Rationing healthcare in New Zealand: the use of clinical guidelines.

A 1991 "Green and White Paper", Your health and the public health. A statement of government health policy, advised that healthcare services in New Zealand could be rationed by a simple list. The Health and Disability Services Act 1993 provided a framework for resource allocation. The Core Services Committee rejected the "Oregon approach" of using a simple list to determine what condition/treatment pairs should be funded, preferring the development of clinical guidelines as a basis for assessment. Clinical priority assessment criteria derived from guidelines are used to define the degree of clinical benefit for public funding. Criteria have been developed for entry into end-stage renal failure programs, access to coronary artery surgery, and entry into booking systems for other elective services. The development of clinical criteria to define access to services has had a difficult road, but is a start in defining public expectations of New Zealand's healthcare system.

A randomized trial of short-term treatment of Graves' disease with high-dose carbimazole plus thyroxine versus low-dose carbimazole.

OBJECTIVE: The optimal treatment regimen with thionamide drugs remains a matter for debate. We have investigated whether high doses of carbimazole, when compared with low doses, reduce relapse rates of Graves' disease. DESIGN: In an open label, randomized, prospective trial of treatment of Graves' disease we compared high doses of carbimazole (6 months of 100 mg carbimazole per day plus thyroxine) to low-dose carbimazole treatment (starting at 25 mg and titrating the carbimazole dose with the aim to maintain serum thyroid function test results within the normal reference range). PATIENTS: Thirty-seven patients with a first episode of Graves' disease were enrolled. MEASUREMENTS: During the 6 months of treatment we evaluated the rate of normalization of serum thyroid function tests, changes in serum thyroid auto-antibody levels and the rate of side-effects during treatment. After completion of the 6-month treatment course patients were observed for 2 years for evidence of relapse of Graves' disease. RESULTS: There were no differences between the two groups either in the rate of normalization of serum thyroid function tests or in serum thyroid auto-antibody levels during treatment. Of the 17 patients randomized to high-dose treatment seven suffered treatment side-effects, compared to only one of the 20 patients receiving low-dose treatment (P < 0.006). There was no significant difference in 2-year post-treatment remission rates on an intention-to-treat basis between the two treatment groups (18.7% vs. 5.9%, P = NS). However, for those patients who completed 6 months of treatment (high-dose group = 9, low-dose group = 16), multivariate survival analysis demonstrated a significantly longer median relapse-free interval (P < 0.04) in the high-dose group (27 weeks; 25th percentile: 9.6 weeks, 75th percentile: 75 weeks) versus the low-dose group (6 weeks; 25th percentile: 4.8 weeks, 75th percentile: 13.1 weeks). CONCLUSIONS: High-dose carbimazole treatment delays, but does not prevent, relapse from Graves' disease in those patients able to tolerate the treatment. However, it leads to more frequent side-effects than conventional dose treatment.

Inhaled beclomethasone dipropionate suppresses the hypothalamo-pituitary-adrenal axis in a dose dependent manner.

OBJECTIVE: Little is known about the dose-response relationship of potential, unwanted, effects of inhaled beclomethasone (BDP) on the hypothalamo-pituitary-adrenal (HPA) axis, particularly in nonspecialist clinic settings. The purpose of our study was to investigate the dose-response relationship of inhaled BDP on the HPA axis in a general practice patient population. We also explored the optimal testing strategy in this population and correlated effects of inhaled BDP on the HPA axis with other systemic corticosteroid side effects. PATIENTS AND DESIGN: Controlled observational study employing 21 patients on inhaled BDP recruited from general practice, with minimal past and no present exposure to other corticosteroids, and 21 age and gender-matched controls. MEASUREMENTS: Twenty-four-hour urinary free cortisol excretion (UFC), serum cortisol before and 30 minutes after injection of 1 microgram and 250 micrograms of tetracosactrin, serum IGF-I and serum osteocalcin were measured. BDP use was estimated by inhaler weighing and prescription count. RESULTS: In subjects on inhaled BDP, 24-hour UFC (P < 0.008), serum cortisol 30 minutes after 250 micrograms tetracosactrin (P < 0.05) and the serum cortisol rise after 250 micrograms tetracosactrin (P < 0.04) were significantly lower when compared with controls. Measurements of HPA function correlated inversely with BDP dose estimated by inhaler weighing (all P < 0.03). Serum IGF-I and osteocalcin levels did not differ. CONCLUSIONS: We have demonstrated hypothalamo-pituitary-adrenal axis suppression in nonspecialist-clinic asthma patients on moderate to large doses of inhaled beclomethasone dipropionate. When accurate measurements of inhaled steroid dose are used, there is an exponential relationship between dose and hypothalamo-pituitary-adrenal axis suppression. There appears to be no 'safe' threshold, and around 15% of patients may have clinically significant suppression. However, the significance of hypothalamo-pituitary-adrenal axis suppression as a marker for concomitant corticosteroid effects on other organ systems remains uncertain.

