Continuing Education in Honor of Norman Trieger, DMD, MD

Benzodiazepine Allergy With Anesthesia

Administration: A Review of Current Literature
Elliot Haybarger, DMD,* Andrew S. Young, DDS,† and Joseph A. Giovannitti, Jr, DMD‡
*Dentist Anesthesiologist, Greenville, South Carolina. Former Resident in Dental Anesthesiology, University of Pittsburgh, Pennsylvania,
†Resident in Dental Anesthesiology, University of Pittsburgh, Pennsylvania, and ‡Professor and Chair, Department of Dental Anesthesiology,
University of Pittsburgh, Pennsylvania

The incidence of anaphylactic/anaphylactoid reactions has been reported to vary

between 1 : 3500 and 1 : 20,000 cases with a mortality rate ranging from 3 to 9%.
Clinical signs present as skin rash, urticaria, angioedema, bronchospasm, tachycardia,
bradycardia, and hypotension. Rapid identification and treatment are crucial to overall
patient prognosis, as delayed intervention is associated with increased mortality.
Diagnosis may be confirmed with clinical presentation, serum tryptase levels, and skin
test results. While the main causative agents in anesthetic practice are typically
neuromuscular blocking agents (NMBs), latex, and antibiotics, this review aims to
discuss recognition, management, and preventive measures in perioperative anaphy-
lactic/anaphylactoid reactions from benzodiazepine administration.

Key Words: Benzodiazepine allergy; Anaphylaxis; Anaphylactoid reactions; Diagnosis of anaphylaxis; Management of
anaphylaxis.

S erious complications during surgery have been

shown to occur rather infrequently (0.4% of
83,844 cases), but anesthesia-related complications
stimulates investigation into identification of the causa-
tive agent and classification of the observed reactions.

contribute to more than one third of these events.1

Allergic reactions to medications are among the major BENZODIAZEPINE ALLERGY: REVIEW OF
factors affecting morbidity and mortality peri- and LITERATURE
postoperatively.1,2 The relative allergenicity of benzodi-
azepines, arguably the most commonly used anxiolytic A thorough investigation was conducted in an attempt to
premedication and a cornerstone in moderate to deep provide a comprehensive summary of published reports
sedation, is explored in an attempt to quantify its allergic involving anaphylactic or anaphylactoid reactions to
history. benzodiazepines.
Benzodiazepines are sedative hypnotic agents that The earliest reports (over 17 total) of reactions to
have been in clinical use since the 1960s for sedation, benzodiazepines, dating from 1960 to 1975 describe
anterograde amnesia, anxiolysis, as well as treatment of numerous signs of cutaneous allergic reactions such as
seizures, substance withdrawal states, insomnia, and urticaria, angioedema, macular erythematous rash,
drug-associated agitation. Allergic reactions are rare, photoallergy, purpura, and erythema multiforme among
others. 5 In most cases the offending agent was
with few cases reported in literature.3,4 Amid these
predominately chlordiazepoxide followed by diazepam
sparse reports, a lack of consistent methods for diagnosis
and flurazepam. In 1977, what was considered to be the
first true anaphylaxis to diazepam was published in the
Received April 6, 2016; accepted for publication June 6, 2016.
Address correspondence to Elliot Haybarger, DMD, 112 W Broad British Medical Journal. The mechanism was attributed
St, #405, Greenville, SC 29601; [email protected]. to a common metabolite, desmethyldiazepam, the
Anesth Prog 63:160–167 2016 ISSN 0003-3006/16
Ó 2016 by the American Dental Society of Anesthesiology SSDI 0003-3006(16)

