Although desensitization with an appropriate cephalosporin is a potential option
for J.A. (see Case 32-9, Question 1), her infection is not life-threatening, and the
organism is probably sensitive to another antimicrobial agents. In this case, it would
be prudent to treat J.A. with a non–β-lactam antibiotic. If J.A.’s skin tests to
cephalosporin were undertaken, and had been negative, she could receive a
cephalosporin despite her positive history beginning with a cautiously administered
small (i.e., “test”) initial dose.
multiple organ systems and variable clinical manifestations. Anaphylactic reactions,
puncture wounds on the volar aspect of the right arm. The area surrounding the wounds is swollen,
subjective and objective evidence support the diagnosis of anaphylaxis in L.P.?
Anaphylaxis is a serious allergic reaction that has a rapid onset and can cause
48 The diagnosis is considered probable if one of three clinical criteria are
an acute onset of a reaction (minutes to hours) with involvement of the skin,
mucosal tissue, or both, and at least one of the following:
reduced blood pressure or symptoms of end-organ dysfunction
two or more of the following that occur rapidly after exposure to a likely allergen
involvement of the skin/mucosal tissue
reduced blood pressure or associated symptoms
persistent gastrointestinal symptoms
reduced blood pressure, after exposure to a known allergen
Anaphylaxis results from the rapid release of immunologic mediators from tissue
mast cells and peripheral blood basophils.
The symptoms of anaphylaxis vary widely, depending on the route of exposure,
rate of exposure, and dose of allergen.
30 Symptoms often begin within minutes of
exposure, as in L.P., and most reactions occur within 1 hour. On rare occasions,
anaphylaxis can appear several hours after exposure, and late phase or biphasic
attacks have occurred 1 to 72 hours after the initial attack (most commonly within 8
hours). In general, the severity of the anaphylaxis is directly proportional to the speed
of onset. L.P. displays symptoms in many of the organs commonly involved in
anaphylaxis. Although almost any organ system can be affected, the cutaneous,
gastrointestinal (GI), respiratory, and cardiovascular systems are involved most
frequently, either singly or in combination.
30 These “shock organs” contain the largest
number of mast cells and are the most highly affected.
L.P. exhibits erythema (flushed appearance) and complains of pruritus of his hands
and feet, both common initial symptoms of anaphylaxis; the groin is also commonly
affected. These symptoms can progress to urticaria and angioedema, especially of the
palms, soles, periorbital tissue, and mucous membranes. L.P. describes the early
manifestations of angioedema (laryngeal edema) with complaints of a lump in his
throat (this may also be described as throat tightness or constriction by some
The upper and lower respiratory tracts can also be involved during an
anaphylactic event. L.P. exhibits stridor, indicating upper airway involvement.
Hoarseness is another sign of upper respiratory tract involvement. In addition, L.P. is
tachypneic with poor airflow, suggesting his lower airway also is affected. L.P. does
not display wheezing or acute emphysema, which are further clues of lower airway
involvement. Respiratory symptoms can lead to suffocation and death. In one autopsy
series, laryngeal edema accounted for 25% of the fatalities and acute emphysema for
50 Cardiovascular symptoms also are ominous.
Cardiovascular collapse and hypotensive shock (anaphylactic shock) are caused by
peripheral vasodilation, enhanced vascular permeability, leakage of plasma, low
cardiac output, and intravascular volume depletion. Thus, hypotension, as seen with
L.P., is a common cardiac manifestation. Tachycardia also commonly occurs in
patients with cardiac complications of anaphylaxis. L.P. does not show a significant
increase in heart rate; however, he is taking the β-blocker atenolol. Other cardiac
manifestations of anaphylaxis include a direct cardiodepressant effect and various
electrocardiographic changes, including arrhythmias and ischemia.
Although not demonstrated by L.P., common GI manifestations such as abdominal
cramping, diarrhea (which can be bloody), nausea, and vomiting are also manifested
during an anaphylactic reaction.
In summary, L.P.’s rapid onset and progression of
symptoms involving multiple organ systems (i.e., cutaneous, respiratory, and
cardiovascular systems) are consistent with an anaphylactic reaction. L.P.’s
anaphylaxis is a severe reaction given its speed of onset, the number of organ systems
involved, and the degree of involvement. In particular, his respiratory and
cardiovascular symptoms indicate a potentially life-threatening reaction.
