Diltiazem overdose: Case report and review

The Journal of Emergency

Medicine,

Vol. 9, pp. 357-366,

Printed in the USA. Copyright 0 1991 Pergamon Press plc

1991

Toxicology

DILTIAZEM Ford C. Erickson,

*Department

of Emergency

OVERDOSE:

CASE REPORT AND REVIEW

Louis J. Ling, MD, FACEP,* Gregory A. Grande, and Deborah L. Anderson, war&t

MD,*

RPh,t

Medicine,

and tHennepin Regional Poison Center, Hennepin County Medical Center, Minneapolis, Minnesota Reprint address: Ford C. Erickson, MD, Emergency Department, North Memorial Medical Center, 3300 Oakdale North, Robbinsdale, MN 55422

0 Abstract - We present a case of diltiazem overdose in which the patient ingested 4.2 grams ln an apparent sultide attempt. He arrived in the emergency department two hours posthgestion with a blood pressure of 60/40 torr and a heart rate of 62 beats/min in a junctional rhythm. Intervention included activated charcoal, gastric lavage, intravenous fluids, calcium (both chloride and gluconate), dopamine, and atropine with improvement in vital signs. Dlltiazem levels were obtained and half-life calculated. This ingestion is one of the largest reported in the literature and is remarkable in that the patient recovered without pacing or other extraordinary measures. All eight previously published cases of diltiazem overdose, including all unpublished reports to the manufacturer, are reviewed and their management strategies examined. Successful treatment in which recovery has occurred ln less than 48 hours, includes pressers, calcium, glucagon, pacing, and charcoal hemoperfusion. A strategy for emergency physicians to use when approaching this problem is suggested from the review.

INTRODUCTION

Since their advent over a decade ago, calcium channel blockers (CCBs) have been used to treat a variety of cardiovascular diseases including supraventricular tachychycardia, ischemic heart disease, hypertrophic cardiomyopathy, and hypertension (1). Of the three most common CCBs on the market today, verapamil was the first to find clinical application with its negative inotropit and AV node conduction effects. Nifedipine, while having a smaller effect on the AV node, causes hypotension and reflex tachycardia, limiting its use clinically. On the other hand, diltiazem offers benefits similar to verapamil without the severity of its complications and, because of this, has become a well-accepted treatment for angina (1,2). Due to its increasing popularity and availability, diltiazem toxicity has been seen with escalating frequency in emergency departments (3-l 1). While the most dramatic presentation is of the intentional overdose, the subtleties of unintentional mild toxic states may go unrecognized. In this paper, we present one of the largest ingestions ever reported and discuss its management and outcome. The other case reports and their management strategies are reviewed to define the best approach to the emergency management of a diltiazem toxic patient.

0 Keywords - diltiazem; calcium channel blocker; overdose; toxicology

Presented at the Annual Scientific Meeting of AACT/AAPCC/ ABMTKAPCC in Baltimore, Maryland, October 4, 1988.

B

Toxicology-one

of the most critical and challenging areas confronting the emergency department staff-is

nated by Kenneth Ku&, MD, of the Rocky Mountain Poison Center. RECEIVED: 13 November 1990; FINALSUBMISSIONRECEIVED:7 December 1990 ACCEPTED: 28 January 1991

coordi-

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358

F. C. Erickson, L. J. Ling, G. A. Grande,

D. L. Anderson

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30 0

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200

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Figure 1. Filled arrow indicates administration of 1Occ 10% calcium. Open arrow indicates admlnlstratlon of atroplne 0.5 SBP = systolic blood pressure. DA = dopamlne. HR = heart rate.

