Transcript Digitalis Intoxication

Suhail Allaqaband
Sinai Samaritan Medical Center
Milwaukee, WI
Digitalis Intoxication
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Cardiac glycoside poisoning is a potentially
life-threatening problem
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In a series of 150 severely affected patients
• 50 % were receiving long-term digitalis therapy,
• 10 %had taken an accidental large overdose, and
• 40 % had ingested an overdose with suicidal intent
Treatment of 150 cases of life-threatening digitalis
intoxication with digoxin-specific Fab antibody fragments.
Final report of a multicenter study.
Circulation 1990; 81:1744
Digitalis Intoxication
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The mortality in different studies has ranged from
3 to 40 percent
 Recent advances have considerably lowered the
incidence of digitalis overdose in patients
receiving chronic therapy. These include:
• A better understanding of pharmacokinetics, leading to
more appropriate maintenance dosing
• Increasing awareness of drugs that can affect digoxin
metabolism
• The development of radioimmunoassays for plasma
digoxin levels
PHARMACOLOGY
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Digitalis acts at the subcellular level by inhibiting
the membrane-bound Na-K-ATPase pump
 The net effect is the intracellular loss of potassium
and the gain of sodium and calcium
 Drug action depends on the tissue conc., which is
relatively constant in relation to plasma levels
 Thus, plasma levels can be used to monitor
compliance and toxicity
PHARMACOLOGY
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The two digitalis preparations used in clinical practice
today are digoxin and digitoxin
The bioavailability of digoxin is about 80 % and
plasma half-life is 1.6 days
Major depot for digitalis in humans is skeletal muscle
As a result, dosage requirements and the likelihood of
toxicity are related to muscle mass rather than total
body weight
Approximately one-third of the body stores of digoxin
is excreted per day – 30 % unchanged in the urine, and
3 % as metabolites in stool
PREDISPOSING FACTORS TO
TOXICITY
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Drug Interactions
• A number of drugs can raise digitalis levels by
interfering with its metabolism or renal excretion
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Renal insufficiency
• End-stage renal disease, prolongs the half-life of
digoxin and reduces its volume of distribution
• There must be reductions both in the loading dose (by
about 40 percent) and in the maintenance dose (by 50
to 75 percent) in this setting
PREDISPOSING FACTORS TO
TOXICITY
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Finally, there are a number of factors that can
increase the sensitivity to digoxin and predispose
to toxicity at plasma levels at the upper limits of
normal
• old age,
• certain cardiac diseases - active ischemia, myocarditis,
cardiomyopathy, cardiac amyloidosis, cor pulmonale
• metabolic factors - hypokalemia, hypomagnesemia,
hypoxemia, hypernatremia, hypercalcemia, and acidbase disturbances
CLINICAL MANIFESTATIONS
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There are multiple, mostly nonspecific
manifestations of digitalis toxicity
 These include fatigue, blurred vision, disturbed
color perception, anorexia, nausea, vomiting,
diarrhea, abdominal pain, headache, dizziness,
confusion, delirium, and occasionally
hallucinations
 Cardiac arrhythmias are responsible for mortality
in this setting and may take almost any form
CLINICAL MANIFESTATIONS
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The combination of SVT and AV block, for
example, is highly suggestive of digitalis toxicity
 Although hypokalemia predisposes to digitalis
toxicity, massive overdose can lead to
hyperkalemia as inhibition of the Na-K-ATPase
pump impairs potassium entry into cells
 Plasma digoxin levels are markedly elevated in
these patients, usually being above 10 ng/mL
Other signs of toxicity can occur at lower levels of
3 to 5 ng/mL
PLASMA DIGOXIN LEVELS
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Plasma digoxin levels should be measured at least
6 hours after the last dose, since this is the time
required for attainment of the steady state
The plasma digoxin concentration should be used only
as a guide to appropriate therapeutic dosing
Several factors (importantly hypokalemia) can
predispose to toxicity at levels below 2 ng/mL, which
is considered the upper limit of normal
On the other hand, clearly elevated levels (above 3
ng/mL) can be seen in asymptomatic patients
PLASMA DIGOXIN LEVELS
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False positive elevations of plasma digoxin can occur in
newborns, pregnant women, and patients with chronic
renal failure or hepatobiliary disease
This problem is thought to result from increased levels
of endogenous digoxin-like substances
The highest values (up to 4 ng/mL) are seen in neonates
Smaller errors of 0.6 to 1.8 ng/mL have been described
in the third trimester of pregnancy, renal failure, and
combined hepatic and renal failure
Large doses of steroid derivatives, such as
spironolactone and methylprednisolone, can cross react
with the digoxin radioimmunoassay
GENERAL PRINCIPLES OF
THERAPY
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Gastrointestinal decontamination
• ipecac-induced emesis or lavage is carried out with
care to avoid vagal stimulation which may worsen
existing conduction block
• activated charcoal effectively adsorbs digitalis, if
ingestion has occurred within 6-8 hours
• repeated doses can be given to adsorb active
metabolites as they are excreted by the biliary tract
• cholestyramine is an alternative to activated
charcoal
GENERAL PRINCIPLES OF
THERAPY
