David Collins gives an excellent lecture on Toxicology at the Sydney Intensive Care Network meeting for the Intensive Care Network (www.intensivecarenetwork.com). The podcast to go with this can be found on iTunes (Oli Flower's ICU Podcasts) or on www.intensivecarenetwork.com

1. David Collins
POWH AICU

2.  Me: What shall I talk on?
 Dr Flower: Toxicology would be good
 Me: But I don’t know any toxicology
 Dr Flower: That will be fine….

3.  79 year old man presented to A&E with
difficulty breathing and pre-syncopal
symptoms
 Previously fit, well and self-caring
 Decreased urine output over last 2 days
 5 minute episode of chest heaviness
 New onset of orthopnoea

4.  Diabetes mellitus (metformin, glibenclamide)
 Hypertension (poor control; on nifedipine SR)
 Recent RTI which improved after starting 2
week course of “triple therapy” for
Helicobacter pylori breath test positive)
 Previous TURP
 Penicillin allergy

5.  On examination in ED
 HR 67
 BP 105/55 (supine)
 RR18
 SpO2 97%
 RA afebrile; BSL 11
 Tremulous with “staggering gait”
 Otherwise NAD: cardio/resp/neuro/general
 Plan: FBC, EUC, TnI, MSU

6.  Initial bloods showed urea of 22.3, creatinine
296 (Creatinine was 108 in 2009)
 WCC 10, Hb 100, TnI <0.1, ECG normal
 Admitted under renal medicine for IV fluids
(@60ml/hr) and IDC
 IDC difficult 2°prostatomegaly; drained 340 mls then
nil
 Other usual meds continued

7.  Over next 48 hours:
 Oliguria; rising creatinine; falling bicarbonate
 After 48 hours Cr 585, Urea 39.1
 Falling blood pressure and heart rate
 90/40 at 50-60 bpm
 Patient unable to mobilise 2° to dizziness and
“staggering gait”
 Fluid loaded by nocte team- 3l normal saline

8.  Renal team withheld metformin and added sodium
bicarbonate tabs.
 Ordered Ca, Mg, Phosphate, Fe studies, 24hr urinary
protein study, B12, folate, EPG, TSH, PTH, vit D,
urine micro for casts, PSA, HbA1C, coagulation
studies, CK, LFTs, CRP,
 Metformin, metronidazole and PPI ceased.
 Ciprofloxacin commenced
 IV fluids slowed to 21 ml/hour

9.  52 hours after admission, ICU asked to see
patient. On admission to ICU:
 In respiratory distress SpO2 94% in 8l/min O2
 HR 60/min, BP 85/40 (supine: marked postural
drop)
 RR 36/min, 34.6° C
 BSL 12.8
 ABG: 7.29 / pO2 79mmHg / pCO2 19 / BE -17 /
lactate 7.1
 JVP raised; CXR: bibasal collapse; increased perihilar
markings
 Drowsy but airway safe

10.  Urgent transfer to ICU
 Intra-arterial line, central line, vascath inserted
 2 sets blood cultures taken
 Rewarming; insulin infusion
 Sodium bicarbonate infusion until dialysis begun
 Urine sent for eosinophils
 TTEcho: moderate LV and RV impairment, normal
valves, no effusion

11.  Provisional Diagnosis: septic shock ? Source
 pneumonia
 Started ceftriaxone 1gm bd initially
 Commenced inotropes and vasopressors to aim for a
MAP >60mmHg

13. Times C. MAP SVRI CVP EVLW NAd Dop Vasop
Index I r.
0430 11 51 503 10 10 0.6 5 2
0530 8 59 1044 4 11 0.64 5 2
0630 10 60 520 23 12 0.62 5 2
1530 9 83 680 24 10 0.18 5 1
2030 7.5 74 982 22 11 0 0 0

15.  Treatment of Helicobacter pylori infection with
mucosal injury
 Lansoprazole, clarithromycin, ampicillin
 Change ampicillin to metronidazole if penicillin allergic
 Patient had been on this for last two weeks…

