Plasma Histamine Concentrations Research Articles

Inactivated antithombin as anticoagulant reversal in a rat model of cardiopulmonary bypass: a potent and potentially safer alternative to protamine.

Heparin anticoagulation followed by protamine reversal is commonly used in cardiopulmonary bypass (CPB). As an alternative to protamine, a recombinant inactive antithrombin (riAT) was designed as an antidote to heparin and was previously shown to be as potent as protamine in-vitro. In the present study, riAT was assessed for its ability to neutralize heparin after CPB in a rat model. After 60min of CPB under heparin, rats received 5mg/kg protamine, 37.5mg/kg riAT or phosphate buffered saline (PBS) as placebo. Residual anticoagulant activity was assessed using the activated partial thromboplastin time assay before, and 10-30min after reversion. Haemodynamic monitoring was performed and plasma histamine concentration was also measured. In this model, riAT appeared to be as efficient as protamine in neutralizing heparin. Ten minutes after injection, riAT and protamine both decreased heparin activity, to 1.8±1.3 and 4.5±1.4u/ml, respectively (23.1±5.1u/ml in placebo group). Furthermore, evolution of mean carotid arterial pressure, heart rate and plasma histamine levels was comparable in rats treated with PBS or riAT, while protamine exhibited haemodynamic side effects and increased histamine plasma concentration. Thus, riAT could represent an advantage over protamine in CPB because it efficiently reverses heparin activity without negative effects on haemodynamic parameters and plasma histamine level.

Antihistaminic and cardiorespiratory effects of diphenhydramine hydrochloride in anesthetized dogs undergoing excision of mast cell tumors.

OBJECTIVE To evaluate the effects of IV diphenhydramine hydrochloride administration on cardiorespiratory variables in anesthetized dogs undergoing mast cell tumor (MCT) excision. DESIGN Randomized, blinded clinical trial. ANIMALS 16 client-owned dogs with MCTs. PROCEDURES In a standardized isoflurane anesthesia session that included mechanical ventilation, dogs received diphenhydramine hydrochloride (1 mg/kg [0.45 mg/lb], IV; n = 8) or an equivalent volume of saline (0.9% NaCl) solution (IV; control treatment; 8) 10 minutes after induction. Cardiorespiratory variables were recorded throughout anesthesia and MCT excision, and blood samples for determination of plasma diphenhydramine and histamine concentrations were collected prior to premedication (baseline), throughout anesthesia, and 2 hours after extubation. RESULTS Cardiorespiratory values in both treatment groups were acceptable for anesthetized dogs. Mean ± SD diastolic arterial blood pressure was significantly lower in the diphenhydramine versus control group during tumor dissection (52 ± 10 mm Hg vs 62 ± 9 mm Hg) and surgical closure (51 ± 10 mm Hg vs 65 ± 9 mm Hg). Mean arterial blood pressure was significantly lower in the diphenhydramine versus control group during surgical closure (65 ± 12 mm Hg vs 78 ± 11 mm Hg), despite a higher cardiac index value. Plasma histamine concentrations were nonsignificantly higher than baseline during maximal manipulation of the tumor and surgical preparation in the diphenhydramine group and during surgical dissection in the control group. CONCLUSIONS AND CLINICAL RELEVANCE IV administration of diphenhydramine prior to MCT excision had no clear clinical cardiorespiratory benefits over placebo in isoflurane-anesthetized dogs.

