Occupational Toxicology & Chemical Asphyxiants Sultana Qureshi, PGY-2 Dr. Ingrid Vicas January 18, 2007

Occupational Occupational Toxicology & Toxicology &

Chemical Chemical AsphyxiantsAsphyxiantsSultana Qureshi, PGY-2Sultana Qureshi, PGY-2

Dr. Ingrid VicasDr. Ingrid Vicas

January 18, 2007January 18, 2007

Bernardino Bernardino Ramazinni Ramazinni (1633-1714)(1633-1714) Considered the father of Occupational MedicineConsidered the father of Occupational Medicine

wrote wrote De Morbis Artificum DiatribaDe Morbis Artificum Diatriba ( (Diseases of Diseases of WorkersWorkers) in 1700 ) in 1700 1st comprehensive text discussing the relationship 1st comprehensive text discussing the relationship

between disease and workplace hazardsbetween disease and workplace hazards

Ramazzini's essential contribution - the addition of Ramazzini's essential contribution - the addition of a question to the medical history:a question to the medical history:

"What occupation does the "What occupation does the patient follow?"patient follow?"

Altogether Ramazzini described diseases Altogether Ramazzini described diseases associated with 54 occupations, incl:associated with 54 occupations, incl: hydrocarbon poisoning in paintershydrocarbon poisoning in painters mercury poisoning in mirror makersmercury poisoning in mirror makers pulmonary diseases in minerspulmonary diseases in miners

Occupational HistoryOccupational HistoryTABLE 118-3. Evidence Supporting Work-Relatedness of Occupational Disease

Known or documented exposure to a causative agent

Symptoms consistent with suspected workplace exposure

Suggested or diagnostic physical signs

Similar problems in coworkers or workers in related occupations

Temporal relationship of complaints related to work

Confirmatory environmental or biologic monitoring data

Scientific biologic plausibility

Absence of a nonoccupational etiology

Resistance to maximum medical treatment because employee continues to be exposed at work

Who was Sir Percivall?Who was Sir Percivall?

Sir Percivall Pott (1714-Sir Percivall Pott (1714-1788)1788)

Hero of Occupational Hero of Occupational ToxicologyToxicology In 1775, Sir Percivall Pott In 1775, Sir Percivall Pott

proposed the first association proposed the first association between workplace exposure between workplace exposure and cancer when he noticed a and cancer when he noticed a high incidence of scrotal cancer high incidence of scrotal cancer in English chimney sweeps.in English chimney sweeps.

Pott's belief that the scrotal Pott's belief that the scrotal cancer was caused by prolonged cancer was caused by prolonged exposure to tar and soot was exposure to tar and soot was confirmed by other investigation confirmed by other investigation in the 1920s, indicating that the in the 1920s, indicating that the polycyclic aromatic polycyclic aromatic hydrocarbons contained in coal hydrocarbons contained in coal tar (including benzo[tar (including benzo[aa]pyrene) ]pyrene) are carcinogenicare carcinogenic

OverviewOverview

Simple AsphyxiantsSimple Asphyxiants Chemical AsphyxiantsChemical Asphyxiants

Carbon MonoxideCarbon Monoxide CyanideCyanide Hydrogen SulfideHydrogen Sulfide

AsphyxiantsAsphyxiants

CaseCase A 50-year-old medical researcher was discovered dead A 50-year-old medical researcher was discovered dead

in a small refrigerated room that contained 10-cubic-in a small refrigerated room that contained 10-cubic-inch blocks of dry ice. Fifteen newly arrived blocks of inch blocks of dry ice. Fifteen newly arrived blocks of dry ice were placed in the refrigerated room (39.2°F dry ice were placed in the refrigerated room (39.2°F [4°C]) at approximately 9 AM on the day of the [4°C]) at approximately 9 AM on the day of the scientist's death. The researcher was last seen at scientist's death. The researcher was last seen at approximately noon, suggesting that at least 3 hours approximately noon, suggesting that at least 3 hours had elapsed between the initial dry ice storage and his had elapsed between the initial dry ice storage and his first exposure. Scene analysis suggested that at the first exposure. Scene analysis suggested that at the time of his death, the decedent was crouching several time of his death, the decedent was crouching several inches from the ground to store samples in a container. inches from the ground to store samples in a container. There were no signs of struggle, and the decedent had There were no signs of struggle, and the decedent had no history of psychiatric disorders, recent personal no history of psychiatric disorders, recent personal crises, or medical illnesses.crises, or medical illnesses.

CaseCase

Differential?Differential? Type of asphyxiant?Type of asphyxiant?

Simple vs. ChemicalSimple vs. Chemical Simple AsphyxiantsSimple Asphyxiants

i.e. CO2, nitrogeni.e. CO2, nitrogen Inert gasesInert gases Produce toxicity by Produce toxicity by

displacing oxygen displacing oxygen and lowering Fio2and lowering Fio2

Exposed patients Exposed patients remain asymptomatic remain asymptomatic if the Fio2 is normalif the Fio2 is normal

Symptoms of hypoxia Symptoms of hypoxia = slower onset = slower onset

Chemical Chemical AsphyxiantsAsphyxiants i.e. CO, CN, H2Si.e. CO, CN, H2S Prevents O2 uptake Prevents O2 uptake

or metabolism by or metabolism by cellscells

Fast onset (e.g. Fast onset (e.g. H2S = suddenly H2S = suddenly pass out)pass out)

Simple AsphyxiantsSimple AsphyxiantsTABLE 119-1. Clinical Findings Associated with Reduction of Inspired

Oxygen

FiO2a Symptoms/signs

21 None

16-12Tachypnea, hyperpnea, (resultant hypocapnia),

tachycardia, reduced attention and alertness, euphoria, headache, mild incoordination

