management of common overdoses: paracetamol and tricyclic poisoning tom heaps consultant acute...

Management of Management of Common Overdoses:Common Overdoses:

Paracetamol and Paracetamol and Tricyclic PoisoningTricyclic Poisoning

Tom HeapsTom Heaps

Consultant Acute MedicineConsultant Acute Medicine

PGD MedToxPGD MedTox

ObjectivesObjectives

By the end of this session you should be able to:By the end of this session you should be able to:

understand the basic pharmacology of…understand the basic pharmacology of…appreciate the clinical features and complications of…appreciate the clinical features and complications of…safely manage patients presenting with…safely manage patients presenting with…

poisoning due to paracetamol and tricyclic antidepressant poisoning due to paracetamol and tricyclic antidepressant overdoseoverdose

interactive case scenarios with true-false questionsinteractive case scenarios with true-false questions

pearls and pitfalls in managementpearls and pitfalls in management

Why bother?Why bother?

deliberate self-poisoning accounts for 10% of all acute medical deliberate self-poisoning accounts for 10% of all acute medical admissions in UKadmissions in UK

education on this subject is generally pooreducation on this subject is generally poor

enthusiasm/interest is often lackingenthusiasm/interest is often lacking

paracetamol is drug of choice in 40% of overdoses in UK (several paracetamol is drug of choice in 40% of overdoses in UK (several hundred deaths per year in UK)hundred deaths per year in UK)

tricyclic antidepressant (TCA) poisoning less common but high tricyclic antidepressant (TCA) poisoning less common but high mortality rate (>12x that of paracetamol)mortality rate (>12x that of paracetamol)

Case Scenario 1: ParacetamolCase Scenario 1: Paracetamol

29-year-old female29-year-old femalearrives in ED at 1100arrives in ED at 110024 x 500mg paracetamol at 2300 24 x 500mg paracetamol at 2300 large quantity of alcohol prior to ODlarge quantity of alcohol prior to ODvomited several timesvomited several timeshistory of depression, recurrent DSH and history of depression, recurrent DSH and alcoholismalcoholismDHx citalopram and olanzepineDHx citalopram and olanzepineobs normalobs normalweight 60kgweight 60kg

Is this a potentially serious OD?Is this a potentially serious OD?

12g paracetamol12g paracetamol

weight 60kgweight 60kg

dose = 200mg/kgdose = 200mg/kg

Threshold for risk of significant toxicity is Threshold for risk of significant toxicity is >150mg/kg (>75mg/kg if high risk) or >12g >150mg/kg (>75mg/kg if high risk) or >12g total paracetamoltotal paracetamol

True or False?True or False?

Activated charcoal should be Activated charcoal should be administered without delayadministered without delay

FALSEFALSE

Gut decontamination with activated charcoal may Gut decontamination with activated charcoal may reduce absorption of paracetamol minimizing the reduce absorption of paracetamol minimizing the need for NAC but is only effective if given within 1h need for NAC but is only effective if given within 1h of overdose; gastric lavage is not recommended of overdose; gastric lavage is not recommended and may actually enhance early absorptionand may actually enhance early absorption

True or False?True or False?An IV infusion of N-Acetylcysteine (Parvolex®) An IV infusion of N-Acetylcysteine (Parvolex®) should be commenced immediately rather than should be commenced immediately rather than waiting for blood results (paracetamol levels)waiting for blood results (paracetamol levels)

TRUETRUE

Efficacy of NAC is maximal when started within 8h Efficacy of NAC is maximal when started within 8h of OD; patients presenting >8h after a potentially of OD; patients presenting >8h after a potentially significant OD should be commenced on NAC significant OD should be commenced on NAC immediately pending the results of blood immediately pending the results of blood tests/paracetamol levelstests/paracetamol levels


Paracetamol levels are irrelevant as the Paracetamol levels are irrelevant as the overdose occurred 12h agooverdose occurred 12h ago

FALSEFALSE

Paracetamol levels are prognostically Paracetamol levels are prognostically accurate and should guide treatment accurate and should guide treatment decisions up to 15h post-OD; they are decisions up to 15h post-OD; they are irrelevant in cases of staggered ODirrelevant in cases of staggered OD


The fact that she drank a significant quantity of alcohol just The fact that she drank a significant quantity of alcohol just prior to the overdose means that her paracetamol level prior to the overdose means that her paracetamol level should be interpreted with respect to the high-risk treatment should be interpreted with respect to the high-risk treatment lineline

FALSEFALSE

The high-risk treatment line should be used but this is due The high-risk treatment line should be used but this is due to her history of chronic alcoholism (glutathione deficiency, to her history of chronic alcoholism (glutathione deficiency, enzyme induction). Acute ethanol ingestion is paradoxically enzyme induction). Acute ethanol ingestion is paradoxically hepatoprotective as it may inhibit conversion of hepatoprotective as it may inhibit conversion of paracetamol to its toxic metabolite (NAPBQI) by the paracetamol to its toxic metabolite (NAPBQI) by the CYP450 enzyme system. CYP450 enzyme system.

