Cardiac agent toxicity

Amiodarone

• Risk assessment
  • Acute oral overdose is benign (regardless of dose), however, delayed cardiac effects (hypotension, A flutter, TWI) have been reported
    • No reported fatalities
  • Chronic toxicity is common
    • Pulmonary toxicity
    • Cardiovascular: Bradycardia, AV blocks, Torsades, hypotension, negative inotropy
    • Thyroid dysfunction (hypo or hyper)
    • Hepatic toxicity
    • Corneal micro-deposits
  • Children who take 1-2 tabs do not need to present to hospital

Amiodarone

• Toxic mechanism
  • Class III (prolonged cardiac action potential and refractory period of atrial and ventricular tissue) + Class I, II, IV
• Toxicokinetics
  • Absorption – Variable but poor
  • Distribution – Completely protein bound with very large Vd (65L/kg)
  • Metabolism – First-pass CytP450 to active metabolite, desethylamiodarone
  • Elimination – Primarily biliary and very slow; Up to 80 hours following acute ingestion and 100 days for chronic therapy (same for active metabolite)

Amiodarone

• Management
  • Cardiac monitoring for 24 hours recommended
  • Bradycardia can be resistant to atropine and may require adrenaline, isoprenaline or pacing
  • Hypotension responds to vasopressors
• Decontamination – Consider AC if within 2 hours
• Enhanced elimination – Not useful
• Antidote – None
• Disposition
  • 24 hours monitoring (however cardiac toxicity can be markedly delayed so somewhat controversial)

ACEi

• Risk assessment
  • Generally benign
  • Mild hypotension usually apparent within 2 hours and may last several hours. Usually responds to IV fluids
  • Children: Ingestion of up to 2x the defined daily dose for adults does not produce toxicity and does not require hospital assessment
• Toxic mechanism
  • Reversible inhibition of ACE leading to loss of vasopressor effect of angiotenin II + reduction in circulating aldosterone, which can lead to hyperkalaemia
• Toxicokinetics
  • Absorption – Rapid and well absorbed. Peak levels at 1-2 hours
  • Distribution – 
  • Metabolism – Many agents are prodrugs requiring hepatic activation
  • Elimination – Renal

ACEi

• Ix – Mild hyperkalaemia and renal impairment may be seen
• Management
  • Fluid boluses for hypotension
  • Decontamination – Oral AC if presents within 1 hour but unlikely to change course of events
  • Enhanced elimination – n/a
  • Antidotes – n/a
• Disposition
  • If well, with normal BP at 4 hours – d/c
  • If symptomatic or hypotensive admit to non-monitored bed until resolved

Beta-blockers

• Isolated beta-blocker overdose usually little or no toxicity with the exception of PROPRANOLOL and SOTALOL (life-threatening)
• Risk assessment
  • Toxicity does not correlate well with ingested dose
  • Increased risk of toxicity: Propranolol or sotalol, underlying heart/lung disease, co-ingestion with CCB or digoxin, advanced age
  • Propranolol threshold for toxicity is 1g
  • Toxicity usually manifests within first few hours (exceptions being SR preparations or sotalol)
  • PR prolongation even in absence of bradycardia is an early sign of toxicity
  • Children: 1-2 tabs of anything but sotalol or propranolol does not cause significant toxicity

Beta-blockers

• Toxic mechanism
  • Competitive beta-1 and beta-2 antagonists
  • Decreased intracellular cAMP and blunting of metabolic, chronotropic, inotropic effects of catecholamines
  • Propranolol also has Na-channel blocking properties and is lipid soluble (enters CNS with direct toxicity)
  • Sotalol also has K channel blocking activity leading to QT prolongation
• Toxicokinetics
  • Absorption – Rapid with peak serum levels at 1-3 hours
  • Distribution – Variable. Propranolol alone is highly lipid soluble and enters CNS
  • Metabolism – Propranolol extensively hepatically metabolised with half-life of 12 hours (prolonged following overdose)