CASE REPORT A 45-year-old male ingested seventy 60-mg tablets of diltiazem (4.2 grams) and four 2OO-mg Clinoril tablets two hours prior to paramedic response. The patient was lethargic but oriented, complaining of generalized abdominal pain, persistent emesis, and dizziness. He had a prehospital blood pressure of 60/40 torr, a pulse of 80 beats/min, and a respiratory rate of 16/min. Oxygen and fluid resuscitation were started while a MAST suit was applied and inflated. Cardiac monitoring displayed a sinus rhythm with occasional premature atria1 contractions. Case management over the first 4 and 24 hours is illustrated in Figures 1 and 2, respectively. Upon arrival to the emergency department, the patient had a systolic blood pressure of 60 torr and received a bolus of 2 g 10% calcium chloride intravenously. Within minutes, his blood pressure improved to 110 torr systolic. The MAST suit was deflated without consequence while maintaining intravenous fluids wide open. The patient’s airway remained patent with an intact gag reflex and a clearing level of consciousness. He was able to report a myocardial infarction with angioplasty 3 months earlier while denying any chest dis-

mg.

comfort. Examination revealed clear lungs, normal heart tones, a benign abdomen, good peripheral pulses, normal rectal tone, and guaiac-negative stool. The patient was given 50 g of activated charcoal with sorbitol before and after a 3-liter gastric lavage. The lavage effluent revealed no pill fragments and was, unfortunately, complicated by emesis around the lavage tube. Arterial blood gases on room air were pH 7.39 units, pC0, 35 torr, pG, 78.4 torr, and HCO, 37 torr. Electrocardiogram (ECG) demonstrated a junctional rhythm with evidence of an old inferior infarction but no acute ischemic changes. After a total of 1200 cc’s of crystalloid was administered intravenously, the patient had stable vital signs. He was transferred to the coronary care unit with a blood pressure of 103/59 torr and a pulse of 54 beats/ min. Shortly after arrival, his blood pressure dropped to 92/60 torr with a heart rate of 45 beats/mm. Atropine 1 mg was given with fluids, and after a transient improvement, his blood pressure decreased to 72 torr systolic, at which time dopamine was started. His nausea and vomiting recurred, and the patient was intubated to protect his airway. Dopamine was titrated to 28 p&kg, and 1 g of 10% calcium gluconate was given

359

Diltiazem Overdose: Report/Review

Case Manaaement

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Time (hr) 10 (cc)

12 11285

14

16

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Figure 2. Filled arrow indicates administration of 10 cc 10% calclum. SBP = systolic blood pressure. DA = dopamlne.

in an attempt to sustain his pressure at 80 torr. Because of persistent hypotension, a Swan-Ganz catheter was placed revealing a pulmonary arterial systolic (PAS) pressure/pulmonary arterial diastolic (PAD) pressure of 33/E, pulmonary arterial mean (PAM) pressure/pulmonary capillary wedge (PCWP) pressure of 21/15, and a (RAP) right atria1 pressure of 14. Chest roentgenogram revealed an early infiltrate consistent with aspiration, and the patient was started on cefotetan (Cefotan) while his p0, was maintained at 80 torr on 50% PIO,. Intravenous fluids were titrated to maintain a pulmonary capillary wedge pressure of 14 to 16 tot-r. Dopamine was increased to 30 pg/kg momentarily with an additional 1 g 10% calcium gluconate as the patient’s blood pressure subsequently increased to 120 torr systolic. Dopamine was weaned over the next 16 hours. The patient’s junctional rhythm with occasional bigeminy converted to a normal sinus rhythm after 8 hours with one episode of 2:l second-degree AV block. He had intermittent asymptomatic bigeminy and unifocal premature ventricular contractions, which went untreated. After 48 hours, he was extubated, and on the 4th hospital day, he was transferred to an inpatient psychiatry unit with a resolving aspiration pneumonia. A urine toxicology screen as well as serum for barbiturate screen, acetaminophen, salicylate, and ethanol

levels were all negative. Diltiazem serum levels (ng/ mL) were obtained at 2, 7, and 10 hours postingestion and were 3323, 1378, and 1050, respectively. DISCUSSION Pharmacokinetics

The three standard CCBs in use today are verapamil, nifedipine, and diltiazem. All three medications cause an increase in coronary blood flow and vasodilatation of vascular smooth muscle to varying degrees (9). While they all inhibit transmembrane ion flux through calcium “slow” channels, their pharmacokinetics, structure, and affinity for specific tissues cause them to have slightly different cardiovascular effects (2). Verapamil has a greater affinity for the calcium “slow” channels in the cardiac conducting system than vascular tissue (2). This is clinically evidenced by its effect of slowing conduction through the AV node (2). It undergoes hepatic metabolism almost exclusively yielding one active metabolite , norverapamil , with 20% of the original activity (1). Plasma levels of verapamil correlate with dosing and toxic effect, producing AV block before cardiac depression (1). Its half-life is prolonged with drug accumulation (1).

