Anaphylaxis in the Operating Room 

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Anaphylactic reactions in the operating room (OR) present unique diagnostic concerns. In this setting, signs and symptoms that alert the provider to a potential problem and that are apparent under other circumstances are often missing, as a consequence of the absence of an alert and communicative patient. ^{[1, 2, 3]}  Surgical drapes obscure any visible signs, making bronchospasm and cardiovascular compromise the first indicators likely to be noted. ^{[1, 2, 3]}  The use of multiple potential allergens in an abbreviated period of time further complicates the diagnostic process. ^[3]  

Although these reactions are rare, the anesthesia provider must nevertheless be well prepared for them, and the best defense is a good offense. ^{[1, 2, 3]}  A thorough patient history is required. In the OR, the ready availability of supplemental oxygen and emergency drugs is obligatory. For the intubated patient, as in all cases, the recommended alarms on the anesthesia machine should be set. Once it has been determined that the patient is having an anaphylactic reaction, there are several critical steps that must be taken, many of which can occur simultaneously.

Anaphylaxis is defined as an acute life-threatening systemic event triggered by the sudden release of mediators from basophils and mast cells after exposure to a triggering agent. ^{[1, 2, 3, 4, 5, 6, 7]}  The pathway typically begins with the initial exposure to an agent and the production of immunoglobulin E (IgE) antibodies that then bind to mast cells and basophils. ^{[1, 2, 4, 5, 8, 6]}  Upon reexposure to that agent or another with a related structure, the allergen forms crosslinks with the preexisting IgE antibodies, and this process culminates in the degranulation of mast cells and basophils and the manufacture of immune mediators. ^{[1, 2, 7]}

The mediators released are numerous and include tryptase, kinins, leukotrienes, prostaglandin D2, platelet-activating factor (PAF), and histamine. ^{[1, 2, 3]}  Histamine is presumed to be the primary mediator of the anaphylactic reaction. However, prostaglandin D2, leukotrienes, and PAF, along with other mediators, contribute to bronchoconstriction and myocardial insufficiency. ^[3]

Within the OR, anaphylactic reactions have a reported incidence of 1 in 4000 to 1 in 25,000 and have a 3-10% mortality. ^{[1, 2, 3, 5, 9, 10, 11]}  Bronchospasm is the most common presenting sign in patients under general anesthesia (78.3%). ^[1]  Other signs and symptoms of anaphylaxis in the OR for patients under general anesthesia include hypotension (63.9%), urticaria (54.2%), desaturation (49.4%), angioedema (16.9%) and cardiovascular collapse (6%). ^{[1, 4, 5]}  Patients undergoing neuraxial or regional anesthesia may present with other signs and symptoms (eg, pruritus or dyspnea), depending on their level of sedation.

Patients with a history of allergies and atopy are more likely to undergo an anaphylactic reaction. ^{[3, 12, 9]}  Moreover, the medical history often impacts the clinical presentation during anaphylaxis. ^[3]  For example, a patient with a history of congestive heart failure is more likely to experience cardiovascular collapse, and a patient with a history of smoking tobacco is more likely to experience bronchospasm. ^[3]

The clinical presentation of anaphylaxis in the OR is varied, ranging from mild to severe respiratory compromise and including cardiac arrest. ^[9]  Rapid diagnosis of the event is critical for achieving a positive patient outcome. ^{[4, 11]}  Ring and Messmer described the following four-grade scale, which may be used to classify intraoperative anaphylactic events:

Approximately 80% of anaphylactic reactions are grade 2 or 3. ^[8]  The speed with which the reaction occurs is often proportional to the severity of the event. ^{[1, 6]}  It may also reflect the mode of transmission of the allergen, with reactions to parenterally delivered agents presenting more rapidly than those to allergens delivered via the mucosa or skin. ^{[1, 9]}

