Toxicology 5 - Calgary Emergency Medicine

TOXICOLOGY 5
Chris McCrossin
Thanks to Dr Ingrid Vicas & Randall Berlin
CASE 1
35 yo Male calls Alberta Poison Center after using what he
thought was paint thinner in his barn.
He first noted pain in his right thumb and fingers two
hours after using the product.
The pain is now persistent and excruciating but there are
no apparent cutaneous changes
Anything you might be worried about?
OUTLINE
Hydrofluoric Acid
Organophosphates
Hydrogen Sulfide
Carbon Monoxide
Cyanide
Methemoglobinemia
HYDROFLUORIC ACID
HYDROFLUORIC ACID
Any exposure to HFA
should be considered
serious
Requires immediate
assessment and treatment
Pain out of proportion to
physical findings is the
norm with HFA exposure
STRENGTH OF
HFA
ONSET OF
SYMPTOMS
< 20%
Pain/erythema
delayed up to 24 hr
20-25%
1-8 hr
> 50%
Immediate pain &
rapid tissue
destruction
HYDROFLUORIC ACID
Pathophysiology
Highly permeable to tissues; penetrates deeply
Dissociates into H+ & F- ions
Highly negative F- ions bind to Ca & Mg
Locally this results in cell death; systemically this
results in arrhythmias, coagulopathies, and
hyperkalemia
prolonged QT, coagulation cascade is disrupted because no calcium
HYDROFLUORIC ACID
If left untreated the burn from HFA exposure may continue
to increase in surface area for 7 days and in depth for 5-8
weeks
Fatal dermal exposures reported form burns ~2.5% of TBSA
Patients die from arrhythmias secondary to hypocalcemia
(myocardial conduction, prolonged QT) and hyperkalemia
this would be from highly concentrated HF exposure
types of exposure: ocular, skin (local or diffuse), inhalational, even one reported case of an HF enema
HYDROFLUORIC ACID
Products containing HFA
Fabric and carpet rust removers used in dry-cleaning
and in hotels
Aluminum wheel cleaners and stainless steel polishes
used at commercial truck cleaning operations
Ceramic tile and glass etching products
Leather tanning
HFA can be found in a variety of common workplaces and is often brought home in unmarked containers
HYDROFLUORIC ACID
Case 1 continued
Are you worried about systemic toxicity in this patient?
HYDROFLUORIC ACID
Assessing Severity of Exposure
Potentially Serious
Low Risk
oral
Delayed onset of pain
inhalational
[HF] < 10%
exposure to face and neck
> 5% TBSA
soaked clothing
burning within minutes
> 20% [HF]
*regardless of TBSA exposed, > 20% still has great potential to cause systemic toxicity
*important to know the timing on onset (delayed versus within minutes)
HYDROFLUORIC ACID
Management
1. Immediate irrigation for a minimum of 15 minutes
2. Urgent topical application of calcium as a specific antidote
3. Consider intra-arterial or intra-venous injection of
calcium gluconate
4. Monitor for systemic toxicity (electrolytes)
5.Use a pain scale to measure your endpoint of treatment
HYDROFLUORIC ACID
HF burn
Immediate water irrigation 15-20 minutes
Calcium gluconate 2.5% gel
(use when affected area is limited to recent exposures involving small BSA exposed to HF
concentrations < 20%. The gel may also be used in all dermal exposures during
preparation for parenteral routes of calcium administration)
Regional intra-venous calcium
Intra-arterial
calcium gluconate
gluconate infusion
calcium infusion
(use when affected area is limited to small surface
(use as alternative to fingernail removal when larger surface areas are involved
areas and when HF concentrations < 20%)
in the distal extremities)
Subcutaneous 5-10 %
(use as an alternative to fingernail
removal or when a large surface area
is involved and/or when HF
concentrations are > 20%)
HYDROFLUORIC ACID
Immediate Irrigation
HFA rapidly penetrates skin
In our case irrigation would have decreased
effectiveness because of the delay of presentation but
still important
HYDROFLUORIC ACID
Topical Calcium
Inactivation of free fluoride ions using calcium
produces raid relief of symptoms and reduction of
tissue damage
Formation of the insoluble calcium salt, CaF, prevents
further F penetration into tissues
HYDROFLUORIC ACID
Topical Calcium
“Gold Standard” first-line topical HFA treatment:
Calcium gluconate jelly 2.5%
Mix 3.5 g calcium gluconate powder with 5 oz
(140g) of surgical lubricant
As most HFA exposures are to the hand the jelly is
often put in a glove
Can use plastic wrap in lieu of glove to cover other exposed body areas.
Calcium chloride has been found to be irritating both topically and intra-arterially.
HYDROFLUORIC ACID
Case 1 continued
So you irrigated the hand
You put the patient’s hand in the calcium gluconate jelly
glove
How long do you want to leave his hand in the glove for?
HYDROFLUORIC ACID
The main endpoint of
treatment is a substantial
decrease in pain
Blanching of the skin should
also normalize
Use of a consistent pain scale
is mandatory before, during,
and after treatment with
CaGlu jelly
Pain should decrease in
the following order
1.
Pain at rest
2.
