A new approach to scoring systems to improve identification of acute medical admissions that will require critical care.

Removal of the intensive care unit (ICU) at the Vale of Leven Hospital mandated the identification and transfer out of those acute medical admissions with a high risk of requiring ICU. The aim of the study was to develop triaging tools that identified such patients and compare them with other scoring systems. The methodology included a retrospective analysis of physiological and arterial gas measurements from 1976 acute medical admissions produced PREEMPT-1 (PRE-critical Emergency Medical Patient Triage). A simpler one for ambulance use (PREAMBLE-1 [PRE-Admission Medical Blue-Light Emergency]) was produced by the addition of peripheral oxygen saturation to a modification of MEWS (Modified Early Warning Score). Prospective application of these tools produced a larger database of 4447 acute admissions from which logistic regression models produced PREEMPT-2 and PREAMBLE-2, which were then compared with the original systems and seven other early warning scoring systems. Results showed that in patients with arterial gases, the area under the receiver operator characteristic curve was significantly higher in PREEMPT-2 (89·1%) and PREAMBLE-2 (84.4%) than all other scoring systems. Similarly, in all patients, it was higher in PREAMBLE-2 (92·4%) than PREAMBLE-1 (88·1%) and the other scoring systems. In conclusion, risk of requiring ICU can be more accurately predicted using PREEMPT-2 and PREAMBLE-2, as described here, than by other early warning scoring systems developed over recent years.

A presentation of anaplastic carcinoma of the thyroid with symptomatic intra-abdominal metastases.

Anaplastic thyroid carcinoma usually presents with symptoms related to local invasion and compression of structures in the neck. We report a patient with intra-abdominal metastases presenting with symptoms suggestive of local gastrointestinal disease. Abdominal CT scan and initial laparotomy findings were suggestive of an abdominal aortic aneurysm.

Increased collagen-linked fluorescence in skin of young patients with type I diabetes mellitus.

Our objective was to determine whether the fluorescence of skin collagen, which may reflect the accumulation of advanced glycosylation end products, is increased in young patients with type I (insulin-dependent) diabetes. Our study design was a cross-sectional case-control study in a referral-based diabetic clinic in an academic hospital. Study subjects comprised a convenience sample of 18 type I diabetic patients aged 17-30 yr and 8 age-matched healthy control subjects. The fluorescence of collagen was measured in skin biopsy material. Collagen-linked fluorescence (CLF) was increased in diabetic patients (mean 10.5 [range 5.8-15.8] U/mg) compared with control subjects (7.6 [5.6-10.1] U/mg, P less than 0.02). In diabetic patients, CLF was related to age (r = 0.581) and duration of diabetes (r = 0.697) but not concentration of glycosylated hemoglobin (r = 0.082). Partial correlation analysis demonstrated that duration of diabetes is the main factor determining the fluorescence of collagen in these patients. There was a relationship between CLF and presence of diabetic retinopathy after the data were adjusted for patient age and duration of diabetes (P = 0.023). Increased fluorescence of skin collagen can be detected in young type I diabetic patients and is primarily related to duration of diabetes.

The role of cortisol in the peripheral granulocyte response to insulin-induced hypoglycaemia in man.

Peripheral blood leukocyte counts and plasma hormonal changes in response to acute insulin-induced hypoglycaemia were examined in 16 patients undergoing assessment of pituitary function. Eight subjects had a normal cortisol secretory response (Group 1), and 8 patients had definite hypopituitarism in whom the cortisol responses were deficient or absent (Group 2). An equivalent degree of hypoglycaemia was achieved in both groups. In Group 1a biphasic rise in leukocyte count occurred following hypoglycaemia, with an early rise in lymphocytes at 15 minutes after the acute hypoglycaemic reaction, and a later rise in granulocytes. A similar rise in lymphocytes was observed in Group 2, but the rise in the granulocyte count was attenuated, increasing from a basal value of 3.6 +/- 0.6 x 10(9) cells/L to a peak of 7.4 +/- 1.1 x 10(9) cells/L, compared with a peak of 11.7 +/- 1.2 x 10(9) cells/L in Group 1 (P less than 0.05). The usual increment in plasma cortisol in response to hypoglycaemia occurred in Group 1, but plasma cortisol did not rise in Group 2. A correlation was observed between the magnitude of the granulocyte rise and the increment in plasma cortisol in individual subjects (r = 0.64, P less than 0.02). This suggests that the rise in peripheral granulocytes following insulin-induced hypoglycaemia in man is mediated by cortisol released from the adrenal gland, following activation of the hypothalamic-pituitary-adrenal axis.

