Abstract
In 2003, U.S. poison control centers were consulted after 9650 ingestions of calcium channel blockers (CCBs), including 57 deaths. This represents more than one-third of the deaths reported to the American Association of Poison Control Centers' Toxic Exposure Surveillance System database that were associated with cardiovascular drugs and emphasizes the importance of developing a guideline for the out-of-hospital management of calcium channel blocker poisoning. The objective of this guideline is to assist poison center personnel in the appropriate out-of-hospital triage and initial management of patients with suspected ingestions of calcium channel blockers. An evidence-based expert consensus process was used to create this guideline. This guideline applies to ingestion of calcium channel blockers alone and is based on an assessment of current scientific and clinical information. The expert consensus panel recognizes that specific patient care decisions may be at variance with this guideline and are the prerogative of the patient and the health professionals providing care, considering all of the circumstances involved. The panel's recommendations follow. The grade of recommendation is in parentheses. 1) All patients with stated or suspected self-harm or the recipient of a potentially malicious administration of a CCB should be referred to an emergency department immediately regardless of the amount ingested (Grade D). 2) Asymptomatic patients are unlikely to develop symptoms if the interval between the ingestion and the call is greater than 6 hours for immediate-release products, 18 hours for modified-release products other than verapamil, and 24 hours for modified-release verapamil. These patients do not need referral or prolonged observation (Grade D). 3) Patients without evidence of self-harm should have further evaluation, including determination of the precise dose ingested, history of other medical conditions, and the presence of co-ingestants. Ingestion of either an amount that exceeds the usual maximum single therapeutic dose or an amount equal to or greater than the lowest reported toxic dose, whichever is lower (see Table ), would warrant consideration of referral to an emergency department (Grade D). 4) Do not induce emesis (Grade D). 5) Consider the administration of activated charcoal orally if available and no contraindications are present. However, do not delay transportation in order to administer charcoal (Grade D). 6) For patients who merit evaluation in an emergency department, ambulance transportation is recommended because of the potential for life-threatening complications. Provide usual supportive care en route to the hospital, including intravenous fluids for hypotension. Consider use of intravenous calcium, glucagon, and epinephrine for severe hypotension during transport, if available (Grade D). 7) Depending on the specific circumstances, follow-up calls should be made to determine outcome at appropriate intervals based on the clinical judgment of the poison center staff (Grade D).
Introduction
Ingestion of a calcium channel blocker (CCB) is a potentially lethal event. In 2003, U.S. poison control centers were consulted after 9650 ingestions of CCBs. Of these, 4834 patients (50%) were evaluated in healthcare facilities, 1481 (15%) experienced major or moderate toxicity, and 57 died. This represents more than one-third of the deaths reported to the American Association of Poison Control Centers' Toxic Exposure Surveillance System (TESS) database that were associated with cardiovascular drugs Citation[1].
The evaluation of possible CCB poisoning has medical, economic, and social costs. Because the toxic doses overlap with the upper therapeutic range for many of these drugs, poison control centers frequently recommend hospital evaluation after any CCB exposure. Moreover, because most CCBs are formulated as modified-release products that might have delayed onsets of symptoms, prolonged observation of asymptomatic patients is widely practiced Citation[2]. Finding a child with an open medicine container that might have contained just one tablet of a CCB is often followed by overnight hospital observation. Patients taking CCBs therapeutically might unintentionally take second doses of their own medications and could be at risk for toxicity if they have underlying heart disease or if the amount of drug in each dosage unit is large. Many such patients are also taking other cardiodepressant drugs that might have additive effects on heart rate or contractility. Thus, poison control center triage of unintentional CCB ingestion is usually based on a low threshold for hospital referral, with transportation often occurring by ambulance. The potential costs of EMS transportation, emergency department evaluation, aggressive gastrointestinal decontamination (including whole bowel irrigation for sustained-release products), and intensive care unit observation are potentially enormous, especially considering that most patients develop no symptoms as a result of an exposure Citation[3]. A review of poison control center management protocols and medical toxicology textbooks suggests that the threshold for triage after acute unintentional CCB ingestion varies widely (see below).
Background and Definitions
Calcium channel blockers (also known as calcium antagonists or calcium entry blockers) are used widely for the treatment of a variety of disorders including hypertension, angina pectoris, coronary artery spasm, supraventricular arrhythmias, and migraine headache. Ten calcium channel blockers are currently marketed in the U.S. (amlodipine, bepridil, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, and verapamil). These drugs block the entry of calcium through cellular membrane voltage-sensitive calcium channels. In vascular tissue, this results in arterial smooth muscle relaxation. In the heart, CCBs inhibit depolarization of cells in the sinoatrial and atrioventricular nodes and depress contractility. At doses used clinically, nifedipine and other dihydropyridines (amlodipine, felodipine, isradipine, nicardipine, and nimodipine) are relatively selective vasodilators and do not usually affect nodal conduction or contractility; however, in overdose this distinction can be lost Citation[4&5]. Patients with pre-existing cardiac dysfunction (e.g., congestive heart failure, cardiomyopathy, conduction disorders) could have pronounced effects. Combination of CCBs with other negative inotropes (e.g., β-blockers) can produce additive toxicity Citation[6].
Toxicity from CCBs can occur as a result of a single acute ingestion, which could be unintentional or intentional, or with repeated or therapeutic use. An acute exposure might involve unintentional ingestion of a second therapeutic dose in a patient already on the drug, unintentional ingestion of someone else's therapeutic dose in a patient naïve to CCBs, unintentional ingestion by a child, or intentional ingestion with suicidal intent.
This guideline focuses on the ingestion of more than a single therapeutic dose (overdose). Therapeutic doses of CCBs can sometimes cause adverse effects in both adults and children—some idiosyncratic and some dose-dependent. Articles that reported adverse effects related to usual therapeutic doses and with therapeutic intent were not included in the review.
For the purpose of this guideline, age groups are defined as 1) children under 6 years of age and 2) older children and adults. The older age group is much more likely to attempt self-harm and to conceal an ingestion. Acute exposures are defined as those occurring over a period of no more than 8 hours, and chronic exposures are those that occur over a period of 8 or more hours. The term out-of-hospital is defined as the period before a patient reaches a healthcare facility.
Intended Users of the Guideline
The intended users of this guideline are personnel in U.S. poison centers. This guideline has been developed for the conditions prevalent in the U.S. While the toxicity of calcium channel blockers is not expected to vary in a clinically significant manner in other nations, the out-of-hospital conditions could be much different. Some calcium channel blockers are not currently marketed in the U.S. These calcium channel blockers are not addressed in this document. This guideline should not be extrapolated to other settings unless it has been determined that the conditions assumed in this guideline are present.
Objective of This Guideline
The objective of this guideline is to assist poison center personnel in the appropriate out-of-hospital triage and initial management of patients with suspected ingestions of calcium channel blockers by
describing the process by which a calcium channel blocker ingestion might be managed,
identifying the key decision elements in managing cases of calcium channel blocker ingestion,
providing clear and practical recommendations that reflect the current state of knowledge, and
identifying needs for research.
This guideline is based on an assessment of current scientific and clinical information. The expert consensus panel recognizes that specific patient care decisions may be at variance with this guideline and are the prerogative of the patient and the health professionals providing care, considering all of the circumstances involved.
Methodology
The methodology used for the preparation of this guideline was developed after reviewing the list of key elements of guidelines described by Shaneyfelt et al. Citation[7]. An expert consensus panel was established to oversee the guideline development process (Appendix 1). The American Association of Poison Control Centers (AAPCC), the American Academy of Clinical Toxicology (AACT), and the American College of Medical Toxicology (ACMT) appointed members of their organizations to serve as panel members. To serve on the expert consensus panel, an individual had to have an exceptional track record in clinical care and scientific research in toxicology, board certification as a clinical or medical toxicologist, significant U.S. poison center experience, and be an opinion leader with broad esteem. Two specialists in poison information were included as full panel members to provide the viewpoint of the end-users of the guideline.
Literature Search
The National Library of Medicine's MEDLINE database was searched (1966–March 2003) using calcium channel blockers (exploded as a MeSH term) with the subheadings poisoning or toxicity, limited to humans. A second MEDLINE search (1966–October 2003) located all calcium channel blocker articles that included patients from 1 through 5 years of age.
The MEDLINE and PreMEDLINE (1966–February 2003) databases were searched using a list of 23 calcium channel blockers as textwords (title, abstract, MeSH term, CAS registry) plus either poison* or overdos* or tox*, limited to humans. This same process was repeated in International Pharmaceutical Abstracts (1970–March 2003, excluding abstracts of meeting presentations), Science Citation Index (1977–March 2003), the Database of Abstracts of Reviews of Effects (accessed March 2003), the Cochrane Database of Systematic Reviews (accessed March 2003), and the Cochrane Central Register of Controlled Trials (accessed March 2003). A similar search was conducted in Excerpta Medica Database (EMBASE, 1990–March 2003). Reactions (1980–March 2003), the calcium channel poisoning management in POISINDEX Citation[8], and the bibliographies of recovered articles were reviewed to identify previously undiscovered articles. Furthermore, NACCT abstracts published in the Journal of Toxicology–Clinical Toxicology (1995–2003) were reviewed for original human data. The chapter bibliographies in four current major toxicology textbooks Citation[9-12] and the reference list of a recent review article Citation[13] were reviewed for citations of additional articles with original human data. Finally, the Toxic Exposure Surveillance System (TESS) maintained by the American Association of Poison Control Centers was searched for deaths resulting from unintentional calcium channel blocker poisoning or any deaths from calcium channel blocker poisoning in children (for the years 1985–2002). These cases were abstracted for use by the panel.
