One drug, two stories

Dr FT LeePMH/YCH AED

History (Patient A)

8-1-05 02:12F/49Known case of CRHD with MVR FU GHOn Digoxin, Lasix, Acertil, Slow K. Aldactone, Warfarin

Attempt suicide with her husband by taking Digoxin >100 tablets (0.25mg/tablet) & Acertil > 60 tablets at around 01:00(1 hour before arrival)

Vomit twice

P/E:

GCS: 14-15, refused to cooperateBP: 152/49, P:49/minRR:22/min, SaO2: 98% (Rm air)Temp: 36°CH’stix: 8.3

Management in AED

100%O2Cardiac monitorNS Q4H CXR: cardiomegalyConsult ICU Standby pacingTransfer to ICU at 02:30 (13 mins)BP:166/70, P:30/min

Progress in ICU

Cardiac arrest at 02:50(38 mins)Pulseless VTDefibrillate 150J then 200J AsystoleTCP given but no cardiac outputCertified dead after 1 hr of active resuscitation Adrenaline 1mg x 7 Atropine 0.6mg x2 NaHCO3 100ml

Digitalis antidote was ordered but only available after prolonged resuscitationRFT: Na: 131, K: 7.3, Urea: 7.4, Cr: 88INR: 1.6

A sad story !!

History (Patient B)

M/58 (Husband)Good past healthAttempt suicide with his wife by taking Digoxin > 60 tabs, Acertil > 100 Tabs, Warfarin > 100 tabs, Piriton> 60 Tabs at 01:00Vomit

P/E

GCS: 15BP: 151/65, P: 93/minRR: 16/min, Sa O2: 99% (Rm air)Temp: 37°C

Management in AED

O2NS Q4HCardiac MonitorCXR: NADActivated charcoal 50g poConsult ICU (Suggest admission to Medical ward)

Progress

Transfer to ICU at 05:40 (BP: 160/80, P: 100/min)RFT: Na: 135, K: 4.8, Urea: 7.2, Cr: 90INR: 1.511:20 (10 hrs postingestion)P: 35-40/min, BP: 140/60, ECG: Complete Heart BlockAtropine 0.6mg ivTransvenous pacing

11:25, 10 hrs postingestionDigoxin Level10.7 nmol/l (1.3-2.6)13:45 (12 hrs postingestion)Digitalis Fab 480mg(6 vials) was given over ½ hour20:40 (7 hrs after Fab)UrticariaPiriton 10mg iv ECG: SR, 100/min

09-01-2005 (Day 2)INR: 2.8 off pacing Vit K1 10mg iv

Digoxin Level

Time & Date

05:408-1-05

11:258-1-05

12:1712-1-05

11:2817-1-05

Hours & days after

ingestion

5 hours post

ingestion

10 hours post

ingestion

4 days post

ingestion

9 days post

ingestion

Serum Digoxin

level

13.4nmol/l

10.7 nmol/l 3.5 nmol/l 1 nmol/l

Digitalis antidote

Progress

To general medical ward on D3Claimed that he would commit suicide againPsychiatric assessment: Adjustment disorderTransfer to KCH by Vol form on D16

An happy ending !!

Acute Digoxin Overdose

Mechanism

Inhibition of the Na-K-ATPase pump (70%)

Normal depolarization & repolarization

Na & Ca

Na-K-ATPase pump

Ca

Depolarization

Toxic Digoxin effect

Elevate the resting potential predispose to dysrhythmia

Toxic Digoxin effect

(Autonom & Anta Pharm, Vol 25(2) 35-52)

Rhythm disturbances

Increase automaticity particularly in the Purkinje fibre

Impaired conduction through the SA & AV node

(Heart 2000;83:301-306)

Extracardiac

Nausea, vomiting almost always present Confusion and delirium Seizure (very rare)

Toxicokinetic

Toxic dose: >3mg in Adults>1mg in Child

Large volume of distribution (Vd: 5-10 l/kg)

Toxicokinetic

Two-compartment system

Compartment 1

(Serum)

Compartment 2

(Tissue)

kak12

k21

kel

Toxicokinetic

Peak effect occurs after a delay of 6-12 hoursEliminated by kidney (60-80%)Elimination half-life: 1.6 days

Hyperkalaemia

An accurate predictor of outcome

(Bismuth et al; J Toxicol Clin Toxicol 6: 153-162, 1973)

Pretreatment serum K(meq/l)

Mortality rate

<5 0%

5- 5.5 ~50%

>5.5 100%

Digoxin Level

Tissue distribution completes in 6-12 hoursNot correlate accurately with severity of intoxicationOther metabolic abnormalities must take into considerationFalsely elevated after Digibind

Management

ABCDecontaminationAntidote

Management of dysrhythmia

Treatment of dysrhythmia

Bradydysrhythmias Atropine Caution with electrical pacing

Trigger fatal arrhythmia or delay Fab

Failed in 23% of patient (vs 8% treated with Digibind)

