Book Text

Toxins

Toxins are high-molecular-weight compounds that are in the middle of the CBW spectrum. They are produced by bacteria and by organisms ranging from protozoans up to

TABLE 64-10 -- Antidotes used in the treatment of cyanide poisoning

Antidote Action Route Dose Concurrent Drugs Duration of Administration Possible Side Effects

Oxygen Increased arterial O₂ content, potentiates activity of other antidotes Inhalation by mask or endotracheal tube (ETT) High flow by mask or 100% by ETT Oxygen used as primary antidote in all cases No more than 24 hr Unlikely—possible in patients with chronic obstructive pulmonary disease

Amyl nitrite Methemoglobin formation Inhalation Adults: 0.2 mL Oxygen (not simultaneously) 30 sec per 1 min Difficult to achieve effective antidotal levels without cardiovascular collapse

Peds: 0.2 mL may need repeating

Sodium nitrite Methemoglobin formation Intravenous injection Adults: 300 mg (10 mL of 30 mg/mL) (3%) Adults: sodium thiosulfate, 25 mL of 500 mg/mL (50%) solution and oxygen No less than 5 min and up to 20 min Methemoglobinemia, vasodilation, and cardiovascular collapse

Peds: 0.13–0.33 mL/kg of 30 mg/mL (3%) solution (i.e., 4 mg to 10 mg/kg body weight) Peds: sodium thiosulfate, 1.65 mL/kg body weight of 250 mg/mL (25%) solution (approx. 400 mg/kg body weight) and oxygen

Dicobalt edetate Binding of cyanide ions by dicobalt edetate and by free cyanide ions Intravenous injection Adults: 300 mg (20 mL of 15 mg/mL) (15%) 50 mL dextrose (500 g/L) IV immediately after each dose and oxygen 1 min Urticaria, edema of face and neck, chest pains, dyspnea, hypotension, convulsions

Peds: 4–7.5 mg/kg (0.3–0.5 mL/kg of 15 mg/mL) (15%)

4-DMAP Methemoglobin formation Intravenous injection Adults: 3.25 mg/kg Oxygen and sodium thiosulfate 1 min Methemoglobinemia vasodilation, and cardiovascular collapse; hemolysis, elevated bilirubin and iron (this is unlikely to be relevant to single-dose exposure)

Peds: 3.25 mg/kg

Hydroxocobalamin Binds cyanide ions Intravenous injection Adults: 5–10 g 5 g reconstituted in 100 mL 0.9% saline; oxygen 20 min Reddish discoloration to skin and mucous membranes

Peds: 70 mg/kg

Sodium thiosulfate Sulfur donor for endogenous enzymatic conversion of cyanide to thiocyanate Intravenous injection Adults: sodium thiosulfate, 25 mL of 500 mg/mL (50%) solution and oxygen Oxygen and sodium nitrite or oxygen and DMAP 10 min Excess administration may cause hypernatremia.

Peds: sodium thiosulfate, 1.65 mL/kg body weight of 250 mg/mL (25%) solution (approx. 400 mg/kg body weight) and oxygen

**TABLE 64-10** -- Antidotes used in the treatment of cyanide poisoning
Antidote	Action	Route	Dose	Concurrent Drugs	Duration of Administration	Possible Side Effects
Oxygen	Increased arterial O₂ content, potentiates activity of other antidotes	Inhalation by mask or endotracheal tube (ETT)	High flow by mask or 100% by ETT	Oxygen used as primary antidote in all cases	No more than 24 hr	Unlikely—possible in patients with chronic obstructive pulmonary disease
Amyl nitrite	Methemoglobin formation	Inhalation	Adults: 0.2 mL	Oxygen (not simultaneously)	30 sec per 1 min	Difficult to achieve effective antidotal levels without cardiovascular collapse
			Peds: 0.2 mL may need repeating
Sodium nitrite	Methemoglobin formation	Intravenous injection	Adults: 300 mg (10 mL of 30 mg/mL) (3%)	Adults: sodium thiosulfate, 25 mL of 500 mg/mL (50%) solution and oxygen	No less than 5 min and up to 20 min	Methemoglobinemia, vasodilation, and cardiovascular collapse
			Peds: 0.13–0.33 mL/kg of 30 mg/mL (3%) solution (i.e., 4 mg to 10 mg/kg body weight)	Peds: sodium thiosulfate, 1.65 mL/kg body weight of 250 mg/mL (25%) solution (approx. 400 mg/kg body weight) and oxygen
Dicobalt edetate	Binding of cyanide ions by dicobalt edetate and by free cyanide ions	Intravenous injection	Adults: 300 mg (20 mL of 15 mg/mL) (15%)	50 mL dextrose (500 g/L) IV immediately after each dose and oxygen	1 min	Urticaria, edema of face and neck, chest pains, dyspnea, hypotension, convulsions
			Peds: 4–7.5 mg/kg (0.3–0.5 mL/kg of 15 mg/mL) (15%)
4-DMAP	Methemoglobin formation	Intravenous injection	Adults: 3.25 mg/kg	Oxygen and sodium thiosulfate	1 min	Methemoglobinemia vasodilation, and cardiovascular collapse; hemolysis, elevated bilirubin and iron (this is unlikely to be relevant to single-dose exposure)
			Peds: 3.25 mg/kg
Hydroxocobalamin	Binds cyanide ions	Intravenous injection	Adults: 5–10 g	5 g reconstituted in 100 mL 0.9% saline; oxygen	20 min	Reddish discoloration to skin and mucous membranes
			Peds: 70 mg/kg
Sodium thiosulfate	Sulfur donor for endogenous enzymatic conversion of cyanide to thiocyanate	Intravenous injection	Adults: sodium thiosulfate, 25 mL of 500 mg/mL (50%) solution and oxygen	Oxygen and sodium nitrite or oxygen and DMAP	10 min	Excess administration may cause hypernatremia.
			Peds: sodium thiosulfate, 1.65 mL/kg body weight of 250 mg/mL (25%) solution (approx. 400 mg/kg body weight) and oxygen

