A Rationale for Allopregnanolone Treatment of Alcohol Use Disorders: Basic and Clinical Studies.

For many years, research from around the world has suggested that the neuroactive steroid (3α,5α)-3-hydroxypregnan-20-one (allopregnanolone or 3α,5α-THP) may have therapeutic potential for treatment of various symptoms of alcohol use disorders (AUDs). In this critical review, we systematically address all the evidence that supports such a suggestion, delineate the etiologies of AUDs that are addressed by treatment with allopregnanolone or its precursor pregnenolone, and the rationale for treatment of various components of the disease based on basic science and clinical evidence. This review presents a theoretical framework for understanding how endogenous steroids that regulate the effects of stress, alcohol, and the innate immune system could play a key role in both the prevention and the treatment of AUDs. We further discuss cautions and limitations of allopregnanolone or pregnenolone therapy with suggestions regarding the management of risk and the potential for helping millions who suffer from AUDs.

Drug-induced anaphylaxis: seven-year single-center survey.

Summary: Background and Objective. Drug-induced anaphylaxis (DIA) is the most common cause of fatal anaphylaxis. We aimed to characterize patients with DIA and their allergological workup. Methods. Systematic review of patients with history of DIA referred to our center over 7 years. Results. Included 125 patients (10% pediatric age), being 36 years the median age of first episode (from 1 to 74 years). The main culprits were nonsteroidal anti-inflammatory drugs (NSAIDs) (43%), antibiotics (42%) and anesthetic agents (6%). In 24% the reactions occurred in hospital setting and 14% perioperative. The etiology was confirmed in 75% through allergological workup. Conclusions. NSAIDs and antibiotics were responsible for most of DIA. The heterogeneity of mechanisms, the severity of the reactions and the lack of standardized in vivo and/or in vitro tests for some drugs do not allow to confirm the diagnosis in all cases. Patients with DIA should be evaluated in specialized centers to perform accurate diagnosis, to prevent recurrence and to find safe alternatives.

Management of Anesthesia in Adult and Pediatric Mastocytosis: A Study of the Spanish Network on Mastocytosis (REMA) Based on 726 Anesthetic Procedures.

BACKGROUND: The role of anesthesia as an elicitor of mast cell (MC) mediator release symptoms in mastocytosis is poorly investigated. OBJECTIVE: To determine the frequency and type of MC mediator release symptoms during anesthetic procedures in mastocytosis patients. METHODS: Medical records were reviewed regarding the anesthetic techniques for 501 mastocytosis patients (459 adults and 42 children; 95 and 5% with systemic involvement, respectively) who were subjected to 676 and 50 anesthetic techniques, respectively. General, sedation, epidural, and local anesthetic techniques were used in 66 (10%), 67 (10%), 76 (11%), and 515 (76%) adult patients and in 24 (48%), 8 (16%), 2 (4%), and 25 (50%) pediatric patients. RESULTS: The frequency of perioperative MC mediator-related symptoms and anaphylaxis was 2 and 0.4% in the adult series and 4 and 2% among children. In the adult series, this frequency was significantly higher in patients who previously presented with anaphylaxis (p = 0.03), underwent major surgeries (p < 0.001) and general anesthesia (p = 0.02), and were not given prophylactic antimediator therapy (PAT) 1 h before the anesthesia (H1/H2 antihistamines and benzodiacepines; p = 0.002).Hypersensitivity and/or allergy to the involved drugs and latex allergy were ruled out in all but one symptomatic case; when PAT was given and sedation was added, some cases later tolerated the same anesthetic drugs. CONCLUSION: The frequency of perioperative anaphylaxis appears to be higher in mastocytosis patients than in the general population. Mastocytosis should not be a contraindication for anesthesia since PAT and adequate anesthetic management using the drugs with the safest profile appears to be effective in preventing/controlling MC mediator-associated symptoms.

The immune response to anesthesia: part 1.

OBJECTIVE: To review the immune response to anesthesia including mechanical ventilation, inhaled anesthetic gases, and injectable anesthetics and sedatives. STUDY DESIGN: Review. METHODS AND DATABASES: Multiple literature searches were performed using PubMed and Google Scholar from spring 2012 through fall 2013. Relevant anesthetic and immune terms were used to search databases without year published or species constraints. The online database for Veterinary Anaesthesia and Analgesia and the Journal of Veterinary Emergency and Critical Care were searched by issue starting in 2000 for relevant articles. CONCLUSION: Recent research data indicate that commonly used volatile anesthetic agents, such as isoflurane and sevoflurane, may have a protective effect on vital organs. With the lung as the target organ, protection using an appropriate anesthetic protocol may be possible during direct pulmonary insults, including mechanical ventilation, and during systemic disease processes, such as endotoxemia, generalized sepsis, and ischemia-reperfusion injury.

