Down on the Pharm: Anaphylaxis Treatment

[26-20-2]

Down on the Pharm: Anaphylaxis Treatment Date: March 12, 2001 by: Charles Stewart MD, FACEP

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Introduction

Anaphylaxis is a life-threatening syndrome that can be triggered by a wide variety of antigens and involves multiple organ systems. A severe anaphylactic reaction can be terrifying for the person who experiences it, frightening for bystanders and gripping drama for EMS providers.

The syndrome of anaphylaxis was first described in 1902 by Portier and Richert. [1] They were trying to develop an antivenom to the Portugese Man ’o War. They noted that some experimental animals died of a sudden allergic reaction when they were given a second very small dose of venom. Because this reaction represented the opposite of their intended prophylaxis, they described it as 'against, or without protection.' For their work on the allergic reaction called anaphylaxis, they received the Nobel Prize.

The incidence of anaphylaxis is unknown and difficult to estimate as it is not a reportable disease. In 1973, the Boston Collaborative Drug Surveillance Program reported six anaphylactic reactions and 0.87 deaths from anaphylaxis per 10,000 patients. [2] About one fatal anaphylactic reaction occurs for each 7.5 million doses of penicillin given. Insect sting reactions cause at least 50 deaths in the United States each year. Overall about to 100 to 500 deaths occur in the United States each year.

There appears to be no increased preval‎ence of allergic reactions in any race, age, occupation, gender, nor by any identifiable geographic factors. Although asthma is more preval‎ent and has a higher mortality rate in blacks, no data exists to suggest that the same risk applies to anaphylaxis. Even atopic individuals who have asthma, allergic rhinitis, and dermatitis have no increase in anaphylaxis. The only factor that identifiably increases the risk of anaphylaxis is a prior anaphylaxis. (Please note the reoccurrence rate is only 40-60% for insect stings, 20-40 percent for radiographic dyes, and 10-20% for penicillin.) [3]

Mechanisms and Causes

Anaphylaxis was originally defined as an IgE mediated response to an allergic challenge. It results from the rapid release of inflammatory mediators.

When a person is exposed to an allergen, IgE antibodies are formed and bind to receptors on mast cells and basophils. When that person comes in contact with the allergen a second time, the allergen binds to the IgE receptors. The mast cells and basophils degranulate and release inflammatory substances (i.e., histamine, prostaglandins, leukotriens, tryptase, and platelet activating factor). These inflammatory substances result in bronchospasm, bronchorrhea, laryngospasm, increased vascular permeability, and vasodilation from decreased vascular tone.

Inflammatory substances may also be released directly into the bloodstream. This occurs when such agents as contrast dye or morphine are given intravenously. This is often called an 'anaphylactoid' reaction since it does not involve IgE. When the immune system has been 'primed' by a previous allergic reaction to another substance, an anaphylactoid reaction can occur with no prior exposure to the new agent. The immediate practical consequences are exactly the same for both anaphylaxis and 'anaphylactoid' reactions.

The difference doesn’t matter to either the patient or the clinician, since the symptoms and treatment are both identical. (Recent research has shown that the anaphylactoid reaction and anaphylaxis share common final pathways, so it is clinically unnecessary to make an artificial difference between them.)

A third mechanism for anaphylaxis occurs when antigen--antibody complexes stimulate the complement cascade to produce C-3a and C-5a which then cause degranulation of mast cells and basophils.

Depending upon the root of exposure to the offending agent, symptoms began in moments or may take hours to develop. Parenteral agents cause symptoms much more quickly then ingested allergens. Anaphylaxis to foods may take an hour to develop.

