I Vanhorebeek

Publications (17)25.96 Total impact

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  Available from: ccforum.com

  Article: Strict blood glucose control with insulin improves hepatic mitochondrial ultrastructure and function in critical illness

  I Vanhorebeek, R De Vos, P Wouters, F Weekers, D Mesotten, G Van den Berghe
  Critical Care 04/2012; 8:1-1. · 4.93 Impact Factor
• Article: Endocrine and metabolic disturbances in critical illness: relation to mechanisms of organ dysfunction and adverse outcome.

  L Langouche, D Mesotten, I Vanhorebeek
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  ABSTRACT: Critically ill patients face a high risk of death, which is mostly due to non-resolving multiple organ failure. The plethora of endocrine and metabolic disturbances that hallmark critical illness may play a key role. The major part of our research performed during the period 2004-2009 focused on the disturbed glucose metabolism that commonly develops during critical illness. The onset of this research interest was the landmark randomized clinical study on strict blood glucose control (80-110 mg/ dl) with intensive insulin therapy performed by Prof. Van den Berghe and our clinical team members. This study, published in 2001 in the New England Journal of Medicine, showed reduced morbidity and improved survival with intensive insulin therapy versus toleration of hyperglycemia up to 215 mg/dl. This review summarizes our findings in both patients and animal models on mechanisms contributing to the clinical benefits of strict blood glucose control. Intensive insulin therapy appeared to lower blood glucose levels by ameliorating insulin sensitivity and stimulation of glucose uptake in skeletal muscle, whereas hepatic insulin resistance was not affected. The therapy also improved the lipid profile and the immune response and attenuated inflammation. Maintenance of strict normoglycemia appeared essentially most important, rather than elevating insulin levels. Avoiding hyperglycemia protected the endothelium and the mitochondria. In our animal model, nutritional interventions counteracted the hypercatabolic state of critical illness and insulin improved myocardial contractility, but only when normoglycemia was maintained. Interestingly, we identified the adipose tissue as a functional storage depot for toxic metabolites during critical illness.
  Verhandelingen - Koninklijke Academie voor Geneeskunde van België 01/2010; 72(3-4):149-63.
• Article: [Glycemic control in the intensive care unit].

  J Gunst, I Vanhorebeek, G Van den Berghe
  Annales francaises d'anesthesie et de reanimation 05/2009; 28(5):e209-16. · 0.77 Impact Factor
• Article: Serial lactate measurements using microdialysis of interstitial fluid do not correlate with plasma lactate in children after cardiac surgery.

  Ingeborg van den Heuvel, Dirk Vlasselaers, Pieter J Wouters, Ilse Milants, Björn Ellger, Ilse Vanhorebeek, Greet Van den Berghe
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  ABSTRACT: Serial postoperative blood lactate (BL) concentrations have been shown to predict outcome of children after congenital heart surgery (CHS), and interventions aimed at lowering lactate can improve the outcome of these children. The cumulative blood loss for diagnostic purposes, such as repetitive arterial blood sampling in the intensive care unit, contributes, especially in small children, to anemia. Techniques to limit blood loss can therefore be of use. Microdialysis is a technique to monitor tissue chemistry in various clinical settings, and we hypothesized that it may be a valuable alternative for frequent blood sampling to monitor lactate in children after CHS. Fifteen children with a mean age of 40 months (range, 4-118 months) were prospectively enrolled after CHS. A CMA double lumen microdialysis catheter was inserted into the subcutaneous adipose tissue of the abdominal wall and infused with an isotone mannitol 5% solution at 1 microL/min via the inlet tubing. Microdialysate fluid was collected every hour for 48 hrs and stored at -80 degrees C for lactate determination (interstitial fluid lactate, IFL). Every hour arterial blood was taken for lactate determination. Individual profiles, correlation coefficient, and Bland-Altman analysis were used to compare BL and IFL results. There were no complications with the microdialysis technique. All patients were discharged alive from hospital. Six hundred twenty paired samples were analyzed. Mean recovery of microdialysate fluid was 84%. Median (interquartile range) was 0.95 (0.70-1.15) mmol/L for BL and 1.13 (0.86-1.48) mmol/L for IFL (p < 0.0001). Individual profiles showed that IFL follows changes in BL in some, but not all children. With this study, we could not explain this discrepancy. The correlation between BL and IFL was poor (r = .77 (p < 0.0001) r = .59). Bland-Altman analysis confirmed the insufficient performance of the current microdialysis-based procedure compared with BL. Serial lactate measurements in microdialysis fluid of subcutaneous adipose tissue are feasible, but cannot be used as a reliable interchangeable method for plasma lactate analysis in children after CHS at this time. Whether this technique has its own place in the assessment of the overall hemodynamic status and tissue perfusion in children after CHS needs to be addressed in future studies.
  Pediatric Critical Care Medicine 01/2009; 10(1):66-70. · 3.13 Impact Factor
• Article: Tissue mRNA expression of the glucocorticoid receptor and its splice variants in fatal critical illness.

