Toxicology CasesTom Heaps

Consultant Acute Physician

Case 1Nothing A Hot Bath Won’t Cure…

Case Presentation• 29-year-old male, history of alcohol dependence

• alcohol intake reduced to 28 units per week for last year

• 3d history of intractable vomiting

• 4th admission in last 4/12 with similar symptoms

• symptoms usually resolved after 2-3 days as inpatient

• OGD after 2nd admission mild gastritis

• taking regular omeprazole 40mg OD

Case Progression• transferred to AMU

• observations all normal

• FBC, U&E, LFT, CRP, amylase NAD

• well groomed and clean!

• OEx mild epigastric tenderness only

• AMU nurse concerned that he was spending an excessive amount of time in the bathroom

• 3 baths since arriving on AMU 24h earlier

What was the single question I asked him to reach a diagnosis?

Do you regularly use cannabis?

• admitted to regular cannabis use for last 4y

• daily use since cutting down alcohol intake

• cyclical episodes of severe nausea/vomiting for last 6/12

• having a hot bath or shower was the only thing which provided temporary relief from his symptoms

DIAGNOSIS = CANNABIS HYPEREMESIS SYNDROME (CHS)

CHS: Diagnostic Criteria (Simonetto et al. 2012)

Essential for Diagnosis• long-term cannabis use, usually 1-5y (32% <1y)

Major Features• at least weekly cannabis use (daily in 59%)• cyclical episodes of severe nausea and vomiting (>7/y in 70%)• epigastric or periumbilical abdominal pain (86%)• temporary relief of symptoms with hot baths/showers (91%)• resolution of symptoms with cessation of cannabis use

CHS: Diagnostic Criteria (Simonetto et al. 2012)

Other supporting features

• weight loss >5kg

• morning predominance of symptoms

• normal bowel habit

• autonomic symptoms e.g. diaphoresis, flushing, polydipsia

• negative laboratory, radiological and endoscopic tests

Pathophysiology of CHS• speculative and paradoxical

• cannabinoids usually antiemetic e.g. nabilone (CNS CB1 receptors)

• downregulation of CB1 receptors in brainstem emetic area?

• delayed gastric emptying (enteric CB1 receptors)?

• disturbance of hippocampal-hypothalamic-pituitary axis?

• toxic accumulation of lipophilic THC in fat stores?

• toxicity of other substances used in preparation of marijuana?

Compulsive Bathing Behaviour

• mean of 5 baths/d (5h bathing time/d) in one case series

• mechanisms of relief again speculative

• increase in body temperature

– may counteract hypothalamic autonomic and thermoregulatory dysfunction seen with chronic cannabis use

• diversion of blood to peripheries

– may counteract cannabinoid receptor-mediated splanchnic dilatation (cutaneous steal syndrome)

Complications of CHS

• profound weight loss

• dehydration

• pneumomediastinum

• oesophagitis

• scalding secondary to compulsive bathing behaviour

Treatment of CHS• IV fluids and electrolyte replacement often required

• PPIs and antiemetics generally ineffective

• cessation of cannabis use is definitive treatment

• symptoms resolve within 2-3d in vast majority

• recurrence common within several weeks of relapse even if prolonged period of abstinence

Case 2Confused or just deliriously happy?

Case Presentation• 82-year-old female, PMHx COPD, HTN, depression

• DHx seretide, tiotropium, ramipril 2.5mg, bendroflumethiazide 2.5mg, citalopram 20mg (no recent changes to medications)

• allergic to penicillin

• presents to ED with increasing SOB and productive cough

• vitals stable, AMTS 10/10

• Na 132, CRP 26, WCC 11.9, CXR unremarkable

• treated for AECOPD (antibiotics, nebs, steroids)

• transferred to AMU

Case Progression• 48h post-admission

• GCS 13/15, delirious +++

• sweating, T 38.9°C, HR 112, BP 137/68, SpO2 95% OA

• CT head NAD

• repeat bloods unremarkable (CK 337)

• dilated pupils

• increased tone and generalized rigidity

• hyperreflexia, bilateral extensor plantars, ankle clonus

Diagnosis?• serotonin syndrome

Mechanism?• reduced metabolism of citalopram due to

introduction of p450 inhibitor (clarithromycin)

Causes of Serotonin Syndrome1. intentional overdose with serotonergic drugs

2. initiating or increasing dose of a serotonergic drug

3. co-prescription of multiple drugs with serotonergic actions (often accidentally)

4. introduction of drugs which inhibit CYP450 enzymes in patients already taking SSRIs

Onset of symptoms usually within 24h (often <6h)

Drugs with Serotonergic Action

• SSRIs

• SNRIs

• MAOIs

• TCAs esp. clomipramine

• trazodone

• lithium

• amphetamines

• MDMA (ecstasy)

• cocaine

• tramadol

• fentanyl

• sibutramine

• linezolid

• carbamazepine

• metoclopramide

• triptans

• St. John’s wort

Drugs with potential to increase SSRI toxicity

CYP2D6 inhibitors• amiodarone• terbinafine• chlorphenamine• cimetidine• metoclopramide• antipsychotics• cocaine

CYP3A4 inhibitors• macrolides• fluconazole• verapamil• ciprofloxacin• metronidazole• antiretrovirals• grapefruit juice

