Role of sugammadex in the treatment of anaphylaxis due to rocuronium in children: Extrapolation from adult and animal reports.

Allergic reactions are generalized hypersensitivity processes triggered by different antigenic stimuli, resulting in the end effect of mast cell degranulation and adverse physiologic effects. During the perioperative period, the most commonly identified agents include antibiotics, neuromuscular blocking agents (rocuronium and succinylcholine), chlorhexidine, and iodinated dyes for radiologic imaging. Sugammadex is a novel agent for the reversal of neuromuscular blockade achieved with rocuronium or vecuronium. Its unique mechanism of action, whereby it encapsulates and forms a one-to-one complex with rocuronium, has led to its anecdotal use as an adjunct in the treatment of anaphylactic and anaphylactoid reactions following rocuronium. The current manuscript discusses the potential use of sugammadex in the treatment of allergic reactions following the administration of rocuronium, reviews previous anecdotal reports of its use in these scenarios, and provides recommendations for future care.

Threshold for Anaphylactoid Reaction to Polysorbate 80 in Canines.

Polysorbate 80 (PS80) functions as a dispersing agent or solubilizer in many pharmaceuticals, and as a stabilizer in biopharmaceuticals. Topical or parenteral administration of low doses of PS80 in biopharmaceuticals has been associated with mild allergic reactions, including local injection site reactions in humans. High doses of PS80, such as levels found in traditional Chinese herbal parenteral medicines, have been linked to systemic effects consistent with anaphylactoid-type reactions, which are characterized by the direct release of histamine from mast cells (degranulation). Nonclinical safety assessments of PS80 in vivo have mainly focused on canine model systems, a species established to be particularly sensitive to PS80. However, there is conflicting data about the dose and route of administration of PS80 required to elicit an anaphylactoid-type reaction in this model system. Therefore, studies using multiple dosing regimens in anesthetized and conscious dogs including a combination of cardiovascular data, clinical signs, and biomarkers of mast cell degranulation were conducted. An intravenous (IV) bolus of 1 mg/kg PS80 (0.25% w/v) elicited a positive anaphylactoid reaction including increased heart rate, hypotension, and clinical signs associated with anaphylactoid reactions (e.g., reddened muzzle). However, a full reaction was not observed with a subcutaneous (SC) injection of PS80 (0.25% w/v) up to 20 mg/kg and IV bolus or IV infusions up to 0.5 mg/kg. These data establish a threshold dose for eliciting an anaphylactoid reaction in canine which varies depending on the route of administration as well as the rate of PS80 infusion.

Sinomenine-induced histamine release-like anaphylactoid reactions are blocked by tranilast via inhibiting NF-κB signaling.

Zhengqing Fengtongning (ZQFTN), the pharmaceutical preparation of sinomenine (SIN) derived from the medicinal plant Sinmenium acutum, is well-known in China as an effective treatment for rheumatoid arthritis (RA). However, its histamine-release anaphylactoid reactions (HRARs) occur often in some patients. Therefore, it is desirable to establish effective clinical protocols to manage such HRARs. In the study, rat models with systemic HRARs and local HRARs of the skin were established. The level of vascular permeability and mast cell numbers was determined by quantitative analysis using Evans blue dye and histological assays. The levels of histamine, leukotriene B4 (LTB4) and IL-33 in plasma were detected by UHPLC-SPE-MS, ELISA and immunohistochemistry assays, respectively. The results demonstrated that SIN significantly induced both systemic and local HRARs in rats, showing significant decrease of body temperature, increases in vascular permeability in skin, injury of lung tissues and mast cell infiltration and IL-33 expression in skin and lung tissues. Mechanistic study showed that tranilast could prevent SIN-triggered HRARs via inhibition of H1 receptor gene expression and NF-κB signaling. Our findings provide evidence that mast cell membrane stabilizers and H1 receptor blockers effectively prevent SIN-induced HRARs, and cromolyn, cetirizine and tranilast can be used in the clinic for the management of HRARs induced by ZQFTN.

Benzodiazepine Allergy With Anesthesia Administration: A Review of Current Literature.

