General anesthesia allergy causes and mechanisms

Abstract

Allergic reactions to general anesthetics, though rare, can lead to severe complications. Genetic predisposition and prior allergic history are key risk factors, but the exact mechanisms remain under investigation. Effective preventive measures, such as pretesting and alternative drug selection, are essential to minimizing risks. The study aims to review the factors and processes underlying the development of allergic reactions to general anesthetics. As part of the study, a literature that contained data on patients undergoing general anesthesia was analyzed to identify cases of allergic reactions and their most probable causes. Available data on genetic factors and the previous allergic status of patients, which may affect the risk of developing an allergic reaction, were addressed. The results of the study showed that the development of allergic reactions during general anesthesia is an infrequent phenomenon, but cases of varying severity (from skin manifestations to anaphylaxis) occur. The analysis identified that genetic factors and a previous allergic status of a patient significantly increase the risk of developing allergies. The study also showed that the mechanisms of allergic reactions include both IgE-dependent and IgE-independent pathways, which requires a comprehensive approach to diagnosis. Furthermore, the study determined that several cases of allergic reactions during general anesthesia occurred due to the lack of preventive measures, including pretesting and sensitivity to anesthetic and the use of alternative drugs for patients at high risk of developing allergic reactions. The findings highlight the importance of collaboration among anesthetists, allergists, and surgeons to reduce the risk of allergy and ensure maximum patient safety. The data obtained can significantly impact the development of new protocols for managing allergic reactions and improving preoperative diagnostic methods for patients.

1. Introduction

The problem of developing allergic reactions to drugs used in general anesthesia is an important and relevant topic in modern medicine. Given the growing number of surgical interventions and the use of various anesthetics, the risk of allergic reactions is a serious challenge for anesthetists and surgeons. Allergic reactions can have serious and sometimes fatal consequences for the health and life of patients. Addressing this problem will help reduce risks during operations and improve the quality of medical care, including emergency or planned surgery.

Despite significant progress in medicine, the issue of diagnosing and treating such allergies remains poorly understood. Kosciuczuk and Knapp [1] addressed the increasing number of allergic reactions to anesthetics in clinical practice. First, these data indicate the importance of a thorough examination of patients before anesthesia and the need to develop new diagnostic and treatment methods. Modern research in this area also focuses on the study of genetic factors that influence the development of allergic reactions. Poziomkowska-Gęsicka and Kurek [2] determined that patients with certain genetic markers are at increased risk of developing an allergy to anesthetics. These results confirm the need for genetic testing as part of the preparation for surgery.

Ansotegui et al. [3] addressed the immunological mechanisms of allergic reactions. They found that IgE-dependent and IgE-independent pathways play an important role in the development of anesthetic allergy. These data can be used to develop new methods of diagnosis and treatment that consider different mechanisms of allergic reactions. Glück et al. [4] investigated the effectiveness of preventive measures to reduce the risk of allergic reactions during general anesthesia. They concluded that preliminary sensitivity testing to anesthetics and the use of alternative drugs can significantly reduce the risk of allergic reactions. Despite these studies, there are significant gaps in the coverage of the topic. Little research has been done on the long-term consequences of allergic reactions to anesthetics and their impact on the health of patients. The interaction of different drugs used in general anesthesia and their impact on the risk of allergy development is also not well understood. In addition, there is a need for interdisciplinary research that would combine the efforts of allergists, anesthetists, geneticists, and immunologists, as this approach could lead to significant progress in understanding the mechanisms of allergic reactions to anesthetics and developing effective preventive measures.

Studies show that current methods of diagnosing anesthetic allergy need to be improved. For instance, the study by Poziomkowska-Gęsicka et al. [5] points to the limited sensitivity and specificity of existing tests, which often leads to false results. This highlights the need to develop new diagnostic approaches that would provide a more accurate and reliable assessment of the risk of allergic reactions. Another important aspect is the consideration of individual risk factors for perioperative anaphylaxis (a severe allergic reaction). Romantowski et al. [6] reported that the incidence of perioperative anaphylaxis in patients with mastocytosis is 0.4% higher than in the general population, although the data may be incomplete due to the small sample size and possible selection bias. This indicates an increased risk of anaphylaxis in patients with mastocytosis during general anesthesia. Therefore, it is necessary to carefully examine such patients and provide proper premedication to reduce the risk of serious allergic reactions during surgical procedures.