Responses of peripheral blood cells and lymphocyte subpopulations to insulin-induced hypoglycaemia in human insulin-dependent (Type 1) diabetes.

Changes in counts of peripheral blood cells including lymphocytes and lymphocyte subpopulations were examined in response to acute insulin-induced hypoglycaemia in fourteen insulin-dependent diabetic patients of differing duration, and in eight normal subjects. In patients with a short duration of diabetes (less than 5 years) an initial lymphocytosis preceded a later granulocytosis, similar to changes in the normal group following hypoglycaemia. The lymphocytosis comprised increments in T11 (total), T4 (helper), and T8 (suppressor/cytotoxic) lymphocyte subsets, but B lymphocytes did not rise. In diabetic patients of longer duration (greater than 15 years) the initial lymphocytosis was attenuated, the T4 subset response being absent and the T11 subset response was diminished. The lower lymphocyte responses in the long-term diabetics were unrelated to differences in the hormonal responses to hypoglycaemia or to the rate of blood glucose recovery. Rapid mobilization of specific lymphocyte subpopulations appears to be abnormal in long-term insulin-dependent diabetes, and may indicate underlying immunological dysfunction.

Duration of antithyroid action of methimazole estimated with an intravenous perchlorate discharge test.

We have used a method based on a perchlorate discharge test to estimate the duration of antithyroid effect of two doses of methimazole (MMI). Six patients with diffuse toxic goitre took 5 mg MMI twice daily and six took 20 mg twice daily over the study period of 12 weeks. Biochemical control of hyperthyroidism was achieved in all patients and thyroid hormone supplementation was required by all of the patients in the higher dose group to avoid hypothyroidism. Discharge of radioiodine from the thyroid by perchlorate diminished in both groups with time after MMI. After 5 mg MMI, perchlorate discharge as a percentage of the 30-min uptake (mean +/- SD), was 81.7 +/- 3.3% at 2.2 h, 69.3 +/- 18.9% at 5.9 h, 22.6-23.4% at 13.4 h and 2.7-6.7% at 25.1 h. After 20 mg MMI, the discharge was 92.5 +/- 1.9% at 2.2 h, 84.3 +/- 8.8% at 6.3 h, 64.8 +/- 24.1% at 13.3 h and 26.9-29.4% at 25.1 h. Only four patients (one in the lower dose group) showed a detectable discharge at 25 h and one of the patients treated with the lower dose showed no discharge at 13 h. These estimates of the effect of MMI on thyroidal iodide organification are not in keeping with published thyroidal MMI concentrations which do not show a fall between 3-6 h and 17-20 h after carbimazole. The explanation for this disparity is not clear but may be based on a redistribution of thioureylenes within the thyroid with time after dosage.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of high and low doses of methimazole in patients with Graves' thyrotoxicosis.

In spite of the long-established use of antithyroid drugs, there are many unsettled questions connected with this treatment of Graves' disease. There is a lack of controlled prospective trials studying the results of antithyroid drug therapy while considering the many variables such as disease heterogeneity, regional differences, drug dosage and duration of treatment. Therefore, a multicenter study has been set up in order to compare the effects of two fixed doses of methimazole (10 vs 40 mg) with thyroid hormone supplementation on the clinical, biochemical and immunological course of Graves' disease and on remission rates. Experience accumulated so far suggests that treatment is safe using either 10 or 40 mg of methimazole. While there is a tendency for an advantage of the higher dose within the first weeks (higher effectiveness in controlling hyperthyroidism), this difference is not significant. The impact of dosage on remission rates remains to be shown.

Kinetics of [123I]iodide uptake and discharge by perchlorate in studies of inhibition of iodide binding by antithyroid drugs.

