CO - The Silent Killer Martin Laliberté MD FRCP ( C ) ABEM McGill University Centre Anti-Poison du...

CO - The Silent Killer

Martin Laliberté MD FRCP ( C ) ABEM

McGill University

Centre Anti-Poison du Québec

Case study - Mrs B.

40 year old female presenting after a syncopal episode at home

Headache, nausea, dizziness x 2 weeksLives in a condominium building downtownHeard the alarm of the CO detector installed in

her apartment ( 100 - 150 ppm )

Incidence of CO poisoning

Leading cause of poisoning mortalityMost common cause of death in combustion

related inhalation injury1000 to 2000 deaths / year ( USA )Difficult diagnosis

incidence of unrecognized cases higher estimated > 42 000 visits / year ED visit rate 16.5 / 100 000 population

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

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

Pathophysiology - Tissue hypoxia

Binding to Hb to form COHbHb affinity for CO 250 times affinity for O2Effect on oxyHb dissociation curve

left shift, distortion of shape

Impaired release of oxygen at tissue levelIncreased minute ventilation with subsequent

increased CO uptake

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

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 perfusionIschemic reperfusion injury

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- )

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

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

Severity of CO intoxication

Inhaled CO concentrationDuration of exposureIndividual susceptibility

minute ventilation pregnancy

Presence of systemic illnesses cardiac and pulmonary diseases

Initial COHb not predictive

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

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

Shimazu et al. ( 2000 )

CO elimination : two-compartment modelShort 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

Delayed or persistent CO toxicity

Persistent : present from exposureDelayed : 2 to 40 days post-exposureDementia, psychosis, memory deficitParkinsonism, paralysis, choreaPersonnality changes, gait disturbanceCortical blindness, apraxia, agnosiaPeripheral neuropathy, urinary incontinence

Delayed or persistent CO toxicity

Reported neurologic impairment varies widely between 3 % and 44 %

Reported at 10 % to 30 % at 1 yearNeuropsychologic deficits often subtleCan be identified by psychometric testing Spontaneous recovery

mild poisoning : 100 % resolve at 2 months severe poisoning : 75 % resolve at 1 year

Delayed CO toxicity

Lesions of cerebral white matter globus pallidus, cerebellum, hippocampus perivascular injury with blood flow abnormalities

Often associated with LOC in acute phaseHypotension is essential to cause white matter

lesions in animal modelPatients > 30 year old more susceptible to

delayed CO toxicity

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

Clinical evaluation

Maintain a high level of suspicionHistory of exposure can be absentCOHb

< 3 % non-smokers or < 10 % in smokers not predictive of outcome correlation with symptoms useless

ABG : metabolic acidosis ( lactate )ECG : ischemia, arrythmias

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

Neurologic evaluation

Neurologic examinationMental status examination

Folstein

Psychometric testing CO Neuropsychological Screening Battery

Neuroradiologic imaging : CT, MRI

Psychometric testing

Lack of standardized methodsNormalisation 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 ?

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 exposureSusceptibility of individual to CO

Case study - Mrs B.

Patient is given O2 100 % on arrivalHBO facility is contacted for consultationBased on the history of LOC and persistent

confusion, transfer for admission is advisedPatient receives 4 treatments of HBO

Management of CO poisoning

Identify the source to correct the problemDomestic 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 !

Case study - Mrs B.

Case reported to public healthHigh CO concentrations measured in buildingTwo other cases diagnosed in building

needing treatmentInvestigation identifies serious flaws in

ventilation system in the basement garage and inadequate CO dectors

Management of CO poisoning

Oxygen 100 % ASAPABGCOHbECGCXRCardiac enzymesCardiac monitoring

Hyperbaric oxygen therapy

Enhanced elimination of COHbImproved tissue oxygenationEnhanced dissociation of CO from

cytochrome oxidaseInhibition of B2 integrin adhesion to vascular

endothelium Prevention of CNS lipid peroxydation

HBO vs NBO studies

Isolated case reportsUncontrolled clinical observationsStudies

small non-randomized unblinded assessment of outcome incomplete assessment of outcome

Raphael et al. - 1989

Prospective randomised clinical trial of NBO ( n=170 ) vs HBO ( n=173 )

Patients without LOC admitted within 12 hours of CO exposure

NBO : 6 hrs of NBO O2HBO : 2 hrs of O2 at 2.0 atm, 4 hrs of NBOEvaluation at 1 month : interview, telephone

Raphael - Results

Time to randomisation shorter in HBO groupLost to follow up : NBO 12.9 % HBO 8.0 %Recovering at 1 month