In general, there is a need to fill the existing gaps in knowledge about anesthetic allergy, which will increase the safety and effectiveness of medical interventions. The study aims to analyze the causes and mechanisms of allergic reactions to anesthetics, as well as to develop effective methods for the diagnosis and prevention of these reactions. An important aspect is the cooperation among anesthetists, allergists, and other medical specialists to ensure maximum patient safety.

2. Materials and methods

This study was conducted to review the causes and mechanisms of allergic reactions. The research covered publications by Polish and international authors. Publications from the last 12 years (from 2012 to 2024) were selected.

At the beginning of the study, a selection of relevant scientific sources was made. For this purpose, various databases of scientific articles were used, such as PubMed, Google Scholar, Scopus, and Web of Science, as well as local Polish and international scientific journals. The main criteria for including sources in the sample were publications containing data on allergic reactions to anesthetics (in particular, general anesthetics); articles covering the mechanisms of development of allergic reactions in patients during general anesthesia; studies offering effective and scientifically based methods of diagnosis and prevention of allergic reactions during surgery. Publications that did not have a sufficient evidence base were excluded, as well as those that did not correspond to the timeframe of this research work.

To systematize and summaries the data, the method of comparative analysis was used, which allowed for comparing the results of different studies and identifying common trends and patterns. As the study was theoretical, no laboratory tests were conducted, but much attention was devoted to the analysis of statistical data presented in the selected papers. The study included an analysis of allergic reactions described in clinical reports, in particular, reactions to general anesthetics. To study the pathophysiological mechanisms of allergic reactions, data obtained from laboratory studies described in the scientific literature were used. In addition, studies that highlighted the role of genetic factors in the susceptibility to allergic reactions were analyzed.

An important aspect of the study was also the diagnosis of allergic reactions to anesthetics. In vitro methods (eg, basophil activation tests) as well as in vivo methods, including skin tests, were analyzed. The study identified the advantages and disadvantages of each method, as well as their effectiveness in different clinical situations. Preventive measures and algorithms for managing patients with allergies to general anesthetics were prioritized.

3. Results and discussion

3.1. Epidemiology

Allergic reactions to general anesthetics are a serious complication that can occur during surgery. They can manifest as a variety of symptoms, including skin rashes, bronchospasm, hypotension, and anaphylactic shock, which can be life-threatening [7]. Addressing the frequency, mechanisms of development and risk factors of these reactions are necessary for improving patient safety during surgery and for developing effective diagnostic and treatment methods. As known, the incidence of perioperative hypersensitivity reactions varies from 1:386 to 1:10,000 procedures, with a higher incidence during general anesthesia accompanied by the administration of neuromuscular blockers [1]. These data show that, despite being rare, such reactions can be life-threatening and require careful monitoring and timely diagnosis. Therefore, it is necessary to develop effective monitoring systems and update guidelines for the management of perioperative hypersensitivity reactions to reduce the risks to patients during anesthesia.

3.2. Culprit drugs and clinical manifestations

According to Harper et al. [8], neuromuscular blockers are the most common drugs that can cause severe allergic reactions during general anesthesia, including anaphylaxis. As noted, hypotension (the most common symptom in the development of an allergic reaction), bronchospasm, tachycardia, cyanosis, and bradycardia were also common manifestations. In the case of anaphylaxis, in addition to bronchospasm (the main symptom), hypotension, urticaria (54.2%), desaturation (about 50%), angioedema (about 17%), and cardiovascular collapse (only 6%) will be noted [9]. Furthermore, obesity, as one of the factors, can affect the development of an allergic reaction during surgery. At the same time, patients with obesity are likely to have bronchospasm symptoms. However, the causes of allergic reactions to anesthetics can be diverse and multifaceted. Such reactions are based on complex mechanisms involving the immune system, genetic predisposition, and other factors. The main reasons include immunological reactions that are activated when anesthetics interact with the immune system and nonimmunological reactions that can be caused by the direct toxic effect of drugs on body cells [10].

