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InternalMed_Harrison. Other agents Chloral hydrate, ethchlorvynol, glutethimide, meprobamate, methaqualone, methyprylon Cytochrome oxidase Cyanide, hydrogen sulfide inhibitors Inhibition of mitochondrial cytochrome oxidase, with consequent blockage of electron transport and oxidative metabolism. Carbon monoxide also binds to hemoglobin and myoglobin and prevents oxygen binding, transport, and tissue uptake. (Binding to hemoglobin shifts the oxygen dissociation curve to the left.) Oxidation of hemoglobin iron from ferrous (Fe2+) to ferric (Fe3+) state prevents oxygen binding, transport, and tissue uptake. (Methemoglobinemia shifts oxygen dissociation curve to the left.) Oxidation of hemoglobin protein causes hemoglobin precipitation and hemolytic anemia (manifesting as Heinz bodies and "bite cells" on peripheral-blood smear).


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InternalMed_Harrison. Ethylene glycol causes CNS depression and increased serum osmolality. Metabolites (primarily glycolic acid) cause AGMA, CNS depression, and renal failure. Precipitation of oxalic acid metabolite as calcium salt in tissues and urine results in hypocalcemia, tissue edema, and crystalluria. Hydration of ferric (Fe3+) ion generates H+. Non-transferrinbound iron catalyzes formation of free radicals that cause mitochondrial injury, lipid peroxidation, increased capillary permeability, vasodilation, and organ toxicity.


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InternalMed_Harrison. Signs and symptoms of hypoxemia with initial physiologic stimulation and subsequent depression (Table 473e-2); lactic acidosis; normal Po2 and calculated oxygen saturation but decreased oxygen saturation by cooximetry. (That measured by pulse oximetry is falsely elevated but is less than normal and less than the calculated value.) Headache and nausea are common with carbon monoxide. Sudden collapse may occur with cyanide and hydrogen sulfide exposure. A bitter almond breath odor may be noted with cyanide ingestion, and hydrogen sulfide smells like rotten eggs.


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InternalMed_Harrison. Signs and symptoms of hypoxemia with initial physiologic stimulation and subsequent depression (Table 473e-2), gray-brown cyanosis unresponsive to oxygen at methemoglobin fractions >15–20%, headache, lactic acidosis (at methemoglobin fractions >45%), normal Po2 and calculated oxygen saturation but decreased oxygen saturation and increased methemoglobin fraction by co-oximetry (Oxygen saturation by pulse oximetry may be falsely increased or decreased but is less than normal and less than the calculated value.) Initial ethanol-like intoxication, nausea, vomiting, increased osmolar gap, calcium oxylate crystalluria; delayed AGMA, back pain, renal failure; coma, seizures, hypotension, ARDS in severe cases Initial nausea, vomiting, abdominal pain, diarrhea; AGMA, cardiovascular and CNS depression, hepatitis, coagulopathy, and seizures in severe cases. Radiopaque iron tablets may be seen on abdominal x-ray.


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InternalMed_Harrison. High-dose oxygen; IV hydroxocobalamin or IV sodium nitrite and sodium thiosulfate (Lilly cyanide antidote kit) for coma, metabolic acidosis, and cardiovascular dysfunction in cyanide poisoning High-dose oxygen; IV methylene blue for methemoglobin fraction >30%, symptomatic hypoxemia, or ischemia (contraindicated in G6PD deficiency); exchange transfusion and hyperbaric oxygen for severe or refractory cases Sodium bicarbonate to correct acidemia; thiamine, folinic acid, magnesium, and high-dose pyridoxine to facilitate metabolism; ethanol or fomepizole for AGMA, crystalluria or renal dysfunction, ethylene glycol level >3 mmol/L (20 mg/ dL), and ethanol-like intoxication or increased osmolal gap if level not readily obtainable; hemodialysis for persistent AGMA, lack of clinical improvement, and renal dysfunction; hemodialysis also useful for enhancing ethylene glycol elimination and shortening duration of treatment when ethylene glycol level is >8 mmol/L (50 mg/dL)


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InternalMed_Harrison. Whole-bowel irrigation for large ingestions; endoscopy and gastrostomy if clinical toxicity and large number of tablets are still visible on x-ray; IV hydration; sodium bicarbonate for acidemia; IV deferoxamine for systemic toxicity, iron level >90 μmol/L (500 μg/dL) Physiologic Condition, Causes Examples Mechanism of Action Clinical Features Specific Treatments PART 18 Poisoning, Drug Overdose, and Envenomation Methanol Methanol causes ethanol-like CNS depression and increased serum osmolality. Formic acid metabolite causes AGMA and retinal toxicity. Initial ethanol-like intoxication, nausea, vomiting, increased osmolar gap; delayed AGMA, visual (clouding, spots, blindness) and retinal (edema, hyperemia) abnormalities; coma, seizures, cardiovascular depression in severe cases; possible pancreatitis


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InternalMed_Harrison. Initial nausea, vomiting, hyperventilation, alkalemia, alkaluria; subsequent alkalemia with both respiratory alkalosis and AGMA and paradoxical aciduria; late acidemia with CNS and respiratory depression; cerebral and pulmonary edema in severe cases. Hypoglycemia, hypocalcemia, hypokalemia, and seizures can occur. Akathisia, dystonia, parkinsonism Nausea, vomiting, agitation, confusion; coma, respiratory depression, seizures, lactic and ketoacidosis in severe cases Nausea, vomiting, diarrhea, ataxia, choreoathetosis, encephalopathy, hyperreflexia, myoclonus, nystagmus, nephrogenic diabetes insipidus, falsely elevated serum chloride with low anion gap, tachycardia; coma, seizures, arrhythmias, hyperthermia, and prolonged or permanent encephalopathy and movement disorders in severe cases; delayed onset after acute overdose, particularly with delayed-release formulations. Toxicity occurs at lower drug levels in chronic poisoning than in acute poisoning.


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InternalMed_Harrison. Gastric aspiration for recent ingestion; sodium bicarbonate to correct acidemia; high-dose folinic acid or folate to facilitate metabolism; ethanol or fomepizole for AGMA, visual symptoms, methanol level >6 mmol/L (20 mg/dL), and ethanol-like intoxication or increased osmolal gap if level not readily obtainable; hemodialysis for persistent AGMA, lack of clinical improvement, and renal dysfunction; hemodialysis also useful for enhancing methanol elimination and shortening duration of treatment when methanol level is >15 mmol/L (50 mg/dL) IV hydration and supplemental glucose; sodium bicarbonate to correct acidemia; urinary alkalinization for systemic toxicity; hemodialysis for coma, cerebral edema, seizures, pulmonary edema, renal failure, progressive acid-base disturbances or clinical toxicity, salicylate level >7 mmol/L (100 mg/dL) following acute overdose Oral or parenteral anticholinergic agent such as benztropine or diphenhydramine


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InternalMed_Harrison. Oral or parenteral anticholinergic agent such as benztropine or diphenhydramine High-dose IV pyridoxine (vitamin B6) for agitation, confusion, coma, and seizures; diazepam or barbiturates for seizures Whole-bowel irrigation for large ingestions; IV hydration; hemodialysis for coma, seizures, encephalopathy or neuromuscular dysfunction (severe, progressive, or persistent), peak lithium level >4 meq/L following acute overdose Physiologic Condition, Causes Examples Mechanism of Action Clinical Features Specific Treatments Serotonin syndrome Amphetamines, cocaine, dextromethorphan, meperidine, MAO inhibitors, selective serotonin (5-HT) reuptake inhibitors, tricyclic antidepressants, tramadol, triptans, tryptophan


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InternalMed_Harrison. Serotonin syndrome Amphetamines, cocaine, dextromethorphan, meperidine, MAO inhibitors, selective serotonin (5-HT) reuptake inhibitors, tricyclic antidepressants, tramadol, triptans, tryptophan Membrane-active Amantadine, anti-arrhythmics agents (class I and III agents; some beta blockers), antipsychotics (see above), antihistamines (particularly diphenhydramine), carbamazepine, local anesthetics (including cocaine), opioids (meperidine, propoxyphene), orphenadrine, quinoline antimalarials (chloroquine, hydroxychloroquine, quinine), cyclic antidepressants (see above) aSee above and Chap. 469e. bSee above and Chap. 468e. Promotion of serotonin release, inhibition of serotonin reuptake, or direct stimulation of CNS and peripheral serotonin receptors (primarily 5-HT-1a and 5-HT-2), alone or in combination


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InternalMed_Harrison. Promotion of serotonin release, inhibition of serotonin reuptake, or direct stimulation of CNS and peripheral serotonin receptors (primarily 5-HT-1a and 5-HT-2), alone or in combination Blockade of fast sodium membrane channels prolongs phase 0 (depolarization) of the cardiac action potential, which prolongs QRS duration and promotes reentrant (monomorphic) ventricular tachycardia. Class Ia, Ic, and III antiarrhythmics also block potassium channels during phases 2 and 3 (repolarization) of the action potential, prolonging the JT interval and promoting early after-depolarizations and polymorphic (tor-sades des pointes) ventricular tachycardia. Similar effects on neuronal membrane channels cause CNS dysfunction. Some agents also block α-adrenergic and cholinergic receptors or have opioid effects (see above and Chap. 468e).


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InternalMed_Harrison. Altered mental status (agitation, confusion, mutism, coma, seizures), neuromuscular hyperactivity (hyperreflexia, myoclonus, rigidity, tremors), and autonomic dysfunction (abdominal pain, diarrhea, diaphoresis, fever, flushing, labile hypertension, mydriasis, tearing, salivation, tachycardia). Complications include hyperthermia, lactic acidosis, rhabdomyolysis, and multisystem organ failure. QRS and JT prolongation (or both) with hypotension, ventricular tachyarrhythmias, CNS depression, seizures; anticholinergic effects with amantadine, antihistamines, carbamazepine, disopyramide, antipsychotics, and cyclic antidepressants (see above); opioid effects with meperidine and propoxyphene (see Chap. 468e); cinchonism (hearing loss, tinnitus, nausea, vomiting, vertigo, ataxia, headache, flushing, diaphoresis) and blindness with quinoline antimalarials Discontinue the offending agent(s); the serotonin receptor antagonist cyproheptadine may be helpful in severe cases.


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InternalMed_Harrison. Hypertonic sodium bicarbonate (or hypertonic saline) for cardiac conduction delays and monomorphic ventricular tachycardia; lidocaine for monomorphic ventricular tachycardia (except when due to class Ib antiarrhythmics); magnesium, isoproterenol, and overdrive pacing for polymorphic ventricular tachycardia; physostigmine for anticholinergic effects (see above); naloxone for opioid effects (see Chap. 468e); extra-corporeal removal for some agents (see text). Abbreviations: AGMA, anion-gap metabolic acidosis; ARDS, adult respiratory distress syndrome; CNS, central nervous system; GABA, γ-aminobutyric acid; GBL, γ-butyrolactone; GHB, γ-hydroxybutyrate; G6PD, glucose-6-phosphate dehydrogenase; MAO, monoamine oxidase; NDMA, N-methyl-D-aspartate; 2-PAM, pralidoxime; SIADH, syndrome of inappropirate antidiuretic hormone secretion.


