Massive Histamine Release Research Articles

Mastocytosis: anaphylaxis following emergency anaesthesia

SummaryGeneral anaesthesia in patients with known mastocytosis can be extremely hazardous. Massive histamine release may be triggered by drugs or by the psychological and environmental stresses associated with surgery and can result in significant cardiovascular collapse, respiratory compromise and even death. We present a case of anaphylaxis following induction of anaesthesia in a patient whose diagnosis of mastocytosis was not disclosed during pre‐assessment for emergency surgery. We believe it is the only case reported where the patient has survived their hospital admission in such circumstances despite significant and prolonged cardiovascular compromise.

The undesirable effects of neuromuscular blocking drugs

Neuromuscular blocking drugs are designed to bind to the nicotinic receptor at the neuromuscular junction. However, they also interact with other acetylcholine receptors in the body. Binding to these receptors causes adverse effects that vary with the specificity for the cholinergic receptor in question. Moreover, all neuromuscular blocking drugs may cause hypersensitivity reactions. Often the symptoms are mild and self-limiting but massive histamine release can cause systematic reactions with circulatory and respiratory symptoms and signs. At the end of anaesthesia, no residual effect of a neuromuscular blocking drug should be present. However, the huge variability in response to neuromuscular blocking drugs makes it impossible to predict which patient will suffer postoperative residual curarization. This article discusses the undesirable effects of the currently available neuromuscular blocking drugs including the definitions, diagnosis and causes of hypersensitivity reactions and postoperative residual curarisation.

Release of prostaglandin D2 and leukotriene C4 in response to hyperosmolar stimulation of mast cells

Mannitol-induced bronchoconstriction in subjects with exercise-induced asthma is associated with increased urinary excretion of 9alpha, 11beta-PGF(2), a metabolite of prostaglandin D(2) (PGD(2)) serving as a mast cell marker. It has however been questioned whether or not human mast cells release PGD(2) and leukotriene C(4) (LTC(4)) after osmotic challenge with mannitol in vitro. Cord blood-derived human mast cells were stimulated osmotically, immunologically or with a combination of both. Supernatants were analysed for PGD(2), LTC(4) and histamine contents with enzyme immunoassays. Significant release of de novo synthesized eicosanoids, predominantly PGD(2) [12 (8.8, 14) pmol/10(6)cells; median (25th, 75th percentile) but also LTC(4) (0.1 (0.08, 0.15) pmol/10(6) cells] were found in mast cells in vitro in response to 0.7 M mannitol stimulation. A massive release of histamine [70 (5.3)% of total; mean (SEM)] was also found. There were no correlations between the levels of released mediators after mannitol stimulation. In contrast, there was a correlation between release of PGD(2) and LTC(4), following immunological stimulation. The findings support that hyperosmolar challenge activates mast cells, but different than antigen stimulation.

Mast cell tryptase and hemolysis after trauma

Background: We have previously found increased mast cell tryptase in accidental deaths due to trauma, indicating that mast cell degranulation had occurred. The present study was designed to confirm the previous observation and to determine if tryptase release after trauma is acute or delayed. Furthermore, the importance of hemolysis and direct trauma to the mast cells was investigated. Materials and methods: Mast cell tryptase was measured in post-mortem blood from the femoral vein in 27 cases of death from trauma and in 27 control cases by means of a commercially available immunoassay. The trauma cases were further classified into groups with single versus multiple trauma, and groups with short survival time (i.e. death at the scene of the accident) versus longer survival time (death in hospital). In five multi-trauma deaths, blood was sampled locally from the sites of crush injury. Results: The mean value of tryptase in femoral vein blood was 35.6±34.6 μg/l in the entire trauma group and 14.7±6.5 μg/l in the controls ( P<0.005). In bloody liquid sampled from crush injuries, tryptase was substantially elevated in all cases, with a mean of 227±146 μg/l. In cases with short survival time, tryptase was significantly higher than in those who died after several hours or days in hospital ( P<0.001). No statistically significant difference was seen between multi- and single-trauma cases. A correlation between hemolysis in the samples and elevated tryptase was found only in the trauma cases ( P<0.05), but experimentally induced hemolysis in vitro was not found to influence the measurements. Conclusion: Mast cell tryptase becomes elevated in trauma deaths and this seems to be ascribable either to direct mechanical injury to tissue mast cells and/or to cell lysis. In patients initially surviving severe injuries, the effects of massive release of histamine and other mast cell mediators might be of importance for treatment strategies and prognosis.

9 Anaphylactic and anaphylactoid reactions

Anaphylaxis is a rare event during anaesthesia but may lead to death, even when expertly treated. Reactions may be immune related (anaphylactic) or as a result of direct stimulation (anaphylactoid). The clinical features result from massive release of histamine and the release of other mediators. There is a wide spectrum of severity of reaction but the mainstay of treatment is adrenaline, intravenous colloid and 100% oxygen. Investigation is important, enabling identification of the agent and other agents potentially causing life-threatening reactions. Mast cell tryptase is measured in the first 6 hours, to identify the reaction as anaphylactic, and skin testing 4–6 weeks later is best at identifying the trigger agent. Giving the patient full documentation of the reaction and investigations along with an explanation of the seriousness of the situation is imperative.