Anaphylaxis occurs through one of three mechanisms.
In the first type of reaction,
exposure to a foreign protein, either in its native state or as a hapten conjugated to a
carrier protein, causes IgE-antibody formation. The IgE antibodies then bind to
receptors on mast cells and basophils. On reexposure, the antigen stimulates cellular
degranulation through both antigen-IgE antibody formation and cross-linking, which
release of preformed immunologic mediators from the mast cells and basophils.
Histamine is the major mediator of anaphylaxis and the primary preformed cellular
constituent. Histamine has multiple effects and is likely responsible for vasodilation,
urticaria, angioedema, hypotension, vomiting, abdominal cramping, and changes in
generated rapidly as a result of cellular degranulation, and other mediators of
anaphylaxis (e.g., tryptase, chymase, carboxypeptidase A, tumor necrosis factor, and
other cytokines and chemokines) are released as well.
Hymenoptera venom (e.g., bee stings), insulin, streptokinase, penicillins,
cephalosporins, local anesthetics, and sulfonamides occur through this IgE-mediated
Anaphylaxis also can occur via the formation of immune complexes that activate
the complement system and the subsequent formation of anaphylatoxins C3a, C4a, and
C5a. Such anaphylatoxins can directly stimulate mast cell and basophil degranulation
and mediator release. In 2008, cases resembling anaphylaxis in patients receiving
heparin, particularly those also undergoing dialysis, were reported with almost 100
deaths occurring internationally. The culprit was found to be a contaminant
(oversulfated chondroitin sulfate) that caused symptoms by this mechanism.
The third mechanism by which substances, such as radiocontrast media and other
hyperosmolar agents, can cause anaphylaxis is by the direct stimulation of mediator
release (primarily histamine). The pathway by which this occurs is as yet unknown,
but it is independent of IgE and complement.
Additionally, when no distinct mechanism can be associated with an anaphylactic
event, the term idiopathic anaphylaxis is applied.
Foods, insect stings, and drugs are the most common causes of anaphylaxis.
chemotherapeutic agents, and monoclonal antibodies are the most common causes of
drug-induced anaphylaxis. L.P.’s anaphylactic episode most likely is related to the
first mechanism (i.e., IgE-antibody formation). L.P. is receiving a drug from a class
of antibiotics well known to cause anaphylaxis. Specifically, L.P. may have received
a prophylactic β-lactam antibiotic prior to his appendectomy, a standard of practice.
Exposure to the antibiotic at that time stimulated IgE-antibody formation. After
exposure to the β-lactam ampicillin/sulbactam in the emergency department,
antibody–antigen complexes were formed, resulting in cellular degranulation and
anaphylaxis. The temporal relationship of L.P.’s anaphylactic reaction to the
administration of the antibiotic also strongly implicates ampicillin/sulbactam as the
precipitating agent. Furthermore, L.P. was not exposed to agents known to cause
anaphylaxis by one of the other known mechanisms. A review of L.P.’s surgical
records is necessary to confirm his prior exposure to a sensitizing antibiotic.
CASE 32-2, QUESTION 3: Given L.P.’s signs and symptoms and the presumed cause of his anaphylactic
reaction, how should he be treated?
Effective management of anaphylaxis requires quick recognition and aggressive
therapeutic intervention because of the immediate life-threatening nature of the
reaction, as illustrated by L.P. The severity of the anaphylactic reaction must be
assessed quickly, the probable causative agent determined, the administration of the
offending substance discontinued, and the absorption of the offending agent
minimized if possible. Recent guidelines on the management of anaphylaxis list the
following treatments in order of importance: epinephrine, patient position, oxygen,
intravenous fluids, nebulized therapy, vasopressors, antihistamines, corticosteroids,
49 All of these interventions must be undertaken promptly and the
clinical status of the patient closely monitored. Vital signs, cardiac and pulmonary
function, oxygenation, cardiac output, and tissue perfusion in particular must be
immediately and continuously assessed.
