Chapter 23: Poisoning in Pregnancy

Poisoning is a morbid state produced by the exposure to a toxic agent (poison) that causes a functional disturbance and/or structural damage. Although the majority of poisonings during pregnancy are accidental, up to one-fifth can be intentional as part of a suicide gesture or attempt.

Two general principles should be kept in mind when treating pregnant women who are poisoned:

1. We treat the fetus by treating the mother.

2. More harm and damage may result from withholding or delaying needed therapy to the mother.

Excluding drugs of abuse, the 3 most common intentional poisonings during pregnancy are those by acetaminophen (aka paracetamol or acetyl-para-aminophenol [APAP]), nonsteroidal anti-inflammatory medications (NSAIDs; we will review salicylate poisoning), and selective serotonin reuptake inhibitors (SSRIs). This chapter specifically addresses the perinatal concerns and management of these 3 poisonings and that of iron, which because of its availability to pregnant women can also be implicated in an acute poisoning.

Pregnancy represents a special population due its physiologic changes affecting drug and toxin absorption, distribution, metabolism, excretion, and transplacental passage with potential fetal effects. General toxicologic and decontamination management principles are the same as for the nonpregnant population. Maternal stabilization is priority, with immediate evaluation of ventilatory, hemodynamic, and mental status. In patient with mental status changes, suspect hypoglycemia or narcotic overdose first and treat accordingly (dextrose and/or naloxone).

Excluding alcohol and drugs of abuse, APAP is the most common drug taken in overdose during pregnancy.

Maternal Concerns

Pathophysiology

Most APAP is metabolized in the liver by being conjugated with sulfate or glucuronide to form nontoxic metabolites that are excreted in the urine (Fig. 23-1). Approximately 7% of APAP, however, is metabolized in the liver and kidneys by cytochrome P450 to form a toxic metabolite, N-acetyl-p-benzoquinoneimine (NAPQI). NAPQI is an extremely reactive molecule that covalently binds to macromolecules, leading to cell injury and death. NAPQI normally undergoes detoxification by combining with glutathione to form a nontoxic mercapturic acid metabolite that is excreted in the urine. With APAP overdose, however, so much NAPQI is formed that glutathione stores become depleted resulting in NAPQI-induced cytotoxicity. Acetaminophen poisoning principally affects the liver and, to a lesser extent, the kidneys.

Toxic Doses and Clinical Course

Patients acutely ingesting more than 140 mg/kg of acetaminophen are at risk for hepatotoxicity. One can predict the risk for developing hepatotoxicity after an acute, single ingestion by obtaining a serum APAP concentration at least 4 hours after ingestion. Plotting the resulting level on a standard nomogram estimates the risk for hepatotoxicity (Fig. 23-2). If an antidote is not given within 8 hours and hepatotoxicity develops, it is associated with prolonged prothrombin time (PT) and elevation of transaminases (commonly into the thousands). Enzyme values usually peak between 72 and 96 hours after ingestion. Jaundice is uncommon. Seriously poisoned patients occasionally suffer from pancreatitis, oliguria, hypotension, myocardial ischemia, and, possibly, necrosis. Persons who take massive overdoses may present in the first few hours (before the onset of liver failure) with coma and severe metabolic acidosis with elevated lactate concentrations.

While nausea and vomiting commonly develop early in APAP poisoning, patients who ingest fatal doses may suffer no symptoms until the onset of symptomatic liver failure, which can occur 1 to 4 days later. Therefore, a serum APAP value must be obtained from both symptomatic and asymptomatic patients in order to properly assess the severity of the overdose.

Patients who habitually take excessive doses of acetaminophen (usually well in excess of 4 g per day) are more likely to develop renal failure along with hepatotoxicity. Serum APAP concentrations in these patients cannot be correlated with severity of illness or risk of hepatotoxicity.

Acetaminophen can cross the placenta and has the potential for fetal hepatotoxicity and in acute intoxications of spontaneous abortion and stillbirth.

Treatment

Supportive therapy, including intravenous (IV) fluids, oxygen, cardiac monitoring, and electronic fetal monitoring (if appropriate for the gestational age of the pregnancy).

• Decontamination procedures: Induced emesis may be indicated for home treatment of a large dose (>100 mg/kg). Gastric lavage and activated charcoal (AC) (1 g/kg in water) can prevent further absorption of acetaminophen. Oral activated charcoal avidly adsorbs acetaminophen and should be administered if the patient presents within 1 hour of ingestion. The network of pores present in AC adsorbs 100 to 1000 mg of drug per gram of charcoal.

  In pregnancy, oral AC may be of benefit greater than 1 hour after the ingestion as the gastric emptying is delayed. Oral AC administered with N-acetylcysteine (NAC) greater than 4 hours after ingestion has been shown in one case series to be effective in reducing the incidence of liver toxicity after toxic acetaminophen ingestion.

• Antidote: The antidote for APAP poisoning is NAC (Mucomyst) (Fig. 23-3). NAC undergoes conversion to cysteine, which, in turn, is metabolized to glutathione. NAC’s main effect is to maintain glutathione stores so that NAPQI can be detoxified. Started within 8 hours of ingestion, NAC prevents serious maternal hepatic and renal toxicity from APAP. To ensure that NAC is started promptly after an acute ingestion, it is generally most prudent to begin NAC therapy immediately and discontinue it only if the serum APAP concentration is found to be in the nontoxic range when plotted on the nomogram. Therapy with NAC provides benefit by lessening the severity of hepatic necrosis and increasing chances for survival, even when begun more than 24 hours after ingestion. Therefore, it is never too late to begin NAC therapy; though efficacy begins to decrease if therapy is delayed beyond 16 hours.

A serum APAP concentration (measured at least 4 hours after ingestion) resulting in a value above the lower line of the nomogram necessitates a full course of NAC therapy (eg, standard oral loading dose of 140 mg/kg of NAC followed by 70 mg/kg every 4 hours for 17 oral doses) be delivered. NAC therapy should not be stopped prematurely simply because a repeat serum APAP concentration falls to zero or plots below the lower line on the nomogram.

Patients commonly experience nausea and vomiting following APAP ingestion, sometimes making it difficult to administer oral NAC therapy. In these cases, NAC has been given intravenously. An intravenous formulation is prepared in the pharmacy by aseptically passing sterile inhalable or oral NAC solution through a 0.2-μm filter and diluting it in 5% dextrose in water, to create an intravenous solution. An intravenous protocol commonly used in the United States is described in Fig. 23-3.

Occasionally, patients suffer symptomatic histamine release from intravenous NAC and require treatment with antihistamines. On rare occasions, patients suffer life-threatening anaphylactoid reactions requiring fluids, epinephrine, antihistamines, and corticosteroids. If the pharmacy cannot timely prepare intravenous NAC, treatment should not be delayed and oral NAC therapy should be started immediately. Treatment for adjunctive complications (eg, liver failure, renal failure) is entirely supportive and identical to that for other pregnant patients.

