6.5.2) PREVENTION OF ABSORPTION
A) GENERAL 1) Although not anticipated, inadvertent oral ingestion may occur with botulinum toxins used for medical therapy. Decontamination should only be considered with a known ingestion.
2) Intentional misuse of botulinum toxin such as deliberate contamination of food may occur as a result of a terrorist act. Currently, commercially available therapeutic botulinum toxin represents an impractical bioterrorist weapon because the United States preparations only contain 0.005% of the estimated lethal oral dose per vial (Arnon et al, 2001).
B) ACTIVATED CHARCOAL 1) As most exposures to pharmaceutical grade botulinum toxin will not involve potentially toxic doses, decontamination is not indicated. Decontamination should be performed following ingestion of research grade products if the dose is potentially toxic. 2) Mice given activated charcoal with type A botulinum toxin-contaminated food experienced significantly less morbidity and mortality than those given the food alone (Gomez et al, 1995). Theoretically, although activated charcoal actively binds to the C. botulinum, it remains uncertain what clinical effect this treatment would have on the course of the disease, such as interfering with other proteins in the gut which may have denaturing and detoxifying effects on the neurotoxin present. a) However, based on these results, activated charcoal is recommended for treatment since it may inactivate type A botulinum toxin.
3) CHARCOAL ADMINISTRATION a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
4) CHARCOAL DOSE a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005). 1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
b) ADVERSE EFFECTS/CONTRAINDICATIONS 1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
6.5.3) TREATMENT
A) SUPPORT 1) Treatment is symptomatic and supportive. Symptoms may take up to several weeks following an inadvertent parenteral injection or oral ingestion of botulinum toxin type A or B. The patient should be medically supervised for several weeks for signs or symptoms of systemic effects including respiratory or muscle paralysis or weakness (Prod Info BOTOX(R) intramuscular intradetrusor intradermal injection powder for solution, 2011; Prod Info Myobloc(R) IM injection, 2010).
2) An antitoxin is available, but it will not reverse botulinum toxin-induced muscle weakness that is already present. Contact your State Health Department to process a request for the antitoxin through the Centers for Disease Control and Prevention (CDC) (Prod Info BOTOX(R) intramuscular intradetrusor intradermal injection powder for solution, 2011; Prod Info Myobloc(R) IM injection, 2010).
B) AIRWAY MANAGEMENT 1) The mainstay of botulism therapy is early, aggressive respiratory support in an intensive care unit. Precipitous respiratory failure is the greatest threat to life. Close observation and assessment of vital capacity and inspiratory force are essential. Consideration should be given to early or elective intubation. Patients with type A botulism are most likely to require ventilatory support (Hughes et al, 1981; MacDonald et al, 1985; Woodruff et al, 1992; Shapiro et al, 1998).
2) INDICATIONS: Respiratory failure, the most immediate threat to life, may develop rapidly. Endotracheal intubation should be performed in patients with falling inspiratory force (less than 25 centimeters H2O) or PO2 (less than 60 mmHg), rising PCO2 (greater than 50 mmHg), or vital capacity less than 40 percent predicted. (NOTE: Arterial blood gases may show only minor abnormalities despite significant ventilatory dysfunction.)
3) In milder cases, endotracheal intubation without tracheostomy may be sufficient and safer when long-term airway control is not anticipated (Werner & Chin, 1973). Tracheostomy may be required for long term ventilatory support.
4) Intubation may be necessary for management of secretions even if ventilation is adequate (Beaty & Graefner, 1977).
5) MEASUREMENTS: Regular measurement of vital capacity is essential. Maximal inspiratory and expiratory pressure estimations may also be helpful (Shneerson, 1989).
C) POSITIONING PATIENT 1) Keeping the patient on a flat, rigid mattress tilted at 20 to 25 degrees in reverse Trendelenburg position with cervical support and a bumper at the feet to prevent downward sliding may reduce the risk of aspiration and maximize respiratory mechanics (Arnon et al, 2001).