The medicinal chemistry and therapeutic potentials of ligands of the histamine H3 receptor.

The monoamine histamine is one of the several chemical messengers involved in the concerted regulation of (patho)physiological processes. In rat brain, histamine can be found in a restricted population of neurons originating from the tuberomammillary nucleus of the hypothalamus [1, 2]. These histaminergic neurons project diffusely to several brain areas and are involved in the regulation of physiological functions (e.g. sleep/wakefullness, feeding, cardiovascular control, neuroendocrine control) [1, 2]. In the periphery histamine is mainly found in mast cells, basophils and enterochrommafin cells. Mast cell degranulation after IgG-allergen interactions results in a massive release of histamine, which is responsible for many of the well-known symptoms of allergic conditions [3, 4]. In gastric mucosa histamine is especially stored in enterochromaffin cells, from which it can be release upon stimulation with gastrin or acetylcholine [5]. In turn, histamine stimulates the parietal cell, resulting in gastric acid secretion [5].

Acute mastocytosis: A potential dermatologic emergency

A comatose patient arrived at the emergency room with apnea and in shock after a grand mal seizure. A maculopapular rash, not initially observed, led to a diagnosis of cutaneous mastocytosis. Degranulation of the mast cells with massive histamine release had resulted in cardiovascular collapse. The authors follow a detailed report of this case history with a discussion of the diagnosis and treatment of the acute systemic stage of this potentially life-threatening illness.

THE HEMODYNAMIC EFFECTS OF CREMOPHOR-EL

A problem associated with parenteral cyclosporine has been the increased incidence of renal toxicity. Cremophor-EL, the vehicle for parenteral cyclosporine has been associated with massive histamine release and anaphylaxis in certain animal models. We investigated the effects of Cremophor-EL on the cardiac output (CO); mean arterial pressure (MAP); and hepatic, renal and pancreatic blood flow in the anesthesized canine model. Doppler flow probes were utilized to calculate individual organ blood flow. Profound adverse affects were noted on the CO, MAP, and hepatic blood flow. There were negative trends noted in the renal and splenic arterial flow that did not reach statistical significance. It was noted that the changes in organ blood flow were partially independent on MAP and the total dose of Cremophor-EL. We therefore conclude that it is prudent to consider the possible adverse hemodynamic role of Cremophor-EL in canine allograft dysfunction.

A non- surfactant formulation for alfaxalone based on an amorphous cyclodextrin: Activity studies in rats and dogs

The steroid anesthetic, alfaxalone, is commercially available for veterinary use in a formulation containing Cremophor-EL® and alfadalone acetate. The allergic sensitivity of some species to this formulation limits its veterinary application and also led to withdrawal of the product for human use. The present studies evaluated alfaxalone formulated as an inclusion complex with a mixture of 2-hydroxypropyl-β-cyclodextrin (HPCD) isomers for anesthetic properties in rats and dogs. Aqueous solutions of alfaxalone-HPCD showed identical anesthetic profiles in rats compared to the commercial formulation. In contrast, the anesthetic response to alfaxalone-HPCD in dogs was not accompanied with massive histamine release and pronounced decrease in respiration and blood pressure seen after the commercial preparation. Anesthesia induction and recovery phases were rapid and uncomplicated after alfaxalone-HPCD. An anaphylactoid-like response did occur in dogs after the same dose of alfaxalone as the commercial preparation. The favorable anesthetic profile of alfaxalone formulated as an HPCD complex together with previous toxicology and stability studies suggest that the steroid may be successfully formulated for intravenous dosing with modified cyclodextrins.

The role of histamine in doxorubicin and teniposide-induced cardiotoxicity in dog and mouse.

