Recommendations for the treatment of calcium channel blocker poisoning
St-Onge M, Anseeuw K, Cantrell L, Gilchrist IC, Hantson P, Bailey B, Gosselin S, Kerns W 2nd
R, Laliberté M, Mégarbane B, Jang D, Lavonas EJ, Juurlink DN, Muscedere J, Yang CC
Sinuff T, Rieder MJ, Lavergne V
ABSTRACT
INTRODUCTION: The main objective of these recommendations is to decrease practice
variation and improve the management of patients with acute calcium channel blocker
(CCB) poisoning by providing evidence-based treatment guidance. These recommendations
are endorsed by 12 international critical care, emergency medicine and toxicology
associations and address interventions for in-hospital management. The target users are
physicians, consultants, other healthcare providers and poison control centres.
METHODS: A working group was established and followed the process outlined by the
AGREE II instrument. The working group initially used the evidence documented in a
systematic review that pre-dated the establishment of the group. The search was then
completed by complementary sources. Members were separated into subgroups to evaluate
each candidate intervention, outlining the level of evidence (based on the GRADE system),
risks, benefits, and costs. Initial voting statements were constructed based on these
evidence summaries, which were then refined using four rounds of modified Delphi. The
strength of recommendation was determined by the vote results, using the median votes,
lower/upper interquartiles and disagreement indexes (RAND/UCLA Appropriateness
Method).
1
RESULTS: The overall level of evidence was very low. The main recommendations are as
follows: 1) In asymptomatic patients, we recommend observation and decontamination
(following the position statement published by the EACCT/AACCT) after an ingestion of a
potentially toxic amount of CCB (1D); 2) As a first-line treatment, we recommend
intravenous calcium (1D), high-dose insulin therapy (in combination with IV fluids, calcium
and vasopressors) (1-2D) and norepinephrine and/or epinephrine (1D) in the presence of
shock. We also suggest dobutamine in presence of cardiogenic shock (2D) and/or atropine
in presence of symptomatic bradycardia or conduction disturbance (2D); 3) In patients
refractory to first-line treatments, we suggest incremental doses of high-dose insulin
therapy if evidence of myocardial dysfunction is present (2D), intravenous lipid emulsion
therapy (2D), and using a pacemaker in presence of unstable bradycardia or high-grade AV
block, without significant alteration in cardiac inotropism (2D); 4) In patients in refractory
shock or peri-arrest, we recommend, as rescue treatments, incremental doses of high-dose
insulin therapy (1D) and/or intravenous lipid emulsion therapy (1D) if not already tried.
We also suggest VA-ECMO (or ECLS) in presence of cardiogenic shock in centres where the
treatment is available (2D), and/or using pacemaker in presence of unstable bradycardia or
high-grade AV block without significant alteration in cardiac inotropism (2D) if not already
tried; 5) In patients in cardiac arrest, we recommend intravenous calcium in addition to
standard advanced cardiac life-support (1D), lipid emulsion therapy (1D), and we suggest
VA-ECMO (or ECLS) in presence of a low flow, for less than 5 min, and in centres where the
treatment is available (2D).
CONCLUSION:
2
These recommendations for the treatment of CCB-poisoned adults include the stepwise
administration of various therapies as a function of poisoning severity. However, the level
of evidence for all interventions was very low in adults and absent in children. Further
research is needed to better characterize the utility and comparative effectiveness of
available treatment options.
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INTRODUCTION
Calcium channel blocker (CCB) poisonings occur relatively frequently and can result in
significant morbidity and mortality. According to the United States National Poison Data
System, cardiovascular drugs are the second most common category associated with the
largest number of fatalities.1 A recent retrospective study found that CCB poisoning is
associated with significant morbidity in 50% of patients including acute renal failure (35%),
aspiration pneumonia (15%) or cerebral anoxia (4%), with a mortality rate of 6%.
Additional reports suggest that only 42% of treatments provided accorded with advice
provided by a regional poison control centre.2 Similar findings were noted by Darracq et al.3
and Espinoza et al.,4 with respect to the use of high-dose insulin (HDI). An evidence-based
consensus guidelines has been published by Olson et al for out-of-hospital management of
calcium channel blocker ingestion,5 but current recommendations for evidence-based inhospital care have not been systematically developed and may vary from one toxicologist to
another due to differences between individual, local, or regional appraisal of the literature
or access to resources. Hence, our goal was to develop evidence-based recommendations to
guide the management of patients with CCB poisoning.
Calcium channel blockers, can be separated into two categories: dihydropyridines such as
nifedipine; and non-dihydropyridines such as diltiazem (a benzothiazepine) and verapamil
(a phenylalkylamine). Dihydropyridines preferentially block calcium channels in vascular
smooth muscles, causing vasoplegic hypotension and, in many patients, compensatory
tachycardia. Dihydropyridines have lower affinity for myocardial calcium channels, but this
4
selectivity attenuates at higher doses.6 In addition to their peripheral effects, nondihydropyridines generally slow the heart rate by inhibiting L-type calcium channels in the
sinoatrial and atrioventricular nodes.7
The oral bioavailability, onset of action and plasma half-life vary among the available CCBs.8
Moreover, it is difficult to estimate the half-life of an individual CCB in an overdose
situation, since the pharmacokinetics may be altered by coingestants, the presence of an
ileus or decreased gut perfusion due to shock, or vasopressor administration. Bezoars have
been reported to occur in patients taking CCBs, notably with certain formulations of
extended release nifedipine.9
In light of the possible loss of selectivity at very high CCB doses and the altered
pharmacokinetics following overdose, the following recommendations adopt a clinicallyoriented approach and do not focus on specific CCBs or formulations.
METHODS
Objective, scope, target users and analytical framework
The objective for the development of recommendations for the treatment of CCB poisoning
was to provide an evidence-based document to help reduce practice variation, with the
ultimate goal of improving the management of CCB-poisoning, The recommendations
address what types of in-hospital interventions should be considered for patients who have
ingested a potentially toxic amount of CCB, according to their clinical status. Targeted users
5
include the following: bedside or telephone-consulting physicians, other healthcare
providers (pharmacists and nurses), and poison control centres.
An analytical framework illustrating the links between key questions to be answered during
the recommendations development process was created (Figure 1). This was done as
suggested by the US Preventive Task Force13 to integrate heterogeneous evidence in the
development of a treatment approach including multiple interventions. The AGREE II
statements10 provided the basis for the process of developing these recommendations.
Recommendations development working group
A working group representing all participating professional international healthcare
organizations in emergency medicine, critical care, paediatrics, and toxicology (Table 1)
was created. Working group members were selected based on their content expertise. The
Canadian Association of Poison Control Centres (CAPCC) acted as the leading association,
named a chair and a co-chair, and a representative was appointment by each participating
organization.
The evidence
As a starting point, the working group used a systematic review that pre-dated the
establishment of the consensus group and had been published as a distinct article (registry
number: CRD42012002823).14 The systematic review included all study types involving
humans or animals poisoned with a CCB and examined the effects of all interventions on the
outcomes targeted by our recommendations up to December 31, 2013 (see online
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Appendices 1 and 2). The eligibility criteria (study types, participants, interventions,
comparisons and outcomes) and search strategy were similar to the ones used for the
systematic review.14 Nevertheless, in order to be thorough and complete, additional
literature brought to the attention of the working group by any member was considered for
inclusion. Data extraction, synthesis and presentation was performed as previously detailed
in the systematic review.14
Type of studies: Systematic reviews, controlled trials, observational studies, case series and
animal studies were considered appropriate evidence for the first three questions in Figure
1. While guidelines often discount animal studies in their synthesis of evidence,
Lamontagne et al. (2010)15 suggest that animal research may enhance knowledge useful for
clinical practice especially when the evidence is limited in human subject trials. In order to
address the fourth key question, we examined any study that could identify an association
between the intermediate outcomes and patient-centered health outcomes. Thus, only
controlled trials and observational studies were included. To answer the fifth key question
(adverse effects of therapy), case reports were considered in addition to other types of
evidence.
Type of study subjects: Studies involving adult and children or on animals poisoned with
any CCB were eligible, but not enough paediatric articles were find to include this
population in the recommendations.
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Type of intervention: Any treatment for the CCB poisoning was eligible as long as outcome
measures were reported.
