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Cardiovascular Meds
Intoxication
fac.ksu.edu.sa/zalaseri
Zohair Al Aseri MD,FRCPC EM & CCM
Cardiovascular BB & CCB
Intoxication
Zohair Al Aseri MD,FRCPC EM & CCM
Introduction
 a 64-year-old man in the critical bay who took
an overdose of his medications.
Zohair Al Aseri MD,FRCPC EM & CCM
 has a history of hypertension, atrial fibrillation,
and depression.
 lethargic but arousable
 reports he took about 40 tablets of immediaterelease metoprolol three hours ago in an attempt
to “end it all.”
Zohair Al Aseri MD,FRCPC EM & CCM
 “Is it too late for gastric decontamination?
 If he is symptomatic, which therapy will you
try first, and what are your options?”
Zohair Al Aseri MD,FRCPC EM & CCM
 a 2-year-old child in the pediatric area who was
found playing with grandma’s bottle of verapamil
controlled release 15 minutes ago.
 The grandmother thinks that at most there are
three tablets missing.
Zohair Al Aseri MD,FRCPC EM & CCM
Child looks great
 “Are three tablets a big deal?
 Can we just watch the child for a couple of
hours?
 Do we need an IV and blood work?
Zohair Al Aseri MD,FRCPC EM & CCM
Principles of Disease
Pathophysiology
 inhibit endogenous catecholamines such as
epinephrine at the beta-receptor.
Zohair Al Aseri MD,FRCPC EM & CCM
Selected Characteristics of Common Beta-Blockers
Zohair Al Aseri MD,FRCPC EM & CCM
Principles of Disease
Pathophysiology
 Beta-blockers are rapidly absorbed after oral
ingestion, and the peak effect of normal-release
preparations occurs in 1 to 4 hours.
 Hepatic metabolism on first pass results in
significantly less bioavailability after oral dosing
than with IV injection (1 : 40 for propranolol).
 Volume of distribution for various beta-blockers
generally exceeds 1 L/kg, meaning tissue
concentrations exceed those of serum.
Zohair Al Aseri MD,FRCPC EM & CCM
Principles of Disease
Pathophysiology
 Therefore, hemodialysis is not efficacious for
most beta-blockers.
 Protein binding varies from 0% for sotalol to 93%
for propranolol.
 Elimination half-lives vary from 8 to 9 minutes for
esmolol to as long as 24 hours for nadolol and
others
Zohair Al Aseri MD,FRCPC EM & CCM
MANIFESTATIONS AND COMPLICATIONS OF
BETA-BLOCKER OVERDOSEIN ORDER OF
DECREASING FREQUENCY
Zohair Al Aseri MD,FRCPC EM & CCM
Diagnostic Strategies
 Diagnosis and management depend on the
clinical picture
 Hypoglycemia is common in children
Zohair Al Aseri MD,FRCPC EM & CCM
Management
 IV fluids
 Oxygen
 Monitoring of card for rhythm and respirations.
 Activated charcoal is unproven treatment.
 Multiple-dose
charcoal without supporting
evidence for an improvement in outcome.
Zohair Al Aseri MD,FRCPC EM & CCM
Management
 Onset of toxicity is so uniformly early that
absence of symptoms 4 hours after ingestion
implies a low risk for subsequent morbidity
unless a delayed-release preparation is involved.
Zohair Al Aseri MD,FRCPC EM & CCM
Management
Hypotension, Bradycardia, and Atrioventricular
Block
 Catecholamines
with
chronotropic
and
dromotropic as well as inotropic and vasopressor
effects should be chosen.
Zohair Al Aseri MD,FRCPC EM & CCM
Management
 It is rare for one catecholamine to be equally
effective against all four toxic effects, so
combinations of drugs are often used in severe
cases.
Zohair Al Aseri MD,FRCPC EM & CCM
Management
The first step in the treatment of beta-blocker
overdose is
 Atropine
 Glucagon
 Crystalloid fluids.
Zohair Al Aseri MD,FRCPC EM & CCM
Management
 A dose of atropine may quickly wear off or be
ineffective, so infusion of more potent drugs or
cardiac pacing is usually necessary.
 Atropine (0.5 mg for adults, 0.02 mg/kg for
children, minimum 0.10 mg) should be given
before vagal stimuli such as tracheal or gastric
intubation.