Article Selection
The recovered citations were entered into an EndNote® library and duplicate entries were eliminated. The abstracts of the remaining articles were reviewed, looking specifically for those that dealt with estimations of mg/kg or ingested doses with or without subsequent signs or symptoms, and management techniques that might be suitable for out-of-hospital use (e.g., gastrointestinal decontamination). Articles excluded were those that did not meet either of the preceding criteria, didn't add new data (e.g., some reviews, editorials), and some that exclusively described inpatient-only procedures (e.g., dialysis).
Data Extraction
All articles that were retrieved from the search were reviewed by a single abstractor. Each article was assigned a level-of-evidence score from 1 to 6 using the rating scheme developed by the Centre for Evidence-Based Medicine at Oxford University (Appendix 2); the complete paper was then reviewed for original human data regarding the toxic effects of calcium channel blockers or original human data directly relevant to the out-of-hospital management of patients with calcium channel blocker toxicity or overdose. Relevant data (e.g., dose of calcium channel blocker, resultant effects, time of onset of effects, therapeutic interventions or decontamination measures given, efficacy or results of any interventions, and overall patient outcome) were compiled into a table and a brief summary description of each article was written. This full evidence table is available at http://www.aapcc.org/DiscGuidelines/CCB%20evidence%20table.pdf. The complete table of all abstracted articles was then forwarded to the panel members for review and consideration in developing the guideline. Every attempt was made to locate significant foreign language articles and have their crucial information extracted, translated, and tabulated. In addition to this evidence table, several brief sub-tables were generated that included all of the articles and data relating to a particular topic (e.g., dose of calcium channel blockers in acute pediatric ingestions reported to cause toxicity). These were also forwarded to the primary author and guideline panel members. Copies of all of the articles were made available for reading by the panel members on a secure AAPCC website.
California Poison Control System Data
The primary author (KO) reviewed data from the California Poison Control System's Visual Dotlab database, including narrative case notes, for cases of calcium channel blocker exposure for the years 2000 through 2003. The cases were reviewed for information about dose, time of onset, and outcome.
Guideline Writing and Review
A guideline draft was prepared by the primary author. The draft was submitted to the expert consensus panel for comment. Using a modified Delphi process, comments from the expert consensus panel members were collected, copied into a table of comments, and submitted to the primary author for response. The primary author responded to each comment in the table and, when appropriate, the guideline draft was modified to incorporate changes suggested by the panel. The revised guideline draft was again reviewed by the panel and, if there was no strong objection by any panelist to any of the changes made by the primary author, the draft was prepared for the external review process. External review of the second draft was conducted by distributing it electronically to AAPCC, AACT, and ACMT members and the secondary review panel. The secondary review panel consisted of representatives from the federal government, public health, emergency services, pediatrics, pharmacy practice, and consumer organizations (Appendix 3). Comments were submitted via a discussion thread on the AAPCC website or privately through e-mail communication to AAPCC staff. All submitted comments were stripped of any information that would identify their sources, copied into a table of comments, and reviewed by the expert consensus panel and the primary author. The primary author responded to each comment in the table and their responses and subsequent changes in the guideline were reviewed and accepted by the panel. Following a meeting of the expert consensus panel, the final revision of the guideline was prepared.
Review of Current Practice
Recommended Therapeutic Doses of Calcium Channel Blockers
Because calcium channel blockers have a low toxic-to-therapeutic dose ratio, and serious effects have been reported at doses only slightly above those used for therapy, the panel reviewed currently available recommendations for therapeutic dosing. presents recommended doses of common calcium channel blockers for children and adults.
Current Poison Control Center Practices
During the preparation of this guideline, the panel investigated poison center referral patterns for calcium channel blocker ingestions. All U.S. poison centers were invited by the AAPCC to provide copies of any protocols or operational guidelines for calcium channel blocker ingestion. Twenty-eight poison centers responded but 14 of these stated they did not have a specific guideline for calcium channel blockers. Fourteen guidelines were received (see ). All 14 advised healthcare facility (HCF) referral for a suspected suicidal ingestion. Nine guidelines recommended HCF referral after ingestion of any amount of a CCB. Of these nine, one specified “any SR preparation,” one commented that it is “prudent to send most small children in,” and one advised referral to an HCF for all CCB ingestions by children. The other five PCC guidelines did not specifically distinguish pediatric from adult exposures or immediate-release vs. modified-release products.
Seven of the PCC guidelines described threshold HCF referral amounts for CCB ingestions by children. However, these varied widely. For example, one center advised HCF referral for pediatric ingestion of more than 80 mg immediate-release (IR) verapamil, of any amount of a modified-release (SR) verapamil, and of any amount of any nifedipine preparation. Another center had a lower threshold for verapamil (2.5 mg/kg) and a higher threshold for nifedipine (1 mg/kg). The latter PCC's guideline indicated that death had been reported after a single 10-mg nifedipine. Another PCC uses the “lowest pediatric therapeutic dose” as a threshold, and refers the guideline user to “pediatric dosing books.”
Recommendations for adults with unintentional ingestion or ingestion of an extra dose were also variable and were specifically addressed by only seven of the 14 PCCs. One advised referral for ingestion of more than the maximum therapeutic adult dose. Three PCCs allowed home observation for a double dose of one's own medicine but added qualifiers that would override the amount taken, such as the caller is alone, is having symptoms, has underlying cardiac disease, or takes other medicines that might contribute to an adverse reaction. One of these three PCCs also suggested that the caller contact the patient's own physician to decide on HCF referral.
Seven PCCs recommended a specific period of observation in an HCF, with range of 6–8 hours for immediate-release and 16–24 hours for modified-release products. Three of these PCCs specifically recommended 24 hours of observation or longer for SR products.
Review of Medical Toxicology Textbooks
A review of textbooks revealed similar variation in recommendations—two texts provide no dose guidelines for HCF referral Citation[10&11] while others recommend any dose greater than the usual therapeutic dose Citation[18], any dose of two to three times the normal dose Citation[19], or various specific doses varying from 5 mg/kg Citation[12] to 720 mg Citation[9] for diltiazem, and similar variations for other calcium channel blockers.
Review of TESS and California Poison Control System Data
During the 18-year period 1985–2002, TESS received reports of 235 deaths involving CCB poisoning. There were 15 cases in which death occurred as a result of acute unintentional ingestion, therapeutic error, or misuse; and the estimated dose of CCB was recorded on the abstract. These cases are summarized in . The lowest reported fatal dose of immediate-release diltiazem in an adult was 360 mg and for modified-release diltiazem it was 240–360 mg. An 11-month-old child died after ingesting 40 mg of immediate-release nifedipine. A 7-day-old child died after receiving 25 mg verapamil. Doses between 360 and 540 mg were associated with death in three adults. An 84-year-old woman with hypertension treated with lisinopril and verapamil died after she accidentally took a second dose of her 240-mg modified-release verapamil 1 hour after her usual dose.
Data recorded in the California Poison Control System database for 2000–2003 were reviewed (obtained through an internal study by the lead author), and cases coded “Major Effect” or “Death” are summarized in . In addition, all pediatric exposures to any calcium channel blocker reported to the CPCS during 2002 and 2003 were reviewed individually. There were no pediatric cases coded as “Major Effect” or “Death.” The only fatal case involved diltiazem 240 mg (controlled-release) that was chewed instead of swallowed (this case occurred in 2003 and is not the same as case 5 in ). Three adults had significant cardiovascular effects after ingesting only mildly supratherapeutic doses of verapamil. A 58-year-old man took his usual dose (240 mg SR) for a migraine headache, then took an additional 120 mg and presented to an emergency department with dizziness, junctional bradycardia, and hypotension. A 69-year-old woman took two 240-mg verapamil SR tablets instead of 1.5 tablets and developed hypotension and bradycardia.
Benson et al. Citation[20] analyzed 2002–2003 TESS data in children under 6 years of age involving unintentional ingestions of amlodipine (as a single agent ingestion) in which estimated doses were recorded. Of 679 cases, estimated amounts ingested ranged from 0.25 to 200 mg. Clinically significant symptoms were recorded for 3.5% of 346 children who ingested between 2.5 and 5 mg, 3.8% of 183 children who ingested between 5 and 10 mg, and 11% of 73 children who were thought to have ingested more than 10 mg. No children ingesting less than 2.5 mg had significant symptoms.
Review of the Medical Literature
Dose of CCBs Resulting in Toxicity
Acute Supratherapeutic Ingestion in Patients 6 Years of Age and Older
No level 1, 2, or 3 studies were found evaluating the threshold dose for the development of toxicity in adults or children 6 years of age and older with acute CCB exposures.
