CC
A 21-year-old female admitted for treatment of an open mandibular body fracture complains of the sudden appearance of a rash and shortness of breath after receiving her intravenous (IV) antibiotics (anaphylaxis is more common with parenteral administration of medications).
HPI
The patient was admitted that day with a diagnosis of an open right mandibular body fracture secondary to assault. The patient did not report any known drug allergies (most frequently, patients do not have a previous history), and the admitting surgeon ordered IV penicillin G, morphine sulfate, and nothing-by-mouth status in preparation for surgical treatment in the operating room. Upon arrival of the patient on the hospital ward, the nursing staff administered the first dose of IV aqueous penicillin G. Approximately 5 to 10 minutes later, the patient developed multiple circumscribed, erythematous, and raised pruritic wheals on her skin. (Symptoms generally develop within 5–60 minutes after exposure; earlier onset is seen with parenteral introduction of the allergen.) The patient also reported feeling short of breath and the onset of wheezing (secondary to bronchospasm), nausea, and cramping abdominal pain.
PMHX/PDHX/medications/allergies/SH/FH
The patient reports no known drug allergies. She has no history of food, environmental, or seasonal allergies. She has no family history of drug allergies. ( Multiple drug allergy syndrome is a term that may be applied to individuals who have experienced allergic reactions to two or more non–cross-reacting medications. People who are allergic to another drug are likely at increased risk of reacting to penicillin. The reasons are not clear, but genetics may play a role. Genetics may also play a role in the expression of penicillin allergy between family members; however, currently, the studies are limited.)
Anaphylaxis is a serious allergic reaction that is rapid in onset and may cause death. Allergic anaphylaxis involves the production of symptoms via an immunologic mechanism. Nonallergic anaphylaxis (previously known as an anaphylactoid reaction) produces a very similar clinical syndrome but is not immune mediated (direct activation of mast cell). Treatment for the two conditions is similar.
Examination
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General. The patient is a well-developed, well-nourished female in moderate distress who is sitting up and leaning forward in bed.
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Vital signs. Her blood pressure is 98/60 mm Hg (hypotension), heart rate is 128 bpm (tachycardia), respirations are 28 breaths per minute (tachypnea), temperature is 36.7°C, and Sa o 2 is 100% on 2 L per nasal cannula.
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Neurologic. The patient’s Glasgow Coma Scale score is 15; she is alert and oriented ×3 (place, time, and person).
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Maxillofacial. Examination is consistent with a mandibular body fracture.
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Cardiovascular. She is tachycardic at 128 bpm. Her heart rate and rhythm are regular, with no murmurs, gallops, or rubs. Cardiovascular symptoms and signs occur in up to 45% of anaphylactic episodes; they include hypotonia (collapse), syncope, dizziness, tachycardia, and hypotension.
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Pulmonary. The patient has bilateral wheezing. Respiratory symptoms and signs occur in up to 70% of anaphylactic episodes; they include nasal congestion and discharge, a change in voice quality, a sensation of throat closure or choking, stridor, shortness of breath, wheezing, and cough.
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Abdominal. The abdomen is soft, tender to palpation (secondary to spasm of intestinal smooth muscles), and nondistended with no rebound tenderness and normal bowel sound. Gastrointestinal (GI) symptoms and signs occur in up to 46% of anaphylactic episodes; they include nausea, vomiting, diarrhea, and crampy abdominal pain.
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Skin. The patient has urticaria. (Commonly known as “hives,” urticaria consists of circumscribed areas of raised erythema and edema of the superficial dermis.) Skin symptoms and signs occur in up to 80% to 90% of anaphylactic episodes; they include generalized hives; itching or flushing; swollen lips, tongue, and uvula; periorbital edema; and conjunctival swelling.
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The clinical presentation of anaphylaxis is variable and may include any combination of common signs and symptoms. Anaphylaxis is underrecognized and undertreated; the goal is early recognition and treatment with epinephrine. Diagnostic criteria were updated by an expert panel in 2020 with the intention of helping clinicians recognize anaphylaxis.
The World Allergy Organization (WAO) has developed a poster that presents the key clinical criteria for both the diagnosis and initial treatment of patients with anaphylaxis ( Fig. 7.1 ). These criteria reflect the different clinical presentations; anaphylaxis is highly likely when any one of the criteria is met. It was acknowledged that no single set of criteria can provide 100% sensitivity and specificity, but it is believed that the WAO’s proposed criteria are likely to capture more than 95% of cases of anaphylaxis. The majority of anaphylactic reactions include skin symptoms, which are noted in more than 80% of cases. Thus at least 80% of anaphylactic reactions should be identified by criterion 1, even when the allergic status of the patient and the potential cause of the reaction might be unknown. One significant change to the previous criteria is the presence of “severe” rather than “persistent” GI symptoms including abdominal cramping, pain, and repetitive vomiting.