The efficacy and safety of mivacurium in pediatric patients

BackgroundMivacurium is the shortest acting nondepolarizing muscle relaxant currently available; however, the effect of different dosages and injection times of intravenous mivacurium administration in children of different ages has rarely been reported. This study was aimed to evaluate the muscle relaxant effects and safety of different mivacurium dosages administered over different injection times in pediatric patients.MethodsSix hundred forty cases of pediatric patients, aged 2 m-14 years, ASA I or II, were divided into four groups (Groups A, B, C, D) according to the age class (2–12 m, 13–35 m, 3–6 years and 7–14 years) respectively, also each group were divided into four subgroups by induction dose (0.15, 0.2 mg/kg in 2–12 m age class; 0.2, 0.25 mg/kg in other three age classes), and mivacurium injection time (20 s, 40 s), totally 16 subgroups. Neuromuscular transmission was monitored with supramaximal train-of-four stimulation of the ulnar nerve. Radial artery blood (1 ml) was sampled to quantify plasma histamine concentrations before and 1, 4, and 7 min after mivacurium injection (P0, P1, P2 and P3).ResultsFive hundred sixty-two cases completed the study. There were no demographic differences within the four groups. The onset time of 0.2 mg/kg groups in 2–12 m aged patients were shorter than those of 0.15 mg/kg groups (189 ± 64 s vs. 220 ± 73 s, 181 ± 60 s vs. 213 ± 71 s, P <0.05), and the recovery times were no statistical differences. The T1 25% recovery time of 0.2 mg/kg in 3–6 years aged patients was shorter than that of 0.25 mg/kg group (693 ± 188 s vs. 800 ± 206 s, P <0.05). The onset and recovery times of mivacurium were not different in 13–35 m and 7–14 years aged patients. The plasma concentrations of histamine at P0, P1, P2 and P3 were not different within four groups.ConclusionsThe induction dose and injection time of mivacurium had mostly insignificant effects on onset and recovery times. The main exception to this was that in 2–12 m aged patients, increasing the dose of mivacurium from 0.15 to 0.2 mg/kg accelerated the onset time by about 30 s. Mivacurium produced no significant release of histamine in any age group at the doses studied.Trial registrationClinicalTrials.gov Identifier-NCT02117401, July 14, 2014. (Retrospectively registered)

Nonclinical Profile of BLZ-100, a Tumor-Targeting Fluorescent Imaging Agent.

BLZ-100 is a single intravenous use, fluorescent imaging agent that labels tumor tissue to enable more complete and precise surgical resection. It is composed of a chlorotoxin peptide covalently bound to the near-infrared fluorophore indocyanine green. BLZ-100 is in clinical development for intraoperative visualization of human tumors. The nonclinical safety and pharmacokinetic (PK) profile of BLZ-100 was evaluated in mice, rats, canines, and nonhuman primates (NHP). Single bolus intravenous administration of BLZ-100 was well tolerated, and no adverse changes were observed in cardiovascular safety pharmacology, PK, and toxicology studies in rats and NHP. The single-dose no-observed-adverse-effect-levels (NOAELs) were 7 mg (28 mg/kg) in rats and 60 mg (20 mg/kg) in NHP, corresponding to peak concentration values of 89 400 and 436 000 ng/mL and area-under-the-curve exposure values of 130 000 and 1 240 000 h·ng/mL, respectively. Based on a human imaging dose of 3 mg, dose safety margins are >100 for rat and monkey. BLZ-100 produced hypersensitivity reactions in canine imaging studies (lethargy, pruritus, swollen muzzle, etc). The severity of the reactions was not dose related. In a follow-up study in dogs, plasma histamine concentrations were increased 5 to 60 minutes after BLZ-100 injection; this coincided with signs of hypersensitivity, supporting the conclusion that the reactions were histamine based. Hypersensitivity reactions were not observed in other species or in BLZ-100 human clinical studies conducted to date. The combined imaging, safety pharmacology, PK, and toxicology studies contributed to an extensive initial nonclinical profile for BLZ-100, supporting first-in-human clinical trials.

Muscle relaxation effect and safety of mivacurium in patients with early hepatocirrhosis

