Digoxin toxicity: Difference between revisions

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==Background==
==Background==
*Cardioactive glycoside, a subset of cardioactive steroids, that comes from the foxglove plant, ''Digitalis lanata''


===Mechanism of Action===
{{Digoxin mechanism}}


Positive inotropic effect
===Adverse Effects===
*'''Increases vagal tone'''
**At toxic levels, digoxin can block the SA node's intrinsic impulses along with blocking AV nodal conductions
**Can lead to bradyarrhythmias (esp in young)
*'''Increases automaticity'''
**Digoxin acts on the Purkinje fibers by decreasing the resting potential, shortening the action potential duration, and causing enhanced automaticity leading to ventricular dysrhythmias (esp in elderly)


inhibits Na-K pump; ultimately increases intracellular Ca which leads to increased contractility
===Risk Factors===
*Recent dose increase
*Electrolyte Imbalance
**[[Hypokalemia]], [[Hyperkalemia]], [[Hypomagnesemia]], [[Hypercalcemia]]
*Hypovolemia
*Renal insufficiency
**Digoxin is renally cleared thus any injury to the kidney can lead to accumulation
*[[Cardiac Ischemia]]
*[[Hypothyroidism]]
*Meds
**[[Calcium_channel_blockers|Calcium-Channel Blockers]], [[Amiodarone]]


AV block
===Environmental Exposures===
*Plants that contain cardiac glycosides:
**Oleander
**Foxglove
**Lily of the valley
**Milkweed


===Acute vs. Chronic===
{| class="wikitable"
| align="center" style="background:#f0f0f0;"|'''Category'''
| align="center" style="background:#f0f0f0;"|'''Acute'''
| align="center" style="background:#f0f0f0;"|'''Chronic'''
|-
| Mortality||Lower||Higher
|-
| Arrythmias||Bradycardia / AV block more common||Ventricular dysrhythmias more common
|-
| Age||Younger||Older
|-
| Therapy||Often do not need Fab||Often need Fab therapy
|}


RISK FACTORS
==Clinical Features==
===Cardiac===
[[File:Digtox.jpg|thumb|Digitalis effect]]
*[[Syncope]]
*[[Dysrhythmias]]
**[[PVCs]] (most common)
**[[Bradycardia]]
**[[SVT]] with AV block
**Junctional escape
**Increased Automaticity: [[atrial tachycardia]], regularized [[atrial fibrillation]]
***Regularized AF is atrial fibrillation with 3rd degree AV block and a junctional escape rhythm
***Atrial fibrillation with an underlying regular ventricular rate is suspicious (but not pathognomonic) for Digoxin toxicity
**[[Ventricular dysrhythmias]], including bidirectional V-tach (esp in chronic toxicity)
***Bidirectional [[vtach]] is pathognomonic for digoxin toxicity
*[[Digitalis Effect]] (seen with therapeutic levels; not indicative of toxicity)
**T wave changes (flattening or inversion)
**QT interval shortening
**Scooped ST segments with depression in lateral leads
***Sometimes referred to as the 'Salvador Dali mustache'
**Increased U-wave amplitude


Increased sensitivity to dig
===GI===
*Often the earliest manifestation of toxicity
**[[Nausea/vomiting]]
**[[Abdominal Pain]]


    -electrolyte disturbances (eg hypoK)
===Neuro===
*[[Confusion]]
*[[Weakness]]
*[[Visual disturbances]]
**Yellow halos
**Scotomas
*[[Delirium]]


    -hypoxia
===Metabolic===
*[[Hyperkalemia]] (acute poisoning)
*[[Hypokalemia]]
*[[Hypomagnesemia]]
**Worsens toxicity


    -cardiac ischemia
==Differential Diagnosis==
{{Symptomatic bradycardia}}
{{Tachycardia (wide) DDX}}


    -Increased Dig levels
==Evaluation==
===Work-Up===
*Digoxin level
**Only useful prior to administration of [[Fab]] (otherwise becomes falsely elevated)
*Chemistry
*Urine output
*[[ECG]] (serial)
**PVCs most common arrhythmia
**May see "regularized AF" on ECG where junctional escape rhythm takes over secondary to complete AV block
**Atach/Aflutter with slow conduction


