Greet Van Den Berghe - Publications#

A total of >300 articles (among which 30 in the top 3 journals: 17 in N Engl J Med of which 4 full research papers, 5 in JAMA of which 2 full research papers, 4 in the Lancet of which 2 full research papers, 29 of these 30 top papers as first or last author), a total of >22400 citations, h-index=63 and 35 papers cited more than 100 times each.

1. Van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, Vlasselaers D, Ferdinande P, Lauwers P, Bouillon R. 2001 Intensive insulin therapy in critically ill patients. New England Journal of Medicine 345: 1359–1367 (ISI IF: 54.420) (cited 4427 times)

This is THE landmark paper showing that preventing the hyperglycemic response to critical illness, previously tolerated for surgical ICU patients, reduces morbidity and mortality of intensive care patients. The staggering number of citations and very high number of editorial comments and reviews reveal the relevance and impact, with citations that continue to increase annually with several hundreds per year, and this after almost 15 years. It has opened the field of (iatrogenic) metabolic insults during critical illness with impact well beyond own field. It is one of the few extremely highly cited papers of the NEJM and the most cited Belgian research paper of the previous decade. It has received enormous lay press attention as well.

2. Van den Berghe G, Wilmer A, Hermans G, Meersseman W, Wouters PJ, Milants I, Van Wijngaerden E, Bobbaers H, Bouillon R. 2006 Intensive insulin therapy of medical intensive care patients. New England Journal of Medicine 354: 449–61. (ISI IF 2013: 54.420) (cited 1644 times)

This is another landmark paper, as it shows the benefit of strict maintenance of normoglycemia also in another adult population. However, the study also showed that when hyperglycemia-induced complications are already present upon admission to ICU, as is often the case for the more chronic medical ICU population, it is much more difficult to reverse them with blood glucose control. Also this paper is highly cited and has received enormous lay press attention as well.

3. Casaer MP, Mesotten D, Hermans G, Wouters PJ, Schetz M, Meyfroidt G, Van Cromphaut S, Ingels C, Meersseman Ph, Muller J, Vlasselaers D, Debaveye Y, Desmet L, Dubois J, Van Assche A, Vanderheyden S, Wilmer A, Van den Berghe G. 2011 Early versus late parenteral nutrition in critically ill adults. New England Journal of Medicine 365: 506-17. (ISI IF 2013: 54.420) (cited 339 times)

This is a landmark paper because it is the first study to show that early intravenous administration of macronutrients during critical illness, even when hyperglycemia is carefully avoided, slows down rather than that it helps recovery from adult critical illness, and that this effect extends far beyond the time window of the intervention. This result challenged the classical dogma that preventing hypercatabolism and forcing anabolism during acute stress conditions and illnesses is a good thing. It formed the basis for the subsequent experimental work of the group that showed that autophagy, a catabolic cellular housekeeping system, is required for recovery from organ failure and that nutrition early in the course of illness suppresses that vital housekeeping mechanism. These findings not only were paradigm-shifting but also opened perspectives for druggable targets. Also this recent paper received a high and rising number of citations, many editorial comments in scientific journals, and extensive lay press attention. It is also ranked among the all-time top 10 “Critical Care and Emergency Medicine” and “Metabolism” in Faculty of 1000.

4. Boonen E, Vervenne H, Meersseman P, Andrew R, Mortier L, Declercq PE, Vanwijngaerden YM, Spriet I, Wouters PJ, Vander Perre S, Langouche L, Vanhorebeek I, Walker BR, Van den Berghe G. 2013 Reduced Cortisol Metabolism during Critical Illness. New England Journal of Medicine 368: 1477-88. (ISI IF 2013: 54.420) (cited 75 times)

This very recent publication shifted another paradigm, more specifically the dogma of the adrenocortical response to stress, and thus again represents a landmark paper. It reports the results of 5 studies, clinical and mechanistic using human material, which together showed that reduced cortisol breakdown evoked by suppressed expression and activity of cortisol-metabolizing enzymes in liver and kidney, rather than an increase in cortisol production, drives hypercortisolism during critical illness. These findings totally changed the understanding of the human stress response in the context of critical illness and also beyond the intensive care unit. It also provided the key observations of one specific possible pathway that could explain part of the neurocognitive and psychosocial legacy of critical illness, which is further addressed in the planned research of the nominee. Also this top publication was accompanied by an editorial in NEJM and was covered in the lay press.

5. Casaer MP, Van den Berghe G. 2014 Nutrition in the acute phase of critical illness. New England Journal of Medicine 370:1227-36. (ISI IF 2013: 54.420) (cited 22 times)

This is an invited review on a topic that was launched by the 2011 NEJM paper from the Van den Berghe Group.