Imaging
In the acute phase of anaphylaxis, no imaging studies are indicated. (Any unnecessary delay may compromise other lifesaving interventions.)
Labs
During an acute anaphylactic episode, no laboratory tests are indicated. However, after the patient’s condition has been stabilized (or if the diagnosis is in question), in addition to a complete blood cell count and comprehensive metabolic panel, the following tests can be obtained:
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Plasma histamine level. This is elevated within 5 to 10 minutes after the onset but remains elevated for only 30 to 60 minutes because of rapid metabolism. (Histamine is released secondary to IgE-mediated mast cell degranulation.)
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Urinary N-methyl histamine. A metabolite of histamine, N-methyl histamine remains elevated for several hours. A 24-hour urine sample for N-methyl histamine may be useful.
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Serum tryptase. This peaks 60 to 90 minutes after the onset of anaphylaxis and remains elevated for up to 5 hours. Tryptase is a protease specific to mast cell activation. It is the only protein that is concentrated selectively in the secretory granules of human mast cells. Normal levels of either tryptase or histamine do not rule out the clinical diagnosis of anaphylaxis. It is recommended to evaluate serum tryptase at least 24 hours after resolution of symptoms from anaphylaxis even if levels did not increase during the episode.
Assessment
Immediate allergic anaphylactic reaction induced by intravenously administered penicillin G.
Box 7.1 outlines the differential diagnosis of anaphylactic shock.
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Anaphylaxis
- A.
Anaphylaxis from foods, drugs, insect stings
- B.
Anaphylaxis from physical factors (exercise, cold, heat)
- C.
Idiopathic (cause undetermined) anaphylaxis
- A.
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Vasodepressor reactions (vasovagal reactions)
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Flushing syndromes
- A.
Carcinoid
- B.
Vasointestinal polypeptide tumors
- C.
Mastocytosis and mast cell activating syndrome
- D.
Medullary carcinoma of the thyroid
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Restaurant syndromes
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- A.
Monosodium glutamate
- B.
Scombroidosis
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Nonorganic disease
- A.
Panic attacks
- B.
Munchausen stridor (factitious anaphylaxis)
- C.
Vocal cord dysfunction syndrome
- D.
Undifferentiated somatoform anaphylaxis
- E.
Prevarication anaphylaxis
- A.
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Miscellaneous
- A.
Hereditary angioedema accompanied by rash
- B.
Paradoxical pheochromocytoma
- C.
Red man syndrome (vancomycin)
- D.
Capillary leak syndrome
- A.
Treatment
The initial management of anaphylaxis is to perform a focused examination, discontinue the suspected medication, call emergency services, administer intramuscular (IM) injection of epinephrine, place the patient in a supine position unless there is respiratory distress (then sitting is indicated) or a semi-recumbent position on the left side if the patient is pregnant (the benefit of elevation of the lower extremities or the Trendelenburg position is controversial and no longer recommended by the American Heart Association), administer supplemental high flow oxygen (preferably 100% using a nonrebreather facemask), establish a stable airway (with intubation if necessary), obtain venous access (preferably with two large-bore [16-gauge] peripheral IV catheters) for volume resuscitation, and continuously monitor the vital signs and level of consciousness.
Immediately upon diagnosis, 0.3 to 0.5 mL of 1:1000 (1 mg/mL) epinephrine (up to 0.5 mg in adults, 0.15–0.3 mg in children, and 0.01 mg/kg in infants) should be injected intramuscularly into the anterolateral thigh. (Injection at this site has been shown to be more effective than subcutaneous or upper arm [deltoid] injection.) The site can be massaged to facilitate absorption. This dose may be repeated every 5 to 15 minutes, up to a total of three doses. The therapeutic effects of epinephrine include:
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α 1 -Adrenergic agonist: increased vasoconstriction, increased peripheral vascular resistance, and decreased mucosal edema (in the upper airway)
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β 1 -Adrenergic agonist: increased inotropy and chronotropy
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β 2 -Adrenergic agonist: increased bronchodilation and decreased release of mediators from mast cells and basophils
Patients with severe upper airway edema, bronchospasm, or significant hypotension or who do not respond to IM injection (may not be perfusing muscle tissue) and fluid resuscitation should receive 0.05 to 1 mg of 0.1 mg/mL epinephrine solution (further diluted in 10 mL of normal saline) intravenously over the course of 1 to 10 minutes. Alternatively, a continuous infusion of 0.1 to 0.2 μg/kg/minute (8–16 μg/min for an 80-kg patient) of epinephrine (titrated to effect) may be administered. (This is preferred over bolus dosing of epinephrine because bolus dosing is associated with more adverse effects including cardiac arrhythmias). Patients receiving IV epinephrine require continuous cardiac monitoring because of the potential for arrhythmias and ischemia, which occur most commonly with this route of administration. If IV access cannot be established, epinephrine can be administered via an endotracheal tube (3–5 mL of 1:10,000 epinephrine).
