TOXICOLOGY
Dr. Lisa Thurgur MD FRCPC Consultant Toxicologist, PADIS
Dr. Ian Ball MD FRCPC Consultant Toxicologist, OntarioManitoba Poison Center
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CONFLICT OF INTEREST
Neither of us have any conflicts of interest to disclose… .
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PLEASE…
Don’t teach me anything new, just teach me what I
need to know for the exam!
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TODAY WE WILL…
• Assume you will study/have learned “the basics”
• Talk about the non-obvious pearls wrt “The Big Eight” that will help you in
practice (and through an exam!)
• Give you a handout with lots of typical short-answer questions and helpful
lists of tidbits
• Answer your questions
• Respect the time allotted, especially for breaks
• Be available later if something wasn’t clear
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ASA
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ASA – QUESTIONS THEY LOVE
• Describe the acid-base pathophysiology
• How do I interpret the level?
• When do I alkalinize the urine?
• How do I alkalinize the urine? What if that doesn’t work?
• What is the easiest way to kill an ASA overdose?
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ACID BASE PATHOPHYSIOLOGY
• 1.
Respiratory alkalosis
• Direct stimulation of medulla
• 2.
Metabolic acidosis
• Uncoupling of oxidative phosphorylation
• 3.
Primary mixed respiratory alkalosis and metabolic acidosis
• All is good without underlying ventilatory compromise
• 4.
Development of acidemia
• Develop respiratory acidosis
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HOW DO I INTERPRET THE LEVEL?
• Treat the patient, not the level !!!
• Use pH and mental status to guide Rx
• Chronic vs acute
• Serum level cannot be interpreted in isolation, without knowing serum pH
• If the patient is acidemic – more salicylate is entering the brain and they are
becoming sicker
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CHRONIC ASA TOXICITY IS A GREAT
“PRETENDER”
Vitals
ENT
Neuro
Acid-base
abn
Cardiac
Resp
GI
Heme
Glucose
metabolism
Sepsis? Delirium? CHF? Stroke?
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INDICATIONS FOR URINE ALKALINIZATION
• Signs and symptoms of salicylate toxicity
• Serum level greater than 2-2.5 mmol/L (or expected to get there!)
• Indications to D/C Urine Alkalinization
• Clinical improvement, normalized metabolic parameters, serum salicylate
consistently trending downward and less than 2.0mmol/L
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HOW DO I ALKALINIZE THE URINE?
• Drain bladder
• 3 amps NaHCO3 in 1L D5W – run at 2 x maintenance
• Either add 40 KCL or add second line of 40 KCL in N/S
• Frequent urine pH testing
• Goal is urine pH 7.5-9.0
• Maintain serum K > 4.5
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INDICATIONS FOR HEMODIALYSIS
• Worsening clinical status despite urine alkalinization
• Inability to alkalinize the urine
• Volume overload
• End organ toxicity (ie RF, pulmonary edema, CNS)
• Severe acid base disturbance
• Salicylate level > 7 mmol/L (acute) or > 4 mmol/L (chronic)
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HOW DO I KILL AN ASA OVERDOSE?
• Forget to order serial ASA levels
• Sedate for agitation or to put in dialysis lines
• Airway management without careful attention to minute ventilation
• Failing to recognize it in the first place
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ASA KEY POINTS TO REMEMBER
• ABC
• Universal antidotes
• GI decontamination (GL, AC, WBI all fair game for ASA)
• Fluids
• Urine alkalinization with K
• Dialysis
• Serial ASA levels
• Intubation/sedation caveats
• Acute vs chronic
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ACETAMINOPHEN
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APAP PEARLS
• What do I do when I can’t use the nomogram?
• When do I stop the antidote?
• Do I worry about coingestants if there is an anion gap metabolic acidosis?
• What do you mean “massive” and how to treat?
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TREAT THE NUMBER NOT THE PATIENT!
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CAN’T USE THE NOMOGRAM?
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CAN’T USE THE NOMOGRAM?
Time unknown
<4 hours*
>20 hours
Chronic ingestion
Taken over >8 hours (staggered/multiple)
Extended release?
