Chapter 194: Beta-Blockers - WordPress.com...polypharmacy "heart or blood pressure medication"...

21
8/7/2018 1/21 Tintinalli’s Emergency Medicine: A Comprehensive Study Guide, 8e > Chapter 194: Beta-Blockers Jennifer L. Englund; William P. Kerns, II INTRODUCTION β-Adrenergic receptor antagonists (β-blockers) are medications used in the treatment of various cardiovascular, neurologic, endocrine, ophthalmologic, and psychiatric disorders. Among all the exposures to cardiovascular agents, β-blocker exposures were the leading cause of poison center calls and ranked among the top three in this class as a cause of severe toxicity and mortality. 1 PHARMACOLOGY The β-adrenergic receptors are membrane glycoproteins present as three subtypes in various tissues (Table 194-1). These receptors play a critical role in cardiovascular physiology by modulating cardiac activity and vascular tone.

Transcript of Chapter 194: Beta-Blockers - WordPress.com...polypharmacy "heart or blood pressure medication"...

Page 1: Chapter 194: Beta-Blockers - WordPress.com...polypharmacy "heart or blood pressure medication" overdose or with suspected chronic drug toxicity in the patient on multiple cardiovascular

8/7/2018

1/21

Tintinalli’s Emergency Medicine: A Comprehensive Study Guide, 8e >

Chapter 194: Beta-BlockersJennifer L. Englund; William P. Kerns, II

INTRODUCTION

β-Adrenergic receptor antagonists (β-blockers) are medications used in the treatment of variouscardiovascular, neurologic, endocrine, ophthalmologic, and psychiatric disorders. Among all the exposuresto cardiovascular agents, β-blocker exposures were the leading cause of poison center calls and ranked

among the top three in this class as a cause of severe toxicity and mortality.1

PHARMACOLOGY

The β-adrenergic receptors are membrane glycoproteins present as three subtypes in various tissues (Table194-1). These receptors play a critical role in cardiovascular physiology by modulating cardiac activity andvascular tone.

Page 2: Chapter 194: Beta-Blockers - WordPress.com...polypharmacy "heart or blood pressure medication" overdose or with suspected chronic drug toxicity in the patient on multiple cardiovascular

8/7/2018

2/21

TABLE 194-1

Location and Activity of β-Adrenergic Receptors

β-Receptor

TypeLocation Agonism Antagonism

β1 Myocardium

Kidney

Eye

Increases inotropy

Increases chronotropy

Stimulates renin release

Stimulates aqueous humor

production

Decreases inotropy

Decreases chronotropy

Inhibits renin release

Inhibits aqueous humor

production

β2 Bronchial smooth

muscle

Visceral smooth

muscle

Skeletal muscle

Liver

Vascular

Causes bronchodilation

Relaxes uterus

Causes ileus

Increases force of contraction

Stimulates glycogenolysis

Stimulates glycogenolysis and

gluconeogenesis

Vasodilation

Causes bronchospasm

Inhibits glycogenolysis and

gluconeogenesis

Minimal vasoconstriction

β3 Adipose tissue

Skeletal muscle

Stimulates lipolysis

Stimulates thermogenesis

Inhibits lipolysis

Inhibits thermogenesis

During times of stress (i.e., catecholamine release), β-adrenergic receptor stimulation increases myocardial

and vascular smooth muscle cell activity through a sequence of intracellular events (Figure 194-1).2,3

FIGURE 194-1.

Cardiac myocyte β1-receptor and calcium signaling. Following myocyte depolarization, extracellular calcium

(Ca2+) enters the cell via the L-type or voltage-gated calcium channel (L-VDCC) and binds to the ryanodine

receptor (RyR) in the sarcoplasmic reticulum, causing an e�lux of sequestered Ca2+ out of the sarcoplasmic

reticulum into the cytosol. Free Ca2+ binds to troponin that allows the myosin and actin interaction, resultingin contraction of the cardiac myocyte. Binding of a β-agonist to the β1-adrenergic receptor (B1) on the cell

surface activates the Gs protein. The Gs protein then activates adenylate cyclase (AC), which convertsadenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP). The increased cAMP activatesprotein kinase A (PKA). Activated PKA serves as further stimulus for the L-VDCC opening. Glucagonindependently activates adenylate cyclase. cAMP is metabolized by phosphodiesterase (PDE) into inactiveadenosine 5'-monophosphate (5'AMP).

Page 3: Chapter 194: Beta-Blockers - WordPress.com...polypharmacy "heart or blood pressure medication" overdose or with suspected chronic drug toxicity in the patient on multiple cardiovascular

8/7/2018

3/21

The β-receptor is coupled to a stimulatory Gs protein. This Gs protein stimulates adenylate cyclase, which in

turn catalyzes the formation of cyclic adenosine monophosphate, the so-called intracellular secondmessenger. Increased cyclic adenosine monophosphate ultimately phosphorylates the L-type calciumchannel, which leads to channel opening and calcium entry into the cell. Extracellular calcium is thencoupled to the ryanodine receptor to carry the calcium current to the sarcoplasmic reticulum, which thenreleases its stored calcium. This process is termed calcium-induced calcium release. Stored calcium becomesavailable to participate in mechanical contraction via the actin and myosin complex. Like the cardiacmyocyte, the vascular smooth muscle uses L-type calcium channels to regulate intracellular calcium andsubsequently coordinate vascular tone. To prevent overdrive of the cell, phosphodiesterase breaks downcyclic adenosine monophosphate to adenosine 5'-monophosphate, thus removing the stimulus for calciumchannel opening, and the contractile process ceases.

