For the treatment of patients who ingested a potentially toxic amount of CCB, the workgroup recommends observation and consideration of decontamination following the position statements previously published jointly by the European Association of Poison Centres and Clinical Toxicologists (EAPCCT) and the American Academy of Clinical Toxicology (AACT) (16) (1D): “Based on volunteer studies, the administration of activated charcoal may be considered if a patient has ingested a potentially toxic amount of a poison (…) up to one hour previously. (…) the potential for benefit after one hour cannot be excluded.”
Based on case series (17–19), it is preferable to observe and monitor in a hospital setting for approximately 24 hours asymptomatic patients who ingested a potentially toxic amount of CCB, defined as more than a single therapeutic dose (5), to consider gastrointestinal decontamination (20–22) and to intervene with other treatments if signs of toxicity develop. The workgroup deferred the indications for, and types of, decontamination to the AACT and the EAPCCT position statement (2005) (16) instead of proposing new recommendations.
The workgroup agreed that each of the treatments here mentioned could be considered as first line alone or in combination. A supplementary round of Delphi did not allow prioritization of one intervention over another. Comparative studies were rare, and more than one interventions were done concurrently in most of the studies reviewed. Therefore, the workgroup emphasized that the first-line treatments should be prioritized based on the desired effect tailored to the individual patient’s clinical condition (Fig. 3; Supplemental Table 1, Supplemental Digital Content 2, http://links.lww.com/CCM/C95).
The workgroup recommended IV calcium as a first-line treatment based on improvement in contractility and blood pressure observed in some case series (23–26) and animal studies (27–33). This therapy is readily available and carries little risk provided central venous or secure peripheral venous access is available. The regimen often used for the administration of 10% calcium chloride in CCB-poisoned adults is 10–20 mL (1–2 g) every 10–20 minutes or an infusion at 0.2–0.4 mL/kg/hr (0.02–0.04 g/kg/hr). When 10% calcium gluconate is given, notably to minimize peripheral vein irritation, the dose regimen frequently used is 30–60 mL (3–6 g) every 10–20 minutes or an infusion at 0.6–1.2 mL/kg/hr (0.06–0.12 g/kg/hr) (23).
The selection of vasopressors should be guided by the type of shock. Based on mechanism of action, the workgroup recommended the use of norepinephrine to increase blood pressure in vasoplegic shock or if myocardial function has not yet been assessed (30, 32, 44). The use of epinephrine is also recommended for a CCB-poisoned patient in shock to increase contractility and heart rate (30, 32, 39). In the presence of confirmed myocardial dysfunction, clinicians can also use dobutamine (44). High infusion rates of vasopressors and inotropes may be required (44).
In situations in which there is symptomatic bradycardia or conduction disturbances, the workgroup suggested using atropine at a dose regimen of 0.5 mg every 3–5 minutes for few doses if needed. This suggestion is supported based on considerations that the therapy may temporarily help, is easily accessible, is inexpensive, and is associated with few risks (30, 32).
Although fluid resuscitation is commonly used, no formal recommendation was made because no fluid repletion studies were found specifically for CCB poisoning. Nonetheless, the workgroup considered fluid administration as a first-line therapy and continued administration as long as the patient demonstrates evidence of fluid responsiveness (e.g., hemodynamic improvement based on hemodynamic parameters and monitoring devices such as echocardiography after receiving 10–20 mL/kg of crystalloid over 10–15 min).
In patients refractory to the first-line treatments, the workgroup considered therapies supported by a limited number of case series and associated with a moderate risk. The workgroup kept therapies associated with higher risks for rescue treatments. Therefore, in the presence of myocardial dysfunction, the workgroup suggested to titrate high-dose insulin infusion rates up to 10 U/kg/hr to improve inotropy and facilitates the use of carbohydrates by the myocardium (43) with a dextrose infusion to maintain euglycemia if needed. Pacing has been associated with frequent capture and pacing problems. However, there may be hemodynamic improvement in patients presenting with unstable bradycardia or high-grade AV block (47–50). To avoid spending time on a therapy that involves risk and may not be effective, the workgroup suggested to attempt transcutaneous pacing first. If transcutaneous pacing is effective, IV pacing can be instituted when clinically appropriate.
Given the high risk of mortality in patients with severe refractory shock or periarrest, the workgroup members considered therapies with less evidence and/or greater risks. Therefore, incremental doses of high-dose insulin therapy are suggested even if no myocardial dysfunction has been documented (43) and the use of lipid-emulsion therapy is recommended in that situation (52,53,55–57).
