Gettin’ Digi Wit it Digoxin Overdose Core Rounds March 6, 2003 A.F. Chad, MD, CCFP Randall Berlin,...

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