Neuromuscular blockers

The most common cause of anaphylaxis in the OR is the neuromuscular blocking agent, which has been cited as causative in 50-70% of cases. ^{[1, 2, 3, 12, 4, 5, 10, 7, 11]}  Clinical presentation is often within minutes of induction or other use of the agent. ^[4]  The mediators of the allergic reaction are IgE antibodies to the tertiary or quaternary ammonium groups to which patients become exposed through prior surgical procedures, other drugs, foods, or household items. ^{[1, 9]}

In one retrospective analysis of the incidence of intraoperative anaphylaxis attributed to neuromuscular blockers over a 10-year period, rocuronium was identified as having the highest rate of causing anaphylaxis ^{[13, 4]} : It was identified by postreaction skin testing as being responsible for 71% of the cases of anaphylaxis, whereas vecuronium and atracurium caused 14% and 11%, respectively. ^{[13, 15, 8, 9]}  No cases of anaphylaxis were positively attributed to cisatracurium or pancuronium, probably because these neuromuscular blockers are used less often than the others. ^[4]

Cross-reactivity among neuromuscular blockers was highest for succinylcholine (47%), followed by rocuronium (32%), vecuronium (28%), atracurium (20%), pancuronium (19%) and cisatracurium (5%). ^{[3, 13, 9, 14]}  Succinylcholine has a configuration that permits it to bind readily to IgE. ^[13]   Neostigmine and morphine, which also have ammonium groups, also have the potential for cross-reacting with neuromuscular blockers. ^[2]

Latex

Latex is responsible for another 16.9% of anaphylactic reactions in the general OR. ^{[1, 12, 5, 9, 7]}  However, for the pediatric population, latex allergy is of particular significance, accounting for 80% of all intraoperative anaphylactic events. ^[1]  Because exposure to latex primarily takes place through the skin or mucosa, presentation is commonly delayed for 15-60 minutes after contact. ^{[1, 10]}

Risk factors for latex allergy include the following ^{[1, 2, 3, 16, 5, 10]} :

Patient with a history of hypersensitivity are often at increased risk for latex allergy. ^{[2, 12, 9, 10]}  Data indicate that anaphylactic events triggered by latex are also more common in certain types of surgical procedures (eg, gynecologic, abdominal, and orthopedic). ^{[1, 17, 10]}  Increased awareness and concern regarding latex in the healthcare industry, as well as the availability of viable alternatives, have led to a decrease in patient and provider exposure to latex products.

Antibiotics

Antibiotics are the third most common causative agent of anaphylactic reactions in the perioperative period (8% incidence). ^{[1, 2, 5, 9, 6, 7]}  The beta-lactams, including penicillin, cephalosporins, ampicillin, amoxicillin, carbapenems, and monobactams, account for as many as 75% of all deaths from anaphylaxis in the United States. ^{[1, 18, 6]}

The incidence of cross-reactivity between penicillin and cephalosporins is on the order of 10%. ^{[3, 18, 6]}  However, the cross-reactivity depends on the cephalosporin used; those with beta-lactam side chains (eg, ceftriaxone) are more likely to be implicated. ^[6]  Cephalosporins may also cause allergic reactions through haptens unique to that class. ^{[18, 6]}

Other antibiotics, including vancomycin, bacitracin, gentamycin, metronidazole and clindamycin, have given rise to multiple reports of hypersensitivity reactions but only rare case reports of perioperative anaphylactic reactions. ^{[1, 2]}  Allergic reactions to antibiotics are generally more common with IV administration than with oral. ^[6]

Other agents

Multiple other agents used in the perioperative period have been implicated in intraoperative anaphylaxis, including the following ^{[1, 2, 3, 4, 19, 7]} :

The incidence of anaphylactic reactions with each of these agents is small. ^{[1, 2, 3, 12, 9, 7]}