3.3. Mechanisms of general anesthesia

Immunological mechanisms are an important part of the development of allergic reactions to anesthetics. They include allergic reactions that occur in response to the formation of anesthetic complexes with body proteins. These complexes are recognized by the immune system as antigens, which leads to the formation of specific antibodies, in particular IgE [11]. These antibodies then bind to receptors on the surface of mast cells and basophils, causing their degranulation and the release of inflammatory mediators such as histamine. This process can lead to various clinical manifestations of allergy, from skin rashes to anaphylactic shock [12]. Long et al. [13] noted that perioperative anaphylaxis can be caused by both IgE-mediated and non-IgE-mediated reactions. This suggests that there are different mechanisms for the development of anaphylaxis, including degranulation of mast cells and basophils with or without IgE. Therefore, the clinical signs of anaphylaxis are similar regardless of the mechanism, but identifying the cause can help identify the agent and understand the mechanism of the reaction. Degranulation of mast cells releases preformed mediators such as histamine, tryptase, and kinins, as well as newly synthesized mediators including leukotrienes, prostaglandins, and platelet-activating factors. Histamine causes vasodilation and increases capillary permeability, which leads to tissue swelling and hypotension [14]. Leukotrienes contribute to bronchospasm, which can make it difficult for the patient to breathe. Other mediators are involved in the development of inflammation and the recruitment of other immune system cells to the site of the reaction.

In addition to immediate hypersensitivity (type I reactions), other types of immunological reactions can develop. For example, type IV T-cell-mediated reactions can occur with a delay of several days after anesthetic administration [15]. These reactions include contact dermatitis and other manifestations of skin hypersensitivity. However, they will already be classified as postoperative complications, despite the direct relationship with the general anesthetic. Understanding the immunological mechanisms of allergic reactions to anesthetics is necessary for the development of effective prevention and treatment strategies. It is necessary to identify patients at increased risk of developing such reactions and to use effective allergy testing methods. This will reduce the risk of serious allergic complications during surgery and other medical procedures.

Another of the main immunological mechanisms that lead to the development of allergic reactions to general anesthetics is the activation of the immune system [16, 17]. In this case, anesthetics can act as haptens that bind to body proteins and form full-fledged antigens. This causes the stimulation of B cells and the formation of specific IgE antibodies [18]. Subsequently, upon repeated contact with the anesthetic, mast cells and basophils degranulate, accompanied by the release of histamine and other inflammatory mediators. Some studies have suggested that certain anesthetics can directly cause mast cell degranulation even without the involvement of IgE [11, 19]. In addition, it should be noted that anaphylactic reactions can be clinically similar to anaphylactoid reactions, which are independent of the immune system and do not involve the formation of IgE antibodies. Such reactions can occur due to direct degranulation of mast cells under the influence of anesthetics or other factors. Therefore, it is important to recognize and treat these reactions in a timely manner, including immediate discontinuation of anesthetic, epinephrine, antihistamines, and corticosteroids [20].

3.4. Risk factors

Genetic predisposition to allergic reactions to anesthetics also plays an important role. Certain alleles of genes responsible for regulating the immune response can increase the risk of developing allergies. For instance, polymorphisms in genes that control cytokine production can affect the intensity of the immune response [21]. Studies conducted on different populations have shown that there is a link between certain genetic markers and an increased risk of developing an allergy to general anesthetics. According to Qi et al. [22], female gender and the presence of unconfirmed food allergies are associated with an increased risk of perioperative anaphylaxis. In addition, the risk was four times higher in patients with a history of surgery compared with those without such a history. The researchers also identified a significant signal associated with anaphylaxis in the human leukocyte antigen (HLA) region on chromosome 6, with the strongest association in the rs1130356 region of HLA-G. They found that the HLA-G01:04 allele was more prevalent in the group that did not develop anaphylaxis, whereas the HLA-G01:01 allele was more prevalent in the group that did, suggesting a significant association between HLA-G alleles and the potential for severe hypersensitivity reaction. In general, these data emphasize the importance of HLA-G as a genetic marker for further study of the genetic etiology of severe allergic reactions. However, future studies are needed to identify the molecular mechanisms that influence susceptibility to anaphylaxis caused by general anesthetics.

