Lippincott Chapter 48: Clinical Toxicology Flashcards
EMERGENCY TREATMENT OF THE POISONED
PATIENT
A. Decontamination
Once the patient is stabilized, the assessment for decontamination
can occur. This may include flushing of the eyes with saline or tepid
water to a neutral pH for ocular exposures, rinsing of the skin for
dermal exposures, as well as administration of gastrointestinal (GI)
decontamination with gastric lavage, activated charcoal, or whole
bowel irrigation (utilizing a polyethylene glycol electrolyte balanced
solution) for selected ingestions. Several substances do not adsorb
to activated charcoal (for example, lead and other heavy metals, iron,
lithium, potassium, and alcohols), limiting the use of activated char-
coal unless there are coingested products.
B. Elimination enhancement
1. Hemodialysis: The elimination of some medications/toxins may be
enhanced by hemodialysis if certain properties are met: low protein
binding, small volume of distribution, small molecular weight, and
water solubility of the toxin. Some examples of medications or sub-
stances that can be removed with hemodialysis include methanol,
ethylene glycol, salicylates, theophylline, phenobarbital, and lithium.
2. Urinary alkalinization: Alkalinization of the urine enhances the
elimination of salicylates or phenobarbital. Increasing the urine pH
with intravenous sodium bicarbonate transforms the drug into an ion-
ized form that prevents reabsorption, thereby trapping it in the urine
to be eliminated by the kidney. The goal urine pH is within the range
of 7.5 to 8, while ensuring that the serum pH does not exceed 7.55.
3. Multiple-dose activated charcoal: Multiple-dose activated
charcoal therapy enhances the elimination of certain drugs (for
example, theophylline, phenobarbital, digoxin, carbamazepine,
valproic acid) by creating a gradient across the lumen of the gut.
Medications traverse from areas of high concentration to low con-
centration, promoting medication already absorbed to cross back
into the gut to be adsorbed by the activated charcoal present. In
addition, activated charcoal blocks the reabsorption of medications
that undergo enterohepatic recirculation (such as phenytoin), by
adsorbing the substance to the activated charcoal. Bowel sounds
must be present prior to each activated charcoal dose to ensure
movement of the GI tract and prevent obstruction.
SELECT PHARMACEUTICAL AND OCCUPATIONAL
TOXICITIES
Acetaminophen
Acetaminophen produces toxicity when its usual metabolic pathways
become saturated. Usually, acetaminophen undergoes metabolism
by sulfation, glucuronidation, and N-hydroxylation by the cytochrome P450 system. When a toxic amount of acetaminophen is ingested,
the first two processes are overwhelmed and more acetaminophen
is metabolized by the cytochrome P450 system to a hepatotoxic
metabolite (N-acetyl-p-benzoquinoneimine, NAPQI). In therapeutic
acetaminophen ingestions, the liver generates glutathione, which
detoxifies NAPQI. However, in overdose, the glutathione is depleted,
leaving the metabolite to produce toxicity. There are four phases typi-
cally describing acetaminophen toxicity (Figure 48.2). The antidote for
acetaminophen toxicity, N-acetylcysteine (NAC), initially works as a
glutathione precursor and glutathione substitute and assists with sul-
fation. Later on, NAC may function as an antioxidant to aid in recovery.
NAC is the most effective when initiated 8 to 10 hours postingestion.
The Rumack-Matthew nomogram (Figure 48.3), which is based on
the time of ingestion and the serum acetaminophen level, is utilized
after an acute ingestion to determine if NAC therapy is needed. The nomogram is helpful for acute acetaminophen ingestions when levels
can be obtained between 4 and 24 hours postingestion.
Alcohol
- Methanol (wood alcohol) and ethylene glycol: Methanol is
found in such products as windshield washer fluid and model air-
plane fuel. Ethylene glycol is most commonly found in radiator anti-
freeze. These primary alcohols are themselves relatively nontoxic
and cause mainly CNS sedation. However, methanol and ethyl-
ene glycol are oxidized to toxic products: formic acid in the case
of methanol and glycolic, glyoxylic, and oxalic acids in the case
of ethylene glycol. Fomepizole inhibits this oxidative pathway by
blocking alcohol dehydrogenase. It prevents the formation of toxic
metabolites and allows the parent alcohols to be excreted by the
kidney (Figure 48.4). Hemodialysis is often utilized to remove the
already-produced toxic acids. In addition, cofactors are adminis-
tered to encourage metabolism to nontoxic metabolites (folate for
methanol, thiamine and pyridoxine for ethylene glycol). If untreated,
methanol ingestion may produce blindness, metabolic acidosis,
seizures, and coma. Ethylene glycol ingestion may lead to renal
failure, hypocalcemia, metabolic acidosis, and heart failure. - Isopropanol (rubbing alcohol, isopropyl alcohol): This second-
ary alcohol is metabolized to acetone via alcohol dehydrogenase.