Beta-blockers

• Clinical features
  • Usually within 4 hours with bradycardia +- more severe manifestations in sotalol/propranolol or with predisposing risk factors
  • Predominant effect of propranolol is its beta-blocker effect vs. Na channel block
  • Propranolol is a reverse agonist (suppresses spontaneous receptor signaling and blocks agonist effect) 
  • CVS: 
    • Hypotension, bradycardia, 1^st to 3^rd degree AV block, junctional or ventricular bradycardia. 
    • QRS widening in propranolol and magnitude is predictor of ventricular dysrhythmias
    • QT prolongation and TdeP in sotalol
  • CNS: Delirium, coma, seizures (propranolol)
  • Other: Bronchospasm, pulmonary oedema, hyperkalaemia, hypo/hyperglycaemia

Beta-blockers

• Management
  • Prompt I&V + sodium bicarbonate for ventricular dysrhythmias
  • Propranolol OD treated as for a TCA OD
  • Bradycardia and hypotension
    • Atropine 0.01-0.03mg/kg IV (temporising)
    • Isoprenaline 20mcg bolus then 4mcg/min infusion
    • Adrenaline infusion
    • High-dose insulin therapy if myocardial depression on bedside echo despite >15mcg/min adrenaline
  • Wide QRS – Sodium bicarb 1-2mmol/kg boluses q1-2min
    • If 200mL provided and no change -> Discontinue as evidence is lacking
  • Torsades – Isoprenaline, Mg 10mmol, Overdrive pacing
• ECG monitoring for at least 4 hours in all patients with invasive monitoring if unwell

Beta-blockers

• Decontamination
  • AC if presents within 2 hours but high caution advised in propranolol OD as coma /seizures can occur rapidly
• Enhanced elimination – Not useful
• Antidotes
  • High-dose insulin therapy 50mL 50% dextrose IV bolus with 1U/kg actrapid then 50mL 50% dextrose over 1 hour titrated to maintain euglycaemia while actrapid infusion runs at 0.5U/kg/hr (can go up to 2U/kg/hr if required)
  • Ensure K, BSL and Mg monitored closely and optimised
• Disposition
  • If asymptomatic and normal ECG at 6 hours can d/c
• Handy tips
  • Approach propranolol as for TCA rather than beta-blocker
  • Glucagon has no advantage over standard inotropes/vasopressors and has no role
  • Intralipid can be considered in life-threatening intoxications refractory to other measures

Calcium channel blockers

• Risk assessment
  • 2-3x normal dose of verapamil/diltiazem XR can cause severe toxicity if susceptible
  • >10 tabs of diltiazem/verapamil XR in an adult is likely to cause life-threatening toxicity
  • Onset of effects is up to 2 hours in IR but can be delayed up to 16 hours in XR preparations
  • Other CCB’s are less likely to cause life-threatening issues
  • Co-ingestion of other cardiotoxic meds significantly increases the risk of toxicity
  • Advanced age and cardiac comorbidities significantly increase toxicity
  • Children:
    • 2 or more tablets of any strength XR verapamil/diltiazem is potentially lethal
    • All should be reviewed in hospital

CCB

• Toxic mechanism
  • Prevent opening of L-type calcium channels causing decreased calcium influx – vascular smooth muscle relaxation, slowed cardiac conduction and reduced inotropy
  • Hypotension results from peripheral vasodilatation, bradycardia, negative inotropy and is associated with hyperglycaemia and lactic acidosis
• Toxicokinetics
  • Absorption – Well absorbed with peak levels at 1-2 hours (IR) or 6-12 hours (XR)
    • In overdose, peak levels may not occur until 6 hours for IR and 22 hours for XR
  • Distribution – High 3-7L/kg and protein bound (free levels increased in OD)
  • Metabolism – Hepatic with high first pass  (BA 40%) but can be saturated in OD leading to higher BA
    • Verapamil metabolised to active norverapamil
    • Diltiazem metabolised to active diacetyldiltiazem (vasodilatory)

