Transcript Clinical Cases in Toxicology

Clinical Cases in Toxicology
Tom Heaps
Consultant Acute Physician
“
All things are poison and
nothing is without poison; only
the dose makes a thing not a
poison.
- Paracelsus, 1538
Case 1
> 82-year-old female; COPD, HTN, depression, dementia
> seretide, tiotropium, risperidone 1mg BD, ramipril 2.5mg,
bendroflumethiazide 2.5mg, citalopram 20mg
> 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 1 cont.
> 48h post-admission
> GCS 13/15
> delirious +++
> sweating, T 38.9°C, HR 112, BP 137/68, SpO2 95% OA
> CT head (why?) NAD
> repeat bloods: CK 397, otherwise unremarkable
> dilated pupils
> increased tone and generalized rigidity
> hyperreflexia, bilateral extensor plantars, ankle clonus
Diagnosis =
serotonin syndrome (severe serotonergic
toxicity)
Mechanism =
reduced metabolism of citalopram due to
introduction of p450 inhibitor (clarithromycin)
Causes of Serotonin Syndrome
1. intentional overdose with serotonergic drugs
2. ingestion of legal / illegal recreational drugs with serotonergic
effects (MDMA, PMA / PMMA, MDAI, 5-APB, 5-IAI, cocaine,
amphetamines, BZP)
3. initiating or increasing dose of a serotonergic drug
4. co-prescription of multiple drugs with serotonergic actions
(often accidentally)
5. introduction of drugs which inhibit CYP450 enzymes in
patients already taking SSRIs
Drugs with Serotonergic Action
 tramadol

