triiodothyronine--reverse and Critical-Illness

The inflammatory response of critical illness is accompanied by nonthyroidal illness syndrome (NTIS). Feeding has been shown to attenuate this process, but this has not been explored prospectively over time in critically ill patients.. To explore the impact of calorie exposure on NTIS over time in critically ill patients.. Mechanically ventilated patients with systemic inflammatory response syndrome (SIRS) were randomized to receive either 100% or 40% of their estimated caloric needs (ECN). Thyroid hormones were measured daily for 7 days or until intensive care unit discharge or death. Mixed level regression modeling was used to explore the effect of randomization group on plasma triiodothyronine (T3), reverse triiodothyronine (rT3), thyroxine (T4), and thyroid stimulating hormone (TSH), as well as the T3/rT3 ratio.. Thirty-five participants (n=19 in 100% ECN; n=16 in 40% ECN) were recruited. Adjusting for group differences in baseline T3/rT3 ratio, the parameters defining the fitted curves (intercept, linear effect of study day, and quadratic effect of study day) differed by randomization group (P = 0.001, P = 0.01, and P = 0.02 respectively). Plots of the fitted curves revealed that participants in the 100% ECN group had a 54% higher T3/rT3 ratio on postintervention day 1 compared with the 40% ECN group, a difference which attenuated over time. This was driven by a 23% higher plasma T3 and 10% lower plasma rT3 levels on postintervention 1.. Higher caloric exposure in NTIS patients transiently attenuates the drop of the plasma T3/rT3 ratio, an effect that is minimized and finally lost over the following 3 days of continued higher caloric exposure.

Topics: Critical Illness; Energy Intake; Enteral Nutrition; Euthyroid Sick Syndromes; Female; Humans; Male; Middle Aged; Regression Analysis; Respiration, Artificial; Thyrotropin; Thyroxine; Treatment Outcome; Triiodothyronine; Triiodothyronine, Reverse

Prolonged critically ill patients have low circulating thyroid hormone (TH) levels without a rise in TSH, a condition labeled 'the low tri-iodothyronine (T(3)) syndrome'. Currently, it is not clear whether this represents an adaptive response. We examined the role of TH transporters monocarboxylate transporter 8 (MCT8, also known as SLC16A2) and MCT10 in the pathogenesis of the low T(3) syndrome in prolonged critical illness.. A clinical observational study in critically ill patients and an intervention study in an in vivo animal model of critical illness. Gene expression levels of MCT8 and MCT10 were measured by real-time PCR.. In prolonged critically ill patients, we measured increased MCT8 but not MCT10 gene expression levels in liver and skeletal muscle as compared with patients undergoing acute surgical stress. In a rabbit model of prolonged critical illness, gene expression levels of MCT8 in liver and of MCT10 in skeletal muscle were increased as compared with healthy controls. Treatment of prolonged critically ill rabbits with TH (thyroxine+T(3)) resulted in a downregulation of gene expression levels of MCT8 in liver and of MCT10 in muscle. Transporter expression levels correlated inversely with circulating TH parameters.. These data suggest that alterations in the expression of TH transporters do not play a major role in the pathogenesis of the 'low T(3) syndrome' but rather reflect a compensatory effort in response to hypothyroidism.

Topics: Aged; Amino Acid Transport Systems, Neutral; Animals; Base Sequence; Critical Illness; Disease Models, Animal; Euthyroid Sick Syndromes; Female; Humans; Liver; Male; Molecular Sequence Data; Monocarboxylic Acid Transporters; Muscle, Skeletal; Rabbits; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Symporters; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

Critical illness is associated with reduced TSH and thyroid hormone secretion, and with changes in peripheral thyroid hormone metabolism, resulting in low serum T3 and high rT3. In 451 critically ill patients who received intensive care for more than 5 d, serum thyroid parameters were determined on d 1, 5, 15, and last day (LD). All patients had been randomized for intensive or conventional insulin treatment. Seventy-one patients died, and postmortem liver and skeletal muscle biopsies were obtained from 50 of them for analysis of deiodinase (D1-3) activities.. Insulin treatment did not affect thyroid parameters. On d 1, rT3 was higher and T3/rT3 was lower in nonsurvivors as compared with survivors (P = 0.001). Odds ratio for survival of the highest vs. the lowest quartile was 0.3 for rT3 and 2.9 for T3/rT3. TSH, T4, and T3 were lower in nonsurvivors from d 5 until LD (P < 0.001). TSH, T4, T3, and T3/rT3 increased over time in survivors, but decreased or remained unaltered in nonsurvivors. Liver D1 activity was positively correlated with LD serum T3/rT3 (R = 0.83, P < 0.001) and negatively correlated with rT3 (R = -0.69, P < 0.001). Both liver and skeletal muscle D3 activity were positively correlated with LD serum rT3 (R = 0.32, P = 0.02 and R = 0.31, P = 0.03).. In critically ill patients who required more than 5 d of intensive care, rT3 and T3/rT3 were already prognostic for survival on d 1. On d 5, T4, T3, but also TSH levels are higher in patients who will survive. Serum rT3 and T3/rT3 were correlated with postmortem tissue deiodinase activities.