14-10Altered judgment, incoordination, muscular fatigue,

cyanosis

10-6Nausea, vomiting, lethargy, air hunger, severe

incoordination, coma

<6 Gasping respiration, seizure, coma, death

CaseCase 38F c/o vomiting, loose stools, light-38F c/o vomiting, loose stools, light-

headedness, and headacheheadedness, and headache

Her husband had similar symptomsHer husband had similar symptoms

The couple arrived 2 days earlier at a The couple arrived 2 days earlier at a resort town after a 3-hour flight on which resort town after a 3-hour flight on which they ate turkey sandwiches of they ate turkey sandwiches of “questionable quality” “questionable quality”

No sig. PMHx. No Meds. No All.No sig. PMHx. No Meds. No All. No ill contacts or recent travelNo ill contacts or recent travel

Chemical Chemical AsphyxiantsAsphyxiants

Carbon MonoxideCarbon Monoxide

IntroductionIntroduction

Colourless, Odourless, non-irritant gasColourless, Odourless, non-irritant gas Most common cause of acute poisoning death Most common cause of acute poisoning death

in U.S.in U.S. Most common cause of fire-related death Most common cause of fire-related death Generated through incomplete combustion of Generated through incomplete combustion of

virtually all carbon-containing productsvirtually all carbon-containing products Most significant problem is long term Most significant problem is long term

neurologic morbidity (not mortality)neurologic morbidity (not mortality) No existing predictors of poor outcome, so all No existing predictors of poor outcome, so all

exposures need to be treated aggressively with exposures need to be treated aggressively with HBOHBO

Sources of COSources of CO

EndogenousEndogenous Hemolytic AnemiaHemolytic Anemia SepsisSepsis Normal heme Normal heme

catabolismcatabolism

ExogenousExogenous Any hydrocarbon Any hydrocarbon

combustion sourcecombustion source Heating and Heating and

cooking sourcescooking sources Propane (especially Propane (especially

indoor vehicles)indoor vehicles) Smoke inhalationSmoke inhalation Methylene chloride Methylene chloride

(paint solvents)*(paint solvents)* Cigarette smokeCigarette smoke Industrial sourcesIndustrial sources

DiagnosisDiagnosis

Co-oximetry (arterial or venous Co-oximetry (arterial or venous sample)sample) Normal 0-5%Normal 0-5% PPD Smokers 6-10%PPD Smokers 6-10% CO Toxicity >15%CO Toxicity >15%

Etiology of exposure Etiology of exposure (U.S. (U.S. Data)Data)

Suicides = 46%Suicides = 46% Involving fires/burns = 28%Involving fires/burns = 28% Unintentional = 21%Unintentional = 21%

Of Unintentional, most common sources:Of Unintentional, most common sources: Auto exhaust and housefiresAuto exhaust and housefires Of consumer products:Of consumer products:

Indoor heating systems (71%)Indoor heating systems (71%) Stoves and other appliances (10%)Stoves and other appliances (10%) Charcoal grills (9%)Charcoal grills (9%) Camp stoves (8%)Camp stoves (8%) Water heaters (4%)Water heaters (4%)

1988 study

1998 study

TABLE 120-1. Sources of Carbon Monoxide Implicated in Poisonings253

Anesthetic lime absorbents122

Automobiles

Banked blood

Boats36

Camp stoves and lanterns

Charcoal grills77

Coffee roasting173

Gasoline powered equipment (eg, generators, power washers)34

Ice resurfacing machines184

Methylene chloride

Natural gas furnaces

Natural gas water heaters

Natural gas ranges and ovens

Propane powered forklifts70

Underground mine explosions147

Wood pellet storage

From Goldfrank’s Toxicologic Emergencies. 8th Edition

Case Case

71 y/o retired male, smoker71 y/o retired male, smoker Presents ED vague H/A, malaise, Presents ED vague H/A, malaise,

intermittent RSCP with exertionintermittent RSCP with exertion Working in garage restoring chest of Working in garage restoring chest of

drawers for granddaughter going off drawers for granddaughter going off to collegeto college

4 hrs in garage with paint stripper4 hrs in garage with paint stripper Thoughts?Thoughts?

CHR ED CO PoisoningsCHR ED CO Poisonings January - December 2004January - December 2004

Patient Disposition ACH FMC PLC RGH Total

Pronounced dead after arrival (DAA) 0 2 0 1 3

Discharged 1 37 33 30 101

Left against medical advice (AMA) 0 0 0 1 1

Admitted to Critical Care unit (ie. ICU) 0 1 0 1 2

Admitted to other unit 0 4 2 5 11

Transferred to another acute care facility 0 2 0 1 3

Total 1 46 35 39 121

From Dr. Clint Drever’s presentation on CO Poisoning, 2005.

PathophysiologyPathophysiology

Goldbaum et alGoldbaum et al

Dogs breathing 13% CO died within Dogs breathing 13% CO died within 1 hour after achieving COHb levels 1 hour after achieving COHb levels of 54% to 90%of 54% to 90%

Exchange transfusion with blood Exchange transfusion with blood containing 80% COHb to otherwise containing 80% COHb to otherwise healthy dogs resulted in no toxic healthy dogs resulted in no toxic effects despite resultant COHb levels effects despite resultant COHb levels of 57% to 64%of 57% to 64%

Suggesting that CO toxicity is not Suggesting that CO toxicity is not dependent on COHb formation alonedependent on COHb formation alone

Pathophysiology…Pathophysiology…simplifiedsimplified

3 main mechanisms:3 main mechanisms: 1) Formation of COHb1) Formation of COHb

Decreased O2 carrying capacityDecreased O2 carrying capacity Shifts O2 saturation curve to left Shifts O2 saturation curve to left

resulting in less O2 delivery to resulting in less O2 delivery to tissuestissues

2) Cellular Toxin2) Cellular Toxin COHB interacts with myoglobin COHB interacts with myoglobin

= rhabdo= rhabdo COHb inhibits cytochrome in COHb inhibits cytochrome in

mitochondria (like CN) causing mitochondria (like CN) causing switch to anarobic respiration switch to anarobic respiration and cell deathand cell death

Formation of free radicals/NOFormation of free radicals/NO 3) Lipid Peroxidation3) Lipid Peroxidation