Prevalence of IgE against neuromuscular blocking agents in hairdressers and bakers.

BACKGROUND: Allergic IgE-mediated reactions to neuromuscular blocking agents (NMBAs) are the main cause of immediate hypersensitivity reactions in anaesthesia; their predominant occurrence in the absence of previous exposure to NMBAs suggests a risk related to environmental exposure. OBJECTIVE: To investigate the prevalence of specific IgE to quaternary ammonium ions in two populations professionally exposed to quaternary ammonium compounds, in the north-eastern France. METHODS: The study had a retrospective follow-up design whereby apprentices were assessed after their 2-year training period as apprentices. The professionally exposed hairdresser populations (n = 128) were compared with baker/pastry makers (n = 108) and 'non-exposed' matched control subjects (n = 379). RESULTS: We observed a 4.6-fold higher frequency of positive IgE against quaternary ammonium ions in hairdressers (HD), compared with baker/pastry makers (BP) and control (C) groups. The competitive inhibition of quaternary ammonium Sepharose radioimmunoassay (QAS-IgE RIA) with succinylcholine was significantly higher in HD, compared with BP and C groups, with inhibition percentage of 66.2 ± 7.4, 39.7 ± 6.0 and 43.8 ± 9.9, respectively (P < 0.001). The specific IgE against quaternary ammonium ions recognized also two compounds widely used by hairdressers, benzalkonium chloride and polyquaternium-10, in competitive inhibition of IgE RIA. When considering the whole study population, hairdresser professional exposure and total IgE > 100 kU/L were the two significant predictors of IgE-sensitization against quaternary ammonium ions in the multivariate analysis of a model that included age, sex, professional exposure, increased concentration of total IgE (IgE > 100 kU/L) and positive IgE against prevalent allergens (Phadiatop(®) ; P = 0.019 and P = 0.001, respectively). CONCLUSION AND CLINICAL RELEVANCE: The exposure to hairdressing professional occupational factors increases IgE-sensitization to NMBAs and quaternary ammonium ion compounds used in hairdressing. Besides the pholcodine hypothesis, our study suggests that repetitive exposure to quaternary ammonium compounds used in hairdressing is a risk factor for NMBAs sensitization.

Is a positive history of non-anaesthetic drug allergy a predictive factor for positive allergy tests to anaesthetics?

AIMS: International recommendations stipulate not performing screening skin tests to a drug in the absence of a clinical history consistent with that specific drug allergy. Nevertheless, two publications showed that a positive history of non-anaesthetic drug allergy was the only predictive factor for a positive skin test when screening for allergy to anaesthetic drugs was done. We selected from a surgical population 40 volunteers with a prior history of allergy to non-anaesthetic drugs in order to analyse the prevalence of positive allergy tests to anaesthetics. METHODS: The selected adult patients were tested for 11 anaesthetic drugs using in vivo tests: skin prick (SPT) and intradermal (IDT) tests and in vitro tests: the basophil activation test (BAT) and detection of drug-specific immunoglobulin E (IgE). RESULTS: The prevalence for the positive SPT and IDT was 1.6% and 5.8% respectively. The result of flow cytometry agreed with the SPT in five out of seven positive SPT (71%). IgEs confirmed two positive SPT with corresponding positive BAT. Ten per cent of the patients had a positive prick test to neuromuscular blocking agents (NMBA). For midazolam none of the SPT was positive, but 11 patients had positive IDT nonconfirmed by BAT. CONCLUSION: The prevalence of positive in vivo and in vitro allergy tests to NMBAs is higher in our study population. This could be an argument for pre-operative SPT to NMBAs for the surgical population with reported non-anaesthetic drug allergies. A larger prospective study is needed to validate changes in clinical practice.

Respuesta metabólica inmunológica e inflamatoria a la agresión anestésico quirúrgica / No disponible

En su conjunto, la respuesta inmune pretende: destruir los elementos extraños o no reparables del organismo; delimitar y aislar el foco inflamatorio, reparar las lesiones promoviendo la cicatrización y la neovascularización, activar los mecanismos generales que aporten células y nutrientes (activación neuroendocrina y metabólica); y evitar la generalización del proceso, induciendo una cierta inmunodepresión sistémica contrarreguladora. En el presente trabajo se hace una revisión sobre los aspectos fisiopatológicos derivados de la respuesta metabólica, inmunológica e inflamatoria a la agresión quirúrgica(AU)

On the Whole, the immune response seeks: to destroy the foreing or not repairable elements of the organism; to limit and to isolate the focus of the inflamation; to repair the lesion by advancyng the cicatrization and the neovascularización; to activate the general mechanisms that bring cells and nutrients (neuroendocrina and metabolic activation); and to avoid the generalization of the process inducing a certain systemic contraregulatory inmunodepression In the present work a review is maid of the physiopatologyc aspects derived from the metabolic, immunological and inflammatory response to the surgical aggression(AU)

Effects of anesthetics and analgesics on natural killer cell activity.

