Toxicology-PHAR 610

Dr. Lama Faddoul

Dr. Rania El Majzoub

Lebanese International University

School of Pharmacy- Spring 2024-2025
PART II
1
 Chapter 7: Carbon
Monoxide Poisoning

2
Introduction
Carbon monoxide (CO) is one
of the most common causes of
fatal poisoning in the U.S

Either intentional (suicidal) or

accidental exposure

CO is a colorless, odorless,
nonirritating gas

Created by incomplete burning

of carbonaceous fossil fuels

3
Introduction
Mild CO poisoning often:
◦ Masquerades as nonspecific headache
◦ Misdiagnosed as viral illness

Moderate to severe CO poisoning produces:

◦ Significant morbidity (e.g., delayed neurologic
dysfunction)
◦ Mortality

4
Exposure
Vehicular emissions were the major source of
carbon monoxide poisoning in adults
◦ Rates have declined by 80% since the introduction of the
catalytic converter in 1975

In recent years, nonvehicular sources have

become more common

Peak incidence occurs in the fall and winter

months
Generally due to increased use of space heaters,
wood-burning stoves, charcoal burning for heat without
adequate ventilation in enclosed areas

5
Exposure
Sources of Carbon Monoxide
Automotive exhaust
Motorboat exhaust
Propane-fueled heaters
Wood- or coal-burning stoves or heaters
Structure fires
Gasoline-powered generators or motors
Natural gas–powered heaters/furnaces/generators
Methylene chloride
Forklifts

6
Exposure
CO is the most toxic component in smoke
inhalation and is a major contributor to
fire-related deaths

Cigarette smoke contains 3-6% CO

Pipes and Cigars contain 15% CO

One other source for CO poisoning is methylene

chloride
◦ Found in varnishes and paint strippers
◦ Routes of exposure are inhalational or by ingestion
◦ Metabolized in the liver to carbon monoxide causing
toxicity in the absence of ambient CO

7
Pharmacokinetics
CO uptake and elimination occur through the lungs

A small amount of CO is metabolized by oxidation to

carbon dioxide

CO diffusion through the alveoli is rapid and

complete → the amount of CO dissolved in arterial
blood is directly related to the concentration of CO in
the air of the patient’s environment

Whole-body equilibrium may be reached after 4 to 6

hours of exposure

8
Pharmacokinetics
The amount of CO absorbed by the body
depends on:
◦ Ambient air CO and oxygen concentrations
◦ Minute ventilation
◦ Duration of exposure

The elimination of CO in room air (21% oxygen)

ranges from 249 - 320 minutes (~ 4-5 hours)

Administration of 100% oxygen shortens the

elimination half-life to:
◦ 47 - 80 minutes at normal atmospheric pressure
◦ 20 minutes at 2.5 to 3 atmospheric pressure

9
Pathophysiology
CO is normally present in air at 10 parts per
million (ppm) or less

The U.S. Occupational Health and Safety

Administration (OSHA) set a permissible
exposure level of CO:
◦ 50 ppm averaged over an 8-hour shift

Toxicity generally begins at ambient levels of

100 ppm

10
Pathophysiology
CO is an endogenous substance

Produced in the body during normal

breakdown of heme

Normal physiologic blood CO (COHb) levels

from this process are:
◦ ~1% in healthy nonsmokers
◦ ~10% in smokers
◦ Levels are somewhat higher in pregnant women,
infants, and patients with hemolytic anemia

11
Pathophysiology
CO enters the body through
the lungs, where it binds to
hemoglobin with an affinity
200-240 times that of oxygen

Approximately 85% of CO is
bound to hemoglobin to form
COHb

The rest is dissolved in

plasma or bound
intracellularly, often to
myoglobin

12
Pathophysiology
Once CO binds to the heme moiety of hemoglobin, it greatly
diminishes the ability of the other three oxygen binding sites to
off-load oxygen to peripheral tissues.
Deformation and leftward shift of the oxyhemoglobin dissociation
curve, and compounds the impairment in tissue oxygen delivery

Hemoglobin and mitochondrial effects of carbon monoxide 13

Pathophysiology
COHb does not
provide oxygen
delivery to the cells
As COHb levels
increase, relative
anemia and
hypoxia occur

Furthermore, CO
shifts the
oxyhemoglobin
dissociation curve
to the left
impairing oxygen
release to the
tissues

14
Pathophysiology
Like hemoglobin, myoglobin has a greater affinity
for CO 60 times than it does for oxygen

CO inhibits intracellular cytochrome oxidase,

interfering with cellular respiration and ATP
generation
◦ This results in a relative uncoupling of oxidative
phosphorylation and produces lactic acidosis

CO also causes endothelial dysfunction and

vasodilatation through the release of guanylate
cyclase and nitric oxide

15
Pathophysiology
CO–induced nitric oxide release:
◦ Cytotoxic effects
◦ Contribute to hypotension

The combination of relative hypoxia and

hypotension can cause ischemia-reperfusion
injury in cardiac myocytes, as well as neuronal
tissue

The damaged endothelium will attract

neutrophils and trigger an inflammatory cascade
resulting in lipid peroxidation and, ultimately,
neuronal cell death

16
Clinical Manifestation
The clinical Signs and Symptoms of Acute Carbon
presentation of CO Monoxide Poisoning
poisoning is highly Headache
variable, which leads Visual disturbances
to misdiagnosis in
Vomiting
many cases
Confusion
Ataxia
The lack of any fixed Dyspnea/tachypnea
set of signs or
symptoms for CO Seizure
poisoning → a strong ECG changes/dysrhythmias
clinical suspicion Syncope
remains the best Retinal hemorrhage
initial method of Chest pain
detection Bullous skin lesions
Focal neurologic deficit

17
Clinical Manifestation
Neurologic sequelae:
◦ May develop at the time of CO poisoning and
continue (persistent neurologic sequelae)

◦ May develop after an asymptomatic interval of 3 to

21 days (delayed neurologic sequelae, or DNS)

◦ DNS is commonly described as:

● Memory loss, confusion, ataxia, incontinence
● Emotional lability, hallucinations, personality changes
● Blindness, and parkinsonism

18
Clinical Manifestation
The severity of poisoning is
the product of the
concentration of CO and the
length of the exposure % COHb Signs & Symptoms
< 10% Asymptomatic
Mild CO poisoning: 10-20% Headache, nausea, dizziness,
headaches, dizziness,
nausea, and vomiting and confusion may develop

> 40% Coma and seizures

Moderate – severe
poisoning: the patient may > 60% Fatal
develop chest pain,
dyspnea, syncope, severe
headache, ataxia, mental
confusion, seizures, coma
and death

19
 Diagnosis
1. Carbon monoxide oximetry:
◦ The diagnosis of CO poisoning is best
made by measuring COHb levels in the
blood
● Standard pulse oximetry
(SpO2) CANNOT screen for CO exposure,
as it does not differentiate
carboxyhemoglobin from oxyhemoglobin

◦ CO oximetry is the only accurate

measurement tool because obtaining free
plasma carbon monoxide is rarely feasible

◦ Levels do not necessarily correlate with

severity of poisoning Effect of
carboxyhemoglobin
◦ Levels > 50% can be fatal on measured oxygen
◦ Levels < 15% → don’t require medical
intervention saturation by pulse
oximetry

20
Diagnosis
A CO-oximeter
is a blood gas
analyzer that
measures:
◦ Oxyhemoglobin
◦ Deoxygenated
hemoglobin
◦ Methemoglobin
◦ COHb as a
percentage of
the total
hemoglobin in
the blood
sample

21
Diagnosis
2. Arterial blood gases:
◦ Routine ABG analyzers without co-oximetry calculate, rather
than measure the saturation

◦ Will not differentiate or identify the contribution of

dyshemoglobinemias to total saturation

◦ As a result, the oxygen saturation may appear artificially high

in routine blood gas analysis

3. Other laboratory tests:

◦ Elevated lactate from the interference in the electron
transport chain
◦ Unexplained elevated anion gap metabolic acidosis
◦ Elevated creatine kinase (rhabdomyolysis)
◦ Elevated troponin

22
Diagnosis
4. ECG findings:
◦ May range from entirely normal to ST elevation
myocardial infarction
◦ There is no classic "carbon monoxide" ECG pattern

5. Radiographic imaging:
◦ Generally of limited utility
◦ CT scan may show lesions in the globus pallidus
● Specifically associated with severe CO poisoning
● Generally bilateral and symmetric

23
Management
Supportive
Oxygen
Hyperbaric oxygen therapy

24
Supportive
Immediate removal from the contaminated
environment is critical

Oxygen

Intravenous access and cardiac monitoring

Correct tissue hypoxemia and hypovolemia

Manage complications such as pulmonary edema

, myocardial infarction , acute renal failure, and
seizures

25
Oxygen
The antidote for CO poisoning is oxygen

Indicated in cases of COHb > 15%

Treat with high-flow oxygen using a non-rebreather

mask (70-90% O2)

