Journal of Clinical Toxicology
Open Access
ISSN: 2161-0495
+44 1478 350008
ISSN: 2161-0495
+44 1478 350008
Case Report - (2019) Volume 9, Issue 4
Background: Verapamil intoxication is a life-threatening condition manifesting as hemodynamic instability requiring vasopressor and ventilator supports and even fatal outcome in some patients.
Case report: A 37-year-old female who intentionally took sustained-release verapamil of 3,600 mg, doxazosin of 20 mg, and chlorpheniramine of 40 mg, presented with sudden cardiac arrest. Intubation with cardiopulmonary resuscitation was promptly initiated, and then intravenous calcium gluconate, sodium bicarbonate, and vasopressor were given to maintain hemodynamic condition. During hospitalization, targeted temperature management, temporary cardiac pacing, renal replacement therapy as well as all essential supportive measures were given. However, the patient eventually expired due to refractory cardiogenic shock 4 days after hospitalization. In addition, we review all reported cases of verapamil intoxication in English literature.
Conclusion: We report herein a fatal case of verapamil intoxication, and have a literature review in all reported cases. Hence, verapamil intentional or accidental overdose, can be lethal that requires the prompt initiation of comprehensive resuscitation.
Keywords: Verapamil intoxication; Verapamil overdose; Verapamil toxicity; Calcium channel blocker; Non-dihydropyridine calcium channel blocker
Verapamil, a non-dihydropyridine Calcium Channel Blocker (CCB), is medically used in patients with hypertension and supraventricular arrhythmias. Verapamil intoxication is a life-threatening condition manifesting as hemodynamic instability requiring ventilator and vasopressor supports and even death in some patients [1,2]. The clinical manifestations are mostly due to cardiovascular dysfunction including hypotension, bradycardia, dysrhythmias, and intraventricular conduction delay, but derangement of other systems such as noncardiogenic pulmonary edema, unconsciousness, hyperglycemia, hypokalemia, can be present. Herein, we report a fatal case of verapamil intoxication, and review the literature of all reported cases.
A 37-year-old female presented to our hospital, King Chulalongkorn Memorial Hospital, Bangkok, Thailand, after an unknown duration of intentional ingestion of sustained-release (SR) verapamil of 3,600 mg, doxazosin of 20 mg, and chlorpheniramine of 40 mg. One hour before arriving emergency department (ED), she suddenly gasped for air and was unconscious. On arrival at ED, electrocardiogram (ECG) showed no electrical activity and then intubation with cardiopulmonary resuscitate (CPR) was promptly initiated; 3 mg of epinephrine, 30 mL of 10% calcium gluconate, and 50 mL of 7.5% sodium bicarbonate were given. After 9 minutes of CPR, a return of spontaneous circulation (ROSC) was noted, and ECG showed sustained junctional rhythm of 40/ minute (Figure 1). Continuous intravenous infusion of norepinephrine, dopamine, and adrenaline were then given to maintain her blood pressure. Initial point of care capillary glucose was 296 mg %, and hence intravenous insulin was continuously dripped at the initial rate of 1 unit/kg/hour. Gut decontamination with gastric lavage and the use of activated charcoal or sorbitol were not performed in our patient because of the unstable hemodynamic condition and marked bowel ileus.
Figure 1: Electrocardiogram showing junctional rhythm with rate of 40/min, left bundle branch block, prolonged QTc interval (480 ms).
Her past medical history was unremarkable except a recent diagnosis of hypertension in the young with suspicion of primary hyperaldosteronism.
During hospitalization in an intensive care unit, the patient had received Targeted Temperature Management (TTM), temporary cardiac pacing, high-dose inotropic therapy, High-Dose Insulin (HDI) Therapy, Renal Replacement Therapy (RRT), and intravenous Lipid- Emulsion Therapy (LET). However, the patient eventually expired due to refractory cardiogenic shock 4 days after hospitalization.
We report herein a patient with intentional ingestion of the overdose of verapamil, in accompanying with other medications. Unfortunately, there is still a fatal outcome despite all best efforts both specific treatment and supportive measures putting on our patient.
In our patient, aggressive decontamination with gastric lavage and the use of activated charcoal or sorbitol were not performed despite the recommendation by the experts [1]. Because of the risks outweighing the benefits.