    -renal insufficiency
===Evaluation===
*Must use H&P and labs in combination; no single element excludes or confirms the diagnosis
*Digoxin level
**Normal = 0.5-2 ng/mL (ideal = 0.7-1.1)
***May have toxicity even with "therapeutic" levels (especially with chronic toxicity)
**Measure at least 6hr after acute ingestion (if stable); immediately for chronic ingestion
***Steady state level (6-8 hours after ingestion) and not peak level is used to guide therapy
***If measure before this may be falsely elevated due to incomplete drug distribution
***Not practical to wait 6-8 hours for intervention so clinical picture should guide decision making
*Potassium level
**Acute toxicity: Degree of [[Hyperkalemia]] correlates with degree of toxicity
***Historical studies show K+ >5.5 mEq/L 100% mortality; K+ < 5 mEq/L 100% Survival <ref>Bismuth C et al. Hyperkalemia in acute digitalis poisoning: prognostic significance and
therapeutic implications. Clin Toxicol. 1973; 6(2): 153–62.</ref>
**Chronic toxicity: K+ may be normal/low (concomitant diuretic use), or high (renal failure)
***Hypokalemia sensitizes myocardium to digoxin <ref>Shapiro W. Correlative studies of serum digitalis levels and the arrhythmias of digitalis intoxication. Am J Cardiol. 1978; 41(5):852-9.</ref>
*Magnesium level
**hypomagnesemia can enhance digoxin's effects


    -CCBs
==Management==
''See [[Stone Heart]] for controversy regarding administration of calcium in digoxin toxicity''
*'''[[Digoxin Immune Fab]]'''
**Indications
***Ventricular dysrhythmias: PVCs most common, Bidirectional [[VTach]] is rare (but pathognomonic for digoxin toxicity)
***Symptomatic bradycardias unresponsive to atropine
***Hyperkalemia >5.0 mEq/L secondary to digitalis intoxication
***Coingestions of cardiotoxic drugs (beta-blockers, cyclic antidepressants)
***Acute digoxin ingestion of greater than 10 mg in adults or greater than 4 mg in children
***Acute digoxin ingestion with post distribution digoxin >10 ng/mL (by 6 hours post ingestion)
***Chronic digoxin ingestion leading to steady state serum digoxin concentrations of >4 ng/ml
*[[Activated Charcoal]]
**Questionable efficacy
**Only an adjunctive treatment; NOT an alternative to fab fragment therapy
**Consider only if present within 1 hr of ingestion
**1 g/kg (max 50 g)
*Digoxin has high volume of distribution so not readily removed by dialysis


===Dysrhythmias===
*[[Digoxin Immune Fab]] is the agent of choice for all dysrhythmias!
*[[Cardioversion]] should only be used as a last resort (may precipitate V-Fib)
**Consider lower energy settings (25-50J)
*Bradyarrhythmias (symptomatic)
**[[Atropine]] 0.5 mg IV
**[[Pacing]]
***Avoid transvenous if possible as myocardium is irritated
*Ventricular dysrhythmias
**[[Dilantin Load|Phenytoin]]
***Enhances AV conduction
***Phenytoin: 15-20 mg/kg at 50 mg/min
***Fosphenytoin: 15-20 mg PE/kg at 100-150 mg/min
**[[Lidocaine]]
***Decreases ventricular automaticity
***1-3 mg/kg over several minutes; follow by 1-4 mg/min
**[[Magnesium]]
***Many patients have [[Hypomagnesemia]] and labs can be unreliable
***2-4 g IV over 20-60 mins


==Diagnosis==
===[[Hyperkalemia]]===
*The most important predictor of outcome in the setting of digoxin toxicity
*Treat with [[Fab]], not with usual meds
**Once Fab is given hyperkalemia will rapidly correct
*If [[Fab]] unavailable and hyperkalemia is life-threatening then treat with:
**[[Dextrose]]-[[insulin]]
**[[Sodium bicarb]]
**[[Kayexylate]]
**[[Dialysis]]
**[[Calcium]] (controversial: some say dangerous, others say not)
***Theoretical concern for inducing "[[stone heart]]"; Ca channels open and may lead to cardiac muscle tetany
***Chronic digoxin toxic patients likely have hyperkalemia from [[renal failure]], and calcium administration is likely safe in these patients<ref>Levine M, Nikkanen H, Pallin DJ. The effects of intravenous calcium in patients with digoxin toxicity. J Emerg Med. 2011 Jan;40(1):41-6. doi: 10.1016/j.jemermed.2008.09.027. Epub 2009 Feb 6.</ref>
***Acutely toxic patients will not benefit from calcium, and priority must be placed on administering DigiFab


===[[Hypokalemia]]===
*Chronic intoxication
**Raise level to 3.5-4
*Acute intoxication
**Do not treat (likely that potassium level is rapidly rising)


