Pascale Dewachter

Anaphylaxis and anesthesia: controversies and new insights.

PERIOPERATIVE anaphylaxis may be a life-threatening clinical condition and is typically a result of drugs or substances used for anesthesia or surgery. After anaphylaxis, allergologic assessment is essential to identify the offending agent and prevent recurrences, because no preemptive therapeutic strategies exist. This review seeks to (1) identify the clinical diagnostic pathway necessary to distinguish anaphylaxis from confounding clinical diagnoses, (2) discuss the more common allergens that cause anaphylaxis during anesthesia, (3) discuss a rational approach to the identification of the offending allergen through blood and skin testing that allows for the safe future clinical management of patients experiencing perioperative anaphylaxis, and (4) discuss new therapeutic perspectives for the management of patients whose hemodynamic collapse is unresponsive to catecholamines, the initial recommended pharmacologic intervention.

Severe anaphylactic shock with methylene blue instillation.

We report a documented severe immunoglobulin E-mediated hypersensitivity reaction associated with use of 1% methylene blue for detection of tubal permeability occurring during general anesthesia. Clinical symptoms, biological assessment results, and cutaneous test positivity confirmed an anaphylactic reaction to methylene blue. This case report confirms the need for systematic allergological investigation of all drugs and substances administered during the perioperative period in the event of a hypersensitivity reaction occurring during anesthesia. Anesthesiologists should be aware of the possibility of hypersensitivity reactions involving any drug or substance used during surgery.

Anaphylaxis to macrogol 4000 after a parenteral corticoid injection

Pentoxyfylline is a purine derivative. The purines include adenine, guanine, and alkaloids-like caffeine and theophylline. Uric acid is the metabolic end-product of purine metabolism. Pentoxyfylline is used as a vasodilator to relieve symptoms in some cases of intermittent claudication. No immediate hypersensitivity reactions have been described with this product to date. We report the case of a 60-year-old man who had been treated for 2 days with Hemovas (Gupo Ferrer, Division Robert, Barcelona, Spain) 400 mg and consulted for the appearance of red macules that developed into highly pruriginous papules that spread until becoming generalized and led the patient to seek emergency care. One month later, administration of the medication was renewed. Immediately after taking the first tablet of pentoxyfylline 400 mg, the patient presented generalized wheals that remitted within hours of taking antihistamines. The patient gave written consent to undergo hypersensitivity studies. Skin prick and intradermal tests were performed with pentoxyfylline, euphylline, theophylline, allopurinol, azathioprine, and 6-mercaptopurine. Results were positive for intradermal pentoxyfylline, 0.2 mg/ml, in the immediate reading. In 10 controls, the readings were uniformly negative. In response to oral challenge with theophylline 200 mg, the patient reached a cumulative dose of 350 mg with good tolerance. When given therapeutic doses of pentoxyfylline 400 mg, the patient presented within 1 h of the last dose (cumulative dose of 540 mg) generalized, highly pruriginous erythematous papules that remitted with outpatient oral treatment. He was diagnosed of immediate hypersensitivity to pentoxyfylline. In the literature we found reports of the pentoxyfylline use as a modulator of immune activity through the production of cytokines with anti-inflammatory effects. Among the xanthine derivatives, there are studies of theophylline, which also has immunomodulator activity (1–3). We found no published reports of immediate hypersensitivity reactions to pentoxyfylline, and few reports of reactions to methylxanthines, including caffeine and cola products (4, 5). The responsible mechanism appears to be immunoglobulin E (IgE)-mediated hypersensitivity in view of the results of allergy tests. In addition, as has been reported by other authors, the patient showed tolerance to oral theophylline exposure, thus excluding pharmacologic cross-reactions because of molecular similarity to pentoxyfylline (Fig. 1). Consequently, we report what we believe is the first case in the literature of acute urticaria triggered by pentoxyfylline and confirmed by skin tests and an oral challenge.

Anaphylactic shock: a form of distributive shock without inhibition of oxygen consumption.