CCB

• Clinical features
  • Symptoms within 1-2 hours of IR and 12-16 hours for XR with peak effects beyond 24 hours
  • Cardiovascular: Bradycardia, AV block, hypotension early. May progress to shock, death, MI, stroke and non-occlusive mesenteric ischaemia
  • CNS: Seizures and coma are rare. Coma usually from co-ingestant
  • Metabolic: Hyperglycaemia and lactic acidosis in severe intoxication
  • Dihydropyridines
    • Mild/moderate: Peripheral vasodilatation and reflex tachycardia
    • Severe: Peripheral vasodilatation, negative inotropy/chronotropy/heart block

CCB

• Investigations
  • Screen BSL, para, ECG
  • U&E, BSL, ABG
  • CXR
  • Echo
  • Invasive monitoring

CCB

• Management
  • Resus – Early identification is key
  • Mentation and airway reflexes usually preserved until cardiac arrest
  • Hypotension refractory to fluid resuscitation indicates onset of severe toxicity and is an indication for high-dose insulin therapy
    • Calcium can be a temporising measure and repeated up to 3 times 
  • Catecholamines are rarely effective in CCB overdose
  • Ventricular pacing can bypass AV block and rates should not exceed 60/min. Electrical capture is often difficult to achieve and may not produce improved perfusion
  • Bypass, ECMO and intra-aortic balloon pumps have been successfully used

CCB

• Decontamination
  • Administer AC to cooperative patients who present within1 hour of IR or 4 hours of XR
  • Administer to all intubated patients
  • Whole bowel irrigation
    • Consider after dose of AC in adults without established toxicity who present within 4 hours of >10 tabs verapamil or diltiazem XR
• Enhanced elimination – Rarely indicated. Albumin dialysis in rare cases
• Antidotes
  • High-dose insulin: Start as soon as toxicity detected
    • 50mL 50% dextrose + 1U/kg actrapid bolus THEN
    • 50mL 50% dextrose / hour titrated to euglycaemia during infusion of 0.5U/kg/hr actrapid (can be titrated up to 2U/kg/hr if required
  • Calcium
    • 20mL CaCl or 60mL CaGluconate IV over 5-10 min, repeated very 20 min up to 3 doses

CCB

• Disposition
  • If well and normal vital signs and ECG at 4 hours (IR) or 16 hours (XR) can be discharged in daylight hours
• Handy tip
  • Avoid agents that will exacerbate hypotension or bradycardia in RSI
    • Ketamine, fentanyl and rocuronium preferred
• Pitfalls
  • Failure to anticipate delayed severe toxicity in XR ingestion
  • Failure to initiation aggressive decontamination in patients who present early with life-threatening XR overdose
  • Delay in institution of high-dose insulin therapy
• Intralipid may play a role in refractory cases for verapamil

Clonidine

• Risk assessment
  • Clinical effects correlate poorly
  • CNS depression may occur with doses >20mcg/kg 
  • Onset of clinical toxicity usually within 2 hours and always within 6
  • Children: 2 tablets is potentially lethal
    • <10mcg/kg: minimal toxicity
    • >10mcg/kg: Bradycardia and hypotension
    • >20mcg/kg: Respiratory depression or apnoea
• Toxic mechanism
  • Centrally acting alpha-2 agonist

uStimulated post-synaptic alpha-2 adrenergic receptors in vasomotor centre of medulla leading to enhanced activity of inhibitory neurons and subsequent decreased sympathetic outflow

uMay also act on peripheral alpha receptors to cause pressor response in overdose

• Sympathoplegic and increases endothelial NO levels and decreases renin activity

Clonidine

• Toxicokinetics
  • Absorption: Rapidly and completely absorbed with peak levels at 1-3 hours
  • Distribution: 3-6L/kg. Protein binding 20-40%
  • Metabolism: Liver but half ingested dose excreted unchanged in urine
  • Elimination: Half-life 6-24 hours. 
• Clinical features
  • Transient early HTN seen in 20-50%
  • Lethargy, miosis, slurred speech and ataxia within 2-6 hours
  • Severe intoxication leads to coma, bradycardia and hypotension
    • Often HR as low as 30 without hypotension. Heart blocks are sometimes seen
  • Symptoms resolve within 24 hours

