Suhail Allaqaband Sinai Samaritan Medical Center Milwaukee, WI

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Suhail AllaqabandSinai Samaritan Medical
CenterMilwaukee, WI
Digitalis Intoxication
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Digitalis Intoxication

• Cardiac glycoside poisoning is a potentially
  life-threatening problem
• 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 811744

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Digitalis Intoxication

• 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

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PHARMACOLOGY

• 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

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PHARMACOLOGY

• 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

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PREDISPOSING FACTORS TO TOXICITY

• Drug Interactions
• A number of drugs can raise digitalis levels by
  interfering with its metabolism or renal
  excretion
• 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

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PREDISPOSING FACTORS TO TOXICITY

• 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
  acid-base disturbances

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CLINICAL MANIFESTATIONS

• 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

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CLINICAL MANIFESTATIONS

• 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

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PLASMA DIGOXIN LEVELS

• 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

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PLASMA DIGOXIN LEVELS

• 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

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GENERAL PRINCIPLES OF THERAPY

• 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

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GENERAL PRINCIPLES OF THERAPY

• 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

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GENERAL PRINCIPLES OF THERAPY

• 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 SVTs
• Cardioversion should be limited to patients with
  life-threatening arrhythmias and used at the
  lowest effective energy level

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DIGOXIN-SPECIFIC ANTIBODY FRAGMENTS

• 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

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Mechanism of action of Digibind

• 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 near-normal renal function
• The elimination half-life of the fragments is 15
  to 20 hours in this setting

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Digibind

• 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

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Efficacy of Digibind

• In the largest series of 150 patients with
  life-threatening digitalis toxicity,
• 80 percent had resolution of all signs and
  symptoms,
• 10 percent improved, and
• 10 percent showed no response
• 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
• 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

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Side effects of digibind therapy

• 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
• 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

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Dosing regimen for digoxin-specific antibody
fragments

• 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

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Dosing regimen for digoxin-specific antibody
fragments

• Number of vials TBL 0.6
• Or
• 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
• With chronic toxicity
• Give 6 vials to an adult, one vial to a child

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EXTRACORPOREAL TECHNIQUES

• 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)