outcome, and WBI can be potentially harmful for patients with hemodynamic instability.[18] Therefore, airway and circulation maintenance is preferable to this approach.

Catecholamines

Catecholamines, such as dopamine, dobutamine, and norepinephrine, appear to be obvious choices in the management of cases of CCB overdose, because most patients present with hypotension and bradyarrhythmias.[19] However, there is no evidence to show the superiority of 1 agent over another in the management of CCB drug toxicity. Catecholamines increase the heart rate and blood pressure and increase systemic vascular resistance, which can potentially decrease the cardiac output by increasing the afterload.

Calcium Salts

In cases of severe overdose, the initial measures are typically not sufficient for stabilizing the patient. Intravenous (IV) calcium salts have been evaluated in animal models[20, 21] and, anecdotally, in human case reports.[22, 23, 24] However, the response to treatment has been mixed, with improvement in hemodynamic parameters in some cases and treatment failures in other cases. Moreover, the effects of these treatments are typically short lived, and repeated dosing might be required. Calcium salts are typically administered with the theoretical scheme of reversing antagonism with a higher calcium load and increasing cardiac inotropy. Calcium gluconate and calcium chloride are 2 frequently used agents, although no clear guidelines exist regarding this approach and the required dosage.[22] There are also published case reports in which refractory hypotension was treated with continuous calcium infusion in an attempt to reach predefined serum calcium levels.[24] However, the fear of iatrogenic hypercalcemia and its consequences is constant.[25] Calcium chloride contains 3 times the calcium for the identical volume compared to calcium gluconate and is more corrosive to the blood vessels; therefore, it is best administered through a central intravenous access. Although the evidence is limited to a few case reports, continuous calcium infusion appears effective and safe as an adjunctive therapy for patients with severe hypotension resulting from CCB overdose.[21, 22, 23, 24, 26]

Glucagon

Although insulin and glucagon are physiologically counter‐regulatory, they have a similar effect on heart stimulation. In animal models, the positive inotropic and chronotropic effects of glucagon have been clearly demonstrated.[27] Glucagon increases intracellular cyclic adenosine monophosphate (AMP) by stimulating adenylyl cyclase, a mechanism by which glucagon possibly exerts its inotropic effect.[7] Most studies conducted on the use of glucagon in the treatment of CCB overdose originated in an era in which bovine or porcine glucagon was used, and these animal glucagon products contained insulin.[9] Glucagon is typically initiated at 50 to 150 g/kg as bolus dosing, with a repeat dosing after 3 to 5 minutes.[9] A continuous IV infusion can then be administered following the initial treatment, because glucagon has a very short half‐life and works rapidly.[7, 9] However, there is no established maximum infusion dose of glucagon, and it should be titrated to the desired clinical outcome. IV glucagon therapy also carries a risk for nausea and vomiting,[7, 28] which in combination with lethargy may increase the risk for aspiration pneumonitis. The evidence for the use of glucagon in cases of CCB overdose is predominantly based on animal models[27]; evidence in human subjects is limited to case reports.[11, 28, 29] Some cases have demonstrated an improvement in hemodynamics with glucagon, whereas in a few cases, glucagon failed to result in such improvement.[30] In cases in which the ingestion history is unclear or there is polysubstance ingestion, as with ‐blockers and CCBs, glucagon is an ideal treatment agent[9]; in contrast, in single CCB overdose, glucagon might not be as helpful as more recent treatment modalities.

Hyperinsulinemia‐Euglycemia Therapy

In recent years, increasing evidence from multiple case reports and case series has shown the superiority of high‐dose insulin therapy over other treatment modalities (Table 3). Insulin acts as a potent inotrope[31, 32] and vasodilator. In their prospective observational series of 7 patients, Greene et al. report the successful use of hyperinsulinemia‐euglycemia therapy (HIET) with no significant adverse events when combined with conventional measures in a critical‐care setting.[33] Similarly, more than 50 cases have been reported in which HIET was used successfully in the management of CCB overdoses.[34]

Although there is wide variation in the insulin dosing regimens in published case reports, hyperinsulinemia therapy is typically initiated with a 0.5 IU/kg to 1 IU/kg bolus, followed by a continuous drip of 0.5 UI/kg per hour to 1 IU/kg per hour. This dose is titrated every 15 to 20 minutes until satisfactory hemodynamic and clinical stability is noted. Titrations are usually avoided for a shorter time interval because insulin must enter cells and initiate intracellular signaling and metabolic activation. However, the response to HIET might be delayed, and other therapeutic modalities could be required simultaneously until the clinical effects of insulin are observed.