Toxic Side Effects
===[[Hypomagnesemia]]===
*Treat with 1-2g over 10-20 min
**Monitor for respiratory depression
**Avoid in patients with:
***Renal failure
***Bradydysrhythmias/conduction blocks


GI
==Disposition==
*Admit for signs of toxicity or history of large ingested dose; admit to ICU if [[Fab]] given
*Discharge after 12hr observation if asymptomatic after accidental overdose
*Of note<ref>Pharmacy Times. Feb 2016. Digoxin Overdose: Still No Role for Dialysis. https://www.pharmacytimes.com/contributor/craig-cocchio-pharmd/2016/02/digoxin-overdose-still-no-role-for-dialysis.</ref>:
**No routine role for hemodialysis
**Rechecking digoxin levels after Digifab is given is clinically useless, as both free and bound levels are measured


    -N/V
==See Also==
*[[Digoxin Immune Fab]]
*[[Toxidromes]]
*[[Digoxin]]


Neurologic
==External Links==
*[http://www.mdcalc.com/corrected-qt-interval-qtc/ MDCalc - Corrected QT Interval]
*[https://emcrit.org/toxhound/bindornot/ Tox and Hound – To Bind or Not To Bind]


    -Classic: yellow hallows around vision
==References==
 
<references/>
Cardiac
[[Category:Cardiology]]
 
[[Category:Pharmacology]]
Vagal
[[Category:Toxicology]]
 
    Rhythm disturbances
 
    -depressed condxn/impulse formation
 
    -enhanced automaticity
 
    -can see almost any rhythm except afib with RVR; hence there is no diagnostic arrhythmia
 
    -serum dig levels often not helpful*
 
HyperK
 
    -asscociated with worse outcomes in acute OD
 
 
 
==Treatment==
 
 
-Gastric empytying if SOON after ingestion
 
Charcoal (need 10x the ingested dose); usually 25-100g PO
 
Toxic effects may be delayed SEVERAL hours (serum/myocardial levels equilibrate in 6-8h)
 
Temporary discontinuation of dig often sufficient
 
Tx of hyperkalemia
 
    -bicarb, glucose/insulin may be ineffective
 
    -calcium contraindicated (usually)
 
    -dig-Ab
 
    -Forced diuresis, hemodialysis, hemoperfusion ineffective in removing dig
 
 
Indications for Rx of rhythm disturbances
 
    -hemodynamic compromise caused by bradycardia or tachycardia
 
    -frequent/complex ventricular ectopy
 
 
Bradycardia
 
    -Atropine
 
    -Electrical pacing
 
    -K contraindicated UNLESS severe hypok*
 
          -if tachycardic, give K*
 
          -if bradycardic, can worsen with K*
 
 
Tachyarrhythmias, increased automaticity
 
    -K
 
    -Mag
 
    -Lidocaine
 
    -Phenytoin
 
    -Cardioversion
 
 
Digibind
 
    -Ab bind to dig, remove drug from serum and myocardium
 
    -Ab-dig complex excreted in the urine
 
 
Indications
 
    -severe rhythm disturbances refractory to conventional therapy
 
    -hyperkalemia >5 after ACUTE OD
 
    -very large ingested dose or very high serum dig level (eg4-10)
 
    -co-ingestion of cardiotoxic drugs: CCBs, beta-blockers, or TCAs
 
 
Empiric Dosages
 
-Acute Ingestion: give 10-20 vials over 30 minutes through 0.22 micron filter
 
-Chronic toxicity and unkown level: 4-6 vials (1/2 vial in child)
 
-Cariac arrest = 20 vials undiluted by IV bolus
 
 
Calculated Dosages: see package insert
 
-1 vial (40mg) binds 0.6mg dig
 
-Dose (vials) = body load (mg)/0.6 (mg/vial)
 
      -dig body load estimated from ingested dose or serum level
 
    -(dig level x wt in kg)/ 100 = # of vials
 
 
Kinetics
 
-Onset: 20mins
 
-Full effect: 90mins
 
 
**Note** digitalis level unreliable after digibind administration, must follow patient clinically
 
 
==Complications==
 
 
-potential allergic reactions
 
-w/d of dig effect:
 
    -CHF
 
    -hypoK
 
    -dig levels not usable
 
 
==Source==
 
 
Adapted from Rosens 7th Edition
 
 
 
 
[[Category:Tox]]