Neurological SequelaeNeurological Sequelae(Also combined with hypoxic insult (Also combined with hypoxic insult

and re-perfusion injury)and re-perfusion injury)

PathophysiologyPathophysiology

Clinical FeaturesClinical Features

TABLE 120-2. Clinical Manifestations of Carbon Monoxide Poisoning

Headache Vomiting

Nausea Ataxia

Dizziness Confusion

Weakness Syncope

Chest pain Cardiac dysrhythmias

Dyspnea Myocardial ischemia

Visual blurred Tachypnea


Clinical FeaturesClinical Features Mild CO PoisoningMild CO Poisoning

Non-specific, mild-mod symptomsNon-specific, mild-mod symptoms Headache, flu-like Headache, flu-like

Severe CO PoisoningSevere CO Poisoning Identical to CN poisoningIdentical to CN poisoning ALOC(coma and seizures), extremely abnormal vital signs ALOC(coma and seizures), extremely abnormal vital signs

(hypotension and cardiac arrest), metabolic acidosis (hypotension and cardiac arrest), metabolic acidosis

Delayed Neurologic SequelaeDelayed Neurologic Sequelae Frequency varies from 12% to 50%, Frequency varies from 12% to 50%, Develop neuro abnormalities after 2 to 40 daysDevelop neuro abnormalities after 2 to 40 days 2 Types: 2 Types:

Primarily neurologic syndromesPrimarily neurologic syndromes (ie focal deficits, seizures) (ie focal deficits, seizures) Primarily psychiatric or cognitive findingsPrimarily psychiatric or cognitive findings (e.g., apathy, (e.g., apathy,

memory deficits) memory deficits) Since most patients survive, prevention of delayed Since most patients survive, prevention of delayed

neurologic and neuropsychiatric sequelae is the neurologic and neuropsychiatric sequelae is the predominant goal of therapypredominant goal of therapy

Determinants of Severity of Determinants of Severity of CO IntoxicationCO Intoxication

Inhaled CO concentrationInhaled CO concentration Duration of exposureDuration of exposure Individual susceptibilityIndividual susceptibility

minute ventilationminute ventilation pregnancy (fetal Hb), extremes of agepregnancy (fetal Hb), extremes of age

ComorbidityComorbidity cardiac and pulmonary diseasescardiac and pulmonary diseases

ED COHb not predictiveED COHb not predictive Late changes on CT Head (new lesions Late changes on CT Head (new lesions

after 24 hours)after 24 hours)

DiagnosisDiagnosis

High index of suspicion!!!High index of suspicion!!! Why is pulse oximetry not useful?Why is pulse oximetry not useful? What is co-oximetry?What is co-oximetry? What would you expect on the ABG?What would you expect on the ABG?

Early vs late ABGEarly vs late ABG

DiagnosisDiagnosis

Co-oximetry (arterial or venous Co-oximetry (arterial or venous sample)sample) Normal 0-5%Normal 0-5% PPD Smokers 6-10%PPD Smokers 6-10% CO Toxicity >15%CO Toxicity >15%

NeuroimagingNeuroimaging Acute changes on Acute changes on

CT visible w/i 12 CT visible w/i 12 hours of exposurehours of exposure

Usually appear as Usually appear as lucencies within lucencies within basal gangliabasal ganglia

Findings on CT Findings on CT after 24 hours after 24 hours usually assoc. w/ usually assoc. w/ poor prognosispoor prognosis

ManagementManagement

ABCDsABCDs 100% O2 100% O2 HBOT HBOT Aggressive supportive careAggressive supportive care Consider co-intoxication (ie. CN in Consider co-intoxication (ie. CN in

fire victims)fire victims) Serial neuro/Mini-mental examsSerial neuro/Mini-mental exams

CO Half LifeCO Half Life

TherapyTherapy Half LifeHalf Life

Room AirRoom Air 4 hours4 hours

100 % Oxygen100 % Oxygen 1 hour1 hour

100% HBOT100% HBOT 15 min.15 min.

DispositionDisposition

Duration of treatment is unclearDuration of treatment is unclear Usual guidelines are to treat until Usual guidelines are to treat until

resolution of symptoms (+/- CoHb resolution of symptoms (+/- CoHb <5%)<5%)

Remember mini-mental!Remember mini-mental!

CHR ED CO PoisoningsCHR ED CO Poisonings January - December 2004January - December 2004

Patient Disposition ACH FMC PLC RGH Total

Pronounced dead after arrival (DAA) 0 2 0 1 3

Discharged 1 37 33 30 101

Left against medical advice (AMA) 0 0 0 1 1

Admitted to Critical Care unit (ie. ICU) 0 1 0 1 2

Admitted to other unit 0 4 2 5 11

Transferred to another acute care facility 0 2 0 1 3

Total 1 46 35 39 121

From Dr. Clint Drever’s presentation on CO Poisoning, 2005.

Case Case

71 y/o retired male, smoker71 y/o retired male, smoker Presents ED vague H/A, malaise, Presents ED vague H/A, malaise,

intermittent RSCP with exertionintermittent RSCP with exertion Working in garage restoring chest of Working in garage restoring chest of

drawers for granddaughter going off drawers for granddaughter going off to collegeto college

4 hrs in garage with paint stripper4 hrs in garage with paint stripper Thoughts?Thoughts?