InternalMed_Harrison

InternalMed_Harrison. Table 473e-4 summarizes the pathophysiology, clinical features, and treatment of toxidromes and poisonings that are common, produce life-threatening toxicity, or require unique therapeutic interventions. In all cases, treatment should include attention to the general principles discussed above and, in particular, supportive care. Poisonings not covered in this chapter are discussed in specialized texts. Alcohol, cocaine, hallucinogen, and opioid poisoning and alcohol and opioid withdrawal are discussed in Chaps. 467–469e; nicotine addiction is discussed in Chap. 470; acetaminophen poisoning is discussed in Chap. 361; the neuroleptic malignant syndrome is discussed in Chap. 449; and heavy metal poisoning is discussed in Chap. 472e. The author acknowledges the contributions of Christopher H. Linden and Michael J. Burns to this chapter in previous editions of this text. Part 18: Poisoning, Drug Overdose, and Envenomation Exposures Robert L. Norris 474


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InternalMed_Harrison. Part 18: Poisoning, Drug Overdose, and Envenomation Exposures Robert L. Norris 474 Charles Lei, Natalie J. Badowski, Paul S. Auerbach, This chapter outlines general principles for the evaluation and management of victims of envenomation and poisoning by venomous snakes and marine animals. Because the incidence of serious bites and stings is relatively low in developed nations, there is a paucity of relevant clinical research; as a result, therapeutic decision making often is based on anecdotal information.


InternalMed_Harrison

InternalMed_Harrison. The venomous snakes of the world belong to the families Viperidae (subfamily Viperinae: Old World vipers; subfamily Crotalinae: New World and Asian pit vipers), Elapidae (including cobras, coral snakes, sea snakes, kraits, and all Australian venomous snakes), Lamprophiidae (subfamily Atractaspidinae: burrowing asps), and Colubridae (a large family in which most species are nonvenomous and only a few are dangerously toxic to humans). Most snakebites occur in developing countries with temperate and tropical climates in which populations subsist on agriculture and fishing. Recent estimates indicate that somewhere between 1.2 million and 5.5 million snakebites occur worldwide each year, with 421,000–1,841,000 envenomations and 20,000–94,000 deaths. Such wide-ranging estimates reflect the challenges of collecting accurate data in the regions most affected by venomous snakes; many victims do not seek hospital treatment, and reporting and record keeping are generally poor.


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InternalMed_Harrison. The typical snake venom delivery apparatus consists of bilateral venom glands situated below and behind the eyes and connected by ducts to hollow anterior maxillary fangs. In viperids (vipers and pit vipers), these fangs are long and highly mobile; they are retracted against the roof of the mouth when the snake is at rest and brought to an upright position for a strike. In elapids, the fangs are smaller and are relatively fixed in an erect position. Approximately 20% of pit viper bites and higher percentages of other snakebites (up to 75% for sea snakes) are “dry” bites, meaning no venom is released. Significant envenomation probably occurs in ~50% of all venomous snakebites.


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InternalMed_Harrison. Differentiation of venomous from nonvenomous snake species can be difficult. Viperids are characterized by somewhat triangular heads (a feature shared with many harmless snakes), elliptical pupils (also seen in some nonvenomous snakes, such as boas and pythons), enlarged maxillary fangs, and, in pit vipers, heat-sensing pits (foveal organs) on each side of the head that assist with locating prey and aiming strikes. The New World rattlesnakes possess a series of interlocking keratin plates (the rattle) on the tip of the tail that emits a buzzing sound when the snake rapidly vibrates its tail; this sound serves as a warning signal to perceived threats. Identifying venomous snakes by color pattern is notoriously misleading, as many harmless snakes have color patterns that closely mimic those of venomous snakes found in the same region.


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InternalMed_Harrison. Snake venoms are highly variable and complex mixtures of enzymes, low-molecular-weight polypeptides, glycoproteins, and other constituents. Among the deleterious components are hemorrhagins that promote vascular leakage and cause both local and systemic bleeding.


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InternalMed_Harrison. 2734 Proteolytic enzymes cause local tissue necrosis, affect the coagulation pathway at various steps, and impair organ function. Hyaluronidases promote the spread of venom through connective tissue. Myocardial depressant factors reduce cardiac output, and bradykinins cause vasodilation and hypotension. Neurotoxins act either preor postsynaptically to block transmission at the neuromuscular junction, causing muscle paralysis. Most snake venoms have multisystem effects on their victims. After a venomous snakebite, the time to symptom onset and clinical presentation can be quite variable and depend on the species involved, the anatomic location of the bite, and the amount of venom injected. Envenomations by most viperids and some elapids with necrotizing venoms cause progressive local pain, swelling, ecchymosis (Fig. 474-1), and (over a period of hours to days) hemorrhagic or serum-filled vesicles and bullae. In serious bites, tissue loss can be significant (Figs. 474-2 and 474-3).


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InternalMed_Harrison. swelling, ecchymosis (Fig. 474-1), and (over a period of hours to days) hemorrhagic or serum-filled vesicles and bullae. In serious bites, tissue loss can be significant (Figs. 474-2 and 474-3). Systemic findings are extremely variable and can include tachycardia or bradycardia, hypotension, generalized weakness, changes in taste, mouth numbness, muscle fasciculations, pulmonary edema, renal dysfunction, and spontaneous hemorrhage (from essentially any anatomic site). Envenomations by neurotoxic elapids such as kraits (Bungarus species), many Australian elapids (e.g., death adders [Acanthophis species] and tiger snakes [Notechis species]), some cobras (Naja species), and some viperids (e.g., the South American rattlesnake [Crotalus durissus] and some Indian Russell’s vipers [Daboia russelii]) cause neurologic dysfunction. Early findings may consist of nausea and vomiting, headache, paresthesias or numbness, and altered mental status. Victims may develop cranial nerve abnormalities


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InternalMed_Harrison. cause neurologic dysfunction. Early findings may consist of nausea and vomiting, headache, paresthesias or numbness, and altered mental status. Victims may develop cranial nerve abnormalities (e.g., ptosis, difficulty swallowing) followed by peripheral motor weakness. Severe envenomation may result in muscle paralysis, including the muscles of respiration, and lead to death from respiratory failure and aspiration. Sea snake envenomation results in


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InternalMed_Harrison. FIGUrE 474-1 Northern Pacific rattlesnake (Crotalus oreganus oreganus) envenomations. A. Moderately severe envenomation. Note edema and early ecchymosis 2 h after a bite to the finger. B. Severe envenomation. Note extensive ecchymosis 5 days after a bite to the ankle. FIGUrE 474-2 Early stages of severe, full-thickness necrosis 5 days after a Russell’s viper (Daboia russelii) bite in southwestern India. local pain (variable), generalized myalgias, trismus, rhabdomyolysis, and progressive flaccid paralysis; these manifestations can be delayed for several hours.


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InternalMed_Harrison. The most important aspect of prehospital care of a person bitten by a venomous snake is rapid transport to a medical facility equipped to provide supportive care (airway, breathing, and circulation) and antivenom therapy. Most of the first-aid measures recommended in the past are of little benefit, and some actually worsen outcome. It is reasonable to apply a splint to the bitten extremity to lessen bleeding and discomfort and, if possible, to keep the extremity at approximately heart level. In developing countries, indigenous people should be encouraged to seek immediate care at a health care facility equipped with antivenom instead of consulting traditional healers and thus incurring significant delays in reaching appropriate care. Attempting to capture and transport the offending snake, alive or dead, is not advised; instead, digital photographs of the snake taken from a safe distance may assist with snake identification and treatment decisions.


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InternalMed_Harrison. FIGUrE 474-3 Severe necrosis 10 days after a pit viper bite in a young child in Colombia. (Courtesy of Jay R. Stanka; with permission.) Incising and/or applying suction to the bite site should be avoided, as these measures are ineffective and exacerbate local tissue damage. Similarly ineffective and potentially harmful are the application of poultices, ice, and electric shock. Techniques or devices used in an effort to limit venom spread (e.g., lymphoocclusive bandages or tourniquets) are ineffective and may result in greater local tissue damage by restricting the spread of potentially necrotizing venom. Tourniquet use can result in loss of function and amputation even in the absence of envenomation.


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InternalMed_Harrison. Elapid venoms that are primarily neurotoxic and have no significant effects on local tissue may be localized by pressure-immobilization, a technique in which the entire limb is wrapped immediately with a bandage (e.g., crepe or elastic) and then immobilized. For this technique to be effective, the wrap pressure must be precise (40–70 mmHg in upper-extremity application and 55–70 mmHg in lower-extremity application) and the victim must be carried out of the field because walking generates muscle-pumping activity that— regardless of the anatomic site of the bite—will disperse venom into the systemic circulation. Pressure-immobilization should be used only in cases in which the offending snake is reliably identified and known to be primarily neurotoxic, the rescuer is skilled in pressure-wrap application, the necessary supplies are readily available, and the victim can be fully immobilized and carried to medical care—an uncommon combination of conditions, particularly in the regions of


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InternalMed_Harrison. application, the necessary supplies are readily available, and the victim can be fully immobilized and carried to medical care—an uncommon combination of conditions, particularly in the regions of the world where such bites are most common.


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InternalMed_Harrison. In the hospital, the victim should be closely monitored (vital signs, cardiac rhythm, oxygen saturation, urine output) while a history is quickly obtained and a rapid, thorough physical examination is performed. To objectively evaluate the progression of local envenomation, the level of swelling in the bitten extremity should be marked and limb circumference should be measured every 15 min until the swelling has stabilized. During this period of observation, the extremity should be positioned at approximately heart level. Measures applied in the field (such as bandages or wraps) should be removed once IV access has been obtained, with cognizance that the release of such ligatures may result in hypotension or dysrhythmias when stagnant acidotic blood containing venom is released into the systemic circulation. Two large-bore IV lines should be established in unaffected extremities. Because of the potential for coagulopathy, venipuncture attempts should be minimized, and noncompressible


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InternalMed_Harrison. circulation. Two large-bore IV lines should be established in unaffected extremities. Because of the potential for coagulopathy, venipuncture attempts should be minimized, and noncompressible sites (e.g., a subclavian vein) should be avoided. Early hypotension is due to pooling of blood in the pulmonary and splanchnic vascular beds. Later, systemic bleeding, hemolysis, and loss of intravascular volume into the soft tissues may play important roles. Fluid resuscitation with isotonic saline (20–40 mL/kg IV) should be initiated if there is any evidence of hemodynamic instability, and a trial of 5% albumin (10–20 mL/kg IV) may be given if the response to saline infusion is inadequate. Only after aggressive volume resuscitation and antivenom administration (see below) are accomplished should vasopressors (e.g., dopamine) be added. Invasive hemodynamic monitoring (central venous and/or continuous arterial pressures) can be helpful in such cases, although obtaining central vascular access is


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InternalMed_Harrison. (e.g., dopamine) be added. Invasive hemodynamic monitoring (central venous and/or continuous arterial pressures) can be helpful in such cases, although obtaining central vascular access is risky if coagulopathy has developed. Victims of neurotoxic envenomation should be watched carefully for evidence of cranial nerve dysfunction (e.g., ptosis) that may precede the onset of difficulty swallowing or respiratory insufficiency that necessitates definitive airway protection by endotracheal intubation.


