W. K. Man

Histamine release in paediatric cardiopulmonary bypass —a possible role in the capillary leak syndrome

Recent studies have reported pathologically elevated plasma histamine levels in adult patients during and after open heart surgery. In paediatric practice, the increased use of donor-blood primes might be expected to produce even greater rises in the histamine levels, by creating histamine release in the prime before initial perfusion commences. The present study covered 40 arbitrarily chosen paediatric cases. Pathologically elevated plasma histamine levels (>1 ng/ml) were found in the prime of 26 out of 37 cases (73%). Histamine levels were substantially higher than levels encountered in previously reported studies, and massively elevated prime histamine levels (>80 ng/ml) were encountered in 9 out of the 40 cases (22%). These results suggest that in conventional paediatric cardiac surgical practice, the prime content of histamine is markedly elevated in the majority of patients. The inevitable delivery of this prime histamine load at the onset of perfusion might be expected to produce systemic pathological effects.

Acid blockade by omeprazole or ICI 162846 in a chronic duodenal ulcer model

Oral treatment with the H2-antagonist ICI 162,846 or omeprazole for five days inhibited both basal and pentagastrin stimulated acid secretion by 50% or more in mice. Either treatment increased the luminal secretion of histamine in the basal (12-fold) and stimulated (9-fold) states. Mice treated with the H2-antagonist had a 27% reduction (p<0.05) in mural histamine in the acid-producing area of the stomach. Mice were treated so as to induce duodenal ulcers (abscopal model) and were then treated with the H2-antagonist ICI 162,846, omeprazole or vehicle, orally for one week. Fewer duodenal ulcers were found in animals receiving drug treatments than in the oral vehicle group. Both the H2-receptor antagonist and the proton pump blocker inhibit acid production; acid blockade by either drug is accompanied by a massive increase in secretion of histamine. This rise was associated with depletion of the gastric histamine store only with H2-receptor blocker. Both means of acid inhibition reduced the formation of ulcers in this model.

Histamine in carcinoid syndrome.

The exact etiology of carcinoid flushing remains unknown, but the symptoms are probably mediated through release of one or several humoral substances. Flushing seen in fore-gut carcinoids (gastric carcinoids) has been ascribed to excessive histamine release, whereas flushing seen in mid-gut carcinoids (ileal carcinoids) tentatively has been ascribed to excessive release of serotonin, bradykinin, substance P, substance K or eledoisin. In this study plasma histamine was measured in 8 patients with mid-gut carcinoids and carcinoid syndrome using an enzymatic isotopic method in order to evaluate histamine as the vasoactive agent in patients with ileal carcinoid tumours and carcinoid syndrome. All patients had raised plasma histamine values. In patients with mid-gut carcinoids histamine may be one of the substances mediating flushing.

Effect of prostacyclin on the circulatory histamine during cardiopulmonary bypass.

Changes in plasma histamien levels were studied in sixteen dogs under cardiopulmonary bypass (CPB) or bypass with the addition of prostacyclin (PGI2) infusion. In both groups, plasma histamine rose immediately after anaesthetic induction (median above pre-induction: 0.4 ng/ml) and following heparin infusion (median above pre-induction: 0.7 ng/ml). During CPB, plasma histamine levels were elevated throughout the 90 minute period of perfusion (median above pre-induction: 0.5–1.2 ng/ml). PGI2 infusion reduced the elevation in plasma histamine levels (median above pre-induction: 0–0.7 ng/ml). These data support the hypothesis that histamine release occurs during CPB. Platelet aggregation in the extracorporeal circuit may be contributory since prostacyclin premedication reduces histamine release.

Effect of gastric irradiation on gastric secretion and histamine in mice.

Gastric irradiation selectively inhibits acid secretion. Histamine may have a role in the inhibitory process. Seven days after gastric irradiation with 9 Gy X-rays, mice underwent a stomach perfusion and secretion test. Under pentagastrin stimulation (62.5 μg/kg), acid and histamine secretion was significantly lower than that of the unirradiated controls, while pepsin and potassium outputs were unchanged. Histamine concentration in the oxyntic region of the stomach assayed after the perfusion test was significantly lower than that of controls. It is postulated that the fall in the endogenous histamine store may contribute to the reduction in acid production.