Although not definitively known to be the cause, the infusion of
ampicillin/sulbactam should be stopped to prevent further exposure to the presumed
precipitating agent. Additionally, the forearm wounds should be flushed with normal
saline to remove any residual cleansing agent in the event that this is the cause of the
Pharmacologic treatment of anaphylaxis has traditionally involved several drugs
and drug classes such as epinephrine, antihistamines, and corticosteroids aimed at
reversing the clinical manifestations of anaphylaxis and interrupting the biological
pathways involved. Recent literature reviews, however, failed to find well-designed
and well-conducted randomized controlled trials to support the use of these
54–56 Recommendations for use are based on tradition, case reports, case series,
L.P. is showing early signs of anaphylactic shock that must be managed
immediately. Epinephrine is the drug of choice for the pharmacologic management of
anaphylaxis and all national and international anaphylaxis guidelines recommend
epinephrine as first-line treatment.
30,49,57 Studies have shown that failure to use
epinephrine early in anaphylaxis is a risk factor for a poor outcome. Use of standard
order sets and auto-injectors by emergency departments have been shown to increase
epinephrine utilization for anaphylactic patients.
The α-adrenergic effects of epinephrine increase systemic vascular resistance and
increase blood pressure while decreasing mucosal edema and relieving upper airway
obstruction, angioedema, and hives. These actions counter the vasodilating and
hypotensive effects of histamine and the other mediators of anaphylaxis. In addition,
the β-adrenergic effects of epinephrine promote bronchodilation and increase cardiac
rate and contractility. Epinephrine also inhibits the release of mediators from
The route of epinephrine administration is important. Most guidelines recommend
IM epinephrine, 0.01 mg/kg of a 1 mg/mL (1:1,000) solution to a maximum dose of
0.5 mg in an adult or 0.3 mg in a child injected into the lateral aspect of the thigh
every 5 to 10 minutes as needed.
58,59 Epinephrine doses should be expressed in mass
concentration (e.g., 1 mg in 1 mL) instead of ratios such as 1:1,000, which have been
confused with epinephrine concentrations used in cardiac arrest (1:10,000) and
57 Epinephrine is vasodilatory in skeletal muscle and because
skeletal muscle is highly vascular absorption is rapid. While some guidelines
propose the subcutaneous route for epinephrine administration, subcutaneous tissue is
less vascular than skeletal muscle, thus there is less rapid absorption of epinephrine.
Additionally, epinephrine causes vasoconstriction in subcutaneous tissue, therefore
slowing its own absorption. Studies have shown that IM epinephrine injections into
the thigh achieve higher blood concentrations more rapidly than do subcutaneous or
IM injections into the arm in healthy subjects.
49 The rate and extent of absorption
from IM and subcutaneous routes of epinephrine administration, however, have not
been studied in patients experiencing anaphylaxis, and there is no evidence that
epinephrine is ineffective when given IM or subcutaneously into the arm.
Epinephrine should be administered via the IV route in cases of anaphylaxis that have
not responded to repeated doses of IM epinephrine and/or are progressing to shock,
where cardiorespiratory arrest appears imminent. Low cardiac output and
intravascular volume depletion from shock decrease tissue perfusion and possibly the
absorption of subcutaneous or IM injections. In animal studies, the benefits of
intermittent IV boluses of epinephrine are short lived and a continuous infusion of
epinephrine provides optimal results.
In L.P.’s case, an initial dose of 0.5 mg of 1
mg/1 mL epinephrine solution should be injected IM into his lateral thigh. This
should be repeated every 5 minutes until symptoms improve.
Some evidence suggests poor outcomes in patients who are in an upright position
60 Placing L.P. in the Trendelenburg position (patient
supine, inclined approximately 45 degrees with head at the lower end and legs at the
upper end) might improve survival by enhancing perfusion to vital organs. After
repositioning, oxygen should be started and normal saline infused at a rate sufficient
to maintain perfusion to vital organs. Normal saline is the preferred crystalloid
because it stays in the intravascular space longer than does dextrose and does not
contain lactate (e.g., Lactated Ringer’s solution), which could worsen metabolic
acidosis. Circulating blood volume can decrease by as much as 35% in the first 10
minutes of anaphylactic shock because of vasodilation and fluid shifting from the
intravascular to the extravascular space.