6. Vlasselaers D, Milants I, Desmet L, Wouters PJ, Vanhorebeek I, van den Heuvel I, Mesotten D, Casaer MP, Meyfroidt G, Ingels C, Muller J, Van Cromphaut S, Schetz M, Van den Berghe G. 2009 Intensive insulin therapy in paediatric Intensive Care Unit patients: a prospective randomized controlled study. Lancet 373: 547-556. (ISI IF 2013: 39.207) (cited 234 times)

This is to be considered a landmark paper for several reasons. First, it reports the results of the first large randomized controlled study in critically ill children, which for the first time proved causality of the association between hyperglycemia and adverse outcome in this age group. Since this young age group does not yet suffer from chronic comorbidities, and the time of onset of hyperglycemia is identifiable in a more accurate manner, the effect of the intervention is much clearer than in the adult studies. Second, the study clearly showed that the threshold for toxicity of hyperglycemia in infants and children is much lower than in adults, which brings the target range for blood glucose much closer to the dangerous level of hypoglycemia. This clearly revealed a need for better tools to implement this life-saving therapy in daily clinical practice.
Received 24 editorial comments in scientific journals, besides the accompanying editorial in the Lancet.
Extensive lay press attention (>48.000 hits via google).

7. Mesotten D, Gielen M, Sterken C, Claessens K, Hermans G, Vlasselaers D, Lemiere J, Gewillig M, Eyskens B, Vanhorebeek I, Wouters PJ, Van den Berghe G. 2012 Neurocognitive Development of Children 4 Years After Critical Illness and Treatment With Tight Glucose Control. A Randomized Controlled Trial. Journal of the American Medical Association 308: 1641-50. (ISI IF 2013: 30.387) (cited 32 times)

This paper reports the results of the longterm neurocognitive outcome of the children participating in the first large randomized controlled study in pediatric critical care. As mentioned by the editor in chief of JAMA during the conference where the paper was first presented in a hot topics session, “sometimes the follow-up study of a large RCT is even more important than the original publication, and this is the case for this study”. Indeed, this landmark study showed for the first time that neurocognitive development in children who have been treated in ICU at such a young age is threatened enormously as compared with their siblings, and that avoiding hyperglycemia prevented only part of that terrible legacy of critical illness. This study is the first to show that critical illness in children evokes possibly permanent sequellae, aggravated by metabolic modifiable risk factors. It raised the hypothesis that epigenetic factors could play a role. Further testing the hypothesis that epigenetic changes can be evoked by illness and by the metabolic interventions during critical illness, forms a large part of the planned research of the Methusalem group. The unique longterm studies that are planned to address this concept tick the boxes for the required methodological aspects to be able to address the issue of causality.
This publication received 2 editorial comments in scientific journals, besides the accompanying editorial in JAMA.

8. Vanhorebeek I, De Vos R, Mesotten M, Wouters PJ, De Wolf-Peeters C, Van den Berghe G. 2005 Protection of hepatocyte mitochondrial ultrastructure and function by strict blood glucose control with insulin in critically ill patients. Lancet 365: 53-59.
(ISI IF 2013: 39.207) (cited 253 times)

This is key translational paper bridging the clinical findings of an RCT to an important mechanistic discovery; the benefit of blood glucose control during critical illness is protective for vital organ function through its effect on mitochondria. It opened a whole new field on the role of mitochondria during critical illness. It is highly cited.

9. Langouche L, Vanhorebeek I, Vlasselaers D, Vander Perre S, Wouters PJ, Hansen TK, Skogstrand K, Van den Berghe G. 2005 Intensive insulin therapy protects the endothelium of critically ill patients. Journal of Clinical Investigation 115: 2277-2286.
(ISI IF 2013: 13.765) (cited 272 times)

This translational paper is a landmark paper as it unraveled the link between the clinical benefits of blood glucose control during critical illness and the protection of the endothelium. It opened a series of new research lines on the role of inflammation, the endothelium and metabolism during critical illness. Also this paper is highly cited.

10. Hermans G*, Casaer M*, Clerckx B, Güiza F, Vanhullebusch T, Derde S, Meersseman P, Derese I, Mesotten D, Wouters P, Van Cromphaut S, Debaveye Y, Gosselink R, Gunst J, Wilmer A, Van den Berghe G*, Vanhorebeek I*. (*contributed equally) Effect of tolerating macronutrient deficit on the development of intensive-care unit acquired weakness: A subanalysis of the epanic trial. The Lancet Respiratory Medicine 2013;1:621-629. (This is a new Lancet subspecialty journal, impact factor should follow) (cited 24 times).

This recent publication is also a landmark paper as it is the first to confirm in human patients the original and quite provocative hypothesis of the team that the catabolic autophagic system is crucial for recovery from critical illness. It is the result of the joint efforts of the mixed clinical/basic research group, underlining the importance and value of a group that operates in such a truly translational setting. The order of the authors in the list is in line with the essential multidisciplinary approach and value.

The study was performed in a unique randomized controlled setting and showed that early supplementation of failing enteral nutrition with parenteral nutrition has no effect at all on muscle atrophy, but suppressed cellular autophagic quality control and increased muscle weakness, as compared with tolerating an important macronutrient deficit up to one week in ICU. Muscle weakness after one week of critical illness was partially explained by impaired autophagy, implying loss of muscle integrity, rather than by muscle atrophy. This opened further perspectives for pharmacological autophagy activation during critical illness for preserving muscle integrity and function and for accelerating recovery. This concept forms the basis of another large part of the planned research, basic and clinical, of the Van den Berghe Methusalem group.

This publication was accompanied by an editorial in Lancet Resp Med and was covered in the lay press.