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An Audit of the Insulin-Tolerance Test in 255 Patients with Pituitary Disease

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An Audit of the Insulin-Tolerance Test in 255 Patients with Pituitary Disease European Journal of Endocrinology (2002) 147 41–47 ISSN 0804-4643 CLINICAL STUDY An audit of the insulin-tolerance test in 255 patients with pituitary disease Martin Lange, Ole L Svendsen, Niels E Skakkebæk1, Jørn Mu¨ller1, Anders Juul1, Marianne Schmiegelow1 and Ulla Feldt-Rasmussen Department of Endocrinology and 1Department of Growth and Reproduction, PE-2132, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark (Correspondence should be addressed to U Feldt-Rasmussen; Email: [email protected]) Abstract Objective: The insulin-tolerance test (ITT) is currently considered to be the gold standard for evalu- ating adults suspected of GH deficiency (GHD). The aim of this study was to determine factors that may influence nadir blood glucose (BG) when using a mean insulin dose of 0.1 IU/kg body weight. Furthermore, we wanted to evaluate the safety and GH-related aspects of the ITT. Design: ITT was performed in 277 patients, of whom 255 (129 females) were eligible for evaluation. Results: Multiple regression analysis, including the whole population, showed that the major deter- mining factors for nadir BG were basal BG and body mass index (BMI) ðP , 0:02Þ: No serious adverse event was recorded. Sixty-three percent of all patients tested had severe GHD with peak GH response to hypoglycaemia below 7.8 mIU/l. The positive predictive value for IGF-I was 0.82 and the negative predictive value was 0.47, using a cut-off value corresponding to 22 S.D. GH peak response to hypo- glycaemia decreased with increasing numbers of other pituitary hormone deficiencies. Conclusions: When determining the dose of insulin based on weight, factors like pre-test BG and BMI should also be considered. We propose an algorithm stating that the dose of insulin should be 0.1 IU insulin/kg body weight minus 2 IU if pre-test BG is ,4.0 mmol/l and minus 2 IU if BMI is ,20 kg/m2 in order to take these factors into account. Our findings furthermore support the concept that the low-dose ITT is a safe test in adults, when performed in experienced hands. It was confirmed that IGF-I is not sufficient when diagnosing GHD in adults, and reliable stimulation tests like ITT are required in the diagnosis. European Journal of Endocrinology 147 41–47 Introduction the widespread use of the ITT and the fact that the test result is considered comparable between centres The insulin-tolerance test (ITT) is currently considered (1), controversy regarding test procedures exists. This to be the gold standard when evaluating adults sus- is especially the case concerning the dose of insulin pected of growth hormone deficiency (GHD) (1), and required to achieve adequate hypoglycaemia (4–9). is also widely used in the diagnosis of adrenal insuffi- In some centres, the test is immediately terminated ciency in adults. In some countries, the test is also (by administering i.v. glucose or feeding the patient) used in the evaluation of children suspected of these once adequate hypoglycaemia has been achieved, diseases, but because of case reports of deaths in while in others i.v. glucose is only administered in the relation to ITT (2, 3) this has been abandoned in case of adverse events or prolonged hypoglycaemia. other countries. The test is also potentially hazardous Some evidence, however, has implied that the test and unpleasant to the adult patient and has contra- should not be terminated because of the risk of false indications such as epilepsy and ischaemic coronary negative results (10). An adequate insulin dose is there- and cerebral disease. fore of utmost importance in order to (a) reach suffi- The importance of a correctly performed ITT cannot cient hypoglycaemia and (b) avoid interruption of the be underestimated since an erroneously performed test test caused by fear of adverse events. may wrongfully result in a lifelong, unnecessary and The aim of this study was to determine factors that potentially harmful substitution therapy with both may influence nadir blood glucose (BG) when using a GH and hydrocortisone. Despite this fact and despite mean insulin dose of 0.1 IU/kg body weight in order q 2002 Society of the European Journal of Endocrinology Online version via http://www.eje.org Downloaded from Bioscientifica.com at 09/28/2021 09:58:05PM via free access 42 M Lange and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2002) 147 to standardize the process of determining the insulin The characteristics of the patients, original diagnosis dose used. Furthermore, we wanted to evaluate safety and the indications for performing ITT are shown in aspects and the GH-related aspects of the ITT. Table 1. Patients and methods ITT procedure In the period 1991–1999, 277 ITTs were performed at The same technician