Zohair Al Aseri MD,FRCPC EM & CCM
Management
Glucagon
 Does not depend on beta-receptors for its action,
has both inotropic and chronotropic effects.
 it helps to counteract the hypoglycemia induced
by beta-blocker overdose.
 is given as a 5- to 10-mg IV bolus
Zohair Al Aseri MD,FRCPC EM & CCM
Management
Glucagon
 Because of its short (20-minute) half-life, an
infusion of 2 to 5 mg/hr (or for children, 0.05–
0.1 mg/kg bolus, then 0.05–0.1 mg/kg/hr) should
be started immediately after the bolus.
 With cumulative large doses, glucagon should be
diluted in 5% glucose in water for constant
infusion.
Zohair Al Aseri MD,FRCPC EM & CCM
Management
Glucagon
 Side effects include nausea and vomiting in most
patients, mild hyperglycemia, hypokalemia, and
allergic reactions.
 The response to glucagon alone is often
inadequate.
Zohair Al Aseri MD,FRCPC EM & CCM
Management
sodium bicarbonate
 Sodium channel blockade, manifested by QRS
widening, occasionally occurs with beta-blocker
intoxication and may respond to infusion of
sodium bicarbonate.
Zohair Al Aseri MD,FRCPC EM & CCM
Management
 In hypotensive patients, 20 to 40 mL/kg of normal
saline or Ringer's lactate solution can be infused
and repeated.
 If hypotension or bradycardia persists, other
cardioactive drugs are indicated.
 dopamine, or epinephrine.
Zohair Al Aseri MD,FRCPC EM & CCM
Management
 Other catecholamines include norepinephrine,
dobutamine, and phenylephrine.
 Often, norepinephrine or dopamine is added to
beta-agonists such as isoproterenol that lack
vasopressor activity.
Zohair Al Aseri MD,FRCPC EM & CCM
Treatment
High-Dose Insulin Euglycemia (HDIE)
Therapy
 There are no randomized controlled human
trials.
 There are multiple case reports of the
hemodynamic improvement after institution of
HDIE.
Stellpflug SJ, Harris CR, Engebretsen KM, et al. Intentional overdose with cardiac arrest treated with intravenous fat
emulsion and high-dose insulin. Clin Toxicol 2010;48: 227-229.42
Zohair Al Aseri MD,FRCPC EM & CCM
Management
Insulin
 High-dose (0.5–1 unit/kg/hr) insulin infusion for
hemodynamically significant toxicity is often
given before traditional pressors.
 Beta-blocker toxicity shifts myocardial energy
preferences
from
free
fatty
acids
to
carbohydrates, and insulin increases myocardial
carbohydrate uptake.
 Recent canine and porcine models showed the
benefit of insulin infusion up to 10 units/kg/hr.
Zohair Al Aseri MD,FRCPC EM & CCM
Management
Insulin
 Glucose, usually in 5 to 10% solutions, is infused
to maintain a serum glucose of approximately
100 mg/dL.
 The combination of glucose and high-dose
insulin
augments
myocardial
contraction
independent of beta-receptors.
 Glucose and potassium should be monitored
frequently during infusion and supplemented as
needed to maintain euglycemia and eukalemia.
Zohair Al Aseri MD,FRCPC EM & CCM
Management
 Refractory cases of bradycardia may respond to
an external or transvenous pacemaker.
Zohair Al Aseri MD,FRCPC EM & CCM
Management
Calcium
 Because deleterious effects on calcium transport
may contribute to beta-blocker toxicity, IV
calcium salts have been suggested for treating
hypotension.
 calcium should be given cautiously and less
aggressively than for cases of calcium channel
blocker overdose.
 Constant infusions are safer than boluses.
 Give 1 to 2 g over 5 to 10 minutes, monitoring
closely for effect.
Zohair Al Aseri MD,FRCPC EM & CCM
Management
Ventricular Dysrhythmias
 Although
uncharacteristic,
ventricular
tachydysrhythmias do occur sometimes.
 Cardioversion and defibrillation are indicated for
ventricular tachycardia and ventricular fibrillation,
respectively,
following
American
Heart
Association guidelines.