Euglycemia should be maintained by checking the blood glucose levels every 30 minutes and using a dextrose solution to maintain the blood glucose within the upper limits of normal.[35] Hyperglycemia noted in CCB overdose cases indicates the degree of insulin resistance and serves as a marker of the severity of the overdose.[14, 15] In particular, patients who are hyperglycemic at presentation may not require supplemental dextrose infusion despite the high‐dose insulin therapy. The blood glucose level should be checked every 30 minutes for the first 4 hours and then hourly to avoid overlooking hypoglycemia during the treatment regimen, especially in intubated and sedated patients. Fluids containing dextrose may be initiated at 0.5 to 1 g/kg per hour and titrated to maintain euglycemia.[9, 11]

However, there is no consensus as to how long the infusion should be continued once initiated. Although insulin has not been shown to induce tachyphylaxis in experimental animal models, many clinicians prefer to discontinue the infusion once hemodynamic stability has been achieved. There is also no evidence indicating whether a weaning protocol would make any difference over abrupt discontinuation.[36] The physiological effects of insulin persist for hours after the discontinuation of the infusion and will gradually taper down with time. Therefore, theoretically, an abrupt cessation should seldom cause any deleterious effects.[11] Dextrose supplementation may be required to maintain euglycemia for up to 24 hours following discontinuation of the insulin drip due to the elevated insulin levels.[11, 36]

Insulin is a potent vasodilator in the coronary and pulmonary vasculature but does not increase the requirement for myocardial oxygen. Instead, insulin facilitates endothelial nitric oxide activity through the phosphoinositide 3‐kinase (PI3K) pathway, which translates into vasodilatation of the capillary microvasculature and better perfusion at the capillary junction. As a result, insulin corrects the capillary dysfunction that is the major pathology in cardiogenic shock and the ultimate presentation in severe CCB overdose.

Gradinac et al. reported that patients with cardiogenic shock, in the postoperative period of coronary artery bypass grafting, showed a better cardiac index with the use of IV insulin therapy.[37] In an experiment on explanted human myocardium, von Lewinski et al. demonstrated the positive inotropic effect of insulin through calcium‐dependent pathways as well as PI3K pathways.[38] Moreover, Hsu et al. demonstrated with human myocardial cells that this inotropic property of insulin was dose dependent, with better responses observed after the use of higher doses of insulin; in addition, this effect was rapid (ie, as fast as 5 minutes after the infusion) and was sustained throughout the duration of insulin treatment.[39] The best clinical translation of this finding was demonstrated by Yuan et al.[11] in their case series of 5 patients with severe cardiogenic shock secondary to CCB overdoses.

There have also been cases of CCB overdoses in which insulin therapy has failed, which may be because the insulin protocol was initiated late as salvage therapy or because of the severity of the events.[35] Insulin therapy should be initiated early in the course of management rather than as salvage therapy.[7, 35] Agarwal et al. reported their experience in treating an patient on 3 separate occasions of CCB overdose. These authors reported rapid improvement on the third occasion, in which insulin therapy was initiated early during the course of management.[40] In recent years, HIET has been shown to be a promising approach in the management of CCB overdose. Patients with third‐degree heart blockage resulting from CCB overdose reverted to a normal sinus rhythm while on an insulin drip protocol without the intervention of a temporary pacemaker.[11]

High‐dose insulin therapy can also result in hypokalemia, which theoretically may represent a beneficial response in the management of CCB overdose, because it provides a membrane stabilizing effect by prolonging repolarization and allowing more calcium to enter the cytoplasm during cardiac systole.[11] Yuan et al. suggested a serum potassium range of 2.8 to 3.2 mEq/L during insulin‐glucose therapy.[11] Hypomagnesemia and hypophosphatemia are other electrolyte derangements reported during treatment that are similar to conditions observed in patients with diabetic ketoacidosis.[41, 42]