The first-line treatment as recommended by the Experts Consensus Recommendations for the Management of Calcium Channel Blocker Poisoning in Adults 1 despite handful cases of verapamil intoxication includes 1) intravenous calcium and/or atropine in the presence of symptomatic bradycardia or conduction delay, 2) epinephrine, norepinephrine, and/or dopamine in the presence of cardiogenic shock, 3) intravenous HDI in the presence of myocardial dysfunction with maintenance of euglycemia, and 4) LET in the setting of refractory to first-line treatment [2]. In our patient, all 4 measures were given but unfortunately without adequate response.
The mechanism of actions of CCBs is blocking the L-type voltagegated calcium channels in the cell membrane, but each member of the CCBs varies in the chemical structure, pharmacokinetics, pharmacodynamics, and tissue selectivity. Verapamil hydrochloride (Figure 2) is a phenylalkylamine-derivate calcium-channel blocking agent. Chemically, it is a basic (log K=9.1) and highly hydrophobic compound (log Po/w=9.1)3. The pharmacokinetics, more than 90% of verapamil is absorbed when given orally, but due to high first-pass metabolism, bioavailability is much lower (10%-35%).
Figure 2: Structural formula of verapamil hydrochloride.
It is 90% bound to plasma proteins, takes 1 to 2 hours to reach peak plasma concentration after oral administration. It is metabolized in the liver, 70% is excreted in the urine and 16% in feces [3-5]. Verapamil is one of the most widely used non-dihydropyridine CCBs, can block the rapid influx of calcium into the cardiac myocytes and conduction system as well as vascular smooth muscle cells. The final results of these blocking are as followed: 1) decreased myocardial contractility, 2) blocked atrioventricular nodal conduction time, and 3) peripheral vasodilatation, leading to congestive heart failure, conduction abnormalities, hypotension, respectively, and cardiac arrest in severe cases [6]. According to American Association of Poison Control Centers in 2009, there were 18 of 52 deaths attributable to CCBs especially to verapamil [7]. Furthermore, the blockage of L-type voltage-gated calcium channels will decrease the release of insulin from the pancreatic beta-islet cells and hence reduce the glucose uptake by peripheral tissues (insulin resistance) [8]. The reported toxic doses of verapamil both nonfatal and fatal cases range from 800 mg to 24,000 mg; however, the correlation between the ingested dosage and the clinical outcome is not demonstrated in every case. In our case, the ingestion of SR verapamil of 3,600 mg can cause the fatal toxicity, likely due to the combination of adverse effects from both verapamil (CCB) and doxazosin (alpha-adrenergic blocking agent) leading to a marked hypotension and peripheral vasodilatation [9-27].
In addition, we review all English literature published from 1977 to 2018 for 50 patients (including our patient) with verapamil intoxication (Table 1).
| Patient | Gender/age (year) | Ingested amount (mg) | Co-ingested drug | Other medical problems | Duration after ingestion (hour) | Hemodynamics at presentation | ECG | Decreased mental status | Hypo-calcemia | Hyper-glycemia | Treatment/vasopressor | Complication | Duration of intubation/hospitalization (day) | Outcome |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 19 (2015) |