Fetal Concerns

Fetal death from APAP overdose has been reported in all trimesters. Maternal NAPQI does not cross the placenta. Maternal APAP, however, does cross and has the potential to produce toxic fetal concentrations. The fetus’s ability to produce NAPQI from APAP begins as early as 14 weeks intrauterine life and increases until term. The fetus’s ability to detoxify APAP by conjugation with sulfate and glucuronide remains impaired until after birth, possibly shunting more APAP through cytochrome P450. The third-trimester fetus, therefore, appears to be at greatest risk for direct toxicity from APAP. Nevertheless, fetal loss appears to be most common in the first trimester—not because the fetus is necessarily poisoned, but because maternal illness is more likely to lead to fetal loss at that time.

Placental transfer of NAC (a class B medication) in humans has been documented with concentrations in the umbilical cord blood similar to maternal levels (Horowitz et al). Because considerations of lack of first-pass effect through the fetal liver (compared to the maternal intake of NAC), most authorities prefer the parenteral use of the antidote during pregnancy. When NAC is given intravenously at currently used therapeutic doses, serum levels are 10 to 100 times higher.

At least one authority has recommended consideration for delivery of the mature fetus by cesarean section so that NAC therapy can be administered directly to the baby at risk (ie, when maternal serum APAP concentrations are toxic). This has to be balanced against the risks of the procedure related to coagulopathy. Advocates of immediate delivery state that the maternal and fetal risk of late third-trimester cesarean section is extremely low in comparison to data from the several case reports describing fetal death from APAP toxicity. The incidence correlates with delays in initiating therapy with NAC. Unfortunately, no animal or human studies have examined the benefits of immediate delivery followed by direct newborn NAC therapy. The published experience does not contain reports of fetal demise following acute single APAP ingestions if NAC therapy is begun promptly. No standard of care to guide clinicians who face this dilemma exists. Given the potential for a nonreassuring fetal condition, fetal monitoring of viable pregnancies is recommended during therapy.

Although it has not been proven, serial assessments of the fetal well-being are recommended upon discharge from a severe exposure to acetaminophen.

Large doses of iron are extremely toxic and may lead to multiorgan system dysfunction and death. Strong evidence indicates that the fetus is protected from elevated maternal iron levels. Iron poisoning is, almost entirely, a situation in which fetal survival depends on maternal survival. Table 23-1 and Fig. 23-4 summarize the pathophysiology and management of iron toxicity, respectively.

Maternal Concerns

Toxic Doses

To determine how much iron was ingested, the elemental iron content must be calculated. On a milligram basis, ferrous sulfate contains 20% elemental iron; ferrous fumarate 33% elemental iron, and ferrous gluconate 12% elemental iron. Any patient who ingests more than 20 mg/kg of elemental iron, any patient with symptoms, and/or any patient in whom the amount of ingested iron is not known requires an evaluation. During pregnancy the prepregnancy weight should be used for calculation of the dose ingested. Keep in mind that if the mechanism of the poisoning was intentional, the history may be unreliable as patients may conceal or minimize the magnitude of the exposure.

Clinical Course

Traditionally, clinical effects of iron poisoning are considered in 4 stages, although the distinctions between stages are not always clear.

• Stage 1 is characterized by abdominal pain, vomiting, and diarrhea, and results from the corrosive effects of iron on the gut. Stage 1 begins 1 to 6 hours after ingestion. Hematemesis is possible, and hypovolemia may result in hypotension and metabolic acidosis. Serum iron levels may be normal or elevated at this stage.

• Stage 2 is not always seen, but, when present, lasts for about 2 to 24 hours or so after Stage 1. Stage 2 is characterized by resolution of gastroenteritis, and patients commonly lie in bed quietly. Pallor, metabolic acidosis, and in the face of uncorrected hypovolemia, tachycardia and hypotension may be noted. Physicians may be falsely reassured by the resolution of gastroenteritis in the face of ensuing systemic iron toxicity as tissue iron stores rise. Tachycardia and hypotension are common if hypovolemia has not been corrected. Metabolic acidosis and hypotension result from uncorrected hypovolemia, venodilation, third-spacing of fluid, and the cytotoxic effects of iron. Serum iron concentration may be elevated and liver enzyme values are normal. PT may be elevated if serum iron concentrations are high from a direct effect of iron on serum proteases such as thrombin. In severe iron poisoning, the patient may rapidly progress from Stage 1 to Stage 3.

• Stage 3 comprises systemic organ damage or failure from the cytotoxic effects of iron. Its onset is observed at any time from ingestion through 48 hours. Stage 3 is characterized by hepatic failure, lethargy/coma/convulsions, renal failure, and, occasionally, heart failure. Hypoglycemia and coagulopathy reflect hepatic damage. In this setting, metabolic acidosis has numerous causes including hepatic failure, low cardiac output, and impaired oxidative phosphorylation. The liver is the major organ affected by the toxicity of iron and typically is the first organ to fail. Stage 3 toxicity is associated with spontaneous abortion, preterm delivery, and maternal death.

• Stage 4 is characterized by recurrence of vomiting (mostly in pediatric population) due to gastric outlet or small bowel obstruction from gastrointestinal scarring of mucosal ulcers several weeks after the poisoning (2-6 weeks).

Evaluation and Treatment

Serum Iron Concentrations

While most patients who suffer iron poisoning of stage 2 or greater are thought to have peak serum concentrations greater than 350 μg/dL, the actual peak level is seldom observed as a consequence of mistiming. Serum iron levels peak sometime between 2 and 6 hours after ingestion. Normal or mildly elevated serum iron concentrations can be misleading, since they do not always reflect the tissue iron burden, which is the one responsible for the systemic toxicity. Therefore, as an isolated finding, a normal serum iron concentration cannot always be used to exclude iron poisoning in the symptomatic patient. Obtaining a normal or low iron level more than 6 hours after ingestion may be misleading as the reason that the level is low is redistribution of iron in the tissues. Toxicity is still possible in these cases and the patient, not the numbers need to be treated. The measurement of total iron binding capacity (TIBC) does not assist in the treatment of acute iron poisoning since it is falsely elevated in the face of high serum iron concentrations by some methods and since serum iron concentrations may be quickly changing in their relationship to TIBC.

Asymptomatic Patients Ipecac emesis may be considered in the conscious patient within the first hour of exposure. Prolonged vomiting (>1 hour) should be attributed to iron toxicity rather than to the effects of ipecac. Generally, patients who remain completely asymptomatic for 6 hours after ingestion and have a normal physical examination do not require treatment for iron poisoning (Fig. 23-5). Asymptomatic patients who ingest more than 20 mg/kg of elemental iron but are seen within 6 hours might benefit from gastric lavage with saline. If vomiting has already occurred, it is not thought that gastric lavage would be of further benefit. One percent bicarbonate (200-300 mL) after lavage or induced emesis may promote the conversion of ferrous iron to ferrous carbonate (less soluble). Alternatively, a single oral dose of 8% magnesium oxide (Milk of Magnesia; 60 mL/g of elemental iron ingested) significantly reduces iron absorption in healthy volunteers.