Intravenous Lipid Emulsion Therapy

CCBs are naturally lipophilic, and intravenous lipid emulsion (ILE) therapy has been attempted with success in cases of severe CCB overdose.[43, 44] A systematic review by Jamaty et al.[45] showed that, although the overall quality of the evidence for this modality was poor, ILE could be beneficial in the management of severe cases of CCB poisoning. ILE therapy was first described by Weinberg et al. for bupivacaine toxicity in the year 2003.[46] ILE is commonly utilized as part of total parenteral nutrition, and several case reports have shown the success of its use in the treatment of local anesthetic toxicity.[47] Although the mechanism remains to be clearly elucidated,[48] it is hypothesized that this emulsion in the circulation creates a lipid channel, which causes sequestration of lipophilic drugs, and stimulates the redistribution of lipophilic drugs from the tissues to this channel.[47] Recent data have further revealed the inotropic properties of lipid emulsion; when used for acute overdose, lipid emulsion improves ventricular contractility and diastolic relaxation, going beyond its role as a simple fuel for cardiac tissue or a lipid sink.[49] Lipid emulsion in the circulation also stimulates insulin secretion, which is beneficial in reversing the antagonism caused by CCB on the cells of the pancreas.[50] However, fat embolism, infection, and the development of acute respiratory distress syndrome have been reported as complications associated with this therapy.[51] Thus, it is prudent to involve a medical toxicologist or the regional poison center to decide whether a patient would be a candidate for this treatment approach. In most cases, this is reserved as a last resort in the management of CCB overdose. Typically, a 20% fat emulsion is used, with 1 mL/kg given as a bolus followed by a continuous infusion of 0.25 to 0.5 mL/kg per hour.[7]

Sodium Bicarbonate

Metabolic acidosis resulting from CCB overdose facilitates the binding of CCB to L‐type calcium channels; thus, correcting this acidemia might improve the hemodynamic profile. Sodium bicarbonate has been suggested as a useful adjunct because it decreases the affinity of the CCB for the calcium channel. In cases of severe toxicity, electrocardiogram (ECG) findings may show widening of the QRS complex; these ECG changes are mediated through the inhibitory action of CCB on fast sodium channels, similar to that observed in cases of overdose from tricyclic antidepressants.[9, 52]

Although the evidence is limited to a few case reports, treatment with 1 to 2 mEq/kg boluses of hypertonic sodium bicarbonate is recommended in cases in which QRS widening is noted on an ECG.[52] In cases of severe toxicity with severe acidosis, dysrhythmia, or persistent QRS widening, a sodium bicarbonate drip could be initiated, with 150 mEq of sodium bicarbonate in 1 L D₅W to run at approximately 100 to 125 mL per hour.[52]

GI Decontamination

In cases of severe overdose, patients may present with lethargy from hypotension and poor cerebral flow, and the risk for aspiration and pneumonitis should be strongly considered in these patients if GI decontamination is considered. GI decontamination is best in cases where the patient is hemodynamically stable and presents early to the emergency department (ED), preferably within 2 hours[7, 9]; early use might decrease drug absorption and enterohepatic circulation, thus lowering the drug levels.[16] However, in cases in which the drug consumed was an extended‐release preparation, GI decontamination is beneficial even when the patient presents late to the ED.[17] GI decontamination is typically achieved using activated charcoal (1 g/kg body weight) or by performing whole bowel irrigation (WBI) with polyethylene glycol.[9] However, there is very little evidence that either approach changes the overall outcome, and WBI can be potentially harmful for patients with hemodynamic instability.[18] Therefore, airway and circulation maintenance is preferable to this approach.

Catecholamines

Catecholamines, such as dopamine, dobutamine, and norepinephrine, appear to be obvious choices in the management of cases of CCB overdose, because most patients present with hypotension and bradyarrhythmias.[19] However, there is no evidence to show the superiority of 1 agent over another in the management of CCB drug toxicity. Catecholamines increase the heart rate and blood pressure and increase systemic vascular resistance, which can potentially decrease the cardiac output by increasing the afterload.

Calcium Salts

In cases of severe overdose, the initial measures are typically not sufficient for stabilizing the patient. Intravenous (IV) calcium salts have been evaluated in animal models[20, 21] and, anecdotally, in human case reports.[22, 23, 24] However, the response to treatment has been mixed, with improvement in hemodynamic parameters in some cases and treatment failures in other cases. Moreover, the effects of these treatments are typically short lived, and repeated dosing might be required. Calcium salts are typically administered with the theoretical scheme of reversing antagonism with a higher calcium load and increasing cardiac inotropy. Calcium gluconate and calcium chloride are 2 frequently used agents, although no clear guidelines exist regarding this approach and the required dosage.[22] There are also published case reports in which refractory hypotension was treated with continuous calcium infusion in an attempt to reach predefined serum calcium levels.[24] However, the fear of iatrogenic hypercalcemia and its consequences is constant.[25] Calcium chloride contains 3 times the calcium for the identical volume compared to calcium gluconate and is more corrosive to the blood vessels; therefore, it is best administered through a central intravenous access. Although the evidence is limited to a few case reports, continuous calcium infusion appears effective and safe as an adjunctive therapy for patients with severe hypotension resulting from CCB overdose.[21, 22, 23, 24, 26]

