Title: Calcium Channel Blocker Overdose
Joshua Donkin, MD PGY1
Spectrum Health / MSU College of Human Medicine
Summary:
A 43-year-old female with a pertinent past medical history of Huntington’s Chorea, bipolar type 2, and hypertension presented to the emergency department with suspected polypharmacy overdose and rapidly became hemodynamically unstable requiring several days of intensive care level treatment. The patient was found to have intentionally overdosed on amlodipine, a dihydropyridine type calcium channel blocker. The patient’s hemodynamics, blood glucose, and fluid status were all very difficult to maintain and required constant titration of medications. She was ultimately treated with a combination of high dose insulin therapy and vasopressor support. Her treatment required intubation for several days and was complicated by kidney failure requiring continuous renal replacement therapy. This case-report summarizes the pathophysiology and current treatment paradigm for calcium channel blocker overdose.
Background:
Calcium channel blocker overdose is a common toxicology due to the high number of patients treated for hypertension with calcium channel blockers. Despite being widely prescribed, they are one of the most dangerous toxic ingestions encountered with a high level of fatality. There are approximately 10,000 overdoses on calcium channel blockers each year, and calcium channel blockers overdose represents 40% of the fatalities from cardiovascular drug exposures. Calcium channel blockers made up almost 4.16% of all fatal overdoses reported to poison control in 2016.1
Despite the danger associated with overdose, the majority of the treatment modalities are poorly studied and consensus on treatment approach and guidelines for management have not been established. The vasodilatory or cardiogenic shock that calcium channel blockers overdose can manifest with can be profound and difficult to correct, and the initial treatment strategy is often hemodynamic support with traditional vasopressor therapy. However, in severe overdoses it is often not possible to support the patient’s blood pressure with pressors alone. This has given way to the development of novel and physiologically fascinating treatment strategies.
Case Presentation:
The patient was a 43 year old female who presented to our emergency department via ambulance after having been found unresponsive with several empty prescription pill bottles. Report from EMS stated that she had initially been alert and following commands with a GCS of 13, however declined rapidly in transit. She had empty prescription bottles of lamotrigine, quetiapine, risperidone, diazepam, and amlodipine on her person. It was later confirmed with urine drug screen that she had taken amlodipine, topiramate, lamotrigine, and venlafaxine within the catchment time of the test.
On arrival to the emergency department vital signs were notable for hypotension to 71/42, heart rate 93, breathing 30 times a minute, O2 90% on room air. The patient’s extremities were warm, repeat blood glucose was 220, up trending from EMS is of 180. Lactic acid on arrival was negative at 1.9 but quickly trended up as the patient experienced hemodynamic collapse to 6.9. All this initial data supported a calcium channel overdose with hypotension secondary to vasodilatory distributive shock. Initial ABG showed alkalosis at 7.43 with a diminished pCO2 of 29 and PO2 of 67. Aggressive fluid resuscitation was attempted with 2 L normal saline with pressure bag infusion, but unsuccessfully. Norepinephrine and subsequent vasopressin were started. The patient’s mental status had declined, and there was concern she would no longer be able to protect her airway, so she was emergently intubated. Following intubation, the patient experienced worsening hemodynamic instability with MAPs in the 40s despite the addition of epinephrine and phenylephrine. Intensive care and toxicology were consulted from the emergency department and toxicology recommended serial calcium infusions, glucagon, insulin drip, and D10 infusion. The patient was originally sedated with Propofol, but was unable to tolerate it from a hemodynamic standpoint and this was discontinued. The patient’s precipitous decline prevented immediate initiation of gastric decontamination with activated charcoal. The patient was emergently transferred to the ICU for further management.
Upon arrival to the intensive care unit the patient underwent a bedside echocardiogram that demonstrated normal right and left heart function, lending further support to the diagnosis of distributive shock. The patient was on high doses of norepinephrine, epinephrine, vasopressin, and phenylephrine still with mean arterial pressures in the high 30’s. High dose vitamin C, thiamine, and hydrocortisone2 were administered to protect against end organ damage secondary to the patient’s profound distributive shock. Toxicology recommended initiation of high dose euglycemic insulin therapy, calcium drips, lipid emulsion therapy, and the addition of methylene blue to improve vascular tone. Activated charcoal was also administered after placement of a feeding tube. Left IJ and right femoral central venous catheters were placed, and an arterial line was placed for tight blood pressure monitoring.
