Supplementary Material - Journal of Allergy and Clinical

Difficult Cases: Perioperative
Joel M. Hartman, MD
Phillip L. Lieberman, MD FAAAAI
Presented February 28th, 2014 AAAAI Annual Meeting
San Diego, CA
• Appreciate common medications associated
with perioperative anaphylaxis and the
complexity of available testing
• Appreciate an uncommon cause of
perioperative anaphylaxis
Case 1
Park YC et al
– 34 year old female, 55 kg
– Scheduled to have elective endovenous laser
surgery and varicosectomy
– No underlying medical disorder
– No past surgeries
– Preoperative evaluation unremarkable including
exam, 12 lead ECG, Chest X-ray, Complete blood
Case 1
– 30 minutes prior to the Operating Room (OR) she
received 2 mg midazolam and 0.2 mg
glycopyrolate intramuscular
– In the OR, pre-anaesthetic vitals:
• Blood Pressure 110/70 mmHg
• Heart Rate 75 bpm
• Pulse oximetry 99%
Case 1
Induction Anesthesia Administered:
– 110 mg propofol mixed with 2% lidocaine injected
– Loss of consciousness verified and patient
ventilated using a mask with 3L/min O2, nitro
oxide 3L/min and sevoflurane 3 vol%
– Endotracheal intubation occurred 1 to 2 minutes
after 40 mg rocuronium provided
Case 1
Intraoperative Course
– 3 minutes after intubation HR and BP were
135/min and 75/35 mmHg, respectively
– Anesthetic agent discontinued (vitals suspected to
be related to inhalation anesthetic)
– HR increased and BP decreased to 60/30 mmHg
– Slight flushing of face and chest
– Angioedema around eyes
Recognize Perioperative Anaphylaxis
• Prompt recognition may be challenging:
– Side effects from anesthetic agents may mask or
simulate findings
– Verbal communication by the patient is limited
– Visual inspection may be compromised by sterile
• Skin manifestations are less common
compared to other causes of anaphylaxis
Case 1
Intraoperative Course
– Patient developed generalized urticaria with
elevated end tidal CO2 consistent with obstructive
– Oxygen was increased to 6L/min, crystalloid and
colloid provided, ephedrine 4 mg was
– Improvement in BP and HR to 110/65 mmHg and
100 bpm, respectively
– The urticaria, flushing and angioedema progressed
Question #1
At this point her physicians are concerned
about an allergic reaction. Which of the
following labs might be helpful?
A.) Serum Tryptase
B.) Urine metanephrines
C.) Serum glucose
D.) Cardiac Biomarkers
ANSWER on next slide
Answer: Serum Tryptase
• Can be detected as soon as 30 minutes but
recommended 60-120 minutes after symptom
• Serum tryptase is increased in 68% of IgEdependent perianesthetic anaphylaxis
• Approx 4% of non-IgE reactions are associated
with increased serum tryptase
• False negatives levels may be seen in basophil
mediated reactions
• False positive levels may be seen in hypoxia and
major trauma
Ebo DG et al. Allergy 2007
Laroche D et al. Anesthesiology 1991
Mertes PM et al. J Investig Allergol Clin Immunol 2011
Case 1
Intraoperative Course
– Patient was given hydrocortisone 250 mg,
pipirinhydrinate 3 mg intravenously followed by
midazolam 3 mg to prevent emergence
– Vitals stabilized within 20 minutes and
urticaria/angioedema resolved within 40 minutes
– Physicians, in discussion with family, decided to
proceed with the planned procedure
– A serum tryptase was sent
Question #2
Which of the following agents is most likely
responsible for our patient’s symptoms?
A.) Propofol
B.) Midazolam
C.) Rocuronium
D.) Latex
ANSWER on next slide
Perioperative Anaphylaxis:
Answer: Rocuronium
• Anaphylaxis is more common with general
anesthesia compared to local or spinal
• Most common overall cause: Neuromuscular
Blocking Agents (NMBA)
– 3 most common causative agents in both adults and
children include NMBA, antibiotics, latex
• Prevalence varies with geographic area:
– Antibiotics likely more common in U.S. (approx 50% of
– Neuromuscular blocking agents are the most common
cause in Europe (approx 70% of cases)
Harboe T et al. Anesthesiology 2005
Simmons FE et al. Curr Opin Allergy Clin Immunol 2012.