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Correction of electrolyte imbalances
• Hypokalemia, hypomagnesemia, and other
electrolyte disorders should be corrected
• Potassium replacement should be given carefully,
since raising the plasma potassium concentration
can increase atrioventricular block
• Some acutely intoxicated patients present with
severe hyperkalemia, requiring therapy with
glucose and insulin and sodium bicarbonate
GENERAL PRINCIPLES OF
THERAPY
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Management of cardiac arrythmias
• Severe bradyarrhythmias are treated with atropine,
electrical pacing is used in unresponsive patients
• Therapy of cardiac ectopy is reserved for more
complex forms
• Lidocaine and phenytoin are antiarrhythmic drugs
of first choice
• Verapamil is useful for SVT’s
• Cardioversion should be limited to patients with
life-threatening arrhythmias and used at the lowest
effective energy level
DIGOXIN-SPECIFIC ANTIBODY
FRAGMENTS
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Digoxin-specific antibody Fab fragments
(Digibind®), purified from sheep IgG, rapidly
bind to circulating digoxin and are indicated in
• Ingestion of more than 10 mg of digoxin in adults or 4
mg in children
• Plasma digoxin concentration above 10 ng/mL
• A plasma potassium concentration above 5 meq/L in the
presence of life-threatening arrhythmia – ventricular
tachycardia or fibrillation, progressive bradycardia, or
high degree AV nodal block
Mechanism of action of Digibind
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The proposed sequence of events that occurs after infusion
of Fab fragments begins with rapid binding of
intravascular digoxin and is followed by diffusion of the
fragments into the interstitial space to bind free digoxin at
that site
 The affinity of the fragments for digoxin is greater than the
affinity of digoxin for Na-K ATPase
 The Fab fragments are relatively small (mol wt 50,000)
which allows them and bound digoxin to be rapidly
excreted by glomerular filtration in patients with nearnormal renal function
 The elimination half-life of the fragments is 15 to 20 hours
in this setting
Digibind
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Digibind can also be successfully in patients with
renal insufficiency, including those on
maintenance dialysis
 In the largest study, 18 patients had a pretreatment
plasma creatinine concentration of more than
5 mg/dL, including five who were on dialysis
 These patients responded to Digibind in a manner
similar to patients with normal renal function
Efficacy of Digibind
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In the largest series of 150 patients with lifethreatening digitalis toxicity,
• 80 percent had resolution of all signs and symptoms,
• 10 percent improved, and
• 10 percent showed no response
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The median time to initial response was 19
minutes and the time to complete response was 88
minutes
 Of the patients who experienced cardiac arrest, 54
percent survived hospitalization
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Several factors which contribute to partial
responses or resistance include,
• underlying heart disease that was the true cause of some
of the presumed manifestations of digitalis toxicity,
• too low a dose of Fab, and
• treatment of patients who were already moribund
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A dramatic fall in the plasma potassium concentration
can occur after digibind therapy
The decline in the plasma potassium concentration
begins within one hour and is complete within 4 hrs
Thus, monitoring of the plasma potassium
concentration should be performed in all patients
receiving this therapy
Side effects of digibind therapy
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Despite the improvement induced by digibind,
potentially important side effects can occur
• exacerbation of congestive heart failure,
• increased ventricular response in patients with A-fib.
• hypokalemia
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Idiosyncratic allergic manifestations are very rare,
occurring in less than one percent of cases
 Plasma digoxin measurements are unreliable for
one to two weeks after fragment therapy
Dosing regimen for digoxin-specific
antibody fragments
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Total body load of digitalis (TBL, in mg) =
SDC (serum digitalis concentration) x volume of
distribution x weight (kg)
 The serum digitalis concentration is measured in
ng/mL and for digoxin, the volume of distribution
is 5.6 L/kg, therefore
• TBL = (SDC x 5.6 x weight) ÷ 1000
 One vial of digibind contains 40 mg, which
neutralizes approximately 0.6 mg of digoxin
Dosing regimen for digoxin-specific
antibody fragments
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Number of vials = TBL ÷ 0.6
Or
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Number of vials = (SDC x weight) ÷ 100
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If the amount ingested is known, then the TBL can
be calculated directly:
 TBL = Dose ingested (mg) x 0.8 for digoxin
which has 80 percent bioavailability
 If the SDC and the amount ingested are not
known, then digibind is given empirically
according to the following regimen
 For an acute overdose in adults:
• Give 10 vials; repeat with another 10 vials if indicated
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With chronic toxicity:
• Give 6 vials to an adult, one vial to a child
EXTRACORPOREAL TECHNIQUES
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Hemodialysis or hemoperfusion can help control
hyperkalemia or volume overload in patients with
concurrent renal failure
 They are, however, of limited utility in removal of
digoxin because of its extensive tissue binding and
very large volume of distribution (5.6 L/kg)