The β-blockers modulate the activity of myocyte and vascular smooth muscle contraction by decreasing

calcium entry into the cell.2,3 Therapeutically, β-blockade lessens the work performed by the diseased or

Page 4: Chapter 194: Beta-Blockers - WordPress.com...polypharmacy "heart or blood pressure medication" overdose or with suspected chronic drug toxicity in the patient on multiple cardiovascular

8/7/2018

4/21

injured myocardium and lowers elevated blood pressure. On the other hand, excessive β-blockade may lead

to profound pump failure, with bradycardia, decreased contractility, and hypotension.2

The pharmacologic properties of various β-blockers influence their spectrum of action, adverse drug

reactions, and toxicity (Table 194-2).4,5 These properties include receptor selectivity, sodium channelblockade (also known as membrane-stabilizing activity), lipid solubility, protein binding, and partial agonistactivity (also known as intrinsic sympathomimetic activity). For example, highly lipid-soluble agents, such as

propranolol, readily cross the blood–brain barrier and achieve high concentrations in brain tissue.2,3 Thismay contribute to the more severe CNS manifestations of mental status depression, seizures, and coma seen

a�er an overdose of such agents.2,3 Several β-blockers inhibit myocardial sodium channels, similar toquinidine and cyclic antidepressants, rendering these drugs potentially more cardiodepressant following

overdose.3 However, in massive overdoses, all β-blockers can be severely cardiodepressive.6

Page 5: Chapter 194: Beta-Blockers - WordPress.com...polypharmacy "heart or blood pressure medication" overdose or with suspected chronic drug toxicity in the patient on multiple cardiovascular

8/7/2018

5/21

Abbreviations: + = some activity; ++ = strong activity; ± = possible activity; 0 = no activity.

TABLE 194-2

β-Blocker Pharmacologic Profiles

Agentβ1

SelectivityLipophilicity

Partial

Agonism

Protein

Binding (%)

Sodium Channel

Blockade

Half-

Life (h)

Acebutolol + Moderate + 25 + 3–4

Atenolol + Weak 0 6–16 0 6–9

Betaxolol + High 0 55 ± 14–22

Bisoprolol ++ Moderate 0 30–40 0 9–12

Carvedilol 0 Moderate 0 >95 ± 7–10

Esmolol + Weak 0 55 ± 9 min

Labetalol + Weak 0 50 ± 3–4

Metoprolol ++ Moderate 0 12 ± 3–4

Nadolol 0 Weak 0 30 0 12–24

Nebivolol +++ Moderate 0 98 0 8–27

Oxprenolol 0 Moderate ++ 80 + 1–2

Pindolol 0 High ++ 40–60 ± 3–4

Penbutolol 0 High + 80–98 0 5–20

Propranolol 0 High 0 >90 ++ 3–4

Sotalol 0 Weak 0 Minimal 0 12

Timolol 0 High ± 10–60 0 4–5

Page 6: Chapter 194: Beta-Blockers - WordPress.com...polypharmacy "heart or blood pressure medication" overdose or with suspected chronic drug toxicity in the patient on multiple cardiovascular

8/7/2018

6/21

Although β1 cardioselective medications have less risk of unwanted β2 e�ects, such as bronchospasm,

selectivity is o�en lost following large overdoses.3 Several β-blockers like pindolol have partial agonistactivity, causing weak stimulation of the β-receptor, with a lessor tendency for bradycardia during

therapeutic use.4 Some β-blockers, such as labetalol and carvedilol, are also antagonists at α1-adrenergic

receptors, which can result in exaggerated hypotension during therapeutic use. Sotalol is unique among β-blockers in its ability to block potassium channels important for repolarization, as do other class III

antiarrhythmic drugs.2,3,4

In addition to having cardiopulmonary e�ects, β-blockers also alter metabolism in the liver, skeletal muscle,and adipose tissue. Under normal conditions, the heart uses free fatty acids as its primary energy source, butduring times of stress, it switches to using carbohydrates to maintain metabolism. Inhibition ofglycogenolysis and gluconeogenesis reduces the availability of carbohydrates for use by metabolically active

cells. Although hypoglycemia can occur as a consequence of β-blocker toxicity, it is actually uncommon.2 Inthe presence of adequate glucose stores, euglycemia and hyperglycemia are more common thanhypoglycemia.

Clinically relevant pharmacokinetic characteristics include drug formulation (regular or extended release),rate of drug absorption, protein binding, lipid solubility, elimination mostly by hepatic metabolism, andvolume of distribution. These properties determine onset of symptoms, duration of symptoms, target organtoxicity, and potential treatment modalities.

CLINICAL FEATURES

Toxicity due to β-blockers can produce a spectrum of clinical symptoms (Table 194-3).2,3,7 The timing ofsymptom appearance depends upon the formulation. Absorption of regular-release β-blockers occursrapidly, o�en with peak e�ects within 1 to 4 hours. However, delays of up to 6 hours following acute ingestion

have occurred.8 Experience is limited regarding onset of symptoms with poisoning following an ingestion ofsustained-release β-blocker formulations, but based on other sustained-release cardiac drugs, it is assumed

that symptoms may be delayed >6 hours a�er ingestion.2,3 Co-ingestants that alter gut function, such as

opioids and anticholinergics, may a�ect absorption of β-blockers and subsequent onset of symptoms.2

Page 7: Chapter 194: Beta-Blockers - WordPress.com...polypharmacy "heart or blood pressure medication" overdose or with suspected chronic drug toxicity in the patient on multiple cardiovascular

8/7/2018

7/21

TABLE 194-3

Common Findings with β-Blocker Toxicity

Cardiovascular

Hypotension

Bradycardia

Conduction delays and blocks (first-degree atrioventricular block)