A large number of case reports and case series with dose-toxicity information were found (level 4). The cases in which the exposure dose was known (or estimated) and reported are summarized in . In the vast majority of cases it was impossible to gauge the accuracy of the estimated dose. Cases in which the exposure dose was either not reported or unknown are not included in the summary but can be found in the full evidence table. Cases in which β-blockers were co-ingested are also not included in because it was felt that the similarity and synergism between the clinical effects of β-blockers and CCBs would make it difficult to determine the contribution of each drug. Cases of CCB and β-blocker co-intoxication are included in the full evidence table.
Acute Supratherapeutic Ingestion in Patients Less Than 6 Years of Age
No level 1, 2, or 3 studies were found evaluating the threshold dose for the development of toxicity in children less than 6 years of age with acute CCB exposures.
A few case reports and two multi-year retrospective chart reviews (level 4) were identified with dose-toxicity information. The results are summarized in . Combined β-blocker/CCB exposures were not summarized nor were cases in which the dose was not known or reported.
Chronic Supratherapeutic Ingestion in Patients 6 Years of Age and Older
No level 1, 2, or 3 studies were found regarding chronic (over 8 or more hours) supratherapeutic CCB ingestions by older children and in adults. Several level 4 reports were reviewed with chronic dose-toxicity information, however. These are summarized in .
Chronic Supratherapeutic Ingestion in Patients Less Than 6 Years of Age
No data were found regarding chronic (over 8 or more hours) supratherapeutic CCB ingestions in children less than 6 years of age.
Time to Onset of Effects After Overdose
The time to onset of effects was recorded for each article because it was felt that this information might be useful in creating the guideline. Specifically, how long after ingestion an asymptomatic patient might be judged unlikely to develop toxicity and, therefore, safe to observe at home; the recommended mode of prehospital transportation; and when to schedule poison control center follow-up calls.
Clinical effects were defined as any sign, symptom, or laboratory/electrocardiographic finding consistent with CCB toxicity. It is important to note that the actual onset of effects likely occurred earlier than reported in many cases because the patients presented to HCFs well into the course of their poisonings. Therefore, the times recorded in the summary tables are estimates of the maximum possible delay to onset of symptoms. In addition, the tables refer only to the time of first effect onset and do not give information on the time-to-peak effects or the total duration of effects. Time-to-peak effects varied and were difficult to discern and summarize in a useful format based solely on the level 4 reports available. However, it was noted that in several instances of overdose with modified-release (SR) products, patients deteriorated clinically many hours into the course of their poisoning Citation[46], Citation[48], Citation[63&64], Citation[101], Citation[103], Citation[105], Citation[107], Citation[109]. In many such cases, there were mild clinical or electrocardiographic signs of toxicity early on, but in others these clues were either not reported or not clearly evident.
Acute Supratherapeutic Ingestion in Patients 6 Years of Age and Older
There were no level 1, 2, or 3 studies investigating the time to onset of clinical effects after CCB overdose in adults. A number of individual case reports and case series (level 4) listed information on time to onset of clinical effects. Time-to-effect onset is shown in when it was known (or estimated) by the authors of the report. Cases in which β-blockers and calcium channel blockers were co-ingested are not included because it was felt that, given the similarity and synergism between the clinical effects of β-blockers and CCBs, it would be difficult to derive meaningful data when the two were combined.
Acute Supratherapeutic Ingestion in Patients Less Than 6 Years of Age
There were no level 1, 2, or 3 studies investigating the time to onset of clinical effects after CCB overdose in children less than 6 years of age. Several level 4 reports were reviewed that contained information on onset of effects. Their data are tabulated in .
Potential Out-of-Hospital Treatments
There were no studies that looked specifically at out-of-hospital decontamination measures. The articles were therefore reviewed for information regarding those decontamination measures evaluated in-hospital that could reasonably be expected to be instituted in an out-of-hospital setting. These were limited to activated charcoal administration and induction of emesis with syrup of ipecac.
Activated Charcoal
One level 1b article was found with information on the efficacy of activated charcoal after CCB ingestion. It was a randomized, controlled trial in healthy volunteers and found that 25 g activated charcoal given immediately after the ingestion of 10 mg amlodipine reduced amlodipine absorption by 99% compared to untreated controls. The same dose of activated charcoal given 2 hours later reduced absorption by about half and, when given 6 hours after ingestion, there was no significant reduction in absorption Citation[131].
The rest of the data on activated charcoal are presented as level 4 data—a large number of case reports and series in which it was used (see full evidence table). It was not possible to detect any benefit or lack of benefit from charcoal administration in such cases. However, no significant detrimental effects were reported with its use.
Emesis Induction
No level 1, 2, or 3 studies were found regarding the utility of emesis induction for patients with CCB overdoses.
Several level 4 articles reported the use of ipecac syrup or other forms of induced emesis in patients with CCB overdose, but in most cases there were either no tablet fragments returned or the results of emesis induction were not reported Citation[2], Citation[30], Citation[36], Citation[39], Citation[54], Citation[88&89], Citation[122]. Only one level 4 report was found in which the authors reported the use of ipecac syrup to be successful in retrieving tablet fragments Citation[95]. No reports of adverse outcomes associated specifically with the use of emesis after calcium channel blocker ingestion were found.
Other Treatments
There were no level 1, 2, or 3 studies that addressed the efficacy of any other treatments for CCB overdose. The data were limited to case reports and a few case series (level 4). There were very few papers that specified a treatment as being performed out-of-hospital or in-hospital. Hence, the articles were reviewed for any interventions that might potentially be instituted in an out-of-hospital setting (i.e., atropine, dobutamine, dopamine, epinephrine, calcium, glucagon, insulin, pacing), and the resultant information is compiled in , which lists the various interventions reported for reversing the major cardiovascular manifestations (e.g., hypotension, bradycardia, conduction abnormalities) of CCB toxicity. Other treatments that were mentioned in the articles as being potentially beneficial but that would not likely be available to, or practicable for, U.S. out-of-hospital personnel are not listed in the table. These include dexamethasone Citation[81], methylscopolamine Citation[91], metaproterenol Citation[66], Citation[139], 4-aminopyridine Citation[134], amrinone Citation[96], Citation[138], angiotensin II Citation[25], theophylline Citation[139], enoxamine Citation[73], and vasopressin Citation[112]. General supportive care measures (e.g., airway management measures, fluids, anticonvulsants, bicarbonate) might have been beneficial in some cases but were difficult to evaluate and are not specifically addressed in the table or this summary. Treatments aimed at treating the non-cardiovascular complications of CCB overdose (e.g., seizures, hyperglycemia, acidosis, renal failure) are also not addressed here. However, all interventions used, their effect, and the context in which they were used are described in the full evidence table.
For each reported intervention, an attempt was made to assess its efficacy based on information about the patient's response, the temporal relationship of any effects, the consequences of either withdrawing or repeating the intervention, any evidence of a dose-response relationship, and the overall physiologic plausibility of the intervention. Clinical responses were grouped into one of four categories: effective (+ +), partially effective (+), not effective (0), or detrimental (−). Effective interventions were those that fully reversed all of the major cardiovascular manifestations of CCB toxicity. Partially effective interventions only partly reversed the negative cardiovascular manifestations of toxicity, fully reversed only one aspect of cardiovascular toxicity (e.g., heart rate or blood pressure), or only reversed cardiovascular toxicity in combination with other agents or interventions. Interventions in the not effective category had no appreciable clinical effect. Included in this group are treatments after which the patient continued to deteriorate clinically consistent with the course of CCB intoxication. Interventions were deemed detrimental if they caused a clinical deterioration that could not otherwise be attributed to the usual course of CCB toxicity alone. If the response to an intervention was not reported in an article, the article was not included in the summary table. The same intervention in the same patient can appear in more than one category of efficacy, if, for example, it was unsuccessful at one dose or time but successful at another. In addition, just because a therapy appears in the effective category does not mean it was the only therapy given throughout the patient's course. It indicates that, to the best that could be ascertained, it was the only therapy associated with the patient's clinical recovery at that time. Other measures, particularly supportive measures, could either have been ongoing or were not specifically listed by the authors.
In reviewing the evidence, it became clear that no intervention was reliably effective alone, although insulin/dextrose shows promise Citation[145] and glucagon animal data are encouraging Citation[146]. In the majority of cases, combinations of agents were necessary to provide hemodynamic support. Some agents seemed to work for some patients but not others. Of note, there were several reports of patients surviving CCB overdoses with supportive measures alone, both adults Citation[22], Citation[33], Citation[71], Citation[147&148] and children [Citation118, Citation129]. In many of these cases, however, the underlying toxicity appears to have been comparatively mild.
Limitations of the Published Data
The case reports and case series varied widely in the extent of clinical detail presented, and the cases varied widely in the severity and clinical effects of poisoning; the timing, combination, dose, and routes of various treatments used; and in a number of other patient- or context-specific factors.