The most common causes of anaphylaxis are:

• Foods: A large variety of foods have been reported to cause anaphylaxis. The most common include peanuts, tree nuts, fish, some spices, and shellfish. [4]
• Drugs: particularly penicillins, anesthetics, and NSAID’s.
• Latex: The folks who are allergic to latex are almost always health care workers, or have had other extensive contact with latex. These people may also get anaphylaxis from bananas, avocados, kiwi, figs, and some other fruits or vegetables. Although an anaphylactic reaction from an inhaled allergen is rare, this can happen when an allergic individual inhales particles from rubber gloves or other latex products. [5]
• Bee or other hymenoptera stings: Please note that swelling at the site of a sting is not an allergic reaction, but simply the effects of the venom. In order to call a bee sting an allergic reaction, you have to have a remote effect of the venom.
• Exercise: Exercise may precipitate anaphylaxis in a small percentage of people. In some of these cases, the patient will only have anaphylaxis with exercise right after ingestion of foods (Exercise-induced food-dependent anaphylaxis).
• Idiopathic: A substantial proportion of patients will have no cause found despite expert eval‎uation. The explanation is NOT psychological.

For some patients, two or more simultaneous factors are needed to cause anaphylaxis. As noted above, some people will only have anaphylaxis if they have a certain food and then exercise. Neither the food alone or the exercise alone will cause a problem for these patients.

It is important to determine all exposures for the hour or so that precedes the reaction. For example, if a patient has been given a dose of oral antibiotic, ate supper, ran over to the neighbor’s house, and then was stung by a bee, the bee sting may be blamed for the anaphylaxis. In a case like this, the antibiotic, the foods eaten, the exercise, and the bee sting are all potential causes for anaphylaxis.

Anaphylaxis is not an "All or nothing" disease. Since anaphylaxis is part of a spectrum of allergic responses, milder disease may not trigger all of the clinical features associated with anaphylaxis. [6] This milder disease may be a harbinger of an acute change for the worse or may imply that the next reaction will be life-threatening. In the field or in the emergency department all such reactions must be taken quite seriously. An observation period of 2-4 hours in an emergency department after milder reactions is quite appropriate.

Clinical Features

Anaphylaxis is a clinical diagnosis. There are no laboratory or x-ray studies that are useful for this condition. It is most often a clear diagnosis with temporal relationship to ingestion/administration of a drug or radiographic dye, a specific food, or a bee sting.

Symptoms and/or signs involving at least 2 of the following organ systems must be present to make the diagnosis.

Cutaneous

• Hives or urticaria
• Angioedema of the face or extremities
• A tingling feeling in the lips or mouth (seen with foods)

Respiratory

• Upper airway edema - may progress to respiratory arrest
• Nasal congestion
• Cough
• Wheezing
• Dyspnea

Gastrointestinal

• Nausea and/or vomiting
• Crampy abdominal pain
• Diarrhea (may be bloody)

Cardiovascular

• Syncope
• Hypotension
• Tachycardia
• Dysrhythmias
• Cardiovascular collapse

Cutaneous symptoms are often the first presentation. The patient may initially complain of hives, itching, swelling, redness in the face, or a stinging or burning sensation about the face or lips.

Respiratory symptoms may start with hoarseness or a feeling of a lump in the throat. Patients may complain of difficulty swallowing. If this airway swelling continues, respiratory distress will occur and the patient may die from respiratory obstruction. Rapid therapy is essential in these patients.

Extreme vasodilation and the loss of fluid from blood vessels causes hypotension. The patient may complain of light-headedness or suffer syncope.

Gastrointestinal symptoms are particularly likely with food allergens. The patient may have severe cramps, nausea, vomiting and diarrhea. Women may have pelvic cramps due to contractions of the uterus.

Not all patients will present in shock. In fact, many patients will have only to organ systems involved. As noted above, anaphylaxis is not an "all or nothing" phenomenon.

Finally, anaphylaxis may have a biphasic presentation. The patient may be treated and all symptoms resolved only to redevelop symptoms some hours later. Although this biphasic presentation is unusual, it occurs in about 1% of patients. The wide range of reported asymptomatic intervals makes it difficult to determine appropriate guidelines for the duration of clinical observation. Most authors recommend that patients who have a serious episode of allergic reaction should be monitored from 8 to 24 hours. [7] A few patients have had protracted episodes of anaphylaxis that have occurred as long as 24 to 48 hours after the initial exposure, so even 24 hours may not be long enough.