D) FLUID/ELECTROLYTE BALANCE REGULATION 1) Establishment of an intravenous line with administration of maintenance fluids is mandatory in symptomatic patients. During routine use, botulinum toxins may produce dysphagia, which can be severe.
E) MONITORING OF PATIENT 1) In most patients, the diagnosis may not be immediately obvious. Monitor serum electrolytes, renal function, and arterial blood gas. Other routine labs, including CSF, are typically normal.
2) Monitor vital signs, negative inspiratory force, peak flow, continuous pulse oximetry and end tidal CO2, and serial neurologic exam.
3) While toxin concentration can be measured in serum, this is not widely available and will not help guide therapy, but can confirm exposure. If inadvertent administration or overdose occurs, 10 mL of serum for determination of toxin should be drawn before treatment. The standard laboratory study is the mouse bioassay. Analysis takes 24 hours to perform, so the results cannot be used to determine treatment. A reference laboratory (CDC, state or local health department) must be consulted; diagnosis confirmed by demonstration of toxin in serum, stool, or food items, or by isolation of organism in stool or food items.
F) BOTULISM ANTITOXIN 1) GENERAL GUIDELINES: Administer as soon as possible. Indication for continued treatment is persistence of toxin by serum analysis. If several days after onset of illness and symptoms not progressing, antitoxin may not be required. a) Investigational heptavalent botulinum antitoxin (HBAT), containing equine-derived antibody to botulinum toxin types A through G, is the only botulinum antitoxin available in the United States for treatment of naturally occurring noninfant botulism and can be obtained from the CDC. As of March 13, 2010, HBAT replaces a licensed bivalent botulinum antitoxin AB (BAT-AB) and an investigational monovalent botulinum antitoxin E (BAT-E). To report suspected botulism cases, healthcare providers should call their State Health Department. For assistance in the diagnosis, management, laboratory and epidemiological evaluation of botulism, and to obtain antitoxin, the State Health Department should call the CDC Emergency Operations Center at 770-488-7100 (Centers for Disease Control and Prevention, 2010).
2) BIOTERRORISM a) INDICATIONS 1) Optimal use is based on early recognition of botulism. Botulinum antitoxin is the only specific pharmacologic treatment available for botulism; most effective if given during the early course of illness. Give antitoxin to patients with neurologic signs of botulism as soon as possible after clinical diagnosis, after specimens of blood for toxin assays have been collected; however, do NOT delay treatment for microbiologic testing. Antitoxin may be withheld at time of diagnosis if it is CERTAIN that the patient is improving from maximal paralysis (Arnon et al, 2001).
2) Following intentional use of botulinum toxin, asymptomatic individuals who are thought to have been exposed should remain under medical observation. If neurotoxic effects appear treat promptly with antitoxin at the first signs of illness (Arnon et al, 2001).
3) Recently, the increased use of botulinum toxins for the treatment of neurologic diseases, hyperhidrosis and cosmetic purposes has resulted in the development of antibodies to these products (or by-products (eg, botulinum toxoid)). The existence of antibodies could potentially interfere with antitoxin efficacy, if treatment became necessary (Vartanian & Dayan, 2003; Gruchalla & Jones, 2003).
b) RECOMMENDATIONS: Skin testing for hypersensitivity to horse serum should precede antitoxin administration. Review package insert with public health authorities before using antitoxin, as the dose and safety precautions have changed over time (Arnon et al, 2001). c) AVAILABLE FORM: Investigational heptavalent botulinum antitoxin (HBAT), containing equine-derived antibody to botulinum toxin types A through G, is the only botulinum antitoxin available in the United States for treatment of naturally occurring noninfant botulism and can be obtained from the CDC. As of March 13, 2010, HBAT replaces a licensed bivalent botulinum antitoxin AB (BAT-AB) and an investigational monovalent botulinum antitoxin E (BAT-E) (Centers for Disease Control and Prevention, 2010). 1) USA: Available from CDC via state and local state health departments. For assistance in the diagnosis, management, laboratory and epidemiological evaluation of botulism, and to obtain antitoxin, the state health department should call 770-488-7100. Antitoxin is released from CDC quarantine stations located in airports throughout the US. States of California and Alaska control release of antitoxin independently of CDC because of the relatively large number of botulism cases in those states and need for local storage of antitoxin in isolated areas of Alaska. In most cases in the US, antitoxin is administered to the patient within 12 hours of decision to release the product.