Data for the amount ingested are often inaccurate or incomplete. The history is frequently obtained from an intoxicated patient or an emotionally stressed or elderly caregiver. Parents might underestimate or overestimate the ingested dose because of denial or anxiety. Poison center staff often use the worst-case scenario to estimate an ingested dose in order to provide a wide margin of safety. In most case reports and case series the history of exposure was not independently verified or confirmed by laboratory testing. Poor correlation between reported estimated doses and subsequent concentrations or toxicity has been documented for children with unintentional ingestions of other drugs, such as acetaminophen, for which quantitative laboratory confirmation is routine Citation[149-151].
In most of the case reports and case series reviewed, the exact time of ingestion was not reported or was not known, or the time of onset of toxicity can only be estimated as occurring within a range of hours after the suspected ingestion.
Conclusions
Key Decision Points for Triage
The expert consensus panel chose to emphasize the importance of information that would be needed in order to make a sound triage decision for the patient with a calcium channel blocker ingestion. These variables include the patient's intent, the time of the ingestion, the patient's symptoms or underlying medical condition, the dose and formulation of the specific product ingested, and any co-ingested drugs. The panel agreed that in each case the judgment of the specialist in poison information, with the assistance of their medical consultant or pre-approved policies, might override any specific recommendation.
Patient Intent
The expert consensus panel concluded that all patients with a suicidal intent or in which a malicious intent was suspected (e.g., child abuse or neglect) should be transported expeditiously by EMS to an emergency department. Patients without these characteristics are candidates for consideration of out-of-hospital management of their ingestion.
Time Since Ingestion
The panel concluded that asymptomatic patients are unlikely to develop symptoms if the interval between the ingestion and the call is greater than 8 hours for immediate-release products, 12–24 hours for most modified-release products, and 24 hours for modified-release verapamil.
Patient's Symptoms or Underlying Medical Condition
The expert consensus panel concluded that referral to an emergency department should be considered for any patient who is experiencing symptoms that might be reasonably related to the CCB (e.g., dizziness, syncope, generalized weakness, shortness of breath), with severe underlying cardiovascular disease (e.g., end-stage cardiomyopathy), or on multiple cardiovascular medicines that could have additive cardiodepressant effects with the dose of CCB taken. The importance of each of these variables can be difficult to judge in a telephone conversation so a low threshold for emergency department evaluation is considered prudent. Symptomatic patients should be transported by EMS.
Dose and Formulation of the Specific Drug Taken
The estimation of dose is based largely on the patient's history and the type of product and its packaging (when available for evaluation). If precise data for the ingestion are unknown or unclear (package size, unit size, number of units ingested), poison centers in the United States often utilize a method in which the maximum potential dose is calculated. For example, if the actual dose ingested cannot be ascertained, the amount of the drug product that is missing from the container is multiplied by the dosage unit or concentration of the formulation. Modified-release products often contain larger amounts of a drug but their rate of absorption could be much slower and toxicity might be delayed.
For asymptomatic patients with an acute, unintentional ingestion of a CCB, the panel concluded that home observation might be allowable for very small exposures. However, the panel recognized that a definite threshold dose for toxicity, based on a confirmed history of exposure, has not been reported. After a thorough review of published case reports, recommended therapeutic dosage regimens, current poison control center practice, and expert experience, the panel concluded that ingestion of either of the following amounts (whichever is lower) should warrant consideration of referral to an emergency department ():
An amount that exceeds the usual maximum single therapeutic dose; or
An amount equal to or greater than the lowest reported toxic dose
Duration of Observation for Asymptomatic Patients
The expert consensus panel concluded that onset and duration of toxicity could be affected by several variables, including the specific type of pharmaceutical product (liquid, tablet, modified-release formulation), the total quantity ingested, and co-ingestants, as well as gastrointestinal decontamination measures such as activated charcoal. After a careful review of the case reports and observational studies summarized in Tables and , and considerable discussion, the panel recommends that the duration of observation of an asymptomatic patient be at least 6 hours for immediate-release products, 18 hours for modified-release products other than verapamil, and 24 hours for modified-release verapamil. Patients who are asymptomatic after these intervals are unlikely to subsequently develop symptoms.
Potential Out-of-Hospital Management
Gastrointestinal Decontamination
The expert consensus panel concluded that out-of-hospital gastrointestinal decontamination offered potential benefit, but the risks and overall benefit to the patient were difficult to determine. Inducing emesis with ipecac syrup was concluded to carry the risk of pulmonary aspiration of gastric contents if the patient became hypotensive or lost consciousness and is not supported by sufficient evidence of benefit to warrant its use. Moreover, ipecac syrup would likely delay or prevent the use of alternative, potentially more effective treatments and it might induce a vagal stimulus that could further depress heart rate. Activated charcoal was determined to be a useful treatment that could be administered orally in the prehospital setting, although its effectiveness and risks have not been evaluated in the prehospital setting. Also, the panel agreed that transportation to an emergency department should not be delayed in order to attempt charcoal administration.
Specific Pharmacological Therapy
The expert consensus panel concluded that although the available literature on in-hospital management of CCB poisoning supports the use of intravenous calcium, glucagon, and epinephrine, which are often available to paramedics, no studies were found addressing the effectiveness or safety of these drugs for the out-of-hospital treatment of CCB-induced hypotension and bradycardia.
Recommendations
These recommendations are provided in chronological order of likely clinical use. The grades of recommendation appear in parentheses.
Patients with stated or suspected self-harm or the recipient of a potentially malicious administration of a CCB should be referred to an emergency department immediately. This activity should be guided by local poison center procedures. In general, this should occur regardless of the dose reported (Grade D).
Asymptomatic patients are unlikely to develop symptoms if the interval between the ingestion and the call is greater than 6 hours for immediate-release products, 18 hours for modified-release products other than verapamil, and 24 hours for modified-release verapamil. These patients do not need referral or prolonged observation (Grade D).
Patients without evidence of self-harm should have further evaluation, including determination of the precise dose ingested, history of other medical conditions, and the presence of co-ingestants. Ingestion of either an amount that exceeds the usual maximum single therapeutic dose or an amount equal to or greater than the lowest reported toxic dose, whichever is lower (see ), would warrant consideration of referral to an emergency department (Grade D).
Do not induce emesis (Grade D).
Consider the administration of activated charcoal orally if available and no contraindications are present. However, do not delay transportation in order to administer charcoal (Grade D).
For patients who merit evaluation in an emergency department, ambulance transportation is recommended because of the potential for life-threatening complications. Provide usual supportive care en route to the hospital, including intravenous fluids for hypotension. Consider use of intravenous calcium, glucagon, and epinephrine for severe hypotension during transport, if available (Grade D).
Depending on the specific circumstances, follow-up calls should be made to determine outcome at appropriate intervals based on the clinical judgment of the poison center staff (Grade D).
Implications for Research
A large-scale prospective study of unintentional CCB ingestions is needed, with a careful attempt to confirm the estimates of the doses taken, the specific formulations, CCB serum concentrations, the presence or absence of underlying illnesses, the use of other medications, the presence or absence of symptoms, the times of onset of any toxicities, the durations of medical observation, and outcomes. Given the low incidence of serious toxicity after unintentional ingestion, especially in children, a multi-center and multi-year study will be needed.
An additional need is better correlation between the estimated ingested dose, clinical symptoms, and serum concentrations of the CCB in patients with serious overdoses.
Prehospital use of calcium, glucagon, insulin/dextrose, epinephrine, and other measures should be studied.
Disclosures
Dr. Booze's husband is employed by AstraZeneca. Dr. Erdman is currently employed by AstraZeneca but was not when this guideline was written. There are no other potential conflicts of interest reported by the expert consensus panel or project staff regarding this guideline.
References
- Watson W A, Litovitz T L, Klein-Schwartz W, Rodgers G C Jr, Youniss J, Reid N, Rouse W G, Rembert R S, Borys D. 2003 Annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med 2004; 22:335–404, [PUBMED], [INFOTRIEVE], [CSA]
- Ramoska E A, Spiller H A, Winter M, Borys D. A one-year evaluation of calcium channel blocker overdoses: toxicity and treatment. Ann Emerg Med 1993; 22:196–200, [PUBMED], [INFOTRIEVE], [CROSSREF], [CSA]
- Belson M G, Gorman S E, Sullivan K, Geller R J. Calcium channel blocker ingestions in children. Am J Emerg Med 2000; 18:581–586, [PUBMED], [INFOTRIEVE], [CROSSREF], [CSA]
- Goodman & Gilman's the Pharmacological Basis of Therapeutics. 10th ed. Hardman J G, Limbird L E, eds. New York: McGraw-Hill, 2001.
- Pearigen P D, Benowitz N L. Poisoning due to calcium antagonists. Experience with verapamil, diltiazem and nifedipine. Drug Safety 1991; 6:408–430, [PUBMED], [INFOTRIEVE], [CSA]
- Kerns W II, Kline J, Ford M D. Beta-blocker and calcium channel blocker toxicity. Emerg Med Clin North Am 1994; 12:365–390, [PUBMED], [INFOTRIEVE], [CSA]
- Shaneyfelt T M, Mayo-Smith M F, Rothwangl J. Are guidelines following guidelines? The methodological quality of clinical practice guidelines in the peer-reviewed medical literature. JAMA 1999; 281:1900–1905, [PUBMED], [INFOTRIEVE], [CROSSREF], [CSA]
- Poisindex System. Klasco R K, ed. Thomson Micromedex: Greenwood Village, CO, edition expires March 2003.
