Procalcitonin (PCT)-guided algorithm reduces length of antibiotic treatment in surgical intensive care patients with severe sepsis: results of a prospective randomized study.

BACKGROUND: Adequate indication and duration of administration are central issues of modern antibiotic treatment in intensive care medicine. The biochemical variable procalcitonin (PCT) is known to indicate systemically relevant bacterial infections with high accuracy. In the present study, we aimed to investigate the clinical usefulness of PCT for guiding antibiotic treatment in surgical intensive care patients with severe sepsis. PATIENTS AND METHODS: Patients were randomly assigned to a PCT-guided or a control group requiring antibiotic treatment. All patients received a calculated antibiotic regimen according to the presumed microbiological spectrum. In the PCT-guided group, antibiotic treatment was discontinued if clinical signs of infection improved and the PCT value was either <1 ng/ml or decreased to <35% of the initial concentration within three consecutive days. In the control group, antibiotic treatment was directed by empirical rules. RESULTS: The PCT-guided group (n = 14 patients) and the control group (n = 13 patients) did not differ in terms of biological variables, underlying diseases, and overall disease severity. PCT guidance led to a significant reduction of antibiotic treatment from 6.6 +/- 1.1 days (mean +/- SD) compared with 8.3 +/- 0.7 days in control patients (p < 0.001) along with a reduction of antibiotic treatment costs of 17.8% (p < 0.01) without any adverse effects on outcome. CONCLUSIONS: Monitoring of PCT is a helpful tool for guiding antibiotic treatment in surgical intensive care patients with severe sepsis. This may contribute to an optimized antibiotic regimen with beneficial effects on microbial resistances and costs in intensive care medicine.

[Antibiotic treatment of surgical intensive care patients: procalcitonin to guide duration of therapy]. / Antibiotikatherapie bei operativen Intensivpatienten: Prokalzitonin zur Steuerung der Therapiedauer.

The development of resistance by infective bacterial species is an incentive to reconsider the indications and administration of available antibiotics. Correct recognition of the indications and duration of therapy are particularly important for the use of highly potent substances in the intensive care situation. There has as yet been no clinical chemical parameter which is capable of specifically distinguishing a bacterial infection from a viral or non-infectious inflammatory reaction, but it now appears that procalcitonin (PCT) offers this possibility. The present study was intended to clarify whether PCT can be used to guide antibiotic therapy in surgical intensive care patients. A total of 110 patients in a surgical intensive care ward receiving antibiotic therapy after confirmed infection or a high grade suspicion of infection were enrolled in this study. In 57 of these patients a new decision was reached each day as to whether the antibiotic therapy should be continued after daily PCT determination and clinical assessment. The control group consisted of 53 patients with a standardized duration of antibiotic therapy over 8 days. Demographic and clinical data were comparable in both groups. However, in the PCT group the duration of antibiotic therapy was significantly shorter compared to controls (5.9+/-1.7 vs. 7.9+/-0.5 days, p<0.001) without unfavorable effects on clinical outcome.

Changes in metabolism of TRH in euthyroid sick syndrome.

OBJECTIVE: The aim of this study was to examine the metabolism of a simple dose, intravenously administered TRH bolus of 200 microg, in patients with euthyroid sick syndrome (ESS). PATIENTS AND METHODS: A TRH test was performed on ten ESS patients and ten controls upon admission (d1) and after recovery (d2). Blood samples were collected at 0, 10, 20 and 30min after TRH injection. We analyzed the volume of distribution (V(d)), the plasma clearance rate (PCR), the fractional clearance rate (FCR), the half-life (t(1/2)) and the TSH response to the injection of TRH. RESULTS: All patients had lower tri-iodothyronine (T(3)) levels compared with controls (0.9 +/- 0. 1nmol/l vs 1.9 +/- 0.1 nmol/l; P < 0.0001; mean +/- S.D.; paired t-test). In addition, the V(d) (16.7 +/- 5.9/l vs 30.6 +/- 0.6/l; P < 0.0005) and PCR (2.0 +/- 0.80 l/min vs 3.3 +/- 0.25 l/min; P <0. 0005) were found statistically lowered in patients than in controls, whereas FCR (0.119 +/- 0.01 permin vs 0.110 +/- 0.01 per min; P < 0. 025) was found increased in patients as opposed to controls. The t(1/2) of exogenously administered TRH was increased in ESS compared with controls (7.2 +/- 0.7 min vs 6.3 +/- 0.6 min; P <0.005). TSH response to TRH was found significantly repressed at 10, 20 and 30 min after TRH injection. On d2, these findings had reverted to normal and no changes regarding the kinetics of TRH and the response of TSH could be detected between patients and controls. CONCLUSIONS: The results demonstrate an impairment of TRH metabolism in ESS. The findings may suggest altered enzymatic activity, responsible for TRH degradation in states of acute ESS. These changes might be involved in the pathogenesis of ESS and represent part of an adaptive mechanism to this syndrome.