Comatose patients should receive 100% oxygen via

endotracheal tube

Consider intubation with administration of 100%

oxygen for:
◦ Conscious patients with COHb levels > 20% who have
symptoms of ischemia, arrhythmia, or acidosis

26
Oxygen
Oxygen therapy is:
◦ Safe
◦ Inexpensive
◦ Convenient and greatly improves the rate of CO
elimination

The 4-hour duration of therapy is chosen for

practicality and because it allows even the
most severely poisoned patients (i.e.,COHb >
40%) to eliminate CO to negligible levels
(<<5%)

27
Hyperbaric Oxygen (HBO)
Is the medical administration
of oxygen within a pressure
chamber at a level higher than
that of atmospheric pressure
by 2 – 3 times

HBO is reasonably safe

More expensive

Less convenient than

administration of normobaric
oxygen, particularly if transfer
to another facility is required

28
Hyperbaric Oxygen (HBO)
HBO enhances the elimination of CO and
increases the amount of oxygen dissolved in
plasma

Increases tissue clearance of residual CO

Reduces cerebral edema

Reduces cytochrome oxidase inhibition

29
Hyperbaric Oxygen (HBO)

30
Hyperbaric Oxygen (HBO)
Before referral or transport for HBO, the
patient needs to be clinically stable:
◦ Secured airway
◦ Stable hemodynamic parameters

Complications related to HBO include:

◦ Pneumothorax
◦ Barotrauma to the ears
◦ Seizures from oxygen toxicity (usually with
prolonged or multiple treatments)
◦ Gas embolism

31
Disposition
Victims of CO poisoning can be released from
the hospital:

◦ After 4 to 6 hours of oxygen therapy (whether NBO

or a combination of HBO)

◦ If they are:
● Neurologically normal
● Have no more than mild symptoms
● Have no unmet medical or psychiatric needs

32
Disposition
Symptom Severity Disposition Comments

Minimal or no Home Assess safety issues.

symptoms
Headache Home after symptom Administer 100% oxygen in
resolution ED.
Vomiting Observe 4 h.
Elevated carbon Assess safety issues.
monoxide level
Ataxia, seizure, Hospitalize Administer 100% oxygen in
syncope, chest pain, ED.
focal neurologic deficit, Consult with CO level, comorbid
dyspnea, ECG changes hyperbaric specialist conditions—including
pregnancy—and age; stability of
the patient must be considered if
considering transfer for
hyperbaric oxygen
33
Special Population
Children:
◦ May be more susceptible to the effects of CO due
to:
● A higher percentage of fetal hemoglobin
● Higher metabolic rates
◦ The indications for pediatric referral are similar to
those for adults
◦ HBO has been used in children with a good safety
profile

34
Special Population
Pregnant:
◦ Should be referred to a hyperbaric center for COHb
levels of 15% or greater

◦ Fetal morbidity has been demonstrated at lower levels

than usual due to the high affinity of carbon monoxide
for fetal hemoglobin

Elderly:
◦ Particularly those with serious comorbid disease, are
also at higher risk from CO poisoning

◦ In patients with known coronary artery disease, even

low levels of COHb (4% to 6%) can cause ECG changes
and myocardial ischemia

35
Prevention
Advising the public about:
◦ Dangers of using wood- or coal-burning appliances
to heat their homes during the winter
◦ Use of adequate ventilation
◦ Reviewing warning signs and symptoms of carbon
monoxide is of primary importance

A relatively inexpensive preventative measure

is the use of CO detectors in the home

36
Algorithm

37
Algorithm (cont’d)

38
Chapter 8: Nitrate
and Nitrite
Intoxication

39
Introduction
Nitrates and Nitrites are powerful oxidizing agents, they are two

of the most common methemoglobin-forming compounds.

Symptoms of Nitrate/Nitrite poisoning are similar regardless of

the nature of the causative poison.

Ingested nitrates are reduced to nitrites by bacteria in the

gastrointestinal (GI) tract (especially in infants) and then can be
absorbed, ultimately leading to methemoglobin production.

40
Introduction

41
Sources
Well water: Nitrogen-based fertilizers and nitrogenous
waste from animal and human sources may
contaminate shallow rural wells.

Food: such as cauliflower, carrots, spinach,

and broccoli have high nitrate content, as do
preservatives in meat products such as hot dogs and
sausage.

Pharmaceuticals: Nitroglycerin (glyceryl trinitrate) and

organic nitrates are more effectively absorbed through
mucous membranes and intact skin than from the GI
tract. They are assumed to form methemoglobin in vivo
by metabolic chemical conversion to some active
intermediates.

42
Drugs Causing
Methemoglobinemia
Oxidant Comments Nitrates/nitrites

Analgesics
Amyl nitrite Cyanide antidote kit and
Phenazopyridine Commonly reported used to enhance sexual
encounters
Phenacetin Rarely used

Antimicrobials
Isobutyl nitrite Used to enhance sexual
Antimalarials Common encounters
Dapsone Hydroxylamine
metabolite formation is
inhibited by cimetidine Sodium nitrite Cyanide antidote kit

Local anesthetics Ammonium nitrate Cold packs

Benzocaine Most commonly reported Silver nitrate Excessive topical use

of the local anesthetics

Nitroglycerin Rare
Lidocaine Rare

Prilocaine Common in topical Sulfonamides

anesthetics

Sulfamethoxazole Uncommon
Dibucaine Rare

43
Mechanism of toxicity
The two major toxicologic concerns resulting from
Nitrate poisoning:
1. Cardiovascular collapse
2. Methemoglobinemia

44
Cardiovascular collapse
Nitrates produce intense vasodilation.
◦ The heart would compensate for the effects of venous pooling and
decreased blood pressure through baroreceptor stimulation and reflex
sympathomimetic activation.

◦ At toxic blood concentration of nitrates, the heart is unable to respond

to sympathetic stimulation which will lead to cardiovascular collapse.

Patients might experience:

◦ Headache
◦ Palpitations
◦ Tachycardia
◦ Hypotension, shock

45
Methemoglobinemia
The iron moiety within deoxyhemoglobin normally exists in the ferrous
(bivalent or Fe2+) state.

Ferrous iron avidly interacts with compounds seeking electrons, such

as oxygen or other oxidizing agent, and in the process is oxidized to the
ferric (trivalent or Fe3+) state.

Hemoglobin in the ferric form is unable to bind oxygen for transport and
is termed methemoglobin.

Under normal circumstances, <1% to 2% of circulating hemoglobin exists

as methemoglobin; higher concentrations define the condition
of methemoglobinemia.

46
Methemoglobinemia

As a result of this oxidation reaction ,

dried arterial blood will have a
chocolate brown appearance which is
characteristic for Methemoglobinemia.

Note the chocolate brown color of

methemoglobinemia. Tube 1 and tube 2 have a
methemoglobin concentration of 70 percent;
tube 3, a concentration of 20 percent; and tube
4, a normal concentration.

47
Methemoglobinemia
Methemoglobin accumulation is enzymatically prevented by the rapid
reduction of the ferric iron back to the ferrous form.

Cytochrome b5 reductase is primarily responsible for this reduction, in

which reduced nicotinamide adenine dinucleotide donates its electrons to
cytochrome b5, which subsequently reduces methemoglobin to
hemoglobin.
◦ This pathway is responsible for reducing nearly 95% of methemoglobin produced
under typical circumstances.

Methemoglobinemia occurs when this enzymatic reduction is

overwhelmed by an exogenous oxidant stress, such as a drug or chemical
agent.

48
Methemoglobinemia

49
Methemoglobinemia
Methemoglobin can also be reduced by a second enzymatic
pathway using the reduced form of nicotinamide adenine
dinucleotide phosphate (or NADPH) and
NADPH-methemoglobin reductase.

This pathway is normally of minimal importance and is

responsible for less than 5% of total reduction under typical
circumstances.
◦ Explains why patients with glucose-6-phosphate dehydrogenase
deficiency with a resultant deficiency in NADPH are not at
increased risk of developing methemoglobinemia

However, this enzyme and pathway are crucial for the

antidotal effect.

50
Clinical features
Healthy patients who have normal hemoglobin
concentrations do not usually develop clinical effects until
the methemoglobin level rises above 20% of the total
hemoglobin.

At methemoglobin levels between 20% and 30%:

◦ Anxiety
◦ Headache
◦ Weakness, and light-headedness
◦ Patients may exhibit tachypnea and sinus tachycardia

Methemoglobin levels of 50% to 60%

impair oxygen delivery to vital tissues, resulting in:
◦ Myocardial ischemia
◦ Dysrhythmias
◦ Depressed mental status (including coma), seizures
◦ Lactate-associated metabolic acidosis.

51
Clinical features
Levels above 70% are largely incompatible with
life.

Cyanosis associated with methemoglobin is often

described as a gray discoloration of skin,
◦ with a detection threshold for methemoglobin of 1.5
grams/dL, corresponding to methemoglobin levels
between 10% and 15% in a nonanemic individual.