Topics: Aged; Biomarkers; Biopsy; Critical Care; Critical Illness; Female; Humans; Hypoglycemic Agents; Insulin; Iodide Peroxidase; Liver; Male; Middle Aged; Muscle, Skeletal; Prognosis; Thyrotropin; Triiodothyronine; Triiodothyronine, Reverse

The catabolic state of prolonged critical illness is associated with a low activity of the thyrotropic and the somatotropic axes. The neuroendocrine component in the pathogenesis of these low activity states was assessed by investigating the effects of continuous intravenous infusions of TRH, GH-releasing peptide-2 (GHRP-2), and GHRH. Twenty adult patients, critically ill for several weeks, were studied during two consecutive nights. They had been randomly allocated to one of three combinations of peptide infusions, each administered in random order: TRH (one night) and placebo (other night), TRH + GHRP-2 (one night) and GHRP-2 (other night), or TRH + GHRH + GHRP-2 (one night) and GHRH + GHRP-2 (other night). The peptide infusions were started after a 1-microgram/kg bolus and infused (1 microgram/kg per h) until 0600 h. Blood sampling was performed every 20 min, and pituitary hormone secretion was quantified by deconvolution analysis. Reduced pulsatile fraction of TSH, GH, and PRL secretion and low serum concentrations of T4, T3, insulin growth factor-I (IGF-I), IGF-binding protein-3 (IGFBP-3), and the acid-labile subunit (ALS) were documented in the untreated state. Infusion of TRH alone or in combination with GH secretagogues augmented nonpulsatile TSH release 2- to 5-fold; only TRH + GHRP-2 increased pulsatile TSH secretion (4-fold). Average rises in T4 (40-54%) and in T3 (52-116%) were obtained with all three combinations, whereas reverse T3 levels did not increase, except when TRH was infused alone. Pulsatile GH secretion was amplified > 6- and > 10-fold, respectively, by GHRP-2 and GHRH + GHRP-2 infusions, generating mean increases of serum IGF-I (66% and 106%), IGFBP-3 (50% and 56%), and ALS (65% and 97%) within 45 h. The addition of TRH did not alter the GH secretory patterns. TRH infusion increased PRL release only when combined with GH secretagogues. No effects on serum cortisol were detected. In conclusion, the pathogenesis of the low activity state of the thyrotropic and somatotropic axes in prolonged critical illness appears to have a neuroendocrine component, because these axes are both readily activated by coinfusion of TRH and GH secretagogues.

Topics: Adult; Aged; Aged, 80 and over; Critical Illness; Female; Growth Hormone-Releasing Hormone; Human Growth Hormone; Humans; Hypothalamus; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Male; Middle Aged; Oligopeptides; Periodicity; Pituitary Gland; Prolactin; Thyrotropin; Thyrotropin-Releasing Hormone; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