Signal-averaged electrocardiogram in patients with insulin-dependent (type 1) diabetes mellitus with and without diabetic neuropathy.

The purpose of this study was to investigate the presence of ventricular late potentials derived from signal-averaged ECG in patients with IDDM with and without diabetic neuropathy. Eighty patients with IDDM but without evidence of cardiac disease and 80 age-matched healthy control subjects were investigated. The corrected QT interval was measured from the standard surface electrocardiogram. Ventricular late potentials were derived from signal-averaged electrocardiogram. Out of the 80 diabetic patients, 20 had an autonomic neuropathy, 20 had an isolated peripheral neuropathy, and 40 had no symptoms of neuropathy. The corrected QT interval was significantly prolonged in patients with an autonomic neuropathy as compared with the control group (436 +/- 23 ms(x 5) vs 384 +/- 23 ms(x 5), p < 0.001). In the other patient groups there was no significant prolongation of the corrected QT interval. Ventricular late potentials were present in 3 diabetic patients with an isolated peripheral neuropathy and in 1 control subject (NS). No diabetic patient with an autonomic neuropathy had ventricular late potentials. Our data did not indicate an increased incidence of ventricular late potentials derived from signal-averaged electrocardiogram in diabetic patients independent of a coexisting diabetic neuropathy or a prolonged corrected QT interval.

Unchanged 5'-deiodinating activity during the induction of a nonthyroidal illness.

We investigated the formation of a "nonthyroidal illness" (NTI) in pigs undergoing ventricular fibrillation (VF) and resuscitation. Seven minutes after VF twenty-one pigs received either Epinephrine (E: 45 micrograms/kg B.W.; n = 7), Norepinephrine (NE: 45 micrograms/kg B.W.; n = 7), or Vasopressin (VP: 0.8 U/kg B.W.; n = 7). We determined the serum concentrations (sc) of total T4 (TT4), FT4, total T3 (TT3) and rT3 120 min before, during (t0), and 5, 15, 60 and 120 min after VF. At the end of the observation period we figured out the in-vitro T3-generation (kM, Vmax), the in-vitro rT3-generation, the in-vitro rT3-decomposition (kM, Vmax) and the content of cytosolic sulfhydryls (total sulfhydryls, non-protein bound sulfhydryls) in liver and kidney specimen. Animals not undergoing VF served as controls (C) for parameters measured in the intracellular compartment. TT4- and TT3-sc decreased to 3.3 +/- 0.6 micrograms/dl (p < 0.05, vs. t0) and 15.2 +/- 4.1 ng/dl (p < 0.05, vs t0), resp. FT4-sc remained stable for five minutes (2.63 +/- 0.41 ng/dl) before declining to 1.8 +/- 0.39 ng/dl (p < 0.05, vs. t0). The rT3-sc raised finally to 46.9 +/- 7.3 ng/dl (p < 0.05, vs t0). Iodothyronine sc did not exhibit differences between E-, NE- and VP-treatment. Neither in-vitro T3-generation, nor in-vitro rT3-generation, nor in-vitro rT3-decomposition nor intracellular sulfhydryl content were affected by the events of VF and resuscitation as compared to the controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of corticotropin releasing factor on atrial natriuretic peptide release from the isolated perfused rat heart.

The effect of corticotropin releasing factor (CRF) on atrial natriuretic peptide (ANP) release and its possible modulation by indomethacin, norepinephrine, propranolol and nitro-L-arginine (an inhibitor of the endothelium-derived relaxing factor (EDRF) release) was investigated, using an isolated perfused rat heart preparation. Bolus injection of 5 micrograms CRF, dissolved in 100 microliters perfusion buffer, provoked a significant (p < 0.01 vs. control) short-time increase of ANP release. Indomethacin (3 x 10(-5) mol/l) inhibited the CRF-stimulated increase of ANP release and decreased the basal ANP secretion (p < 0.01 vs. CRF group). Norepinephrine (10(-9) mol/l) slightly, but not significantly, decreased the CRF-stimulated ANP release and did not change the basal ANP output. Propranolol (3 x 10(-6) mol/l) did not alter ANP release. Nitro-L-arginine (3 x 10(-5) mol/l) increased the basal ANP release (p < 0.01 vs. CRF group) and prolonged the CRF-induced rise of the ANP secretion. The present data suggest that prostaglandins are important mediators of basal and CRF-stimulated ANP release and that EDRF might be a physiological inhibitor of ANP release.