It has been recommended that the epinephrine be administered early because this can prevent progression to severe symptoms. Delayed administration has been implicated in contributing to fatalities.
Nebulized albuterol (β 2 agonist) for respiratory symptoms may be administered, and IV aminophylline (bronchodilator) can be considered, although its effectiveness for anaphylaxis is questionable. These are adjunctive treatments to epinephrine. Large volumes of fluids may be required to treat hypotension caused by increased vascular permeability and vasodilatation. Patients with evidence of intravascular volume depletion (e.g., hypotension, low urine output, low or no response to injected epinephrine) should receive volume replacement. Normal saline is preferred initially. Additional pressors, such as dopamine (5–20 μg/kg/min), norepinephrine (0.05–0.4 μg/kg/min), or phenylephrine (100–200 μg/min), may be required.
Antihistamines also are considered adjunctive to epinephrine. The purpose of using antihistamines is to relive itch and hives. A combination of H 1 and H 2 blockers may be superior to either agent alone. Thus, diphenhydramine (H 1 -receptor blocker) 25 to 50 mg intravenously or intramuscularly every 4 to 6 hours can be used with famotidine (H 2 -receptor antagonist) 20 mg intravenously given over 2 minutes.
Most authorities also advocate the administration of corticosteroids (methylprednisolone 1–2 mg/kg/day); their benefit is not realized for 6 to 12 hours after administration, but they may be helpful in the prevention of biphasic reactions. They can be stopped after 72 hours, because all biphasic reactions reported to date have occurred within 72 hours.
Glucocorticosteroids are often used in the management of anaphylaxis to prevent protracted symptoms. However, evidence is increasingly showing that they may be of no benefit in the acute management of anaphylaxis. In fact, they may be harmful. Thus, routine use is controversial.
Patients currently taking β-blockers pose a challenge because these drugs may limit the effectiveness of epinephrine. These patients may develop resistant hypotension, bradycardia, and a prolonged course. Atropine (anticholinergic) may be given for bradycardia. Some clinicians recommend administering glucagon. Glucagon exerts a positive inotropic and chronotropic effect on the heart independent of catecholamines. A 1 to 5 mg slow IV bolus followed by an infusion of 5 to 15 μg/minute titrated to effect may improve hypotension in 1 to 5 minutes, with maximal benefit at 5 to 15 minutes. All patients with anaphylaxis should be monitored for the possibility of recurrent symptoms after initial resolution.
In the current patient, penicillin was immediately discontinued, and 0.3 mg of 1:1000 epinephrine was injected intramuscularly into the right anterolateral thigh. Synchronously, a code was called, the patient was placed in a supine position, and supplemental oxygen at 10 L/minute was administered via a nonrebreather mask. Two 16-gauge peripheral IV lines were started at each antecubital fossa, and a bolus of normal saline was given. The patient also received IV medications (i.e., 50 mg diphenhydramine, 20 mg famotidine, 100 mg methylprednisone) and nebulized albuterol. The vital signs were continuously monitored. An additional 0.3 mg of 1:1000 epinephrine was given intramuscularly after 12 minutes. The patient remained stable, and marked improvement was noted. She was subsequently transferred to the intensive care unit (ICU) for observation.
After an uneventful overnight stay in the ICU, the patient was taken to the operating room the next day, where she underwent open reduction with internal fixation of the mandibular fracture. The anesthesia team was informed of her hospital course (in case the patient experienced a biphasic recurrence, with the signs and symptoms of anaphylaxis occurring during anesthesia). Approximately 50% of biphasic reactions occur within the first 6 to 12 hours after the initial reaction. All early symptoms of anaphylaxis usually observed in the awake patient (e.g., malaise, pruritus, dizziness, and dyspnea) are absent in the anesthetized patient. The most commonly reported initial features are pulselessness, difficulty in ventilating, desaturation, and decreased end-tidal CO 2 . Also, cutaneous signs may be difficult to notice in a completely draped patient.
Upon discharge, the patient was thoroughly informed of her allergy. She was provided with a medical alert bracelet, and follow-up was arranged with allergy care specialists.
