Editorial II

Preanaesthetic H2 antagonists for acid aspiration pneumonia prophylaxis. Is there evidence of tolerance?

K. Hirota1 and T. Kushikata1

1 Department of Anesthesiology, University of Hirosaki, School of Medicine, Hirosaki 036-8562, Japan. E-mail: masuika@cc.hirosaki-u.ac.jp

Acid aspiration during induction of anaesthesia resulting in pneumonia is rare, with an incidence of about three per 10 000 general anaesthetics.1 2 However, this complication has a high morbidity and mortality. Rosenstock and colleagues3 reported patients’ complaints against anaesthetic and intensive care personnel made to a national board in Denmark between 1994 and 1998. Sixty of the complaints (20% of the total) were related to adverse respiratory events, for example equipment misuse, difficult intubation. Seven patients suffered from pulmonary aspiration of gastric contents, in this report, six of whom died. All the deaths occurred in patients who had been in a poor general condition before operation.

Economic constraints and the expansion of day care units have increased the number of surgical day-cases, but it has been reported that outpatients have a higher risk of aspiration pneumonia than inpatients, as outpatients often have a larger residual gastric volume.4 Prophylaxis against aspiration pneumonia is therefore important in preanaesthetic management. Critical risk factors for aspiration pneumonia in adults are: (i) a gastric pH less than 2.5; and (ii) a gastric fluid volume >25 ml.5 Animal investigations6 7 indicate that pH is more important than volume in determining lung injury and mortality. Various prophylactic regimens have been investigated with H2 antagonists being shown to be the most effective agents for increasing gastric pH and decreasing gastric fluid volume.8 9 However, several reports1013 suggest that regular medication with H2 antagonists may induce tolerance. Tolerance may occur at a cellular level within the stomach but not by enzyme induction in the liver. If tolerance to these drugs has been established in surgical patients, is preanaesthetic H2 antagonist use effective for prevention of aspiration pneumonia? In this editorial, the efficacy of preanaesthetic H2 antagonists and tolerance to them is discussed.

Regulation of gastric acid secretion

Gastric acid secretion is controlled by both neural and endocrine reflexes (Fig. 1). Neurally, stimulation of the vagus nerve induces acetylcholine release from the postganglionic nerve fibres. Local release of acetylcholine stimulates gastric parietal cells by direct activation of muscarinic receptors subtype 3 (M3) to increase gastric acid secretion.14 Although M1 antagonists such as pirenzepine reduce acid secretion, presumably these antagonists also inhibit transmission of neural signalling via M1 receptors, to suppress gastric secretion.15 The endocrine systems of the antrum and corpus of the stomach contribute to control of gastric acid secretion in different ways.16 In the antrum, gastrin released from G-cells in response to the presence of luminal protein and amino acids is a major stimulant of gastric acid secretion. In contrast, somatostatin (SST), released from antral D-cells that respond to a luminal pH below 3.5, suppresses G-cell function.16 Thus, these hormones complete a negative feedback loop regulating acid secretion. In the corpus of the stomach, the two main endocrine cell types, parietal cells and enterochromaffin-like cells, do not respond directly to luminal chemicals, but act as integrators of neurohumoural signals.16 Thus, gastrin stimulates enterochromaffin-like cells by activating cholecystokinin (CCK) receptor subtype 2 to secret histamine, which in turn stimulates parietal cells by excitation of H2 receptors to increase acid secretion. Recently, pituitary adenylate cyclase-activating peptide has been considered as another important hormone in the regulation of gastric acid secretion.17 Pituitary adenylate cyclase-activating peptide has been reported to stimulate the enterochromaffin-like cells producing histamine release. Its receptors are expressed on enterochromaffin-like cells (Fig. 1). Both parietal and enterochromaffin-like cell activity are inhibited by SST, which is secreted from corpus D-cells, activating SST2 receptors.16 As CCK2 receptors exist on the parietal cells, gastrin may also directly increase acid secretion from parietal cells. However, quantitative pharmacological studies show that the major effect of gastrin on gastric acid secretion in vivo is secondary to histamine release.16 In addition, clinical reports10 11 suggest that gastrin may not directly increase gastric acid secretion. Gastric pH increases after administration of H2 antagonists, despite the hypergastrinaemia they induce.



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Fig 1 Schematic representation of the mechanism(s) of acid secretion from parietal cells and the site of H2 antagonist and proton pump inhibitor (PPI) block. H2-R, histamine (H) receptor subtype 2; M3-R, muscarinic (M) receptor subtype 3; CCK2-R, cholecystokinin (CCK) receptor subtype 2; SST2-R, somatostatin (SST) receptor subtype 2; PACAP-R, pituitary adenylate cyclase-activating peptide (PACAP) receptor; ECL cells, enterochromaffin-like (ECL) cells. In the ECL cells, the solid dots represent histamine.

