Toxicology Grand Rounds: Carbon Monoxide Poisoning

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Toxicology Grand RoundsCarbon Monoxide Poisoning

• Mark Yarema, MD FRCPC
• Poison and Drug Information Service
• Calgary, Alberta
• PADIS/Emergency Medicine/Critical Care Rounds
• January 27, 2011

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Acknowledgements

• PADIS Rosalee Sears-Ford, Nina Walny
• Critical Care Paul Boiteau, Sid Viner
• Emergency Medicine Ian Rigby, Jay Green, Kevin
  Hanrahan
• Miscericordia Hospital Malcolm Young
• HBOT Clinics Terry Stewart, Karen Keats,
  Caroline Bain
• AHS Telehealth
• PLP Marianna Hofmeister, Holly Donaldson, Kyle
  Dormer
• Podcast website http//www.ucalgary.ca/plppodcast
  s/

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Disclosure

• I have no commercial interest in any of the
  products or therapies discussed in this
  presentation.

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Outline

• Cases
• Intro to CO
• Pathophysiology
• Clinical features
• Diagnosis
• Management
• Special presentations
• Misericordia Hospital HBO Unit
• HBOT Clinics Inc.
• Q and A

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Case 1

• 63 y.o. male
• Last seen July 1
• Found by wife July 2 AM in garage with riding
  tractor running
• EMS called, pt. in cardiorespiratory arrest
• Intubated, ventilated, CPR
• Return of spontaneous circulation 15 minutes
  after resuscitation initiated

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Case 1

• In E.D.
• ABG pH lt 6.8 PC02 58, p02 31, HC03 15, Lactate
  gt 20, COHb 61
• ST depression on EKG
• Another cardiac arrest ? resuscitated
• Multiple pressors
• PADIS consulted candidate for HBO?

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Case 1

• d/w PADIS meets accepted criteria for HBO.
  Recommended speaking with Misericordia HBO MD on
  call
• Transferred to Misericordia
• 1 HBO treatment given July 2
• Transferred to ICU July 3
• Died 1929 hours July 3

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Case 1.5

• 4 days after death of Case 1
• 21 y.o. male
• Texted girlfriend at 0400, found asystolic in car
  by EMS at 0500
• ROSC after 30 minutes CPR by EMS
• In E.D.
• intubated, unresponsive
• ABG pH 6.82, COHb 57.3, Lactate 22

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Case 1.5

• d/w PADIS meets accepted criteria for HBO.
  Recommended speaking with Misericordia HBO MD on
  call
• Pt. deemed not appropriate candidate
• Died 1700 hrs July 7th

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Case 2

• 62 y.o. female, 16 y.o. male, 35 y.o. male
• Hx of faulty furnace in home
• Furnace turned on during last period of Canucks
  game, then everyone fell asleep
• 4.5 hour soaking period

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Case 2

• 100am 16 y.o. gets up to go to fridge, falls
• 62 y.o. hears the fall and wakes up
• EMS called
• 16 y.o. and 35 y.o. headache, nausea, no other
  symptoms
• 62 y.o. disoriented, combative, vomiting,
  headache
• Does anyone need HBO?

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Case 2

• d/w PADIS 62 y.o. most concerning, meets
  accepted criteria for HBO. Recommended speaking
  with HBOT Clinics MD on call
• MD speaks with HBOT clinics HBO MD on call
• Patient accepted by HBOT, treated with HBO

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Intro to CO

• Colorless, odorless, tasteless gas
• Formed by incomplete combustion of
  carbon-containing compounds
• Normal byproduct of hemoglobin degradation
• Many different sources of exposure

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Sources of CO

• Fires
• Auto exhaust
• Cigarette smoke
• Malfunctioning water heaters, gas stoves,
  furnaces
• Wood-burning fireplaces, blocked chimneys
• Propane forklifts
• Ice resurfacing machines
• Generators
• Inappropriate heat sources (e.g. barbecues)

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www.coolestspringbreak.com
Source The Arizona Republic, November 29, 2000
(Maureen West and Judd Slivka, reporters)
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Deadly houseboats
CO concentration in ppm Scenario
25 Maximum exposure allowed by Can. OSHA for 8 hours
300 Home CO detector cutoff level (10 minute exposure)
800 CNS symptoms, Death 2 hours
1200 Immediately Dangerous to Life and Health (IDLH)
5000-10,000 Measured in open air near swim platform
12,000 Death within 2-3 minutes
7000-30,000 Measured under houseboat swim platforms
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Physiology