360

F. C. Erickson, L. J. Ling, G. A. Grande, D. L. Anderson Table 1. Dlltlazem Overdose Management Strategies Amount Ingested Report Buffet (1984) Gibelin (1984) Rey (1984) Christiansen (1988) Anthony (1988) Malcolm (1986) Snover (1986) Jakubowski (1987) Erickson (1991) M841658” M851408” M851635” M851895” M860728” M861417” M862161” M862228” M870797” M882080” M882684” M883890” M881199” Ma901 16” M890378”

Age (year) 58 72 54 44 49 58 74 41 45 46 37 NA 76 66 26 46 69 52 NA 52 82 84 13 41

Peak Bloodt

(grams)* Level (ng/mL) 1.8 2.84 1.8 6.0 1.2 10.8 1.5 1.8 4.2 1.8-3.0 NA 3.0 0.15 NA NA 6.0 0.9 NA

1.8-3.0 NA 3.6 0.72-2.88 12.0 NA

118Ol8 NA NA NA 1085.811 16701439 4000/NA NA 332312 NA 4600INA NA 611.4/NA 2400/NA NA NA NA > 1OOlNA NA NA 3000INA 0.27INA 114lNA 186lNA

Co-ingestants TiaprideS None NitrazepamS NitrazepamS Metoprolol None None None Sulindac None TolazimidelETOH NA Triazolam None NA None Metoprolol NA NA ETOH None DoxepinKarbamazepine Meprobamateq PhenytoinRheophylline

‘Drugs are given as total doses or maximum rates when possible. tReported as: peak level/time from ingestion (hours). STiapride: a neuroleptic not used in U.S.A.; Nitrazepam: investigational benzodiazepine in U.S.A. §First level obtained on patient. IlCases reported to Marion Laboratories but unpublished. NA = information not available. “Also took ethyl biscoumacetate and Aceprometazine.

Nifedipine has a greater affinity for vascular tissue and has its marked effects against vascular spasm and hypertension with no AV nodal interference (1,2). Nifedipine has no active metabolites with variable interpatient bioavailability, reaching its peak drug level between 2 and 6 hours postingestion (1). It is unclear how the plasma level correlates with its toxicity (1). Diltiazem has affinity for both conductive tissue and vascular tissue, but in general, is more analogous to verapamil than to nifedipine, evidenced by its ability to also slow conduction through the AV node (1,2). Diltiazem prolongs the AV node functional refractory period 6% to 18% and the effective refractory period 10% to 25%; verapamil’s effect is twice that (2). At normal SA nodes, diltiazem generally acts to reduce the heart rate while verapamil accelerates it; however, diseased SA nodes have significantly prolonged recovery times, and SA node arrest has been reported with both agents (2). The question of whether diltiazem affects normal SA nodes came under dispute in 1983 when sinus arrest was reported in patients with previously normal SA nodes taking normal adult doses (12). McGraw and colleagues (33) followed almost 4000 Japanese patients

taking normal doses during a marketing study and reported SA-block and AV-block incidences of 0.03% each. Both verapamil and diltiazem have negative inotropic effects; however, in the case of the latter, it is offset by peripheral dilatation (10). Diltiazem is subject to a large first-pass effect with wide interpatient variability giving no correlation between dosing and plasma levels (1). This is demonstrated in Table 1 by comparing the amount ingested and peak blood level in our case with Snover and colleagues (9). It undergoes hepatic metabolism and has one active metabolite, desacetyl diltiazem, which has 25% to 50% of the original activity (14). While the therapeutic plasma level of diltiazem is 50 to 200 ng/ mL, there is also no correlation between plasma levels and toxicity in limited studies making the clinical usefulness of plasma levels questionable (1). Time to peak plasma concentrations postingestion has been reported to range from 2 to 8 hours, suggesting theoretical benefit from late gastric lavage (1,3). Diltiazem’s clearance is independent of the amount ingested. In reports by Malcom and colleagues (8) and Buffet and colleagues (3), even large ingestions of dil-