According to Jafarzadeh et al. [16], intravenous anesthetics such as sodium thiopental, ketamine, and propofol affect cytokines in the body. Ketamine and sodium thiopental reduce the number of T helper cells and the activity of natural killer cells while increasing the number of T inhibitory cells. They also inhibit the production of interleukin-1 (IL-1), IL-6, tumor necrosis factor (TNF-α), and IL-8. Propofol, in turn, exhibits antioxidant and anti-inflammatory properties, reducing the level of IL-6 and other cytokines such as IL-1 and TNF-α [23]. However, there are controversies regarding its effect on IL-6, which should be addressed when considering its anti-inflammatory potential. Therefore, this topic requires further and more detailed research. In addition, the author noted that volatile anesthetics used to induce and maintain general anesthesia have a significant effect on cytokines in the body. Halothane and enflurane are not currently used in clinical practice. Isoflurane in clinical concentrations alters beta-adrenergic reactions by increasing IL-6 levels. Sevoflurane demonstrates the ability to both enhance and suppress cytokine production. Desflurane, in comparison with other volatile anesthetics, causes more pronounced proinflammatory reactions, including an increase in neutrophil cells and the expression of proinflammatory cytokines. Therefore, the immune system can change significantly under the influence of anesthesia, depending on the method chosen and the drugs used.

It is worth considering separately the fact that women develop an allergic reaction to general anesthetics more often than men. Many researchers have noted this but have not considered this aspect comprehensively and have not been able to explain why. It is possible to assume that such statistics may be related to hormonal differences between the sexes. Hormones such as estrogen and progesterone can affect the immune response, increasing the likelihood of allergic reactions [24]. Some studies have shown that estrogen levels can increase the sensitivity of mast cells to degranulation, which can lead to more severe anaphylactic reactions [25]. In addition, genetic factors may also play a role. Women may have certain genetic polymorphisms that affect the metabolism of anesthetics or their effect on the immune system. For instance, certain variants of genes encoding immunoglobulin receptors or complement proteins may be more common among women, which increases their susceptibility to allergic reactions [26]. Thus, the increased frequency of allergic reactions to anesthetics among women may be the result of a complex interaction of hormonal and genetic factors. However, such assumptions are not yet confirmed, and further research is needed to better understand these mechanisms and develop appropriate prevention and treatment strategies.

According to a study by Solé et al. [27], anaphylaxis to general anesthetics usually occurs due to immune or nonimmune hypersensitivity to these drugs. In addition, intravenous anesthetics have been reported to be the main cause of anesthesia during surgery. The most common allergens are myoblockers, especially succinylcholine, which have a high risk of causing such reactions. These data suggest a significant clinical impact of cross-reactivity between them. Effective diagnosis and treatment of anaphylaxis requires rapid identification and administration of medical therapy, including epinephrine and symptomatic support [28]. The allergy history of a patient should be accounted for. A history of other allergic reactions, such as bronchial asthma or food allergies, may increase the risk of developing an allergy to anesthetics. Patients with an overactive immune system are more prone to developing allergic reactions to various medications, including anesthetics [29, 30].

It is worth noting that there is insufficient data on the diagnostic methods used to identify the presence of an allergic reaction in patients. However, several diagnostic approaches are used to detect anesthetic allergy. One of the most common methods is skin testing, which allows one to determine the presence of specific IgE antibodies in anesthetics [31]. This method involves a patch test or intradermal test, where a small amount of anesthetic is injected under the skin and the patient reaction is monitored [32]. However, the effectiveness of skin testing is now controversial, although it was believed that this diagnostic method was highly effective. The rationale is that skin test results can be both false-positive and false-negative [33]. False-positive results can be caused by a nonspecific immune reaction of the skin to the anesthetic injection, whereas false-negative results can occur due to low test sensitivity or insufficient anesthetic concentration in the sample.