Additional history was gathered from family and chart review.
Medical History
Huntington’s Disease – diagnosed 2 years ago, follows with neurology
Bipolar Type II
Hypertension
GERD
Migraines
Surgical
Cesarean Section – 1994
Cholecystectomy – 2006
Family History
Mother (Deceased): Huntington’s Disease
Father: Hypertension, Diabetes, CAD
Sister (Younger): Huntington’s Disease
Brother (Deceased): Huntington’s Disease
Maternal Grandfather (Deceased): Huntington’s Disease
Son (19): Huntington’s Disease
Son (17): Huntington’s Disease
Social History
Tobacco: Never Smoked
Alcohol: Occasional use
Illicit Drug Use: None reported
Patient lives at home with her two sons.
Prescribed Home Medications
diazepam 5 mg nightly
Flonase 1 spray in each nares twice daily
lamotrigine 50 mg daily
Risperidone 0.25 mg daily
Topiramate 50 mg twice daily
Venlafaxine 75 mg daily
Amlodipine 10 mg daily
Treatment:
Administration of methylene blue resulted in some improvement in the patient’s blood pressure but it was still more than 24 hours before we could down titrate any of the vasopressors. We managed her respiratory status with lung protective ventilation. Calcium drip and serial calcium infusions with a goal serum calcium 12 were administered, however we were never able to increase serum calcium above 10.7. The patient was placed on a glucagon drip. Lipid emulsion therapy was initiated as a temporizing measure. High dose euglycemic insulin therapy was initiated and up titrated to a maximum rate of 10 U/kg/hr, in this case 744 Units of insulin an hour. Despite this insulin regimen the patient remained hyperglycemic with blood glucose numbers in the 300s for almost the first 48 hour of admission.
Due to the aggressive attempts at fluid resuscitation and the fluid requirements for administration of high dose insulin therapy, the patient became profoundly fluid overloaded with a net balance of 36L. Nephrology was consulted and recommended placing the patient on continuous venovenous hemodiafiltration with heparin antic coagulation, initially at a rate of removal of 125ml/hr and titrated up.
The administration of such high dose insulin required constant monitoring of the patient’s blood sugar. By the end of the second day it started to trend down, an indication that the effects of the amlodipine overdose were beginning to clear. The insulin was titrated down slowly and the patient was supplemented with dextrose to prevent hypoglycemia. At the same time methylene blue, calcium infusions, and glucagon were stopped. Vasopressor support began to be weaned.
As the effects of the calcium channel blocker overdose resolved, the patient’s hemodynamic status improved. Vasopressor support was weaned off slowly. The patient’s intensive care stay was further complicated by the development of a right arterial line thrombus, ventilator associated pneumonia, acute kidney injury stage 3, and a gastrointestinal bleed likely secondary to profound gut edema necessitating a transfusion of 2 units of packed red blood cells. The patient also developed critical illness myopathy that she was relatively quick to recover from with assistance from physical therapy.
On the eighth day of admission the patient was successfully extubated to BiPAP and was rapidly able to de-escalate to nasal cannula. Continuous renal replacement therapy was discontinued two days later. The patient had stable urine output with quick resolution to her acute kidney injury. Hemoglobin remained stable following transfusion. The patient was very weak following her ICU stay and was transferred to a progressive nursing unit in stable condition on the nineth day of her admission. There she was evaluated by psychiatry and recommended for inpatient psychiatric admission following medical stabilization. She was discharged in stable condition for psychiatric evaluation and treatment after a 14 day hospital stay.
Outcome and Follow Up:
The patient followed the treatment plan with admission to inpatient psychiatry following her hospital stay. Records from the psychiatric facility are not available, however she seems to have been discharged after a 15 day inpatient stay.
