Toxicology Grand Rounds:Carbon Monoxide

Poisoning

Mark Yarema, MD FRCPCPoison and Drug Information Service

Calgary, Alberta

PADIS/Emergency Medicine/Critical Care RoundsJanuary 27, 2011

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/plppodcasts/

Disclosure

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

Cases Intro to CO Pathophysiology Clinical features Diagnosis Management Special presentations:

Misericordia Hospital HBO Unit HBOT Clinics Inc.

Q and A

Outline

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

Case 1

In E.D.: ABG: pH < 6.8 PC02 58, p02 31, HC03 15,

Lactate > 20, COHb 61% ST depression on EKG Another cardiac arrest resuscitated Multiple pressors

PADIS consulted: candidate for HBO?

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 19:29 hours July 3

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

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

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’

Case 2 1:00am: 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?

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

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

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)

Source: The Arizona Republic,November 29, 2000 (Maureen West and Judd Slivka, reporters)

www.coolestspringbreak.com

Deadly houseboatsCO

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

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

Pathophysiology

Pathophysiology

Left shift oxyhemoglobin dissociation curve

Binding to cytochrome oxidase Activation of excitatory amino acids Binding to myoglobin Nitric oxide (NO)

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

www.modernmedicine.com

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

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

Yong-Ling P. Ow, Douglas R. Green, Zhenyue Hao & Tak W. MakNature Reviews Molecular Cell Biology 9, 532-542 (July 2008)

Cytochrome oxidase

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

Myoglobin CO binds with 60X > 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

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

Weaver. NEJM 2009

Simpler version of previous slide Too much CO = Bad

Clinical features of poisoning

Clinical features

Early symptoms very nonspecific Often confused with other illnesses:

Influenza Food poisoning Gastroenteritis Colic

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)

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)

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 (> 24 hours) Age > 36 COHb > 25%*

*Randomized trial data only, not separate NBO patients

Weaver et al. Am J Resp Crit Care Med 2007;176:491-7.

Cardiac

PVC’s and other dysrhythmias Myocardial ischemia Myocardial stunning With CAD, exacerbation of angina and

arrhythmias can occur with COHb < 10%

Acute mortality from CO usually from ventricular arrhythmias

230 pts with moderate/severe poisoning all treated with HBO

Indications for HBO: LOC Seizure Focal neuro deficit Ischemic chest pain Dysrhythmias COHb > 40% COHb> 25% with Hx CV disease, age > 60, Hgb

< 100, exposure > 2 hours

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

Diagnosis History and physical

Mini mental status exam Laboratory tests

CO pulse oximetry COHb / VBG Select patients: EKG, cardiac markers

Imaging CT MRI

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 UCC’s

www.masimo.com

[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

Blood gas Some HBO trials have used lactate >

2.5 or base excess < -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

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

cerebellum

caudate

globus pallidus

www.learningradiology.com

Management ABC’s O2 via nonrebreather

Alters t ½ of COHb 5-6 hours at room air 40-90 minutes on 02 via NRB

Hyperbaric oxygen

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?

Non-blinded, randomized study of 629 adults, Rx within 12 h exposure pregnant women, pts < 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

% 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

Randomized, non-blinded, 65 patients with mild poisoning , <6 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

Incidence of DNS: 23% NBO group, 0% HBO group

Conclusion: HBO decreased incidence of DNS after CO poisoning

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

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

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.

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

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

% 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

> NBO in patients with LOC. 2 HBO treatments associated with worse outcomes.

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 2005;24(2):75-92

HBO-suggested indications* Syncope Altered LOC Coma Seizure Abnormal cerebellar function Age > 36 years Prolonged CO exposure (> 24 hours) COHb > 25%

Missing: myocardial ischemia

Goldfrank’s Toxicologic Emergencies, 2011

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

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

Outcomes

Cardiac arrest patients

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%

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

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)

How to reach us

Poison and Drug Information Service: 403- 944-1414 (Calgary) 1-800-332-1414 (Alberta)

Mark.yarema@albertahealthservices.ca