What evidence is available investigating the use of high-dose insulin for calcium channel blocker and beta blocker overdose?

Comment by InpharmD Researcher

Available data regarding the use of high-dose insulin for calcium channel blocker and beta-blocker toxicity in humans is primarily derived from case reports. Continuous insulin infusion, followed by a bolus dose, have ranged from 0.5 units/kg/hr to 10 units/kg/hr. However, there does not appear to be a recommended concentration for high-dose insulin infusions in this setting. One retrospective chart review (Table 1) described outcomes with high-dose insulin infusions while highlighting the importance of close monitoring for metabolic abnormalities. Overall, there is a lack of consensus on efficacy targets, and therefore treatment should be individualized based on patients’ responses.

Expert consensus recommendations on the management of calcium channel blocker (CCB) poisoning in adults state IV calcium, high-dose insulin, and norepinephrine (and/or epinephrine) are first-line therapies. Dobutamine or epinephrine can be used in the presence of cardiogenic shock and atropine in the presence of symptomatic bradycardia or conduction disturbance. In patients refractory to first-line treatments, recommendations are incremental doses of high-dose insulin if there is myocardial dysfunction present, IV lipid-emulsion therapy, and using a pacemaker in the presence of unstable bradycardia or high-grade arteriovenous block without significant alteration in cardiac inotropism. [1]

A 2020 systematic review evaluated various pharmacological interventions in managing beta-blocker (BB) poisoning. A total of 141 articles were evaluated for treatment and their effect on mortality and improvement in hemodynamic parameters. While the use of insulin for BB poisoning has been observed in several case series and case reports, no controlled human trials or observational studies were identified. Based on available evidence of high-dose insulin euglycemic therapy (HIET), mortality benefits were reported in 10 case series and clear hemodynamic improvement was observed in 2 case reports. The insulin dosing regimen ranged from 1 unit/kg/h up to 10 units/kg/h. Notably, in five case series, adverse effects such as hypoglycemia and hypokalemia occurred in 195 cases (42.6%). The majority of evidence that has observed an improvement in hemodynamic response for high-dose insulin euglycemic therapy is drawn from low-quality studies and is confounded by the use of multiple interventions and unclear treatment timelines and responsiveness. [2]

A 2018 review discussing the use of HIET in BB and CCB overdose stated the major mechanism of insulin during these toxicities is to potentiate myocardial cells to uptake and effectively exploit glucose as a source of energy. Additionally, insulin also exhibits concentration-dependent inotropic effects on human myocardial cells. Compared to other clinical scenarios utilizing intravenous insulin, the most common insulin bolus dose in successful cases where HIET is utilized is 1 unit/kg, followed by infusion at 0.5 to 1 unit/kg/hour. Based on existing evidence, the authors recommended the reasonable maximum dose of regular insulin IV infusion to be 10 units/kg/hr titrated up every 10 to 15 min to clinical response. It is worth noting that this intense HIET requires continuous dextrose infusion and close monitoring of electrolytes, vital signs, blood glucose, and serial electrocardiogram. Ideally, the blood glucose should be maintained at greater than 100 mg/mL with an initial dextrose dose of 0.5 g/kg/hr. If blood glucose increases above 200 mg/dL, dextrose should be temporarily suspended. The duration of therapy typically depends on the achievement of hemodynamic stability. While there is no consensus on ideal efficacy targets in published literature, it is reasonable to target systolic blood pressure of ≥ 90 mmHg and heart rate of ≥ 50 beats per minute. If present at baseline, abnormalities in mental status and electrocardiogram readings should resolve. In a brief summary of case reports conducted by the authors, the maximal intravenous insulin infusion was initiated at 1.25 units/kg/hr and subsequently increased to 4.5 units/kg/hr in one patient with diltiazem overdose at 3,360 mg. [3]

Symptomatic BB and CCB poisoning require supportive therapy through respiratory assistance and 1 to 2 liters of intravenous fluid to manage hypertension and avoiding fluid overload. The mainstay treatment of cardiogenic shock in beta-blocker and CCB overdose includes high-dose insulin euglycemia therapy loading dose 1 IU/kg then infusion rate of 1 to 10 IU/kg/hour with 50% glucose infusion to maintain euglycemia and catecholamine infusions titrated to effect to improve inotropy and chronotropy. Second-line therapies include phosphodiesterase inhibitors to improve contractility, glucagon to improve bradycardia, or intravenous calcium infusion specifically for CCB poisoning to increase cardiac output and vascular tone. [4]