Gurrieri C et al. Anesth Analg 2011
Suspected Agents:
Timing of symptoms is important
Symptoms within First 30 Minutes of Anesthesia
– Antibiotics
– Neuromuscular blocking agents
– Hypnotic inducing agents
Symptoms After 30 Minutes of Anesthesia
Supravital dyes (ex. Isosulfan blue)
Plasma expanders
Blood products
Laxenaire MC. Ann Fr Anesth Reanim 1999
Case 1
Intra- and Postoperative
– No additional muscle relaxants during the
remaining 2 hour procedure
– Operation completed without further
– Successfully extubated with normal recovery in
the post-anesthesia care unit
– serum tryptase was elevated at 42
Question #3
Which of the following is an appropriate next
step in the diagnosis of this patient?
A.) Skin testing to agents used during the case
B.) Bone marrow biopsy
C.) Office based open challenge to rocuronium
D.) Perform a methacholine challenge
ANSWER on next slide
Answer: Skin testing to agents used
• Few culprit drugs have reliable or standardized
testing available
• 72% of perioperative anaphylaxis is due to
specific IgE
– Understanding underlying mechanisms helps with
choosing appropriate testing
Mertes PM et al. J Investig Allergol Immunol 2005
Mertes PM et al. J Allergy Clin Immunol 2011
Testing: Understanding Mechanisms
Proposed Mechanism
Direct Mast Cell/Basophil
Ig-E Mediated
Immunologic Non-IgE due
to immune complexes
Example Agent
Radiocontrast agents
● Opioids
● Some neuromuscular
blocking agents
● Antibiotics
● Latex
● Neuromuscular blocking
● Blood transfusion
Agents with Probable IgE Mediated
Neuromuscular Blocking Agents
Blood transfusions containing IgA in IgA deficient subjects
Isosulfan blue (sentinel node dissection)
• In vitro testing for allergen-specific IgE is
reported for latex, succinylcholine, thiopental and
– In vitro testing is generally less sensitive compared to
skin testing
• Skin testing can be performed for agents
commonly associated with IgE-mediated
– Commercial preparations for latex are not available
Ebo et al. Allergy 2007
Suggested skin testing concentrations
Skin Prick Tests
Intradermal Tests
Adapted from PM Mertes et al. J Investig Allergol Clinic Immunol 2011.
Why Some Agents Need Dilution? (next slide)
Some Agents Require Dilution
• Some agents, such as succinylcholine,
atracurium, and mevacurium, may cause
direct mast cell degranulation
– Must dilute such agents for initial prick
• May start with concentrate with other agents
Caveat: “Perfect” skin testing
concentrations not known
• Additional references for suggested testing
concentrations are available
• Appendix WEB Supplement. Mayo Clinic Allergy
Division protocol for assessment of
Screening Testing
• Screening subjects without a prior history of
allergic drug reaction is not recommended
– Data suggests a discrepancy between skin prick
test results and clinical outcomes
– One study screening anesthesia-naïve subjects
reports that 9.3% had either a positive test to one
or more NMBAs or the presence of specific IgE to
quaternary ammonium ions
Lexenaire MC et al. Ann Fr Anesth Reanim 2002
Porri F et al. Clin Exp Allergy 1999.
Back to Case 1
Postoperative Testing performed several
weeks later
– Rocuronium showed positivity at 1/100 dilution
with intradermal testing
– All other agents used during surgery were tested
and negative
– Serum tryptase was normal
Case 1
Postoperative Testing
– Vecuronium was tested and also positive at 1/100
dilution with intradermal testing
Question #4
Which of the following statements regarding
neuromuscular blocking agents is correct?
A.) Skin testing is recommended for preanesthesia
screening of subjects without a history of anaphylaxis.
B.) The adamantium core is responsible for crossreactivity among neuromuscular blocking agents.
C.) Neuromuscular blocking agents cause only IgEdependent reactions.
D.) Neuromuscular blocking agent reactions are more
common in women.