Symptomatic Patients Patients are considered symptomatic when they present with more than minimal symptoms (eg, more than 1 emesis). These patients require treatment with fluids and deferoxamine mesylate, in addition to magnesium oxide (Table 23-2). When a patient has significant clinical symptoms, it is never prudent to wait for results of a serum iron concentration before beginning therapy, including deferoxamine. The traditional dose of deferoxamine is 15 mg/kg/h intravenously, not to exceed a daily dose of 6 grams.

Fetal Concerns

The placenta selectively transports maternal transferrin-bound iron only when it is required by the fetus. Animal models of iron poisoning in pregnancy, along with human experience, lead to the conclusion that the fetus does not develop elevated iron burdens in the face of maternal iron poisoning (Fig. 23-4). Fetal demise appears to be due, entirely, to maternal illness or death. Fetal outcome depends on the well-being of the mother; it is in the interest of both mother and child that significant poisoning be treated promptly with deferoxamine. Pregnancy or fetal concerns are never reasons to withhold deferoxamine therapy.

In a review of 61 cases of iron overdose in pregnancy, Tran and colleagues noted that the degree of maternal toxicity was directly related to the risk of fetal loss. Fetal demise appeared to be related to the timing and severity of the maternal illness, rather than to fetal toxicity directly from iron.

Prior to discharging the patient, always evaluate the mechanism of the exposure and obtain other consultations as required by the particular case (psychiatry; social services, etc).

Sources of salicylate include aspirin (acetylsalicylic acid), oil of wintergreen (methyl salicylate), salicylic acid, and salsalate. All of these compounds are converted to salicylate after absorption. With the exception of aspirin’s ability to inhibit platelet function, salicylate is responsible for most of the observed toxic effects.

Salicylate poisoning remains one of the most underestimated and mismanaged poisonings in medicine. This problem is further compounded by pregnancy, when only moderate maternal toxicity may result in fetal demise secondary to the ability of the drug to freely cross the placenta and the propensity of the drug to concentrate in the fetus, particularly the central nervous system (CNS).

Maternal Concerns

Pharmacokinetics and Toxic Doses

Significant salicylate toxicity is said to develop after the acute, single ingestion of at least 150 mg/kg of aspirin (or its equivalent). However, given the fetus’s ability to concentrate salicylate, concern arises when an acute, single maternal ingestion exceeds 75 mg/kg. Salicylate levels may not peak until 24 hours after the drug is absorbed. Enteric-coated aspirin may not produce toxic serum concentrations for many hours after ingestion.

Salicylate exists in blood as an equilibrium between the ionized and the nonionized form (Fig. 23-6). The nonionized, nonprotein-bound fraction of salicylate is in equilibrium with tissue stores. This nonionized form easily moves into body compartments because of its lipophilic nature. As serum salicylate levels rise, protein binding becomes saturated, producing a higher free (nonionized) fraction of the drug (from approximately 10%-25%). As pH falls, the nonionized fraction of salicylate increases. Therefore, rises in serum salicylate concentration or falls in blood pH result in an increase in the apparent volume of distribution of salicylate as salicylate moves from blood into tissue. This important concept is critical in understanding both the pathophysiology and the management of salicylate toxicity, since the serum salicylate concentrations can fall while tissue concentrations and severity of toxicity increase.

In salicylate poisoning, most salicylate is eliminated unchanged by the kidneys. Elimination half-lives can be as long as 1½ to 2 days in untreated patients because of saturable elimination kinetics.

Pathophysiology and Clinical Effects

Salicylate produces numerous actions that produce various effects in many organ systems. These diverse clinical manifestations result, in part, because of impaired adenosine triphosphate (ATP) formation from salicylate’s actions on cellular metabolism.

Gastrointestinal Irritation

Direct corrosive injury to the gut is responsible for abdominal pain, nausea, vomiting, gastrointestinal bleeding, and rare reports of gastric perforation.

Respiratory Alkalosis

Salicylate directly stimulates the brain stem to cause hyperventilation. However, the onset of coma may mask hyperventilation, and can even produce hypoventilation and hypercapnia.

Metabolic Acidosis

Salicylate affects numerous metabolic pathways to inhibit ATP formation. Salicylate inhibits the Krebs’ cycle, uncouples oxidative phosphorylation, and enhances lipolysis. All of these actions serve to produce metabolic acidosis. Ketonuria is usually present, and lactate levels are usually normal. The anion gap can be normal or frequently elevated.

Glucose Metabolism

Increased glucose demand accompanied by glycogenolysis explains occasional hyperglycemia seen early in poisoning. However, salicylate inhibits gluconeogenesis so when glycogen stores become depleted, hypoglycemia is possible.

Fluid and Electrolytes

Dehydration from gastrointestinal losses and hyperventilation is common. Patients may lose 1 to 2 L/h from severe diaphoresis, alone. The average patient with moderate to severe salicylate poisoning has a 6-L fluid deficit. Both hypokalemia and hyperkalemia may be observed. Hypokalemia results from gastrointestinal losses and obligatory urinary excretion of potassium with organic acids (eg, salicylate). Hyperkalemia usually reflects acidosis, severe dehydration, and prerenal azotemia, sometimes with rhabdomyolysis.

Pulmonary

Noncardiogenic (low pressure) pulmonary edema can develop with salicylate poisoning; however, hydrostatic (high pressure) pulmonary edema may also occur in persons with chronic heart disease or salicylate-induced heart failure, or in those whose fluid therapy has not been carefully monitored for fluid balance.

Cardiovascular

The metabolic insult to myocardium induced by salicylate results in tachycardia, ventricular arrhythmias, heart failure, hypotension, and sudden death. In the absence of heart disease, metabolic acidosis and neurotoxicity almost always precede severe cardiac dysfunction and shock if the patient has been adequately fluid resuscitated.

Central Nervous System

Impaired ATP production produces neurotoxicity which is manifested by hallucinations, agitation, delirium, lethargy, coma, convulsions, malignant cerebral edema, and brain death.

Coagulation and Platelets

Salicylate impairs vitamin K–dependent coagulation factors to prolong PT in a manner similar to Coumadin. Aspirin (acetylsalicylic acid) also inhibits platelet function, though this is rarely responsible for major morbidity.

Miscellaneous

Hyperthermia may be observed, but is the exception. When present, it portends a poor prognosis. Acute tubular necrosis has been reported. Rhabdomyolysis contributes to hyperkalemia, coagulopathy, and renal failure. Tinnitus is common when serum salicylate levels exceed about 25 mg/dL.

Clinical Presentation

Patients who present shortly after an overdose are usually awake and complain of tinnitus, abdominal pain, nausea, and vomiting. Other abnormalities include tachypnea, respiratory alkalosis with alkalemia, hypovolemia, hypokalemia, and gastrointestinal bleeding.