Glucagon

Although insulin and glucagon are physiologically counter‐regulatory, they have a similar effect on heart stimulation. In animal models, the positive inotropic and chronotropic effects of glucagon have been clearly demonstrated.[27] Glucagon increases intracellular cyclic adenosine monophosphate (AMP) by stimulating adenylyl cyclase, a mechanism by which glucagon possibly exerts its inotropic effect.[7] Most studies conducted on the use of glucagon in the treatment of CCB overdose originated in an era in which bovine or porcine glucagon was used, and these animal glucagon products contained insulin.[9] Glucagon is typically initiated at 50 to 150 g/kg as bolus dosing, with a repeat dosing after 3 to 5 minutes.[9] A continuous IV infusion can then be administered following the initial treatment, because glucagon has a very short half‐life and works rapidly.[7, 9] However, there is no established maximum infusion dose of glucagon, and it should be titrated to the desired clinical outcome. IV glucagon therapy also carries a risk for nausea and vomiting,[7, 28] which in combination with lethargy may increase the risk for aspiration pneumonitis. The evidence for the use of glucagon in cases of CCB overdose is predominantly based on animal models[27]; evidence in human subjects is limited to case reports.[11, 28, 29] Some cases have demonstrated an improvement in hemodynamics with glucagon, whereas in a few cases, glucagon failed to result in such improvement.[30] In cases in which the ingestion history is unclear or there is polysubstance ingestion, as with ‐blockers and CCBs, glucagon is an ideal treatment agent[9]; in contrast, in single CCB overdose, glucagon might not be as helpful as more recent treatment modalities.

Hyperinsulinemia‐Euglycemia Therapy

In recent years, increasing evidence from multiple case reports and case series has shown the superiority of high‐dose insulin therapy over other treatment modalities (Table 3). Insulin acts as a potent inotrope[31, 32] and vasodilator. In their prospective observational series of 7 patients, Greene et al. report the successful use of hyperinsulinemia‐euglycemia therapy (HIET) with no significant adverse events when combined with conventional measures in a critical‐care setting.[33] Similarly, more than 50 cases have been reported in which HIET was used successfully in the management of CCB overdoses.[34]

Although there is wide variation in the insulin dosing regimens in published case reports, hyperinsulinemia therapy is typically initiated with a 0.5 IU/kg to 1 IU/kg bolus, followed by a continuous drip of 0.5 UI/kg per hour to 1 IU/kg per hour. This dose is titrated every 15 to 20 minutes until satisfactory hemodynamic and clinical stability is noted. Titrations are usually avoided for a shorter time interval because insulin must enter cells and initiate intracellular signaling and metabolic activation. However, the response to HIET might be delayed, and other therapeutic modalities could be required simultaneously until the clinical effects of insulin are observed.

Euglycemia should be maintained by checking the blood glucose levels every 30 minutes and using a dextrose solution to maintain the blood glucose within the upper limits of normal.[35] Hyperglycemia noted in CCB overdose cases indicates the degree of insulin resistance and serves as a marker of the severity of the overdose.[14, 15] In particular, patients who are hyperglycemic at presentation may not require supplemental dextrose infusion despite the high‐dose insulin therapy. The blood glucose level should be checked every 30 minutes for the first 4 hours and then hourly to avoid overlooking hypoglycemia during the treatment regimen, especially in intubated and sedated patients. Fluids containing dextrose may be initiated at 0.5 to 1 g/kg per hour and titrated to maintain euglycemia.[9, 11]

However, there is no consensus as to how long the infusion should be continued once initiated. Although insulin has not been shown to induce tachyphylaxis in experimental animal models, many clinicians prefer to discontinue the infusion once hemodynamic stability has been achieved. There is also no evidence indicating whether a weaning protocol would make any difference over abrupt discontinuation.[36] The physiological effects of insulin persist for hours after the discontinuation of the infusion and will gradually taper down with time. Therefore, theoretically, an abrupt cessation should seldom cause any deleterious effects.[11] Dextrose supplementation may be required to maintain euglycemia for up to 24 hours following discontinuation of the insulin drip due to the elevated insulin levels.[11, 36]

Insulin is a potent vasodilator in the coronary and pulmonary vasculature but does not increase the requirement for myocardial oxygen. Instead, insulin facilitates endothelial nitric oxide activity through the phosphoinositide 3‐kinase (PI3K) pathway, which translates into vasodilatation of the capillary microvasculature and better perfusion at the capillary junction. As a result, insulin corrects the capillary dysfunction that is the major pathology in cardiogenic shock and the ultimate presentation in severe CCB overdose.

