Berghe, G. van den

Increasing glucose load while maintaining normoglycemia does not evoke neuronal damage in prolonged critically ill rabbits (Article)

2013-01-24T00:00:00Z

Background & aims: Preventing severe hyperglycemia with insulin reduced the neuropathological alterations in frontal cortex during critical illness. We investigated the impact of increasing glucose load under normoglycemia on neurons and glial cells. Methods: Hyperinflammatory critically ill rabbits were randomized to fasting or combined parenteral nutrition containing progressively increasing amounts of glucose (low, intermediate, high) within the physiological range but with a similar amount of amino acids and lipids. In all groups, normoglycemia was maintained with insulin. On day 7, we studied the neuropathological alterations in frontal cortex neurons, astrocytes and microglia, and MnSOD as marker of oxidative stress. Results: The percentage of damaged neurons was comparable among all critically ill and healthy rabbits. Critical illness induced an overall 1.8-fold increase in astrocyte density and activation status, largely irrespective of the nutritional intake. The percentage of microglia activation in critically ill rabbits was comparable with that in healthy rabbits, irrespective of glucose load. Likewise, MnSOD expression was comparable in critically ill and healthy rabbits without any clear impact of the nutritional interventions. Conclusions: During prolonged critical illness, increasing intravenous glucose infusion while strictly maintaining normoglycemia appeared safe for neuronal integrity and did not substantially affect glial cells in frontal cortex.

Effect of intensive insulin therapy on the somatotropic axis of critically ill children (Article)

2011-08-01T00:00:00Z

Context: Intensive insulin therapy (IIT) improved outcome in the adult and pediatric intensive care unit (PICU) compared with conventional insulin therapy (CIT). IIT did not increase the anabolic hormone IGF-I in critically ill adults, but feeding in critically ill children and pediatric hormonal responses may differ. Twenty-five percent of the children with IIT experienced hypoglycemia, which may have evoked counterregulatory responses. Objective: We hypothesized that IIT reactivates the somatotropic axis and anabolism in PICU patients. Design: This was a preplanned subanalysis of a randomized controlled trial on IIT. Patients: We studied 369 patients who stayed in PICU for at least 3 d (study 1) and 126 patients in a nested case-control study (study 2). Main Outcome Measures: Circulating insulin, C-peptide, GH, IGF-I, bioavailable IGF-I, IGF-binding protein (IGFBP)-1, IGFBP-3, and acid-labile subunit were analyzed upon admission and d 3. In the nested case-control study, the somatotropic axis, cortisol, and glucagon were analyzed before and after hypoglycemia. Results: On d 3, C-peptide was more than 10-fold lower (P < 0.0001) in the IIT group than in theCIT group. IIT increased circulating GH (P = 0.04) and lowered bioavailable IGF-I (P = 0.002). IIT also decreased IGFBP-3 (P = 0.0005) and acid-labile subunit (P = 0.007), while increasing IGFBP-1 (P = 0.04) and the urea/creatinine ratio, a marker of catabolism (P = 0.03). In the nested case-control study, IGFBP-1 was increased after hypoglycemia, whereas the somatotropic axis and the counterregulatory hormones cortisol and glucagon did not change. Conclusions: Despite improved PICU outcome, IIT did not counteract the catabolic state of critical illness. Suppression of portal insulin may have resulted in lower bioavailable IGF-I. Copyright

Guidelines for pre-operative cardiac risk assessment and perioperative cardiac management in non-cardiac surgery: The task force for preoperative cardiac risk assessment and perioperative cardiac management in non-cardiac surgery of the European society of Cardiology (ESC) and endorsed by the European society of anaesthesiology (ESA) (Article)

2010-02-01T00:00:00Z

The disclosure forms of all the authors and reviewers are available on the ESC website www.escardio.org/guidelines.