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InternalMed_Harrison. Blood should be drawn for typing and cross-matching and for laboratory evaluation as soon as possible. Important studies include a complete blood count to determine the degree of hemorrhage or hemolysis and to identify thrombocytopenia; studies of renal and hepatic function; coagulation studies to diagnose consumptive 2735 coagulopathy; creatine kinase for suspected rhabdomyolysis; and testing of urine for blood or myoglobin. In developing regions, the 20-min whole-blood clotting test can be used to reliably diagnose coagulopathy. A few milliliters of fresh blood are placed in a new, clean, plain glass receptacle (e.g., a test tube) and left undisturbed for 20 min. The tube is then tipped once to 45° to determine whether a clot has formed. If it has not, coagulopathy is diagnosed. Arterial blood gas studies, electrocardiography, and chest radiography may be helpful in severe envenomations or when there is significant comorbidity. Any arterial puncture in the setting of coagulopathy


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InternalMed_Harrison. blood gas studies, electrocardiography, and chest radiography may be helpful in severe envenomations or when there is significant comorbidity. Any arterial puncture in the setting of coagulopathy requires great caution and must be performed at an anatomic site amenable to direct-pressure tamponade. After antivenom therapy (see below), laboratory values should be rechecked every 6 h until clinical stability is achieved. If initial laboratory values are normal, the complete blood count and coagulation studies should be repeated every hour until it is clear that no systemic envenomation has occurred.


InternalMed_Harrison

InternalMed_Harrison. The mainstay of treatment of a venomous snakebite resulting in significant envenomation is prompt administration of specific antivenom. Antivenoms are produced by injecting animals (generally horses or sheep) with venoms from medically important snakes. Once the stock animals develop antibodies to the venoms, their serum is harvested and the antibodies are isolated for antivenom preparation, which may involve varying degrees of digestion and purification of the IgG molecules. The goal of antivenom administration is to allow antibodies (or antibody fragments) to bind and deactivate circulating venom components before they can attach to target tissues and cause deleterious effects. Antivenoms may be monospecific (directed against a particular snake species) or polyspecific (covering several medically important species in the region) but rarely offer cross-protection against snake species other than those used in their production unless the species are known to have homologous venoms.


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InternalMed_Harrison. medically important species in the region) but rarely offer cross-protection against snake species other than those used in their production unless the species are known to have homologous venoms. Thus, antivenom selection must be specific for the offending snake; if the antivenom chosen does not contain antibodies to that snake’s venom components, it will provide no benefit and may lead to unnecessary complications (see below). In the United States, assistance in finding appropriate antivenom can be obtained from regional poison control centers.


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InternalMed_Harrison. For victims of bites by viperids or cytotoxic elapids, indications for antivenom administration include significant progressive local findings (e.g., soft tissue swelling crossing a joint or involving more than half the bitten limb) and any evidence of systemic envenomation (systemic symptoms or signs, laboratory abnormalities). Caution must be used in determining the significance of isolated soft tissue swelling after the bite of an unidentified snake because the saliva of some relatively harmless species can cause mild edema at the bite site; in such bites, antivenoms are useless and potentially harmful. Antivenoms have limited efficacy in preventing tissue damage caused by necrotizing venoms, as venom components bind to local tissues very quickly, before antivenom administration can be initiated. Nevertheless, antivenom should be administered as soon as the need for it is identified to limit further tissue damage and systemic effects. Antivenom administration after bites by


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InternalMed_Harrison. can be initiated. Nevertheless, antivenom should be administered as soon as the need for it is identified to limit further tissue damage and systemic effects. Antivenom administration after bites by neurotoxic elapids is indicated at the first sign of any evidence of neurotoxicity (e.g., cranial nerve dysfunction, peripheral neuropathy). In general, antivenom is effective only in reversing active venom toxicity; it is of no benefit in reversing effects that already have been established (e.g., renal failure, established paralysis) and that will improve only with time and other supportive therapies.


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InternalMed_Harrison. Specific comments related to the management of venomous snakebites in the United States and Canada appear in Table 474-1. The package insert for the selected antivenom can be consulted regarding species covered, method of administration, starting dose, and need (if any) for re-dosing. The information in antivenom package inserts, however, is not always accurate and reliable. Whenever possible, it is advisable for treating physicians to seek advice from experts in snakebite management regarding indications for and dosing of antivenom. Pit viper bites (rattlesnakes [Crotalus and Sistrurus spp.], cottonmouth water moccasins [Agkistrodon piscivorus], and copperheads [Agkistrodon contortrix]) airway, breathing, and circulation. monitoring (vital signs, cardiac rhythm, and oxygen saturation). two large-bore IV lines. the patient is hypotensive, administer a normal saline bolus (20–40 mL/kg IV). hypotension persists, consider 5% albumin (10–20 mL/kg IV).


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InternalMed_Harrison. two large-bore IV lines. the patient is hypotensive, administer a normal saline bolus (20–40 mL/kg IV). hypotension persists, consider 5% albumin (10–20 mL/kg IV). rapid history and perform thorough physical examination. offending snake if possible. and record circumference of bitten extremity every 15 min until swelling has stabilized. laboratory studies (CBC, metabolic panel, PT/INR/PTT, fibrinogen level, FDP, blood type and cross-matching, urinalysis). normal, repeat CBC and coagulation studies every hour until it is clear that no systemic envenomation has occurred. abnormal, repeat 6 h after antivenom administration (see below). severity of envenomation.


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InternalMed_Harrison. abnormal, repeat 6 h after antivenom administration (see below). severity of envenomation. • None: • Mild: local findings only (e.g., pain, ecchymosis, nonprogressive swelling) • Moderate: swelling that is clearly progressing, systemic symptoms or signs, and/or laboratory abnormalities • Severe: neurologic dysfunction, respiratory distress, and/or cardiovascular instability/shock regional poison control center. and administer antivenom as indicated: Crotalidae Polyvalent Immune Fab (CroFab) (Ovine) (BTG International Inc., West Conshohocken, PA). on severity of envenomation or mild: none • Moderate: • Severe: reconstituted vials in 250 mL of normal saline. IV over 1 h (with physician in close attendance). acute reaction to antivenom: infusion. with standard doses of epinephrine (IM or IV; latter route only in setting of severe hypotension), antihistamines (IV), and glucocorticoids (IV).


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InternalMed_Harrison. acute reaction to antivenom: infusion. with standard doses of epinephrine (IM or IV; latter route only in setting of severe hypotension), antihistamines (IV), and glucocorticoids (IV). reaction is controlled, restart antivenom as soon as possible (may further dilute in larger volume of normal saline). clinical status over 1 h. or improved: Admit to hospital. or unimproved: Repeat starting dose (and continue this pattern until patient’s condition is stable or improved). products are rarely needed; if required, they should be given only after antivenom administration. tetanus immunization as needed. antibiotics are unnecessary unless prehospital care included incision or mouth suction. management: acetaminophen and/or narcotics as needed; avoidance of salicylates and nonsteroidal anti-inflammatory agents to hospital. (If no evidence of envenomation, monitor for 8 h before discharge.) additional CroFab (2 vials every 6 h for 3 additional doses, with close monitoring).


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InternalMed_Harrison. for evidence of rising intracompartmental pressures (see text). wound care (see text). physical therapy (see text). discharge, warn patient of possible recurrent coagulopathy and symptoms/signs of delayed serum sickness. Coral snakebites (Micrurus spp. and Micruroides euryxanthus) airway, breathing, and circulation. monitoring (vital signs, cardiac rhythm, and oxygen saturation). one large-bore IV line and initiate normal saline infusion. rapid history and perform thorough physical examination. offending snake if possible. studies are unlikely to be helpful. regional poison control center. and administer antivenom as indicated: Antivenin (Micrurus fulvius) (equine) (commonly referred to as North American Coral Snake Antivenin; Wyeth Pharmaceuticals, New York, NY).b to antivenom package insert. 3–5 reconstituted vials of antivenom in 250 mL of normal saline. IV over 1 h (with physician in close attendance).


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InternalMed_Harrison. 3–5 reconstituted vials of antivenom in 250 mL of normal saline. IV over 1 h (with physician in close attendance). signs of envenomation progress despite initial antivenom, repeat the starting dose (up to 10 vials total may be required). (Continued ) acute adverse reaction to antivenom: infusion. with standard doses of epinephrine (IM or IV; latter route only in setting of severe hypotension), antihistamines (IV), and glucocorticoids (IV). reaction is controlled, restart antivenom as soon as possible (may further dilute in larger volume of normal saline). any evidence of neurologic dysfunction (e.g., any cranial nerve abnormalities such as ptosis): any evidence of difficulty swallowing or breathing, proceed with endotracheal intubation and ventilatory support (may be required for days or weeks). tetanus immunization as needed. antibiotics are unnecessary unless prehospital care included incision or mouth suction.


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InternalMed_Harrison. tetanus immunization as needed. antibiotics are unnecessary unless prehospital care included incision or mouth suction. to hospital (intensive care unit) even if there is no evidence of envenomation; monitor for at least 24 h. aThese recommendations are specific to the care of victims of venomous snakebites in the United States and Canada and should not be applied to bites in other regions of the world. bAt the time of publication, a single lot of antivenom remains, with an extended expiration date of April 30, 2015. Abbreviations: CBC, complete blood count; FDP, fibrin degradation products; PT/INR/PTT, prothrombin time/international normalized ratio/partial thromboplastin time.


