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EM Critical Care
UNDERSTANDING AND CARING FOR
CRITICAL ILLNESS IN EMERGENCY MEDICINE
Emergency Department
Treatment Of Beta Blocker
And Calcium-Channel Blocker
Poisoning
May/June 2014
Volume 4, Number 3
Authors
Anthony J. Tomassoni, MD, MS
Yale School of Medicine, Medical Director, Yale New Haven
Hospital System Center for Emergency Preparedness and
Disaster Response, New Haven, CT
Stephen Sanders, MD
Assistant Professor of Emergency Medicine, Emory
University School of Medicine, Atlanta, GA
Evie G. Marcolini, MD, FAAEM
Abstract
The treatment of a patient who has sustained an overdose of a beta
blocker and/or calcium channel-blocking agent can be challenging and time-sensitive, with few proven treatment options beyond
supportive care. Such cases present relatively infrequently in the
spectrum of emergency medicine and critical care practice. This issue reviews the pharmacology of beta blocker and calcium-channel
blocker agents as well as the pathophysiology and clinical course
of their associated toxicity. Historically accepted treatment modalities, such as administration of calcium or glucagon, are reviewed.
Some newer options, such as high-dose euglycemic insulin therapy
and lipid rescue therapy, have shown promising results, but in order
to apply these treatments effectively and in a timely fashion, emergency physicians must have a support system prepared to treat these
critically ill patients. This system should include ready availability of
the agents, defined treatment protocols, and pharmacy and nursing
staff familiar with these therapies in advance of patient presentation.
Assistant Professor of Emergency Medicine, Surgical, and
Neurocritical Care, Yale University School of Medicine, New
Haven, CT
Peer Reviewers
Michael Policastro, MD, FACEP, FACMT
Attending Emergency Physician, Medical Toxicologist,
Qualified Emergency Specialist, Inc. Good Samaritan
Hospital, Bethesda North Hospital, Cincinnati, OH
Jon Rittenberger, MD, MS, FACEP
Assistant Professor, Department of Emergency Medicine,
University of Pittsburgh School of Medicine; Attending
Physician, Emergency Medicine and Post-Cardiac Arrest
Services, UPMC Presbyterian Hospital, Pittsburgh, PA
CME Objectives
Upon completion of this article, you should be able to:
1.
2.
3.
4.
Describe the potential consequences of beta blocker
and calcium-channel blocker poisoning.
Identify the role of glucagon in stabilizing beta blocker
and calcium-channel blocker-poisoned patients and
explain an appropriate dosing scheme.
Discuss the role of euglycemic insulin therapy.
Summarize the role of lipid rescue therapy for patients
for whom other interventions have failed.
Prior to beginning this activity, see “Physician CME
Information” on the back page.
Editor-in-Chief
Editorial Board
William A. Knight, IV, MD, FACEP
Assistant Professor of
Emergency Medicine and
Neurosurgery, Medical Director,
Emergency Medicine Midlevel
Provider Program, Associate
Medical Director, Neuroscience
ICU, University of Cincinnati,
Cincinnati, OH
Benjamin S. Abella, MD, MPhil,
FACEP
Assistant Professor, Department
of Emergency Medicine and
Department of Medicine, Section
of Pulmonary, Allergy, and Critical
Care, University of Pennsylvania
School of Medicine; Clinical
Research Director, Center
for Resuscitation Science,
Philadelphia, PA
Associate Editors-inChief
Robert T. Arntfield, MD, FACEP,
FRCPC, FCCP
Assistant Professor, Division
of Critical Care, Division of
Emergency Medicine, Western
University, London, Ontario,
Canada
Scott D. Weingart, MD, FCCM
Associate Professor, Department
of Emergency Medicine,
Director, Division of Emergency
Department Critical Care, Icahn
School of Medicine at Mount
Sinai, New York, NY
Robert Green, MD, DABEM,
FRCPC
Professor, Department of
Anaesthesia, Division of Critical
Care Medicine, Department of
Emergency Medicine, Dalhousie
University, Halifax, Nova Scotia,
Canada
Julie Mayglothling, MD
Assistant Professor, Department
of Emergency Medicine,
Department of Surgery, Division
of Trauma/Critical Care, Virginia
Commonwealth University,
Richmond, VA
Christopher P. Nickson, MBChB,
Andy Jagoda, MD, FACEP
MClinEpid, FACEM
Professor and Chair, Department
Senior Registrar, Intensive Care
of Emergency Medicine, Icahn
Unit, Royal Darwin Hospital,
School of Medicine at Mount Sinai;
Darwin, Australia
Medical
Director,
Mount
Sinai
Lillian L. Emlet, MD, MS, FACEP
Hospital,
New
York,
NY
Jon
Rittenberger, MD, MS, FACEP
Assistant Professor, Department of
Assistant Professor, Department
Critical Care Medicine, Department
of Emergency Medicine, University
of Emergency Medicine, University Haney Mallemat, MD
Assistant Professor, Department
of Pittsburgh School of Medicine;
of Pittsburgh Medical Center;
of
Emergency
Medicine,
University
Attending Physician, Emergency
Program Director, EM-CCM
of Maryland School of Medicine,
Medicine and Post Cardiac Arrest
Fellowship of the Multidisciplinary
Baltimore, MD
Services, UPMC Presbyterian
Critical Care Training Program,
Hospital, Pittsburgh, PA
Pittsburgh, PA
Evie Marcolini, MD, FAAEM
Assistant Professor of Emergency
Michael A. Gibbs, MD, FACEP
Medicine, Surgical, and Neurocritical
Professor and Chair, Department
Care, Yale University School of
of Emergency Medicine, Carolinas
Medicine, New Haven, CT
Medical Center, University of North
Carolina School of Medicine,
Chapel Hill, NC
Emanuel P. Rivers, MD, MPH, IOM
Vice Chairman and Director
of Research, Department of
Emergency Medicine, Senior
Staff Attending, Departments of
Emergency Medicine and Surgery
(Surgical Critical Care), Henry
Ford Hospital; Clinical Professor,
Department of Emergency
Medicine and Surgery, Wayne
State University School of
Medicine, Detroit, MI
Isaac Tawil, MD, FCCM
Assistant Professor, Department
of Anesthesia and Critical Care,
Department of Emergency Medicine,
Director, Neurosciences ICU,
University of New Mexico Health
Science Center, Albuquerque, NM
Research Editor
Bourke Tillman, MD, BHSc
Critical Care Fellow, PGY4 FRCP(C) Emergency Medicine,
London Health Sciences Centre,
University of Western Ontario,
London, Ontario, Canada
blockers, outcome data have been reported for
2793 exposures; 68 experienced a major effect and
24 died.1 These data represent collected voluntary
reports to regional poison centers, and inherently
represent an underestimation of the total number of
cases and deaths. Despite the efforts of many poison
centers to collect data from medical examiners, it is
also likely that poisonings discovered postmortem
are underreported in AAPCC data.
When clinicians report cases to regional poison
centers, the centers assist in data collection and
gain access to the most current patient management
guidelines, including real-time toxicology consultation. It is important to note that toxicologists and
pathologists are not always in agreement on the
cause of death,2 and the documented cause of death
is not always specific to the agent ingested. According to the National Poison Data System (NPDS)
2012 report, cardiovascular drugs accounted for the
seventh most frequently found category of substance involved in human exposures, as well as the
substance with the third greatest rate of exposure
increase (closely following analgesics and sedatives/
hypnotics/antipsychotics). Cardiovascular drugs
were the fourth most common category of substances involved in adult exposures, and miscellaneous
cardiovascular drugs were the category with the
second highest number of fatalities.1
Case Presentation
During a busy evening shift in the ED, EMS providers
present you with a 21-year-old patient who reportedly
ingested her father-in-law’s “blood pressure pills.” No
further identification of the medication is forthcoming, the
pill bottles were not found at the scene, and the in-laws
are on vacation out of the country. Bystanders report that
the ingestion occurred approximately 50 minutes before
the patient’s arrival in the ED. On arrival, the patient’s
heart rate is 60 beats/min, blood pressure is 105/65 mm
Hg, respiration and temperature are normal, and she is
alert. The critical care units at your hospital are overloaded, and you are asked to board the patient in your ED for
several hours until a bed becomes available. You provide
supportive care, but over the next 90 minutes, her clinical
condition progressively deteriorates despite attempted
interventions. Her heart rate and blood pressure become
unresponsive to fluids, calcium, high doses of glucagon,
atropine, and vasopressors. Her mental status also deteriorates, and she is endotracheally intubated and placed
on mechanical ventilation. Attempts at transcutaneous
pacing yield intermittent capture without significant
improvement in heart rate or blood pressure. Evidence of
tissue hypoperfusion is present, based on your observation
of end-organ failure. It seems that her refractory hypotension and bradycardia may be leading to an impending
arrest. What salvage options remain? Was there anything
that could have been done to avoid this condition?