Hyperbaric Oxygen Hyperbaric Oxygen TherapyTherapy

Hyperbaric Oxygen TherapyHyperbaric Oxygen Therapy

Enhanced elimination of COHbEnhanced elimination of COHb Improved tissue oxygenationImproved tissue oxygenation Enhanced dissociation of CO from Enhanced dissociation of CO from

cytochrome oxidasecytochrome oxidase Inhibition of B2 integrin adhesion to Inhibition of B2 integrin adhesion to

vascular endothelium vascular endothelium Prevention of CNS lipid peroxidationPrevention of CNS lipid peroxidation

TABLE 120-3. Summary of Randomized Clinical Trials of Hyperbaric Oxygen in Carbon Monoxide

StudyRaphael19

3 Thom241 Ducasse65

Scheinkestel2

05 Weaver259

N 343 65 26 191 152

Double blind No No No Yes Yes

Syncope (%) 0 0 0 53 53

Suicide (%) 0Unknow

nUnknown 69 31

Treatments 1 1 2 3-6 3

Time to treatment (h)

<12 2 0.2 <2 7.1 5.8 2.9

Lost to followup (%)

10 11 ~35 54 2

Time to followup (mo)

1 1 0.75 1 1.5

HBO benefit No Yes Yes No Yes


Hyperbaric oxygen for carbon monoxide Hyperbaric oxygen for carbon monoxide poisoning.poisoning.

Cochrane Database of Systematic Cochrane Database of Systematic Reviews. 4, 2006.Reviews. 4, 2006.

Existing RCTs provide conflicting resultsExisting RCTs provide conflicting results All have limitations that may threaten and All have limitations that may threaten and

invalidate their conclusionsinvalidate their conclusions Based on trials, HBO cannot routinely be Based on trials, HBO cannot routinely be

recommended for treatment of CO recommended for treatment of CO poisoningpoisoning

Some patients may benefit from treatmentSome patients may benefit from treatment Multicenter, randomized controlled trial Multicenter, randomized controlled trial

neededneeded

DB RCTDB RCT Referred patients, all severity of Referred patients, all severity of

poisoningpoisoning Cluster randomization to HBO Cluster randomization to HBO

( n=104 ) vs NBO ( n=87 )( n=104 ) vs NBO ( n=87 ) Excluded: pregnant, burn pt. & Excluded: pregnant, burn pt. &

childrenchildren 73 % with severe poisoning73 % with severe poisoning Psychometric testing : 0 and 1 monthPsychometric testing : 0 and 1 month

Scheinkestel et al. Med J Aust Scheinkestel et al. Med J Aust 1999;170:203-101999;170:203-10

Daily Rxs x 3 days 60 % O2 daily in Daily Rxs x 3 days 60 % O2 daily in between Rxbetween Rx

HBO :100 % O2 x 60 min at 2.8 atmHBO :100 % O2 x 60 min at 2.8 atm NBO : 100 % O2 x 100 min at 1.0 atmNBO : 100 % O2 x 100 min at 1.0 atm Patients with abnormal clinical Patients with abnormal clinical

evaluation or poor psychometric evaluation or poor psychometric testing had 3 more txs (28% HBOT, testing had 3 more txs (28% HBOT, 15% NBOT)15% NBOT)


Outcomes:Outcomes: neuropsych testing & PE after therapy neuropsych testing & PE after therapy

& at 1/12& at 1/12 HBO patients required more txsHBO patients required more txs HBO patients had worse outcome in HBO patients had worse outcome in

learning testlearning test Greater % of severely poisoned patients Greater % of severely poisoned patients

in HBO group had a poor outcome at in HBO group had a poor outcome at end of txend of tx


Limitations:Limitations:

- Only 46 % had 1 month follow up- Only 46 % had 1 month follow up

- Baseline O2 x 3 days different from other - Baseline O2 x 3 days different from other studiesstudies

- 44 % with possibility of co-ingestants- 44 % with possibility of co-ingestants

- High proportion of depressed/suicidal - High proportion of depressed/suicidal patientspatients

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

-Large number of severely poisoned patients-Large number of severely poisoned patients


Weaver et al. N Engl J Med 2002;347:1057-Weaver et al. N Engl J Med 2002;347:1057-6767

DB RCTDB RCT Patients presenting <24 hours post exposure Patients presenting <24 hours post exposure

with symptoms or elevated COHbwith symptoms or elevated COHb Patients received a total of three treatments of Patients received a total of three treatments of

either HBOT or NBOeither HBOT or NBO HBOT = 60 min at 3.0 ATA, followed by 60 min HBOT = 60 min at 3.0 ATA, followed by 60 min

at 2.0 ATA for the first session, followed by 120 at 2.0 ATA for the first session, followed by 120 min of HBOT at 2.0 ATA 6 to 12 hours apart for min of HBOT at 2.0 ATA 6 to 12 hours apart for two more sessions (two more sessions (nn = 76). = 76).

NBO = 120 to 150 minutes of 100% NBO 6 to 12 NBO = 120 to 150 minutes of 100% NBO 6 to 12 hours apart, administered in the HBOT chamber hours apart, administered in the HBOT chamber (“sham” HBOT) ((“sham” HBOT) (nn = 76). = 76).


Outcomes:Outcomes: Neuropsychometric testing performed after the first Neuropsychometric testing performed after the first

and third treatments, 2 weeks, 6 weeks, 6 months, and and third treatments, 2 weeks, 6 weeks, 6 months, and 1 year 1 year

PE before the first and after the third treatmentsPE before the first and after the third treatments Questionnaires were administered at 2 weeks and 6 Questionnaires were administered at 2 weeks and 6

weeksweeks Cognitive sequelae were diagnosed based on having at Cognitive sequelae were diagnosed based on having at

least one abnormal neuropsychometric subtest at 6 least one abnormal neuropsychometric subtest at 6 weeksweeks

Cognitive sequelae less frequent in the HBO Cognitive sequelae less frequent in the HBO group at 6 weeks (odds ratio 0.39, 95% group at 6 weeks (odds ratio 0.39, 95% confidence interval 0.2–0.78, confidence interval 0.2–0.78, PP = .007) = .007)


Considered the most rigorous and well-Considered the most rigorous and well-controlled study performed to datecontrolled study performed to date

Criticism:Criticism: Small number of intubated patientsSmall number of intubated patients Lack of functional performance as an outcome Lack of functional performance as an outcome

measure (no change in ADLs)measure (no change in ADLs) Increased incidence of cerebellar dysfunction in Increased incidence of cerebellar dysfunction in

the NBO group at randomizationthe NBO group at randomization Choice of neuropsychometric testingChoice of neuropsychometric testing Inclusion of patients with exposure to gases Inclusion of patients with exposure to gases

other than COother than CO Using a nonstandard HBOT protocol Using a nonstandard HBOT protocol