Progression of the poisoning is characterized by diaphoresis, tachycardia despite correction of hypovolemia, metabolic acidosis and acidemia, progressively severe neurotoxicity, alterations of glucose homeostasis, elevated PT, pulmonary edema, and cardiotoxicity. The combination of acidemia and neurotoxicity carries a grave prognosis unless aggressive treatment is initiated promptly.

As compared to acute salicylate poisoning, serum salicylate concentrations are lower for any given degree of toxicity in chronic poisoning because of larger tissue burdens of salicylate, reflecting a larger volume of distribution.

Evaluation and Treatment

Serum Salicylate Concentrations

Interpretation of serum salicylate concentrations can be difficult. Similar levels can have varied effects because of changing tissue burdens of the drug depending on blood pH, protein binding, and other factors. Because of these factors, tissue concentrations of salicylate can actually rise while serum levels are falling, causing the patient’s condition to deteriorate while the physician is falsely reassured by falling serum drug concentrations. It is always more important to treat the patient than the serum salicylate concentration.

Basing treatment and disposition on a single serum salicylate concentration can be misleading and is to be discouraged. Though a serum salicylate level less than 30 mg/dL (and known to be falling) would be reassuring for an asymptomatic mother, because the fetus develops higher serum salicylate concentrations than the mother, it is possible for fetus to develop significant toxicity.

Hyperbilirubinemia can cause falsely elevated salicylate concentrations when levels are measured using a colorimetric method. In these cases, serum salicylate concentrations should be measured by an immunoassay or by a chromatographic method.

General Principles

All patients with salicylate poisoning should be admitted to an intensive care setting, whether in labor and delivery or in a medical intensive care unit. Successful maternal management of acute salicylate poisoning hinges on intensive and attentive medical care (Fig. 23-7). Specifically, frequent attention to fluid balance, electrolyte and acid-base status, bedside examination, and rapid institution of hemodialysis at the earliest signs of CNS deterioration are required. It is also recommended that hemodialysis be performed earlier during pregnancy, given ability of the fetus to concentrate salicylate.

Airway As with many patients, immediate attention to airway and adequate oxygenation are mandatory. If a patient receives narcotics or sedatives, including when used for endotracheal intubation and mechanical ventilation, a drop in an elevated minute ventilation (from salicylate-induced hyperventilation) to normal values can precipitate a rapid decline in blood pH, movement of salicylate into tissues and fetus, and rapid deterioration. Therefore, close attention must be given to maintaining alkalemia (ABGs + potassium every 2-4 hours) with additional doses of IV sodium bicarbonate when sedation or mechanical ventilation is instituted.

Glucose Abnormalities Patients must be monitored for hypoglycemia (every 2 hours), especially in the face of any mental status changes. Treatment comprises IV boluses of 50% dextrose and infusions of dextrose solutions to keep the glycemia above 90 mg/dL.

Gastrointestinal Decontamination A single dose of 1 g AC per kilogram body weight should be given initially if it is immediately available, no contraindications are present and the patient is not vomiting. Most patients suffering from acute salicylate poisoning vomit repeatedly, rendering further attempts at gastric emptying (lavage and ipecac) unnecessary. If salicylate levels continue to rise, repeated doses of 0.25 g AC per kilogram body weight, every 4 to 6 hours until levels begin to fall, may be considered if the patient has normal gastrointestinal motility. Phenothiazines are to be discouraged, as they usually are ineffective and lower the seizure threshold.

Fluid and Electrolyte Therapy Most patients are moderately to severely dehydrated and require immediate fluid challenges with normal saline or Ringer lactate until urine output is 2 to 3 mL/kg/h. Initial sodium bicarbonate boluses of 2 mEq/kg are given, if needed, to raise arterial blood pH from 7.45 to 7.5. A typical patient with moderate to severe salicylate toxicity has a 6-L fluid deficit on presentation.

A recommended initial regimen for maintenance fluid therapy after fluid resuscitation and establishment of good urine flow is a continuous infusion of 1000 mL of 5% dextrose in water to which is added 150 mEq sodium bicarbonate (3 ampules of 8.4% NaHCO₃) and 40 mEq potassium chloride to run at 2 to 3 mL/kg/h. Hypokalemia must be treated aggressively. Urine alkalinity cannot be achieved in the setting of hypokalemia because the kidney will secrete protons rather than potassium ions when reabsorbing sodium. Additionally, for the reasons outlined above, the patient usually presents with a total body potassium debt, and ongoing losses continue as salicylate anions combine with potassium cations in the urine during elimination. Despite intravenous infusions containing 40 mEq/L of KCl, patients almost always require regular additional potassium supplementation. Oral potassium solutions can be used when vomiting has halted.

The rationale behind sodium bicarbonate therapy outlined below has 2 principal purposes (see Fig. 23-6). Most important, alkalinization of blood helps prevent movement of salicylate out of the serum into target organs. The prime concern is preventing movement of salicylate into the CNS and the fetus. Blood pH should be kept between 7.45 and 7.50. A drop in blood pH from 7.45 to 7.20 can almost double the concentration of nonionized salicylate that is able to move into the brain and fetus. Of lesser importance, alkalinization of urine promotes “ionic trapping” of salicylate in urine, preventing reabsorption, and enhancing elimination. Urinary salicylate excretion can increase 15 times as urine pH increases to pH 8.0, above which there is no additional benefit. Monitoring the urinary ph every hour during treatment is recommended.

Fluid and electrolyte infusions are modified as needed to prevent hypovolemia, fluid overload, normalize electrolytes, ensure adequate urine output, and prevent acidemia and hypoglycemia. Because of fluid losses through hyperventilation, diaphoresis, vomiting, and sometimes, hyperthermia, it is common for moderately to severely ill patients to require more than 500 mL/h of intravenous fluid to maintain euvolemia and prevent the rises in serum creatinine, sodium, and hematocrit typical of hemoconcentration.

Serum salicylate concentrations should be obtained every 2 hours until a declining trend is noted and the levels fall under 30 mg/dl, with findings interpreted in the context of the patient’s condition.

Noncardiogenic Pulmonary Edema Adult respiratory distress syndrome (ARDS) is more common in chronic toxicity and should be treated with oxygen and continuous positive airway pressure (CPAP) or positive end-expiratory pressure (PEEP), if required. Only cautious use of diuretics is recommended, as these patients are usually volume depleted. If mechanical ventilation is required, hyperventilation (rates of 16-20/min) might be needed to keep the PaCO₂ around 35 mm Hg.

Miscellaneous A 10-mg parenteral dose of vitamin K₁ reverses elevated PT produced by salicylate over several hours. In an emergency, fresh frozen plasma rapidly corrects coagulopathy (but not platelet dysfunction). Serial blood hemoglobin values should be followed to determine if gastrointestinal bleeding develops and becomes severe enough to require transfusions. Antacid therapy with proton pump inhibitors or H₂ antagonists are commonly used, but have not been studied in the setting of salicylate poisoning. Serial measurements of serum creatine kinase (CK) activity should be evaluated to rule out rhabdomyolysis, which, if present, will require specific therapy.