Methemoglobin levels above 20% will discolor the

blood a chocolate brown.

52
Methemoglobinemia in infants
Nitrate induced methemoglobinemia is of special
concern in infants for 3 reasons:

1.Fetal hemoglobin is more susceptible to oxidation to

methemoglobin than is adult hemoglobin because
methemoglobin reductase enzyme system lacks full activity
until approximately 4 months of age.

2. The gastric pH of infants is less acidic compared to

children and adults
Normally , when gastric pH is low ,microorganisms such as E
coli which convert nitrate to its toxic form nitrite are
retarted. When less acid is present , bacteria will proliferate.

53
Methemoglobinemia in
infants
3. Infants have an incompletely developed hepatic
microsomal enzyme. Absorbed nitrite is not
metabolized in the liver to its inactive form as rapidly
as older children and adults.

"blue-baby" syndrome!!

54
Diagnosis
Whenever cyanosis is present and persists after administration of
oxygen, methemoglobinemia is suspected.
◦ Cyanosis may be a manifestation of methemoglobin concentration as low as
10%.
◦ Source for the oxidant stress should be sought.

Arterial blood gas sampling may reveal blood with a characteristic

chocolate brown color.

The fractional saturation of the different hemoglobin species must be

determined by co-oximetry.

55
Management of methemoglobinemia
1. Assess airway, breathing, and circulation; exclude other causes
of cyanosis
2. Insert an IV line
3. Administer oxygen
4. Attach the patient to a cardiac and pulse oximeter or
co-oximeter
5. Obtain an ECG
6. Decontaminate the patient as needed
7. Administer methylene blue: if symptomatic or methemoglobin
>25%
8. Consider: cimetidine for patients taking dapsone
9. The offending agent should also be identified and removed.

56
Management of methemoglobinemia

In lesser degrees of methemoglobinemia (ie, an

asymptomatic patient with a methemoglobin level <20
percent)
No therapy other than discontinuation of the offending agent(s)
may be required

Because reduction of the methemoglobin will occur by normal

reconversion mechanisms (NADH methemoglobin reductase).

Patients with symptomatic and severe degrees of

methemoglobinemia should be managed in the ICU

57
Management of methemoglobinemia
Methylene blue:
◦ Specific antidote for methemoglobinemia
◦ It is a dye that serves as an intermediate in electron transfer
between methemoglobin reductase and methemoglobin.
◦ A reversal of the toxic events of methemoglobinemia should be
noted within 1 hour of initiation of methylene blue therapy.
◦ In patients with methemoglobin less than 25% , treatment
consists of removing the offending agent and if necessary giving
oxygen 100%.

58
Management of methemoglobinemia

Methylene blue:
◦ 1-2 mg/kg of methylene blue infused intravenously (IV) over 5
minutes
◦ This is 0.1 to 0.2 mL/kg of 1% solution.
◦ The use of a slow 5-minute infusion helps prevent painful local
responses from rapid infusion.

◦ Clinical improvement should be noted within minutes of

methylene blue administration (rapidly reduces toxic levels of
methemoglobin to non-toxic levels (eg, <10 percent) within 10
to 60 minutes)

◦ If cyanosis has not disappeared within 1 hour of the infusion, a

second dose should be given and other factors considered
◦ Larger dose of methylene blue can cause methemoglobinemia.

◦ Doses greater than 15mg/kg are associated with hemolysis.

59
Other therpaies
Exchange transfusion or hyperbaric oxygen (HBO) may
be beneficial when methylene blue is ineffective (severe
cases).

◦ Both interventions are time consuming and costly, but HBO

allows the dissolved oxygen time to protect the patient while
endogenous methemoglobin reduction occurs.

Ascorbic acid is not indicated in the management of

acquired methemoglobinemia if methylene blue is
unavailable because the rate at which ascorbic acid
reduces methemoglobin is considerably slower than the
rate of normal intrinsic mechanisms.

◦ Ascorbic acid may be helpful in settings of suspected or proven G6PD

deficiency

60
61
Chapter 9: Cyanide
and Sulfide
Intoxication

62
Introduction
Cyanide is among the most rapidly lethal poisons
known to man.

Used in both ancient and modern times as a method of

execution, cyanide causes death within minutes to
hours of exposure.

Though significant cyanide poisoning is uncommon, it

must be recognized rapidly to ensure prompt
administration of life-saving treatment.

Cyanide can be a salt, a liquid or a gas.

63
Sources of cyanide
exposure
Industrial sources
◦ Insecticides
◦ Photographic solutions
◦ Metal polishing materials
◦ Jewelry cleaners
◦ Acetonitrile
◦ Electroplating materials
◦ Synthetic products such as rayon, nylon, polyurethane foam, insulation,
and adhesive resins

Natural sources
◦ Seeds and fruit pits of Prunus species (eg, apple seeds and cherry and
apricot pits)

Environmental sources
◦ Smoke inhalation in closed-space fires

Iatrogenic sources
◦ Sodium nitroprusside infusion

64
Toxicokinetics
Cyanide is rapidly absorbed through the respiratory tract and mucous
membranes
◦ Also through the gastrointestinal tract and skin.

The most rapidly acting cyanide compound is readily volatilized to

hydrogen cyanide, producing the characteristic odor of bitter almond.
Oral or transdermal ingestion may produce a delay in signs and
symptoms as concentrations increase in the bloodstream
Cyanide salts are most frequently encountered of all cyanide containing
compounds.
LD50 of salts is 2mg/kg.
Ingestion of 50-75 mg produces syncope, respiratory distress in few
minutes.

65
Pathophysiology
Cyanide is highly lethal because it
diffuses into tissues and binds to target
sites within seconds.

The primary mechanism of cyanide

excretion is formation of thiocyanate
within the liver.

Rhodanese catalyzes the conversion of

cyanide to thiocyanate
◦ Thiocyanate is then excreted via the kidneys

This mechanism is overwhelmed by high

doses of cyanide in acute poisoning or in
patients with decreased kidney function

66
Pathophysiology
The toxicity of cyanide is largely attributed to the
cessation of aerobic cell metabolism.
◦ Cyanide causes intracellular hypoxia by reversibly binding to
the cytochrome oxidase a3 within the mitochondria.

◦ Cytochrome oxidase a3 is necessary for the reduction of

oxygen to water in the fourth complex of oxidative
phosphorylation.

◦ Binding of cyanide to the ferric ion in cytochrome oxidase a3

inhibits the terminal enzyme in the respiratory chain and halts
electron transport and oxidative phosphorylation.

◦ This downward cascade is fatal if not reversed.

67
68
Clinical presentation
Clinical features of cyanide poisoning are dependent upon:
◦ Route, duration, and amount of exposure

69
Delayed complications
Survivors of severe cyanide poisoning may develop
delayed-onset Parkinsonism or other neurologic
sequelae.

The basal ganglia in particular are sensitive to

cyanide toxicity.

CT scan and MRI of the brain may demonstrate

radiologic changes several weeks after the
exposure.

70
Laboratory evaluation
Specific testing — Specific testing in cases of potential
cyanide poisoning should also include the following:

Basic chemistries (Na+, Cl-, K+, HCO3-) and arterial

blood gas to assess for anion gap metabolic acidosis

Serum lactate to confirm lactic acidosis

Central venous blood gas, if possible, to assess

venous-arterial PO2 gradient

Carboxyhemoglobin and methemoglobin levels

(measured by co-oximetry), particularly if there is
any concern for concomitant carbon monoxide
exposure (eg, house or vehicle fire) or exposure to
drugs that produce methemoglobinemia.

71
Laboratory evaluation
Cyanide level — Whole-blood cyanide concentration (for later
confirmation only)

◦ Antidotal treatment must be administered as soon as possible,

based on the clinical presentation.

◦ Blood cyanide levels may also be unreliable, as testing requires

proper storage conditions and must be prompt.

• Blood cyanide levels of 0.5 to 1 mg/L correlate

with tachycardia/flushing
• 1 to 2.5 mg/L with obtundation
• 2.5 to 3 mg/L with coma
• Greater than 3 mg/L with death

72
Diagnosis
Cyanide poisoning is an uncommon entity.

Making the diagnosis requires that the clinician maintain a high

index of suspicion based on history and clinical presentation.

When a clear history is unavailable, clinicians should consider any

patient with altered mental status and a metabolic acidosis of
unknown etiology a possible cyanide poisoning.

When to suspect cyanide

• Sudden collapse of laboratory or industrial worker
• Fire victim with coma or academia
• Suicide with unexplained coma or acidemia
• Ingestion of artificial nail remover
• Ingestion of seeds or pits from Prunus species
• Patient with altered mental status, acidemia, and tachyphylaxis to nitroprusside

73
Differential diagnosis
• Due to cyanide's wide range of possible symptoms and signs,
the clinician must consider a number of potential diagnoses

• A patient with altered • Patient who suddenly

mental status, seizures, collapsed after exposure to
hypotension, and lactic a gas may be poisoned
acidosis may be poisoned with:
with:
– Carbon monoxide
– Tricyclic antidepressants – Hydrogen sulfide gas
– Isoniazid – Phosphine
– Organophosphates – Arsine
– Salicylates – Asphyxiants (eg, methane)
– Methemoglobin producing – Also, exposure to cyanogen
– Strychnine chloride can mimic exposure
to any chemical irritant (eg,
chlorine)

74
Management
Untreated, cyanide poisoning is rapidly lethal.

If clinical history and examination are suggestive of

cyanide poisoning, antidotal therapy must be given
immediately, barring any contraindications.