2515

reptiles such as snakes and arachnids such as scorpions. Toxins pose a considerable everyday hazard to humans in many parts of the world, and this has fueled much research into their actions and treatment.^[73] Scientifically, they are of considerable interest when used as research tools to probe natural processes such as nerve conduction and neuromuscular transmission. Toxins such as black widow spider venom have long been used in this way. In the context of toxic warfare, toxins have often been cited as doomsday weapons, and there is considerable public fear about their actions. Because they are produced by living organisms and do not reproduce themselves, they are akin to conventional chemical agents. More than 500 toxins have been described, but only a few are suitable for battlefield and terrorist attack because of the difficulties in production and lack of stability in a released aerosol.^[74] The characteristics of some common toxins are shown in Table 64-11 .

In the chemical warfare context, the anesthesiologist may encounter toxins with short latencies (e.g., neurotoxins such as botulinum toxin), requiring immediate life support and treatment, or with long latencies (e.g., DNA toxins such as ricin), which cause major organ dysfunction and present intensive care problems.

Botulinum Toxin

Botulinum toxin is produced by the anaerobe Clostridium botulinum and has the reputation of being the most toxic substance by weight known to man; it is at least 5000 times more toxic than sarin in this respect. Botulism, the natural occurrence of the toxin in food poisoning, is a disease of humans and animals. Seven different functionally related neurotoxins (A through G) are produced by the patent

TABLE 64-11 -- Characteristics of some common toxins

Source Toxin Action

Bacteria

Bacillus anthracis Anthrax toxin DNA toxin

Staphylococcus aureus Staphylococcal enterotoxin B Enterotoxin

Vibrio cholerae Cholera toxin Enterotoxin

Clostridium botulinum Botulinum toxins Prejunctional decrease in acetylcholine release

Clostridium perfringens Perfringens toxin Necrosis through phospholipase C

Clostridium tetani Tetanus toxin Neurotoxin increase in excitability of motor neurons

Protozoa

Ganaulux cotanella Saxitoxin Depolarization block

Fungi

Fusarium spp. Tricothecenes DNA toxin; hemorrhagic syndrome

Plants

Ricinus communis (castor bean) Ricin DNA toxin; hepatorenal failure

Amphibia

Colombian frog Batrachotoxin Irreversible; Na⁺ channel blockade; depolarization block

Reptilia

Asiatic cobra (Naja naja oxiana) Cobratoxin Postsynaptic neurotoxin via phospholipase A₂

Taiwan banded krait (Bungarus multicinctus) Alpha bungarotoxin Acetylcholine receptor blocker

Fish

Deadly pufferfish Tetrodotoxin Depolarization block

Adapted from Baker DJ: Anesthesia in extreme environmental conditions. Part 2. Chemical and biologic warfare. In Grande CG (ed): Textbook of Trauma Anesthesia and Critical Care. Baltimore. Mosby-Year Book, 1993, pp 1320–1354.

organism. Botulism is essentially an intoxication brought on by ingestion of the toxin produced by clostridial infection of food, usually incorrectly canned meats. Primary botulism, a direct infection, is rare and affects only infants in the human species.

