Van Den Berghe Research Articles

What Is a NICE-SUGAR for Patients in the Intensive Care Unit?

What Is a NICE-SUGAR for Patients in the Intensive Care Unit?

Glucose control in the intensive care unit

Hyperglycemia, be it secondary to diabetes, impaired glucose tolerance, impaired fasting glucose, or stress-induced is common in the critically ill. Hyperglycemia and glucose variability in intensive care unit (ICU) patients has some experts calling for routine administration of intensive insulin therapy to normalize glucose levels in hyperglycemic patients. Others, however, have raised concerns over the optimal glucose level, the accuracy of measurements, the resources required to attain tight glycemic control (TGC), and the impact of TGC across the heterogeneous ICU population in patients with diabetes, previously undiagnosed diabetes or stress-induced hyperglycemia. Increased variability in glucose levels during critical illness and the therapeutic intervention thereof have recently been reported to have a deleterious impact on survival, particularly in nondiabetic hyperglycemic patients. The incidence of hypoglycemia (<40 mg/dL or 2.2 mmol) associated with TGC is reported to be as high as 18.7%, by Van den Berghe in a medical ICU, although application of various approaches and computer-based algorithms may improve this. The impact of hypoglycemia, particularly in patients with septic shock and those with neurologic compromise, warrants further evaluation. This review briefly discusses the epidemiology of hyperglycemia in the acutely ill and glucose metabolism in the critically ill. It comments on present limitations in glucose monitoring, outlines current glucose management approaches in the critically ill, and the transition from the ICU to the intermediate care unit or ward. It closes with comment on future developments in glycemic care of the critically ill. The awareness of the potential deleterious impact of hyperglycemia was heightened after Van den Berghe et al presented their prospective trial in 2001. Therefore, source data were obtained from PubMed and Cochrane Analysis searches of the medical literature, with emphasis on the time period after 2000. Recent meta-analyses were reviewed, expert editorial opinion collated, and the Web site of the Normoglycemia in Intensive Care Evaluation and Survival Using Glucose Algorithm Regulation Trial investigated. Hyperglycemia develops commonly in the critically ill and impacts outcome in patients with diabetes but, even more so, in patients with stress-induced hyperglycemia. Despite calls for TGC by various experts and regulatory agencies, supporting data remain somewhat incomplete and conflicting. A recently completed large international study, Normoglycemia in Intensive Care Evaluation and Survival Using Glucose Algorithm Regulation, should provide information to further guide best practice. This concise review interprets the current state of adult glycemic management guidelines to provide a template for care as new information becomes available.

Inpatient Glycemic Control: An Evolving Paradigm

In 2001, Van den Berghe et al published a landmark study of intensive insulin therapy in the setting of a surgical intensive care unit (ICU). Increased attention was also focused on the observational evidence indicating that hyperglycemia is associated with increased morbidity and mortality among diverse patient populations. Because of the dramatic reduction in mortality with normalization of glucose levels in the single center, the Van den Berghe study led to widespread adoption of this practice in ICUs worldwide. Hospitals also began to implement rational subcutaneous insulin protocols based on the American Diabetes Association technical review, replacing the ineffective practice of sliding-scale insulin. Logistical challenges have included coordination of multiple hospital departments and achieving multidisciplinary consensus on goals and methods. Subsequent to the initial Van den Berghe study, other multicenter trials have been fraught with an increased frequency of hypoglycemia and have failed to consistently demonstrate improved outcomes with intensive insulin therapy. Hospitals and expert panels are in the process of examining the combined evidence and considering modifying treatment goals. We recommend continued focus on avoiding hyperglycemia with less aggressive glycemic targets in the critically ill and rational subcutaneous insulin in the noncritically ill, avoiding a return to the obsolescence of sliding-scale insulin.

