J.A.L. Amess

Megaloblastic haemopoiesis in patients receiving nitrous oxide.

In a prospective study the incidence of megaloblastic change after ventilation with nitrous oxide for periods of up to 24 h has been determined and the cause of the altered D.N.A. synthesis studied with the deoxyuridine (dU) suppression test in 22 patients undergoing cardiac bypass surgery. 8 patients who received nitrous oxide and oxygen for 24 h had megaloblastic bone-marrow aspirates and abnormal dU suppression tests at the end of ventilation. 5 patients who received no nitrous oxide had normoblastic aspirates and normal dU suppression test. Of the remaining 9 patients, who received nitrous oxide during the operation only, 3 had abnormal dU suppression tests at 24 h. The abnormality revealed by the dU suppression tests was identical with that found in vitamin-B12 deficiency, but the patients serum-B12 concentrations were normal. These results suggest that nitrous oxide interferes with the function of vitamin B12. Nitrous oxide oxidises vitamin B12 in vitro, and probably also in vivo when premixed 50% nitrous oxide and 50% oxygen mixture (Entonox) is given.

MIGRAINE: A PLATELET DISORDER

The hypothesis that migraine is caused by a primary abnormality of platelet behaviour was investigated in a total of 77 migraine patients and control subjects. Platelets taken from patients with classical migraine during a headache-free period demonstrated significantly higher spontaneous platelet aggregation and platelet adhesion than platelets from controls. Platelet 5-hydroxytryptamine release within three days of a migraine attack was significantly less than that measured during a migraine-free interval. Platelets from migraine patients differ significantly in their behaviour from normal platelets, and these differences can explain the onset and recurrence of attacks.

INCIDENCE AND PATHOGENESIS OF ACUTE MEGALOBLASTIC BONE-MARROW CHANGE IN PATIENTS RECEIVING INTENSIVE CARE

The incidence and pathogenesis of acute megaloblastic bone-marrow change and of abnormalities in DNA synthesis, as assessed with the deoxyuridine(dU) suppression test, have been investigated in a prospective study of 70 seriously ill patients admitted to an intensive-care unit. On admission megaloblastic bone-marrow change was present in 22 patients, 18 of whom had been anaesthetised with nitrous oxide for 2-6 h during surgical procedures before admission. 16 of these 18 patients died, compared with 7 of 22 patients in whom haemopoiesis remained normoblastic despite receiving equivalent amounts of nitrous oxide. An abnormal dU-suppression test developed only in patients who had received nitrous oxide; on admission an abnormal dU-suppression test was found in 39 of the 42 patients tested who had been exposed to the anaesthetic. The abnormality produced in the dU-suppression test by nitrous oxide in patients admitted to the intensive-care unit was more severe and recovery was slower than the abnormality seen in patients undergoing cardiac-bypass surgery. During the recovery period from the effects of nitrous oxide the pattern of correction of the dU-suppression test changed from that of vitamin-B12 deficiency to folate deficiency.

PLATELET AGGREGATION IN RESPONSE TO 5-HT IN MIGRAINE PATIENTS TAKING ORAL CONTRACEPTIVES

About 1 in 4 of the unselected new female patients seen by one of us (E.H.) at a migraine clinic has migraine attacks associated with taking oral contraception (OC). In some such patients the attacks began after OC was started (group 1) and in others attacks have become more frequent and severe since the patient began to take OCs (group 2). The fact that headaches can occur as a side effect of the pill was recognized in 1962. Other workers have reported changes in platelet behavior in patients on OCs. We found that platelets from patients with severe classical migraine showed a significant increase in aggregation in response to 5-hydroxy-tryptamine (5-HT). We therefore decided to investigate the rate and extent of platelet aggregation in response to 5-HT in the 2 groups of migraine patients on the pill. All patients were taking estrogen-containing preparations but had taken no other drugs during the 10 days before blood samples were taken. In addition we tested platelet aggregation using adenosine diphosphate (ADP) noradrenaline and adrenaline. Migraine was defined as a severe recurrent headache ususally affecting 1 side of the head more than the other and often associated with vomiting. Prodromal symptoms usually visual were mentioned by some patients. The studies were repeated 4-6 months after the patients had stopped taking the pill by which time there had been a marked improvement in the symptoms in every case. This improvement was gradual and usually spread over several weeks or even months. Our results to date show significant differences in the 2 groups (seen in table). Group 1 patients (no migraine attacks before starting the pill) showed a significant reduction in the extent of platelet aggregation induced by 5-HT after they stopped taking the pill (P<0.05). In addition the group 1 patients off the pill showed a significant reduction in extent and rate of platelet aggregation with 5-HT when compared with group 2 also off the pill (P<0.05). There was no significant changes in platelet aggregation induced by ADP noradrenaline and adrenaline. Had we considered the patients with increasingly severe migraine on the pill as a single group the significant changes in platelet behavior would have been overlooked. Our findings indicate that the pill can produce changes in platelet behavior which are found in nonpill-taking migraine patients. Patients starting OC should be questioned both about their own and their close family history of migraine. An awareness of the relation between platelet changes on the pill and migraine is clinically important. (full text)

Bone Marrow Hypoplasia During Intensive Care: Bone Marrow Culture Studies Implicating Ranitidine in the Suppression of Haemopoiesis

Two seriously ill patients with renal failure developed bone marrow hypoplasia and peripheral blood cytopenias during admission to an Intensive Care Unit (ICU). Both patients were being treated with ranitidine and, in both, there was evidence of drug accumulation. Serum from the patient with the highest concentration of ranitidine inhibited granulocyte-macrophage colony growth from normal bone marrow. The addition of ranitidine to cultures of normal bone marrow also produced a concentration-dependent inhibition of colony growth. Ranitidine should be used with caution in patients with renal failure where drug accumulation may seriously impair bone marrow function.