Objective To observe muscle relaxation effect and safety of mivacurium in hepatocirrhosis patients, and provide a guidance in its clinical application. Methods Candidates for elective laparoscopic surgery were divided into a hepatocirrhosis group(group C, n=32) and a non hepatocirrhosis group (group N, n=25). Muscular relaxation monitor was applied with a train of four stimulation(TOF). The intubation dosage was 0.2 mg/kg. Tracheal intubation was performed when train of four stimulation ratio(TOFr, T4∶T1) was 0, and pump infusion of mivacurium was started when muscle relaxation began to recover (TOFr>0) with a velocity of 0.6 mg·kg-1·h-1, which was switched to 0.3 mg·kg-1·h-1 and then stopped in 30 min and 20 min prior to end of suturing in group C and group N respectively. The key parameter included plasma cholinesterase(PchE) activity, histamine concentration, variation of MAP, HR, onset time of mivacurium, acting duration of the first dose, time of TOFr recovery, time from drug withdrawal to extubation, and recovery index. Results The PchE activity were(4 304±901) U/L and (6 227±1 289) U/L in two groups (P 0.05). The mean histamine concentrations of all patients were (0.196±0.020), (0.238±0.021), (0.278±0.024) μg/L prior to intravenous injection of mivacurium and in 5 min and 10 min post to injection, there were significant differences between the three times points(P 0.05). The duration of the first dose were(20±4) min and (16±3) min respectively, the recovery of TOFr to 75% were (35±10) min and (24±5) min, time from drug withdrawal to extubation were (35±9) min and (24±7) min, and there were significant differences between the two groups (P<0.05). Conclusions The plasma histamine concentration increase slightly without significant influence on MAP and HR, with satisfactory intubation conditions, good muscle relaxation and fast recovery from muscle relaxation when mivacurium was applied in patients with early hepatic cirrhosis. Compared with non hepatic cirrhosis patients, the time of muscle relaxation recovery induced by mivacurium was longer in hepatic cirrhosis patients, but compared with other muscle relaxant, it still had obvious advantages. Because mivacurium didn't directly depend on the liver to metabolize, so it could reduce the burden of liver on drug metabolism. It is recommended to be applied in patients with early hepatic cirrhosis. Key words: Cirrhosis of liver; Mivacurium chloride; Histamine; Cholinesterase; Monitoring of muscle relaxation

Incidence of anaphylactic reactions after propofol administration in dogs.

Propofol is an anesthetic agent suspended in an emulsion system that includes egg yolk lecithin and soybean oil, because of which, there is concern about the use of propofol in patients allergic to these substances. We examined the association between propofol administration and incidence of adverse events in dogs with allergy to egg yolk lecithin and soybean oil. On the basis of the findings of an allergen-specific immunoglobulin E (IgE) test, 14 dogs with high levels (high-IgE group) and 7 dogs with low levels (normal-IgE group) of IgE were selected. Following intravenous administration of propofol, the incidence of anaphylactic reactions and plasma histamine concentrations under general anesthesia maintained with isoflurane throughout surgery were compared between the two groups. The frequency of anaphylactic reactions and plasma histamine concentrations were compared by the chi-square test and Student t-test, respectively. The statistical significance for both tests was set at P<0.05. In the high- and normal-IgE groups, the average frequencies of anaphylactic reactions after propofol administration were 21.4 and 14.3%, and the mean plasma histamine concentrations were 167.9 ± 94.5 nM and 65.7 ± 40.3 nM, respectively. Animals of neither groups experienced shock-like symptoms. These results revealed that propofol might be relatively safe, although careful perioperative anesthesia monitoring and standby protocols are required when using propofol in dogs with a history of allergic diseases or high chicken- or soybean-specific IgE levels.

The Pathogenesis of Alcohol-Induced Airflow Limitation in Acetaldehyde Dehydrogenase 2-Deficient Mice

Background: In Japanese patients, alcohol-induced asthma is attributed to elevated plasma concentrations of acetaldehyde following alcohol consumption because of an acetaldehyde dehydrogenase 2 gene (ALDH2) polymorphism. The resulting increase in plasma histamine concentrations seems to trigger the onset of asthma symptoms. However, the specific pathogenic mechanism underlying this response remains unclear. ALDH2-deficient mice were therefore generated to investigate the pathogenesis of alcohol-induced asthma. Methods: ALDH2-deficient mice were generated using embryonic stem cells that were derived from C57BL/6 mice. The resulting mice were backcrossed into the BALB/c mice background. Exon 1 of ALDH2 was replaced with the Neo cassette. Pure ethanol was orally administered to ALDH2-deficient and wild-type mice, and the plasma concentrations of ethanol, acetaldehyde, and histamine, in addition to enhanced pause (Penh) values, were determined and compared between the 2 groups. Results: We established an ALDH2-deficient mouse line to compare responses between wild-type and ALDH2-deficient mice receiving orally administered ethanol. The results showed that the plasma concentrations of acetaldehyde (p < 0.0001) and histamine (p < 0.005) were significantly higher, and the Penh values (p < 0.01) were significantly greater in the ALDH2-deficient mice, although plasma ethanol levels were not different. Conclusions: We studied the pathogenesis of alcohol-induced asthma using ALDH2-deficient mice. The results demonstrated that alcohol intake resulted in an increase in acetaldehyde levels, and a subsequent increase in histamine levels, which induced airway constriction. Alcohol consumption is known to be an important factor that exacerbates bronchial asthma, and studies investigating this factor are useful for the treatment of patients with alcohol-induced asthma.

