Abstract
Antibiotics commonly administered in the operating room for infection prophylaxis may cause mild to life-threatening complications. The frequency and type of complications depend on the antibiotic class. Vancomycin is a glycopeptide antibiotic used for bacterial prophylaxis in surgery and as an alternative for patients allergic to penicillin-based antibiotics and cephalosporins or for patients harboring drug-resistant organisms. Vancomycin may cause red man syndrome due to massive histamine release with potentially important physiologic consequences. Anesthesiologists should be prepared to immediately diagnose and treat this syndrome in a timely manner.
Keywords
anaphylaxis, antibiotic, hypersensitivity reaction, red man syndrome, vancomycin
Case Synopsis
A 23-year-old man presents for reduction and fixation of an open tibial fracture after falling off a horse. During the presurgical briefing/time-out, the surgeon requests that the patient be given vancomycin, 1 g, before incision. After propofol and succinylcholine administration and successful endotracheal intubation, anesthesia is maintained with sevoflurane, N 2 O 50%/O 2 50%, and fentanyl, 2 μg/kg/h. Four minutes after vancomycin is given, the patient suffers cardiovascular collapse.
Problem Analysis
Definition
Anesthesiologists frequently administer antibiotic prophylaxis to surgical patients to ensure patient benefits related to the Surgical Care Improvement Project (i.e., SCIP-Inf 1). For this reason, anesthesiologists should be knowledgeable regarding indications, dosage, complications, and interactions of antibiotics with anesthetics and other medications used in the perioperative period. Antibiotics possess a diverse spectrum of side effects and interact with a number of anesthetic adjuvants ( Table 82.1 ). Antibiotics also account for the majority of self-reported drug-allergy entries. For these reasons, anesthesiologists must understand and anticipate possible complications associated with antibiotic administration.
| Complications | |||
|---|---|---|---|
| Antibiotic | Common | Occasional | Rare |
| Aminoglycosides | Nephrotoxicity Ototoxicity | Rash Nausea, vomiting Potentiation of neuromuscular blockade | Peripheral neuritis Anaphylaxis Electrolyte disturbances |
| Cephalosporins | Painful when given intramuscularly (IM) | Nausea Drug fever Diarrhea Phlebitis | Anaphylaxis Hypotension Bronchospasm Angioedema Urticaria |
| Clindamycin | Diarrhea Pseudomembranous colitis Rash Metallic taste Inhibition of neuromuscular transmission Potentiation of neuromuscular blockade | Anaphylaxis Cardiac arrest Erythema Granulocytopenia Thrombocytopenia | |
| Erythromycin | Phlebitis when given intravenously Painful when given IM | Nausea, vomiting Diarrhea Pseudomembranous colitis | Long QT syndrome Fever Rash Eosinophilia |
| Metronidazole | Nausea, vomiting Metallic taste Disulfiram-like reaction if alcohol consumed | Burning tongue Urethral/vaginal burning Dark urine Rash | Convulsions Ataxia Peripheral neuropathy Encephalopathy Cerebellar dysfunction |
| Penicillin G, ampicillin | Rash Drug fever Diarrhea Leukopenia | Anaphylaxis Bronchospasm Angioedema Electrolyte disturbances Interstitial nephritis | |
| Trimethoprim-sulfamethoxazole | Rash | Erythema multiforme Diarrhea Aplastic anemia Neutropenia Thrombocytopenia | |
| Vancomycin | Phlebitis Severe pain when given IM | “Red man” syndrome “Pain and spasm” syndrome Hypotension Anaphylaxis Nephrotoxicity Ototoxicity | Neutropenia |
Vancomycin is a glycopeptide antibiotic commonly used for bacterial prophylaxis in orthopedic, neurologic, and vascular surgery and as an alternative antibiotic for patients allergic to penicillin-based antibiotics and cephalosporins or for patients harboring drug-resistant organisms. When a life-threatening reaction occurs after the initiation of vancomycin, the possibility of a hypersensitivity reaction must be considered. Vancomycin administration can lead to multiple types of hypersensitivity reactions, two of which are (1) “red man” syndrome (RMS) and (2) anaphylaxis.