The diagnosis is made by means of serologic or skin testing. ^{[2, 7]}

Tryptase, one of the mediators released from mast cells and basophil degranulation, is the primary biomarker used for retrospective determination of anaphylaxis. ^{[2, 11, 20]} It has a half-life of 2 hours, and total serum levels should be measured within 1-2 hours after anaphylactic symptoms are noted. Serum tryptase levels usually peak within 60-90 minutes after symptoms but may remain elevated for several days. ^{[2, 20]}  If there is no hypotension, however, serum levels may not be elevated, and the value of the test is thereby decreased. Additionally, elevated total serum tryptase levels may not distinguish between anaphylactic and anaphylactoid reactions. ^{[2, 3]}

Histamine, by contrast, is transiently available in the blood for 30 minutes and in urine for 24 hours, and thus its diagnostic value is limited. ^{[2, 3, 11]}

Skin tests may also be performed 4-6 weeks after an anaphylactic event. ^{[2, 4]}  A dilute portion of the presumed allergen is introduced into the skin or intradermally with a needle, and the mast cell response is evaluated. ^[2] Skin-prick testing may be done for antibiotics, local anesthetics, propofol, and neuromuscular blockers. ^{[2, 3]}  Approximately 10% of patients will have a positive test result after skin testing without having an anaphylactic response. ^{[2, 9, 7]}  Accordingly, skin testing is not recommended without a preceding clinical history. ^[2]

IgE specific levels are commonly used to evaluate for latex allergy. ^{[3, 17]}  Radioallergosorbent tests (RASTs) may also be used for muscle relaxants, antibiotics, latex, and other agents. ^[7]  The value of diagnostic testing after anaphylaxis is underscored by data indicating that in almost 70% of cases, the provider could not correctly identify the causative agent. ^[3]  

Anaphylaxis may present as a biphasic entity. ^{[2, 11]}  Management of the acute phase of anaphylaxis intraoperatively requires discontinuing the presumed allergen, obtaining and maintaining a secure airway, and managing potential cardiovascular compromise. ^{[1, 2]}  In most instances, particularly where the anaphylactic reaction is at grade 2 or higher and where the surgical procedure has yet to begin or has just begun, the operation should be canceled and the patient stabilized.

The drug of choice in the management of anaphylaxis is epinephrine. ^{[1, 2, 4, 7, 11]}  (See Practice Essentials above.) As many as 80% of deaths related to anaphylaxis generally have been attributed to failure to treat with epinephrine early. ^[11] As an alpha agonist, epinephrine decreases the vasodilatory effects of histamine release, and its beta properties relax smooth muscle in the airway and prevent the release of additional immune mediators. ^{[1, 2]}  Epinephrine also has a positive inotropic effect. ^[11]

For patients with refractory hypotension, additional boluses of epinephrine and even an epinephrine infusion may be required to maintain hemodynamic stability. ^[1] In some instances, other vasoactive agents (eg, vasopressin), Trendelenburg position, and IV fluids may be required. ^{[1, 2, 8, 7]}  Patients who are on beta blockers and are nonresponsive to epinephrine should be treated with IV fluids and glucagon. ^{[1, 4, 7]}

Otherwise, the strategy employed intraoperatively is often dictated by the clinical presentation. Bronchospasm is the most common presentation intraoperatively and often necessitates intubation and ventilation with 100% oxygen, in addition to the use of epinephrine. ^{[2, 8, 7]}  Providers may often include bronchodilators (eg, albuterol and ipratropium bromide) and inhalation anesthetics to relax airway tone. ^[2]

Corticosteroids are administered to decrease edema and to block the release of immune mediators. ^{[1, 2, 4, 7]}  Hydrocortisone has a rapid onset of action and is the preferred steroid in this circumstance. ^[2]  

H1 blockers (eg, diphenhydramine) and H2 blockers (eg, ranitidine and famotidine) may be beneficial in both early and late phases of the reaction for as long as 24 hours after the event and should be strongly considered as adjuncts. ^{[1, 7]}  There is no evidence to indicate that premedication with H1 and H2 blockers for future surgical procedures is of any benefit. ^[2]   

A 77-year-old man presents to the OR for emergency repair of a cerebrospinal fluid (CSF) leak and a possible latissimus flap. He denies having any allergen history and reports no previous surgical procedures or prior health issues. On arrival in the OR, rapid sequence induction is performed with fentanyl, lidocaine, propofol, and succinylcholine. Rocuronium 40 mg IV is administered before placement of the arterial and central lines. Vital signs are as follows: blood pressure (BP), 124/86 mm Hg; heart rate (HR), 74 beats/min; and oxygen saturation (SaO₂), 100%.

