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Calcium Channel Antagonist Toxicity
Author: Kristen Kent, MD, Fellow in Medical Toxicology, Department of Emergency Medicine, University of Massachusetts Medical Center, Worcester, MA.
Peer Reviewers: David E. Manthey, MD, Associate Professor, Director, Undergraduate Medical Education, Department of Emergency Medicine, Wake Forest University School of Medicine, Winston-Salem, NC; and Jennifer Hannum, MD, Assistant Professor, Department of Emergency Medicine, Wake Forest University School of Medicine, Winston-Salem, NC.
Calcium channel antagonists (CCAs) are generally safe medications when taken as prescribed. However, at toxic doses, CCAs cause potentially lethal decreases in systemic vascular resistance and negative inotropic, chronotropic, and dromotropic effects, as well as a decreased insulin release from the pancreas.
As with much toxicology knowledge, the information available for treatment of CCA toxicity is based on case reports, animal studies, and recommendations from experts in the field, rather than large clinical randomized controlled trials. The relative infrequence of severe CCA poisoning, frequency of co-ingestants, and ethical dilemma of consenting intoxicated patients to an "experiment" make randomized controlled trials for treatment of CCA difficult at best.
This article reviews recent case reports, retrospective studies, reviews of specific therapies, and animal studies involving CCAs toxicity. The goal is to discuss the major aspects of CCA from presentation to treatment.
Could this patient have CCA overdose?
Source: Connolly PT, Harris C. Unusual ECG findings mimicking complete heart block in an unrecognised calcium antagonist overdose. Resuscitation 2006;68:429-432.
CCA toxicity should be on the differential diagnosis of any patient with cardiovascular collapse. Connolly and Harris report a case of CCA toxicity initially diagnosed as myocardial infarction with complete heart block and severe cardiovascular instability. A 50-year-old male, who had been taking amlodipine, atenolol, and diclofenac-misoprostol, presented with bradycardia and hypotension. He was treated with atropine, endotracheal intubation, crystalloid and colloid solutions, cardiac pacing, and vasopressors. He also received calcium gluconate and insulin to correct hyperkalemia and hyperglycemia. A second look at the electrocardiogram revealed junctional escape rhythm with retrograde p waves, not complete heart block. Myocardial infarction was excluded after a normal echocardiogram and normal 24-hour troponin T level. A normal cardiac index with low systemic vascular resistance and no overt evidence of sepsis suggested the presence of an exogenous vasodilator, most likely toxicity from amlodipine. After a prolonged period of supportive care, he was discharged with no evidence of cerebral injury or continued cardiovascular dysfunction.
Evaluation of critically ill patients is difficult. This case is a careful reminder that without a clear history, CCA toxicity can be difficult to diagnose and should be on the differential diagnosis of patients with cardiovascular collapse. CCAs block the L-type calcium channels in vascular smooth muscle, cardiac myocytes, cardiac conductive tissue, and pancreatic beta islet cells. At therapeutic doses, each class of CCA exhibits cardiac versus vasculature selectivity for calcium channels; however, in an overdose, this selectivity is decreased. Metabolic acidosis with hyperglycemia is common. ECG findings in CCA toxicity include sinus bradycardia, AV conduction abnormalities, junctional escape rhythms, idioventricular rhythms, and complete heart block. Altered mental status, seizures, strokes, pulmonary edema, and hypoxia also may be seen.
As shown in this case, appreciation of the long duration of CCA and awareness of the reversible nature of CCA toxicity is imperative. As opposed to other diagnoses, like cardiogenic shock from myocardial infarction, full recovery from toxicity is likely with adequate support.
How long do I have to watch them?
Source: Cantrell FL, Clark RF, Manoguerra AS. Determining triage guidelines for unintentional overdoses with calcium channel antagonists. Clin Toxicol 2005;43:849-853.
Cantrell, Clark, and Manoguerra performed a retrospective chart review of poison center calls from the California Poison Control System from 1999 to 2001 to determine if unintentional overdoses of CCA led to clinically significant cardiovascular symptoms. In all, 225 cases coded as therapeutic errors involving CCA managed at health care facilities were included. Of these, 64 cases were excluded for multiple ingestions, unclear history, ingestion over 2 hours, or inadequate records.