Ventricular dysrhythmias (sotalol)

Asystole

Decreased contractility

CNS

Depressed mental status

Coma

Psychosis

Seizures

Respiratory arrest

Pulmonary

Bronchospasm

Electrolytes

Hypoglycemia

Hyperkalemia

The primary organ system a�ected by β-blocker toxicity is the cardiovascular system, and the hallmark of

severe toxicity is bradycardia and shock.2,3,7,9 Bradycardia due to sinus node suppression or conductionabnormalities occurs in virtually all significant β-blocker intoxications, although ingestion of β-blockers with

partial agonist activity may initially present with hypertension and tachycardia.9 The β-blockers with sodiumchannel antagonism can worsen conduction abnormalities, causing a wide-complex bradycardia (especially

when the QRS interval is >100 milliseconds).9

The cardiotoxic profile of sotalol is di�erent from that of other β-blockers due to its ability to block potassium

channels and prolong the QT interval.3 Thus, sotalol is more o�en associated with ventricular dysrhythmias,including premature ventricular contractions, bigeminy, ventricular tachycardia, ventricular fibrillation, and

torsades de pointes.3

β-Blockers also a�ect the CNS and pulmonary system. Neurologic manifestations include depressed mental

status, coma, and seizures.2 These symptoms most likely occur as a result of a combination of hypoxia due to

Page 8: Chapter 194: Beta-Blockers - WordPress.com...polypharmacy "heart or blood pressure medication" overdose or with suspected chronic drug toxicity in the patient on multiple cardiovascular

8/7/2018

8/21

poor perfusion, sodium channel antagonism, and direct neuronal toxicity.2 More lipophilic β-blockers, such

as propranolol, cause greater neurologic toxicity than the less lipophilic agents.9 Seizures are generally brief,

and status epilepticus is rare.2 Nonselective β-blockers may antagonize the β2-receptor in bronchial smooth

muscle causing bronchospasm. Similarly, in large ingestions of cardioselective β-blockers, the β1 selectivity

may be lost.

DIAGNOSIS

The diagnosis of β-blocker toxicity is primarily made on clinical grounds, including patient history, physicalexamination findings, and results of basic diagnostic testing. Patients commonly present with a history ofintentional overdose or therapeutic misadventure. The diagnosis may be more challenging in the case ofpolypharmacy "heart or blood pressure medication" overdose or with suspected chronic drug toxicity in thepatient on multiple cardiovascular drugs. Exposure to other drugs and toxins can present with bradycardiaand hypotension, but useful features can help di�erentiate toxicity from these agents from that due to β-blockers (Table 194-4).

Page 9: Chapter 194: Beta-Blockers - WordPress.com...polypharmacy "heart or blood pressure medication" overdose or with suspected chronic drug toxicity in the patient on multiple cardiovascular

8/7/2018

9/21

TABLE 194-4

Toxicologic Causes of Bradycardia and Hypotension

Cause Di�erentiating Features

Calcium channel blockers Elevated lactate level and

hyperglycemia

Naturally occurring cardiac glycosides (oleander, foxglove, lily of the

valley, rhododendron, and toad-derived bufotoxin)

Ventricular ectopy

May cross-react with digoxin

immunoassay

Class IC antiarrhythmic drugs (propafenone) Wide-complex bradycardia

Clonidine Opioid-like manifestations: coma,

miosis, decreased respirations

Cyanide Profound metabolic acidosis and

elevated lactate level

Digoxin (acute) Hyperkalemia

Elevated level on digoxin

immunoassay

Organophosphates Muscarinic toxidrome

Laboratory testing is recommended to assess renal function, glucose level, oxygenation, and acid-basestatus. Although specific β-blocker drug levels might be of value for later confirmation of an ingestion, theselevels are not helpful initially because they do not correlate with the degree of toxicity and are generally not

available in a timely fashion to a�ect acute management.2,3,7 False-positive amphetamine results can beseen on urine drug screens from labetalol, because one of its metabolites is structurally similar to

amphetamine and methamphetamine.10 Cardiac function is evaluated with a 12-lead ECG, rhythm monitor,

and bedside cardiac US.11 A drug-induced Brugada pattern may be observed in an overdose of propranolol, a

β-blocker that also a�ects cardiac sodium channels.12

TREATMENT

GENERAL MANAGEMENT

Page 10: Chapter 194: Beta-Blockers - WordPress.com...polypharmacy "heart or blood pressure medication" overdose or with suspected chronic drug toxicity in the patient on multiple cardiovascular

8/7/2018

10/21

Evaluate patients with suspected β-blocker overdose in a critical-care area of the ED with appropriatemonitoring because these patients may experience abrupt cardiovascular collapse or neurologic depression.If orotracheal intubation is needed, the drugs used to sedate and paralyze may worsen hypotension in the

face of an already depressed myocardium.2,3,7

GI DECONTAMINATION

Although there is little evidence to support routine GI decontamination following overdose of mostsubstances, ingestion of a significant quantity of β-blockers with the risk of severe toxicity is a circumstance

in which decontamination should be considered.13 Activated charcoal may be of benefit if it can be given

within 1 hour a�er ingestion and the patient is able to maintain the airway.14,15 There may be an additionalwindow of opportunity for activated charcoal therapy following ingestion of sustained-release β-blockers.