Answer on next slide
Neuromuscular blocking agents
Answer: Reactions are more common
in women
• Agents are responsible for both IgEdependent and IgE-independent reactions
– Direct histamine release from mast cells and
basophils is implicated
• 3 out of 4 reactions occur in women
– Suggesting cross-reactions with ammonium
compounds in make-up and personal care
Baldo BA et al. Ann Fr Anesth Reanim 1993
Birnbaum J et al. Clin Exp Allergy 1994
Neuromuscular blocking agents:
Cross Reactivity
• The tertiary or quaternary ammonium
structure likely responsible for cross reactivity
– Estimated 65% by skin tests
– 80% by radioimmuno assay inhibition
• Patterns of cross-reactivity vary between
– Most consistent between vecuronium and
Ebo et al. Allergy 2007
Leynadier F et al. Br J Anesth 1987
Cross reactivity and testing
(next slide)
Variable Pattern of Cross Reactivity
• Given the variable pattern of cross reactivity it is
advised to:
– Perform testing to suspect agent
– Perform testing to any agent that may be used in
future planned procedures
• General agreement that succinylcholine carries
the highest risk for anaphylaxis
• Diagnostic management of anaphylaxis from
NMBA rests upon an evocative history
corroborated by appropriate skin tests
Ebo et al. Allergy 2007
Case 1
– Rocuronium was identified as the causative agent
for this patient’s anaphylaxis
– Patient and family also informed about positive
result to vecuronium
– Recommend avoiding both rocuronium and
vecuronium, AND testing to potential
neuromuscular agents prior to future planned
Risk Mitigation
• Primary Prevention
– Screening subjects without a prior history of
allergic drug reactions is not recommended
• Secondary Prevention
– Accurate documentation of prior reactions
– Make every effort to identify the responsible
– Avoid the culprit drug
Next Case…
Case 2
– A 52 year-old male seen in the office as a new
patient for consultation for ‘shock’ occurring
during lumbar laminectomy 2 years ago
– He now has spinal stenosis and requires semielective laminectomy with spinal fusion
Case 2
• Past History
– Status post tonsillectomy and adenoidectomy at age 3
years (reportedly uneventful)
– Hospitalized for dehydration with gastroenteritis at
age 13 years
– Takes omeprazole for gastroesophageal reflux
– Carries an epipen due to several allergic reactions
from bee stings
• Physical exam, including vitals, all normal
Case 2
• Review of Anesthesia Records
– Prior to entering the Operating Room, he was
given intravenous Rocephin and Versed
– In the OR he was given succinylcholine
– Within 30 minutes he developed profound
hypotension requiring intravenous epinephrine
and fluid replacement
Case 2
• Skin testing was performed to each agent
used during his procedure and these were all
• A baseline serum tryptase was sent:
18 ng/mL
Question # 5
Based on these results what would you
advise the patient?
A.) No further work-up is indicated and he may
proceed with planned surgery.
B.) Mastocytosis is unlikely.
C.) Further work-up for mastocytosis is
Answer on next slide
Answer: Further Evaluation
Threshold for further Work-up
• Baseline total serum tryptase levels greater than
20 ng/mL are highly suggestive of systemic
• One study evaluating the incidence of mast cell
disorders in subjects with systemic reactions to
Hymenoptera stings shows higher frequency of
systemic mastocytosis diagnosis when a baseline
serum tryptase cut off of 11.4 ng/mL was used
• Given the clinical history in our patient, proceeding with
further work-up for clonal mast cell disease would be
indicated despite baseline serum tryptase less than 20
Valent P et al. Int Arch Allergy Immunol 2012.
Bonadonna et al J Allergy Clin Immunol 2009.
Case 2:
816V Analysis
• 816V mutational blood analysis showed a ckit 816V mutation
– Can be performed on peripheral white blood cells,
bone marrow or cells from skin or other organs
– Bone marrow yields most sensitive results
Sporadic vs. Familial occurrence of Mastocytosis (next slide)
816V KIT Mutation in a Case of
Familial Mastocytosis
• Most clustered cases of mastocytosis are
pediatric, without KIT mutations
• May also present with uncommon KIT lesions
• Generally accepted that adult patients with
sporadic mastocytosis express activating
mutations in D816V
• A recent case was reported describing familial
systemic mastocytosis in two adults, a mother
and her son, both carrying the D816V mutation
Zanotti R et al. J Allergy Clin Immunol 2013.
Case 2:
Bone Marrow Biopsy was Performed
• Bone marrow sampling revealed the
– Multifocal aggregates of spindle-shaped mast cells
with 15 mast cells per aggregate
– Mutational analysis revealed presence of 816V KIT
Question # 6
In a patient with mastocytosis which of the
following statements is correct?
A.) Increasing serum tryptase levels are not
associated with an increased risk for anaphylaxis.
B.) Minor procedures such as endoscopy are not
associated with an increased risk for anaphylaxis.
C.) Inhalation agents are generally preferred during
Answer on next slide
C.) Inhalation agents are generally
preferred during surgery.