In 104 cases, the ingestion was twice the patient's therapeutic dose; 9% developed cardiovascular effects. In 57 cases, the ingestion was greater than twice the patient's therapeutic dose; 14% developed cardiovascular effects. In 65% of cases in which cardiovascular effects occurred, the effects occurred within 5 hours. There were no fatalities or patients with long-term disabilities. The authors conclude that toxicity following an unintentional CCA overdose can be highly variable, and the dose producing a toxic effect on the cardiovascular system may be within the range of therapeutic doses. Therefore, evaluation should be conservative.
This study emphasizes the low toxic-to-therapeutic dose ratio of CCAs, with even one extra dose leading to toxicity. Rather than just isolated case reports, this study summarizes age, dose, signs of toxicity, and treatments for unintentional CCA toxicity from one region. However, there are several limitations of this study. First, it only includes cases where calls were made to the poison center and were managed at a health care facility, allowing for selection bias. Baseline vital signs were not recorded, allowing for a questionable degree of toxicity in some cases. Also, the chart review did not identify concurrent medications.
Despite the limitations, this study is consistent with a consensus guideline for out-of-hospital management that recommends consideration of referral to an emergency department for ingestion of an amount over the usual maximum single therapeutic dose or an amount more than the lowest reported toxic dose, whichever is lower.1
This study concludes that cardiovascular toxicity developed in most patients within 5 hours. Recommendations for observation of asymptomatic patients vary but are typically longer than 5 hours. It is reasonable to observe patients in a monitored setting for 12 hours for immediate release CCAs and 24 hours for extended-release CCAs.
Are there options other than calcium and atropine?
Source: Harris NS. Case 24-2006: A 40-year-old woman with hypotension after an overdose of amlodipine. N Engl J Med 2006;355:602-611.
Harris presents a case of a 40-year-old woman with severe CCA toxicity and reviews the management of CCA toxicity. The patient presented to the emergency department after reportedly taking 1000 mg of amlodipine. While in the emergency department her condition deteriorated with hypotension, somnolence, and a junctional rhythm. Her treatment included intravenous fluids, insulin, dopamine, norepinephrine, phenylephrine, calcium chloride and calcium gluconate, endotracheal intubation, and whole bowel irrigation.
After securing the A, B, Cs, the history and physical examination provide important clues to toxicity. Often, the overdosed patient cannot give a clear history, so it is important to speak with relatives, EMTs, pharmacists, and the patient's primary physician, and to search the patient's belongings for pill bottles. When performing a physical exam, it is important to recognize toxidromes that provide important clues to common poisonings. A CCA poisoned patient will not display one of the classic toxidromes, but will likely show dry skin, hypotension, and variable heart rate. Laboratory evaluation may be helpful, especially when other life-threatening ingestions, like acetaminophen, are present. Activated charcoal may be administered in cases in which the ingestion has occurred within less than one hour or is potentially lethal. Activated charcoal is contraindicated in patients who cannot protect their airways.
Once a CCA overdose is recognized, it is important to assess clinical effects of toxicity. CCAs block the movement of calcium into cells by interfering with the L-type calcium channel, which exert the most important effects on cardiac myocytes, cardiac conductive tissue, vascular smooth muscle, and pancreatic beta cells. Toxicity may present as decreased blood pressure, decrease pulse, altered mental status, sinus arrest, cardiac conduction delays, nausea, vomiting, and metabolic acidosis with hyperglycemia.
Specific treatment first involves appropriate intravascular volume replacement with normal saline. When there is hemodynamic instability, a pulmonary artery catheter to monitor central pressures may be considered.