Hemodialysis Any deterioration in neurologic function, especially if associated with acidemia, is an indication for immediate hemodialysis. Hemodialysis is effective and life saving in that it removes salicylate and corrects acid-base electrolyte abnormalities. It is best performed using high-flux hemodialysis with the largest-surface area cartridge available. Hemodialysis may be indicated in the following situations:

1. Moderately to severely ill patients with renal insufficiency.

2. Seizures or other severe CNS symptoms or worsening neurotoxicity, even if serum salicylate concentrations are falling.

3. Other life-threatening complications (pulmonary edema) accompanied by elevated serum salicylate concentrations.

4. Salicylate level greater than 90 mg/dL (or 60 mg/dL with a chronic overdose).

5. No improvement of acidemia with decontamination and urine alkalinization.

6. Hypotension refractory to optimal supportive care.

7. To ensure fetal survival (see further on).

Fetal Concerns

Salicylate crosses the placenta and concentrates in the fetus at higher levels than in the mother, at least in part, by differences in protein binding. The relative acidemia of the fetus also contributes to a higher relative volume of distribution and, therefore, higher tissue levels for a given serum salicylate concentration. In addition, the fetus has a lower capacity to buffer the acidemic stress imposed by salicylate and, relative to the mother, a reduced capacity to excrete the toxin. Collectively, this places the fetus at greater risk for death and forms the basis for the subsequent recommendation of hemodialysis and/or possible cesarean section. Given that the fetus concentrates salicylate and suffers greater toxicity than the mother, it seems wise to institute hemodialysis for lesser degrees of maternal toxicity than would be done in nonpregnant patients. Unfortunately, there are no studies to guide clinicians in this setting. It would be advisable to recommend immediate hemodialysis in the face of any signs of fetal distress, in the face of chronic maternal salicylate poisoning (where high tissue levels predominate), or whenever maternal serum salicylate concentrations exceed 40 mg/dL.

In term pregnancies, it has been proposed that delivery should be considered when deemed safe for the mother. However, there are no studies that have addressed this issue, and decisions must be made on an individual basis. It is possible that hemodialysis would result in falls in both maternal and fetal salicylate concentrations from the redistribution of salicylate across the placenta. Fetal monitoring is certainly part of the adequacy assessment of the supportive measures implemented.

Commonly used selective SSRIs include fluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil), and citalopram (Celexa). There has been an increase in exposures reported to US Poison Control Centers involving SSRIs. Besides its neurotransmitter action in the central nervous system, SSRIs act directly on the myometrium via 5-HT2a receptors.

In most instances, isolated SSRI poisoning has no clinical significance. At very high doses, SSRIs may trigger serotoninergic syndrome with or without signs of the anticholinergic syndrome. Most fatalities have been reported with either large doses (>150 times the daily dose) or with the presence of coingestants such as ethanol, benzodiazepines, or tricyclic antidepressants. Transplacental transference of SSRIs has been documented.

Serotoninergic syndrome is characterized by the simultaneous presence of at least 3 of the following signs: confusion, agitation, delirium, hallucinations, mania, coma, seizures, ocular clonus (slow, continuous, horizontal eye movements), myoclonus, hyperreflexia, sweating, shivering, trembling, diarrhea, hyperthermia, or lack of motor coordination. Myoclonus is the most specific sign.

The anticholinergic syndrome is characterized by agitation, delirium, tremor in the extremities, mydriasis, dryness of the mucous membranes, urinary retention, constipation, and sinusal tachycardia.

During pregnancy, particularly in the third trimester, intense uterine contractions and fetal heart rate anomalies have been reported as a consequence of SSRI intoxication.

Supportive care and decontamination are the most important aspect of treatment.

All pregnant patients with suicidal intent or SSRI abuse should be admitted.

Following initial patient stabilization, administer AC (1 g/kg; standard adult dose is 50 g). Greatest benefit from charcoal decontamination occurs if given within 1 to 2 hours following the ingestion. Do not induce emesis. The use of oral AC can be considered since the likelihood of SSRI-induced loss of consciousness or seizures is small. As for most toxic agents a specific SSRI-antidote does not exist. There is no role for hemodialysis.

Secure airway, breathing, and circulation; intubate as clinically indicated.

If a patient is clinically sick or comatose, consider the presence of coingestants or an underlying nontoxicologic condition. Significant toxicity in an isolated SSRI ingestion is unlikely.

If patient is hyperthermic (>104°F [>40°C]), use benzodiazepines and external cooling measures.

Seizures generally are best treated with benzodiazepines (Lorazepam 1-2 mg IV every 5 minutes prn). Drug-associated agitated behavior is generally best treated with benzodiazepine administration, supplemented with high potency neuroleptics (haloperidol) prn. Agitation associated with the anticholinergic syndrome may be best treated with physostigmine (initial dose: 0.5-2.0 mg slow IV over 3-5 minutes).

If hypotension does not respond to intravenous fluids, vasopressors will be required. Direct-acting vasopressors, such as norepinephrine can be used safely in pregnancy. If severely hypertensive, use nifedipine or labetalol. Ventricular tachycardias are generally treated with lidocaine. Symptomatic bradyarrhythmias (eg, with hypotension) should be treated with atropine or temporary pacing).

• L&D management: Tocodynamometry must be maintained during the first 12 to 24 hours following ingestion. Prophylactic tocolysis (calcium channel blocker) to reduce the strength of uterine contractions and reduce risk of preterm delivery has been advocated.

• Fetal heart rate abnormalities: Unless persistently nonreassuring (category III) tracing is present, expectant management is recommended given that premature birth will likely be complicated by severe neonatal withdrawal syndrome (irritability, vomiting, and convulsions, etc).

Antenatal steroids is recommended if fetus is viable and at less than 34 weeks’ gestation. With SSRI use during pregnancy, there is the additional small risk of persistent pulmonary hypertension in the neonate.

In the United States, approximately 6% of the reported toxic exposures during pregnancy are the result of bites or envenomations. The latter term is used to describe toxic exposures resulting from the contact with biologic substances (toxins or venoms) produced in specialized glands or tissues from animals, usually by cutaneous (eg, in the case of jellyfish) or transdermal (parenteral) injection (in the case of snakebites, scorpion stings or bee stings).

In the assessment of a potentially venomous bite, one must distinguish the bite from one from a nonvenomous snake, bites from other animals, and puncture wounds caused by inanimate objects. In occasions the animal responsible for the envenomation is not seen or recognized. In these cases, the circumstances of the envenomation including the geographical location of the sting or bite and the clinical presentation assist in making a presumptive diagnosis.

The clinical manifestations and severity of an envenomation depend on the particular species of the animal responsible (and therefore the geographical location of the incident), the amount of toxin(s) exposed to, the size of the victim, the site of exposure, and the implementation or not of supportive and specific treatment (in the form of an antidote), if available. Anaphylactic shock can result from the repeated exposure to certain stings (eg, bees), the management of which is not addressed here as it is dealt with in a specific chapter of this book.