A review of articles from 1975-2010 for high-dose insulin therapy in relation to BB and CCB poisoning noted that human case reports of high dose insulin included insulin boluses ranging from 0.1 to 10 U/kg. Continuous insulin infusion rates ranged from 0.015 to 22 U/kg/h with the majority of patients receiving between 0.5 and 2 U/kg/h. Several case reports told of patients getting doses higher than 10 U/kg/h without having hypoglycemic effects. A dextrose infusion should be initiated at the beginning of therapy in order to prevent hypoglycemia. [5]

High-dose insulin euglycemic therapy for CCB toxicity typically starts with a bolus dose of 1 unit/kg of regular insulin followed by an infusion of 1 unit/kg/hr. Animal data suggest increased insulin doses are associated with increased cardiac output. Despite expert recommendation of titration of insulin doses up to 10 units/kg/hr for refractory patients, a stepwise approach may be more beneficial to prevent volume overload and worsening vasodilation; however, stepwise approaches to insulin titration in CCB therapy are still being investigated. [6]


[1] St-Onge M, Anseeuw K, Cantrell FL, et al. Experts Consensus Recommendations for the Management of Calcium Channel Blocker Poisoning in Adults. Crit Care Med. 2017;45(3):e306-e315.
[2] Rotella JA, Greene SL, Koutsogiannis Z, et al. Treatment for beta-blocker poisoning: a systematic review. Clin Toxicol (Phila). 2020;58(10):943-983. doi:10.1080/15563650.2020.1752918
[3] Krenz JR, Kaakeh Y. An Overview of Hyperinsulinemic-Euglycemic Therapy in Calcium Channel Blocker and β-blocker Overdose. Pharmacotherapy. 2018;38(11):1130-1142. doi:10.1002/phar.2177
[4] Graudins A, Lee HM, Druda D. Calcium channel antagonist and beta-blocker overdose: antidotes and adjunct therapies. Br J Clin Pharmacol. 2016;81(3):453-61.
[5] Engebretsen KM, Kaczmarek KM, Morgan J, Holger JS. High-dose insulin therapy in beta-blocker and calcium channel-blocker poisoning. Clin Toxicol (Phila). 2011;49(4):277-83.
[6] Alshaya OA, Alhamed A, Althewaibi S, et al. Calcium Channel Blocker Toxicity: A Practical Approach. J Multidiscip Healthc. 2022;15:1851-1862. Published 2022 Aug 30. doi:10.2147/JMDH.S374887

Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

What evidence is available investigating the use of high-dose insulin for calcium channel blocker and beta blocker overdose?

Please see Tables 1-2 for your response.


High dose insulin for beta-blocker and calcium channel-blocker poisoning


Retrospective chart review 

N= 199


To describe clinical characteristics and adverse events associated with high dose insulin (HDI)

Study Groups

Beta-blocker (BB; n= 88)

Dihydropyridine calcium channel blocker (DHP CCB; n= 22)

Non-dihydropyridine calcium channel blocker (non-DHP CCB; n= 44)

BB + CCB (n= 45)

Inclusion Criteria

Patients treated with HDI for BB or CCB poisoning 

Exclusion Criteria

HDI was recommended but not performed; received an insulin bolus only with no subsequent infusion; received an insulin infusion but no infusion dose was recorded; patient received an insulin infusion at a rate below the definition of HDI (0.5 U/kg/h or 25 U/h)


An electronic patient database at a single poison control center was retrospectively reviewed to identify eligible patients and collect relevant clinical data and outcomes defined by the National Poison Data System (NPDS). 

HDI was comprised of an initial dose of 1 U/kg of regular insulin IV push, followed by an infusion of 1 U/kg/hr of regular insulin along with an infusion of dextrose. Initial effects of HDI take at least 5-10 minutes to manifest. Then insulin infusion was increased 1-2 U/kg/hr every 10-15 minutes to a maximum of 10 U/kg/hr until shock improved (doses up to 22 U/kg/hr have been safely used).


From 2000 to 2016

Outcome Measures

Clinical outcomes, metabolic adverse effects related to HDI (hypoglycemia defined as blood glucose < 70 mg/dL), use of other clinical therapies 

Baseline Characteristics


All included patients (N= 199)


Median age, years (range)

48 (14 to 89)  


100 (50%)  

Beta blockers





40 (20%)

32 (16%)

27 (12%)


Calcium channel blockers 





40 (20%)

22 (11%)

20 (10%) 


Co-ingested drugs 


Antihypertensive (other) 


Antidepressants (other) 




57 (39%)

52 (26%)

45 (23%)

39 (20%)

23 (12%)

19 (10%)




BB (n= 88)

BB + CCB (n= 45)



Major effect


13 (15%)

55 (62%)


7 (16%)

25 (56%)

