Physiology and Pathophysiology
1) ionotropy:
- Binds and inactivates membrane bound Na/K ATPase which is responsible for mainataining the normal Na/K gradiants
- This results in increased intracellular Na, decreased intracellular K ( at toxic levels it results in extracellular hyperkalemia)
Therefore get increased Na / Ca exchange via Na/Ca pump which leads to increased intracellular Calcium concentrations, the calcium interacts with actin-myosin and increases force of contraction
When toxic levels of digoxin poison the Na/K ATPase pump, K+ cannot enter cells and K+ levels as high as 13.5mEq/L have been reported
Because intracellular calcium levels are increased, administering calcium ( a common treatment for hyperkalemia) can be dangerous in the dig-poisoned patient
2) direct and indirect effects on electrical activity including SA and AV nodes ( slows ventricular rate in A Fib):
- Low (therapeutic) concentrations do not affect the AV node directly. It acts indirectly via increased vagal influences and decreased sympathetic influences - slows AV conduction and variably decreases sinus rate
- At toxic concentrations the indirect effects combine with direct conduction inhibition on SA and AV nodes resulting in sinus arrest, bradycardias, high degree AV block
- Low concentrations in atrial conduction fibres, Purkinje, atrial and ventricular muscle, increase slope of phase 4 depolarization, decrease resting potential, decrease ADP. This combination of effects produces the "dig effect" on EKG.
Toxic concentrations produce increased automaticity especially in hypokalemia by sharply increasing phase 4 depolarization = non re-entrant atrial, junctional, ventricular tachycardias. Toxic concentrations also increase SA and AV node sensitivity to catecholamines making tachydysrhythmias more likely with endogenously administered catecholamines.
Digitalis also exerts three primary effects on Purkinje fibres - it decreases resting potential resulting in slowed phase 0 depolarization and thus conduction, It decreases action potential duration which increases sensitivity to electrical stimulation; and it enhances automaticity due to increased rate of phase 4 repolarization. These mechanisms account for PVC's which are the most common manifestations of dig toxicity.
Bradydysrhythmias and tachydysrhythmias can appear and alternate in the same patient - treating one aggressively may lead to the opposite.
Thus at toxic levels digoxin has the following effects:
1) inhibition of Na/K ATPase pump - hyperkalemia
2) increases vagal tone, decreases SNS tone - decreases AV conduction
3) enhances automaticity - decreases resting membrane potential, ADP, increase slope of phase 4
4) enhances afterdepolarizations
the combination of increased automaticity with decreased AV conduction ( i.e.,rapid atrial or ventricular rhythms with evidence of high grade AV block) is highly suggestive of digoxin toxicity along with hyperkalemia
Clinical Findings
noncardiac - anorexia, n, v, weakness, malaise, headache, visual disturbance, confusion, hallucinations, delirium
General - weakness, fatigue, malaise
GI - nausea, vomiting, anorexia, abdominal pain, diarrhea
Opthalmologic - blurred vision, photophobia, yellow vision
Neurologic - headache, dizzyness, confusion, somnolence. Paranoia
CVS - palpitations, presyncope, syncope
- electrolytes abnormalities, BUN/Cr, Ca, Mg, dig level, EKG
-"dig effects" on EKG - downward sloping of ST segment, inverted T, subtle PR shortening
- Digoxin toxicity can produce virtually any dysrhythmia or conduction block. Afib/flutter with rapid ventricular response is the rhythm least likely to be associated. Every other type of ectopy, bradydysrhythmia, tachycardia, or conduction defect can occur.
Dysrhythmias associated with Digoxin Toxicityclassic dig toxic dysrhythmias - accelerated junctional, nonparoxysmal atrial tachycardia with 2:1 block, bidirectional VT, PVC
Nonspecific
PVC's, especially multiform or bigeminy
AV block ( any degree )
Sinus brady
Sinus tachy
SA node block or arrest
A fib with slow ventricular response
Atrial tachycardia
Junctional escape
AV dissociation
V tach
VF
Torsade
More specific ( But not pathognomonic)
A fib with slow, regular ventricular rate
Nonparoxysmal junctional tachycardia ( rate 70 -130)
Atrial tachy with block
Bidirectional V Tach
All of the above have evidence of both ectopy and block
Chronic vs. Acute
Chronic toxicity has higher mortality at lower levels ( lower LD50), generally normal or low serum potassium levels, and ventricular dysrhythmias are more common. Chronic toxicity more often occurs in the elderly with underlying heart diseaseand the onset is usually insidious. In acute toxicity ( intentional overdose) the potassium is often high, and bradycardias and heart blocks are more common.