Complications
Complications of anaphylaxis range from full recovery to anoxic brain injury and death despite adequate response and treatment. The factors that determine the course of anaphylaxis are not understood. At the onset of an episode, it is not possible to predict how severe it will become, how rapidly it will progress, or whether it will resolve spontaneously (as a result of endogenous production of compensatory mediators, such as epinephrine) or become biphasic or protracted. The rapidity of onset of symptoms makes this uncommon condition difficult to treat. Early recognition and treatment are essential. It is estimated that anaphylaxis causes approximately 1400 to 1500 fatalities per year in the United States. Between 5% and 20% of patients experience biphasic anaphylaxis, with a recurrence of symptoms after apparent initial resolution (typically 1–10 hours after initial resolution). Some cases of recurrence have been reported up to 72 hours later. Protracted anaphylaxis also has been reported, with persistence of symptoms for hours, days, or even weeks despite therapy.
Anaphylaxis is known to be difficult to recognize clinically for several reasons, including the broad differential that needs to be considered. Concurrent use of central nervous system–active medications, such as sedatives, hypnotics, antidepressants, and first-generation sedating H 1 antihistamines, can interfere with recognition of anaphylaxis triggers and symptoms and with the ability to describe symptoms. In patients with concomitant medical conditions, such as asthma, chronic obstructive pulmonary disease, or congestive heart failure, symptoms and signs of these diseases can also cause confusion in the differential diagnosis of anaphylaxis. Death most commonly results from intractable bronchospasm, asphyxiation from upper airway edema, or cardiovascular collapse.
Perioperative anaphylaxis is a serious and unpredictable adverse event with an estimated incidence of 1 in 10,000. Many challenges exist to recognizing anaphylaxis in an anesthetic setting because of the variety of drugs administered intravenously and difficulty distinguishing anesthetic drug hemodynamic effects from anaphylaxis. Also, detecting cutaneous changes in draped patients is very challenging. Anaphylaxis can occur at any time during anesthesia but is most common at induction. The clinical features of perioperative anaphylaxis are the same in the nonanesthetic setting. Severe hypotension is widely observed because the trigger is most often administered intravenously.
Discussion
Penicillin allergy is reported by up to 10% of all patients and 15% of hospitalized patients in the United States. Penicillin-induced anaphylaxis occurs at an incidence between 0.02% to 0.04%. In large-scale studies of penicillin allergy skin testing, it has also been observed that more than 90% of patients who report a penicillin allergy are not truly allergic to the drug. Of significance is that many people are falsely labeled as being penicillin allergic.
Clinicians often prescribe different treatments for patients with a history of penicillin allergy, including broad-spectrum antibiotics and clindamycin, which carry many side effects and risk of antimicrobial resistance. A recent study by Roistacher et al. found that penicillin allergy was significantly associated with surgical site infection after oral and maxillofacial surgical procedures. They identified that this was specifically because these patients received non–β-lactam antibiotics during the perioperative period. The authors of the study thus recommended that patients with a history of penicillin allergy who have not had a recent anaphylaxis episode should be referred for definitive allergy testing to reduce their risk of postoperative complications.
An additional study from Chadha et al. found that while patients with a reported penicillin allergy did not have significantly different outcomes following odontogenic infections compared to non-allergic patients, they did have a much higher risk for antibiotic resistance, namely clindamycin resistance. In addition, a 2023 systematic review from Edibam et al. found that self-reported penicillin allergy paired with administration of clindamycin are over three times more likely to undergo implant failure. Patients who were administered clindamycin had an average failure rate of 11% compared to 3.8% in patients administered amoxicillin. The authors emphasize the importance of allergy testing as up to 10% of patients may report a penicillin allergy, only 0.01% of patients will experience a life-threatening adverse event from administration. In addition, the authors note that it is unclear whether penicillin allergy or the addition of clindamycin is the cause of this higher failure rate. Quantities of Prevotella bacterial species in saliva may rise as a result of clindamycin administration and have been identified in implants with peri-implantitis. However, additional studies are needed to determine if clindamycin is directly damaging to implant health. Each of these studies emphasizes the importance of allergy testing for patients with a history of penicillin allergy as the true incidence of a penicillin allergy is quite low while the risk of complications due to alternative antibiotic prescriptions can be high.
Most clinicians simply accept a diagnosis of penicillin allergy without obtaining a detailed history of the reaction. In their review, Salkind and colleagues stressed the importance of a thorough history when faced with a penicillin-allergic patient ( Box 7.2 ). However, it has been shown that patients with a vague history have also been found to have an IgE-mediated allergy. The time elapsed since the last reaction is important because penicillin-specific IgE antibodies decrease with time. (Approximately 80% of patients with IgE-mediated penicillin allergy have lost sensitivity after 10 years.) Nonetheless, it is prudent to refer any patient with a history of IgE-mediated penicillin allergy for testing. Penicillin is the most common cause of drug-induced anaphylaxis. It causes an estimated 40% to 50% of all anaphylactic deaths in the United States.