Ipecac syrup and cathartic agents are not recommended.16 Gastric lavage is not recommended.13 Whole-

bowel irrigation may be beneficial a�er a large ingestion of an extended-release product.17

PHARMACOLOGIC TREATMENT

Specific pharmacologic therapies are directed at restoring perfusion to critical organ systems by improving

myocardial contractility, increasing heart rate, or both.2,3,7 This is done through fluid resuscitation andadministration of glucagon, adrenergic agonists, high-dose insulin, calcium, and phosphodiesteraseinhibitors (Figure 194-2). Individual pharmacologic therapies have variable e�ectiveness and are o�en used

simultaneously.7 Aggressive measures such as hemodialysis, hemoperfusion, cardiac pacing, placement ofintra-aortic balloon pumps, and extracorporeal circulatory support have also been used when patients are

refractory to pharmacologic therapy.18

FIGURE 194-2.

Management strategies in β-blocker toxicity. Cardiac function is evaluated using ECG, cardiac US, and/orcentral hemodynamic monitoring. For wide QRS interval, consider sodium bicarbonate therapy. For impairedmyocardial contractility, consider glucagon, high-dose insulin, adrenergic agents, and calcium therapy. Fordecreased systemic vascular resistance, consider vasopressors, such as norepinephrine, epinephrine,dopamine, and phenylephrine. For bradycardia, consider glucagon, adrenergic agents, and cardiac pacing.(See text for details.) SVR = systemic vascular resistance.

Page 11: Chapter 194: Beta-Blockers - WordPress.com...polypharmacy "heart or blood pressure medication" overdose or with suspected chronic drug toxicity in the patient on multiple cardiovascular

8/7/2018

11/21

GLUCAGON

Glucagon is a first-line agent in the treatment of acute β-blocker–induced bradycardia and hypotension.2,19

Glucagon, produced in the pancreatic α-cells from proglucagon, independently activates myocardialadenylate cyclase, bypassing the impaired β-receptor (Figure 194-1). E�ects from an IV bolus of glucagon areseen within 1 to 2 minutes, reach a peak in 5 to 7 minutes, and have a duration of action of 10 to 15

minutes.2,3 Due to the short duration of e�ect, a continuous infusion is o�en necessary a�er bolusadministration. The bolus dose of glucagon is 3 to 10 milligrams (30 to 150 micrograms/kg in children), and ifa response is not seen within 15 minutes, a repeat bolus can be given. If a beneficial e�ect is seen from theglucagon bolus, a continuous infusion of 1 to 5 milligrams/h (20 to 70 micrograms/kg per hour in children)can be used to maintain this e�ect. Glucagon infusion should be titrated to rate to achieve adequate

hemodynamic response. There is no identified maximum therapeutic dose or duration of treatment.19

The amount of glucagon required to treat a significant β-blocker overdose may exceed the total amount

available at any given hospital.19 The positive inotropic and chronotropic e�ects of glucagon may not bemaintained for a prolonged period due to possible tachyphylaxis. Nausea and vomiting are commonlyreported side e�ects of high-dose glucagon therapy and may be related to esophageal sphincter relaxation.Intubation prior to glucagon administration may be warranted in any patient with altered mental status to

limit the risk of aspiration.2,3,7

Prior to 1998, glucagon was derived from porcine and bovine pancreas and contained other pancreatic

compounds such as insulin and phenol as a preservative.2 The contribution of this insulin content to theoriginal glucagon's overall e�icacy is unclear (see discussion below in "High-Dose Insulin Therapy"). Since1998, glucagon has been produced via recombinant technology and is devoid of insulin or phenol.

ADRENERGIC RECEPTOR AGONISTS

Page 12: Chapter 194: Beta-Blockers - WordPress.com...polypharmacy "heart or blood pressure medication" overdose or with suspected chronic drug toxicity in the patient on multiple cardiovascular

8/7/2018

12/21

The β-adrenergic receptor agonists—such as norepinephrine, dopamine, epinephrine, and isoproterenol—

are used routinely to treat β-blocker toxicity.2,19 However, results have been variable even when dosages far

exceed those recommended in standard guidelines for cardiac resuscitation.3 The most e�ective adrenergicreceptor agonists may be norepinephrine and epinephrine due to their chronotropic and vasopressor e�ects.Phenylephrine may also be beneficial as a vasopressor. Although isoproterenol may increase heart rate, itdoes so at the expense of vasodilation. Dobutamine has a similar downside: potential improvement ininotropy but worsening of hypotension due to vasodilation.

HIGH-DOSE INSULIN THERAPY

High-dose insulin therapy, sometimes called hyperinsulinemia-euglycemia therapy, is an important

treatment modality for β-blocker toxicity.17,20,21,22 Insulin acts as an inotrope by facilitating myocardialutilization of glucose, the desired energy substrate during stress, in contrast to glucagon, epinephrine, and

calcium, which promote free fatty acid utilization.20,21,22,23 In animal models, high-dose insulin therapyimproved survival in severe β-blocker overdose compared with glucagon, epinephrine, or vasopressin

administration.24,25 The most consistent cardiodynamic e�ect in these models was an increase incontractility.

High-dose insulin therapy dosing used for treatment of β-blocker toxicity is much higher than that used fortraditional glucose control in diabetes (Table 194-5). The initial dose is regular insulin 1 unit/kg IV bolus andis followed by a continuous infusion of 0.5 to 1 unit/kg per hour that is titrated to the desired hemodynamicresponse of a heart rate at least 50 beats/min and systolic blood pressure of at least 100 mm Hg (13.3

kPa).20,21,22 The maximum dose has not yet been established, although an animal model of propranolol

overdose26 found that cardiac output increased in a dose-response manner when the insulin dose was raised

from 1 to 10 units/kg per hour, and human case reports have used doses this high.22

Page 13: Chapter 194: Beta-Blockers - WordPress.com...polypharmacy "heart or blood pressure medication" overdose or with suspected chronic drug toxicity in the patient on multiple cardiovascular

8/7/2018

13/21

Abbreviations: HR = heart rate; SBP = systolic blood pressure.