Treatment of hypothyroidism with once weekly thyroxine.

We compared daily T4 therapy with 7 times the normal daily dose administered once weekly in 12 hypothyroid subjects in a randomized cross-over trial. At the end of each treatment we measured serum free T4 (FT4), free T3 (FT3), rT3, and TSH levels and multiple markers of thyroid hormone effects at the tissue level repeatedly for 24 h. Compared with daily administration, the mean serum TSH before the administration of weekly T4 was higher (weekly, 6.61; daily, 3.92 microIU/mL; P < 0.0001), and the mean FT4 (weekly, 0.98; daily, 1.35 ng/dL; P < 0.01) and FT3 (weekly, 208, daily, 242 pg/dL; P < 0.01) were lower. A minimally elevated serum total cholesterol during weekly administration (weekly, 246.8; daily, 232.6 mg/dL; P < 0.03) was the only evidence of hypothyroidism at the tissue level. Compared with daily administration, the mean peak FT4 following weekly administration of T4 was significantly higher (weekly, 2.71; daily, 1.59 ng/dL; P < 0.0001), as was the mean peak FT3 level (weekly, 285; daily, 246 pg/dL; P < 0.01). None of the tissue markers of thyroid hormone effect changed compared to daily T4, and there was no evidence of treatment toxicity, including cardiac toxicity. During weekly T4 administration, autoregulatory mechanisms maintain near-euthyroidism. For complete biochemical euthyroidism a slightly larger dose than 7 times the normal daily dose may be required.

Lack of evidence for pituitary thyrotroph down-regulation after 1 week of oral thyrotrophin-releasing hormone and metoclopramide under conditions of constant peripheral thyroid hormone levels.

We investigated the pituitary thyrotrophin (TSH) response to repeated oral (non-pulsatile) thyrotrophin-releasing hormone (TRH) administration and potential modifying effects of dopamine antagonist treatment under conditions of constant peripheral thyroid hormone levels. In a randomized double-blind crossover trial, seven hypothyroid subjects, euthyroid on L-thyroxine, received 1 week each of oral TRH (40 mg, 12 hourly) plus metoclopramide (10 mg, 8 hourly) and TRH (40 mg, 12 hourly) plus placebo (one capsule, 8 hourly). At the beginning and end of each treatment period five samples of blood for estimation of serum TSH were taken over 1 h before ("baseline") and seven samples over 2 h after the treatment combination was given ("stimulated"). Serum free thyroxine, free triiodothyronine and prolactin levels also were measured. Mean log10 +/- SEM (log10 mIU/l) "baseline" serum levels TSH were -0.177 +/- 0.183 (median 0.345 mIU/l (untransformed); range (r) 0.03-10.11 mIU/l; first quartile (1q) 0.22 mIU/l; third quartile (3q) 2.48 mIU/l) before and 0.182 +/- 0.107 (median 1.385 mIU/l; r = 0.45-19.8 mIU/l; 1q = 0.9 mIU/l; 3q = 1.78 mIU/l) after 1 week of treatment (p < 0.02). There were no significant differences between oral TRH plus metoclopramide and oral TRH plus placebo. Peripheral thyroid hormone levels and the "stimulated" TSH response (expressed as area under curve after TRH and metoclopramide or placebo; min.log10 mIU/l) remained unchanged after 1 week. In the absence of changes in peripheral thyroid hormone levels, oral TRH over 1 week may not result in down-regulation of anterior pituitary thyrotrophs.2+ f2p4

Serum enzymes in hypothyroidism.