Efficacy of clemastine fumarate in antagonizing atracurium-induced release of histamine in patients undergoing surgery under general anesthesia

Objective To evaluate the efficacy of clemastine fumarate in antagonizing atracurium-induced release of histamine in the patients undergoing surgery under general anesthesia. Methods Eighty American Society of Anesthesiologists physical statusⅠ or Ⅱ patients, aged 21-59 yr, with body mass index of 17-26 kg/m2, scheduled for elective modified radical mastectomy, were divided into 2 groups (n=40 each) using a random number table: control group (group C) and clemastine fumarat group (group CF). Clemastine fumarate 2 mg was injected intramuscularly at 20 min before induction of anesthesia.Anesthesia was induced with iv midazolam 0.1 mg/kg, etomidate 0.3 mg/kg, fentanyl 4-6μg/kg and atracurium 0.8 mg/kg.The patients were mechanically ventilated after insertion of the larygeal mask airway.Anesthesia was maintained with inhalation of 2% sevoflurane.Before administration of clemastine fumarate, at 20 min after administration, immediately before administration of atracurium, and at 2, 5, 10 and 20 min after administration of atracurium, arterial blood samples were taken for determination of plasma histamine concentrations, and the peak airway pressure and degree of cutaneous color were recorded.The development of histaminemia and adverse cardiovascular events was assessed.Steward recovery scores and Ramsay sedation scores were recorded at 10 min after removal of the laryngeal mask airway. Results The incidence of histaminemia was 60% and 8% in C and CF groups, respectively.Compared with group C, the plasma histamine concentrations, incidence of histaminemia, degree of cutaneous color, and incidence of hypotension and tachycardia were significantly decreased (P 0.05). Conclusion For atracurium-induced release of histamine in the patients undergoing surgery under general anesthesia, clemastine fumarate 2 mg injected intramuscularly before operation can not only antagonize histamine at H1 level, but also reduce histamine release, and exerts no influence on recovery from anesthesia and produces good antihistamine efficacy. Key words: Histamine H1 antagonists; Atracurium; Histamine release; Anesthesia, general

Dose-response and Cardiopulmonary Side Effects of the Novel Neuromuscular-blocking Drug CW002 in Man.

CW002 is a benzylisoquinolinium nondepolarizing neuromuscular-blocking drug found to be inactivated by cysteine in preclinical studies. The current study represents a dose escalation clinical trial designed to describe CW002 potency, duration, cardiopulmonary side effects, and histamine release. Healthy subjects anesthetized with sevoflurane/nitrous oxide were divided into five groups (n = 6), each receiving a fixed CW002 dose (0.02, 0.04, 0.06, 0.08, or 0.10 mg/kg), and one group (n = 4) receiving 0.14 mg/kg. Blood pressure and heart rate were continuously recorded along with airway dynamic compliance. Neuromuscular blockade was assessed with mechanomyography at the adductor pollicis. Arterial blood was obtained before and after CW002 injection for analysis of plasma histamine concentration. Potency was estimated from a baseline sigmoid Emax model. ED50 was found to be 0.036 mg/kg (95% CI, 0.020 to 0.053 mg/kg) and ED95 0.077 mg/kg (95% CI, 0.044 to 0.114 mg/kg). At 0.14 mg/kg (1.8 × ED95), 80% twitch depression occurred in 94 ± 18 s with complete block in 200 ± 87 s. Clinical recovery (25% of maximum twitch) occurred in 34 ± 3.4 min, with a 5 to 95% recovery interval of 35.0 ± 2.7 min. The time to a train-of-four ratio greater than 0.9 ranged from 59 to 86 min. CW002 did not elicit histamine release or significant (greater than 10%) changes in blood pressure, heart rate, or dynamic airway compliance. In healthy subjects receiving sevoflurane/nitrous oxide, CW002 at 1.8 × estimated ED95 produces a clinical duration less than 40 min, elicits no histamine release, and has minimal cardiopulmonary side effects.