Critical Appraisal Of The Literature
Introduction
A literature search was performed using Ovid
MEDLINE® and PubMed. Search terms included
calcium-channel blocker poisoning, beta blocker poisoning, molecular adsorbent recirculating system, and
toxicity. The Poisindex guidelines and references
were reviewed. The website www.lipidrescue.org
was also reviewed. A search of the National Guideline Clearinghouse (www.guideline.gov) revealed
no published guidelines addressing the treatment of
beta blocker or calcium-channel blocker overdose. Human studies in toxicology are often limited
by variables that are difficult to control, and a randomized double-blind placebo-controlled study of
lethal doses of medications is unethical. Therefore,
searches of the literature on human poisoning with
beta blockers and calcium-channel blockers yield a
preponderance of case reports and animal studies.
Identification and treatment of patients with significant beta blocker and/or calcium-channel blocker
toxicity can be challenging. Optimal management of
these patients in the emergency department (ED) can
have a meaningful impact on their hospital course.
Timely, focused treatment of these patients in the ED
sets the stage for successful ongoing management of
these challenging critical care cases. The numbers and potential mortality represented by beta blockers and calcium-channel blockers in the United States are substantial. In 2012, the
annual report of the American Association of Poison
Control Centers (AAPCC) documented 10,691 cases
of reported single-agent exposures to beta blockers
and 5076 single-agent exposures to calcium-channel
blockers; the sum of these cases more than doubles
when considering the number of exposures to these
medications in combination with other substances.
Of the single-agent exposures to beta blockers
reported, outcome data are recorded for 5567 cases,
and, of those, 70 experienced a “major” effect and 13
died.1 The AAPCC defines a major effect of toxin exposure as one in which “the patient exhibited signs
or symptoms as a result of the exposure that were
life-threatening or resulted in significant residual
disability or disfigurement.” For calcium-channel
Copyright © 2014 EB Medicine. All rights reserved.
Pharmacology Of Beta Blockers And
Calcium-Channel Blockers
It is important to be familiar with characteristics of
the different classes of beta blockers and calciumchannel blockers in order to anticipate the clinical
course that may await the poisoned patient.
2
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Beta-Adrenergic Blockers
also demonstrate Vaughan Williams class I sodium
channel-blocking properties (similar to quinidine,
disopyramide, and procainamide). Sotalol is unique,
due to its class III effects (potassium-channel blockade), resulting in prolonged action potential and
delayed repolarization of cardiac muscle cells.
The clinical course for a beta blocker overdose
will typically involve bradycardia and hypotension. Other possible signs include hypothermia, hypoglycemia (due to inhibited glycogenolysis), and
seizures. It may be difficult to determine an occult
overdose, since bradycardia is a therapeutic effect
of beta blockers. Onset of symptoms can be from 20
minutes to several hours, depending on the patient’s tolerance and cardiovascular reserve as well
as the type of agent ingested. Sustained-release
agents may take longer to produce clinical effects,
but all significant beta blocker overdoses should
be clinically apparent within 6 hours. Patients may
develop seizures (occurring more commonly with
propranolol), but they are usually brief. Finally,
bronchospasm can occur with beta blocker overdose, and it is more likely in patients with preexisting bronchospastic disease.
Beta-adrenergic blockers act by competitive antagonism of catecholamines at beta-adrenergic receptors.
Beta blockers vary in their beta1 and beta2 antagonism, lipid solubility, and other properties. (See
Table 1.) In overdose, selectivity is diminished or
even lost. The mechanism of action appears not to be
restricted to beta-adrenergic receptor-blocking properties. Propranolol, for example, exhibits significant
membrane stabilizing activity and is lipid soluble.
Propranolol overdose is often lethal; poisoning with
this agent may be characterized by seizures, coma,
bradycardia, hypotension, abnormal atrioventricular
conduction, QRS widening, or ventricular tachydysrhythmias.3 The central nervous system effects stem,
in part, from this lipid-soluble drug’s ability to cross
the blood–brain barrier.
The individual properties of beta blockers may
influence their effects in overdose. Beta blockers may
be classified into 2 groups, according to their solubility and route of elimination: (1) lipid-soluble agents
and (2) water-soluble agents. Lipid-soluble agents
(such as propranolol and metoprolol) are cleared
via the liver, have significant central nervous system
distribution, and are well absorbed by the gut. They
readily enter the central nervous system and have
variable bioavailability and relatively short plasma
half-lives. Conversely, water-soluble agents (such as
atenolol) are less completely absorbed through the
gut, not as well distributed to the central nervous
system, have relatively longer plasma half-lives, and
are eliminated via the kidneys, unchanged.
Other beta blockers of note have special properties. Some have intrinsic sympathomimetic properties (such as acebutolol and pindolol) and may,
therefore, have a less suppressive effect on heart
rate. Labetalol has beta-blocker activity combined
with substantially less alpha- (than beta) blocking activity. Esmolol is an ultra-short-acting beta
blocker whose brief half-life is due to rapid clearance
by hepatic and blood esterases. Beta blockers may
Calcium-Channel Blockers
There are 3 classes of calcium-channel blockers
available in the United States: (1) dihydropyridines (nifedipine, amlodipine, and nicardipine);
(2) phenylalkylamines (verapamil); and (3) benzothiazepines (diltiazem). It is clinically useful,
however, to think of calcium-channel blockers as
either dihydropyridine agents or nondihydropyridine agents because of their different mechanisms
of action and the resulting differences in clinical
course following overdose. Dihydropyridines are smooth-muscle selective
agents that have relatively little myocardial depressant activity at therapeutic doses when compared
with nondihydropyridines. Dihydropyridines may
even increase cardiac output, due to resultant reflex
Table 1. Pharmacologic Properties Of Selected Beta Blockers
Agent
Beta1 Selective?
Lipid Solubility
Route of Elimination
Intrinsic Sympathomimetic
Activity
Notes
Acebutolol
Yes
Moderate
Renal/hepatic
Mild
Antioxidant
Atenolol
Yes
Low
Renal
NA
NA
Carvedilol
No
Moderate
Hepatic
NA
NA
Esmolol
Yes
Low
NA
NA
NA
Labetalol
No
High
Hepatic
Mild
Some alpha blockade
Metoprolol
Yes
High
Hepatic
NA
NA
Pindolol
No
Moderate
Renal/hepatic
High
NA
Propranolol
No
High
Hepatic
NA
Possible altered glucose
metabolism
Abbreviations: NA, not applicable.
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tachycardia (as in their role in blood pressure management). Dihydropyridines are efficient antihypertensive agents that act by inhibiting Ca2+ ion movement across cardiac and vascular cell membranes,
resulting in dilation of main coronary and systemic
arteries and decreased preload and afterload. In
overdose, dihydropyridine selectivity may diminish
and result in impaired myocardial conduction and
myocardial depression. In contrast, nondihydropyridines block L-type calcium channels, causing
impaired myocardial contractility and conduction
(as in their applications in controlling tachycardia).
See Table 2 for the differences between the classes of
calcium-channel blockers and their sites of action.
Calcium-channel blockers currently in use bind
to the pore-forming subunit of the L-type calcium
channel where they prevent calcium influx into all
types of muscle cells. Under normal conditions,
they allow the calcium ions needed for excitationcontraction coupling to flow intracellularly down
electrical and concentration gradients, causing
muscular contraction. This ion flow is critical to
cardiac muscle excitation.4,5 In smooth-muscle
cells, this calcium flow indirectly activates myosin,
which then binds actin, thereby causing contraction. In cardiac muscle cells, slow inward calcium
flow creates the plateau phase of the cardiac action
potential, which causes calcium-induced calcium
release from the sarcoplasmic reticulum. The additional calcium released binds troponin C, causing
a conformational change that removes troponin
and tropomyosin from actin. This allows actin and
myosin to couple, creating a contraction.6
All calcium-channel blocker overdoses may
result in hypotension, bradycardia, and death, in
part because receptor selectivity may be lost in overdose.7 Pharmacology and experience indicate that
the most severe cardiotoxic effects result from the
strong negative inotropic and chronotropic effects of
the nondihydropyridines.8 Verapamil overdoses, in
particular, are challenging to manage and carry the
potential for high lethality. Calcium-channel blockers are highly protein-bound and verapamil and
diltiazem both have large volumes of distribution,
making extracorporeal removal via standard hemodialysis or hemoperfusion ineffective.
