No.

• Quetiapine overdose characteristically causes brisk sinus tachycardia (e.g. 120-150 bpm) and QTc prolongation.
• Sinus bradycardia with a normal QTc is not consistent with quetiapine poisoning as the cause of coma.
• Fixed dilated pupils and loss of brainstem reflexes are also not consistent with quetiapine — despite having antimuscarinic effects, quetiapine normally causes paradoxically small pupils.

See an example ECG of a patient with quetiapine toxicity.

Baclofen

Baclofen is a synthetic derivative of GABA, used primarily for management of painful muscle spasms in conditions such as spinal cord injury, cerebral palsy and multiple sclerosis. It is closely related to the recreational drug, Gamma-Hydroxybutyrate (GHB).

In overdose, it causes a picture similar to barbiturate coma:

• Profound CNS depression with loss of brainstem reflexes.
• Flaccid tone with absent deep tendon reflexes.
• Bradycardia.
• Respiratory depression.
• Need for intubation and mechanical ventilation.
• Hypothermia.

Other effects seen with baclofen overdose:

• Hypertension or hypotension (the former is more commonly reported — the mechanism of this is unknown).
• Paradoxical seizures.
• Pupil abnormalitites — miosis or mydriasis.
• Agitated delirium.
• 1st degree AV block and QT prolongation are rarely reported.

The duration of coma is usually 24 to 48 hours but may be prolonged (i.e. several days) with massive doses or in patients with renal failure. 

• Baclofen acts as an agonist at pre- and postsynaptic GABA-B receptors in the brain and spinal cord.
• Therapeutic (antispasmodic) effects occur primarily at the spinal cord level; in overdose there is also increased GABA activity within the brain.
• Activation of presynaptic GABA-B receptors causes inhibition of excitatory neurotransmitter release within the CNS.
• The mechanism is thought to involve hyperpolarisation of the presynaptic membrane and reduced calcium influx into the nerve terminal with resultant impairment of calcium-dependent exocytosis of excitatory neurotransmitters.
• The net result is a generalised CNS depression similar to that seen with barbiturates, propofol and other general anaesthetics.
• Paradoxical seizures occur due to presynaptic inhibition of inhibitory neurons (i.e. disinhibition).

• Rapidly and completely absorbed following oral administration.
• Peak serum levels occur at ~ 2 hours post ingestion.
• Lipophilic so readily crosses the blood-brain barrier.
• Relatively small Vd (0.7 L/kg).
• Primarily excreted unchanged in the urine.
• 15% metabolised by the liver.
• The mean elimination half-life is 3.5 hours, although this may be prolonged in overdose (15-35 hours in some case reports).

• Acute ingestion of > 200 mg is expected to produce significant CNS toxicity, with delirium, coma and paradoxical seizures.
• This amounts to only 8 x 25 mg tablets or 20 x 10 mg tablets.
• Smaller doses may cause mild drowsiness and delirium.

Our patient had ingested an enormous overdose of 2,500 mg of baclofen (a entire bottle of 100 x 25 mg tablets)!

Other agents that may cause coma with transient loss of brainstem reflexes:

• Barbiturates (e.g. phenobarbitone, primidone)
• Carbamazepine

Barbiturate and carbamazepine levels — readily available in most big centres — are useful in ruling out poisoning with these agents. Baclofen levels are less widely available, hence this diagnosis is usually a clinical one (often made retrospectively once collateral history becomes available).

Carbamazepine overdose was discussed in Toxicology Conundrum 046.

Resuscitation

• Early intubation and ventilation is indicated for patients with coma or respiratory depression.
• Paradoxical seizures are treated with benzodiazepines.
• Hypotension usually responds to fluid resuscitation.

Decontamination

• Nasogastric activated charcoal (50g) given following intubation may reduce the total dose of baclofen absorbed. It is given with the intention of reducing the duration of coma and length of ICU stay. Due to the rapid absorption kinetics of baclofen, charcoal is only likely to be useful if given within the first few hours.
• Conversely, activated charcoal is not recommended in the patient with an unprotected airway due to rapid onset of coma and seizures with the potential for charcoal pulmonary aspiration.

Enhanced Elimination

• Enhanced elimination is not normally necessary as patients do well with supportive care alone.
• However, a recent case report has suggested that there may be some benefit from haemodialysis (HD) in reducing duration of coma in large baclofen overdose — the authors reported an elimination half life of 15.7 hours before and 3.1 hours after instigation of HD in a 420 mg baclofen ingestion.

No!

• Benzodiazepine overdose typically produces mild sedation, lethargy, slurred speech and ataxia.
• More significant CNS depression may be seen with ingestion of alprazolam or in the presence of co-ingestants (alcohol, opioids).
• Massive benzodiazepine ingestion may result in hypothermia, bradycardia and hypotension.

However… agitation, tachycardia, urinary retention and dilated pupils are not features of benzodiazepine overdose.

This presentation is not consistent with isolated benzodiazepine overdose. 

This patient has developed a classic anticholinergic toxidrome.

The hallmark of this toxidrome is an agitated delirium accompanied by variable signs of central and peripheral muscarinic (acetylcholine) receptor blockade.

Signs of central muscarinic blockade:

Agitated delirium characterised by

• Fluctuating mental status
• Confusion
• Restlessness
• Fidgeting
• Visual hallucinations
• Picking at objects in the air
• Mumbling slurred speech
• Disruptive behaviour

Tremor, myoclonus, coma, seizures (rare)

“A fumbling, mumbling mess”

Signs of peripheral muscarinic blockade:

• Dilated pupils
• Sinus tachycardia
• Dry mouth
• Hot, flushed, dry skin
• Increased temperature
• Urinary retention
• Ileus

There are numerous agents that may produce an anticholinergic toxidrome. The most important ones are summarised below.