Doppler echocardiographic evaluation of left ventricular diastolic function in acute hypothyroidism.

OBJECTIVE: Left ventricular diastolic dysfunction is an important cause of symptomatic heart failure. Previous studies suggest that thyroid dysfunction affects left ventricular diastolic function but the underlying mechanisms remain controversial. The study was undertaken to asses the influence of acute hypothyroidism on left ventricular diastolic function and to elucidate possible underlying mechanisms by means of Doppler echocardiography in a group of athyreotic patients, whose thyroid state depended only on external thyroid hormone supply and could therefore easily be controlled. PATIENTS: Eleven patients (5 men, 6 women, aged 20-55 years), who had had total thyroidectomy, were investigated during mild hyperthyroidism and during acute hypothyroidism. Additionally, 11 healthy control subjects aged 25-51 years were included in the study. DESIGN: M-mode echocardiography of the left ventricle and pulsed-wave Doppler echocardiography of the transmitral flow velocity pattern were carried out. RESULTS: Acute hypothyroidism produced a decrease of left ventricular end-diastolic diameter from 48 +/- 5 to 46 +/- 5 mm (mean +/- SD P < 0.05), of peak velocity of early diastolic filling from 0.52 +/- 0.10 to 0.42 +/- 0.05 m/s (P < 0.05), of peak velocity of late diastolic filling from 0.42 +/- 0.10 to 0.36 +/- 0.09 m/s (P < 0.05), and a decreased time-velocity integral of early diastolic filling (6.2 +/- 1.8 vs 5.1 +/- 0.7 cm, P < 0.05). The other M-mode and Doppler echocardiographic parameters did not differ between the hyperthyroid and the hypothyroid states. CONCLUSIONS: The observed changes of the trans-mitral flow velocity pattern during acute hypothyroidism can be attributed to a reduction of pre-load. There is no direct evidence that acute hypothyroidism affects the intrinsic diastolic properties of the left ventricle.

Systolic ventricular function in acute hypothyroidism: a study using Doppler echocardiography.

The influence of thyroid state on left ventricular systolic function was studied in 11 patients (5 men, 6 women, aged 20-55 years) without cardiac disease, who had undergone total thyroidectomy and radioiodine treatment for thyroid cancer before. Pulsed-wave Doppler echocardiographic measuring of aortic blood flow and two-dimensional/time-motion (2D/M-mode) echocardiography were performed on two occasions once while the patients were mildly hyperthyroid on thyroxine replacement therapy and once when they were hypothyroid. During hypothyroidism left ventricular end-diastolic diameter decreased from 48 +/- 5 mm to 46 +/- 5 mm (p < 0.05). The diameter of the aortic ring, the left ventricular end-systolic diameter, the thickness of the interventricular septum and posterior wall, and fractional shortening did not differ significantly between the two studies. The following parameter of aortic blood flow changed significantly when passing from the hyperthyroid to the hypothyroid state: peak velocity (0.86 +/- 0.15 m/s versus 0.72 +/- 0.15 m/s, p < 0.01); mean velocity (0.49 +/- 0.08 m/s versus 0.44 +/- 0.08 m/s, p < 0.01); time- velocity integral (14.1 +/- 3.0 cm versus 12.3 +/- 3.1 cm, p < 0.05); stroke volume (43.0 +/- 9.7 ml versus 35.2 +/- 8.2 ml, p < 0.05); and preejection period (124 +/- 23 ms versus 147 +/- 21 ms, p < 0.01). Peak acceleration, mean acceleration, acceleration time and left ventricular ejection time did not change when the thyroid state was altered. It is concluded that left ventricular contractile function was not affected by acute hypothyroidism.(ABSTRACT TRUNCATED AT 250 WORDS)

Evaluation of thyrotropin secretion before and after TRH by third generation chemiluminescent assay. Assessment of subclinical hyperthyroidism.