Other pharmacologic actions of calcium-channel
blockers may also contribute to their lethality. When
calcium-channel blockers block L-type calcium channels on pancreatic islet cells, calcium entry into those
cells is limited. The limited calcium entry can result
in decreased insulin release by pancreatic islet cells,
low insulin levels, resultant hyperglycemia, and
poor glucose utilization by target tissues. Finally, at
high doses, calcium-channel blockers may also block
sodium channels, resulting in QRS prolongation
similar to that induced by Vaughan Williams class Ia
antiarrhythmics and cyclic antidepressants.
Prehospital Care
The mainstays of prehospital care of the poisoned
patient revolve around recognizing and confirming the toxidrome, initiating supportive care, and
acquiring information and/or orders needed to optimize care from medical control or the regional poison center according to local protocols and practices.
Prehospital care providers are often in a unique position to gather history at the scene and from bystanders, as patients are frequently unable or unwilling
to relate a reliable ingestion history. A quick search
of the scene for pill containers (bedroom, bathroom,
kitchen, and trash containers, etc) often yields
information regarding the identity of ingestants/coingestants, estimated quantity ingested, the presence
or absence of emesis, and more. Questioning of fam-
Table 2. Pharmacologic Properties Of Classes Of Calcium-Channel Blockers9
Agent (L-type Ca2+
Channel Binding Site)
Example Drugs
Peripheral and Coronary Vasodilation
Negative Inotropic Effect
SA Node
Suppression
AV Node
Suppression
Notes
Dihydropyridine
(N site)
•
•
•
•
•
•
•
+++++
+
+
0
Potential reflex tachycardia due to arteriolar vasodilation
Benzothiazepine
(D site)
Diltiazem
+++
++
+++++
++++
Phenylalkylamine
(V site)
Verapamil
++++
++++
+++++
+++++
Possible advantages
in chronic kidney
disease and diabetic
nephropathy
Amlodipine
Bepridil
Felodipine
Isradipine
Nicardipine
Nifedipine
Nisoldipine
Abbreviations: AV, atrioventricular; SA, sinoatrial.
Adapted and reprinted with permission from Dr. Flavio Guzman, www.pharmacologycorner.com. Available at: http://pharmacologycorner.com/calciumchannel-blockers-classification-mechanism-of-action-indications/.
Copyright © 2014 EB Medicine. All rights reserved.
4
www.ebmedicine.net • Volume 4, Number 3
For similar reasons, special attention must be
focused on the selection of adjunctive medications
used in supportive care in order to avoid further
(or inadvertent) myocardial depression that may
worsen cardiac output. For example, it is important
to avoid agents that may cause or worsen hypotension and bradycardia during rapid sequence intubation and subsequent sedation for the maintenance
of ventilation. Agents with myocardial depressant
effects (such as propofol, thiopental, or dexmedetomidine) should be avoided. Benzodiazepine administration may result in bradycardia and concomitant
hypotension, especially in hypotension. Specifically,
diazepam and midazolam have a direct myocardial
depressant effect at the cellular level, which is mainly mediated by an inhibition of the sarcolemmal Ltype Ca2+ channel.10 In contrast, agents preferred in
cardiac anesthesia offer some advantages. Ketamine
is an acceptable choice due to its sympathomimetic
effect. Fentanyl may be an acceptable choice; however, in cases of multiple ingestions, it can worsen
hypotension.
Neuromuscular blockade may be used to
improve patient-ventilator synchrony and gas exchange, to lower the risk of barotrauma, to reduce
muscle oxygen utilization, and to prevent inadvertent extubation. Succinylcholine, a depolarizing
agent, has the potential to cause hyperkalemia,
bradycardia, and other ventricular arrhythmias,
and it is, perhaps, best avoided in the setting of
beta blocker and calcium-channel blocker overdose.
The short duration of action is also a limitation.
The nondepolarizing agents may offer advantages
in this context. For rapid sequence intubation,
rocuronium (a short-acting agent) offers the advantage of having few cardiovascular effects. Similarly,
vecuronium (an agent of intermediate duration of
action) has few cardiovascular effects. For longer
duration of paralysis, pancuronium offers the
theoretical advantage of vagolysis, which, under
ordinary circumstances, may induce tachycardia
and hypertension and increase cardiac output. Loss
of cardiac responsiveness due to poisoning may
negate these potential benefits.
ily and friends, the identity of pharmacies and prescribing physicians, and the examination of medical
records on scene by prehospital providers may assist
physicians in the management of these patients. This
information may help emergency physicians confirm
or refute their working hypotheses, estimate the direction the clinical course may take, and identify and
treat mixed toxidromes and ingestants that might
otherwise have been missed.
Although prehospital providers may also be
in a position to provide the earliest possible gastric
decontamination with activated charcoal (where
indicated and allowed), the decision to administer
activated charcoal should not be taken lightly. Aspiration of charcoal can result in significant morbidity
and mortality. If this intervention is considered, it
should only be done in patients who will be able to
protect their airway throughout transport and early
ED management. This condition often applies only
to patients with relatively small ingestions, while
those with substantial overdoses are at greatest risk
for aspiration. Therefore, consultation with an online
medical command physician and, potentially, a toxicologist is advised before administration of activated
charcoal in the field.
Treatment
Patient Selection
In cases of beta blocker and calcium-channel blocker
poisoning, supportive care may include vital sign
and cardiac monitoring, fluid resuscitation, endotracheal intubation, and, for calcium-channel blocker
toxicity, calcium administration. It is highly recommended that physicians consult their regional
poison control centers and an experienced medical
toxicologist in all cases of beta blocker and calciumchannel blocker exposure. These resources have
the extensive experience required to risk stratify
patients and guide therapy and patient disposition.
Poison centers in the United States may be reached
by calling 1-800-222-1222, 24 hours a day, 7 days a
week. Medical toxicologists are available for direct
consultation upon request.
Common Treatment Options
Supportive Care
Multiple modalities have been utilized to attempt to
restore myocardial conduction and contractility after
beta blocker and calcium-channel blocker overdoses.
These include infusion of crystalloid solutions,
calcium, atropine, sodium bicarbonate, adrenergic
agents, glucagon, cardiac pacing, intra-aortic balloon
counterpulsation, extracorporeal bypass, and, more
recently, euglycemic insulin therapy, infusion of
lipid emulsion, and extracorporeal albumin dialysis.
The following sections will expand on the treatments typically used by emergency physicians.
Recognition of the potential for lethal myocardial
depression should guide the selection of basic
measures to stabilize and support the patient who is
poisoned with a beta blocker or a calcium-channel
blocker. Excessive fluid administration during resuscitation of patients poisoned with beta blockers and
calcium-channel antagonists is not advised due to
the myocardial depressant activity of these agents.
Once the patient has adequate preload, additional
(or aggressive) fluid resuscitation is more likely to
result in overload of the failing heart and acute onset
of pulmonary edema than in other forms of shock.
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Glucagon Therapy
Glucagon has been shown to reduce myocardial depression in beta blocker and calcium-channel blocker
poisoning, and it should be used early in the course
of poisoning.11-15 When glucagon binds to receptors
in the liver, the synthesis of cyclic adenosine monophosphate (cAMP) is increased, thereby stimulating
gluconeogenesis, glycogenolysis, and ketogenesis.16
Agonism of cardiac glucagon receptors also increases cAMP concentrations and results in increased inotropy and chronotropy. The effects of a
bolus dose of 50 mcg/kg of glucagon last about 15
minutes. Bolus doses often range from 2 mg to 10
mg, depending on the degree of hypotension and
the resultant response to therapy. Boluses that do
not yield the desired response must be “stacked”
in rapid succession, due to the short duration of
effect. The effect may be prolonged by the administration of a continuous infusion of glucagon.17,18
Typical infusion rates for adults range from 2 to 5
or 10 mg/h. Of note, combining glucagon with the
phosphodiesterase inhibitors amrinone and milrinone may result in decreased mean arterial pressure and increased tachycardia, respectively.19,20 It
is important to recognize that both hypocalcemia
and hypercalcemia lessen the chronotropic effect of
glucagon administration; glucagon’s chronotropic
effect seems to be optimal in the presence of normal
ionized calcium concentrations.21
Adequate dosing of glucagon is essential to
provide the desired increase in mean arterial pressure. Rapid administration of glucagon may result
in vomiting, yet slow administration of boluses may
not be effective. Boluses and infusions may require
some titration to effect. The recommended initial
bolus dose is 50 mcg/kg administered over 1 to 2
minutes, but it may range as high as 5 to 10 mg in
an adult if the initial bolus does not produce sufficient hemodynamic improvement. The bolus should
be followed immediately by a continuous infusion
of 2 mg to 10 mg/h, titrated to effect and weaned
slowly, as hemodynamics permit.22,23 Infusions may
be mixed in 5% dextrose in water after reconstitution
of glucagon according to the manufacturer’s instructions. Antiemetic therapy may help to prevent or
limit the nausea and vomiting that may result from
glucagon use.
