1. Tom Heaps Consultant Acute Physician
Toxicology Cases
Tom Heaps
Consultant Acute Physician

2. Case 1
Nothing A Hot Bath Won’t Cure…

3. 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

4. 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

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

6. 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)

7. 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

8. 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

9. 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?

10. 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)

11. Complications of CHS profound weight loss dehydration
pneumomediastinum
oesophagitis
scalding secondary to compulsive bathing behaviour

12. 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

13. Case 2
Confused or just deliriously happy?

14. 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

15. 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

16. Diagnosis? Mechanism? serotonin syndrome
reduced metabolism of citalopram due to introduction of p450 inhibitor (clarithromycin)

17. Causes of Serotonin Syndrome
intentional overdose with serotonergic drugs
initiating or increasing dose of a serotonergic drug
co-prescription of multiple drugs with serotonergic actions (often accidentally)
introduction of drugs which inhibit CYP450 enzymes in patients already taking SSRIs
Onset of symptoms usually within 24h (often <6h)

18. Drugs with Serotonergic Action
tramadol
fentanyl
sibutramine
linezolid
carbamazepine
metoclopramide
triptans
St. John’s wort
SSRIs
SNRIs
MAOIs
TCAs esp. clomipramine
trazodone
lithium
amphetamines
MDMA (ecstasy)
cocaine

19. 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

20. Diagnostic Features of Serotonin Syndrome
1. altered mental status
agitation, confusion, disorientation, delirium
hallucinations
drowsiness, coma
2. neuromuscular hyperactivity
profound shivering, tremor, teeth grinding
hypertonia, hyperreflexia, bilateral Babinski
spontaneous or inducible clonus, ocular clonus, myoclonus
3. autonomic instability
tachycardia, hypertension or hypotension
flushing, sweating
diarrhoea and vomiting

21. Other Features of Serotonin Syndrome
leucocytosis
elevated CK
transaminitis
metabolic acidosis
DIC
AKI secondary to rhabdomyolysis
ARDS
seizures
malignant hyperthermia
fulminant hepatic failure

22. 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

23. Case 3
A sink to save the sinking patient!

24. 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

25. 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

26. 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

27. 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

28. 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

29. 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
increased pH favours neutral form of tricyclic drug reducing receptor binding
sodium load increases extracellular [Na+] attenuating blockade of rapid sodium channels

30. How should arrhythmias and seizures after TCA overdose be treated?
CORRECT HYPOXAEMIA, ELECTROLYTE DISTURBANCES AND ACIDOSIS
IV Magnesium
IV Benzodiazepines
IV Lignocaine
CONTRAINDICATED
Class 1a e.g. quinidine
IV Phenytoin
Class 1c e.g. flecainide

31. 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

32. 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

33. 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

34. Key Learning Points
remember to ask about cannabis use in recurrent attenders with cyclical vomiting (especially if unusually clean!)
serotonin syndrome may affect all ages and can be caused by introduction of CYP450 inhibitors in patients on SSRIs
when running out of options in TCA/CCB/BB poisoning, consider grabbing the fat!