 Pulsatile ventricular tachycardia or frequent
ventricular ectopy can most safely be treated
with lidocaine.
Zohair Al Aseri MD,FRCPC EM & CCM
Management
Extracorporeal Elimination and
Circulatory Assistance
 Hemodialysis or hemoperfusion may be
beneficial for atenolol, nadolol, sotalol, and
timolol, the beta-blockers with lower Vd, lower
protein binding, and greater hydrophilicity.
Zohair Al Aseri MD,FRCPC EM & CCM
Management
Extracorporeal Elimination and
Circulatory Assistance
 can be lifesaving
hypotension.
in
cases
of
refractory
 To be successful, such heroic measures must be
taken before prolonged hypotension leads to
multiorgan ischemic injury.
Zohair Al Aseri MD,FRCPC EM & CCM
TREATMENT OF BETA-BLOCKER POISONING
Zohair Al Aseri MD,FRCPC EM & CCM
Zohair Al Aseri MD,FRCPC EM & CCM
Disposition
 Patients who remain completely asymptomatic for
6 hours after an oral overdose of normal-release
preparations can be safely referred for psychiatric
evaluation, with medical consultation for the first
24 hours.
Zohair Al Aseri MD,FRCPC EM & CCM
CALCIUM CHANNEL BLOCKERS
Perspective
 Most fatalities occur with verapamil, but severe
toxicity and death have been reported for most
drugs of this class.
Zohair Al Aseri MD,FRCPC EM & CCM
Pathophysiology
Calcium channel antagonists
 block the slow calcium channels in the
myocardium and vascular smooth muscle,
leading to coronary and peripheral vasodilation.
 reduce cardiac contractility
 depress SA nodal activity
 slow AV conduction.
Zohair Al Aseri MD,FRCPC EM & CCM
Pathophysiology
 Both verapamil and diltiazem act on the heart
and blood vessels, whereas nifedipine causes
primarily vasodilation.
 In the pancreas, calcium channel blockade
inhibits
insulin
release,
resulting
in
hyperglycemia.
 As with beta-blockers, selectivity is lost in cases
of overdose
Zohair Al Aseri MD,FRCPC EM & CCM
Pathophysiology
 All
calcium channel blockers are rapidly
absorbed
 Onset of action and toxicity ranges from less
than 30 minutes to 60 minutes
 Peak effect of nifedipine can occur as early as
20 minutes after ingestion,
Zohair Al Aseri MD,FRCPC EM & CCM
Pathophysiology
 Peak effect of sustained-release verapamil can
be delayed for many hours.
 High protein binding and Vd greater than 1 to
2 L/kg make hemodialysis or hemoperfusion
ineffective.
 Fortunately (except with sustained-release
preparations), their half-lives are relatively short,
limiting toxicity to 24 to 36 hours.
Zohair Al Aseri MD,FRCPC EM & CCM
Selected Characteristics of Some Calcium Channel
Blockers
Zohair Al Aseri MD,FRCPC EM & CCM
MANIFESTATIONS AND COMPLICATIONS OF
CALCIUM CHANNEL BLOCKER POISONING
Zohair Al Aseri MD,FRCPC EM & CCM
Diagnostic Strategies
 Serum levels of calcium antagonists are not
available
 Glucose and Electrolytes (including calcium and
magnesium). Hyperglycemia secondary to
insulin inhibition occurs occasionally, but mild
and short-lived requires no treatment.
 Lactic acidosis occurs with hypotension and
hypoperfusion.
Zohair Al Aseri MD,FRCPC EM & CCM
Diagnostic Strategies
 ECG
 A prolonged QRS or QT interval suggests
bepridil or a co-ingested cardiac toxin such as a
TCA.
Zohair Al Aseri MD,FRCPC EM & CCM
Management
 IV
 O2
 Cardiac monitoring
 Vomiting is a powerful vagal stimulus that can
exacerbate bradycardia and heart block.
 No evidence for activated charcoal
Zohair Al Aseri MD,FRCPC EM & CCM
Hypotension and Bradycardia
 Atropine (0.5–1 mg, up to 3 mg for adults, and
0.02 mg/kg for children, minimum 0.1 mg).
 Atropine's effect is short-lived
 If symptomatic bradycardia or heart block
persists, the next step is a pacemaker or
chronotrope such as isoproterenol.