F/24 | 7,200 | None | None | 1-2 | BP 65/30 mmHg HR 80 bpm |
NA | NA | NA | NA | Fluid, Ca, glucagon, HDI, LET (via intra-osseous), ETT, NE 20 mcg/min | None | 2/2 | Died |
| 210 (2014) |
F/36 | 2,000 | None | None | 1 | BP 60/40 mmHg HR 40 bpm |
NA | + | NA | NA | Fluid, Ca, HDI, plasma exchange, ETT, Dopamine 30 mcg/kg/min, Dobutamine 10 mcg/kg/min | ARDS | 0.5/NA | Survived |
| 311 (2014) |
M/40 | 3,600 | Fluoxetine 400 mg, carbamazepine SR 1800 mg, alcohol, oxycodone SR, amlodipine, valsartan, simvastatin, trazodone metformin, | HT MDD Obesity |
3 | BP 110/70 mmHg HR 97 bpm |
Sinus rhythm | + | NA | + | Fluid, Ca, atropine, HDI, LET, RRT (due to carbamazepine intoxication), ETT, NE 120 mcg/min, E 30 mcg/min, vasopressin 0.03 units/min | Alcohol and opioid withdrawal, non-cardiogenic pulmonary edema | 7/NA | Survived |
| 412 (2014) |
F/51 | 9,600 | None | MDD | 8 | NA HR 38 bpm |
Sinus bradycardia | - | NA | NA | Fluid, Ca, LET, RRT, ECMO, ETT, NE 10 mcg/min, E 10 mcg/min | None | 7/18 | Survived |
| 58 (2013) |
F/27 | 2,400 | Furosemide 4,000 mg | None | NA | BP 60/35 mmHg HR 40 bpm |
First degree AV block | - | NA | NA | Activated charcoal, fluid, Ca, atropine, TPM, HDI, LET, E 9 mcg/min | None | NA/4 | Survived |
| 613 (2011) |
F/41 | 19,200 | None | None | 6 | SBP 115/73 mmHg HR 59 bpm |
Third degree AV block | - | - | NA | Activated charcoal, fluid, Ca, TPM, HDI, LET, RRT, ETT, NE 0.75 mcg/kg/min, E 0.04 mcg/kg/min, vasopressin 0.05 units/min | Ischemic colitis | NA/55 | Survived |
| 714 (2011) |
M/47 | 6,300 | None | HT | 3 | SBP 80 mmHg HR 40 bpm |
Third degree AV block | + | NA | NA | Fluid, Ca, atropine, glucagon, HDI, LET, TPM, ETT | None | 7/NA | Survived |
| 815 (2009) |
M/32 | 13,400 | Levothyroxine 1,125 mg, bupropion 4,800 mg, zolpidem CR 200 mg, clonazepam, benazepril | Hypo-thyroidism MDD |
12 | BP 69/26 mmHg HR 55 bpm |
NA | + | NA | NA | Activated charcoal, fluid, Ca, glucagon, LET, ETT, NE | None | 2/5 | Survived |
| 916 (2007) |
F/15 | 960 | Propranolol 550 mg | None | 8 | BP 55/30 mmHg HR 40 bpm |
Broad complex bradycardia, then asystole | + | + | + | CPR (70 minutes), activated charcoal, fluid, Ca, glucagon, bicarbonate, TPM, plasma exchange, ETT, E 0.2 mcg/kg/min, dopamine 10 mcg/kg/min, ECMO (70 hours) | Ventricular fibrillation | 13/32 | Survived |
| 1017 (2004) |
M/57 | 1,600 | Atenolol 2,800 mg | IHD MDD |
1 | BP 80/50 mmHg HR 40 bpm |
First degree AV block | + | - | NA | Activated charcoal, fluid, Ca, enoximone, ETT, E 10 mcg/kg/min, dopamine 30 mcg/kg/min | None | 5/15 | Survived |
| 1118 (2002) |
F/19 | 6,000 | None | None | 5 | BP 69/42 mmHg HR 56 bpm |
Sinus bradycardia | - | NA | NA | Fluid, Ca, ETT, dopamine | Non-cardiogenic pulmonary edema | 5/NA | Survived |
| 1218 (2002) |
F/19 | 7,200 | Paracetamol 6,500 mg | None | 7 | BP 70/40 mmHg HR 45 bpm |
Third degree AV block | - | NA | - | Fluid, Ca, ETT, dopamine | Non-cardiogenic pulmonary edema | 6/NA | Survived |
| 1319 (1996) |
F/22 | 4,800 | Alcohol | None | 1 | SBP 48 mmHg HR 45 bpm |
Left bundle branch block pattern | + | - | + | Activated charcoal, fluid, Ca, glucagon, bicarbonate, atropine, naloxone, ETT, dopamine | Non-cardiogenic pulmonary edema, seizure | 1.5/1.5 | Died |