InternalMed_Harrison

InternalMed_Harrison. Antivenom should be administered only by the IV route, and the infusion should be started slowly, with the physician at the bedside ready to intervene immediately at the first signs of an acute adverse reaction. In the absence of an adverse reaction, the rate of infusion can be increased gradually until the full starting dose has been administered (over a total period of ~1 h). Further antivenom may be necessary if the patient’s acute clinical condition worsens or fails to stabilize or if venom effects that were initially controlled recur. The decision to administer further antivenom to a stabilized patient should be based on clinical evidence of persistent circulation of unbound venom components. For viperid bites, antivenom administration generally should be continued until the victim shows definite improvement (e.g., stabilized vital signs, reduced pain, restored coagulation). Neurotoxicity from elapid bites may be more difficult to reverse with antivenom. Once neurotoxicity is


InternalMed_Harrison

InternalMed_Harrison. shows definite improvement (e.g., stabilized vital signs, reduced pain, restored coagulation). Neurotoxicity from elapid bites may be more difficult to reverse with antivenom. Once neurotoxicity is established and endotracheal intubation is required, further doses of antivenom are unlikely to be beneficial. In such cases, the victim must be maintained on mechanical ventilation until recovery, which may take days or weeks.


InternalMed_Harrison

InternalMed_Harrison. Adverse reactions to antivenom administration include immediate (nonallergic and, less commonly, allergic anaphylaxis) and delayed-type hypersensitivity reactions (serum sickness). Clinical manifestations of immediate hypersensitivity include urticaria, laryngeal edema, bronchospasm, and hypotension. Skin testing for potential hypersensitivity, although recommended by some antivenom manufacturers, is insensitive and nonspecific and should be omitted. Worldwide, the quality of antivenoms is highly variable. Rates of acute nonallergic anaphylactic reactions to some of these products exceed 50%. For this reason, some authorities have recommended pretreatment with IV antihistamines (e.g., diphenhydramine, 1 mg/kg to a maximum of 100 mg; and cimetidine, 5–10 mg/kg to a maximum of 300 mg) or even a prophylactic SC or IM dose of epinephrine (0.01 mg/kg, up to 0.3 mg). Further research is necessary, however, to determine whether any pretreatment measures are truly beneficial. Modest expansion


InternalMed_Harrison

InternalMed_Harrison. a prophylactic SC or IM dose of epinephrine (0.01 mg/kg, up to 0.3 mg). Further research is necessary, however, to determine whether any pretreatment measures are truly beneficial. Modest expansion of the patient’s intra-vascular volume with crystalloids may blunt acute adverse blood pressure decline. Epinephrine and airway equipment should always be immediately available during antivenom infusion. An acute anaphylactic reaction may be heralded by a single hive or mild itching or may present as bronchospasm or acute cardiovascular collapse. If the patient develops an acute reaction to antivenom, the infusion should be temporarily stopped and the reaction immediately treated with IM epinephrine and IV antihistamines and glucocorticoids. Once the reaction has been controlled, if the severity of the envenomation warrants additional antivenom, the dose should be diluted further in isotonic saline and restarted as soon as possible. Rarely, in cases of recalcitrant hypotension, a


InternalMed_Harrison

InternalMed_Harrison. severity of the envenomation warrants additional antivenom, the dose should be diluted further in isotonic saline and restarted as soon as possible. Rarely, in cases of recalcitrant hypotension, a concomitant IV infusion of epinephrine may be initiated and titrated to clinical effect while antivenom is administered. The patient must be monitored very closely during such therapy, preferably in an intensive care setting. Serum sickness typically develops 1–2 weeks after antivenom administration and may present as fever, chills, urticaria, myalgias, arthralgias, lymphadenopathy, and renal or neurologic dysfunction. Treatment of serum sickness consists of systemic glucocorticoids (e.g., oral prednisone, 1–2 mg/kg daily) until all symptoms have resolved, followed by a taper over 1–2 weeks. Oral antihistamines and analgesics may provide additional relief of symptoms.


InternalMed_Harrison

InternalMed_Harrison. Blood products are rarely necessary in the management of an envenomed patient. The venoms of many snake species can deplete coagulation factors and cause a decrease in platelet count or hematocrit. Nevertheless, these components usually rebound within hours after administration of adequate antivenom. If the need for blood products is thought to be great (e.g., a dangerously low platelet count in a hemorrhaging patient), these products should be given only after adequate antivenom administration to avoid fueling ongoing consumptive coagulopathy.


InternalMed_Harrison

InternalMed_Harrison. Rhabdomyolysis and hemolysis should be managed in standard fashion. Victims who develop acute renal failure should be evaluated by a nephrologist and referred for hemodialysis or peritoneal dialysis as needed. Such renal failure, which usually is due to acute tubular necrosis, is frequently reversible. If bilateral cortical necrosis occurs, however, the prognosis for renal recovery is less favorable, and longterm dialysis with possible renal transplantation may be necessary.


InternalMed_Harrison

InternalMed_Harrison. Acetylcholinesterase inhibitors (e.g., edrophonium and neostigmine) may promote neurologic improvement in patients bitten by snakes with postsynaptic neurotoxins. Snakebite victims with objective evidence of neurologic dysfunction should receive a test dose of acetylcholinesterase inhibitors, as outlined in Table 474-2. If they exhibit improvement, additional doses of long-acting neostigmine can be administered as needed. Close monitoring is required to prevent aspiration if repetitive dosing of neostigmine is used in an 1. Patients with clear, objective evidence of neurotoxicity (e.g., ptosis or inability to maintain upward gaze) should receive a test dose of edrophonium (if available) or neostigmine. a. Pretreat with atropine: 0.6 mg IV (children, 0.02 mg/kg with a minimum of 0.1 mg) b. Treat with: Edrophonium: 10 mg IV (children, 0.25 mg/kg)


InternalMed_Harrison

InternalMed_Harrison. a. Pretreat with atropine: 0.6 mg IV (children, 0.02 mg/kg with a minimum of 0.1 mg) b. Treat with: Edrophonium: 10 mg IV (children, 0.25 mg/kg) Neostigmine: 1.5–2.0 mg IM (children, 0.025–0.08 mg/kg) 2. If objective improvement is evident after 5 min, treat with: a. Neostigmine: 0.5 mg IV or SC (children, 0.01 mg/kg) every 30 min as b. Atropine: 0.6 mg IV continuous infusion over 8 h (children, 0.02 mg/kg over 8 h) 3. Closely monitor the airway and perform endotracheal intubation as needed.


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InternalMed_Harrison. 2738 attempt to obviate endotracheal intubation. Acetylcholinesterase inhibitors are not a substitute for administration of an appropriate antivenom when available. Care of the bite wound includes simple cleansing with soap and water; application of a dry, sterile dressing; and splinting of the affected extremity with padding between the digits. Once antivenom therapy has been initiated, the extremity should be elevated above heart level to reduce swelling. Tetanus immunization should be updated as appropriate. Prophylactic antibiotics are generally unnecessary after bites by North American snakes, as the incidence of secondary infection is low. In some regions, secondary bacterial infection is more common and the consequences are dire; in these regions, prophylactic antibiotics (e.g., cephalosporins) are used commonly. Antibiotics may also be considered if misguided first aid efforts have included incision or mouth suction of the bite site. Pain control should be achieved with


InternalMed_Harrison

InternalMed_Harrison. cephalosporins) are used commonly. Antibiotics may also be considered if misguided first aid efforts have included incision or mouth suction of the bite site. Pain control should be achieved with acetaminophen or narcotic analgesics. Salicylates and nonsteroidal anti-inflammatory agents should be avoided because of their effects on blood clotting. Most snake envenomations involve SC deposition of venom. On occasion, however, venom can be injected more deeply into muscle compartments, particularly if the offending snake was large and the bite occurred on the lower leg, forearm, or hand. Intramuscular swelling of the affected extremity may be accompanied by severe pain, decreased strength, altered sensation, cyanosis, and apparent pulselessness—signs suggesting a muscle compartment syndrome. If there is clinical concern that subfascial muscle edema may be impeding tissue perfusion, intracompartmental pressures should be measured by a minimally invasive technique (e.g., wick catheter or


InternalMed_Harrison

InternalMed_Harrison. If there is clinical concern that subfascial muscle edema may be impeding tissue perfusion, intracompartmental pressures should be measured by a minimally invasive technique (e.g., wick catheter or digital readout device). If the intracompartmental pressure is high (>30–40 mmHg), the extremity should be kept elevated while antivenom is administered. A dose of IV mannitol (1 g/kg) can be given in an effort to reduce muscle edema if the patient is hemodynamically stable. If the intracompartmental pressure remains elevated after 1 h of such therapy, a surgical consultation should be obtained for possible fasciotomy. Although evidence from animal studies suggests that fasciotomy may actually worsen myonecrosis, compartmental decompression is still necessary to preserve nerve function. Fortunately, the incidence of compartment syndrome is very low after a snakebite, with fasciotomies required in <1% of cases. Nevertheless, vigilance is essential. If a fasciotomy is deemed necessary, it


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InternalMed_Harrison. the incidence of compartment syndrome is very low after a snakebite, with fasciotomies required in <1% of cases. Nevertheless, vigilance is essential. If a fasciotomy is deemed necessary, it should be undertaken with the patient’s informed consent whenever possible. Wound care in the days after the bite should include careful aseptic debridement of clearly necrotic tissue once coagulation has been restored. Intact serum-filled vesicles or hemorrhagic blebs should be left undisturbed. If ruptured, they should be debrided with sterile technique. Any debridement of damaged muscle should be conservative because there is evidence that such muscle may recover to a significant degree after antivenom therapy. Physical therapy should be started as soon as possible so that the victim can return to a functional state. The incidence of long-term loss of function (e.g., reduced range of motion, impaired sensory function) is unclear but is probably quite high (>30%), particularly after viperid


InternalMed_Harrison

InternalMed_Harrison. to a functional state. The incidence of long-term loss of function (e.g., reduced range of motion, impaired sensory function) is unclear but is probably quite high (>30%), particularly after viperid bites. Any patient with signs of envenomation should be observed in the hospital for at least 24 h. In North America, a patient with an apparently “dry” viperid bite should be watched for at least 8 h before discharge, as significant toxicity occasionally develops after a delay of several hours. The onset of systemic symptoms commonly is delayed for a number of hours after bites by several of the elapids (including coral snakes, Micrurus species), some non–North American viperids (e.g., the hump-nosed pit viper [Hypnale hypnale]), and sea snakes. Patients bitten by these snakes should be observed in the hospital for at least 24 h. Patients whose condition is not stable should be admitted to an intensive care setting. At hospital discharge, victims of venomous snakebites should be warned


InternalMed_Harrison

InternalMed_Harrison. in the hospital for at least 24 h. Patients whose condition is not stable should be admitted to an intensive care setting. At hospital discharge, victims of venomous snakebites should be warned about symptoms and signs of wound infection, antivenomrelated serum sickness, and potential long-term sequelae, such as pituitary insufficiency from Russell’s viper (D. russelii) bites. If coagulopathy developed in the acute stages of envenomation, it can recur during the first 2–3 weeks after the bite. In such cases, victims should be warned to avoid elective surgery or activities posing a high risk of trauma during this period. Outpatient analgesic treatment, wound management, and physical therapy should be provided.