- Ellenhorn's Medical Toxicology: Diagnosis and Treatment of Human Poisoning. 2nd ed. Ellenhorn M J, ed. Baltimore: Williams & Wilkins, 1997.
- Ford M D, Delaney K A, Ling L J, Erickson T. Clinical Toxicology. Philadelphia: WB Saunders, 2000.
- Goldfrank's Toxicologic Emergencies. 7th ed. Goldfrank L R, Flomenbaum N E, Lewin N A, Howland M A, Hoffman R S, Nelson L S, eds. New York: McGraw-Hill, 2002.
- Clinical Management of Poisoning and Drug Overdose. 3rd ed. Haddad L M, Shannon M W, Winchester J F, eds. Philadelphia: WB Saunders, 1998.
- Salhanick S D, Shannon M W. Management of calcium channel antagonist overdose. Drug Safety 2003; 26:65–79, [PUBMED], [INFOTRIEVE], [CSA]
- Nelson Textbook of Pediatrics. 17th ed. Behrman R E, Kliegman R M, Jenson H B, eds. Philadelphia: WB Saunders, 2004.
- The Science and Practice of Pediatric Cardiology. 2nd ed. Garson A, Bricker J T, Fisher D J, Neish S R, eds. Baltimore: Williams & Wilkins, 1998.
- The Harriet Lane Handbook: A Manual for Pediatric House Officers. 16th ed. Philadelphia: Mosby, 2002.
- USP DI. Drug Information for the Health Care Professional. 24th ed. Englewood, CO: Thomson Micromedex, 2004.
- Poisoning & Drug Overdose. 4th ed. Olson K R, ed. New York: McGraw-Hill, 2004.
- Medical Toxicology. 3rd ed. Dart R C, ed. Philadelphia: Lippincott, Williams & Wilkins, 2003.
- Benson B E, Spyker D A, Troutman W G, Watson W A. TESS-based amlodipine dose-response in pediatric exposures. J Toxicol Clin Toxicol 2004; 42:753–754 [abstract], , [CSA]
- Boyer E W, Shannon M. Treatment of calcium channel blocker intoxication with insulin infusion. N Engl J Med 2001; 344:1721–1722, [PUBMED], [INFOTRIEVE], [CROSSREF], [CSA]
- Stanek E J, Nelson C E, DeNofrio D. Amlodipine overdose. Ann Pharmacother 1997; 31:853–856, [PUBMED], [INFOTRIEVE], [CSA]
- Koch A R, Vogelaers D P, Decruyenaere J M, Callens B, Verstraete A, Buylaert W A. Fatal intoxication with amlodipine. J Toxicol Clin Toxicol 1995; 33:253–256, [PUBMED], [INFOTRIEVE], [CSA]
- Cosbey S H, Carson D J. A fatal case of amlodipine poisoning. J Anal Toxicol 1997; 21:221–222, [PUBMED], [INFOTRIEVE], [CSA]
- Tovar J L, Bujons I, Ruiz J C, Ibanez L, Salgado A. Treatment of severe combined overdose of calcium antagonists and converting enzyme inhibitors with angiotensin II. Nephron 1997; 77:239, [PUBMED], [INFOTRIEVE], [CSA]
- Mahr N C, Valdes A, Lamas G. Use of glucagon for acute intravenous diltiazem toxicity. Am J Cardiol 1997; 79:1570–1571, [PUBMED], [INFOTRIEVE], [CSA]
- Lambert H, Weber M, Renaud D. Intoxications aiguës par diltiazem (DTZ). Bilan des Centres Anti-Poisons Français. J Toxicol Clin Exp 1990; 10:229–242, [PUBMED], [INFOTRIEVE], [CSA]
- Fang C C, Tsai L M. Hematologic complications of diltiazem overdose. Am Heart J 1993; 126:1017–1018, [PUBMED], [INFOTRIEVE], [CROSSREF], [CSA]
- Ramoska E A, Spiller H A, Myers A. Calcium channel blocker toxicity. Ann Emerg Med 1990; 19:649–653, [PUBMED], [INFOTRIEVE], [CROSSREF], [CSA]
- Roberts D, Honcharik N, Sitar D S, Tenenbein M. Diltiazem overdose: pharmacokinetics of diltiazem and its metabolites and effect of multiple dose charcoal therapy. J Toxicol Clin Toxicol 1991; 29:45–52, [PUBMED], [INFOTRIEVE], [CSA]
- Oliver T B, Awunor-Renner C. Isoprenaline infusion and right ventricular pacing in severe diltiazem poisoning. N Z Med J 1992; 105:483, [PUBMED], [INFOTRIEVE], [CSA]
- Jaeger A, Sauder P, Bianchetti G, Kopferschmitt J, Dahlet M, Tritsch L, Flesch F. Intoxications aiguës par le diltiazem: étude cinétique et hémodynamique. J Toxicol Clin Exp 1990; 10:243–248, [PUBMED], [INFOTRIEVE], [CSA]
- Garcia del Pozo J M, Siquier B, Vicens C. Intento de autólisis con diltiacem. Rev Esp Cardiol 1991; 44:355–357, [PUBMED], [INFOTRIEVE], [CSA]
- Snover S W, Bocchino V. Massive diltiazem overdose. Ann Emerg Med 1986; 15:1221–1224, [PUBMED], [INFOTRIEVE], [CROSSREF], [CSA]
- Darmanaden R, Kienlen J, Rouve M B. One case of fatal poisoning by diltiazem. Therapie 1992; 47:80–81, [PUBMED], [INFOTRIEVE], [CSA]
- Jakubowski A T, Mizgala H F. Effect of diltiazem overdose. Am J Cardiol 1987; 60:932–933, [PUBMED], [INFOTRIEVE], [CROSSREF], [CSA]
- Buffet M, Ostermann G, Raclot P, Bertault R, Rambourg M O, Jaussand M, Journe B, Seys G A. Cinétique du diltiazem au cours d'un surdosage volontaire. Presse Med 1984; 13:1338. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieved&db=pubmedd&dopt=Abstract&list_uids=6233565&query_h1=1, , [PUBMED], [INFOTRIEVE], [CSA]
- Gibelin P, Maccario M, Lapalus P, Morand P. Intoxication volontaire par le diltiazem. Presse Med 1984; 13:745, [PUBMED], [INFOTRIEVE], [CSA]
- Howarth D M, Dawson A H, Smith A J, Buckley N, Whyte I M. Calcium channel blocking drug overdose: an Australian series. Human Exp Toxicol 1994; 13:161–166, [CSA]
- Erickson F C, Ling L J, Grande G A, Anderson D L. Diltiazem overdose: case report and review. J Emerg Med 1991; 9:357–366, [PUBMED], [INFOTRIEVE], [CROSSREF], [CSA]
- Fauville J P, Hantson P, Honore P, Belpaire F, Rosseel M T, Mahieu P. Severe diltiazem poisoning with intestinal pseudo-obstruction: case report and toxicological data. J Toxicol Clin Toxicol 1995; 33:273–277, [PUBMED], [INFOTRIEVE], [CSA]
- Henderson A, Stevenson N, Hackett L P, Pond S M. Diltiazem overdose in an elderly patient: efficacy of adrenaline. Anaesth Intensive Care 1992; 20:507–510, [PUBMED], [INFOTRIEVE], [CSA]
- Ferner R E, Odemuyiwa O, Field A B, Walker S, Volans G N, Bateman D N. Pharmacokinetics and toxic effects of diltiazem in massive overdose. Human Toxicol 1989; 8:497–499, [CSA]
- Connolly D L, Nettleton M A, Bastow M D. Massive diltiazem overdose. Am J Cardiol 1993; 72:742–743, [PUBMED], [INFOTRIEVE], [CROSSREF], [CSA]
- Malcolm N, Callegari P, Goldberg J, Strauss H, Caillé G, Vezina M, Spenard J. Massive diltiazem overdosage: clinical and pharmacokinetic observations. Drug Intell Clin Pharm 1986; 20:888. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieved&db=pubmedd&dopt=Abstract&list_uids=3780429&query_h1=2, , [PUBMED], [INFOTRIEVE], [CSA]
- Morimoto S, Sasaki S, Kiyama M, Hatta T, Moriguchi J, Miki S, Kawa T, Nakamura K, Itoh H, Nakata T, Takeda K, Nakagawa M. Sustained-release diltiazem overdose. J Hum Hypertens 1999; 13:643–644, http://ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieved&db=pubmedd&dopt=Abstract&list_uids=10482975&query_h1=3, [PUBMED], [INFOTRIEVE], [CROSSREF], [CSA]
- Satchithananda D K, Stone D L, Chauhan A, Ritchie A J. Unrecognized accidental overdose with diltiazem. Br Med J 2000; 321:160–161., [CSA]
- Isbister G K. Delayed asystolic cardiac arrest after diltiazem overdose; resuscitation with high dose intravenous calcium. Emerg Med J 2002; 19:355–357, [PUBMED], [INFOTRIEVE], [CROSSREF], [CSA]
- Cimpello L B, Craig S, Lawrence E, Baker M D. A calcium channel blocker and ibuprofen overdose. Curr Opin Pediatr 1998; 10:303–307, [PUBMED], [INFOTRIEVE], [CSA]
- Luomanmaki K, Tiula E, Kivisto K T, Neuvonen P J. Pharmacokinetics of diltiazem in massive overdose. Ther Drug Monit 1997; 19:240–242, [PUBMED], [INFOTRIEVE], [CROSSREF], [CSA]