Given the risk of mortality in severely poisoned patients and the potential survival benefit demonstrated in an observational study conducted in experienced centers (61), the workgroup members suggested venoarterial extracorporeal membrane oxygenation (VA-ECMO), which allows gas exchange and hemodynamic support, while blood is pumped from the venous to the arterial side, as a rescue therapy in CCB-poisoned patients presenting with cardiogenic shock or mixed shock involving a significant cardiogenic part in centers where the treatment is available. In this clinical scenario, the workgroup concluded that the benefits outweigh the risks of limb ischemia, bleeding, or thrombosis. The members were neutral with regard to the use of the Impella catheter (Abiomed, Danvers, MA) or other ventricular-assisted devices as potential alternatives to VA-ECMO as there is simply insufficient clinical or research experience (62).
Studies looking specifically at CCB-poisoned patients in cardiac arrest are scarce. Most recommendations other than use of VA-ECMO are extrapolated from studies conducted in severely ill patients not in cardiac arrest. Therefore, the workgroup emphasized the importance of aggressive resuscitation with the previously mentioned modalities. Consequently, the workgroup members recommended the use of IV calcium and lipid-emulsion therapy at the same dose regimen described earlier. Furthermore, a second dose of lipid-emulsion therapy overall is suggested even if the patient already received a bolus before the cardiac arrest.
Concerning the use of VA-ECMO in experienced centers, observational studies and case reports have demonstrated a survival benefit in cardiac arrest patients (61, 63–67). The workgroup members estimated that the benefit of saving a life outweighs the risks of initiating such invasive therapy as long as there is a reasonable chance of surviving without significant deficit. The workgroup recognized that a long period of low flow may be associated with poorer outcomes, but the evidence is unclear regarding the time to declare futility.
The rationale for not recommending or suggesting other treatments such as glucagon or methylene blue is available in Appendix 7 (Supplemental Digital Content 1, http://links.lww.com/CCM/C94). A description of values and preferences, the result of the review process, and the planned implementation and revisions are available in Appendix 2 (Supplemental Digital Content 1, http://links.lww.com/CCM/C94).
The target population for these recommendations includes CCB-poisoned adults. However, given the paucity of literature for the treatment of CCB-poisoned children and the absence of evidence that children respond differently than adults to CCB poisoning, the workgroup believes that it is reasonable to apply the recommendations to the pediatric population.
Even if articles were found to answer some KQs (1–5), the overall evidence available to develop these recommendations was of very low quality. Many interventions had only been studied for surrogate outcomes. With the exception of VA-ECMO for cardiotoxicant poisonings, the use of and costs associated with these resources had not been described (KQ5) (Fig. 1) (68). Hence, many questions within our proposed analytic framework remain unanswered (Fig. 1). These represent potential areas for future research.
First, comparative studies should be conducted to identify which intervention improves intermediate and health outcome (KQ 1, 3, and 4) for each specific class of CCB (KQ 2) with acceptable adverse effects and cost (KQ 5). Second, observational studies should identify prognostic factors, which is particularly imperative in severe cases that may potentially require VA-ECMO (KQ 2). Third, scientists should conduct clinical trials to identify factors associated with favorable responses to high-dose insulin therapies (KQ 2). Prospective, controlled clinical trials are needed to evaluate currently recommended antidotes or to assess new ones (KQ 1, 3, 4, and 5) (Table 3).
Those recommendations have been developed to help improve current treatment of CCB-poisoned patients by reducing physician practice variation. The workgroup also identified potential areas for future research.
For his participation to the workgroup and for reviewing the article, we would like to thank David H. Jang, medical toxicologist and emergency physician for the Department of Emergency Medicine, NYU School of Medicine. For his initial participation to the workgroup and for reviewing the article, we would like to thank Reza Afshari, Immediate Past President of Asia Pacific Association of Medical Toxicology, BC Center for Disease Control. For reviewing the article, we would like to thank the Canadian Critical Care Trials Group. For sharing unpublished data from their work, we would like to thank Pierre-André Dubé, Chantal Guimont, Jesse Godwin, Patrick Archambault, Jean-Marc Chauny, Anne-Julie Frenette, Martin Darveau, Natalie Lesage, Julien Poitras, Joanne Provencher, and René Blais, co-authors of a previously published systematic review (19).
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