InternalMed_Harrison

InternalMed_Harrison. The overall mortality rates for victims of venomous snakebites are low in regions with rapid access to medical care and appropriate antivenoms. In the United States, for example, the mortality rate is <1% for victims who receive antivenom. Eastern and western diamondback rattlesnakes (Crotalus adamanteus and Crotalus atrox, respectively) are responsible for the majority of snakebite deaths in the United States. Snakes responsible for large numbers of deaths in other countries include cobras (Naja spp.), carpet and saw-scaled vipers (Echis spp.), Russell’s vipers (D. russelii), large African vipers (Bitis spp.), lancehead pit vipers (Bothrops spp.), and tropical rattlesnakes (C. durissus).


InternalMed_Harrison

InternalMed_Harrison. The incidence of morbidity—defined as permanent functional loss in a bitten extremity—is difficult to estimate but is substantial. Morbidity may be due to muscle, nerve, or vascular injury or to scar contracture. Such morbidity can have devastating consequences for victims in the developing world when they lose the ability to work and provide for their families. In the United States, functional loss tends to be more common and severe after rattlesnake bites than after bites by copperheads (Agkistrodon contortrix) or water moccasins (Agkistrodon piscivorus).


InternalMed_Harrison

InternalMed_Harrison. In many developing countries where snakebites are common, scarce access to medical care and antivenom resources con tributes to high rates of morbidity and mortality. In many countries, the available antivenoms are inappropriate and ineffective against the venoms of medically important indigenous snakes. In those regions, further research is necessary to determine the actual impact of venomous snakebites and the specific antivenom needs in terms of both quantity and spectrum of coverage. Without accurate statistics, it is difficult to persuade antivenom manufacturers to begin and sustain production of appropriate antisera in developing nations. There is evidence that antivenoms can be produced in much more cost-effective ways than those currently being used. Just as important as getting the correct antivenoms into underserved regions is the need to educate populations about snakebite prevention and to train medical care providers in proper management approaches. Local protocols


InternalMed_Harrison

InternalMed_Harrison. the correct antivenoms into underserved regions is the need to educate populations about snakebite prevention and to train medical care providers in proper management approaches. Local protocols written with significant input from experienced providers in the region of concern should be developed and distributed. Appropriate antivenoms must be available at the likely first point of medical contact for patients (e.g., primary health centers) in order to minimize the common practice of referring victims to more distant, higher levels of care for the initiation of antivenom therapy. Those who care for snakebite victims in these often-remote clinics must have the skills and confidence required to begin antivenom treatment (and to treat possible reactions) as soon as possible when needed.


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InternalMed_Harrison. Much of the management of envenomation by marine creatures is supportive in nature. A specific marine antivenom can be used when appropriate.


InternalMed_Harrison

InternalMed_Harrison. INVErtEBratES Cnidarians The Golgi apparatus of the cnidoblast cells within cnidarians, such as hydroids, fire coral, jellyfish, Portuguese men-of-war, and sea anemones, secretes specialized living stinging organelles called cnidae (also referred to as cnidocysts, a term that encompasses nematocysts, ptychocysts, and spirocysts). Within each organelle resides a stinging mechanism (“thread tube”) and venom. In the stinging process, cnidocysts are released and discharged upon mechanosensory stimulation. The venoms from these organisms contain bioactive substances such as tetramine, 5-hydroxytryptamine, histamine, serotonin, and high-molecular-weight toxins, all of which can, among other effects, change the permeability of cells to ions. Victims usually report immediate prickling or burning, pruritus, paresthesias, and painful throbbing with radiation. The skin becomes reddened, darkened, edematous, and blistered and may show signs of superficial necrosis. A legion of neurologic,


InternalMed_Harrison

InternalMed_Harrison. pruritus, paresthesias, and painful throbbing with radiation. The skin becomes reddened, darkened, edematous, and blistered and may show signs of superficial necrosis. A legion of neurologic, cardiovascular, respiratory, rheumatologic, gastrointestinal, renal, and ocular symptoms has been described, especially following stings from anemones, Physalia species, and scyphozoans. Anaphylaxis is possible. Hundreds of deaths have been reported, many of them caused by Chironex fleckeri, Stomolophus nomurai, Physalia physalis, and Chiropsalmus quadrumanus. Irukandji syndrome, associated with the Australian jellyfish Carukia barnesi and other species, is a potentially fatal condition that most commonly is characterized by hypertension; severe back, chest, and abdominal pain; nausea and vomiting; headache; sweating; and, in the most serious cases, myocardial troponin leak, pulmonary edema, and ultimately hypotension. This syndrome is thought to be mediated, at least in part, by the release of


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InternalMed_Harrison. headache; sweating; and, in the most serious cases, myocardial troponin leak, pulmonary edema, and ultimately hypotension. This syndrome is thought to be mediated, at least in part, by the release of endogenous catecholamines followed by cytokines and nitric oxide.


InternalMed_Harrison

InternalMed_Harrison. Rescuers should note that envenomations by different cnidarians (typified by jellyfish) may respond differently to similar topical therapies; thus, the recommendations in this chapter must be tailored to local species and clinical practices. During stabilization, the skin should be decontaminated immediately with a generous application of lidocaine (up to 4%), an all-purpose agent that appears to be useful for relieving pain caused by a large number of species. Vinegar (5% acetic acid), rubbing alcohol (40–70% isopropyl alcohol), baking soda (sodium bicarbonate, especially for sea nettle stings), papain (unseasoned meat tenderizer), fresh lemon or lime juice, olive oil, or sugar may be effective, depending on the species of stinging creature. Household ammonia may in and of itself cause skin irritation.


InternalMed_Harrison

InternalMed_Harrison. The pressure-immobilization technique is no longer recommended for venom containment in the setting of any jellyfish sting. For the sting of the venomous box jellyfish (C. fleckeri), vinegar should be used. Local application of heat (up to 45°C/113°F), commonly by immersion in hot water, may be as effective. A baking soda slurry (50% baking soda, 50% water) has been recommended for Cyanea and Chrysaora species. Commercial (chemical) cold packs or real ice packs applied over a thin dry cloth or a plastic membrane have been shown to be effective in alleviating mild or moderate Physalia utriculus (bluebottle jellyfish) stings but may be less effective than application of heat. Perfume, aftershave lotion, and high-proof ethanol are not efficacious and may be detrimental; formalin, ether, gasoline, and other organic solvents should not be used. Shaving the skin helps remove remaining nematocysts. Freshwater irrigation and rubbing lead to further stinging by adherent nematocysts and should


InternalMed_Harrison

InternalMed_Harrison. and other organic solvents should not be used. Shaving the skin helps remove remaining nematocysts. Freshwater irrigation and rubbing lead to further stinging by adherent nematocysts and should be avoided.


InternalMed_Harrison

InternalMed_Harrison. After decontamination, topical application of an anesthetic ointment (lidocaine, benzocaine), an antihistamine (diphenhydramine), or a glucocorticoid (hydrocortisone) may be helpful. Persistent severe pain after decontamination may be treated with morphine, meperidine, fentanyl, or another narcotic analgesic. Muscle spasms may respond to diazepam (2–5 mg, titrated upward as necessary) or 10% calcium gluconate (5–10 mL) given IV. An ovine-derived IgG antivenom is available from Commonwealth Serum Laboratories (see “Sources of Antivenoms and Other Assistance,” below) for stings from the box jellyfish found in Australian and Indo-Pacific waters. However, despite its reported clinical efficacy, one school of thought holds that perhaps the antivenom is unable to bind the venom rapidly enough to account for its effects. Until further notice, current recommendations for its use apply. Treatment for Irukandji syndrome may require administration of opioid analgesics and MgSO4 as well as


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InternalMed_Harrison. to account for its effects. Until further notice, current recommendations for its use apply. Treatment for Irukandji syndrome may require administration of opioid analgesics and MgSO4 as well as aggressive treatment (phentolamine, 5 mg IV) of hypertension. All victims with systemic reactions should be observed for at least 6–8 h for rebound from any therapy, and all elderly adults should be checked for cardiac arrhythmias. Patients may suffer postinflammatory hyperpigmentation and persistent cutaneous hypersensitivity in areas of skin contact.


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InternalMed_Harrison. Safe Sea, a “jellyfish-safe” sunblock (www.nidaria.com) applied to the skin before an individual enters the water, inactivates the recognition and discharge mechanisms of nematocysts, has been tested successfully against a number of marine stingers, and may prevent or 2739 diminish the effects of coelenterate stings. Whenever possible, a dive skin or wet suit should be worn when entering ocean waters.


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InternalMed_Harrison. Sea Sponges Many sponges produce crinotoxins that are present on their surface or in their internal secretions. As a result, touching a sea sponge may result in dermatitis or “sponge diver’s disease,” a necrotic skin reaction. Irritant dermatitis may result if small spicules of silica or calcium carbonate penetrate the skin. It is impossible to distinguish between the allergic and spicule reactions, so the treatment is the same for both. Afflicted skin should be gently dried and adhesive tape used to remove embedded spicules. Vinegar should be applied immediately and then for 10–30 min three or four times a day. Rubbing alcohol may be used if vinegar is unavailable. After spicule removal and skin decontamination, glucocorticoid or antihistamine cream may be applied to the skin. Severe vesiculation should be treated with a 2-week tapering course of systemic glucocorticoids. Mild reactions subside in 3–7 days, while involvement of large areas of the skin may result in systemic symptoms


InternalMed_Harrison

InternalMed_Harrison. should be treated with a 2-week tapering course of systemic glucocorticoids. Mild reactions subside in 3–7 days, while involvement of large areas of the skin may result in systemic symptoms of fever, dizziness, nausea, muscle cramps, and formication.


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InternalMed_Harrison. annelid Worms Annelid worms (bristleworms) possess rows of soft, cactus-like spines capable of inflicting painful stings. Contact results in symptoms similar to those of nematocyst envenomation. Without treatment, pain usually subsides over several hours, but inflammation may persist for up to a week (Fig. 474-4). Victims should resist the urge to scratch because scratching may fracture retrievable spines. Visible bristles should be removed with forceps and adhesive tape or a commercial facial peel; alternatively, a thin layer of rubber cement can be used to entrap and then peel away the spines. Use of vinegar or rubbing alcohol or a brief application of lidocaine or unseasoned meat tenderizer (papain) may provide additional relief. Local inflammation should be treated with topical or systemic glucocorticoids.


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InternalMed_Harrison. Sea Urchins Venomous sea urchins possess either hollow, venom-filled calcified spines or triple-jawed, globiferous pedicellariae with venom glands. Venom may also be found within the integumentary sheath on the external spine surface of certain species. The venom contains toxic components, including steroid glycosides, hemolysins, proteases, serotonin, and cholinergic substances. Contact with either venom apparatus produces immediate and intensely painful stings. One or more spines entering a joint can cause synovitis that may, over time, progress to arthritis if the spine(s) remain in or near the joint. If multiple spines penetrate the skin, the patient may develop systemic symptoms, including nausea, vomiting, numbness, muscular paralysis, and respiratory distress. A delayed hypersensitivity reaction 7–10 days after resolution of primary symptoms has been described.