• Rapidly diffuses across alveolar-capillary
  membranes
• Binds to hemoglobin with 200-250X greater
  affinity than oxygen
• 10-15 of total body CO taken up by tissue, bound
  to extravascular proteins
• Myoglobin
• Cytochrome oxidase
• Catalase
• Peroxidases

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Pathophysiology
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Pathophysiology

• Left shift oxyhemoglobin dissociation curve
• Binding to cytochrome oxidase
• Activation of excitatory amino acids
• Binding to myoglobin
• Nitric oxide (NO)

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Left shift

• CO increases the affinity of oxygen for
  hemoglobin
• Oxygen not displaced by CO is bound more tightly
  to Hb
• Lower oxygen delivery to cells
• Hypoxia

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www.modernmedicine.com
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Left shift / hypoxia

• Does not explain all manifestations of poisoning
• Patients may remain comatose even after COHb
  undetectable
• Dissolved CO in plasma and delivery to target
  organs also important

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Cytochrome oxidase inhibition

• CO interferes with cellular respiration
• Decreased ATP production
• Initiates inflammatory cascade
• Lipid peroxidation
• Ischemic brain injury
• Binding may be increased under hypotensive or
  hypoxic conditions

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Cytochrome oxidase
25
Activation of excitatory amino acids

• Tissue hypoxia increases excitatory amino acid
  levels
• Glutamate stimulates NMDA receptors and causes
  intracellular Ca release
• Delayed neuronal cell death

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Myoglobin

• CO binds with 60X gt affinity than O2
• Binding enhanced under hypoxic conditions
• Leads to myocardial depression
• Carboxymyoglobin may explain dysrhythmias and
  ischemia that may occur with mild exposures
• Especially with pre-existing CAD

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Oh NO!

• CO displaces nitric oxide (NO) from platelets
• Actions of NO
• Vasodilator
• Forms peroxynitrite radicals ? inactivate
  cytochrome oxidase
• Formation of platelet-neutrophil aggregates ?
  neutrophil adhesion in brain microvasculature
• End result delayed lipid peroxidation

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Weaver. NEJM 2009
29
Simpler version of previous slide

• Too much CO Bad

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Clinical features of poisoning
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Clinical features

• Early symptoms very nonspecific
• Often confused with other illnesses
• Influenza
• Food poisoning
• Gastroenteritis
• Colic

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Neurologic

• Initial
• Headache, dizziness, nausea
• Later (higher levels/longer exposures)
• Syncope, focal neuro sx suggesting CVA, LOC,
  confusion, seizures, coma
• Persistent neurologic sequelae
• Delayed neurologic sequelae (DNS)

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Delayed Neurologic Sequelae

• Incidence between 2-43
• 2 days 5 weeks after initial poisoning
• Neurologic and psychiatric symptoms
• amnesia headaches
• psychosis apraxia
• parkinsonism incontinence
• paralysis periph. neuropathy
• chorea dementia
• 50-75 of cases resolve (may take months ? 1 year)

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Who is at risk for DNS?

• post-hoc analysis of Weaver 2002 RCT
• plus additional pts treated only with NBO not in
  trial
• Those most at risk of DNS
• History of LOC
• Patients with long exposures (gt 24 hours)
• Age gt 36
• COHb gt 25
• Randomized trial data only, not separate NBO
  patients

Weaver et al. Am J Resp Crit Care Med
2007176491-7.
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Cardiac

• PVCs and other dysrhythmias
• Myocardial ischemia
• Myocardial stunning
• With CAD, exacerbation of angina and arrhythmias
  can occur with COHb lt 10
• Acute mortality from CO usually from ventricular
  arrhythmias

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• 230 pts with moderate/severe poisoning all
  treated with HBO
• Indications for HBO
• LOC
• Seizure
• Focal neuro deficit
• Ischemic chest pain
• Dysrhythmias
• COHb gt 40
• COHbgt 25 with Hx CV disease, age gt 60, Hgb lt
  100, exposure gt 2 hours

