Development of Nonketotic Hyperglycemia Requiring High-Dose Insulin After Supratherapeutic Amlodipine Ingestion

Abstract

Background/Objective

Calcium channel blockers, when taken in overdose quantities, can cause hyperglycemia requiring so-called hyperinsulinemic-euglycemic therapy. The objective of this report was to describe a patient with calcium channel blocker toxicity resulting from overdose of amlodipine.

Case Report

A 74-year-old man presented with a fall and loss of consciousness. Prior to this event, he consumed 88 tablets of amlodipine. Medical history was significant for hypertension, hyperlipidemia, and cerebrovascular accident. His vital signs were heart rate of 51 beats/min, blood pressure of 162/137 mm Hg, oxygen saturation of 94% on room air, and respiratory rate of 16 breaths/min. The patient soon became hypotensive. The blood glucose level was 227 mg/dL. Urinalysis was negative for ketones. The patient was diagnosed with calcium channel blocker toxicity and admitted to the intensive care unit. He received continuous insulin infusion and dextrose 25% in water for 5 and 7 days respectively, with a peak insulin infusion rate of 850 U/h. After discontinuation of medications, the glucose level, blood pressure, and heart rate were 82 mg/dL, 127/68 mm Hg, and 86 beats/min, respectively, and he returned to prior functional status.

Discussion

Amlodipine is a long-acting dihydropyridine class calcium channel blocking drug. In the overdose setting, amlodipine inhibits calcium uptake by myocytes and release of insulin from pancreatic beta cells.

Conclusion

In this case, high-dose insulin euglycemic therapy was effective in the treatment of amlodipine overdose and should be considered in similar cases.

Highlights

• •Amlodipine overdose can cause severe bradycardia, hypotension and hyperglycemia.
• •High-dose insulin euglycemic therapy treats amlodipine overdose.
• •Amlodipine toxicity requires upwards of ten times normal continuous insulin dose.

Clinical Relevance

Calcium channel blockers are one of the most prescribed antihypertensives with a high potential for overdose. This case report details the manifestations and management of calcium channel blocker toxicity, requiring high doses of insulin therapy. This case report adds valuable insight into treating this condition, which is associated with high fatality.

Introduction

Calcium channel blockers typically do not cause elevations in blood glucose at therapeutic doses.^1,2 Despite conflicting evidence detailing the glycemic effects of amlodipine, in the overdose setting, calcium channel blockers are well established to cause hyperglycemia.3, 4, 5 Based on 12 deaths in the review of 76 reports of calcium channel blocker overdose, a mortality rate of 16% was estimated.^6,7 In this case, we report a patient who consumed 88 amlodipine 5 mg tablets. This patient was quite unusual considering the very high amounts that was ingested and the fact that other drugs were not ingested at the same time.⁷ The first-line treatment of calcium channel blocker overdose is high-dose insulin therapy.⁸ This case demonstrates treatment response to high-dose insulin therapy in the setting of a high-dose amlodipine overdose.

Case Report

A 74-year-old man fell down a set of stairs. The family could not rouse him and called 911. Upon paramedic arrival, the patient was on the ground leaning against the wall, oriented to name but not time, place, and events prior to falling. Medical history at this time was noted to be cerebrovascular accident without deficits. The initial vital signs were heart rate of 51 beats/min, blood pressure of 162/137 mm Hg, oxygen saturation of 94% on room air, and respiratory rate of 16 breaths/min. Physical examination was notable for small laceration on top of forehead at hairline, small abrasion alongside of face, and pupils 2 to 3 mm sluggish but reactive and able to track. The glucose level was 179 mg/dL, and electrocardiography showed sinus bradycardia. The patient was transported to a community hospital in suburban Maryland. Enroute, the patient developed nausea and was given ondansetron. On provider examination, he admitted to consuming 88 tablets of 5 mg amlodipine with suicidal intent. Medical history was additionally noted to be significant for hypertension and hyperlipidemia. Vital signs at the hospital were blood pressure of 96/78 mm Hg, heart rate of 56 beats/min, temperature of 97.3°F, respiratory rate of 22 breaths/min, and oxygen saturation of 87% on room air. On examination, bradycardia, regular rhythm, normal S1, and S2 without murmurs were appreciated. The patient was mildly confused with no focal neurologic deficits. The white blood count was 15 000/mm³ (reference, 4500-11 000/mm³), and the levels of blood glucose, hemoglobin A1c was 5.7% (39 mmol/mol), and blood pH were 227 mg/dL (reference, 70-99 mg/dL), 5.7%, and 7.386, respectively. The levels of thyroid-stimulating hormone, free thyroxine, random cortisol, and ionized calcium were 9.29 mcIU/mL (reference, 0.50-4.50 mcIU/mL), 1.2 ng/dL (reference, 0.9-1.7 ng/dL), 26.8 mcg/dL, and 1.14 mmol/L (reference, 1.12-1.32 mmol/L), respectively (Table). Sepsis workup was unremarkable. Computed tomography examinations of the head, spine, chest, abdomen, and pelvis were unremarkable.