InternalMed_Harrison

InternalMed_Harrison. The affected part should be immersed immediately in hot water to tolerance (up to 45°C/113°F). Pedicellariae should be removed by shaving so that envenomation cannot continue. Accessible embedded spines should be removed but may break off and remain lodged in


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InternalMed_Harrison. FIGUrE 474-4 Rash on the hand of a diver from the spines of a bristleworm. (Courtesy of Paul Auerbach, with permission.) 2740 the victim. Residual dye from the surface of a spine remaining after the spine’s removal may mimic a retained spine but is otherwise of no consequence. Soft tissue radiography or MRI can confirm the presence of retained spines, which may warrant referral for attempted surgical removal if the spines are near vital structures (e.g., joints, neurovascular bundles). Retained spines may cause the formation of granulomas that are amenable to excision or to intralesional injection with triamcinolone hexacetonide (5 mg/mL). Chronic granulomatous arthritis of the proximal interphalangeal joints has been treated with synovectomy and removal of granulation tissue. Erbium-YAG laser ablation has been deployed to destroy multiple sea urchin spines embedded in the foot and identified visually at the surface level without causing thermal necrosis of the adjacent tissues.


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InternalMed_Harrison. laser ablation has been deployed to destroy multiple sea urchin spines embedded in the foot and identified visually at the surface level without causing thermal necrosis of the adjacent tissues. Eosinophilic pneumonia and local and diffuse neuropathies have been observed separately after penetration by multiple spines of the black sea urchin (presumed Diadema species). The pathophysiologies of these phenomena have not been determined.


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InternalMed_Harrison. Starfish The crown-of-thorns Acanthaster planci produces venom in glandular tissue underneath the epidermis, which is released via its spiny surfaces (Fig. 474-5). Skin puncture causes pain, bleeding, and local edema, usually with remission over 30–180 min. Multiple punctures may result in reactions such as local muscle paralysis; retained fragments may cause granulomatous lesions and synovitis. There has also been a case report of elevated liver enzymes after A. planci envenomation. Envenomed persons benefit from acute immersion therapy in hot water, local anesthesia, wound cleansing, and possible exploration to remove foreign material.


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InternalMed_Harrison. Sea Cucumbers Sea cucumbers produce holothurin (a cantharin-like liquid toxin) in their body walls. This toxin is concentrated in the tentacular organs that are projected when the animal is threatened. Underwater, holothurin induces minimal contact dermatitis in the skin but can cause significant corneal and conjunctival irritation. A severe reaction can lead to blindness. Skin should be detoxified with 5% acetic acid (vinegar), papain, or isopropyl alcohol. The eye should be anesthetized with one or two drops of 0.5% proparacaine and irrigated with 100–250 mL of normal saline, with subsequent slit-lamp examination to identify corneal defects.


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InternalMed_Harrison. Cone Snails Cone snails use a detachable dartlike tooth to inject conotoxins into prey, inducing tetanus followed by paralysis. In an unknowing handler, stings result in small, burning punctate wounds followed by local ischemia, cyanosis, and numbness. Dysphagia, syncope, dysarthria, ptosis, blurred vision, and pruritus have also been documented. Some envenomations induce paralysis leading to respiratory failure, coma, and death. There is no antivenom. Pressure-immobilization (see “Octopuses,” below), hot-water soaks, and local anesthetics have been used empirically with success. The wound should be inspected for a foreign body. Edrophonium has been recommended as therapy for paralysis if a Tensilon test is positive.


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InternalMed_Harrison. Octopuses Serious envenomations and deaths have followed bites of Australian blue-ringed octopuses (Octopus maculosus and Octopus lunulata). Although these animals rarely exceed 20 cm in length, their salivary venom contains a potent neurotoxin (maculotoxin) that inhibits peripheral nerve transmission by blocking sodium conductance. Oral numbness and facial numbness develop within several minutes of a serious envenomation and rapidly progress to total flaccid paralysis, including failure of respiratory muscles. Immediately after envenomation, a circumferential pressure-immobilization dressing 15 cm wide should be applied over a gauze pad (~7 × 7 × 2 cm) that has been placed directly over the sting. The dressing should be applied at venous-lymphatic pressure, with the preservation of distal arterial pulses. The limb should then be splinted. Once the victim has been transported to the nearest medical facility, the bandage can be released. Because there is no antidote and passive


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InternalMed_Harrison. distal arterial pulses. The limb should then be splinted. Once the victim has been transported to the nearest medical facility, the bandage can be released. Because there is no antidote and passive immunotherapy (rabbit IgG antibody) has been proven effective only against tetrodotoxin in mice, treatment is supportive. Patients with respiratory failure may need to be mechanically ventilated. If respirations are assisted, the victim may remain awake although completely paralyzed. Even with serious envenomations, significant recovery often takes place within 4–10 h, although complete recovery may require 2–4 days. Sequelae are uncommon unless related to hypoxia.


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InternalMed_Harrison. FIGUrE 474-5 Spines on the crown-of-thorns sea star (Acanthaster planci).(Courtesy of Paul Auerbach, with permission.) As for all penetrating injuries, first-aid care should be undertaken. In addition, consideration must be given to local wound infection by marine Vibrio species and freshwater Aeromonas hydrophila as well as other “aquatic bacteria,” particularly if spines and needles remain embedded.


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InternalMed_Harrison. Stingrays A stingray injury is both an envenomation and a traumatic wound. Thoracic and cardiac penetration, major vessel laceration, and compartment syndrome have all been observed. The venom, which contains serotonin, 5′-nucleotidase, and phosphodiesterase, causes immediate, intense pain that may last up to 48 h. The wound is very painful (with the pain peaking at 30–60 min and lasting up to 48 h), often becomes ischemic in appearance, and heals poorly, with adjacent soft tissue swelling and prolonged disability. Systemic effects include weakness, diaphoresis, nausea, vomiting, diarrhea, dysrhythmias, syncope, hypotension, muscle cramps, fasciculations, paralysis, and (in rare cases) death. Because of differences in the toxins present on the tissues covering the stingers, freshwater stingrays may cause more severe injuries than marine stingrays.


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InternalMed_Harrison. Scorpionfish The designation scorpionfish encompasses members of the family Scorpaenidae and includes not only scorpionfish but also lionfish and stonefish. A complex venom with neuromuscular toxicity is delivered through 12 or 13 dorsal, 2 pelvic, and 3 anal spines. In general, the sting of a stonefish is regarded as the most serious (severe to life-threatening); that of the scorpionfish is of intermediate seriousness; and that of the lionfish is the least serious. Like that of a stingray, the sting of a scorpionfish is immediately and intensely painful. Pain from a stonefish envenomation may last for days. Systemic manifestations of scorpionfish stings are similar to those of stingray envenomations but may be more pronounced, particularly in the case of a stonefish sting, which may cause severe local tissue necrosis in addition to vital organ failure. The rare deaths that follow stonefish envenomation usually occur within 6–8 h. There is a commercially available stonefish antivenom.


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InternalMed_Harrison. Other Fish Three species of marine catfish—Plotosus lineatus (oriental catfish), Bagre marinus (sail catfish), and Galeichthys felis (common sea catfish)—as well as several species of freshwater catfish are capable of stinging humans. Venom is delivered through a single dorsal spine and two pectoral spines. Clinically, a catfish sting is comparable to that of a stingray, although marine catfish envenomations are generally more severe than those of their freshwater counterparts. Surgeonfish (doctorfish, tang), weeverfish, ratfish, and horned venomous sharks have also envenomed humans. Platypus The platypus is a venomous mammal. The male has a keratinous spur on each hind limb; the spur is connected to a venom gland within the upper thigh. Skin puncture causes soft tissue edema and pain that may last for days or weeks. Care is supportive, and hot-water therapy does not appear to benefit the victim.


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InternalMed_Harrison. The stings of all marine vertebrates are treated in a similar fashion. Except for stonefish and serious scorpionfish envenomations (see below), no antivenom is available. The affected part should be immersed immediately in nonscalding hot water (45°C/113°F) for 30–90 min or until there is significant relief from pain. Recurrent pain may respond to repeated hot-water treatment. Cryotherapy is contraindicated, and no data support the use of antihistamines or steroids. Opiates will help alleviate the pain, as will local wound infiltration or regional nerve block with 1% lidocaine, 0.5% bupivacaine, and sodium bicarbonate mixed in a 5:5:1 ratio. After soaking and anesthetic administration, the wound must be explored and debrided. Radiography (in particular, MRI) may be helpful in identification of foreign bodies. After exploration and debridement, the wound should be irrigated vigorously with warm sterile water, saline, or 1% povidone-iodine in solution. Bleeding usually can be controlled


InternalMed_Harrison

InternalMed_Harrison. of foreign bodies. After exploration and debridement, the wound should be irrigated vigorously with warm sterile water, saline, or 1% povidone-iodine in solution. Bleeding usually can be controlled by sustained local pressure for 10–15 min. In general, wounds should be left open to heal by secondary intention or treated by delayed primary closure. Tetanus immunization should be updated. Antibiotic treatment should be considered for serious wounds and for envenomation in immunocompromised hosts. The initial antibiotics should cover Staphylococcus and Streptococcus species. If the victim is immunocompromised, if a wound is primarily repaired and is more than minor, or if an infection develops, antibiotic coverage should be broadened to include Vibrio species. Infection with Aeromonas species is of similar concern for wounds associated with natural freshwater.


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InternalMed_Harrison. APPROACH TO THE PATIENT: It is useful to be familiar with the local marine fauna and to recognize patterns of injury. A large puncture wound or jagged laceration (particularly on the lower extremity) that is more painful than one would expect from the size and configuration of the wound is likely to be a stingray envenomation. Smaller punctures, as described above, represent the activity of a sea urchin (Fig. 474-6) or starfish. Stony corals cause rough abrasions and, in rare instances, lacerations or puncture wounds.


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InternalMed_Harrison. Coelenterate (marine invertebrate) stings sometimes create diagnostic skin patterns. A diffuse urticarial rash on exposed skin is often indicative of exposure to fragmented hydroids or larval anemones. A linear, whiplike print pattern appears where a jellyfish tentacle has contacted the skin. In the case of the dreaded box jellyfish, a cross-hatched appearance, followed by development of dark purple coloration within a few hours of the sting, heralds skin necrosis. A frosted appearance may be created by aluminum salt– based remedies applied to the wound. An encounter with fire coral causes immediate pain and swollen red skin irritation in the pattern of contact, similar to but more severe than the imprint left by exposure to an intact feather hydroid. Seabather’s eruption, caused by thimble jellyfishes and larval anemones, may produce a diffuse rash that consists of clusters of erythematous macules or raised papules and is accompanied by intense itching (Fig. 474-7). Toxic sponges


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InternalMed_Harrison. jellyfishes and larval anemones, may produce a diffuse rash that consists of clusters of erythematous macules or raised papules and is accompanied by intense itching (Fig. 474-7). Toxic sponges create a burning and painful red rash on exposed skin, which may blister and later desquamate. Because virtually all marine stingers invoke the sequelae of inflammation, local erythema, swelling, and adenopathy are fairly nonspecific.