- Williamson K M, Dunham G D. Plasma concentrations of diltiazem and desacetyldiltiazem in an overdose situation. Ann Pharmacother 1996; 30:608–611, [PUBMED], [INFOTRIEVE], [CSA]
- Frese J H, Rohland L, Schulz M, Schmoldt A. Intoxikation mit gallopamil. Dtsch Med Wochenschr 1988; 113:770–772, [PUBMED], [INFOTRIEVE], [CSA]
- Droy J M, Daridon E, Leroy J, Massari P. Intoxications aiguës par nicardipine et nifédepine. Etude multicentrique. J Toxicol Clin Exp 1990; 10:249–256, [PUBMED], [INFOTRIEVE], [CSA]
- Welch R D, Todd K. Nifedipine overdose accompanied by ethanol intoxication in a patient with congenital heart disease. J Emerg Med 1990; 8:169–172, [PUBMED], [INFOTRIEVE], [CROSSREF], [CSA]
- Schiffl H, Ziupa J, Schollmeyer P. Clinical features and management of nifedipine overdosage in a patient with renal insufficiency. J Toxicol Clin Toxicol 1984; 22:387–395, [PUBMED], [INFOTRIEVE], [CSA]
- Whitebloom D, Fitzharris J. Nifedipine overdose. Clin Cardiol 1988; 11:505–506, [PUBMED], [INFOTRIEVE], [CSA]
- Walter F G, Frye G, Mullen J T, Ekins B R, Khasigian P A. Amelioration of nifedipine poisoning associated with glucagon therapy. Ann Emerg Med 1993; 22:1234–1237, [PUBMED], [INFOTRIEVE], [CROSSREF], [CSA]
- Herrington D M, Insley B M, Weinmann G G. Nifedipine overdose. Am J Med 1986; 81:344–346, [PUBMED], [INFOTRIEVE], [CROSSREF], [CSA]
- Lam Y M, Tse H F, Lau C P. Continuous calcium chloride infusion for massive nifedipine overdose. Chest 2001; 119:1280–1282, [PUBMED], [INFOTRIEVE], [CROSSREF], [CSA]
- Fant J S, James L P, Fiser R T, Kearns G L. The use of glucagon in nifedipine poisoning complicated by clonidine ingestion. Pediatr Emerg Care 1997; 13:417–419, [PUBMED], [INFOTRIEVE], [CSA]
- Cavagnaro F, Aglony M, Rios J C, Paris E. A suicide attempt with an oral calcium channel blocker. Vet Hum Toxicol 2000; 42:99–100, [PUBMED], [INFOTRIEVE], [CSA]
- Ferner R E, Monkman S, Riley J, Cholerton S, Idle J R, Bateman D N. Pharmacokinetics and toxic effects of nifedipine in massive overdose. Human Exp Toxicol 1990; 9:309–311, [CSA]
- Wax P M. Intestinal infarction due to nifedipine overdose. J Toxicol Clin Toxicol 1995; 33:725–728, [PUBMED], [INFOTRIEVE], [CSA]
- Papadopoulos J, O'Neil M G. Utilization of a glucagon infusion in the management of a massive nifedipine overdose. J Emerg Med 2000; 18:453–455, [PUBMED], [INFOTRIEVE], [CSA]
- Haddad L M. Resuscitation after nifedipine overdose exclusively with intravenous calcium chloride. Am J Emerg Med 1996; 14:602–603, [PUBMED], [INFOTRIEVE], [CROSSREF], [CSA]
- Immonen P, Linkola A, Waris E. Three cases of severe verapamil poisoning. Int J Cardiol 1981; 1:101–105, [PUBMED], [INFOTRIEVE], [CROSSREF], [CSA]
- Crump B J, Hot D W, Vale J A. Lack of response to intravenous calcium in severe verapamil poisoning. Lancet 1982; 2:939–940, [PUBMED], [INFOTRIEVE], [CROSSREF], [CSA]
- Sauder P, Kopferschmitt J, Dahlet M, Tritsch L, Flesch F, Siard P, Manz J M, Jaeger A. Les intoxications aiguës par le vérapamil. A propos de 6 cas. Revue de la littérature. J Toxicol Clin Exp 1990; 10:261–270. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieved&db=pubmedd&dopt=Abstract&list_uids=2262922&query_h1=4, , [PUBMED], [INFOTRIEVE], [CSA]
- Gutierrez H, Horgensen M. Colonic ischemia after verapamil overdose. Ann Intern Med 1996; 124:535, [PUBMED], [INFOTRIEVE], [CSA]
- Leesar M A, Martyn R, Talley J D, Frumin H. Noncardiogenic pulmonary edema complicating massive verapamil overdose. Chest 1994; 105:606–607, [PUBMED], [INFOTRIEVE], [CSA]
- Candell J, Valle V, Soler M, Rius J. Acute intoxication with verapamil. Chest 1979; 75:200–201, [PUBMED], [INFOTRIEVE], [CSA]
- Lapostolle F, Bourdain F, Adnet F, Benaissa A, Muszynski J, Baud F. Intoxication aiguë par le vérapamil. Proposition d'une stratégie de prise en charge therapeutique. Ann Fr Anesth Reanim 2000; 19:607–610, [PUBMED], [INFOTRIEVE], [CROSSREF], [CSA]
- Link A, Hammer B, Weisgerber K, Bohm M. Therapie der verapamil-intoxikation mit noradrenalin und dem phosphodiesterasehemmer enoximon. Dtsch Med Wochenschr 2002; 127:2006–2008, [PUBMED], [INFOTRIEVE], [CROSSREF], [CSA]
- Kuhlmann U, Schoenemann H, Muller T, Keuchel M, Lange H. Plasmapheresis in life-threatening verapamil intoxication. Artif Cells Blood Substit Immobil Biotechnol 2000; 28:429–440, [PUBMED], [INFOTRIEVE], [CSA]
- Buckley C D, Aronson J K. Prolonged half-life of verapamil in a case of overdose: implications for therapy. Br J Clin Pharmacol 1995; 39:680–683, [PUBMED], [INFOTRIEVE], [CSA]
- Enyeart J J, Price W A, Hoffman D A, Woods L. Profound hyperglycemia and metabolic acidosis after verapamil overdose. J Am Coll Cardiol 1983; 2:1228–1231, [PUBMED], [INFOTRIEVE], [CSA]
- Chimienti M, Previtali M, Medicia A, Piccinini M. Acute verapamil poisoning: successful treatment with epinephrine. Clin Cardiol 1982; 5:219–222, [PUBMED], [INFOTRIEVE], [CSA]
- da Silva O A, de Melo R A, Jorge Filho J P. Verapamil acute self-poisoning. Clin Toxicol 1979; 14:361–367, [PUBMED], [INFOTRIEVE], [CSA]
- Woie L, Storstein L. Successful treatment of suicidal verapamil poisoning with calcium gluconate. Eur Heart J 1981; 2:239–242, [PUBMED], [INFOTRIEVE], [CSA]
- Perkins C M. Serious verapamil poisoning: treatment with intravenous calcium gluconate. Br Med J 1978; 2:1127, [PUBMED], [INFOTRIEVE], [CSA]
- Moroni F, Mannaioni P F, Dolara A, Ciaccheri M. Calcium gluconate and hypertonic sodium chloride in a case of massive verapamil poisoning. Clin Toxicol 1980; 17:395–400, [PUBMED], [INFOTRIEVE], [CSA]
- Miller A RO, Ingamells C J. Gastrointestinal hemorrhage associated with an overdose of verapamil. Br Med J 1984; 288:1346, [CSA]
- Kivisto K T, Neuvonen P J, Tarssanen L. Pharmacokinetics of verapamil in overdose. Human Exp Toxicol 1997; 16:35–37, [CSA]
- Watling S M, Crain J L, Edwards T D, Stiller R A. Verapamil overdose: case report and review of the literature. Ann Pharmacother 1992; 26:1373–1378, [PUBMED], [INFOTRIEVE], [CSA]
- Brass B J, Winchester-Penny S, Lipper B L. Massive verapamil overdose complicated by noncardiogenic pulmonary edema. Am J Emerg Med 1996; 14:459–461, [PUBMED], [INFOTRIEVE], [CROSSREF], [CSA]
- Oe H, Taniura T, Ohgitani N. A case of severe verapamil overdose. Jpn Circ J 1998; 62:72–76, [PUBMED], [INFOTRIEVE], [CROSSREF], [CSA]
- Kuo M J, Tseng Y Z, Chen T F, Fong D E. Verapamil overdose and severe hypocalcemia. J Toxicol Clin Toxicol 1992; 30:309–311, [PUBMED], [INFOTRIEVE], [CSA]
- Minella R A, Schulman D S. Fatal verapamil toxicity and hypokalemia. Am Heart J 1991; 121:1810–1812, [PUBMED], [INFOTRIEVE], [CROSSREF], [CSA]
- Spurlock B W, Virani N A, Henry C A. Verapamil overdose. West J Med 1991; 154:208–211, [PUBMED], [INFOTRIEVE], [CSA]
- Watson N A, FitzGerald C P. Management of massive verapamil overdose. Med J Aust 1991; 155:124–125, [PUBMED], [INFOTRIEVE], [CSA]