AIM: To report three cases of hypothyroidism detected because of unexplained elevation of serum enzyme levels on biochemical testing. METHODS: Clinical details and serum enzyme results were obtained before and after L-thyroxine (T4) replacement therapy. RESULTS: The three patients all had serum creatine kinase (CK) levels > 2000 U/L, aspartate aminotransferase (AST) > 90 U/L, and lactate dehydrogenase (LD) > 300 U/L at presentation, with these levels being 10-15, 2-6, and 2-3 times the upper reference limits respectively. CK isoenzyme determination was consistent with skeletal muscle origin. Thyroid function tests performed after consultation with the clinical biochemist confirmed the biochemical diagnosis of primary hypothyroidism. A rapid fall toward normal serum enzyme levels occurred in response to T4 replacement therapy. CONCLUSIONS: Although serum enzymes are an integral part of both the liver and cardiac profiles provided by laboratory, they are not organ specific, and changes may reflect dysfunction elsewhere in the body. Elevations of serum CK (and other muscle enzymes) may occur in hypothyroid subjects, the cause of which has not been established. The clinical diagnosis of hypothyroidism requires a high index of suspicion and should be considered in patients with unexplained persistent elevations of serum muscle enzymes.

Serum free thyroxine levels respond inversely to changes in levels of dietary iodine in the domestic cat.

Because of a perceived increase in the incidence of toxic multinodular goitres in cats in recent years, we investigated the iodine content of three varieties of commercial canned cat foods and studied the acute effects of 'ingestion of these preparations on urinary iodine excretion and serum free thyroxine levels in young, healthy cats. Ten castrated male cats were fed from a common source. The type of food was changed every 2 weeks. Urine and blood specimens were obtained weekly. Serum free thyroxine levels were determined and iodine concentrations in urine were assayed. The iodine content of the cats' food was also assayed. Food varieties of high, intermediate and low iodine content were fed for 2-week periods. There was a consistent, reciprocal relationship between the mean urinary iodine concentration and the mean serum free thyroxine level for each 2-week period. The difference in the mean serum free thyroxine concentrations for the high and low iodine intake periods was highly significant (p<0.01). When the serum free thyroxine level and the urinary iodine level for each cat at each collection throughout the 12-week study were analysed (66 paired results), a strong inverse correlation (r=0.59, p<0.01) was found. We concluded that the serum free thyroxine level in cats, as measured by a kit designed for human serum, is acutely responsive to changes in iodine intake.

Treatment of extensively invasive (giant) prolactinomas with bromocriptine.

We report four cases of extensively invasive giant prolactinomas. No tumour was suitable for total or near total resection because of invasion into surrounding bone. All had undergone radiotherapy prior to dopamine agonist therapy. Prolactin levels were between 103,000 mlU/L and 1,700,000 mlU/L at presentation, but all tumours responded to bromocriptine therapy and prolactin levels fell into the normal range in three patients within two to 24 months. The fourth patient's level fell to just above the reference range (700 mlU/L) within 36 months. None of the patients has died of their pituitary tumour or related complications to date. Giant prolactinomas appear to be exquisitely sensitive to treatment with bromocriptine. The role of radiotherapy is unclear, but it might contribute to long term control. Surgery should be limited to control of local complications.

A study of L-thyroxine replacement.