The incidence of anaphylactic/anaphylactoid reactions has been reported to vary between 1 : 3500 and 1 : 20,000 cases with a mortality rate ranging from 3 to 9%. Clinical signs present as skin rash, urticaria, angioedema, bronchospasm, tachycardia, bradycardia, and hypotension. Rapid identification and treatment are crucial to overall patient prognosis, as delayed intervention is associated with increased mortality. Diagnosis may be confirmed with clinical presentation, serum tryptase levels, and skin test results. While the main causative agents in anesthetic practice are typically neuromuscular blocking agents (NMBs), latex, and antibiotics, this review aims to discuss recognition, management, and preventive measures in perioperative anaphylactic/anaphylactoid reactions from benzodiazepine administration.

Investigating a Novel Two-Bag N-Acetylcysteine Regimen for Acetaminophen Toxicity.

BACKGROUND: Acetaminophen toxicity remains one of the most common causes of liver failure and is treated with a course of n-acetylcysteine (NAC). This exceptionally effective medication is traditionally administered using a complicated three-bag protocol that is prone to administration errors. OBJECTIVE: We aimed to assess whether switching to a novel two-bag protocol (150 mg/kg over 1 h followed by 150 mg/kg over 20 h) reduced administration errors while not increasing liver injury or anaphylactoid reactions. METHODS: This was a retrospective chart review of hospital encounters for patients with acetaminophen toxicity, comparing outcomes before and after the change from a three-bag protocol to a two-bag protocol at two affiliated institutions. The primary outcome was incidence of medication errors with secondary outcomes including acute liver injury (ALI) and incidence of non-anaphylactoid allergic reactions (NAAR). The study was approved by the health system's Institutional Review Board. RESULTS: 483 encounters were included for analysis (239 in the three-bag and 244 in the two-bag groups). NAAR were identified in 11 patients with no difference seen between groups. Similarly, no differences were seen in ALI. Medication administration errors were observed significantly less often in the two-bag group (OR 0.24) after adjusting for confounders. CONCLUSION: Transitioning to a novel two-bag NAC regimen decreased administration errors. This adds to the literature that two-bag NAC regimens are not only safe but also may have significant benefits over the traditional NAC protocol.

A prospective observation of PICC related anaphylactoid reactions.

PURPOSE: To explore the incidence, signs and symptoms, causes and prognosis of anaphylactoid reactions in PICC catheterization. METHODS: Prospectively observe the occurrence of anaphylactoid reactions in coated and uncoated PICC during insertion from November 2018 to April 2020. A diagnosis of anaphylactoid reactions was based on the signs and symptoms and laboratory results, and then collect data for analysis. RESULTS: A total of 1439 coated catheters were inserted, of which 30 resulted in anaphylactoid reactions (2.08%). The signs and symptoms were mainly skin system symptoms, combined with respiratory, cardiovascular, and digestive system symptoms. The anaphylactoid reaction rates of coated catheters were higher than those of uncoated catheters (χ2 = 38.417, 19.352, p < .01). A 29 of 30 patients completed catheterization after symptoms were resolved, these catheters were removed after treatment completion. Catheterization was terminated in one patient. There were no anaphylactoid reactions in 2850 uncoated catheters. CONCLUSION: Anaphylactoid reactions may occur during catheterization when using the coated PICC, which should be paid attention to in clinical application.

Anaphylactoid reactions induced by Shuanghuanglian injection and Shenmai injection and metabolomics analysis.