Plasma histamine in pig: Effect of food and pentagastrin

Histamine may have a role in the physiological control of gastric acid secretion. We aimed to detect histamine release into the circulation during food and pentagastrin. Non-parametric statistical analysis was used. Seven pigs bearing iliac artery, iliac vein and portal vein cannulae were given a standard meal. Blood samples were collected at 10-minute intervals over a period of 2 hours for histamine assay. There were no significant changes in whole blood and plasma histamine concentrations in the iliac arterial or venous blood. In portal venous blood, no significant changes were observed in whole blood histamine, but there were signficant increases in plasma histamine 40 minutes after food (basal median: 149.0; range: 50.3–258.6 pmol ml−1; 40 minutes, median 214.9; range: 64.2–319.6 pmol ml−1).Four pigs were given pentagastrin, 6 μ kg−1 h−1 i.v. Iliac and portal venous bloods were collected for histamine assay before and 15 minutes after pentagastrin infusion. There were no significant changes in the whole blood histamine concentration in either iliac or portal venous blood. A small increase, mean 5%, of plasma histamine concentration was detected in the iliac venous blood (basal mena 242.9±21.7 pmol ml−1; stimulated mean 256.9±39.1 pmol ml−1). A 20% increase in the portal plasma histamine concentration was observed after pentagastrin (basal mean 240.1±13.2; stimulated mean 288.4±18.8 pmol ml−1).Both food and pentagastrin increase plasma histamine concentration in the portal vein. Pentagastrin has a greater effect than food.

The effect of some gastrointestinal peptides on pentagastrin-stimulated acid secretion and oxyntic mucosal histamine in rats

In addition to gastrin many incretin hormones are capable of regulating gastric acid secretion, particularly the glucagon-like family ofpeptides such as glucagon-like peptide (7-36)amide (GLP-l) and oxyntomodulin (OXM) from the L-cell of the ileal mucosa. Both peptides have been reported to be potent inhibitors of stimulated acid secretion in vivo and vitro, in man and in the conscious rat [1, 2]. This effect may involve several pathways, including stimulation of somatostatin (SMS) release [3]. The aims of this study were to investigate the effect of the glucagon-like peptides and related gastrointestinal hormones on pentagastrin-stimulated acid secretion and on oxyntic mucosal histamine in anaesthetized rats.

Effect of gastric stimulants on histamine release and circulatory responses

The effects of pentagastrin (6 μg/kg/h) or insulin (0.15 U/kg/h) on histamine release and blood circulation in nine anaesthetized dogs were studied by measuring (1) plasma histamine concentrations in the iliac artery, iliac vein, hepatic vein and portal vein, (2) the corresponding blood pressures, and (3) blood flow in the hepatic artery and the portal vein. In the portal vein, pentagastrin induced an overall 204% rise (p<0.01) in plasma histamine and a 28% rise (p<0.01) in blood flow while other measurements did not change significantly. Insulin did not induce similar rises. Three patients with duodenal ulcer (DU) undergoing proximal gastric vagotomy (PGV) were given pentagastrin (6 μg/kg) by bolus injection. Plasma histamine concentrations in the gastric veins draining the oxyntic cell area rose by 68%, 15 min after injection. Thus, specific histamine release may act as a mediator for pentagastrin-stimulated gastric acid secretion and as a vasodilator to facilitate gastric circulation. Insulin did not promote histamine release in the present study.

Gastric histamine in a chronic duodenal ulcer model induced by partial thoracic irradiation.

In a new model, chronic duodenal ulcers are generated by irradiating the lower mediastinum of mice with single doses of X-rays. Histamine, a potent secretagogue, may have a role in the aetiology. Seven days after irradiation, the lag period for ulcerogenesis, mice were given a gastric perfusion test. In mice given irradiation to the lower mediastinum tissue histamine in the oxyntic region of the stomach assayed after perfusion was significantly lower than that of controls. Acid and peptic activity were not different from controls. Histamine release may mediate the abscopal ulcer without increasing acid and peptic activity.

Paediatric extracorporeal priming procedures: does low temperature priming promote histamine release?

We have recently reported pathologically elevated plasma histamine levels in adult patients undergoing cardiac surgery throughout the perioperative period. We have found markedly higher histamine levels in paediatric practice. The priming volume of the smallest extracorporeal systems is invariably greater than the circulating blood volume of neonates and infants, necessitating the use of stored donor blood in the initial priming procedure. In 40 paediatric cases, arbitrarily selected, sampling from the arterial port of the oxygenator prior to the initiation of bypass revealed massively elevated plasma histamine levels (>30ng/ml) in those extracorporeal circuits in which the priming volume was smallest and the priming temperature lowest - at 10-12°C. It is clear that the use of donor blood (in this series less than five days old) may contribute to the delivery of histamine into the paediatric patients circulation at the onset of cardiopulmonary bypass and that the priming temperature may play a role.