Infusion of GH secretagogues appears to be a novel endocrine approach to reverse the catabolic state of critical illness, through amplification of the endogenously blunted GH secretion associated with a substantial IGF-I rise. Here we report the dynamic characteristics of spontaneous nightly TSH and PRL secretion during prolonged critical illness, together with the concomitant effects exerted by the administration of GH-secretagogues, GH-releasing hormone (GHRH) and GH-releasing peptide-2 (GHRP-2) in particular, on night-time TSH and PRL secretion.. Twenty-six critically ill adults (mean +/- SEM age: 63 +/- 2 years) were studied during two consecutive nights (2100-0600 h). According to a weighed randomization, they received 1 of 4 combinations of infusions, within a randomized, cross-over design for each combination: placebo (one night) and GHRH (the next night) (n = 4); placebo and GHRP-2 (n = 10); GHRH and GHRP-2 (n = 6); GHRP-2 and GHRH + GHRP-2 (n = 6). Peptide infusions (duration 21 hours) were started after a bolus of 1 microgram/kg at 0900 h and infused (1 microgram/kg/h) until 0600 h.. Serum concentrations of TSH and PRL were determined by IRMA every 20 minutes and T4, T3 and rT3 by RIA at 2100 h and 0600 h in each study night. Hormone secretion was quantified using deconvolution analysis.. During prolonged critical illness, mean night-time serum concentrations of TSH (1.25 +/- 0.42 mlU/l) and PRL (9.4 +/- 0.9 micrograms/l) were low-normal. However, the proportion of TSH and PRL that was released in a pulsatile fashion was low (32 +/- 6% and 16 +/- 2.6%) and no nocturnal TSH or PRL surges were observed. The serum levels of T3 (0.64 +/- 0.06 nmol/l) were low and were positively related to the number of TSH bursts (R2 = 0.32; P = 0.03) and to the log of pulsatile TSH production (R2 = 0.34; P = 0.03). GHRP-2 infusion further reduced the proportion of TSH released in a pulsatile fashion to half that during placebo infusion (P = 0.02), without altering mean TSH levels. GHRH infusion increased mean TSH levels and pulsatile TSH production, 2-fold compared to placebo (P = 0.03) and 3-fold compared to GHRP-2 (P = 0.008). The addition of GHRP-2 to GHRH infusion abolished the stimulatory effect of GHRH on pulsatile TSH secretion. GHRP-2 infusion induced a small increase in mean PRL levels (21%; P = 0.02) and basal PRL secretion rate (49%; P = 0.02) compared to placebo, as did GHRH and GHRH + GHRP-2.. The characterization of the specific pattern of anterior pituitary function during prolonged critical illness is herewith extended to the dynamics of TSH and PRL secretion: mean serum levels are low-normal, no noctumal surge is observed and the pulsatile fractions of TSH and PRL release are reduced, as was shown previously for GH. Low circulating thyroid hormone levels appear positively correlated with the reduced pulsatile TSH secretion, suggesting that they have, at least in part, a neuroendocrine origin. Finally, the opposite effects of different GH-secretagogues on TSH secretion further delineate particular linkages between the somatotrophic and thyrotrophic axes during critical illness.

Topics: Adult; Aged; Critical Illness; Cross-Over Studies; Female; Growth Hormone-Releasing Hormone; Half-Life; Hormones; Humans; Male; Middle Aged; Oligopeptides; Pituitary Gland, Anterior; Prolactin; Secretory Rate; Thyrotropin; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

The sick euthyroid syndrome is a poorly understood hallmark of critical illness. Dopamine is a natural catecholamine with hypophysiotrophic properties, that is used as an inotropic agent of first choice in intensive care medicine. We explored the effect of dopamine infusion (5 micrograms/kg/min) on the sick euthyroid syndrome of critically ill patients.. In a prospective, randomized, controlled and open-labelled study of critically ill, adult polytrauma patients (n = 12), we evaluated the effect of prolonged (83-296 hours) dopamine infusion (5 micrograms/kg/min i.v.) on the thyroid axis. The effect of brief (15-21 hours) dopamine administration was documented in an additional randomized, controlled, cross-over study involving 10 patients. The median age of the studied patients was 29 (16-83) years.. Serum TSH concentrations were measured by IRMA. The TSH profiles were obtained by blood sampling every 20 minutes for 9 hours during two consecutive nights. Serum T4, T3 and reverse T3 concentrations were measured by RIA once per study night.. Withdrawal of prolonged dopamine infusion was found to elicit a tenfold increase of serum thyrotrophin concentrations, a 57 and 82% rise of T4 and T3 respectively, and an increase of the T3/rT3 ratio, resulting in virtual normalization of the thyroid axis within 24 hours. The brief dopamine infusion was documented to have a suppressive effect on the thyroid axis within 24 hours.. Dopamine infusion appears to induce or aggravate the sick euthyroid syndrome in critical illness. As a consequence, the sick euthyroid syndrome of severely ill patients receiving dopamine may be not an adaptive mechanism, but a condition of iatrogenic hypothyroidism.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Critical Illness; Depression, Chemical; Dopamine; Euthyroid Sick Syndromes; Humans; Middle Aged; Prospective Studies; Thyroid Gland; Thyroid Hormones; Thyrotropin; Thyroxine; Time Factors; Triiodothyronine; Triiodothyronine, Reverse