- de Faire U, Lundman T. Attempted suicide with verapamil. Eur J Cardiol 1977; 6:195–198, [PUBMED], [INFOTRIEVE], [CSA]
- Croker J R, Vaile J H. Management of massive verapamil overdose. Med J Aust 1991; 155:728, [PUBMED], [INFOTRIEVE], [CSA]
- McMillan R. Management of acute severe verapamil intoxication. J Emerg Med 1988; 6:193–196, [PUBMED], [INFOTRIEVE], [CROSSREF], [CSA]
- Horowitz B Z, Rhee K J. Massive verapamil ingestion: a report of two cases and a review of the literature. Am J Emerg Med 1989; 7:624–631, [PUBMED], [INFOTRIEVE], [CROSSREF], [CSA]
- Coaldrake L A. Verapamil overdose. Anaesth Intensive Care 1984; 12:174–175, [PUBMED], [INFOTRIEVE], [CSA]
- Goenen M, Col J, Compere A, Bonte J. Treatment of severe verapamil poisoning with combined amrinone-isoproterenol therapy. Am J Cardiol 1986; 58:1142–1143, [PUBMED], [INFOTRIEVE], [CROSSREF], [CSA]
- van der Meer J, van der Wall E. Fatal acute intoxication with verapamil. Neth J Med 1983; 26:130–132, [PUBMED], [INFOTRIEVE], [CSA]
- Jain S C, Bharadwaj R P, Shukla R K, Ahmad M, Mathur S P. Severe hypotension and bradycardia after suicidal consumption of 100 tablets of verapamil: a case report. Indian Heart J 1982; 34:175–176, [PUBMED], [INFOTRIEVE], [CSA]
- Sporer K A, Manning J J. Massive ingestion of sustained-release verapamil with a concretion and bowel infarction. Ann Emerg Med 1993; 22:603–605, [PUBMED], [INFOTRIEVE], [CROSSREF], [CSA]
- Tom P A, Morrow C T, Kelen G D. Delayed hypotension after overdose of sustained release verapamil. J Emerg Med 1994; 12:621–625, [PUBMED], [INFOTRIEVE], [CROSSREF], [CSA]
- Yuan T H, Kerns W P II, Tomaszewski C A, Ford M D, Kline J A. Insulin-glucose as adjunctive therapy for severe calcium channel antagonist poisoning. J Toxicol Clin Toxicol 1999; 37:463–474, [PUBMED], [INFOTRIEVE], [CROSSREF], [CSA]
- Mayer U, Buhl N, Sachs H, Sigel H. Tödliche vergiftung mit verapamil in retard-form. Therapeutische überlegungen. Dtsch Med Wochenschr 1985; 110:1293–1296, [PUBMED], [INFOTRIEVE], [CSA]
- Spiller H A, Meyers A, Ziemba T, Riley M. Delayed onset of cardiac arrhythmias from sustained-release verapamil. Ann Emerg Med 1991; 20:201–203, [PUBMED], [INFOTRIEVE], [CROSSREF], [CSA]
- Doyon S, Roberts J R. The use of glucagon in a case of calcium channel blocker overdose. Ann Emerg Med 1993; 22:1229–1233, [PUBMED], [INFOTRIEVE], [CROSSREF], [CSA]
- Buckley N, Dawson A H, Howarth D, Whyte I M. Slow-release verapamil poisoning. Use of polyethylene glycol whole-bowel lavage and high-dose calcium. Med J Aust 1993; 158:202–204, [PUBMED], [INFOTRIEVE], [CSA]
- Quezado Z, Lippmann M, Wertheimer J. Severe cardiac, respiratory, and metabolic complications of massive verapamil overdose. Crit Care Med 1991; 19:436–438, [PUBMED], [INFOTRIEVE], [CSA]
- Sami Karti S, Ulusoy H, Yandi M, Güdüz A, Koşucum M, Erol K, Ratip S. Non-cardiogenic pulmonary œdema in the course of verapamil intoxication. Emerg Med J 2002; 19:458–459, [PUBMED], [INFOTRIEVE], [CROSSREF], [CSA]
- Ori Y, Korzets A, Caneti M, Weinstein T, Chagnac A, Salman H, , et al. Lymphocytic intracellular calcium in a patient with complicated verapamil overdose. Am J Med Sci 2000; 319:63–67. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieved&db=pubmedd&dopt=Abstract&list_uids=10653445&query_h1=5, , [PUBMED], [INFOTRIEVE], [CROSSREF], [CSA]
- Barrow P M, Houston P L, Wong D T. Overdose of sustained-release verapamil. Br J Anaesth 1994; 72:361–365, [PUBMED], [INFOTRIEVE], [CSA]
- Shah A R, Passalacqua B R. Case report: sustained-release verapamil overdose causing stroke: an unusual complication. Am J Med Sci 1992; 304:357–359, [PUBMED], [INFOTRIEVE], [CSA]
- Krick S E, Gums J G, Grauer K, Cooper G R. Severe verapamil (sustained-release) overdose. DICP 1990; 24:705–706, [PUBMED], [INFOTRIEVE], [CSA]
- Vadlamudi L, Wijdicks E F. Multifocal myoclonus due to verapamil overdose. Neurology 2002; 58:984, [PUBMED], [INFOTRIEVE], [CSA]
- MacDonald D, Alguire P C. Case report: fatal overdose with sustained-release verapamil. Am J Med Sci 1992; 303:115–117, [PUBMED], [INFOTRIEVE], [CSA]
- Kozlowski J H, Kozlowski J A, Schuller D. Poisoning with sustained-release verapamil. Am J Med 1988; 85:127, [PUBMED], [INFOTRIEVE], [CSA]
- Hofer C A, Smith J K, Tenholder M F. Verapamil intoxication: a literature review of overdoses and discussion of therapeutic options. Am J Med 1993; 95:431–438, [PUBMED], [INFOTRIEVE], [CSA]
- Hagege A, Masquet C, Beaufils P, Slama R. Intoxication massive par le vérapamil à libération prolongée. Arch Mal Coeur Vaiss 1990; 83:1745–1747, [PUBMED], [INFOTRIEVE], [CSA]
- Ashraf M, Chaudhary K, Nelson J, Thompson W. Massive overdose of sustained-release verapamil: a case report and review of literature. Am J Med Sci 1995; 310:258–263, [PUBMED], [INFOTRIEVE], [CSA]
- Spiller H A, Ramoska E A. Isradipine ingestion in a two-year-old child. Vet Hum Toxicol 1993; 35:233, [PUBMED], [INFOTRIEVE], [CSA]
- Boyer E W, Duic P A, Evans A. Hyperinsulinemia/euglycemia therapy for calcium channel blocker poisoning. Pediatr Emerg Care 2002; 18:36–37, [PUBMED], [INFOTRIEVE], [CROSSREF], [CSA]
- Wells T G, Graham C J, Moss M M, Kearns G L. Nifedipine poisoning in a child. Pediatrics 1990; 86:91–94, [PUBMED], [INFOTRIEVE], [CSA]
- Lee D C, Greene T, Dougherty T, Pearigen P. Fatal nifedipine ingestions in children. J Emerg Med 2000; 19:359–361, [PUBMED], [INFOTRIEVE], [CROSSREF], [CSA]
- Brayer A F, Wax P. Accidental ingestion of sustained release calcium channel blockers in children. Vet Hum Toxicol 1998; 40:104–106, [PUBMED], [INFOTRIEVE], [CSA]
- Passal D B, Crespin F H. Verapamil poisoning in an infant. Pediatrics 1984; 73:543–545, [PUBMED], [INFOTRIEVE], [CSA]
- Adams B D, Browne W T. Amlodipine overdose causes prolonged calcium channel blocker toxicity. Am J Emerg Med 1998; 16:527–528, [PUBMED], [INFOTRIEVE], [CROSSREF], [CSA]
- Proano L, Chiang W K, Wang R Y. Calcium channel blocker overdose. Am J Emerg Med 1995; 13:444–450, [PUBMED], [INFOTRIEVE], [CROSSREF], [CSA]
- Orr G M, Bodansky H J, Dymond D S, Taylor M. Fatal verapamil overdose. Lancet 1982; 2:1218–1219, [PUBMED], [INFOTRIEVE], [CROSSREF], [CSA]
- Li Saw F, Hee F L, Lip G Y. Case report: fatal verapamil overdosage despite intensive therapy and use of high dose intravenous calcium. J Hum Hypertens 1996; 10:495–496, [CSA]
- Rankin R J, Edwards I R. Overdose of sustained release verapamil. N Z Med J 1990; 103:165, [PUBMED], [INFOTRIEVE], [CSA]
- Kardevandian E, Marcus S. Accidental ingestion of sustained release calcium channel blockers in children. Vet Hum Toxicol 1998; 40:237–238, [PUBMED], [INFOTRIEVE], [CSA]
- Hendren W G, Schieber R S, Garrettson L K. Extracorporeal bypass for the treatment of verapamil poisoning. Ann Emerg Med 1989; 18:984–987, [PUBMED], [INFOTRIEVE], [CROSSREF], [CSA]
- Laine K, Kivisto K T, Laakso I, Neuvonen P J. Prevention of amlodipine absorption by activated charcoal: effect of delay in charcoal administration. Br J Clin Pharmacol 1997; 43:29–33, [PUBMED], [INFOTRIEVE], [CSA]
