CO The Silent Killer

1
CO - The Silent Killer

• Martin Laliberté MD FRCP ( C ) ABEM
• McGill University
• Centre Anti-Poison du Québec

2
Case study - Mrs B.

• 40 year old female presenting after a syncopal
  episode at home
• Headache, nausea, dizziness x 2 weeks
• Lives in a condominium building downtown
• Heard the alarm of the CO detector installed in
  her apartment ( 100 - 150 ppm )

3
Incidence of CO poisoning

• Leading cause of poisoning mortality
• Most common cause of death in combustion related
  inhalation injury
• 1000 to 2000 deaths / year ( USA )
• Difficult diagnosis
• incidence of unrecognized cases higher
• estimated gt 42 000 visits / year
• ED visit rate 16.5 / 100 000 population

4
Sources of CO

• Motor vehicle exhaust
• running engine in closed space
• faulty exhaust systems
• Propane-powered equipement
• lift, water heater, concrete saw, polishers
• Combustion for heating or cooking
• camping equipment, heating systems
• Smoke inhalation in fires

5
Xenobiotics metabolism

• Methylene chloride
• peak of 50 in humans
• Dibromomethane
• peak of 27 in rodents
• Diiodomethane
• peak of 14.2 in humans
• Bromochloromethane
• peak of 11 in rodents

6
Pathophysiology - Tissue hypoxia

• Binding to Hb to form COHb
• Hb affinity for CO 250 times affinity for O2
• Effect on oxyHb dissociation curve
• left shift, distortion of shape
• Impaired release of oxygen at tissue level
• Increased minute ventilation with subsequent
  increased CO uptake

7
Pathophysiology - Cellular level

• 15 of CO bound to extravascular heme-containing
  proteins
• Cytochrome oxidase ( aa3 )
• alteration in ATP production
• intracellular acidosis
• persists after exposure
• Cardiac and skeletal myoglobin
• occuring at COHb 2
• alteration in tissue O2 uptake

8
Pathophysiology - Cardiovascular

• Myocardial depression consequence of
• hypoxic stress
• cytochrome a3 dysfunction
• CO binding to cardiac myoglobin
• Arterial hypotension
• myocardial depression
• NO-related peripheral vasodilatation
• LOC with reduction of cerebral perfusion
• Ischemic reperfusion injury

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Pathophysiology - Neurovascular

• CO in circulation associated with massive
  increase in NO in perivascular tissues
• NO released from vascular endothelial cells and
  platelets
• Production of oxygen radicals from impaired
  mitochondrial function
• Reaction NO with oxygen radicals to form
  peroxynitrite ( ONOO- )

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Pathophysiology - Neurovascular

• Peroxynitrite binds to perivascular tissue
  proteins causing injury
• Increased capillary permeability in CNS and
  pulmonary vascular beds
• Endothelial injury causing expression of
  adherence molecules - beta 2 integrins
• Leucocytes bind to injured endothelium reducing
  cerebral perfusion
• Initiation of CNS lipid peroxidation

11
Clinical manifestations

• General
• headache, nausea, vomiting, weakness
• Cardiovascular
• chest pain, tachypnea, tachycardia, hypotension
• pulmonary edema, arrythmias, cardiac arrest
• Neurologic
• dizziness, ataxia, seizures, coma
• Others
• retinal hemorrhages, metabolic acidosis

12
Severity of CO intoxication

• Inhaled CO concentration
• Duration of exposure
• Individual susceptibility
• minute ventilation
• pregnancy
• Presence of systemic illnesses
• cardiac and pulmonary diseases
• Initial COHb not predictive

13
Case study - Mrs B.

• Neurologic examination reveals that the patient
  is confused and disoriented
• COHb measured on admission is 15
• Patient is a non-smoker
• Head CT Scan and ECG is normal

14
COHb elimination half-life

• O2 20.9 1 atm
• 320 min ( 128-409 ) - Peterson
• O2 100 1 atm
• 131 min ( 27-462 ) - Myers
• 72 min ( 26-146 ) - Weaver
• O2 100 HBO
• 3 atm 23 min - Peterson
• 1.58 atm 27 min - Jay
• 2.5 atm 22 min - Pace

15
Shimazu et al. ( 2000 )

• CO elimination two-compartment model
• Short term exposure
• initial phase - half life 5.7 minutes
• slower phase - half life 103 minutes
• Long terme exposure
• initial phase - half life 21.5 minutes
• slower phase - half life 118 minutes
• Two compartments
• intravascular and extravascular

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Delayed or persistent CO toxicity

• Persistent present from exposure
• Delayed 2 to 40 days post-exposure
• Dementia, psychosis, memory deficit
• Parkinsonism, paralysis, chorea
• Personnality changes, gait disturbance
• Cortical blindness, apraxia, agnosia
• Peripheral neuropathy, urinary incontinence

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Delayed or persistent CO toxicity