Differential diagnosis

The differential diagnosis of anaphylaxis is extensive. Anaphylaxis is sometimes mistaken for other diseases such as anxiety reactions or low blood sugar. The patient who has been drinking who ingests a food allergen may be thought to be simply intoxicated. Other medical conditions that have mimicked anaphylaxis include.

• Angioedema
• Aspirated foreign body
• Asthma
• Bee and hymenoptera stings (venom reaction alone)
• Cardiogenic shock
• Carcinoid syndrome
• Epiglottitis
• Hypovolemic shock
• Pheochromocytoma
• Serum sickness
• Syncope

Syncope is the most common problem confused with anaphylaxis. Syncope may present with hypotension, bradycardia, pallor, and/or profuse sweating. Recovery from syncope is usually rapid after the patient is placed in the supine position. Other signs of anaphylaxis such as urticaria are not part of syncopal episodes.

Pheochromocytoma (an adrenal tumor that secretes epinephrine) and carcinoid are neoplastic syndromes associated with the release of vasoactive substances. Patients with these diseases may have an abrupt onset of elevated blood pressure and flushing as the vasoactive substances are released.

Serum sickness is a clinical syndrome caused by an allergic agent. It occurs about 7-10 days after exposure to large amounts of an allergic agent and is due to the formation of immune complexes. Serum sickness is associated with urticaria, fever and joint aches.

Angioedema may be noted after administration of ACE inhibitors (for hypertension), and may be idiopathic. Angioedema may involve the lips, tongue, or upper airway. Angioedema of the GI tract may cause cramping, abdominal pain, nausea, and diarrhea. Angioedema may be quite difficult to differentiate from anaphylaxis, in the field. Fortunately, immediate therapy for angioedema is not different from that of anaphylaxis.

Treatment

As always, prehospital care should first be directed at stabilization of the airway, breathing, and circulation. Supplemental high flow oxygen therapy and intravenous access should be established rapidly on all patients with a suspected anaphylactic reaction. If the patient is still being given a medication, this should be stopped immediately.

Advanced airway management (endotracheal intubation) should be considered early in the course of all patients with anaphylaxis. When oxygen saturation falls or the patient develops a decreasing level of consciousness from hypoxia, intubation may be quite difficult.

First line therapy

First line therapies for anaphylaxis are epinephrine, IV fluids, and oxygen. All of these drugs have immediate effect during the acute stage of anaphylaxis.

Epinephrine

Epinephrine is the drug of choice for the treatment of anaphylaxis. Early use can relieve symptoms and can reverse many of the pathologic changes of anaphylaxis. Indeed, in multiple studies, delay in the use of epinephrine has been shown to increase mortality. [8]

Epinephrine is a physiologic antagonist of histamine. Epinephrine has alpha agonist effects including increased peripheral vascular resistance, peripheral vasoconstriction, systemic hypertension, and reversal of the vascular permeability. Beta agonist effects of epinephrine include bronchodilation, chronotropic cardiac activity, and positive inotropic activity. Epinephrine and other beta agonists increase the intracellular cyclic AMP. This decreases mediator release in mast cells.

1:1000 epinephrine given as a intramuscular or subcutaneous dose of 0.5 ml may be given every 20 minutes (with 3 doses the usual maximum). In children a dose of 0.01 mg per kg may be given as 1:1000 epinephrine. Again, either the intramuscular or subcutaneous route may be used.

If the patient is hypertensive, consider epinephrine as a drip. Continuous infusion is given at a 0.1 to 1 mcg per kg per minute rate in both children and adults. Titrate the infusion to effect.

Recent reports indicate that intramuscular administration may achieve a faster and higher rate of absorption than subcutaneous administration. The Epi-Pen will only allow intramuscular administration.

Inhaled epinephrine has been recommended by the European Academy of Allergy and Clinical Immunology. The recommended dose is inhalation of 20 puffs for adults and 10 to 15 puffs in a child. In the adults this gives an equivalent to injection of 0.3 to 0.5 mg of epinephrine. 10 to 15 puffs in a child can deliver the equivalent of 0.15 milligrams injected subcutaneously. Inhaled epinephrine may be beneficial to reverse laryngeal edema or persistent bronchospasm. Epinephrine may be dispensed by either nebulization or with a metered dose inhaler. Nebulization is the only mode of inhalation epinephrine that is readily available to EMS.

