The Crashing Calcium Channel Blocker Overdose Patient

Although calcium channel blockers (CCB) are one of the more commonly prescribed medications, they are also one of the more toxic ones when ingested at supratherapeutic doses. As a class, antihypertensives are second only to antipsychotics in mortality when overdosed, and calcium channel blockers are the most toxic antihypertensives.[1] This is especially true for children, for whom the toxic dose can be as little as one to two pills. Calcium channel blocker ingestions should be taken seriously.

As a class, CCBs can be divided into non-dihydropyridines (verapamil and diltiazem) and dihydropyridines (amlodipine, nifedipine, and nimodipine). The nondihydropyridines are more specific to the cardiac myocardium and are quicker to cause bradycardia and hypotension. The dihydropyridines are more specific to the peripheral vasculature and can present with reflex tachycardia; however, at late stages or in high concentration, the specificity becomes overwhelmed and bradycardia will result.[2]^,[3]^,[4]

In both therapy and overdose, CCBs work via the L-type calcium receptor, which is primarily located in the myocardium. Outside of the therapeutic window, interaction with this channel results in myocardial depression, negative inotropy, and possible AV nodal blockade.[5]

At supratherapeutic levels, CCBs will also interact with the L-type calcium channel receptor in the pancreas. This effect is usually insignificant, but overdose leads to a decrease in insulin secretion, as well as a decrease in peripheral insulin resistance and a decrease in glucose uptake. The end result of this interaction is that even non-diabetic patients with a calcium channel blocker overdose will present with elevated glucose and ketones with an elevated anion gap acidosis.[6]

In additional to a “DKA-like” picture, these patients may be hypoperfused, leading to a lactate buildup. To further exacerbate the issue, blocking L-type calcium channels interferes with the calcium-dependent portions of the Krebs cycle, resulting in a further lactic acidosis. The acidity of the blood, in turn, facilitates the binding of the CCB to the calcium channel, and the patient enters a pathophysiological death spiral.

 

The patient’s ABG results roll in:

pH:  6.84

PaCO₂: 18.5 mm Hg

PaO₂: 117 mm Hg

HCO₃: 5.1 mEq/L

Lactate: 20 mmol/L

As well as the metabolic panel:

Na: 149 mEq/L

K: 5.4 mEq/L

Cl: 91 mEq/L

HCO3: 3 mEq/L

BUN: 14 mEq/L

Cr: 2.4 mEq/L

Glucose: 350 mEq/L

Anion gap: 55

Given the seriousness of this particular overdose, even patients with reported ingestion but stable vital signs and no symptoms should be observed for 12 – 24 hours. Charcoal and/or whole bowel irrigation may be considered within four hours of ingestion, but the patient must be cooperative/protecting his/her airway (or intubated).[7]

In the case of hypotension, a bolus of IV fluids may initially be effective to address the vasodilation. Care should be taken after the first liter, as patients are subject to pulmonary edema due to decreased cardiac contractility.^7,[8]^,[9]

Traditionally, the staple in calcium channel overdose has been to provide calcium in an effort to overwhelm the antagonized calcium receptor. Recent data suggests that its effect is less robust than initially believed and may be only short live. Calcium is relatively benign and even the most critical authors still recommend its use as an adjunct at least. The dosing is a 3 – 6 g bolus of calcium gluconate or 1 – 2 g bolus of calcium chloride; if effective, it should be followed by an infusion, titrated to blood pressure.^7,8,9

As calcium is likely to be a shorter-acting treatment of vasodilation, vasopressors may be started concurrently. There’s no real data suggesting that one is better than the other in this particular toxidrome, but expert opinion recommends epinephrine if there is decreased contractility on bedside echo and norepinephrine if contractility is normal.⁷

Given the pathophysiology of calcium channel blockers discussed, it shouldn’t be a surprise that providing insulin may be effective as an antidote. In animal studies, it’s been shown to improve survival when compared to calcium and fluids. Observational studies on humans also agree with this data.[10] In addition to counteracting the decrease in insulin secretion via the L-type calcium channel receptor pathway, exogenous insulin has been shown to independently increase cardiac contractility, vasodilate the cardiac capillary bed, and increase cardiac myocyte carbohydrate uptake. [11]^,[12]^,[13]^,[14]