Type of outcome measures: Outcomes included mortality (survival at discharge for human
studies or LD50 or time of survival for animal studies), functional outcomes (defined as a
return to functional baseline), and duration of stay in intensive care unit or in hospital.
Intermediate outcomes included prevention of (or attenuation of) toxicity, a decrease in
CCB serum level, improved hemodynamics and a decrease in duration of vasopressor use.
Differences in outcome were evaluated on experience, preferences and values. Studies
measuring the association between intermediate outcomes and health outcomes were
selected in order to answer the fourth key question. Adverse effects of treatment and costs
were also documented to answer the fifth key question. Adverse effects were documented
by the systematic review previously mentioned.14 However, since costs were not reported,
two working group members conducted a cost-effectiveness analysis with other co-authors
concerning the use of venoarterial extracorporeal membrane oxygenation (VA-ECMO), the
most expensive intervention.16
Definitions and terminology
The stepwise approach used by the working group included the following clinical
categories: asymptomatic patients, symptomatic patients requiring first-line treatment,
patients refractory to first-line treatment, patients in refractory shock or peri-arrest,
patients in cardiac arrest. First-line treatment was defined as treatments initially provided
8
to a symptomatic CCB-poisoned patient. Patients refractory to first-line treatment were
classified as such when desired effects (see Table 3) were not significantly reached with
first-line treatments, whereas rescue treatments were those provided to patients in
refractory shock or peri-arrest. Refractory shock was defined as persistent cardiovascular
failure associated with organ failure despite the administration of supportive care and
adequate antidotes.
The members defined signs of CCB toxicity as hemodynamic abnormalities, such as low
heart rate (60 per minute in adults), low blood pressure (systolic 100 mmHg or mean
arterial pressure 65 mmHg in adults), myocardial dysfunction or abnormal peripheral
vascular resistances. Reference values and definitions supported by the American Heart
Association17 were adopted by the working group, but the members also recognized the
importance of clinical judgement. Therefore, as suggested by the American Heart
Association (2008),17 myocardial dysfunction was defined as a decrease in myocardial
contractility seen on the echocardiography or a documented cardiac index of less than 2.2
L/min/m2; while shock was defined as a state characterized by inadequate blood flow and
oxygen delivery to organs and tissues.17
The recommendation statements
The working group was divided in subgroups. Each subgroup responsible for a specific
intervention presented a summary outlining the evidence, the benefits and the risks and
costs. The subgroups developed statements focusing on specific interventions to be used in
certain clinical presentations (asymptomatic patients, symptomatic patients needing first-
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line treatments, patients refractory to first-line treatments, patients in refractory shock or
peri-arrest requiring rescue treatments or patients in cardiac arrest) in order to achieve a
specific outcome. Those statements were used for the subsequent modified Delphi process.
Each statement was associated with a specific level of evidence, which was determined
using the GRADE11 system (Table 2). In order to determine the strength of recommendation
(Table 2), the working group proceeded to a modified Delphi method (four rounds of
anonymous online votes using a 9-point Likert scale followed by telephone meetings and a
face-to-face meeting held in Brussels in May 2014). When a statement needed to be
clarified, it was modified and voted on again until the working group members agreed that
the results reflected a clear understanding of what the statements meant and implied. For
each statement, the strength of recommendation (Table 2) was determined by the results of
the votes at the last round using the medians, the lower/upper interquartiles, and the
disagreement indexes (RAND/UCLA Appropriateness Method)12 as described in Figure 2.
Values and preferences
In accordance with AGREE II methodology, the perceived influence of the working group
values and preferences on the vote results was documented at each round. In addition to
considering values and preferences of decision makers, clinicians, patients and relatives,
the draft recommendations were posted on a blog for two weeks. The public was asked to
provide comments and suggestions to which the working group responded. In order to
encourage participation, messages were posted on social media websites (Facebook,
Twitter, Google +) of relevant organizations of patients and relatives (search key words:
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patient care, suicide prevention, mental health, substance of abuse, heart disease,
hypertension, health ethics, research ethics), poison control centers, and professional
organizations (search key words: emergency medicine, critical care medicine, toxicology,
psychiatry, pharmacy).19
Internal and external review
The recommendations for the treatment of CCB poisoning were submitted to all
participating association for internal review and to anonymous reviewers chosen by the
associations for external review. The external reviewers evaluated the guideline
development process with the AGREE tool.10 A second face-to-face meeting was held in New
Orleans in October 2014 to discuss the documented values, preferences, and the results of
the internal and external reviews.
RESULTS
Table 3 details of the rationale for each recommendation and Figure 3 illustrates the
progression of care for key recommendations.
RECOMMENDATIONS
Therapy in asymptomatic patients
For the treatment of patients who ingested a potentially toxic amount of CCB, the working
group recommends observation and decontamination following the position statement
published by the EACCT/AACCT22 (1D).
11
Rationale
Based on case series20, 21 of fair quality 14 it is safe to monitor for approximately 24h
asymptomatic patients who ingested a potentially toxic amount of CCB defined as more
than a single therapeutic dose,5 to consider decontamination to prevent toxicity, and to
intervene with other treatments if they develop signs of toxicity. The working group
decided to defer to the American Academy of Clinical Toxicology (AACT) and the European
Association of Poison Centres and Clinical Toxicologists (EAPCCT) position statement
(2005)22 instead of proposing new recommendations for decontamination in order to avoid
confusion and favour consistency.
First-line therapy for symptomatic patients
For the first-line therapy of symptomatic CCB-poisoned patients, the working group
recommends the use of:
-Intravenous calcium (1D),
-High-dose insulin therapy (in combination with IV fluids, calcium and vasopressors)
if evidence of myocardial dysfunction is present (1D),
-Norepinephrine and/or epinephrine in the presence of shock (even if the
myocardial function has not yet been assessed), and preferentially norepinephrine in
the presence of vasodilatory shock (1D).
For the first-line therapy of symptomatic CCB-poisoned patients, the working group
suggests the use of:
12
-High-dose insulin therapy as a single therapy in the presence of myocardial
dysfunction, or even in the absence of documented myocardial dysfunction if used in
combination with IV fluids, calcium and vasopressors (2D),
-Dobutamine in the presence of cardiogenic shock (2D),
-Atropine in the presence of symptomatic bradycardia or conduction disturbances
(2D).
For the first-line therapy of symptomatic CCB-poisoned patients, the working group
suggests not to use:
-Dopamine in the presence of shock (2D),
-Vasopressin in the presence of documented cardiogenic shock (2D).
Rationale
Although fluid resuscitation is commonly used, no formal recommendation was made
because there are no fluid repletion studies available specifically for CCB poisoning.
Nonetheless, the working group considered fluid administration as a first line and
continued administration as long as the patient demonstrates signs of fluid responsiveness
(e.g. hemodynamic improvement after receiving 10-20 ml/kg of crystalloid over 10-15
minutes). The working group also recommended intravenous calcium as a first line
treatment based on hemodynamic improvement observed in some case series32-35 and
animal studies.36-42 This therapy is readily available and carries little risk provided central
venous or secure peripheral venous access is available, particularly when the chloride salt
is used. The proposed regimen for the administration of calcium chloride 10% in CCBpoisoned adults is 10-20 ml q10-20 min or an infusion at 0.2-0.4 ml/kg/h. If calcium
13
gluconate 10% is given, the dose regimen is 30-60 ml q10-20 min or an infusion at 0.6-1.2
ml/kg/h.