TABLE 194-5

Protocol for High-Dose Insulin Therapy in Severe β-Blocker Overdose

Check serum glucose, and if <200 milligrams/dL (<11 mmol/L), administer 50 mL of 50% dextrose (0.5

gram/mL) in water IV (children 1 mL/kg of 25% dextrose).

Administer regular insulin 1 unit/kg IV bolus.

Begin regular insulin infusion at 0.5–1.0 unit/kg per hour along with dextrose 10% (0.1 gram/mL) in water at

200 mL/h (adult) or 5 mL/kg per hour (pediatric).

Titrate infusion rate up to 10 units/kg per hour according the hemodynamic goal of HR >50 beats/min and SBP

>100 mm Hg (>13.3 kPa).

Monitor serum glucose every 15–20 min.

Titrate dextrose infusion rate to maintain serum glucose level between 100 and 200 milligrams/dL (5.3 and

10.7 mmol/L).

Once dextrose infusion rates have been stable for 60 min, glucose monitoring may be decreased to hourly.

Monitor serum potassium level and start IV potassium infusion if serum potassium level is <2.8 mEq/L (<2.8

mmol/L).

Maintain serum potassium between 2.8 and 3.2 mEq/L (2.8 and 3.2 mmol/L).

The onset of action with high-dose insulin therapy is reported to be 15 to 45 minutes, but a delayed response

of several hours has been noted.20 High-dose insulin therapy is continued until resolution of toxicity; the

duration of high-dose insulin therapy infusion described in case reports ranges from 9 to 49 hours.22 Theinsulin infusion can be gradually weaned or abruptly halted. Reinstitute the insulin infusion if the heart rateor blood pressure falls a�er cessation of high-dose insulin therapy.

Potential adverse e�ects from high-dose insulin therapy are hypoglycemia and lowered serum potassium.

Dextrose infusion is used to prevent hypoglycemia and o�en required during the duration of therapy.22

Serum potassium is monitored and supplemental replacement is given if the level is below 2.8 mEq/L (2.8

mmol/L).20,22 An increase in the dextrose infusion rate required to maintain serum glucose between 100 and200 milligrams/dL (5.3 and 10.7 mmol/L), along with signs of clinical improvement, may be an indication thatmetabolic status is normalizing; that is, that the stress response is diminishing, the heart is reverting back tobasal energy substrates, and extra insulin is no longer needed.

INTRAVENOUS LIPID EMULSION THERAPY

Intravenous lipid emulsion therapy, also known as fat emulsion therapy or lipid rescue, is e�ective in treatingtoxicity from local anesthetics, calcium channel blockers, typical and atypical antipsychotics, cyclic and

other antidepressants, and some β-blockers.27,28,29 The exact mechanism is not fully understood, but the

Page 14: Chapter 194: Beta-Blockers - WordPress.com...polypharmacy "heart or blood pressure medication" overdose or with suspected chronic drug toxicity in the patient on multiple cardiovascular

8/7/2018

14/21

likely explanation is that lipid emulsion acts as a pharmacologic sink, by sequestering lipophilic drugs into aseparate lipid compartment, and the amount of free drug available to target tissues is reduced ("lipid sink"

model).30 Other potential mechanisms may include supplying the myocardium with free fatty acids andphospholipids, increasing myocardial contractility by increasing myocyte calcium concentration, andelevating blood pressure by central sympathetic activation.

Animal models suggest that intravenous lipid emulsion may be most e�ective in the lipophilic β-blockers(Table 194-2), such as propranolol and carvedilol, and may be less e�ective in more hydrophilic agents, such

as metoprolol and atenolol.31

The dosing regimen for intravenous lipid emulsion is based on treatment of local anesthetic systemictoxicity. The standard 20% lipid emulsion is given as a 1.5 mL/kg bolus over 1 minute, followed by a infusion

at 0.25 mL/kg per minute.30 If the blood pressure remains low, an additional 1.5 mL/kg bolus may berepeated followed by an increase in the infusion rate to 0.5 mL/kg per minute. The recommended upper limitis about 10 mL/kg over the initial 30 minutes. If the patient's hemodynamic stability is dependent oncontinued lipid infusion, the treatment may be continued beyond this level. Duration of therapy has not beenfully established. If cardiac arrest occurs, a bolus dose can be given during the resuscitation.

Adverse e�ects reported with the use of lipid emulsion for the treatment of overdose and toxicity includelipemia causing interference with laboratory analysis, hypertriglyceridemia, pancreatitis, and possibly acute

lung injury, acute renal failure, deep vein thrombosis, and cardiac arrest.32,33,34 Lipid emulsion may clog thehemofiltration filter precluding renal replacement therapy during the infusion and until the lipid has been

cleared from the blood.35 Given the current understanding and limited clinical experience using intravenouslipid emulsion as an antidote, this treatment should be reserved for refractory shock.

ATROPINE

Atropine, a muscarinic blocker, is unlikely to be e�ective in the management of β-blocker–induced

bradycardia and hypotension, although its use is unlikely to cause harm.3,4,7 Its use may be beneficial for co-ingestants.