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InternalMed_Harrison. The best way to locate a specific antivenom in the United States is to call a regional poison control center and ask for assistance. FIGUrE 474-6 Spiny sea urchins. (Courtesy of Dr. Paul Auerbach, with permission.) Divers Alert Network, a nonprofit organization designed to assist in the care of injured divers, also may help with the treatment of marine injuries. The network can be reached on the Internet at www .diversalertnetwork.org or by telephone 24 h a day at (919) 684-9111. An antivenom for the box jellyfish (C. fleckeri) and another for stonefish FIGUrE 474-7 Erythematous, papular rash typical of seabather’s eruption causedbythimblejellyfishandlarvalanemones.


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InternalMed_Harrison. FIGUrE 474-7 Erythematous, papular rash typical of seabather’s eruption causedbythimblejellyfishandlarvalanemones. 2742 (and severe scorpionfish) envenomation are made in Australia by the Commonwealth Serum Laboratories (CSL; 45 Poplar Road, Parkville, Victoria, Australia 3052; www.csl.com.au; 61-3-9389-1911). When administering the box jellyfish antivenom, time is of the essence. For cardiac or respiratory decompensation, give a minimum of one ampoule and up to six ampoules consecutively IV, preferably in a 1:10 dilution with normal saline. For stonefish (or severe scorpionfish) envenomation, give one ampoule of specific antivenom IM for every one or two punctures, to a maximum of three ampoules.


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InternalMed_Harrison. CIGUatEra Epidemiology and Pathogenesis Ciguatera poisoning is the most common nonbacterial food poisoning associated with fish in the United States; most U.S. cases occur in Florida and Hawaii, although, with transportation of imported fish nationwide, all clinicians need to be aware of ciguatera. The poisoning almost exclusively involves tropical and semitropical marine coral reef fish common in the Indian Ocean, the South Pacific, and the Caribbean Sea. Global estimates predict that 20,000–50,000 people may be affected by this poisoning each year. More than 400 different fish have been associated with ciguatera toxicity, but 75% of poisonings involve the reef-dwelling barracuda, snapper, jack, or grouper. Ciguatera toxin is created by warm-water ocean reef microalgae of the genus Gambierdiscus toxicus, whose consumption by grazing fish allows the toxin to bioaccumulate in the food chain. Three major ciguatoxins are found in the flesh and viscera of ciguateric fish: CTX-1, -2, and


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InternalMed_Harrison. toxicus, whose consumption by grazing fish allows the toxin to bioaccumulate in the food chain. Three major ciguatoxins are found in the flesh and viscera of ciguateric fish: CTX-1, -2, and -3. Recent research suggests that CTX-1 activates astrocytes and astroglia. In addition, TRPV1, a nonselective cation channel expressed in nociceptive neurons, may play a role in the neurologic disturbances unique to ciguatera poisoning. Most, if not all, ciguatoxins are unaffected by freeze-drying, heat, cold, and gastric acid. None of the toxins affects the odor, color, or taste of fish. Cooking methods may alter the relative concentrations of the various toxins.


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InternalMed_Harrison. Clinical Manifestations The onset of symptoms may come within 15–30 min of ingestion and typically takes place within 2–6 h. Symptoms increase in severity over the ensuing 4–6 h. Most victims develop symptoms within 12 h of ingestion, and virtually all are afflicted within 24 h. The more than 150 signs and symptoms reported include those shown in Table 474-3. Diarrhea, vomiting, and abdominal pain usually develop 3–6 h after ingestion of a ciguatoxic fish. Symptoms may persist for 48 h and then generally resolve (even without treatment). A pathognomonic symptom is the reversal of hot and cold tactile perception, which develops in some persons after 3–5 days and may last for months. More severe reactions tend to occur in persons previously stricken with the disease. Persons who have ingested parrotfish (scaritoxin) may develop classic ciguatera poisoning as well as a “second-phase” syndrome (after 5–10 days’ delay) of disequilibrium


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InternalMed_Harrison. Gastrointestinal Abdominal pain, nausea, vomiting, diarrhea Neurologic Paresthesias, pruritus, tongue and throat numbness or burning, sensation of “carbonation” during swallowing, odontalgia or dental dysesthesias, dysphagia, tremor, fasciculations, athetosis, meningismus, aphonia, ataxia, vertigo, pain and weakness in the lower extremities, visual blurring, transient blindness, hyporeflexia, seizures, coma Dermatologic Conjunctivitis, maculopapular rash, skin vesiculations, dermatographism Cardiovascular Bradycardia, heart block, hypotension, central respiratory failurea Other Chills, dysuria, dyspnea, dyspareunia, weakness, fatigue, nasal congestion and dryness, insomnia, sialorrhea, diaphoresis, headache, arthralgias, myalgias aTachycardia and hypertension may occur after potentially severe transient bradycardia and hypotension. Death is rare. with locomotor ataxia, dysmetria, and resting or kinetic tremor. This syndrome may persist for 2–6 weeks.


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InternalMed_Harrison. Diagnosis The differential diagnosis of ciguatera includes paralytic shellfish poisoning, eosinophilic meningitis, type E botulism, organophosphate insecticide poisoning, tetrodotoxin poisoning, and psychogenic hyperventilation. At present, the diagnosis of ciguatera poisoning is made on clinical grounds because no routinely used laboratory test detects ciguatoxin in human blood. Liquid chromatography–mass spectrometry is available for ciguatoxins but is of limited clinical value because most health care institutions do not have the equipment needed to perform the test. A ciguatoxin enzyme immunoassay or radioimmunoassay may be used to test small portions of the suspected fish, but even these tests may not detect the very small amount of toxin (0.1 ppb) necessary to render fish flesh toxic. A newer neuroblastoma assay may be sufficiently sensitive to detect small amounts of toxin but is not readily available for clinical use.


InternalMed_Harrison

InternalMed_Harrison. Therapy is supportive and based on symptoms. Nausea and vomiting may be controlled with an antiemetic such as ondansetron (4–8 mg IV). Syrup of ipecac and activated charcoal are not recommended for ciguatera poisoning. Hypotension may require the administration of IV crystalloid and, in rare cases, a pressor drug. Bradyarrhythmias that lead to cardiac insufficiency and hypotension generally respond well to atropine (0.5 mg IV, up to 2 mg). Goal-directed combination cardiovascular fluid and pressor therapy may be required. Cool showers or the administration of hydroxyzine (25 mg PO every 6–8 h) may relieve pruritus. Amitriptyline (25 mg PO twice a day) reportedly alleviates pruritus and dysesthesias. In three cases unresponsive to amitriptyline, tocainide has appeared to be efficacious. Nifedipine has been used to treat headache and poor circulation in order to prevent hypotension, but only after the initial acute phase of the poisoning has passed. IV infusion of mannitol may be


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InternalMed_Harrison. Nifedipine has been used to treat headache and poor circulation in order to prevent hypotension, but only after the initial acute phase of the poisoning has passed. IV infusion of mannitol may be beneficial in moderate or severe cases in fluid-repleted patients, particularly for the relief of distressing neurologic or cardiovascular symptoms, although the efficacy of this therapy has been challenged and has not been definitively proved. The infusion is rendered initially as 1 g/kg per day over 45–60 min during the acute phase (days 1–5). If symptoms improve, a second dose may be given within 3–4 h and a third dose may be administered the next day. Care must be taken to avoid dehydration in a treated patient. The mechanism of the benefit against ciguatera intoxication is perhaps hyperosmotic water-drawing action, which reverses ciguatoxin-induced Schwann cell edema. Mannitol may also act in some fashion as a “hydroxyl scavenger” or may competitively inhibit ciguatoxin at the cell


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InternalMed_Harrison. water-drawing action, which reverses ciguatoxin-induced Schwann cell edema. Mannitol may also act in some fashion as a “hydroxyl scavenger” or may competitively inhibit ciguatoxin at the cell membrane.


InternalMed_Harrison

InternalMed_Harrison. During recovery from ciguatera poisoning, the victim should exclude the following from the diet for 6 months: fish (fresh or preserved), fish sauces, shellfish, shellfish sauces, alcoholic beverages, nuts, and nut oils. Consumption of fish in ciguatera-endemic regions should be avoided. All oversized fish of any predacious reef species should be suspected of harboring ciguatoxin. Neither moray eels nor the viscera of tropical marine fish should ever be eaten.


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InternalMed_Harrison. Diarrhetic shellfish poisoning occurs with consumption of shellfish producing diarrheal illness. The first suspected incident, which occurred in the Netherlands in 1961, was followed by outbreaks in Japan, the United Kingdom, and (most recently) China. The causative agents are the lipophilic compound okadaic acid and the dinophysistoxins, which inhibit serine and threonine protein phosphatases, with consequent protein accumulation and continued secretion of fluid in intestinal cells leading to diarrhea. Shellfish acquire these toxins by feeding on dinoflagellates, particularly of the genera Dinophysis and Prorocentrum.


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InternalMed_Harrison. Symptoms include diarrhea, nausea, vomiting, abdominal pain, and chills. Onset occurs within 30 min to 12 h. The illness is usually self-limited; most patients recover in 3 or 4 days, and only a few require hospitalization. Treatment is supportive and focused on hydration. Toxins can be detected in food samples by a mouse bioassay, an immunoassay, and high-performance liquid chromatography with fluorometric detection (HPLC-FLD).


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InternalMed_Harrison. Paralytic shellfish poisoning is induced by ingestion of any of a variety of feral or aquacultured filter-feeding organisms, including clams, oysters, scallops, mussels, chitons, limpets, starfish, and sand crabs. The origin of their toxicity is the chemical toxin they accumulate and concentrate by feeding on various planktonic dinoflagellates (e.g., Protogonyaulax, Ptychodiscus, and Gymnodinium) and protozoan organisms. The unicellular phytoplanktonic organisms form the foundation of the food chain, and in warm summer months these organisms “bloom” in nutrient-rich coastal temperate and semitropical waters. In the United States, paralytic shellfish poisoning is acquired primarily from seafood harvested in the Northeast, the Pacific Northwest, and Alaska. These planktonic species can release massive amounts of toxic metabolites into the water and cause mortality in bird and marine populations. The paralytic shellfish toxins are water soluble as well as heat and acid stable; they


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InternalMed_Harrison. release massive amounts of toxic metabolites into the water and cause mortality in bird and marine populations. The paralytic shellfish toxins are water soluble as well as heat and acid stable; they cannot be destroyed by ordinary cooking or freezing. Contaminated seafood looks, smells, and tastes normal. The best-characterized, most potent, and most frequently identified paralytic shellfish toxin is saxitoxin, which takes its name from the Alaska butter clam Saxidomus giganteus. Saxitoxin appears to block sodium conductance, inhibiting neuromuscular transmission at the axonal and muscle membrane levels. A toxin concentration of >75 µg/100 g of foodstuff is considered hazardous to humans. In the 1972 New England “red tide,” the concentration of saxitoxin in blue mussels exceeded 9000 µg/100 g of foodstuff.