Weaver et al. N Engl J Med Weaver et al. N Engl J Med 2002;347:1057-672002;347:1057-67

In a subgroup analysis, HBOT was In a subgroup analysis, HBOT was found to improve outcome specifically found to improve outcome specifically in patients with loss of consciousness, in patients with loss of consciousness, metabolic acidosis, CO-Hgb level metabolic acidosis, CO-Hgb level greater than 25%, and age older than greater than 25%, and age older than 5050

Number needed to treat to prevent 1 Number needed to treat to prevent 1 negative cognitive sequelae is 5negative cognitive sequelae is 5

TABLE 120-4. Suggested Indications for Hyperbaric Oxygen

Syncope

Coma

Seizure

Altered mental status or confusion

Carboxyhemoglobin >25%

Abnormal cerebellar examination

Fetal distress in pregnancy

Suggested Indications for Suggested Indications for HBOHBO

-Loss of conciousness

-Seizures

-Coma

-Altered mental status

-Neurologic symptoms not resolving after

several hours of oxygen treatment

-Pregnancy

-Persistent cardiac ischemia

-Age > 50 years and COHb > 25%

Possible Future Possible Future TherapiesTherapies

Free radical scavengersFree radical scavengers Monoamine oxidase inhibitorsMonoamine oxidase inhibitors NN-methyl-d-aspartate blockers-methyl-d-aspartate blockers

QuizQuiz Which of the following is Which of the following is NOTNOT true about carbon true about carbon

monoxide?monoxide?

A. It has an affinity 200250 times greater than A. It has an affinity 200250 times greater than oxygen for hemoglobinoxygen for hemoglobin

B. It has an affinity 40 times greater than oxygen B. It has an affinity 40 times greater than oxygen for myoglobinfor myoglobin

C. It is a product of heme degradationC. It is a product of heme degradation

D. It binds to cytochrome oxidaseD. It binds to cytochrome oxidase

E. It causes a rightward shift in the oxyhemoglobin E. It causes a rightward shift in the oxyhemoglobin dissociation curvedissociation curve

QuizQuiz Delayed or persistent neuropsychological Delayed or persistent neuropsychological

sequelae after CO poisoning include:sequelae after CO poisoning include:

A. Memory and learning problemsA. Memory and learning problems

B. Cortical blindnessB. Cortical blindness

C. ParkinsonismC. Parkinsonism

D. IncontinenceD. Incontinence

E. All of the aboveE. All of the above

QuizQuiz All of the following statements are true about All of the following statements are true about

carbon monoxide carbon monoxide EXCEPTEXCEPT::

A. It is denser than airA. It is denser than air

B. It is nonirritatingB. It is nonirritating

C. It is colorlessC. It is colorless

D. It is odorlessD. It is odorless

E. It binds to myoglobinE. It binds to myoglobin

QuizQuiz The elimination half-life of carboxyhemoglobin The elimination half-life of carboxyhemoglobin

with 100% oxygen at room pressure is closest to:with 100% oxygen at room pressure is closest to:

A. 5 hoursA. 5 hours

B. 4 hoursB. 4 hours

C. 2 hoursC. 2 hours

D. 1 hourD. 1 hour

E. 15 minutesE. 15 minutes

QuizQuiz Which of the following is reliably associated with Which of the following is reliably associated with

potential neuropsychological sequelae from potential neuropsychological sequelae from carbon monoxide poisoning?carbon monoxide poisoning?

A. SyncopeA. Syncope

B. HeadacheB. Headache

C. Carboxyhemoglobin (COHb) >20%C. Carboxyhemoglobin (COHb) >20%

D. Metabolic alkalosisD. Metabolic alkalosis

E. None of the aboveE. None of the above

Dr. Alice Hamilton

(1869-1970)“Physician,

Scientist,

Humanitarian,

Social Reformer…”

Alice Hamilton (Alice Hamilton (1869-1869-1970)1970)

First female professor at Harvard Medical SchoolFirst female professor at Harvard Medical School ““A Woman on Harvard Faculty—The Last Citadel Has A Woman on Harvard Faculty—The Last Citadel Has

Fallen—The Sex Has Come Into Its Own,"Fallen—The Sex Has Come Into Its Own," – New York – New York Tribune 1919Tribune 1919

Only woman member of League of Nations Health Only woman member of League of Nations Health CommitteeCommittee

Conducted groundbreaking studies of many Conducted groundbreaking studies of many different occupational exposures and problems, different occupational exposures and problems, CO poisoning in steelworkersCO poisoning in steelworkers Mercury poisoning in hattersMercury poisoning in hatters Wrist drop in lead workersWrist drop in lead workers

Her overriding concerns about these "dangerous Her overriding concerns about these "dangerous trades" and her commitment to improve the health trades" and her commitment to improve the health of workers would lead to extensive voluntary and of workers would lead to extensive voluntary and regulatory reforms in the workplace regulatory reforms in the workplace

CaseCase

25F – victim of housefire25F – victim of housefire GCS 9, Burns to face and 15% of GCS 9, Burns to face and 15% of

torsotorso V: 100/60, 95, 25, 100% on NRBV: 100/60, 95, 25, 100% on NRB Management?Management? Specific therapies?Specific therapies?