Mastocytosis and Surgery
• Patients with mastocytosis are at increased
risk for adverse events
• The stress of surgery and perioperative
medications are potentially fatal triggers
• Shock has been reported in minor procedures
such as upper endoscopy
Schwab et al Gastrointest Endosc 1999.
Serum Tryptase and Anaphylaxis
• Baseline serum tryptase levels are higher in
mastocytosis subjects with anaphylaxis
compared to those without anaphylaxis
Brockow et al Allergy 2008.
Medication use in Mastocytosis
• Medications may cause mast cell activation in subjects
with either cutaneous or systemic mastocytosis
– Specific medications may have varying effect on histamine
– Dermal mast cells express opioid receptors that stimulate
mediator release without specific IgE.
• Generally recommended to avoid higher risk
• Volatile (inhalation) anesthetics are generally safe
– Inhalation agents generally do not cause histamine
Ochoa Chaar C. The American
Surgeon 2009
List of Medications and Risk
(next slide)
Higher Risk Meds
Muscle Relaxants
Local Anesthetics
Konrad FM Acta Anesthesiol Scand 2009.
Lower Risk Meds
Muscle Relaxants
Local Anesthetics
Konrad FM Acta Anesthesiol Scand 2009.
Ochoa Chaar C. The American Surgeon 2009.
Bains S. Ann Allergy Asthma Immunol 2010.
Question # 7
Which of the following has been shown to
improve safety in subjects with mastocytosis
undergoing surgery?
A.) Using NSAIDs as premedication prior to
B.) Preoperative skin testing.
C.) Preoperative exercise echocardiogram.
D.) Administration of H1 and H2 blockers 30
minutes prior to surgery.
Answer on next slide
Data is Case-based
• Combination of H1, H2 blockers and steroids
have been shown to be successful
– Provided 30 minutes prior to surgery
• Anxiolytics have also been used with success
• There are varying reports with preoperative
skin testing
Possible Management
Strategies (next slide)
Ochoa Chaar C. et al The American Surgeon 2009.
Potential Recommendations
Recommended one hour prior to procedure
Diphenhydramine 25 to 50 mg orally or IV
Ranitidine 150 mg orally, or 50 mg IV
Optional one hour prior to procedure
Anxiolytic to minimize stress and emotional factors
Montelukast 10 mg orally
Prednisone 25 to 50 mg orally, 12 hours and 2 hours prior to procedure (or equivalent
of other systemic steroid)
Comment on Preoperative NSAID Use (next slide)
Adapted from Ochoa Chaar C. et al The American Surgeon 2009.
Non-Steroidal Anti-inflammatory
(NSAID) Agents Prior to Surgery
• Prostaglandin D2 levels shown to be increased
in patients with systemic mastocytosis
• Few reports exist using aspirin or NSAIDs for
pre-treatment to prevent formation of
prostaglandin D2
– Use of NSAIDs can be considered though data for
preoperative use is limited and there may be an
increased bleeding risk
Roberts LJ et al. N Engl J Med 1980.
Potential Recommendations in our
Patient Case
• Avoid high risk meds if possible
– Advise use of inhalation agents
• Continue combination H1 and H2 blockers
until after patient is fully recovered
• Close monitoring throughout the
perioperative period, including until after
patient has fully recovered
Laroche D, Vergnaud MC, Sillard B, et al. Biochemical markers of anaphylactoid reactions to
drugs. Comparison of plasma histamine and tryptase. Anesthesiology 1991; 75:945-49.
Mertes PM, Malinovsky JM, Jouffroy L, et al. Reducing the risk of anaphylaxis during
anesthesia: 2011 updated guidelines for clinical practice. J Investig Allergol Clin Immunol
2011; 21:442.
Harboe T, Guttormsen AB, Irgens A, et al. Anaphylaxis during anesthesia in Norway: a 6-year
single-center follow up study. Anesthesiology 2005; 102:897.
Simmons FE, Ardusso LR, Bilo MB, Dimov V, Ebisawa M, El-Gamal YM, Ledford DK, Lockey RF,
Ring J, Sanchez-Borges M, Senna GE, Sheikh A, Thong BY, Worm M. World Allergy
Organization. 2012 Update: World Allergy Organization Guidelines for the assessment and
management of anaphylaxis. Curr Opin Allergy Clin Immunol 2012; 12(4):389-399.