To delineate the metabolic fate of thyroid hormone in prolonged critically ill rabbits, we investigated the impact of two dose regimes of thyroid hormone on plasma 3,3'-diiodothyronine (T(2)) and T(4)S, deiodinase type 1 (D1) and D3 activity, and tissue iodothyronine levels in liver and kidney, as compared with saline and TRH. D2-expressing tissues were ignored. The regimens comprised either substitution dose or a 3- to 5- fold higher dose of T(4) and T(3), either alone or combined, targeted to achieve plasma thyroid hormone levels obtained by TRH. Compared with healthy animals, saline-treated ill rabbits revealed lower plasma T(3) (P=0.006), hepatic T(3) (P=0.02), and hepatic D1 activity (P=0.01). Substitution-dosed thyroid hormone therapy did not affect these changes except a further decline in plasma (P=0.0006) and tissue T(4) (P=0.04). High-dosed thyroid hormone therapy elevated plasma and tissue iodothyronine levels and hepatic D1 activity, as did TRH. Changes in iodothyronine tissue levels mimicked changes in plasma. Tissue T(3) and tissue T(3)/reverse T(3) ratio correlated with deiodinase activities. Neither substitution- nor high-dose treatment altered plasma T(2). Plasma T(4)S was increased only by T(4) in high dose. We conclude that in prolonged critically ill rabbits, low plasma T(3) levels were associated with low liver and kidney T(3) levels. Restoration of plasma and liver and kidney tissue iodothyronine levels was not achieved by thyroid hormone in substitution dose but instead required severalfold this dose. This indicates thyroid hormone hypermetabolism, which in this model of critical illness is not entirely explained by deiodination or by sulfoconjugation.

Topics: Animals; Critical Illness; Diiodothyronines; Dose-Response Relationship, Drug; Gene Expression Regulation, Enzymologic; Iodide Peroxidase; Kidney; Liver; Male; Rabbits; Sulfates; Thyroid Hormones; Thyrotropin; Triiodothyronine, Reverse

To evaluate the course of hormonal parameters in relation to clinical parameters, illness severity and nutritional intake in children admitted to the pediatric ICU during the first week of admission.. Prospective, observational study. Levels of triiodothyronine (T3), reverse T3 (rT3), ratio T3/rT3 and insulin-like growth factor I (IGF-1) were evaluated in 84 critically ill children (50 term neonates and 34 children aged 32 d-15 yr) admitted to our multidisciplinary tertiary pediatric intensive care unit within 24 h after admission, on days 4 and 6 after admission. Changes in hormones levels over time were related to illness severity, C-reactive protein-levels and the adequacy of feeding.. For both age groups IGF-1 levels remained low until day 4, but at day 6 IGF-1 levels were significantly higher than admission level. In 88% and 89% of the older children, T3 levels remained below normal at days 4 and 6, respectively. In both age groups, rT3 levels declined significantly over time, whereas the ratio T3/rT3 increased. The increases in IGF-1, T3 and ratio T3/rT3 and decrease in rT3 were significantly associated with decreases in CRP-levels. No significant relations were found between changes in IGF-1 and thyroid hormone levels during admission and the adequacy of energy and protein intake.. During the first week of ICU-admission, abnormalities in levels of IGF-1, T3 and rT3 were frequently observed in critically ill children, especially in the children aged >1 month. The adequacy of feeding did not seem to affect the normalization of IGF-1 and thyroid hormone levels.

Topics: Adolescent; Biomarkers; C-Reactive Protein; Child; Child, Preschool; Critical Illness; Female; Humans; Infant; Infant, Newborn; Insulin-Like Growth Factor I; Intensive Care Units, Pediatric; Length of Stay; Male; Nutrition Assessment; Nutritional Status; Prognosis; Prospective Studies; Severity of Illness Index; Triiodothyronine; Triiodothyronine, Reverse

Pronounced alterations in serum thyroid hormone levels occur during critical illness. T3 decreases and rT3 increases, the magnitudes of which are related to the severity of disease. It is unclear whether these changes are associated with decreased tissue T3 concentrations and, thus, reduced thyroid hormone bioactivity. PATIENTS AND STUDY QUESTIONS: We therefore investigated, in 79 patients who died after intensive care and who did or did not receive thyroid hormone treatment, whether total serum thyroid hormone levels correspond to tissue levels in liver and muscle. Furthermore, we investigated the relationship between tissue thyroid hormone levels, deiodinase activities, and monocarboxylate transporter 8 expression.. Tissue iodothyronine levels were positively correlated with serum levels, indicating that the decrease in serum T3 during illness is associated with decreased levels of tissue T3. Higher serum T3 levels in patients who received thyroid hormone treatment were accompanied by higher levels of liver and muscle T3, with evidence for tissue-specific regulation. Tissue rT3 and the T3/rT3 ratio were correlated with tissue deiodinase activities. Monocarboxylate transporter 8 expression was not related to the ratio of the serum over tissue concentration of the different iodothyronines.. Our results suggest that, in addition to changes in the hypothalamus-pituitary-thyroid axis, tissue-specific mechanisms are involved in the reduced supply of bioactive thyroid hormone in critical illness.

Topics: Aged; Critical Illness; Female; Humans; Insulin; Iodide Peroxidase; Liver; Male; Middle Aged; Monocarboxylic Acid Transporters; Muscle, Skeletal; Randomized Controlled Trials as Topic; Symporters; Triiodothyronine; Triiodothyronine, Reverse