血漿ヒスタミン測定が診断に有用であった食物依存性運動誘発アナフィラキシーの1例

症例は15歳男児. ラーメン1杯を摂取後に行ったランニング中に顔面の発赤・腫脹, 呼吸困難などのアナフィラキシー症状を認めた. それまで小麦製品摂取による即時型の誘発症状はなく, 小麦による食物依存性運動誘発アナフィラキシー (FDEIA) を疑い誘発試験を実施した. 誘発試験において症状は認めなかったが, 小麦負荷と運動負荷, アスピリン負荷と小麦負荷, アスピリン負荷と小麦負荷と運動負荷のいずれの組み合わせにおいても, 血漿ヒスタミン濃度が誘発試験前値の200%, 190%, 248%と上昇を認めたため, 小麦によるFDEIAと診断した. エピペン®を所持してもらい, 小麦製品摂取後2時間以内の運動制限と解熱鎮痛薬使用中の小麦製品摂取の制限ならびに運動制限について指導した. 血漿ヒスタミン濃度の上昇を診断に用いることで, 誘発症状がないために偽陰性と判断されることの危険を回避しうることは, 臨床上極めて有用である.

The Incidence of Perioperative Hypersensitivity Reactions

The incidence of perioperative hypersensitivity reactions, which can be life-threatening, ranges from 1 in 20,000 to 1 in 1361. These reactions are usually classified as IgE or non-IgE mediated. The aim of this study was to determine the incidence of allergic reactions during general anesthesia in our hospital, to establish the incidence of the allergic reactions for each drug used, to assess the frequency of IgE-mediated reactions in even mild reactions, and to compare the degree of agreement between anesthesiologist suspicion and allergy diagnosis. We included patients diagnosed with a clinical hypersensitivity reaction during a procedure under general anesthesia over a 30-month period (February 2008 to August 2010). Plasma histamine and serum tryptase concentrations were determined in these patients. We performed skin tests to diagnose the causative agent. Data from the hospital electronic prescribing system were collected to determine the ratio of reactions for each drug. During the study period, 16,946 anesthetic procedures were performed (53% involved males; mean age, 51.6 years). Forty-four perianesthetic reactions were recorded, and the ratio of reactions was 1 in 385 operations (95% confidence interval, 1/529-1/287). Twenty-five reactions (25/44; 57%) occurred during the induction of anesthesia. Twenty-one reactions (21/44; 48%) were mild, involving only skin, and 23 of 44 (52%) were anaphylactic reactions. Four of 10 patients who had only a rash experienced IgE-mediated reactions. Five surgeries (11%) were suspended because of the severity of the reactions. Fifteen reactions (15/30; 50%) were IgE mediated, and, in 2 of 30 (7%), a non-IgE agent was found (cold urticaria and nonsteroidal anti-inflammatory drug intolerance). The ratio of reactions for each drug was as follows: protamine, 1 in 468; cisatracurium, 1 in 1388; amoxicillin-clavulanate, 1 in 1968; atracurium, 1 in 2039; and dipyrone, 1 in 3159. Perioperative reactions are more common than previously reported. Mild hypersensitivity perioperative reactions-involving only skin-should be considered in evaluating patients because a substantial number of these reactions are IgE mediated.

Uremic pruritus

Uremic pruritus

Is Sarcoptes scabiei infection in pigs a major welfare concern? A quantitative assessment of its effect in the host's nocturnal rubbing and lying behavior

