Calcium Channel Blocker Ingestion and Pharmacokinetics

Welcome to PICU Doc On Call, A Podcast Dedicated to Current and Aspiring Intensivists.

I'm Pradip Kamat and I'm Rahul Damania. We are coming to you from Children's Healthcare of Atlanta - Emory University School of Medicine.

Welcome to our Episode about a 14- year- old female who presented with hypotension after a suicide attempt.

Here's the case:

A 14 yo F with PMH of depression and oppositional defiant disorder presents with dizziness. Her mother states she was in her normal state of health when on the day of admission she noticed the patient to be dizzy, slurring speech, and pale. The mother became very concerned about the dizziness as the patient was stumbling and a few hours prior to presentation, became increasingly sleepy. The patient does have a history of depression and is controlled on sertraline. Other medications in the home include Metformin, Amlodipine, and Clonidine. The patient denies ingesting any substance. She does have a prior attempt two years prior, after an argument with her mother; however, her mother was able to “stop” her prior to the attempt. She presents to the ER via EMS. Her vital signs are notable for HR 50 bpm with occasional PACs and non-conducted QRS complexes on telemetry; BP of 75/40. A physical exam is notable for AMS and GCS of 10. She is noted to have clear breath sounds, with a cardiac exam notable for slowed and delayed pulses. Initial laboratory work is notable for serum glucose 180 mg/dL and B HCG negative. Initial resuscitation is begun with IV fluids and atropine. Serum acetaminophen and ASA levels are sent and upon stabilization, the patient presents to the PICU for admission.

To summarize key elements from this case, this patient has:

• A history of depression with prior attempt
• An acute bout of altered mental status
• Bradycardia, hypotension, and hyperglycemia.
• All of which brings up a concern for an acute ingestion
• Let’s take a step back and talk about the approach to ingestions in the PICU.

1. What are key aspects to consider in the work-up of these patients?

• History and physical are key:
• Stratifying acute or chronic ingestions
• Baseline prescription medications a patient may be taking or have access to in the household
• Whether the ingestion involves a single drug or co-ingestants are all first steps in evaluating your patient.
• In an undifferentiated patient, management is paramount. Initial management is focused on pattern recognition and acute stabilization.
• A brief initial screening examination should be performed on all patients to identify immediate measures required to stabilize and prevent deterioration of the patient. Assess the airway, vital signs, mental status, pupil size, and skin temperature and moisture.

These components of your physical exam should help allude to a toxidrome, and these syndromes are frequently tested on board examinations. Any time a patient has hypotension and bradycardia other drugs that should be considered include beta blockers, digoxin, clonidine, as well as ingestion of barbiturates, opioids, and even benzodiazepines.

1. What are some diagnostic studies you will want to send immediately in a patient with suspected ingestion?
2. Immediate diagnostic studies to be performed include pulse oximetry, continuous cardiac monitoring, an electrocardiogram (ECG), and a capillary glucose measurement (in altered patients). Intravenous (IV) access should be obtained in all cases of serious ingestion.
3. You also want to send beta-hcg and acetaminophen and salicylate levels. an extended toxicology screen may be required on a case-by-case basis.

One study found detectable serum acetaminophen concentrations in 9.6 percent of all overdose patients; almost one-third of this subset denied ingestion of acetaminophen.

1. Now that you’ve focused on ABCs are there more detailed laboratory studies to send in patients with toxidromes?
2. Symptomatic patients and those with an unreliable or unknown history should, at a minimum, undergo urinalysis and measurement of serum electrolytes, blood urea nitrogen (BUN), creatinine, and glucose. Measurements of serum ketones, creatine kinase, liver function tests, lipase, ionized calcium, and magnesium should also be performed in most significantly ill patients.
3. Additional testing may be useful in specific circumstances, such as serum osmolality in suspected toxic alcohol ingestion. We will discuss these in a separate episode.
4. Patients who continue to be altered may also undergo head CT as head trauma is frequently associated with ingestions.
5. ECG, Echocardiography helps to distinguish refractory hypotension due to vasodilatation from pump failure. CXR may be needed to evaluate pulmonary edema and guide fluid management. Abdominal radiograph or US may be required in cases of suspected bowel ischemia/perforation. Ingestion of a large number of CCB tablets, especially sustained-release tablets, the pills may aggregate to form bezoars and the drug can be continuously absorbed for long periods.
6. To go back to our case, with history and initial diagnostics only, how are we able to stratify whether this patient took a CCB versus a beta-blocker?
7. This is a great question. This patient had an electrocardiogram, which showed changes associated with CCB poisoning including a PR interval prolongation and bradydysrhythmia. Importantly, our patient’s serum glucose was >150 mg/dL and thus, the presence of hyperglycemia in a non-diabetic patient may help to distinguish CCB from beta-blocker poisoning.