 
Evidence of tolerance to H2 antagonists

Diminution of the anti-secretory effect of H2 antagonists with long-term medication, known as tolerance, has been reported clinically.1013 I.V. or frequent and/or high dose oral administration particularly causes rapid development of tolerance. Netzer and colleagues12 studied the effect of repeated i.v. injections or a continuous infusion of ranitidine (100 mg every 6 h, or 50 mg bolus i.v. + 0.25 mg kg–1 h–1, respectively). Surprisingly, they found a rapid loss of the anti-acid effects of ranitidine on days 2 and 3, as gastric pH in more than 95% of volunteers was <4 (mean pH: 2.93 and 2.58 in injection group, 3.18 and 2.69 in infusion group, respectively). This suggests that i.v. H2 antagonists rapidly induce full tolerance; that is, there is not further increase in gastric pH produced by further H2 antagonist administration. Hurlimann and colleagues11 reported that high dose oral ranitidine 600 mg day–1, caused a rapid fade-out of acid inhibition from day 2 to 7, and Lachman and colleagues13 reported that frequent oral doses of ranitidine (150 mg, four times a day) produced full tolerance within 5 days. The data suggest that large oral doses of H2 antagonists and i.v. administration will rapidly produce full tolerance.

Mechanism of tolerance

The mechanism of H2 antagonist tolerance is unclear. However, several reports10 11 suggest that prolonged hypergastrinaemia with long-term use of an H2 antagonist induces tolerance. Gastrin induces enterochromaffin-like cell hyperactivity, including an increase in histamine release in minutes to hours.18 If gastrin stimulation is sustained for hours to days, the enterochromaffin-like cells will respond by hypertrophying.19 If sustained for weeks to months, hyperplasia will be induced.18 Over years, dysplasia or neoplasia may be produced.18 This time course of enterochromaffin-like cell responsiveness to gastrin suggests that tolerance may be because of hypergastrinaemia-induced up-regulation of histamine synthesis by enterochromaffin-like cells. The histamine produced competes with the H2 antagonist. Another possible mechanism has been suggested by Smit and colleagues.19 They found that H2 receptors transfected into Chinese hamster ovary cells are up-regulated in a time- and concentration-dependent manner by exposure to the H2 antagonists, cimetidine and ranitidine. Moreover, these up-regulated H2 receptors (increased density) display agonist-independent basal activity, for which cimetidine and ranitidine displayed inverse agonism that is negative intrinsic activity. In contrast, burimamide, a neutral H2 antagonist with no inverse agonist action, did not induce H2 receptor up-regulation. The data led to speculation that the inverse agonism displayed by some H2 antagonists, which results from H2 receptor up-regulation, contributes to the development of tolerance with chronic treatment.

Tolerance to H2 antagonists and anaesthetic practice

Several H2 antagonists are given as premedication to surgical patients for the prevention of acid aspiration pneumonia, 90–120 min20 before arrival in the operating theatre. If patients do not receive a H2 antagonist, what is the gastric fluid volume and pH on induction of general anaesthesia? Haavik and colleagues21 reported that mean gastric fluid volume and pH were 20 (SD 18) ml and 2.2 (1.2), respectively (n=246). The proportion of patients with more than 25 ml of gastric fluid and a pH of less than 2.5 was 26%. If tolerance to H2 antagonists has developed preoperatively, similar gastric fluid volume and pH values would be predicted. Tolerance could increase the risk of aspiration pneumonia in such patients.

In addition, in the intensive care unit, i.v. H2 antagonists are routinely administered to artificially ventilated patients to prevent stress ulceration and bleeding from the ulcer without monitoring gastric pH. A recent review article22 suggests that a pH >4 may be necessary to render pepsin inactive and a pH of 6 to inhibit fibrinolysis and to prevent the dissolution of blood clots. However, as tolerance to H2 antagonists could develop within a few days of initiating treatment,12 we suspect that long-term administration of i.v. H2 antagonists in this setting is of little use. Other agents should be considered for suppression of gastric acid secretion, prevention of stress ulceration and maintenance of clotting in patients who have been receiving regular high doses of H2 antagonists. However, as clinical evidence in ICU patients or during anaesthesia of tolerance to H2 antagonists remains to be reported, such prospective studies investigating the development of tolerance in such patient groups should be performed without delay.

Proton pump inhibitors

Recent reports suggest that proton pump inhibitors may be suitable alternatives for increasing gastric pH and decreasing gastric volume. Clinical studies suggest that proton pump inhibitors may produce a similar or more potent inhibitory effect on gastric acid secretion than H2 antagonists, without the development of tolerance.11 12 As proton pump inhibitors inhibit H+/K+-adenosine triphosphatase, which is the final step in gastric acid secretion from the parietal cell16 (Fig. 1), tolerance to these agents may not be induced with chronic treatment. Moreover, clinical reports23 24 showed that proton pump inhibitors are significantly more effective than H2 antagonists or placebo in reducing the rate of rebleeding after haemostasis in bleeding peptic ulcer patients. Therefore, proton pump inhibitors would be ideal therapy for surgical or ICU patients who have developed tolerance to H2 antagonists. What about patients receiving proton pump inhibitors long-term? Qvigstad and colleagues25 reported that treatment with a proton pump inhibitor induces tolerance to H2 antagonists in Helicobacter pylori-negative patients. This tolerance may be explained by proton pump inhibitor-induced hypergastrinaemia causing up-regulation of histamine synthesis by enterochromaffin-like cells. Thus, in surgical patients, proton pump inhibitors may be preferable to H2 antagonists.

We recommend that anaesthetists should check for any history of treatment with H2 antagonists or proton pump inhibitors in preoperative patients. When tolerance to H2 antagonists is possible, proton pump inhibitors should be given as preanaesthetic medication to reduce gastric volume and acidity. Insertion of a nasogastric tube after induction of anaesthesia should be considered. These small steps can effectively reduce the risk of aspiration pneumonia, one of the most feared complications of anaesthesia.

References

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