We studied consecutive requests for in vitro thyroid function tests on patients receiving L-thyroxine (T4) for primary hypothyroidism for a three month period May to July 1990, and waited a further three months before ascertaining any changes made to the daily dose of T4. Serum sensitive TSH (sTSH) concentrations were normalised in only 43% of patients treated by a hospital general physician, 50% of patients treated by a specialist endocrinologist and 52% of patients treated by their primary care physician. The respective figures for elevated serum sTSH concentrations were 43%, 33% and 32% and for suppressed levels 15%, 17% and 15%. The dose of T4 required to normalise serum sTSH levels was approximately 110 micrograms/d. In 36% of those patients with suppressed serum sTSH levels the daily dose of thyroxine was reduced. This achieved a mean reduction in the daily dose of 20 micrograms. In 30% of those with raised serum sTSH levels the daily dose of thyroxine was increased. This achieved a mean increase in the daily dose of 15 micrograms. Patients receiving T4 may have raised serum free T4 (fT4) despite normal sTSH levels indicating that serum fT4 measurement is not the test of choice for screening for adequacy of T4 replacement.

Iodine content of commercially-prepared cat foods.

Twenty-eight varieties of commercially-available cat food (23 canned, 5 dried) were analysed for iodine. The iodine concentration varied from less than 0.37 micromol/kg to 41.8 pmol/kg, wet weight (less than 1.48 micromol/kg to 167 micromol/kg, dry weight). Excessive or insufficient iodine intake or wide swings in iodine intake over prolonged periods may contribute to thyroid disorders in cats.

Serum levels of free and bound testosterone in hyperthyroidism.

OBJECTIVE: The aim of this study was to improve knowledge about the relationships between free and bound forms of testosterone in serum and the major testosterone-binding proteins during hyperthyroidism. DESIGN: Nine men and 11 women were studied when hyperthyroid due to Graves' disease and again after at least 3 months of euthyroidism. MEASUREMENTS: The serum concentrations of free T3, free T4, TSH, sex hormone-binding globulin (SHBG), LH, progesterone and free, non-SHBG bound and total testosterone were determined. RESULTS: For both sexes, hyperthyroidism was associated with significant elevations of the mean total testosterone and sex hormone-binding globulin (SHBG) levels and significant depressions of the mean percentage and concentration of non-SHBG-bound testosterone and the mean percentage of free testosterone. For women, the mean free testosterone concentration was significantly lower during hyperthyroidism than during euthyroidism; no significant difference in mean free testosterone concentration was observed between hyperthyroid and euthyroid men. When the experimentally derived data were analysed according to a model based on the binding constants of testosterone with SHBG and albumin, the simulated results for each patient when hyperthyroid and euthyroid paralleled the actual results. However, the model consistently overestimated the actual amounts of non-SHBG-bound testosterone. There was a significant correlation between SHBG concentration and the severity of thyrotoxicosis as measured by the change in thyroid hormone levels between euthyroidism and hyperthyroidism. CONCLUSIONS: Our results support the following pathogenetic sequence: thyrotoxicosis leads to a rise in serum SHBG concentration which is accompanied by an increase in testosterone concentration, a fall in the concentration of non-SHBG-bound testosterone and little or no change in the concentration of free testosterone.

The management of Graves' disease in New Zealand: results of a national survey.

OBJECT: to compare treatment of Graves' disease in New Zealand with treatment in Europe and the United States of America (USA). METHODS: we circulated a questionnaire used in recent surveys in Europe and USA to all specialist physicians in New Zealand registered with the Medical Council. In the questionnaire a patient with uncomplicated Graves' disease was given as an index case, followed by eight clinical variations with regard to goitre size, severity, sex, age and previous treatment. RESULTS: two hundred and ninety-six (79%) out of 374 physicians responded to a preliminary letter asking whether they would be willing to participate in the survey. Of the respondents 71 (24%) saw more than two patients with Graves' disease per year and were included in the analysis (186 saw fewer than two cases per year and 39 failed to return questionnaires). For the index case, 55% of New Zealand respondents would treat with antithyroid drugs, 41% with radioiodine and 4% with surgery. For the index case and its variations the use of radioactive iodine by New Zealand physicians was greater than their European, but less than their American, counterparts. Surgery was infrequently recommended in any of the countries except for the patient with a large goitre, for whom 24% of New Zealand and 51% of European respondents would recommend subtotal thyroidectomy. CONCLUSION: we have demonstrated a spectrum of behaviour by physicians in the treatment of Graves' disease based on infrequent use of surgery and the willingness to use radioactive iodine instead of treatment with antithyroid drugs. New Zealand physicians appear to be more conservative in the use of radioiodine than their American, but less than their European counterparts.