Introduction: Shuanghuanglian injection (lyophilized) (SHLI) is commonly used to treat respiratory tract infection. Shenmai injection (SMI) is mainly used to treat cardiovascular diseases. Despite their widespread clinical use, anaphylactoid reactions (ARs) induced by SHLI and SMI have been reported, which have attracted broad attention. However, the impact of ARs on metabolic changes and the underlying mechanisms are still unclear. Methods: ICR mice were used as model animals and were treated with normal saline, C48/80, SHLI and SMI, respectively. The behavior of mice, auricle blue staining and Evans Blue exudation were used as indexes to evaluate the sensitization of SHLI and SMI and determine the optimal sensitization dose. Anaphylactoid mice model was established based on the optimal dose and enzyme-linked immunosorbent assay (ELISA) was used to model verification. Afterwards, plasma samples of administered mice were profiled by LC-MS metabolomics and analyzed to evaluate the changes in metabolites. Results: High doses of both SHLI and SMI can induce severe anaphylactoid reactions while the reaction induced by SMI was weaker. A Partial Least-Squares Discriminant Analysis (PLS-DA) score plot indicated that following administration, significant metabolic changes occurred in mice. 23 distinct metabolites, including deoxycholic acid, histamine, and 5-hydroxytryptophan, were identified in the SHLI groups. 11 distinct metabolites, including androsterone, 17α-hydroxypregnenolone, and 5-hydroxyindoleacetate, were identified in the SMI groups. Meanwhile, different metabolic pathways of SHLI and SMI were predicted by different metabolites. The associated metabolic pathways include steroid hormone biosynthesis, tryptophan metabolism, histidine metabolism, arachidonic acid metabolism, nicotinate and nicotinamide metabolism, and primary bile acid biosynthesis. Conclusion: Study showed that both SHLI and SMI can induce varying degrees of anaphylactoid reactions, a positive correlation between response intensity and dose was observed. Metabolomics showed that SHLI and SMI may promote the simultaneous release of hormones and inflammatory factors by disturbing relevant metabolic pathways, while SMI may also inhibit the release of inflammatory factors in arachidonic acid metabolic pathway, indicating both pro-inflammatory and anti-inflammatory effects. This study will serve as a reference for developing a new approach to evaluate the safety of SHLI and SMI from perspective of susceptible drug varieties. However, ARs mechanism requires further verification.

Anaphylactoid reaction during hemodiafiltration on AN69 membrane in a patient with atypical hemolytic uremic syndrome: A pediatric case report.

Reactions associated with hemodiafiltration can be life threatening if not recognized early in the course of dialysis. AN69 (acrylonitrile and sodium methallyl sulfonate copolymer) membrane-associated reactions during hemodialysis have been documented in adult patients receiving angiotensin converting enzyme inhibitors, which are thought to be triggered by the negative charge of the AN69 membrane. Here, we present a 5-month-old girl requiring continuous renal replacement therapy (CRRT) for acute kidney injury secondary to atypical hemolytic uremic syndrome who experienced acute cyanosis, angioedema, tachycardia, and impaired circulation during CRRT. After switching to a different type of hemofiltration membrane, her clinical findings improved and she was able to tolerate hemodialysis. We concluded that she had experienced an anaphylactoid reaction to the AN69 membrane. To our knowledge, this case is the first pediatric case report of AN69 membrane-associated anaphylactoid reaction.

Intraoperative Anaphylaxis Following Injection of a Bleomycin-Gelatin Solution for Sclerotherapy.

During the perioperative period, the most commonly identified agents that are responsible for acute allergic reactions include antibiotics, neuromuscular blocking agents, opioids, chlorhexidine, and iodinated dyes for radiologic imaging. However, whenever an allergic reaction is suspected, all of the agents to which the patient has been exposed must be considered. Although bleomycin is utilized as the primary agent for sclerotherapy in the treatment of vascular malformations, other substances such as Surgiflo® may be added to the bleomycin solution to increase its efficacy and promote thrombosis of the smaller vessels. These products are derived from animal collagen and contain gelatin which may lead to an allergic reaction. We present an 11-year-old girl undergoing sclerotherapy treatment of an extensive left lower extremity venous malformation who subsequently developed perioperative hemodynamic instability requiring intervention after receiving an injection of a bleomycin and Surgiflo® solution. Further investigation identified gelatin in the Surgiflo® as the causative agent of the allergic event. Previous reports of such reactions are reviewed and the perioperative care and treatment of patients who experience anaphylaxis is addressed.

Macromolecules in polysorbate 80 for injection: an important cause of anaphylactoid reactions.