Background:The pathophysiology of anaphylactic shock during anesthesia is incompletely characterized. It is described as distributive by analogy with septic shock (anaerobic metabolism, high tissue oxygen pressure [Ptio2] values). The Ptio2 profile and its metabolic consequences during anaphylaxis are not known. Methods:Ovalbumin-sensitized anaphylactic shock rats (n = 11) were compared to nicardipine-induced hypotension rats (n = 12) for systemic hemodynamics, Ptio2, sympathetic nervous system activation, skeletal muscle blood flow, and interstitial lactate and pyruvate concentrations using combined microdialysis and polarographic Clark-type oxygen probes. Results:In both groups, the time course and the magnitude of arterial hypotension were similar. The ovalbumin group but not the nicardipine group displayed decreased skeletal muscle blood flow (from 45 ± 6.2 ml · 100 g−1·min−1 to 24.3 ± 5 ml·100 g−1·min−1; P < 0.0001) and Ptio2 values (from 42 ± 5 to 5 ± 2; P < 0.0001). The ovalbumin group had more intense sympathetic nervous system activation with higher plasma epinephrine and interstitial norepinephrine concentrations. For the ovalbumin group, there was skeletal muscle anaerobic metabolism (lactate concentration increased from 0.446 ± 0.105 to 1.741 ± 0.459 mm; P < 0.05) and substrate depletion (pyruvate concentration decreased from 0.034 ± 0.01 mm to 0.006 ± 0.002 mm; P < 0.05) leading to increased interstitial lactate/pyruvate ratios (from 17 ± 6 to 311 ± 115; P < 0.05). Conclusions:This profile suggests decreased skeletal muscle blood flow and oxygen delivery. Persistent energy consumption results in decreased Ptio2 and substrate depletion through anaerobic glycolysis leading to complete failure of cellular energy production. This could explain rapid organ dysfunction and resuscitation difficulties.

Anesthesia in the patient with multiple drug allergies: are all allergies the same?

Purpose of review During the preoperative evaluation, patients frequently indicate ‘multiple drug allergies’, most of which have not been validated. Potential allergic cross-reactivity between drugs and foods is frequently considered as a risk factor for perioperative hypersensitivity. The aim of this review is to facilitate the recognition of risk factors for perioperative anaphylaxis and help the management of patients with ‘multiple drug allergies’ during the perioperative period. Recent findings Neuromuscular blocking agents (NMBAs) and antibiotics are the most common drugs triggering perioperative anaphylaxis. Quaternary ammonium ions have been suggested to be the allergenic determinant of NMBAs. Even though the ‘pholcodine hypothesis’ has been suggested to explain the occurrence of NMBA-induced allergy, this concept remains unclear. Although many practitioners believe that certain food allergies present an issue with the use of propofol, there is no role to contraindicate propofol in egg-allergic, soy-allergic or peanut-allergic patients. IgE-mediated hypersensitivity has been reported with seafood and iodinated drugs, IgE-mediated hypersensitivity has been reported with seafood and iodinated drugs, but there is no cross-reactivity between them. The allergenic determinants have been characterized for fish, shellfish and povidone iodine and remain unknown for contrast agents. Summary There are many false assumptions regarding drug allergies. The main goal of this article is to review the potential cross-reactivity among specific families of drugs and foods in order to facilitate the anesthetic management of patients with ‘multiple drug allergies’.

What investigation after an anaphylactic reaction during anaesthesia

Purpose of review Anaphylactic reactions occurring during anaesthesia may be life threatening. Lethal issues may be involved in up to 3–10% of the cases. The allergological assessment (including biochemical tests and skin tests) is the key to the management of these reactions. The scope of this review is to focus on the allergological assessment required to prove the immune mechanism, to identify the culprit drug or substance and the cross-reactive molecules, especially for neuromuscular blocking agents, allowing preventive measures for future anaesthetic procedures. Recent findings To describe the allergological assessment (including biochemical tests and skin tests performed according to the current guidelines) in order to prove the immune mechanism as the responsibility of the culprit allergen. The most frequent and less frequent drugs involved are described. The different biological tools available are detailed. To ensure an accurate diagnosis, the interpretation of the allergological assessment should be linked to the description of the clinical events as their time onset following the injection/administration of the suspected drug(s)/substance. Summary To describe the different tools (biochemical tests and skin tests) available in order to prove the diagnosis of an anaphylactic reaction occurring during anaesthesia.

A comparison of epinephrine only, arginine vasopressin only, and epinephrine followed by arginine vasopressin on the survival rate in a rat model of anaphylactic shock

Background:Epinephrine and more recently arginine vasopressin (AVP) alone or in combination have been proposed in patients with anaphylactic shock, but few experimental data exist. The authors investigated the effects of epinephrine only, AVP only, or epinephrine followed by AVP in a model of anaphylactic shock. Methods:Ovalbumin-sensitized Brown Norway rats were anesthetized, intubated, and shock induced with ovalbumin. Rats (n = 6/group) were randomly allocated to receive 5 min after shock onset: (1) saline (no-treatment group); (2) two boluses of epinephrine followed by continuous infusion (epinephrine group); (3) AVP bolus followed by continuous infusion (AVP group); (4) epinephrine bolus followed by AVP continuous infusion (epinephrine + AVP group). Mean arterial pressure (MAP) and skeletal muscle oxygen pressure (Ptio2) were measured. Continuous infusion rates were titrated to reach MAP values of 60 mmHg. Survival was analyzed. Results:Without treatment, MAP and Ptio2 decreased rapidly with 0% survival. In the epinephrine group, MAP and Ptio2 recovered after an initial decrease, with 84% survival. In the AVP group, MAP was partially restored and subsequently decreased; Ptio2 values decreased to values similar to those in the no-treatment group; survival was 0%. In the epinephrine + AVP group, MAP and Ptio2 values increased more slowly as compared with the epinephrine group; survival was 100%. Conclusions:In this model of anaphylactic shock, early treatment with epinephrine followed by continuous epinephrine or vasopressin infusion resulted in an excellent survival rate, whereas vasopressin only resulted in a 100% death rate. These experimental results suggest that epinephrine must still be considered as the first-line drug to treat anaphylactic shock.