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• 85 (37) had elevated TnI or CK-MB or diagnostic
  EKG changes of ischemia
• 32 (38) eventually died compared with 22 (15)
  of patients who had no myocardial injury
• Effect persisted over many years

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Diagnosis

• History and physical
• Mini mental status exam
• Laboratory tests
• CO pulse oximetry
• COHb / VBG
• Select patients EKG, cardiac markers
• Imaging
• CT
• MRI

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COHb pulse oximeters

• Accurate ?3 from COHb of 0-40
• Some false ves
• More during early use?
• Pre-hospital
• Incident response paramedics
• Calgary Zone availability
• FMC, PLC, RGH triage
• UCCs

www.masimo.com
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COHb

• Measured with co-oximeter
• Venous blood as accurate as arterial
• Normal levels 0-5, up to 10 in smokers
• Wide variation in clinical manifestations with
  identical levels
• Inaccurate predictor of peak levels
• Variations in half lives
• Effect of 02 given prior to sampling
• Not predictive of symptoms or final outcome

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Blood gas

• Some HBO trials have used lactate gt 2.5 or base
  excess lt -2 as indications for HBO
• Metabolic acidosis (hydrogen ion concentration)
  on presentation a better predictor of need for
  multiple HBO treatments than COHb

Turner et al. J Accid Emerg Med 1999
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Neuroimaging

• Abnormalities may be seen within 12 hours of CO
  exposure causing LOC
• Basal ganglia most commonly affected
• Caudate
• Putamen
• Globus pallidus
• Also subcortical white matter and hippocampus

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caudate
globus pallidus
cerebellum
www.learningradiology.com
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Management

• ABCs
• O2 via nonrebreather
• Alters t ½ of COHb
• 5-6 hours at room air
• 40-90 minutes on 02 via NRB
• Hyperbaric oxygen

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HBO

• 100 O2 while exposed to increased atmospheric
  pressure
• Reduces the half-life of COHb to 23 minutes
• Mechanisms
• Increases dissolved plasma 02 tenfold
• May help regenerate cytochrome oxidase
• Inhibits leukocyte adherence to the microvascular
  endothelium
• Does HBO prevent development of delayed
  neurologic sequelae?

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• Non-blinded, randomized study of 629 adults, Rx
  within 12 h exposure
• pregnant women, pts lt 15 y.o. excluded
• Patients separated into LOC vs. no LOC prior to
  randomization into one of four groups
• No LOC 6h NBO vs 4h NBO 1 HBO Rx (2.0 ATA X 1
  hour)
• LOC 4h NBO 1 HBO vs 4h NBO 2 HBO Rx (all
  4h NBO)
• Self-assessment questionnaire at 1 month
  following Rx re neurologic sequelae

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• complete recovery at 1 month
• No LOC 66 NBO vs 68 HBO
• LOC 54 1 HBO vs 52 2 HBO
• Conclusion HBO not useful in pts with no LOC,
  and 2 sessions not useful in those who did have
  LOC

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• Randomized, non-blinded, 65 patients with mild
  poisoning , lt6 hours of removal from exposure
• LOC, cardiac compromise excluded
• 1 HBO Rx (120 mins, 2.8 ATA) vs NBO until Sx
  resolved
• Mean time from randomization to HBO 2 hours
• Neuropsych tests done after Rx (baseline) then
  3-4 weeks after poisoning

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• Incidence of DNS 23 NBO group, 0 HBO group
• Conclusion HBO decreased incidence of DNS after
  CO poisoning

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Scheinkestel et al, Med J Aust March 1999

• Randomized, double-blind trial with 191 patients,
  all severities included
• pregnancy, peds excluded
• Time to treatment 6.6-7.5h
• HBO 3 days of 60 min Rx at 2.8 ATA continuous
  NBO
• potentially 3 more HBO Rx if clinically abN after
  the first 3
• NBO continuous hi flow 02 for 3 days sham
  dives

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Scheinkestel et al, Med J Aust March 1999

• 46 lost to follow up
• Incidence of DNS HBO 5/104 NBO 0/87
• Conclusion No benefit from HBO and may have
  worsened outcome, cannot be recommended

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• Randomized trial of 152 patients
• Extensive inclusion criteria
• HBO group 3 treatments (1 X 2.8 ATA, 2 X 2.0
  ATA)
• NBO group 100 02 via NRB during 3 sham dives
• Neuropsych testing after chamber sessions 1 and
  3, then 2 wks, 6 wks, 6 mos, 12 mos
• Primary outcome cognitive sequelae at 6 wks.