CALCIUM

Canine studies and limited case reports suggest that calcium therapy may reverse depression of the

myocardium via positive inotropic action, although with few chronotropic e�ects.2,3 Calcium administrationis not routinely recommended in β-blocker overdose, but may be considered in patients with refractoryshock unresponsive to other therapies. Calcium for IV administration is available in two forms, gluconate andchloride, both in a 10% solution. A 10-mL dose of 10% calcium chloride solution contains three times moreelemental calcium, 13.6 mEq (6.8 mmol), than 10 mL of 10% calcium gluconate solution, 4.5 mEq (2.23mmol). Thus, one 10-mL ampule of 10% calcium chloride equals three 10-mL ampules of 10% calciumgluconate.

Page 15: Chapter 194: Beta-Blockers - WordPress.com...polypharmacy "heart or blood pressure medication" overdose or with suspected chronic drug toxicity in the patient on multiple cardiovascular

8/7/2018

15/21

Potential adverse e�ects of calcium therapy include hypercalcemia, conduction blocks, worseningbradycardia, and ine�icient cardiac energetics during shock (see "High-Dose Insulin Therapy"). Most patientstolerate transient increases in total calcium level without di�iculty, and conduction blocks are rare. Severeso� tissue injury associated with inadvertent IV infiltration of the chloride formulation is the most concerningadverse event. Thus, calcium chloride is ideally given via a central line. Calcium gluconate is only rarelyassociated with tissue injury and is the preferred form for peripheral administration.

The optimum dose of calcium in β-blocker toxicity is unknown. Animal studies and limited human studiessuggest that large amounts of calcium are needed to treat drug-induced cardiac toxicity, but these data come

from experience derived from treating calcium channel blocker toxicity.2,3 The recommended dose of 10%calcium gluconate is 0.6 mL/kg given over 5 to 10 minutes, followed by a continuous infusion of 0.6 to 1.5

mL/kg per h.2,3 The equivalent dosage of 10% calcium chloride is 0.2 mL/kg given via central line over 5 to 10minutes, followed by a continuous infusion of 0.2 to 0.5 mL/kg per h. Ionized calcium levels should bechecked every 30 minutes initially and then every 2 hours to achieve an ionized calcium level of twice the

normal value.2

PHOSPHODIESTERASE INHIBITORS

Phosphodiesterase inhibitors such as milrinone have been used to treat β-blocker toxicity. These agentsinhibit the breakdown of cyclic adenosine monophosphate, thereby sustaining intracellular calcium levels

(Figure 194-1).2,3 In animal models, phosphodiesterase inhibitors produce positive inotropic e�ects withoutincreasing myocardial oxygen demand but have no appreciable e�ect on heart rate. Compared withglucagon, phosphodiesterase inhibitors do not provide any additional benefit and therefore have noadvantage over glucagon. However, if glucagon is not available or pharmacy stores have been exhausted, aphosphodiesterase inhibitor is a reasonable alternative. In the setting of a β-blocker overdose, milrinone isadministrated as a continuous IV infusion, starting with a 50 micrograms/kg IV bolus, followed by an IV

infusion of 0.375 to 0.75 micrograms/kg per minute for milrinone.36

SODIUM BICARBONATE

Sodium bicarbonate is used to treat severe acidosis and wide QRS-interval dysrhythmias secondary tosodium channel blockade. β-Blockers with sodium channel–blocking ability (Table 194-2) can interfere withventricular depolarization, predisposing to cardiac dysrhythmias. When the QRS interval is longer than 120 to

140 milliseconds, it is reasonable to administer sodium bicarbonate.2 The suggested dose is a rapid bolus of

2 to 3 mEq/kg over 1 to 2 min.2,3,6 Thus, a 70-kg adult receives a bolus of 140 to 210 mEq of sodiumbicarbonate, or three to four ampules (50 mL each) of 8.4% sodium bicarbonate. Repeat boluses or aninfusion may be required to maintain the QRS interval at <120 milliseconds.

CARDIAC PACING

Page 16: Chapter 194: Beta-Blockers - WordPress.com...polypharmacy "heart or blood pressure medication" overdose or with suspected chronic drug toxicity in the patient on multiple cardiovascular

8/7/2018

16/21

Internal or external pacing may be considered to treat bradycardia in the setting of β-blocker toxicity.2,3

Electrical capture and restoration of blood pressure is not always successful, potentially due to the lack of

intracellular calcium needed for contraction.2,3 Cardiac pacing may be most beneficial in treating torsadesde pointes associated with sotalol toxicity.

EXTRACORPOREAL ELIMINATION (HEMODIALYSIS)

The high degree of protein binding and lipid solubility of β-blockers, as well as their large volume ofdistribution, renders extracorporeal drug removal useless for most drugs in this class. Acebutolol, atenolol,nadolol, and sotalol may be amenable to removal through hemodialysis owing to their lower protein

binding, water solubility, and lower volume of distribution.37

EXTRACORPOREAL CIRCULATION

Occasionally, extreme means of resuscitation, including extracorporeal circulation (extracorporealmembrane oxygenation) and intra-aortic balloon pumps, have been successful when pharmacologic

measures have failed to reverse cardiogenic shock.38,39

TREATMENT OF SOTALOL TOXICITY

Treatment of sotalol toxicity may require pharmacologic measures di�erent from those required for other β-blockers due to its potassium channel e�ects. In addition to the therapies discussed above, magnesiumsupplementation, lidocaine, and cardiac overdrive pacing may be of specific benefit.

SUMMARY

No one particular treatment is consistently e�ective in cases of β-blocker toxicity, and multiple simultaneoustreatment measures may be required to resuscitate the critically ill patient. Tailor therapy based on the ECG,bedside cardiac US, and/or central hemodynamic monitoring. The goal of resuscitation is to improvehemodynamics and organ perfusion. Specific end points of therapy may include a cardiac ejection fraction of50% or greater, a reduction of the QRS interval to <120 milliseconds, a heart rate of >50 to 60 beats/min, asystolic blood pressure of >90 to 100 mm Hg (12.0 to 13.3 kPa) in an adult, a urine output of 1 to 2 mL/kg perhour, and improved mentation.