75
Resuscitation
First, clinicians must stabilize the patient's airway, breathing, and circulation.

The patient's airway should be secured as necessary and high-flow oxygen

should be given, regardless of pulse oximetry readings.

◦ Mouth-to-mouth resuscitation is contraindicated in cyanide poisoning due to the risk

of exposure to the provider of cardiopulmonary resuscitation (CPR)

Seizures should be treated with benzodiazepines.

Comorbid conditions and concurrent exposures are treated as necessary.

Supportive care

• Control airway, ventilate, and give 100% oxygen

• Crystalloids and vasopressors for hypotension
• Administer sodium bicarbonate; titrate according to ABG and serum HCO3

76
Decontamination
Patients poisoned by cyanide through inhalation or topical exposure must be

rapidly removed from the source, and their clothing taken off and

appropriately discarded.

In dermal exposures, wounds must be cleansed with soap and water to

prevent further absorption.

Rescuers should wear protective suits and respirators until proper

decontamination is completed.

GID should be performed rapidly in cases of oral ingestion, as cyanide is

quickly absorbed.

◦ SDAC should be administered (50 g in adults; 1 g/kg, up to 50 g maximum, in children).

◦ Orogastric lavage is not recommended.

● It may be attempted only if ingestion occurred within 60 minutes of presentation and a large amount of
cyanide is thought to be present in the upper gastrointestinal tract

77
Antidotes
Clinical history and examination are suggestive of
cyanide poisoning, antidotal therapy must be given
immediately, barring any contraindications.

Antidotal treatment of cyanide poisoning involves

three strategies:
1. Binding of cyanide
2. Induction of methemoglobinemia
3. Use of sulfur donors

78
Direct cyanide binding
Hydroxocobalamin:

◦ A precursor of vitamin B12, contains a cobalt moiety that avidly binds to

intracellular cyanide (with greater affinity than cytochrome oxidase)
forming cyanocobalamin

◦ This molecule is stable, with few side effects, and is readily excreted in the
urine.

◦ The dose is 70 mg/kg (typical adult dose is 5 g) given intravenously (IV).

This dose is effective for the majority of adult patients

◦ A second half-dose may be given depending upon the severity of poisoning

or the clinical response to treatment

◦ Although optimum pediatric dosing is not well established, some

recommend 70 mg/kg IV (maximum dose 5 g)
◦ The half-life is 24 to 48 hours.

79
Direct cyanide binding
Hydroxycobalamin is commonly used in
conjunction with sodium thiosulfate, a combination
shown to be effective and safe in severe cyanide
poisoning

Hydroxycobalamin side effects:

◦ Transient hypertension and slowing of the heart rate
◦ Temporary reddish discoloration of the skin, plasma, urine,
and mucous membranes
● These changes last for approximately two to three days, altering the
laboratory values of colorimetric tests (eg, serum creatinine, serum
aspartate aminotransferase (AST), bilirubin, and magnesium)

80
Direct cyanide binding
Hydroxycobalamin side effects: cont’d

◦ IV infusion of hydroxycobalamin appears to interfere

with co-oximetry measurements of total hemoglobin,
carboxyhemoglobin, methemoglobin, and
oxyhemoglobin

◦ This may complicate the assessment of smoke

inhalation victims (who may suffer from both cyanide
and carbon monoxide poisoning) if hydroxocobalamin is
administered before blood is obtained for co-oximetry

81
Direct cyanide binding
Dicobalt edetate:
◦ An intravenous chelator of cyanide, with a rapid onset of
action

◦ The dose is 20 mL of a 1.5 percent solution given over

one minute. It is associated with multiple severe side
effects including seizures, anaphylactic shock,
hypotension, and cardiac dysrhythmias

◦ It is administered only when the diagnosis of cyanide is

nearly certain and alternative treatments are unavailable

82
Induction of
methemoglobinemia
The formation of methemoglobin entails the oxidation of the
ferrous (Fe2+) moiety in hemoglobin to the ferric (Fe3+) form.

This provides an attractive alternative binding site for cyanide,

in direct competition with the site on the cytochrome complex

When cyanide binds methemoglobin, a relatively less toxic

cyanomethemoglobin is formed.

The induction of
methemoglobinemia
is accomplished by
the administration of:
1. Amyl nitrite
2. Sodium nitrite
3. Dimethylaminophenol

83
Induction of
methemoglobinemia
Amyl nitrite:
◦ The ampules are crushed and then inhaled by the
patient (either from under the patient's nose or via the
endotracheal tube) for 30 seconds of each minute

◦ Thirty second pauses allow for adequate oxygenation

during treatment

◦ Amyl nitrite induces only a 5 percent

methemoglobinemia, and is thus only a temporizing
measure

◦ It may be used when intravenous access is unavailable,

such as in the prehospital setting

84
Induction of
methemoglobinemia
Sodium nitrite
◦ 300 mg (or 10 mg/kg) is administered intravenously, inducing a 15
to 20 percent methemoglobinemia

◦ This level of methemoglobinemia is easily tolerated by most

patients

◦ However, methemoglobin shifts the oxygen-hemoglobin

dissociation curve to the left further hindering oxygen delivery to
tissues

◦ A decreased dose is required for children weighing less than 25 kg

and patients with anemia

◦ A 20 to 30 percent level of methemoglobinemia, the goal of

cyanide treatment in the average adult patient, may be lethal in
children or anemic patients, who have little reserve

85
Induction of
methemoglobinemia
Patients receiving nitrites may develop hypotension and
tachycardia

Arthralgias, myalgias, vomiting, and psychosis may also

occur.

Nitrites should be avoided in pregnant women.

In addition to inducing a methemoglobinemia, nitrites

may provide benefit by causing vasodilation.

Nitrites release nitrous oxide , a vasodilator, leading to

increased blood flow to the liver and other organs,
thereby enhancing the metabolism of cyanide.

86
Induction of
methemoglobinemia
Dimethylaminophenol (4-DMAP):
◦ An agent introduced in Germany, is another inducer of
methemoglobin.

◦ 4-DMAP is given in a dose of 5 mL of a 5 percent solution

IV over one minute.

◦ It is potent and rapidly acting, achieving peak levels of

methemoglobin within five minutes of administration.

◦ The potency of 4-DMAP, which can require methylene blue

to reverse the extent of methemoglobinemia, is
problematic.
● Methylene blue should be avoided in the setting of cyanide
poisoning because its use can release free cyanide.

◦ Other potential adverse effects: reticulocytosis,

nephrotoxicity, and hemolysis

87
Induction of
methemoglobinemia
Of special note, patients who are victims of fires
may be suffering from both carbon monoxide and
cyanide toxicity.

Carboxyhemoglobin causes the

oxygen-hemoglobin dissociation curve to be shifted
to the left creating tissue hypoxia.

In these patients, the induction of

methemoglobinemia could be lethal

88
Sulfur donors
A third antidotal strategy involves:

◦ Maximizing the availability of sulfur donors for

rhodanese, a ubiquitous enzyme that detoxifies
cyanide by transforming it to thiocyanate

◦ Thiocyanate is then renally excreted

89
Sulfur donors
Sodium thiosulfate:
◦ Is the therapeutic sulfur donor of choice

◦ In theory, a 3:1 ratio of Sodium thiosulfate to cyanide is required

for complete detoxification

◦ The standard adult dose of sodium thiosulfate is 50 mL of a 25

percent solution, or 12.5 g

◦ The onset of action may be slow (up to 30 minutes)

◦ Because thiocyanate levels of 10 mg/dL or higher may cause

psychosis, arthralgias, vomiting, and myalgias, patients with renal
failure may require hemodialysis to remove it from the blood
stream
◦ In most patients sodium thiosulfate is safe and well tolerated.

90
Pediatric Considerations
The epidemiology and clinical manifestations
of acute cyanide for children and adults are
similar

Hydroxycobalamin, the preferred treatment

for cyanide intoxication, is considered safe in
children.

Although optimum pediatric dosing is not

well established, some recommend 70 mg/kg
IV.

