Hypersensitivity to Opioids: Prevalence, Mechanisms, Diagnosis and Management.

A method for perfusion of cat paws with constant flow and temperature is described. This technique has been used to study the relationship between the efflux of histamine and slow reacting substance (SRS) from cat paws perfused with compound 48/80. The threshold dose of compound 48/80 was 0.001–0.01 μg/ml for both histamine and SRS releasing effects. No correlation between the yields of histamine and SRS was noted. On repeated administration of compound 48/80 the histamine releasing effect declined and the output of SRS was cor respondingly reduced. The release of histamine and the formation of SRS were inhibited by ninhydrin, N‐ethylmaleimide and potassium cyanide indicating that both processes are dependent on energy‐requiring enzymatic reactions. Apart from their antagonism of the histamine releasing effect of compound 48/80, ninhydrin and N‐ethylmaleimide released histamine per se. No SRS was detected in the effluents from paws perfused with these agents alone. The yields of both histamine and SRS were higher at 22o C than at 37oC. Regardless of temperature the efflux of histamine consistently preceded that of SRS. A temperature dependent inactivation of SRS by cat serum was demonstrated. The results suggest that the initial reaction(s) activated by compound 48/80 is common for the release of histamine and the formation of SRS in the cat paw but that these processes then proceed independently.

Rapid intravenous administration of the glycopeptide antibiotic, vancomycin, may cause a hypotensive reaction which can usually be prevented by infusing vancomycin in dilute solutions. The release of histamine from circulating cells such as basophils and tissue mast cells has been implicated in hypotensive reactions since the effects can be prevented by antihistamine pretreatment. The direct effects of vancomycin on histamine release were therefore investigated in rat peritoneal mast cells and rat leukemic basophils (RBL-1 cells). Suspension cultures of mast cells or RBL-1 cells were exposed to vancomycin for 30-60 minutes at concentrations comparable to those infused clinically (2.28 or 4.56 mg/ml). Vancomycin induced a time- and dose-dependent release of histamine into the culture media from both cell types. The reference degranulating agent, Compound 48/80 (CP 48/80), was also shown to induce histamine release from mast cells and RBL-1 cells. Mast cells were significantly more sensitive to vancomycin and CP 48/80 than RBL-1 cells and, unlike RBL-1 cells, were responsive to the inhibitory effects of cromolyn sodium on histamine release. Cromolyn sodium did not inhibit vancomycin-induced histamine release in RBL-1 or mast cells. Morphologically, mast cells exposed to either vancomycin or CP 48/80 exhibited dose-related degranulation. On the other hand, treatment-related degranulation effects of either vancomycin or CP 48/80 on RBL-1 cells could not be reliably distinguished from controls by qualitative evaluation. Based upon these findings it is concluded that mast cells may represent a more useful model to evaluate the potential of investigational agents to release histamine and to study mechanisms of histamine release than RBL-1 cells.

A prospective, randomized, double-blind study was performed in 40 patients (ASA class I-III) treated with atracurium to ascertain whether histamine release caused hemodynamic or cutaneous changes. The treated group of 20 patients was premedicated with the H1 antagonist dimetindene (0.2 mg/kg) and the H2 antagonist ranitidine (1.25 mg/kg); the control group of 20 patients received saline. Six minutes after the induction of anesthesia with thiopental/fentanyl, patients received atracurium 0.5 mg/kg over 5 s. Plasma histamine levels were measured fluorometrically 5 min after administration of thiopental/fentanyl and 2 and 5 min after atracurium. Arterial blood pressure and heart rate were recorded every 2 min. Histamine levels (0.24 ng/mL) did not change significantly after thiopental/fentanyl. In the control group, 2 min after injection of atracurium, plasma histamine levels were 0.76 +/- 0.76 ng/mL, and in the antihistamine-treated group, 0.39 +/- 0.24 ng/mL (P < 0.05 control versus treated), suggesting that pretreatment with antihistamines may attenuate atracurium-induced histamine release. Systolic and diastolic blood pressure decreased significantly in both groups after thiopental (P < 0.05), but did not decrease further after the administration of atracurium. There were cutaneous manifestations in 7 of 20 patients in the control group and in none of the 20 patients treated with H1 and H2 antagonists (P < 0.0005). We conclude that atracurium caused modest histamine release in our patients but that the decrease in arterial blood pressure may have been due, in part, to thiopental. Cutaneous manifestations of histamine release did not correlate with hemodynamic events or with plasma histamine levels, but were prevented with antihistamine pretreatment.