Clonidine

• Management
  • Bradycardia only treated if hypotension or reduced end-organ perfusion (i.e. atropine, catecholamine infusion or pacing)
  • IV fluids
• Decontamination
  • Oral AC contraindicated unless intubated due to risk of coma
• Enhanced elimination n/a
• Antidotes
  • Naloxone 
    • Inconsistent reversal of CNS and respiratory depression
    • Trial can be performed but I&V more reliable in setting of this
    • 0.1mg IV every 30-60 seconds up to 0.4mg

Clonidine

• Disposition
  • Patients well at 6 hours can be discharged in daylight
• Handy tips
  • Consider in any small child with bradycardia, miosis, lethargy
  • Adults are often opioid dependent and use clonidine to treat opioid withdrawal – avoid naloxone in these patients as it will exacerbate acute opioid withdrawal
• Pitfalls
  • Failure to recognise potential lethality in children
  • Failure to recognise respiratory depression in children (esp. at night)
  • Iatrogenic anticholinergic delirium from excessive atropine dosing

Acute Digoxin Overdose

• Early onset vomiting and hyperkalaemia with progression to cardiac dysrhythmia and collapse
• Risk assessment
  • Need >10x daily defined dose (average maintenance dose per day for a drug)
  • Potentially lethal ingestion predicted by:
    • >10mg (adult) or >4mg (child)
    • Serum dig level >15nmol/L (12ng/mL) at any stage
    • Serum K > 5.5
  • Natural cardiac glycoside intoxications can occur
  • Children: >75mcg/kg requires hospital assessment

Acute dig overdose

• Toxic mechanism
  • Na/K-ATPase inhibition leading to reduced sodium gradient and reduced calcium extrusion from cells
  • Leads to increased intracellular calcium (enhanced automaticity and inotropy) and extracellular potassium
  • Direct vagal effect results in decreased sinoatrial and AV nodal conduction velocities
• Toxicokinetics
  • Absorption – Well absorbed BA 60-80%. Peak effects at 6 hours
  • Distribution – Large Vd 5-10L/kg
  • Metabolism – Minimal
  • Elimination – Renal excretion unchanged. Half-life 30-40 hours and prolonged in renal impairment

Acute dig overdose

• Clinical features
  • Early nausea and vomiting within 2-4 hours
  • Death at 8-12 hours
  • GI: Nausea, vomiting, abdo pain
  • Cardiovascular: 
    • Bradycardias: AV block, slow AF
    • Increased automaticity: Ventricular ectopics/bigeminy, SVT (PAT) with AV block, VT
    • Hypotension
  • CNS: Lethargy, confusion, delirium
• Liquid natural cardiac glycosides can have more rapid onset of symptoms

Acute dig overdose

• Investigations
  • Screen BSL, ECG, para
  • Serum dig levels – Confirms poisoning, an indication of digifab and should be performed at presentation, at 4 hours post-ingestion and then every 2 hours
  • UEC – Hyperkalaemia of any magnitude indicates severe dig toxicity. Important to assess renal function
  • Serial 12-lead ECG’s

Acute dig overdose

• Management
  • In cardiac arrest, standard measures are futile. Continue ACLS while 20 ampoules of digibind are sourced and provided
  • Continue attempts at resuscitation for 30 minutes after digibind delivered
  • Temporising measures
    • Hyperkalaemia:
      • Bicarb 100mmol (1mmol/kg) IV bolus
      • Insulin 10U Actrapid in 50mL 50% dextrose (0.1U/kg and 2mL/kg 10% dextrose)
      • CaGluconate 30mL or CaCl 10mL over 5-10min q10-15min targeting narrow QRS <100ms (previously CI) (TOX BOOK SAYS CONTRAINDICATED!)
    • AV block
      • Atropine 0.6mg up to 3 times (20mcg/kg/dose in children)
    • Ventricular dysrhythmias
      • Lignocaine 1mg/kg IV over 2 minutes