Several medications are used in the treatment of calcium channel antagonist toxicity. Calcium salts are clinically indicated and physiologically reasonable to attempt to overcome the calcium-channel antagonism although, even at supratherapeutic doses, they may have a limited effect. Dosing requirements for calcium salts have not been studied adequately, but 10 to 20 mL of 10% calcium chloride or 20 to 60 mL of 10% calcium gluconate over 5 minutes repeated every 15 minutes for at least 3 doses is reasonable. If the patient is bradycardic, atropine is potentially useful, but the effects may be transient. Increasing evidence supports the use of hyperinsulinemia-euglycemia therapy for CCA toxicity (this is an off-label use). This therapy involves administering 1 U/kg bolus of regular insulin followed by an infusion of 0.5 U/kg/h with careful monitoring of glucose and potassium. Adrenergic-receptor stimulation also may be necessary. Epinephrine, norepinephrine, phenylephrine, isoproterenol, dobutamine, and dopamine all have been used with varied effects, but the action of dopamine is indirect; direct-acting adrenergic agonists like norepinephrine or phenylephrine may be more beneficial. There also are reports of successful use with phosphodiesterase inhibitors. However, the class of calcium channel blockers should be kept in mind; dihydropyridines have more peripheral vasodilation effect; non-dihydropyridines affect both cardiac and peripheral vasculature. Glucagon also should be considered, especially if there is concern for possible beta-blocker induced cardiac effects, because it activates adenylate cyclase independently of the beta-adrenergic receptor.
There are several options for toxin removal. Ipecac has not been found to improve outcomes and can cause complications. Whole-bowel irrigation is a reasonable intervention when large quantities of CCAs have been ingested. CCAs have large volumes of distribution and are highly protein bound, making toxin removal by hemodialysis difficult.
Other therapeutic interventions may be necessary as well. Bradycardic patients may need transthoracic and intravenous cardiac pacing; however, success is variable with failure to capture and failure to increase blood pressure even with successful increases in heart rate. When other treatments have failed, last efforts to consider include extracorporeal bypass or use of intraaortic balloon counterpulsation.
This article reviews basic management of the CCA poisoned patient, using amlodipine, a dihydropyridine, as an example. It systematically reviews the major considerations for this toxicity. However, there are some controversial points made in the discussion. The article implies that aggressive fluid resuscitation is needed; however, hypotension in CCA toxicity is not due to inadequate intravenous volume. If a patient does not respond to a couple liters of normal saline, aggressively employ other treatment options. The article advocates hyperinsulinemia-euglycemic therapy as first-line therapy. Most consider it beneficial and use it along with intravenous fluids, calcium, glucagon, and atropine, but it may not be widely accepted as "first line" with the current available evidence. The article also advocates the use of whole bowel irrigation. Although this should be considered for decontamination in CCA toxicity, clinicians should be cautious in using it in a patient who is hemodynamically unstable. Regarding glucagons, the authors emphasize using it for possible beta-blocker toxicity. Some advocate its use in CCA toxicity because through a second messenger pathway it leads to opening of dormant calcium channels enhancing the release of calcium from the sarcoplasmic reticulum, admittedly with varying effects.
What about high-dose insulin?
Source: Shepherd G, Klein-Schwartz W. High-dose insulin therapy for calcium-channel blocker overdose. Ann Pharmacother 2005;39:923-930.
In severe CCA toxicity, animal studies and human case reports suggest that high-dose insulin therapy (which is an off-label use) is beneficial. Shepherd and Klein-Schwartz searched MEDLINE and Toxline between 1966 and July 2004, as well as abstracts from the NACCT (North American Congress of Clinical Toxicology) from 1996 to 2003, for high-dose insulin therapy in CCA toxicity. The paper starts with a mechanistic review, summarizes the animal studies and published human case reports, and offers guidelines for using high-dose insulin with supplemental dextrose and potassium (HDIDK).
Therapeutic interventions in CCA toxicity, including decontamination, atropine, calcium, glucagon, adrenergic drugs, and phosphodiesterase inhibitors, do not consistently improve hemodynamic parameters and ensure survival. HDIDK has been evaluated in severely life-threatening shock states, including CCA toxicity. The rationale is that insulin promotes cellular uptake of glucose in muscle and adipose tissue and promotes inotropy by stimulating myocardial energy production via activating calcium and potassium channels to regenerate ATP and promote aerobic metabolism. Insulin also appears to be cardioprotective by inhibiting inflammatory processes.
