A 40 year old woman presents to the ED two hours after ingesting twenty of her own antihypertensive medications. The patient offers no complaints, has normal vital signs (BP 110/60, 68, 16, afebrile), and her initial physical exam finds no abnormalities. She is placed in a room and given a bottle of activated charcoal to drink. Thirty minutes later, upon reevaluation, the patient is obtunded, hypotensive and bradycardic.
Could this have been avoided?
This case is both common and difficult. Two hours after ingesting a significant number of pills, most clinicians would expect to note abnormalities in either the patient's physical examination or the vital signs. In this patient such finding were, in fact, overlooked. The patient is known to have hypertension, so the finding of "normal" vital signs may be an early clue to the impending decompensation. Furthermore, antihypertensive medications are commonly available as sustained release preparations to reduce side effects and perhaps enhance efficacy. Such formulations may cause delayed decompensation since only small amounts of drug are released initially, and it may take several hours for significant systemic absorption to occur.
What agents are used to treat hypertension?
Although many agents have been used (and are still used) in the antihypertensive pharmacopoeia, only sympatholytics (e.g. clonidine, methyldopa, prazosin), diuretics, angiotensin converting enzyme inhibitors (ACE inhibitors), calcium channel blockers (CCB), and beta adrenergic antagonists (beta blockers) remain in use. The sympatholytics, although decreasing in popularity, still produce occasional toxicity, especially in children, in whom even small doses may produce profound toxicity. However, symptomatology from these agents is generally noted rapidly in adults with significant ingestions, and treatment with fluids and activated charcoal is usually sufficient. Patients with altered mental status due to centrally acting agents (clonidine) may improve with naloxone. Toxicity from orally administered diuretics and ACE inhibitors is generally inconsequential.
Calcium channel blockers and beta blockers account for more poisonings and deaths annually than all other antihypertensive agents combined. Through competitive antagonism of norepinephrine at the beta adrenergic receptor, beta blockers reduce vascular tone and cardiac workload, resulting in decreased blood pressure. The calcium channel blockers are a heterogeneous group of agents having in common the ability to "cover" the slow, L-type, voltage dependent calcium channels located on the myocardial and vascular smooth muscle.
How do patients with calcium channel blocker overdoses present? What is effective therapy?
The patient had, in fact, ingested twenty sustained release verapamil tablets. Clinically, there are more differences between the various calcium channel blockers available, than between CCB's and beta blockers in general. The dihydropyridine CCB's, including nifedipine, isradipine, amlodipine, nicardipine and felodipine, are primarily vasodilators. Hypotension is responsive to fluid, and cardiac dysfunction does not occur. The dihydropyridine class agents differ from one another on the basis of their kinetics; e.g. amlodipine has a longer duration of action than nifedipine (thus, sustained release nifedipine).
Verapamil has significant myocardial effects; negative inotropic effects, suppression of AV nodal conduction, and reduction of SA nodal automaticity. Diltiazem has properties midway between the dihydropyridines and verapamil. Patients ingesting verapamil or diltiazem present with hypotension secondary to combined peripheral vasodilation and negative inotropy, often compounded by bradycardia. Although patients often appear clinically well at profound levels of hypotension, mental status depression is common in severe poisonings. Electrocardiogram findings include sinus bradycardia, first degree AV block (due to reduced AV conduction) and escape rhythms. Initial drug therapy for symptomatic patients or those with significant vital sign abnormalities should include atropine, which is often ineffective, and calcium ions. Calcium ions are available as two different salts, either of which is effective is given in appropriate doses. The chloride salt contains three times the amount of calcium ion per mL (both formulated as the 10% solution) as the gluconate salt, so threefold more volume need to be administered for equivalent effect. One gram of calcium chloride (10%) or three grams of calcium gluconate (10%) given by intravenous bolus through a well positioned peripheral catheter may be repeated safely several times over the initial fifteen minutes. With higher doses, symptoms of hypercalcemia may develop, since only one type (the L type) of calcium channel is blocked by the CCB's. Calcium salts need to be given rapidly and not infused since the desired effect is to maximally raise the local calcium concentration at the channel site to create the largest trans-channel gradient. This will "push" the calcium into the cell and overcome the channel blockade. Raising the "serum calcium level" per se is not effective.
Second line agent include agents with vasopressor or positive inotropic effect, notably catecholamines. The choice of agents should be guided by invasive hemodynamic parameters if possible; if not available norepinephrine would be an adequate starting agent. This agent result in both peripheral vasoconstriction and positive inotropy, both of which are adversely effected by CCB's. Glucagon has no added benefit (unlike in beta blocker poisoned patients), may have adverse effects, and is not familiar to most clinicians.
Of critical importance in the management of poisoned patients is gastrointestinal decontamination. Preventing absorption prevents toxicity. Most sustained release preparations are too large to be removed by a lavage tube and do not disintegrate like other formulations. Activated charcoal, although able to bind the drug, may have difficulty remaining in constant contact with the constantly releasing tablets as gastrointestinal transit times may differ for both. Therefore, whole bowel irrigation (WBI) with a polyethylene glycol solution may be most effective. By rapid infusion at 2 liters per hour into a nasogastric tube, WBI allows the pills to be washed through the gastrointestinal tract before significant drug release occurs. WBI must be started early, and should probably not be used late if several doses of activated charcoal have been administered since already bound drug may be displaced from the charcoal permitting absorption.
What happened to this patient?
She received three grams of calcium chloride with a partial response; her electrocardiogram (which was finally done!) went from complete heart block to first degree AV block at 50, and her blood pressure rose to 100/60. WBI was initiated and completed within 6 hours. Although she remained hypotensive for 24 hours, she eventually stabilized and was discharged from intensive care.