Though the number of animals responsible for envenomations is large (including species of fish, lizards, insects, and jellyfish) we will limit the discussion to snakebites, spider bites, and scorpion stings in North America. Given the increasing popularity of exotic animals (snakes, spider, and scorpions) as pets the possibility of envenomation by a nonendemic species exists. In these cases, expert consultation with a herpetologist or arthropod expert will be beneficial. Most zoos or poison control centers have specific information on unusual breeds of snakes. Timely consultation is highly recommended.

Snakebites

Snakebites during pregnancy are an uncommon event. Most fatalities associated to snake bites occur in developing countries where venomous snakes are plentiful, human populations are dense, and rapid transport and intensive medical treatment facilities are lacking.

Of the more than 120 species of snakes indigenous to the United States only 25 are venomous. The majority of these snakes belong to the subfamily Crotalinae (pit vipers: rattlesnakes, cottonmouths, and copperheads). The coral snake (Elapidae) is the only other native venomous snake. Common pit vipers in the United States include the rattle snakes (Sistrurus and Crotalus) and the moccasins snakes: cotton-mouths (Agkistrodon piscivorus) and copperheads (Agkistrodon contortrix).

Rattlesnakes cause two-thirds of all bites by identified venomous snakes in the United States.

Snake venoms are primarily composed of mixtures of proteins and polypeptides with various properties. Many proteins have enzymatic activities, whereas others produce toxic cellular effects. Actions of snake venoms can be broadly classified as inflammatory, cytotoxic, neurotoxic, and hemotoxic though this is an oversimplification as the peptides of snake venom appear to bind to multiple receptor sites in the prey. The composition of venom varies with the species and age of the snake, geographic location and time of year. Venom usually is injected into subcutaneous tissue via fangs; occasionally, intramuscular or intravenous injection can occur.

Clinically, local effects most commonly predominate, progressing from pain and edema to ecchymosis and bullae. Hematologic abnormalities, including benign defibrination with or without thrombocytopenia, may result, but severe generalized bleeding is uncommon. Local or diffuse myotoxicity and edema may result in complications such as rhabdomyolysis or compartment syndromes. Other rare general effects include cardiotoxicity, fasciculations, and shock.

About 25% of all pit viper bites and 50% of all coral snakebites in the United States do not result in envenomation and are considered “dry" bites. In the absence of positive identification, objective symptoms and signs of an envenomation become the focus of diagnosis. In some cases the appearance of the bite can be of assistance to expert herpetologists in the identification of the snake responsible for it.

The case-fatality rate of reported snake envenomations during pregnancy is approximately 4% to 5%. The case-fatality rate for fetus and neonates is approximately 20%. Both figures represent an improvement over previously reported numbers (38%-43% and 10%, respectively).

The vast majority of these losses are in utero fetal deaths. The deaths in the neonates may occur from 30 minutes to 8 days after birth.

Bleeding diathesis results from pit viper envenomation. Fetal and placental effects from the anticoagulation are postulated to produce the fetal losses. Although the specific effects of venom on the human fetus are unknown, there is evidence that snake venom may cross the placenta affecting the fetus even without evidence of envenomation in the mother. Snake venom has been shown to have uterotonic properties and fetal loss during early gestation may be due to intrauterine bleeding, hypoxia, and pyrexia.

Local measures include positive identification of the type of snake (venomous snakes generally have a triangle-shaped head). Following a bite from a venomous snake, the victim should be moved beyond striking distance, placed at rest, reassured, kept warm, and transported to the nearest medical facility as soon as possible for definitive medical care. The injured area should be immobilized in a functional position below the level of the heart. All rings, watches, and constrictive clothing should be removed. No stimulants such as caffeine or alcohol should be administered. Signs and symptoms of an envenomation might not develop immediately, which makes transportation to the nearest medical facility essential to ensure prompt and ongoing evaluation and necessary treatment if envenomation has occurred. Previously recommended first aid measures involving the use of tourniquets, incision and suction, cryotherapy, and electric shock therapy are strongly discouraged. Paramedical personnel should focus treatment on support of airway/breathing, circulation, administration of oxygen, establishment of intravenous (IV) access on the contralateral side, and transportation of the victim to the nearest medical facility. Tourniquets are not recommended but those that are not producing limb-threatening ischemia and constriction bands that have been placed as first aid should be left in place until the victim is evaluated. Because venom may be transported, a loose constriction bandage may be used to delay spread of the venom.

The snake (dead or alive) can be brought in with the victim. If possible they should be placed in a canvas bag or container. Snake parts should not be handled directly since even dead or decapitated snakes retain a bite reflex rendering them capable of inflicting a secondary bite.

Local and supportive measures for poisonous snakebite include careful cleaning of the wound, maintaining the extremity in neutral position, supportive care, potential use of antibiotics, and tetanus prophylaxis. Tetanus prophylaxis is not contraindicated in any pregnant snakebite or trauma victim who otherwise would be a candidate for the toxoid booster or antiglobulin. Mouth suction is contraindicated.

The management of snakebites is summarized in the algorithm included in Fig. 23-8. It pertains to the treatment of patients bitten by pit viper snakes (family Viperidae, subfamily Crotalinae) in the United States, including the rattlesnakes (genus Crotalus), pygmy rattlesnakes (Sistrurus), and moccasin snakes (genus Agkistrodon). Within the Agkistrodon genus are the copperhead snakes (A. contortrix) and the water moccasin (cottonmouth) snake (A. piscivorus). This proposed algorithm is not a substitute for clinical judgment. The care of these victims may vary based on the patient presentation, available treatment resources, patient comorbidities, and patient preference among other factors. Because of the many variables inherent in the management of snakebite victims, consultation with a physician specialist is recommended.

From the obstetric standpoint, there should be concern for threatened abortion, vaginal bleeding, and fetal distress (revealed by fetal bradycardia). Monitoring of uterine contractions (with fetal heart rate monitoring if indicated) is recommended.

Immunotherapy (antivenom) is based on administration of antibodies produced by an animal that has been previously hyper-immunized against the venom of the corresponding or a very close species.

Most cases are mild and do not preclude continued administration of antivenom. When considering its use, the risk of adverse reaction to antivenom must be weighed against the benefits of reducing venom toxicity. While the safety of antivenom in pregnancy is unclear, the risks of withholding likely outweigh the risks of administering in correct clinical scenarios. Because copperheads carry a lesser potent venom, their bites may not require antivenin. Hypersensitivity reactions are common with antivenin use. Symptoms of acute anaphylactoid reactions, such as pruritus, urticaria, or wheezing occur in approximately 6% of patients. However, severe acute allergic reactions, including reactions involving airway compromise, have been described. For these reasons, antivenom should not be given in the field.

Spider Bites

In the United States, mainly 2 types of poisonous spider bites are of concern, the black widow and the brown recluse. These spiders bite only when trapped or crushed against the skin. In 90 percent of suspected spider bites, the actual arachnid has been unavailable for identification. The diagnosis of spider bites is mainly clinical.