Fingertip pain upon
palpation
3. Fingernail pain - if there is
fluid build-up under the nail,
it may need to be drained
Blocking the patients pain with local anaesthesia would inhibit your ability to
HYDROFLUORIC ACID
If there is significant (i.e. 50%) improvement in the pain and
discomfort, leave the hand out of the glove for 1 hour and
then re-apply the glove for 4 hours. Continue the 1 hour rest
periods and 4 hour glove treatments over a 24 hour period
HYDROFLUORIC ACID
Case 1 continued
Three hours after the application of the jelly glove your
patient is still having uncontrolled pain
Do you want to:
A. Perform nerve blocks to the hand
B. Inject calcium gluconate subcutaneously
C. Inject calcium gluconate intra-arterially
D. Sign him over to ‘BCY’ and catch the rest of the Flames game
HYDROFLUORIC ACID
Case 1 continued
Because the patient’s pain is uncontrolled 3 hours after
initiation of topical treatment and the inherent
problems with local calcium injection it was decided to
give intra-arterial calcium gluconate
The decision to give intra-arterial calcium should be
made in conjunction with a toxicologist
HYDROFLUORIC ACID
Digital burns from high HFA concentrations are difficult to
neutralize because large amounts of F need to be neutralized
but the tissue space is limited
Intraarterial or intravenous injections allow a large amount
of calcium to be delivered and to overcome the problems
associated with local calcium injection
HYDROFLUORIC ACID
Intra-arterial Calcium Gluconate Injection
Need to monitor serum Ca, Mg, PO4
Dose depends on severity of pain
Generally a 4 hour infusion
Average length of treatment ~ 3 days
HYDROFLUORIC ACID
Intravenous Calcium Injection
Bier Block Method:
IV cannula in dorsum of affected hand
Superficial veins exsanguinated by elevation
Double cuffed pneumatic tourniquet 100 mmHg above patient’s
systolic BP
10 mL of 10% calcium gluconate sol’n diluted with 30-40 mL of NS
Ischemia maintained for 25 minutes
Cuffs sequentially released over 3-5 minutes
HYDROFLUORIC ACID
Additional Points
Ocular exposure requires irrigation to an endpoint of pH 7-7.5
Oral injection of as little as 7 mL is fatal as can large dermal exposures
HFA will bind ALL of your free Ca
Need to monitor Ca, Mg, PO4, K (risk of hyperK)
Need to have a on a monitor to look for QT prolongation and
ventricular arrhythmias
Any blisters should be debrided because they can contain HFA
Wear glove, mask, and eye protection!!!!
Repeated ocular irrigations once the pH is normal can increase the incidence of corneal ulceration. Use of Ca solutions in the eye is of
no benefit.
Ca will be given IV to replace hypocalcemia
HYDROFLUORIC ACID
Take-Home Points
HF acid can cause significant damage without obvious
cutaneous signs
HF can cause significant systemic toxicity with
seemingly trivial exposure amounts
Calcium is the primary ‘antidote’
Monitor patients closely for hypocalcemia,
hyperkalemia and dysrhythmias
CASE 2
Patient 1
86 yo M Hutterite retired farmer developed nausea, vomiting, and abdominal pain 1 hour after
dinner
Three hours later he was unarousable and was transported 30 km by ambulance to the Brooks
ED
O/E
GCS 8 (E1V2M5), BP 90/72, HR 54, RR 10, afebrile
HEENT: Copious clear secretions were noted in the oropharynx,
Neuro: pupils 2mm min reactive, fundi normal, absent gag reflex, corneal reflex present,
localizes x 4, reflexes 1+ (symmetric), plantars downgoing bilaterally
Resp/CVS: lungs were clear to auscultation, cardiac exam otherwise unremarkable
Abdo: soft, no guarding, BS present but decreased, no organomegaly or distension
CASE 2
Patient 2
HPI
46 yo daughter of patient 1, Shared the same meal
3 hours after dinner she developed nausea, vomiting, abdominal pain
LOC decreased over the next hour after complaining of weakness and diploplia
She was transported in the same ambulance as her father
O/E
On arrival developed generalized tonic clonic seizure and sinus bradycardia
Both resolved with IV ativan and atropine
Within 10 min had three more seizures and was intubated (copious secretions suctioned during intubation)
CVS, Resp, & abdo exams all normal
Neuro (after intubation): withdraws x 4, reflexes normal, PERL @ 3 mm bilat
CASE 2
Patient 3
HPI
53 yo daughter of patient 1 (sister of patient 2)
3 hours after meal with her family developed nausea, vomiting, abdominal pain, and generalized
weakness
Neighbours drove her to the ED
On arrival she was alert but confused
O/E
BP 160/100, HR 80, RR 14, afebrile
CVS, Resp both N
Abdo distended with decreased bowel sounds, no guarding or focal tenderness
Neuro: pupils 3 mm reactive, strength symmetrically decreased (4/5), reflexes normal
CASE 2
Patient 3 continued...
Course in ED
Developed 30 second TC seizure, responded to ativan
over 4 hours developed progressive muscle weakness
(prox > distal), bilat disconjugate gaze, and a
progressive decrease in her LOC and subsequently
intubated
CASE 2
Summary
Three family members
Rapid onset of symptoms 1 hour post ingestion of same
food
Prominent symptoms of ‘gastro prodrome’ followed by
altered LOC, bradycardia, miosis, hypotension, copious
oral secretions, seizures, and eventually progressive
muscle weakness
Case follow-up (true case repored in JEM 1996): Patient 3 who did not live in or routinely cook in the family home had mistaken an
unmarked spice container for pepper. The unmarked spice container contained “fensulfothion”. The fenosulfothion had been used by
another family member to control garden worms. The unlabelled container had mistakenly been placed in the kitchen cupboard after
renovations following a house fire several years previous.
ORGANOPHOSPHATES
ORGANOPHOSPHATES
Exposure
Used as pesticides and as military biological weapons
Oral, dermal, respiratory
At risk population:
Chemical manufacturer workers
Farmers
Truck drivers
Military personnel
General public (contaminated food, home gardening, suicides, bioterrorism)
Organophosphates can be absorbed dermally, through the respiratory tract, or ingested
ORGANOPHOSPHATES
Pathophysiology
Acetylcholine is a neurotransmitter that acts at
numerous anatomic sites
Acetylcholine has two main receptors: Muscarinic and
Nicotinic
Neurotransmission is a fast process that involves rapid
activation of the receptors followed by rapid
degradation of acetylcholine by acetylcholinesterase
ORGANOPHOSPHATES
Pathophysiology
Organophosphates and carbamates inactivate
acetylcholinesterase and plasma cholinesterase
(pseudocholinesterase)
Organophosphates permanently inhibit cholinesterases
Carbamates temporarily inhibit cholinesterases
ORGANOPHOSPHATES
Pathophysiology
Signs and symptoms result from too much acetylcholine
at various anatomic sites
Too much acetylcholine at muscarinic sites leads to
prolonged activation followed by inactivation of the
receptors
Too much acetylcholine at nicotinic sites leads to short
lived activation followed by inactivation of the receptors
ACh-R rapidly desensitize to the presence of acetylcholine and are forced into a prolonged refractory state. Acetylcholine needs to be
removed from the synapse or NMJ in order for the receptors to resensitize. This is how succinylcholine works - it mimics acetylcholine
except that it stays around longer at the NMJ increasing the refractory period of the NMJ.