The mechanism of hyperglycemia in CCB involves the CCB causing inhibition of calcium-mediated insulin release; remember that the serum glucose elevation is rarely clinically significant, and is used for diagnostic purposes to stratify between bb and CCB overdose.

Per history, our patient had access to amlodipine which is the likely agent she ingested. Can you shed some light on how non-DHP CCB overdoses are different than DHP overdoses?

• Let’s review some basic science & pharmacology:
• Calcium channel blockers (CCBs) can be divided into two major categories based on their predominant physiologic effects: dihydropyridines, which preferentially block the L-type calcium channels in the vasculature; and non-dihydropyridines, such as verapamil and diltiazem which selectively block L-type calcium channels in the myocardium.
• L-type calcium channels are responsible for myocardial contractility and vascular smooth muscle contractility; they also affect conducting and pacemaker cells.
• In general DHP (which has the suffix dipine) are potent vasodilators that have little negative effect upon cardiac contractility or conduction at standard doses.
• In contrast, verapamil and diltiazem are relatively weak vasodilators but have a depressive effect on cardiac conduction and contractility.
• How does this framework help with our understanding of CCB ingestions?
• Overdose with dihydropyridine CCBs (amlodipine/nifedipine) causes hypotension coupled with reflex tachycardia, although severe toxicity may result in hypotension and bradycardia. This is what we saw in our patient — severe toxicity.
• Overdose with non-DHP CCB like verapamil or diltiazem also causes a dangerous combination of hypotension and bradycardia. As these are cardiac-specific, other findings may include signs of heart failure (eg, pulmonary crackles or jugular venous distension). In anecdotal articles, CCB-poisoned patients may maintain a surprisingly clear mental status in the setting of hypotension.

Let’s conclude our episode by focusing on the management of CCB overdose. We will break this section down into initial resuscitation, the role of gastrointestinal decontamination, and specific medial therapies.

Let’s start with the ABC approach and initial resuscitation. What are some key management pearls?

An immediate consult with Poison control center is a must: PCC can help guide monitoring, investigational studies as well as patient management.

Empiric use of Glucagon 5-15mg IV may be warranted when patient presents with hypotension/bradycardia. Glucagon promotes calcium entry into cells via stimulation of a receptor that is considered to be separate from adrenergic receptors.

• Circulation is the main focus of the treatment of calcium channel blocker (CCB) exposures. Hypotension and bradycardia can be profound and refractory even to maximal treatment.
• Judicious use of Intravenous (IV) fluids, as well as vasopressors, are the initial therapy for hypotension, and atropine for the initial treatment for bradycardia, but both may be insufficient.

Our patient in our case maintained clear mental status despite hypotension and bradycardia. However, we need to reassess these patients frequently, as precipitous deterioration is common, and many will eventually require intubation and mechanical ventilation. With the exception of nimodipine, calcium channel blockers have poor CNS penetration. Therefore, drowsiness, seizures, or altered mental status in the absence of hemodynamic collapse should alert the physician to the possibility of co-ingestions.

For patients with CCB overdose, is there a role for orogastric lavage?

• Oro-gastric lavage and activated charcoal may be necessary for patients who present within one to two hours, however, make sure to use caution in a patient who has borderline mental status and who may not be able to protect their airway.
• Another clinical pearl to consider is that the vagal stimulation from orogastric lavage may exacerbate CCB-induced hypotension and bradycardia.