16.  Cytochrome P450 (3A4 subtype) is the main
enzyme responsible for all calcium-channel
blocker metabolism
 Clarithromycin (and other macrolides) profoundly
inhibit CYP3A4

20.  Reasonably common
 Can be problematic
 Intense channel blockade can be difficult to
overcome
 Long-acting formulations extend effects
considerably (eg verapamil SR effects may peak after
24 hours)

21. Dihydropyridines Benzothiazepines
Nifedipine Verapamil
Felodipine  Strong myocardial
 Strong vasodilators depressant / negative
chronotrope
Phenylalkylamines
Diltiazem
Vasodilator / myocardial
depressant / negative
chronotrope

22.  Frequently
 Hypotension and bradycardia / heart block
 Less common
 Hyperglycaemia
 Lactic acidosis
 Ischaemic colitis

23.  A
 B
 C- hypotension

24.  C- hypotension
 Fluids (with care in view of LV depression)
 Atropine for bradycardia (up to 3mg) (often unhelpful!)
 Calcium (10mls of 10% CaCl, then infusion ~5ml/hour
if required- beware extravasation!!!)
 Inotropes (choose according to apparent mechanism of
hypotension)
 Glucagon

25.  Glucagon has been shown to have its own
receptors on myocardium
 Increases intracellular cAMP independent of B-
receptor
 Dose 5-10mg boluses, then 5-10mg per hour
 Main adverse effects hyperglycaemia and vomiting

27.  Other considerations:
 Gastric lavage esp. in SR poisoning
 Activated charcoal
 Whole bowel irrigation in SR poisoning
 Amrinone / milrinone have been suggested

28.  A calcium-sensitiser
 Ie for the same level of intracellular calcium, more
myofibrillar cross-bridges are formed
 Less calcium pumping in and out of SR required
 Therefore more inotropy for little increase in
myocardial oxygen demand
 Case reports of good results from levosimendan in
CCB poisoning
 Beware vasodilation!!

29.  56yo man presented to an Emergency
Department by ambulance
 Found with decreased level of consciousness
 Said to have been unwell for 24 hours and
vomiting this morning

30.  On examination:
 Rubicond, flushed, sweaty, saliva running from mouth
 SpO2 98% 15l NRBM; HR 100/min; RR 42/min
 36°C NIBP 140/90mmHg
 HSDNM, no bruits
 Chest clear but multiple transmitted upper airway
sounds
 Abdominal examination normal
 Confused (GCS E2V4M4= 10), marked nystagmus

31.  Background:
 Major depression 10 years (escitalopram 20mg
daily)
 Hypertension (indapamide 10mg; verapamil SR
240mg; perindopril 10mg daily)
 MCA aneurysm clipped 2010
 First degree heart block 2010
 ? Indication for coenzyme Q10 daily
 Lives on a working farm

32.  In view of confusion and hypoxia, patient was
orotracheally intubated promptly
 Propofol, vecuronium, suxamethonium
 Started IV fluids @ 500ml/hour saline
 Sedated with fentanyl and midazolam and
transferred to a tertiary hospital

34.  Salivation
 Lacrimation
 Urination
 Defaecation
 Gastrointestinal motility
 Emesis
 Seizures
 Bradycardia
 Meiosis
 Weakness

35.  Given multiple boluses of atropine, titrated
against airway secretions
 1.2+1.2+3+1.2+1.2+1.2+1.2+
=about 10 000 micrograms pre-flight
 Paracetamol level <20
 CXR normal
 FBC / UEC coags all normal

36.  Pupils small, nonreactive (on sedation ++)
 34.3°C HR 75 SR
 140/85 SpO2 100% on PEEP 10cmH2O and
FiO2 0.5
 No secretions
 No diarrhoea
 No fasciculations

37.  Small, unimportant organophosphate ingestion
 No cholinergic phenomena now
 Plan:
 Pralidoxime as requested by toxicologists
 extubate in the morning.