From a practical standpoint, this therapy often takes up to 20 minutes to take effect. Therefore, if your patient is actively crashing, insulin therapy should be started concurrently with more immediately acting calcium, fluid resuscitation, and pressors. The recommendation is to start the titration at 1U/kg/hr and titrate up to effect. It’s worth noting that some authors recommend going as high as 10U/kg/hr if necessary, with case reports of dosing as high as 22 U/kg/hr without serious adverse effects. Compare this to the logarithmically lower dosing for diabetic ketoacidosis!^11,12,13,14

The adverse effects of high-dose insulin are hypoglycemia and hypokalemia, which are easily treated with a glucose drip and potassium supplementation. Interestingly, a glucose drip is never needed in some patients – the underlying physiology of this is unclear. Some authors believe that hypokalemia may actually be helpful, as it prolongs the repolarization phase and allows more time for calcium to enter the myocytes.[15] This “permissive hypokalemia” is controversial.

You’ve tried fluids and calcium, pressors are running, and you’ve initiated high-dose insulin therapy. Your patient is still in shock, and it looks to be a sign of things to come. Now what? The following therapies have little data to support their use, but they have little downside in the peri-arrest patient. ^{7,8,9,14,15,[16]}

Lipid emulsion therapy is theorized to be helpful, as it sequesters CCBs within the bloodstream. It’s also thought to independently improve cardiac contractility and stimulate insulin secretion. However, it comes at the risk of fat embolism, infection, and ARDS, so should only be used for patients in which the aforementioned therapies have not been sufficient. Of note, the initial bolus of 1.5 ml/kg and maintenance infusion of 0.25ml/kg/min (about a liter an hour) is faster than most IV pumps can handle.

As there is no physiological nodal blockade, atropine is unlikely to have a real effect, but is still recommended by expert consensus and ACLS.[17]Dosing is 0.5 mg every two minutes as with symptomatic bradycardia.

Cardiac pacing is also unlikely to have an effect, as the entire myocardium is poisoned (as opposed to an isolated issue with the conduction system). However, if your patient is about to die, slap those pads on. Note that there’s no data that transvenous pacing is any more effective.

Glucagon is the mainstay of beta blocker toxicity and has been shown to have some benefit in calcium channel blocker overdose, although studies evaluation this therapy were performed using porcine glucagon which contains insulin. The 2017 guidelines recommend against using this.⁸ Expect copious vomiting.

Bicarbonate can be attempted for severe acidosis, but it should be noted that it will precipitate out as a salt if given in the same line as calcium.

Methylene blue prevents vasodilation by inhibiting the NO pathway, and there is data to support its use in refractory shock. Consider it a desperate measure.

Lastly, levosimendan sensitizes the myocardium to calcium and may be helpful, although it is not yet available in the US.

If none (or most) of these drugs haven’t worked, and you’re at a hospital with ECMO or intra-aortic balloon pumps, this might be a situation where both may be considered, since CCB toxicity is reversible.[18]

This post would be remiss without mentioning the general lack of high-level evidence for all of the above interventions (evidence is mostly from case reports). In the most recent 2017 guidelines of calcium channel overdose therapy, no level of evidence higher than a 1D (expert opinion) was given for any treatment,⁸ and according to ACLS, “There are no data to support the use of specific antidotes in the setting of cardiac arrest due to calcium channel blocker overdose.”¹⁷

You continue to bolus your patient with another liter of NS and 3 g of calcium gluconate. After performing a bedside echo and finding “poor squeeze”, you initiate a  epinephrine drip through adequate, large-bore peripheral access. As your junior resident places a central line, you run a high-dose insulin drip while monitoring potassium and glucose. These interventions are effective enough to stabilize the patient for admission to the ICU. You hope that they will be able to wean the insulin and epinephrine drips as the patient metabolizes the drug. You leave your ICU consult in awe as you ride off into the sunset.