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''


*Positive inotropic effect
===Mechanism of Action===
** Inhibits Na-K pump -> incr extracelluar K, incr intracellular Na -> incr intracellular Ca
{{Digoxin mechanism}}
*Increases vagal tone
**Bradyarrhythmias (esp in young)
*Increases automaticity
**Tachyarrhythmias (esp in elderly)
*Renally cleared
*Hemodialysis does not work
*1 fab vial binds 0.5mg of digoxin


== Risk Factors ==
===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)


*Electrolyte
===Risk Factors===
**Hypokalemia, hypomagnesemia, Hypercalcemia
*Recent dose increase
*Hypovolemia
*Electrolyte Imbalance
*Cardiac ischemia
**[[Hypokalemia]], [[Hyperkalemia]], [[Hypomagnesemia]], [[Hypercalcemia]]
*Renal insufficiency
*Hypovolemia  
*Hypothyroidism
*Renal insufficiency
*Meds
**Digoxin is renally cleared thus any injury to the kidney can lead to accumulation
**CCBs, amiodarone
*[[Cardiac Ischemia]]
*[[Hypothyroidism]]
*Meds  
**[[Calcium_channel_blockers|Calcium-Channel Blockers]], [[Amiodarone]]


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


Cardiac
===Acute vs. Chronic===
*Any type of dysrhythmia is possible except for rapidly conducted atrial arrhythmias
{| class="wikitable"
*Most common:
| align="center" style="background:#f0f0f0;"|'''Category'''
**PVCs
| align="center" style="background:#f0f0f0;"|'''Acute'''
**Bradycardia
| align="center" style="background:#f0f0f0;"|'''Chronic'''
*Digitalis Effect
|-
** T wave changes
| Mortality||Lower||Higher
** QT interval shortening
|-
** Scooped ST segments with depression in lateral leads
| Arrythmias||Bradycardia / AV block more common||Ventricular dysrhythmias more common
|-
| Age||Younger||Older
|-
| Therapy||Often do not need Fab||Often need Fab therapy
|}


GI
==Clinical Features==
*Nausea/vomiting
===Cardiac===
*Abdominal pain
[[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


Neuro
===GI===
*Confusion
*Often the earliest manifestation of toxicity
*Weakness
**[[Nausea/vomiting]]
*Visual disturbances
**[[Abdominal Pain]]
 
===Neuro===
*[[Confusion]]
*[[Weakness]]
*[[Visual disturbances]]
**Yellow halos
**Yellow halos
**Scotomas
**Scotomas
*Delirium
*[[Delirium]]


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


== Work-Up ==
==Differential Diagnosis==
{{Symptomatic bradycardia}}
{{Tachycardia (wide) DDX}}


*Dig level
==Evaluation==
**Normal = 0.8-2 ng/mL
===Work-Up===
***May have toxicity even with "therapeutic" levels
*Digoxin level
**Measure serum level at least 6 hours after acute ingestion, immediately for chronic ingestion
**Only useful prior to administration of [[Fab]] (otherwise becomes falsely elevated)
***If measure before this may be falsely elevated due to incomplete drug distribution
*Chemistry
*Chemistry
**Hyperkalemia level correlates with degree of toxicity
*** Hyperkalemia does not cause death; lowering K+ does not reduce mortality
**Hypokalemia increases susceptibility in chronic toxicity
**Hypomagnesemia is common
*Cr/BUN
*Urine output
*Urine output
* ECG (serial)
*[[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 <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


== Treatment ==
==Management==
 
''See [[Stone Heart]] for controversy regarding administration of calcium in digoxin toxicity''
'''Fab Fragment Therapy'''
*'''[[Digoxin Immune Fab]]'''
 