‘Magic is no magic’, the wonderful world of Simon Stevin - by Jozef T. Devreese and Guido Vanden Berghe

‘Magic is no magic’, the wonderful world of Simon Stevin - by Jozef T. Devreese and Guido Vanden Berghe

Changes in Management of Septic Shock in Scottish Intensive Care Units after the Publication of the Surviving Sepsis Campaign Guidelines 2008

The 2004 guidelines of the Surviving Sepsis Campaign (SSC)1 for the management of severe sepsis and septic shock included recommendations about glucose control, the use of recombinant human activated protein C (rhAPC) and intravenous steroid replacement, based on original trials by van den Berghe and Annane in 2001 and Bernard (PROWESS) in 2002. In 2008, the SSC revised the international guidelines2 to reflect the results of recent trials (VISEP, CORTICUS, ADDRESS, RESOLVE). Some of these studies completely or partially contradicted results of the earlier trials. We conducted a questionnaire survey of all intensive care units (ICUs) in Scotland six months after publication of the 2008 SSC guidelines to assess current practice.

Critical Care Nephrology: Core Curriculum 2009

In the inpatient setting, a high proportion of nephrology consultations are requested for patients in the Intensive Care Unit (ICU). These patients may have acute kidney injury (AKI) or may be critically ill and have end-stage renal disease (ESRD). Thus, nephrologists need to understand recent evidence-based advances in the field of critical care, as well as areas of ongoing controversy and investigation. In this article, we summarize the diagnosis and management of shock, as well as the management of sepsis, acute lung injury/acute respiratory distress syndrome (ALI/ARDS), and fulminant hepatic failure, all of which are associated with high mortality in the critical care setting. We discuss infectious complications of critical care, including ventilator associated pneumonia and catheter related infections. Supportive care, including nutrition, insulin therapy and anemia management are reviewed. Dialysis considerations in critically ill patients are discussed. Lastly, we review the management of several life-threatening intoxications, many of which require early recognition and consideration of dialysis.

Does intensive insulin therapy really reduce the incidence of acute renal injury in critically ill patients? An analysis using the rifle criteria

In 2001, Van den Berghe and colleagues introduced the concept of strict glycemic control in the critically ill patient [1]. The impact of this new approach was particularly significant when the renal outcome of the patients was evaluated. While some subsequent studies corroborated Van den Berghe and colleagues' results, others could not demonstrate any benefit of intensive insulin therapy on mortality and renal outcome. One of the difficulties in comparing the incidence of acute renal dysfunction is the lack of consensus about its definition. The RIFLE criteria, proposed in 2004 [2], had the objective of standardizing this definition.

Blood glucose control in patients with severe sepsis and septic shock

The main pathophysiological feature of sepsis is the uncontrollable activation of both pro- and anti-inflammatory responses arising from the overwhelming production of mediators such as pro- and anti-inflammatory cytokines. Such an uncontrollable inflammatory response would cause many kinds of metabolic derangements. One such metabolic derangement is hyperglycemia. Accordingly, control of hyperglycemia in sepsis is considered to be a very effective therapeutic approach. However, despite the initial enthusiasm, recent studies reported that tight glycemic control with intensive insulin therapy failed to show a beneficial effect on mortality of patients with severe sepsis and septic shock. One of the main reasons for this disappointing result is the incidence of harmful hypoglycemia during intensive insulin therapy. Therefore, avoidance of hypoglycemia during intensive insulin therapy may be a key issue in effective tight glycemic control. It is generally accepted that glycemic control aimed at a blood glucose level of 80-100 mg/dL, as initially proposed by van den Berghe, seems to be too tight and that such a level of tight glycemic control puts septic patients at increased risk of hypoglycemia. Therefore, now many researchers suggest less strict glycemic control with a target blood glucose level of 140-180 mg/dL. Also specific targeting of glycemic control in diabetic patients should be considered. Since there is a significant correlation between success rate of glycemic control and the degree of hypercytokinemia in septic patients, some countermeasures to hypercytokinemia may be an important aspect of successful glycemic control. Thus, in future, use of an artificial pancreas to avoid hypoglycemia during insulin therapy, special consideration of septic diabetic patients, and control of hypercytokinemia should be considered for more effective glycemic control in patients with severe sepsis and septic shock.