• Antihistamines – promethazine, doxylamine, diphenhydramine, chlorpheniramine.
• Antipsychotics (phenothiazines and butyrophenones) – chlorpromazine, droperidol, haloperidol.
• Atypical antipsychotics – olanzapine, quetiapine.
• Anticonvulsants – carbamazepine.
• Antidepressants – tricyclic antidepressants.
• Antispasmodics – hyoscine butylbromide (Buscopan), oxybutynin.
• Antiemetics – hyoscine hydrobromide (Kwells).
• Antiparkinsonian agents  – benztropine.
• Antimuscarinics – atropine, glycopyrrolate (usually only peripheral symptoms).
• Plants – Datura species (Jimsonweed), certain mushrooms.

With difficulty!

These patients are very demanding and require scrupulous supportive care to manage the behavioural effects of delirium and prevent complications such as dehydration, injury and pulmonary aspiration:

• Sedation is usually required for behavioural control. Benzodiazepines are the first-line therapy, e.g. IV diazepam in 5mg-10mg  increments, aiming for a patient that is sleepy but easily roused. Avoid over-sedating the patient as this will increase the risk of aspiration.
• One-to-one nursing is frequently necessary to maintain adequete supervision.
• Intravenous fluids should be prescribed as patients are typically unable to eat and drink and may be dehydrated at presentation.
• Insertion of a urinary catheter is usually required for management of urinary retention.
• Avoid using sedative drugs with anticholinergic properties (e.g. antipsychotics such as olanzapine) as this will exacerbate the delirium.

Physostigmine is the specific antidote to anticholinergic delirium and may be used for behavioural control in carefully selected cases.

Mechanism of action

• Physostigmine is a reversible acetylcholinesterase inhibitor (similar to carbamate insecticides).
• It temporarily blocks the breakdown of acetylcholine, thus enhancing its effects at muscarinic and nicotinic receptors.
• This increased cholinergic activity overcomes muscarinic receptor blockade, transiently reversing the effects of the anticholinergic agents.

Toxicological Indications

• Severe anticholinergic delirium unresponsive to benzodiazepine sedation.
• Poisoning with a pure anticholinergic agent (e.g. atropine).

Contraindications

• Bradycardia
• AV block
• Interventricular conduction abnormality (QRS >100ms)
• Bronchospasm

Adverse Effects

Excessive dosing may produce side-effects due to excess cholinergic activity, resulting in a clinical picture similar to organophosphate poisoning.

• Bronchospasm, Bronchorrhoea and Bradycardia (the “killer bees”)
• “SLUDGE syndrome” with excess Salivation, Lacrimation, Urinary incontinence, Diarrhoea, Gastrointestinal upset and Emesis.
• Seizures may occur with rapid IV administration due to central cholinergic hyperactivity.
• Muscle weakness due to excess acetylcholine at the neuromuscular junction (suxamethonium-like effect).

Dosage and Administration

• Must be given in a monitored setting with appropriate staff and resources to manage adverse effects such as seizures, bradyarrhythmias and respiratory distress.
• Ensure there is no bradycardia / AV block / broad QRS on the 12-lead ECG.
• Give IV physostigmine 0.5 – 1mg as a slow push over 5 mins; repeat every 10 mins up to a maximum of 4mg.
• The clinical end-point of therapy is resolution of delirium.
• Delirium may reoccur in 1-4 hours as the effects of physostigmine wear off, at which time the dose may be cautiously repeated.

The response to therapy may be very dramatic (“end of the needle” response), with patients converted from a “fumbling, mumbling mess” into well-behaved, coherent individuals within seconds.

In this case, physostigmine was avoided as the patient had a history of seizures. He ultimately required intubation for florid delirium unresponsive to benzodiazepine sedation. Subsequently it emerged that he had been admitted under Toxicology earlier in the year for a large olanzapine overdose.

Yes and no.

• Olanzapine overdose may produce drowsiness and anticholinergic delirium.
• However, like other atypical antipsychotic drugs (quetiapine, clozapine), olanzapine causes paradoxically small pupils (due to peripheral alpha blockade) rather than the dilated pupils seen in this case.

The following day he is extubated in ICU. He tells you that he took an overdose of his girlfriend’s epileptic medications. He cannot remember the name of the medication but states that they were 400mg tablets that came in a yellow-and-white box; he took around 25 tablets in total.

Carbamazepine

• The history of anticonvulsant ingestion causing gradual onset of progressive drowsiness and anticholinergic delirium with deterioration over an 8-hour period is consistent with an extended-release carbamazepine preparation.
• He had taken 25 x 400mg Tegretol CR tablets (= 10g carbamazepine or ~140mg/kg)
• Carbamazepine level added onto his admission bloods confirmed ingestion, with a serum level of 39 mg/L.

Carbamazepine (Tegretol) CR 400mg tablets

• Absorption: Carbamazepine is slowly and erratically absorbed. Peak plasma concentrations are typically delayed for 8-12 hours following ingestion. In overdose, ileus secondary to anticholinergic effects may result in ongoing absorption over several days. There are reports of peak levels being delayed by up to 96 hours following massive overdose with controlled-release tablets.
• Bioavailability is approximately 100% for the standard release preparation and 85% for the controlled release preparation.
• Distribution: Small volume of distribution (0.8 – 1.2 L/kg), hence may be cleared by dialysis.
• Protein Binding: 70-80% protein bound.
• Metabolism: Metabolised in the liver by cytochrome P450 3A4 to an active metabolite, carbamazepine 10,11 epoxide. This is further metabolised to inactive metabolites that are excreted in the urine.
• Excretion: Approximately 70% of an ingested dose is excreted in the urine as epoxidated, hydroxylated or conjugated metabolites; the remaining 30% is excreted in the faeces.