Observational studies,43, 44 case series4, 45-47 and animal studies,48-50 showed hemodynamic
improvement and a potential increase in survival with the use of high-dose insulin in CCBpoisoned patients. However, most of the studies used it in combination with fluids,
intravenous calcium and vasopressors. Considering that high-dose insulin seems to have a
direct positive inotropic effect,48, 51 the working group made a recommendation for its use
when there is documented myocardial dysfunction, but still suggested it in patients without
a documented myocardial dysfunction. Despite the fact that high-dose insulin requires
intensive monitoring, its benefits were thought to outweigh the risks4. This intervention can
also be considered alone in the presence of myocardial dysfunction. The proposed dose
regimen of high-dose insulin (regular insulin) includes a bolus of 1 Units/kg followed by an
infusion of 1 Units/kg/h with maintenance of euglycemia with a dextrose infusion if
needed. Because titrated doses of high dose insulin (up to 10 Units/kg/hr) are supported by
weaker evidence, the working group suggests this only for patients who do not respond to
first-line therapies (see below).52
The selection of vasopressors should be guided by the type of shock the patient is
experiencing and the required doses are likely to be high. In a retrospective study published
by Levine et al (2013), the maximal infusion rate reported was 100 ug/min for
norepinephrine, 150 ug/min for epinephrine and 245 ug/kg/min for dobutamine.53 Based
on mechanism of action, the working group recommended the use of norepinephrine in
14
vasoplegic shock or if myocardial function has not yet been assessed, but had a neutral
position when the patient was presenting with cardiogenic shock.39, 41, 48, 53 The use of
epinephrine is also recommended for a CCB-poisoned patient experiencing shock with or
without myocardial dysfunction and is supported by a similar evidence base.39, 41, 48, 53 In the
presence of confirmed myocardial dysfunction, clinicians can also use dobutamine.
However, this therapy would not be suggested in other circumstances given the risk of
hypotension.53 Based on unclear hemodynamic improvement in case series,32-34, 54, 55 the
working group did not suggest the use of dopamine. The use of vasopressin alone was
discouraged due to lack of efficacy and worsened survival in animal models.32, 56, 57 The
working group could not make recommendations regarding the use of vasopressin as an
adjunct to other vasopressors as there is little documented clinical experience and no
preclinical studies. No agreement was reached for the use of phenylephrine in CCBpoisoned patients.
In situations where there is symptomatic bradycardia or conduction disturbances, the
working group members suggested using atropine at a dose regimen of 0.5 mg (paediatric
population: 0.02 mg/kg, min 0.1 mg, max 0.5 mg) q3-5 minutes. This suggestion is
supported based on considerations that the therapy may temporarily help, is easily
accessible, inexpensive and is not associated with important risks.33, 34, 39, 41
Therapy for patients refractory to first-line treatments
For the therapy of CCB-poisoned patients refractory to first-line treatments, the working
group suggests the use of:
15
-Incremental doses of high-dose insulin therapy (up to 10 Units/kg/h) if evidence of
myocardial dysfunction is present (2D),
-Pacemaker in the presence of unstable bradycardia or high-grade AV block, without
significant alteration in cardiac inotropism (2D),
-Intravenous lipid emulsion therapy (2D).
Rationale
In patients refractory to the previously described first-line treatments, the working group
members considered therapy supported by weaker evidence, but associated with less risk
than rescue treatments. Therefore, in the presence of myocardial dysfunction, the working
group suggested to titrate the high-dose insulin infusion rate up to 10 Units/kg/h.52 The
patient would need to be closely monitored and will likely require a dextrose infusion to
maintain euglycemia. Electrical cardiac pacing has been associated with frequent capture
and pacing problems, however, there may be potential hemodynamic improvement in
patients presenting with unstable bradycardia or high-grade AV block.34, 58-61 To avoid
spending time on a therapy that involves risk and may not be effective, the working group
suggested transcutaneous pacing attempts first. Based on possible hemodynamic
improvement documented in two animal studies62, 63 and case reports, the working group
members also suggested the use of lipid emulsion therapy. However, this is not
recommended for consideration earlier on in treatment given the concern of potentially
increasing the absorption of medications still present in the stomach. This concern was
raised by an animal study showing worse outcomes.64 when using oral models CCB
poisoning instead of intravenous, but that study has only been published as an abstract. The
16
working group members felt that there were insufficient data to recommend a specific dose
regimen of lipid emulsion therapy. The most commonly recommended dose is 1.5 mL/kg of
20% lipid emulsion administered as a bolus, repeated up to 2 times as needed until clinical
stability is achieved, and followed by an infusion of 0.25mL/kg/min for 30 to 60 minutes.65
Therapy for patients in refractory shock or peri-arrest
For the therapy of CCB-poisoned patients in refractory shock or peri-arrest, the working
group recommends, as rescue treatments, the use of:
-Incremental doses of high-dose insulin therapy (up to 10 Units/kg/h) if evidence of
myocardial dysfunction is present if not administered previously (1D),
-Lipid emulsion therapy (1D).
For the therapy of CCB-poisoned patients in refractory shock or peri-arrest, the working
group suggests, as rescue treatments, the use of:
-Incremental doses of high-dose insulin therapy (up to 10 Units/kg/h) even in the
absence of myocardial dysfunction if not administered previously (2D),
-VA-ECMO (or ECLS) in presence of cardiogenic shock in centres where the
treatment is available (2D),
-Pacemaker in the presence of unstable bradycardia or high-grade AV block, without
significant alteration in cardiac inotropism if not administered previously (2D).
Rationale
Given the high risk of mortality in patients with severe refractory shock or peri-arrest, the
working group members considered therapies with less evidence or higher risks. Therefore,
17
incremental doses of high-dose insulin therapy would be considered even if no myocardial
dysfunction has been documented52 and the use of lipid emulsion therapy is now
recommended.62, 63
Given the risk of mortality in severely poisoned patients and the potential survival benefit
demonstrated in an observational study conducted in experienced centres,66 the working
group members suggested VA-ECMO (or ECLS) as a rescue therapy in CCB-poisoned
patients presenting with cardiogenic shock in centres where the treatment is available. In
this clinical scenario, the working group concluded that the benefits outweigh the risks of
limb ischemia, bleeding or thrombosis. The members were neutral in regards to the use of
the Impella® catheter or other left ventricular or biventricular assisted devices as potential
alternatives to VA-ECMO (or ECLS) as there is simply insufficient clinical or research
experience.67
Therapy for patients in cardiac arrest
For therapy of CCB-poisoned patients in cardiac arrest, the working group recommends, in
addition to standard advanced cardiac life-support (ACLS), the use of:
-Intravenous calcium, even if previously administered (1D),
-Lipid emulsion therapy if not administered previously (1D).
For therapy of CCB-poisoned patients in cardiac arrest, the working group suggests the use
of:
-Lipid emulsion therapy, even if previously administered (2D),
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-VA-ECMO (or ECLS) in the presence of a low flow, for less than 5 minutes, and in
centres where the treatment is available (2D).
Rationale
Studies looking specifically at CCB-poisoned patients in cardiac arrest are scarce. Most of
the recommendations except one for the use of VA-ECMO (or ECLS) are extrapolated from
studies conducted in severely-ill patients, but that were not in cardiac arrest. Therefore, the
working group reinforced the importance of performing adequate and aggressive
resuscitation with previously mentioned modalities. Consequently, the working group
members recommended the use of intravenous calcium and lipid emulsion therapy at the
same dose regimen previously mentioned. Further, a second dose of lipid emulsion therapy
could be considered if the patient already received a bolus before the cardiac arrest.
Concerning the use of VA-ECMO (or ECLS) in experienced centres, observational studies
have demonstrated a potential survival benefit in cardiac arrest patients.66, 68-70 The
working group members estimated that the benefit of saving a life outweigh the risks of
initiating that invasive therapy, if there is reasonable chances of surviving without
significant deficit. Therefore, they suggested this therapy if the chest compressions have
being ongoing for less than 5 min (low flow period). The working group 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.
Rationale for not recommending or not suggesting some treatments
19
- The working group recommends not to use methylene blue as a first-line treatment given
experience is limited to a few case reports.71-73 (1D).
- The working group recommends not to use levosimendan, a calcium channel opening drug
based on lack of efficacy in animal studies and unknown risks versus benefits in the clinical
setting83 (1D).
- The working group suggests not to use glucagon because case series reported variable
effects.74-76 Vomiting77-78 and hyperglycemia78-82 had been noticed in several case reports,
and more effective interventions for the treatment of CCB poisoning are available (2D).