Tight Glucose Control in Critically Ill Adults

To the Editor: Dr Soylemez Wiener and colleagues reported the results of a meta-analysis that included 29 studies on tight glucose control in critically ill adults. Several methodological issues limit the conclusions to be drawn from this study. First, the included studies have substantial differences, most importantly concerning the type of intervention (fixed vs titrated insulin dose) and the glucose levels actually achieved. The proof-of-concept study on tight glucose control in the intensive care unit (ICU) hypothesized that normalization of blood glucose (80-110 mg/dL) with insulin protects against complications (eg, severe infections, organ failure, death). (To convert glucose values to mmol/L, multiply by 0.0555.) The scientific concept was that any degree of hyperglycemia above normal ( 110 mg/dL) in a condition of ischemia/reperfusion additionally damages those cells that take up glucose passively. The study by Soylemez Wiener et al pooled all published studies on insulin therapy (including glucose-insulin-potassium) and those that targeted glucose of 150 mg/dL or lower. Studies not achieving normoglycemia in the majority of patients should not be expected to provide the same benefit as in the original Leuven study. Methodological quality assessment in the metaanalysis should have addressed this issue of achievement of normoglycemia, as well as the varying blood glucose levels in the different control groups. Overlap of glucose levels in controls and the intervention groups should not exceed 20%. Achieving a glycemic target cannot be assessed using mean glycemia levels; high and low values may cancel out and falsely suggest goal achievement. The number of patients on average within the target would have been a better parameter. Second, the primary outcome measure used in the metaanalysis was inaccurate because hospital mortality is not identical to 30-day mortality. Benefit from tight glucose control in this population can only be expected after at least 30 days. Pooling lacks a scientific basis and predictably negates any possible benefit of tight glucose control. Third, presence of heterogeneity was not handled according to Cochrane guidelines. Studies contributing to statistical heterogeneity were identified and subsequently eliminated. This is methodologically inadequate as heterogeneity may indicate a true difference in effect size among studies differing in certain clinical or methodological characteristics (eg, actual achievement of normoglycemia). Cochrane guidelines advise the use of meta-regression for this purpose rather than calculating a summary effect estimate across a series of very different studies. This was not performed in the meta-analysis. Greet Hermans, MD Department of General Internal Medicine Miet Schetz, MD, PhD Greet van den Berghe, MD, PhD greet.vandenberghe@med.kuleuven.be Department of Intensive Care Medicine Catholic University of Leuven Leuven, Belgium

Van‐den Berghe’s 5q‐ syndrome in 2008

Van Den Berghe established 5q- syndrome as a discrete clinical entity in 1974 when he described patients with macrocytic anaemia, thrombocytosis, dyserythropoiesis, hypolobulated megakaryocytes and an interstitial deletion within chromosome 5q. With del(5q) as the sole cytogenetic abnormality, 5q- syndrome represents an opportunity to define precisely the molecular defect(s) underlying the pathogenesis of this disease. The commonly deleted region in 5q- syndrome, which is distinct from that in patients with complex cytogenetic changes that include del(5q), includes the ribosomal protein S14 locus and it has been proposed that that loss of an RPS14 allele accounts for the 5q- syndrome phenotype. However, this hypothesis fails to explain the growth advantage of the 5q- syndrome clone and it is evident that ribosomal protein defects are not specific to 5q- syndrome, as they are found in other bone marrow failure syndromes. Lenalidomide therapy leads to normalization of both haematological and cytogenetic parameters in the majority of 5q- syndrome patients. This review examines the potential role of several genes, including RPS14, in the pathogenesis of the 5q- syndrome and recent advances in clinical management, with particular emphasis on the role and mechanism of action of lenalidomide.