The effect of rosiglitazone on asymmetric dimethylarginine (ADMA) in critically ill patients (Article)

2009-12-01T00:00:00Z

Asymmetric dimethylarginine (ADMA) plays a crucial role in the arginine-nitric oxide pathway. Critically ill patients have elevated levels of ADMA which proved to be a strong and independent risk factor for ICU mortality. The aim of this study was to investigate the effect of the peroxisome proliferator-activated receptor (PPAR)-gamma agonist rosiglitazone on ADMA plasma levels in critically ill patients. In a randomized controlled pilot study, ADMA, arginine and symmetric dimethylarginine (SDMA) were measured in 21 critically ill patients on the intensive care unit (ICU). Twelve patients received 4 mg rosiglitazone once a day for a maximum of 6 weeks or until discharge or death. Nine patients served as control patients. In addition, total sequential organ failure assessment (SOFA score), kidney function and liver function were determined. Compared to the ADMA levels of healthy individuals as specified in earlier studies, ADMA plasma levels of critically ill patients were significantly higher (0.42 ± 0.06 versus 0.73 ± 0.2 μmol/L, respectively; p < 0.001). Both ADMA (B = 3.5; 95% CI: 0.5-6.5; p = 0.023) and SDMA (B = 1.7; 95% CI: 0.7-2.7; p = 0.001) were independently related to SOFA scores. Overall, rosiglitazone treatment had no effect on ADMA levels, which only significantly differed between the rosiglitazone and control groups at day 7 (p = 0.028). The SOFA score in the rosiglitazone group was lower compared to the control group but the difference was only statistically significant at day 10 (p = 0.01). In conclusion, in critically ill patients plasma ADMA levels were elevated and associated with the extent of multiple organ failure, but no significant ADMA-lowering effect of the PPAR-gamma agonist rosiglitazone was observed.

Expression of thyroid hormone transporters during critical illness (Article)

2009-11-27T00:00:00Z

Objective: Prolonged critically ill patients have low circulating thyroid hormone (TH) levels without a rise in TSH, a condition labeled 'the low tri-iodothyronine (T3) 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 T3 syndrome in prolonged critical illness. Methods: 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 realtime PCR. Results: 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 (thyroxineCT3) 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. Conclusions: These data suggest that alterations in the expression of TH transporters do not play a major role in the pathogenesis of the 'low T3 syndrome' but rather reflect a compensatory effort in response to hypothyroidism.

Changes in the central component of the hypothalamus-pituitary-thyroid axis in a rabbit model of prolonged critical illness (Article)

2009-09-11T00:00:00Z

Introduction: Prolonged critically ill patients reveal low circulating thyroid hormone levels without a rise in thyroid stimulating hormone (TSH). This condition is labeled "low 3,5,3'-tri-iodothyronine (T3) syndrome" or "nonthyroidal illness syndrome (NTI)" or "euthyroid sick syndrome". Despite the low circulating and peripheral tissue thyroid hormone levels, thyrotropin releasing hormone (TRH) expression in the hypothalamus is reduced and it remains unclear which mechanism is responsible. We set out to study whether increased hypothalamic T3availability could reflect local thyrotoxicosis and explain feedback inhibition-induced suppression of the TRH gene in the context of the low T3syndrome in prolonged critical illness.Methods: Healthy rabbits were compared with prolonged critically ill, parenterally fed animals. We visualized TRH mRNA in the hypothalamus by in situ-hybridization and measured mRNA levels for the type II iodothyronine diodinase (D2), the thyroid hormone transporters monocarboxylate transporter (MCT) 8, MCT10 and organic anion co-transporting polypeptide 1C1 (OATP1C1) and the thyroid hormone receptors α (TRα) and β (TRβ) in the hypothalamus. We also measured the activity of the D2 and type III iodothyronine deiodinase (D3) enzymes.Results: In the hypothalamus of prolonged critically ill rabbits with low circulating T3 and TSH, we observed decreased TRH mRNA, increased D2 mRNA and increased MCT10 and OATP1C1 mRNA while MCT8 gene expression was unaltered as compared with healthy controls. This coincided with low hypothalamic thyroxine (T4) and low-normal T3concentrations, without a change at the thyroid hormone receptor level.Conclusions: Although expression of D2 and of the thyroid hormone transporters MCT10 and OATP1C1 were increased in the hypothalamus of prolonged critical ill animals, hypothalamic T4and T3content or thyroid hormone receptor expression were not elevated. Hence, decreased TRH gene expression, and hereby low TSH and T3 during prolonged critical illness, is not exclusively brought about by hypothalamic thyrotoxicosis, and infer other TRH suppressing factors to play a role.