Carbamazepine causes gradual onset (over 8-12 hours) of the following symptoms:

• CNS effects – Cerebellar signs (ataxia, dysarthria, nystagmus, ophthalmoplegia), myoclonus, drowsiness, coma.
• Anticholinergic effects – See above.
• Sodium-channel blockade – Carbamazepine is structurally similar to the TCA imipramine and exerts similar (albeit less pronounced) sodium-channel blocking effects in overdose. Massive overdoses (>>50mg/kg) may be complicated by paradoxical seizures, hypotension and cardiac conduction abnormalities (1st degree AV block, QRS prolongation) with potential for ventricular dysrhythmias (rare).

Some example ECGs of carbamazepine cardiotoxicity can be found here. 

The dose-related risk assessment for carbamazepine is summarised below:

• 20-50mg/kg  -  Mild-moderate CNS and anticholinergic effects.
• > 50mg/kg  -  Fluctuating mental status with intermittent agitation and risk of progression to coma within the first 12 hours. Risk of hypotension and cardiotoxicity with massive doses.

Hence 140mg/kg is a sigificant carbamazepine overdose.

Our patient did have some initial hypotension that responded to fluids and ECG changes suggestive of cardiotoxicity (QRS broadening to 120ms, R’ wave in aVR of 2-3mm), but never became cardiovascularly unstable.

• 8-12 mg/L = Normal therapeutic range
• >12mg/L - Nystagmus and ataxia
• >20mg/L - Drowsiness and anticholinergic delirium
• >40mg/L - Coma, seizures and cardiac conduction abnormalities

The level of 39 mg/L is consistent with his symptoms.

Resuscitation

• Intubation and ventilation may be required for coma with loss of airway reflexes or for florid combative delirium not responsive to other measures.
• Paradoxical seizures are managed with titrated doses of benzodiazepines (e.g. diazepam 5-10mg IV). Barbiturates are second-line agents for refractory toxicological seizures (e.g. RSI with thiopentone 3-5 mg/kg).
• Ventricular dysrhythmias due to sodium-channel blockade are treated with boluses of IV sodium bicarbonate.

Investigations

• Paracetamol level, 12-lead ECG, blood sugar (= routine toxicological screening tests).
• Serum carbamazepine level (repeat every 6 hours in comatose patients).
• Serial ECGs to assess for cardiotoxicity.

Decontamination

• Oral activated charcoal (50g) may be given to patients who present early and asymptomatic with ingestions <50mg/kg.
• In patients with established CNS toxicity, charcoal is only given once the patient has been intubated and nasogastric tube position has been confirmed on chest x-ray.

Enhanced Elimination

Enhanced elimination techniques are used with aim of reducing the duration of mechanical ventilation and ICU stay.

• Carbamazepine coma is the most common indication for multiple-dose activated charcoal (MDAC). This treatment works by interrupting enterohepatic circulation and reducing ongoing absorption from the gut. Doses of nasogastric charcoal (25g) are given every 2-4 hours until levels are falling, the patient is improving or bowel sounds disappear (e.g. due to anticholinergic ileus). There is a potential risk of bowel obstruction from charcoal concretions.
• Carbamazepine and its active metabolite (10,11 epoxide) can be removed by haemodialysis / CVVHD. Indications for extracorporeal elimination are not clear but it may be considered in comatose patients with large ingestions and evidence of haemodynamic instability or rising serum levels after 48 hours.

• The 10-hour level of 182mg/L is well above the treatment line, so the NAC infusion should continue for a full course of treatment (minimum of 20 hours), with repeat ALT testing at the end of the infusion.
• If the ALT remains abnormal at the end of the 20-hour infusion, NAC is continued at a rate of 100mg/kg every 16 hours.
• ALT is checked every 12-24 hours until it begins to normalise.
• NAC infusion must continue until the ALT is stable or falling.
• As the ALT is abnormal, bloods should also be sent for coagulation profile, renal function and platelet count to monitor for impending liver failure. These additional markers should also be repeated every 12-24 hours during treatment.

By 56 hours post-ingestion, ALT has risen to 9000, with an INR of 2.5 and a platelet count of 200.  She has some RUQ tenderness and nausea. You start to wonder whether you should consider aeromedical retrieval to a tertiary hospital.

Paracetamol-induced hepatotoxicity is defined as a peak elevation in hepatic transaminases (ALT or AST) > 1000 IU/L in the context of paracetamol overdose.

This patient clearly has paracetamol-induced hepatotoxicity, along with evidence of impaired liver synthetic function (abnormal INR).

High-risk features mandating admission to a liver transplant centre are:

• INR >3.0 at 48 hours or >4.5 at any time.
• Oliguria or creatinine > 200 micromol/L
• Acidosis with pH < 7.3 after resuscitation
• Systolic hypotension with BP < 80mmHg
• Hypoglycaemia
• Severe thrombocytopenia
• Encephalopathy of any degree

Our patient has an INR <3.0 with normal renal function, pH, blood pressure, blood sugar and platelet count and no evidence of encephalopathy – so she does not meet criteria for transfer at this stage.

However, given that transfer to a tertiary centre may take several hours to organise, it would be useful to be able to predict whether this patient is likely to develop fulminant hepatic failure.

The risk of hepatic encephalopathy can be predicted by calculating the Schiodt score.