2) INTERNATIONALLY: The CDC has an agreement with the Pan American Health Organization to supply botulism antitoxin to other countries in the Western Hemisphere (with exception of Canada, which maintains its own supply). There is no reliable source of antitoxin elsewhere in the world.
3) DOSING IN SPECIAL SITUATIONS: Contact CDC for special dosing situations. Pregnancy is not a contraindication.
3) MAJOR ADVERSE REACTIONS: Hypersensitivity reactions (serum sickness, anaphylactic and other allergic reactions) occur in 15% to 20% of patients. Since serum sickness reactions are more likely to occur with doses of 40 mL of antitoxin or more, the lowest effective dose is recommended (Gruchalla & Jones, 2003). 4) Healthcare providers with a suspected case of botulism should contact their state health department and the CDC. The CDC may be called at 770-488-7100. 5) PRECAUTIONS a) Use only in patients who have had sensitivity tests for equine serum. Skin testing for hypersensitivity to horse serum should be done initially; patients who react to this test should be desensitized prior to treatment. During infusion of antitoxin, diphenhydramine and epinephrine should be available for rapid administration in case of adverse reaction.
b) Prior to administering any serum or antitoxin, the manufacturer advises that the healthcare provider determine if the patient has a history of asthma or hay fever (especially when near horses), has any known or suspected hypersensitivity to horse serum, or has had prior exposure to horse serum. Patients with such histories are at greater risk of serious anaphylactic reactions if given the heptavalent botulinum antitoxin.
6) SENSITIVITY TESTING a) For further information regarding the heptavalent botulinum antitoxin, including sensitivity testing, contact the CDC Emergency Operations Center at 770-488-7100.
7) DOSE a) For further information regarding the heptavalent botulinum antitoxin, including dosing recommendations, contact the CDC Emergency Operations Center at 770-488-7100.
8) OBSERVATION a) Closely observe for evidence of allergic reaction. Careful observation is particularly important in cases with a history of sensitization.
G) ACUTE ALLERGIC REACTION 1) SUMMARY a) Mild to moderate allergic reactions may be treated with antihistamines with or without inhaled beta adrenergic agonists, corticosteroids or epinephrine. Treatment of severe anaphylaxis also includes oxygen supplementation, aggressive airway management, epinephrine, ECG monitoring, and IV fluids.
2) BRONCHOSPASM a) ALBUTEROL 1) ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007). CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 mg/kg (up to 10 mg) every 1 to 4 hours as needed, or 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
3) CORTICOSTEROIDS a) Consider systemic corticosteroids in patients with significant bronchospasm.
b) PREDNISONE: ADULT: 40 to 80 milligrams/day. CHILD: 1 to 2 milligrams/kilogram/day (maximum 60 mg) in 1 to 2 divided doses divided twice daily (National Heart,Lung,and Blood Institute, 2007).
4) MILD CASES a) DIPHENHYDRAMINE 1) SUMMARY: Oral diphenhydramine, as well as other H1 antihistamines can be used as indicated (Lieberman et al, 2010).
2) ADULT: 50 milligrams orally, or 10 to 50 mg intravenously at a rate not to exceed 25 mg/min or may be given by deep intramuscular injection. A total of 100 mg may be administered if needed. Maximum daily dosage is 400 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
3) CHILD: 5 mg/kg/24 hours or 150 mg/m(2)/24 hours. Divided into 4 doses, administered intravenously at a rate not exceeding 25 mg/min or by deep intramuscular injection. Maximum daily dosage is 300 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
5) MODERATE CASES a) EPINEPHRINE: INJECTABLE SOLUTION: It should be administered early in patients by IM injection. Using a 1:1000 (1 mg/mL) solution of epinephrine. Initial Dose: 0.01 mg/kg intramuscularly with a maximum dose of 0.5 mg in adults and 0.3 mg in children. The dose may be repeated every 5 to 15 minutes, if no clinical improvement. Most patients respond to 1 or 2 doses (Nowak & Macias, 2014).