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InternalMed_Harrison. The onset of intraoral and perioral paresthesias (notably of the lips, tongue, and gums) comes within minutes to a few hours after ingestion of contaminated shellfish, and these paresthesias progress rapidly to involve the neck and distal extremities. The tingling or burning sensation later changes to numbness. Other symptoms rapidly develop and include light-headedness, disequilibrium, incoordination, weakness, hyperreflexia, incoherence, dysarthria, sialorrhea, dysphagia, thirst, diarrhea, abdominal pain, nausea, vomiting, nystagmus, dysmetria, headache, diaphoresis, loss of vision, chest pain, and tachycardia. Flaccid paralysis and respiratory insufficiency may follow 2–12 h after ingestion. In the absence of hypoxia, the victim often remains alert but paralyzed. Up to 12% of patients die.


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InternalMed_Harrison. Treatment is supportive and based on symptoms. If the victim comes to medical attention within the first few hours after poison ingestion, the stomach should be emptied by gastric lavage and then irrigated with 2 L (in 200-mL aliquots) of a solution of 2% sodium bicarbonate; this intervention has not been proved to be of benefit but is based on the notion that gastric acidity may enhance the potency of saxitoxin. Because breathing difficulty can be rapid in onset, induction of emesis is not advised. The administration of activated charcoal (50–100 g) and a cathartic (sorbitol, 20–50 g) makes empirical sense because these shellfish toxins are believed to bind well to charcoal. Some authors advise against administration of magnesium-based solutions (e.g., certain cathartics), cautioning that hypermagnesemia may contribute to suppression of nerve conduction.


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InternalMed_Harrison. The most serious problem is respiratory paralysis. The victim should be closely observed for respiratory distress for at least 24 h in a hospital. With prompt recognition of ventilatory failure, endotracheal intubation, and assisted ventilation, anoxic myocardial and brain injury may be prevented. If the patient survives for 18 h, the prognosis is good for a complete recovery. A direct human serum assay to identify the toxin responsible for paralytic shellfish poisoning is not yet clinically available; the mouse bioassay in widespread use may be replaced by an automated tissue-culture bioassay. A polyclonal enzyme-linked immunosor-2743 bent assay (ELISA) to measure specific toxins is under development, as is HPLC-FLD. In addition, an inhibition immunoassay that may be able to simultaneously detect paralytic shellfish, diarrhetic shellfish, and amnesic shellfish toxins is being investigated.


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InternalMed_Harrison. In late 1987 in eastern Canada, an outbreak of gastrointestinal and neurologic symptoms (amnestic shellfish poisoning) was documented in persons who had consumed mussels found to be contaminated with domoic acid. In this outbreak, the source of the toxin was Nitzschia pungens, a diatom ingested by the mussels. Since the Canadian outbreak, the toxin has been found in shellfish from the United States, the United Kingdom, and Spain. In 1991, an epidemic of domoic acid poisoning in the state of Washington was attributed to the consumption of razor clams. A water-soluble, heat-stable neuroexcitatory amino acid with biochemical analogues of kainic acid and glutamic acid, domoic acid binds to the kainate type of glutamate receptor with three times the affinity of kainic acid and is 20 times as powerful a toxin. Shellfish can be tested for domoic acid by mouse bioassay and HPLC. The regulatory limit for domoic acid in shellfish is 20 parts per million.


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InternalMed_Harrison. The abnormalities noted within 24 h of ingesting contaminated mussels (Mytilus edulis) include arousal, confusion, disorientation, and memory loss. The median time of onset is 5.5 h. Other prominent signs and symptoms include severe headache, nausea, vomiting, diarrhea, abdominal cramps, hiccups, arrhythmias, hypotension, seizures, ophthalmoplegia, pupillary dilation, piloerection, hemiparesis, mutism, grimacing, agitation, emotional lability, coma, copious bronchial secretions, and pulmonary edema. Histologic study of brain tissue taken at autopsy has shown neuronal necrosis or cell loss and astrocytosis, most prominently in the hippocampus and the amygdaloid nucleus—findings similar to those in animals poisoned with kainic acid. Several months after the primary intoxication, victims still display chronic residual memory deficits and motor neuronopathy or axonopathy. Nonneurologic illness does not persist.


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InternalMed_Harrison. Therapy is supportive and based on symptoms. Because kainic acid neuropathology seems to be nearly entirely seizure mediated, the emphasis should be on anticonvulsive therapy, for which diazepam appears to be as effective as any other drug. Scombroid fish poisoning may be the most common type of seafood poisoning worldwide. It follows consumption of scombroid (mackerellike) fish, which include albacore, bluefin, and yellowfin tuna; mackerel; saury; needlefish; wahoo; skipjack; and bonito, as well as nonscombroid fish, such as dolphinfish (Hawaiian mahimahi, Coryphaena hippurus), kahawai, sardine, black marlin, pilchard, anchovy, herring, amberjack, and Australian ocean salmon. In the northeastern and mid-Atlantic United States, bluefish (Pomatomus saltatrix) has been linked to scombroid poisoning. Because greater numbers of nonscombroid fish are being recognized as scombrotoxic, the syndrome may more appropriately be called pseudoallergic fish poisoning.


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InternalMed_Harrison. Under conditions of inadequate preservation or refrigeration, the musculature of these darkor red-fleshed fish undergoes decomposition by Proteus morganii and Klebsiella pneumoniae bacteria, with consequent decarboxylation of the amino acid l-histidine to histamine, histamine phosphate, and histamine hydrochloride. Histamine levels of 20–50 mg/100 g are noted in toxic fish, with levels >400 mg/100 g on occasion. However, it is possible that some other compound may be responsible for this intoxication, because large doses of oral histamine do not reproduce the affliction. It is proposed that this unknown agent works by inhibiting the metabolism of histamine, promoting degranulation of mast cells to release endogenous histamine, or acting as a histamine receptor agonist. Whatever toxin or toxins are involved 2744 are heat stable and are not destroyed by domestic or commercial cooking. Affected fish typically have a sharply metallic or peppery taste; however, they may be normal in


InternalMed_Harrison

InternalMed_Harrison. or toxins are involved 2744 are heat stable and are not destroyed by domestic or commercial cooking. Affected fish typically have a sharply metallic or peppery taste; however, they may be normal in appearance, color, and flavor. Not all persons who eat a contaminated fish necessarily become ill, perhaps because of uneven distribution of decay within the fish. Symptoms develop within 15–90 min of ingestion. Most cases are mild, with tingling of lips and mouth, mild abdominal discomfort, and nausea. The more severe and commonly described presentation includes flushing (sharply demarcated; exacerbated by ultraviolet exposure; particularly pronounced on the face, neck, and upper trunk), a sensation of warmth without elevated core temperature, conjunctival hyperemia, pruritus, urticaria, and angioneurotic edema. This syndrome may progress to bronchospasm, nausea, vomiting, diarrhea, epigastric pain, abdominal cramps, dysphagia, headache, thirst, pharyngitis, gingival burning, palpitations,


InternalMed_Harrison

InternalMed_Harrison. edema. This syndrome may progress to bronchospasm, nausea, vomiting, diarrhea, epigastric pain, abdominal cramps, dysphagia, headache, thirst, pharyngitis, gingival burning, palpitations, tachycardia, dizziness, and hypotension. Without treatment, the symptoms generally resolve within 8–12 h. Because of blockade of gastrointestinal tract histaminase, the reaction may be more severe in a person who is concurrently ingesting isoniazid.


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InternalMed_Harrison. Therapy is directed at reversing the histamine effect with antihistamines, either H-1 or H-2. If bronchospasm is severe, an inhaled bronchodilator—or in rare, extremely severe circumstances, injected epinephrine—may be used. Glucocorticoids are of no proven benefit. Protracted nausea and vomiting, which may empty the stomach of toxin, may be controlled with a specific antiemetic, such as ondansetron or prochlorperazine. The persistent headache of scombroid poisoning may respond to cimetidine or a similar antihistamine if standard analgesics are not effective.


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InternalMed_Harrison. Poisoning, Drug Overdose, and Envenomation Ectoparasite Infestations and Arthropod Injuries Richard J. Pollack, Scott A. Norton Ectoparasites include arthropods and creatures from other phyla that infest the skin or hair of animals; the host animals provide them with sustenance and shelter. The ectoparasites may penetrate within or beneath the surface of the host or may attach by mouthparts and spe-cialized claws. These organisms may inflict direct mechanical injury, consume blood or nutrients, induce hypersensitivity reactions, inocu-late toxins, transmit pathogens, and incite fear or disgust. Humans are the sole or obligate hosts for many kinds of ectoparasites and serve as facultative or paratenic (accidental) hosts for many others. Arthropods that are ectoparasitic or otherwise cause injury include insects (such as lice, fleas, bedbugs, wasps, ants, bees, and flies), arach-nids (spiders, scorpions, mites, and ticks), millipedes, and centipedes. Certain nematodes (helminths), such


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InternalMed_Harrison. injury include insects (such as lice, fleas, bedbugs, wasps, ants, bees, and flies), arach-nids (spiders, scorpions, mites, and ticks), millipedes, and centipedes. Certain nematodes (helminths), such as the hookworms (Chap. 256), are ectoparasitic in that they penetrate and migrate through the skin. Infrequently encountered ectoparasites in other phyla include the pen-tastomes (tongue worms) and leeches. Arthropods may also cause injury when they attempt to take a blood meal or as they defend themselves by biting, stinging, or exuding ven-oms. Various arachnids (spiders and scorpions), insects (bees, hornets, wasps, ants, flies, true bugs, caterpillars, and beetles), millipedes, and centipedes produce ill effects during these behaviors. Similarly, certain ectoparasites (e.g., ticks, biting mites, and fleas) that typically infest nonhuman animals can be medically significant. In the United States, lesions caused by arthropod bites and stings are so diverse and vari-able that it is


InternalMed_Harrison

InternalMed_Harrison. mites, and fleas) that typically infest nonhuman animals can be medically significant. In the United States, lesions caused by arthropod bites and stings are so diverse and vari-able that it is rarely possible to identify the precise causative organism without a bona fide specimen and taxonomic expertise. 475