Some allergists use PrimateneR mist or Medihaler-EpiR, sprayed twice onto the tongue and in the airway for treatment of allergic reactions. [9] The Medihaler-EpiR has been withdrawn from the market by the manufacturer because of stability problems. PrimateneR mist is thought to be ineffective by many clinicians. [10]

Rapid IV infusions of epinephrine have caused deaths from cerebral vascular hemorrhage or cardiac arrhythmias. Extreme caution should be used in patients over the age of 40 as previously unrecognized cardiac disease may exist. Caution should be used in patients with known hypertension, cardiovascular disease, diabetes, hyperthyroidism, and cerebrovascular insufficiency.

For minor allergic reactions where hypotension or respiratory symptoms are not a factor, epinephrine is not needed.

Some hypertensive patients who are taking beta blockers are at increased risk for severe anaphylaxis. The presence of beta-blockers may counteract the effectiveness of epinephrine, making the anaphylactic reaction more severe, more prolonged, and refractory to treatment.

Fluids

Hypotension caused by a shift in fluid from the intravascular to the extravascular space may be severe and may be refractory to epinephrine and antihistamines. Depending on the blood-pressure, large volumes of crystalline solutions (e. g., lactated Ringers solution or normal saline may be required to reverse hypotension. Children may need as much as 30 ml per kg of crystalline over the first hour. Adults may need up to two liters over the first hour to control hypotension. Patients taking beta blockers may require as much as 5 to 7 liters of fluids before the pressure is stabilized.

An alternative to crystalline solutions is the administration of colloids such as 6% hetastarch in normal saline solution or 5% human albumin. These colloids will remain in the intravascular space and may draw fluid from the extracellular spaces into the vessels. The larger colloid molecules will not extravasate from leaky micro vessels as easily as saline solutions.

Second line therapy

Second line therapy for anaphylaxis includes drugs that prevent recurrences and treat anaphylaxis refractory to first line therapy. In moderate to severe cases of anaphylaxis, symptoms can persist or worsen despite epinephrine in adequate doses at appropriate times. Generally second line therapy will take longer to take effect and may act to prevent progression of the disease rather than reverse the symptoms.

Antihistamines

The mast cell several initiates the immediate response of anaphylaxis and may be responsible for the late phase response. Histamine is released by the mast cell as one of the prime mediators of both local and systemic manifestations of anaphylaxis. It is quite logical, therefore to use antihistamines as treatment for anaphylaxis. Antihistamines are also useful as second line therapy when a prolonged course is suspected. The medical provider should remember that antihistamines do not reverse anaphylaxis. Antihistamines do not prevent all of the effects of histamine on the heart. Histamine is not the only dangerous substance released during anaphylaxis.

Diphenhydramine hydrochloride (BenadrylR) can be given orally, intramuscularly, or intravenously at a dose of 1 mg per kg to a maximum of 50 mg every six hours. The combined use of histamine1 and histamine2 histamine antagonists is thought to be more useful and histamine 1 antagonists alone.

BenadrylR is a potentiator of the effects of CNS depressants such as alcohol. It may also cause paradoxical excitation, particularly in children. BenadrylR may exacerbate hyperthyroidism, peptic ulcers, and cause urinary tract obstruction.

Hydroxyzine (AtaraxR) antagonizes H1 receptors in both the CNS and the periphery. Use of hydroxyzine is limited to oral and intramuscular administration. These routes may not be effective in the hypotensive and or vomiting patient. IV and subcutaneous administration of hydroxyzine is associated with thrombosis and digital gangrene. EKG abnormalities may occur after administration of AtaraxR.

Steroids

Steroids have uncertain place in the management of acute allergic reactions. Steroids reverse capillary permeability and suppress the effects of the polymorphic neucleocytes (PMN). Steroids also block the release of inflammatory mediators by inhibition of phospholipase.

