Gettin’ Digi Wit it

Digoxin Overdose

Core Rounds March 6, 2003

A.F. Chad, MD, CCFP

Randall Berlin, MD

The Fresh Prince

• After years of getting jiggy, Will Smith develops CHF and is Rx Digoxin

• He presents to the FHH feeling “not jiggy”

• What should you do?

Wild Wild West• Digoxin is a cardiac

glycoside from Foxglove plant– Other cardiac glycosides from

oleander, foxglove, and lily-of-the-valley

• Used in ancient Roman as cardiac med

• Physicians first studied 18th C

• Digoxin toxicity 1st described in 1785

Gettin’ Jiggy

• Inotropic effects via inhibition Na/K ATPase pump -> incr myocardial Ca -> more forceful contraction

• Increases automaticity in atrial and ventricular tissue

• Slows conduction through AV node (via parasympathomimetic tone)

Gettin’ Jiggy : ECG Effects

• Downward scooping of ST segment• Inverted T waves• Reduced T wave amplitude• Short QT interval• U waves• Prolonged PR interval• Does NOT affect QRS duration

Gettin’ Jiggy• Onset 5-30 mins IV, peak 1-4 hrs• Onset 30-120 mins po, peak 2-6 hrs• “N” levels = 0.6-2.6 nmol/L, most reliable 6 hrs post

ingestion• Narrow therapeutic window• Large Vd (5.6L/Kg)• Crosses BBB, placenta• Hepatic degredation (15%), excreted in urine (85%)• T1/2= 30-40hrs (4-6d in RF)

So Fresh• USA:

– 0.4% hospital admissions

– 1.1% of outpatients on digoxin

– 10-18% nursing home patients

• Internationally: – 2.1% of inpatients on

digoxin

– 0.3% of admissions

Yes, Yes, Y’all: ?Not that common?

• Williamson, KM, et al. Digoxin Toxicity:An Evaluation in Current Clinical Practice. Arch Intern Med. 1998;158:2444-2449

• 5 hospitals, dig levels taken in 3434, 2009 >2.6 nmol/L, only 83 (4.1%) clinical tox, 16% had levels < 6hrs

Men in Black

• Morbidity = 4.6-10%• 50% if digoxin level >

7.7nmol/L

Not So Fresh Prince

• Will Smith: “ My breathin’ is ill G, I gots me some palpitations, my guts be groovin’ like DJ Jazzy Jeff, and I be seein’ yellow-green, like them aliens in Men in Black.”

• Does this sound like he’s digi wit’ it?

Nod Ya Head

• Constitutional symptoms – (weakness, fatigue)

• CVS – (Palpitations, Syncope, Dyspnea)

• CNS – (Confusion and somnolence, Dizziness w/o vertigo,

Agitation, delirium, hallucinations, h/a, Paresthesias, neuropathic pain, Seizures (extremely rare)

Nod Ya Head

• Ocular – (Disturbances color vision with tendency to

yellow-green , Blurring, diplopia, Halos, scotomas, Photophobia)

• GI – (N&V&D, anorexia, Abdo pain (uncommon))

Nod Ya Head

• Acute

– Mainly Cardiac ad GI

• Chronic

– Can have any of the Symptoms

Big Willie Style• ANY arrhythmia • Classically: paroxysmal atrial tachycardia + 2:1

block, accelerated jnc, bidirectional VT, TdP• Typically: combo of increased ectopy or

automaticity with block• Acute or healthy heart more typical to have

bradyarrhythmias and blocks • Chronic or diseased hearts: enhanced automaticity

+ impaired conduction

Big Willie Style• Hemodynamic instability -> arrhythmia or CHF• PVCs most common arrhythmia • Sinus brad & bradyarrhythmias very common:

Slow a.fib with little variation in ventricular rate (regularization of the R-R interval)

• Heart block• Rapid a.fib or flutter is rare• VT• Cardiac arrest from asystole or VF usually fatal

Big Willie Style

• GI symptoms common, abdo exam nonspecific.• Neurological findings related to changes in

sensorium or mental status– Lateralizing findings usually indicate another disease

process.

• Visual changes occur, pupils are spared, objective findings few

• Drug-induced fever does not occur

Not So Fresh Prince

• Will Smith: “Dr Dre, my beat physician put me on lasix, spironolactone, ibuprofen, amiodarone, and propafenone.”

• “Is tryin’ to do me like Biggie?”