Black Widow Spider

The black widow spider occasionally has been reported to envenomate a pregnant victim. The adult female black widow spider (Latrodectus mactans) has a highly neurotoxic venom (α-latrotoxin), which destabilizes the cell membranes and degranulates the nerve terminals resulting in massive noradrenaline (norepinephrine) and acetylcholine release into synapses causing excessive stimulation and fatigue of the motor end plate and muscle.

In contrast to the dermo-necrotic effects of the Loxosceles bite, the site lesion secondary to Latrodectus is unremarkable (similar to coral snake’s bite). Within about 1 hour of the bite, patients develop an autonomic and neuromuscular syndrome characterized by hypertension, tachycardia and diaphoresis, abdominal pain and tenderness, and back, chest or lower extremity pain (painful muscle spasms and cramping), and weakness within minutes to hours of envenomation These neuromuscular symptoms progress over several hours, then subside over 2 to 3 days. Severe Latrodectus envenomation is characterized by: generalized muscular pain in the back, abdomen, and chest refractory to analgesics, diaphoresis remote from envenomation site, abnormal vital signs (blood pressure >140/90 mm Hg, pulse >100), nausea and vomiting and headache. Black widow envenomations can mimic acute intra-abdominal processes and preeclampsia (abdominal pain, headache, hypertension, and proteinuria).

Laboratory workup may include a CBC, acute abdominal series, ECG and CPK to evaluate acute abdominal and chest pain syndromes.

General supportive management (airway protection, breathing and circulation per Advanced cardiac life support [ACLS] protocols) must be instituted as soon as possible. Most widow spider envenomations may be managed with opioid analgesics and sedative-hypnotics. Analgesics (morphine) and benzodiazepines (midazolam) are effective adjuvant treatment for the neuromuscular symptoms. Studies suggest benzodiazepines are more efficacious than muscle relaxants for treatment of widow spider envenomation. Antibiotics are not indicated. Tetanus immunization should be instituted following a black widow spider bite.

Though a specific antivenin for black widow bites is available and can result in resolution of most symptoms within 30 minutes from administration and decrease the need for hospitalization, it should be cautiously restricted for severe envenomation (eg, severe hypertension, unstable angina). Due to hypersensitivity, anaphylaxis, and serum sickness reactions, it should be given only in the hospital setting. The antivenin must be diluted and administered slowly (200 mL over an hour) after skin testing and antihistamines (diphenhydramine) is administered to reduce acute adverse reactions to the antivenom. Symptoms have been shown to improve within 1 hour of antivenom administration and for as long as 48 hours after envenomation. No more than 1 vial of antivenom is usually required.

Brown Recluse Spider

There are 11 species of native Loxosceles spiders in North America. Loxosceles reclusa, also known as the brown recluse spider (BRS), are found in the United States widely, though not in the whole country. Characteristic violin-shaped markings on their backs have led brown recluses to also be known as “fiddle-back" spiders. A more distinguishing feature is the number of eyes. Whereas most spiders have 8, L. reclusa has 6 eyes arranged in a distinctive pattern of 3 pairs, known as dyads. They are nocturnal and are considered to be house spiders, as their habitat includes attics, basements, boxes, sheds, and woodpiles. The spiders are not known to migrate out of their native areas, but may be moved from place to place by humans, leading to reports of bites in nonendemic areas. Nonetheless, many bites attributed to BRS are likely not arachnid accidents or caused by other species of spiders. Physicians should be especially cautious of a history of presumptive Loxosceles envenomation from a patient in an area in which BRS are not endemic.

In South America, the more potent venom of the species Loxosceles laeta is responsible for several deaths each year.

The venom contains at least 8 enzymes, consisting of various lysins (facilitating venom spread) and sphingomyelinase D, which causes cell membrane injury and lysis, thrombosis, local ischemia, and chemotaxis.

Although most bites are asymptomatic, envenomation can begin with pain and itching that progresses to vesiculation (single clear or hemorrhagic vesicle) with violaceous necrosis and surrounding erythema, and ultimately ulcer formation and necrosis (dermonecrotic arachnidism). Differential diagnosis includes several bacterial infections, herpes simplex, Stevens-Johnson syndrome, factitious injuries, and toxic epidermal necrolysis.

Treatment of local envenomations is conservative (local wound care, cryotherapy, elevation, tetanus prophylaxis, and close follow-up). Bites may be cleaned and treated with rest-ice-compression-elevation (RICE). Mild bites may be treated symptomatically with analgesics and antihistamines. Most BRS bites heal without aggressive medical treatment.

Severe brown recluse spider bites produce dermonecrosis within 72 to 96 hours, which might be treated with rest, ice compresses, antibiotics, dapsone, and surgery delayed for several weeks. There is no consensus concerning the efficacy of any reported therapy including dapsone, colchicine, steroids, antivenom, nitroglycerin patches, surgical excision, and hyperbaric oxygen. Insufficient data exist to support their clinical use at this time. Skin grafting may be necessary after 4 to 6 weeks of standard therapy or until the lesion borders are well defined. Antivenom is not commercially available for L. reclusa. The only commercially available antivenom is for L. laeta in South America.

Loxoscelism is the term used to describe the systemic clinical syndrome caused by envenomation from the brown spiders. Systemic involvement, although uncommon, occurs more frequently in children than in adults. Systemic envenomations may be life threatening, and present with fever, constitutional symptoms, petechial eruptions, thrombocytopenia, and hemolysis with hemoglobinuric renal failure, seizures or coma, usually associated with minimal skin changes. Systemic envenomation requires supportive care and treatment of arising complications, corticosteroids to stabilize red blood cell membranes, and support of renal function.

Cases of envenomation by L. reclusa in pregnant patients have been reported. No special risks or complications resulted from these bites when managed conservatively only with low-dose prednisone No episodes of hemolysis, disorders of coagulation, or renal damage have been described.

Scorpions

The estimated global incidence of scorpion envenoming is about 1.5 million involving 2600 deaths per year, the majority of which occur in the Middle East and North of Africa. Over 650 species of scorpions are known to cause envenomation, of which about 30, all belonging to the family Buthidae, are potentially dangerous to humans. Scorpions are endemic mostly in arid and tropical areas. They are shy creatures, active at night during the hot season, but often live in houses or near inhabited areas which explains the high incidence of scorpion stings involving children in many parts of the world. Different venoms and clinical presentations are seen across different species. The most important clinical effects of envenomations are neuromuscular, neuroautonomic, or local tissue effects. Systemic envenoming is caused by members of the genera Centruroides (found in the Southwest region of the United States and in Mexico); Tityus (in Brazil and Trinidad); Androctonus, Buthus, Leiurus, and Nebo (in North Africa and the Near and Middle East); Hemiscorpius (in Iran, Iraq, and Baluchistan); Parabuthus (in South Africa); and Mesobuthus (in the Indian subcontinent).