Although steroids have substantial anti-inflammatory and anti- chemotactic effects that appear to stabilize the mast cell membrane, it is four to six hours before they become particularly effective. Steroids diminish the likelihood of rebound effect (biphasic response), but are not completely effective. There are no studies that set the specific dose of any steroid that would surely prevent a biphasic response.

Current recommendations are for a dose of 82 120 mg of intravenous methylprednisolone (Solu-MedrolR). Dexamethasone has been used in children in a dose of 0.3 to 0.6 mg per kilogram and may be given intravenously or intramuscularly. Alternatively prednisone (1 mg per kg orally) for mild to moderate episodes of anaphylaxis may be appropriate.

Bronchodilators

Although it is not present in every case, bronchospasm is a major component of most cases of anaphylaxis. If stridor is present, the patient should be intubated as soon as possible. Bronchospasm may be treated without intubation as long as the patient does not have evidence of airway compromise.

Aerosolized bronchodilators such as albuterol should be employed for bronchospasm. Albuterol may be given either intermittently or continuously, depending on the patients symptoms and the availability of cardiac moderate. As noted above aerosolized epinephrine may be useful for preventing life-threatening upper airway edema.

The most commonly employed bronchodilator is albuterol (VentolinR or ProventilR). This drug will relax bronchial smooth muscle and may decrease mediator release from mast cells and basophils. It may also inhibit airway microvascular leakage. The usual dose of albuterol is 2.5 to 5 mg in 2 cc of normal saline every 20 minutes by nebulizer. The pediatric dose is about 0.15 mg/kg/dose every 20 minutes. Do not exceed 15 mg/hour.

Inhaled ipratropium (AtroventR) may increase the duration of bronchodilation by albuterol. Cardiovascular effects may increase with concomitant use of sympathomimetic agents such as epinephrine. Tachycardia may result in cardiac arrhythmias.

Use of beta blocking agents may inhibit the cardiac, bronchodilation, and vasodilation effects of all beta agonists, including the bronchodilators. If the patient is taking monoamine oxidase inhibitor antidepressant (MAOI), albuterol may cause headache, hypertension, and high fever. In some patients taking MAOI, albuterol has caused hypertensive crisis.

Vasopressors

In some patients, epinephrine will not be sufficient to prevent hypotension. After an appropriate fluid challenge, use of other vasopressors may be appropriate. Dopamine stimulates both the adrenergic and the dopaminergic receptors. The hemodynamic effect is dependent upon the dose. A lower dose (< micrograms per kilogram per minute) will predominantly stimulate the dopaminergic receptors and cause renal and mesenteric vasodilation. Higher doses will stimulate the heart and cause renal vasoconstriction. The usual dose in both adults and children is 2-20 micrograms per kilogram per minute, titrated to effect.

Dobutamine will stimulate the heart and cause vasodilation. At higher doses, dobutamine may cause increased heart rate and exacerbate myocardial ischema. The usual dose in both adults and children is 5-20 micrograms per kilogram per minute, titrated to effect.

Some obstetricians and anesthesiologist recommend ephedrine for refractory hypotension during pregnancy. Ephedrine has a greater beta adrenergic activity than epinephrine and may result in less uterine vessel vasoconstriction than epinephrine. Most authorities will agree that epinephrine remains the appropriate treatment of anaphylaxis in the pregnant patient. [11]

Although epinephrine and fluids are the mainstay of treatment for hypotension, the use of other vasopressor drugs may be necessary. Dopamine administration at a rate of 2 to 20 mcg per kg per minute may be literally lifesaving.

Useful additional agents

There are some agents that have been found to be useful in the treatment of anaphylaxis that simply aren’t available to the EMS provider. These agents are most often found in hospital-based medicine. Other agents useful in the treatment of anaphylaxis may not seem to be an obvious choice, such as glucagon and atropine.