Co-ingestants?
Children (i.e. <6 yr)?
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NEED TO LOWER THE LINE?
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NEED TO LOWER THE LINE?
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NEED TO LOWER THE LINE?
Not in Canada!
150 µg/mL = 1000 µM @ 4hr
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WHEN IN DOUBT…
…TREAT UNTIL RECOVERED OR DEAD
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WHEN TO STOP NAC?
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TRUITT, ET AL., CLIN TOXICOL 2010; 48(6):610
(ABSTRACT)
• 19 year old male
• [APAP] 600 µg/mL (4000 µM) at 8 hours post single ingestion
• [EtOH] 31 mM
• fixed, dilated pupils
• GCS = 3/15
• Temp 33°C
• pH 6.86
• Glc 19.4 mM
• lactate 35.8 mM
DDX OF AG METABOLIC ACIDOSIS
•
•
•
•
•
•
•
•
•
•
•
C CO, CN
A AKA
T Toluene, Theophylline
M Methanol, Metformin
U Uremia
D DKA
P Paraldehyde, Phenformin, Paracetamol
I Iron, INH, Ibuprofen
L Lactate
E Ethylene Glycol
S Salicylate, SKA
MASSIVE
10x treatment threshold
≥ 1,000 mg/kg
“MITOCHONDRIAL PARALYSIS”
1.lactic acidosis
2.coma
3.hyperglycemia
4.hypothermia
•reversible
•not predictive of hepatic injury or failure
DIALYZABLE?
APAP
Molecular weight
(daltons)
151
Volume of distribution
(L/kg)
0.95
Protein binding
Low
Intercompartment
equilibration
Rapid
Endogenous clearance
(mL/kg/min)
5.0
DIALYZABLE?
APAP
N-AC
Molecular weight
(daltons)
151
163
Volume of distribution
(L/kg)
0.95
~0.6*
Protein binding
Low
Low
Intercompartment
equilibration
Rapid
Rapid
Endogenous clearance
(mL/kg/min)
5.0
3.2*
*Prescott et al., Eur J Clin Pharmacol 1989; 37:501-506; Brown et al., ibid 2004; 60:717-723
IS THE ANTIDOTE REMOVED FASTER
THAN THE TOXIN?
APPROACH TO MASSIVE APAP
Early lactic acidosis and decreased mental status with serum
acetaminophen concentration > 10x over treatment line is common, and
should not be confused with late acidosis and encephalopathy.
Acetaminophen is rapidly cleared during hemodialysis, accelerating the
reversal of the mitochondrial “paralysis.”
21-hour protocol may not administer enough N-AC.
Recognizing that N-AC dosing is largely empirical, the dose should be at
least doubled whenever patients receiving acetylcysteine are being
hemodialyzed.
WHAT TEST TO ORDER?
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CYANIDE
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CYANIDE – QUESTIONS THEY LOVE
• When to suspect
• Clinical presentation
• How to rule out
• When to pull the trigger on the antidote
• Damage control post antidote
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WHEN TO EXPECT IT
• Random sources:
• Occupational – jewelers, photographers, lab techs, fumigation
• Smoke inhalation from fires
• Intentional
• Medicinal sources
• Nitroprusside
• Food sources
• Amygdalin in pits of apricots, bitter almond, cherry, peaches
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CLINICAL PRESENTATION
• Catastrophic symptomatology with organ failure
• Headache, anxiety, agitation, confusion, seizure
• Hypotension, bradycardia
• Tachypnea, then bradypnea, plumonary edema
• Abdo pain, vomiting
• Cherry red skin
• Severe lactic acidosis
• Chronic – Parkinsonian symptoms, progressive visual loss, ataxic
neuropathy
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HOW TO DIAGNOSE IT
• Clinical scenario/exposure
• Clinical symptoms
• Bitter almond odour
• Fire victim with coma and acidosis – lactate >10
• Unexplained coma and acidosis
• Labs
• Severe metabolic acidosis with increased AG and lactate
• Elevated central venous O2 saturation (reduced O2 extraction)
• CN concentrations – no role in acute management
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MANAGEMENT AND PULLING THE TRIGGER ON
THE ANTIDOTE
• ABC
• Decontamination (consider before ABC?)