Polysorbate 80 for injection (TW80) is a common excipient used for injection whose macromolecular impurities, including those that cause anaphylactoid reactions, are frequently ignored. The main aim of this study was to prove that the macromolecular impurities in the excipient are an important cause of anaphylactoid reactions. Component A (containing macromolecules > 100 kDa), Component B (containing macromolecules from 10 to 100 kDa), and Component C (containing substances < 10 kDa) were prepaired from the original TW80 using ultrafilters. The original TW80 contained numerous substances with molecular weights > 10kD. The original TW80 and Components A and B caused strong anaphylactoid reactions in both guinea pigs and rabbits by intravenous administration. Moreover, the original TW80 and Components A and B even caused strong passive cutaneous anaphylactoid (PCA) reactions and pulmonary capillary permeability. The PCA reaction and increased permeability were partly prevented by cromolyn sodium. Additionally, the original TW80 and Components A and B caused vasodilation and severe hemolysis in vitro. The anaphylactoid reactions were associated with histamine release but not with mast cell degranulation. Nevertheless, Component C almost caused no anaphylactoid reactions or hemolysis and was weaker in the few reactions that ocurred. Taken together, these results suggest that macromolecular substances are one of the main risk factors responsible for anaphylactoid reactions and hemolysis caused by TW80.

Nonrenal Complications of Contrast Media.

Injection of contrast media is the foundation of invasive and interventional cardiovascular practice. Iodine-based contrast was first used in the 1920s for urologic procedures and examinations. The initially used agents had high ionic and osmolar concentrations, which led to significant side effects, namely nausea, vomiting, and hypotension. Newer contrast agents had lower ionic concentrations and lower osmolarity. Modifications to the ionic structure and iodine content led to the development of ionic low-osmolar, nonionic low-osmolar, and nonionic iso-osmolar contrast media. Contemporary contrast agents are better tolerated and produce fewer major side effects.

Human Clinical Relevance of the Porcine Model of Pseudoallergic Infusion Reactions.

Pigs provide a highly sensitive animal model for pseudoallergic infusion reactions, which are mild-to-severe hypersensitivity reactions (HSRs) that arise following intravenous administration of certain nanoparticulate drugs (nanomedicines) and other macromolecular structures. This model has been used in research for three decades and was also proposed by regulatory bodies for preclinical assessment of the risk of HSRs in the clinical stages of nano-drug development. However, there are views challenging the human relevance of the model and its utility in preclinical safety evaluation of nanomedicines. The argument challenging the model refers to the "global response" of pulmonary intravascular macrophages (PIM cells) in the lung of pigs, preventing the distinction of reactogenic from non-reactogenic particles, therefore overestimating the risk of HSRs relative to its occurrence in the normal human population. The goal of this review is to present the large body of experimental and clinical evidence negating the "global response" claim, while also showing the concordance of symptoms caused by different reactogenic nanoparticles in pigs and hypersensitive man. Contrary to the model's demotion, we propose that the above features, together with the high reproducibility of quantifiable physiological endpoints, validate the porcine "complement activation-related pseudoallergy" (CARPA) model for safety evaluations. However, it needs to be kept in mind that the model is a disease model in the context of hypersensitivity to certain nanomedicines. Rather than toxicity screening, its main purpose is specific identification of HSR hazard, also enabling studies on the mechanism and mitigation of potentially serious HSRs.

Liquid Chromatography Tandem Mass Spectrometry Based Label-Free Quantification Method for Assessment of Allergen-Induced Anaphylactoid Reactions.

Mast cells are essential in mediating inflammatory processes. When activated, mast cells can rapidly release characteristic granules and various mediators into the interstitium. Tryptase (TPS) and ß-hexosaminidase (HEXB) are typical protease mediators stored in granules and released upon activation. They have been recognized as important biomarkers of anaphylaxis, and the released level is associated with the severity of allergic reactions. In this study, a sensitive, accurate, and selective liquid chromatography tandem mass spectrometry (LC-MS/MS) method for simultaneously quantifying the two biomarkers was developed and validated in LAD2 cell culture supernatant, and P14R was used as internal standard. Good linearity was observed in the range of 50-2500 ng/mL for TPS and 10-2000 ng/mL for HEXB both with R2 > 0.99. The matrix effect and recovery were both within acceptable limits. We quantified TPS and HEXB released from Laboratory of Allergic Disease 2 (LAD2) mast cells treated with several potential allergens, and the results demonstrate that the method can be used to investigate TPS and HEXB levels in LAD2 mast cell model during allergy research. We anticipate our approach to be a robust and sensitive assessment method for more biomarkers with similar kinetics characteristics and to be a major tool of allergic drug assessment or antiallergic drug development in research.