91
Treatment guidelines
For patients in locations For patients without contraindication to
where hydroxocobalamin is available, it is nitrites, in locations
the preferred treatment and we where hydroxocobalamin is not available,
recommend: we recommend the Cyanide Antidote Kit, if
•Sodium thiosulfate AND available, which consists of the following
•Hydroxocobalamin three medications:
•Amyl nitrite inhaled
•Sodium nitrite AND
•Sodium thiosulfate

For patients with contraindications to In locations where 4-dimethylaminophenol

nitrites or with smoke inhalation (pending (4-DMAP) or dicobalt edetate is available,
test results for carboxyhemoglobin), in and there are no contraindications to either
locations where hydroxocobalamin is not drug, and neither hydroxocobalamin nor
available: the Cyanide Antidote Kit is available:
•Sodium thiosulfate only •4-DMAP
•If 4-DMAP is unavailable and the diagnosis is clear,
dicobalt edetate ONLY if cyanide poisoning is highly
suspected or confirmed

92
 Chapter 9- Part II:
Sulfide Intoxication

93
Introduction
Hydrogen sulfide (H2S) exposures are often dramatic and
can be fatal.
Most often, serious consequences of hydrogen sulfide
exposures occur through workplace exposures but are also
implicated in environmental disasters and most recently in
suicides.
Hydrogen sulfide is a major industrial hazard in oil and gas
production, particularly in sour gas fields (natural gas
containing sulfur).
Decay of sulfur-containing products such as fish, sewage,
and manure also produces hydrogen sulfide.
Natural sources of hydrogen sulfide are volcanoes, caves,
sulfur springs, and underground deposits of natural gas
Many died while working in confined spaces.

94
Toxicokinetics
Hydrogen sulfide is a colorless gas, more dense
than air, with an irritating odor of "rotten eggs.“

It is highly lipid soluble, a property that allows

easy penetration of biologic membranes.

Systemic absorption usually occurs through

inhalation, and it is rapidly distributed to tissues.

95
Pathophysiology
The tissues most sensitive to hydrogen sulfide are those
with high oxygen demand (CNS and respiratory)

The systemic toxicity of hydrogen sulfide results from its

potent inhibition of cytochrome oxidase, thereby
interrupting oxidative phosphorylation.
◦ Hydrogen sulfide binds to the ferric (Fe3+) moiety of cytochrome a3
oxidase complex with a higher affinity than does cyanide.

◦ The resulting inhibition of oxidative phosphorylation produces cellular

hypoxia and anaerobic metabolism.

96
Pathophysiology
Other enzymes, such as carbonic anhydrase and
monoamine oxidase, are inhibited by hydrogen
sulfide and may contribute to its toxic effects.

It alters brain neurotransmitter release and

transmission through potassium
channel—mediated hyperpolarization of neurons
and other neuronal inhibitory mechanisms.

A proposed mechanism of death is poisoning of

the brainstem respiratory center through selective
uptake by lipophilic white matter in this region.

97
Pathophysiology
The olfactory nerve is a specific target of
great interest.
◦ Not only does the toxic gas cause olfactory nerve
paralysis but it is also thought to be a portal of
entry into the CNS because of its direct contact
with the brain.

The eyes and nasal and respiratory mucous

membranes are the tissues most
susceptible to direct injury.
◦ Hydrogen sulfide reacts with the moisture on the
surface of mucous membranes to produce
intense irritation and corrosive injury, it has little
dermal absorption.

98
When to suspect hydrogen sulfide poisoning
Rapid loss of 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, sudden cardiac
arrest
Central nervous Headache, weakness, syncope, convulsions,
rapid onset of coma

Gastrointestinal Nausea, vomiting

Ophthalmic Conjunctivitis
Pulmonary Dyspnea, cyanosis, crackles, apnea

Metabolic Metabolic acidosis

99
Chronic intoxication
Mucous membrane irritation seems to be the most prominent problem in
patients with low-concentration exposures.
◦ Workers report nasal, pharyngeal, and eye irritation; fatigue; headache; dizziness;
and poor memory with low-concentration, chronic exposures.

Single or repeated high-concentration exposures resulting in

unconsciousness may cause serious cognitive dysfunction.

Low-concentration exposure may produce nonspecific signs and

symptoms that could closely mimic psychogenic illness.

The liver, kidneys, and endocrine system are unaffected.

10
0
Diagnostic testing
Diagnostic testing is of limited value for clinical decision making
after acute exposures.
◦ Used for acute exposures confirmation, occupational monitoring, and
forensic analysis after fatal accidents.

Circumstances surrounding the patient's illness often provide the

best evidence for hydrogen sulfide poisoning
Environmental testing:
◦ The presence of hydrogen sulfide is best confirmed by directly measuring
the gas in the environment.

10
1
Diagnostic testing
The smell of rotten eggs on clothing or emanating from
the blood, exhaled air, or gastric secretions

Darkening of silver jewelry is a clue to exposure.

Paper impregnated with lead acetate changes color when

exposed to hydrogen sulfide and is used to detect its
presence in the patient's exhaled air but is not rapidly
available.

10
2
Diagnostic testing
Whole-blood sulfide concentrations above 0.05 mg/L are considered
abnormal.
◦ Reliable measurements are ensured only if the concentration is obtained within 2
hours after the exposure and analyzed immediately.

In acute exposures, blood and urine thiosulfate concentrations may be

reflective of exposure.
◦ Urinary thiosulfate excretion is used to monitor chronic low-concentration
exposure in the workplace.

ABG analysis
◦ Metabolic acidosis with an associated elevated serum lactate concentration is expected

Brain MRI and head CT

◦ Structural changes such as globus pallidus degeneration and subcortical white matter
demyelination.
◦ Remain abnormal for weeks or months

10
3
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
Treat metabolic acidosis based on arterial pH and serum bicarbonate analysis
Administer crystalloid and vasopressors for hypotension
Antidote
Sodium nitrite: 300 mg (ie, 10 mL) IV infused at rate of 2.5-5 mL/minute

Caution:
Monitor blood pressure frequently
Obtain methemoglobin level 30 minutes after dose
Consider HBO if immediately available

10
4
Management
The initial treatment is immediate removal of the victim from
the contaminated area into a fresh air environment.

High-flow oxygen should be administered as soon as

possible. Optimal supportive care has the greatest influence
on the patient's outcome.

Because death from inhalation of hydrogen sulfide is rapid,

limited patients reaching the hospital for treatment are
reported in the literature.

Most patients experience significant delays before receiving

treatment.

Therefore, specific treatments and antidotal therapies do not

show definitive improvement in patient outcome

10
5
Management
The similarities in the toxic mechanism between hydrogen sulfide
and cyanide created an interest in the use of nitrite-induced
methemoglobin as an antidote.

Nitrite-generated methemoglobin acts as a scavenger of sulfide

When hydrogen sulfide binds to methemoglobin, it forms

sulfmethemoglobin excreted by the kidneys.

Although approved for use in cyanide poisoning, sodium nitrite is

the initial drug of choice for hydrogen sulfide poisoning

Because high methemoglobin concentrations can cause fatal

reduction of oxygenation and perfusion, methemoglobin
concentrations should be closely monitored and kept below 30%.

10
6
 Chapter 10:
Corrosives Poisoning

10
7
Introduction
Corrosives are a group of chemicals that have the
capacity to cause tissue injury on contact with multiple
organ systems

Also known as caustics

Commonly affected systems:

◦ Gastrointestinal
◦ Respiratory
◦ Ophthalmologic
◦ Dermatologic

Examples of agents capable of causing chemical burn

injuries include:
◦ Alkalis (pH >7) e.g., NaOH, KOH
◦ Acids (pH <7) e.g., HCl, H2SO4

10
8
Introduction
Many household and industrial chemicals
have caustic potential

In developed nations, increased education

and product regulation have led to
significantly decreased morbidity and
mortality from caustic exposures

However, in underdeveloped parts of the

world, exposure to caustics remains a
significant problem

10
9
Exposure
Nature of caustic exposures:
◦ Intentional teen or adult ingestions with suicidal
intent
◦ Unintentional exposures (the majority of which are
by curious children in the toddler age group)
◦ Occupational exposures

The majority of reported exposures were

unintentional or accidental

11
0
Exposure
Common Caustic Compounds (Alaklis)
Sodium hydroxide • Industrial chemicals, drain openers, oven
cleaners, urinary sugar testing tablets
Potassium hydroxide • Drain openers, batteries

Calcium hydroxide • Cement, hair relaxers, and perm products

Ammonium hydroxide • Hair relaxers and perm products, dermal
peeling/exfoliation, toilet bowl cleaners, glass
cleaners, fertilizers
Lithium hydroxide • Photographic developer, batteries
Sodium tripolyphosphate • Detergents

Sodium hypochlorite • Bleach

11
1
Exposure
Common Caustic Compounds (Acids)
Sulfuric acid • Automobile batteries, drain openers, explosives,
fertilizer
Acetic acid • Printing and photography, disinfectants, hair perm
neutralizer
Hydrochloric acid • Cleaning agents, metal cleaning, chemical
production, swimming pool products
Hydrofluoric acids • Rust remover, petroleum industry, glass and
microchip etching, jewelry cleaners
Formic acid • Model glue, leather and textile manufacturing, tissue
preservation
Chromic acid • Metal plating, photography
Nitric acid • Fertilizer, engraving, electroplating
Phosphoric acid • Rustproofing, metal cleaners, disinfectants
11
2
Structure-Activity
Relationship
The degree to which a caustic substance
produces tissue injury is determined by a
number of factors:

1. pH
● Acids tend to cause significant injuries at a pH <3 and
alkalis at a pH >11

2. Concentration

3. Duration of contact

4. Volume present

11
3
Structure-Activity
Relationship
5. Titratable acid or alkaline reserve
● Refers to the amount of acid or base required to neutralize
the agent of interest
● The greater this value, the greater the potential for tissue
injury

6. Physical properties:
● Liquid, gel, granular, or solid

● Influence the nature of the contact with the tissue

● Solid or granular caustics often injure the oropharynx and

proximal esophagus

● Liquid alkali ingestions are characterized by more extensive

esophageal and gastric injuries

11
4
Pathophysiology-Alkali
The hydroxide ion easily penetrates tissues →
immediate cellular destruction via:

◦ Producing saponification of the fatty acids within cell

membranes, resulting in the loss of membrane integrity

◦ The reaction of hydroxide ions with collagen may cause

protein disruption and considerable edema

Followed by thrombosis of local microvasculature

that leads to further tissue necrosis

11
5
Pathophysiology-Alkali
Alkali injuries induce a deep tissue injury
called liquefaction necrosis

Severe intentional alkali ingestion may cause

deep penetration into surrounding tissues →
multisystem organ injuries, including:

◦ Ocular, esophageal, gastric perforation

◦ Necrosis of abdominal and mediastinal structures

11
6
Pathophysiology-Acid
Strong acids produce coagulation necrosis

Dissociated hydrogen ions and their associated

anions penetrate tissues, leading to cell death and
eschar formation

This process is believed to limit continued hydrogen

ion penetration and protect against deeper injury

When ingested acids settle in the stomach, gastric

necrosis, perforation, and hemorrhage may result

Esophageal and gastric injury

11
7
Pathophysiology-Acid
Duodenal injury may also occur, but this is appears to
be less common

◦ Possibly because of pylorospasm induced by the acid or the

neutralization of the acid by duodenal contents

Strong acid compared to strong alkali ingestions:

◦ Less tissue destruction

◦ High-grade gastric injuries (secondary to pylorospasm and
pooling)
◦ Higher mortality rate

◦ Complications of acid ingestions: systemic absorption with

associated metabolic acidosis, hemolysis, and renal failure

11
8
Pathophysiology

Caustic injuries are

categorized as:
◦ First-, second-, and
third-degree burns,
similar to thermal burns

Based on their
appearance at
endoscopy

11
9
Clinical Manifestations-
Acute
Some of the most common complaints are:
◦ Oral pain (41%)
◦ Abdominal pain (34%)
◦ Vomiting (19%)
● Spontaneous vomiting is associated with a higher incidence of
more severe esophageal injury
◦ Drooling (19%)

Other clinical features may include:

◦ Crying, dysphagia, odynophagia, hematemesis (suggest
GI injury)
◦ Wheezing, coughing, stridor, dysphonia, chest pain, and
respiratory distress (suggest laryngotracheal injury)

12
0
Clinical Manifestations-
Acute
Visible burns:
◦ Face, lips, and oral cavity
◦ Appear as white or gray patches with an erythematous
border

Laryngeal edema:
◦ Occurs over minutes to hours
◦ Require rapid intubation

Systemic toxicity:
◦ Hypovolemic shock
◦ Hemodynamic instability manifested as hypotension,
tachycardia, fever, and acidosis may occur in these
cases

12
1
Clinical Manifestations-
Chronic
The two major long-term concerns after alkali ingestion are:
◦ Stricture
◦ Esophageal carcinoma (latent period as long as 40-50 years)

80% of strictures first become apparent in 2 to 8 weeks

Symptoms include dysphagia and food impactions

The risk for stricture can be predicted based on the degree of

burn visualized at endoscopy
◦ First-degree burns do not progress to stricture
◦ Second-degree burns may progress to stricture in at least 15% to
20% of cases
◦ Third-degree burns carry the worst prognosis for stricture, with a
risk for at least 90%
12
2
Clinical Manifestations-
Chronic

Sequelae of acid ingestion include:

◦ Esophageal stricture
◦ Pyloric and antral stenosis
◦ Duodenal atonicity
◦ Gastric metaplasia, and carcinoma

The risk for carcinoma after caustic acid

ingestion is unknown

12
3
Diagnosis- Lab Testing
No specific laboratory tests are available that predict
severity of poisoning after corrosive ingestion

General laboratory studies should include:

◦ Complete blood count
◦ Serum electrolytes
◦ Blood type
◦ Renal and liver function tests
◦ Coagulation studies

ABG measurement:
◦ Should be obtained if there is ongoing stridor or evidence of
hemodynamic compromise
◦ Particularly useful after significant acid ingestions given the
propensity for severe acid–base disturbances

12
4
Diagnosis- Imaging
Chest X-ray
Abdominal radiograph

● Should be obtained to look for evidence of peritoneal

perforation & mediastinal air denoting perforation or pleural
effusion, suggesting esophageal leak

● These noninvasive techniques suggest or detect perforation

but do not provide sufficient information about the depth of
burn injury

12
5
Diagnosis- Endoscopy
The test of choice for proper staging of burn severity
The main indication for endoscopy is a symptomatic
patient who exhibits:
◦ Vomiting, drooling, dysphagia, odynophagia, stridor, or
dyspnea

Endoscopy may also be warranted in less

symptomatic cases if the ingestion is intentional

Ideally, endoscopy should be performed within 12 to

24 hours after ingestion
◦ Endoscopy performed before 12 hours may not delineate the
extent of injury
◦ Wound softening makes endoscopy initiated after 24 hours
more hazardous

12
6
Management
Supportive
Dilution
Neutralization
Decontamination
Corticosteroids-Antibiotics
Surgical measures

12
7
Supportive Care
The first priority is airway maintenance
◦ Patients with respiratory distress require emergent
airway management

◦ Blind nasotracheal intubation is contraindicated

secondary to the potential for exacerbating airway
injuries

◦ Awake oral intubation with direct visualization is the

first choice for definitive airway management

◦ Surgical cricothyrotomy may be required if oral

intubation is not possible
● oropharyngeal edema, tissue friability, and bleeding may
make oropharyngeal or nasopharyngeal intubation difficult
or impossible

12
8
Supportive Care
Intravenous access should be established

Fluid resuscitation
◦ With significant exposures, vigorous fluid resuscitation
may be required

Continuous hemodynamic monitoring to evaluate

for evidence of shock and volume depletion

Analgesics should be provided as clinically

indicated, with care taken not to oversedate the
patient

12
9
Dilution
Treatment often begins at the scene of the ingestion

Sips of water or milk can dilute material residing in

the stomach

May cause an exothermic reaction

In alert patients who are not vomiting and can

tolerate liquids, small volumes (1–2cups) of water or
milk may be considered within the first few minutes
after ingestion (<<30 minutes)

Because injuries occur almost immediately, later

dilution is not warranted

13
0
Neutralization
Neutralization approaches to caustic
ingestions such as:
◦ Treating alkali ingestion with dilute acetic acid
(vinegar)
◦ Treating acid ingestion with sodium bicarbonate
◦ Have been frowned on

Such therapy may produce gas-forming

exothermic reactions, potentially stressing
already compromised tissues

13
1
GI Decontamination
Activated charcoal administration and gastric
lavage, are usually not indicated

Activated charcoal would obscure endoscopic

visualization of the mucosa and increase the
risk for vomiting

Ipecac is always contraindicated

13
2
Corticosteroids
Their use is the most controversial aspects of caustic
ingestion management

The ability of steroids to inhibit the inflammatory

response led to the hypothesis that:
“Steroids may decrease stricture formation after caustic
ingestion”

Individual human trials and pooled meta-analysis have

been unable to show positive benefit

Opponents of steroid use believe that steroids may

increase the risk of infection, perforation, and
hemorrhage

13
3
Corticosteroids
Systemic steroids were formerly recommended
only for:
◦ Endoscopic grade 2B lesions (circumferential, deep,
ulcerated lesions)

◦ Not for grade 1 and grade 2A lesions (because strictures

are not a significant complication)

◦ Not for grade 3 lesions (because strictures are inevitable

and probably best handled by surgical resection)

Currently, because there is no evidence of

consistent benefit, systemic steroids cannot be
recommended as standard care

13
4
Corticosteroids
If the decision is made to treat with steroids
◦ The choice of corticosteroid is largely left to the
individual physician

The studies to date have included

methylprednisolone, prednisolone, and
prednisone

The recommended dose of prednisolone is:

◦ 2 mg/kg/day in children or 40 mg three times daily
in adults for 14 to 21 days, followed by a taper

13
5
Antibiotics
Antibiotics are only indicated if:
◦ There is clinical or endoscopic evidence of perforation or
infection
◦ Corticosteroid therapy is used