NBO 66 % HBO 68 % p=0.75

> 90 % patients functional at 1 monthHBO at a low pressure ( 2 vs 2.5-3 atm )HBO after > 6 hours in 50 % casesSoft outcome measures at 1 month

Ducasse et al. - 1995

Prospective randomised clinical trial of NBO ( n=13 ) vs HBO ( n=13 )

Patients exposed to CO without LOCDiscovery to admission < 2 hrsNBO : O2 100 % x 6 hrs, 50 % x 6 hrsHBO : O2 100 % 2.5 atm x 2 hrs, 100 % x 4

hrs, 50 % x 6 hrs

Ducasse - Results

Clinical abnormalities at 2 hrs reflex impairment, headache, asthenia NBO 9 HBO 2 p < 0.01

Clinical abnormalities at 12 hrs headache, moderate pulmonary edema NBO 5 HBO 0 p < 0.05

Patients treated with HBO at 3 weeks ( n=18 ) fewer EEG abnormalities abnormalities normal reactivity to CO2 on SPECT scans

Thom et al. - 1995

Prospective randomized study NBO ( n=32 ) vs HBO ( n=33 )

Reffered patients with mild to moderate CO poisoning no history of LOC no cardiac instability

Outcome : delayed neurologic sequelaeNeither patients nor investigators blinded to

treatment

Thom - Interventions

NBO : 100 % O2 until all symptoms resolvedHBO : 100 % O2 at 2.8 atm x 30 minutes and

at 2.0 atm x 90 minutesTreatment given within 6 hours in all cases

Thom - Results

NBO : 7 / 30 patients ( 23 % ) with DNSHBO : 0 / 30 patients ( 0 % ) with DNSDNS persisted for a mean of 41 daysAll patients eventually recovered

Scheinkestel et al. - 1999

Randomised controlled double-blind trialReferred patients, all severity of poisoningCluster randomisation to HBO ( n=104 ) vs

NBO ( n=87 )73 % with severe poisoningStratified in 4 groups : suicide, accidental,

ventilated, not ventilatedPsychometric testing : 0 and 1 month

Scheinkestel - Interventions

All patients had daily txs x 3 days100 % O2 daily to everyone between txsHBO :100 % O2 x 100 min, 60 min at 2.8

atmNBO : 100 % O2 x 100 min at 1.0 atmPatients with abnormal clinical evaluation or

poor psychometric testing had 3 more txs

Scheinkestel - Results

HBO patients required more txsHBO patients had worse outcome in learning

testGreater % of severely poisoned patients in HBO

group had a poor outcome at end of txDNS restricted to HBO patientsNo difference if tx < 4 hours or with accidental

poisoning

Scheinkestel - Limitations

Mean delay to treatment 7.1 hours ( 95 % CI 1.9-26.5 )

Large number of severily poisoned patients46 % had 1 month follow up44 % with possibility of co-ingestantsHigh proportion of depressed patientsBaseline O2 100 % x 3 days different from other

studies

Weaver et al. - Abstract - 1995

Undersea Hyperbar Med 1995 ; 22 : 14Reported - Dr K. Olson - October 1st 1999Prospective double-blind RCT with 152

patients ( last update May 1999 )No difference in outcome between HBO vs

NBO

Mathieu et al. - 1996

Undersea Hyperbar Med 1996;23 (suppl) : 7-8Prospective unblinded RCT with 575 non-

comatose patientsRandomisation to HBO at 2.5 atm vs NBOTime to treatment < 12 hoursNo difference in outcome at 1 year between

HBO vs NBO

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

Classic indications for HBO

Coma or loss of consciousnessNeurologic abnormalitiesCardiovascular dysfunctionSevere metabolic acidosisCOHb > 40 %COHb > 15 %

Timing of HBO

Patients treated at > 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

Adverse effects of HBO

Need for transfer to HBO facility with risk of deterioration

Otic barotrauma effusion, hemorrahge, TM rupture

CNS oxygen toxicity : seizuresEpistaxis

CO poisoning in pregnancy

High incidence of neurologic abnormalities and stillbirth after CO poisoning

Fetal Hb binds CO more avidly that Hb ACO absorption and elimination slower in fetal

circulationHBO felt to be safe in pregnancyNo scientifically established role for HBO in

pregnancy : COHb > 15 % suggested

Prevention of CO poisoning

Public education about CO poisoningIdentification of activities at riskTraining of workers for proper use of propane-

powered toolsAppropriate ventilation of confined placesIndustrial and domestic use of CO detectorsReporting to public health services

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