Surgical excision of cancerous tumors and the human stress response can lead to metastasis of tumor cells. Furthermore, the medications used during the perioperative period (eg, opioids and anesthetic agents) have been shown to inhibit or suppress natural killer (NK) cell activity, one of the body's main defenses against spread of cancer. There are currently no anesthetic regimens that have been shown to completely reverse surgical stress-induced suppression of NK cell activity. However, there may be anesthetic techniques that attenuate surgical suppression of NK cell activity. This article reviews the effects of various anesthetics and analgesics on NK cell activity and suggests techniques to attenuate the suppressive effects of these compounds.

IP-10 protects while MIP-2 promotes experimental anesthetic hapten - induced hepatitis.

MIP-2 and IFN-gamma inducible protein-10 (IP-10) and their respective receptors, CXCR2 and CXCR3, modulate tissue inflammation by recruiting neutrophils or T cells from the spleen or bone marrow. Yet, how these chemokines modulate diseases such as immune-mediated drug-induced liver injury (DILI) is essentially unknown. To investigate how chemokines modulate experimental DILI in our model we used susceptible BALB/c (WT) and IL-4-/- (KO) mice that develop significantly reduced hepatitis and splenic T cell priming to anesthetic haptens and self proteins following TFA-S100 immunizations. We detected CXCR2+ splenic granulocytes in all mice two weeks following immunizations; by three weeks, MIP-2 levels (p<0.001) and GR1+ cells were elevated in WT livers, suggesting MIP-2-recruited granulocytes. Elevated splenic CXCR3+CD4+T cells were identified after two weeks in KO mice indicating elevated IP-10 levels which were confirmed during T cell priming. This result suggested that IP-10 reduced T cell priming to critical DILI antigens. Increased T cell proliferation following co-culture of TFA-S100-primed WT splenocytes with anti-IP-10 (p<0.05) confirmed that IP-10 reduced T cell priming to CYP2E1 and TFA. We propose that MIP-2 promotes and IP-10 protects against the development of hepatitis and T cell priming in this murine model.

Anesthetics, immune cells, and immune responses.

General anesthesia accompanied by surgical stress is considered to suppress immunity, presumably by directly affecting the immune system or activating the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system. Along with stress such as surgery, blood transfusion, hypothermia, hyperglycemia, and postoperative pain, anesthetics per se are associated with suppressed immunity during perioperative periods because every anesthetic has direct suppressive effects on cellular and neurohumoral immunity through influencing the functions of immunocompetent cells and inflammatory mediator gene expression and secretion. Particularly in cancer patients, immunosuppression attributable to anesthetics, such as the dysfunction of natural killer cells and lymphocytes, may accelerate the growth and metastases of residual malignant cells, thereby worsening prognoses. Alternatively, the anti-inflammatory effects of anesthetics may be beneficial in distinct situations involving ischemia and reperfusion injury or the systemic inflammatory response syndrome (SIRS). Clinical anesthesiologists should select anesthetics and choose anesthetic methods with careful consideration of the clinical situation and the immune status of critically ill patients, in regard to long-term mortality, morbidity, and the optimal prognosis.

Peri-anesthetic anaphylaxis.

General anesthesia and anaphylaxis cause profound physiologic changes. When both occur simultaneously, it is often difficult to recognize and identify the medication or product responsible for the latter. Following such an event, the proper assessment, diagnosis, and recommendations are essential to prevent future reactions. This article reviews the more common causes of anaphylaxis during anesthesia.

Estudio sobre la respuesta de estrés, hemodinámica e inmunológica de dos técnicas anestésicas (inhalatoria e intravenosa) en colecistectomías videolaparoscópicas / Stress, hemodynamic and immunological responses to inhaled and intravenous anesthetic techniques for video-assisted laparoscopic cholecystectomy