In the past, glucagon was supplied with a
phenol-containing diluent. Due to the large doses
of glucagon necessary for treating beta blocker and
calcium-channel blocker poisoning, if the glucagon
was reconstituted using the diluent, the cumulative
amounts of phenol administered could result in
phenol toxicity and exacerbate hypotension. Current United States supplies of glucagon no longer
contain phenol.
Copyright © 2014 EB Medicine. All rights reserved.
Insulin Therapy
Insulin works to reverse the effects of beta blocker/
calcium-channel blocker overdose by 2 mechanisms.
In the toxicity-induced shock state, cardiac cells preferentially use carbohydrate instead of free fatty acid
for metabolism, which is compensated by hepatic
glycogenolysis. Calcium-channel blockers also inhibit pancreatic insulin secretion via blockade of L-type
calcium channels on islet cells. This causes insulin
deficiency, hyperglycemia, and acidosis. High-dose
insulin/euglycemic therapy enables cardiac cells to
metabolize carbohydrates without increasing myocardial oxygen demand. It also allows cells to take in
glucose from the bloodstream via activation of the
glucose transporter family of receptors, improving
both hyperglycemia and acidemia. It is theorized
that insulin therapy is more effective than calcium,
glucagon, or epinephrine because it does not induce
free fatty acid use or increase myocardial work.24,25
Insulin has also been shown to improve myocardial
contractility and vasomotor tone and to increase the
uptake of lactate, all of which aid in the resolution
of shock in the beta blocker and calcium-channel
blocker overdose patient.
Euglycemic High-Dose Insulin Therapy
Euglycemic high-dose insulin therapy has improved outcomes in severe cases of beta blocker
or calcium-channel blocker poisoning, and, in the
authors’ clinical experience, it often succeeds when
other modalities (including glucagon) have failed
to improve hemodynamic parameters.24 Consultation with a medical toxicologist may help to guide
physicians who are not familiar with this therapy
and its indications, and consultation is strongly
encouraged. This therapy takes effect gradually,
often requiring as long as an hour to improve the
patient’s hemodynamic status, when dosing is
optimized. Because of this slow onset, the need for
euglycemic insulin therapy must be anticipated
and the infusion should be instituted when it first
becomes apparent that the patient will suffer refractory hypotension due to lack of response to standard therapy (including glucagon).
High-dose insulin therapy will require frequent
glucose monitoring (as often as every 15 minutes
or more frequently) and glucose supplementation
until the patient’s serum glucose is stabilized on a
given insulin dose. Serum potassium will shift to the
intracellular compartment during therapy and back
into serum when therapy is terminated, so potassium should be supplemented conservatively and
with caution. As with any insulin infusion, the intravenous tubing used must be flushed with insulincontaining solution to saturate binding sites on the
tubing with insulin to ensure delivery of prescribed
amounts of insulin.
Currently, an insulin bolus of 1 unit/kg body
weight has become an accepted starting point, fol6
www.ebmedicine.net • Volume 4, Number 3
lowed by insulin infusions started in the range of 1
unit/kg body weight/h and titrated upward to as
high as 10 units/kg/h, depending on the degree of
hypotension present.24 Toxicology consultation is
advised to assist with dosing. This therapy should be
started as early as possible, before the patient is in extremis. Insulin dosing requirements for beta blockerpoisoned patients may be lower than those required
to treat calcium-channel blocker-poisoned patients.
Insulin therapy requires time to produce hemodynamic improvement, and care should be taken not to
taper insulin therapy too rapidly upon hemodynamic
improvement or the benefit may be lost.
Vasopressors
Atropine and conventional vasopressors (such as
dopamine and norepinephrine) may not yield the
expected benefits in significant overdoses due to the
myocardial depressant effects of beta blocker and
calcium-channel blocker toxicity. Phosphodiesterase
inhibitors (such as amrinone and milrinone) have
historically been used, but they do not seem to offer
any benefit over glucagon and may even decrease
mean arterial pressure, when used.19 The use of cardiac pacing, extracorporeal membrane oxygenation,
cardiopulmonary bypass, and intra-aortic balloon
counterpulsation have been reported for severe cases
of beta blocker/calcium-channel blocker toxicity
in order to temporize until further clearance of the
toxin occurs. Indications for glucagon, euglycemic
insulin therapy, and lipid rescue may be best understood as points along the continuum of progressive
hypotension as beta blocker or calcium-channel
blocker poisoning progresses.26-28
Gastric Decontamination
Patients who ingest life-threatening amounts of
calcium-channel blocker and/or beta blocker agents
may potentially be candidates for gastric decontamination. Immediate toxicology consultation is recommended when making this decision, due to significant risks and unproven benefit. Gastric decontamination via activated charcoal may be provided for
patients who present within approximately 1 hour
after ingestion, and perhaps longer in cases where
a co-ingestant (such as an anticholinergic agent)
may delay gastric emptying or drug absorption. The
patient must remain alert and able to protect his airway (hemodynamics and mental status stability or
improving trajectory) or be endotracheally intubated
in order to receive activated charcoal therapy, since
aspiration of activated charcoal may lead to respiratory failure and death. Endotracheal intubation is
not a fail-safe method of preventing charcoal aspiration, however. While activated charcoal administration may decrease the area under the concentrationversus-time curve of a drug, no clinical studies have
been performed to assess the effect of activated charcoal on outcome in cases of poisoning. If performed,
active charcoal administration should be reserved
for recent (usually < 60 min prior) ingestion of a lifethreatening amount of a life-threatening agent. It is
strongly recommended that emergency physicians
caring for patients who have ingested a beta blocker
or calcium-channel blocker consult a toxicologist to
weigh the theoretical advantage of activated charcoal administration versus the potential life-threatening risk of aspiration of activated charcoal.
Whole-bowel irrigation with polyethylene glycol
electrolyte lavage solution is reserved for patients
who have ingested sustained-release preparations,
with the goal being to speed the passage of the drug
through the gut before it can be entirely absorbed.
When indicated, polyethylene glycol electrolyte
lavage is best administered as early in the course of
poisoning as possible, although, given the extended
liberation period of many sustained-release agents,
there may be some theoretical (but, as yet, clinically
unproven) benefit to administration even several
hours after ingestion of sustained-release agents.
www.ebmedicine.net • Volume 4, Number 3
Using Multispecialty Teams
It is imperative that team members be familiar with
advanced therapies before critical cases present
in order to initiate timely action when needed.
Pharmacists may be unfamiliar with high-dose
glucagon, high-dose euglycemic insulin, or lipid
rescue therapies. It is best to enlist their assistance
in developing institutional guidelines for these
infrequently used (but potentially life-saving) treatments. Similarly, nephrologists should be involved
regarding available hemoperfusion/molecular adsorbent modalities available and their indications.
Cardiologists and cardiothoracic surgeons must
become familiar with potential uses for intra-aortic
balloon counterpulsation and cardiopulmonary
bypass in poisoning. Neurologists may be involved
for continuous electroencephalographic monitoring that may be needed to detect subclinical status
epilepticus, especially if paralytics are used in the
poisoned patient.
The practice of using a multispecialty team to
provide care to the severely poisoned patient may
prove beneficial for all. Institutions or practitioners
with little experience managing these cases may
find it advantageous to transfer these patients to a
higher level of care. If transfer is contemplated, it
should, ideally, be accomplished early in the course
of poisoning, before severe hemodynamic compromise increases the risk to the patient. Hospital
practice teams should receive education in advance
on the need to manage these potentially critically
ill patients so that antidotes and other care may be
rendered in a timely and efficient manner.
7
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Clinical Pathway For Management Of Beta Blocker And
Calcium-Channel Blocker Toxicity
Identify patient with beta blocker or
calcium-channel blocker toxicity
Is the patient protecting the airway?
NO
• Intubate patient (Class I)
• Go to “severe toxicity” treatment pathway
YES
• Immediate resuscitation required (Class I)
• Go to “severe toxicity” treatment pathway
YES
Deteriorating vital signs
or
Signs of systemic shock?