| 1419 (1996) |
M/43 | 8,640 | None | HT | 5 | SBP 50 mmHg HR 50 bpm |
Junctional rhythm | + | NA | NA | Activated charcoal, fluid, Ca, glucagon, atropine, TPM, ETT, NA 5.3 mcg/min, dopamine 3.3 mcg/kg/min | Non-cardiogenic pulmonary edema | 3/NA | Survived |
| 1520 (1994) |
F/27 | 1,800 | Ibuprofen 4,000 mg, paracetamol 5,000 mg | None | 5 | NA | NA | NA | NA | NA | Fluid, Ca, ETT | Non-cardiogenic pulmonary edema | 3/NA | Survived |
| 1621 (1994) |
F/65 | NA | None | HT | NA | BP 83/63 mmHg HR 42 bpm |
AV nodal rhythm, right bundle branch block | + | NA | NA | Gastric lavage, fluid, Ca, TPM, ETT, E | None | 1/NA | Survived |
| 1722 (1994) |
F/25 | 1,200-2,400 | None | None | 1 | BP 120/70 mmHg HR 100 bpm |
First degree AV block | - | - | - | Activated charcoal, fluid No Ca, no intubation, Dopamine |
Delayed hypotension | None/2 | Survived |
| 1823 (1993) |
M/33 | 12,000 | None | None | NA | SBP 70 mmHg HR 40 bpm | Third degree AV block | - | NA | NA | Activated charcoal, fluid, Ca, atropine, TPM, ETT, isoproterenol 20 mcg/kg/min, E 20 mcg/kg/min, dopamine 20 mcg/kg/min | Severe metabolic acidosis | 1.5/1.5 | Died |
| 1924 (1991) |
M/33 | 4,160 | None | None | 1 | BP 97/50 mmHg HR 61 bpm |
First degree AV block | - | - | + | Activated charcoal, fluid, Ca, atropine, naloxone, TPM, ETT, E, dopamine 30 mcg/kg/min, dobutamine 20 mcg/kg/min | Severe metabolic acidosis, hypokalemia | 2.5 hours/2.5 hours | Died |
| 2025 (1991) |
F/38 | 4,800 | None | HT Migraine headache |
1 | BP 58/30 mmHg HR 45 bpm |
Sinus bradycardia | - | + | NA | Fluid, Ca, ETT, dopamine 20 mcg/kg/min | None | 1/2 | Survived |
| 2126 (1991) |
M/48 | 480 | Cimetidine 400 mg | HT | NA | Hypotension HR 38 bpm |
First degree AV block, left anterior fascicular block | NA | NA | NA | Activated charcoal, fluid, Ca, TPM, RRT, hemoperfusion, ETT, dopamine | Severe metabolic acidosis | 0.5/0.5 | Died |
| 2227 (1990) |
F/27 | 2,900 | NA | NA | NA | No hypotension | AV dissociation | + | + | NA | NA | NA | NA/NA | Survived |
| 2328 (1990) |
M/56 | NA | NA | NA | NA | NA | Asystole | + | NA | NA | NA | NA | 2.5/2.5 | Died |
| 2429 (1990) |
M/37 | 7,200 | Alcohol | HT | 1 | BP 140/78 mmHg HR 70 bpm |
Junctional rhythm, premature ventricular contractions | + | - | - | Activated charcoal, fluid, Ca No intubation |
None | None/4 | Survived |
| 2530 (1989) |
M/22 | 16,000 | None | Hyper-trophic subaortic stenosis, AF | 1 | SBP 65 mmHg HR 72 bpm |
AV dissociation | + | NA | NA | Activated charcoal, fluid, Ca, NE 20 mcg/min, dopamine 32 mcg/kg/min, dobutamine 5 mcg/kg/min | None | NA/NA | Survived |
| 2630 (1989) |
M/31 | 8,000 | None | HT | 1 | SBP 40 mmHg HR 60 bpm |
Second degree AV block with 2:1 conduction | - | NA | NA | Activated charcoal, fluid, Ca, atropine, glucagon, TPM, ETT, NE, E, dopamine, CPR | Tonic-clonic seizure | 65 min/65 min | Died |
| 2731 (1988) |
M/41 | 6,800 | None | HT | 2.5 | SBP 60 mmHg HR 50 bpm |
AV dissociation, trifasicular block | + | NA | + | Activated charcoal, fluid, Ca, TPM, NE 4 mcg/min, dopamine 20 mcg/kg/min | None | NA/NA | Survived |
| 2832 (1988) |
M/23 | 7,200-9,600 | None | None | 9 | SBP 40 mmHg HR 45 bpm |