The first symptom of scorpion envenoming is localized pain, which reflects the penetration of the venom and is a valuable warning signal. Systemic manifestations occur in less than a third of victims of scorpion stings.

Overstimulation of the sympathetic system results in a characteristic “adrenergic (autonomic) storm” with cardiac (tachycardia, peripheral vasoconstriction, hypertension, diaphoresis), metabolic (hyperthermia, hyperglycemia), urogenital (bladder dilatation, urinary retention), respiratory (bronchial dilation, tachypnea), and neuromuscular (mydriasis, tremor, agitation, convulsions) manifestations. In contrast, a cholinergic (or muscarinic) syndrome can occur with the combination of a hypersecretion syndrome (salivation, sweating, vomiting, urinary incontinence, bronchial hypersecretion, and diarrhea), abdominal pain, myosis, bronchospasm, bradycardia with hypotension. This syndrome seems to be rarer, delayed, or masked by the adrenergic storm. In addition, the release of inflammatory substances or vasodilators (kinins, prostaglandins) reinforces and exacerbates some symptoms (fever, dyspnea, visceral, particularly infarction) which can become dominant.

The severity of scorpion envenoming may be evaluated by a scoring system. Three grades are generally used, that is, grade I for local events, grade II for mild systemic symptoms, and grade III for life-threatening envenoming.(see Table 23-3)

Symptomatic treatment only is recommended in grade I (local) envenoming, for which immunotherapy is not helpful and too expensive. Acetaminophen and even a short course of NSAID’s can be considered during pregnancy. Use of analgesics, even if they are not the most essential drugs in envenoming, is still important because pain is frequent and intense. Morphine or its derivatives or analogs (codeine, tramadol), although very effective, should be avoided because the opioid receptor agonists inhibit noradrenaline reuptake, which may potentiate their effects; these agents also cause respiratory depression, worsening the patient’s respiratory condition. Systemic envenoming (grade II and III) require immunotherapy. The antivenom dosage depends on its neutralizing titer. Administration should be done via the intravenous route, either as a direct slow intravenous push in cases of severe envenoming (grade III) or by infusion in 250 mL of saline administered over 30 minutes. Immunotherapy might be repeated after 2 hours if cure is not obtained on the first attempt. In cases of cardiac arrhythmia or hypertension, prazosin (30 μg/kg orally every 6 hours for 48 hours or until clinical improvement) can be used. Prazosin is more effective than nifedipine which blocks calcium ion influx of smooth muscle cells in the arterioles and inhibits their contraction. Hydralazine inhibits release of calcium ions in the smooth muscle of the vascular wall. Although effective, hydralazine has several disadvantages, including sympathetic stimulation which increases heart rate, with a risk of myocardial infarction, and an increase in plasma renin, leading to urinary retention requiring treatment with a β2-adrenergic blocker and diuretic. Further, hydralazine administered parenterally produces a prolonged hypotensive response which is difficult to control. Clonidine could be an alternative to prazosin as it causes a decrease in heart rate and peripheral blood pressure. Dobutamine can be used alone or in combination with diuretics or antiarrhythmics in cases of heart failure (infusion of 10 μg/kg/minute until normalization of left ventricular ejection fraction, then 5 μg/kg every 12 hours). Neuromuscular disorders (tremors, cramps, convulsions) may be treated with benzodiazepines, based on clinical signs and response to treatment, that is, midazolam (0.05–0.2 mg/kg orally or intravenously) or diazepam (0.5 mg/kg intravenously or rectally) every 12 hours.

Antiparasympathetic drugs, such as atropine, are not recommended routinely in the treatment of scorpion envenoming. These cause blockage of sweating and potentiate the adrenergic effects of scorpion venom, increasing hypertension and ischemic complications.

Reactions to Antivenoms

Improvement of antivenomous sera is obtained by first separating the antibodies from other plasma components, followed by enzymatic digestion of IgG, then purification of the final product. As a consequence, efficacy and safety are significantly increased. Most of the antivenoms currently manufactured are purified fragments of immunoglobulin G (IgG) [F(ab’)2], which reduces potential adverse effects. However, poorly refined antivenoms may induce severe adverse reactions, such as shock or anaphylaxis.

A proportion of patients (usually 6%-10%), develop a reaction either early (within a few hours) or late (5 days or more) after being given an antivenom. The risk of reactions is dose-related, except in rare cases in which there has been sensitization (IgE-mediated Type I hypersensitivity) by previous exposure to animal serum, for example, to equine antivenom, tetanus-immune globulin, or rabies-immune globulin.

1. Early anaphylactic reactions: Usually within 10 to 180 minutes of starting antivenom, the patient begins to itch (often over the scalp) and develops urticarial, dry cough, fever, nausea, vomiting, abdominal colic, diarrhea, and tachycardia. A minority of these patients may develop severe life-threatening anaphylaxis: hypotension, bronchospasm, and angioedema. Some fatal reactions have probably been under-reported as death after snakebite is usually attributed to the venom. In most cases, these reactions are not truly “allergic". They are not IgE-mediated type I hypersensitivity reactions to horse or sheep proteins as there is no evidence of specific IgE, either by skin testing or radioallergosorbent tests (RAST). Complement activation by IgG aggregates or residual Fc fragments or direct stimulation of mast cells or basophils by antivenom protein are more likely mechanisms for these reactions.

2. Pyrogenic (endotoxin) reactions: Usually develop 1 to 2 hours after treatment. Symptoms include shaking chills (rigors), fever, vasodilatation, and a fall in blood pressure. Febrile convulsions may be precipitated in children. These reactions are caused by pyrogen contamination during the manufacturing process. They are commonly reported.

3. Late (serum sickness type) reactions: Develop 1 to 12 (mean 7) days after treatment. Clinical features include fever, nausea, vomiting, diarrhea, itching, recurrent urticaria, arthralgia, myalgia, lymphadenopathy, periarticular swellings, mononeuritis multiplex, proteinuria with immune complex nephritis and, rarely, encephalopathy. Patients who suffer early reactions and are treated with antihistamines and corticosteroid are less likely to develop late reactions.

Prophylaxis of Antivenom Reactions

There is no absolute contraindication to antivenom treatment, but patients who have reacted to horse (equine) or sheep (ovine) serum in the past (eg, after treatment with equine antitetanus serum, equine antirabies serum or equine or ovine antivenom) and those with a strong history of atopic diseases (especially severe asthma) are at high risk of severe reactions and should therefore be given antivenom only if they have signs of systemic envenoming.

In the absence of any prophylactic regimen that has proved effective in clinical trials these high risk patients may be pretreated empirically with subcutaneous epinephrine (adrenaline), intravenous antihistamines (both anti-H₁, such as promethazine or chlorpheniramine; and anti-H₂, such as cimetidine or ranitidine), and corticosteroids. In asthmatic patients, prophylactic use of an inhaled adrenergic β₂ agonist such as salbutamol may prevent bronchospasm.