Diltiazem

Overdose:

361

Report/Review

Diltiazem Kinetics

Halt-life

D

i 1

= 0.693Irate

Rate of Elimination

t i a z 8 m

Slope of Logarithmic Regression Curve

m

.

of elimination

ln(!irst

level)

second

- ln(second

time

Half-li!e

;

level)

- first time

= 4.6 hours

-

m 1

Time

zero is

900 0

2

4

6

8

10

12

Flgum 3. Half-life calculated using first-order klnetlcs equations.

tiazem follow linear, first-order kinetics with a half-life of 5 to 8 hours. In our report using standard first-order kinetics equations, the calculated half-life of 4.6 hours is consistent with Buffet and colleagues (3) (see Figure 3).

Most resolved their signs of toxicity within 3 days, although 6 expired. Two patients known to develop asystole recovered. The 6 patients who expired come from unpublished reports, and limited information is available ( 11). Treatment

Demographics and Side Effects of Overdose

Currently, there are 24 known reports of diltiazem overdose of which 8 are published and an additional 15 have been reported to the manufacturer (Tables la) (3-11). Patient age ranges from 13 to 76, with an average age of 50. Amounts ingested range from 150 mg (maximum therapeutic dosing schedule is 120 mg qid) to 12 g, with half involving known co-ingestants. Almost all patients developed bradycardia and hypotension with rhythms of first, second, and third-degree AV block, sinus bradycardia, sinus arrest with junctional escapes, accelerated junctional rhythm, and asystole.

Treatment of diltiazem overdose consists of pressors and fluid infusions to counteract vasodilatation, with chronotropic agents and electrical pacing for bradycardia (15,16). Medications most commonly used in the 24 reported cases include calcium, an-opine, dopamine, and isoproterenol in order of decreasing frequency (Tables 2 through 5). The use of glucagon has revealed mixed success. Glucagon is a polypeptide hormone that promotes glycogenolysis and hyperglycemia, but also has chronotropit and inotropic cardiovascular effects (18,19). Its postulated mechanism of action is through glucagon-

F.

C. Erickson, L. J. Ling, G. A. Grande, D. L. Anderson

Table 2. Diitiazem Overdose Management Stategies

Report Buffet (1984) Gibelin (1984) Rey (1984) Christiansen (1986) Anthony (1986) Malcolm (1986) Snover (1986) Jakubowski (1987) Erickson (1991) M6416585 M8514085 M8516359 M851895§ Ma607285 Ma614175 Ma821615 M6622285 M6707975 M8820805 Ma826845 MB836905 M881199§ Ma901 1Sf$ Ma903769

Lowest Systolic BP

Lowest Heart Rate

Predominant Rhythm

70 70 70 60 60 80 0 140 60 130 0 NA NA 0 NA NA 78 NA NA NA 40 NA NA NA

50 48 50 27 25 80 0 35* 45 38 0 NA NA 0 NA NA 42 NA NA NA 42 NA NA NA

Complete AV block Complete AV block Complete AV block Complete AV block Complete AV block Complete AV block Asystolic arrest Accelerated junctional 2:l AV block

Calcium*

;;I NA Junctional Bradycardia Asystolic arrest NA Complete AV block Junctional Bradycardia NA NA NA NA NA Complete AV block NA