OBJETIVO: Dados los efectos inmunomodulatorios de la anestesia y la cirugía, se compararon dos regímenes anestésicos en uso clínico, evaluando la respuesta hemodinámica, de estrés e inmunológica en pacientes de colecistectomía laparoscópica (CVL). PACIENTES Y MÉTODOS: Estudio clínico prospectivo randomizado en pacientes ASA I de CVL electivas. Los pacientes fueron asignados al azar al grupo Inhalatorio (13 pacientes anestesiados con propofol-fentanilo-isoflurano) o al grupo TIVA (14 pacientes, recibieron anestesia con propofol-remifentanilo). Se administró vecuronio en ambos grupos como relajante neuromuscular. La evaluación incluyó variables hemodinámicas, niveles de cortisol, prolactina e interleucina-6, así como recuentos leucocitarios y linfocitarios, que fueron registrados antes de la cirugía, intraoperatorio (1 hora después del comienzo de la anestesia) y en el postoperatorio (24 horas y 7 días). RESULTADOS: En ambos grupos se verificó buen control hemodinámico. En cada grupo, en los diferentes momentos anestésico quirúrgicos se produjeron cambios significativos con respecto a los valores basales en cortisol, prolactina y marcadores de la respuesta inmune-inflamatoria. Los pacientes que recibieron TIVA no modificaron sus niveles de cortisol a lo largo del estudio. Al comparar entre las dos técnicas anestésicas se observó en TIVAmenores niveles de cortisol (207 ± 100 ng/ml), y niveles más altos de neutrófilos (75 ± 12,5%) y linfocitos TCD4 (53 ± 11,6%) que en el grupo inhalatorio: cortisol 293 ± 97 ng/ml, p<0,05; neutrófilos 62 ± 20%, p<0,05 y LTCD4 42 ± 17,6%, p<0,001. CONCLUSIONES: Si bien ambas técnicas brindaron estabilidad hemodinámica, la técnica intravenosa (propofol-remifentanilo) mostró menor respuesta de cortisol y sería de elección en pacientes con compromiso de la respuesta inmunológica

OBJECTIVE: Given the immunomodulatory effects of anesthesia and surgery, 2 anesthetic regimens in clinical use were compared to evaluate hemodynamic, stress, and immunologic response in patients undergoing laparoscopic cholecystectomy. PATIENTS AND METHODS: Randomized controlled trial in patients classified ASA I and scheduled for laparoscopic cholecystectomy. Patients were randomly assigned to the inhaled anesthetic group (13 anesthetized with propofol– fentanyl–isoflurane) or the total intravenous anesthesia (TIVA) group (14 patients anesthetized with propofol– remifentanil). Patients in both groups received the muscle relaxant vecuronium. We assessed hemodynamic variables, cortisol levels, prolactin, interleukin 6, white cell and lymphocyte counts before, during (1 hour after induction) and after (24 hours and 7 days) surgery. RESULTS: Hemodynamic variables were stable in both groups. Significant changes in prolactin levels and markers of immune and inflammatory responses between baseline and later measurements occurred in both groups. Patients who received TIVA had no change in cortisol levels at any time during the study. The TIVA group had lower levels of cortisol than did the inhaled anesthesia group (TIVA, 207 [SD, 100] ng/mL; inhaled 293 [97] ng/mL; P<0.05)), higher neutrophil counts (TIVA, 75 [12.5]%; inhaled: 62 [20]%; P<0.05) and higher CD4+ T lymphocyte counts (TIVA, 53 [11.6]%; inhaled: 42 [17.6]%; P<0.001). CONCLUSION: Although both techniques afford hemodynamic stability, lower cortisol levels were observed with the application of TIVA with propofol–remifentanil. That would be the technique of choice for patients with compromised immune response

Intraoperative anaphylaxis: verba volant, scripta manent!

We describe a case of intraoperative gelatine-induced anaphylaxis whose diagnosis was delayed as the use of gelatine during surgical procedures was omitted for two times in patient's medical records. The subject is a 66-year old woman, with a negative medical history of atopy, food and drug allergy, with arterial hypertension on a course of beta-blockers and with bladder carcinoma requiring surgery. The patient had tolerated both general and local anaesthesia on several previous occasions. On the first occasion she experienced arterial fibrillation secondary to a severe episode of hypotension following local anaesthesia, while on a course of beta-blockers. On the second occasion she developed a very severe episode of hypotension followed by the outbreak of a generalised rash during general anaesthesia. The tryptase sera level was 109 mg/L one hour after the reaction had subsided, while the basal values were normal. On the third occasion the patient redeveloped severe hypotension and a generalised rash during general anaesthesia. The allergological work-up was negative, except for intradermal test with gelatine. A study of the intra-cellular cytokines in blood lymphocytes showed a production of IL4 from CD4+ lymphocytes after stimulation by gelatine. The patient underwent a successive surgical procedure without any adverse event.

Anaphylaxis during anaesthesia: diagnosis and treatment.

Anaphylactic and anaphylactoid reactions during anaesthesia are rare, but potentially life-threatening allergic events. The worst manifestations are cardiovascular collapse, bronchospasm and laryngeal oedema. Anaphylactic and anaphylactoid reactions are clinically indistinguishable. The most incriminated agents are neuromuscular blocking drugs and latex. Treatment consists of instant interruption of contact with possible antigens, 100% oxygen, intubation, adrenaline and volume expansion. The incidence of cross-reactivity between neuromuscular blocking drugs is high. Further investigation of a suspected anaphylactic reaction is mandatory to find the responsible drug and to make future anaesthesia safe. Diagnosis is made with intraoperative tests (serum histamine and mast cell tryptase) and postoperative tests (skin tests and RASTs for specific IgE antibodies).