This scoring system uses three main factors to predict the risk of hepatic encephalopathy:

• Time interval between paracetamol ingestion and commencement of NAC
• INR
• Platelet count

Each of these risk factors is converted to a points score as follows:

[NB. In-between values are interpolated to give an intermediate risk score, e.g. time to NAC of 3 hours gives a point score (A) of 18]

The Schiodt score is calculated by the following equation:

 Overall score = (A + B + C – 99) / 10

This score is then converted to a probability of developing hepatic encephalopathy:

For our patient, the point scores are as follows:

•  Time to NAC of 10 hours gives (A) = 40
• INR of 2.5 gives (B) = 51
• Platelet count of 200 at 56 hours gives (C) = –30

Hence:

Overall score = (40 + 51 – 30 – 99) / 10 =  –3.8

This gives our patient an approximately 2-3% probability of developing hepatic encephalopathy.

Given that our patient is still relatively low risk, it is probably safe to leave them in the rural hospital for the time being. Serial blood tests and NAC infusion will need to continue until transaminases are falling and coagulopathy is improving.

•  The patient remained in the rural hospital on a NAC infusion.
• By 72 hours, ALT had fallen to 6000 and INR to 1.9
• By 84 hours, ALT had fallen to 3600, INR to 1.1 and she was feeling much better, with resolution of her RUQ tenderness and nausea.
• Following a further period of observation she was subsequently discharged to the care of psychiatry with no long term sequelae; ALT normalised over the following few days.

Propranolol is a lipid soluble, non-cardioselective beta blocker with sodium-channel blocking effects.

Propranolol

• Absorption: Rapidly absorbed orally. Peak blood levels occur at 1-3 hours following oral administration.
• Distribution: Highly lipophilic agent with a wide volume of distribution. Rapidly distributed to all tissues, including CNS.
• Protein Binding: Approximately 93% protein bound.
• Metabolism: Undergoes extensive hepatic metabolism, with hydroxylation of the aromatic nucleus and degradation of the isoprenaline side-chain. Over 20 metabolites identified. The 4-hydroxy metabolite has active beta-blocking properties.
• Elimination: 95-100% of an ingested dose is excreted in the urine as metabolites and their conjugates.
• Half-life: Plasma half-life is around 3-6 hours. The pharmacological effects last much longer than this. Elimination half-life is 12 hours and may be prolonged following overdose.

Propranolol exerts its toxic effects via two main mechanisms:

• Beta-adrenergic receptor blockade (B1 and B2 receptors)
• Sodium-channel blockade (class I or “TCA-like” effect)

• Competitive antagonism of beta receptors leads to decreased intracellular cAMP with blunting of the chronotropic, inotropic and metabolic effects of catecholamines.
• Sodium-channel blockade in the myocardium leads to prolongation of the cardiac action potential with resultant QRS widening and potential for ventricular arrhythmias.
• Blockade of sodium channels in the CNS produces neurotoxic effects, i.e. seizures and coma.

Effects of Na-channel blockade on the cardiac action potential and ECG tracing

Sodium-channel blockade causes prolongation of phase zero of the cardiac action potential with resultant widening of the QRS complex. Image reproduced from Holstege et al (2006).

Excess beta-adrenergic blockade causes:

• Hypotension and bradycardia
• Bradyarrhythmias, including sinus bradycardia, 1st-3rd degree heart block, junctional or ventricular bradycardia
• Bronchospasm
• Hyperkalaemia and hypo/hyperglycaemia

Sodium-channel blockade causes:

• Cardiotoxicity – QRS widening, ventricular arrhythmias and cardiac arrest
• Neurotoxicity – coma, seizures and delirium

Massive propranolol overdose typically presents with coma, seizures, bradycardia and progressive cardiogenic shock.

The ECG changes are similar to those seen in tricyclic antidepressant poisoning, except with a much slower ventricular rate.

Beta blockade produces:

• Sinus, junctional or ventricular bradycardia
• Prolonged PR interval
• Atrioventricular block (1st-3rd degree)

Sodium-channel blockade produces:

• Broad QRS (> 100 ms in lead II)
• Right axis deviation of the terminal QRS:
  • Terminal R wave > 3 mm in aVR
  • R/S ratio > 0.7 in aVR

R' wave in aVR

The degree of QRS broadening on the ECG is correlated with adverse events:

• QRS > 100 ms is predictive of seizures
• QRS > 160 ms is predictive of ventricular arrhythmias

An ECG showing sinus bradycardia with a 1st degree AV block and minor QRS widening (>100ms) indicates early propranolol toxicity.

Example ECG

Sodium-channel blocker toxicity

• This ECG demonstrates marked sodium-channel blockade with first degree AV block and a relatively slow ventricular rate, in this case due to flecainide poisoning.
• Propranolol overdose would produce a very similar ECG pattern, albeit with a slower venticular rate.

• Any ingested dose of propranolol > 1 g is considered to be potentially lethal.
• Hence, this history of a 2.8 g ingestion is extremely worrying!

This patient has taken a lethal dose of propranolol and is already manifesting early signs of toxicity, as evidenced by:

• Mild sedation (GCS 13)
• Bradycardia (46 bpm)
• Borderline blood pressure (100/60)
• First degree AV block (PR 210 ms)
• QRS broadening (115 ms)

Peak toxicity occurs early with propranolol (within the first 1-3 hours). This patient is likely to develop rapid onset of:

• Coma
• Seizures
• Profound hypotension and bradycardia

She will almost certainly die without aggressive medical management.

The decline in GCS over the past 15 minutes is also worrying, suggesting that this patient is going to crash and burn very soon!

 Propranolol overdose is managed primarily as a tricyclic antidepressant overdose (as early life-threats are due to its sodium-channel blocking effects) and secondarily as a beta-blocker overdose.

Basic Supportive Care and Monitoring

• This patient needs to be managed in a monitored area equipped for airway management and resuscitation.
• Secure IV access, adminster high flow oxygen and attach monitoring equipment.
• Treat seizures with IV benzodiazepines (e.g. diazepam 5-10mg).
• Insert an arterial line for close haemodynamic monitoring.
• Perform serial 12-lead ECGs to assess for sodium-channel blockade (QRS>100ms).