Thyroidal binding of iodide was studied by kinetic analysis of [123I]iodide uptake and its discharge by perchlorate in 80 hyperthyroid subjects receiving antithyroid drug therapy. Five dosage regimens ranging from 5 mg carbimazole twice daily to 15 mg methimazole twice daily were studied. Binding inhibition was estimated at 5-7 h after drug as an index of the mean effect of the 12 hourly regimen. In all cases, except one in the lowest dose group, binding was found to be markedly reduced with mean binding rates ranging from 0.002 to 0.020 min-1 (normal greater than 0.15 min-1). The net clearance of iodide in the lowest dose group was reduced to a mean value near the upper limit of the euthyroid range, whereas in the highest dose group it lay at the lower limit of the euthyroid range. These results were reflected in the serum thyroid hormone response. There was a reducing incidence of inadequate control of hyperthyroidism and an increasing incidence of hypothyroidism with increasing thiourylene dose. The exit rate constant of free iodide for the various doses showed values from 0.048 to 0.055 min-1. Corresponding mean values for the discharge rate constant after perchlorate were 0.087 to 0.105 min-1. This suggests that perchlorate increases the rate of iodide release from the thyroid gland. Studies at a later interval after drug (12-14 h) showed no change in discharge rate constant. This leads to the conclusion that perchlorate may further inhibit iodide binding in subjects receiving antithyroid drug therapy.

Body composition, blood pressure and the renin-angiotensin system in acromegaly before and after treatment.

Serial measurements of exchangeable sodium (Nae), blood pressure, circulating concentrations of growth hormone and the components of the renin-angiotensin-aldosterone system were made in 39 acromegalic patients: 26 patients were studied before and after treatment. Mean Nae was considerably increased, frequently being greater than values found in Conn's syndrome. Nine of the 26 untreated patients were hypertensive (35%) and of these seven were female and over the age of 52 years. In the untreated patients, Nae was positively correlated with age, blood pressure and growth hormone log concentration: the strongest correlation between Nae and growth hormone was obtained when the duration of the acromegalic process was taken into account. Following treatment there was often considerable reduction in Nae and this correlated closely with the fall in growth hormone: the relation between the fall in Nae and fall in blood pressure was less marked. The sodium retaining properties of growth hormone may cause a rise of blood pressure in a susceptible minority of acromegalics.

Treatment of presumed prolactinoma by transsphenoidal operation: early and late results.

Seventy seven patients who were presumed to have a prolactinoma on the basis of biochemical findings underwent transsphenoidal operation between October 1977 and September 1983. Sixty one patients were found to have a microadenoma, and hyperprolactinaemia was cured in 46 of these, amenorrhoea in 39 (80% of those with the symptom), galactorrhoea in 32 (80%), and infertility in 31 (82%). Four of eight patients found to have a macroadenoma were also satisfactorily treated with surgery. Two patients had a lesion other than a prolactinoma, and in six a tumour could not be found at operation; four of these last eight patients had a normal serum prolactin concentration after operation. Recurrent hyperprolactinaemia was rare, occurring in only three patients in the series overall; among the 32 patients followed up for more than five years only two of the 22 whose operation had initially been successful developed recurrent hyperprolactinaemia.

Peroxidase activity in relation to iodide, 17 beta-oestradiol and thioureylene drug uptake in human polymorphoneutrophils.

In polymorphoneutrophils (PMNs) phagocytosis is accompanied by an increase in peroxidase activity. Accumulation of iodide, thioureylene antithyroid drugs and 17 beta-oestradiol also occurs during the process. There is no evidence of an active iodide transport system in the PMNs as pertechnetate is not concentrated and neither ouabain nor perchlorate abolishes iodide accumulation. The uptakes of 125I, [35S]PTU and [3H]-17 beta-oestradiol were compared in phagocytosing PMNs and the effects of various compounds examined. In addition, chemiluminescence generation from luminol by PMNs and by horseradish peroxidase was studied. This indicated that uptake of all three compounds could be associated with activation of the peroxidase system, and inhibition of this enzyme system caused a reduction in their accumulation.

Effect of pretreatment with carbimazole on early outcome following radio-iodine (131I) therapy.

Of a group of 55 thyrotoxic patients given therapeutic radio-iodine (131I), 24 were made euthyroid with carbimazole before 131I: the remainder were given 131I alone. Carbimazole was discontinued 5 days before 131I was administered. By 3 months after 131I treatment there was a greater incidence of hypothyroidism in the group given 131I alone (42% vs 25%), but a lower incidence of persistent thyrotoxicosis (16% vs 46%), (P less than 0.05). One year after treatment a similar proportion of each group had persistent thyrotoxicosis (21% vs 23%), but there remained a lower incidence of hypothyroidism in the group pretreated with carbimazole (25% vs 45%). It is suggested that pretreatment with carbimazole reduces the degree of radiation induced thyroid damage.