6) SEVERE CASES a) EPINEPHRINE 1) INTRAVENOUS BOLUS: ADULT: 1 mg intravenously as a 1:10,000 (0.1 mg/mL) solution; CHILD: 0.01 mL/kg intravenously to a maximum single dose of 1 mg given as a 1:10,000 (0.1 mg/mL) solution. It can be repeated every 3 to 5 minutes as needed. The dose can also be given by the intraosseous route if IV access cannot be established (Lieberman et al, 2015). ALTERNATIVE ROUTE: ENDOTRACHEAL ADMINISTRATION: If IV/IO access is unavailable. DOSE: ADULT: Administer 2 to 2.5 mg of 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube. CHILD: DOSE: 0.1 mg/kg to a maximum of 2.5 mg administered as a 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube (Lieberman et al, 2015).
2) INTRAVENOUS INFUSION: Intravenous administration may be considered in patients poorly responsive to IM or SubQ epinephrine. An epinephrine infusion may be prepared by adding 1 mg (1 mL of 1:1000 (1 mg/mL) solution) to 250 mL D5W, yielding a concentration of 4 mcg/mL, and infuse this solution IV at a rate of 1 mcg/min to 10 mcg/min (maximum rate). CHILD: A dosage of 0.01 mg/kg (0.1 mL/kg of a 1:10,000 (0.1 mg/mL) solution up to 10 mcg/min (maximum dose 0.3 mg) is recommended for children (Lieberman et al, 2010). Careful titration of a continuous infusion of IV epinephrine, based on the severity of the reaction, along with a crystalloid infusion can be considered in the treatment of anaphylactic shock. It appears to be a reasonable alternative to IV boluses, if the patient is not in cardiac arrest (Vanden Hoek,TL,et al).
7) AIRWAY MANAGEMENT a) OXYGEN: 5 to 10 liters/minute via high flow mask.
b) INTUBATION: Perform early if any stridor or signs of airway obstruction.
c) CRICOTHYROTOMY: Use if unable to intubate with complete airway obstruction (Vanden Hoek,TL,et al).
d) BRONCHODILATORS are recommended for mild to severe bronchospasm.
e) ALBUTEROL: ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007).
f) ALBUTEROL: CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 milligram/kilogram (maximum 10 milligrams) every 1 to 4 hours as needed OR administer 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
8) MONITORING a) CARDIAC MONITOR: All complicated cases.
b) IV ACCESS: Routine in all complicated cases.
9) HYPOTENSION a) If hypotensive give 500 to 2000 milliliters crystalloid initially (20 milliliters/kilogram in children) and titrate to desired effect (stabilization of vital signs, mentation, urine output); adults may require up to 6 to 10 L/24 hours. Central venous or pulmonary artery pressure monitoring is recommended in patients with persistent hypotension. 1) VASOPRESSORS: Should be used in refractory cases unresponsive to repeated doses of epinephrine and after vigorous intravenous crystalloid rehydration (Lieberman et al, 2010).
2) DOPAMINE: Initial Dose: 2 to 20 micrograms/kilogram/minute intravenously; titrate to maintain systolic blood pressure greater than 90 mm Hg (Lieberman et al, 2010).