- Bonechi F, Brandinelli Geri A, Maioli M, Ieri A. Avvelenamento da verapamile a scopo suicida. Descrizione di un caso. G Ital Cardiol 1993; 23:69–72, [PUBMED], [INFOTRIEVE], [CSA]
- Rosansky S J. Verapamil toxicity—treatment with hemoperfusion. Ann Intern Med 1991; 114:340–341, [PUBMED], [INFOTRIEVE], [CSA]
- ter Wee P M, Kremer Hovinga T K, Uges D R, van der Geest S. 4-Aminopyridine and haemodialysis in the treatment of verapamil intoxication. Human Toxicol 1985; 4:327–329, [CSA]
- Kalman S, Berg S, Lisander B. Combined overdose with verapamil and atenolol: treatment with high doses of adrenergic agonists. Acta Anaesthesiol Scand 1998; 42:379–382, [PUBMED], [INFOTRIEVE], [CSA]
- Samniah N, Schlaeffer F. Cerebral infarction associated with oral verapamil overdose. J Toxicol Clin Toxicol 1988; 26:365–369, [PUBMED], [INFOTRIEVE], [CSA]
- Humbert V H Jr, Munn N J, Hawkins R F. Noncardiogenic pulmonary edema complicating massive diltiazem overdose. Chest 1991; 99:258–259, [PUBMED], [INFOTRIEVE], [CSA]
- Wolf L R, Spadafora M P, Otten E J. Use of amrinone and glucagon in a case of calcium channel blocker overdose. Ann Emerg Med 1993; 22:1225–1228, [PUBMED], [INFOTRIEVE], [CROSSREF], [CSA]
- Holzer M, Sterz F, Schoerkhuber W, Behringer W, Domanovits H, Weinmar D, Weinstabl C, Stimpfl T. Successful resuscitation of a verapamil-intoxicated patient with percutaneous cardiopulmonary bypass. Crit Care Med 1999; 27:2818–2823. http://ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieved&db=pubmedd&dopt=Abstract&list_uids=10628632&query_h1=6, , [PUBMED], [INFOTRIEVE], [CROSSREF], [CSA]
- Romano M J, Gaylor A, Sang C J. Life-threatening isradipine poisoning in a child. Pharmacotherapy 2002; 22:766–770, [PUBMED], [INFOTRIEVE], [CROSSREF], [CSA]
- Hattori V T, Mandel W J, Peter D. Calcium for myocardial depression from verapamil. N Engl J Med 1982; 306:238, [PUBMED], [INFOTRIEVE], [CSA]
- Lipman J, Jardine I, Roos C, Dreosti L. Intravenous calcium chloride as an antidote to verapamil-induced hypotension. Intensive Care Med 1982; 8:55–57, [PUBMED], [INFOTRIEVE], [CROSSREF], [CSA]
- Luscher T F, Noll G, Sturmer T, Huser B, Wenk M. Calcium gluconate in severe verapamil intoxication. N Engl J Med 1994; 330:718–720, [PUBMED], [INFOTRIEVE], [CROSSREF], [CSA]
- Passeron D, Peschaud J L. Intoxication aiguë par la nicardipine. J Toxicol Clin Exp 1990; 10:257–259, [PUBMED], [INFOTRIEVE], [CSA]
- Shepherd G, Klein-Schwartz W. High-dose insulin therapy for calcium-channel blocker overdose. Ann Pharmacother 2005; 39:923–930, [PUBMED], [INFOTRIEVE], [CROSSREF], [CSA]
- Bailey B. Glucagon in beta-blocker and calcium channel blocker overdoses: a systematic review. J Toxicol Clin Toxicol 2003; 41:595–602, [PUBMED], [INFOTRIEVE], [CROSSREF], [CSA]
- Robles N R, Garcia Diaz M C, Fernandez Mora G, Sanchez Casado E. Intoxicación por verapamilo de liberación lenta en un enfermo urémico. Med Clin (Barc) 1992; 99:741–742., [CSA]
- Jaeger A, Berton C, Sauder P, Kopferschmitt J. Toxicité des inhibiteurs calcique. J Toxicol Clin Exp 1990; 10:219–228, [PUBMED], [INFOTRIEVE], [CSA]
- Rumack B H. Acetaminophen overdose in young children. Treatment and effects of alcohol and other additional ingestants in 417 cases. Am J Dis Child 1984 May; 138(5):428–433, [PUBMED], [INFOTRIEVE], [CSA]
- Gee P, Ardagh M. Paediatric exploratory ingestions of paracetamol. N Z Med J 1998; 111:186–188, [PUBMED], [INFOTRIEVE], [CSA]
- Caravati E M. Unintentional acetaminophen ingestion in children and the potential for hepatotoxicity. J Toxicol Clin Toxicol 2000; 38:291–296, [PUBMED], [INFOTRIEVE], [CROSSREF], [CSA]
Expert Consensus Panel Members
Lisa L. Booze, Pharm.D.
Certified Specialist in Poison Information
Maryland Poison Center
University of Maryland School of Pharmacy
Baltimore, Maryland
E. Martin Caravati, M.D., M.P.H., F.A.C.M.T., F.A.C.E.P.
Professor of Surgery (Emergency Medicine)
University of Utah
Medical Director
Utah Poison Center
Salt Lake City, Utah
Gwenn Christianson, R.N., M.S.N.
Certified Specialist in Poison Information
Indiana Poison Center
Indianapolis, Indiana
Peter A. Chyka, Pharm.D., F.A.A.C.T., D.A.B.A.T.
Professor, Department of Pharmacy
University of Tennessee Health Science Center
Memphis, Tennessee
Daniel C. Keyes, M.D., M.P.H.
Medical Director
Pine Bluff Chemical Demilitarization Facility
Associate Professor, Southwestern Toxicology Training Program
Dallas, Texas
Anthony S. Manoguerra, Pharm.D., D.A.B.A.T., F.A.A.C.T.
Professor of Clinical Pharmacy and Associate Dean
School of Pharmacy and Pharmaceutical Sciences
University of California San Diego
Former Director, California Poison Control System, San Diego Division
San Diego, California
Kent R. Olson, M.D., F.A.C.E.P., F.A.A.C.T., F.A.C.M.T.
Medical Director
California Poison Control System, San Francisco Division
Clinical Professor of Medicine and Pharmacy
University of California, San Francisco
San Francisco, California
Elizabeth J. Scharman, Pharm.D., D.A.B.A.T., B.C.P.S., F.A.A.C.T.
Director, West Virginia Poison Center
Professor, West Virginia University School of Pharmacy, Department of Clinical Pharmacy
Charleston, West Virginia
Paul M. Wax, M.D., F.A.C.M.T.
Managing Director
Banner Poison Center
Professor of Clinical Emergency Medicine
University of Arizona School of Medicine
Phoenix, Arizona
Alan D. Woolf, M.D., M.P.H., F.A.C.M.T.
Director, Program in Environmental Medicine
Children's Hospital, Boston
Associate Professor of Pediatrics
Harvard Medical School
Boston, Massachusetts
Grades of Recommendation and Levels of Evidence
Secondary Review Panel Organizations
Ambulatory Pediatric Association
American Academy of Breastfeeding Medicine
American Academy of Emergency Medicine
American Academy of Pediatrics
American Association for Health Education
American College of Clinical Pharmacy
American College of Emergency Physicians
American College of Occupational and Environmental Medicine
American Public Health Association
American Society of Health-System Pharmacists
Association of Maternal and Child Health Programs
Association of Occupational and Environmental Clinics
Association of State and Territorial Health Officials
Canadian Association of Poison Control Centres
Centers for Disease Control and Prevention—National Center for Injury Prevention and Control
Consumer Federation of America
Consumer Product Safety Commission
Department of Transportation
Emergency Medical Services for Children
Emergency Nurses Association
Environmental Protection Agency
European Association of Poisons Control Centres and Clinical Toxicologists
Food and Drug Administration
National Association of Children's Hospitals and Related Institutions
National Association of Emergency Medical Services Physicians
National Association of Emergency Medical Technicians
National Association of School Nurses
National Association of State Emergency Medical Services Directors
National Safe Kids Campaign
Teratology Society
World Health Organization International Programme on Chemical Safety