Rumack-Matthew Nomogram Rumack-Matthew Nomogram High-Risk FactorsHigh-Risk Factors

Enzyme inducing drugsEnzyme inducing drugs

Eating disordersEating disorders

Chronic liver diseaseChronic liver disease

AlcoholismAlcoholism

HIVHIV


If IV access proves difficult then oral methionine If IV access proves difficult then oral methionine can be given instead of NACcan be given instead of NAC

FALSEFALSE

There is no evidence that oral methionine is There is no evidence that oral methionine is effective in later presentations of paracetamol OD effective in later presentations of paracetamol OD (>8h) and its use is not generally recommended by (>8h) and its use is not generally recommended by the NPIS; oral NAC is an effective alternative but is the NPIS; oral NAC is an effective alternative but is not widely available in the UK not widely available in the UK


If our patient was found to be pregnant then the If our patient was found to be pregnant then the dose of NAC administered should be halved to dose of NAC administered should be halved to avoid fetal toxicityavoid fetal toxicity

FALSEFALSE

The risks of fetal toxicity with NAC are minimal The risks of fetal toxicity with NAC are minimal whereas witholding treatment may pose significant whereas witholding treatment may pose significant risks both to the mother and developing child; risks both to the mother and developing child; there is no evidence to support reduced doses of there is no evidence to support reduced doses of NAC irrespective of pregnancyNAC irrespective of pregnancy

Case Scenario 1 Cont.Case Scenario 1 Cont.

30min into the parvolex infusion30min into the parvolex infusion

patient becomes distressedpatient becomes distressed

feels ‘dreadful’feels ‘dreadful’

vomitingvomiting

flushed red faceflushed red face

tachypnoeic and wheezytachypnoeic and wheezy

BP 134/78, HR 90/minBP 134/78, HR 90/min

True or False?True or False?Parvolex should be stopped immediately and Parvolex should be stopped immediately and anaphylaxis treated with IM adrenaline, IV anaphylaxis treated with IM adrenaline, IV antihistamines, nebulized beta-agonists and IV antihistamines, nebulized beta-agonists and IV hydrocortisonehydrocortisone

FALSEFALSE

This is not anaphylaxis (BP is normal); this is a This is not anaphylaxis (BP is normal); this is a pseudoallergic (anaphylactoid) reaction which pseudoallergic (anaphylactoid) reaction which occurs in up to 20% of people given IV NAC; treat occurs in up to 20% of people given IV NAC; treat with antihistamines only ± bronchodilators if with antihistamines only ± bronchodilators if wheezy (may precipitate acute asthma); parvolex wheezy (may precipitate acute asthma); parvolex can usually be restarted after a short interval e.g. can usually be restarted after a short interval e.g. 22ndnd bag or at half the rate (conc. dependent) bag or at half the rate (conc. dependent)


completes remainder of course of NAC without completes remainder of course of NAC without complicationcomplication

receives treatment for alcohol withdrawal symptomsreceives treatment for alcohol withdrawal symptoms

Post-parvolex bloods;Post-parvolex bloods;

Na Na 138138 (140)(140)KK 3.53.5 (4.1)(4.1)Ur Ur 3.23.2 (4.0)(4.0)CrCr 7777 (80)(80)INR INR 1.31.3 (1.0)(1.0)ALT ALT 4545 (46)(46)

True or False?True or False?The ward FY1 should have taken a repeat The ward FY1 should have taken a repeat paracetamol level along with the other post-paracetamol level along with the other post-parvolex bloodsparvolex bloods

FALSEFALSE

If the initial paracetamol level was taken at ≥4h If the initial paracetamol level was taken at ≥4h post-OD then repeat levels are generally NOT post-OD then repeat levels are generally NOT required as absorption is maximal by 4h (unlike required as absorption is maximal by 4h (unlike poisoning with other drugs e.g. NSAIDs, lithium, poisoning with other drugs e.g. NSAIDs, lithium, FeSOFeSO4 4 where repeated levels are indicated)where repeated levels are indicated)