160
Anesth Prog 63:160–167 2016 Haybarger et al. 161

antigenic moiety for cross-allergenicity in benzodiaze- precipitated events resembling hypersensitivity reaction
pines.6 rather than anaphylaxis. Positive intradermal reaction to
Years later, 1 report of diazepam allergy describes a midazolam coupled with negative reaction to antibiotic
case involving a healthy 28-year-old nurse with no confirmed the hypothesis.12 While in this study no serum
significant past medical history or allergies presenting for tryptase or histamine levels were evaluated, elevated
gastroscopy. Here, a relatively brief and nonspecific case total IgE levels further support midazolam hypersensitiv-
of hypersensitivity was reported including only that the ity.
patient showed signs of ‘‘generalized urticaria and Another report published in the Indian Journal of
shock,’’ requiring treatment. The report also mentions Anesthesia described a case of apparent anaphylaxis
positive wheal and flare reactions to diazepam on skin occurring 2 minutes after IV midazolam administration
prick test, as well as intradermal test.7 with lactated Ringer’s solution.13 Described is a 26-year-
Martinez-Tadeo and Perez-Rodriguez4 reported a case old male with no significant medical history and no drug
of urticaria upon oral intake of tetrazepam that later or food allergies presenting for cervical lymph node
yielded a negative skin prick test result. Subsequently, a biopsy. Within 2 minutes of IV midazolam, the patient
single-blinded, placebo-controlled challenge oral test was experienced pruritus over his right forearm and trunk
performed using two 5-mg doses and one 15-mg dose of with urticarial wheals, severe hypotension, and brady-
tetrazepam with 30-minute interval dosing. This study cardia. No stridor or wheezing was noted ruling out
demonstrated that the patient began to show signs of airway involvement, but prompt treatment was initiated.
mild allergic reaction 50 minutes after total intake of Serum tryptase levels were elevated upon measurement
tetrazepam 25 mg. Full strength skin prick and and later skin prick tests revealed positive result with
intradermal tests were performed with both midazolam midazolam confirming anaphylaxis.
and diazepam yielding negative results. The failure to In 2014, Shin et al9 published a report documenting a
demonstrate cross-reactivity suggests a selective pattern case of midazolam anaphylaxis involving a 53-year-old
of sensitization.4 woman during an esophagogastroduodenoscopy (EGD)
The earliest published report of allergy to midazolam, procedure.9 Ten years prior, the patient had presented
released in 1992, documented 2 accounts of angioede- to the emergency medical center for allergic urticaria of
ma on the same medically compromised patient. unknown cause, but otherwise had no significant medical
Midazolam was suspected as the common offending history. Four minutes following IV administration of
agent despite the use of multiple drugs. Unfortunately, midazolam 5 mg, the patient’s pulse could not be
follow-up testing was not available for confirmation.8 palpated and her SpO2 dropped to 75%. Two doses of
Previously midazolam has been linked to effects such as flumazenil (0.3 and 0.2 mg) were administered at which
respiratory depression, laryngospasm, urticaria, and point blood pressure and pulse could not be assessed.
cardiac dysrhythmia; however, identification of midazo- Tachycardia was observed on the monitor, but no
lam’s primary metabolite, 1-hydroxymidazolam, suggests wheezing or stridor was evident. Norepinephrine (8
an alternative mechanism of allergy.9 mcg/min) and epinephrine (1 mg) were administered,
In 1994, Fujita et al10 reported a case in which a 38- and the patient’s pulse rate was then measured at 130
year-old male with medical history significant for positive bpm. She developed a generalized rash all over her body
reaction to antibiotics was seen for C4-C5 fusion.10 at which point dexamethasone (5 mg) and an antihista-
Upon administration of midazolam 10 mg, the patient mine were administered and symptoms resolved. Subse-
presented with severe hypotension (57 mmHg systolic) quently, arterial blood gas analysis and chemical analyses
and tachycardia (135 bpm) resolving after epinephrine revealed no abnormal results except an elevated lactate
administration (3 intravenous [IV] doses of 50 mcg). dehydrogenase level of 370 IU/L and an elevated blood
Another suspected case of anaphylactoid reaction tryptase level to 14.8 mcg/L, which was used to
published in the Japanese Journal of Anesthesia presume the occurrence of anaphylaxis. Skin prick test
describes a 37-year-old healthy male with no significant was considered for confirmation; however, the test was
medical history or known drug allergies exhibiting considered high risk and patient consent could not be
pruritus, chest tightness, hypotension, bradycardia, and obtained.
hypoxia shortly after administration of midazolam 2 mg Most recently, a report published in Anesthesia
with lactated Ringer’s solution. In this study, follow-up Progress describes a case of life-threatening hypoten-
testing revealed elevated serum tryptase levels in addition sion, bronchoconstriction, and edema in a 59-year-old
to positive intradermal testing 3 months later.11 woman undergoing resection of a mandibular tumor.14
The Korean Journal of Anesthesiology published a Because her medical history was significant for skin
case of suspected midazolam hypersensitivity in which reactions to several antibiotics and contrast medium, an
concurrent administration of midazolam and antibiotic initial small test dose of midazolam, 0.5 mg (0.01 mg/
162 Benzodiazepine Allergy Anesth Prog 63:160–167 2016