Differential Diagnosis
- Symptoms and signs are very nonspecific
- dig toxicity only distinguished by EKG and level
- nonparoxysmal atrial tach with block, accelerated jn rhythm, bidirectional tachycardia always implies digitalis toxicity
- hyperkalemia in the abscence of renal failure or other causes
- r/o hypoxia, lyte, other drug effects, MI
Treatment
- ABC, O2, iv, monitor
- consider gastric emptying if within 2 hours and no bradycardias or conduction defects, this is controversial because the vagal stimulation of lavage can result in bradycardias or asystole
- MDAC ( multi-dose activated charcoal ) 50 g q2h if digitoxin ingested ( less effective for digoxin)
- large Vd and high degree of protein binding limits efficacy of Hemodialysis or HP
correct lytes including K, Mg but do not rx hyperK if giving digibind as this will cause K+ level to drop on its own. Do not treat hyperkalemia with calcium.!!
MgSO4 1-2 g iv push useful in VT, VF ( case reports)
atropine failure is indication for digibind, pacer
Transvenous pacer for atropine unrepsonsive bradycardias - but this may induce VF! It may be safer to temporize with a transcutaneous pacer followed by Digibind
- avoid class 1A antidysrhythmics, bretylium, isoproterenol - all may worsen dysrhytmias and further depress AV conduction -use dilantin, lidocaine, MgSO4
avoid Bretylium - releases catecholamines
Phenytoin (dilantin) may enhance AV conduction
- avoid cardioversion because digoxin lowers fibrillation threshold and refractory asystole has been reported, use lowest energy level if absolutely necessary
- avoid CaCl in unknown hypotensive, bradycardic patient with hyperkalemia (i.e., avoid calcium if digoxin toxicity is suspected and not rule out by level) Calcium could lead to systolic tetany and asystolic cardiac arrest.
Digibind
Mortality was high before digibind despite all the above interventions
Response rate 90% ( nonresponders get too little or too late )
- Fab fragment from sheep immunized with digoxin
- 50,000 daltons
- Fab is less immunogenic, larger Vd, eliminated renally
- binds free digoxin
- rapidly reverses conduction defects, ventricular dysrhythmias, pump failure, hyperkalemia
-can precipitate CHF or increase ventricular rate with A Fib ( also removes the therapeutic effects of dig as well as the toxicity)
- Can cause hypokalemia
- clinical response in 20 - 30 minutes
Indications
1) K > 5.0 with acute digoxin toxicity highly suspected ( 100 % mortality without digibind in acute tocicity with K+ > 5.5)
2) significant EKG abnormalities ( evidence of increased vagal tone and automaticity )
3) random levels > 15 ng/ml, staedy state level > 6 ng/ml
4) VT, VF, severe ventricular dysrhythmias, high degree AV block
5) symptomatic atropine resistant bradycardia
6) Acute ingestion > 10 mg plus any of the above
7) rapidly progressive rhythym disturbances of rising potassium level
8) Hemodynamic compromise with any digoxin-toxic dysrhythmia or block
The median time to initial response is 20 minutes and complete resolution may take hours, thus if you wait until cardiac arrest Digibind is not likely to be successful (54%)
Dose
- one 40 mg vial binds 0.6 mg digoxin
# vials required = total body load ( mg ) / 0.6 mg/vial
total body load = steady state serum level ( ng/ml ) x 0.56 L/kg x wt/1000
- in true emergency give 10 vials empirically without waiting for level
Cost
$250 - $300 per vial !!
Thus can cost $ 3000 - $ 6000 per treatment
Therefore should be used for life-threatening toxicity or potentially life-threatening toxicity although there is no clear consensus on these definitions.
References
Bismuth C, Gaultier FC, Efthymoiu ML: Hyperkalemia in acute digitalis poisoning: prognostic significance and therapeutic implications. Clin Toxicol 6:153,1973
Smith TW et al: reversal of advanced digoxin intoxication with Fab fragments of digoxin-specific antibodies. N Engl J Med 294:797,1976
Bismuth C et al: Acute digitoxin intoxication treated with intracardiac pacemaker. Experience in 68 patients. Clin Toxicol 10:443,1977
Taboulet P et al: Acute digitalis toxicity - Is pacing still appropriate? Clin Toxicol 31:261,1993
Kelly RA, Smith Tw: Recognition and management of digoxin toxicity. Am J cardiol 69:108G,1992
Cohen L, Kitzes R: Magnesium sulfate and digitalis-toxic arrhythmias. JAMA 249:2808,1983