- The working group recommends not to or suggests not to use, the following treatments
based on insufficient experience and scientific scrutiny: digoxin, liposomes, fructose 1,6
diphosphate, PK11195, BK8644, CPG28932, potassium antagonists, triidothyronine,
cyclodextrin, amrinone or other PDE-inhibitors, L-carnitine, plasma exchange, CVVHDF,
charcoal hemoperfusion, albumin dialysis, MARS, intra-aortic balloon pump.14 (1-2D)
VALUES AND PREFERENCES
The members reported the following factors as influencing their vote the most (6/9 on a
Likert scale): 1) the evidence (8/9); 2) the balance between risks and benefits (7/9); 3) the
feasibility and applicability of the intervention (7/9) and; 4) their experience and training
(7/9). Their discussions with the other guideline working group members were perceived
to have more influence during the final rounds of voting (first round: 4/9, second round:
5/9, third round: 5/9, fourth round: 6/9). In terms of public involvement, the blog
(http://poisoningsguidelines.com; 37 followers on Twitter, 189 followers on Facebook)
documented 796 visitors from 61 countries and 1,529 views during the period the draft of
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recommendations were posted for public feedback (between October 13th and October 27th
2014). Suggestions were made to clarify statements and facilitate its application, but no
disagreement was expressed. The working group made the appropriate corrections.
INTERNAL AND EXTERNAL REVIEWS
Based on the comments received by the associations, the working group withdrew the
recommendations related to decontamination since those were generating significant
disagreement, and that there was an already existing position statement published by the
AACT and the EAPCCT.22 Finally, the working group underlined that the recommendations
applied mainly to adults, clarified some statements to facilitate its application and added in
areas for future research questions raised by the reviewers that could not be answered with
the current evidence.
The external reviewers (3) gave a global score of 6/7 to the recommendations development
process. The main suggestions for improvement concerned the need for more
implementation tools and a better defined update process.
IMPLEMENTATION AND APPLICABILITY
Considering that effective implementation strategies include multifaceted interventions,
interactive education and clinical reminder systems,84 we intend to post the algorithm on
our blog where a checklist, a video, and a quiz will be available. The blog users will also
have the opportunity to provide feedback that will be taken into account when the
recommendations will be update. The blog link (http://poisoningsguidelines.com) will be
21
sent to all relevant professional associations and training programs. Interactive educational
meetings and workshops will be encouraged. Interventions that are not widely available,
such as VA-ECMO (or ECLS), or those that are not performed on a regular basis by nontoxicologists, such as high-dose insulin, may still be difficult to integrate into practice.
Therefore, professional associations must use proactive knowledge translation strategies
by using the implementation tools created by the working group.
To monitor the impact of the guideline implementation, the working group plan to conduct
a survey two years post implementation to assess barriers, facilitators and impact on
resources use. Decision makers should consider monitoring adherence to recommendations
and outcomes (mortality, functional outcome, ICU and in-hospital length of stay).
DISCUSSION
Guided by the evidence, the balance between risks and benefits, the costs and the use of
resources, the working group used a rigorous methodology (including the AGREE II
instrument, GRADE system, a modified Delphi technique, and a standardized voting
procedure) to build recommendations for the in-hospital treatment of CCB-poisoned
patients. The working group recommended a complementary patient-tailored use of
calcium, high-dose insulin and vasopressors as first line treatments; incremental doses of
high-dose insulin and pacemaker for some patients refractory to first line treatments; and
considered incremental doses of high-dose insulin, lipid emulsion therapy and the use of
VA-ECMO (or ECLS) as potential rescue treatments.
22
The working group encourages clinicians to focus on therapies supported by higher levels
of evidence rather than those using therapies for which the level of evidence is lower
and/or for which there are alternatives with a better safety profile. The target population of
our recommendations are CCB-poisoned adults given that most of the studies available
were based on that population. 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 working group believes that it may be reasonable for the
recommendations in this guideline to the paediatric population.
The overall evidence available to develop these guidelines was of very low quality. Many
interventions had only been studied for surrogate outcomes. With the exception of VAECMO for cardiotoxicant poisonings, the use of and costs associated with these resources
had not been described.85 Hence, some of the questions within our proposed analytic
framework remain unanswered. Therefore, the working group identified potential areas for
future research that may help to improve the care provided to CCB-poisoned patients.
First, observational studies should be conducted to identify which intervention improves
the outcome for each specific class of CCB (dihydropyridine or nondihydropyridine,
sustained-release, etc). Currently, there is not enough evidence to be able to establish
distinctive approaches. Second, observational studies should identify prognostic factors,
which is particularly imperative in severe cases potentially that may require VA-ECMO (or
ECLS). Third, scientists should conduct observational studies to identify which type of
patient (with or without myocardial dysfunction) are likely to respond to high-dose insulin
23
therapies, and the appropriate dose of these therapies. Prospective, controlled clinical trials
are needed to evaluate currently recommended antidotes or to assess new antidotes .
Finally, clinicians are encouraged to publish both favorable and unfavorable experiences in
order to minimize publication bias.
PLANNED REVISIONS
These guidelines will be updated if there is a significant change in the evidence or every five
years. The first author will register to Medline, EMBASE and Google Scholar search
strategies updates and will notify the rest of the working group if a new article may require
an update ad hoc. Comments and suggestions will be collected on the working group’s blog
in future revisions, and studies will be conducted to monitor adherence to the current
guidelines.
CONCLUSION
The recommendations for the treatment of CCB-poisoned patients, endorsed by
international critical care, emergency medicine and toxicology associations are built to
decrease practice variation and hopefully the care gap. These recommendations include
intravenous calcium, high-dose insulin, vasopressors, incremental doses of high-dose
insulin, pacemaker stimulation, lipid emulsion therapy and VA-ECMO(or ECLS) in a stepwise treatment approach. The working group also identified potential areas for future
research that may help improve the care provided to CCB-poisoned patients.
24
Conflict of interests
Each working group member completed the International Committee of Medical Journal
Editors form for disclosure of potential conflicts of interest (COI). No relevant COI was
identified.
Funding
The guideline development process was not externally funded. All working group members
were volunteers and only in-kind donations from participating organizations helped
organize the in-person meetings.
25
REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
Mowry JB, Spyker DA, Cantilena LR Jd, Bailey JE, Ford M. 2012 Annual report of the American
Association of Poison Control Centers’ National Poison Data System (NPDS): 30th annual
report. Clin Toxicol 2013; 51:949-1229.
St-Onge M, Archambault P, LeSage N, Guimont C, Poitras J, Blais R. Adherence to calcium
channel blocker poisoning treatment recommendations in two Canadian cities. Clin Toxicol
2012; 50:424-430.
Darracq MA, Thornton SL, Do HM, Clark RF, Cantrell FL. Utilization of hyperinsulinemia
euglycemia and intravenous fat emulsion following poison center recommendations. J Med
Toxicol 2013; 9:226-30.
Espinoza T, Bryant SM, Aks SE. Hyperinsulin therapy for calcium channel antagonist
poisoning: a seven-year retrospective study. Am J Ther 2013; 20:29-31.
Olson KR, Erdman AR, Woolf AD, Scharman EJ, Christianson G, Caravati EM, Wax PM, Booze
LL, Monoguerra AS, Keyes DC, Chyka PA, Troutman WG. Calcium channel blocker ingestion:
An evidence-based consensus guideline for out-of-hospital management. Clin Toxicol 2005;
43:797-922.
Böhm M, Schwinger RH, Erdmann E. Different cardiodepressant potency of various calcium
antagonists in human myocardium. Am J Cardiol 1990;65:1039-41.
Brunton L, Parker K, Blumenthal D, Buxton I. Name of the chapter. In: Goodman & Gilman's:
Manual of Pharmacology and Therapeutics. Place of edition, McGraw Hill 2008,1219pp.
Katzung BG. Calcium Channel Antagonists In: Basic and Clinical Pharmacology, LANGE 9th
edition, USA, 2004, p. 155-158.
Jarry J, Sassoust G. A rare case of nifedipine bezoar. Presse Med 2008; 37:428-30.
Brouwers M, Kho ME, Browman GP, Cluzeau F, Feder G, Fervers B Hanna S, Makarski J on
behalf of the AGREE Next Steps Consortium. AGREEII: Advancing guideline development,
reporting and evaluation in healthcare. Can Med Assoc J 2010; 182:E839-842.
Guyatt G, Oxman AD, Akl EA, Kunz R, Vist G, Brozek J, Norris S, Falck-Ytter Y, Glasziou P,
deBeer H, Jaeschke R, Rind D, Meerpohl J, Dahm P, Schünemann HJ. GRADE guidelines: 1.
