CO - The Silent Killer

1. CO - The Silent Killer Martin Lalibert� MD FRCP ( C ) ABEM McGill University Centre Anti-Poison du Qu�bec

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 > 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

9. 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- )

10. 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

16. 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

17. 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

18. 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 > 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 < 3 % non-smokers or < 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

26. 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 !

27. 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

28. 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 ( n=170 ) vs HBO ( n=173 ) 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

32. 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 % p=0.75 > 90 % patients functional at 1 month HBO at a low pressure ( 2 vs 2.5-3 atm ) HBO after > 6 hours in 50 % cases Soft outcome measures at 1 month

33. Ducasse et al. - 1995 Prospective randomised clinical trial of NBO ( n=13 ) vs HBO ( n=13 ) Patients exposed to CO without LOC Discovery to admission < 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

34. 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

35. 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 sequelae Neither patients nor investigators blinded to treatment

36. 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

37. 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 ( n=104 ) vs NBO ( n=87 ) 73 % with severe poisoning Stratified in 4 groups : suicide, accidental, ventilated, not ventilated Psychometric testing : 0 and 1 month

39. 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

40. 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 < 4 hours or with accidental poisoning

41. 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 1996;23 (suppl) : 7-8 Prospective unblinded RCT with 575 non-comatose patients Randomisation to HBO at 2.5 atm vs NBO Time to treatment < 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 > 40 % COHb > 15 %

46. 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

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 > 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