**Indications
*Indications
***Ventricular dysrhythmias: PVCs most common, Bidirectional [[VTach]] is rare (but pathognomonic for digoxin toxicity)
**Severe rhythm disturbances refractory to conventional therapy
***Symptomatic bradycardias unresponsive to atropine
**End-organ dysfunction
***Hyperkalemia >5.0 mEq/L secondary to digitalis intoxication
**Hyperkalemia >5 after acute overdose
***Coingestions of cardiotoxic drugs (beta-blockers, cyclic antidepressants)
**Pacemaker (may mask cardiac dysrhythmia)
***Acute digoxin ingestion of greater than 10 mg in adults or greater than 4 mg in children
**Consider for:
***Acute digoxin ingestion with post distribution digoxin >10 ng/mL (by 6 hours post ingestion)
***Dig level > 10 in acute ingestion
***Chronic digoxin ingestion leading to steady state serum digoxin concentrations of >4 ng/ml
***Dig level > 4 in chronic ingestion
*[[Activated Charcoal]]
***If adult acutely ingests > 10mg
**Questionable efficacy
***If child acutely ingests > 4mg
**Only an adjunctive treatment; NOT an alternative to fab fragment therapy
*Side effects
**Consider only if present within 1 hr of ingestion
**Allergic reaction
**1 g/kg (max 50 g)
**Withdrawal of dig effect:
*Digoxin has high volume of distribution so not readily removed by dialysis
***CHF, a fib w/ RVR
**Hypokalemia
 
*How To Use
**'''1. Neither amount ingested nor digoxin level are known:'''
***Adult dose
****10 vials over 30 min
***Peds dose
****5 vials over 30 min
***Peak effect occurs after 90min, initial response after 20min
****Repeat dose if clinical response is inadequate
**'''2. Amount ingested is known but digoxin level is unknown'''
**Step 1: Calculate total body load (TBL)
***TBL = dose (in mg) ingested
**Step 2: Calculate number of vials needed
***Number of vials = TBL X 2 (round up to nearest whole number)
**'''3. Steady state digoxin level is known'''
**Number of vials = (dig level(in ng/mL) X pt wt) / 100
**'''4. Chronic toxicity without severe signs'''
**Give half the recommended dose
***Otherwise may unmask the condition for which the pt is taking digoxin


'''Activated charcoal'''
===Dysrhythmias===
*Only an adjunctive tx; NOT an alternative to fab fragment therapy
*[[Digoxin Immune Fab]] is the agent of choice for all dysrhythmias!
*Consider only if present within 2 hr of ingestion
*[[Cardioversion]] should only be used as a last resort (may precipitate V-Fib)
*1g/kg (max 50g)
**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


'''Hyperkalemia'''
===[[Hyperkalemia]]===
*Do not treat! Do not give calcium!
*The most important predictor of outcome in the setting of digoxin toxicity
**Once fab is given hyperkalemia will rapidly correct
*Treat with [[Fab]], not with usual meds
***Aggressive tx with potassium-lowering agents could cause sig hypokalemia following therapy
**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'''
===[[Hypokalemia]]===
*Treat!
*Chronic intoxication
**Raise level to 3.5-4
*Acute intoxication
**Do not treat (likely that potassium level is rapidly rising)


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


*Rhythm Disturbance
==Disposition==
**Bradycardia (symptomatic)
*Admit for signs of toxicity or history of large ingested dose; admit to ICU if [[Fab]] given
***Atropine 0.5mg IV
*Discharge after 12hr observation if asymptomatic after accidental overdose
***Pacing
*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>:
**Tachyarrhythmias
**No routine role for hemodialysis
***K
**Rechecking digoxin levels after Digifab is given is clinically useless, as both free and bound levels are measured
***Mag
***Lidocaine
***Phenytoin
***Cardioversion


== Source ==
==See Also==
*[[Digoxin Immune Fab]]
*[[Toxidromes]]
*[[Digoxin]]


Rosen's, UpToDate
==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]


<br/>[[Category:Tox]] <br/><br/>
==References==
<references/>
[[Category:Cardiology]]
[[Category:Pharmacology]]
[[Category:Toxicology]]

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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