True or False?True or False?The Parvolex infusion should be continued The Parvolex infusion should be continued as her INR has risen from 1.0 to 1.3 as her INR has risen from 1.0 to 1.3 indicating early hepatotoxicityindicating early hepatotoxicity

FALSEFALSE

Parvolex itself may cause mild increases in Parvolex itself may cause mild increases in PT (destabilizes proteins including clotting PT (destabilizes proteins including clotting factors) and an INR of ≤1.3 post-infusion is factors) and an INR of ≤1.3 post-infusion is acceptable (especially as her ALT has not acceptable (especially as her ALT has not risen from baseline)risen from baseline)


6h later patient is still waiting by her bed 6h later patient is still waiting by her bed for psychiatry reviewfor psychiatry review

suddenly becomes unresponsive and suddenly becomes unresponsive and loses cardiac outputloses cardiac output

monitor shows VTmonitor shows VT

CPR and a 360J shock successfully CPR and a 360J shock successfully restore cardiac output and she regains restore cardiac output and she regains consciousnessconsciousness

post-arrest bloods show a Kpost-arrest bloods show a K++ of 2.0 of 2.0

Post-Arrest ECGPost-Arrest ECG

prolonged QTc (560ms)prolonged QTc (560ms)

460ms (upper limit of normal) on admission ECG460ms (upper limit of normal) on admission ECG

More Questions…More Questions…

What factors caused her hypokalaemia?What factors caused her hypokalaemia?

vomitingvomiting

stress hormones (catecholamines, cortisol)stress hormones (catecholamines, cortisol)

IV dextrose (dilutional ± insulin release)IV dextrose (dilutional ± insulin release)

alcoholism/withdrawalalcoholism/withdrawal

direct toxic effect of paracetamoldirect toxic effect of paracetamol (decreased (decreased prostaglandins reduce renal perfusion resulting in prostaglandins reduce renal perfusion resulting in release of renin/aldosterone)release of renin/aldosterone)

More Questions…More Questions…

What caused her cardiac arrest?What caused her cardiac arrest?

arrhythmia (VT) caused by QTc arrhythmia (VT) caused by QTc prolongation due to:prolongation due to:– hypokalaemiahypokalaemia– hypomagnesaemiahypomagnesaemia– drugs (olanzepine and citalopram)drugs (olanzepine and citalopram)– IV antihistaminesIV antihistamines

Summary: Paracetamol ODSummary: Paracetamol OD

calculate dose/kg to estimate toxicitycalculate dose/kg to estimate toxicity

take levels once at ≥4htake levels once at ≥4h

establish whether low or high-risk on nomogramestablish whether low or high-risk on nomogram

start treatment immediately if ≥8h since OD and review with levelsstart treatment immediately if ≥8h since OD and review with levels

levels are useful up to 15h but irrelevant in staggered ODlevels are useful up to 15h but irrelevant in staggered OD

anaphylactoid reactions to NAC are common and are not an ‘allergy’anaphylactoid reactions to NAC are common and are not an ‘allergy’

parvolex may cause slight increase in INRparvolex may cause slight increase in INR

continue Rx if INR >1.3 or significant elevation in transaminasescontinue Rx if INR >1.3 or significant elevation in transaminases

beware hypokalaemia (consider IVI with KCl if other risk factors for beware hypokalaemia (consider IVI with KCl if other risk factors for hypokalaemia and/or arrhythmia)hypokalaemia and/or arrhythmia)

Case Scenario 2: TricyclicsCase Scenario 2: Tricyclics

60-year-old female60-year-old femalefound unconscious at home by daughterfound unconscious at home by daughtersuicide note and empty packet of amitriptyline (28 x suicide note and empty packet of amitriptyline (28 x 50mg)50mg)daughter had spoken to her 4h priordaughter had spoken to her 4h priorhistory of bipolar disorderhistory of bipolar disorderother prescribed medications include lithium and other prescribed medications include lithium and temazepamtemazepamsinus tachycardia (130), BP 96/44sinus tachycardia (130), BP 96/44GCS 4, dilated pupils, increased tone and hyperreflexia GCS 4, dilated pupils, increased tone and hyperreflexia bilaterally with extensor plantarsbilaterally with extensor plantarsestimated weight 60kgestimated weight 60kg

True or False?True or False?An urgent CT head is mandatory given her An urgent CT head is mandatory given her GCS and neurological examinationGCS and neurological examination

FALSEFALSE

her presentation is entirely consistent with her presentation is entirely consistent with severe tricyclic poisoning and in the severe tricyclic poisoning and in the absence of other features (head injury, absence of other features (head injury, meningism, lateralizing neurology) a head meningism, lateralizing neurology) a head CT is not requiredCT is not required