Chemical Chemical AsphyxiantsAsphyxiantsHCN & HCN &

H2SH2S

IntroductionIntroduction(Hydrogen Cyanide)(Hydrogen Cyanide)

Many commercial uses, particularly in synthetic fiber Many commercial uses, particularly in synthetic fiber manufacture and fumigation (also capital punishment)manufacture and fumigation (also capital punishment)

Odour of bitter almonds Odour of bitter almonds

In salt form (e.g. NaCN, KCN) is much safer (low In salt form (e.g. NaCN, KCN) is much safer (low volatility) & important in jewelry and photographic volatility) & important in jewelry and photographic industries industries

However, if salts dissolved in water, HCN can leave However, if salts dissolved in water, HCN can leave the surface, particularly under acidic conditionsthe surface, particularly under acidic conditions

Cyanide is generated in vivo from precursors Cyanide is generated in vivo from precursors (cyanogens) in some fruits(cyanogens) in some fruits

IntroductionIntroduction(Hydrogen Sulfide)(Hydrogen Sulfide)

Rotten eggs odourRotten eggs odour Olfactory fatigueOlfactory fatigue Sources:Sources:

Oil industry Oil industry Decaying organic material Decaying organic material

manure pitmanure pit SwampsSwamps SewersSewers

MinesMines AsphaltAsphalt Volcanic LakesVolcanic Lakes

Lake Nyos Disaster 1986Lake Nyos Disaster 1986 Limnic Eruption Limnic Eruption

on August 21, on August 21, 1986 in Cameroon1986 in Cameroon

2000 locals died 2000 locals died (w/i 20 km radius)(w/i 20 km radius)

5 degassing vents 5 degassing vents needed, and only needed, and only 1 built since1 built since

Pathophysiology (HCN)Pathophysiology (HCN)

HCN rapidly absorbed once inhaled HCN rapidly absorbed once inhaled and binds to complex 4 of the electron and binds to complex 4 of the electron transport chain in the mitochondriatransport chain in the mitochondria

Poisoned tissue rapidly depletes ATP Poisoned tissue rapidly depletes ATP stores and cannot regeneratestores and cannot regenerate

Eventually pushed into anaerobic Eventually pushed into anaerobic metabolism and then cell deathmetabolism and then cell death

Does not affect other O2 systems (i.e. Does not affect other O2 systems (i.e. Hb)Hb)

Pathophysiology (H2S)Pathophysiology (H2S)

Same as HCN, however H2S has a Same as HCN, however H2S has a more rapid sponatneous dissociation more rapid sponatneous dissociation from the mitochondria, therefore from the mitochondria, therefore allows victim to survive after brief allows victim to survive after brief exposureexposure

Also a pulmonary irritantAlso a pulmonary irritant

Clinical FeaturesClinical Features Tissue hypoxia occurs within seconds to minutesTissue hypoxia occurs within seconds to minutes

Dysfunction of the heart & CNS, manifesting as coma, Dysfunction of the heart & CNS, manifesting as coma, seizures, cardiovascular collapse, and severe metabolic seizures, cardiovascular collapse, and severe metabolic acidosisacidosis

Given extreme toxicity of CN, mild acute poisoning is Given extreme toxicity of CN, mild acute poisoning is uncommonuncommon

Acute H2S poisoning has similar features, although many pts Acute H2S poisoning has similar features, although many pts are recovering on arrival to EDare recovering on arrival to ED

““Arterialization” of bloodArterialization” of blood

Mild H2S symptoms also include: local tissue irritation (esp. Mild H2S symptoms also include: local tissue irritation (esp. eyes, lungs, GI), “gas eye” or keratoconjunctivitis – resolve eyes, lungs, GI), “gas eye” or keratoconjunctivitis – resolve spontaneouslyspontaneously

Long-term neuro sequelae similar to CO poisoning in Long-term neuro sequelae similar to CO poisoning in survivorssurvivors

DiagnosisDiagnosis

Based on clinical suspicion of Based on clinical suspicion of exposureexposure

ABGs show AG-MA secondary to ABGs show AG-MA secondary to lactatelactate

Lactate >10 in fire victim strongly Lactate >10 in fire victim strongly suggestive of CNsuggestive of CN

Serum tests for HCN or H2S too Serum tests for HCN or H2S too slow for use in EDslow for use in ED

ManagementManagement

ABCsABCs Aggressive supportive measuresAggressive supportive measures DecontaminationDecontamination Specific antidotes empiricallySpecific antidotes empirically

CaseCase A 60-year-old man with a history of untreated A 60-year-old man with a history of untreated

hypertension presented to the ED complaining of chest hypertension presented to the ED complaining of chest pain. The diagnosis of aortic dissection was confirmed, pain. The diagnosis of aortic dissection was confirmed, and the patient was started on nitroprusside and and the patient was started on nitroprusside and esmolol to control his blood pressure, which on esmolol to control his blood pressure, which on presentation was 220/130 mm Hg. As his aortic presentation was 220/130 mm Hg. As his aortic dissection was distal, medical rather than surgical dissection was distal, medical rather than surgical management was provided, and his blood pressure was management was provided, and his blood pressure was reduced to 170/80 mm Hg while receiving 200 mg/min reduced to 170/80 mm Hg while receiving 200 mg/min of a nitroprusside infusion. After 2 days of continuous of a nitroprusside infusion. After 2 days of continuous medical therapy in the ICU, the patient became medical therapy in the ICU, the patient became confused, although his level of consciousness was confused, although his level of consciousness was normal. His arterial blood pH was 7.35, his PCO2 was normal. His arterial blood pH was 7.35, his PCO2 was 37 mm Hg, his lactate concentration was minimally 37 mm Hg, his lactate concentration was minimally elevated, and his renal function was modestly abnormal.elevated, and his renal function was modestly abnormal.