Gradinac et al. reported that patients with cardiogenic shock, in the postoperative period of coronary artery bypass grafting, showed a better cardiac index with the use of IV insulin therapy.[37] In an experiment on explanted human myocardium, von Lewinski et al. demonstrated the positive inotropic effect of insulin through calcium‐dependent pathways as well as PI3K pathways.[38] Moreover, Hsu et al. demonstrated with human myocardial cells that this inotropic property of insulin was dose dependent, with better responses observed after the use of higher doses of insulin; in addition, this effect was rapid (ie, as fast as 5 minutes after the infusion) and was sustained throughout the duration of insulin treatment.[39] The best clinical translation of this finding was demonstrated by Yuan et al.[11] in their case series of 5 patients with severe cardiogenic shock secondary to CCB overdoses.

There have also been cases of CCB overdoses in which insulin therapy has failed, which may be because the insulin protocol was initiated late as salvage therapy or because of the severity of the events.[35] Insulin therapy should be initiated early in the course of management rather than as salvage therapy.[7, 35] Agarwal et al. reported their experience in treating an patient on 3 separate occasions of CCB overdose. These authors reported rapid improvement on the third occasion, in which insulin therapy was initiated early during the course of management.[40] In recent years, HIET has been shown to be a promising approach in the management of CCB overdose. Patients with third‐degree heart blockage resulting from CCB overdose reverted to a normal sinus rhythm while on an insulin drip protocol without the intervention of a temporary pacemaker.[11]

High‐dose insulin therapy can also result in hypokalemia, which theoretically may represent a beneficial response in the management of CCB overdose, because it provides a membrane stabilizing effect by prolonging repolarization and allowing more calcium to enter the cytoplasm during cardiac systole.[11] Yuan et al. suggested a serum potassium range of 2.8 to 3.2 mEq/L during insulin‐glucose therapy.[11] Hypomagnesemia and hypophosphatemia are other electrolyte derangements reported during treatment that are similar to conditions observed in patients with diabetic ketoacidosis.[41, 42]

Intravenous Lipid Emulsion Therapy

CCBs are naturally lipophilic, and intravenous lipid emulsion (ILE) therapy has been attempted with success in cases of severe CCB overdose.[43, 44] A systematic review by Jamaty et al.[45] showed that, although the overall quality of the evidence for this modality was poor, ILE could be beneficial in the management of severe cases of CCB poisoning. ILE therapy was first described by Weinberg et al. for bupivacaine toxicity in the year 2003.[46] ILE is commonly utilized as part of total parenteral nutrition, and several case reports have shown the success of its use in the treatment of local anesthetic toxicity.[47] Although the mechanism remains to be clearly elucidated,[48] it is hypothesized that this emulsion in the circulation creates a lipid channel, which causes sequestration of lipophilic drugs, and stimulates the redistribution of lipophilic drugs from the tissues to this channel.[47] Recent data have further revealed the inotropic properties of lipid emulsion; when used for acute overdose, lipid emulsion improves ventricular contractility and diastolic relaxation, going beyond its role as a simple fuel for cardiac tissue or a lipid sink.[49] Lipid emulsion in the circulation also stimulates insulin secretion, which is beneficial in reversing the antagonism caused by CCB on the cells of the pancreas.[50] However, fat embolism, infection, and the development of acute respiratory distress syndrome have been reported as complications associated with this therapy.[51] Thus, it is prudent to involve a medical toxicologist or the regional poison center to decide whether a patient would be a candidate for this treatment approach. In most cases, this is reserved as a last resort in the management of CCB overdose. Typically, a 20% fat emulsion is used, with 1 mL/kg given as a bolus followed by a continuous infusion of 0.25 to 0.5 mL/kg per hour.[7]

Sodium Bicarbonate

Metabolic acidosis resulting from CCB overdose facilitates the binding of CCB to L‐type calcium channels; thus, correcting this acidemia might improve the hemodynamic profile. Sodium bicarbonate has been suggested as a useful adjunct because it decreases the affinity of the CCB for the calcium channel. In cases of severe toxicity, electrocardiogram (ECG) findings may show widening of the QRS complex; these ECG changes are mediated through the inhibitory action of CCB on fast sodium channels, similar to that observed in cases of overdose from tricyclic antidepressants.[9, 52]

Although the evidence is limited to a few case reports, treatment with 1 to 2 mEq/kg boluses of hypertonic sodium bicarbonate is recommended in cases in which QRS widening is noted on an ECG.[52] In cases of severe toxicity with severe acidosis, dysrhythmia, or persistent QRS widening, a sodium bicarbonate drip could be initiated, with 150 mEq of sodium bicarbonate in 1 L D₅W to run at approximately 100 to 125 mL per hour.[52]