Iodine intake and the seasonal incidence of thyrotoxicosis in New Zealand.

We explored a possible relationship between the seasonal variation in the incidence of thyrotoxicosis in our area and iodine intake, as assessed by measuring the 24-h urinary iodide excretion rate eight times at 3-month intervals in a group of normal subjects and in 992 outpatient specimens over a 2-year period (1988-1990). For the period 1978-1990, 139 cases of thyrotoxicosis were diagnosed during the warmer half of the year (November-April) and 100 cases during the cooler half (May-October). This difference was statistically highly significant (P = 0.013). A similar disproportionality in the incidence of thyrotoxicosis was observed between the warmer (57%) and cooler (43%) halves of the year for the period 1988-1990. During the 1988-1990 period there was no discernible seasonal variation in either the milk iodide concentration or in the cumulative mean 24-h urinary iodide excretion rates for the normal subjects or the outpatients. We conclude that the higher proportion of thyrotoxic patients diagnosed during the warmer 6-month period of the year in our area is best explained by the fact that symptoms tend to be less tolerable in warm weather. A comparison of our findings on 24-h urinary iodide excretion rates with data collected in our area 25 years ago suggested that iodine intake may have declined.

Once daily, low dose, short term antithyroid drug treatment of Graves' disease is followed by an unacceptably high relapse rate.

Thirty-six patients with hyperthyroid Graves' disease were treated with low doses of antithyroid drugs until thyroid function test results indicated euthyroidism or mild hypothyroidism (median treatment period three months, range 1.5-8 months). Less than one-half (42%) of the patients remained hyperthyroid after two months of treatment, but 21% were still thyrotoxic after three months of treatment. Of 32 patients who completed treatment and entered the observation period after treatment was withdrawn, 27 (84%) have relapsed, two have remitted for one year or more and three have been followed for less than one year without relapse. Although once daily, low dose, short term antithyroid drug treatment of patients with Graves' disease in the Wellington area satisfactorily controls the hyperthyroidism in the majority of cases, it is followed by an unacceptably high relapse rate.

Adrenalectomy does not influence basal secretion of testosterone in rat in vivo.

We have studied the effect of adrenalectomy on the testicular secretion of testosterone in the rat. In the acute period following adrenalectomy plasma testosterone levels were reduced but this was no different from those levels in appropriate sham-operated controls. This reduction in plasma testosterone levels is probably a result of direct effects of anaesthesia and surgical stress. Whilst studies on the late effect of adrenalectomy avoided this problem, plasma testosterone levels were normal in both adrenalectomised and sham-operated animals. Resetting of anterior pituitary-gonadal relationships may mask the absence of any contribution made by the adrenal gland to testicular steroidogenesis. In contrast to previous data we were unable to demonstrate that adrenalectomy influenced the secretion of testosterone in the male rat.

The adrenal gland and progesterone stimulates testicular steroidogenesis in the rat in vivo.

Administration of pharmacological doses of glucocorticoid to male rats in vivo suppresses adrenal steroidogenesis and inhibits testicular steroidogenesis by inhibiting the anterior pituitary secretion of LH. In contrast, administration of ACTH to these pharmacologically-suppressed rats stimulates the adrenal secretion of progesterone and testicular steroidogenesis. The mechanism by which ACTH increases testicular steroidogenesis is dependent on the presence of the adrenal gland and is reproduced by the administration of progesterone. The conclusion from these data is that the adrenal gland has an important role in generating external signals that modulate the hypothalamic-pituitary-gonadal axis in male rats. The adrenal secretion of glucocorticoid acts as a negative signal to testicular steroidogenesis whereas progesterone acts as a positive signal. The adrenal secretion of progesterone and its conversion to testosterone by steroidogenic enzymes in the cytoplasm of the Leydig cell may provide an alternative pathway for testosterone biosynthesis and may account for the increased plasma testosterone levels during the acute phase of stress and mating.