NO
Determine level of toxicity (clinical presentation)
Mild toxicity; consider:
• Cardiac monitoring
• IV fluids
• Correction of electrolytes
• Calcium
• Glucagon bolus/infusion
• Atropine
Moderate toxicity; consider:
• All options in “mild toxicity” pathway and
• High-dose insulin (with glucose)
• Vasopressors
Patient improving?
Severe toxicity; consider:
• All options in “mild toxicity” and “moderate
toxicity” pathways and
• Intubation
• Lipid rescue therapy
• Cardiac pacing
• Intra-aortic balloon counterpulsation
• Cardiopulmonary bypass
• Molecular adsorbent recirculating system
Patient improving?
Patient improving?
YES
NO
YES
NO
YES
• Continue to
monitor
• Consider additional treatment
with above
• Consider hospital admission
Go to “moderate
toxicity” treatment
pathway (above)
• Continue to
monitor
• Consider additional treatment
with above
• Likely hospital
admission (consider ICU)
Go to “severe
toxicity” treatment
pathway (above)
• Continue to
monitor
• Consider additional treatment
as needed
• Admit to hospital, likely to ICU
setting
NO
• Consider additional aggressive treatment
• Obtain toxicology consult,
if not already
done
• Consider alternate diagnosis
Abbreviations: ICU, intensive care unit; IV, intravenous.
For class of evidence definitions, see page 9.
Copyright © 2014 EB Medicine. All rights reserved.
8
www.ebmedicine.net • Volume 4, Number 3
Determining Stability And Identifying And
Managing Deterioration
Clinical Course In The Emergency
Department
Once the patient with beta blocker/calcium-channel
blocker toxicity has been identified, the first priority
is to protect the airway, which may require intubation. Vital signs, including hemodynamic stability,
will guide the subsequent course of action. If the
patient is asymptomatic, activated charcoal or orogastric lavage may be considered if it has been
< 1 hour since ingestion. Systolic blood pressure
< 100 mm Hg or heart rate < 60 beats/min may
mandate fluid boluses and/or atropine. If this does
not result in hemodynamic stability or the condition
worsens, intubation, glucagon, additional atropine,
calcium, and/or high-dose insulin with glucose may
be warranted. If glucagon is ineffective in improving
the hemodynamics of a calcium-channel blocker-poisoned patient, no time should be lost before advancing to euglycemic insulin therapy.
A patient in systemic shock will require aggressive management, including all of the interventions
noted previously, and may require vasoactive therapy,
lipid rescue, cardiac pacing, or more invasive maneuvers such as intra-aortic balloon counterpulsation,
cardiopulmonary bypass, and/or the use of molecular adsorbent recirculating system. Once resuscitation
has occurred and the patient is temporarily stabilized,
the decision on admission location within the hospital
will depend on whether or not intubation has occurred, the patient’s hemodynamic stability, and the
resources available at the local institution. Twentyfour-hour inhouse presence of attending-level critical
care providers is highly desirable for the management
of these complex patients. Transfer of the patient to a
tertiary care center should be considered if the patient
is hemodynamically unstable or if the anticipated
course includes therapies that are not available at
the original institution. Continuous hemodynamic
monitoring as well as neurologic and airway monitoring are necessary, regardless of therapy applied, in all
beta blocker and calcium-channel blocker overdoses.
Potential for severe declines in clinical status exists
Continuous monitoring of hemodynamics, serum
chemistries (especially glucose and electrolytes), and
mental status are essential in order for the physician
to anticipate the escalation in doses and therapies
that may be required to optimize patient salvage.
Hyperglycemia is a hallmark of significant calciumchannel blocker overdose, and in the altered patient
presenting without history of ingestion, unexplained
hyperglycemia should raise concern for calciumchannel blocker poisoning. While further work is
needed to correlate glucose levels with therapies
indicated, glucose levels may be a better indicator of
the severity of poisoning and of the need for euglycemic insulin therapy.29
In contrast, beta-blocker poisoning may present with hypoglycemia (rarely) or hyperglycemia.30
Lactate levels, bicarbonate, and serum pH may help
to assess the adequacy of end-organ perfusion. In
conjunction with supportive care, escalating doses/
infusions of glucagon, insulin/glucose/potassium,
and/or parenteral lipid infusion may be required,
in succession, as hemodynamics deteriorate. Evidence of cerebral/tissue hypoxemia and/or acidosis
indicates the need for escalation of therapy. In the
absence of signs of severe hypoperfusion, lowerthan-average blood pressures may be acceptable.
Middle-aged patients will often tolerate/survive
with target blood pressures as low as 80 mm Hg,
systolic. In severe cases of cardioactive agent poisoning, it is often impossible to reach optimal perfusion
rates. Although suboptimal in terms of optimal cerebral and core organ perfusion goals, blood pressures
such as 90/60 mm Hg may be an acceptable pressure in patient with severe beta blocker or calciumchannel blocker poisoning.
Class Of Evidence Definitions
Each action in the clinical pathways section of EM Critical Care receives a score based on the following definitions.
Class I
Class II
• Always acceptable, safe
• Safe, acceptable
• Definitely useful
• Probably useful
• Proven in both efficacy and effectiveness
Level of Evidence:
Level of Evidence:
• Generally higher levels of evidence
• One or more large prospective studies
• Nonrandomized or retrospective studies:
are present (with rare exceptions)
historic, cohort, or case control studies
• High-quality meta-analyses
• Less robust randomized controlled trials
• Study results consistently positive and
• Results consistently positive
compelling
Class III
• May be acceptable
• Possibly useful
• Considered optional or alternative treatments
Level of Evidence:
• Generally lower or intermediate levels
of evidence
• Case series, animal studies, consensus panels
• Occasionally positive results
Indeterminate
• Continuing area of research
• No recommendations until further
research
Level of Evidence:
• Evidence not available
• Higher studies in progress
• Results inconsistent, contradictory
• Results not compelling
This clinical pathway is intended to supplement, rather than substitute for, professional judgment and may be changed depending upon a patient’s individual
needs. Failure to comply with this pathway does not represent a breach of the standard of care.
Copyright © 2014 EB Medicine. 1-800-249-5770. No part of this publication may be reproduced in any format without written consent of EB Medicine.
www.ebmedicine.net • Volume 4, Number 3
9
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support the use of lipid resuscitation therapy. The
very nature of clinical toxicology, however, often
precludes the conduction of such studies. Therefore, many therapies are transitioned into widespread use based on a preponderance of available
evidence, which, in the case of lipid resuscitation
therapy, has shown promise in recent years. No
definitive optimal dose or dosing schedule has
been proven, as yet. A currently published position
statement from the American College of Medical
Toxicology is shown in Table 3.
even in seemingly stable patients. Such declines may
be dependent on time of exposure, immediate versus
sustained-release product ingested, comorbidities,
time of presentation, and other variables.
Special Circumstances
Mixed or multidrug overdoses are common and
present special challenges. Many drugs (such as cyclic antidepressants) have complicating cardiovascular and vasoactive effects, and all warrant supportive care. Opportunities for specific antidote therapy
for agents involved should be sought. Lipid rescue
should be considered in cases of severe poisoning
resulting in hypotension and/or impending arrest,
even if other modalities are in place.
Molecular Adsorbent Recirculating System
The molecular adsorbent recirculating system
(MARS) is an albumin-based dialysis system designed to remove both water-soluble and albuminbound toxins from the blood. Initially developed to
treat liver failure by removal of bile acids, amino acids, fatty acids, and ammonia from the bloodstream,
MARS has also been shown to remove fentanyl, theophylline, acetaminophen, midazolam, and phenytoin from the blood.51-54 More recently, case reports
detailing the use of MARS to treat patients with diltiazem or verapamil toxicity and refractory cardiogenic shock have been published.55,56 In 1 series, not
only did all 3 patients survive to hospital discharge,
but all were still asymptomatic at 2-year follow-up.56
While initially designed as a “liver dialysis” system,
MARS is approved only for use in the treatment of
drug overdose and poisonings in the United States
and, currently, has limited availability.
Controversies And Cutting Edge
Lipid Resuscitation Therapy
For the treatment of the poisoned patient, lipid
resuscitation therapy involves the intravenous
injection of a lipid solution.31 Intralipid®, a solution
of soybean oil that also contains egg lecithin and
glycerol, is manufactured by Fresenius Kabi (Uppsala, Sweden). Although several concentrations are
available, most published animal studies and human
case reports concerning lipid resuscitation therapy
deal with Intralipid® 20%; thus, it is the American
College of Toxicology’s recommended agent for
lipid resuscitation therapy.32 Lipid rescue may be
attempted when significant hemodynamic instability
unresponsive to traditional therapy is present or if
cardiac arrest is impending or has occurred. Intractable lipid-soluble drug-induced seizures (such as
those caused by propranolol or tricyclic antidepressants) may also respond to this therapy.