The recent introduction of third generation assays for TSH has led to a considerable improvement of assay sensitivity. To assess the clinical significance of subnormal basal TSH (b-TSH) values (< 0.2 microU/ml), we investigated b-TSH and TRH-stimulated TSH (r-TSH) by means of a new, highly sensitive immunochemiluminometric assay in 105 euthyroid subjects, 45 patients with overt hyperthyroidism and 18 patients suspected of having subclinical hyperthyroidism. A weak, albeit statistically significant, correlation (r = 0.48) was found between b-TSH and r-TSH and also between b-TSH and delta-TSH (r = 0.31) in euthyroid subjects. Consideration of b-TSH alone correctly identified 90 % of euthyroid subjects in this group; 10 of 105 apparently euthyroid subjects presented delta-TSH suggesting subclinical hyperthyroidism. While b-TSH was detectable (> 0.04 microU/ml) in 8 of 45 (18%) of hyperthyroid patients, all (100%) were abnormal in both b-TSH and r-TSH. 14 of 18 (78%) of patients with subclinical hyperthyroidism exhibited a blunted TSH response to stimulation (delta-TSH < 2 microU/ml). These results suggest that although the new generation of TSH assays can be a valuable addition to the diagnostic arsenal of thyroid function tests, certain limitations must still be accepted. Specifically, b-TSH in the "grey zone" (0.1-0.2 microU/ml) appears to be a less than reliable predictor of thyroid function.

On line continuous monitoring of subcutaneous tissue glucose is feasible by combining portable glucosensor with microdialysis.

A new method for continuous measurement of subcutaneous tissue glucose content is introduced: by combining the microdialysis technique with a wearable amperometric glucose sensor, a device for continuous glucose measurement in the subcutaneous tissue was obtained. This device was applied to healthy volunteers (n = 10) over the period of an oral glucose load and to type I diabetic patients (n = 10) under the conditions of daily life. Glucose profiles in both healthy and diabetic persons were followed in the subcutaneous tissue up to 27 hours. This technique will certainly open new perspectives of monitoring and treating diabetic patients.

The function of a hydrogen peroxide-detecting electroenzymatic glucose electrode is markedly impaired in human sub-cutaneous tissue and plasma.

Electroenzymatic glucose sensors implanted into sub-cutaneous (s.c.) tissue of human subjects and experimental animals exhibit lower sensitivities to glucose than in buffer solutions before implantation. The mechanism of the decrease of sensitivity is not known. Sensors used in this study were fabricated from platinum wires (diameter 0.125 mm) with covalently bound glucose oxidase at the tip of the wire. After coating the tip with polyurethane, wires were placed into 27 gauge steel needles. Sensors were operated potentiostatically at 700 mV against Ag/AgCl pseudo-reference electrodes. These sensors were implanted s.c. in 6 diabetic patients for 7 h. In 4 patients, sensors were responsive to successive increases of plasma glucose levels. Mean sensitivity to glucose in s.c. tissue was 29% of in vitro sensitivity. In 2 patients there was a sudden decrease of sensor currents, unrelated to glucose, shortly after implantation. Sensors were inhibited in human plasma to a similar extent. When sensors were exposed to native plasma and to plasma ultrafiltrate (mol. wt. < 10 kDa) for 10 h, identical decreases of signals were found. Exposure to dialysed plasma (mol. wt. > 12 kDa) caused much less decrease of sensor signals. Losses of sensor sensitivities to glucose in s.c. tissue and in plasma were totally reversible upon re-exposure of sensors to buffer solutions. We conclude that sensor inactivation in plasma and possibly in s.c. tissue is caused by low molecular weight substances not retained by the polyurethane membrane.

Combination of microdialysis and glucosensor permits continuous (on line) SC glucose monitoring in a patient operated device. II. Evaluation in animals.

The microdialysis technique was used for following the glucose content of the extracellular subcutaneous (SC) fluid under varying blood glucose levels in rats. The glucose content in the microdialysis perfusion fluid was continuously analyzed by means of the measuring flow chamber of an ex vivo glucose monitor. In six ChBB rats blood glucose levels were varied between 40 mg/dl and 575 mg/dl by intravenous (IV) infusion of glucose and by SC injections of insulin, respectively. After a running-in period of about half an hour, the glucose content in the perfusion fluid was closely related to the blood glucose concentration (r > 0.92) up to a time period of 6 hrs. The "relative recovery" rate of glucose by the microdialysis probe in the SC tissue varied within the 6 experimental sessions. The relative recovery rate could be shown to be not dependent on the absolute blood glucose levels in the individual rat within the glucose concentration range tested.