Several studies inducing verapamil toxicity in a canine model have shown that HDIDK is likely an effective therapy. There are several important results from these studies. First, HDIDK increased survival in verapamil-toxic canines compared to normal saline, epinephrine, glucagon, and calcium; insulin increased the lethal dose of verapamil when compared to epinephrine, glucagon, and normal saline. When comparing HDIDK, normal saline, epinephrine, glucagon, and calcium, only the HDIDK group was able to maintain improvements in myocardial oxygen delivery to work ratio. This correlated to an increase in carbohydrate uptake by myocytes. Also, negative inotropy observed in verapamil toxicity correlated with the inability of the myocardium to utilize carbohydrate. Insulin improved carbohydrate uptake, as opposed to glucagons and epinephrine, which enhanced fatty acid metabolism leading to ketosis and only transient benefits. The studies also showed that 1 U/min of insulin was well tolerated in dogs with verapamil toxicity.
Thirteen published human cases of CCA toxicity treated with HDIDK infusions were reviewed. In 12/13 cases, HDIDK was considered beneficial with resolution of hypotension and eventual discharge without sequelae. In the one case where HDIDK was not beneficial, there was a significant delay in recognition of the overdose and initiation of HDIDK. Potential adverse effects of HDIDK include hypoglycemia and hypokalemia. All but one of the 13 patients required supplemental dextrose during HDIDK therapy. Hypokalemia was only mentioned for 4 of the 13 patients, with only 3 of the patients receiving potassium supplementation.
A guideline has been developed for HDIDK therapy. In CCA toxicity, if there is inadequate response to fluid resuscitation, calcium, and vasopressors, then administer dextrose if the glucose level is less than 200 mg/dL and potassium if the level is less than 2.5 mEq/L. Give 1 unit/kg insulin bolus followed by 0.5 to 1.0 units/kg/hour of regular insulin. Titrate insulin to clinical response with the a goal of systolic blood pressure above 100 mmHg and a heart rate above 50 beats per minute in adults. Check capillary glucose every 20 minutes for the first hour, then check both serum potassium and capillary glucose every hour. This guideline for HDIDK is based on 5 cases and has not been evaluated prospectively.
This article is important because it reviews the evidence available regarding high-dose insulin therapy for CCA toxicity. Although a randomized controlled trial would provide stronger, more objective evidence for this treatment option, none have been done to date. Despite this, medical toxicologists have been using high-dose insulin in CCA toxicity with success for a number of years.
As mentioned in Shepherd and Klein-Schwartz's article, there are no data evaluating the synergies between HDIDK and other therapies. Also, it is difficult to compare the human cases reported because HDIDK was not the sole treatment employed in the cases, and HDIDK was considered rescue, as opposed to early, treatment in many cases. Furthermore, in the cases reported, there was a lack of standardized dosing of HDIDK, with insulin boluses ranging from none to inadvertently administrating 1000 Units and infusions ranging from 0.1 Units/kg/h to 1.0 Units/kg/h. Other limitations include co-ingestants in 4 of the 13 cases and publication bias that portends the possibility of underreporting negative findings. Given the clinical experience and lack of clinical trials, HDIDK cannot be recommended as a sole therapy or first-line at this time. However, animal data and lack of evidence of serious adverse effects associated with HDIDK suggest that it may have a role earlier, rather than later, in the management of serious CCA toxicity.
Other recent review articles cite the same animal studies and case reports and also draw the conclusion that, based on the information available, high-dose insulin is beneficial for CCA toxicity.2-5 There also are a few other recent case reports of CCA toxicity where insulin was involved in successful treatment since Shepherd and Klein-Schwartz's article publication.6,7 The hypothesized mechanism is that high-dose insulin improves myocardial glucose uptake, allowing for a more efficient metabolism, and, therefore, improved myocardial contraction. Recommendations on exactly how to use high-dose insulin vary slightly but the important points are that the dose is 1 unit/kg bolus followed by 0.5 to 1.0 unit/kg/h, titrated to response, with repletion of potassium and glucose as needed after frequent checks.
What adjunctive therapies are on the horizon?
Source: Tebbutt S, Harvey M, Nicholson T, et al. Intralipid prolongs survival in a rat model of verapamil toxicity. Acad Emerg Med 2006;13:134-139.