A mast-cell-specific receptor mediates Iopamidol induced immediate IgE-independent anaphylactoid reactions.

Iopamidol is a radiographic contrast media which caused a very high incidence of anaphylactic reactions. Mast cells are sentinel cells in host defense reactions during immediate hypersensitivity responses and anaphylactic responses. Mas-related G protein-coupled receptor X2 (MRGPRX2) is a kind of mast cell specific receptor, which triggers mast cell degranulation in anaphylactic reactions. Mice MrgprB2 is a homologous gene of MRGPRX2. We sought to better understand the anaphylactic reactions induced by Iopamidol and the mechanisms involving MRGPRX2. The MRGPRX2-related anaphylactic reactions induced by Iopamidol were investigated using the hindpaw swelling and extravasation assay in vivo and a calcium imaging assay was used for mast cell intracellular calcium responses detection and mast cell release of anaphylactic mediators, such as ß-hexosaminidase, histamine and TNF-α, was also detected in vitro. The mast cell deficient KitW-sh/W-sh mice and MrgprB2 knockout mice exhibited a reduced Iopamidol-induced inflammation effect compared with wild type mice. Furthermore, human mast cells that express MRGPRX2 were activated by Iopamidol in a dose-dependent manner, meanwhile MRGPRX2 knockdown mast cells showed reduced intracellular calcium responses and anaphylactic mediators release effect. It could be concluded that Iopamidol-induced anaphylactoid reactions were MRGPRX2 mediated to provoke mast cells Ca2+ mobilization and degranulation.

Fewer adverse effects with a modified two-bag acetylcysteine protocol in paracetamol overdose.

OBJECTIVE: Acetylcysteine (NAC), an effective antidote for paracetamol poisoning, is commonly associated with adverse reactions. This has been postulated to be related to the rapid initial infusion rate (150 mg/kg over 1 h) of the traditional three-bag protocol. We hypothesized that a slower rate would result in fewer adverse reactions. Our institution in Western Sydney moved to a modified two-bag protocol in February 2015 - first bag: 200 mg/kg over 4 h (50 mg/kg/h) and second bag: (100 mg/kg over 16 h). METHODS: Data was extracted from our database on paracetamol overdoses treated with NAC from August 2010 to September 2016. We compared adverse reactions in patients receiving the modified two-bag protocol with a historical control (traditional three-bag regimen with initial bolus of 150 mg/kg/h). RESULTS: Over the study period 1011 paracetamol poisonings presented to our toxicology service, of which 476 required NAC (three-bag = 313, two-bag = 163). Demographic characteristics of the two groups were similar. Fewer anaphylactoid reactions (itch, rash, and swelling) occurred using the two-bag regimen (14% versus 5%, p = .002), a relative reduction of 66%. Similarly, there were fewer prescriptions of anti-allergy medications in the two-bag group (11% versus 4%, p = .01). There was no difference in incidence of hepatotoxicity. CONCLUSIONS: Adverse reactions to NAC were less common with the two-bag regimen. These results add to the accumulating evidence that reducing the initial NAC infusion rate reduces the risk of adverse reactions.

Cisatracurium induces mast cell activation and pseudo-allergic reactions via MRGPRX2.

BACKGROUND: Pseudo-allergic reactions occur when patients receive muscle relaxants during perioperative anesthesia. These reactions may result in a serious threat to the patient's life, particularly to a child's life. Cisatracurium, a relatively new NMBA, has resulted in bronchospasms and cardiovascular collapse. However, the mechanisms underlying the anaphylactoid reactions caused by cisatracurium have not been fully elucidated. METHODS: In the present study, the MRGPRX2-related pseudo-allergic reactions induced by cisatracurium were investigated using hindpaw swelling and extravasation assays in vivo and mast cell degranulation assays. RESULTS: Cisatracurium caused anaphylactoid reactions in wild-type mice. However, cisatracurium did not induce a similar phenomenon in KitW-sh/W-sh mice. Furthermore, mast cell-related G protein-coupled receptor B2-knockout mice did not display an inflammatory response upon treatment with cisatracurium. Cisatracurium induced LAD2 cell degranulation, leading to the dose-dependent release of ß-hexosaminidase, histamine and TNF-α. However, cisatracurium only induced the release of low levels of these mediator LAD2 cells transfected with MRGPRX2 siRNA. Cisatracurium also stimulated intracellular Ca2+ influx in MRGPRX2-HEK293 cells compared with that in NC-HKE293 cells. Interestingly, cytokine release was not observed in LAD2 cells even with high dose of cisatracurium. CONCLUSIONS: Cisatracurium activated MRGPRX2 and triggered mast cell degranulation, leading to anaphylactoid reactions. Therefore, strategies targeting MRGPRX2 might potentially block cisatracurium-induced pseudo-allergic reactions.