The perioperative use of colloidal plasma substitutes is still under discussion. We therefore conducted a prospective randomised study with three commonly used plasma substitutes to examine their histamine releasing effects in 21 volunteers. MATERIAL OR SUBJETS: 21 male volunteers were enrolled in this prospective, randomised, controlled clinical study. Endpoints were the incidence of early and late histamine release and the time course of the release kinetics. Normovolemic hemodilution technique was used with hydroxyethyl starch (n = 6), human albumin (n = 6) and polygeline (n = 9). Measurement and observation period was 240 min after the start of the plasma substitute infusion. Heart rate, blood pressure, SaO(2), clinical symptoms/signs and plasma histamine were measured during the observation period. The incidence of histamine release over the whole observation period in all three groups was 100%. Histamine release occurred frequently in all three groups until 30 min (50%-78%) and up to 240 min (late release reaction: 67%-83%) after the start of infusion. Surprisingly even hydroxyethyl starch, which is regarded as a generally safe and effective plasma substitute, caused high incidences of late histamine release (67%). Histamine release is a well known side effect of polygeline and - to a lesser extent - also of albumin, but was a novel finding for hydroxyethyl starch. We demonstrated for the first time histamine releasing effects of hydroxyethyl starch over a long period of time after administration. This perioperatively and for intensive care possibly relevant finding should make clinicians aware of late side effects not yet connected with the clinical use of these colloidal plasma substitutes.

To study the human intestinal mast cell of children and adults, we combined a sensitive glassfibre-based histamine assay with the enzymatic and mechanical dispersion of surgical specimens or mucosal biopsies. The method yields between 1.2 x 10(3) to 4.6 x 10(3) mast cells/mg tissue constituting 1.2% to 5.3% of total cell count. The mast cell yield, however, depends on the intestinal tissue specimen used for dispersion. Aliquots containing 1500 mast cells per sample are sufficient for measuring significant amounts of histamine (greater than or equal to 0.15 ng histamine per sample), thus making it possible, to carry out approximately 75 tests for four mucosal biopsies of 10 mg each. The intestinal mast cell releases histamine in a dose-dependent manner on challenge with anti-IgE (6-600 U/ml), ionophore A23187 (0.25-1.0 microM), and Concanavalin A (0.7-25.0 micrograms/ml). The histamine release shows interindividual variation with a net histamine release between 0 to 2.5 ng/samples dependent on the secretatogue. In general, it is not necessary to passively sensitize the mast cells to obtain a sufficient histamine release response to anti-IgE challenge, indicating the presence of intact and functional cell-bound IgE. However, it is shown that four of 10 non-atopic intestinal mast cell samples could be passively sensitized with human plasma containing either mite- or grass-specific IgE without stripping off the IgE first. This indicates the presence of free and preserved Fc-receptors on the dispersed mast cells in some subjects. In addition, it is found that the phorbolester TPA increases the histamine release response to A23187 and turns anti-IgE non-responding mast cells into responding mast cells, but TPA alone at 2 to 16 ng/ml has no histamine releasing effect. In patients with anti-IgE responding mast cells no additional effect of TPA is seen. Finally, no substantial differences between mast cells of children and adults are demonstrated.

The histamine release induced in isolated perfused sensitised guinea-pig lungs by antigen, trypsin, Russell viper venom, and compound 48/80 has been compared. At equi-active dosage for histamine release, these four substances released varying amounts of slow reacting substances. Neither histamine release nor the release of slow reacting substances appeared to be responsible for the changes in cholesterol, glyceride or lipid phosphorus of the lung tissue observed in these experiments.