TABLE 121-1. Cyanide Poisoning: Emergency Management Guidelines

When to suspect cyanide

Sudden collapse of laboratory or industrial worker

Fire victim with coma or acidosis

Suicide with unexplained coma or acidosis

Ingestion of artificial nail remover

Ingestion of seeds or pits from Prunus species

ICU patient with altered mental status, acidosis, and tachyphylaxis to nitroprusside

Supportive care

Control airway, ventilate, and give 100% oxygen

Crystalloids and vasopressors for hypotension

Administer NaHCO3; titrate according to ABG and serum HCO3

HCN ManagementHCN Management

Cyanide Antidote KitCyanide Antidote Kit Exact mechanism of kit is Exact mechanism of kit is

controversialcontroversial Basic goal of antidote is to reactivate Basic goal of antidote is to reactivate

the cytochrome oxidase system by the cytochrome oxidase system by providing an alternative, high-providing an alternative, high-affinity source of ferric ions (Fe3+) affinity source of ferric ions (Fe3+) for cyanide to bind for cyanide to bind

CN KitCN Kit

Kit has 3 componentsKit has 3 components Amyl nitrite pearls (provider caution)Amyl nitrite pearls (provider caution) IV sodium nitrite (300mg IV over 2-4 IV sodium nitrite (300mg IV over 2-4

min)min) Monitor for hypotensionMonitor for hypotension

Sodium thiosulfate (12.5g IV)Sodium thiosulfate (12.5g IV)

Mechanism is to create methemoglobin

Mechanism is to provide sulfur to elimiate cyanomethemoglobin

(only use this in fire victims!!)

Mechanism of Mechanism of DetoxificationDetoxification

Peds TreatmentPeds Treatment

TABLE 121-2. Cyanide Management: Pediatric Nitrite Guidelinesa

Hemoglobin (g) NaNO2 (mg/kg)3% NaNO2 solution

(mL/kg)

7.0 5.8 0.19

8.0 6.6 0.22

9.0 7.5 0.25

10.0 8.3 0.27

11.0 9.1 0.30

12.0 10.0 0.33

13.0 10.8 0.36

14.0 11.6 0.39aPediatric thiosulfate dose: 1.65 mL/kg of 25% solution. Adapted, with

permission, from Berlin CM: The treatment of cyanide poisoning in children. Pediatrics 1976;46:793-796.

Other AntidotesOther Antidotes

France = Vitamin B12France = Vitamin B12 Germany = 4-DMAPGermany = 4-DMAP UK = Cobalt saltsUK = Cobalt salts Solutions A & B (ferrous sulphate & Solutions A & B (ferrous sulphate &

citric acid in aqueous HCO3)citric acid in aqueous HCO3)

RasputinRasputinMagically immune to CN??Magically immune to CN??

H2S AntidoteH2S Antidote

Usually removal from exposure and Usually removal from exposure and ventilatory support adequate since ventilatory support adequate since H2S rapidly spontaneously H2S rapidly spontaneously dissociatesdissociates

Nitrites not indicatedNitrites not indicated

CaseCase Three male coworkers at a dye manufacturing plant Three male coworkers at a dye manufacturing plant

inadvertently mixed two chemicals. One employee, inadvertently mixed two chemicals. One employee, not wearing his respirator, was immediately overcome not wearing his respirator, was immediately overcome and collapsed. A second employee removed his and collapsed. A second employee removed his respirator to call for help and also succumbed. The respirator to call for help and also succumbed. The third employee fled the area to seek help, leaving his third employee fled the area to seek help, leaving his respirator in place. The two collapsed employees were respirator in place. The two collapsed employees were safely evacuated by appropriately protected rescuers. safely evacuated by appropriately protected rescuers. EMS arrived and intubated both patients, who were EMS arrived and intubated both patients, who were apneic. A weak carotid pulse of 110-120 beats/min apneic. A weak carotid pulse of 110-120 beats/min was obtained in both patients and an ECG monitor was obtained in both patients and an ECG monitor recorded a sinus tachycardia en route to the recorded a sinus tachycardia en route to the emergency department.emergency department.

CaseCase On arrival in the emergency department, the physical On arrival in the emergency department, the physical

examinations of both patients were remarkably examinations of both patients were remarkably similar. Vital signs on one patient revealed a blood similar. Vital signs on one patient revealed a blood pressure of 170/108 mm Hg; heart rate of 120 pressure of 170/108 mm Hg; heart rate of 120 beats/min; mechanical ventilation on an FiO2 100% at beats/min; mechanical ventilation on an FiO2 100% at 24 breaths/min, and a temperature of 99°F (37.2°C). 24 breaths/min, and a temperature of 99°F (37.2°C). Head and neck were atraumatic with 3-mm pupils Head and neck were atraumatic with 3-mm pupils and pink mucous membranes. Heart and lung and pink mucous membranes. Heart and lung examination was significant for clear breath sounds examination was significant for clear breath sounds without wheezing or crackles. The skin color was without wheezing or crackles. The skin color was normal, without cutaneous burns, and was well normal, without cutaneous burns, and was well perfused. A carboxyhemoglobin concentration was perfused. A carboxyhemoglobin concentration was 4% and an ABG on 100% oxygenwas pH 7.37; PCO2, 4% and an ABG on 100% oxygenwas pH 7.37; PCO2, 32 mm Hg; and PO2, 242 mm Hg. The chest 32 mm Hg; and PO2, 242 mm Hg. The chest radiograph was normal radiograph was normal

CaseCase

1. What is the differential diagnosis for 1. What is the differential diagnosis for these patients symptoms?these patients symptoms?

2. How does this exposure typically 2. How does this exposure typically occur?occur?

3. What are the expected clinical effects 3. What are the expected clinical effects following exposure to this xenobiotic?following exposure to this xenobiotic?

4. What treatment is indicated?4. What treatment is indicated?

TABLE 121-3. Hydrogen Sulfide Poisoning

When to suspect hydrogen sulfide poisoning

Person rapidly loses consciousness ("knocked down")

Rotten eggs odor

Rescue from enclosed space, such as sewer or manure pit

Multiple victims with sudden death syndrome

Collapse of a previously healthy worker at work site

Clinical Manifestations

System Signs and Symptoms

Cardiovascular Chest pain, bradycardia

Central nervousHeadache, weakness, dysequilibrium,

convulsions, coma

Gastrointestinal Pharyngitis, nausea, vomiting

Ophthalmic Conjunctivitis

Pulmonary Dyspnea, cyanosis, hemoptysis, crackles

TABLE 121-4. Hydrogen Sulfide Poisoning: Emergency Management

Supportive care

Prehospital

Attempt rescue only if using SCBA

Move victim to fresh air

Administer 100% oxygen

During extrication, consider traumatic injuries from falls

Apply ACLS protocols as indicated

Emergency department

Maximize ventilation and oxygenation

Consider PEEP for ALI

Treat acidosis based on arterial pH and serum bicarbonate analysis

Administer crystalloid and vasopressors for hypotension

Antidote

Give sodium nitrite (3% NaNO2) IV over 2-4 minutes

Adult dose: 10 mL (300 mg)