ORGANOPHOSPHATES
Clinical Presentation
Variable in onset and severity
Skin exposures may take > 24 hours to present
Inhalational exposure may result in respiratory arrest
within minutes
Ingestions result in symptoms after 30-90 minutes
Onset and severity depends on what agent, the dose, route of exposure, and duration of exposure
ORGANOPHOSPHATES
Clinical Presentation
Muscarinic and Nicotinic “toxidromes”
CNS Effects
Intermediate syndrome
Respiratory failure
CNS respiratory center depression via muscarinic
receptor pathway
Intermediate syndrome is characterized by paralysis of proximal limb muscles, neck flexors, motor cranial nerves, and respiratory
muscles 24-96 hours after poisoning and following the resolution of a well defined cholinergic phase.
ORGANOPHOSPHATES
Autonomic Nervous
System
Scan picture of autonomic nervous system
Blue corresponds to muscarinic receptors, red corresponds to nicotinic
Ask Ingrid why you don!t get inhibition of the parasympathetics b/c you have nicotinic receptors in front of muscarinic receptors in the
PNS?
ORGANOPHOSPHATES
Muscarinic Receptors
located in heart, smooth muscle, and glands
are inhibitory in the heart (activation of the receptor results in decreased
HR)
are excitatory in smooth muscle and glands (increased GI motility,
secretions)
are activated by ACh
are blocked by atropine
MOA: 1. Heart SA node: inhibition of adenylate cyclase (cell membrane protein), this opens K channels, increased K efflux leads
to slower rate of spontaneous phase 4 membrane depolarization and therefore it takes longer before the action potential threshold
is reached. 2. Smooth muscle and glands: formation of IP3 via adenylate cyclase activation results in increased Ca channel
permeability and therefore increased Ca influx (with increased smooth muscle contraction)
ORGANOPHOSPHATES
Nicotinic Receptors
located in the autonomic ganglia of the SNS and PNS, at the NMJ,
and in the adrenal medulla
receptors at all these locations are similar but not identical
are activated by ACh
produce excitation
are blocked by ganglionic blockers (e.g. hexamethonium) in the
autonomic ganglia, but not at the NMJ
MOA: The nACh-R is also an ion channel for K and Na. When ACh binds the ion channel opens.
ORGANOPHOSPHATES
ORGANOPHOSPHATES
Clinical Effects from the
autonomic nervous system
ORGANOPHOSPHATES
Muscarinic Effects
Nicotinic Effects
S - salivation, secretions,
sweating
M - mydriasis, muscle
twitching, muscle cramps
L - lacrimation
T - tachycardia
U - urination
W - weakness
G - gastrointestinal upset
tH - hypertension,
hyperglycemia
B - bradycardia,
bronchoconstriction, bowel
movement, blood pressure
decrease
F - fasciculations
ORGANOPHOSPHATES
Diagnosis
Based on history and findings consistent with muscarinic
and nicotinic toxidromes
Cholinesterase Levels
not typically available in time
ORGANOPHOSPHATES
back to the patients...
Muscarinic Features:
Nicotinic Features:
Muscle weakness
all had GI prodrome
CNS Effects
copious oral and
bronchial secretions
confusion
miosis
bradycardia
seizures
ORGANOPHOSPHATES
Management
1. Decontamination
2. Supportive care
3. Antidotes
4. Seizure management
ORGANOPHOSPHATES
Management: Decontamination
Health care worker protection
Clothing removal
Wash skin with soap and water, follow with EthOH rinse
Flush eyes for 15 min if ocular exposure
No reports of significant care giver toxicity
ORGANOPHOSPHATES
Monitoring
The standards: CBC, lytes, creatinine
Monitor lipase in severe poisonings
Cholinesterase activity
RBC cholinesterase activity has a stronger correlation with clinical
effects than pseudocholinesterase
symptoms are generally not evident unless there is > 50% inhibition of RBC cholinesterase.
Regenerates at a rate of ~ 1% per day; may take several months to reach normal values in severe intoxications.
ORGANOPHOSPHATES
Management: Supportive Care
1. Airway
Non-depolarizing agents preferable to depolarizing (e.g. succinylcholine)
2. Breathing
Suction, atropine to control secretions
3. Circulation
Fluid resuscitation (significant GI losses and nitric oxide induced
vasodilation results in hypotension)
Direct alpha agonist (e.g. phenylephrine) preferred to other vasopressors
*depolarizing muscle relaxants are metabolized by pseudocholinesterase which is inhibited by organophosphates; non-depolarizing
muscle relaxants are not metabolized by any cholinesterase (they disappear by gradual redistribution and metabolism and excretion)
*alpha agonist preferred because patients have reduced systemic vascular resistance and relatively normal inotropic activity (dopamine,
NE may have some added benefit depending upon the HR)
ORGANOPHOSPHATES
Management: Atropine
protects against the increased amount of ACh (blocks
ACh-R); Acts only on the muscarinic receptors
Reverses bronchospasm, excessive respiratory
secretions, and intestinal hypermotility
Therapeutic Endpoints
Control of secretions, correction of bradycardia
Although some texts state that the patient should be oxygenated (concern is for myocardial oxygen demand and cardiac toxicity without
adequate oxygenation) before atropine administration it may be impossible to oxygenate until secretions are controlled (via atropine)
ORGANOPHOSPHATES
Management: Atropine
Dosing:
Adults:
Diagnostic dose 1-2 mg IV;
Therapeutic dose 2-5 mg IV;
Repeat 10-30 min until adequate atropinization is achieved
Continuous IV infusion: 0.02-0.08 mg/kg/hour (recommended)
Peds: 0.05 mg/kg/dose (max 1-2 mg per dose)
*2.4 mg/kg/hour infusion has been reported in one adult
*> 1000 mg/day during the early stages of severe poisoning is reported. Prolonged treatment is not usually required in carbamate
insecticide or muscarinic mushroom poisoning.