Junctional rhythm, AV dissociation | + | NA | NA | Fluid, Ca, atropine, TPM, isoproterenol, dopamine | None | NA/NA | Survived |
| 2933 (1988) |
F/39 | 2,280 | Propranolol 120 mg, opipramol 400 mg | None | NA | Undetectable BP HR 55 bpm |
AV dissociation | + | NA | - | Isoproterenol | Acute ischemic stroke | NA/NA | Survived |
| 3034 (1986) |
F/16 | 8,000 | None | None | 5 | SBP 45 mmHg HR 40 bpm |
Third degree AV block | + | - | + | Gastric lavage, fluid, Ca, bicarbonate, TPM, ETT, isoproterenol 4 mcg/min, dopamine 10 mcg/kg/min, amrinone 3.5 mcg/kg/min | None | 1/NA | Survived |
| 3135 (1985) |
M/67 | 600 | NA | NA | NA | Hypotension | Third degree AV block | - | NA | NA | NA | NA | NA/NA | Survived |
| 3236 (1985) |
F/21 | NA | Atenolol | NA | 1 | SBP 70 mmHg HR 75 bpm |
Sinus rhythm | + | - | NA | Activated charcoal, fluid, Ca, isoproterenol 5 mcg/min | None | None/2 | Survived |
| 3337 (1984) |
F/25 | 8,000 | NA | NA | NA | Hypotension | Sinus rhythm | - | NA | NA | NA | NA | NA/NA | Survived |
| 3438 (1983) |
F/22 | 2,400 | None | MDD | 3 | SBP 60 mmHg HR 30 bpm |
Idio-ventricular rhythm | + | - | + | Gastric lavage, fluid, Ca, ETT, isoproterenol, dopamine | None | NA/NA | Survived |
| 3539 (1983) |
F/16 | 9,600 | NA | NA | NA | Hypotension | Sinus rhythm | - | NA | NA | NA | NA | 7 hours/7 hours | Died |
| 3640 (1982) |
F/38 | 2,400 | None | MDD | 2.5 | SBP 50 mmHg HR 45 bpm |
AV dissociation | + | NA | NA | Gastric lavage, fluid, Ca, dopamine 30 mcg/kg/min, E 0.8 mcg/kg/min | None | NA/NA | Survived |
| 3741 (1982) |
F/17 | NA | None | None | 1-2 | Undetectable BP HR 30 bpm |
Third degree AV block | + | NA | NA | Fluid, Ca, atropine, TPM, ETT, isoprenaline 270 mcg/min, dopamine 1 mg/min | Asystole | 19 hours/19hours | Died |
| 3842 (1982) |
F/39 | 1,200 | None | None | NA | Undetectable BP HR 48 bpm |
First degree AV block | + | NA | + | Fluid, Ca, glucagon, atropine, prenalterol, ETT, dopamine 2.5 mcg/kg/min, dobutamine 40 mcg/kg/min, isoprenaline 15 mcg/min | Haematemesis, pneumonia, cerebral anoxia | NA/NA | Survived |
| 3943 (1982) |
F/20 | 8,000 | NA | NA | NA | Hypotension | Sinoatrial arrest | + | NA | NA | NA | NA | NA/NA | Survived |
| 4044 (1981) |
M/33 | 3,000 | None | AF | 3 | SBP 60 mmHg HR 79 bpm |
AV dissociation | NA | NA | NA | Fluid, Ca, no intubation | None | NA/NA | Survived |
| 4145 (1981) |
F/68 | 6,400 | Aspirin | MDD | 7 | Hypotension HR 63 bpm |
Occasional idio-ventricular bradycardia | + | NA | NA | Activated charcoal, fluid, Ca, orciprenaline, TPM | None | NA/NA | Survived |
| 4245 (1981) |
M/30 | 7,200 | Medazepam 400 mg | MDD | 2 | SBP 50 mmHg | Third degree AV block, then asystole | + | NA | NA | Fluid, Ca, isoprenaline, TPM, ETT, dopamine | Asystole | NA/NA | Survived |
| 4345 (1981) |
M/69 | 800 | Alcohol | IHD, AF | NA | Hypotension | Third degree AV block | + | NA | NA | NA | None | NA/NA | Survived |
| 4446 (1981) |
F/40 | NA | NA | NA | NA | Hypotension | Sinus rhythm | - | NA | NA | NA | NA | NA/NA | Died |
| 4547 (1980) |
M/31 | 3,200 | Alcohol | None | 3 | BP 60/40 mmHg HR 57 bpm |
AV dissociation | + | + | NA | Fluid, hypertonic sodium chloride, Ca, dexamethasone, no intubation | None | None/14 | Survived |
| 4648 (1979) |
M/18 | 2,000 | None | None | 2 | BP 90/60 mmHg HR 65 bpm |