• IV fluids and vasopressors for hypotension
• NaHCO3
• Treat associated conditions – ie CO poisoning
• Antidote
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DAMAGE CONTROL
POST-ANTIDOTE
• Chromaturia and red skin discoloration
• Interferes with colorimetric lab tests
• Hypertension
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CYANIDE – KEY POINTS
• ABC
• Decontamination
• Fluids and pressors
• Antidote
• Treat concomitant CO poisoning
• Sources
• Antidote’s mechanism of action
• The “old” cyanide antidote kit - ?worth knowing?
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IRON
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IRON
• How to rule it out without a lab test
• Can you use other lab tests when the level is unavailable?
• How to GI decontaminate a patient who is vomiting
• Nasty antidote… how to make it less nasty
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WHAT ROSEN TAUGHT ME ABOUT
FE…
• Beware stage II = asymptomatic
• ↑WBC and ↑Glc predictive
• Serum Fe < TIBC protective
• CXR = CHIPES helpful
• Antidote saves lives
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WHAT ROSEN TAUGHT ME ABOUT
FE…
• Beware stage II = asymptomatic
• ↑WBC and ↑Glc predictive
• Serum Fe < TIBC protective
• CXR = CHIPES helpful
• Antidote saves lives
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MYTH BUSTERS:
• Stage II less aweful than Stage I
• ↑WBC and ↑Glc non-specific
• CXR can suggest, but not exclude
• Antidote is nasty
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HOW TO RULE OUT?
• If < 20 mg/kg elemental, the PCC says “home observation.”
• 20-40mg/kg, “could be trouble”
• >60 mg/kg --- toxic
• If no GI symptoms by 6 hours, home with poison-proof advice.
• 30-20-10 rule for fumarate-sulfate-gluconate
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HOW TO RULE IN?
• i.e. symptomatic, large ingestion
• Forget WBC, Glc
• Forget TIBC
• Can do a CXR but more out of interest
• Serum Fe is the “go to” test
• While you are waiting…
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Blood Gas!
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DDX OF AG METABOLIC ACIDOSIS
•
•
•
•
•
•
•
•
•
•
•
C CO, CN
A AKA
T Toluene, Theophylline
M Methanol, Metformin
U Uremia
D DKA
P Paraldehyde, Phenformin, Paracetamol
I Iron, INH, Ibuprofen
L Lactate
E Ethylene Glycol
S Salicylate, SKA
FREE FE++ IS BAD!
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INTERPRETING SERUM FE:
>90 uM
Free (unbound) Fe++
30-90 uM
Transferrin becoming saturated
15-30 uM
Normal
<15 uM
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Iron deficient!
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WHAT TO DO WHILE WAITING FOR
[FE]?
• GI decontamination?
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DEFEROXAMINE
• Not a benign antidote
• Need to find it first… start looking early
• Indication is free Fe++
• Direct evidence vs indirect evidence
• Unfamiliar antidote
• Pay attention to dosing
• Watch for hypotension
• Respect maximum dosing esp. in kids
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Time to take a break…..
QUESTIONS?
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“Inhaling smoke causes smoke inhalation” CJEM 2012;14(1):3-4
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CARBON MONOXIDE – QUESTIONS THEY LOVE
• When to suspect it
• 5 pathophysiologic mechanisms of CO
• How to screen for it
• How to interpret the level
• Is there a treatment? And if so – for who?
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WHEN TO EXPECT IT
• Incomplete combustion of carbonaceous fossil fuel
• Fires
• Engine exhaust
• Propane powered vehicles or boats
• Home sources
• Halogenated hydrocarbons
• Methylene chlorine (paint thinners)
• Inhalational anesthetics
• Clinical symptoms / patients presenting in groups
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PATHOPHYSIOLOGY OF CO
• COHb does not carry O2
• Shifts O2-Hb dissociation curve to the left
• CO binds to myoglobin
• Binds to cytochrome oxidase
• Induces CNS lipid peroxidation
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CARBON MONOXIDE - LEVELS
• Mild (5-10%) - mild headache, mild dyspnea
• Mod (10-30%) - headache, weakness, dizziness,
dyspnea, irritability, N/V, impaired judgement
• Severe (>30-50%) - coma, seizures, death
• Pulse oximeter falsely normal
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IS THERE A TREATMENT?