*Glycopyrrolate is another anticholinergic drug but it does not cross the BBB, acts by binding to the ACh-R (competitive antagonist to
ACh) same as atropine
ORGANOPHOSPHATES
Management: Pralidoxime
Reactivates cholinesterase that has been inhibited by
organophosphates if “aging” has not yet occurred
Acts primarily at nicotinic sites but may help reverse some
muscarinic and neurological effects
Most effective if given within 24-36 hours
Indications
All patients with significant symptoms requiring atropine
Consider early use in patients with history of significant exposure
**Aging = irreversible binding - variable pharmacokinetic properties of organophosphates means that they may be leaking into the
system over extended periods of time suggesting that pralidoxime may be beneficial beyond the 24 hour quoted time limit
Use in carbamate poisoning is controversial because of the temporary toxicity of carbamates
**Side Effects of pralidoxime: in man are absent or minimal.15-20 mg/kg administered to 18 normal subjects resulted in transient
dizziness (100%), blurred vision (72%), diplopia (50%), tachycardia (33%), headache, nausea
ORGANOPHOSPHATES
Management: Pralidoxime
Dosing
Rosen’s: 1-2 g IV or IM followed by 1 g q6-12h (this
dosing may not be adequate)
goal is [serum] > 4 mg/L
WHO: 30 mg/kg IV followed by infusion of 8 mg/kg/hr
Discuss with PADIS for appropriate dosing
ORGANOPHOSPHATES
Management: Seizures
GABA activation
Treat with BZD
NMDA - glutamate inhibition
Addition of propofol may be of benefit in seizures
that are difficult to control
ORGANOPHOSPHATES
Summary
Presentation highly variable depending on what side of the autonomic
nervous system is most affected
Suspect organophosphates in patients presenting with GI prodrome,
excessive oral secretions, fasciculations, weakness, and non-cardiogenic
pulmonary crackles
Atropine is frequently underdosed in serious poisonings and should be
titrated to clearing of pulmonary secretions and adequate oxygenation
BZD may be cerebroprotective and should be used liberally when indicated
Oxime therapy should be used in all patients requiring atropine
CASE 3
50 yo M presents with back pain & dyspnea
Profile: previous CBD adenocarcinoma in remission
following tx with chemoradiation 5 years ago. Recently had
MRI following progressive R sided weakness that showed
expansile mass of the medulla (glioblastoma).
Patient was started on radiation tx and temozolomide;
Dapsone was prescribed for PJP prophylaxis
Patient is now in your ED 4 days after all this has been
started
CASE 3
O/E
BP 128/72, HR 140, RR 36, SaO2 86%
CVS: Tachy, regular rhythm, soft SEM, JVP normal, no
peripheral edema
Resp: Clear to bases, tachypneic, good air entry
bilaterally
Neuro: Right sided weakness as expected -> nil acute
CASE 3
Investigations:
CXR - portable, nil acute
ECG - sinus tach
ABG - pH 7.34, CO2 30 mmHg, PO2 435 mmHg, SaO2
99% (calculated)
Thoughts?
CASE 3
Case summary:
50 yo M with recent hx of glioblastoma cancer, started on
chemo and dapsone
Presents with SOB & tachycardia & hypoxia (decreased
SaO2 on pulse oximeter)
Has normal CVS & Resp exams
Has a normal CXR and ECG
ABG shows adequate PaO2 and SaO2
METHEMOGLOBINEMIA
METHEMOGLOBINEMIA
Pathophysiology
During oxygen transport, Hgb transfers an electron to
oxygen
Sometimes oxygen takes the electron with it when it is
released from Hgb, leaving Fe in an oxidized state
(Fe3+)
Methemoglobin is formed when a water molecule binds
to the oxidized Fe3+
Methemoglobin forms normally in the body but defenses keep it to
less than 1%.
Mechanisms to protect Hgb from becoming oxidized:
1. NADH (serves and an electron donor) - Many cases of hereditary
NADH methemoglobin reductase; individuals who are homozygous
for this enzyme deficiency normally have levels ~10-15% under
normal conditions without any clinical or xenobiotic stressors. Also
because this enzyme system lacks full activity until approximately 4
months of age, infants are more susceptible to oxidizing stresses
METHEMOGLOBINEMIA
Pathophysiology
Methemoglobin occurs naturally but our bodies have several defenses to
prevent too much from forming and to remove the small amounts that do
form
Most important system is the NADH reductase system
Infants are more sensitive to oxidants b/c NADH reductase system
is immature
Some people have genetic defects in this system
NADPH reductase system is a less important pathway but is the
MOA of our treatment...
METHEMOGLOBINEMIA
Etiology
Hereditary
Nitrates and nitrites
from food and water
Topical anaesthetics
Dapsone
Nitrates and nitrites are two of the most powerful oxidizing agents
and the most common methemoglobin forming compounds
(contamination of well water, food, industrial compounds, and
pharmaceuticals)
When water containing nitrogen based fertilizers and nitrogenous
waste from animal and human sources is allowed to run o! fields it
easily contaminates shallow rural wells.