Y’all Know

• Drug interactions most common cause

• directly increase plasma levels, alter renal excretion, induce electrolyte abnormalities.

• Amiloride • Amiodarone • Calcium channel blockers • Propafenone • Quinidine • Quinine • Indomethacin • Spironolactone • Hydrochlorothiazide • Other loop diuretics • Triamterene • Amphotericin B

Y’all Know

• Hypokalemia, hyperkalemia, hypernatremia increase the toxic CVS effects of digoxin re: effects on NA+/K+ ATPase pump.– Digoxin toxicity does not cause

hypokalemia, but hypokalemia can worsen digoxin toxicity.

– Hyperkalemia is usual lyte abnormality ppt by digoxin toxicity, esp acute

Y’all Know

• Hypomagnesemia– increases myocardial digoxin uptake and

decreases cellular NaK ATPase activity– makes correcting hypokalemia very difficult

• Acidosis depresses Na+/K+ ATPase pump and may cause digoxin toxicity

• Dehydration

Y’all Know

• Ischemia suppresses Na+/K+ ATPase pump and independently alters automaticity

• Hypothyroid re decreased renal excretion, smaller volume of distribution.

• Bioavailability varies depending on formulation– Toxicity may occur by increasing

bioavailability.

Y’all Know

• Deteriorating renal function, dehydration, lytes, ischemia precipitate chronic toxicity.

• Acute overdose or accidental exposure to plants containing cardiac glycosides may cause acute toxicity.

Y’all Know

• Complex interaction between digoxin and various lyte & renal abnormalities

• normal digoxin levels (0.6-2.6 nmol/L) & renal insufficiency or severe hypokalemia may have more serious cardiotoxicity than patient with high digoxin levels and no renal or electrolyte disturbances

Not So Fresh Prince

• Will Smith: “If y’all help me out, I’ll put yo on my next album … you can bust rhymes with me & Puffy.”

• After a Mic check, What tests should you do?

Tests for the Willenium

• Digoxin level• Electrolytes, Mg, Ca,

Renal Fnc tests• ECG• CXR• ?Echo• ?Cath

Tests for the Willenium

• Acute toxicity, repeat the dig level q 2-4 hours

• Levels do not necessarily correlate with toxicity, esp acute ingestion.

• Acutely digoxin levels do not equilibrate quickly re variable absorption and tissue distribution.

Tests for the Willenium

• Toxicity related to intracellular levels, not serum

• Digoxin level drawn <4 hrs of acute ingestion may be incredibly high with no apparent toxicity.

• Rx guided by digoxin level and serum K+ and patient's clinical and ECG

Not So Fresh Prince #1

• Big Willie all of a sudden becomes less jiggy and hypotensive

• Monitor shows a bradysrhythmia

• Now What?

• Should I pace him (to the beat of Wild Wild West)?

Not So Fresh Prince #2

• Big Willie all of a sudden becomes less jiggy and hypotensive,

• Monitor shows a tachydysrhythmia

• Now What?

• Should I cardiovert him (like a glock to the chest)?

Not So Fresh Prince #3

• Big Willie all of a sudden becomes less jiggy and hypotensive,

• Monitor shows peaked T’s, widened QRS.

• K+ comes back @ 7mmol/L

• Should I give him Ca++?

Not So Fresh Prince #4

• Big Willie all of a sudden becomes less jiggy and hypotensive

• Your Rx to date have done nothing (including your attempt at rappin’ Parents Just Don’t Understand)

• Is there anything else you could use?

Just the two of Us

• ABCD!!!!

• IV’s, Monitors

• Consider AC & Lavage if acute

• Anti-arrhythmics

• Lyte Abn

• Digibind

Black Suits Coming: CVS

• ANY Arrhythmia!!!• Unstable = digibind

• Brady = atropine, ?pacing (lowers Fib threshold)?

Black Suits Coming: CVS

• Stable VT / Ventricular arrhythmias – digibind, dilantin, lido, Mg, avoid cardioversion– Lido, dilantin 1st line antiarrhythmic, case / dog

studies, decrease ventricular ectopy w/o slowing nodal activity

• Unstable VT or VF– digibind + cardioversion, defibrillate vfib

• Do not cardiovert SVTs

Black Suits Coming: CVS• Ca++ = BAD

– increase: dig effects?, contractions?, tetany?