True or False?True or False?This is a potentially life-threatening overdoseThis is a potentially life-threatening overdose

TRUETRUE

possible total ingestion of 1400mgpossible total ingestion of 1400mg

weight = 60kgweight = 60kg

maximal possible ingested dose = 23mg/kgmaximal possible ingested dose = 23mg/kg

risk of fatality with TCA OD at >15mg/kgrisk of fatality with TCA OD at >15mg/kg

Pharmacology…Pharmacology…

Which of the following receptors do TCAs act upon and Which of the following receptors do TCAs act upon and what clinical effects does each action cause in what clinical effects does each action cause in overdose?overdose?

acetylcholineacetylcholinehistaminehistamineGABAGABAcardiac sodium channelscardiac sodium channelscardiac delayed rectifier potassium channels (Icardiac delayed rectifier potassium channels (Ikrkr) ) noradrenalinenoradrenalineserotoninserotoninαα-adrenergic-adrenergic

AnswerAnswerAll of these receptors:All of these receptors:

anticholinergic:anticholinergic: tachycardia, confusion, pyrexia, dry skin, dilated pupils, urinary tachycardia, confusion, pyrexia, dry skin, dilated pupils, urinary retention and ileus retention and ileus

αα11-adrenergic blockade:-adrenergic blockade: vasodilatation and hypotension vasodilatation and hypotension

histamine:histamine: confusion, hallucinations and drowsiness confusion, hallucinations and drowsiness

GABA:GABA: drowsiness, ataxia, divergent squint, nystagmus (potentiated by drowsiness, ataxia, divergent squint, nystagmus (potentiated by benzodiazepines, alcohol etc.)benzodiazepines, alcohol etc.)

cardiac sodium and Icardiac sodium and Ikrkr channel blockade channel blockade :: sinus tachycardia, PR/QRS/QTc sinus tachycardia, PR/QRS/QTc prolongation, RBBB, AVBprolongation, RBBB, AVB

serotonin:serotonin: features of serotonin syndrome especially if coningestion of other features of serotonin syndrome especially if coningestion of other serotonergic drugsserotonergic drugs

other effects:other effects: increased tone, hyperreflexia, seizures, metabolic acidosis, increased tone, hyperreflexia, seizures, metabolic acidosis, hypothermia, rhabdomyolysis, ARDShypothermia, rhabdomyolysis, ARDS

True or False?True or False?In view of her low GCS and airway risk our patient In view of her low GCS and airway risk our patient should be given IV flumazenil to reverse the CNS should be given IV flumazenil to reverse the CNS sedative effects of temazepam which she may sedative effects of temazepam which she may have coingestedhave coingested

FALSEFALSE

flumazenil is rarely indicated in benzodiazepine flumazenil is rarely indicated in benzodiazepine overdose and in the case of mixed overdose overdose and in the case of mixed overdose (especially with TCAs) it is contraindicated due to (especially with TCAs) it is contraindicated due to risk of precipitating seizuresrisk of precipitating seizures

Another Question…Another Question…Which of the following would be an Which of the following would be an indication for IV sodium bicarbonate indication for IV sodium bicarbonate administration in the context of TCA OD:administration in the context of TCA OD:

metabolic acidosismetabolic acidosis

hypotension despite fluid resuscitationhypotension despite fluid resuscitation

cardiac arrhythmiacardiac arrhythmia

QRS prolongation >120msQRS prolongation >120ms

AnswerAnswer

all of these are indications for administration of all of these are indications for administration of IV sodium bicarbonate as 50ml boluses of 8.4% IV sodium bicarbonate as 50ml boluses of 8.4% aiming for arterial pH of 7.5-7.55aiming for arterial pH of 7.5-7.55

increased pH favours neutral form of tricyclic increased pH favours neutral form of tricyclic drug reducing receptor bindingdrug reducing receptor binding

sodium load increases extracellular [Nasodium load increases extracellular [Na++] ] attenuating blockade of rapid sodium channelsattenuating blockade of rapid sodium channels

True or False?True or False?Arrhythmias which do not correct with sodium Arrhythmias which do not correct with sodium bicarbonate may be treated with IV magnesiumbicarbonate may be treated with IV magnesium

and/or lignocaine and/or lignocaine

TRUETRUE

Initial treatment should aim to correct hypoxaemia Initial treatment should aim to correct hypoxaemia and acidosis. Class Ia (quinidine, disopyramide, and acidosis. Class Ia (quinidine, disopyramide, procainamide) and Ic (flecainide, propafenone) procainamide) and Ic (flecainide, propafenone) antiarrhythmics are contraindicated as these antiarrhythmics are contraindicated as these exacerbate cardiac sodium channel blockadeexacerbate cardiac sodium channel blockade