Unfortunately, 2 days following her discharge from inpatient psychiatry, the patient again overdosed on amlodipine. The medication had not been continued on discharge, however, she had apparently had residual prescription medications available to her despite attempt to discontinue. The second stay initially proceeded in a very similar fashion to the first with rapid development of profound distributive shock. Treatment with insulin, glucagon, calcium, and lipid rescue therapy was again initiated. The patient was started on norepinephrine, vasopressin, and epinephrine with little improvement in her hypotension. The patient then experienced profound bradycardia and transcutaneous pacing was initiated. Angiotensin II drip was started, but a short time later the patient went into PEA arrest and ACLS protocol was initiated with termination of resuscitative efforts after 25 minutes without ROSC.
Discussion:
In this case we dealt with a dihydropyridine calcium channel blocker overdose. These medications preferentially block L type calcium channels in the vasculature, in contrast to the nondihydropyridine medications that preferentially block cardiac L type calcium channels. The dihydropyridines affect peripheral resistance and vasodilation, but have negligible negative inotropic effect. Most clinically important formulations of calcium channel blockers, including amlodipine, are manufactured in an extended release form to allow for once daily dosing. This makes their absorption unpredictable and prolongs the course of toxicity in overdose.
Calcium channel blockers also seem to have a complex effect on the endocrine system, particularly on insulin release and utilization. L type calcium channels are involved in the release of insulin from the pancreatic islet cells, and reducing calcium’s effects at these channels seems to result in refractory hyperglycemia and reduced cardiac glucose utilization.3
Initial treatment centers around maintaining hemodynamic stability and securing the airway. The profound hypotension produced by these medications will often require pressor support. There is some evidence to suggest that norepinephrine should be preferential initiated over epinephrine due to its actions in the vasculature. Higher doses of vasopressors may need to be used than is typical in other forms of vasodilatory shock.5
The next step in management of overdose with calcium channel blockers is gastric decontamination. If the patient presents within two hours of ingestion it is reasonable to attempt decontamination with activated charcoal, orogastric lavage, or consider whole bowel irrigation.5
Intravenous supplementation of calcium using either calcium gluconate, calcium chloride, or calcium acetate has been shown to improve cardiac contractility and increase vasoconstriction. Theoretically, you are attempting to out compete the binding of the calcium channel blocker by increasing the osmotic gradient.
High dose insulin therapy is the mainstay of treatment of calcium channel blocker overdose. The literature supported dose is initially a 1 U/kg bolus followed by 1 U/kg/hr maintenance with up titration if there is no improvement in blood pressure to a max dose of 10 U/k/hr. It has been shown to increase cardiac contractility by increasing the influx of glucose into the myocardium which at physiologic levels of insulin would preferentially use free fatty acids. The influx of glucose is thought to shift the myocardium from using primarily fatty acids to using glucose as its fuel source. Even at these very high insulin doses, the calcium channel blocker induced hyperglycemia prevents the patient from becoming hypoglycemic. Insulin should be titrated down once the blood glucose begins to fall. This signifies the clearance of the calcium channel blocker from the patient’s system.5
Lipid emulsion therapy is performed by administering the fats used in total parenteral nutrition to attempt to create a lipid sink, and temporarily sequester the toxin in a lipid micelle.4
Glucagon has a less clear role in management of dihydropyridine calcium channel blockers because it is functioning by increasing cyclic AMP to increase heart rate and contractility. In dihydropyridine (amlodipine) calcium channel blocker overdose, heart rate and heart function are typically maintained. This makes glucagon a relatively ineffective therapy in dihydropyridine calcium channel blocker overdose.5
Methylene blue can be used to treat hypotension by blocking the production and action of nitric oxide in the periphery and preventing vasodilation. This results in improvement in blood pressure. Clinicians should be aware of the possibility of inducing hemolytic anemia with high doses of methylene blue as well as the propensity to cause serotonin syndrome in patients on other serotonergic medications.6
The treatment of calcium channel blocker overdose remains a complex problem without a clear treatment algorithm. However, some of these novel therapies have been shown to be successful, as they were in our patient. Despite the advances in recent years at treating this dangerous drug overdose, it remains one of the most fatal toxic ingestions and should be used cautiously in vulnerable patient populations. As demonstrated by our patients, access to these medications can have devastating consequences in patients where accidental or intentional overdose are a concern.