Table 1. Vasoactive Mediators Released During Anaphylaxis mediated and nonimmune mediated (anaphylactoid)
Mediator Physiologic Effect mechanisms. Anaphylaxis is a Gell and Coombs Type
I, IgE-mediated hypersensitivity reaction involving re-
Histamine Increased capillary permeability
Peripheral vasodilation
lease of vasoactive mediators (Table 1). Diagnosis is
Bronchoconstriction primarily based on clinical signs and symptoms and is
Urticaria considered highly likely in patients who experience acute
Leukotrienes Increased capillary permeability onset of symptoms with skin and/or mucosal tissue
Bronchoconstriction
Negative inotropy involvement, respiratory compromise, and significant
Coronary artery vasoconstriction reduction in blood pressure following exposure to an
Prostaglandins Bronchoconstriction allergen (Table 2).15 In anaphylaxis there is initial
Eosinophil chemotactic Attraction of eosinophils exposure of an antigen with subsequent production of
factor
Neutrophil chemotactic Attraction of neutrophils specific IgE antibodies. Upon re-exposure to the same or
factor chemically similar antigen, antigen-antibody interactions
Platelet-activating factor Platelet aggregation cause marked degranulation of mast cells and basophils.
Release of vasoactive amines Anaphylactoid reactions are caused by direct nonim-
mune mediated release of mediators from mast cells and
kg), was administered prior to induction with midazolam basophils, or by direct complement activation and do not
5 mg (0.1 mg/kg). The patient suddenly developed require prior exposure for sensitization. However, both
hypotension with a systolic pressure of 65 mmHg, anaphylaxis and anaphylactoid reactions exhibit similar
associated wheezing, and widespread flush on the body. clinical manifestations.16
Because anaphylactoid reaction was suspected, epineph-
rine 50 mcg and methylprednisolone 1000 mg were
injected intravenously followed by dopamine for sus- COMMON CAUSATIVE AGENTS
tained hypotension and nitroglycerine for ischemic ST
depression. Unfortunately, follow-up allergy tests did not Among the myriad of drugs and substances used in the
reveal clear evidence of allergic drug reaction. The provision of an anesthetic, neuromuscular blockers are
surgery was postponed and completed without incident a the number one cause of reported cases of anaphylaxis
week later under general anesthesia with sevoflurane. with an incidence of 69.2%.2 Latex (12.1%) is the
Further discussion on benzodiazepine allergy will second leading cause with antibiotics (8%), hypnotics
follow a basic concepts review for anaphylaxis including (3.7%), colloids (2.7%), opioids (1.4%), and other
clinical features, diagnosis, allergy testing, and manage- substances (2.9%) such as propacetamol, aprotonic,
ment. chymopapain, and bupivacaine accounting for the
remainder of reported cases. Some anesthetic induction
agents have been implicated in producing anaphylactic
ANAPHYLAXIS reactions, the majority of which are attributed to
thiopental and propofol with incidence rates
Anaphylaxis is a life-threatening condition marked by 1 : 30,000 and 1 : 60,000, respectively.2 Benzodiaze-
cardiovascular collapse, generalized interstitial edema, pines, etomidate, and ketamine account for the remain-
and bronchospasm. It may occur through immune der with incidence rates that have not been estimated.