True or False?True or False?IV phenytoin is the drug of choice for IV phenytoin is the drug of choice for refractory seizures in TCA OD refractory seizures in TCA OD

FALSEFALSE

Phenytoin acts by blocking sodium channels Phenytoin acts by blocking sodium channels and therefore increases the risk of and therefore increases the risk of arrhythmias. Seizures should be managed arrhythmias. Seizures should be managed by correcting hypoxaemia/acidosis and by correcting hypoxaemia/acidosis and giving IV lorazepamgiving IV lorazepam

True or False?True or False?Despite aggressive fluid resuscitaion and IV bicarbonate Despite aggressive fluid resuscitaion and IV bicarbonate our patient becomes progressively hypotensive. Her BP is our patient becomes progressively hypotensive. Her BP is now 67/35 and she is oliguric. The Medical SpR thinks she now 67/35 and she is oliguric. The Medical SpR thinks she should be transferred to HDU for IV noradrenaline to should be transferred to HDU for IV noradrenaline to restore her BP and renal perfusion.restore her BP and renal perfusion.

TRUETRUE

Noradrenaline is the vasopressor of choice in severe TCA Noradrenaline is the vasopressor of choice in severe TCA OD with refractory hypotension due to its OD with refractory hypotension due to its αα11-agonist -agonist properties. IV glucagon 10mg may also be given if properties. IV glucagon 10mg may also be given if significant myocardial depression. IV fat emulsion significant myocardial depression. IV fat emulsion (Intralipid®) has been used as a rescue therapy.(Intralipid®) has been used as a rescue therapy.

True or False?True or False?24h later the patient is haemodynamically stable and off 24h later the patient is haemodynamically stable and off inotropes. Her electrolytes and acid base balance are inotropes. Her electrolytes and acid base balance are normal. She has not had a seizure or arrhythmia since normal. She has not had a seizure or arrhythmia since admission and is stepped down to AMU. Her GCS is 13-14 admission and is stepped down to AMU. Her GCS is 13-14 and she is intermittently agitated, confused and appears to and she is intermittently agitated, confused and appears to be hallucinating. The ward sister thinks you should request be hallucinating. The ward sister thinks you should request a CT head and refer her to the psychiatrists. a CT head and refer her to the psychiatrists.

FALSEFALSE

Following severe TCA posioning a prolonged phase of Following severe TCA posioning a prolonged phase of delirium (lasting several days) is common after all the other delirium (lasting several days) is common after all the other signs of toxicity have subsided. The patient should be signs of toxicity have subsided. The patient should be treated supportively ± benzodiazepines (large doses may treated supportively ± benzodiazepines (large doses may be required)be required)

Summary: TCA ODSummary: TCA OD>300 deaths per year in UK (22% of all drug-related suicides) with case fatality rate of up to 3% (12x greater >300 deaths per year in UK (22% of all drug-related suicides) with case fatality rate of up to 3% (12x greater than paracetamol)than paracetamol)

calculate dose/kg to estimate toxicitycalculate dose/kg to estimate toxicity

profound confusion and depression of GCS/respiration may occur after period of relative lucidityprofound confusion and depression of GCS/respiration may occur after period of relative lucidity

management is largely supportive (correct hypoxaemia, hypovolaemia, electrolyte abnormalities and management is largely supportive (correct hypoxaemia, hypovolaemia, electrolyte abnormalities and acidosis)acidosis)

close attention to ABC with support from ITUclose attention to ABC with support from ITU

IV sodium bicarbonate 50mmol 8.4% for acidosis, QRS prolongation, arrhythmias and refractory hypotensionIV sodium bicarbonate 50mmol 8.4% for acidosis, QRS prolongation, arrhythmias and refractory hypotension

IV lorazepam for delirium/seizures (avoid PHT)IV lorazepam for delirium/seizures (avoid PHT)

IV MgIV Mg2+2+/lidocaine for refractory arrhythmias (avoid class Ia and Ic)/lidocaine for refractory arrhythmias (avoid class Ia and Ic)

IV noradrenaline ± glucagon for refractory hypotensionIV noradrenaline ± glucagon for refractory hypotension

prolonged delirium is common during recoveryprolonged delirium is common during recovery

management of common overdoses: paracetamol and tricyclic poisoning tom heaps consultant acute...

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