SSRIs

SNRIs

MAOIs

TCAs esp. clomipramine

trazodone
 carbamazepine

lithium
 metoclopramide

recreational / illicit
 triptans
 fentanyl
 sibutramine
 linezolid
 St. John’s wort
Drugs that may 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 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
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 benzodiazepines + + +
 IV sodium bicarbonate for persistent
/ arrhythmias
1mg /acidosis
kg bolus
 5HT2A antagonists (cyproheptadine, chlorpromazine, olanzapine)
repeated up to 10mg / kg in 24h
 IV labetalol/GTN or noradrenaline for hyper/hypotension
 conventional cooling measures (paracetamol ineffective)
 ice baths, IV dantrolene, paralysis/intubation for hyperpyrexia
 rapid improvement within 24-48h is the rule (unless MOF)
SS vs. NLMS
Serotonin Syndrome
Neuroleptic Malignant
Syndrome
Onset
Acute, <24h
Insidious, days-weeks
Neuromuscular
Hyperreactivity, tremor, clonus,
hyperreflexia
Muscular rigidity,
bradyreflexia
Causative agents
Serotonergic agonists
Dopaminergic antagonists
Treatment
Benzodiazepines,
cyproheptadine
Dantrolene, bromocriptine
Resolution
Rapid, 24-48h
Slow, days-weeks
Prognosis
Generally good
Variable, mortality up to
20%
Case 2
> 84-year-old female
> 2/52 Hx of vomiting, reduced oral intake and increasing confusion
> HTN, AF, MVD, bowel cancer, hypothyroidism
> furosemide 80mg OD, lansoprazole 30mg OD, digoxin 250mcg OD,
levothyroxine 50mcg OD
> observations unremarkable
> confused on examination, no other significant signs
> initial ED impression ?bowel obstruction
> ECG – ‘LVH, ST elevation in aVR, inferolateral ST depression’
> no chest/abdominal pain or breathlessness
Case 2
 Seen by Cardiac ANP – ‘unlikely STEMI ?falls due to chronic valvular
disease’
Diagnosis =
 Referred to Cardiology SpR for ECHO – ‘no RWMAs to suggest acute MI,
admit under medics for Ix of falls’
AKI
digoxin toxicity
 WCC 16, CRP 15, urea 9.9, creatinine 169 (120), K+ 3.1, hs-TnI 135
 Seen by RMO3 – ‘Imp
Acute5.3µg/L
MI, ACS treatment,
cardiology review ?for
- level
(0.8-2.0)
angiogram’
Digoxin Toxicity: Sx
 Acute-on-chronic > acute > chronic
 Increased risk with AKI / CKD (reduce dose) and thiazides
 Nausea, vomiting, diarrhoea, delirium, xanthopsia
 Hyperkalaemia due to blockade of Na-K-ATPase pump
- prognostic marker in ACUTE overdose
 Bradycardia, hypotension, AV block, sinus arrest, atrial
tachycardia, ectopics, bigeminy, TdP, VT/VF
 Risk of arrhythmias increased by hypokalaemia
Digoxin Toxicity: Rx
 stop digoxin (and nephrotoxics / diuretics)
 cardiac monitor
 IV fluids
 correct electrolytes (especially hypokalaemia / magnesaemia)
 IV bicarbonate (QRS prolongation / metabolic acidosis)
 IV magnesium (QTc prolongation / ventricular arrhythmias)
 IV atropine / isoprenaline / pacing (bradycardia)
 digoxin-specific antibodies
®
Digibind
&
®
DigiFab
 Indications:
>
>
>
>
>
>
Acute overdose of ≥10mg
Severe hyperkalaemia
Digoxin level ≥10ng/mL 6h post acute overdose or ≥15ng/mL at any time
Chronic toxicity associated with significant arrhythmias or confusion
Bradyarrhythmias unresponsive to atropine
Life-threatening ventricular arrhythmias
 Dosing information on Toxbase® (half dose if acute or chronic)
 effective within 15-30min of administration
 Risk of anaphylactoid reactions
 Rebound effect if low GFR (reduced excretion of Fab-digoxin complexes)
 ‘Falsely’ elevated digoxin levels post-administration
Case 3
> 57-year-old female
> Background of HTN, AF, depression
> Overdose of 17x verapamil 240mg MR 8h prior to admission
> Sweating ++, mildly confused, CRT 5s, GCS 14/15
> HR 78 (Mobitz type 1 AVB on ECG)
> BP 68/45mmHg
> CBG 11.2
> Bloods unremarkable
> Venous lactate 3.2, pH7.21, BE -7.5
Management?
> Activated charcoal 50g (sustained release preparation)
> IV Hartmann’s x3L
> IV calcium gluconate 30mL 10% followed by infusion @ 30mL/h
> IV sodium bicarbonate 50mmol (333mL of 1.26%)
> BP 76/50mmHg
> HR 64/min
> Catheterized: urine output 20mL over 2h
Other Rx Options?
> Vasopressors
Hyperinsulinaemia Euglycaemia Therapy Protocol
> 1.
Glucagon
(directly
stimulates
Check plasma
glucose
and K+ cAMP, more effective in β-blocker OD)
> 2.
High
dose insulin
(increases
myocardial
If plasma
glucose
<10mmol/L
give 50mL carbohydrate
of 50% glucoseutilization,
improves endovascular perfusion, prevents formation of FFAs)
3. Correct hypokalaemia
> 4.
Levosimendan
(inotropic
agent) titrated
IV actrapid 1unit/kg
boluscalcium
followedchannel-sensitizing
by infusion 0.5-2unit/kg/hour
to clinical response
> Atropine / isoprenaline / temporary pacing
5. Maintain on 10% glucose (5-10mL/kg/h) during insulin infusion
> IABP
6. CBG every 20min during dose changes then hourly when on stable dose
> 7.
ECMO
Check potassium hourly
8. Target sBP >100mmHg and heart rate >50/min for 6h
Case progression
> Glucagon 10mg IV (plus ondansetron)
> Started on noradrenaline
> Transferred to ITU
> BP dropped further 66/40mmHg, anuric
> Adrenaline commenced
> Bradycardic @ 37/min with prolonged QRS
> GCS 10
> Periarrest
What did we try next?
 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, HR and urine output
 adrenaline discontinued and noradrenaline weaned down
 no arrhythmias
 discharged from ITU 24h later
IV Lipid Emulsion (20% Intralipid®)
 originally used for TPN
 antidote for LA (bupivacaine) toxicity since late 1990s
 growing body of evidence for use in overdose with other drugs




tricyclic antidepressants
lipophilic calcium channel blockers e.g. diltiazem, verapamil
lipophilic β-blockers e.g. propanolol, metoprolol, carvedilol, labetalol
antipsychotics e.g. quetiapine
 mechanism of action becoming more clear
 ‘lipid sink’ which reduces free active drug concentrations and redistributes drug
away from site of cardiotoxic action (usually to liver)
 energy source (free fatty acids) for supressed myocardium (inotropic effect)
Key Learning Points
1. consider effects of drugs (prescribed or otherwise) and effects
on drugs in every presentation
2. serotonin syndrome may affect all ages and can be caused by
introduction of CYP450 inhibitors in patients on SSRIs
3. chronic digoxin toxicity is common; use Digibind® or DigiFab®
in selected cases
4. remember HDI and ‘Lipid Resus’ in severe CCB (and other
drug) poisonings