Originally studied as an antidote to local anesthetic toxicity,33 reports of lipid resuscitation
therapy’s efficacy in dire cases of beta blocker and
calcium-channel blocker toxicity have surfaced in
recent years.34-40 Similarly, reports of success in
cases of tricyclic antidepressant, anticonvulsant,
and antipsychotic drug overdose have also been
published.41-46 Several hypotheses exist regarding
the lipid resuscitation therapy mechanism of action,
with the initially accepted theory being the “lipid
sink” theory. This theory holds that the injected lipid
solution creates an additional lipid compartment
into which lipid-soluble toxins will diffuse, thereby
making them less available to target organs.47-49 Two
different possible mechanisms mentioned in the literature include a direct positive inotropic effect from
Intralipid® and augmentation of mitochondrial fatty
acid oxidation by Intralipid.®47,50 To date, the mechanism whereby lipid resuscitation therapy exerts its
beneficial effects has not been definitively proven.
No randomized controlled studies exist to
Copyright © 2014 EB Medicine. All rights reserved.
Methylene Blue
Methylene blue has been used to support cardiovascular collapse after cardiac surgery and has been
studied in that context and for septic, anaphylactic,
and toxin-induced shock states.57 Successful use of
methylene blue to support blood pressure in a case of
combined calcium-channel blocker and beta blocker
poisoning resulting in refractory vasodilatory hypotension has recently been reported.58 The use of meth-
Table 3. American College Of Medical
Toxicology Position Statement On Lipid
Resuscitation Therapy32
1.
2.
3.
4.
5.
10
If the treating clinician deems use of lipid resuscitation therapy
appropriate, a 1.5 mL/kg bolus of 20% lipid emulsion (Intralipid®)
should be used.
The bolus should be followed by an infusion at 0.25 mL/kg/min.
The bolus dose may be repeated for patients in pulseless electrical activity or asystole who do not respond to the initial bolus.
If an initial response to the bolus is observed and the patient
redevelops hemodynamic instability, the physician may increase
the infusion rate or repeat the bolus dose.
When possible, treatment with lipid resuscitation therapy should
last no more than 1 h, but the duration may be extended if the
patient’s stability is dependent on such therapy.
www.ebmedicine.net • Volume 4, Number 3
ylene blue in this case followed the unsuccessful use
of calcium, glucagon, euglycemic insulin therapy, and
3 vasopressors. The patient suffered 2 cardiac arrests,
and a transvenous pacer was placed. Despite these
measures, the patient remained severely hypotensive.
Initiation of a methylene blue infusion was reported
to have resulted in a dramatic improvement in blood
pressure.58 The methylene blue dose reported was a
1 mg/kg bolus over 10 minutes, followed by an infusion at 1 mg/kg/h that was continued for 10 hours.
Improvement in blood pressure was noted 20 minutes
after the bolus. The mechanism of action of methylene
blue in this context is thought to result from interference with the action of endothelial nitric oxide.
Calcium-channel blockers (such as amlodipine) block
transmembrane influx of Ca2+ into vascular smooth
muscle and increase endothelial nitric oxide levels.
Nitric oxide binds with guanylate cyclase to form nitric oxide-activated guanylate cyclase (NO-GC). NOGC increases conversion of guanosine triphosphate to
cyclic guanosine monophosphate (cGMP), leading to
smooth-muscle relaxation in the arterioles. Methylene
blue inhibits guanylate cyclase, and, in turn, decreases cGMP and vascular smooth-muscle relaxation. In
addition, methylene blue scavenges nitric oxide and
inhibits nitric oxide synthesis. In sum, methylene blue
counteracts the effect that calcium-channel blockers
(such as amlodipine) have on smooth muscle.58
Observation Periods For Beta Blocker Ingestion
In general, beta blocker toxicity from ingestion of
immediate-release agents begins within 6 to 8 hours
after ingestion (with the exception of sotalol). Therefore, patients who have ingested an immediate-release beta blocker (except sotalol) may be medically
discharged after 6 to 8 hours of observation if they
remain asymptomatic. Patients who have ingested
sotalol are at risk for delayed onset of ventricular
arrhythmias and must be monitored for a minimum
of 12 hours (preferably longer). After this time, they
may be released from a monitored setting if they
remain stable and without QTc prolongation or
other symptoms.59 Patients who intentionally ingest
extended-release formulations of a beta blocker must
be admitted to a closely monitored environment
(step-down or critical care) with immediate access
to a critical care unit capable of advanced airway
management for 24 hours due to the potential for
delayed onset of life-threatening symptoms.59 For
patients with unintentional ingestion of a sustainedrelease beta blocker who have no symptoms, routine
24-hour admission is not recommended.59 The same
literature suggests that an 8-hour period of observation may be sufficient in this instance, with the
caveats that the patient: (1) should have no predisposing factors for orthostasis, (2) has ingested only a
therapeutic/near-therapeutic dose, and (3) is asymptomatic throughout the course of observation.59
Disposition
Observation Periods For Calcium-Channel Blocker
Ingestion
Following presumed calcium-channel blocker
ingestion, patients who remain asymptomatic for
8 hours following ingestion of immediate-release
products, 12 to 24 hours following ingestion of
modified- (sustained) release nonphenylalkylamine
(nonverapamil) products, and 24 hours following
ingestion of modified- (sustained) release verapamil are generally regarded as unlikely to develop
All symptomatic beta blocker and calcium-channel
blocker overdose patients should be admitted to a
high level of care (intensive care unit, critical care
unit, or step-down unit, as appropriate), with continuous cardiac monitoring. Timely gastric decontamination with activated charcoal (and possibly wholebowel irrigation with polyethylene glycol electrolyte
lavage in the case of extended-release formulations)
should be considered and discussed with a toxicologist. Patients who have intentionally ingested
overdoses of these potentially lethal agents with
suicidal ideation or intent must be continuously attended (eg, by a “sitter”) to prevent further attempts
at self-harm, and then they should be evaluated by
psychiatry when clinically cleared. Patients who
remain asymptomatic may, on occasion, be cleared
for psychiatric evaluation or they may be discharged
with the caveat that patients who ingest sustainedrelease products must be admitted for observation
because of a potential delayed effect of the medication. Co-ingestions of agents that may delay absorption of beta blockers and calcium-channel blockers
(such as opioids and anticholinergics) and patients
with significant gastrointestinal disease or postsurgical changes may also warrant prolonged observation
after ingestion and may be exceptions to the general
disposition guidelines that follow.
www.ebmedicine.net • Volume 4, Number 3
Time- And Cost-Effective
Strategies
Given the complexity and potential severity of beta
blocker and calcium-channel blocker ingestions,
there are no broadly applicable cost-effective pathways aside from sequential and timely institution
of the interventions described in this review. Fortunately, this intensity of care is relatively infrequently
needed. The most effective plan in managing overdoses is to get ahead of potential decline in clinical
status early on, with glucose and insulin, to minimize complications and the need for other therapies. As noted earlier, aggressive care in the face of
cardiovascular collapse can yield good outcomes in
this population.
11
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dose insulin therapy, and, in certain cases, gastric
decontamination. Vasoactive agents may become
necessary in the setting of hemodynamic instability, and this may progress to requiring invasive
efforts such as hemoperfusion, molecular adsorbent
therapies, intra-aortic balloon counterpulsation, or
cardiopulmonary bypass. Methylene blue has been
reported to reverse refractory shock.
The standard emergency medicine modalities of
protecting the airway and addressing other comorbidities that may confound the situation are key.
The cardioactive overdose patient will require monitoring, and emergency physicians should err in favor
of admission and observation to a high level of care
(such as an intensive care unit) because of the potentially dire consequences of these overdoses. The key
to excellent patient outcome is early recognition of
potentially severe toxicity and focused treatment, taking into consideration the agent(s) ingested.
significant symptoms. All other patients should be
admitted to a high level of care for close observation
and treatment. Toxicology and poison control center
consultants may help individualize disposition and
treatment options on a case-by-case basis.
Summary
Beta blocking and calcium-channel blocking agents
are common in overdose situations, and efficient action can mean the difference in outcome for patients.