METHEMOGLOBINEMIA
METHEMOGLOBINEMIA
Clinical Features
Related to hypoxemia
decreases O2 carrying
capacity of Hgb
shifts O2 dissociation
curve to the left
Can be exacerbated by
concurrent diseases that
impair O2 delivery to tissues
•Gives you a “functional anemia”
•Examples: CHF, anemia, COPD, pneumonia, asthma
METHEMOGLOBINEMIA
•In patients who were previously healthy, methemoglobin
concentrations of 10-20% usually result in cyanosis without
apparent adverse clinical manifestations
•At 20-50% methemoglobin levels, dizziness, fatigue, headache,
and exertional dyspnea may develop.
•At levels around 50% patients become stuporous and lethargic
•At levels greater than 70% they die
METHEMOGLOBINEMIA
Diagnosis
Appearance of arterial blood
PO2 will be normal
Methemoglobin levels
Saturation gap
•Pulse oximeters are all di!erent but generally read wavelengths of 660
and 940 nm which are selected to e"ciently separate oxyhemoglobin and
deoxyhemoglobin. However, methemoglobin absorption at these
wavelenghts is greater than that of either oxyhemoglobin or
deoxyhemoglobin. This results in the pulse ox being inaccurate. As
methemoglobin levels rise the trend is for the pulse ox to read ~ 86%
regardless of how much higher the methemoglobin levels become.
•Another clue to methemoglobinemia would be if your calculated SaO2 on
your ABG is di!erent from the measured SaO2 from the pulse oximeter
resulting in a “saturation Gap”
METHEMOGLOBINEMIA
Back to our case:
His methemoglobin level: 18%
How do you want to treat him?
METHEMOGLOBINEMIA
Management
Withdrawal of oxidizing agent
Oxygen
Methylene blue 1 mg/kg over 5 min
Cimetidine (specifically indicated in Dapsone induced
methemoglobinemia)
•Patients can also have an AGMA secondary to tissue hypoxia or the functional anemia.
•Many recommend treatment above a level of 25% however, using an absolute level may not be
reliable and treatment should be guided by patient symptoms and signs of end-organ hypoxia
•Methylene blue acts as an electron donor that can help the NADPH system reduce oxidized
hemoglobin
•Clinical improvement should be noted within 1 hour, if not a second dose can be
administered
•Methylene blue is an electron carrier that provides the NADPH methemoglobin reductase
system with electrons that assist in the reduction of oxidized hemoglobin
•Remember that methylene blue causes a transient decrease in the pulse oximeter reading
METHEMOGLOBINEMIA
CASE 4
17 yo M
@ classmate’s house when he complained of “not feeling
well”, slumped over and began having “seizure like”
activity
EMS called, patient intubated because of apnea in field
and brought to your ED. Given 2 mg naloxone in field
with no response
PMHx: Nil, no meds, no drug use
CASE 4
case continued...
Vitals: 37.8, BP 98/49, HR 79, RR 4, SaO2 100% with
BVM 100% FiO2
GCS 3, absent corneal, gag, and cough reflexes, pupils 5
mm non reactive
CVS/Resp normal except weak peripheral pulses and
delayed cap refill
What do you want next?
CASE 4
case continued...
CXR: ETT in good position, nil else
CT Head: normal, no ICH
ABG: pH 7.25, HCO3 9, PCO2 32
Lytes: Na 147, K 3.1, Cl 105
Lactate: 10
CASE 4
case continued...
Within 1 hour of arrival the patient was hypotensive and
not responding to fluids
Inotropes started, developed Afib, cardioverted, and
loaded with amiodarone, developed bradycardia, issues
with bradycardia and hypotension persisted
Venous O2 saturation: 98%
Arterial O2 saturation: 100%
CASE 4
DDx for AGMA?
Mudpiles anyone?
CYANIDE
CYANIDE
Pathophysiology
Similar to H2S & CO
Blocks the cytochrome
oxidase in the electron
transport chain
CN is also a potent
neurotoxin
Inhibits multiple other
enzymes
Blocking the electron transport chain results in cellular hypoxia and
promotes the production of lactic acid from pyruvate as a result of
stimulation of anaerobic glycolysis (CN -> NADH can’t be
converted to NAD+ -> NADH favors the reverse reaction which is
glycolysis where pyruvate is converted to lactic acid)
Cyanide a!ects the most oxygen sensitive areas of the brain basal ganglia, cerbellum, sensorimotor cortex.
CYANIDE
Etiology
Smoke inhalation
Oil & gas industry
Gold industry
Chemistry labs
Nitroprusside
Household toxins (nail polish remover)
types of exposures: dermal, ingestion, inhalation, parenteral
onset with inhalation or gaseous HCN or IV of water soluble
cyanide sals occurs within seconds to minutes.
CYANIDE
Clinical Features
No reliable pathognomonic symptom or toxic
syndrome
Clinical effects reflect dysfunction of oxygen-sensitive
organs with CNS and CVS predominating
CNS signs and symptoms are typical of progressive hypoxia and
include headache, anxiety, agitation, confusion, lethargy, seizures,
and coma
A centrally mediated tachypnea occurs initially followed by
bradypnea
CVS signs are complex: rate and loss of contactile force (bradycardia, hypertension -> hypotension with reflex tachycardia
-> bradycardia and hypotension (terminal event)
CYANIDE
Management
Decontamination
Supportive Therapy
Antidotal Therapy
Cyanide is rapidly absorbed through skin (it is in an unionized
form)
Charcoal -> not great at binding but if a few hundred milligrams
have been ingested then charcoal might be a reasonable option to
try (1g binds 35 mg of cyanide)
Bicarb given b/c of acidosis
Bicarb and oxygen can actually enhance the e!ectiveness of
antidotes
Give the cyanide antidote kit ASAP when you suspect cyanide
CYANIDE
Management
Antidotes
Nitrites
Thiosulfate
induce methemoglobinemia
catalyst for cyanide biotransformation
Hydroxycobalamin
formation of cyanocobalamin
both nitrite and thiosulfate have evidence on their own, but more e!ective when given in
combination
Major route for detoxification of CN is by conversion to thiocyanate (you need a sulfur atom).