The antibiotics chosen should have coverage against

a broad spectrum of oral and enteral pathogens
(gram positive and gram-negative and anaerobes)

Initial parenteral therapy with:

◦ Piperacillin-tazobactam or Plus Clindamycin
◦ A third-generation cephalosporin

◦ Followed by oral therapy with a fluoroquinolone

13
6
Surgical Measures
Esophageal stricture begins early and remains
a lifelong problem
◦ Treatment with repeated bougienage can be started
as early as 3 weeks after ingestion

Some experts reported good results with

early surgical resection in cases of severe
esophageal injuries, grade 2B and 3

13
7
Ocular Exposure
Caustic alkali injuries to the eye are generally more
severe than acid-related eye injuries

Alkali injuries penetrate deep into ocular tissue and

continue to be destructive after superficial removal

The coagulation necrosis after acid injury limits

penetration, and acid injuries are more superficial

Ocular injuries should be immediately treated with

copious irrigation by:
◦ Tap water
◦ Normal saline or lactated ringers
◦ Continue irrigation until ocular PH returns to normal

13
8
Dermal Exposure
Caustic injuries to the skin most frequently occur
on the extremities

Most acid injuries respond well to local copious

saline or water irrigation

Alkali dermal exposures may appear deceptively

superficial, yet burn more deeply and for
extended periods
◦ Management of these injuries should include copious
irrigation and local wound debridement to remove
residual compound

13
9
Disposition
Asymptomatic patients can be observed in the
emergency department

Discharge if they are able to ingest fluids with no

discomfort

The development of signs and symptoms after

discharge warrants further medical attention

All symptomatic patients require admission to the ICU

and should remain NPO pending GI consultation

Psychiatric evaluation is warranted for patients with

intentional ingestion

14
0
Chapter 11: Pesticides
Poisoning

14
1
Introduction
Pesticides, a generic term used to refer to all
pest-killing agents, include numerous
chemicals intended for use as:
◦ Insecticides
◦ Herbicides
◦ Rodenticides
◦ Fungicides

Many of these chemicals are general

protoplasmic poisons affecting a wide range
of organisms, including humans

14
2
Introduction
These chemicals can be organized in general classes

The associated characteristic clinical pictures are

important to recognize exposures to these agents

Pesticide intoxication results from:

◦ Intentional
◦ Accidental
◦ Occupational exposures

Pesticides are marketed as multiple formulations

◦ Therefore, complex clinical syndromes can result from
exposure to both active and other ingredients

14
3
Insecticides

14
4
Insecticides
Chemical insecticides are toxic to the nervous
system

Toxicity may include acute, chronic, and delayed

sequelae of acute exposure

The five major classes of insecticides used today

are the:
◦ Organophosphates
◦ Carbamates
◦ Organochlorines
◦ Pyrethroids
◦ Neonicotinoids

14
5
Organophosphates

14
6
Introduction
Commonly used organophosphates:
◦ Diazinon, Acephate, Malathion, Parathion

Have been used as chemical warfare agents since

World War II

Organophosphate and carbamate compounds are the

most common insecticides associated with systemic
illness

Potency among organophosphates does vary

◦ Highly potent compounds such as parathion are used
primarily in agriculture
◦ Those of intermediate potency include coumaphos and
trichlorfon, which are used in animal care

14
7
Introduction
Organophosphate poisoning results primarily
from:
◦ Accidental exposure in the home
◦ Recently sprayed or fogged areas using pesticide
applicators
◦ Agriculture
◦ Industry
◦ The transport of these products

14
8
Kinetics
Organophosphorus insecticides are highly
lipid soluble

Readily absorbed through dermal,

gastrointestinal, and respiratory routes

Their lipid solubility results in the buildup of

organophosphorus compounds in body fat

Toxic systemic levels often occur from

repeated low-level exposures

14
9
Pathophysiology
Organophosphates inhibit the enzyme
acetylcholinesterase (AchE)
◦ Tissue AchE (true or RBC AchE) is found primarily in
erythrocyte membranes, nervous tissue, and
skeletal muscle

◦ Plasma cholinesterase (pseudocholinesterase or

butyrylcholinesterase) is found in the serum, liver,
pancreas, heart, and brain

15
0
Pathophysiology
→ Acetylcholine
accumulates at nerve
synapses and
neuromuscular
junctions

→ Overstimulation of
acetylcholine
receptors

→ Followed by paralysis
of cholinergic
synaptic transmission

15
1
Pathophysiology
Organophosphate compounds bind irreversibly to
AchE
◦ Inactivate the enzyme through the process of
phosphorylation

Aging is the permanent, irreversible binding of

the organophosphate to AchE
◦ The time to aging ranges from minutes to a day or more

◦ New enzyme must be resynthesized over a period of

weeks before clinical symptoms resolve and normal
enzymatic function returns

◦ Antidote agents must be given before aging occurs to

be effective

15
2
Clinical Features
Clinical presentations depend on:
◦ The specific agent involved
◦ The quantity absorbed
◦ The route of exposure

Acute systemic organophosphate poisoning

results in a variety of clinical manifestations:
◦ CNS
◦ Muscarinic
◦ Nicotinic

15
3
Clinical Features
In mild to moderate poisoning, symptoms
occur in various combinations

Time to onset of symptoms is variable

◦ Onset is most rapid with inhalation and least rapid
with transdermal absorption

Symptoms can occur within minutes with

massive ingestion

15
4
Clinical Features
SLUDGE, DUMBELS, and "Killer Bees" Mnemonics for the
Muscarinic Effects of Cholinesterase Inhibition
Excessive
S Salivation
muscarinic L Lacrimation
activity can U Urinary incontinence
be D Defecation
G GI pain
characterize
E Emesis
d by:
D Defecation
U Urination
M Muscle weakness, miosis
B Bradycardia, bronchorrhea,
bronchospasm
E Emesis
L Lacrimation
S Salivation

Killer Bees Bradycardia, bronchorrhea,

bronchospasm
15
5
Clinical Features
Central neurologic symptoms of cholinergic excess
include:
◦ Anxiety, restlessness, emotional lability, tremor, headache,
dizziness, mental confusion, delirium, hallucinations, and seizures
◦ Coma with depression of respiratory and circulatory centers may
result

Nicotinic manifestations:
◦ Muscle twitches, weakness, fasiculation
◦ Paralysis of skeletal muscles (respiratory muscles)

Organophosphate-induced delayed neuropathy:

◦ Occurs 1 to 3 weeks after acute poisoning
◦ This mixed sensorimotor syndrome is due to the inhibition of
neuropathy target esterase
◦ Begin with leg cramps, may progress to weakness and paralysis

15
6
Clinical Features

15
7
Diagnosis
Diagnosis is based on:
◦ History
◦ The presence of a suggestive toxidrome
◦ Laboratory cholinesterase assays

Functional assays of plasma and red blood cell cholinesterases

have variable utility for diagnosis

Red cell cholinesterase enzymatic activity is a more accurate

indicator of synaptic cholinesterase inhibition

Plasma cholinesterase is easier to assay and more available

Plasma cholinesterase takes up to 4 to 6 weeks and red blood cell

acetylcholinesterase as long as 90 to 120 days to return to
baseline after exposure

15
8
Management
Treatment is directed toward four goals:
1. Supportive care
2. Decontamination
3. Reversal of acetylcholine excess at
muscarinic sites
4. Reversal of toxin binding at active sites on
the cholinesterase molecule

15
9
Management-Supportive
Supportive care should be directed primarily
toward airway management and include:
◦ Suctioning of secretions and vomitus
◦ Oxygenation
◦ Ventilatory support

Because most deaths are due to airway and

respiratory failure

16
0
Management-Decontaminati
on
Skin Decontamination:
◦ Clothing removal
◦ Skin should be washed repeatedly with water and soap

GI Decontamination:
◦ Of questionable benefit because of the rapid absorption
of these compounds

◦ Profuse vomiting and diarrhea are seen early in

ingestion and may limit or negate any beneficial effect
of additional GI decontamination

◦ The administration of activated charcoal after ingestion

has no proven benefit in these poisonings

16
1
Management-Atropine
Control excessive muscarinic activity

Competitively antagonizes ACh at muscarinic

receptors to reverse excessive secretions, miosis,
bronchospasm, vomiting, diarrhea, diaphoresis, and
urinary incontinence

Does not reverse muscle weakness

Large doses of atropine may be required

May prevent or abort seizures due to cholinergic

overstimulation that occur within the first few
minutes

16
2
Management-Atropine
Dose:
◦ The dose is titrated until copious tracheobronchial secretions
attenuate

◦ Pupillary dilatation is not a therapeutic end point

◦ Atropine should not be withheld in the face of a tachycardia that

may be the result of hypoxia due to secretions, respiratory muscle
paralysis, or ganglionic stimulation

◦ The initial atropine dose is 1 milligram or more IV in an adult and

0.01 to 0.04 milligram/kg (but never <0.1 milligram) IV in children
◦ IM administration up to 6 milligrams is possible, when IV access is
not possible