79 None None 19 29 >4 9t None 1g 49 None Yesll NA NA None None None None None NA NA Yesll None None None

‘Drugs are given as total doses or maximumrates when possible. tTotal calcium dose unknown: patient received 1 g IV every 2 hours for unknown time. *Heart rate of 35 secondary to initial sinus bradycardia. §Cases repolted to Marion Laboratories but unpublished. NA = information not available. IrCardiopulmonaryarrest with unknown rhythm. ITotal calcium dose unknown.

specific receptors on the cell membrane mediated by CAMP. Activation results in alterations of calcium ion fluxes across the cell membrane, totally independent of alpha and beta adrenergic receptors (1819). In 1985, Zaloga and colleagues (19) demonstrated reversal of verapamil-induced hypotension and bradycardia by glucagon in rats. He drew a distinction between “highdose” therapy (1 mg/kg) not blocked by verapamil and “low-dose” therapy (0.1 mg/kg), which was. Zaritsky and colleagues (18) found that complete antagonism of diltiazem-induced myocardial depression could be achieved in rat hearts at a dose comparable to 5 mg of glucagon in a 70 kg human. However, Crump and colleagues (20) used 10 mg of glucagon in human verapamil overdose without success, and Anthony and colleagues (7) used only 2 mg of glucagon in human diltiazem overdose without success. Further experience is needed to determine the usefulness of glucagon in humans. Intravenous calcium was initially thought to be an obvious antidote for CCB toxicity, but has also met with limited success. In 1978, Perkins (21) used a calcium gluconate bolus followed by an intravenous drip (5 mmol/h) to treat a verapamil overdose successfully.

Others have reported that a combination of hypertonic solution, with its sodium ions, and calcium can treat verapamil toxicity successfully (15,16). Crump and colleagues (20) in 1982, after administering 10 mg glucagon in a verapamil overdose, used 24 g of calcium gluconate over 44 hours with little response. One of the first reports using calcium successfully for diltiazem toxicity was from Henry and colleagues (17). He documented a patient on normal doses of diltiazem presenting in third-degree AV block, who was treated with 3 g of calcium chloride. Success using intravenous calcium to reverse the hypotensive effects of therapeutic doses of verapamil has also been reported (22). Of the 24 cases of diltiazem overdose, several were known to have been treated with calcium at various doses with mixed success. Table 5 summarizes frequency of use and response to the treatment used in the 8 published cases, along with the one reported here. The fact that some of the agents were used in asystolic cardiac arrest complicates any conclusion about whether they would be a successful pharmacologic agent in a non-arrest state, as asystole carries a grim prognosis. The agents and number

Diltiazem

Overdose:

363

Report/Review

Table 3. Dlltiszem Overdose Report

Management

Dopamine’

Buffet (1984) No Gibelin (1984) No No Rey (1984) Christiansen (1988) No Anthony (1988) Yes 20 pgikglmin Malcolm (1988) 42 mg/hf Snover (1986) Jakubowski (1987) No 30 pglkglmin Erickson (1991) No MB41 858$ MB51 408$ Yes NA MB51 635$ NA MB51 8954 M860728$ Yes NA M881417$ M862161$ No M862228$ Yes M870797$ No NA M882080$ NA M882684$ M883690$ No No MB81 199* MB901 16$ No No M890378$

Strategies

Epinephrine* No No No 1 mg 100 pglmin No

1 mg No No No Yes NA NA No NA No No No NA NA No No No No

Norepinephrine’ No No No No

Yes No No No

No No No NA NA No NA No No No NA NA No No No No

Isoproterenol’

Atropine’ Glucagorf

No No No

No No No

Yes

1 mg 1 mg

2 pglmin 0.24 pglkglmin 1 mg No No No Yes NA NA No NA Yes No No NA NA No No No No

No

1 mg 0.6 mg 1 mg Yes Yes NA NA No NA No No No NA NA No No Yes No

No No No No

2 mg No No No No No No NA NA No NA No No No NA NA No No No No

*Cases reported to Marion Laboratories but unpublished. ‘Drugs are given as total doses or maximum rates when possible. tAs reported in the literature. NA = information not available.