In order to do this you need a sulfur donor. because in acute poisonings with CN sulfur is
rapidly used up, the detoxification slows. This is the rationale behind giving thiosulfate - to
provide additional sulfur donors for the conversion.
mechanism of nitrite is less clear but methemoglobin has a higher a"nity cyanide than
cytochrome oxidase and therefore cellular respiration is restored.
Hydroxycobalamin binds with cyanide and it is believed that this is eliminated in the urine or at
least releases cyanide at such a slow rate the body is able to detoxify
CYANIDE
Management
Antidotes
Sodium Nitrite 10 mL of 3% (300mg)
Sodium Thiosulfate 50 mL of 25% (12.5g)
Amyl Nitrite glass pearls
Hydroxycobalamin (Europe) 4 grams (binds 200
mg cyanide)
the goal of IV nitrite therapy is to achieve a methemoglobin level of
20-30%
Level is not based on cyanide treatment but rather on maximal
tolerated concentrations without adverse symptoms from
methemoglobinemia.
Adverse e!ects: hypotension (vasodilation), tachycardia,
methemoglobinemia (pediatrics!)
Thiosulfate is not associated with adverse reactions.
CYANIDE
Case continued...
Patient treated empirically with 600 mg of sodium nitrite
followed by 25 g of sodium thiosulfate
Within minutes the bradycardia resolved and venous O2 sat’s
started to decline
Neuro exam showed some improvement with flexion to pain
Ongoing blood gases showed fluctuating SaO2-SvO2 and the
antidote was readministered (300 mg of nitrite, 12.5 g of
thiosulfate) four separate times
CYANIDE
Case continued...
17 hours after admission with close monitoring of the methemoglobin
levels infusions of sodium nitrite and sodium thiosulfate were started
Patient continued to be hemodynamically unstable
After an MRI showed complete cerebellar infarction, cerebellar
tonsillar herniation, severe diffuse infarcts throughout the frontal and
parietal lobes, and severe edema at the brainstem
Patient was declared brain dead and organs were successfully donated
Police investigation confirmed 1.5g of KCN bought by “friend” off the
internet and put in his drink
CYANIDE
Summary
Don’t give the nitrite portion of the cyanide kit in cases of smoke
inhalation unless the CO level is very low (ie. less than 10%)
CASE 5
31 yo M
Refinery worker collapsed in an empty petroleum storage
tank
Two co-workers attempted rescue but both collapsed
Three pulled from the tank by firefighter wearing SCBA
HYDROGEN SULFIDE
HYDROGEN SULFIDE
H2S is released from
decaying organic material,
natural gas, volcanic gases,
petroleum, sulfur deposits
and sulfur springs
Petroleum industry is the
foremost source of H2S
exposure
Other sources: paper mills, iron smelters, food
processing plants, leather industry, farmers (liquid
manure pits), vulcanization of rubber, coke
manufacturing from coal, viscose rayon production
Concentration
(ppm)
Effect
0.02
Odor threshold
100-150
Nose/eye irritation
250-500
Sore throat, cough,
keratoconjunctivities,
pulmonary edema
500-1000
Headache,
disorientation, coma
> 1000
Death
HYDROGEN SULFIDE
Mechanism of Action
Inhibits mitochondrial
cytochrome-c oxidase
This shuts down the
electron transport system
thereby inhibiting oxidative
phosphorylation
Without cellular respiration
tissue anoxia rapidly occurs
When cellular respiration is inhibited, tissue anoxia occurs rapidly and metabolic acidosis ensues
HYDROGEN SULFIDE
Clinical Manifestations
Effects are dose
dependent
Olfactory nerve endings
are rapidly paralyzed at
concentrations ~ 125
ppm
Slaughterhouse
Sledgehammer effect
Concentration
(ppm)
Effect
0.02
Odor threshold
100-150
Nose/eye irritation
250-500
Sore throat, cough,
keratoconjunctivities,
pulmonary edema
500-1000
Headache,
disorientation, coma
> 1000
Death
Odor may disappear giving victim a false sense of security
SSE: coined because of H2S!s rapid and deadly onset of clinical effects where worker!s are knocked down (25% of would be
HYDROGEN SULFIDE
Neurological
Manifestations
Immediate
Delayed
dementia
“knockdown”
headache
ataxia
agitation
tremor
convulsions
sensory impairments
opisthotonus
Sensory impairments: hearing, smell, taste, vision
Knockdown thought to be secondary to H2S toxicity on the brain (brain suffers more quickly to the cytochrome oxidase system)
HYDROGEN SULFIDE
Cardio-Pulmonary Manifestations
Cardio-pulmonary arrest usually occurs @ concentrations
~700 ppm b/c of anoxia or direct cardiac toxicity
Cough
Hemoptysis
Pulmonary Edema
Aspiration
Once respirations cease, they do not resume spontaneously even f the patient is removed from the exposure.
20% of patients arriving in the ED after H2S exposure have pulmonary edema
HYDROGEN SULFIDE
Case 5 continued
the first patient now arrives in the ED intubated with
SaO2 100%
Vitals: BP 110/72, HR 140, RR 34 bpm, T 38.4
Exam: dilated pupils, marked conjunctival injection,
diffuse crackles in lungs bilaterally
What do you expect to see on ABG? Interventions?
AGMA secondary to lactate
HYDROGEN SULFIDE
Supportive Management
Airway
100% humidified O2 x 12-24 hours
Suctioning
Fluids, Pressors for hypotension
Bicarb for acidosis
IV benzodiazepines for seizures
Patients with respiratory paralysis may not start breathing again for min to hours after removal from exposure
Randall!s approach - either severe exposure and the patients die, or mild exposure and the patient!s live
Admit if symptomatic after 4 hours, good prognosis if alive after 4 hours
HYDROGEN SULFIDE
Hyperbaric Oxygen?