Table 4 summarizes the treatment modalities available for beta blocker and calcium-channel blocker
poisoning. In general, early use of more-aggressive
therapeutic options (eg, glucagon, high-dose insulin/euglycemic therapy, lipid resuscitation therapy)
improves outcome. It is advisable to consult with a
poison control center to assist in optimizing early
and supportive care.
It is important to be aware of the class of the
beta blocker or calcium-channel blocker involved.
Beta blockers are either lipid soluble or water
soluble. Lipid-soluble agents are more dangerous
in that they are well absorbed by the gut and have
significant central nervous system distribution.
Water-soluble agents are not as completely absorbed
through the gut, are not as well distributed in the
central nervous system, and are eliminated by the
renal system unchanged.
Calcium channel blockers fall into 2 broad categories: dihydropyridines or nondihydropyridines.
Dihydropyridines have a less significant myocardial
depressant action, and may even increase cardiac
output due to reflex tachycardia. Nondihydropyridines will cause decreased myocardial contractility
and conduction. However, either one of these classes
can cause hypotension, bradycardia, and death in an
overdose situation.
Common treatment options for the emergency
physician include glucagon, insulin therapy, high-
Case Conclusion
It was ultimately determined that the 21-year-old patient
who took her father-in-law’s blood pressure pills had
ingested a large dose of sustained-release metoprolol, a
long-acting beta blocking agent. In addition to intubation,
she required vasoactive agents to support hemodynamic
stability and CNS perfusion. You followed this with highdose insulin therapy, as vasopressors alone began to be incapable of maintaining adequate perfusion. This resulted
in a period of stability, followed by recurrent hypotension.
You initiated lipid emulsion therapy, which was successful, though the patient required vasoactive agents and
intensive critical care for 48 hours. The efficient action
of the emergency medicine team, along with consultation
by the regional poison center, identification of the cardiovascular poison toxidrome, toxicologic consultation, and
anticipatory support of hemodynamics helped to stabilize
this patient and avoid cardiac collapse.
Must-Do Markers Of Quality ED Critical Care
Table 4. Types Of Interventions For Beta
Blocker And Calcium-Channel Blocker
Toxicity
Basic Supportive
Care
Toxin-Specific
Interventions
Mechanical Assistance
• Cardiac monitoring
• Intravenous fluids
• Correction of
electrolytes
• Atropine
• Vasopressors
• Endotracheal
intubation
• Calcium (for
calcium-channel
blocker)
• Glucagon bolus
and infusion
• High-dose insulin
and glucose
• Lipid rescue
therapy
• Molecular adsorbent recirculating
system
• Cardiac pacing
• Intra-aortic balloon counterpulsation
• Cardiopulmonary
bypass
Copyright © 2014 EB Medicine. All rights reserved.
• Recognition of the toxidrome of depressive
cardiotoxicity.
• Timely initiation of monitoring and cautious
fluid resuscitation, as discussed in the “Supportive Care” section (see page 5).
• Correct patient selection for glucagon therapy,
and, if warranted, correct dosing of glucagon
and timely initiation of continuous glucagon
infusion.
• Early institution of high-dose insulin euglycemic
therapy for patients with hypotension unresponsive to other measures.
• Identification of refractory cases that may benefit from lipid resuscitation therapy (or MARS,
where available).
12
www.ebmedicine.net • Volume 4, Number 3
channel blocker overdose. Ann Emerg Med. 1993;22(7):12291233. (Case report; 1 patient)
15. Walter FG, Frye G, Mullen JT, et al. Amelioration of nifedipine poisoning associated with glucagon therapy. Ann Emerg
Med. 1993;22(7):1234-1237. (Case report; 1 patient)
16. Levey GS, Fletcher MA, Klein I, et al. Characterisation of
l25l-glucagon binding in a solubilized preparation of cat
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17. Parmley WW, Glick G, Sonnenblick EH. Cardiovascular
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18. Parmley W. The role of glucagon in cardiac therapy. N Engl J
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19. Sato S, Tsuhi M, Okubo N, et al. Combined use of glucagon
and milrinone may not be preferable for severe propranolol
poisoning in the canine model. Clin Toxicol. 1995;33(4):337342. (Animal study)
20. Love J, Leasure J, Mundt DJ. A comparison of combined amrinone and glucagon therapy to glucagon alone for cardiovascular depression associated with propranolol toxicity in a
canine model. Am J Emerg Med. 1993;11(4):360-363. (Animal
study)
21. Chernow B, Zaloga G, Malcolm D, et al. Glucagon’s chronotropic action is calcium dependent. J Pharm Exp Ther.
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23. Illingworth RN. Glucagon for beta blocker poisoning. Practitioner. 1979;223(1337):683-685. (Case report)
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29. Levine M, Boyer EW, Pozner CN, et al. Assessment of hyperglycemia after calcium channel blocker overdoses involving
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30. Kerns W 2nd. Management of beta-adrenergic blocker and
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31. Weinberg G. Lipid rescue resuscitation. Available at http://
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32.* American College of Medical Toxicology. Position statement:
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References
Evidence-based medicine requires a critical appraisal of the literature based upon study methodology and number of subjects. Not all references are
equally robust. The findings of a large, prospective,
randomized, and blinded trial should carry more
weight than a case report.
To help the reader judge the strength of each
reference, pertinent information about the study,
such as the type of study and the number of patients
in the study, will be included in bold type following
the reference, where available. In addition, the most
informative references cited in this paper, as determined by the authors, will be noted by an asterisk (*)
next to the number of the reference.
1.
Mowry JB, Spyker DA, Cantilena LR Jr, et al. 2012 Annual report of the American Association of Poison Control
Centers’ National Poison Data System (NPDS): 30th annual
report. Clin Toxicol. 2013;51(10):949-1229. (Aggregate data)
2. Manini A, Nelson L, Olsen D, et al. Medical examiner and
medical toxicologist agreement on cause of death. Forensic
Sci Int. 2011;206(1-3):71-76. (Retrospective review; 321 patients)
3. Love JN, Litovitz TL, Howell JM, et al. Characterization of
fatal beta blocker ingestion: a review of the American Association of Poison Control Centers data from 1985-1995. Clin
Toxicol. 1997;35(4):353-359. (Review article)
4. Hockermon GH, Peterson BZ, Johnson BD, et al. Molecular
determinants of drug binding and action on L-type calcium
channels. Ann Rev Pharmacol Toxicol. 1997;37:361-369. (Basic
science)
5. Katz A. Contractile proteins of the heart. Phisiol Rev.
1970;50(1):63-158. (Basic science)
6. Goldfrank LR, Flomenbaum NE, Lewin NA, et al. Goldfrank’s
Toxicologic Emergencies, 7th ed. New York, NY: McGraw-Hill
Professional; 2002:765. (Textbook)
7. Schoffstall J, Spivey W, Gambone LM, et al. Effects of calcium channel blocker overdose-induced toxicity in the conscious dog. Ann Emerg Med. 1991;20(10):1104-1108. (Animal
study)
8. Ramoska EA, Spiller HA, Myers A. Calcium channel blocker
toxicity. Ann Emerg Med. 1990;19(6):649-653. (Case series; 91
patients)
9. Guzman F. Pharmacology Corner. Calcium channel blockers:
classification, mechanism of action and indications. Available at http://pharmacologycorner.com/calcium-channelblockers-classification-mechanism-of-action-indications/.
Accessed January 29, 2014. (Website)
10. Nakae Y, Kanaya N, Namiki A, et al. The direct effects of
diazepam and midazolam on myocardial depression in cultured rat ventricular myocytes. Anesth Analg. 1997;85(4):729733. (Animal study)
11.* Peterson CD, Leeder JS, Sterner S. Glucagon therapy for beta
blocker overdose. Drug Intell Clin Pharm. 1984;18(5):394-398.
(Case report; 2 patients)
12. Yagami T. Differential coupling of glucagon and beta-adrenergic receptors with the small and large forms of the stimulatory G protein. Mol Pharmacol. 1995;48(5):849-854. (Animal
study)
13. Glick G, Parmley WW, Wechsler AS, et al. Glucagon: its
enhancement of cardiac performance in the cat and dog and
persistence of its inotropic action despite beta receptor blockade with propanolol. Circ Res. 1968;22(6):789-799. (Animal
study)
14. Doyon S, Roberts J. The use of glucagon in a case of calcium
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Reprints: www.ebmedicine.net/emccissues
2006;13(2):134-139. (Animal study)
36. Liang CW, Diamond SJ, Hagg DS. Lipid rescue of massive
verapamil overdose: a case report. J Med Case Rep. 2011;5:399.