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CARBON MONOXIDE
• 1/2 life carboxyhemoglobin on room air = 5-6 hrs
• 1/2 life 100% O2 = 45-90 min
• 1/2 life HBO (3 atm) = 15-30 min*
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BOTTOM LINE:
“There is insufficient evidence to support the use of hyperbaric
oxygen for treatment of patients with carbon monoxide
poisoning”
Juurlink et al., Cochrane Database Sys Rev 2000
Weaver et al., NEJM 2002
Thom et al., Ann Emerg Med 1995
Kao & Nanogas, Med Clin NA, 2005 - Review
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INDICATIONS FOR HBO
•
Evidence of end organ damage
• LOC, coma, seizure
• Focal neurolgical findings, visual symptoms, cognitive defecits
• Myocardial ischemia, arrhythmias
• Metabolic acidosis
•
COHb levels
• COHb > 25%
• COHb > 15 % in pregnant patients
•
Any abnormal neuropsych exam with CO exposure
•
Inability to oxygenate (associated pulmonary injury)
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CO – KEY POINTS
• Must have a high suspicion if you are going to diagnose CO poisoning in the ED
• Headache and flu-like symptoms
• Treatment is 100% O2 and supportive care
• Consider Hyperbaric O2 in certain populations
• Call the HBO physician on call or the Poison Centre
• Know the pathophys and t1/2 lives
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METHANOL
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METHANOL
• The lab tells me that the methanol level is a “send out” and the patient is
sick!
• Does anyone still use ethanol as an antidote?
• Antidote: check. Dialysis: check. Are the cofactors important?
• Recreational misadventures
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WHEN TO SUSPECT?
• AG met acid insufficient, especially if OG small
• Need suggestive history:
• Self-harm
• Recreational misadventure
• Under age
• “Dry” jurisdiction
• Jail
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“VOLATILES” ARE A SEND-OUT
• Extremely low pH
• Extremely large Osmolar Gap
• End-organ damage
• Methanol = retina, brain
• Ethylene glycol = kidney
VBG!
• Forget urine crystals/fluorescence
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INTERPRETING THE OSMOLAR GAP
• Initially high, then falls as AG develops
• Mild elevations often false positive
• Inflate the ethanol by 20% to correct
…only worth doing if “over the limit”
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RISK-BENEFIT CALLS
• If history strongly suggestive
…empirically administer fomepizole
(unless ethanol on board)
• If metabolic acidosis
…empirically initiate hemodialysis
(other forms of renal replacement therapy insufficient)
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ONE MORE PEARL…
Brought from jail, recreational misadventure, pupils fixed and dilated, agonal
respirations, pH 6.7, bicarb <4mM
What two life-saving interventions are required?
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HOT AND CRAZY
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CASE
• 20 year old male presents to the ED
• Picked up by police and EMS at a party where his friends were
concerned that he was acting bizarre, confused and aggressive
• In the ED, 4 security guards have trouble holding him down
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PHYSICAL EXAMINATION
• Vitals: BP 150/95, HR 140, RR 20, T 42.0 C rectal, SaO 2 100% on RA
• Thrashing wildly
• Soaked with sweat
• Pupils 7 mm and reactive
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THE CONFESSION
• He tells you he took 4 or 5 ecstasy tablets, drank 3 beer and smoked
marijuana – not necessarily in that order
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DISCUSSION
• What, if anything, will kill this patient?
• Tell me about the “hot and crazy” differential diagnosis
• What is your initial management of this patient?
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DISCUSSION
• Key to preventing mortality = Rapid Cooling !!!