Tissue mRNA expression of the glucocorticoid receptor and its splice variants in fatal critical illness (Article)

2009-07-01T00:00:00Z

Background Critical illness results in activation of the hypothalamic-pituitary-adrenal (HPA) axis, which might be accompanied by a peripheral adaptation in glucocorticoid sensitivity. Tissue sensitivity is determined by the active glucocorticoid receptor GRα, of which two splice variants involving the hormone-binding domain exist, GRβ and GR-P. Objective To study tissue mRNA expression of the GR and its splice variants in fatal critical illness. Design and methods We assessed mRNA expression of the GRα, GRβ and GR-P variants in liver (n = 58) and muscle (n = 65) of patients who had died after intensive care, and had been randomized for insulin treatment. We analysed whether GR mRNA expression was associated with insulin treatment, cortisol levels and glucocorticoid treatment. Results GRα and GR-P mRNA constituted 87 ± 8% and 13 ± 2%, respectively, of total GR mRNA in liver. GRβ mRNA could only be amplified in five liver samples. All variants were present in most muscle samples (α = 96 ± 11%, P = 3·9 ± 0·4%, β = 0·010 ± 0·002%). GR expression was not associated with insulin therapy. A strong positive relationship was observed between the different GR variants in both liver and muscle (P < 0·001 for all). Serum cortisol levels were negatively associated with liver GRα and muscle GR-P expression (P < 0·05). mRNA expression of both liver GRα and GR-P, but not muscle GR, was substantially lower in patients who had received exogenous glucocorticoids (P < 0·01). Conclusion We demonstrate the presence of GRα and GR-P mRNA in liver and of GRα, GRβ and GR-P mRNA in muscle, with no evidence for altered splicing in critical illness. In contrast to muscle GR, liver GR expression was substantially lower in patients receiving exogenous glucocorticoids.

Thyroid hormones and multiple organ dysfunction syndrome (Article)

2009-03-01T00:00:00Z

Marked changes in thyroid hormone levels occur in critical illness and multiple organ dysfunction syndrome (MODS), with a decrease in the active hormone T3 and an increase in the inactive metabolite rT3. The magnitude of these changes is related to the severity of the disease. Studies addressing the thyrotropic axis in critical illness do not make a clear distinction between patients with and without MODS. However, a distinction can be made between the acute and the more chronic phase of critical illness, and it can be assumed that patients who require intensive care for several days will have some degree of MODS. This review therefore focuses on the thyroid axis in patients receiving intensive care for several days. The mechanisms behind the observed changes, the potential positive and/or negative effects of them and their possible therapeutic consequences will be discussed.

Effects of substitution and high-dose thyroid hormone therapy on deiodination, sulfoconjugation, and tissue thyroid hormone levels in prolonged critically ill rabbits (Article)

2008-08-01T00:00:00Z

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 (T2) and T4S, 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 T4and T3, 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 T3(P = 0.006), hepatic T3(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 T4(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 T3and tissue T3/reverse T3ratio correlated with deiodinase activities. Neither substitution- nor high-dose treatment altered plasma T2. Plasma T4S was increased only by T4in high dose. We conclude that in prolonged critically ill rabbits, low plasma T3levels were associated with low liver and kidney T3levels. 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. Copyright

Brief report: The type II iodothyronine deiodinase is up-regulated in skeletal muscle during prolonged critical illness (Article)

2007-08-01T00:00:00Z

Context: Critical illness is associated with the low T3syndrome. It remains unclear whether altered type II deiodinase activity (D2) in skeletal muscle contributes to this syndrome. Objective: Our objective was to study D2 expression and activity in skeletal muscle of acute and prolonged critically ill patients. Design and Setting: We conducted a clinical observational study in acute and prolonged critical illness with comparison with healthy controls at a university hospital surgical intensive care unit. Patients: Subjects included 63 prolonged critically ill patients who died in the intensive care unit, 21 acutely ill patients, and 38 controls matched for age, gender, and body mass index. Results: Elevated expression of the D2 gene and D2 activity in skeletal muscle of prolonged, but not acute, critically ill patients were observed in the face of low circulating thyroid hormone levels. Conclusions: Reduced D2 activity does not appear to play a role in the pathogenesis of the low T3syndrome of critical illness. Copyright

Thyroid hormone receptor isoforni expression in livers of critically ill patients (Article)