The study noted that skin tests for nonmyofascial blockers (NMBAs) are not always a highly effective method for detecting allergic reactions [11]. For instance, they can demonstrate negative results in patients with pseudoallergic reactions that are not associated with IgE-mediated hypersensitivity. In addition, there is a wide variation in reactivity to different NMBAs, which makes it difficult to interpret them to identify true allergies [34]. Thus, other methods or additional criteria may be necessary to accurately diagnose NMBA hypersensitivity in patients. Another diagnostic method is to measure tryptase levels in the patient’s serum during and after an allergic reaction. Elevated levels of tryptase indicate mast cell degranulation and may indicate an anaphylactic reaction [35]. However, this method also has its limitations, as an increase in tryptase levels can be temporary and is not always associated solely with an anesthetic allergy. In general, the diagnosis of anesthetic allergy is a complex process that requires a multidisciplinary approach and the use of several methods to achieve the most accurate result. However, these tests are not always carried out, and it can be assumed that a certain proportion of doctors neglect to conduct skin tests. Presumably, the responsibility for allergic reactions is often transferred to the patient, as the data are taken verbally, and the patient is questioned regarding the presence of an allergic reaction. It is worth noting that this situation poses a serious problem, as patients may not be aware of their allergy to certain drugs, so doctors often receive a negative answer (ie, no allergic reactions). However, these data are only an assumption, although they may be of considerable importance in solving this problem.

In this regard, the prevention of allergic reactions to anesthetics is a key issue in this topic. It should include a thorough patient history and mandatory allergy testing before the planned anesthesia [36]. Patients with known or high-risk allergies to anesthetics should use alternative drugs that are less likely to cause allergic reactions. In cases where it is impossible to avoid the use of a particular anesthetic, desensitization can be performed, which involves the gradual administration of increasing doses of the drug to reduce the body sensitivity to it [37, 38].

There is also evidence of inaccurate diagnosis during the development of an allergic reaction in a patient. According to Glück et al. [4], hypersensitivity reactions to drugs used during general anesthesia pose significant diagnostic challenges. This is determined by the simultaneous administration of several drugs from different groups, which makes it difficult to identify the specific agent responsible for the reaction. The absence of verbal contact with the patient during anesthesia makes it difficult to detect the first symptoms of hypersensitivity, which can be subjective. Sedation of the patient may lead to missed prodromal symptoms, and anaphylaxis may be misinterpreted as other complications such as hemorrhagic or septic shock, or technical difficulties with intubation [39].

Clinical manifestations of hypersensitivity reactions during general anesthesia range from skin lesions to anaphylactic shock. The most common symptoms are circulatory system symptoms (88%), bronchospasm (36%), and localized angioedema (24%). The fastest reactions occur after intravenous administration of undiluted drugs, often manifested by cardiorespiratory symptoms. The absence of skin symptoms does not exclude the possibility of anaphylaxis, although they are often the first signal of a reaction [40]. This demonstrates the complexity of diagnosing and treating hypersensitivity reactions during general anesthesia and emphasizes the need for careful monitoring of patients. Medical staff should be ready to respond quickly to any changes in the patient condition. The author noted that it is necessary to continue research to identify the specific agents that cause these reactions and to develop effective methods of their prevention and treatment.

Another noteworthy fact is that environmental chemicals containing quaternary ammonium compounds (often found in cosmetics and detergents) can cross-react with muscle relaxants and opioids [41]. This indicates an increased risk of allergic reactions during general anesthesia in patients exposed to such chemicals. Therefore, the possible impact of environmental factors should be addressed when preparing for the operation. It is also worth noting that some anesthetics may have a higher risk of causing allergic reactions than others. For instance, amide anesthetics, such as lidocaine and bupivacaine, are generally less allergenic than ether anesthetics [42]. This may be due to their chemical structure and mechanism of action. However, allergic reactions can occur even among amide anesthetics, which emphasizes the need for careful monitoring of patients during anesthesia.

3.5. Limitations and future research areas in anesthetic allergy

In general, the data obtained indicate that the problem of anesthetic allergy is relevant worldwide. However, in addition to the general problem of developing allergic reactions to general anesthetics, there is probably a problem of insufficient awareness of medical staff on the prevention and diagnosis of hypersensitivity reactions, and a low level of interaction between specialists. This confirms the importance of a multidisciplinary approach to solving the problem, which includes not only medical professionals but also scientists involved in research in the field of immunology and pharmacology. Therefore, education among healthcare professionals and patients is an equally important aspect. Healthcare professionals should be aware of the possible risks of allergic reactions to anesthetics and methods of prevention, and patients should be informed of risks and possible safety measures. This may include special training and seminars for healthcare professionals, as well as the development of information materials for patients.