• Reported neurologic impairment varies widely
• between 3 and 44
• Reported at 10 to 30 at 1 year
• Neuropsychologic deficits often subtle
• Can be identified by psychometric testing
• Spontaneous recovery
• mild poisoning 100 resolve at 2 months
• severe poisoning 75 resolve at 1 year

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Delayed CO toxicity

• Lesions of cerebral white matter
• globus pallidus, cerebellum, hippocampus
• perivascular injury with blood flow abnormalities
• Often associated with LOC in acute phase
• Hypotension is essential to cause white matter
  lesions in animal model
• Patients gt 30 year old more susceptible to
  delayed CO toxicity

19
Low dose / chronic CO exposure

• CO 61 ppm and COHb 4 - effect on memory and
  learning abilities
• COHb 2 - 3.9 - worsening ischemia in patients
  with pre-existing CAD
• COHb 6 - exercise-induced ventricular arythmias
  in patients with CAD
• CO 38 ppm - 35 cardiovascular mortality excess
  in workers

20
Clinical evaluation

• Maintain a high level of suspicion
• History of exposure can be absent
• COHb
• lt 3 non-smokers or lt 10 in smokers
• not predictive of outcome
• correlation with symptoms useless
• ABG metabolic acidosis ( lactate )
• ECG ischemia, arrythmias

21
Pulse oximetry in CO poisoning

• Pulse oximetry HbO2 and RHb at two wavelengths
  660 nm and 940 nm
• Unreliable with significant amount of abnormal Hb
  MetHb, COHb, SHb
• Pulse oximetry overestimates true fractional
  arterial oxygen saturation
• Elevation of COHb level falsely elevates the SaO2
  by an amount less than the COHb level

22
Neurologic evaluation

• Neurologic examination
• Mental status examination
• Folstein
• Psychometric testing
• CO Neuropsychological Screening Battery
• Neuroradiologic imaging CT, MRI

23
Psychometric testing

• Lack of standardized methods
• Normalisation of psychometric testing
• practice effect when repeated
• decreasing effect of other toxins with time
• very subjective, tester can be biased
• Abnormal testing at risk of persistent or
  delayed neurologic sequelae
• Predictive of need for HBO therapy in mild
  toxicity ?

24
Severity of CO poisoning

• COHb level does not correlate with severity or
  outcome
• Severity of neurologic lesions correlate better
  with hypotension than with hypoxia
• Duration of exposure as important as
  concentration
• Total CO load x ventilation x exposure
• Susceptibility of individual to CO

25
Case study - Mrs B.

• Patient is given O2 100 on arrival
• HBO facility is contacted for consultation
• Based on the history of LOC and persistent
  confusion, transfer for admission is advised
• Patient receives 4 treatments of HBO

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Management of CO poisoning

• Identify the source to correct the problem
• Domestic exposition
• verification of heating or cooking appliances
• Occupational exposition
• CSST investigation
• CO poisoning mandatory reporting to public
  health services
• Making the diagnosis can save lives !

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Case study - Mrs B.

• Case reported to public health
• High CO concentrations measured in building
• Two other cases diagnosed in building needing
  treatment
• Investigation identifies serious flaws in
  ventilation system in the basement garage and
  inadequate CO dectors

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Management of CO poisoning

• Oxygen 100 ASAP
• ABG
• COHb
• ECG
• CXR
• Cardiac enzymes
• Cardiac monitoring

29
Hyperbaric oxygen therapy

• Enhanced elimination of COHb
• Improved tissue oxygenation
• Enhanced dissociation of CO from cytochrome
  oxidase
• Inhibition of B2 integrin adhesion to vascular
  endothelium
• Prevention of CNS lipid peroxydation

30
HBO vs NBO studies

• Isolated case reports
• Uncontrolled clinical observations
• Studies
• small
• non-randomized
• unblinded assessment of outcome
• incomplete assessment of outcome

31
Raphael et al. - 1989

• Prospective randomised clinical trial of NBO (
  n170 ) vs HBO ( n173 )
• Patients without LOC admitted within 12 hours of
  CO exposure
• NBO 6 hrs of NBO O2
• HBO 2 hrs of O2 at 2.0 atm, 4 hrs of NBO
• Evaluation at 1 month interview, telephone

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Raphael - Results

• Time to randomisation shorter in HBO group
• Lost to follow up NBO 12.9 HBO 8.0
• Recovering at 1 month
• NBO 66 HBO 68 p0.75
• gt 90 patients functional at 1 month
• HBO at a low pressure ( 2 vs 2.5-3 atm )
• HBO after gt 6 hours in 50 cases
• Soft outcome measures at 1 month

33
Ducasse et al. - 1995

• Prospective randomised clinical trial of NBO (
  n13 ) vs HBO ( n13 )
• Patients exposed to CO without LOC
• Discovery to admission lt 2 hrs
• NBO O2 100 x 6 hrs, 50 x 6 hrs
• HBO O2 100 2.5 atm x 2 hrs, 100 x 4 hrs, 50
  x 6 hrs