Tight Glucose Control in Critically Ill Adults

To the Editor: Dr Soylemez Wiener and colleagues reported the results of a meta-analysis that included 29 studies on tight glucose control in critically ill adults. Several methodological issues limit the conclusions to be drawn from this study. First, the included studies have substantial differences, most importantly concerning the type of intervention (fixed vs titrated insulin dose) and the glucose levels actually achieved. The proof-of-concept study on tight glucose control in the intensive care unit (ICU) hypothesized that normalization of blood glucose (80-110 mg/dL) with insulin protects against complications (eg, severe infections, organ failure, death). (To convert glucose values to mmol/L, multiply by 0.0555.) The scientific concept was that any degree of hyperglycemia above normal ( 110 mg/dL) in a condition of ischemia/reperfusion additionally damages those cells that take up glucose passively. The study by Soylemez Wiener et al pooled all published studies on insulin therapy (including glucose-insulin-potassium) and those that targeted glucose of 150 mg/dL or lower. Studies not achieving normoglycemia in the majority of patients should not be expected to provide the same benefit as in the original Leuven study. Methodological quality assessment in the metaanalysis should have addressed this issue of achievement of normoglycemia, as well as the varying blood glucose levels in the different control groups. Overlap of glucose levels in controls and the intervention groups should not exceed 20%. Achieving a glycemic target cannot be assessed using mean glycemia levels; high and low values may cancel out and falsely suggest goal achievement. The number of patients on average within the target would have been a better parameter. Second, the primary outcome measure used in the metaanalysis was inaccurate because hospital mortality is not identical to 30-day mortality. Benefit from tight glucose control in this population can only be expected after at least 30 days. Pooling lacks a scientific basis and predictably negates any possible benefit of tight glucose control. Third, presence of heterogeneity was not handled according to Cochrane guidelines. Studies contributing to statistical heterogeneity were identified and subsequently eliminated. This is methodologically inadequate as heterogeneity may indicate a true difference in effect size among studies differing in certain clinical or methodological characteristics (eg, actual achievement of normoglycemia). Cochrane guidelines advise the use of meta-regression for this purpose rather than calculating a summary effect estimate across a series of very different studies. This was not performed in the meta-analysis. Greet Hermans, MD Department of General Internal Medicine Miet Schetz, MD, PhD Greet van den Berghe, MD, PhD greet.vandenberghe@med.kuleuven.be Department of Intensive Care Medicine Catholic University of Leuven Leuven, Belgium

Potential Molecular Targets for Translational Stroke Research

The stroke research community is currently at a crossroads, and a shift in focus is necessary to propel basic research forward to develop clinically effective therapeutics. In-depth analysis of the past failures and imposing more stringent standards on future basic research experiments will greatly improve the success of translational research. The purpose of this review is to outline proposed revisions in basic research criteria and offer attractive molecular candidates to mitigate brain damage after cerebral ischemia. A major pitfall encompassing translational stroke research is that a majority of clinical trials conducted have focused on agents involving recanalization of vessels and on excitotoxicity to reduce neuronal death in the penumbra.1 Recanalization using tissue plasminogen activator only modestly improves patient outcome, and inhibiting excitotoxicity has shown no clinical benefit.2 The short duration of excitotoxicity after ischemia does not provide an adequate time window for effective stroke therapy in clinical practice because the exact onset of stroke is often indeterminate and a majority of patients do not seek medical treatment for many hours after the insult. A more reasonable therapeutic window, and hence a greater potential for clinical success, is likely to be attained by placing emphasis on ameliorating the effects of the synergistic processes of programmed cell death (PCD) and inflammation that are active for hours to days after ischemia.3 In addition, it is necessary to identify molecular mediators of ischemic neuroprotection suitable for translation to human clinical trials. Accordingly, more stringent criteria for selection of targets are required. The following criteria will facilitate development of translatable …

:Renaissance Art Reconsidered: An Anthology of Primary Sources

:<i>Renaissance Art Reconsidered: An Anthology of Primary Sources</i>

The optimal exponentially-fitted Numerov method for solving two-point boundary value problems

Second order boundary value problems are solved by means of exponentially-fitted Numerov methods. These methods, which depend on a parameter, can be constructed following a six-step flow chart of Ixaru and Vanden Berghe [L.Gr. Ixaru, G. Vanden Berghe, Exponential Fitting, Kluwer Academic Publishers, Dordrecht, 2004]. Special attention is paid to the expression of the error term of such methods. An algorithm concerning the choice of the best suited method and its parameter is discussed. Several numerical examples are given to sustain the theory.

FOXO, the spindle in the net for wasting diseases?

FOXO, the spindle in the net for wasting diseases?