Transient hypothyroidism following radioiodine therapy for thyrotoxicosis.

A prospective study of thyroid function including serial tracer radioisotope uptake measurements in 55 patients treated with 131I therapy is described. Five patients had an episode of transient hypothyroidism within eight months of treatment: in three of these patients this was due to impaired organification of iodide, with normal iodide trapping by the thyroid (as measured by a twenty minute 123I uptake) being preserved. In contrast, in all patients who developed permanent hypothyroidism, iodide trapping was markedly diminished and did not recover. It is suggested that hypothyroidism due to organification failure following 131I therapy is potentially short-lived; where hypothyroidism is associated with gross impairment of iodide trapping, recovery is unlikely. Early iodine uptake measurements may be of value in selecting those patients whose hypothyroidism is transient and who do not require permanent thyroid hormone replacement.

Accumulation of thiourylene antithyroid drugs in mouse salivary gland.

[35S]Methimazole and [35S]propylthiouracil were shown to accumulate in mouse submandibular gland in vivo, with maximal tissue: plasma ratios being achieved at the lowest dose of drug studied (0.1 microgram/animal). Autoradiography of submandibular glands showed that the drugs were localized to the intralobular ductal epithelium and within the lumen of the convoluted granular tubule, which was identical to the localization of radiolabelled iodide. Histochemical studies indicated that this was the site of peroxidase activity within the gland. Drug accumulation persisted when iodide trapping was competitively inhibited using perchlorate. These data suggest that antithyroid drug accumulation by this tissue is not dependent on the anion trap; the localization of drug and iodide at the site of peroxidase activity suggest that this may be an important factor in the mechanism of drug accumulation, possibly related to subsequent drug metabolism.

Defects in intrathyroid binding of iodine and the perchlorate discharge test.

The kinetics of [123I]iodide uptake were studied when organification of iodine by the thyroid gland was normal and when this binding function was diminished by drugs or disease. Each study was terminated by a sodium perchlorate discharge test (300--600 mg iv) at 60 min or, in some cases, 10--30 min. The results confirmed that binding takes place rapidly in the uninhibited gland with the binding rate constant being at least 0.150 min-1. Discharge from the uninhibited gland is less than 3.5% of the gland uptake when perchlorate is given 60 min after the radioiodide. Subjects with an intrinsic binding defect manifested discharges of 11% of greater of the 60 min uptake and the estimated binding rate constants ranged from 0.003--0.057 min-1. Thyrotoxic subjects receiving 5 mg carbimazole twice daily manifested discharges ranging from 5.4--64.2%, and in those receiving 20 mg twice daily the observed discharges were 67.6--94.6% of the 60 min uptake. The study shows that a correctly performed perchlorate discharge test will detect minimal inhibition of iodine binding. An important factor is the duration of the follow-up period after perchlorate is given. In some of the cases studied discharge was not complete until 60 min after the perchlorate.

Cryosurgery or microsurgery in the management of acromegaly.

Fifty-six patients with growth hormone-secreting pituitary adenomas, 28 treated by cryoablation and 28 by microsurgery, have been followed up from three to eight years. Mean serum growth hormone concentrations were less than 10 mU/L in 19 patients (68%) after microsurgery as compared with seven (25%) after cryosurgery. Hypopituitarism and operative complications were more frequent after cryosurgery. Transsphenoidal microsurgery was particularly successful in reducing growth hormone secretion without impairing normal pituitary function, when the patient had not been previously treated by another method.

Intrathyroidal iodide binding rates and plasma methimazole concentrations in hyperthyroid patients on small doses of carbimazole.

1 The effect of small doses of carbimazole on the binding rate constant of intrathyroidal iodide, plasma methimazole concentrations and circulating thyroid hormone concentrations in five hyperthyroid patients is presented. 2 In all patients there was a marked reduction in iodide binding with carbimazole doses as low as 5 to 10 mg daily. 3 In three patients little further reduction in the observed binding rate occurred with daily doses in excess of 10 mg despite progressive increases in plasma methimazole concentrations. 4 At the end of 4 weeks' treatment with 10 mg carbimazole daily, the reduction in thyroid hormone concentrations and clinical improvement were such as to suggest that this dose may be an effective starting dose in many patients.