Introduction – GRADE evidence profiles and summary of findings tables. J Clin Epidemiol
2011; 64:383-394.
Fitch K, Bernstein SJ, Aguilar MD, Burnand B, LaCalle JR, Lazaro P, van het Loo M, McDonnell
J, Vader JP, Kahan JP. The RAND/UCLA Appropriateness Method User’s Manual 2001, USA,
123pp.
Harris NS. Case 24: A 40-year-old woman with hypotension after an overdose of amlodipine.
NEJM 2006; 355:602-611.
St-Onge M, Dubé PA, Gosselin S, Guimont C, Godwin J, Archambault P, Chauny JM, Frenette
AJ, Darveau M, LeSage N, Poitras J, Provencher J, Juurlink D, Blais R. Treatment of calcium
channel blocker poisoning: A systematic review. Clin Toxicol 2014;52:926-44.
Lamontagne F, Briel M, Duffett M, Fox-Robichaud A, Cook DJ, Guyatt G, Lesur O, Meade MO. Systematic
review of reviews including animal studies addressing therapeutic interventions for sepsis. Crit Care
Med 2010; 38:2401-08.
St-Onge M, Fan E, Mégarbane B, Hancock-Howard R, Coyte P. Venoarterial extracorporeal membrane
oxygenation for patients in shock or cardiac arrest secondary to cardiotoxican poisoning: a costeffectiveness analysis. J Crit Care early online 16 October 2014.
American Heart Association. ACLS resource text for instructors and experienced providers.
American Heart Association 2008, Texas, 444p.
Lavergne V, Nolin TD, Hoffman RS, Roberts D, Gosselin S, Goldfarb DS, Kielstein JT, Mactier R,
Maclaren R, Mowry JB, Buchman TE, Juurlink D, Mégarbane B, Answeeuw K, Winchester JF, Dargan PI,
Liu KD, Hoegberg LC, Li Y, Calello DP, Burdmann EA, Yates C, Laliberté M, Becker BS, Mello-Da-Silva
CA, Lavonas E, Ghannoum M. The EXTRIP (EXtracorporeal TReatments In Poisoning working group:
Guideline methodology. Clin Toxicol 2012; 50:403-413.
De Breejen E ME, Nelen W LDM, Knijnenburg J ML, Burgers JS, Hermens R PMG, Kremer J AM.
Feasibility of a Wiki as a Participatory Tool for Patients in Clinical Guideline Development. J
Med Internet Res 2012;e138.
26
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
Belson MG, Gorman SE, Sullivan K, Geller R. Calcium channel blocker ingestions in children.
Am J Emerg Med 2000; 18:581-586.
Truitt CA, Brooks DE, Dommer P, LoVecchio F. Outcomes of unintentional beta-blocker or calcium
channel blocker overdose: a retrospective review of poison center data. J Med Toxicol 2012; 8:135-9.
American Academy of Clinical Toxicology and European Association of Poisons Centres and Clinical
Toxicologists. Position paper: Single-dose activated charcoal. Clin Toxicol 2005; 43:61-87.
Lapatto-Reiniluoto O, Kivistö KT, Neuvonen PJ. Gastric decontamination performed 5 min after the
ingestion of temazepam, verapamil and moclobemide: charcoal is superior to lavage. Br J Clin
Pharmacol 2000; 49:274-8.
Laine K, Kivistö KT, Neuvonen PJ. Effect of delayed administration of activated charcoal on the
absorption of conventional and slow-release verapamil. J Toxicol Clin Toxicol 1997; 35:263-8.
Barrow PM, Houston PL, Wong DT. Overdose of sustained-release verapamil. Br J Anaesth 1994;
72:361-365.
Benson BE, Hoppu K, Troutman WG, Bedry R, Erdman A, Höjer J, Mégarbane B, Thanacoody R, Caravati
EM. Position paper update: gastric lavage for gastrointestinal decontamination. Clin Toxicol 2013;
51:140-146.
Bausch R, Dirschedl P, Fahrenkrog U, Löllgen H. Clinical observations of calcium-channelblocker intoxication. Intensivemed 1991; 28:120-123.
Madera F, Wenger R. About intoxication with Isoptin S (verapamil and pentobarbital).
Intensivmedizin 1977; 14:373-377.
Lo JC, Ubaldo C, Cantrell FL. A retrospective review of whole bowel irrigation in paediatric patients.
Clin Toxicol 2012; 50:414-417.
Cumpston KL, Aks SE, Sigg T, Pallasch E. Whole bowel irrigation and the hemodynamically
unstable calcium channel blocker overdose: primum non nocere. J Emerg Med 2010; 38:1714.
Buckley N, Dawson AH, Whyte IM. Slow-release verapamil poisoning. Use of polyethylene
glycol whole-bowel lavage and high-dose calcium. Med J Aust 1993; 158:202-4.
Konca C, Yildizdas RD, Sari MY, Yükselmis U, Horoz OO, Yilmaz HL. Evaluation of children
poisoned with calcium channel blocker or beta blocker drugs. Turk Arch Ped 2013; 138-144.
Howarth DM, Dawson AH, Smith AJ, Buckley N, Whyte IM. Calcium channel blocking drug overdose: an
Australian series. Hum Exp Toxicol 1994; 13: 161-6.
Ramoska EA, Spiller HA, Winter M, Borys D. A one-year evaluation of calcium channel blocker
overdoses: Toxicity and treatment. Ann Emerg Med 1993; 22:196-200.
Henry M, Kay MM, Viccellio P. Cardiogenic shock associated with calcium-channel and beta
blockers: reversal with intravenous calcium chloride. Am J Em Med 1985; 3:334-336.
Graudins A., Wong KKL. Comparative hemodynamic effects of levosimendan alone and in conjunction
with 4-aminopyridine or calcium chloride in a rodent model of severe verapamil poisoning. J Med
Toxicol 2010; 6:85-93.
Graudins A, Najafi J, Rur-SC MP. Treatment of experimental verapamil poisoning with levosimendan
utilizing a rodent model of drug toxicity. Clin Toxicol 2008; 46:50-6.
Strubelt O, Diederich KW. Studies of antidote therapy for nisoldipine intoxication in experimental
animals. Arzneimittelforschung 1990; 40:747-51.
Gay R, Algeo S, Lee R, Olajos M, Morkin E, Goldman S. Treatment of verapamil toxicity in intact dogs. J
Clin Invest 1986; 77:1805-11.
Strubelt O, Diederich KW. Experimental investigations on the antidotal treatment of
nifedipine overdosage. J Toxicol Clin Toxicol 1986; 24:135-49.
Strubelt O. Antidotal treatment of the acute cardiovascular toxicity of verapamil. Acta
Pharmacol et Toxicol 1984; 55:231-237.
Vick JA, Kandil A, Herman EH, Balazs T. Reversal of proprabolol and verapamil toxicity by
calcium. Vet Hum Toxicol 1983; 25:8-10.
Bryant SM, Espinoza TR, Aks SE. Seven years of high dose insulin therapy for calcium channel
antagonist poisoning. Clin Toxicol 2009; 47:751.
Greene SL, Gawarammana I, Wood DM, Jones AL, Dargan PI. Relative Safety of
Hyperinsulinaemia/Euglycaemia Therapy in the Management of Calcium Channel Blocker
Overdose: A Prospective Observational Study. Intensive Care Med 2007; 33: 2019-2024.
27
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
Boyer EW, Duic PA, Evans A. Hyperinsulinemia/euglycemia therapy for calcium channel blocker
poisoning. Pediatr Emerg Care 2002; 18: 36-37.
Boyer EW, Shannon M. Treatment of calcium-channel-blocker intoxication with insulin infusion. N
Engl J Med 2001; 344:1721-2.
Yuan TH, Kerns WP 2nd, Tomaszewski CA, Ford MD, Kline JA. Insulin-glucose as adjunctive therapy
for severe calcium channel antagonist poisoning. J Toxicol Clin Toxicol 1999; 37:463-74.
Kline JA, Tomaszewski C, Schroeder JD, Raymon RM. Insulin is a superior antidote for cardiovascular
toxicity induced by verapamil in the anesthethetized canine. J Pharmacol Exp Ther 1993; 267:744750.