49 Therefore, vigorous fluid resuscitation
might be necessary (e.g., 1–2 L of normal saline at a rate of 5–10 mL/kg in the first 5
minutes). Cerebral perfusion, as evidenced by adequate mentation, must always take
precedence over BP readings when managing shock.
The effect of L.P.’s atenolol must also be considered. Patients taking a β-blocker,
whether cardioselective or not cardioselective, could experience more severe
to treat anaphylaxis, resulting in refractory hypotension, bradycardia, and
If L.P.’s BP and heart rate do not substantially improve shortly after
initiating epinephrine, IV glucagon, which can stimulate heart rate and cardiac
contractility independent of β-adrenergic blockade, should be given (Table 32-5).
Airway protection is important because glucagon may cause emesis and there is a
risk of aspiration, especially in drowsy or obtunded patients. Methylene blue, through
its ability to reduce nitric oxide production (a known potent vasodilator) has been
found to be effective in a small number of cases of anaphylaxis with refractory
53,60 Other vasopressors such as dopamine (2–20 mcg/kg/minute) may be
needed to maintain blood pressure if there is poor response to epinephrine and
glucagon. Second-line treatment for anaphylaxis includes inhaled β-agonists, H1 and
H2 antihistamines, and corticosteroids. In light of L.P.’s severe pulmonary reaction,
he should receive a nebulized β-agonist (e.g., albuterol). If L.P.’s respiratory status
fails to improve after pharmacologic intervention, intubation must be considered.
Atenolol would not be expected to diminish the effect of albuterol because atenolol
is a β1 cardioselective β-blocker and the dose is low. Because histamine is the
primary mediator of anaphylaxis, IV administration of an H1 antihistamine such as
diphenhydramine (50 mg every 6 hours until the reaction resolves) should be
considered. Similarly, giving an H2 antihistamine is a common practice. Both
therapies present little acute risk to the patient, but as already noted, there are few
data supporting their efficacy in treating anaphylaxis.
Lastly, given the severity of his reaction and his pulmonary involvement, L.P. is a
candidate for IV corticosteroids. Methylprednisolone, 125 mg every 6 hours for four
doses, might be beneficial and is associated with minimal risk. Although commonly
used, corticosteroids will not affect the acute course of the reaction because of their
delayed onset of action (typically 4–6 hours after administration). Corticosteroids
may impact a prolonged episode of anaphylaxis and could prevent or minimize the
because his condition is potentially life-threatening. Once stabilized, L.P. should be
transferred to a critical care setting and monitored for a minimum of 24 hours
because relapses of the anaphylactic reaction can occur.
Serum sickness is a type III hypersensitivity reaction that results from the production
of antibodies directed against heterologous protein or drug haptens with subsequent
tissue deposition. The typical presentation of serum sickness includes fever,
cutaneous eruptions (95%), lymphadenopathy, and joint symptoms (10%–50%).
Symptoms usually occur 1 to 2 weeks after exposure, but accelerated reactions can
occur within 2 to 4 days in previously sensitized persons. Laboratory data are
relatively nonspecific and are of little diagnostic value. For example, the erythrocyte
sedimentation rate (ESR) and the serum concentration of circulating immune
complexes usually are increased. Complements C3 and C4 are often low, whereas
activation products C3a and C3a desarginine are elevated. Urinalysis might reveal
proteinuria, hematuria, or an occasional cast.
In most cases, serum sickness reactions are mild and self-limiting and resolve
within a few days to weeks after withdrawal of the inciting agent. Antihistamines and
aspirin can be used to relieve pruritus and arthralgias. In severe cases,
corticosteroids might be used and can be tapered during 10 to 14 days.
time, heterologous serum (e.g., anti-thymocyte globulin made from rabbit or equine
serum) was a leading cause of serum sickness. With the decline in use of these
products, however, the most common causes of serum sickness today are penicillins
and cephalosporins, although biological agents such as rituximab, infliximab, and
natalizumab are increasingly associated with serum sickness.