AV dissociation | - | NA | NA | Atropine, TPM | None | None/1 | Survived |
| 4749 (1979) |
F/14 | 2,400 | None | None | 2 | BP 70/50 mmHg HR 40 bpm |
Third degree AV block | + | + | + | Gastric lavage, Ca, atropine, bicarbonate, no intubation | None | NA/NA | Survived |
| 4850 (1978) |
F/19 | 3,200 | None | Prolapsed mitral valve | 5 | BP 80/60 mmHg HR 55 bpm |
Nodal bradycardia | + | NA | NA | Ca | None | NA/NA | Survived |
| 4951 (1977) |
F/28 | 5,600 | NA | NA | NA | Hypotension | AV dissociation | + | NA | NA | NA | NA | NA/NA | Survived |
| 50 (our case, 2018) | F/37 | 3,600 | Doxazosin 20 mg, chlorpheniramine 40 mg | HT | Within 1-24 | Asystole | Junctional bradycardia | + | - | + | CPR (9min), fluid, Ca, bicarbonate, HDI, LET, TPM, RRT, ETT, NE 1 mcg/kg/min, dopamine 30 mcg/kg/min, adrenaline 1 mcg/kg/min | Cardiogenic shock | 4/4 | Died |
Table 1: A summary of all 50 cases (8-50) with verapamil intoxication reported from 1977 to 2018.
There are 20 males and 30 females with the mean age of 33.7+14.8 (range: 14-69) years. The amount of verapamil ingestion ranges from 480 to 19,200 mg, which ranges from 480 to 12,000 mg and from 600 to 19,200 mg in fatal and survived cases, respectively. The lowest dose in the fatal case is 480 mg, and on the other hand, the highest dose in the survived case is 19,200 mg. Clinical presentations vary from hypotension, bradycardia, conduct abnormalities, and cardiac arrest of 50 cases, hypotension is the most common presenting symptom (40 cases, 80.0%). Two patients including our patient, developed asystole upon arrival to the hospital. In addition, the ECG ranges from normal sinus rhythm (5 cases, 10.0%), sinus bradycardia (3, 6.0%), first (6, 12.0%), second (1, 2.0%), and third-degree atrioventricular block including of AV dissociation (20, 40.0%), junctional rhythm (4, 8.0%), right and left bundle branch block (4, 8.0%), and asystole (2, 4.0%). Our patient had cardiac asystole and junctional rhythm after ROSC. There are 18 (36.0%) cases with severe cardiac conduction block requiring temporary cardiac pacing. Apart from cardiovascular involvement of verapamil, the adverse effects of the other systems include the airway compromise requiring assisted ventilation (28 cases, 56.0%), noncardiogenic pulmonary edema (7, 14.0%), altered mental status (31, 62.0%), hyperglycemia (10, 20.0%), and hypocalcemia (5, 10.0%). The complications after the treatment include severe metabolic acidosis (3, 6.0%), seizure (2, 4.0%), acute ischemic stroke (1, 2.0%), cerebral anoxia (1, 2.0%), pneumonia (1, 2.0%), ischemic colitis (1, 2.0%), and cardiogenic shock (1, 2.0%). Of 50 cases, there are 39 (78.0%) and 11 (22.0%) survived and fatal cases, respectively. The duration of respiratory support ranges from 0.5 to 13 days and the length of hospitalization ranges from 1 to 55 days [28-51].
We report herein a fatal case of verapamil intoxication, and have a literature review in all reported cases of 50 patients, there are 11 (22.0%) patients died, including our case, regardless of amount of verapamil ingestion. Hence, verapamil intentional or accidental overdose, can be lethal that requires the prompt initiation of comprehensive resuscitation.
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