•
75% of drug overdose patients with temperature > 40.5 C for over 1 hour die
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THE “HOT AND CRAZY” DIFFERENTIAL
• Sympathomimetics
• Anticholinergics
• Sepsis
• Serotonin Syndrome
• Meningitis/Encephalitis
• Neuroleptic Malignant
Syndrome
• Environmental Heat Injury
• Thyrotoxicosis
• Malignant Hyperthermia
• ASA
• Withdrawal
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WHAT WE SEE
• Tachycardia
• Hypertension
• HYPERTHERMIA
• Agitation, Aggression
• Confusion
• Mydriasis
• Skin varies
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“HOT AND CRAZY” MANAGEMENT PEARLS
• ABCs and supportive care
• RAPID SEDATION AND AGGRESSIVE COOLING
• Physical and chemical restraints
• IV Benzodiazepines – avoid IM neuroleptics
• And more Benzos
• Cool IV fluids
• Pack with ice; cold, wet towels plus fans
• Consider paralysis if temperature does not fall
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MORE MANAGEMENT PEARLS
☠ Temperature must be obtained for all agitated or intoxicated patients
☠ Psychomotor agitation and hyperthermia are the major causes of
death from toxicologic agitated delirium
☠ Think outside the box when patients have elevated temperatures
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LOW AND SLOW
Beta-Blockers and Calcium Channel Blockers
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PICTURE IS WORTH A THOUSAND WORDS
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TOXICOKINETICS
•
Rapidly absorbed
•
Action / toxicity less than 30-60 mins
•
Sustained release may cause toxicity for 48 hours
•
Action may be delayed for 15 hours
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BASIC PRINCIPLES OF TREATMENT
• Resuscitate
• Prevent Further Absorption
• Enhance Elimination
• *Antidotes / Novel Therapies
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Glucagon
Pharmacologically elegant
Expensive
May cause vomiting
Unproven
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PHOSPHODIESTERASE INHIBITOR
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DIALYSIS (NASA)
• Nadolol
• Acetebutolol
• Sotalol
• Atenolol
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BETA BLOCKER BOTTOM LINE
• Majority only require supportive care
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CALCIUM CHANNEL BLOCKERS
• ABC, decontaminate as appropriate
• Fluid challenge
• Calcium bolus
• Calcium infusion – goal high normal, supratherapeutic level
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HIGH DOSE INSULIN
• Letter to editor 2001 NEJM
• 2 patients with good outcomes...
• Under stress, myocardium preferentially metabolizes carbohydrates instead
of fatty acids
• Decreased pancreatic insulin secretion
» Treatment of Calcium-Channel-Blocker Intoxication with Insulin Infusion NEJM 344:1721-1722.
» High Dose Insulin Reverses Calcium Channel Blocker Inhibition of Glucose Uptake in an Adipocyte Model Acad Emerg Med 2007:
14:5;195.
» The role of insulin and glucose (hyperinsulinemia/euglycemia therapy in acute calcium channel antagonist and beta blocker poi soning.
Toxicol Rev. 2004;23(4): 215-22.
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INSULIN DOSING
• Glucose level correlates with severity
• Bolus Humulin R 0.25 -1.0 U/kg
• Infuse at 0.25-1.0 U/kg/hr and titrate like a pressor
• Frequent glucose checks (Q15-30 min)
• Q1H electrolytes
• Decrease infusion when blood glucose falls
•
Assessment of hyperglycemia after calcium channel blocker overdoses involving diltiazem or verapamil. Crit Care Med 2007
Sep;35(9):2071-5.
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OTHER TREATMENTS
• www.lipidrescue.org
• Cardiopulmonary Bypass
• Arteriovenous ECMO
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BETA BLOCKER SUMMARY
☠ Resuscitate; prevent further absorption
☠ Consider glucagon
☠ Use a vasopressor / inotrope
☠ High dose insulin (need to be more careful with serum glucose than with
CCBs)
☠ Consider dialysis (NASA)
☠ Extracorporeal supports
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CALCIUM CHANNEL BLOCKER SUMMARY
☠ Resuscitate; prevent further absorption
☠ Calcium bolus and infusion
☠ No glucagon or phosphodiesterase inhibitor
☠ High dose insulin
☠ Consider lipid therapy
☠ Extracorporeal support in refractory cases
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