Histamine2 antagonists

Evidence shows that stimulation of both the H1 and H2 receptors is found in anaphylaxis. Histamine H2 receptor activity increases gastric acid secretion and capillary leakage. Use of the H2 blocking agents such as ranitidine or cimetidine will augment the effects of the H1 blocking agents such as diphenhydramine or hydroxyzine. It is considered appropriate therapy to add H2 blockers to the treatment of anaphylaxis when the H1 blocking agent is not effective. The H2 blockers may also be used to treat flushing and itching in cases of urticaria.

Ranitidine (ZantacR) and Cimetidine (TagametR) are the usual H2 blocking agents employed in conjunction with H1 blockers. Ranitidine is the drug of choice because cimetidine can alter the levels of many other drugs and can cause confusion, particularly in elderly patients. The usual dose of ranitidine is 150 mg PO or 50 mg IV or IM every 6-8 hours. The pediatric dose is 0.75 to 1.5 mg/kg to a maximum of 50 mg every 6-8 hours.

Glucagon

Glucagon has both positive inotropic and chronotropic effects on the heart due to an increase in cardiac cyclic AMP. 1-5 mg of glucagon given as a bolus followed by an infusion of 5-15 micrograms per minute titrated for clinical effect may be helpful in refractory cases and in patients taking beta blockers. Alternatively, 1 milligram of glucagon may be given every 5 minutes due to the short half life.

If the patient has been using inhaled bronchodilators (albuterol) for chronic therapy of asthma or COPD, then efficacy of the bronchodilator may be impaired.

Atropine

Atropine can reduce secretions and reverse bronchoconstriction. It is usually administered by nebulization in a dose of 0.05 to 0.075 mg per kilogram per hour. It should be considered when bronchospasm persists despite albuterol and ipratropium inhalation treatment or when beta blockers are present.

Aminophylline

Aminophylline is an older oral or intravenous bronchodilator. Inhaled bronchodilators have largely supplanted aminophylline. Since the therapeutic window of aminophylline or theophylline is quite small, side effects of aminophylline and aminophylline overdoses were very common.

Aminophylline may be useful in the treatment of anaphylaxis when inhaled bronchodilators are not effective. When bronchospasm is persistent despite appropriate doses of albuterol, then aminophylline should be considered. The usual dose is 5-6 mg per kilogram loading dose over 20 minutes followed by a continuous infusion at 0l.7 to 0.9 mg/kg/hour. Theophylline levels should be monitored.

Isoproterenol

Isoproterenol is a potent beta agonist. In patients who are taking beta blockers, isoproterenol may be useful in an attempt to overcome the beta blockade. Isoproterenol binds the beta-receptors of heart, smooth muscle, vessels, and GI tract. Isoproterenol increases both the speed and power of the cardiac muscle.

Isoproterenol hydrochloride is usually given intravenously at an initial rate of 0.1 mcg per kg per minute. The agent is then increased every 10 minutes by this amount until either the blood-pressure stabilizes or the heart rate increases to 200 beats per minute.

Isoproterenol should be used with extreme caution in adults, particularly those with heart disease, since myocardial ischemia is quite possible with this agent. By increasing myocardial oxygen consumption while decreasing myocardial perfusion, isoproterenol may hurt the injured or failing heart.

Prevention

To prevent anaphylaxis, the patient must avoid the allergen that causes the reaction. This may not be an easy task. In some patients, identification of the allergen may be a major problem. Stinging insects abound in summertime and allergenic foods can be found in a wide variety of formats.

Precautions can lower the risk of anaphylaxis or minimize the severity of reactions. Immunotherapy (allergy shots) is a therapy that will help many people who have had anaphylactic reactions. For example, immunotherapy for bee, wasp, yellow jacket, and hornet stings gives about 98% protection. This protection can be literally lifesaving and should be recommended to all patients who have a severe allergic reaction. [12]

In some cases immunotherapy is either not practical or not available. This may happen when antibiotics are needed for life threatening infections in an allergic patient. In most cases, different classes of antibiotics are available. In some cases, the physician must hospitalize the patient, start intravenous lines, and give protective medications prior to the use of a critical medication for a procedure or an infection. In some cases, rapidly increasing oral doses of the antibiotic under carefully controlled conditions can possibly desensitize the patient.