Approximately 10 minutes after line placement, the neurosurgical team begins to prepare with chlorhexidine and drape the patient for surgery while ceftriaxone 1 gm IV is administered. Five minutes later, the peak air alarm on the anesthesia machine begins to sound, and pressures are noted to have risen to 55 mm Hg from a prior baseline of 24 mm Hg. Auscultation of the lungs reveals diffuse wheezing. The patient’s BP is now 100/60 mm Hg, and her HR is 115 beats/min.

The surgical staff was notified, and the drapes were removed while the patient was ventilated by hand with 100% oxygen and albuterol was administered. The inhalational agent was maintained to aid in bronchodilation. Removal of the surgical drapes showed diffuse areas of redness throughout the body.

The antibiotics that were being administered through the peripheral IV line were stopped and the tubing discarded. Epinephrine was administered via the central line with fluids opened wide. Diphenhydramine ranitidine and hydrocortisone were also administered, and the bronchospasm resolved. The patient was transferred to the neurosurgical intensive care unit (ICU) for monitoring.  

Although there are many potential allergens in this case, the timing of the reaction suggests that the antibiotic was responsible. Anaphylactic reactions may occur within seconds to minutes after IV administration of an antibiotic. Typical signs and symptoms include bronchospasm, hypotension, urticaria and angioedema. Of the antibiotics, beta-lactam agents (eg, penicillins and cephalosporins) are the primary causes of anaphylaxis, with a frequency of 1-5 cases per 10,000 administrations. ^{[1, 6]}  It is estimated that 2% of the surgical population is allergic to penicillins and that penicillin-related anaphylaxis occurs in 0.01% of patients.

A 38-year-old tertigravida secundipara parturient presents for an elective repeat cesarean section (C-section). Her past medical history is notable for chronic hypertension and preeclampsia that necessitated one prior C-section. She also reports an allergy to avocado. On admission, her vitals are as follows: BP, 135/76 mm Hg; HR, 89 beats/min; respiratory rate (RR), 20 breaths/min; SaO₂, 99% on room air (RA).

In the OR, spinal anesthesia is performed with a T4 level attained and a Foley catheter placed. The patient is delivered of a healthy baby girl. To this point, the anesthetic course has been uneventful, with intermittent doses of phenylephrine required to maintain adequate uterine perfusion. Oxytocin 30 mg IV is started.

Immediately after the delivery, the patient begins to report difficulty breathing. The anesthetic level is checked and noted to be at T6. Vitals are now as follows: BP, 115/72 mm Hg; HR, 115 beats/min; SaO₂, 95% on 4 L O₂ via nasal cannula (4LNC). The patient is reassured. However, she continues to complain of difficulty breathing and begins to thrash around on the OR table. Her SaO₂ is noted to be 92% and falling.

Mask ventilation was attempted but proved inadequate because of increased facial edema. An attempt at intubation was precluded by swelling of the tongue. An emergency tracheostomy was performed. Epinephrine 1 mg IV was given, together with famotidine 20 mg IV and diphenhydramine 50 mg IV. All latex gloves worn were discarded, and the uterine and abdominal incisions were closed. The patient was intubated and transported to the ICU, where she also received hydrocortisone 100 mg IV. Latex-specific IgE testing was subsequently performed and showed elevated titers.