Comparison of arginine vasopressin, terlipressin, or epinephrine to correct hypotension in a model of anaphylactic shock in anesthetized brown Norway rats.

Background: Arginine vasopressin (AVP) and terlipressin were proposed as alternatives to catecholamines in shock states characterized by decreased plasma AVP concentrations. The endogenous plasma AVP profile in anaphylactic shock is unknown. In an ovalbumin-sensitized anesthetized anaphylactic shock rat model, the authors investigated (1) plasma AVP concentrations and (2) the dose versus mean arterial pressure response for exogenous AVP and terlipressin and compared them with those of epinephrine. Methods: In a first series of rats (n = 12), endogenous plasma AVP concentrations were compared with a model of pharmacologically induced hypotension (nicardipine, n = 12). A second series was randomly assigned to three groups (AVP, n = 7; terlipressin, n = 7; epinephrine, n = 7) and dose (AVP: 8 doses, 0.03–100 U/kg; terlipressin: 7 doses, 0.03–30 &mgr;g/kg; epinephrine: 7 doses, 0.3–300 &mgr;g/kg)–response mean arterial pressure curves were plotted. Data are expressed as mean ± SD. Results: Endogenous plasma AVP concentrations were significantly lower in anaphylactic shock (57 ± 26 pg/ml) than in the nicardipine group (91 ± 43 pg/ml; P < 0.05). The ED50 was 10.6 &mgr;g/kg (95% confidence interval, 7.1–15.9) for epinephrine and 4.1 U/kg (95% confidence interval, 3.0–5.6) for AVP. Terlipressin did not change mean arterial pressure, regardless of the dose used. Conclusions: In a rat model, anaphylactic shock is associated with inadequately low plasma AVP concentrations. For clinically relevant doses, AVP and epinephrine had comparable effects on mean arterial pressure and heart rate values, whereas, unexpectedly, terlipressin was ineffective. These results are consistent with reports in humans experiencing anaphylaxis where AVP injection restored arterial pressure.

Case Scenario: Bronchospasm during Anesthetic Induction

This article has been selected for the ANESTHESIOLOGY CME Program. Learning objectives and disclosure and ordering information can be found in the CME section at the front of this issue.

Perioperative management of patients with mastocytosis.

753 March 2014 M ASTOCYTOSIS may be associated with the occurrence of perioperative immediate hypersensitivity reactions. Hypersensitivity corresponds to the reproducible signs or symptoms, initiated by exposure to a defined stimulus at a dose tolerated by normal subjects.1 It is generally accepted that immediate reactions may be delayed for up to an hour.2 Two phenotypes of immediate-type hypersensitivity may occur during the perioperative setting. Although immediate nonallergic hypersensitivity refers to clinical reactions where an immune mechanism can be ruled out (e.g., histamine release belongs to nonallergic hypersensitivity), immediate allergic hypersensitivity refers to those where an immune mechanism can be demonstrated (usually immunoglobulin E [IgE]-mediated).1 Basophil and mast cell degranulation and corresponding inflammatory mediators release occur through a specific IgE-mediated mechanism with subsequent clinical features.3 Mastocytosis is not an allergic disorder but a rare clinical condition with an estimated incidence of 1:150,000.4 In mastocytosis, immediate hypersensitivity usually arises after mast cell degranulation elicited by various nonspecific triggers including psychological, pharmacological and mechanical factors, and temperature changes (table 1). Nevertheless, a concurrent drug-induced IgEmediated reaction may also occur in patients with mastocytosis. The overall incidence of perioperative IgE-mediated anaphylaxis is estimated at 1 in 10,000–20,000 anesthesia procedures.2,5,6 Little is known about the perioperative management of patients with mastocytosis. It remains poorly understood by anesthesiologists, as existing information consists of single-case reports and a few case series. Moreover, there are currently no European or North-American guidelines regarding its perioperative management. The main anesthetic concern is the avoidance of release of histamine and other mast cell mediators. This review seeks to discuss: (1) the various nonspecific triggers that may cause perioperative mast cell degranulation in mastocytosis; (2) a preemptive strategy that allows for a safe perioperative management; (3) the management of immediate hypersensitivity in mastocytosis; and (4) the diagnostic pathway necessary to distinguish nonspecific mast cell degranulation in mastocytosis from other clinical entities.