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Ducasse - Results

• Clinical abnormalities at 2 hrs
• reflex impairment, headache, asthenia
• NBO 9 HBO 2 p lt 0.01
• Clinical abnormalities at 12 hrs
• headache, moderate pulmonary edema
• NBO 5 HBO 0 p lt 0.05
• Patients treated with HBO at 3 weeks ( n18 )
• fewer EEG abnormalities abnormalities
• normal reactivity to CO2 on SPECT scans

35
Thom et al. - 1995

• Prospective randomized study NBO ( n32 ) vs HBO
  ( n33 )
• Reffered patients with mild to moderate CO
  poisoning
• no history of LOC
• no cardiac instability
• Outcome delayed neurologic sequelae
• Neither patients nor investigators blinded to
  treatment

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Thom - Interventions

• NBO 100 O2 until all symptoms resolved
• HBO 100 O2 at 2.8 atm x 30 minutes and at 2.0
  atm x 90 minutes
• Treatment given within 6 hours in all cases

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Thom - Results

• NBO 7 / 30 patients ( 23 ) with DNS
• HBO 0 / 30 patients ( 0 ) with DNS
• DNS persisted for a mean of 41 days
• All patients eventually recovered

38
Scheinkestel et al. - 1999

• Randomised controlled double-blind trial
• Referred patients, all severity of poisoning
• Cluster randomisation to HBO ( n104 ) vs NBO (
  n87 )
• 73 with severe poisoning
• Stratified in 4 groups suicide, accidental,
  ventilated, not ventilated
• Psychometric testing 0 and 1 month

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Scheinkestel - Interventions

• All patients had daily txs x 3 days
• 100 O2 daily to everyone between txs
• HBO 100 O2 x 100 min, 60 min at 2.8 atm
• NBO 100 O2 x 100 min at 1.0 atm
• Patients with abnormal clinical evaluation or
  poor psychometric testing had 3 more txs

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Scheinkestel - Results

• HBO patients required more txs
• HBO patients had worse outcome in learning test
• Greater of severely poisoned patients in HBO
  group had a poor outcome at end of tx
• DNS restricted to HBO patients
• No difference if tx lt 4 hours or with accidental
  poisoning

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Scheinkestel - Limitations

• Mean delay to treatment 7.1 hours ( 95 CI
  1.9-26.5 )
• Large number of severily poisoned patients
• 46 had 1 month follow up
• 44 with possibility of co-ingestants
• High proportion of depressed patients
• Baseline O2 100 x 3 days different from other
  studies

42
Weaver et al. - Abstract - 1995

• Undersea Hyperbar Med 1995 22 14
• Reported - Dr K. Olson - October 1st 1999
• Prospective double-blind RCT with 152 patients (
  last update May 1999 )
• No difference in outcome between HBO vs NBO

43
Mathieu et al. - 1996

• Undersea Hyperbar Med 199623 (suppl) 7-8
• Prospective unblinded RCT with 575 non-comatose
  patients
• Randomisation to HBO at 2.5 atm vs NBO
• Time to treatment lt 12 hours
• No difference in outcome at 1 year between HBO vs
  NBO

44
Uncontrolled case series

• Relation suggested between favorable outcome and
  HBO therapy in severe poisoning
• Severely poisoned patients ( comatose ) can have
  a normal outcome without HBO
• Poisoned patients can have a bad outcome despite
  HBO
• Variability in severity, treatment modalities,
  psychometric testing, length of follow up with
  potential for selection bias

45
Classic indications for HBO

• Coma or loss of consciousness
• Neurologic abnormalities
• Cardiovascular dysfunction
• Severe metabolic acidosis
• COHb gt 40
• COHb gt 15

46
Timing of HBO

• Patients treated at gt 6 hours tend to do worse
• delayed CO toxicity 30 vs 19
• mortality 30 vs 14
• Benefit shown as late as 21 days in anecdotal,
  uncontrolled case reports
• Natural history of delayed neurologic toxicity
• mild poisoning 100 resolve at 2 months
• severe poisoning 75 resolve at 1 year

47
Adverse effects of HBO

• Need for transfer to HBO facility with risk of
  deterioration
• Otic barotrauma
• effusion, hemorrahge, TM rupture
• CNS oxygen toxicity seizures
• Epistaxis

48
CO poisoning in pregnancy

• High incidence of neurologic abnormalities and
  stillbirth after CO poisoning
• Fetal Hb binds CO more avidly that Hb A
• CO absorption and elimination slower in fetal
  circulation
• HBO felt to be safe in pregnancy
• No scientifically established role for HBO in
  pregnancy COHb gt 15 suggested

49
Prevention of CO poisoning

• Public education about CO poisoning
• Identification of activities at risk
• Training of workers for proper use of
  propane-powered tools
• Appropriate ventilation of confined places
• Industrial and domestic use of CO detectors
• Reporting to public health services

50
Problems in CO poisoning

• Absence of reliable method to estimate
  prospectively the severity of CO poisoning
• Difficulty in comparing results of studies
  because no staging in severity of disease
• Misleading information and myths are perpetuated
  in the literature
• Making the diagnosis and preventing further
  exposure to CO is too often forgotten