In previous studies we reported that teniposide (VM26) induced acute cardiac effects in dogs seem to be related to a release of histamine and that a prior treatment with chlorpheniramine, an H1 histamine blocker, prevents the onset of this phenomenon. Since histamine and other vasoactive substances also seem to be involved in doxorubicin (DXR)-induced acute cardiac effects, experiments were undertaken in the aim to prevent, as in the case of VM26, the onset of this phenomenon by administering chlorpheniramine. Since DXR-induced chronic cardiomyopathy also seems to be related to the same mechanisms involved in the onset of acute cardiac effects induced by this drug, additional studies were carried out to investigate whether a long-term treatment with VM26 could induce in mouse alterations of cardiac morphology similar to those of DXR. In addition, because the mouse is known to be extremely insensitive to histamine, further studies were performed to investigate whether DXR or VM26 administration could induce in this animal model a massive histamine release and whether a long-term treatment with high doses of histamine could elicit, similarly to DXR, alterations in cardiac morphology. The results of our experiments demonstrated that DXR (1.5 mg/kg i.v.) caused in the dog a massive histamine release and a marked impairment of cardiac inotropism. As previously described for VM26, prior treatments with chlorpheniramine completely prevented this phenomenon. Furthermore, DXR administration, at a dose level able to induce cardiac damage in the mouse (2.5 mg/kg i.v.), or that of VM26 (2 mg/kg i.v.) failed to induce a massive histamine release. In addition, long-term treatment with VM26 (2 mg/kg i.v.) or high doses of histamine (100 mg/kg i.v.), unlike DXR, did not elicit in this animal alterations of cardiac morphology. Finally, chlorpheniramine (0.15 or 0.45 mg/kg i.v.) did not prevent the onset of chronic cardiomyopathy induced by DXR in mouse. In conclusion, our results show that the role of histamine in the onset of DXR-induced chronic cardiomyopathy, at least in mouse, remains questionable and suggest that this animal, because of its high natural resistance to histamine, is not a suitable experimental model to investigate the cardiovascular pharmacology of drug-induced histamine release.

Apomorphine‐induced inhibition of histamine release in rat peritoneal mast cells

The apomorphine-induced inhibition of histamine release in rat peritoneal mast cells was studied by means of secretagogues stimulating different pathways of mast cell activation. Apomorphine inhibited the mast cell response to all releasing agents (lysophosphatidylserine plus nerve growth factor, compound 48/80, substance P, ATP, tetradecanoylphorbolacetate, melittin). The IC50 ranged from 4 microM to 24 microM at concentrations of secretagogues releasing 30-50% of mast cell histamine. However, the potency of the drug decreased at higher secretagogue concentrations. Mast cells, pretreated with apomorphine and washed, released little histamine upon stimulation. The secretory response could be partially restored on increasing the concentration of secretagogues. The results suggest that apomorphine affects a regulatory step controlling the terminal sequence of mast cell secretory activity. As indicated by the reduced potency of the drug, the control by the apomorphine-sensitive reaction loses efficiency under conditions of massive histamine release.

Respiratory Distress and Hypoxemia in Systemic Mastocytosis

A 25-year-old woman with documented mastocytosis developed hypoxemia with pruritus, diarrhea, headache, and hypotension on two separate occasions. The hypoxemia appeared to be related to a massive release of histamine. Resolution of the patient's symptoms was accompanied by the return of her arterial oxygen tension to normal levels.

Effects of isoprenaline and cooling on histamine induced changes of capillary permeability in the rat hindquarter vascular bed.

Histamine infused intra-arterially into artificially perfused, maximally dilated rat hindquarters markedly increased fluid filtration and CFC but had essentially no effect on the diffusion capacity to small molecules. Isoprenaline largely prevented the increase in fluid filtration and CFC if infused prior to the start of the histamine infusion and, if infused after the start of the histamine infusion, promptly reduced fluid filtration and CFC to near control levels. Additionally, it was noted that severe cooling of the perfusate also largely prevented the marked increase in fluid filtration and CFC by histamine. This antagonism of histamine induced increases in macromolecular permeability represents a direct action of isoprenaline on the microvascular membrane which effectively counteracts that of histamine. The data also suggest that the large pores created by histamine are different from the large pore through which macromolecules normally transverse the microvascular membrane, and that catecholamines may exert a regulatory function in the control of microvascular permeability to macromolecules in pathophysiological states associated with massive histamine release.

HISTAMINE RELEASE IN MAN BY PROPANIDID AND THIOPENTONE: PHARMACOLOGICAL EFFECTS AND CLINICAL CONSEQUENCES

SUMMARY Using a new, highly sensitive and specific method for the determination of histamine in human plasma, it was shown that release of histamine followed injection of propanidid and thiopentone. Observations of gastric secretion, arterial pressure and pulse rate supported these findings. In normal persons the release of histamine had no special clinical significance. On the other hand, when anaphylactoid reactions occurred following propanidid injection histamine release was so massive as to explain the severe clinical signs and symptoms observed. In this study no reactions occurred following thiopentone injection. Although it seems likely that massive histamine release can occur during anaphylactoid reactions with this anaesthetic, we have no observations to confirm this. In one case it was shown that premedication with glucocorticoids and anti-histaminics and therapy with plasma substitutes could prevent the development of a severe reaction.

Release of histamine from mast cells by blood treated with dextran.

HALPERN1 has shown that the injection of dextran into albino rats causes increased capillary permeability and shock. Coincident with the appearance of shock, there is a massive release of histamine into the blood stream of injected animals. The liberated histamine probably accounts for the greater part of the increased capillary permeability and shock resulting from the administration of dextran. It seemed of interest, therefore, to investigate the mechanism of the release of histamine. It was found that dextran reacts with a plasma protein to produce a substance which acts on mast cells to release histamine.