Inflammatory Pathways Are Activated during Cardiomyocyte Hypertrophy and Attenuated by Peroxisome Proliferator-activated Receptors PPARα and PPARδ

Accumulating evidence indicates an important role for inflammation in cardiac hypertrophy and failure. Peroxisome proliferator-activated receptors (PPARs) have been reported to attenuate inflammatory signaling pathways and, as such, may interfere with cardiac remodeling. Accordingly, the objectives of the present study were to explore the relationship between cardiomyocyte hypertrophy and inflammation and to investigate whether PPARalpha and PPARdelta are able to inhibit NF-kappaB activation and, consequently, the hypertrophic growth response of neonatal rat cardiomyocytes (NCM). mRNA levels of markers of both hypertrophy and inflammation were increased following treatment with the pro-hypertrophic factor phenylephrine (PE) or the chemokine TNF-alpha. Induction of inflammatory genes was found to be fast (within 2 h after stimulation) and transient, while induction of hypertrophic marker genes was more gradual (peaking at 24-48 h). Inflammatory and hypertrophic pathways appeared to converge on NF-kappaB as both PE and TNF-alpha increased NF-kappaB binding activity as measured by electrophoretic mobility shift assay. Following transient transfection, the p65-induced transcriptional activation of a NF-kappaB reporter construct was significantly blunted after co-transfection of PPARalpha or PPARdelta in the presence of their respective ligands. Finally, adenoviral overexpression of PPARalpha and PPARdelta markedly attenuated cell enlargement and the expression of hypertrophic marker genes in PE-stimulated NCM. The collective findings reveal a close relationship between hypertrophic and inflammatory signaling pathways in the cardiomyocyte. It was shown that both PPARalpha and PPARdelta are able to mitigate cardiomyocyte hypertrophy in vitro by inhibiting NF-kappaB activation.

Rapid UPLC-MS/MS method for routine analysis of plasma pristanic, phytanic, and very long chain fatty acid markers of peroxisomal disorders

Quantification of pristanic acid, phytanic acid, and very long chain fatty acids (i.e., hexacosanoic, tetracosanoic, and docosanoic acids) in plasma is the primary method for investigateing a multitude of peroxisomal disorders (PDs). Typically based on GC-MS, existing methods are time-consuming and laborious. In this paper, we present a rapid and specific liquid chromatography tandem mass spectrometric method based on derivatization with 4-[2-(N,N-dimethylamino)ethylaminosulfonyl]-7-(2-aminoethylamino)-2,1,3-benzoxadiazole (DAABD-AE). Derivatization was undertaken to improve the poor mass spectrometric properties of these fatty acids. Analytes in plasma (20 mul) were hydrolyzed, extracted, and derivatized with DAABD-AE in approximately 2 h. Derivatives were separated on a reverse-phase column and detected by positive-ion electrospray ionization tandem mass spectrometry with a 5 min injection-to-injection time. Calibration plots were linear over ranges that cover physiological and pathological concentrations. Intraday (n = 12) and interday (n = 10) variations at low and high concentrations were less than 9.2%. Reference intervals in normal plasma (n = 250) were established for each compound and were in agreement with the literature. Using specimens from patients with established diagnosis (n = 20), various PDs were reliably detected. In conclusion, this method allows for the detection of at least nine PDs in a 5 min analytical run. Furthermore, this derivatization approach is potentially applicable to other disease markers carrying the carboxylic group.

Interaction and Functional Interference of Glucocorticoid Receptor and SOCS1

Cytokine and glucocorticoid (GC) hormone signaling act in an integrated fashion to control inflammation and immune response. Here we establish a new mode of interaction of these two pathways and propose Suppressor of Cytokine Signaling (SOCS)-1 as an essential player in mediating cross-talk. We observed that glucocorticoid receptor (GR) and SOCS1 form an intracellular complex through an interaction, which required the SH2 domain of SOCS1 and the ligand binding domain of GR. Furthermore, GC stimulation was found to increase the nuclear level of SOCS1. SOCS1 binding to the GR did not require ligand binding of the receptor; however, it was abolished after long term GC stimulation, suggesting a functional role of the interaction for the early phase of GC action. The interaction between GR and SOCS1 appeared to negatively influence the transcription of the two GR-regulated genes, FKBP5 and MKP1, because the GC-dependent expression of these genes was inhibited by the SOCS1 inducer IFNgamma and enhanced in SOCS1-deficient murine embryonic fibroblasts as compared with IFNgamma treated wild-type cells. Our results suggest a prominent role of SOCS1 in the early phase of cross-talk between GR and cytokine signaling.