• Administer IV sodium bicarbonate 100 mEq (1-2 mEq / kg).
• Intubate as soon as possible.
• Hyperventilate to maintain a pH of 7.50 – 7.55.
• If ventricular arrhythmias occur, the first step is to give more sodium bicarbonate. Lidocaine (1.5mg/kg) IV is a third-line agent (after bicarbonate and hyperventilation) once pH is > 7.5.
• In established cardiotoxicity, the dose of sodium bicarbonate can be repeated every few minutes until the BP improves and QRS complexes begin to narrow.
• Avoid Ia (procainamide) and Ic (flecainide) antiarrhythmics and amiodarone as they may worsen hypotension and conduction abnormalities.

• Treat hypotension with an initial crystalloid bolus (10-20 mL/kg). If this is unsuccessful in restoring BP, be prepared to rapidly escalate to more advanced circulatory support using inotropes and chronotropes.
• Atropine (10-30 mcg/kg) can be used as a temporising measure for bradycardia.
• Persistent bradycardia and hypotension is better treated with a titrated infusion of adrenaline or isoprenaline via a central venous catheter.
• If inotropes are required, consider early initiation of high-dose insulin euglycaemic therapy (as described in toxicology conundrum 028). This treatment appears to be very effective in massive propranolol overdose but takes time to work (30-45 minutes).
• Glucagon (once considered to be the “antidote” to beta-blocker poisoning) is no longer recommended as it  is difficult to source in adequate quantities and offers no advantages over standard inotropes and chronotropes.

• Admit the patient to the intensive care unit for ongoing monitoring and supportive care.

Cardiac arrest may occur in propranolol overdose due to sudden ventricular arrhythmias (i.e. pulseless VT) or progressive cardiogenic shock culminating in bradycardic PEA.

• Start CPR – Good quality CPR may be life saving. Conversely, cardioversion / defibrillation is unlikely to be successful in the poisoned heart.
• Call for help! – Toxicological arrest is approached differently to cardiac arrest from other causes. If you have not yet enlisted the advice and support of a clinical toxicologist in managing this patient, then get them on the phone now! (this is assuming that you have a spare person to talk to them… ideally get help before they arrest!)
• Push bicarb – Give boluses of IV sodium bicarbonate 1-2 mEq/kg every 1-2 minutes until return of perfusing rhythm.
• Intubate and hyperventilate (if you have not done so already).
• Give adrenaline – 1mg every 3-5 minutes as per standard cardiac arrest algorithms.
• Avoid amiodarone – It will only make things worse.
• Consider intralipid – The role of intravenous lipid emulsion (IVLE) in propranolol poisoning is not clearly defined, but it may be considered in cardiac arrest refractory to other measures. The dose is 100ml of 20% IVLE (1-1.5ml/kg) as an IV bolus over 1 minute; repeated once or twice at 3-5 minute intervals if required, followed by an infusion.
• Don’t give up! – There are numerous case reports of excellent outcomes after prolonged CPR (>45 minutes) in patients who have arrested due to poisoning.

To illustrate this last point, we had a 55-year old lady come through our department recently with a 4 gram (i.e. absolutely massive) propranolol ingestion. She had a tonic-clonic seizure in front of paramedics and promptly arrested. The paramedics continued CPR (with no drugs) for 30 minutes prior to arrival in hospital. On arrival to ED, she was treated aggressively with bicarbonate, adrenaline and high-dose insulin and achieved return of spontaneous circulation after a further 15 minutes of CPR. She was transferred to ICU on high-dose insulin (2 units/kg/hr) and adrenaline infusions, which were subsequently weaned off over the following 24-48 hours. Post-arrest echocardiogram was entirely normal (no evidence of LV dysfunction) and serial bloods showed only trivial elevations in troponin and transaminases with preserved renal function (i.e. no evidence of ischaemic ATN). She was discharged home on day 4 entirely neurologically intact!

• Hauswald M. Percutaneous transtracheal jet ventilation. Acad Emerg Med. 2011 Oct;18(10):1109. doi: 10.1111/j.1553-2712.2011.01180.x. Epub 2011 Sep 26. PMID: 21951972.

Interesting description of needle cricothyroidotomy and jet ventilation with intermittent closure of mouth and nose!

Recommended by MLC

• Kofke WA, Horak J, Stiefel M, Pascual J. Viable oxygenation with cannula-over-needle cricothyrotomy for asphyxial airway occlusion. Br J Anaesth. 2011 Oct;107(4):642-3. PMID: 21903652.

A supportive case for needle cricothyroidotomy in an anaesthetic crisis

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• Naff N, Williams MA, Keyl PM, Tuhrim S, Bullock MR, Mayer SA, Coplin W, Narayan R, Haines S, Cruz-Flores S, Zuccarello M, Brock D, Awad I, Ziai WC, Marmarou A, Rhoney D, McBee N, Lane K, Hanley DF Jr. Low-dose recombinant tissue-type plasminogen activator enhances clot resolution in brain hemorrhage: the intraventricular hemorrhage thrombolysis trial. Stroke. 2011 Nov;42(11):3009-16. Epub 2011 Aug 25. PMID: 21868730.

Another step forward in new treatments for intracerebral haemorrhage.

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• Ng R, Yeghiazarians Y. Post Myocardial Infarction Cardiogenic Shock: A Review of Current Therapies. J Intensive Care Med. 2011 Jul 11. [Epub ahead of print]  PMID: 21747126

A decent review of treatment options for cardiogenic shock post MI.

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• Shayne P, Coates WC, Farrell SE, Kuhn DO GJ, Lin M, Maggio LA, Fisher J. Critical Appraisal of Emergency Medicine Educational Research: The Best Publications of 2010. Acad Emerg Med. 2011 Oct;18(10):1081-1089.  PMID: 21996074

This is the third edition of an annual series that I started in Academic EM which highlights the highest ranked, methodologically-sound educational research studies in EM for 2010.