Polymorphonuclear neutrophil leukocytes (PMN), 83% (normal, 45%–79%)
Lymphocytes, 10% (normal, 16%–47%)
Eosinophils, 1% (normal, 1%–2%)
every 4 to 6 hours as needed for temperature greater than 38°C, oral famotidine 20 mg BID, and oral
Drug Indication Adult Dosage Complications
001 mg/kg to a maximum of 0.5 mg of a 1
mg/1 mL solution IM every 5 minutes PRN;
if progressing to cardiorespiratory arrest 1–
3 mL of 1:10,000 (0.1–0.3 mg) IV for 3
1 mL of 1 mg/mL (1:1,000) in 250 mL of
normalsaline IV at a rate of 4–10
3–5 mL of 0.1 mg/mL (1:10,000)
intratracheally every 10–20 minutes PRN
Oxygen Hypoxemia 40%–100% None
Albuterol 0.5 mL of 0.5% solution in 2.5 mL of saline
IV fluids Hypotension 1 L of normalsaline every 20–30 minutes
PRN (rates as high as 1–2 mL/kg/minute
Diphenhydramine 25–50 mg IV over 10–15
antagonists may be used in less
Ranitidine 50 mg IV over 10–15 minutes or
Famotidine 20 mg IV over 10–15 minutes
Hydrocortisone sodium succinate 100 mg
IV every 3–6 hours for two to four doses
Methylprednisolone sodium succinate 40–
125 mg IV every 6 hours for two to four
400 mg in 500 mL dextrose 5% at 2–20
4 mg in 1 L dextrose 5% IV at a rate of 2–
1 mg IV for 5 minutes, followed by 5–15
resuscitation by taking time to draw up and administer a second-line medication.
IM, intramuscularly; IV, intravenously; PO, orally; PRN, as needed.
Drug fever is described as a febrile reaction to a drug without cutaneous symptoms
and is estimated to occur in 3% to 5% of inpatients.
67 Drug fever can be challenging
to identify and can be misinterpreted as a new infectious process or failure of an
existing infection to respond to treatment. Such failure to recognize a drug fever can
lead to prolonged hospitalization and unnecessary tests or medications.
lists the characteristics of hypersensitivity drug-induced fever. The most important
finding in the case of M.M. is her clinical improvement with respect to her
pulmonary status despite a high-grade fever and persistent leukocytosis; she also
appears healthier than expected if she had an untreated infection. Whereas a drop in
her WBC count would be anticipated given her improving respiratory function, her
WBC count remains elevated, consistent with hypersensitivity drug fever. Notably,
her eosinophil count is increased, a frequent sign of hypersensitivity reactions.
Despite her high-grade fever, she has a relative bradycardia; that is, her heart rate is
not as elevated as expected if an infectious process were ongoing. Further, the timing
of the symptoms favors a drug-induced fever (i.e., within days of starting a new
medication). A definitive diagnosis can be made only by stopping the suspected
offending agent, however, because fever generally resolves within 48 to 72 hours if a
rash is not present. When a rash is present, on the other hand, the fever may persist
for several days after stopping the implicated drug.
Hypersensitivity Reactions to Drugs: Drug-Induced Fever
Frequency True frequency is unknown because fever is a common manifestation and
almost any drug can cause fever. Estimate is that 3%–5% of hospitalized
patients experiencing adverse drug reaction suffer from drug fever alone or as
Clinical manifestations Temperatures may be 38°C or higher and do not follow a consistent pattern.
Although patients may have high fevers with shaking chills, patients generally
have few symptoms or serious systemic illness. Skin rash (18%), eosinophilia
(22%), chills (53%), headache (16%), myalgias (25%), and bradycardia (11%)
can occur in patients with drug fever. Onset of fever after exposure to the
offending agent is highly variable, ranging from an average of 6 days for
antineoplastics to 45 days for cardiovascular agents. Occurrence of fever is
independent of the dose of the offending agent.
Treatment Although drug fever can be treated symptomatically (e.g., with antipyretics,
cooling blankets), stopping the offending agent is the only therapy that will
eliminate fevers. Patients generally defervesce within 48–72 hours of stopping
Prognosis Drug fever is usually benign, although one review
length of hospitalization of 9 days per episode of drug fever. Rechallenge with
the offending drug usually results in rapid return of the fever. Although
reexposure to the suspect drug was previously thought to be potentially
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