Acute dig overdose

• Decontamination
  • Oral AC if cooperative within first hour
  • Give after secured airway if intubated
• Enhanced elimination n/a
• Antidote
  • Digifab indications (controversial)
    • Cardiac arrest
    • Life-threatening cardiac dysrhythmia
    • Ingested dose >10mg (adult) or >4mg (child)
    • Serum dig >15nmol/L (>12ng/mL)
    • Serum K >5

Acute dig overdose

• Digifab dosing
  • Cardiac arrest – 20 ampoules + 5 amps q30min
  • Unstable – 10 ampoules + 5 amps q30min until toxicity resolved
  • Stable – 5 ampoules + 5 amps q30min until toxicity resolved
  • Known dose = Dose (mg) x 0.8 x 2
  • Known level = ng/L x kg / 100 = # of ampoules
• Response normally apparent within 20 minutes and maximal by 4 hours
• Endpoints: Restoration of normal cardiac rhythm and conduction + resolution of GI symptoms
• Dig levels may still appear very high as most assays measure bound and unbound fractions together

Acute dig overdose

• Disposition
  • Falling serum dig levels, normal serum K, no GI symptoms and no evidence of cardiotoxicity at 6 hours can be discharged
  • If received digifab, need 24 hours of observation before discharge
• Handy tips
  • Serum K >5.5 predicts 100% mortality without Digifab (classic teaching)
  • Therapeutic trial of digifab in mixed cardiotoxic OD may assist in risk assessment
  • Serum dig levels are unreliable following natural cardiac glycoside ingestion
• Pitfalls
  • Failure to stock sufficient digifab

Chronic digoxin overdose

• Underdiagnosed condition with significant morbidity and mortality
• Narrow therapeutic index and comorbidities often play a role in toxicity
• Use of digifab reduces mortality, LOS and cost of care
• Risk assessment
  • Life-threatening
  • Untreated mortality within a week is 15-30%
  • Probability predicted based on serum dig level and symptoms
    • See next slide

Chronic dig overdose

Chronic dig toxicity

• Clinical features
  • Typically elderly with intercurrent illness, particularly if associated with impaired renal function
  • Onset is insidious over days to weeks
  • Cardiovascular
    • Bradycardias, increased automaticity, hypotension, syncope
  • GI: Nausea, vomiting, abdominal pain (less pronounced than acute)
  • CNS: Lethargy, confusion, delirium
  • Visual: Decreased visual acuity, aberration of colour vision (chromatopsia) and yellow haloes (xanthopsia)

Chronic dig toxicity

• Investigations
  • Screen BSL, ECG, para
  • Serum dig levels
    • Steady state level at 6 hours or more after last dose is warranted
    • Level near therapeutic range (0.5-1.0ng/mL or 0.6-1.3nmol/L) correlates poorly with symptoms of intoxication (see table)
  • UEC
  • Investigation of intercurrent illness

Chronic dig toxicity

• Management
  • As for acute
  • Correct hypovolaemia
  • Correct hypokalaemia
  • Assess and manage intercurrent illness
• Decontamination n/a
• Enhanced elimination n/a
• Antidotes
  • Digifab
    • Indicated whenever clinical features exist with elevated steady-state level
    • 1-2 ampoules is usually sufficient to reverse all features within 12 hours
    • End point is always resolution of cardiac and gastrointestial toxidrome

Chronic dig toxicity

• Digiffab dosing
  • Indications
    • Cardiac arrest
    • Life-threatening cardiac dysrhythmia
    • Cardiac dysrhythmia or increased automaticity not likely to be tolerated for long
    • Moderate-to-severe GI symptoms
    • Any symptoms in presence of renal impairment
  • Dosing
    • Serum dig (ng/mL) x kg / 100
    • Empiric dosing is 2 ampoules repeated very 30 minutes until resolution
    • 5 amps if cardiac arrest