Zohair Al Aseri MD,FRCPC EM & CCM
Hypotension and Bradycardia
Intravenous calcium
 have considerable effect on contractility but their
effect on bradycardia, AV block, and peripheral
vasodilation is often poor.
Zohair Al Aseri MD,FRCPC EM & CCM
Hypotension and Bradycardia
 Epinephrine, norepinephrine, and dobutamine
have also led to successful outcomes.
Zohair Al Aseri MD,FRCPC EM & CCM
Hypotension and Bradycardia
 Glucagon has also been used for its inotropic
and chronotropic effects.
Zohair Al Aseri MD,FRCPC EM & CCM
Hypotension and Bradycardia
Insulin
 (0.5–1 iu/kg/hr) infusion has been effective in
both animal trials and human cases.
 Glucose (5–10% solutions usually suffice) is
infused concurrently to maintain serum glucose
at 100 mg/dL (usually 10–30 g/hr).
 Insulin euglycemia is thought to act by improving
myocardial carbohydrate metabolism, thereby
augmenting myocardial contraction.
Zohair Al Aseri MD,FRCPC EM & CCM
Hypotension and Bradycardia
Insulin
 Serum glucose and potassium levels should be
checked frequently to ensure that normal levels
are maintained.
Zohair Al Aseri MD,FRCPC EM & CCM
Treatment
High-Dose Insulin Euglycemia (HDIE)
Therapy
 may be administered to increase inotropy.
 Its proposed mechanism of action is by
improving calcium use in the myocytes,
although the exact mechanism is unclear.
Megarbane B, Karyo S, Baud FJ. The role of insulin and glucose (hyperinsulinaemie/ euglycaemia) therapy in acute calcium
channel antagonist and beta-blocker poisoning. Toxicol Rev 2004;23:215-222
Kline JA, Leonova E, Raymond R. Beneficial myocardial metabolic effects of insuin during verapamil toxicity in the
anesthetized canine. Crit Care Med 1995;3:1251-63
Tune JD, Mallet RT, Downey HF. Insulin improves contractile function during moderate ischemia in canine left ventricle.
Am J Physiol 1998;274:1574-81
Zohair Al Aseri MD,FRCPC EM & CCM
TREATMENT OF CALCIUM CHANNEL BLOCKER
INTOXICATION
Zohair Al Aseri MD,FRCPC EM & CCM
Zohair Al Aseri MD,FRCPC EM & CCM
Disposition
 Because the peak effect occurs in 90 minutes to
6 hours, patients who are totally asymptomatic
for 6 hours can be safely discharged
 For delayed-release preparations should be
admitted for at least 24 hours of continuous
cardiac monitoring.
Zohair Al Aseri MD,FRCPC EM & CCM
NITRATES AND NITRITES
 Widely used as vasodilators in the treatment of
heart failure and ischemic heart disease.
 augment coronary blood flow as well as reduce
myocardial oxygen consumption by reducing
afterload.
 At lower doses nitrates primarily dilate veins
 At higher doses they also dilate arteries.
Zohair Al Aseri MD,FRCPC EM & CCM
NITRATES AND NITRITES
 Hypotension is a common complication, but
usually responds to supine positioning, IV fluids,
and reduction of dose.
 Hypotension is usually transient.
 Low-dose pressors are occasionally needed, but
it is best to avoid them in the setting of acute
coronary syndromes.
Zohair Al Aseri MD,FRCPC EM & CCM
NITRATES AND NITRITES
 Nitrites are also oxidizing agents that convert
hemoglobin to methemoglobin, impairing oxygen
delivery.
Zohair Al Aseri MD,FRCPC EM & CCM
NITRATES AND NITRITES
 When methemoglobin levels exceed 15%, a
venous blood sample appears chocolate brown,
and the skin appears blue even while patients
look remarkably comfortable.
 Unlike most cases of cyanosis, supplemental
oxygen does not improve the patient's color.
Zohair Al Aseri MD,FRCPC EM & CCM
NITRATES AND NITRITES
 Pulse oximetry is not reliable,
Treatment
 IV methylene blue, but this antidote is usually
not
needed
unless
methemoglobinemia
approaches 30%
 The usual dose of methylene blue in adults is 1
to 2 mg IV over 5 minutes.