Red Man Syndrome
RMS or “red neck” syndrome manifests as hypotension, cutaneous flushing, erythema, urticaria, pruritus, and maculopapular rash, primarily of the face, neck, arms, and chest. The constellation of symptoms may be mild in its presentation or severe to the point of life threatening. Signs may occur as early as 4 to 10 minutes after the start of infusion and can be precipitated by an infusion rate of less than an hour in duration. An unusual feature of vancomycin is its ability to nearly double histamine release from basophils and cutaneous mast cells through a poorly understood dose-dependent mechanism. Although it may be clinically indistinguishable from anaphylaxis in the operating room, RMS does not involve immunoglobulin E (IgE) sensitization. Previously described as an anaphylactoid reaction, it is currently described in the literature as non-IgE immunologic anaphylaxis. Diagnosis relies primarily on (1) the exclusion of other intraoperative events that may produce hypotension; (2) the temporal relationship of cardiovascular instability to vancomycin infusion and the observation of other manifestations of histamine release, such as perioral, periocular, and facial edema; (3) bronchospasm due to stimulation of bronchial histamine receptors; and (4) hypoxia secondary to histamine-induced inhibition of hypoxic pulmonary vasoconstriction and subsequent formation of pulmonary shunts. Attention should be given to other histamine-inducing drugs that may potentiate the symptoms of RMS (see Table 82.1 ). As a marker for immunologic mast-cell activation, tryptase release does not occur in vancomycin-induced anaphylactoid reactions. Assays for histamine release are usually impractical because histamine concentrations peak 5 minutes after onset and return to baseline within an hour after release.
The liberated histamine causes dilation of peripheral blood vessels and simultaneously increases cardiac output, stroke volume, and pulmonary artery blood pressure. However, the peripheral vascular dilation is the most prominent physiologic feature and may induce severe hypotension and cardiovascular collapse. Treatment options become more aggressive with later detection, more histamine release, and more severe hypotension. Management options include the following:
- •
Discontinue or slow the vancomycin infusion
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Administer an intravenous (IV) fluid bolus
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Discontinue or decrease concentrations of other agents capable of inducing hypotension (e.g., anesthetics or sodium nitroprusside)
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Administer H 1 -antihistamines (e.g., diphenhydramine)
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Consider inhaled β-agonists if bronchospasm is present
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Administer vasopressors (e.g., ephedrine, phenylephrine, and epinephrine) for severe hypotension
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Initiate advanced cardiac life-support maneuvers in case of cardiac arrest
Immunoglobulin E–Mediated Anaphylaxis
The potential cause of cardiovascular collapse after vancomycin infusion may also be related to IgE-mediated anaphylaxis. Signs of anaphylaxis include rapid-onset morbilliform rash or hives, urticaria, flushing, angioedema, vomiting, diarrhea, rhinoconjunctivitis, and tachycardia. These symptoms may persist for up to 48 hours. Because these signs are more difficult to detect in a patient covered in surgical drapes and sedated or under general anesthesia, the presence of hypotension and bronchospasm in a patient previously exposed to vancomycin should immediately result in the consideration of IgE-mediated anaphylaxis as a cause ( Box 82.1 ). Previous exposure to vancomycin results in the production of vancomycin-specific IgE and, on repeat administration, the sensitized mast cells release histamine, leukotriene C 4 , and prostaglandin D 2 . Cytokines such as tumor necrosis factor–alpha and interleukins 4, 5, 6, 8, and 13 may amplify the type-I hypersensitivity reaction as the inflammatory cascade escalates. Cytotoxic T cells may play a part in the pathogenesis of the morbilliform rash. Serum β-tryptase levels, a marker of IgE-crosslinked mast-cell degranulation, should be performed 1 to 2 hours after the onset of the reaction. Total serum tryptase levels (α-protryptase and β-tryptase) above 25 μg/L, an increase of 2 ng/mL or 135% above baseline levels, and a ratio or peak total tryptase to peak β-tryptase greater than 10 are suggestive of IgE-mediated anaphylaxis. Another blood sample should be drawn for comparison at least 2 days after the initial draw because the expectation is that levels will return to baseline values within 12 to 14 hours.
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