Patients who have a history of severe reactions to medications should take a new medication by mouth if at all possible, since the risk of anaphylaxis is higher with an injection. Medical identification jewelry will prevent the administration of allergens if the patient is unable to give an appropriate history and may help the physician to identify anaphylaxis in unusual presentations of the disease.

Physicians will often suggest that the allergic patient carry an epinephrine syringe designed for self-administration. This is most often done for idiopathic food allergies or bee stings. These kits are sold under the name Ana-Kit, EpiPen, or EpiPen Jr. (for children). In order for these devices to be effective, they must be carried with the patient and available in school (for children) or work. [13] If a friend or family member also is instructed in the use of these devices, they are more likely to be used in an emergency.

Those allergic individuals with high blood pressure who are taking beta blockers and have an allergic reaction should ask their physician about switching to a different type of high blood pressure medication. Beta-blockers can be discontinued when procedures such as radiographic studies are scheduled.

Disposition:

An unstable patient should be admitted to the intensive care unit. All patients who receive epinephrine should be observed in the emergency department. Factors to consider in the disposition include the distance from medical care, whether the patient lives alone, any co-existing diseases, age, past medical history of severe allergic reaction, or the use of beta-blocking agents. [14]

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Tables: Anaphylaxis therapy

Class	Drug Name	Route		Comments
Oxygen		Available: nasal cannula, mask, ET tube		Always start with supplemental oxygen
Epinephrine	Adrenaline 1:1,000 aqueous solution 1 mg/ml	SC: 0.01 ml/kg	0.01 mg/kg pediatric dose up to 3 doses	May be poorly absorbed in the shocky patient. Use with caution in older patients due to myocardial ischemia.
	Adrenaline 1:10,000 aqueous solution 0.1 mg/ml		0.1-1 mcg per kg per minute may be given IV or IO	IV administration can be associated with ventricular arrhythmias and myocardial ischemia. Infusion rate of about 1-4 micrograms per minute. Must use EKG monitoring during administration. Use with caution in older patients due to myocardial ischemia.
Fluids	Normal Saline	10-20 ml/kg bolus
	Ringer’s lactate
	hetastarch in normal saline			Colloids may be retained somewhat better in leaky capillaries than simple salt solutions
	5% albumin solution			May be retained somewhat better in leaky capillaries than simple salt solutions
H1 blocker	Diphenhydramine (Benadryl)	50 mg	PO, IM, IO, or IV	Histamine blocking agents decrease histamine activity by reversible inhibition. This does not reverse anaphylaxis, but may prevent further progression. PO Dosing not recommended in anaphylaxis
	Hydroxyzine (Atarax)	25-100 mg IM q6h	Peds 0.5-1 mg/kg	Do not use this drug intravenously. Associated with thrombosis and gangrene when given IV.
H2 blocker	Cimetidine	300 mg IV	4 mg/kg	Acts synergistically with H1 blockers to decrease histamine reactions. H2 receptors increase gastric acid stimulation and pacemaker rate. PO dosing not recommended in anaphylaxis.
	Ranitidine	50 mg IV	0.75-1.5 mg/kg IV/IM/IO	Same mechanism as cimetidine. PO Dosing not recommended in anaphylaxis.
Bronchodilators	Ventolin/Albuterol	2.5-5 mg in 2 ml NS Nebulized inhalation	0.15 mg/kg	Relaxes the bronchial smooth muscles and may decrease mediator release from mast cells and basophils. It may also inhibit airway microvascular leakage. Do not exceed 15 mg per hour. Watch for tachycardia.
Steroids	Methylprednisolone sodium succinate (Solumedrol)	125 mg IV		Takes about 2-6 hours to take effect.
Vasopressors	Dobutamine	5-20 mcg/kg/min	IV or IO titrate to effect	Produces vasodilation and increases cardiac contractility. At higher doses may increase heart rate and exacerbate myocardial ischemia
	Dopamine	2-20 mcg/kg/min	IV titrate to effect	Hemodynamic effect dependent on the dose. Lower doses produce renal and mesenteric vasodilation. Cardiac stimulation and renal vasodilation produced by higher doses
	Norepinepherine
	Isoproterenol (Beta 1 and Beta 2 Agonist)	0.1 micrograms per kilogram per minute	Increase every 10 minutes until effect or pulse > 200 per minute	Increase drip until heart rate increases to 200/min or blood pressure is stabilized. AVOID this agent if possible in adults because it will increase myocardial ischemia. May be useful in patients who have taken beta blockers
Miscellaneous Agents	Glucagon	1mg vial	May be given as often as every 5 minutes	Increases cardiac cyclic AMP and enhances cardiac output. May be useful in patients who are concurrently taking beta blockers
	Atropine sulfate
	Aminophylline			Narrow therapeutic window and may be too slow to be effective for treatment of acute reaction. May be useful in bronchospasm resistant to inhaled bronchodilators