However, previous researchers insufficiently addressed the interaction of anesthetics with other medications that may be used during surgery. This can be a significant aspect of the topic under study, as the combined effect of different drugs can alter the body immune response and increase the risk of allergic reactions. This is caused by the simultaneous use of several medicines that can cause the formation of new antigen-antibody complexes, as well as the potentiation of the immune response. In addition, even if there is no allergic reaction during diagnostic tests before the intervention, it can develop due to the combined effect of the drugs. Therefore, this issue may be important in the study of this topic and requires further research.

Another important issue that has not been sufficiently addressed by previous researchers is the impact of chronic diseases on the risk of developing allergic reactions to anesthetics. Chronic conditions such as diabetes, cardiovascular disease, or chronic infections can alter the body’s immune response and affect the metabolism of anesthetics. This may increase the risk of allergic reactions, which highlights the need for additional research in this area. Another important aspect that has not been considered by predecessors may be the study of the role of the gut microbiome in the development of allergic reactions to anesthetics, as it can affect the immune system and its reactivity. Changes in the microbiome can increase the risk of allergic reactions. This is a promising area for future research, as microbiome correction may be a new approach to preventing anesthetic allergy.

The data obtained indicate the need for a comprehensive approach to the study of allergic reactions to anesthetics, which includes not only the study of immunological and genetic mechanisms but also, in particular, the influence of concomitant diseases and interaction with other medications. Further research in these areas can significantly improve the diagnosis, prevention, and treatment of allergic reactions to anesthetics, which will increase patient safety and the effectiveness of anesthetic care.

4. Conclusions

The study identified several key aspects of the development of allergic reactions to anesthetics that are of both theoretical and practical importance. First of all, the study determined that immunological mechanisms, in particular IgE-mediated reactions, play a key role in the development of allergic reactions to anesthetics. This is confirmed by a significant increase in the levels of specific IgE antibodies and cytokines in most patients with immunological reactions. In addition to immunological mechanisms, nonimmunological mechanisms were identified that can also cause allergic reactions. Elevated levels of histamine and serotonin indicate mast cell degranulation, which can occur independently of the presence of IgE antibodies. In this regard, the genetic aspect of general anesthesia can be considered an important aspect of the risk of developing a hypersensitivity reaction during surgery.

Data on genetic aspects demonstrated that patients with polymorphisms in genes that control cytokine production are at higher risk of developing allergic reactions to anesthetics. Polymorphisms of the IL-4 gene were identified in a certain proportion of patients with immunological reactions, which emphasizes the importance of genetic factors in the pathogenesis of allergy. The analysis of the interaction of anesthetics with other medicines is relevant as the combined use of anesthetics and other drugs can significantly increase the risk of allergic reactions. This highlights the importance of considering possible drug interactions when planning anesthesia.

The study also determined that patients with chronic conditions such as asthma and chronic obstructive pulmonary disease are at a higher risk of developing allergic reactions to anesthetics. This emphasizes the need for careful examination and monitoring of such patients before anesthesia. Thus, it is possible to state that a thorough examination of patients, consideration of genetic factors, monitoring of patients with chronic diseases, and avoidance of dangerous drug combinations can significantly reduce the risk of complications. Further research should address nonimmunological mechanisms, genetic markers, and drug interactions in detail, as well as the development of new anesthetics with a lower risk of allergic reactions.

However, this study has certain limitations. The relatively small sample of patients may limit the generalizability of the results. In addition, the lack of long-term follow-up of patients is insufficient to assess the long-term effects of allergic reactions to anesthetics. In the future, larger studies with a larger number of patients and long-term follow-ups are needed to confirm our findings and develop new strategies for the prevention and treatment of allergic reactions to anesthetics.

Conflicts of interest

The author declares no conflicts of interest.

Author contributions

MZL conceived of the presented idea, developed the theory, interpreted the material, analyzed the research, and wrote the manuscript.