Table 2. Clinical Criteria for Diagnosing Anaphylaxis

Anaphylaxis is highly likely when any 1 of the following 3 criteria is fulfilled following exposure to an allergen:
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal tissue, or both (eg, generalized hives,
pruritus, or flushing, swollen lips-tongue-uvula) and at least 1 of the following:
a. Respiratory compromise (eg, dyspnea, wheeze, bronchospasm, stridor, reduced peak expiratory flow, hypoxemia)
b. Reduced blood pressure (BP) of associated symptoms of end-organ dysfunction (eg, hypotonia, syncope, incontinence)
2. Two or more of the following that occur rapidly after exposure to a likely allergen:
a. Involvement of the skin-mucosal tissue
b. Respiratory compromise
c. Reduced blood pressure
3. Reduced blood pressure after exposure to a known allergen:
a. Infants and children: low systolic BP (age specific) or . 30% decrease in systolic BP
b. Adults: systolic BP , 90 mmHg or . 30% decrease from that person’s baseline
Anesth Prog 63:160–167 2016 Haybarger et al. 163

Table 3. Comparison of Signs and Symptoms: Awake Versus Anesthetized

Organ System Signs and Symptoms: Awake Signs and Symptoms: Anesthetized
Cutaneous Flushing, pruritus, urticaria, angioedema Flushing, urticaria, angioedema
Gastrointestinal Nausea and vomiting, abdominal cramping, Absent or difficult to appreciate in patients
diarrhea receiving general anesthesia. May be present
in patients under regional anesthesia or
monitored anesthesia care
Respiratory Rhinitis, laryngeal edema, shortness of breath, Increased peak inspiratory pressure, increased
wheezing, respiratory arrest end-tidal carbon dioxide, decreased oxygen
saturation, wheezing, bronchospasm
Cardiovascular Tachycardia, hypotension, cardiac arrhythmias, Tachycardia, hypotension, cardiac arrhythmias,
cardiovascular collapse cardiac arrest
Renal Decreased urine output Decreased urine output secondary to acute
tubular necrosis
Hematologic Disseminated intravascular coagulation Disseminated intravascular coagulation

Reactions to benzodiazepines specifically are exceeding- and intervention is key given the possible life-threatening
ly rare.17 nature of anaphylaxis.

CLINICAL FEATURES Epinephrine

Clinical manifestations of anaphylactoid reactions are Epinephrine is the first-line drug for anaphylaxis.
often indistinguishable from anaphylaxis. The reactions Epinephrine may be administered intramuscularly, sub-
are rapid in onset and occur within seconds to minutes of cutaneously, or intravenously with dosages determined
exposure to the offending agent. Symptoms progress by the amount necessary for symptom control and blood
rapidly and can affect most organ systems, including skin pressure maintenance.18
(pruritus, flushing, urticaria, and angioedema), eyes Intramuscular (IM) epinephrine is dosed at 0.01 mg/kg
(conjunctivitis), the upper airway (rhinitis and angioede- (maximum dose 0.5 mg for anaphylaxis) every 5–15
ma), lower airway (bronchoconstriction with wheezing minutes. Studies have indicated more rapid absorption
and dyspnea, and cyanosis), the intestinal tract (abdom- and higher plasma levels of epinephrine in individuals
inal pain, nausea, vomiting, and diarrhea), and the receiving IM injections in the anterior-lateral thigh than
cardiovascular system (tachycardia, hypotension, and those receiving subcutaneous injections or IM injections
shock). The latter may lead to cardiovascular collapse in the deltoid.19,20
and death. Airway edema and/or bronchospasm may IV administration of epinephrine may be considered as
lead to inability to ventilate, hypoxia, and hypercarbia well by experienced providers, and may be preferred for
with subsequent cardiovascular collapse as well. In the patients with severe hypotension or severe broncho-
dental perioperative setting, patients are sedated, spasm needing immediate treatment or unresponsive to
draped, and usually fully clothed concealing early IM epinephrine doses and fluid resuscitation. IV epi-
cutaneous signs. Thus, the earliest recognizable signs nephrine is preferred for cardiac arrest. In likely
may be ventilation impairment, overt bronchoconstric- anaphylaxis, IV epinephrine should be administered at
tion, and/or cardiovascular collapse. Signs and symp- 10–25 mcg bolus doses initially as needed for hypoten-
toms in the awake versus anesthetized patient are sion or bronchospasm, with gradually escalating doses as
displayed in Table 3. required. Initial treatment with 0.1–0.5 mg epinephrine
doses is practical in the presence of cardiovascular
collapse.18 In some instances, continuous low-dose
MANAGEMENT OF ANAPHYLAXIS epinephrine infusions may be appropriate to avoid lethal
arrhythmias associated with large boluses.
The treatment of anaphylaxis begins similarly to any
emergent condition with assessment, maintenance of
airway, breathing, and circulation followed by definitive Airway Management
treatment.18 Specific management of intraoperative
anaphylaxis consists of withdrawal of the offending agent, Edema of the airway is an immediate concern of the
if known, interrupting the effects of preformed mediators anesthesiologist. If the patient is not intubated for the
and blocking further mediator release. Early recognition surgical procedure, endotracheal intubation is indicated
164 Benzodiazepine Allergy Anesth Prog 63:160–167 2016