Let’s transition and talk about specific medical therapies. In diving deep into the literature, we will talk about the role of catecholamines/vasopressors, Atropine, IV Ca, Glucagon, Insulin & Dextrose, and Lipid emulsion therapies.

What vasopressors/catecholamines are used in CCB?

• Direct-acting vasopressors such as norepinephrine/epinephrine infusion is preferred in CCB. Angiotensin II (Giapreza) -a vasoconstrictor can be considered in patients 18 years of age and above.

How does atropine help in CCB overdose?

• Atropine is a muscarinic antagonistic and thus should be administered to any patient with symptomatic bradycardia after CCB. Pediatric dosing is 0.02 mg/kg IV, with a minimum dose of 0.1 mg to avoid the paradoxical bradycardia that may result from very small doses of this medication.
• What about IV Calcium?

• Calcium salts are often used to overcome the cardiovascular effects of CCBs.
• As calcium channel blockers as the name implies, inhibit calcium it is important for us to understand that CCB poisoning interferes with both the serum concentration and the intracellular handling of calcium.
• Anecdotally high-dose continuous infusion of calcium should be administered — after bolus dosing, a reasonable infusion of Ca Cl to consider is 0.5 mEq of calcium/kg per hour. Close monitoring of the serum or ionized calcium concentration (measurements every two hours) and serial electrocardiograms (ECGs) are necessary to avoid clinically significant hypercalcemia, which has been reported with intensive calcium therapy. The use of an aline for serial labs and hemodynamic monitoring is essential.
• What about Glucose and Insulin:
• High dose insulin (1-10U/KG/hr after a 1U/kg bolus dose) is required in CCB along with dextrose which helps to counteract the hypoglycemia. Hypokalemia can occur due to a shift in K intracellularly and requires close monitoring. It generally takes approximately 30 minutes to see the effects from HIE. The main beneficial effect is on myocardial function (ie, ejection fraction and cardiac output), with subsequent improvement in blood pressure and perfusion although improvement in cardiac rhythm has also been reported.
• Investigational therapies: use of methylene blue (1-2mg/kg), lipid emulsion can be tried as a last resort in those with severe hemodynamic issues and can be used even if the patient is not in cardiac arrest.
• Please visit our episode entitled PICU Applications of Lipid Emulsion Therapy. The use of lipids is controversial however in general: an IV bolus of 1 to 1.5 mL/kg is given over one minute of a 20 percent lipid emulsion solution. If there is no response, the same dose may be repeated in cases of cardiac arrest every three to five minutes for a total of three bolus doses. Following the initial bolus, an infusion is started at a rate of 0.25 to 0.5 mL/kg per minute until hemodynamic recovery occurs. The infusion is generally maintained for 30 to 60 minutes. The infusion rate may be increased if the patient's blood pressure drops.
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• Procedures that may be required in CCB include: 1) A transvenous pacemaker may be placed if the transthoracic cutaneous pacer fails to capture in the face of symptomatic bradycardia. Pacing may decrease the need for pressors in a patient who may not tolerate a positive cardiac inotrope because of cardiac ischemia, although this likely is not a concern in children. Cardiac pacing is typically required for 12-48 hours.
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• 2) Extracorporeal membrane oxygenation (ECMO) has also been attempted in patients who have hypotension refractory to all pharmacologic therapies.
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• Rahul what are Key objective take-aways from today’s episode:

1. Hypotension & bradycardia is a life-threatening toxidrome that is related to circulatory collapse and poor cerebral perfusion.
2. Differential includes:
3. CCB
4. BB
5. Digoxin
6. Clonidine
7. CNS depressants
8. A stepwise approach to CCB includes — close monitoring of ABCs, and in severely symptomatic patients: IV boluses of isotonic crystalloid, IV calcium salts, IV glucagon, IV high-dose insulin and glucose, IV vasopressor (eg, norepinephrine), and IV lipid emulsion therapy in refractory cases.

This concludes our episode on Approach to Calcium Channel Blockers. We hope you found value in our short, case-based podcast. We welcome you to share your feedback, subscribe & place a review on our podcast! Please visit our website picudoconcall.org which showcases our episodes as well as...