Background: Beta-adrenergic antagonists (ie,
beta-blocker) have been in use for nearly 50 years. In addition to their
traditional role in treating hypertension, beta-blockers are also used for
additional purposes such as migraine headaches, hyperthyroidism, glaucoma,
anxiety, and various other disorders. As a result of their expanded use, the
incidence of overdose with these agents has also increased.
Pathophysiology: Understanding the direct and indirect
effects of beta-receptor blockade is crucial to rapid identification and
appropriate treatment of beta-blocker toxicity. Beta-blockers act as
competitive inhibitors of catecholamines, exerting their effects at both
central and peripheral receptors. Blockade of beta-receptors results in
decreased production of intracellular cyclic adenosine monophosphate (cAMP)
with a resultant blunting of multiple metabolic and cardiovascular effects of
circulating catecholamines. Beta1-blockers blockers reduce heart rate, blood
pressure, myocardial contractility, and myocardial oxygen consumption.
Beta2-receptor blockade inhibits relaxation of smooth muscle in blood vessels,
bronchi, the gastrointestinal system, and the genitourinary tract. In addition,
beta-adrenergic receptor antagonism inhibits both glycogenolysis and
gluconeogenesis, which may result in hypoglycemia
History:
Determining
the specific type of beta-blocker, quantity, and time of the overdose is
ideal. Unfortunately, these details are often not immediately available.
Information regarding the patient's underlying medical condition may clue
the clinician to the possibility of an overdose.
Physical: The initial evaluation of a comatose patient should include
consideration of an occult overdose. If a patient is bradycardic and
hypotensive, the clinician should consider a beta-blocker or calcium blocker
overdose. Other symptoms include hypothermia, hypoglycemia, and seizures.
Myocardial conduction delays with decreased contractility typify the acute
beta-blocker ingestion.
Beta-blockers
that are not sustained-release formulations are all rapidly absorbed from
the gastrointestinal tract.
The
first critical signs of overdose can appear 20 minutes postingestion but
are more commonly observed within 1-2 hours.
All
clinically significant beta-blocker overdoses develop symptoms within 6
hours.
While the
half-life of these compounds is usually short (2-12 h), half-lives in the
overdose patient may be prolonged because of a depressed cardiac output
reducing blood flow to the liver and kidneys or because of the formation
of active metabolites.
Saturation
kinetics prolong elimination at high plasma concentrations, and delayed
absorption from long-acting preparation can significantly increase the
apparent elimination half-life. Prolonged effects (>72 h) after massive
overdoses are not uncommon.
Conversely,
circulatory collapse may occur in patients with preexisting cardiac
failure when sympathetic drive is inhibited by even a small dose of a
particular beta-blocker.
Intermediate
toxicity results in a moderate drop in blood pressure (systolic BP >80
mm Hg) and/or bradycardia (heart rate <60 BPM).
Bradycardia
with associated hypotension and shock (systolic BP <80 mm Hg, HR <60
BPM) defines severe beta-blocker toxicity. Patients with severe toxicity
often manifest extracardiac manifestations of intoxication.
Bradycardia,
by itself, is not necessarily helpful as a warning sign because slowing
of the heart rate and damping of tachycardia in response to stress is
observed with therapeutic doses.
While
case reports have documented hypotension in the absence of bradycardia,
blood pressure usually does not fall before the onset of bradycardia.
Bradycardia
may be isolated or accompanied by mild conduction disturbances.
Tachycardia,
while unusual, has been reported with practolol, pindolol, and sotalol.
A
depressed level of consciousness and seizures may occur as a result of
cellular hypoxia from poor cardiac output, a direct CNS effect caused by
sodium channel blocking, or even hypoglycemia.
Seizures
are generalized and may be multiple but are usually brief, lasting seconds
to minutes.
Coma
may be prolonged, depending on the half-life of the agent involved and
the coexisting morbidity.