Zohair Al Aseri MD,FRCPC EM & CCM
Digitalis Intoxication
Zohair Al Aseri MD,FRCPC EM & CCM
The foxglove plant, from which digitalis is derived.
DIGITALIS
Perspective
Zohair Al Aseri MD,FRCPC EM & CCM
Principles of Disease
Pathophysiology
In therapeutic doses, digitalis has two effects:
(1) increasing the force of myocardial contraction to
increase cardiac output in patients with heart
failure.
(2) decreasing atrioventricular (AV) conduction to
slow the ventricular rate in atrial fibrillation.
Zohair Al Aseri MD,FRCPC EM & CCM
Principles of Disease
Pathophysiology
 It
inhibits
membrane
sodium-potassium
adenosine triphosphatase (ATPase), which
increases intracellular sodium and calcium and
increases extracellular potassium.
 At therapeutic doses, the effects on serum
electrolyte levels are minimal.
Zohair Al Aseri MD,FRCPC EM & CCM
Principles of Disease
Pathophysiology
 With toxic levels, digitalis paralyzes the Na-K
pump, potassium cannot be transported into
cells, and serum potassium can rise as high as
13.5 mEq/L.
Zohair Al Aseri MD,FRCPC EM & CCM
Principles of Disease
Pathophysiology
 At therapeutic levels, digitalis indirectly increases
vagal activity and decreases sympathetic activity.
 At toxic levels, digitalis can directly halt the
generation of impulses in the SA node, depress
conduction through the AV node, and increase
the sensitivity of the SA and AV nodes to
catecholamines.
Zohair Al Aseri MD,FRCPC EM & CCM
Principles of Disease
Pathophysiology
 Digitalis can produce virtually any dysrhythmia or
conduction block, and bradycardias are as
common as tachycardias.
Zohair Al Aseri MD,FRCPC EM & CCM
DYSRHYTHMIAS ASSOCIATED WITH DIGITALIS TOXICITY
Zohair Al Aseri MD,FRCPC EM & CCM
Principles of Disease
Pathophysiology
 The significant protein binding and large volume
of distribution suggest that hemodialysis,
hemoperfusion, and exchange transfusion are
ineffective.
Zohair Al Aseri MD,FRCPC EM & CCM
FACTORS ASSOCIATED WITH INCREASED RISK
OF DIGITALIS TOXICITY
Zohair Al Aseri MD,FRCPC EM & CCM
NONCARDIAC SYMPTOMS OF DIGITALIS
INTOXICATION IN ADULTS AND CHILDREN
Zohair Al Aseri MD,FRCPC EM & CCM
Diagnostic Strategies
 Serum digoxin levels.
 It is the steady state, rather than peak level, that
correlates with tissue toxicity and is used to
calculate antidote dosages.
Zohair Al Aseri MD,FRCPC EM & CCM
Diagnostic Strategies
 Peak levels after an oral dose of digoxin occur in
1.5 to 2 hours, with a range of 0.5 to 6 hours.
 Steady-state serum concentrations are not
achieved until after distribution, or 6 to 8 hours
after a dose or overdose, and may be only one
fourth to one fifth of the peak level.
Zohair Al Aseri MD,FRCPC EM & CCM
Diagnostic Strategies
 The ideal serum digoxin concentration for
patients with heart failure is considered to be
0.7 to 1.1 ng/mL.
Zohair Al Aseri MD,FRCPC EM & CCM
Diagnostic Strategies
 After an acute massive overdose in a patient
who is rapidly becoming symptomatic, however,
it may be impractical to wait 6 to 8 hours for the
first reading.
 It is unlikely that early levels exceeding 10 to
20 ng/mL will fade to clinical insignificance at 6
to 8 hours after ingestion.
Zohair Al Aseri MD,FRCPC EM & CCM
Diagnostic Strategies
 Patients taking digitalis therapeutically often
take diuretics as well, and they often have low
serum and total body potassium levels.
 The acutely poisoned patient, in contrast, may
have life-threatening hyperkalemia.
Zohair Al Aseri MD,FRCPC EM & CCM
Management
 There is no evidence to support gastric emptying
for the treatment of digoxin overdose.
 Activated charcoal, no improvement in outcome
has been established.