DISPOSITION AND FOLLOW-UP

Patients who develop altered mental status, bradycardia, conduction delays, or hypotension should bemanaged in an intensive care unit. A patient who ingests a sustained-released β-blocker product warrants

admission and monitoring for the development of delayed toxicity.2,3,9 Patients ingesting an overdose ofregular-release β-blocker tablets who remain asymptomatic and have normal vital signs for 6 hours a�er

ingestion can be deemed medically safe for discharge or admission to a psychiatric facility.9

Page 17: Chapter 194: Beta-Blockers - WordPress.com...polypharmacy "heart or blood pressure medication" overdose or with suspected chronic drug toxicity in the patient on multiple cardiovascular

8/7/2018

17/21

1. 

2. 

3. 

4. 

5. 

6. 

7. 

8. 

9. 

10. 

REFERENCES

Mowry  JB, Spyker  DA, Cantilena  LR  Jr  et al.: 2013 Annual report of the American Association of PoisonControl Centers' National Poison Data System (NPDS): 31st annual report. Clin Toxicol (Phila) 51: 949, 2014.

[PubMed: 25559822]

Kerns  W: Management of beta-adrenergic blocker and calcium channel antagonist toxicity. Emerg MedClin North Am 25: 309, 2007.

[PubMed: 17482022]  

DeWitt  CR, Waksman  JC: Pharmacology, pathophysiology, and management of calcium channel blockerand beta-blocker toxicity. Toxicol Rev 23: 223, 2004.

[PubMed: 15898828]  

Poirier  L, Tobe  SW: Contemporary use of β-blockers: clinical relevance of subclassification. Can J Cardiol30 (5 Suppl): S9, 2014.

[PubMed: 24684855]  

Ripley  TL, Saseen  JJ: β-blockers: a review of their pharmacological and physiological diversity inhypertension. Ann Pharmacother 48: 723, 2014.

[PubMed: 24687542]  

Love  JN, Elshami  J: Cardiovascular depression resulting from atenolol intoxication. Eur J Emerg Med 9:111, 2002.

[PubMed: 12131631]  

Palatnick  W, Jelic  T: Emergency department management of calcium channel blocker, beta-blocker, anddigoxin toxicity. Emerg Med Pract 16: 1, 2014.

[PubMed: 24883458]  

Love  JN, Howell  JM, Litovitz  TL, Klein-Schwartz  W: Acute beta-blocker overdose: factors associated withthe development of cardiovascular morbidity. J Toxicol Clin Toxicol 38: 275, 2000.

[PubMed: 10866327]  

Reith  D, Dawson  A, Epid  D  et al.: Relative toxicity of beta-blockers in overdose. J Toxicol Clin Toxicol 34:273, 1996.

[PubMed: 8667464]  

Yee  LM, Wu  D: False-positive amphetamine toxicology screen results in three pregnant women usinglabetalol. Obstet Gynecol 117: 503, 2011.

[PubMed: 21252805]  

Page 18: Chapter 194: Beta-Blockers - WordPress.com...polypharmacy "heart or blood pressure medication" overdose or with suspected chronic drug toxicity in the patient on multiple cardiovascular

8/7/2018

18/21

11. 

12. 

13. 

14. 

15. 

16. 

17. 

18. 

19. 

20. 

Young  AT, Merkel  MJ, Heitner  SB, Schulman  PM: Focused echocardiography during glucagonadministration to diagnose beta-blocker-induced cardiomyopathy. J Cardiothorac Vasc Anesth January 6,2015. [Epub ahead of print]

[PubMed: 25575407]

Rennyson  SL, Littmann  L: Brugada-pattern electrocardiogram in propranolol intoxication. Am J EmergMed 28: 256.e7, 2010.

[PubMed: 20159410]

Heard  K: Gastrointestinal decontamination. Med Clin North Am 89: 1067, 2005. [PubMed: 16227054]  

Wax  PM, Erdman  AR, Chyka  PA  et al.: Beta-blocker ingestion: an evidence-based consensus guideline forout-of-hospital management. Clin Toxicol (Phila) 43: 131, 2005.

[PubMed: 15906457]  

Isbister  GK, Kumar  VV: Indications for single-dose activated charcoal administration in acute overdose.Curr Opin Crit Care 17: 351, 2011.

[PubMed: 21716104]  

Höjer  J, Troutman  WG, Hoppu  K  et al.: Position paper update: Ipecac syrup for gastrointestinaldecontamination. Clin Toxicol (Phila) 51: 134, 2013.

[PubMed: 23406298]  

Thanacoody  R, Caravati  EM, Troutman  B  et al.: Position paper update: whole bowel irrigation forgastrointestinal decontamination of overdose patients. Clin Toxicol (Phila) 53: 5, 2015.

[PubMed: 25511637]  

Jang  DH, Spyres  MB, Fox  L, Manini  AF: Toxin-induced cardiovascular failure. Emerg Med Clin North Am32: 79, 2014.

[PubMed: 24275170]  

Shepherd  G: Treatment of poisoning caused by beta-adrenergic and calcium channel blockers. Am JHealth Syst Pharm 63: 1828, 2006 (review). Erratum in: Am J Health Syst Pharm 65: 1592, 2008.

[PubMed: 16990629]  

Megarbane  B, Karyo  S, Baud  F: The role of insulin and glucose (hyperinsulinaemia/euglycaemia) therapyin acute calcium channel antagonist and beta-blocker poisoning. Toxicol Rev 23: 215, 2004.