GurrieriC, Weingarten TN, Martin DP, et al. Allergic reactions during anesthesia at a large
United States referral center, Anesth Analg 2011; 113:1202.
Laxenaire MC. Epidemiology of anesthetic anaphylactoid reactions. Fourth multicenter survey
(July 1994-December 1996). Ann Fr Anesth Reanim 1999; 18:796.
Mertes PM, Laxenaire MC, Lienhart A et al. Reducing the risk of anaphylaxis during
anaesthesia: guidelines for clinical practice. J Investig Allergol Clin Immunol 2005; 15:91.
Mertes PM, Malinovsky JM, Jouffroy L, and the Working Group of the SFAR and SFA and
Aberer W, Tereehorst I, Brockow K, Demoly P for EDNA and the EAACI Interest Group on Drug
Allergy. Reducing the risk for anaphylaxis during anesthesia: 2011 updated guidelines for
clinical practice. J Investig Allergol Clin Immunol 2011; 21(6): 442-453.
Lexenaire MC. Management of the anesthetic allergic patient. Ann Fr Anesth Reanim 2002;
Porri F, Lemiere C, Birnbaum J et al. Prevalence of muscle relaxant sensitivity in a general
population: implications for a preoperative screening. Clin Exp Allergy 1999; 29:72-75.
Baldo BA, Fisher MM. Mechanisms in IgE-dependent anaphylaxis to anesthetic drugs. Ann Fr
Anesth Reanim 1993; 12:131.
Birnbaum J, Porri F, Pradal M, et al. Allergy during anesthesia. Clin Exp Allergy 1994; 24:915.
Ebo DG, Fisher MM, Hagendorens MM, et al. Anaphylaxis during anesthesia: diagnositc
approach. Allergy 2007; 62:471-487
Leynadier F, Sansarricq M, Didier JM, et al. Prick tests in the diagnosis of anaphylaxis to
general anesthetics. Br J Anesth 1987; 59:683-9.
Mertes PM, Alla F, Trechot P, et al. Anaphylaxis during anesthesia in France: An 8 year
national survey. J Allergy Clin Immunol 2011; 128(2): 366-73
Brockow K, Jofer C, Behrendt H, et al. Anaphylaxis in patients with mastocytosis: a study on
history, clinical features and risk factors in 120 patient. Allergy 2008; 63:226-32.
Valent P, Akin C, Arock M, Brockow K, Butterfield JH, Carter MC, Castells M, Esribano L,
Hartmann K, Lieberman P, Nedoszytko B, Orfao A, Schwartz LB, Sotlar K, Sperr WR, Triggiani
M, Valenta R, Horny H, Metcalfe D. Definitions, Criteria and Global Classification of Mast Cell
Disorders with Special Reference to Mast Cell Activation Syndromes: A consensus Proposal.
Int Arch Allergy Immunol 2012; 157:215-225.
Bonadonna P, Perbellini O, Passalacqua G, et al. Clonal mast cell disorders in patients with
systemic reactions to Hymenoptera stings and increased serum tryptase levels. J Allergy Clin
Immunol 2009; 123:680-6.
Zanotti R, Simioni L, Garcia-Montero AC, Perbellini O, Caruso B, Jara-Acevedo, Bonaficio M,
Matteis G. Somatic D816V KIT mutation in a case of adult-onset familial mastocytosis. J
Allergy Clin Immunol 2013; 131(2):605-607.
• Akin C, Valent P, Metcalfe D. Mast cell activation syndrome: Proposed
diagnostic criteria. J Allergy Clin Immunol 2010; 126:1099-104.
• Schwab D, Raithel M, Ell C, et al. Severe shock during GI endoscopy in a
patient with systemic mastocytosis. Gastrointest Endosc 1999; 50:264-7.
• Bains SN, Hseih FH. Current approaches to the diagnosis and treatment of
systemic mastocytosis. Ann Allergy Asthma Immunol 2010; 104:1-10.
• Ochoa Chaar C, Bell RL, Duffy TP, et al. Guidelines for safe surgery in
patients with systemic mastocytosis. The American Surgeon 2009; 75:7480.
• Konrad FM, Schroeder TH. Anaesthesia in patients with mastocytosis. Acta
Anaesthesiol Scand 2009; 53(2):270-1.
• Roberts LJ, Sweetman BJ, Lewis RA, Austen KF, Oates JF. Increased
production of prostaglandin D2 in patients with systemic mastocytosis. N
Engl J Med 1980; 303:1400-1404.