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

3. 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?

4. 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

5. 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)

6. 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

8. 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)

9. 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

10. 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

11. Men in Black Morbidity = 4.6-10% 50% if digoxin level > 7.7nmol/L

12. 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?

13. 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)

14. 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))

15. Nod Ya Head Acute –Mainly Cardiac ad GI Chronic –Can have any of the Symptoms

16. 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

17. 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

25. 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

26. 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?”

27. 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

28. 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

29. 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

30. 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.

31. 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.

32. 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

33. 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?

34. Tests for the Willenium Digoxin level Electrolytes, Mg, Ca, Renal Fnc tests ECG CXR ?Echo ?Cath

35. 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.

36. 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

37. 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)?

38. 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)?

39. 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++?

40. 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?

41. Just the two of Us ABCD!!!! IV’s, Monitors Consider AC & Lavage if acute Anti-arrhythmics Lyte Abn Digibind

42. Black Suits Coming: CVS ANY Arrhythmia!!! Unstable = digibind Brady = atropine, ?pacing (lowers Fib threshold)?

43. 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

44. 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

45. 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

46. 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+!!!

47. 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

48. 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

49. 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

51. 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!

52. 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

53. 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.

55. 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.

56. 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

57. Miami ABCD’s Monitors, IV’s Lytes, dig level, ECG If toxic: –Supportive Rx –Rx hyperkalemia –Rx Digibind FAB if unstable

58. 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