Pediatric dose: see Table 121-2

Caution:

Monitor blood pressure frequently

Obtain methemoglobin level 30 minutes after dose

Consider HBO if immediately available

Nitrite Rx in H2S toxicity - Nitrite Rx in H2S toxicity - evidenceevidence

Few case reports onlyFew case reports only Stine RJ. Slosberg B. Beacham BE. Stine RJ. Slosberg B. Beacham BE. HydrogenHydrogen sulfidesulfide

intoxication. A case report and discussion of treatment. intoxication. A case report and discussion of treatment. Annals of Internal Medicine. 85(6):756-8, 1976 Dec.Annals of Internal Medicine. 85(6):756-8, 1976 Dec.

Hall AH. Rumack BH. Hall AH. Rumack BH. HydrogenHydrogen sulfidesulfide poisoning: an poisoning: an antidotal role for sodium nitrite?. antidotal role for sodium nitrite?. Veterinary & Human Veterinary & Human Toxicology. 39(3):152-4, 1997 Jun.Toxicology. 39(3):152-4, 1997 Jun.

Huang CC. Chu NS. A case of acute Huang CC. Chu NS. A case of acute hydrogenhydrogen sulfidesulfide (H2S) intoxication successfully treated with (H2S) intoxication successfully treated with nitritesnitrites..Taiwan i Hsueh Hui Tsa Chih - Journal of the Taiwan i Hsueh Hui Tsa Chih - Journal of the Formosan Medical Association. 86(9):1018-20, 1987 Sep.Formosan Medical Association. 86(9):1018-20, 1987 Sep.

Not indicated.

HBOTHBOT

Limited studies with conflicting Limited studies with conflicting results in both treatment of CN and results in both treatment of CN and H2SH2S

More evidence in support in More evidence in support in situation of co-toxicity of CO and CNsituation of co-toxicity of CO and CN

Only indicated in severe cases if Only indicated in severe cases if available immediately as a adjunct to available immediately as a adjunct to other therapiesother therapies

DispositionDisposition

Most cases require admission to ICU Most cases require admission to ICU for monitoringfor monitoring

Will need long term neuropsychiatric Will need long term neuropsychiatric evaluationevaluation

QuizQuiz Which of the following is/are adverse effects of Which of the following is/are adverse effects of

nitrite administration?nitrite administration?

A. RhabdomyolysisA. Rhabdomyolysis

B. Hair lossB. Hair loss

C. Diminished PO2C. Diminished PO2

D. HypotensionD. Hypotension

E. Red, flushed skinE. Red, flushed skin

QuizQuiz What is the most likely clinical manifestation What is the most likely clinical manifestation

following exposure to cyanide gas?following exposure to cyanide gas?

A. Ventricular tachycardiaA. Ventricular tachycardia

B. HematemesisB. Hematemesis

C. ConvulsionsC. Convulsions

D. Abdominal painD. Abdominal pain

E. CyanosisE. Cyanosis

QuizQuiz A person survives severe cyanide poisoning, but A person survives severe cyanide poisoning, but

over a period of several days the patient develops over a period of several days the patient develops bradykinesia and a tremor. What area of the brain bradykinesia and a tremor. What area of the brain is likely to be abnormal on CT imaging of this is likely to be abnormal on CT imaging of this patient?patient?

A. Vermis of cerebellumA. Vermis of cerebellum

B. Basal gangliaB. Basal ganglia

C. Reticular activating systemC. Reticular activating system

D. Frontal loves of the cerebral cortexD. Frontal loves of the cerebral cortex

E. Temporal loves of the cerebral cortexE. Temporal loves of the cerebral cortex

QuizQuiz Which of the following physiologic manifestations Which of the following physiologic manifestations

is consistent with cyanide poisoning?is consistent with cyanide poisoning?

A. Lowered central venous oxygen saturationA. Lowered central venous oxygen saturation

B. Normal gap metabolic acidosisB. Normal gap metabolic acidosis

C. HypoglycemiaC. Hypoglycemia

D. HypophosphatemiaD. Hypophosphatemia

E. Elevated blood lactateE. Elevated blood lactate

QuizQuiz Which of the following is Which of the following is NOTNOT a potential source a potential source

of cyanide poisoning?of cyanide poisoning?

A. Incomplete combustion of nitrogen-containing A. Incomplete combustion of nitrogen-containing organic compoundsorganic compounds

B. Ingestion of acrylonitrileB. Ingestion of acrylonitrile

C. Apricot seed ingestionC. Apricot seed ingestion

D. Nitroprusside therapyD. Nitroprusside therapy

E. Burning of woodE. Burning of wood

QuizQuiz Which of the following is a source of Which of the following is a source of

hydrogen sulfide?hydrogen sulfide?

A. Decomposition of grain in silosA. Decomposition of grain in silos

B. Incomplete combustion of silkB. Incomplete combustion of silk

C. Combination ammonia and hypochloriteC. Combination ammonia and hypochlorite

D. SewersD. Sewers

E. Mercury refiningE. Mercury refining

QuizQuiz Which of the following is Which of the following is NOTNOT a common clinical a common clinical

manifestation of hydrogen sulfide poisoning?manifestation of hydrogen sulfide poisoning?

A. Ocular painA. Ocular pain

B. DiarrheaB. Diarrhea

C. Acute lung injuryC. Acute lung injury

D. Respiratory paralysisD. Respiratory paralysis

E. Metabolic acidosisE. Metabolic acidosis

Take Home PointsTake Home Points

Documents

Occupational Toxicology & Chemical Asphyxiants Sultana Qureshi, PGY-2 Dr. Ingrid Vicas January 18, 2007