ALLERGIC or pseudoallergic reactions that occur during anesthesia have been increasing over the last few years. 1 Muscle-relaxant drugs are responsible for at least half of these life-threatening adverse reactions. 1,2 The diagnosis of drug allergy is mainly based on a detailed clinical history, positive skin tests, and detection of specific immunoglobulin E (IgE). Nevertheless, the biologic results are not always closely correlated with clinical assessment of the disease, and discrepancies between skin tests and specific IgE are reported, 2,3 In these cases, in vitro investigations to identify the responsible drug are needed, and the histamine release (HR) test is usually performed. 2 HR reflects basophil degranulation, but the very small number of circulating basophils is a limitation to this test, and its clinical benefit remains controversial. Because flow cytometry is a valuable tool for identifying cell populations even at low concentrations, we developed a tricolor flow cytometric method (FCM) for the study of allergen-induced basophil activation. 4 Briefly, identification of basophils is based both on CD45 expression (a common leukocyte antigen) and on the presence of IgE on the cell surface, because basophils express high-affinity receptor for IgE. Cell activation on allergen or drug challenge is assessed by the expression of CD63 on the plasma membrane. 5 After the publication of preliminary data (only focused on usual allergens), we initiated studies to evaluate the usefulness of the method in the diagnosis of drug allergy. We report here results of the first four cases of allergy to muscle-relaxant drugs since this FCM was introduced in our laboratory. The patients were recruited from different associated hospitals in Lyon, France, and rapidly developed clinical features evocative of anaphylactic reaction after induction of anesthesia, e.g., hypotension, bronchospasm, and cutaneous signs. Investigations of the responsible drug were performed in the outpatient unit of the Department of Anesthesia (screening for drug allergy unit) at least 2 months after the allergic reaction. Skin prick and intradermal reaction (IDR) tests 3 were performed using various dilutions of drug solutions, specific IgE antibodies (against ammonium group) were measured using radioallergosorbent techniques (Capsystem; Pharmacia, Uppsala, Sweden), histamine was measured using a radioimmunoassay (Immunotech, Marseille, France), and HR test was considered positive when superior to 10% of total HR. Basophil degranulation by FCM was detected by CD63 expression on the cell surface. A positive threshold is defined with a negative control without any drug. Results are positive when > 10% of basophils express CD63.

Opioid-free Anesthesia: Time to Regain Our Balance.

Midkine is a product of a retinoic acid-responsive gene and exerts a variety of biological activities. The aim of our investigation is to determine whether human midkine have histamine-releasing effects on mast cells, and to show the evidence of the inflammation induced by midkine. Midkine induced histamine release from rat peritoneal mast cells with a rapid response in a dose-dependent manner. Extracellular calcium inhibited the histamine release induced by midkine in a dose-dependent manner. Pertussis toxin and benzalkonium chloride inhibited the histamine release induced by midkine. Gi-proteins exert an effect on the histamine release of midkine. The immediate cutaneous response induced by midkine was positive. These results suggest that midkine may take part in some inflammation via histamine release from mast cells.

The histamine releasing properties of glucose (mannose)-specific lectins isolated from Brazilian beans was examined. The Canavalia brasiliensis, Dioclea rostrata, and Dioclea virgata lectins induced histamine release in rat peritoneal mast cells similar to concanavalin A. Less potency and efficacy was observed for Canavalia maritima, Dioclea guianensis, and Dioclea violacea while very low activities were seen for the lectins from Dioclea grandiflora, Canavalia bonariensis, and Cratylia floribunda. The histamine releasing effect was quenched by higher doses of D. virgata lectin similar to what was reported for concanavalin A. This effect was abrogated by increasing the concentration of calcium in the incubating medium. As these above proteins have sites that bind calcium, higher doses of the lectins might withdraw the calcium which is essential for the mast cell secretion.

The traditional view of opioids held that the individual opioid agonists shared the same mechanism of action, differing only in their potency and pharmacokinetic properties. However, recent advances in opioid receptor pharmacology have made this view obsolete. Distinguishing features of the synthetic opioid agonists are related, at least in part, to variation in affinity and intrinsic efficacy at multiple opioid receptors. Respiratory depression is the opioid adverse effect most feared by anaesthesiologists. Specific kappa-receptor agonists produce analgesia with little or no respiratory depression. There are a number of commercially available kappa-receptor partial agonist drugs, the so-called agonist-antagonist or nalorphine-like opioids, which appear to have a limited effect on breathing. Within the series of fentanyl analogues there are differences in behaviour towards particular opioid receptors and there is evidence for subtle differences in respiratory depressant effects. Pethidine (meperidine) causes histamine release and myocardial depression, while the fentanyl analogues do not. Pethidine has atropine-like effects on heart rate, while fentanyl analogues reduce heart rate by a vagomimetic action. Severe bradycardia or even asystole is possible with fentanyl analogues, especially in conjunction with the vagal stimulating effects of laryngoscopy. Fentanyl analogues often produce minor reductions in blood pressure, and occasionally severe hypotension by centrally mediated reduction in systemic vascular resistance. Muscle rigidity and myoclonic movement occurs frequently during induction of anaesthesia with larger doses of opioids. Fentanyl and alfentanil have been reported to produce localised temporal lobe electrical seizure activity in patients with complex partial epilepsy. There are probably fewer biliary effects with agonist-antagonist opioids than the agonist opioids. The mechanism of adverse effects after spinal administration is distinctly different for morphine, which is very water soluble, compared with more lipid-soluble opioids. The systemic absorption of morphine after intrathecal or epidural administration is very slow, resulting in long duration of analgesia and low plasma concentrations, while lipid-soluble opioids are rapidly absorbed into the circulation and redistributed to the brain. The serotonin syndrome may result from coadministration of pethidine, dextromethorphan, pentazocine or tramadol with monoamine oxidase inhibitors (MAOIs) or selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors (SSRIs). There are clinically important interactions between opioids and hypnosedatives, resulting in synergistic effects on sedation, breathing and blood pressure.