• Cardioversion / defib relatively contraindicated re ventricular ectopy -> “safe if not toxic”– Ditchey RV, Curtis GP. Effects of apparently nontoxic doses

of digoxin on ventricular ectopy after direct-current electrical shocks in dogs. J Pharmacol Exp Ther 1981 Jul;218(1):212-6.

– Ditchey RV, Karliner JS. Safety of electrical cardioversion in patients without digitalis toxicity. Ann Intern Med. 1981 Dec;95(6):676-9.

– N=21

Black Suits Coming: Pacing?• Taboulet, P, et al. Acute Digitalis Intoxication - Is pacing Still

Appropriate? Clin Tox, 31(2), 261-273 (1993).• ?No?• N=92• 41 Rx Lavage, AC, +/- atropine -> all survived• 51 Rx, as above, but pace vs FAB vs both• 23 paced, 12 FAB, 16 both• 9 / 39 paced -> 7 VF, 2 VA 2 to pacer use (7 prior to FAB), also

infxn, pacer malfnc• 3 / 28 FAB -> 2 in VF / VA prior -> died, one died later of VF

100 hrs later

Will 2K+

• Usual Rx• Insulin + glucose, B2 ags, Kayexelate, NaHCO3 /

correct acidosis, dialysis• Avoid Ca++ -> ppt ventricular dysrrhythmias• Caution with digibind if using other means to

correct hyperkalemia prior to digibind Rx-> will result in markedly decreased K+!!!

Block Party: When Digibind• Arrhythmias associated with hemodynamic

instability• Altered LOC attributed to digoxin toxicity• Hyperkalemia K+ > 5 mEq/L• Digoxin level > 10 nmol/L in adults at steady state

(ie, 6-8 h postingestion)• Ingestion > 10 mg in adults (40 X 0.25 mg tablets)

or > 0.3 mg/kg in children• Hypotension not responsive to fluids

Block Party: Digibind• Digoxin-FAB fragments• From IgG of Sheep• Excreted renally• Each vial contains 40mg• Each Vial binds 0.5mg digoxin• $4121 Cn for 10 vials • 10 vials accute, 5 chronic

Block Party: Digibind• Chronic toxicity: number of vials = digoxin level

(ng/mL) X weight (kg)/100 • Acute overdose: number of vials = total amount

ingested (mg) X 0.8 / 0.5 • Give IV over 30 mins• Effect by then, peak in 4 hrs• Check levels in 4-6 hrs

– Levels post digibind will be markedly elevated and are uninterpretable unless you are able to get free digoxin levels

Block Party: Digibind

• Saluk, S et al. Treatment of severe digitalis intoxication with digoxin-specific antibody fragments: A clinical review. Crit Care Med June 1988;16, 6: 629-635.

• 20 papers, N=255, mainly case reports• FAB is GREAT and safe!

Block Party: Digibind• Hickey, et al. Digoxin-Specific FAB, Expanded

Data on Safety. JACC Vol 17, No.3, March 1, 1991:590-8.

• N=717, form filled out if FAB used, F/U form post Rx

• 357 responded, 172 partially, 89 none• No response usually incorrect Dx or inadequate

dosing• No deaths attributed to FAB, 6 allergic responses

Block Party: Digibind

• Smith, TW, et al. Treatment of life-threatening digitalis intoxication with digoxin-specific Fab antibody fragments: experience in 26 cases. NEJM. 1982, 307:1357-1361.

Block Party: Digibind

• Antman EM, et al. Treatment of 150 cases of life-threatening digitalis intoxication with digoxin-specific Fab antibody fragments: final report of a multicentre trial. Circulation 1990;81:1744-1752.

Block Party: Digibind• N=150• 75 long term, 15 accidental, 59 suicidal, 1 fetal• 148 responses documented, 80% resolved, 10%

improved, 10% no response• Median time to response = 19 mins, 75% response

<60 mins• 14 adverse effects (hypoK, CHF)• Poor / non-response-> CAD, wrong Dx, inadequate

dose, pts moribund

Miami

• ABCD’s• Monitors, IV’s• Lytes, dig level, ECG• If toxic:

– Supportive Rx – Rx hyperkalemia – Rx Digibind FAB if unstable

Residents DO just Understand!• Thanks to Dr Ber(lin),

he doper than Dre• You, for keepin’ it real• My hommies back in

tha projects in East Saskatoon

• Biggie & Tupac• Peace Out