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• Higher cerebellar dysfunction in NBO group (15
  vs 4)
• At 6 wks, lower incidence DNS in HBO group (25
  vs 46)
• persisted when adjusting for cerebellar
  dysfunction and also at 12 months (ITT analysis)
• Conclusion 3 HBO Rx within 24h period reduced
  risk of cognitive sequelae at 6 weeks and 12
  months

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• Non blinded, randomized trial of 385 pts. aged 15
  years and up
• Domestic CO poisoning only, October 1989- January
  2000
• Patients separated into LOC vs. coma prior to
  randomization into one of four groups
• LOC NBO vs NBO 1 HBO Rx (2.0 ATA X 1 hour)
• coma NBO 1 HBO Rx (2.0 ATA X 1 hour) vs 2 HBO
  Rx
• Self-assessment questionnaire at 1 month re
  neurologic sequelae

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• complete recovery at one month following
  treatment
• LOC 58 NBO vs. 61 HBO
• Coma 68 HBO X 1 vs. 47 HBO X 2 (significant)
• Conclusion no evidence superiority of HBO gt NBO
  in patients with LOC. 2 HBO treatments associated
  with worse outcomes.

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HBO Clinical Trials

• Study design flaws
• Randomization procedures
• Blinding
• Intent to treat analyses
• Follow up (most 15-20 lost to f/u except one at
  46)
• Outcomes (questionnaires vs neuropsych battery,
  complete recovery vs. cognitive sequelae)
• NBO and HBO therapies used (duration, number of
  treatments)
• Excluded patients (pregnant, peds)

Buckley et al. Toxicol Rev 200524(2)75-92
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HBO-suggested indications

• Syncope
• Altered LOC
• Coma
• Seizure
• Abnormal cerebellar function
• Age gt 36 years
• Prolonged CO exposure (gt 24 hours)
• COHb gt 25
• Missing myocardial ischemia

Goldfranks Toxicologic Emergencies, 2011
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Pregnant patients

• Fetal COHb concentrations tend to be higher than
  maternal levels (animal studies)
• Human studies suggest fetal Hgb affinity is
  similar to maternal Hgb affinity in low 02 states
• More important issue is fetal hypoxia
• Maternal COHb does not predict fetal outcome
• Normal mental status with no LOC in mother good
  outcomes, normal deliveries

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Pregnant patients

• NBO treatment of pregnant patients
• similar to nonpregnant patients
• treat until mother is asymptomatic
• benefit of prolonged Rx to mother unclear
• Indications for HBO in pregnant patients
• same as for nonpregnant patients except
• lower COHb in mother at which HBO recommended
  (arbitrarily set at 15-20)
• any features of fetal distress

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Outcomes

• Cardiac arrest patients

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• 18 patients given HBO after cardiac arrest with
  ROSC
• Resuscitation time range 19-45 min.
• Mean time to HBO 4.3 hours post exposure
• COHb range 14-55
• All patients died during hospitalization (range 9
  hours-7 days post discovery)
• HBO director survey of fictitious CO-induced
  arrest case
• 100 recommended HBO
• Chance of survival 74
• Chance of recovery w/o neurologic sequelae 28

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CO poisoning and cardiac arrest

• Quick summary of other studies
• 5 peds smoke inhalations 0 survivors
• 10 peds CO patients 8 died, 2 had DNS
• 10 adult smoke inhalations 0 survivors
• 11 adult CO patients 0 survivors
• 23 adult CO patients 17 died, 6 unknown outcome
• ? Role of CN poisoning in smoke inhalation victims

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Objectives

• By the end of the presentation, the participant
  should be able to
• List the mechanisms by which carbon monoxide (CO)
  causes toxicity
• Describe the clinical features seen with acute
  and delayed toxicity from CO
• Discuss the controversies in the management of CO
  poisoning, including the role of hyperbaric
  oxygen (HBO)

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How to reach us

• Poison and Drug Information Service
• 403- 944-1414 (Calgary)
• 1-800-332-1414 (Alberta)
• Mark.yarema_at_albertahealthservices.ca