Recommended by ML

• Blaivas M, Adhikari S, Lander L. A prospective comparison of procedural sedation and ultrasound-guided interscalene nerve block for shoulder reduction in the emergency department. Acad Emerg Med. 2011 Sep;18(9):922-7. doi: 10.1111/j.1553-2712.2011.01140.x. Epub 2011 Aug 30. PMID: 21883635.

Trial of scalene block v sedation for dislocated shoulder. By experienced guys but the LOS was a lot less in the scalene block group.

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• Centers for Disease Control and Prevention. Infectious disease. Antiviral agents for the treatment and chemoprophylaxis of influenza. Ann Emerg Med. 2011 Sep;58(3):299-303; discussion 303-4. PMID: 21871233

<	Aaa-choo! Influenza season is coming (in the northern hemisphere!). The IDSA 2011 guidelines on antiviral agents and treatment indications for the 2011-12 season.

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• Grady D, Berkowitz SA. Why is a good clinical prediction rule so hard to find? Arch Intern Med. 2011 Oct 24;171(19):1701-2. PMID: 22025427.

Clinical prediction rules must be easy to incorporate, generalizable, reproducible, and lead to improved clinical outcomes.

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• Herring AA, Stone MB, Nagdev A. Ultrasound-guided suprascapular nerve block for shoulder reduction and adhesive capsulitis in the ED. Am J Emerg Med. 2011 Oct;29(8):963.e1-3. Epub 2010 Dec 15. PMID: 21109384.

Only a case report but yet another lovely way to anaesthetise the shoulder joint; nice description of the technique too.

Recommended by AJN

• Lucassen W, Geersing GJ, Erkens PM, Reitsma JB, Moons KG, Büller H, van Weert HC. Clinical decision rules for excluding pulmonary embolism: a meta-analysis. Ann Intern Med. 2011 Oct 4;155(7):448-60. PMID: 21969343.

An overview of Clinical Decision Rules combined with D-dimer results in the evaluation of pulmonary embolism

Recommended by MJ

• Tarnutzer AA, Berkowitz AL, Robinson KA, Hsieh YH, Newman-Toker DE. Does my dizzy patient have a stroke? A systematic review of bedside diagnosis in acute vestibular syndrome. CMAJ. 2011 Jun 14;183(9):E571-92. Epub 2011 May 16. PMID: 21576300

The best review of all the data of distinguishing benign vertigo from acute posterior stroke.

Recommended by SDW
Learn more: EMCrit — Diagnosis of Posterior Stroke

• Neunert C, Lim W, Crowther M, Cohen A, Solberg L Jr, Crowther MA; American Society of Hematology. The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. Blood. 2011 Apr 21;117(16):4190-207. Epub 2011 Feb 16. Review.  PMID: 21325604.

Excellent update on the current approach to ITP in children and adults.  Always important to know how our consultants approach the issues we are dealing with.

Recommended by SMF
Learn more:  Pediatric EM Morsels — ITP — Immune Thrombocytopenic Purpura

• Paquette K, Cheng MP, McGillivray D, Lam C, Quach C. Is a lumbar puncture necessary when evaluating febrile infants (30 to 90 days of age) with an abnormal urinalysis? Pediatr Emerg Care. 2011 Nov;27(11):1057-61. PMID: 22068068

Here’s one that will likely gain more support in the future. I still think the un-immunized child with an abnormal U/A is too risky, but perhaps the 9 week old who has had the first set of vaccinations can be saved from the LP when there is an abnormal U/A.

Recommended by SMF
Learn more: Journal Watch

• Simpson E, Moon M, Lantos JD.  When parents refuse a septic workup for a newborn.  Pediatrics. 2011 Nov;128(5):966-9. Epub 2011 Oct 24.  PMID: 22025599

An overview of the ethical issues involved when evaluating a child for possible sepsis against the parents wishes.

Recommended by RPR

• Dewall CN, Macdonald G, Webster GD, Masten CL, Baumeister RF, Powell C, Combs D, Schurtz DR, Stillman TF, Tice DM, Eisenberger NI. Acetaminophen reduces social pain: behavioral and neural evidence. Psychol Sci. 2010 Jul;21(7):931-7. Epub 2010 Jun 14. PMID: 20548058.

Some of us are more prone to social pain, awkwardness and rejection than others. This study demonstrates (via MRI activity) that regular panadol (acetaminophen) may help alleviate the pain of modern day life.

Recommended by MAJ
Learn more: LITFL — A Cure for Hurt Feelings

• Lell B, Binh VQ, Kremsner PG. Effect of alcohol on growth of Plasmodium falciparum. Wien Klin Wochenschr. 2000 May 19;112(10):451-2. PMID: 10890137.

Although just an in-vitro study, I would put forward that this treatment is dear to most critical care physicians’ hearts. It also justifies the symbiosis of gin and tonic.

Recommended by MAJ

• Rogozov V, Bermel N. Auto-appendectomy in the Antarctic: case report. BMJ. 2009 Dec 10;339:b4965. PMID: 20008968.

History’s best recommendation for the use of procaine, self-confidence, tactile surgery and the boundaries of human possibility.

Recommended by MAJ

• Sanchez LD, Straszewski S, Saghir A, Khan A, Horn E, Fischer C, Khosa F, Camacho MA. Anterior versus lateral needle decompression of tension pneumothorax: comparison by computed tomography chest wall measurement. Acad Emerg Med. 2011Oct;18(10):1022-6. doi: 10.1111/j.1553-2712.2011.01159.x. Epub 2011 Sep 26. PMID: 21951681.