Table.

Laboratory Data at the Time of Admission to the Community Hospital

Test	Laboratory value at admission	Normal range
White blood cell count	15.16	4500-11 000/mm3
Hemoglobin	13.3	12.0-15.0 g/dL
Hematocrit	39.8	36.0%-46.0%
Mean corpuscular volume	91.9	80.0-100.0 fL
Mean corpuscular hemoglobin	30.7	26.0-34.0 pg
Mean corpus hemoglobin level	33.4	31.0-37.0 g/dL
Red blood cell distribution width	13.5	11.5%-14.5%
Platelet count	261	150 000-350 000/mm3
Sodium	137	135-148 mmol/L
Potassium	3.8	3.5-5.1 mmol/L
Chloride	103	98-110 mmol/L
Urea nitrogen	28	7-30 mg/dL
Glucose	227	71-99 mg/dL
Calcium	9.3	8.4-10.5 mg/dL
Anion gap	14	7-16 mmol/L
Blood urea nitrogen/creatinine ratio	14	…
Carbon dioxide	20	21-31 mmol/dL
Creatinine	2	0.5-1.2 mg/dL
Estimated glomerular filtration rate	33	>60 mL/min/1.73 m2
Lactate	2.5	<2.0 mmol/L

A working diagnosis of calcium channel blocker toxicity was made. The patient was given 2 1-L boluses of lactated ringers. Systolic blood pressure was measured to be 50 mm Hg on arterial line with no change despite fluids and multiple calcium and glucagon infusions. High-dose norepinephrine infusion was started, resulting in the heart rate increasing from 45 to 75 beats/min. Vasopressin infusion was started. Systolic blood pressure improved from 50 mm Hg to 75 mm Hg. Epinephrine infusion followed. The systolic blood pressure increased to 90 mm Hg. Hours after initiation of vasopressors, the glucose level increased to 342 mg/dL. An initial dose of 15 U/h of continuous insulin and 25 mL/h of dextrose 25% in water was administered. Insulin infusion was uptitrated to 850 U/kg/h over next 4 hours with the goal for glucose being 140 to 180 mg/dL. Continuous glucose monitoring was instituted. The point-of-care glucose levels were 268 mg/dL at 600 U/h and 166 mg/dL at 850 U/h. The patient remained borderline hypotensive with a blood pressure of 97/53 mm Hg. Continuous calcium gluconate infusion was started. The systolic blood pressure improved to 100 mm Hg. The Figure shows the glucose levels during insulin infusion. After 5 days, insulin infusion was discontinued. After insulin infusion was stopped, the patient became agitated; his glucose level was 62 mg/dL. Hypoglycemia was treated with intravenous dextrose. After an additional 2 days, infusion of dextrose 25% in water was discontinued. Blood pressure was 127/68 mm Hg, heart rate was 86 beats/min, glucose level was 82 mg/dL, and oxygen saturation was 93% on room air. After the continuous medication was discontinued, the patient was alert and oriented to person, place, time, and location.

Fig.

Blood levels in milligrams per deciliter during various rates of insulin infusion as a function of hospital days 1 to 7. Values for the rate of insulin infusion were calculated based on dosing protocol recommended by the poison control center, and the vehicle for insulin infusion was by intravenous administration of dextrose 25% in water.

Discussion

In this case, we presented a 74-year-old man who was admitted after consuming 440 mg of amlodipine with a fall and confusion. His condition responded to high-dose insulin therapy up to 850 U/h with full resolution of symptoms. Amlodipine, one of many dihydropydrine calcium channel blockers, is one of the most prescribed antihypertensive medications. Although calcium channel blockers accounted for only 13% of substance exposures, they ranked as the sixth highest contributor to fatalities among all substances.⁹ Because of widespread use, the potential for overdose is high. Overdose symptoms include dizziness, lightheadedness, and fatigue.¹⁰ Severe toxicity is additionally linked to prolonged hypotension, hyperglycemia, and electrocardiogram changes. Despite treatment, isolated calcium channel blocker toxicity mortality has 37 deaths reported among 15 381 exposures, the highest number of deaths among all cardiovascular medication overdoses.⁹