Tebbutt and colleagues performed a blinded, randomized controlled trial on 30 female rats to evaluate the ability of intralipid to ameliorate clinically relevant toxicity of verapamil, a lipophilic agent. Each animal received 37.5 mg/kg/h of verapamil. Five minutes later the control group received 12.4 mL/kg of normal saline over 5 minutes, while the treatment group received 12.4 mL/kg of 20% intralipid. Intralipid-treated animals survived almost twice as long as the control group. The mean lethal dose of verapamil in the intralipid group was almost twice that of the control group. Also, the decrease in heart rate was significantly slower in the intralipid group compared with the saline group.
In their discussion, the authors explain how intralipid may sequester fat-soluble toxins within an intravascular lipid compartment, decreasing the free drug and possibly enhancing clearance as intralipid chylomicrons deliver compounds to the liver within the lipid phase.
This article proposes a potential adjunct to CCA toxicity management. Although not currently used for CCA toxicity, it is innovative with possible benefits. Limitations of the study are those inherent to animal studies. The optimal dose, concentration, infusion ratio, and timing of administration of intralipid rescue, as well as risks of administrating intralipid for CCA toxicity remains to be elucidated. Also, the LD50 in the study is theoretical, as the animals were not allowed to recover.
What about something other than epinephrine?
Source: Sztajnkrycer MD, Bond GR, Johnson SB, et al. Use of vasopressin in a canine model of severe verapamil poisoning: A preliminary descriptive study. Acad Emerg Med 2004;11:1253-1261.
No single agent has been consistently effective in managing critically ill CCA toxic patients. Numerous studies have demonstrated vasopressin's efficacy in reversing intractable hypotension associated with catecholamine-resistant shock.
In this study, Sztajnkrycer and colleagues evaluate the effects of exogenous arginine vasopressin (AVP) in a canine model of CCA-induced shock. They also determine serum AVP concentrations in CCA-induced shock.
In this randomized, controlled laboratory study, verapamil was used to induce CCA shock in 12 adult hound dogs. The experimental group received escalating doses of AVP, and the control group received normal saline infusion. Cardiovascular measurements in both groups, as well as blood AVP determinations in the control group, were performed throughout the experiment.
The results were not as expected. Low-dose AVP did not significantly change mean arterial pressure and lead to a decrease in cardiac index and heart rate when compared to the shock-induced state. After escalating doses of AVP, there was further decrease in heart rate and a negligible effect on cardiac index. With both escalating doses of AVP and equivalent volumes of normal saline, there was a slight increase in mean arterial pressure. By the end of the experiment, mean arterial pressures in both the experimental and control group where similar.
All (6) of the experimental animals survived while 4/6 of the control animals survived. Unexpectedly, when AVP was measured in the control group, endogenous AVP levels during CCA toxicity increased nearly 40-fold compared with baseline levels. To conclude, this study does not support the use of AVP monotherapy in shock secondary to CCA toxicity.
The pathophysiology of therapeutic interventions in calcium channel blocker toxicity is not completely understood. This study characterizes CCA-induced shock as an AVP resistant, rather than an AVP deficient shock. Therefore, vasopressin may not be the best modality in the treatment of CCA-induced shock. This understanding may help in choosing vasopressors in the management of CCA-induced shock.
There are a few weaknesses of this study. The investigators were not blinded to the study and, as an animal study, it may lack direct applicability to clinical practice. In clinical practice, multiple therapeutic modalities are typically used, but only vasopressin was used in this study and vasopressin was not compared against the other treatment modalities. Parameters such as SVR (systemic vascular resistance) and mixed venous oxygen saturation were not measured in the study, and these also may be important considerations. Also, in the design of the study, a continuous infusion of verapamil was used to simulate extended-release CCA toxicity, which may not be an accurate model.
The results of this study differ from other studies that have found that vasopressin is beneficial in shock states. In a recent case report by Kanagarajan and colleagues, two patients with severe CCA toxicity were treated successfully with vasopressin after inadequate response to glucagon, calcium, insulin, and conventional vasopressor therapies.8 Although vasopressors are just one of the multiple modalities used in treatment, it is difficult to know if vasopressin is the optimal choice when choosing a medication for cardiovascular support in CCA-induced shock.
Other than mean arterial pressure and heart rate, what other parameters can I use?
Source: Kamijo Y, Yoshida T, Ide A, et al. Mixed venous oxygen saturation monitoring in calcium channel blocker poisoning: tissue hypoxia avoidance despite hypotension. Am J Emerg Med 2006;24:357-360.