◦ The dose may be repeated every 5 minutes until muscarinic

symptoms subside

16
3
Management-Atropine
Tachycardia and mydriasis may occur at these
doses, but they are not indications to stop
atropine administration

The endpoint of atropinization is:

◦ Drying of respiratory secretions
◦ Easing of respiration
◦ Mean arterial pressure greater than 60 mm Hg

16
4
Management-Pralidoxime
Used to displace organophosphates from the active site of
acetylcholinesterase, thus reactivating the enzyme
Regenerates phosphorylated AchE

Ameliorates muscarinic, nicotinic, and central neurologic

symptoms

Because atropine cannot reverse nicotinic findings, pralidoxime is

administered when either nicotinic toxicity is present or atropine
doses exceed standard ACLS recommendations

Reverses muscle paralysis if given early, before aging occurs

Pralidoxime is not recommended for asymptomatic patients or

for patients with known carbamate exposures presenting with
minimal symptoms

16
5
Management-Pralidoxime
Dose:
◦ The initial dose in adolescents and adults is 2 g
intravenously over 10–15 minutes (25–50 mg/kg IV)

◦ Rapid infusion should be avoided as it can

exacerbate toxicity by transiently blocking AChE

◦ Administer every 6 hours until the patient remains

asymptomatic for at least 24 hours

◦ In more severe cases, a continuous infusion is

started at 250–500 mg/h (10–20 mg/kg/h in
children) and titrated to clinical effect

16
6
Carbamates

16
7
Introduction
N-methyl carbamates:
◦ Carbaryl
◦ Pirimicarb
◦ Propoxur
◦ Trimethacarb

These are cholinesterase inhibitors that are

structurally related to the organophosphates

Medicinal forms include physostigmine,

pyridostigmine, and neostigmine

16
8
Pathophysiology
Carbamates can be toxic after dermal, inhalation, and GI
exposure

Transiently and reversibly bind to and inhibit the

cholinesterase enzyme through carbamylation

This occurs by transiently binding to a serine hydroxyl

residue at the active site of the cholinesterase enzyme

Regeneration of enzyme activity by dissociation

(hydrolysis) of the carbamyl-cholinesterase bond occurs
within minutes to a few hours

Aging does not occur

16
9
Clinical Features
In adults:
◦ Symptoms of acute carbamate poisoning are similar
to the cholinergic crisis of organophosphates but
are of shorter duration

◦ Do not effectively penetrate the CNS in adults →

less central toxicity and seizures do not occur

In children:
◦ Presentation of carbamate poisoning differs, with a
predominance of CNS depression and nicotinic
effects

17
0
Management
Initial treatment of carbamate poisoning is the same as for
organophosphorus compounds

Atropine is the antidote of choice and is administered for

muscarinic symptoms

This is usually all that is necessary while waiting for the

carbamylated acetylcholinesterase complex to dissociate
spontaneously and recover function, usually within 24 hours

Therapy usually is not needed for more than 6 to 12 hours

The use of pralidoxime in carbamate poisoning is controversial

◦ The carbamate-binding half-life to cholinesterase is approximately 30
minutes, and irreversible binding does not occur; therefore, there is little
need for pralidoxime

17
1
Organochlorines

17
2
Introduction
Dichlorodiphenyltrichloroethane (DDT) is the prototype
insecticide of these chlorinated hydrocarbons

Chlordane, heptachlor, dieldrin, and aldrin are compounds used

for termite and roach control

Most have been restricted or banned in the U.S. because of their:

◦ Persistence in the environment
◦ Long half-life in the human body
◦ Toxicity
Worldwide, these insecticides continue to be used

Hexachlorocyclohexane (lindane) is a general garden

organochlorine insecticide that is also used to treat scabies and
head lice infestations

17
3
Kinetics
All of the organic chlorine pesticides are well absorbed orally and
by inhalation

Transdermal absorption is variable

◦ DDT is very poorly absorbed transdermally

All organic chlorines are lipophilic, a property that allows

penetration to their sites of action
Accumulate in human tissues

Metabolized by the hepatic microsomal enzyme systems by

dechlorination, oxidation, most with subsequent conjugation

The primary route of excretion is in the bile & appear in urine

17
4
Pathophysiology
Primarily affect axonal membranes, resulting in neuronal irritability and
excitation

Toxicity occurs in central and peripheral neurons

Inhibit the chloride channel of GABA receptors, leading to decreased

inhibition of the central nervous system

Affects the axon, by causing the voltage-dependent Na+ channels to

remain open after depolarization, allowing repetitive action potentials

Induce hepatic microsomal enzymes and produce hepatic tumors in some

animals
◦ This potential carcinogenicity is the basis for human health concerns, but it is only
theoretic

Sensitize the myocardium to circulating catecholamines and increase

susceptibility to ventricular dysrhythmias

17
5
Clinical Features
Neurologic symptoms predominate in acute
organochlorine intoxication

Mild poisoning presents with:

◦ Dizziness, ataxia, N/V, fatigue, malaise, headache,
neurologic stimulation with hyperexcitability,
irritability, and delirium, apprehension,
tremulousness, myoclonus, and facial paresthesias

Severe exposures may result in:

◦ Cardiac dysrhythmias, seizures, coma, respiratory
failure, and death

17
6
Diagnosis
The history of exposure to an organic chlorine
pesticide is the most critical piece of information

Gas chromatography can detect organic chlorine

pesticides in serum, adipose tissue, and urine

Laboratory evaluation will not alter the course of

management

These blood tests are not available on an

emergent basis

17
7
Management
Supportive & symptomatic care:
◦ Administration of oxygen
◦ Intubation indicated to treat hypoxia secondary to
seizures, aspiration, and respiratory failure

◦ Benzodiazepines are indicated for seizure control

◦ Dysrhythmia control may be indicated

◦ Epinephrine should be avoided

◦ Hyperthermia is managed by external cooling

techniques
17
8
Management
Decontamination:
◦ Removal of clothing and skin decontamination with
mild detergent and water are important

◦ Avoid using oils on the skin because they promote

absorption

◦ Activated charcoal and possibly gastric lavage in

large, recent ingestions are potentially useful

17
9
Bipyridyl Herbicides

18
0
Introduction
The bipyridyl compounds, paraquat and diquat

Both are still used widely and are responsible for

significant morbidity

Paraquat is a fast-acting, nonselective herbicide

◦ It is used for killing grass and weeds and is manufactured as a
liquid, granules, or an aerosol and is commonly combined with
diquat and other herbicides

Deaths have been reported after transdermal exposure,

ingestion, and inhalation

Inhalation exposures to sprays are very irritating to

conjunctiva and the airway, but are unlikely to cause
systemic toxicity

18
1
Kinetics
There is minimal transdermal absorption

Ingested paraquat is absorbed rapidly,

particularly if the stomach is empty

Plasma concentration peaks within minutes to

2 hours after ingestion

Paraquat is then distributed to most organs,

with the highest concentrations found in the
kidneys and lungs

18
2
Pathophysiology
Paraquat is a severe local irritant and devastating systemic toxin

The lethal oral dose of the 20% solution is 10 to 20 mL in an

adult and 4 to 5 mL in a child

Paraquat actively accumulates in the alveolar cells of the lungs,

where it is transformed into a reactive oxygen species, the
superoxide radical

This anion is responsible for lipid peroxidation that leads to

degradation of cell membranes, cell dysfunction, and death→
lung injury (phase 1: destructive, phase 2: fibrosis)

Myocardial injury and necrosis of the adrenal glands may occur

Diquat less toxic, can cause renal and liver necrosis

18
3
Clinical Manifestations
Stage 1 (minutes-2 days):
◦ Local corrosive action, ulceration, N/V/D

Stage 2 (2-5 days):

◦ Renal failure, hepatocellular necrosis, cardiac
damage

Stage 3 (5 days-several weeks):

◦ Progressive pulmonary fibrosis

18
4
Management
The goal of early and vigorous
decontamination is to prevent pulmonary
toxicity

Any exposure to paraquat is a medical

emergency

Hospitalization indicated even if the patient is

asymptomatic

18
5
Management
Supportive care:
◦ Prevent superoxide radical formation by using low
inspired oxygen to produce a therapeutic hypoxemia
with the goal of reducing pulmonary injury

◦ The use of low oxygen mixtures (fraction of inspired

oxygen<21%) with positive pressure ventilation reduces
pulmonary toxicity in experimental models and may be
of therapeutic benefit

◦ Supplemental oxygen should be avoided except for

severe respiratory failure

18
6
Management
Decontamination:
◦ Skin
◦ Gastric lavage
◦ Immediate GI decontamination with absorbents that
bind paraquat is indicated
● Activated charcoal (1 to 2 grams/kg)
● Fuller's earth (1 to 2 grams/kg in 15% aqueous suspension)
should be used and repeated every 4 hours

Elimination:
◦ Charcoal hemoperfusion can remove paraquat and
should be instituted as soon as possible and continued
for 6 to 8 hours

18
7