Therapeutic plasma exchange: a second-line treatment for brodifacoum poisoning following an anaphylactoid reaction to vitamin K.

Vitamin K1 is the first-line therapy to brodifacoum poisoning. Anaphylactoid reactions may occur anytime during intravenous administration of vitamin K1 injection. Vitamin K1 must be ceased when anaphylactoid reactions emerge, and therapeutic plasma exchange could be a second-line option.

MRGPRX2 is essential for sinomenine hydrochloride induced anaphylactoid reactions.

Mast cells are unique immunocytes that function as sentinel cells in host defense reactions such as immediate hypersensitivity responses and anaphylactic responses. The mast cell specific receptor MRGPRX2 (Mas-related G protein-coupled receptor X2) triggers mast cell degranulation-a key process in anaphylactic reactions. We sought to better understand anaphylactic reaction induced by sinomenine hydrochloride (SH). MRGPRX2-related pseudo-allergic reactions induced by SH were investigated using the hindpaw swelling and extravasation assay in vivo and mast cell degranulation assays in vitro. MrgprB2 knockout mice exhibit a reduced SH-induced inflammation effect. Furthermore, MRGPRX2 (the orthologous gene of MrgprB2) related human mast cells are activated by SH in a dose-dependent manner; however, MRGPRX2 knockdown mast cells showed reduced degranulation. The results showed a kind of mechanism that SH-induced anaphylactoid reactions were mediated by MRGPRX2 via activating PLC molecular signaling pathways to provoke mast cells Ca2+ mobilization and degranulation.

Nonrenal Complications of Contrast Media.

Nonrenal complications of contrast media are caused by chemotoxic or anaphylactoid reactions related to the contrast agent used. Chemotoxicity is mainly attributed to ionic concentration and osmolality. Anaphylactoid reactions are typically caused by direct activation of basophils, mast cells, and complement rather than an observable antigen-antibody interaction, and may be acute or delayed. History of an adverse reaction following prior exposure is the strongest predictor of a subsequent adverse reaction to contrast. Premedication regimens of corticosteroids or antihistamines can lower the risk of repeat adverse reactions. Treatment of anaphylactoid reactions depends on the severity of symptoms.

Pathogenic mechanisms underlying adverse reactions induced by intravenous administration of snake antivenoms.

Snake antivenoms are formulations of immunoglobulins, or immunoglobulin fragments, purified from the plasma of animals immunized with snake venoms. Their therapeutic success lies in their ability to mitigate the progress of toxic effects induced by snake venom components, when administered intravenously. However, due to diverse factors, such as deficient manufacturing practices, physicochemical characteristics of formulations, or inherent properties of heterologous immunoglobulins, antivenoms can induce undesirable adverse reactions. Based on the time lapse between antivenom administration and the onset of clinical manifestations, the World Health Organization has classified these adverse reactions as: 1 - Early reactions, if they occur within the first hours after antivenom infusion, or 2 - late reactions, when occurring between 5 and 20 days after treatment. While all late reactions are mediated by IgM or IgG antibodies raised in the patient against antivenom proteins, and the consequent formation of immune complexes, several mechanisms may be responsible for the early reactions, such as pyrogenic reactions, IgE-mediated reactions, or non IgE-mediated reactions. This work reviews the hypotheses that have been proposed to explain the mechanisms involved in these adverse reactions to antivenoms. The understanding of these pathogenic mechanisms is necessary for the development of safer products and for the improvement of snakebite envenomation treatment.