HYDROGEN SULFIDE
Hyperbaric Oxygen: Theory
1. Inhibition of hydrogen sulfide-cytochrome binding
2.Increased oxyhemoglobin is a natural catalyst of sulfide
oxidation (enhanced detoxification)
3.Increased oxygen plasma diffusion results in improved
oxygenation of marginally perfused tissue; improved
oxygenation in setting of pulmonary edema
would treat if severe exposure with continued altered mental status or AGMA
HYDROGEN SULFIDE
Hyperbaric Oxygen: Conclusions
Uncertain if confers benefit but it makes sense
theoretically
Consider in patients who
A. CNS symptoms are not resolving
B. No response with nitrite therapy
HYDROGEN SULFIDE
Hyperbaric Oxygen: Evidence
evidence is anecdotal
2 case reports suggest benefit
1 case report suggests persistent cognitive deficits
despite therapy
2 case reports suggest no benefit
HYDROGEN SULFIDE
Nitrites?
any evidence we have for nitrites comes from animal studies
HYDROGEN SULFIDE
Nitrites: Theory
H2S preferentially binds to nitrite-generated
methemoglobin forming sulfmethemoglobin (SMH)
SMH is non-toxic and is harmlessly degraded to
sulfur moieties and excreted by the kidneys
Uncertain as to the applicability in clinical practice
H2S preferentially binds to methemoglobin over cytochrome oxidase
controversy over this mechanism exists because sulfide isn!t as strongly bound to methemoglobin as CN, nitrates have been effective in
animal experiments in which the formation of methemoglobin has been blocked by methylene blue, response to therapy occurs more
quickly than the formation of methemoglobin
Alternative explainations as to why nitrites may be effective: 1. vasoactive changes in microcirculation, 2. a direct cytochrome-c oxidase
stimulating effect, 3. a direct effect on H2S cytochrome-c oxidase binding that is not mediated by methemoglobin induction.
HYDROGEN SULFIDE
Nitrates: Experimental Evidence
pretreatment in animals prior to H2S exposure decreases
mortality
pretreatment with methemoglobin protects mice from
lethal exposures of H2S
nitrate tx after H2S exposure decreases mortality in
animal models; however, doses required are 20-fold that
used in CN, tx was administered within 2 min of
exposure, and it produced 82% methemoglobinemia
HYDROGEN SULFIDE
Nitrites: Conclusions
Evidence for their use is inconclusive
Nitrites are only likely effective if given very early on; if
given beyond 10 minutes it is unlikely to confer any
benefit
Methemoglobinemia production from nitrites is a
relatively slow process
In vitro evidence: oxyhemoglobin (95% of sulfide within 20 minutes) and methemoglobin catalyzed reactions that oxidize sulfide (and turn
it into a non-toxic, excretable substrate) both occur rapidly. Methemoglobin catalyzed reactions may occur slightly more rapidly than the
oxyhemoglobin catalyzed reactions. Evidence also suggests that sulfide really only exists in an oxygenated blood stream is on the order
of “minutes”. From this data the conclusions as above
** none of this data has been demonstrated in vivo animal or human studies
HYDROGEN SULFIDE
Nitrites: Conclusions
Use is controversial
Consider single dose early in markedly symptomatic patients
Beware of hypotension, do not exceed methemoglobin level > 25%
Not indicated in the following:
Asymptomatic or minimal symptoms
Short lived symptomatic episode (e.g. brief loss of
consciousness)
Pregnant
HYDROGEN SULFIDE
Summary of management
1. Rescuer protection
2. Basic life support
3. Aggressive supportive care
•
NaHCO3 for acidosis
4. Sodium nitrite (3%)
•
Adult: 10 mL @ 2.5-5 mL/min
•
Peds: 0.2 mL/kg
5. Hyperbaric oxygen therapy may be considered under select circumstances
Questions for Ingrid: management of pulmonary edema? treat as ARDS???? Diuresis???
Review when you would consider sodium nitrite
Continue to work case into the lecture
Look at hadley!s book for more info
HYDROGEN SULFIDE
Summary
CARBON MONOXIDE
CARBON MONOXIDE
Exposure
Motor vehicles
Propane powered equipment (zamboni’s)
Propane powered appliances (stoves, furnaces, hot-water
heaters)
Fires
CARBON MONOXIDE
Pathophysiology
CO binds to hemoglobin with an affinity
210 x that of O2 therefore decreases the
oxygen carrying capacity of hemoglobin
Shifts oxygen dissociation curve to the
left decreasing ability of Hgb to offload
O2 to the tissues
Also causes harm through other
mechanisms:
disrupts cellular oxidative processes
(binds to mitochondrial cytochrome
oxidase and impairs cellular
respiration) - similar to H2S & CN
peroxidation of brain lipids
both secondary processes result in generalized hypoxia and varying degrees of end organ damage.
CO toxicity cannot be attributed solely to COHb mediated hypoxia because neither clinical effects nor the phenomenon of delayed
neurologic deficits can be completely predicted by the extent of binding between hemoglobin and CO.
Furthermore such a model fails to explain why even negligible levels of COHb (4-5%) can result in cognitive impairment
Inactivation of cytochrome oxidase & CO induced displacement of NO from platelets -> NO and inhibition of cellular respiration results in
damaged endothelium -> increased WBC!s attracted to and adhere to the damaged brain microvasculature -> Leukocytes attach
themselves to the damaged endothelium and release proteases that convert xanthin dehydrogenase to xanthine oxidase, an enzyme
that promotes formation of free radicals. The end result of this process is delayed lipid peroxidation of the brain, which can be correlated
with decrements in learning in rodents. (NO inhibitors in animals shows decreased damage to the brain when exposed to CO)
CARBON MONOXIDE
Clinical Features: Acute
Non-Specific
Common misdiagnosis: influenzae, headache NYD, food
poisoning, and gastroenteritis
Continued exposure leads to ACS type symptoms secondary to
myocardial ischemia
CNS is the most sensitive organ to CO poisoning
Cardiogenic Pulmonary Edema
AGMA
b/c headache, dizziness, and nausea are the earliest symptoms and most frequent exposures occur during the winter months influenzae
is the most common misdiagnosis
headache is usually described as “dull, frontal, and continuous”
Patients may develop neuological symptoms with CO levels as low as 15-20% (initally headache, dizziness, and ataxia then eventually
syncope, seizures, coma and death)
Pulmonary edema is not secondary to direct pulmonary toxicity
AGAMA - secondary to arrest of cellular respiration and required utilization of anaerobic metabolism (similar to H2S and CN) - this
results in a lactic acidosis
CARBON MONOXIDE
Clinical Features: Chronic
Two syndromes
Persistent Neurological Sequelae
Delayed Neurological Sequelae
Dementia, amnestic syndromes, psychosis,
parkinsonism, paralysis, chorea, cortical blindness,
aprexia, agnosias, peripheral neuropathy, incontinence
PNS refers to symptoms or signs referable to CO poisoning that may improve although not to the premorbid state.