Thyrotropin-releasing hormone: pharmacokinetic and pharmacodynamic properties in chronic renal failure.

The pharmacokinetics of thyrotropin-releasing hormone (TRH) were determined following a single i.v. administration in ten patients with chronic renal failure (CRF) maintained on chronic hemodialysis and in six normal subjects. A TRH-test (200 micrograms) was performed in all subjects on nondialysis days and was followed by sequential venous blood sampling at 0, 2, 5, 10, 20, 30 and 60 min. Plasma TRH and serum concentrations of TSH, T4, FT4 and T3 were measured by specific and sensitive RIA's. Serum thyroid hormone concentrations were lower in the hemodialysis patients than in the normals (p < 0.001). Basal TRH and TSH levels were similar in patients and in controls, however, a blunted response of TSH to TRH in CRF (3.8 +/- 2.4 vs. 11.2 +/- 2.6 mU/l, p < 0.001) was observed. Mean peak TRH concentrations (Cmax) were 34.445 (11.085, SD) fmoles/ml in CRF and only (13,400 (1.020) in the normals 2 min after TRH administration (tmax). The mean elimination half-life (t1/2) of TRH was 16 min in CRF and 6.5 min in normals (p < 0.001). The metabolic clearance rate (MCR) was markedly lowered in CRF, 58.3 (19.1) compared to normals (82.2 [15.3] l/m2/day, p < 0.001). The area under the plasma concentration-time curve (AUC) was 57.529 (28.562) fmoles.ml-1.min in CRF and 37.339 (5.026) (p < 0.005) in normals. These findings indicate that the pharmacokinetic properties of TRH are impaired in CRF. The kidney might be an important catabolic organ for exogenous TRH. Dosing schedules of TRH require possible adaptation to renal function.

Serum angiotensin-converting enzyme activity and active renin plasma concentrations in insulin-dependent diabetes mellitus.

We report here the alterations of serum angiotensin-converting enzyme activity (S-ACE) and of active renin plasma concentrations (ARPC) in 41 insulin-dependent diabetes mellitus (IDDM) patients compared with those of 26 control subjects. The IDDM patients had S-ACE activity (54 +/- 16 I.E.) in the upper normal range (controls, 39 +/- 7). When the patients were subclassified according to their diabetic complications, a significant increase of S-ACE within the IDDM group compared to the controls was observed in patients with nephropathy (68 +/- 13, P less than 0.001) with persistent proteinuria and with retinopathy (63 +/- 14, P less than 0.001). A significant correlation was found between proteinuria and S-ACE (r = 0.98, P less than 0.001) and between retinopathy and S-ACE levels (r = 64, P less than 0.001). No correlation between blood pressure and S-ACE or between blood glucose and S-ACE was observed. The ARPC were within the normal range in the IDDM (21 +/- 9 ng/l) and in control (19 +/- 3) groups. No correlations between ARPC and blood pressure or blood glucose or the degree of diabetic complications were registered. These data show that S-ACE activity is elevated in IDDM patients with nephropathy-proteinuria and/or with retinopathy and the circulating renin may not represent the renal renin-angiotensin vascular system.

Thyroid status and hepatic thyroxine deiodinating activity under high-dose long-term nitrendipine.

The influence of high doses of oral nitrendipine on the hypophyseal-thyroid axis and on peripheral thyroxine metabolism was studied in baboons. Administration of 320 mg oral nitrendipine per kg body weight (b.wt.) for three months caused a hypothyroid state with decreased values for thyroxine and reverse triiodothyronine, elevated TSH, but unchanged triiodothyronine; the lower doses investigated (24 and 48 mg/kg b.wt.) were without any effect. High doses of nitrendipine concomitantly increased hepatic 5'-deiodinating activity by a rise in Vmax, which could be attributed to an increase in the deiodinating enzyme content. Normal T3 serum levels in the presence of low T4 serum concentrations under high dose nitrendipine can be ascribed, at least in part, to the enhanced peripheral 5'-deiodination.

Combination of microdialysis and Glucosensor permits continuous (on line) s.c. glucose monitoring in a patient operated device: I. In vitro evaluation.

A device for continuous glucose monitoring in fluids was obtained by combining the microdialysis technique with a measuring flow chamber of the "Glucosensor Unitec Ulm" using the GOD method for determining amperometrically blood glucose profiles. The in vitro experiments demonstrate that the relative recovery of glucose by this device is inversely related to the flow rate of the microdialysis perfusion fluid, which, in turn, is inversely related to the response time of the device. The glucose signal increases linearly with the area of the microdialysis working membrane (r = 0.98), and with the glucose concentrations of the standard solutions (r greater than 0.95). The variation coefficient for repeated measurements is below 8%. The accuracy of the device as demonstrated by mean measuring deviation ranges between 1 and 3.8%.