Kline JA, Leonova E, Williams TC, Schroeder JD, Watts JA. Myocardial metabolism during graded
intraportal verapamil infusion in awake dogs. J Cardiovasc Pharmacol 1996; 27: 719-726.
Kline JA, Raymon RM, Leonova ED, Williams TC, Watts JA. Insulin improves heart function and
metabolism during non-ischemic cardiogenic shock in awake canines. Cardiovasc Res 1997; 34:289298.
Engebretsen KM, Kaczmarek KM, Morgan J, Holger JS. High-dose insulin therapy in betablocker and calcium channel blocker poisoning. Clin Toxicol 2011; 49:277-83.
Holger JS, Stellpflug SJ, Cole JB, Harris CR, Engebretsen KM. High-dose insulin: a consecutive case
series in toxin-induced cardioganic shock. Clin Toxicol 2011; 49:653-8.
Levine M, Curry SC, Padilla—Jones A, Ruha AM. Critical care management of verapamil and
diltiazem overdose with a focus on vasopressors: a 25-year experience at a single centre.
Ann Emerg Med 2013; 62:252-258.
Groszek B, Szpak D, Klys M, Scislowski M. Acute poisoning with nifedipine and acebutol, two
cases. Przegl Lek 2003; 60:262-4.
Karti SS, Ulusoy H, Yandi M, Gunduz A, Kosucu M, Erol K, Ratip S. Non-cardiogenic pulmonary oedema
in the course of verapamil intoxication. Emerg Med J 2002; 19:458-9.
Barry JD, Durkovich D, Cantrell L, Richardson W, Tong T, Offerman S, Clark RF, Tanen DA, Williams S.
Vasopressin treatment of verapamil toxicity in the porcine model. J Med Toxicol 2005; 1:3-10.
Sztajnkrycer MD, Bond GR, Johnson SB, Weaver AL. Use of vasopressin in a canine model of
severe verapamil poisoning: a preliminary descriptive study. Acad Emerg Med 2004;
11:1253-61.
Stachon K, Dabek J, Jakubowski D, Rychlik W. Clinical implications in patients after ingestions of
excessive doses of calcium channel blockers - our observations. Pol. Merk. Lek. 2011; 31:145-149.
McGlinchey PG, McNeill AJ. Drug overdoses requiring temporary cardiac pacing; a study of six cases
treated at Altnagelvin Hospital, Londonderry. Ulster Med J 1998; 67:13-8.
Beiträge ZK. Suicide attempt with verapamil, Therapiewoche 1984; 34:2483-2491.
Immonen P, Linkola A, Waris E. Three cases of severe verapamil poisoning. In J Cardiol 1981;
1:101-5.
Tebbbutt S, Harvey M, Nicholson T, Cave G. Intralipid prolongs survival in a rat model of
verapamil toxicity. Acad Emerg Med 2006;13:134-9.
Perez E, Bania TC, Medlej K, Chu J. Determining the optimal dose of intravenous fat emulsion
for the treatment of severe verapamil toxicity in a rodent model. Acad Emerg Med
2008;15:1284-1289.
Perichon D, Turfus S, Graudins A. Intravenous lipid emulsion does not improve
hemodynamics or survival in a rodent model of oral verapamil poisoning. Clin Tox 2013;
51:252-378.
Association of Anaesthetists of Great Britain and Ireland, AAGBI Safety Guideline: Management of
Severe Local Anaesthetic Toxicity, 2010.
Masson R, Colas V, Parienti JJ, Lehoux P, Massetti M, Charbonneau P, Saulnier F, Daubin C. A
comparison of survival with and without extracorporeal life support treatment for severe poisoning
due to drug intoxication. Resuscitation 2012; 83:1413-1417.
Laes J, Orozco BS, Cole JB. Use of percutaneous left ventricular assist device (Impella) in vasodilatory
poison-induced shock [abstract]. Clin Toxicol 2013; 51:673.
Daubin C, Lehoux P, Ivascau C, Tasle M, Bousta M, Lepage O, Quentin C, Massetti M,
Charbonneau P. Extracorporeal life support in severe drug intoxication: a retrospective
cohort study of seventeen cases. Crit Care 2009; 13:R138.
28
69.
70.
71.
72.
73.
74.
75.
76.
77.
78.
79.
80.
81.
82.
83.
84.
Mégarbane B, Leprince P, Deye N, Résière D, Guerrier F, Rettab S, Théodore J, Karyo S,
Gandjbakhch I, Baud FJ. Emergency feasibility in medical intensive care unit of extracorporeal
life support for refractory cardiac arrest. Intensive Care Med 2007; 33:758-764.
Babatasi G, Massetti M, Verrier V, Lehoux P, LePage O, Bruno PG, Khayat A. Severe intoxication
with cardiotoxic drugs: value of emergency percutaneous cardiocirculatory assistance. Arch
Mal Coeur Vaiss 2001; 94:1386-92.
Aggarwal N, Kupfer Y, Seneviratne C, Tessler S. Methylene blue reverses recalcitrant shock in betablocker and calcium channel blocker overdose. BMJ Case Rep 2013;2013.
Jang DH, Nelson LS, Hoffman RS. Methylene blue in the treatment of refractory shock from an
amlodipine overdose. Ann Emerg Med 2011; 58: 565-567.
Kim HK, Hoffman RS, Nelson LS, Jang DH. Methylene blue for refractory hypotension in cardiovascular
drug overdose. EAPCCT abstract 2012, p.365.
Supradip G, Mrinal S. Calcium channel blocker overdose: experience with amlodipine. Indian J Crit
Care Med 2008; 12:190-193.
Love JN, Sachdeva DK, Curtis LA, Howell JM, Bessman ES. A potential role for glucagon in the
treatment of drug-induced sympatomatic bradycardia. Chest 1998; 114-323-326.
Roper TA, Sykes R, Gray C. Fatal diltiazem overdose: report of four cases and review of the
literature. Postgrad Med J 1993; 69:474-6.
Cohen V, Jellinek SP, Fancher L, Sangwan G, Wakslak M, Marquart E, Farahani C. Tarka
(trandolapril/verapamil hydrochloride extended release) overdose. J Emerg Med 2011; 40:291-295.
Fant JS, James LP, Fiser RT, Kearns GL. The use of glucagon in nifedipine poisoning complicated by
clonidine ingestion. Ped Emerg Care 1997; 13:417-419.
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.
Buylaert WA, Callens B, Decruyenaere JM, Koch AR, Verstraete A, Vogelaers DP. Fatal intoxication with
amlodipine. J Toxicol Clin Toxicol 1995; 33:253.
Doyon S, Roberts JR. The use of glucagon in a calcium channel blocker overdose. Ann Emerg Med
1993; 22:1229-1233.
Mahr NC, Valdes A, Lamas G. Use of glucagon for acute intravenous diltiazem toxicity. Am J of
Cardiology 1997; 79:1570-1571.
Abraham MK, Scott SB, Meltzer A, Barrueto F. Levosimendan does not improve survival time in a rat
model of verapamil poisoning. J Med Toxicol 2009; 5:3-7.
Prior M, Guerin M, Grimmers-Somers K. The effectiveness of clinical guideline implementation
strategies – a synthesis of systematic review findings. J Eval Clin Pract 2008; 14:888-897.
29
Table 1: Participating organizations












American Academy of Clinical Toxicology (David Jang)
American Association of Poison Control Centres (Lee Cantrell)
American College of Medical Toxicology (Eric Lavonas and Russ Kerns)
Asia Pacific Association of Medical Toxicology (Chen-Chang Yang)
Canadian Association of Emergency Physicians (Sophie Gosselin)
Canadian Association of Poison Control Centres (Martin Laliberté)
Canadian Critical Care Society (John Muscedere and Tasnim Sinuff)
Canadian Paediatric Society (Michael Rieder)
European Association of Poison Centres and Clinical Toxicologists (Philippe Hantson)
European Society of Emergency Medicine (Kurt Answeeuw)
European Society of Intensive Care Medicine (Bruno Mégarbane)
Society of Critical Care Medicine (Ian Gilchrist)
30
Table 2: Levels of evidence and strength of recommendation
Strengths of recommendation:
Levels of evidence:




Level 1: Strong recommendation (appropriate by the
large majority of experts with no major dissension).