  R P Peeters, A Hagendorf, I Vanhorebeek, T J Visser, W Klootwijk, D Mesotten, P J Wouters, J W Koper, F H de Jong, R A Feelders, S W J Lamberts, G Van den Berghe
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  ABSTRACT: 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 GRalpha, of which two splice variants involving the hormone-binding domain exist, GRbeta and GR-P. To study tissue mRNA expression of the GR and its splice variants in fatal critical illness. We assessed mRNA expression of the GRalpha, GRbeta 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. GRalpha and GR-P mRNA constituted 87 +/- 8% and 13 +/- 2%, respectively, of total GR mRNA in liver. GRbeta mRNA could only be amplified in five liver samples. All variants were present in most muscle samples (alpha = 96 +/- 11%, P = 3.9 +/- 0.4%, beta = 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 GRalpha and muscle GR-P expression (P < 0.05). mRNA expression of both liver GRalpha and GR-P, but not muscle GR, was substantially lower in patients who had received exogenous glucocorticoids (P < 0.01). We demonstrate the presence of GRalpha and GR-P mRNA in liver and of GRalpha, GRbeta 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.
  Clinical Endocrinology 10/2008; 71(1):145-53. · 3.17 Impact Factor
• Article: Glucose metabolism and insulin resistance in sepsis.

  S J Van Cromphaut, I Vanhorebeek, G Van den Berghe
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  ABSTRACT: Hyperglycemia is a common feature of the critically ill in general and of patients with sepsis in particular. Even a moderate degree of hyperglycemia appears detrimental for the outcome of critically ill patients, since maintenance of normoglycemia (blood glucose levels <or=110 mg/dL) with intensive insulin therapy has shown to improve survival and reduce morbidity in prolonged critically ill patients in both surgical and medical intensive care units, as revealed by two large randomized controlled studies. Subsequently, questions have been raised regarding the efficacy and safety of this intervention, above all in the major subpopulation of intensive care patients presenting with sepsis, who are particularly susceptible to hypoglycemia as well. Adequately powered and executed randomized controlled trials addressing explicitly the impact of hyperglycemia, tight blood glucose control and the inherently increased risk of hypoglycemia on mortality and morbidity in patients with sepsis are presently lacking. However, the available literature suggests a causal link between hyperglycemia and adverse outcome in sepsis and a benefit of intensive insulin therapy in sepsis equal to the benefit found in critical illness without sepsis and critical illness in general. Though a high frequency of hypoglycemia may be noted during insulin treatment of patients with sepsis, the present observations define hypoglycemia as a marker of disease severity rather than a harmful treatment side-effect. Prevention of cellular glucose toxicity by strict glycemic control appears to play a predominant role, but other metabolic and non-metabolic, anti-inflammatory effects of insulin seem to contribute to the clinical benefits realized.
  Current pharmaceutical design 01/2008; 14(19):1887-99. · 4.41 Impact Factor
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  Available from: fk.uwks.ac.id