Iatrogenic accidents in 36% vs 0% in Digibind (p<0.05)

(Taboulet et al; J Toxicol Clin Toxicol 31: 261-273, 1993)

Treatment of dysrhythmia

Tachydysrhythmia Cardioversion may precipitate

refractory VT, VF or asystole Start with very low energy (10-25J) Pretreated with Lidocaine or

Amiodarone Digitalis Fab

GI decontamination

Orogastric larvage increase vagal tone

Activated Charcoal

Multiple dose Activated Charcoal is effective

(Silva et al; Lancet 2003;361:1935-38)

Treatment of Hyperkalaemia

K>5mmol/l is an absolute indication for Digibind

(Elliot et al; Circulation 1990;81;1744-52)

Treatment of Hyperkalaemia

Insulin/glucose, NaHCO3Ca must not be given except after DigibindCorrection of hyperkalaemia does not improve survival

(Bismuth et al; J Toxicol Clin Toxicol 6: 153-162, 1973)

Antidote Digoxin Immune Fab

Digoxin Immune Fab

Produced in immunize sheepGreater binding affinity for digoxin than Na-K ATPaseFab fragment-digoxin complex eliminated through kidney (T1/2: 15-20 hrs)

Pharmakokinetic

Creates a concentration gradient to dissociate digoxin from the heart

Compartment 1

Serum & Intersitial free Digoxin

Compartment 2

Digoxin at

Myocardial receptor

Increase renal clearance by 20-30%

Effectiveness

Resolution of all signs/symptoms (80%)Improvement (10%)No response (10%)Response within 1 hour (mean:19 mins) and complete within 4 hours

(TW. Smith American J of Emerg Med, March 191:1-6)

Decrease mortality

(Antman et al; Circulation 1990;81;1744-52)

Pretreatment serum K(meq/l)

Gaultier et al (1978)

Mortality rate

Antman et al (1990)

Mortality rate

<5 2% 3%

> 5 < 6.4 35% 25%

>6.4 90% 12.5%

Improve survival rate in digitalis-induced cardiac arrest

(Gaultier et al La Rev d Practicien 1978; 28:4565-4579)(Elliot et al; Circulation 1990;81;1744-52)

Patients number

Gaultier et al

(1978)

Antman et al(1990)

Experienced cardiac arrest

9 56

Died 9 26

Mortality (%) 100 46

Indications

Rhythm & Conduction disturbancesHyperkalaemia (>5mmol/l)Digoxin ingestion >10mg (>4mg in child)Serum digoxin level 15ng/ml (19nmol/l) at any timeor >10ng/ml (13nmol/l) 6h postingestion

Factors affecting the efficacy

Time of administrationDosageRate of administration

Dosage

Amount of ingestion and post distribution Digoxin level is unknownAmount of ingestion is knownPost distribution Digoxin level is known

Dosage

The brand of Digoxin Fab

Digitalis Antidote(Roche)

Available in PMH80mg/vialEach vial binds 1 mg digoxin

Digibind (Glaxo)

38mg/vialEach vial binds 0.5mg digoxin

Amount ingested or post distribution level is unknown

Digibind (38mg/vial)Recommendations vary from 5-20 vials10 vials for both adult or child Administered ivi over 30 minsGiven as a bolus injection in cardiac arrest

(Glaxo Wellcome)

Amount ingested is known

No. of vials = Total digitalis body load in mg

0.5mg of digoxin bound per vial

Mulitply amount ingested in mg by 0.8 if Digoxin tablets involved

Dosage of Digibind

Tablets ingested0.125mg/

tabs

Tablets ingested

0.25mg/tabs

No of vials

5 2.5 110 5 220 10 450 25 10

100 50 20Olson, Poisoning & Drug overdose 4th ediiton

Dosage

The brand of Digoxin FabPost distribution Digoxin levelnmol/l vs ng/ml

Postdistribution level is known

Calculations Based on Steady-State Serum Digoxin Concentrations No. of vials

= serum digoxin level (nmol/l X 0.781) X body wt (kg)100

Conversion factor = Serum Digoxin Concentration (SDC) nmol/L x 0.78 = SDC ng/mL.

(Glaxo Wellcome)

Dosage

The brand of Digoxin FabPost distribution Digoxin levelSerum Digoxin level (nmol/l vs ng/ml)Use the highest calculated dose

Adverse reaction

Allergy is rare Skin test for patients with known sensitivity

to sheep products

HypokalaemiaWithdrawal of digoxin effects CHF Atrial fibrillation or flutter

Digoxin levels are not meaningful Falsely elevated

Bring home messages

Digoxin Fab is cost effectiveElectrical therapy has to be used cautiouslySerum K is a accurate prognostic pointerHyperkalaemia is an indication for Digoxin Fab

Thank you