Chronic dig toxicity

• Disposition
  • If no significant cardiac dysrhythmias for 6 hours post-digifab, no further cardiac monitoring is required
  • Vast majority will require admission for intercurrent illness
• Handy tips
  • Consider in any patient on digoxin who presents with collapse, hypotension, bradycardia, dysrhythmia, GI complaints, ALOC or general decline
  • If dysrhythmias continue beyond 12 hours after definitive dose of digifab, an alternative cause is likely
• Pitfalls
  • Failure to appreciate life-threatening nature of chronic dig toxicity
  • Failure to treat with digifab

NOAC’s

• Most bleeding occurs in the context of therapeutic administration, often due to drug interactions, renal failure or significant predispositions to bleeding
• Deliberate self-poisoning is rare
• Risk assessment
  • Overdose with any amount could result in clinically significant bleeding
  • Classic coagulation tests correlate poorly
  • Children: 1-2 tablets will produce significant anticoagulant effect and bleeding risk

NOAC’s

• Toxic mechanism
  • Dabigatran: Direct competitive inhibitor of both free and fibrin-bound thrombin
  • Apixaban/Rivaroxaban: Direct Factor Xa inhibitors
• Toxicokinetics
  • Dabigatran
    • Absorption – BA of only 6% (increased to 75% if granules removed from capsules prior to ingestion). Peak concentrations at 2-4 hours. 
    • Distribution – Vd 50-70L and 35% protein-bound
    • Metabolism – Hepatic to active metabolites. 
    • Elimination – Renal with elimination half-life of 12-24 hours
  • Apixaban/rivaroxaban
    • Absorption – BA >50%. Peak concentrations at 3-4 hours.
    • Distribution – Vd <50L and highly protein bound
    • Elimination – Renal and hepatic elimination with half-lives 5-14 hours

NOAC’s

• Clinical features
  • Only bleeding
  • Seizures/coma suggestive of ICH
• Ix
  • FBC, UEC, LFT, G&S, Coag studies (see next slide)
  • Dabigatran level
  • Anti-Xa level

NOACS

NOACs

• INR >2 and APTT >90s suggests high levels of dabigatran
• Normal INR and normal APTT suggest low levels of dabigatran
• Combination of normal PT and APTT suggests low level of apixaban/rivaroxaban
• TEG is effective but specific assays not yet validated

NOAC’s

• Management
  • Treat any active bleeding as per local protocols (see over)
  • Deliver platelets if <70 or on antiplatelet agent
  • Consider interventional radiology to control non-compressible bleeding
  • Early haematology consult
  • General supportive care
  • Decontamination
    • In deliberate self-poisoning presenting within 4 hours, administer AC 50g to cooperative or intubated patients (Qld Health guideline suggests 8 hours)
  • Enhanced elimination
    • Dabigatran is dialysable – consider early in acute overdose or dabigatran-related haemorrahge with impaired renal fx
    • Haemodialysis not useful for Xa inhibitors
  • Antidotes (see over)

NOAC’s

• Reversal agents and antidotes
  • Dabigatran
    • Consider idarucizumab (Praxbind) 2.5g IV infusion over 5-10 min x 2
    • Consider dialysis
      • Renal impairment
      • APTT >80s
      • Dabigatran level >500mg/mL
  • Rivaroxaban/Apixaban
    • Highly protein bound and therefore not dialysable
    • Prothrombinex 50IU/kg IV infusion
    • Consider anti-fibinolytic TXA 15-30mg/kg then infusion 1mg/kg
    • Recombinant Factor VIIa IV 50mcg/kg bolus if critical

NOAC’s

• Disposition
  • Medically cleared after dabigatran if INR and APTT normal at 12 hours post-ingestion
  • Medically cleared after Factor Xa inhibitor if PT and APTT normal at 12 hours
• Pitfalls
  • Relying on point of care coagulation testing
  • Failure to admit and monitor patients after small overdoses
  • Failure to prevent falls in patients with significant anticoagulation
  • Administration of coagulation factors in absence of significant bleeding – carries risk of thromboembolic complications