  Chapter: The Role of Insulin and Blood Glucose Control

  L. Langouche, I. Vanhorebeek, G. Van den Berghe
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  ABSTRACT: Hyperglycemia in critically ill patients is a result of an altered glucose metabolism. Apart from the upregulated glucose production (both gluconeogenesis and glycogenolysis), glucose uptake mechanisms are also affected during critical illness and contribute to the development of hyperglycemia. The higher levels of insulin, impaired peripheral glucoseuptake and elevated hepatic glucose production reflect the development of insulin resistance during critical illness. Hyperglycemia in critically ill patients has been associated with increased mortality. Simply maintaining normoglycemia with insulin therapy improves survival and reduces morbidity in surgical and medical ICU patients, as shown by two large, randomized controlled studies. These results obtained from clinical studies were also confirmed in ‘real-life’ intensive care of a heterogeneous patient population admitted to a mixed medical/surgical ICU. Prevention of glucose toxicity by strict glycemic control appears to be crucial, although other metabolic and non-metabolic effects of insulin, independent of glycemic control, may contribute to the clinical benefits.
  12/2006: pages 287-297;
• Article: Mitochondrial alterations caused by defective peroxisomal biogenesis in a mouse model for Zellweger syndrome (PEX5 knockout mouse).

  E Baumgart, I Vanhorebeek, M Grabenbauer, M Borgers, P E Declercq, H D Fahimi, M Baes
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  ABSTRACT: Zellweger syndrome (cerebro-hepato-renal syndrome) is the most severe form of the peroxisomal biogenesis disorders leading to early death of the affected children. To study the pathogenetic mechanisms causing organ dysfunctions in Zellweger syndrome, we have recently developed a knockout-mouse model by disrupting the PEX5 gene, encoding the targeting receptor for most peroxisomal matrix proteins (M Baes, P Gressens, E Baumgart, P Carmeliet, M Casteels, M Fransen, P Evrard, D Fahimi, PE Declercq, D Collen, PP van Veldhoven, GP Mannaerts: A mouse model for Zellweger syndrome. Nat Genet 1997, 17:49-57). In this study, we present evidence that the absence of functional peroxisomes, causing a general defect in peroxisomal metabolism, leads to proliferation of pleomorphic mitochondria with severe alterations of the mitochondrial ultrastructure, changes in the expression and activities of mitochondrial respiratory chain complexes, and an increase in the heterogeneity of the mitochondrial compartment in various organs and specific cell types (eg, liver, proximal tubules of the kidney, adrenal cortex, heart, skeletal and smooth muscle cells, neutrophils). The changes of mitochondrial respiratory chain enzymes are accompanied by a marked increase of mitochondrial manganese-superoxide dismutase, as revealed by in situ hybridization and immunocytochemistry, suggesting increased production of reactive oxygen species in altered mitochondria. This increased oxidative stress induced probably by defective peroxisomal antioxidant mechanisms combined with accumulation of lipid intermediates of peroxisomal beta-oxidation system could contribute significantly to the pathogenesis of multiple organ dysfunctions in Zellweger syndrome.
  American Journal Of Pathology 11/2001; 159(4):1477-94. · 4.89 Impact Factor
• Article: Isoprenoid biosynthesis is not compromised in a Zellweger syndrome mouse model.

  I Vanhorebeek, M Baes, P E Declercq
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  ABSTRACT: Because several studies indicated that peroxisomes are important for the biosynthesis of isoprenoids, we wanted to investigate whether a reduced availability of isoprenoids could be one of the pathogenic factors contributing to the severe phenotype of the Pex5(-/-) mouse, a model for Zellweger syndrome. Total cholesterol was determined in plasma, brain and liver of newborn mice. In none of these tissues a significant difference was observed between Pex5(-/-) and wild type or heterozygous mice. The hepatic ubiquinone content was found to be even higher in Pex5(-/-) mice as compared to wild type or heterozygous littermates. To investigate whether the Pex5(-/-) fetuses are able to synthesise their own isoprenoids, fibroblasts derived from these mice were incubated with radiolabeled mevalonolactone as a substrate for isoprenoid synthesis. No significant difference was observed between the cholesterol production rates of Pex5(-/-) and normal fibroblasts. Our results show that there is no deficiency of isoprenoids in newborn Pex5(-/-) mice, excluding the possibility that a lack of these compounds is a determinant factor in the development of the disease state before birth.
  Biochimica et Biophysica Acta 06/2001; 1532(1-2):28-36. · 4.66 Impact Factor
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  Available from: srlf.org