2007-02-01T00:00:00Z

Objective: The THRA gene encodes two isoforms of the thyroid hormone receptor (TR), TRα1 and TRα2. The ratio of these splice variants could have a marked influence on T3-regulated gene expression, especially during illness. Design: We studied the expression of the isoforms TRβ1, TRα1, and TRα2 and 5′-deiodinase in postmortem liver biopsies of 58 patients who were critically ill and died in the intensive care unit (ICU). All mRNA levels were determined using real-time PCR. Main outcome: All ratios of the biopsies were higher than those found in three normal liver biopsies due to an increased TRα1 level. The TRα1/TRα2 ratio increased with age and severity of illness following the equation: TRα1/TRα2 ratio = - 1.854 + (0.0323×age) + (0.0431×Therapeutic Intervention Scoring System score) indicating that 28% of the changed TRα1/TRα2 ratio can be predicted by these clinical variables. There was no effect of randomization to intensive insulin therapy or glucocorticoid or thyroid hormone treatment on the TRα1/TRα2 ratio or TRβ1. Furthermore, no relation was seen between the expression levels of the 5′-deiodinase mRNA and TR isoforms or the triiodothyronine (T3) levels. Conclusion: It appears that in critically ill patients the ratio of TRα1/TRα2 expression increases with age and severity of illness, possibly indicating a mechanism to enhance sensitivity to T3in the oldest and sickest patients.

Serum 3,3',5'-triiodothyronine (rT3) and 3,5,3'-triiodothyronine/rT3 are prognostic markers in critically ill patients and are associated with postmortem tissue deiodinase activities. (Article)

2005-08-01T00:00:00Z

INTRODUCTION AND METHODS: 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. RESULTS: 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). CONCLUSION: 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.

Reduced activation and increased inactivation of thyroid hormone in tissues of critically ill patients (Article)

2003-01-01T00:00:00Z

Critical illness is often associated with reduced TSH and thyroid hormone secretion as well as marked changes in peripheral thyroid hormone metabolism, resulting in low serum T(3) and high rT(3) levels. To study the mechanism(s) of the latter changes, we determined serum thyroid hormone levels and the expression of the type 1, 2, and 3 iodothyronine deiodinases (D1, D2, and D3) in liver and skeletal muscle from deceased intensive care patients. To study mechanisms underlying these changes, 65 blood samples, 65 liver, and 66 skeletal muscle biopsies were obtained within minutes after death from 80 intensive care unit patients randomized for intensive or conventional insulin treatment. Serum thyroid parameters and the expression of tissue D1-D3 were determined. Serum TSH, T(4), T(3), and the T(3)/rT(3) ratio were lower, whereas serum rT(3) was higher than in normal subjects (P < 0.0001). Liver D1 activity was down-regulated and D3 activity was induced in liver and skeletal muscle. Serum T(3)/rT(3) ratio correlated positively with liver D1 activity (P < 0.001) and negatively with liver D3 activity (ns). These parameters were independent of the type of insulin treatment. Liver D1 and serum T(3)/rT(3) were highest in patients who died from severe brain damage, intermediate in those who died from sepsis or excessive inflammation, and lowest in patients who died from cardiovascular collapse (P < 0.01). Liver D3 showed an opposite relationship. Acute renal failure requiring dialysis and need of inotropes were associated with low liver D1 activity (P < 0.01 and P = 0.06) and high liver D3 (P < 0.01) and skeletal muscle D3 (P < 0.05) activity. Liver D1 activity was negatively correlated with plasma urea (P = 0.002), creatinine (P = 0.06), and bilirubin (P < 0.0001). D1 and D3 mRNA levels corresponded with enzyme activities (both P < 0.001), suggesting regulation of the expression of both deiodinases at the pretranslational level. This is the first study relating tissue deiodinase activities with serum thyroid hormone levels and clinical parameters in a large group of critically ill patients. Liver D1 is down-regulated and D3 (which is not present in liver and skeletal muscle of healthy individuals) is induced, particularly in disease states associated with poor tissue perfusion. These observed changes, in correlation with a low T(3)/rT(3) ratio, may represent tissue-specific ways to reduce thyroid hormone bioactivity during cellular hypoxia and contribute to the low T(3) syndrome of severe illness.