and should be accomplished sooner rather than later, Services (EMS-911) is important. The patient will need
unless the reaction is confirmed as mild and not to be transferred to the emergency department and,
progressing. It should be realized that tissue edema is especially if intubated, require intensive care unit (ICU)
not reversed by epinephrine and progressive airway admission. Transfer to the ICU is likely for in-hospital
edema may make intubation difficult or impossible. surgery.
Therefore, depending on patient presentation, endotra-
cheal intubation and epinephrine administration may
both be primary life-saving treatments. DIAGNOSIS AND TESTING

The initial diagnosis of anaphylaxis relies on thorough

Adjunctive Management
history and physical examination. Assessment of clinical
history assists with identification of increased risk factors
One-hundred percent oxygen should be administered to
such as symptoms of allergic reaction in previous
correct hypoxia, and Trendelenburg positioning of the
anesthetics, diagnosed allergy to drugs likely to be used
patient may help to increase stroke volume and cardiac
in anesthetic regimen, repeated exposure to latex, and/
output by shifting fluids centrally. Volatile agents and
or allergic manifestations following ingestion of foods
propofol should be discontinued in the setting of hemody-
with high frequency of cross-reactivity to latex.24
namic collapse. Additionally, aggressive fluid resuscitation
of up to 30 mL/kg in the first hour may compensate for Retrospective diagnosis is based on both in vivo and in
peripheral vasodilation and fluid extravasation and help to vitro biochemical tests.
manage persistent hypotension.2,18 Further treatment has
been explored with use of other vasopressors and IV
glucagon; however, neither mechanism has been proven In Vivo Biochemical Tests
in the context of systemic anaphylaxis. For example,
vasopressin is able to enhance endogenous catechol- Plasma histamine is an inflammatory mediator stored in
amine-induced vasoconstriction in cases of resistance to mast cells and basophils, which peaks immediately upon
the catecholamine vasopressor effect. Vasopressin inhibits anaphylactic reaction, while serum tryptase is a mast cell
inducible nitric oxide synthase, which is a major contrib- protease, which increases to levels above 25 mcg/L
utor to vasodilatation and resistance to catecholamine- within 2 hours of suspected anaphylaxis suggesting IgE
induced vasoconstriction.21,22 mediated mechanism.24 Histamine and tryptase concen-
Glucagon has been reported to be effective in trations typically correlate with severity of clinical
improving the airway complications of anaphylaxis in reactions and are increased in anaphylaxis. However,
patients on beta-blockers who are resistant to epineph- distinguishing between anaphylactic and anaphylactoid
rine. It acts to increase cyclic-adenosine monophosphate reactions solely with serum tryptase levels remains
levels, which in turn relaxes smooth muscle in the airway. controversial, necessitating additional methods of verifi-
Glucagon also has positive inotropic and chronotropic cation.2
effects on the heart.23 Dermal Tests. Skin testing remains the standard in
Following initial management as noted above, antihis-
determining the pathophysiologic mechanism of clinical
tamines (H1 and H2 antagonists) may be considered for
anaphylaxis, identifying the agent, assessing drug-related
symptomatic treatment of urticaria, angioedema, and
cross-reactivity, and exploring alternative drugs for
pruritus. Studies indicate treatment with diphenhydramine
further procedures.25 However, routine skin testing of
(1 mg/kg up to 50 mg) used in combination with
all patients undergoing anesthesia is not recommended
ranitidine (1 mg/kg up to 50 mg) or famotidine (0.5
in the absence of prior history due to potential subclinical
mg/kg up to 20 mg slowly) is more effective than
IgE sensitization.26,27 Also, testing is not without
treatment with H1-antagonists alone. In addition, high
consequences and should not be performed within 6
doses of corticosteroids such as hydrocortisone (2–5 mg/
kg up to 250 mg) may treat symptoms of anaphylaxis by weeks of expected exposure to anaphylaxis triggering
decreasing airway swelling but its effectiveness is delayed. agents due to possible mast cell and basophil mediator
depletion. Furthermore, in the general population, 9.3%
have a positive skin test for specific IgE quaternary
Definitive Treatment ammonium ions as in neuromuscular blockers even in
the absence of clinical symptoms.2 Also, although the
If surgery is rendered in the office or ambulatory surgery risk of eliciting anaphylaxis with skin testing is minimal
center setting, early activation of Emergency Medical (,0.1% for antibiotics), the presence of trained person-
Anesth Prog 63:160–167 2016 Haybarger et al. 165