  Article: Rôle de l'insuline et du contrôle de la glycémie en réanimation

  C. Ingels, I. Vanhorebeek, L. Langouche, G. Van den Berghe
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  ABSTRACT: Hyperglycemia is a common feature of the critically ill and has been associated with increased mortality. Maintaining normoglycemia with insulin therapy improves survival and reduces morbidity in prolonged critically ill patients in both surgical and medical ICU, as shown by two large randomized controlled studies. Prevention of cellular glucose toxicity by strict glycemic control appears to play a predominant role, but also other metabolic and non-metabolic effects of insulin appear to contribute to the clinical benefits.
  Réanimation.
• Article: Intensive insulin therapy and brief hypoglycemia do not increase neurological injury markers in critically ill children

  M Gielen, I Vanhorebeek, M Boussemaere, PJ Wouters, D Mesotten, G Van den Berghe
• Article: Monitoring enteral nutrition efficacy in ICU patients: is there a place for the Brix value-derived fraction of enteral formula in gastric residual volume?

  JS Stuer, M Casaer, D Lerouge, J Helderweirt, N Nijs, G Van den Berghe, I Vanhorebeek
• Source

  Available from: Sarah Derde

  Article: Insufficient activation of autophagy allows accumulation of cellular damage and may contribute to sustained organ failure in prolonged critically ill patients

  J Gunst, S Derde, I Derese, M Boussemaere, F Güiza, W Martinet, JP Timmermans, A D'Hoore, PJ Wouters, G Van den Berghe, I Vanhorebeek
• Source

  Available from: Romain Sonneville

  Article: Effects of hyperglycemia and intensive insulin therapy on neurons and glial cells during critical illness

  R Sonneville, H Den Hertog, F Güiza, I Derese, JP Brouland, F Gray, F Chrétien, T Sharshar, D Annane, G Van den Berghe, I Vanhorebeek
• Article: Absence of peroxisomes in mouse hepatocytes causes mitochondrial and ER abnormalities

  R. Dirkx, I. Vanhorebeek, K. Martens, A Schad, M. Grabenbauer, D. Fahimi, P Declercq, P P Van Veldhoven, M Baes
  Hepatology, v.41, 868-878 (2005).
• Article: Neuronal migration depends on intact peroxisomal function in brain and in extraneuronal tissues

  A Janssen, P Gressens, M. Grabenbauer, E Baumgart, A Schad, I. Vanhorebeek, A. Brouwers, P E Declercq, D. Fahimi, P Evrard, L Schoonjans, S. Collen, P Carmeliet, G. Mannaerts, P Van Veldhoven, M Baes
  Journal of Neuroscience, v.23, 9732-9741 (2003).
• Article: Tissue-specific glucose toxicity induces mitochondrial damage in a burn injury model of critical illness

  I. Vanhorebeek, B. Ellger, R. De Vos, M. Boussemaere, Y. Debaveye, S. Vander Perre, N. Rabbani, P.J. Thornalley, G. Van den Berghe
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  ABSTRACT: Objective: In critically ill patients, preventing hyperglycemia (HG) with insulin therapy partially prevented organ dysfunction and protected mitochondria. A study in a rabbit model of critical Illness indicated that lower blood glucose level, rather than higher insulinemia, is a key factor in such organ protection. In this model, we now Investigated the Impact of blood glucose lowering vs. hyperinsulinemia (HI) on mitochondria in relation to organ damage. We assessed whether such effects on mitochondria are mediated indirectly via organ perfusion or directly via reducing cellular glucose toxicity. Design: Prospective, randomized laboratory investigation. Setting: University laboratory. Subjects: Three-month-old male rabbits. Interventions. After induction of critical illness by burn injury, followed by fluid-resuscitation and parenteral nutrition, rabbits were allocated to four groups, each a combination of normal or elevated blood glucose levels with normal or elevated insulin levels. This required a
  Critical Care Medicine. 37(4):1355-1364.