The desirable effects of adherence to the
recommendation outweigh the undesirable effects.
o In favour: “we recommend”
o Against: “is not recommended”
Level 2: Weak recommendation (appropriate by the
majority of experts, but some degree of dissension
exists). The desirable effects of adherence to the
recommendation probably outweigh the undesirable
effects.
o In favour: “we suggest”
o Against: “is not suggested”
Level 3: Neutral recommendation. The course of
action could be considered appropriate in the right
context.



Grade A: High level of evidence. We are confident
that the true effect is close to our estimate of the
effect.
Grade B: Moderate level of evidence. The true effect
is likely to be close to our estimate of the effect, but
there is a possibility that it is substantially different.
Grade C: Low level of evidence. The true effect may
be substantially different from our estimate of the
effect.
Grade D: Very low level of evidence. Our estimate of
the effect is just a guess, and it is very likely that the
true effect is substantially different from our
estimate of the effect.
31
Table 3: Recommendation table
Intervention
Clinical presentation(s)
for which the
recommendation applies
Desired
effects
Risks
Resources
and costs
Level of
evidenc
Decrease absorption
and monitor to
intervene if needed
Increase
transmembrane
gradient which may
overcome
competitive
antagonism of CCB
Decrease toxicity
None documented
Available
D: case serie
of fair qualit
Hemodynamic
improvement in
some cases
(blood pressure,
contractility)
- Extravasation of
chloride salt may
lead to severe local
tissue injury
- Hypercalcemia
Available
D: case serie
and animal
studies of po
to fair qualit
- Direct positive
inotropic effect while
increasing calcium
entry into the cell
- Facilitates the use of
carbohydrates by the
myocardium
- Possible
improvement in
survival
- Hemodynamic
improvement
(blood pressure,
contractility)
- Decrease in
vasopressors
requirement
- Hypoglycemia
- Hypokalemia
- Volume overload
- Available
- Requires
intensive
monitoring
and additional
resources
D:
observationa
studies of po
quality, case
series of poo
to fair qualit
and animal
studies of go
quality
Inhibits action of
acetylcholine on
autonomic effectors
Possible
hemodynamic
improvement
(heart rate)
- Anticholinergic
effects
Available
D: case serie
and animal
studies of po
to fair qualit
NE has a strong alpha
and moderate beta-1
effects; epinephrine
has a strong beta-1,
alpha with moderate
beta-2 effects
Hemodynamic
improvement
(blood pressure,
+/- contractility,
+/- heart rate)
- Organ/tissue
ischemia
- Increase in lactate
and glucose with
epinephrine
Available
D: case serie
and animal
studies of po
to fair qualit
Strong beta-1 and
weak beta-2 effects
Possible
hemodynamic
improvement
(contractility,
heart rate)
Worsening
hypotension
Available
D: case serie
of fair qualit
but small
number of
patients
In cardiac arrest
Refractory shock
or peri-arrest
(rescue treatment)
Refractory to
first line
Symptomatic
(first line)
Asymptomatic
Rationale
IN FAVOUR
Observation +/decontamination
Calcium IV
X
X
X
X
X
High-dose
insulin
X
X
X
Atropine
X
X
X
X
Norepinephrine
(NE),
epinephrine
X
X
X
X
Dobutamine
X
X
X
32
Incremental
doses of highdose insulin
X
X
Pacemaker
X
X
Lipid emulsion
therapy
X
X
X
X
X
VA-ECMO (or
ECLS)
- Direct positive
inotropic effect while
increasing calcium
entry into the cell
- Aids the heart to
use carbohydrates as
a source of
metabolism
- Hemodynamic
improvement
(blood pressure,
contractility)
- Decrease in
vasopressors
requirement
- Hypoglycemia
- Hypokalemia
- Volume overload
- Available
- Requires
intensive
monitoring
and additional
resources
D: one small
case series o
fair quality
Direct chronotropic
stimulation
Possible
hemodynamic
improvement
(heart rate)
- Discomfort
- Capture and
pacing problems
Transcutaneou
s more
available and
faster to
initiate than
transvenous
D: case serie
of poor qual
- Lipid sink for
redistribution of the
toxicant
- Provides fatty acids
that may be used by
the myocardium
Possible
hemodynamic
improvement
(blood pressure
+/- heart rate)
- Hyperlipemia
- Venous
thrombosis
- Possible fat
embolism
- Possible decrease
efficacy of other
treatments
- Laboratory
interference: ABG,
SatO2, CBC, lytes
Available in
most centers
D: animal
studies of fai
quality and
case reports
Hemodynamic
support as a bridge
to recovery
- Survival benefit
- Hemodynamic
improvement
(mean arterial
pressure)
- Limb ischemia
- Thrombosis
- Bleeding
- Available only
in certain
centers
- Cost should
not preclude
consideration
of the therapy
where it is
available (StOnge et al.,
2014)
D: one
observationa
study of goo
quality
including all
cardiotoxica
and case ser
of fair qualit
Bypasses the beta
receptors to activate
the same secondary
messengers and
improve inotropism
Acts on
dopaminergic, beta-1
and alpha receptors
Unclear
- Vomiting
- Hyperglycemia
- Tachyphylaxis
Limited
availability
D: case series o
fair quality
Unclear
Ischemic
complications
Available
D: case series
and animal
studies of poor
fair quality
AGAINST
Glucagon
X
X
Dopamine
X
X
X
X
X
33
Vasopressin
X
X
Vasopressin agonist
Unclear
- Inhibits guanylate
cyclase, thus
decreasing cGMP and
vascular tone
- Scavenges NO and
inhibit NO synthesis
Possible
hemodynamic
improvement
when used as a
last resort
Ischemic
complications
Available
D: case series
and animal
studies of poor
fair quality
D: Case report
- Vomiting
Available
- Blue-green
discoloration of
body fluids
- Serotonin
syndrome in
patients taking
serotonin agents
- Large doses:
methemoglobinemi
a, hypoxia
Other treatments not recommended or not suggested: intra-aortic balloon pump, CVVHDF, charcoal hemoperfusion, albumin dialysis, MARS, plasma exchange
carnitine, levosimendan, digoxin, , liposomes, fructose 1,6 diphosphate, cyclodextrin, triidothyronine, PK11195, BK8644, CPG28932 or potassium antagonists.
Methylene blue
X
X
34
Figure 1: Analytical framework for CCB poisoning treatment guidelines
Key questions
1. Is there direct evidence that one (or more than one) intervention reduces mortality, improves functional outcomes,
reduces hospital length of stay or reduces intensive care unit length of stay?
2. Does the patient clinical presentation or type of ingestion influence the intervention(s) provided and the outcomes?
3. Does one (or more than one) intervention decrease CCB serum concentration, improve hemodynamics or reduce the
duration of vasopressor use?
4. Are the intermediate outcomes reliably associated with reduced mortality or improved functional outcomes?
5. Does one (or more than one) intervention(s) result in adverse effects or demonstrate a lack of cost-effectiveness?
35
Figure 2: Voting process for recommendations
Reproduced with permission from: Lavergne et al., 201217
36
Figure 3: Progression of care for key recommendations.
37
APPENDIX 1 (online): Flow diagram and search strategy
Reproduced with permission from: St-Onge et al., 201414
38
We searched Medline/OVID, Pubmed, EMBASE, Cochrane Library, Toxline and
International pharmaceutical abstracts up to December, 2013 (inclusively) without
time restrictions. Two librarians developed the search strategy with the following
keywords: [calcium channel blockers OR calcium channel antagonist OR calcium
channel blocking agent OR (amlodipine or bencyclane or bepridil or cinnarizine or
felodipine or fendiline or flunarizine or gallopamil or isradipine or lidoflazine or
mibefradil or nicardipine or nifedipine or nimodipine or nisoldipine or nitrendipine
or prenylamine or verapamil or diltiazem)] AND [overdose OR medication errors OR
poisoning OR intoxication OR toxicity OR adverse effect]. We also searched
conference proceedings and meeting abstracts of the EAPCCT and NACCT (20082013), trial registries and Google Scholar. Authors of selected publications (except
for case reports) were contacted. Please see the example of search strategy for
Medline/OVID. A list of excluded article is available on demand.
Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations and Ovid MEDLINE(R) <1946 to
Present>
-------------------------------------------------------------------------------1 exp Calcium Channel Blockers/ae, po, to [Adverse Effects, Poisoning, Toxicity]
2 exp Calcium Channel Blockers/
3 exp Drug Overdose/
4 exp Medication Errors/
5 exp Poisoning/
6 3 or 4 or 5
7 2 and 6
8 1 or 7
9 overdose*.tw.
10 poisoning.tw.
11 toxicity.tw.
12 "adverse effect*".tw.
13 medication error*.tw.
14 or/9-13
15 calcium channel antagonist*.tw.
16 (Amlodipine or Amrinone or Bencyclane or Bepridil or Cinnarizine or Conotoxins or Diltiazem
or Felodipine or Fendiline or Flunarizine or Gallopamil or Isradipine or Lidoflazine or Mibefradil or
Nicardipine or Nifedipine or Nimodipine or Nisoldipine or Nitrendipine or Perhexiline or
Prenylamine or Verapamil).tw.
17 Calcium Channel Blocker*.tw.
18 or/15-17
19 14 and 18
20 8 or 19
21 limit 20 to yr="1946 - 2012"
22 limit 21 to yr="2012"
23 limit 22 to ed=20120101-20120810
24 limit 20 to yr="1946 - 2011"
25 23 or 24
26 limit 25 to (comment or editorial or letter)
27 25 not 26
28 limit 27 to "all child (0 to 18 years)"
29 limit 28 to "all adult (19 plus years)"
39
30
31
32
33
34
35
36
28 not 29
27 not 30
from 31 keep 1-6000
remove duplicates from 32
from 31 keep 6001-8193
remove duplicates from 34
33 or 35
***************************
40
APPENDIX 2 (online): Number of articles reporting each outcome per
intervention (unpublished results from St-Onge et al., 2014)14
Intervention
Observational studies
Case series
Case reports
Animal studies
Total number of articles
High-dose insulin
3
5
22
4
34
- Mortality
2
3
18
2
25
- Hemodynamics
2
4
15
4
25
- Functional outcomes
-
-
1
-
1
- Other outcomes
2
2
10
-
14
- Adverse effects
1
4
3
2
10
Extracorporeal life support
1
3
7
0
11
- Mortality
1
3
7
-
11
- Hemodynamics
-
-
6
-
6
- Functional outcomes
-
2
5
-
7
- Other outcomes
-
1
3
-
4
- Adverse effects
1
3
1
-
5
Calcium *
0
11
20 (1)
8
39 (1)
- Mortality
-
9
17
8
34
- Hemodynamics
-
7
16
6
29
- Functional outcomes
-
-
2
-
2
- Other outcomes
-
1
6
-
7
- Adverse effects
-
2
2
1
5
Vasopressors
0
10
10
9
29
- Mortality
-
9
7
8
24
- Hemodynamics
-
8
9
9
26
- Functional outcomes
-
1
-
-
1
- Other outcomes
-
3
8
-
11
- Adverse effects
-
2
1
3
6
Decontamination
0
8
2
0
10
- Mortality
-
7
2
-
9
- Hemodynamics
-
3
-
-
3
- Functional outcomes
-
1
-
-
1
- Other outcomes
-
-
1
-
1
- Adverse effects
-
2
-
-
2
Pacemaker **
0
6
2 (1)
0
8 (1)
- Mortality
-
4
2
-
6
- Hemodynamics
-
5
2
-
7
- Other outcomes
-
-
1
-
1
Glucagon
0
3
10
3
16
- Mortality
-
2
10
3
15
- Hemodynamics
-
2
6
3
11
- Other outcomes
-
1
4
-
5
- Adverse effects
-
1
6
1
8
No controlled trials were found. Some studies evaluated more than one outcome.
*1 case report full text article not found (not included in appendix 2)
**1 case report full text article not found (not included in appendix 2)
***3 case reports full text article not found (not included in appendix 2)
41
(Appendix 2: Number of articles reporting each outcome per intervention)
Intervention
Observational studies
Case series
Case reports
Animal studies
Total number of articles
Atropine
0
3
0
2
5
- Mortality
-
1
-
2
3
- Hemodynamics
-
2
-
2
4
4-aminopyridine or 3,4-
0
2
0
8
10
- Mortality
-
2
-
8
10
- Hemodynamics
-
2
-
8
10
- Other outcomes
-
2
-
-
2
- Adverse effects
-
-
-
1
1
Lipid emulsion
0
2
16
5
23
- Mortality
-
2
16
5
23
- Hemodynamics
-
-
16
5
19
- Functional outcomes
-
-
3
-
3
- Other outcomes
-
-
4
1
5
- Adverse effects
-
-
2
-
2
Levosimendan
0
1
3
4
8
- Mortality
-
1
3
4
8
- Hemodynamics
-
1
3
3
7
- Other outcomes
-
1
3
-
4
- Adverse effects
-
1
-
-
1
Plasma exchange ***
0
1
2 (3)
0
3 (3)
- Mortality
-
1
2
-
3
- Hemodynamics
-
1
2
-
3
- Other outcomes
-
1
2
-
3
Bay K 8644 and CGP 28932
0
0
0
3
3
- Mortality
-
-
-
3
3
- Hemodynamics
-
-
-
3
3
- Adverse effects
-
-
-
1
1
Digoxin
0
0
0
3
3
- Mortality
-
-
-
2
2
- Hemodynamics
-
-
-
3
3
Phosphodiesterase
0
0
4
2
6
- Mortality
-
-
2
1
3
- Hemodynamics
-
-
3
2
5
- Other outcomes
-
-
2
-
2
Cyclodextrin
0
0
0
2
2
- Mortality
-
-
-
2
2
- Hemodynamics
-
-
-
2
2
diaminopyridine
inhibitors
No controlled trials were found. Some studies evaluated more than one outcome.
*1 case report full text article not found (not included in appendix 2)
**1 case report full text article not found (not included in appendix 2)
***3 case reports full text articles not found (not included in appendix 2)
42
(Appendix 2: Number of articles reporting each outcome per intervention)
Intervention
Observational studies
Case series
Case reports
Animal studies
Total number of articles
Suggamadex
0
0
0
1
1
- Mortality
-
-
-
1
1
- Hemodynamics
-
-
-
1
1
Liposomes
0
0
0
2
2
- Hemodynamics
-
-
-
2
2
- Other outcomes
-
-
-
1
1
Albumin dialysis
0
0
2
1
3
- Mortality
-
-
2
1
3
- Hemodynamics
-
-
2
1
3
- Other outcomes
-
-
1
1
2
- Adverse effects
-
-
1
-
1
Carnitine
0
0
0
3
3
- Mortality
-
-
-
3
3
- Hemodynamics
-
-
-
2
2
Fructose-1,6-diphosphate
0
0
0
1
1
- Mortality
-
-
-
1
1
- Hemodynamics
-
-
-
1
1
PK 11195
0
0
0
1
1
- Mortality
-
-
-
1
1
- Hemodynamics
-
-
-
1
1
Triiodothyronine
0
0
0
1
1
- Mortality
-
-
-
1
1
- Hemodynamics
-
-
-
1
1
Charcoal hemoperfusion
0
0
4
0
4
- Mortality
-
-
3
-
3
- Hemodynamics
-
-
4
-
4
- Functional outcomes
-
-
2
-
2
- Other outcomes
-
-
4
-
4
Dialysis
0
0
3
0
3
- Mortality
-
-
3
-
3
- Hemodynamics
-
-
1
-
1
- Functional outcomes
-
-
2
-
2
- Other outcomes
-
-
1
-
1
Intra-aortic balloon pump
0
0
2
0
2
- Mortality
-
-
2
-
2
- Hemodynamics
-
-
2
-
2
- Functional outcomes
-
-
2
-
2
- Other outcomes
-
-
2
-
2
Methylene blue
0
0
1
0
1
- Mortality
-
-
1
-
1
- Hemodynamics
-
-
1
-
1
- Other outcomes
-
-
1
-
1
No controlled trials were found. Some studies evaluated more than one outcome.
43
*1 case report articles not found (not included in appendix 2)
**1 case report articles not found (not included in appendix 2)
***3 case reports articles not found (not included in appendix 2
44
45