Comparative effects of dopamine and dobutamine on glucoregulation in a rat model.

The influence of dopamine as compared with dobutamine on glucose homeostasis has been assessed in thyroidectomized euthyroid rats. Both sympathomimetic agents were given intravenously over 6 h at four dosages, varying from 2 to 30 micrograms.kg-1.min-1. Immediately before the end of the infusion period, serum concentrations of glucose and insulin as well as plasma glucagon concentrations were measured. Dobutamine infusions did not exert any influence on these parameters. At a dose of 7.5 micrograms.kg-1.min-1, dopamine infusion caused a decrease in glucose concentrations, accompanied by a rise of glucagon and insulin levels. Glucose levels were significantly increased in the presence of unaltered insulin and decreasing glucagon levels at higher dopamine doses. The rise in glucose levels was reversed by 8 micrograms.kg-1.min-1 and inverted to a decrease by 12 micrograms.kg-1.min-1 of the alpha-adrenergic blocking agent phentolamine, simultaneously infused with 15 micrograms.kg-1.min-1 dopamine, while the insulin levels were increased and glucagon levels remained elevated. These findings demonstrate that dopamine acts on glucoregulation divergently, according to the dosage applied. The data suggest that dopamine rather than dobutamine treatment may disturb glucose homeostasis.

Thyroxine and reverse T3 5'deiodination in the cells of human adipose tissue.

The intracellular 5'deiodination (5'D) of T4 and rT3 has been investigated in human adipose tissue. We studied 5'D in intact adipose tissue, its morphological components and in 3T3-L1-cells. 5'D as assessed by T3-production out of T4 and by rT3-decomposition was not inhibited by propylthiouracil (PTU), but by iopodate (IOP). The apparent Michaelis constants were kM = 3 nM for rT3 and kM = 1 microM for T4. The rT3-degradation was linear over 25 h (115 pg/h.mg (prot.)) both at 37 degrees C and at 4 degrees C. The same type of 5'D was observed in adipocytes, stromal-vascular cells and in 3T3-L1-cells regarding T4 to T3 degradation (244 +/- 30, 181 +/- 27, 227 +/- 37 pg T3/mg.min), resp.; PTU did not exert any influence upon 5'D in the cells investigated. We conclude, that i. the intracellular generation of T3 in adipose tissue does not derive from type I deiodination; ii. 5'D in adipocyte precursors and differentiated adipocytes is identical and iii. there is no difference between human cells and 3T3-L1-cells regarding 5'D.

Thyrotropin-releasing hormone degradation in patients with insulin dependent diabetes mellitus. Effects of metabolic control.

We investigated thyrotropin releasing hormone (TRH) degradation in terms of half-life (t1/2) and metabolic clearance rate (MCR) in eight subjects with insulin dependent diabetes mellitus (IDDM) before and after strict metabolic control. The results were compared with those of six healthy control subjects. The basal plasma TRH-IR levels (31 +/- 9 fmoles/ml) were on the lowest normal limit in the IDDM patients and were not considerably changed (24 +/- 10) after strict metabolic control. The basal and delta max rise of TSH to TRH (200 micrograms i.v.) were not significantly different before or after improved metabolic control in IDDM and as compared to controls. The TRH-degradation curves showed similar exponential decay before and after improvement of metabolic control (t1/2: 7.6 +/- 0.4 min and 7.3 +/- 0.3 respectively; 6.5 +/- 0.4 min for the controls). The MCR of exogenously administered TRH in IDDM before (65.5 +/- 8.6 l/m2/day) and after (65.0 +/- 8.9) control was not different compared to the normals (76.5 +/- 9.6). The area under the plasma concentration-time curve (AUC) in IDDM before (52.193 +/- 6.773 fmoles.ml-1.min) and after improvement of metabolic control (53.186 +/- 7.856) was slightly higher than in the healthy subjects (40.151 +/- 3.741, n.s.). These findings demonstrate that a) the degradation of exogenous TRH is not dependent on the glucose metabolic state, b) insulin deficient diabetes mellitus does not affect the enzymatic system responsible for TRH degradation and, c) the hypothalamic-pituitary axis appears to be intact in IDDM.