Activation of Liver X Receptors Prevents Statin-induced Death of 3T3-L1 Preadipocytes

The biological functions of liver X receptors (LXRs) alpha and beta have primarily been linked to pathways involved in fatty acid and cholesterol homeostasis. Here we report a novel role of LXR activation in protecting cells from statin-induced death. When 3T3-L1 preadipocytes were induced to differentiate by standard isobutylmethylxanthine/dexamethasone/insulin treatment in the presence of statins, they failed to differentiate and underwent massive apoptosis. The simultaneous addition of selective LXR agonists prevented the statin-induced apoptosis. By using mouse embryo fibroblasts from wild-type (LXRalpha+/+/LXRbeta+/+), LXRalpha knock-out mice (LXRalpha(-/-)/LXRbeta+/+), LXRbeta knock-out mice (LXRalpha+/-/LXRbeta(-/-)), and LXR double knock-out mice (LXRalpha(-/-)/LXRbeta(-/-)) as well as 3T3-L1 cells transduced with retroviruses expressing either wild-type LXRalpha or a dominant negative version of LXRalpha, we demonstrate that the response to LXR agonists is LXR-dependent. Interestingly, LXR-mediated rescue of statin-induced apoptosis was not related to up-regulation of genes previously shown to be involved in the antiapoptotic action of LXR. Furthermore, forced expression of Bcl-2 did not prevent statin-induced apoptosis; nor did LXR action depend on protein kinase B, whose activation by insulin was impaired in statin-treated cells. Rather, LXR-dependent rescue of statin-induced apoptosis in 3T3-L1 preadipocytes required NF-kappaB activity, since expression of a dominant negative version of IkappaBalpha prevented LXR agonist-dependent rescue of statin-induced apoptosis. Thus, the results presented in this paper provide novel insight into the action of statins on and LXR-dependent inhibition of apoptosis.

Molecular Dissection of the Human α2-Macroglobulin Subunit Reveals Domains with Antagonistic Activities in Cell Signaling

alpha(2)-Macroglobulin (alpha(2)M) is a plasma protease inhibitor, which reversibly binds growth factors and, in its activated form, binds to low density lipoprotein receptor-related protein (LRP-1), an endocytic receptor with cell signaling activity. Because distinct domains in alpha(2)M are responsible for its various functions, we hypothesized that the overall effects of alpha(2)M on cell physiology reflect the integrated activities of multiple domains, some of which may be antagonistic. To test this hypothesis, we expressed the growth factor carrier site and the LRP-1 recognition domain (RBD) as separate GST fusion proteins (FP3 and FP6, respectively). FP6 rapidly and robustly activated Akt and ERK/MAP kinase in Schwann cells and PC12 cells. This response was blocked by LRP-1 gene silencing or by co-incubation with the LRP-1 antagonist, receptor-associated protein. The activity of FP6 also was blocked by mutating Lys(1370) and Lys(1374), which precludes LRP-1 binding. FP3 blocked activation of Akt and ERK/MAP kinase in response to nerve growth factor-beta (NGF-beta) but not FP6. In PC12 cells, FP6 promoted neurite outgrowth and expression of growth-associated protein-43, whereas FP3 antagonized the same responses when NGF-beta was added. The ability of FP6 to trigger LRP-1-dependent cell signaling in PC12 cells was reproduced by the 18-kDa RBD, isolated from plasma-purified alpha(2)M by proteolysis and chromatography. We propose that the effects of intact alpha(2)M on cell physiology reflect the degree of penetration of activities associated with different domains, such as FP3 and FP6, which may be regulated asynchronously by conformational change and by other regulatory proteins in the cellular microenvironment.