The nocturnal rubbing and lying behaviorof commercialfattening pigs from moderately (M)and heavily (H) Sarcoptes scabieieinfected farms was investigated. The study included 4 cohorts (2 per farm) of 11-15 acaricide-treated (uninfected) and untreated (infected) 4- to 7-month-old pigs, and the time and number of behavioral bouts were monitored for 350 hours over 101 days. Auricular mites, dermatitis, and plasma histamine concentration were investigated postmortem at the age of 7 months, and histamine concentration was also analyzed at the age of 3 months in 3 cohorts. The percentage of pigs with mites was 27% and 79% in untreatedfarmMandHcohortsand0%intreatedpigs.Erythematoushypersensitivedermatitiswasobserved inbothtreated anduntreatedanimals;however,histamine levelsweremuchgreaterinuntreatedcompared with treated pigs and increased with time in the former group. Rubbing was significantly increased in untreated compared with treated pigs, but it was generally low and with small variations over time. The mean rubbingtimeper210minutes(1daysample)was0.00-0.79and0.00-0.65minutesinuntreatedpigsinfarms MandH,respectively,and0.00-0.15and0.00-0.03minutesintreatedpigsinfarmsMandH,respectively.The mean lying time and number of events of standing up were similar for treated and untreated pigs, and differencesbetweenfarmcohortswerenotassociatedtoS.scabieiinfection.Moreover,theaveragepig’slifelong weight gain also appeared to be independent of infection. The small effect of S. scabiei on pig behavior and growthcontrastswiththemuchgreatereffectthatthenonburrowingmitePsoroptesovishasbeenreportedto

Evaluation of mivacurium-induced release of histamine in patients undergoing general anesthesia

Objective To evaluate mivacurium-induced release of histamine in the patients undergoing general anesthesia.Methods Eighty patients of both sexes,aged 19-58 yr,weighing 42-75 kg,of ASA physical status Ⅰ or Ⅱ,undergoing ureteroscopy under general anesthesia,were randomly divided into 2 groups (n =40 each) using a random number table:rocuronium group (group R) and mivacurium group (group M).Anesthesia was induced with iv midazolam 0.04 mg/kg,fentanyl 3 μg/kg,etomidate 0.3 mg/kg,and mivacurium 0.20 mg/kg (group M) or rocuronium 0.75 mg/kg (group R).Streamlined liner of the pharynx airway (SLIPA) was inserted for mechanical ventilation.PET CO2 was maintained at 35-40 mmHg.Anesthesia was maintained with fentanyl and propofol.Before muscle relaxant administration,at 3 min after muscle relaxant administration and at 5 min after insertion of SLIPA,venous blood samples were collected for determination of plasma histamine concentrations (by HPLC) and the histamine release was classified.Results Compared with group R,the plasma histamine concentration and histamine release were increased at 3 min after muscle relaxant administration in group M.No fatal responses caused by histamine release were found in the two groups.Conclusion Although mivacurium induces release of histamine,it can still be safely used for the patients undergoing ureteroscopy under general anesthesia. Key words: Androstanols ; Histamine ; Anesthesia, general

Diagnostic value of histamine and tryptase concentrations in severe anaphylaxis with shock or cardiac arrest during anesthesia.

The diagnosis of acute life-threatening allergic reactions during anesthesia relies on clinical signs, histamine and/or tryptase measurements, and allergic testing. In patients who die after the reaction, skin tests cannot be performed, and the effect of resuscitation manoeuvres on mediator concentrations is unknown. The authors compared plasma histamine and tryptase concentrations in patients with severe allergic reactions during anesthesia with those measured in patients with shock due to other causes. Patients with life-threatening allergic reactions were retrieved from a previous database (Group ALLERGY). All had positive allergy tests to administered agents. Patients with severe septic/cardiogenic shock or cardiac arrest (Group CONTROL) had histamine and tryptase measurements during resuscitation manoeuvres. Receiver operating characteristics curves were built to calculate the optimal mediator thresholds differentiating allergic reactions from others. One hundred patients were included, 75 in Group ALLERGY (cardiovascular collapse, 67; cardiac arrest, 8) and 25 in Group CONTROL (shock, 11; cardiac arrest, 14). Mean histamine and tryptase concentrations remained unchanged throughout resuscitation in Group CONTROL and were significantly higher in Group ALLERGY. The optimal thresholds indicating an allergic mechanism were determined as 6.35 nmol/l for histamine (sensitivity: 90.7% [95% CI, 81.7 to 96.1]; specificity: 91.7% [73.0 to 98.9]) and 7.35 μg/l for tryptase (sensitivity: 92% [83.4 to 97.0]; specificity: 92% [73.9 to 99.0]). Resuscitation manoeuvres by themselves did not modify mediator concentrations. Virtually all life-threatening reactions during anesthesia associated with mediator concentrations exceeding the thresholds were allergic events. These findings have potential forensic interest when a patient dies during anesthesia.