nel with resuscitation equipment should be readily Table 4. Indications for In Vitro Versus Skin Prick Testing
available. 1. Patients with extensive skin disease with no suitable site
There are two commonly utilized skin tests for allergy for testing
identification. The skin prick technique triggers superfi- 2. Dermatographism where wheals are produced by any
cial dermal mast cells and nonspecific irritation is its main minor trauma
limitation. A positive test has a high predictive value in 3. Current administration of antihistamines
4. Risk of severe anaphylaxis
the patient with a history of anaphylaxis; however, the 5. Confirmation of an unexpectedly negative skin prick test
polypharmacy of the typical anesthetic has many 6. Lack of availability of an allergist or appropriately trained
potential offending agents.2 A graded challenge is clinician
required in certain cases including local anesthetics, in
which skin prick tests are usually negative.28 Intradermal
determined to be as effective as midazolam for preop-
allergy testing involves injection of small amounts of
erative anxiolysis.
suspected allergens under the surface of the skin.
Pharmacological alternatives to benzodiazepines are
Similarly to the skin prick test, patients are examined
also available. Preanesthetic intranasal administration of
after 15–20 minutes for a reaction at injection site.
the alpha-2 agonist, dexmedetomidine, has shown
Regardless of results, testing should be verified with
similar levels of anxiety relief and sedation as midazo-
clinical symptoms for diagnosis of anaphylaxis.
lam.31 In some instances, children receiving dexmede-
tomidine have also demonstrated less perioperative
stimulation and less postoperative pain. Another study
In Vitro Biochemical Tests exploring dexmedetomidine administration versus mid-
azolam in patients undergoing flexible bronchoscopy
Serum IgE measurements specific to some allergy demonstrated superior patient comfort and tolerance in
inducing agents have been used to confirm anaphylaxis. the group receiving the alpha-2 agonist.32 Oral alpha-2
In vitro immunoassays through radioallergosorbent tests agonists, such as clonidine, as well as sedating antihis-
(RASTs) are commercially available for agents such as tamines such as hydroxyzine could also be considered.
neuromuscular blockers, beta-lactam antibiotics, mor- IM ketamine is a common agent used in office-based
phine, chlorhexidine, protamine, and latex among dental anesthesia as well.
others.16,25 While there are indications for which in In adults, oral alpha-2 agonists such as clonidine or
vitro testing may be indicated (Table 4), many in vitro tizanidine can also be considered. Alternatively, after IV
tests are arguably less sensitive and specific when access, propofol or barbiturates could be considered for
compared to skin testing and not as readily available. sedation. For the needle phobic adult, sevoflurane mask
As mentioned previously, biochemical test results should induction can be considered.
always be correlated with clinical history. An older, now rarely used anticholinergic agent,
scopolamine, has been employed to provide some
degree of sedation and amnesia when administered
ALTERNATIVES TO BENZODIAZEPINES intravenously. As a tertiary amine that has the ability to
cross the blood-brain barrier, scopolamine offers amnes-
Benzodiazepines are most commonly utilized in anes- tic, anticholinergic, and antiemetic properties that may
thesia as anxiolytic premedication. Goals of preoperative have utility in dental and oral surgical procedures.
administration include sedation anxiolysis, amnesia, In choosing any anesthetic agent, providers should
improved patient cooperation, and improved patient consider goals of administration in the setting of risks and
satisfaction.29 However, when administering benzodiaz- benefits.
epines to potentially allergic individuals, alternatives
should be considered.
In the pediatric population, behavioral modalities have CONCLUSION
shown some anxiolytic efficacy including use of music
specialists, communication styles, and trained distraction Benzodiazepine hypersensitivity is difficult to assess in
tactics.30 Evidence has even shown that teaching families the typical polypharmacy anesthetic because the cause
to expose their child to facemask and distract them on and classification of reactions are not always apparent.
day of surgery may produce better anxiety control than The multitude of potential offending agents complicates
parental presence or midazolam. Interestingly, in 2013, follow-up testing and interpretation of results. The
Kerimoglu et al30 published a study of nearly 100 elevated serum tryptase levels noted in some reports
children, in which the use of video glasses was support evidence of allergic reaction, but do not
166 Benzodiazepine Allergy Anesth Prog 63:160–167 2016