Acetone cannot be further oxidized to carboxylic acids, and there-
fore, acidemia does not occur. Isopropanol is a known CNS depres-
sant (approximately twice as intoxicating as ethanol) and GI irritant.
No antidote is necessary to treat an isopropyl alcohol ingestion.
Carbon monoxide
Carbon monoxide is a colorless, odorless, and tasteless gas, which is
impossible for individuals to detect without a carbon monoxide detec-
tor. It is a natural by-product of the combustion of carbonaceous mate-
rials, and common sources of this gas include automobiles, poorly
vented furnaces, fireplaces, wood-burning stoves, kerosene space
heaters, house fires, and charcoal grills. Following inhalation, carbon
monoxide rapidly binds to hemoglobin to produce carboxyhemoglobin.
The binding affinity of carbon monoxide to hemoglobin is 230 to 270
times greater than that of oxygen. Consequently, even low concentra-
tions of carbon monoxide in the air can produce significant levels of
carboxyhemoglobin. In addition, bound carbon monoxide increases
hemoglobin affinity for oxygen at the other oxygen-binding sites. This
high-affinity binding of oxygen prevents the unloading of oxygen at the
tissues, further reducing oxygen delivery (Figure 48.5). The presence
of this highly oxygenated blood may produce “cherry red” skin. Carbon
monoxide toxicity can occur following the inhalation or ingestion of
methylene chloride found in paint strippers also. Once absorbed,
methylene chloride is metabolized by the liver to carbon monoxide
through the cytochrome P450 pathway. The symptoms of carbon mon-
oxide intoxication are consistent with hypoxia, with the brain and heart
showing the greatest sensitivity. Symptoms include headache, dys-
pnea, lethargy, confusion, and drowsiness, whereas higher exposure
levels can lead to seizures, coma, and death. The management of a carbon monoxide–poisoned patient includes prompt removal from the
source of carbon monoxide and institution of 100% oxygen by non-
rebreathing face mask or endotracheal tube. In patients with severe
intoxication, oxygenation in a hyperbaric chamber is recommended.
Cyanide
Cyanide is just one of the toxic products of combustion produced dur-
ing house fires. Additionally, cyanide salts are used in electroplating,
and hydrogen cyanide may be produced during photographic devel-
oping and petroleum refining. Once absorbed into the body, cyanide
quickly binds to many metalloenzymes, thereby rendering them inac-
tive. Its principal toxicity occurs as a result of the inactivation of the
enzyme cytochrome oxidase (cytochrome a3
), leading to the inhibi-
tion of cellular respiration. Therefore, even in the presence of oxygen,
tissues such as the brain and heart, which require a high oxygen
demand, are adversely affected. Death can occur quickly due to
respiratory arrest of oxidative phosphorylation and production of ade-
nosine triphosphate. The most recently developed antidote, hydroxo-
cobalamin (vitamin B12a), is administered intravenously to bind the
cyanide and produce cyanocobalamin (vitamin B12) without the worry
of hypotension or methemoglobin production. The older cyanide anti-
dote kit comprises sodium nitrite to form cyanomethemoglobin and
sodium thiosulfate to accelerate the production of thiocyanate, which
is much less toxic than cyanide and is also quickly excreted in urine.
In patients with smoke inhalation and cyanide toxicity, the induction
of methemoglobin with sodium nitrite should be avoided unless the
carboxyhemoglobin concentration is less than 10%. Otherwise, the
oxygen-carrying capacity of blood becomes too low.
Iron
Previously, ingestion of iron was the leading cause of poisoning
death in children. However, the incidence of pediatric iron toxicity has
greatly diminished during the past two decades due to education and
changes in packaging. Iron is radiopaque and may show up on an
abdominal radiograph if the product contains a sufficient concentra-
tion of elemental iron. Toxic effects can be expected with as little as
20 mg/kg of elemental iron ingested, and doses of 60 mg/kg may be
lethal. Each iron salt contains a different concentration of elemen-
tal iron (Figure 48.6). Based on the quantity ingested, the patient’s
weight, and the elemental iron concentration, an assessment of
potential toxicity can be made. A serum iron level should be obtained,
since levels between 500 and 1000 μg/dL have been associated with
shock and levels higher than 1000 μg/dL with morbidity and mortality.