Diagnostic Features of Serotonin Syndrome1. altered mental status

agitation, confusion, disorientation, deliriumhallucinationsdrowsiness, coma

2. neuromuscular hyperactivityprofound shivering, tremor, teeth grindinghypertonia, hyperreflexia, bilateral Babinskispontaneous or inducible clonus, ocular clonus, myoclonus

3. autonomic instabilitytachycardia, hypertension or hypotensionflushing, sweatingdiarrhoea and vomiting

Other Features of Serotonin Syndrome• leucocytosis

• elevated CK

• transaminitis

• metabolic acidosis

• DIC

• AKI secondary to rhabdomyolysis

• ARDS

• seizures

• malignant hyperthermia

• fulminant hepatic failure

Management of Serotonin Syndrome• stop all offending drugs

• fluid and electrolyte replacement

• IV sodium bicarbonate for persistent acidosis

• IV benzodiazepines

• 5HT2A antagonists (cyproheptadine, chlorpromazine, olanzapine)

• IV labetalol/GTN or noradrenaline for hyper/hypotension

• conventional cooling measures (paracetamol ineffective)

• ice bath, IV dantrolene, paralysis/intubation for hyperpyrexia

• rapid improvement within 24-48h is the rule

Case 3A sink to save the sinking patient!

Case Presentation• 60-year-old female with history of bipolar depression

• found ‘unconscious’ at home (daughter spoke to her 4h prior)

• suicide note and empty packet of amitriptyline (28 x 50mg)

• also takes temazepam and lithium

• HR 130, BP 96/44, GCS 8, BM 5.9, RR 24 • warm peripheries, dilated pupils• increased tone and hyperreflexia bilaterally with extensor plantars• ECG sinus tachycardia

• ABG (FiO2 0.4) pH 7.31, pO2 19.6, pCO2 3.5, BE -5.1, lactate 1.9

Which of the following receptors do TCAs act on?

• acetylcholine

• histamine

• GABA

• cardiac sodium channels

• cardiac delayed rectifier potassium channels (Ikr)

• noradrenaline

• serotonin

• α-adrenergic

TCAs are ‘dirty drugs’• anticholinergic: tachycardia, confusion, pyrexia, dry skin, dilated pupils,

urinary retention and ileus

• α1-adrenergic blockade: vasodilatation and hypotension

• histamine: confusion, hallucinations and drowsiness

• GABA: drowsiness, ataxia, divergent squint, nystagmus

• cardiac sodium and Ikr channel blockade : sinus tachycardia, PR/QRS/QTc prolongation, RBBB, AVB

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

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

True or False?in view of her low GCS and airway risk, our patient should be given a trial of IV flumazenil to reverse any CNS sedative effects of temazepam which she may have coingested

FALSE

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

Which of the following is an indication for IV sodium bicarbonate administration in

the context of TCA OD?

•metabolic acidosis

•hypotension despite fluid resuscitation

•cardiac arrhythmia

•QRS prolongation >120ms

Answer:• all of these are indications for administration of IV sodium bicarbonate in

TCA poisoning

• give 50ml 8.4% or 333ml 1.26% NaHCO3 aiming for arterial pH of 7.5-7.55

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

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

How should arrhythmias and seizures after TCA overdose be treated?

Arrhythmias Seizures

CORRECT HYPOXAEMIA, ELECTROLYTE DISTURBANCES AND ACIDOSIS

IV Magnesium IV Benzodiazepines

IV Lignocaine

CONTRAINDICATED CONTRAINDICATED

Class 1a e.g. quinidine IV Phenytoin

Class 1c e.g. flecainide

Case Progression• GCS dropped to 3 after a seizure, intubated by ITU

• IV bicarbonate administered until pH 7.48

• 3l of crystalloid given for falling BP

• BP 67/35, oligoanuric

• started on noradrenaline and adrenaline infusions

• BP still only 79/44

• 10mg IV glucagon given with minimal effect

• episode of VT which responded to single shock

• remained peri-arrest

What rescue treatment did we give?

• IV fat emulsion (20% Intralipid®) 90ml bolus (1.5mg/kg) followed by 30ml/min (0.5ml/kg/min) until 500ml total given

• rapid sustained improvement in BP and urine output

• adrenaline discontinued and noradrenaline weaned down

• no further arrhythmias

• discharged from ITU 48h later

IV Fat Emulsion (20% Intralipid®)• previously used as an antidote for local anaesthetic toxicity

• growing body of evidence for use in overdose with other drugs– tricyclics– lipophilic calcium channel blockers e.g. diltiazem, verapamil– lipophilic β-blockers e.g. propanolol, metoprolol, carvedilol, labetalol– antipsychotics

• mechanism of action uncertain– ‘lipid sink’ reducing free active drug concentrations– modulation of intracellular metabolism by free fatty acids– direct activation of myocardial Ca2+ channels

Key Learning Points

1. remember to ask about cannabis use in recurrent attenders with cyclical vomiting (especially if unusually clean!)

2. serotonin syndrome may affect all ages and can be caused by introduction of CYP450 inhibitors in patients on SSRIs

3. when running out of options in TCA/CCB/BB poisoning, consider grabbing the fat!