[PubMed: 15898827]  

Page 19: Chapter 194: Beta-Blockers - WordPress.com...polypharmacy "heart or blood pressure medication" overdose or with suspected chronic drug toxicity in the patient on multiple cardiovascular

8/7/2018

19/21

21. 

22. 

23. 

24. 

25. 

26. 

27. 

28. 

29. 

30. 

Engebretsen  KM, Kaczmarek  KM, Morgan  J, Holger  JS: High-dose insulin therapy in beta-blocker andcalcium channel blocker poisoning. Clin Toxicol (Phila) 49: 277, 2011.

[PubMed: PMID: 21563902]  

Woodward  C, Pourmand  A, Mazer-Amirshahi  M: High dose insulin therapy, an evidence based approachto beta-blocker/calcium channel blocker toxicity. Daru 22: 36, 2014.

[PubMed: 24713415]  

Holger  JS, Stellpflug  SJ, Cole  JB  et al.: High-dose insulin: a consecutive case series in toxin-inducedcardiogenic shock. Clin Tox 49: 653, 2011.

[PubMed: 21819291]

Kerns  W  II, Schroeder  D, Williams  C  et al.: Insulin improves survival in a canine model of acute beta-blocker toxicity. Ann Emerg Med 29: 748, 1997.

[PubMed: 9174520]  

Holger  JS, Engebretsen  KM, Fritzlar  SJ  et al.: Insulin versus vasopressin and epinephrine to treat beta-blocker toxicity. Clin Toxicol (Phila) 45: 396, 2007.

[PubMed: 17486481]  

Cole  JB, Stellpflug  SJ, Ellsworth  H  et al.: A blinded, randomized, controlled trial of three doses of high-dose insulin in poison-induced cardiogenic shock. Clin Toxicol (Phila) 51: 201, 2013. Erratum in: Clin Toxicol(Phila) 51: 1246, 2013.

[PubMed: 23530460]  

Weinberg  GL: Lipid emulsion infusion. Resuscitation for local anesthetic and other drug overdose.Anesthesiology 117:180, 2012.

[PubMed: 22627464]  

Ozcan  MS, Weinberg  G: Intravenous lipid emulsion for the treatment of drug toxicity. J Intensive CareMed 29: 59, 2014.

[PubMed: 22733724]  

Cao  D, Heard  K, Foran  M, Koyfman  A: Intravenous lipid emulsion in the emergency department: asystematic review of recent literature. J Emerg Med 48: 387, 2015.

[PubMed: 25534900]  

American College of Medical Toxicology: ACMT Position Statement: interim guidance for the use of lipidresuscitation therapy. J Med Toxicol 7: 81, 2011.

[PubMed: 21327839]  

Page 20: Chapter 194: Beta-Blockers - WordPress.com...polypharmacy "heart or blood pressure medication" overdose or with suspected chronic drug toxicity in the patient on multiple cardiovascular

8/7/2018

20/21

31. 

32. 

33. 

34. 

35. 

36. 

37. 

38. 

39. 

Browne  A, Harvey  M, Cave  G: Intravenous emulsion does not augment blood pressure recovery in arabbit model of metoprolol toxicity. J Med Toxicol 6: 373, 2010.

[PubMed: 20354918]  

Geib  AJ, Liebelt  E, Manini  AF: Clinical experience with intravenous lipid emulsion for drug-inducedcardiovascular collapse. J Med Toxicol 8: 10, 2012.

[PubMed: 21989640]  

Levine  M, Skolnik  AB, Ruha  AM  et al.: Complications following antidotal use of intravenous lipidemulsion therapy. J Med Toxicol 10: 10, 2014.

[PubMed: 24338451]  

Cole  JB, Stellpflug  SJ, Engebretsen  KM: Asystole immediately following intravenous fat emulsion foroverdose. J Med Toxicol 10: 307, 2014.

[PubMed: 24519703]  

Rodríguez  B, Wilhelm  A, Kokko  KE: Lipid emulsion use precluding renal replacement therapy. J EmergMed 47: 635, 2014.

[PubMed: 25271183]  

Sandroni  C, Cavallaro  F, Caricato  A  et al.: Enoximone in cardiac arrest caused by propranolol: two casereports. Acta Anaesthesiol Scand 50: 759, 2006.

[PubMed: 16987374]  

Pfaender  M, Casetti  PG, Azzolini  M  et al.: Successful treatment of a massive atenolol and nifedipineoverdose with CVVHDF. Minerva Anestesiol 74: 97, 2008.

[PubMed: 18288073]  

Masson  R, Colas  V, Parienti  JJ  et al.: A comparison of survival with and without extracorporeal lifesupport treatment for severe poisoning due to drug intoxication. Resuscitation 83: 1413, 2012.

[PubMed: 22469751]  

Johnson  NJ, Gaieski  DF, Allen  SR, Perrone  J, DeRoos  F: A review of emergency cardiopulmonary bypassfor severe poisoning by cardiotoxic drugs. J Med Toxicol 9: 54, 2013.

[PubMed: 23238774]  

McGraw HillCopyright © McGraw-Hill Global Education Holdings, LLC.

All rights reserved. Your IP address is 50.26.48.115

Terms of Use   •  Privacy Policy   •  Notice   •  Accessibility

Page 21: Chapter 194: Beta-Blockers - WordPress.com...polypharmacy "heart or blood pressure medication" overdose or with suspected chronic drug toxicity in the patient on multiple cardiovascular

8/7/2018

21/21

Access Provided by: Brookdale University Medical CenterSilverchair