Clinical effects 



Cardiac arrest 



< 70 mg/dL

Hypoglycemia treated

Electrolyte abnormality



32 (36%)

57 (65%)

18 (21%)

27 (31%)


24 (27%)

12 (14%)

28 (32%)

83 (94%) 


18 (40%)

37 (84%)

11 (24%)

9 (20%)


5 (11%)

5 (11%)

18 (40%)

44 (98%)

Selected other therapies 












12 (14%)

20 (23%)

43 (49%)

83 (94%)

41 (47%)


40 (45%)

28 (32%)

31 (35%)

13 (15%)


4 (9%)

7 (16%)

38 (84%)

41 (91%)

23 (51%)


32 (71%)

27 (60%)

19 (42%)

14 (31%)

aBradycardia = pulse < 60 beats/min. bHypoglycemia = blood glucose < 70 mg/dL. cHypotension = systolic blood pressure (SBP) < 90 mm Hg OR > 15% decrease from baseline SBP. 

Adverse Events

See results 

Study Author Conclusions

HDI, initiated by emergency physicians in consultation with a poison center, was feasible and safe in this large series. Metabolic abnormalities were common, highlighting the need for close monitoring. Hypoglycemia was more common when less concentrated dextrose maintenance infusions were utilized.

InpharmD Researcher Critique

The study is subject to inherent limitations of a retrospective chart review, such as a precise evaluation of complications, missing data, and confounding effects of concurrent treatments, such as vasopressors. Also, as the study mainly utilized descriptive statistics, true clinical efficacy of HDI required further investigation. 



Cole JB, Arens AM, Laes JR, Klein LR, Bangh SA, Olives TD. High dose insulin for beta-blocker and calcium channel-blocker poisoning. Am J Emerg Med. 2018;36(10):1817-1824. doi:10.1016/j.ajem.2018.02.004


Successful treatment of metoprolol-induced cardiac arrest with high-dose insulin, lipid emulsion, and ECMO


Case report 

Case presentation

A 47-year-old man with a medical history significant for alcohol abuse, hypertension, and major depressive disorder presented to a quaternary care emergency department (ED) after an intentional ingestion of approximately 10 g of prescribed metoprolol tartrate (100 mg × 100) in a suicide attempt. Upon arrival at the ED, his heart rate was 53 beats/minute with a narrow complex rhythm and an initial blood pressure (BP) of 110/70 mm Hg. He was unresponsive and rapidly became apneic. After intubation, he received 5 mg intravenous (IV) glucagon but unfortunately continued to deteriorate regardless of epinephrine infusion. The patient then suffered narrow-complex pulseless electrical activity (PEA), and cardiopulmonary resuscitation was initiated with additional doses of glucagon, vasopressin, dobutamine, and norepinephrine infusions with minimal improvements. Subsequently, intralipid therapy (100 mL bolus with 200 mL/30 min infusion) in addition to hyperinsulin therapy (250 U regular insulin IV bolus) were given.

After consulting the cardiothoracic surgery extracorporeal membrane oxygenation (ECMO) team, venoarterial-ECMO (VA-ECMO) was placed on the patient 95 minutes after ED arrival (55 minutes of PEA arrest) via cannulation of both the left femoral artery (15 F) and vein (27 F) with a flow rate of 5 L/min. He was maintained on VA- ECMO, intralipid, epinephrine, vasopressin, norepinephrine, and dobutamine infusions as well as heparin infusion per ECMO standard PTT titration at the time of admission to the intensive care unit. Approximately 8 hours after VA-ECMO initiation, patient's neurologic status improved significantly with spontaneous movements of all extremities, and started to follow commands. The patient’s VA-ECMO was set to 4.1 L/min on hospital day 3 and eventually decannulated after 50 hours of treatment. At discharge, he recovered from acute kidney injury, transaminitis, and lactic acidosis. 

Study Author Conclusions

When VA-ECMO is available, rapid consultation via telephone with the aforementioned specialists and utilization of such resources should be considered in cardiac arrest secondary to β-adrenergic toxicity. Venoarterial extracorporeal membrane oxygenation allows for perfusion of vital organs and intrinsic drug elimination to occur. Additional intralipids and high-dose insulin have demonstrated promise in refractory β-adrenergic toxicity. These therapies should be considered in cases of refractory cardiac arrest secondary to β-blockade. 



Escajeda JT, Katz KD, Rittenberger JC. Successful treatment of metoprolol-induced cardiac arrest with high-dose insulin, lipid emulsion, and ECMO. Am J Emerg Med. 2015;33(8):1111.e1-1111.e11114. doi:10.1016/j.ajem.2015.01.012