10) H1 and H2 ANTIHISTAMINES a) SUMMARY: Antihistamines are second-line therapy and are used as supportive therapy and should not be used in place of epinephrine (Lieberman et al, 2010). 1) DIPHENHYDRAMINE: ADULT: 25 to 50 milligrams via a slow intravenous infusion or IM. PEDIATRIC: 1 milligram/kilogram via slow intravenous infusion or IM up to 50 mg in children (Lieberman et al, 2010).
b) RANITIDINE: ADULT: 1 mg/kg parenterally; CHILD: 12.5 to 50 mg parenterally. If the intravenous route is used, ranitidine should be infused over 10 to 15 minutes or diluted in 5% dextrose to a volume of 20 mL and injected over 5 minutes (Lieberman et al, 2010). c) Oral diphenhydramine, as well as other H1 antihistamines, can also be used as indicated (Lieberman et al, 2010). 11) DYSRHYTHMIAS a) Dysrhythmias and cardiac dysfunction may occur primarily or iatrogenically as a result of pharmacologic treatment (epinephrine) (Vanden Hoek,TL,et al). Monitor and correct serum electrolytes, oxygenation and tissue perfusion. Treat with antiarrhythmic agents as indicated.
12) OTHER THERAPIES a) There have been a few reports of patients with anaphylaxis, with or without cardiac arrest, that have responded to vasopressin therapy that did not respond to standard therapy. Although there are no randomized controlled trials, other alternative vasoactive therapies (ie, vasopressin, norepinephrine, methoxamine, and metaraminol) may be considered in patients in cardiac arrest secondary to anaphylaxis that do not respond to epinephrine (Vanden Hoek,TL,et al).
13) CASE REPORT: A 47-year-old man experienced severe anaphylaxis following injection of 90 units of botulinum toxin into his lower esophageal sphincter for treatment of achalasia cardia, an esophageal motility disorder. Shortly after the injection, the patient experienced facial edema, and he became hypertensive (systolic blood pressure increased to the 220s) and tachycardic (heart rate was in the 120s). His oxygen saturation decreased to approximately 70; however, intubation was unsuccessful due to severe vocal cord edema and an emergency cricothyroidotomy was performed. Additionally, he was given IV corticosteroids and diphenhydramine. Epinephrine was not administered due his hypertension and tachycardia. With therapy, the patient's condition improved and he was discharged home (Aggarwal et al, 2014). H) INSERTION OF NASOGASTRIC TUBE 1) Nasogastric suction should be instituted early if there is any evidence of ileus (Werner & Chin, 1973).
I) INSERTION OF CATHETER INTO URINARY BLADDER 1) Bladder catheterization is necessary if the bladder is atonic (Werner & Chin, 1973)
J) INTESTINAL OBSTRUCTION 1) Intravenous hydration with maintenance solutions may be required if short-term adynamic ileus is present (Werner & Chin, 1973).
2) With prolonged ileus, hyperalimentation via a central venous catheter may be necessary until bowel sounds return (Werner & Chin, 1973).
K) ANTIBIOTIC 1) Antibiotics should only be used to treat complications such as respiratory or urinary tract infections or wound infections (Werner & Chin, 1973).
L) EXPERIMENTAL THERAPY 1) PYRIDOSTIGMINE: A retrospective case study was conducted, involving 20 patients who were successfully treated with pyridostigmine, an acetylcholinesterase inhibitor, after developing adverse effects from botulinum toxin therapy. The patients (ages ranging from 36 to 78 years) were given botulinum toxin therapy, at doses ranging from 0.6 units to 90 units, to treat laryngeal dystonias, tremors, tardive dyskinesia, and cricopharyngeal achalasia. Adverse effects, including dyspnea, stridor, choking, dysphagia, breathiness, and vocal fatigue, were reported several days to weeks after therapy. With no improvement following supportive care, treatment with pyridostigmine was initiated at a dose of 60 mg orally three times daily. Significant improvement in symptoms was reported in 19 of the 20 patients, with time to maximal improvement ranging from immediate (n=3) to over a 2-week period. Pyridostigmine was well tolerated in the majority of patients, with bradycardia reported in one patient who had a history of cardiac disease. Based on these results, it is suggested that pyridostigmine may be a viable option for treatment in patients who develop adverse effects following botulinum toxin therapy and are not responsive to conservative management (Young & Halstead, 2014).
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