of times used in asystole are found in the first column of Table 5 and represent the uses reported by the only published asystolic case, by Snover and colleagues (9). Norepinephrine and glucagon were each used once by Anthony and colleagues (7) with no apparent therapeutic effect. Epineprhine was used as a one-time 1 mg bolus, by both Christiansen (6) and Snover and colleagues (9) without success (the latter in asystole) while Anthony and colleagues (7) used a high-dose epinephtine infusion with therapeutic benefit. Since overall experience with epinephrine, norepinephrine, and glucagon as pressor agents is limited, an estimate of their therapeutic efficacy is unreliable. Dopamine was used in 4 cases, with a beneficial response seen in 3 of the 4, giving it a therapeutic response of 75% in published cases. A beneficial therapeutic response with isoproterenol was reported by Malcom and colleagues (8) and Christensen (6), while Snover and colleagues (9) and Anthony and colleagues (7) reported no benefit; again, Snover and colleagues (9) used isoproterenol in asystole that finally responded to pacing. Since 2 of 4 cases clearly responded to isoproterenol, it has, at minimum, a beneficial therapeutic response of 50% in published cases.

Atropine was used in over half of the published cases, but a therapeutic beneficial response was reported by only Jakubowski and colleagues (10) and our own. The rhythms in these two were accelerated junctional and 2:l AV block, respectively. Atropine was reported to be ineffective in 3 other cases, 2 of which had third-degree AV block and one of which had asystole. These results are not totally unexpected since these rhythms in other clinical situations exhibit less responsiveness to atropine. Of the 6 uses listed in Table 5, only Malcolm and colleagues (8) (high-dose) and Christensen (6) (lowdose) reported beneficial effects with calcium. Our case appeared to have substantial improvement initially with intravenous calcium although other interventions were ongoing. Cardiac pacing, when used, was very successful and decreased the need for pressor agents. Pacing was unusually successful in stabilizing an asystolic rhythm and was responsible for these patients survival. Of the three published uses of pacing, all responded (Table 5). An additional treatment is charcoal hemoperfusion, which Anthony and colleagues (7) used in 1986 to treat a mixed diltiazem/metoprolol overdose. Blood levels demonstrated that hemoperfusion was effective in en-

364

F. C. Erickson, L. J. Ling, G. A. Grande,

D. L. Anderson

Table 4. Diltlazem Overdose Management Strategles

Report Buffet (1984) Gibelin (1984) Rey (1984) Christiansen (1988) Anthony (1988) Malcolm (1988) Snover (1988) Jakubowski (1987) Erickson (1991) M841658$ : M851408$ M851835$ M851895$ M860728$ M861417$ M862181$ M862228$ M870797$ M882080$ M882884$ M883690$ M881199$ Ma901 16$ M890378$

Pacer

Other Treatment*

Yes Precautionaryt Precautionaryt No Yes No Yes No No No No NA NA Yes NA No No No NA NA No No No No

Lavage; Albumin Lavage Lavage None Charcoal hemoperfusion Lavage; Charcoal None Ipecac; Charcoal Lavage; Charcoal None Lavage; Charcoal NA NA Dobutamine NA None None None NA NA Lavage; Charcoal None Hyperosmolar infusion None

Time On Pressors

Time of Discharge/ Outcome

None None None NA 18 hours 38, hours 48 hours None 22 hours None NA NA NA NA NA NA NA None NA NA None None None

NAtRecovered NAIRecovered NAIRecovered NA/Recovered 3 days/Recovered >4 days/Recovered 32 days/Recovered 3 days/Recovered 4 days/Recovered NAIRecovered NA/Expired NA/Recovered NAIRecovered NA/Recovered NAJExpired NAtRecovered NA/Recovered NA/Expired NA/Recovered NA/Expired NA/Recovered NA!Expired NAIRecovered

None

NA/Expired

*Drugs are given as total doses or maximum rates when possible. tPacer applied as a precaution only; the patients were not paced. *Cases reported to Marion Laboratories but unpublished. NA = information not available:

hancing the elimination of both agents, which paralleled clinical improvements.