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Assessment/Treatment priorities for anaphylaxis

Airway open and ventilations assisted

• (Intubation as needed)

High concentration oxygen by mask or ET tube

Assess hemodynamic stability

Epinephrine (1:1000)

• 0.3 mg - 0.5 mg SQ - May repeat q 5 minutes x 3 doses total

Large bore IV with normal saline

Benadryl 25-50 mg IV.

Albuterol 0.5% via nebulizer

Solu-Medrol 125 mg IV (if available)

Initiate transport as soon as possible.

If hypotension:

• Consider rapid fluid bolus
• Consider dopamine or dobutamine
• Consider glucagon

If airway swelling:

• Intubate rapidly (early intubation is MUCH easier)
• Consider nebulized epinephrine if intubation is not possible due to patient condition (awake and RSI not available)
• Consider cricothyrotomy or needle cricothyrotomy

If bronchospasm persists despite albuterol:

• Consider glucagon
• Consider inhaled atropine
• Consider inhaled ipratropium

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Prevention of Anaphylaxis

• Identify the allergen responsible
• Encourage those patients who have known allergic reactions to wear medical jewelry that identifies the allergens.
• Whenever possible administer drugs orally to patients with known allergies.
• Recommend an allergist and immunotherapy for patients with known allergies
• Observe patients for 30 minutes after administration of a high risk drug.
• Advise patients to discontinue beta-blocker therapy during periods of high risk.
• Have a physician prescribe epinephrine kit (Ana Kit or EpiPen) for patients at risk.
• Instruct family and friends in the use of the epinephrine kit.

References:

[1] Portier P, Richet C. De l’action anaphylactique de certains venis. C R Soc Biol (Paris) 1902;54:170.

[2] Boston collaborative drug surveillance program. Drug induced anaphylaxis. J. A. M. A. 1973;224 (5): 613 -- 5

[3] Bochner BS, Lichenstein LM. Anaphylaxis. NEJM 1991;324:1785.

[4] Burks AW, Jones SM, Wheeler JG, Sampson HA. Food allergy: Current knowledge and future directions. Immun Allerg Clin NA 1999;19:533.

[5] Freeman TM. Anaphylaxis: Diagnosis and treatment. Primary Care Clinics 1998;25:809-817.

[6] Weiler JM. Anaphylaxis in the general population: A frequent and occasionally fatal disorder that is underrecognized. J Allergy Clin Immun 1999;104:271-273.

[7] Lee JM, Greenes DS. Biphasic anaphylactic reaction in pediatrics. Pediatrics 2000;106:106.

[8] Lee JM, Greenes DS. Biphasic anaphylactic reaction in pediatrics. Pediatrics 2000;106:106. OP CIT.

[9] Thiers BH, Beltrani VS. Urticaria and angioedema: Current therapy. Dermatologic Clinics 1996;14:171-198.

[10] Anaphylaxis ? Life-threatening allergy. AAIR (Asthma and Allergy Information and Research) http:/www.users.globalnet.co.uk/~aair/anaphylaxis.htm. Accessed 20Feb2001.

[11] Heinly TL, Lieberman P. Anaphylaxis in pregnancy. Immun Allerg Clinics NA 2000;20:106.

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