If a significant amount of iron has been ingested, the patient usually
presents with nausea, vomiting, and abdominal pain. Depending on
the amount of elemental iron ingested, the patient may experience
a latent period or may progress quickly to hypovolemia, metabolic
acidosis, hypotension, and coagulopathy. Ultimately, hepatic failure
and multisystem failure, coma, and death may occur. Deferoxamine,
an iron-specific chelator, binds free iron, creating ferrioxamine to be
excreted in the urine. The intravenous route for deferoxamine is pre-
ferred, but hypotension may occur if rapid boluses are administered
instead of a continuous infusion.
Lead
Lead is ubiquitous in the environment, with sources of exposure
including old paint, drinking water, industrial pollution, food, and con-
taminated dust. However, with the elimination of tetraethyl lead in
gasoline during the mid-1980s in the United States, environmental
exposure to organic lead has been reduced, and most chronic expo-
sure to lead occurs with inorganic lead salts, such as those in paint
used in housing constructed prior to 1978. Age-dependent differences
in the absorption of ingested lead are known to occur. Adults absorb
about 10% of an ingested dose, whereas children absorb about 40%.
Inorganic forms of lead are initially distributed to the soft tissues and
more slowly redistribute to bone, teeth, and hair. When lead makes its
way to the bone, it impairs new bone formation and causes increased
calcium deposition in long bones visible on x-ray. Ingested lead is radi-
opaque and may appear on an abdominal radiograph if present in the
GI tract. Lead has an apparent blood half-life of about 1 to 2 months,
whereas its half-life in the bone is 20 to 30 years. Chronic exposure to
lead can have serious effects on several tissues (Figure 48.7).
- Central nervous system: The CNS effects of lead have often
been termed lead encephalopathy. Symptoms include headaches,
confusion, clumsiness, insomnia, fatigue, and impaired concentra-
tion. As the disease progresses, clonic convulsions and coma can
occur. Death is rare, given the ability to treat lead intoxication with
chelation therapy. Children are more susceptible than adults to the
CNS effects of lead. Furthermore, blood levels of 5 to 20 μg/dL
in children have been shown to lower IQ in the absence of other
symptoms. It has been estimated that as many as 9% of the chil-
dren in the United States may have blood lead levels greater than
10 μg/dL. - Gastrointestinal system: Early symptoms can include discom-
fort and constipation (and, occasionally, diarrhea), whereas higher
exposures can produce painful intestinal spasms. - Blood: Lead has complex effects on the constituents of blood,
leading to hypochromic, microcytic anemia as a result of a short-
ened erythrocyte life span and disruption of heme synthesis.
Elevated blood lead levels can be used diagnostically for deter-
mining lead intoxication, provided that blood lead levels are greater
than about 25 μg/dL.
Multiple chelators can be utilized in the treatment of lead toxicity.
When levels are greater than 45 μg/dL, but less than 70 μg/dL in
children, succimer (dimercaptosuccinic acid, DMSA), an oral chela-
tor, is the treatment of choice. With lead levels greater than 70 μg/dL
or if encephalopathy is present, dual parenteral therapy is required
with dimercaprol given intramuscularly and calcium disodium edetate
given intravenously. Dimercaprol is suspended in peanut oil and
should not be given to those with a peanut allergy.
Organophosphate and carbamate insecticides
These insecticides exert their toxicity through inhibition of ace-
tylcholinesterase, with subsequent accumulation of excess ace-
tylcholine producing nicotinic (mydriasis, fasciculations, muscle
weakness, hypertension) and muscarinic (diarrhea, urination, mio-
sis, bradycardia, bronchorrhea, emesis, lacrimation, salivation)
effects. Carbamates reversibly bind to acetylcholinesterase, whereas
organophosphates undergo an aging process to ultimately irrevers-
ibly inactivate the enzyme. Organophosphate nerve agents, such
as sarin, soman, and tabun, have the same mechanism of action,
but the aging process is much more rapid compared to insecticides.
Atropine, a muscarinic receptor antagonist, and pralidoxime, an
oxime to reactivate cholinesterase, should be administered intrave-
nously or intramuscularly to treat the muscarinic and nicotinic effects,
respectively.
Acetaminophen antidote
N-acetylcysteine
Anticholinergic
agents
(antihistamines, etc.) Antidotes
Physostigmine
Arsenic antidote
Succimer (dimer-
captosuccinic acid,
DMSA), dimercaprol
Benzodiazepine antidote
Flumazenil
Carbon monoxide antidote
Oxygen
(± hyperbaric
chamber)
Cyanide antidote
Hydroxocobalamin
Sodium nitrite and
sodium thiosulfate
Digitalis antidote
Digoxin-immune
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