Bronchospasm
is a rare complication of beta-blocker therapy or overdose, except in
patients who already have bronchospastic disease. Hypoglycemia is
relatively uncommon but described in unstable diabetics and children.
Beta-blocking drugs may cause hypoglycemia by inhibiting glycogenolysis.
Bedside
glucose (fingerstick): Beta-blockers may be associated with hypoglycemia,
especially in diabetics and children.
Serum
electrolytes
Hypokalemia
may contribute to cardiac arrhythmias.
Acidosis
from poor cardiac perfusion may be manifested by low serum bicarbonate.
Co-ingestions
or concomitant medical conditions also may alter all other serum
electrolytes that should be monitored closely, especially in patients
with seizures or altered mental status.
Measure
cardiac enzymes to rule out myocardial infarction in any hemodynamically
unstable patient.
No
studies have been performed to correlate the serum beta-blocker
concentration with the outcome of beta-blocker overdose.
Blood
gases (arterial or venous) may be helpful for managing metabolic acidosis
from seizures or cardiogenic shock or rare cases of severe bronchospasm,
respiratory acidosis, or hypoxia.
Imaging Studies:
Chest
radiographs may show evidence of pulmonary edema.
Other Tests:
Electrocardiogram
ECG
results may indicate progressively severe sinus bradycardia increased PR
intervals, loss of atrial activity, atrioventricular junctional rhythm,
widening of the QRS complex, atrioventricular block, idioventricular
rhythm, and asystole.
A
prolonged QT interval has been observed after sotalol overdose.
Ventricular
fibrillation and ventricular tachycardia are uncommon because of the
antidysrhythmic effects of most beta-blockers.
Asystole
is rare, except in cases of apnea.
TREATMENT
Prehospital Care:
Follow
standard protocols for bradycardia, hypotension, and seizures. Cardiac
monitoring, oxygen administration, and good intravenous access are
essential.
Activated
charcoal
No
benefit exists for prehospital administration of charcoal; the decision
to administer activated charcoal should be made in the ED.
Ipecac
syrup is contraindicated.
Emergency Department Care: The goal of therapy in beta-blocker toxicity is to
restore perfusion to critical organ systems by increasing cardiac output. This
may be accomplished by improving myocardial contractility, increasing heart rate,
or both.
Crystalloid:
If hypotensive, administer 20 mL/kg of isotonic intravenous fluids and
place the patient in Trendelenburg position. If the patient is
unresponsive to these measures, administer pharmacologic therapies as
discussed in the following section.
Glucagon:
Because a glucagon bolus can be diagnostic and therapeutic, the clinician
can empirically administer glucagon and check for a response.
Gastric
decontamination: Gastric lavage is preferred over emesis because of the
rapid absorption and occasionally precipitous onset of toxicity that may
place the patient at risk for aspiration. Gastric lavage may be beneficial
if the patient presents to the ED within 1-2 hours of ingestion. Volunteer
studies have indicated that multiple dose activated charcoal (MDAC) may be
useful in reducing bioavailability of nadolol, probably by removal of the
drug through the enterohepatic circulation.
Enhanced
elimination: Hemodialysis may be useful in severe cases of atenolol
overdoses because atenolol is less than 5% protein bound and 40-50% is
excreted unchanged in urine. Nadolol, sotalol, and atenolol (low lipid
solubility, low protein binding) reportedly are removed by hemodialysis.
Acebutolol is dialyzable. Propranolol, metoprolol, and timolol are not
removed by hemodialysis. Consider hemodialysis or hemoperfusion only when
treatment with glucagon and other pharmacotherapy fails.
Cardiac
pacing/cardiopulmonary resuscitation: Cardiac pacing may be effective in
increasing the rate of myocardial contraction. Electrical capture is not
always successful and, if capture does occur, blood pressure is not always
restored
Reserve
cardiac pacing for patients unresponsive to pharmacological therapy or
for those with torsade de pointes unresponsive to magnesium.
Resuscitation should, therefore, be aggressive and
prolonged