Approximately 50% of the anaphylactic reactions due to latex happen in gynecologic procedures. ^{[1, 2, 17, 10]}  This may in part be due to the greater predisposition of women to atopy as compared with men. ^{[1, 2]}  It may also be due to the repeated exposure of latex products in barrier contraception, as well as to multiple gynecologic and obstetric procedures. ^{[17, 10]}  

In this case, it is likely that the patient was previously exposed to latex in Foley catheters and gloves during her first C-section. It should be kept in mind that she also reported an allergy to avocado; fruit and nut allergies have an 11% association with concurrent latex allergy. ^{[17, 10]}  In addition, administration of oxytocin in the course of a C-section has been known to precipitate the release of latex particles into the bloodstream when it stimulates uterine contractions. ^[17]  Finally, the slow onset of anaphylaxis in this patient is characteristic of a latex reaction. ^[17]   

A 6-year-old girl complaining of chest pain is brought to the OR for retrieval of a quarter lodged in the midportion of the esophagus. Rapid sequence induction is performed with glycopyrrolate, midazolam, fentanyl, propofol, and rocuronium. After a cuffed endotracheal tube is secured, an endoscope is advanced into the esophagus, and the coin is withdrawn uneventfully with a forceps.

Upon replacement of the endoscope into the esophagus, the patient’s SaO₂ falls from 100% to 85% and then to 65%, with HR falling from 72 to 40 beats/min and BP recorded as 50/32 mm Hg. The patient is also noted to have facial edema, an urticarial rash throughout her body, and rhonchi throughout all lung fields.

The endoscope was withdrawn, and the crash cart was brought into the OR. Epinephrine 200 μg IV was administered twice with IV fluid opened wide, and the patient was placed on 100% oxygen. Hydrocortisone 40 mg IV was given, together with famotidine 20 mg IV and diphenhydramine 20 mg IV. An epinephrine infusion was started at a rate of 0.1 μg/kg/min, and the patient was transported to the ICU.

In this case, there were few potential causes for anaphylaxis other than the neuromuscular blocking agent. In one retrospective analysis of the incidence of intraoperative anaphylaxis attributed to neuromuscular blockers over a 10-year period, rocuronium was identified as having the highest rate of causing anaphylaxis. ^{[13, 4]}  Cross-sensitivity among muscle relaxants is high. ^{[3, 9, 14]}  This child should be given an allergy alert bracelet. Rapid sequence induction with rocuronium would not be a viable plan for her in the future.  

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Abiona V Berkeley, MD, JD Associate Professor of Clinical Anesthesiology, Director, Anesthesiology Residency Program, Department of Anesthesiology, Lewis Katz School of Medicine at Temple University

Abiona V Berkeley, MD, JD is a member of the following medical societies: American Society of Anesthesiologists, Pennsylvania Society of Anesthesiologists, Society for Education in Anesthesia

Disclosure: Nothing to disclose.

Muhammad F Ahmed, MBBS Resident Physician, Department of Anesthesiology, Temple University Hospital

Disclosure: Nothing to disclose.

Jessica M Reardon, DO Associate Program Director, Director of Experiential Learning, Chair of Clinical Competency Committee, Department of Anesthesiology, Temple University Hospital

Jessica M Reardon, DO is a member of the following medical societies: American Osteopathic Association, American Society of Anesthesiologists, Society for Education in Anesthesia, Society of Critical Care Anesthesiologists, Society of Critical Care Medicine

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Sheela Pai Cole, MD Clinical Associate Professor of Cardiothoracic Anesthesiology and Critical Care Medicine, Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine

Sheela Pai Cole, MD is a member of the following medical societies: American Medical Association, American Society of Anesthesiologists, American Society of Echocardiography, California Society of Anesthesiologists, International Anesthesia Research Society, Pennsylvania Society of Anesthesiologists, Society of Cardiovascular Anesthesiologists, Society of Critical Care Anesthesiologists, Society of Critical Care Medicine

Disclosure: Nothing to disclose.

Anaphylaxis in the Operating Room 

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