 Multidose charcoal has no proven benefit
Zohair Al Aseri MD,FRCPC EM & CCM
Electrolyte Correction
K
 In cases of chronic intoxication, often
exacerbated by hypokalemia, raising the serum
potassium level to 3.5 to 4 mEq/L is an important
early treatment.
 Potassium can be administered orally (which is
safer) or intravenously (IV) although a rate more
rapid than 10 to 40 mEq/hour is dangerous.
Zohair Al Aseri MD,FRCPC EM & CCM
Electrolyte Correction
K
 In acute poisoning, serum potassium may begin
to rise rapidly within 1 to 2 hours of ingestion,
potassium should be withheld, even if mild
hypokalemia is measured initially.
Zohair Al Aseri MD,FRCPC EM & CCM
Electrolyte Correction
K
 A serum potassium level greater than 5 mEq/L
warrants consideration of digitalis antibody (ovine
Fab fragment) treatment.
 If digitalis antibodies are not immediately
available, severe hyperkalemia should be treated
with IV glucose, insulin, and sodium bicarbonate.
Zohair Al Aseri MD,FRCPC EM & CCM
Electrolyte Correction
Mg
 Many patients on diuretic therapy are also
magnesium-depleted, even when the measured
serum magnesium level is normal.
 If significant magnesium depletion is suggested,
1 to 2 g of magnesium sulfate can be given over
10 to 20 minutes (child: 25 mg/kg), followed by a
constant infusion of 1 to 2 g/hour.
Zohair Al Aseri MD,FRCPC EM & CCM
Atropine
 Atropine is generally used for severe
bradycardia and advanced AV block, with mixed
results.
 Generally,
an external or transvenous
pacemaker
should
be
prepared
when
bradycardia or AV block appears.
Zohair Al Aseri MD,FRCPC EM & CCM
Pacing
 It may be safer to temporize with an external
rather than a transvenous pacemaker while
waiting for Fab fragments to take effect.
 Cardioversion
and
asystole
after
tachydysrhythmias.
defibrillation
attempts
can
to
cause
treat
 Lower energy settings, such as 25 to 50 J, may
be less hazardous.
Zohair Al Aseri MD,FRCPC EM & CCM
Fab Fragments (Digibind or Digifab)
 Digitalis
antibodies are derived from sheep
immunized with digoxin.
Side Effect
 Reactions have included erythema, urticaria, and
facial edema, all of which are responsive to the
usual treatment.
 Hypokalemia
 Exacerbation of congestive heart failure
 Increase in ventricular rate with atrial fibrillation.
Zohair Al Aseri MD,FRCPC EM & CCM
Fab Fragments (Digibind or Digifab)
 Indicated for serious cardiovascular toxicity
 Not for prophylactic administration of higher
than expected serum levels.
 The primary indication for antibody treatment in
cases of acute poisoning is hyperkalemia with a
serum potassium level greater than 5.5 mEq/L
or ECG changes.
Zohair Al Aseri MD,FRCPC EM & CCM
Fab Fragments (Digibind or Digifab)
 Fab fragment therapy should be used before
transvenous pacing, which carries significant
risk.
Zohair Al Aseri MD,FRCPC EM & CCM
RECOMMENDATIONS FOR ADMINISTRATION
OF DIGITALIS ANTIBODY FRAGMENTS
Zohair Al Aseri MD,FRCPC EM & CCM
Disposition and
Summary
 All patients who are symptomatic for digitalis
intoxication with hyperkalemia, dysrhythmia, AV
block, or significant comorbidity should be
admitted to the hospital or the emergency
department observation unit for at least 12 hours
of continuous cardiac monitoring.
 All patients treated with antibodies require
admission to an intensive care unit.
Zohair Al Aseri MD,FRCPC EM & CCM
ED Evaluation
Important to know:
 time of ingestion
 specific name of the medication
 number of pills ingested
 formulation
(i.e., immediate release vs. sustained release)
 dose per tablet
 co-ingestants
 chronic medications taken as prescribed
 alcohol, or illicit drugs.
Zohair Al Aseri MD,FRCPC EM & CCM
Zohair Al Aseri MD,FRCPC EM & CCM
Main reference is Rosen Text book of EM
Thank you
Zohair Al Aseri MD,FRCPC EM & CCM