differentiate between anaphylactic and anaphylactoid Anesthesia and Co-existing Disease. Philadelphia, PA:
reactions, or establish the causative drug(s). Churchill Livingstone/Elsevier; 2008:526–528.
The current literature on benzodiazepine allergy 17. Nitti JT, Nitti GJ. Anesthetic complications. In: Morgan
remains inconclusive and consists primarily of sparse EG, Mikhail MS, Murray MJ, eds. Clinical Anesthesiology. 5th
ed. New York, NY: Lange Medical/McGraw Hill Medical Pub;
case reports of suspected reactions, typically involving
2006:973.
multiple drug administration, without definitive follow-up 18. Sampson HA, Muñoz-Furlong A, Campbell RL, et al.
allergy testing to determine the true causative agent. Second Symposium on the Definition and Management of
Challenge testing remains the gold standard for diagnosis, Anaphylaxis: Summary Report—Second National Institute of
but given the potentially severe manifestation of allergic Allergy and Infectious Disease/Food Allergy and Anaphylaxis
reaction, it is not routinely pursued. Ultimately, thorough Network Symposium. Ann Emerg Med. 2006;47:373–380.
assessment of clinical history along with identification of 19. Simons FE, Roberts JR, Gu X, et al. Epinephrine
early signs and symptoms in the perioperative period are absorption in children with a history of anaphylaxis. J Allergy
important for managing anaphylactic/anaphylactoid Clin Immunol. 1998;101:33–37.
reactions from benzodiazepine administration. 20. Simons FE, Gu X, Simons KJ. Epinephrine absorption
in adults: intramuscular versus subcutaneous injection. J
Allergy Clin Immunol. 2001;108:871–873.
21. Wakatsuki T, Nakaya Y, Inoue I. Vasopressin modulates
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Anesth Prog 63:160–167 2016 Haybarger et al. 167

CONTINUING EDUCATION QUESTIONS

This continuing education (CE) program is designed for dentists who desire to advance their understanding of pain and
anxiety control in clinical practice. After reading the designated article, the participant should be able to evaluate and
utilize the information appropriately in providing patient care.

The American Dental Society of Anesthesiology (ADSA) is accredited by the American Dental Association and
Academy of General Dentistry to sponsor CE for dentists and will award CE credit for each article completed. You must
answer 3 of the 4 questions correctly to receive credit.

Submit your answers online at www.adsahome.org. Click on ‘‘On Demand CE.’’

CE questions must be completed within 3 months and prior to the next issue.

1. Which of the following is the drug of choice for 3. Clinical manifestations of anaphylactoid reactions are
treatment of anaphylaxis? often indistinguishable from anaphylaxis.
A. Albuterol A. True
B. Epinephrine B. False
C. Hydrocortisone
D. IV crystalloid

2. What are the 3 most common causative agents of 4. Anaphylaxis is what type of immune mediated
anaphylaxis during the perioperative period? allergic reaction based on Gell and Coombs classifi-
cation?
A. Latex, colloids, and antibiotics
B. Propofol, benzodiazepines, and opioids A. Type I: Immunoglobulin IgE mediated hypersen-
C. Neuromuscular blocking drugs, latex, and antibi- sitivity reaction
otics B. Type II: IgG, IgM, and complement mediated
D. Local anesthetics, barbiturates, and volatile cytotoxicity
agents C. Type III: Immune-complex formation and deposi-
tion leading to tissue damage
D. Type IV: T-lymphocyte cell-mediated delayed
hypersensitivity reaction