Allergy warnings against opioids are often registered in patient notes which may limit options for pain management. IgE-mediated allergic reactions and anaphylaxis to opioids are infrequent. More frequently, morphine and other opioids cause non-IgE-mediated histamine release leading to milder symptoms which may partly mimic an anaphylactic reaction and cause clinicians to treat it as such. This case report describes a 28-year-old female whose mild reactions were repeatedly misinterpreted as severe allergic reactions, leading to incorrect allergy labels and surgery delay.

9525 Background: The long-term benefit of adjuvant dab + tram in pts with resected stage III BRAF V600E/K–mutant melanoma was demonstrated in COMBI-AD where AEs led to permanent discontinuation of dab + tram in 26% of pts, most often due to pyrexia (9%). The COMBI-APlus trial (NCT03551626) is designed to evaluate whether an adapted pyrexia management algorithm could reduce high-grade pyrexia and other pyrexia-related adverse outcomes, such as treatment cessation and hospitalization. Methods: COMBI-APlus is an open-label, Phase IIIb trial evaluating an adapted pyrexia management algorithm in pts with high-risk resected stage III BRAF V600E/K–mutant melanoma treated with 12 mo of adjuvant dab + tram. In the adapted algorithm, both dab and tram were interrupted promptly at the onset of pyrexia (temperature ≥ 38°C). In the event of suspected recurrent pyrexia, treatment may be interrupted in the presence of pyrexia syndrome (ie, chills, rigors, night sweats, or influenza-like symptoms without temperature ≥ 38°C) at investigator discretion. Treatment with dab + tram was restarted at the same dose level once pts were symptom free for ≥ 24 hours. The primary endpoint is the composite rate of grade 3/4 pyrexia, hospitalization due to pyrexia, or permanent discontinuation due to pyrexia vs a historical control from COMBI-AD (20%; 95% CI, 16.3%-24.1%). Secondary endpoints include relapse-free survival (RFS) and safety. Results: A total of 552 pts were enrolled. At the data cutoff (5 Oct 2020), all pts had completed 12 mo of treatment; median duration of follow-up was 18.4 mo. COMBI-APlus met its primary endpoint of significant improvement in composite rate of pyrexia. The composite rate was 8.0% (95% CI, 5.9%-10.6%), with rates of 3.8% for grade 3/4 pyrexia, 4.3% for hospitalization due to pyrexia, and 2.4% for discontinuation due to pyrexia. The estimated 12-mo RFS rate was 91.8% (95% CI, 89.0%-93.9%). The most common AEs (≥ 20%) were pyrexia (67.8%), headache (31.7%), blood creatine phosphokinase increase (27.9%), diarrhoea (27.0%), chills (26.4%), fatigue (25.7%), asthenia (23.6%), nausea (23.4%), rash (21.4%), and arthralgia (21.0%). AEs of any type led to permanent dab + tram discontinuation in 14.7% of pts. Conclusions: This primary analysis suggests the new adapted pyrexia management algorithm is effective in reducing grade 3/4 pyrexia, pyrexia-related hospitalization, and treatment discontinuation in pts receiving adjuvant dab + tram. The early efficacy appears consistent with that observed in COMBI-AD. The growing experience of oncologists in managing pyrexia with this simple algorithm may reduce the need for hospitalization or visits to a healthcare provider, which is highly desirable during the current COVID-19 pandemic. Thus, more pts can remain on treatment and derive benefit. Clinical trial information: NCT03551626.

Participation of mast cell 5-hydroxytryptamine in the vasoconstrictor effect of neurotensin in the rat perfused hindquarter

The problem of painless or silent myocardial ischemia (SMI), defined as objective evidence for transient ischemia without symptoms, has recently received considerable attention [1, 2]. SMI is very common and may be present in patients with all forms of coronary artery disease (CAD). Although precise data are not obtainable, the prevalence of this problem in the USA alone is estimated to be in the millions (Table 1) and is likely to involve many more millions world wide. The purpose of this paper is to review the incidence, characteristics, and significance of this problem. This information will be used to provide an algorithm for clinical management of patients with suspected SMI.