Kamijo and colleagues report two patients with dihydropyridine overdose successfully managed with supportive care along with continuous monitoring to exclude tissue hypoxia. A 29-year-old female presented with bradycardia and hypotension after an overdose of amlodipine, candesartan-cilexetil, and aspirin. Despite intravenous fluids, calcium gluconate, atropine, and vasopressors, she remained hypotensive. However, her mixed venous oxygen saturation remained 70% or better and she did not develop metabolic acidosis.
A 72-year-old female presented with bradycardia and hypotension after an overdose of benidipine and clotiazepam. She was treated with intravenous fluids, calcium gluconate, atropine, and dopamine. Despite sustained hypotension in the intensive care unit, her mixed venous oxygen saturation remained between 71% and 85% and she did not develop metabolic acidosis.
The authors claim that these two cases suggest inotropic and/or vasopressor agents in the amounts required to restore normal blood pressure may not always be necessary to treat CCA-induced hypotension as long as tissue hypoxia can be excluded. In these two patients, vasopressor doses were intended to avoid tissue hypoxia rather than to raise blood pressure.
Mixed venous oxygen saturation is a functional marker of adequate oxygen delivery to the tissues. Although mixed venous oxygen saturation monitoring is helpful in the intensive care of patients, mixed venous oxygen saturation above 70% may be falsely reassuring. With CCAs, patients may decompensate quickly; aggressive therapy is needed in this setting. When refractory hypotension occurs in severe CCA toxicity, attempts should be made to correct blood pressure with vasopressors, high-dose insulin, as well as cardiac pacing and possible intra-aortic balloon counterpulsation, focusing on improving both cardiac output and peripheral vascular tone. Two cases are not sufficient to show that adequate mixed venous oxygen saturation with persistent hypotension is within the standard of care. At this time, mean arterial pressure has been important as well as SvO2 (not just a determinant of it), and although this is interesting data, more studies are needed before the standard of care is changed. As with many case reports of overdoses, these patients had multiple ingestions, which could contribute to their toxicity and possibly make conclusions directed solely to treatment of CCA difficult.
CCA toxicity can be lethal, and sometimes difficult to manage. One of the greatest challenges to clinicians is early recognition of patients at risk for developing refractory shock. As with any critically ill patient, toxicologic entities should be high on the differential diagnosis, and CCA toxicity should be considered in any patient with cardiovascular collapse, especially with metabolic acidosis and hyperglycemia.
CCAs have a low toxic-to-therapeutic ratio, and asymptomatic patients who have ingested what may not seem like an "overdose" may decompensate. Therefore, even if only one extra dose of CCA is taken, it is reasonable to observe patients in a monitored setting for 12 hours for immediate release CCAs and 24 hours for extended release CCAs.
When cardiovascular signs of toxicity appear, aggressive management is warranted. Decontamination with activated charcoal and whole bowel irrigation should be considered, as well as using atropine, calcium salts, and glucagon.
It is important to recognize the hypoinsulinemia state induced by CCA toxicity and the benefit of adding exogenous insulin to improve glucose uptake in the myocardium. High-dose insulin therapy may improve contractility of the myocardium and the clinical outcome. The evidence available suggests that high-dose insulin should be considered early in severe toxicity.
When vasopressors are used, there is little evidence to show that one is superior. However, it may be that in CCA toxicity, the peripheral vasculature is resistant to vasopressin. Until we have stronger evidence, the choice of vasopressor support depends on the clinical picture of the patient, the response to other treatments, and the clinician's comfort with the agents available.
Finally, although the course of CCA toxicity may be prolonged, these patients can have a full recovery with little to no sequelae.
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6. Harris NS. Case 24-2006: A 40-year-old woman with hypotension after an overdose of amlodipine. N Engl J Med 2006;355:602-611.
7. Vogt S, Mehlig A, Hunziker P, et al. Survival of severe amlodipine intoxication due to medical intensive care. Forensic Sci Int 2006; 161:216-220.
8. Kanagarajan K, Marraffa JM, Bouchard NC, et al. The use of vasopressin in the setting of recalcitrant hypotension due to calcium channel blocker overdose. Clin Toxicol (Phila) 2007;45:56-59.