DNS refers to a relapse of symptoms or signs referable to CO poisoning occuring after a transient period of improvement.
In both instances the symptoms are non specific and the entities may be difficult to distinguish from each other
CARBON MONOXIDE
Clinical Features: Pediatrics
Children can become symptomatic @ levels < 10%
Isolated seizure or vomiting may be the only clinical
manifestation
Co-oximetry may give falsely elevated COHb levels in infants
Presence of fetal hemoglobin
Bkdwn protoporphyrin to bili produces CO
CARBON MONOXIDE
Diagnosis
Maintain high index of suspicion (multiple family members)
PaO2 & SaO2 on ABG + Pulse Oximetry not useful!
Initial CO level correlates poorly with outcome
pH is more predictive of outcome than CO levels (although it
isn’t very good at predicting outcome either!)
resp alkalosis (mild); met acidosis (severe)
respiratory alkalosis typically develops first in mild cases to compensate for the reduction in oxygen-carrying capacity and delivery
metabolic acidosis results from more prolonged exposures because of lactate production
ABG cannot be used as a diagnostic test for CO poisoning other than to identify the presence of a metabolic acidosis and a normal
partial pressure of PO2. CO does NOT affect the amount of oxygen dissolved in the serum
Pulse oximeter inadequate b/c COHb is essentially misinterpreted as oxyhemoglobin
CARBON MONOXIDE
Diagnosis
Making the diagnosis is based on CO levels
Normal: 0-2 %
Smokers: 6-10%
Pretreatment with oxygen may return CO levels to
normal before the blood test has been sent
Pulse oximeter usually gives a falsely elevated saturation
CARBON MONOXIDE
Management
Supportive
Normo-baric Oxygen (100% FiO2)
Hyperbaric Oxygen
CARBON MONOXIDE
Should this patient be transferred to Edmonton for
hyperbaric O2 treatment?
CARBON MONOXIDE
Hyperbaric Oxygen
Main theoretical reason to use HBO is to prevent lipid peroxidation and NOT to
decrease the 1/2 life of CO in the blood
accelerates regeneration of cytochrome oxidase
Prevents leukocyte adherence to brain microvasculature
HBO increases the amount of dissolved oxygen 10 x
Elimination 1/2 life:
HBO: 20 min
Room air: 6 hours
100% FiO2: 1 hour
HBO helps support metabolic means by increasing the amount of oxygen dissolved in the blood.
HBO is more than just a modality for clearing COHb more quickly than ambient oxygen.
It prevents brain lipid peroxidation via several mechanisms: a. accelerates regeneration of inactivated cytochrome oxidase which may be
the initiating site for CO neuronal damage. B. HBO prevents subsequent leukocyte adherance to brain microvascular endothelium, a
process essential for amplification of central nervous system damage from CO. (all of this comes from basic science evidence, this has
not played out in human studies with real cases of CO exposure)
CARBON MONOXIDE
Hyperbaric Oxygen
Major randomized trials to date:
1989: Raphael; Lancet
1995: Thom; Ann Emerg Med
1996: Mathieu; Undersea & Hyperbaric Medicine
1999: Scheinkestel; Med J Aus
2002: Weaver et al; NEJM
2004: Raphael; J Tox Clin Tox
CARBON MONOXIDE
Hyperbaric Oxygen
Cochrane Review (re-published Jan 2009 with updates)
6 RCT’s evaluating clinical outcomes
4 found no benefit
2 found benefit
pooled data showed no benefit (OR 0.78: 95% CI 0.54-1.12)
design or analysis flaws evident in all trials
Authors concluded that existing RCT’s do not tell us if HBO therapy reduces
the neurological sequelae in cases of acute CO poisoning
Authors caution that the methodoligic and statistical heterogeneity of the 6 trials renders the analysis difficult to interpret
Subanalysis by severity, intent, and duration of poisoning were not possible
“It is possible that some patients, particularly those with more severe poisoning, may derive benefit from treatment, but this remains
unproven”
CARBON MONOXIDE
Indications for Hyperbaric Oxygen Therapy
Coma
Cardiac ischemia
Cerebellar dysfunction
Metabolic acidosis
CO level > 30%
CO level > 20% in pregnant patients
Remember that levels correlate only weakly with outcomes and true toxicity
Different institutions have different criteria for when to transfer
Discuss with toxicologist
Goldfrank!s: Syncope, coma, seizure, AMS, carboxyhemoglobin > 25%, abnormal cerebellar exam, fetal distress in pregnancy (affinity of
fetal hemoglobin for CO is even greater than that of adult hemoglobin suggesting that the fetal exposure exceeds that predicted by
maternal COHb levels
Suggest optimal timing to be 6 hours after exposure
CARBON MONOXIDE
Conclusions
Most important aspect of management is to consider the
diagnosis and then identify the source of CO*
Careful of the pitfalls in measuring CO levels
Primary treatment is supportive and 100% FiO2
Hyperbaric O2 has theoretical but no proven benefit;
decision to send to Edmonton should be made on a case
by case basis
Can call the fire department and they will go test the air in the home for free
THE END!