Nice CT based study of chest wall thickness, giving much needed caution to the common ATLS dogma of needle decompression.

Recommended by MLC

• Mycyk MB, Szyszko AL, Aks SE. Nebulized naloxone gently and effectively reverses methadone intoxication. J Emerg Med. 2003 Feb;24(2):185-7. PMID: 12609650

Nebulized naloxone can be an alternative to an IV naloxone drip for patients who ingest long-acting opiates. This case report from 2003 describes gentle reversal using the nebulized approach. This is especially helpful because patients on methadone and chronic opiates may be difficult IV access patients.

Recommended by ML
Learn more: Trick of the Trade — Nebulised naloxone

• Daulaire S. Ultrasound assessment of optic disc edema in patients with headache. AM J Emerg Med 2011 Oct 24 [Epub ahead of print] PMID: 22030203

Ultrasound detection of papilledema and papillitis

Recommended by LG

Cannabinoid Hyperemesis Syndrome

Cannabinoid hyperemesis syndrome is a rare condition associated with long-term or excessive  cannabis use that is characterised by recurrent episode of cyclical vomiting associated with episodes of abdominal pain. Patients are often noted to be compulsive showerers as it provides transient symptomatic relief.

Evidence is scarce but the following theories are postulated:

• Susceptible patients develop a hypersensitivity to cannabis following several years of exposure.
• Cannabis has a long half-life of weeks or months in the body. Regular use is accumulative and this gives rise to toxicity in the hypersensitive patient.
• It has been shown that cannabis delays gastric emptying and in the toxic patient this may lead to gastric stasis and hence hyperemesis.
• The patient may compulsively bathe because of the presence of the cannabinoid receptors in the limbic system of the brain.  The toxicity may disrupt the thermoregulatory systems of the hypothalmus and this disruption might settle with hot bathing or showering.

Features of cannabinoid hyperemesis syndrome include:

• A history of several years of cannabis abuse prior to the onset of  hyperemesis in susceptible individuals.
• The hyperemesis will follow a cyclical pattern every few weeks or months, often for many years, against a background of regular cannabis abuse.
• Cessation of cannabis leads to cessation of the hyperemesis in the presence of a negative urine drug screen for cannabinoids.
• A return to cannabis use will see a return of the hyperemesis many weeks or months later.
• The patient will compulsively bathe i.e. will take multiple hot showers or baths during the acute phase of the illness in an attempt to quell the hyperemesis.

Yes that’s true.

• Cannabinoids do have an active compound (delta-nine-tetrahydrocannabinol) that has been shown to act on the CB1 receptors in the brain to suppress emesis.
• However the majority of research is from animal trials and only limited human data is available to support this theory.

Cyclical vomiting is characterised as a phenomena of intermittent episodes of nausea and vomiting, separated in time by symptoms free periods.

• Hyperemesis gravidarum (always check beta-HCG in women of child-bearing age)
• Metabolic disorders (Addison’s disease, porphyria)
• Paediatric cyclical vomiting
• Migraine variants
• Drug withdrawal syndrome
• Bulimia and anorexia nervosa

These patients are often extensively worked up on previous presentations to the emergency department. Be sure to determine what previous investigations they have had and the results obtained.

Investigations may include:

• Bedside —
  BSL, VBG for acid-base status, lactate and electrolytes, urinalysis including bHCG
• Laboratory —
  FBC, U&E, LFT, lipase
• Consider a drug screen —
  may assist in the diagnosis of patients that deny cannabis use but clinical suspicion remains. Cannabinoids can be detected up to six weeks post-cessation of chronic use.

Management involves supportive care, symptom relief and behavioural modification.

Initial measures

• Attend to life threats:  airway,breathing and circulation and check glucose
• Commence cannabis withdrawal chart (if available)
• Consider intravenous hydration if dehydrated.
• Correct any electrolyte imbalances (especially potassium and magnesium)
• Administer antiemetics:
  e.g. Metoclopromide 10-20mg IV, ondansetron 4-8mg IV, or prochlorperazine 12.5mg
• Consider an antispasmodic: buscopan 10-20mg IV

If nausea and vomiting persists consider:

• Antipsychotics and low dose benzodiazepines —
  these have antiemetic effects and help relieve agitation:
  Droperidal 1-2.5mg IV
  Midazalam 0.5-1mg IV boluses titrated to effect

Long-term management

• Abstinence is the definitive treatment. Cessation of canabinoid use will lead to resolution of all symptoms and recommencement will lead to a relapse of the canabinoid hyperemesis syndrome.
• Follow-up by drug and alcohol counselling service.

There is hyperbilirubinemia and markedly raised ALT/AST (“transaminitis”), with relatively normal ALP and GGT. This is suggestive of a ‘hepatocellular’ or ‘hepatitic’ picture, rather than a cholestatic picture. The elevated INR of 1.5 is consistent with liver synthetic dysfunction.

Overall, this suggests liver failure due to hepatitis.

Important causes of hepatitis include the following (although some, such as hepatitis A, do not result in liver failure):

• viruses — Hepatitis virues A to E; HSV, EBV, CMV
• drugs and toxins — e.g. paracetamol, halothane, isoniazid, Amanita mushrooms, herbal medicines.
• alcoholic hepatitis
• non-alcoholic steatohepatitis and acute fatty liver of pregnancy (unlikely in this case!)
• ischemic hepatitis, veno-occlusive disease and Budd-Chiari syndrome
• autoimmune hepatitis

“Do you use khat?”

The chewing of khat leaves (Catha edulis) is a widespread recreational custom in East Africa and the Arabian Peninsula. Leaves are chewed for several minutes and then placed into the cheek as the juice is slowly swallowed. The plant contains the alkaloids cathine and cathinone, which have amphetamine-like stimulant properties.