in co-operation with an experi- the Department of Endocrinology, National University enced physician performed all the ITTs. The patients Hospital, Copenhagen. had fasted from 2300 h on the day before the test. If Patient records were retrospectively obtained from the patients were on hydrocortisone substitution 268 patients (nine were not found). Thirteen patients, therapy, the last dose was at least 12 h before the test. considered to be insulin insensitive or with diabetes All tests were performed at 0900 h. Intravenous (BG .7.0 mmol/l, according to WHO (11) and Ameri- access was obtained in an antecubital vein and blood can Diabetes Association criteria) were excluded samples were taken at 215, 0, 15, 30, 45, 60, 75 because they received very high insulin doses and and 90 min for GH, cortisol and BG analyses. For therefore it was considered that they might interfere immediate BG measurements, a photometric B-Glucose with the analyses. Thus, 255 patients were eligible analyser from HemoCue was used at the same time- for evaluation of the ITT procedure. In most of the intervals. At 0 min, i.v. insulin (actrapid; Novo Nordisk, tests where indication for performing ITT was evalu- Gentofte, Danmark) was administered. The insulin dose ation of the pituitary–adrenal axis, GH was neverthe- was determined from body weight at the relatively low less measured, and these patients were included in dose of 0.1 IU/kg. The dose was adjusted if the patient the evaluation of the GH–insulin-like growth factor-I was considered to be insulin resistant or likely to be (IGF-I) axis. In seven patients evaluated for adrenal very insulin sensitive. These adjustments were based deficiency only, GH was, however, not measured, and on the experience of the technician and physician in 20 patients IGF-I was not measured in relation to rather than on measurable facts. The tests were not the ITT. Two hundred and thirty patients were there- routinely terminated by administering i.v. glucose fore eligible for evaluation of the GH–IGF-I axis. None once adequate hypoglycaemia was reached except in of the patients had, according to their records, factors case of adverse events or prolonged hypoglycaemia. such as liver disease or malnutrition that might have After 90 min the patients were given a meal after affected IGF-I levels. Cortisol levels were obtained which they left the Department. from 229 patients. Body mass index (BMI) was avail- Permission to perform this audit was obtained from able in 241 patients. Of the patients tested for GHD, the local ethical committee and registration board. 69 had childhood onset (CO) GHD. Methods Table 1 Patient characteristics expressed in median (range), original diagnosis and indication for performing ITT in 255 BG was measured using full blood in a HemoCue B-Glu- patients. cose analyzer (precision: S.D. #0.3 mmol/l). Plasma cortisol was analysed using high pressure Patient characteristics Females/males 129/126 liquid chromatography (HPLC) from 1991 to 1995, a Age (years) 35 (14–80) fluorescence immunometric assay (Delfia, Wallac, Fin- Height (m) 169 (141–198) land) from 1995 to 1997, a fluorometric assay (auto- Weight (kg) 75 (41–136) Delfia, Wallac) from 1997 and another fluorometric 2 BMI (kg/m ) 26 (15–56) assay from 1999 to the present day. To ensure the stab- Original diagnosis Pituitary adenoma 44.5% ility of the analysis, the Delfia assays were calibrated Craniopharyngioma 9% against the HPLC at regular intervals. Other intracranial neoplasm Plasma GH was measured using a polyclonal radio- þradiation 17.5% immunoassay (Pharmacia hGH RIA; Pharmacia, 2radiation 0.5% Idiopathic pituitary deficiency 10% Stockholm, Sweden) from 1991–1994, a fluorescence Other 18.5% immunometric assay (Delfia, Wallac) from 1994 to Indication for ITT 1997 and another fluorescence immunoassay (auto- Evaluation of GH status 66.4% Delfia, Wallac) from 1997 to the present day. To Evaluation of pituitary–adrenal axis 11.6% ensure the stability of the analysis, the same standard A combination of both 20.9% Others 0.1% (WHO 1st IRP 80/505) was used at regular intervals throughout the period. www.eje.org Downloaded from Bioscientifica.com at 09/28/2021 09:58:05PM via free access EUROPEAN JOURNAL OF ENDOCRINOLOGY (2002) 147 ITT in pituitary disease 43 Statistics As shown in Fig. 1, NBG, BBG, GH peak, IGF SDS and basal and peak cortisol decreased significantly with The test values examined (height, weight, BMI, insulin increasing numbers of additional pituitary deficiencies. dose, insulin dose/kg body weight, basal blood glucose The mean NBG and insulin dose in the patients who (BBG), nadir blood glucose (NBG), IGF standard devi- experienced adverse events were comparable with those ation score (SDS), and cortisol) followed a normal distri- of the total population (1.2 vs 1.3 mmol/l and 0.104 vs bution. GH peak and age did not follow a normal 0.105 IU/kg body weight respectively).
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