(Case report; 1 patient)
37. Jovic-Stosic J, Gligic B, Putic V. Severe propranolol and
ethanol overdose with wide complex tachycardia treated
with intravenous lipid emulsion: a case report. Clin Toxicol.
2011;49(5):426-430. (Case report; 1 patient)
38. Montiel V, Gougnard T, Hanson P. Diltiazem poisoning
treated with hyperinsulinemic euglycemia therapy and
intravenous lipid emulsion. Eur J Emerg Med. 2011;18(2):121123. (Case report; 1 patient)
39. Young A, Velez L, Kleinschmidt KC. Intravenous fat emulsion therapy for intentional sustained-release verapamil
overdose. Resuscitation. 2009;80(5):591-593. (Case report; 1
patient)
40. Stellpflug S, Harris C, Engebretsen KM, et al. Intentional
overdose with cardiac arrest treated with intravenous fat
emulsion and high-dose insulin. Clin Toxicol. 2010;48(3):227229. (Case report; 1 patient)
41. Engels P, Davidow J. Intravenous fat emulsion to reverse
haemodynamic instability from intentional amitriptyline
overdose. Resuscitation. 2010;81(8):1037-1039. (Case report; 1
patient)
42. Levine M, Brooks DE, Franken A, et al. Delayed-onset
seizure and cardiac arrest after amitriptyline overdose,
treated with intravenous lipid emulsion therapy. Pediatrics.
2012;130(2):e432-e438. (Case report; 1 patient)
43. Sirianni AJ, Osterhoudt KC, Calello DP, et al. Use of lipid
emulsion in the resuscitation of a patient with prolonged
cardiovascular collapse after overdose of buproprion and lamotrigine. Ann Emerg Med. 2008;51(4):412-415. (Case report;
1 patient)
44. Kiberd M, Minor S. Lipid therapy for the treatment of a
refractory amitriptyline overdose. CJEM. 2012;14(3):194-197.
(Case report; 1 patient)
45. Castanares-Zapatero D, Wittebole X, Huberlant V, et al.
Lipid emulsion as rescue therapy in lamotrigine overdose. J
Emerg Med. 2012;42(1):48-51. (Case report; 1 patient)
46. Hendron D, Menagh G, Snadilands EA, et al. Tricyclic antidepressant overdose in a toddler treated with intravenous
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report; 1 patient)
47. Weinberg G. Lipid infusion therapy: translation to clinical
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48. Litz RJ, Roessel T, Heller AR, et al. Reversal of central
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intoxication by lipid emulsion injection. Anesth Analges.
2008;106(5):1575-1577. (Case report; 1 patient)
49.* Weinberg GL, VadeBoncouer T, Ramaruju GA, et al.
Pretreatment or resuscitation with a lipid infusion shifts
the dose-response to bupivicaine-induced asystole in rats.
Anesthesiology. 1998;88(4):1071-1075. (Animal study)
50. Stehr SN, Ziegeler JC, Pexa A, et al. The effects of lipid infusion on myocardial function and bioenergentics in l-bupivicaine toxicity in the isolated rat heart. Anesthes & Analges.
2007;104(1):186-192. (Animal study)
51. Sen S, Ytrebo LM, Rose C, et al. Albumin dialysis: a new
therapeutic strategy for intoxication from protein-bound
drugs. Int Care Med. 2004;30(3):496-501. (Animal study)
52. Korsheed S, Selby NM, Fluck RJ. Treatment of severe theophylline poisoning the the molecular adsorbent recirculating system (MARS). Nephrol Dial Transplant. 2007;22(3):968970. (Case report; 1 patient)
53. Wittebole X, Hantson P. Use of the molecular adsorbent
recirculating system (MARS) for the management of acute
poisoning with or without liver failure. Clin Toxicol (Phila).
2011;49(9):782-793. (Review article)
54. Sen S, Ratnaraj N, Davies NA, et al. Treatment of phenytoin
toxicity by the molecular adsorbent recirculating system
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(MARS). Epilepsia. 2003;44(2):265-267. (Case report; 1 patient)
55. de Pont AC. Extracorporeal treatment of intoxications. Curr
Opin Crit Care. 2007;13(6):668-673. (Review article)
56. Pichon N, Dugard P, Clavel M, et al. Extracorporeal albumin
dialysis in three cases of acute calcium channel blocker
poisoning with life-threatening refractory cardiogenic shock.
Ann Emerg Med. 2012;59(6):540-544. (Case series; 3 patients)
57. Lo JC, Darracq MA, Clark RF. A Review of methylene blue
treatment for cardiovascular collapse. J Emerg Med. 2014 Feb
6. [Epub ahead of print] (Review article)
58. Aggarwal N, Kupfer Y, Seneviratne C, et al. Methylene blue
reverses recalcitrant shock in beta-blocker and calcium channel blocker overdose. BMJ Case Rep 2013. 2013 Jan 18. (Case
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59.* Wax PM, Erdman A, Chyka PA, et al. Beta blocker ingestion:
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consensus)
CME Questions
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1. Which of the following beta-adrenergic antagonists is MOST likely to cause central nervous
system effects in moderate overdose?
a. Acebutolol
b. Atenolol
c. Pindolol
d. Propranolol
2. Which of the following calcium-channel antagonists is associated with the greatest likelihood of mortality in significant overdose?
a. Amlodipine
b. Nicardipine
c. Nifedipine
d. Verapamil
14
www.ebmedicine.net • Volume 4, Number 3
3. Excessive fluid resuscitation is not advised for
patients with beta blocker or calcium channel
blocker poisoning. Which of the following is
the reason for this recommendation?
a. The electrolyte concentrations in most crystalloid solutions cause untoward interactions with antidotal therapies, such as glucagon and insulin.
b. Excessive administration of normal saline (0.9%) can cause a non-anion-gap metabolic acidosis, which may inhibit myocardial function.
c. Most patients who present with beta blocker or calcium channel blocker poisonings are already hypervolemic.
d. Patients who have been poisoned with
these agents have depressed myocardial function and, therefore, have a lower tolerance for excessive preload (fluids).
7. Assuming adequate fluid resuscitation, supportive care, and glucagon administration for
progressive signs of hypotension, the most
promising life-saving antidotal therapy for
patients with severe beta-adrenergic antagonist
poisoning is likely to be:
a. Amrinone infusion
b. Atropine bolus
c. Euglycemic insulin therapy
d. Octreotide injection
8. What is the recommended bolus dose of
insulin when initiating euglycemic high-dose
insulin therapy?
a. 0.1 units/kg
b. 0.5 units/kg
c. 1 unit/kg
d. 2 units/kg
9. Successful patient salvage in cases of severe
calcium-channel blocker and beta blocker poisoning has been reported with the use of lipid
emulsion. Theories about potential mechanisms for this beneficial effect include all of
the following EXCEPT:
a. Direct effect on cAMP-mediated inotropic mechanisms
b. “Lipid sink” effect (in which lipid-soluble drug partitions into the expanded lipid compartment, leaving poisoned compartments)
c. Increased volume of distribution for the lipid soluble drug
d. Augmentation of mitochondrial fatty acid oxidation by the administered lipid
4.
Which of the following is the MOST
acceptable agent to induce anesthesia during
rapid sequence intubation of a patient with
severe beta blocker or calcium-channel blocker
poisoning?
a. Propofol
b. Ketamine
c. Thiopental
d. Midazolam
5. Which of the following is the mechanism by
which glucagon exerts its effects on myocardial
tissue that has been poisoned by beta blockers
or calcium channel blockers?
a. It increases cAMP concentrations within
cardiac myocytes, thereby increasing
inotropy and chronotropy.
b. It binds to myocardial beta-adrenergic
receptors, thereby preventing beta-blocking
agents from binding to these receptors.
c. It decreases expression of beta-adrenergic
receptors on the myocardial surface.
d. It inhibits the activation of L-type calcium
channels.
10. For cases in which lipid resuscitation therapy
is used, what is the recommended initial bolus
dose of 20% lipid emulsion, according to the
American College of Medical Toxicology?
a. 0.5 mL/kg body weight
b. 1 mL/kg body weight
c. 1.5 mL/kg body weight
d. 2 mL/kg body weight
6.
Which of the following would prolong the
absorption of beta blocking or calcium-channel
blocking agents?
a. Alcohol ingestion b. Concomitant opioid ingestion
c. Seizures
d. Diabetes
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Antidotes For The Poisoned Patient
Managing Status Epilepticus
Ventilator Troubleshooting
Alcohol Withdrawal in the Emergency
Department
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