Latest revision as of 20:10, 17 April 2024

Background

  • Cardioactive glycoside, a subset of cardioactive steroids, that comes from the foxglove plant, Digitalis lanata

Mechanism of Action

  • Inhibits Na+/K+ ATPase in the myocardium[1]
    • Causes increase in intracellular sodium levels
    • Results in reversal of sodium-calcium exchanger
      • Normally imports three extracellular sodium ions into the cardiac myocyte in exchange for one intracellular calcium being exported
    • Sodium accumulates intracellularly and is exchanged for Calcium.
    • Causes an increase in the intracellular calcium concentration increasing contractility
      • Also a lengthening of phase 4 and phase 0 of the cardiac action potential which ultimately decreases heart rate
  • Summary
    • Inhibits NaK pump
      • Positive inotropy
    • Negative chronotropy/dromotropy
      • Indirect vagal stimulator

Adverse Effects

  • Increases vagal tone
    • At toxic levels, digoxin can block the SA node's intrinsic impulses along with blocking AV nodal conductions
    • Can lead to bradyarrhythmias (esp in young)
  • Increases automaticity
    • Digoxin acts on the Purkinje fibers by decreasing the resting potential, shortening the action potential duration, and causing enhanced automaticity leading to ventricular dysrhythmias (esp in elderly)

Risk Factors

Environmental Exposures

  • Plants that contain cardiac glycosides:
    • Oleander
    • Foxglove
    • Lily of the valley
    • Milkweed

Acute vs. Chronic

Category Acute Chronic
Mortality Lower Higher
Arrythmias Bradycardia / AV block more common Ventricular dysrhythmias more common
Age Younger Older
Therapy Often do not need Fab Often need Fab therapy

Clinical Features

Cardiac

Digitalis effect
  • Syncope
  • Dysrhythmias
    • PVCs (most common)
    • Bradycardia
    • SVT with AV block
    • Junctional escape
    • Increased Automaticity: atrial tachycardia, regularized atrial fibrillation
      • Regularized AF is atrial fibrillation with 3rd degree AV block and a junctional escape rhythm
      • Atrial fibrillation with an underlying regular ventricular rate is suspicious (but not pathognomonic) for Digoxin toxicity
    • Ventricular dysrhythmias, including bidirectional V-tach (esp in chronic toxicity)
      • Bidirectional vtach is pathognomonic for digoxin toxicity
  • Digitalis Effect (seen with therapeutic levels; not indicative of toxicity)
    • T wave changes (flattening or inversion)
    • QT interval shortening
    • Scooped ST segments with depression in lateral leads
      • Sometimes referred to as the 'Salvador Dali mustache'
    • Increased U-wave amplitude

GI

Neuro

Metabolic

Differential Diagnosis

Symptomatic bradycardia

Wide-complex tachycardia

Assume any wide-complex tachycardia is ventricular tachycardia until proven otherwise (it is safer to incorrectly assume a ventricular dysrhythmia than supraventricular tachycardia with abberancy)

^Fixed or rate-related

Evaluation

Work-Up

  • Digoxin level
    • Only useful prior to administration of Fab (otherwise becomes falsely elevated)
  • Chemistry
  • Urine output
  • ECG (serial)
    • PVCs most common arrhythmia
    • May see "regularized AF" on ECG where junctional escape rhythm takes over secondary to complete AV block
    • Atach/Aflutter with slow conduction

Evaluation

  • Must use H&P and labs in combination; no single element excludes or confirms the diagnosis
  • Digoxin level
    • Normal = 0.5-2 ng/mL (ideal = 0.7-1.1)
      • May have toxicity even with "therapeutic" levels (especially with chronic toxicity)
    • Measure at least 6hr after acute ingestion (if stable); immediately for chronic ingestion
      • Steady state level (6-8 hours after ingestion) and not peak level is used to guide therapy
      • If measure before this may be falsely elevated due to incomplete drug distribution
      • Not practical to wait 6-8 hours for intervention so clinical picture should guide decision making
  • Potassium level
    • Acute toxicity: Degree of Hyperkalemia correlates with degree of toxicity
      • Historical studies show K+ >5.5 mEq/L 100% mortality; K+ < 5 mEq/L 100% Survival [2]
    • Chronic toxicity: K+ may be normal/low (concomitant diuretic use), or high (renal failure)
      • Hypokalemia sensitizes myocardium to digoxin [3]
  • Magnesium level
    • hypomagnesemia can enhance digoxin's effects

Management

See Stone Heart for controversy regarding administration of calcium in digoxin toxicity