Calcium channel blockers act by blocking calcium influx through the L-type calcium channels in excitable membranes resulting in a reduction in blood pressure.¹¹ The reduction in blood pressure noted during use of amlodipine is mediated by the regulation of vascular smooth muscle tone, which decreases as a function of reduced cytosolic calcium concentration. Calcium also plays a crucial role in a multitude of physiologic functions, such as mediation of hormone responses.¹² One such hormone is insulin, whose secretion at the level of the beta cell is dependent on calcium.¹³ In the setting of overdose, without endogenous insulin release, myocytes are not able to metabolize glucose needed to respond to stress-evoking circumstances resulting in decreased cardiac contractility and vascular tone.¹⁴

The mainstay treatment, addressing both hypotension and hyperglycemia, is hyperinsulinemic-euglycemic therapy.^8,10,14 Some of the mechanisms by which insulin counteracts calcium channel blocker toxicity include allowing myocytes to uptake glucose and mediating the activity of the Na⁺/Ca²⁺ exchanger on cardiac myocytes, thus increasing contractility.15, 16, 17 During admission, the case patient’s presentation was discussed with Maryland poison control center. Insulin was recommended to be uptitrated up to 10 U/kg/h, 850 U/h for this patient. The goal glucose level was 100 to 200 mg/dL. The dosing protocol recommended by the poison control center was bolus 0.5 to 1.0 U/kg with 25 g intravenously to be given for a glucose level of <200 mg/dL, followed by starting 0.5 to 1.0 U/kg/h of continuous insulin infusion and dextrose 25% in water starting at 0.5 mg/kg/h.^18,19 During therapy, blood glucose, cardiac function, blood pressure, potassium, and acid-base status should be monitored every 15 to 30 minutes and corrected per protocol with the goal of improved organ perfusion and decreased vasopressor requirements. If no significant response is achieved in 30 minutes of initiation, the infusion rate should be increased by 0.5 U every 15 minutes until hemodynamics improve. The maximum dose of infusion is not clear, with cases reporting improvement with up to 22 U/kg/h.¹⁸ Once glucose has consistently been 100 to 200 mg/dL for 4 hours, the frequency of checks can be decreased to hourly. As organ perfusion improves, increases in dextrose requirements should be expected and may persist even after discontinuation of insulin infusion.

Despite strong rationale for the use of high-dose insulin therapy in the setting of calcium channel blocker overdose, it should be noted that recommendations for its use are based on low levels of evidence.⁸ Dosing protocols for high-dose insulin therapy are based primarily on case studies and testing in animal models.^14,18 In addition, isolated calcium channel blocker overdose, as noted in this case, is only one of many potential presentations, and in some cases, high-dose insulin therapy may not be adequate due to the presence of coingested substances.⁷ For example, Murati et al²⁰ report a case of a patient who ingested 240 mg of Cardizem and whose blood levels showed elevated alcohol, salicylates, and cannabinoids and who did not respond to high-dose insulin therapy, expiring despite multiple heroic interventions.²⁰

Conclusion

Farmer et al⁷ conducted a review of amlodipine overdose identifying 68 cases on PubMed and 8 cases from their affiliated institution.⁷ In comparison with the 76 cases reviewed, our patient had the second highest maintenance insulin hourly infusion rate. Chudow and Ferguson⁶ report of a patient who consumed 800 mg of amlodipine respectively, 360 mg higher than our case patient. The patient did not survive despite receiving high-dose insulin therapy and multiple salvage therapies. In contrast, our patient, despite requiring 3 vasopressors and high-dose insulin therapy, responded well hemodynamically, never requiring intubation, methylene blue, or extracorporeal membrane oxygenation. We believe that this case serves as evidence advocating for use of high-dose insulin euglycemic therapy, we acknowledge that its use does not guarantee survival in every case of calcium channel blocker overdose. We hope that our case provides some reassurance to clinicians that the relatively high doses of insulin required for hyperinsulinemic-euglycemic therapy will be potentially beneficial in patients similar to our case provided care is taken to maintain blood glucose levels in an acceptable range.

Ethics Approval Statement

No approval from the Institutional Review Board was required.

Patient Consent Statement

Written informed consent for publication of their details was obtained from the patient.

Disclaimers

This article has not been submitted for publication in other journals nor presented at any conferences or meetings at this time

Disclosure

M.Z. reports consulting for DexCom, Inc. The other author has no conflicts of interest to disclose.