The Severe Adverse Reaction to Vitamin K1 Injection Is Anaphylactoid Reaction but Not Anaphylaxis

The severe adverse reaction to vitamin K1 injection is always remarkable and is thought to result from anaphylaxis. Paradoxically, however, some patients administered vitamin K1 injection for the first time have adverse reactions. Using beagle dogs, the present study tested the hypothesis that the response to vitamin K1 is an anaphylactoid reaction. The results showed that serious anaphylaxis-like symptoms appeared in beagle dogs after the administration of vitamin K1 injection for the first time. The plasma histamine concentration increased, and blood pressure decreased sharply. After sensitization, dogs were challenged with vitamin K1 injection and displayed the same degree of symptoms as prior to sensitization. However, when the vitamin K1 injection-sensitized dogs were challenged with a vitamin K1-fat emulsion without solubilizers such asTween-80, the abnormal reactions did not occur. Furthermore, there was no significant change in the plasma immunoglobulin E concentration after vitamin K1 challenge. Following treatment with vitamin K1 injection, the release of histamine and β-hexosaminidase by rat basophilic leukemia-2H3 cells as well as the rate of apoptosis increased. The Tween-80 group displayed results similar to those observed following vitamin K1 injection in vivo. However, the dogs in the vitamin K1-fat emulsion group did not display any abnormal behavior or significant change in plasma histamine. Additionally, degranulation and apoptosis did not occur in rat basophilic leukemia-2H3 cells. Our results indicate that the adverse reaction induced by vitamin K1 injection is an anaphylactoid reaction, not anaphylaxis. Vitamin K1 injection induces the release of inflammatory factors via a non-IgE-mediated immune pathway, for which the trigger may be the solubilizer.

Effects of promethazine or dexamethasone pretreatment on mivacurium‐induced histamine release in children

To determine the effects of pretreatment with either promethazine or dexamethasone on mivacurium-induced histamine release in children. Eighty ASA I-II children (4-10years of age) scheduled for tonsillectomy and/or adenoidectomy were randomly divided into 4 groups (n=20 per group) designated as either the rocuronium, mivacurium, dexamethasone (DXM), or promethazine group. Children in the DXM and promethazine groups were treated separately with intramuscular DXM 0.2mg·kg(-1) or promethazine 0.5mg·kg(-1) injections 60min before operation. Radial artery blood samples were collected to quantify plasma histamine concentrations 1min before and 1, 3, and 5min after administration of the relaxant. Mean arterial pressure (MAP), heart rate (HR), and skin flushing were recorded at the same time. No significant decreases in plasma histamine concentrations were observed between groups; however, more stable MAP and HR and less skin flushing were observed in DXM group participants compared with individuals in the mivacurium group (P<0.05). By contrast, children in the promethazine group had significantly decreased plasma histamine concentrations and stable MAP and HR (without a significant increase in HR) compared with patients in mivacurium group. In addition, skin flushing was significantly decreased compared with that observed in the rocuronium group (P<0.05). Pretreatment with promethazine significantly decreased mivacurium-induced histamine release in children and provided stable hemodynamics during administration of anesthesia.

Lack of Association of Plasma Histamine with Diamine Oxidase in Chronic Idiopathic Urticaria