  • Digoxin Immune Fab
    • Indications
      • Ventricular dysrhythmias: PVCs most common, Bidirectional VTach is rare (but pathognomonic for digoxin toxicity)
      • Symptomatic bradycardias unresponsive to atropine
      • Hyperkalemia >5.0 mEq/L secondary to digitalis intoxication
      • Coingestions of cardiotoxic drugs (beta-blockers, cyclic antidepressants)
      • Acute digoxin ingestion of greater than 10 mg in adults or greater than 4 mg in children
      • Acute digoxin ingestion with post distribution digoxin >10 ng/mL (by 6 hours post ingestion)
      • Chronic digoxin ingestion leading to steady state serum digoxin concentrations of >4 ng/ml
  • Activated Charcoal
    • Questionable efficacy
    • Only an adjunctive treatment; NOT an alternative to fab fragment therapy
    • Consider only if present within 1 hr of ingestion
    • 1 g/kg (max 50 g)
  • Digoxin has high volume of distribution so not readily removed by dialysis

Dysrhythmias

  • Digoxin Immune Fab is the agent of choice for all dysrhythmias!
  • Cardioversion should only be used as a last resort (may precipitate V-Fib)
    • Consider lower energy settings (25-50J)
  • Bradyarrhythmias (symptomatic)
    • Atropine 0.5 mg IV
    • Pacing
      • Avoid transvenous if possible as myocardium is irritated
  • Ventricular dysrhythmias
    • Phenytoin
      • Enhances AV conduction
      • Phenytoin: 15-20 mg/kg at 50 mg/min
      • Fosphenytoin: 15-20 mg PE/kg at 100-150 mg/min
    • Lidocaine
      • Decreases ventricular automaticity
      • 1-3 mg/kg over several minutes; follow by 1-4 mg/min
    • Magnesium
      • Many patients have Hypomagnesemia and labs can be unreliable
      • 2-4 g IV over 20-60 mins

Hyperkalemia

  • The most important predictor of outcome in the setting of digoxin toxicity
  • Treat with Fab, not with usual meds
    • Once Fab is given hyperkalemia will rapidly correct
  • If Fab unavailable and hyperkalemia is life-threatening then treat with:
    • Dextrose-insulin
    • Sodium bicarb
    • Kayexylate
    • Dialysis
    • Calcium (controversial: some say dangerous, others say not)
      • Theoretical concern for inducing "stone heart"; Ca channels open and may lead to cardiac muscle tetany
      • Chronic digoxin toxic patients likely have hyperkalemia from renal failure, and calcium administration is likely safe in these patients[4]
      • Acutely toxic patients will not benefit from calcium, and priority must be placed on administering DigiFab

Hypokalemia

  • Chronic intoxication
    • Raise level to 3.5-4
  • Acute intoxication
    • Do not treat (likely that potassium level is rapidly rising)

Hypomagnesemia

  • Treat with 1-2g over 10-20 min
    • Monitor for respiratory depression
    • Avoid in patients with:
      • Renal failure
      • Bradydysrhythmias/conduction blocks

Disposition

  • Admit for signs of toxicity or history of large ingested dose; admit to ICU if Fab given
  • Discharge after 12hr observation if asymptomatic after accidental overdose
  • Of note[5]:
    • No routine role for hemodialysis
    • Rechecking digoxin levels after Digifab is given is clinically useless, as both free and bound levels are measured

See Also

External Links

References

  1. ↑ Gheorghiade M. et al. Digoxin in the Management of Cardiovascular Disorders. Circulation. 2004; 109: 2959-2964
  2. ↑ Bismuth C et al. Hyperkalemia in acute digitalis poisoning: prognostic significance and therapeutic implications. Clin Toxicol. 1973; 6(2): 153–62.
  3. ↑ Shapiro W. Correlative studies of serum digitalis levels and the arrhythmias of digitalis intoxication. Am J Cardiol. 1978; 41(5):852-9.
  4. ↑ Levine M, Nikkanen H, Pallin DJ. The effects of intravenous calcium in patients with digoxin toxicity. J Emerg Med. 2011 Jan;40(1):41-6. doi: 10.1016/j.jemermed.2008.09.027. Epub 2009 Feb 6.
  5. ↑ Pharmacy Times. Feb 2016. Digoxin Overdose: Still No Role for Dialysis. https://www.pharmacytimes.com/contributor/craig-cocchio-pharmd/2016/02/digoxin-overdose-still-no-role-for-dialysis.
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