38.  S/B toxicology
 Some periorbital fasciculations
 No other cholinergic phenomena
IMPRESSION:
Life-threatening OP poisoning
Please keep intubated for a few days…

39.  Over first 48 hours
 HR 60-80, BP stable, pupils small, no diarrhoea,
normal bowel sounds, no vomiting, no fasciculations
 Pt woke when sedation weaned
 No atropine for 36 hours
 Plan; remove CVC, IAL; aim to extubate in the
afternoon…

40.  Patient awake, obeying commands..
 Profoundly weak
 0-1/5 all limbs
 Widely depressed reflexes
 Tox plan: stay intubated 7 days
 ICU plan: aim to extubate in am!

41.  72 hours post exposure:
 Bradycardia to 25/min
 Dramatic increase in secretions
 Frank dramatic diarrhoea
 Diaphoresis
 Confusion
 Periocular and lingual fasciculations
 Weakness continued

42.  Toxicology:
 Cease pralidoxime
 Not suitable for extubation
 ICU
 Not suitable for extubation- replace CVC / IAL
 Boluses then infusion of atropine for secretions
 12 000-24 000micrograms / day
 Antihypertensives for instability
 Midazolam for “neuroprotection”

43.  Cholinergic toxidrome ran its course
 Heart rate and BP all over the place
 Secretions persisted requiring atropine
 Diarrhoea persisted
 Failed extubation day 7 due to airway swelling,
secretions and weakness

44.  Day 11
 Finally extubated!
 Mild diarrhoea persisted
 Atropine ceased day 15
 Lots of psychiatry input
 Ready for transfer to ward medically well day 17
 Repatriated to original hospital day 18

45.  Widely used insecticides
 Also manufactured as weapons (sarin, tabun)
 Available as concentrates for commercial use
 Irreversibly inactivate acetylcholinesterase
 Phosphorylate serine hydroxyl residues
 With time, “aging” makes bond permanent

46.  Highly fat soluble
 This was evident in our case, as redistribution from
fat stores was thought to be the main mechanism of
the late decompensation

47.  Absorbed readily through gut, skin, lung,
mucous membranes
 Hepatically metabolised by hydrolysis
 Highly toxic 3-25% fatalities
 LD50 in rats is about 150mg/kg
 Commercial concentrate contains 550g/l
 So an LD50 volume is about 20 mls

50.  Accumulation of acetylcholine results
 Overstimulation of cholinergic receptors leading to a
constellation of problems

51. Muscarinic
 Lungs and airway Nicotinic
 Upper GI tract  Neuromuscular
junction
 Heart
 Autonomic ganglia
 CNS / PNS
 CNS
 Pupillary miosis
 Blocked by NMBA eg
 Blocked by atropine
rocuronium

52.  Intermediate Syndrome
 1-4 days post-exposure
 Worsening muscle weakness (esp. proximal
including respiratory)
 Cranial nerves sometimes involved
 Unclear etiology and possibly due to inadequate initial
treatment

53.  OPIDP (Organophosphate-Induced Delayed
Polyneuropathy)
 2-3 weeks after high-dose exposure
 Due to inhibition of NTE “neuropathy target
esterase”
 Distal muscle weakness for months to years

54.  Decontamination
 Neoprene gloves
 Soap and water
 A-B-C
 Secretions, bronchospasm, seizures and muscle
weakness pose biggest threats

55.  Atropine for muscarinic symptoms
(salivation/bradycardia)
 IV boluses then infusion titrated to salivation and
bradycardia; up to 300mg / day!
 Pralidoxime (2-PAM) for enzyme reactivation
at extra-cerebral sites in severe case 1-
2gm/30min
 Controversial- use early, use by infusion, NOT for
carbamates

56.  Benzodiazepines
 A little controversial
 Good for seizure prophylaxis and treatment
 Some evidence form animal models that it improves
the long-term subtle neurological outcomes
 No evidence in humans
 Prevent re-exposure as even trace amounts will
cause recrudescence of symptoms

57.  Baseline cholinesterase (RBC or plasma) levels
vary between individuals so are not diagnostic
in any one case
 ChE levels should be taken post-exposure to
compare to those during illness

58. David Collins
POWH AICU