BackgroundChronic idiopathic urticaria (CIU) is considered a complex and multifactorial disease. Excessive histamine intake may induce an attack of urticaria. The main enzyme for histamine metabolism is diamine oxidase (DAO).ObjectivePlasma histamine concentrations and DAO activities were evaluated to determine whether there are abnormalities in the histamine metabolism of CIU patients.MethodsSeventy-five CIU patients and twenty-five healthy control subjects were included in the study. Blood was taken from all subjects to measure plasma levels of the histamine and DAO.ResultsMean plasma histamine levels were significantly higher in CIU patients (11.59±10.98 nM) than in the control subjects (8.75±2.55 nM) (p=0.04). Mean DAO activities were lower in patients of CIU (80.86±26.81 histamine degrading unit [HDU]/ml) than in the controls (81.60±9.67 HDU/ml), but without significant difference. In 15 CIU patients with gastrointestinal symptoms, the mean histamine concentration was higher (12.43±7.97 nM) and DAO activity was lower (77.93±27.53 HDU/ml) than in the remaining 60 CIU patients without gastrointestinal symptoms (11.38±11.67 nM and 81.58±26.82 HDU/ml), without significant difference. The relationship between DAO activity and plasma histamine concentrations showed a significant negative linear value (p=0.001). There were no significant relationships between plasma histamine concentrations and symptom severity score.ConclusionIn CIU patients, a high plasma histamine concentration may not be explained by DAO activity. CIU patients with gastrointestinal (GI) symptoms showed no significantly lower DAO activity. Larger group studies are required to elucidate the relationship between plasma histamine concentrations and DAO activity, especially of CIU patients with GI symptomsto understand the difference in CIU patients with and without GI symptoms.

Hypersensitivity reactions to Patent Blue V in breast cancer surgery: a prospective multicentre study

An increasing number of immediate hypersensitivity reactions (HSR) have been reported after the use of Patent Blue V (PBV) for breast cancer surgery. This is the first study to publish prospective data with systematic allergological assessment. We conducted a multicentre study in 10 French cancer centres for over 6 months. All patients scheduled for breast surgery with injection of PBV were included in the study. Patients were screened for past medical history, atopy, and known food and drug allergies. When suspected HSR or unexplained reactions occurred after injection of PBV, blood samples were taken, and plasma histamine and serum tryptase concentrations were measured. HSR to PBV was suggested if skin tests performed 6 weeks later were positive. Nine suspected HSR to PBV were observed in 1742 patients. Skin tests were positive in six patients, giving an incidence of 0.34%. Four grade I and two grade III HSR were observed, both requiring intensive care unit treatment. Mean onset time of the reaction was 55 ± 37 min. Plasma histamine was elevated in four patients, while serum tryptase was normal. We found no risk factors associated with HSR to PBV. An incidence rate of one in 300 HSR to PBV was observed for patients exposed to PBV during sentinel lymph node detection. This rate is higher than rates reported after the use of neuromuscular blocking agents, latex or antibiotics.

Starch source in high concentrate rations does not affect rumen pH, histamine and lipopolysaccharide concentrations in dairy cows

The replacement of ground corn by cassava meal on rumen pH, lipopolysaccharide (LPS) and histamine concentrations under typical Thai feeding conditions (high concentrate diets and rice straw as the sole source of roughage) was investigated. Four rumen-fistulated crossbred Holstein, non-pregnant, dry cows were randomly assigned to the four experimental rations in a 4×4 Latin square design with 21-d periods. Each period consisted of a 14-d run-in/wash out period, followed by a 7-d experimental period. During the run-in/wash out period, the cows were offered 5.4kg DM of concentrate containing 4.6% cassava meal and rice straw was provided ad libitum. During the 7 day of each experimental period, cows were offered 10.5kg DM of concentrate containing either 4.6% or 18.3% or 32.4% or 46.2% cassava meal and 1.5kg of rice straw. Irrespective of dietary treatments, rumen total VFA and lactate concentrations were significantly affected by sampling day, which were significantly higher on day 1 versus days 3 and 7 of the experimental periods. Mean postprandial rumen pH was reduced to values <5.6 for at least 6h on days 3 and 7 of each experimental period. However, the relationship between rumen pH, total VFA and lactate concentrations was not straight forward. Rumen LPS and histamine concentrations were not affected by either ground corn or cassava mean, but values significantly increased from day 1 to 7 of each experimental period with the values ranging from 10.3×103 to 40.3×103EU/ml and 11.5 to 33.2μM, respectively. Both plasma LPS and histamine concentrations were below the detection limit. It can be concluded that the amount of concentrate but not the replacement of ground corn by cassava meal, affect rumen pH, rumen fluid concentrations of total volatile fatty acids, lactate, histamine and LPS. Irrespective of the dietary treatments, the results suggested that a low rumen pH is associated with an increase in rumen histamine and LPS concentration, which is not accompanied by an increase in plasma histamine or LPS concentration.