New Calcium Channel Blocking Agents Two agents, nicardipine and nimodipine, have been introduced on the market in the last two years and deserve mention. Like their counterparts, they also inhibit transmembrane ion flux through calcium “slow” channels and cause vasodilatation of vascular smooth muscle (23,24). Both agents are structurally related to nifedipine and, therefore, possess greater activity on vascular smooth muscle than on cardiac muscle or cardiac conducting tissue; however, their affinities for specific vascular tissues impart to them distinctive characteristics (23,24). Nicardipine has been shown to have more vascular smooth muscle selectivity than nifedipine, with minimal negative inotropic properties and no effect on AV node conduction (23). Its effect on vascular smooth muscle is more pronounced on coronary vasculature, increasing coronary blood flow and limiting infarct size to a higher degree than other CCBs (23). A negative

inotropic effect has been reported in patients receiving intravenous nicardipine; however, these patients had preexistent severe heart failure (25). While nicardipine can have a profound hypotensive effect, its coronary vascular selectivity limits the reflex tachycardia commonly seen with nifedipine at normal doses (23). Nimodipine’s vascular smooth muscle selectivity is directed at cerebral vasculature due to its lipid solubility and ability to cross the blood-brain barrier (24). Clinically, it is approved for treatment of cerebral Table 5. Interventlonal Succes8 In Published Dlltlazem Overdose

Intervention Norepinephrine Glucagon Epinephrine Dopamine lsoproterenol Atropine Calcium Pacer

Times Used in Asvstole

Total Times Used

Total Beneficial Response O(O%) O(O%) 1(33%) 3(75%) 2(50%) 2(40%) 3(50%) 3(100%)

365

Diltiazem Overdose: Report/Review

&hernia following subarachnoid hemorrhage. It also has minimal negative inotropic effect and no AV node conduction effects (24). While there are no published reports of overdose with these two CCBs, hypotension is a common adverse reaction (23,24). One would expect an overdose to have similar findings, as with other CCBs, except for the profound AV node conduction disturbances seen with verapamil and diltiazem.

CONCLUSION While still relatively rare, diltiazem overdose is being seen more often. If recognized and treated appropriately, it is a survivable overdose even with massive ingestions. The typical patient presenting with a diltiazem overdose is middle-aged. Invariably, hypotension and bradycardia exist with several possible rhythms, most commonly involving AV block. Toxicity is not dependent upon dose or plasma level, so care needs to be taken in cases of even relatively modest ingestions. The peak toxic effect most commonly occurs in 90 minutes to 6 hours, but additional deterioration may occur 10 to 12 hours postingestion (3). Successful pressor treatment includes dopamine, epinephrine, and isoproterenol, with dopamine being the pressor of choice. An-opine, in the absence of third-degree AV block or asystole, may be

successful. Intravenous glucagon and calcium should be considered for adjunctive therapy, as they are theoretically beneficial; however, the doses for a clinical response are unknown. When needed, the time course for electrical pacing is typically 24 to 48 hours, which makes the use of an external pacer a realistic alternative. If the patient has contraindications to pressor treatment, pacing may decrease the need for pressor support. Any patient who either presents with or deteriorates to asystole should have a pacer placed without delay. Additional decontamination efforts should include gastric lavage followed by charcoal, even if the patient presents late, because of the theoretical delay in gastric emptying and absorption (3). Since the patient’s condition often deteriorates after arrival in the emergency department and even after admission, additional pressor support, pacing, and airway management problems should be anticipated (3,7,8,9). While treatment is mainly supportive, recognition of diltiazem toxicity and knowledge of its pathophysiology should precipitate the initiation of the specific therapies and treatment modalities mentioned above.

Acknowledgments Marion

Laboratories

-

Special thanks to Jack Cavness, Division

of Research

RPh,

and Development,

for providing analysis of our diltiazem blood levels and manufacturers reports on unpublished overdoses.

REFERENCES 1

2.

3. 4. 5.

6. 7.

8.

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