The use of khat may not be considered a drug or a herbal medicine by the patient.

A child selling khat in Somalia (Photo by G.A. Hussein - click image for source)

The toxic effects of khat include:

• sympathomimetic effects due to increased release of dopamine and other neurotransmitters from presynaptic neuronal storage.
• overdose may result in:
  • psychosis with visual hallucinations and mania
  • rhabdomyolysis
  • cardiac dysrhythmias
  • stroke
  • altered sensorium
  • convulsions
• chronic use may result in:
  • myocardial infarction and ischemic cardiomyopathy
  • strokes
  • oral carcinomas
• hepatitis (acute or chronic)

That’s right, hepatitis.

Repeated use of khat may result in multiple episodes of subclinical hepatitis, eventually resulting in chronic liver disease. However, acute severe hepatotoxicity can occur even in the absence of chronic liver disease. A high concentration of cathionine may be detected in liver tissue at  biopsy.

Patients with khat-induced hepatoxicity may develop acute liver failure due to multilobar necrosis. This may ultimately require liver transplantation, or failing that, result in death.

The person that this case-based Q&A was inspired by ultimately received a liver transplant.

CO poisoning may present with non-specific symptoms, typically headache, or mimic gastroenteritis, influenza, or other viral syndromes, especially in children.

Unless CO exposure is considered the diagnosis is easily missed.

In colder climates CO poisoning is often a seasonal diagnosis related to the incomplete burning of carbon-containing fuels in poorly ventilated settings. Affected patients need not be directly exposed to smoke. If a single person was exposed, others nearby may also have been affected.

Clinical assessment, involving history, examination and investigations, should focus on these priorities:

confirm CO exposure and commence treatment with 100% oxygen
(based on history and COHb levels)

use a team-based systematic approach to trauma
(if co-existent traumatic injury is possible based on the history)

consider the potential for co-inhalants
(e.g. hyperlactemia suggests cyanide toxicity; inhalational injury from smoke)

assess the severity of acute CO poisoning
(particularly neurological and cardiovascular manifestations)

assess the potential for delayed neuropsychiatric sequelae.

is the patient an index case? Could there be other people affected by CO poisoning from the same source?
(e.g. occupational exposure, other home occupants)

Is the patient pregnant?

Was there suicidal intent?

Yes!

COHb levels correlate poorly with the severity of CO toxicity. The levels may vary depending on:

the timing of exposure relative to sampling

length of exposure

degree of exposure

oxygen therapy initiated prior to sampling

In general, a COHb level greater than 3% in non-smokers or greater than 10% in smokers suggests an abnormal CO exposure.

Loss of consciousness

Regardless of the measured level of COHb, loss of consciousness or syncope in the context of CO exposure should be considered a marker of severity.

The main role of the CT head in the patient with CO poisoning is to rule out coexistent traumatic brain injury. Direct effects of CO on the brain are not seen for the first 12 hours or so after exposure, and do not affect early management. Changes are typically seen in those parts of the brain that are most sensitive to hypoxia. Common abnormalities include hypodense lesions in the globus pallidus, caudate, and putamen.

The effects of CO poisoning do not solely reflect hypoxia resulting from impaired oxygen delivery. Indeed, dealyed neuropsychiatric sequelae are believed to be largely mediated by:

• reactive oxygen species
• lipid peroxidation
• neuronal apoptosis

Oxygen is the mainstay of treatment of CO poisoning. However, the role of hyperbaric oxygen remains highly controversial.

Suggested indications for HBO include:

loss of consciousness/syncope, coma, seizure

profound acidosis (pH < 7.1)

neuropsychological abnormalities

fetal distress in pregnancy

evidence of myocardial ischemia

However, based on the published literature, the final recommendations of the ACEP clinical policy are:

1. Hyperbaric oxygen therapy is a therapeutic option for CO-poisoned patients; however, its use cannot be mandated.
2. No clinical variables, including carboxyhemoglobin levels, identify a subgroup of CO- poisoned patients for whom hyperbaric oxygen therapy is most likely to provide benefit or cause harm.

Furthermore, the authors of this EBMedicine review state that:

“taking all RCTs into account, systematic reviews have found insufficient evidence to demonstrate improvement in delayed neuropsychological sequelae following CO poisoning in patients who receive hyperbaric therapy”.

Though there is no real evidence for it, many experts have a lower threshold for using HBO to treat pregnant patients. Some retrospective studies suggest worse fetal outcomes in mothers who are not treated with HBO. Evidence of fetal distress is often considered an indication for HBO treatment. Pregnant patients were not included in the RCTs on HBO for CO poisoning.

In general, as with any CO poisoned patient, it is probably best to use clinical severity markers as a guide to treatment options, with the additional consideration of fetal distress.

Pregnant patients should be treated with oxygen longer than equivalent non-pregnant patient, as CO has higher affinity for HbF and is thus slower to eliminate from the fetal circulation.

Standard pulse oximetry determines SpO2 by measuring the absoprtion of light at two different wavelengths. Unfortunately the overlapping absorption spectra of COHb and oxyHb makes these measurements unreliable in the context of CO poisoning. Accurate measurements of SaO2 and COHb can be obtained using co-oximetry (e.g. using a blood gas analyser), which measures the absorption of light at multiple different wavelengths. Non-invasive pulse co-oximeters are now available, and (according to the authors of this review) appear to be accurate (see comments questioning this conclusion below).

Methylene chloride exposure can result in endogenous CO production

Methylene chloride is a chemical commonly found in commercial paint removers. It is metabolised by the liver to produce CO, which continues long after the source is removed. In this setting the apparent half-life of CO elimination is markedly increased, to about 13 hours. Serial COHb levels may be useful in this setting to monitor for ongoing CO production and response to treatment.