**TABLE 64-11** -- Characteristics of some common toxins
Source	Toxin	Action
Bacteria
Bacillus anthracis	Anthrax toxin	DNA toxin
Staphylococcus aureus	Staphylococcal enterotoxin B	Enterotoxin
Vibrio cholerae	Cholera toxin	Enterotoxin
Clostridium botulinum	Botulinum toxins	Prejunctional decrease in acetylcholine release
Clostridium perfringens	Perfringens toxin	Necrosis through phospholipase C
Clostridium tetani	Tetanus toxin	Neurotoxin increase in excitability of motor neurons
Protozoa
Ganaulux cotanella	Saxitoxin	Depolarization block
Fungi
Fusarium spp.	Tricothecenes	DNA toxin; hemorrhagic syndrome
Plants
Ricinus communis (castor bean)	Ricin	DNA toxin; hepatorenal failure
Amphibia
Colombian frog	Batrachotoxin	Irreversible; Na⁺ channel blockade; depolarization block
Reptilia
Asiatic cobra (Naja naja oxiana)	Cobratoxin	Postsynaptic neurotoxin via phospholipase A₂
Taiwan banded krait (Bungarus multicinctus)	Alpha bungarotoxin	Acetylcholine receptor blocker
Fish
Deadly pufferfish	Tetrodotoxin	Depolarization block
Adapted from Baker DJ: Anesthesia in extreme environmental conditions. Part 2. Chemical and biologic warfare. In Grande CG (ed): Textbook of Trauma Anesthesia and Critical Care. Baltimore. Mosby-Year Book, 1993, pp 1320–1354.

Botulinum toxin is of interest as a toxic agent because it can be relatively easily produced by fermentation processes (which have been developed to produce antitoxins) and it is stable as an aerosol, making mass delivery a theoretical possibility. Calculations that 1 kg of the toxin would be sufficient to destroy every human on the planet have rested on this fact. However, botulinum intoxication can be treated, and this modifies the toxicity considerably. It is estimated that less than 10% of natural cases receiving ventilatory and antitoxin support are fatal. A consensus document exploring botulinum toxin as a biological weapon has appeared as part of the increasing concern about the possible exposure of civilian populations to bioweapons.^[75]

Signs and Symptoms

Botulinum toxin acts at the nerve terminal of cholinergic synapses and blocks the release of acetylcholine by being taken up into the vesicles and translocated to the cytoplasm, where it catalyzes the proteolysis of components involved in the calcium-mediated exocytosis of acetylcholine. The inhibition is permanent, and recovery occurs only after the creation of new terminal boutons. The toxin blocks neurotransmission, parasympathetic synapses, and peripheral ganglia. The signs and symptoms of the intoxication can be explained on this basis. After ingestion of the toxin (the usual route), the parasympathetic action typically produces a dry mouth, followed

2516

by signs of a progressive bulbar palsy (i.e., dysarthria, dysphasia, and dysphagia) and ocular signs (i.e., diplopia and ptosis). This is followed by progressive symmetric descending muscular weakness that leads to respiratory failure requiring prolonged ventilatory support. Neuromuscular testing shows a classic presynaptic decremental pattern to repeated stimuli with post-tetanic facilitation. Single-fiber electromyography can detect the neuromuscular changes before conventional nerve stimulation; there is increased jitter and blocking, which is reduced by increasing the nerve firing rate.^[76] The pattern of signs and symptoms after a deliberate mass inhalation release is not known, but botulinum toxin must be considered along with the nerve agents in any cases presenting with sudden disturbances of cholinergic transmission.

Conventional level C protection (see "Personal Protection") and decontamination procedures are effective against the toxin, and several antisera exist. A heptavalent antitoxin exists for all the serotypes, but the human efficacy is not known with certainty.^[77] Established cases require supportive treatment with antitoxin and positive-pressure ventilation. The latter may be required for some time.

Saxitoxin

Saxitoxin has been suggested as a possible terrorist toxic agent, but there is no record of its production or use in a military context. It is produced naturally by dinoflagellate sea organisms (which cause the red tide), including Alexandrium tamarense, Gymnodinium catenatum, and Pyridinium hamense. The toxin is concentrated in shellfish and is the cause of paralytic shellfish poisoning.^[73] The toxin is about 20 times more toxic than sarin, having an LD₅₀ in mice of 8 µg/kg. Saxitoxin is active by the inhalational route, causing bulbar palsy and respiratory and cardiovascular failure. The toxin acts by blocking voltage-gated sodium channels.^[78] Treatment is based on ventilatory and organ support. An antitoxin has been developed in guinea pigs.^[79]

Ricin

Ricin is considered a serious terrorist threat because it can be extracted relatively easily from the seeds of the castor bean plant, Ricinus communis. Waste from the production of castor oil contains about 5% ricin, making it a potential source for terrorists. Ricin has been used in assassination, ^[13] and high inhaled concentrations are thought to be fatal. There is a substantial latent period before generalized signs and symptoms of the inhibition of protein synthesis occur, including fever, abdominal pain, diarrhea, drowsiness, confusion, convulsions, coma, weakness, cardiovascular collapse, and respiratory failure, all progressing toward multiple organ failure and death within 36 to 72 hours. Ricin therefore poses a considerable ICU problem. Treatment is supportive, but an antitoxin has been developed for use in animals.^[80]