Warfarin

• Risk assessment
  • Risk of bleeding rises progressively as INR >5
  • If not on therapeutic warfarin and take intentional OD
    • <0.5mg/kg unlikely to cause significant rise in INR
    • >2mg/kg can produce significant rise in INR within 72 hours
  • Children: Acute unintentional ingestion of <0.5mg/kg does not require Ix or Rx
• Toxic mechanism
  • Inhibits metabolism of Vitamin K to active form, thus preventing synthesis of Vitamin K dependent coagulation factors II, VII, IX, X + Protein C/S
  • >12 hour delay in anticoagulant effect is due to half-life of pre-formed Vitamin K dependent clotting factors (6, 24, 40 and 70 hours for VII, IX, X and II respectively)
  • Peak effect at 72 hours

Warfarin

• Toxicokinetics
  • Absorption – 100% BA and rapid
  • Distribution – Small 0.2L/kg. 99% protein bound
  • Metabolism – CytP450 with metabolites that undergo enterohepatic circulation
  • Elimination – Warfarin and metabolites excreted in urine and faeces with half-life of 35 hours
• Investigations
  • Screen BSL, ECG, Para
  • INR
    • If not previously anticoagulated – INR normal for first 12-24 hours and if remains normal at 48 hours this excludes warfarin intoxication
    • If on warfarin normally, measure INR at presentation and q6h

Warfarin

• Management
  • Supportive care
  • If active uncontrolled bleeding
    • Prothrombinex 50IU/kg + Vitamin K 5-10mg IV
• Decontamination
  • If deliberate self-poisoning and cooperative, 50g AC if within 1 hour of ingestion
• Enhanced elimination n/a
• Antidote
  • Vitamin K – 10mg IV if no indication for anticoagulation as obviates need for ongoing anticoagulation testing
  • If have an indication for warfarin, need to titrate Vitamin K dosing to maintain optimal INR
    • 0.5-2mg IV if INR >5 with close INR monitoring and repeat dosing if INR remains above or rises again above 5
    • Heparin infusion if INR falls below 2 and absolute indication exists e.g. mechanical heart valve

Warfarin

• Disposition
  • <0.5mg/kg in children does not require assessment
  • >0.5mg/kg in children: 10mg vitamin K PO and discharged. Do not require INR testing or follow-up
  • Patients with no therapeutic indication need Vitamin K 5mg BD for 2 days and are medically cleared. Repeat INR at 48 hours
• Handy tip
  • Consider warfarin levels in paediatric NAI or occult poisoning is suspected
• Pitfalls
  • Failure to carefully titrate Vitamin K dosing in those with a therapeutic indication for it

Therapeutic over-warfarinisation

• With bleeding
  • INR >1.5 with critical bleeding
    • Cease warfarin, Vit K 5-10mg IV, Prothrombinex 50IU/kg, FFP 150-300mL
  • INR >2 with significant (but not life-threatening) bleeding
    • Cease warfarin, Vit K 5-10mg IV and prothrombinex 35-50IU/kg
  • Any INR with minor bleeding
    • Omit warfarin, repeat INR next day and adjust dosing to therapeutic range
    • If bleeding risk high (major bleed in last 4 weeks, major surgery in last 2 weeks, platelets <50, known liver disease or concurrent antiplatelet therapy) OR INR >4.5 consider Vitamin K 1-2mg PO or 0.5-1mg IV

Therapeutic overwarfarinisation

• No bleeding
  • INR <4.5 – Lower or omit next dose and resume therapy at lower warfarin dose once INR approaching therapeutic range
  • INR 4.5-10 – Cease warfarin, consider reason for raised INR
    • If bleeding risk high (see previous slide) consider Vitamin K 1-2mg PO or 0.5-1mg IV
    • Re-measure INR at 24 hours
    • Resume warfarin at reduced dose once near therapeutic range
  • INR >10 – Cease warfarin and given Vitamin K 3-5mg PO or IV
    • Measure INR 12-24 hourly 
    • Resume warfarin at reduced dose once near therapeutic range
    • If bleeding risk if high (see previous slide) consider Prothrombinex 15-30IU/kg IV

Last Updated on October 14, 2020 by Andrew Crofton