Research
Introduction
Critical Care Medicine started with the 1950s polio epidemics in Scandinavia and the construction of the iron lung. This young medical specialty has evolved, over only a few decades, into a high-tech branch of medicine that uses sophisticated mechanical devices to support the function of vital organs and a wide array of powerful drugs and monitoring systems, allowing patients to survive a variety of previously lethal insults such as multiple trauma, extensive surgery or severe illness.
However, approximately 30% of patients who survive the initial shock phase of such conditions continue to remain dependent upon these interventions for a longer time, hereby entering a chronic phase of critical illness. Despite best efforts, mortality among such patients, who require intensive care for more than a few days, has remained around 20% worldwide. For the majority of patients who do not survive after extended critical care dependency, the cause of death is therapy-resistant, non-resolving multiple organ failure and weakness. The exact pathophysiology of this condition, which affects millions of patients each year worldwide and consumes a large fraction of health care resources, remains incompletely understood.
Our research
The first contribution by our research group has been to introduce, by carefully designed studies in critically ill patients, the distinction between the initial acute stress response, presumably appropriate, and the distinct neuroendocrine responses to prolonged critical illness of patients in the ICU for weeks or months (1-2). Furthermore, the research group has established a unique animal model of prolonged critical illness, which displays the human bi-phasic neuroendocrine responses to severe stress (3). The novel concept of a bi-phasic stress response clarifies many of the apparent paradoxes in the literature and provides a pathophysiological basis for the development of new therapeutic strategies.
The second focus of our research group comprised the research on the so-called “diabetes of injury”. Hyperglycemia and insulin resistance are common in patients with critical illness, even when glucose homeostasis was previously normal. Increased availability of glucose to important tissues such as the brain, nerves and blood cells was previously thought to be an appropriate adaptation to stress. Hence, elevated blood glucose levels were widely accepted as beneficial and thus left untreated in intensive care patients. However, in several conditions the degree of stress hyperglycemia was associated with risk of adverse outcome. We hypothesized that hyperglycemia, even to a moderate degree as observed in the critically ill, is directly or indirectly harmful to vital organs and systems hence contributing to adverse outcome. Two large, prospective, randomized, controlled investigator-initiated studies in two adult populations of critically ill patients demonstrated a 3% to 4% absolute reduction of mortality with insulin-titrated blood glucose control below 110 mg/dl during intensive care (4-5). When this intervention is continued for at least a few days in ICU, the impact is twice as large, with risk of death reduced from 38% to 30% (mixed study), which implies that thousands of lives could be saved in ICUs worldwide via this relatively simple intervention (6-7). The intervention also reduced morbidity (8-11).
Further evidence for this concept was added recently by a large randomized controlled trial in critically ill infants and children, 75% of whom were admitted to Paediatric ICU after cardiac surgery, a well identifiable hyperglycaemia-inducing ischemia/reperfusion hit (18). Targeting - and reaching - normal fasting levels of blood glucose for the age, which are much lower than the ranges in the adult population, using the appropriate tools, reduced morbidity and mortality to a similar extent as in adult surgical ICU patients.
Concomitantly, our research group has focused on unraveling the mechanisms underlying the life-saving and organ protective effects of the novel intervention. This was done by specific molecular and biochemical analyses of the precious patient blood and tissue samples that were obtained during the clinical studies, as well as by specifically addressing mechanistic questions in the original rabbit model developed by the group, and by going back and forth between the different levels of translational research (patient, animal, bench) (12-17).
In view of our previous work showing beneficial effects of tight blood glucose control, we hypothesize that maintenance of euglycemia may decrease the parenteral nutrition related risk of damage to organ systems and infectious complications. In other words, the reported risk of parenteral nutrition may in part be related to the nutrition-induced aggravation of hyperglycemia, which would counteract any potential benefit of early feeding. In a randomized, multicenter trial, we compared early initiation of parenteral nutrition (European guidelines) with late initiation (American and Canadian guidelines) in adults in the intensive care unit (ICU) to supplement insufficient enteral nutrition (19). Patients in the late-initiation group displayed shorter ICU and hospital stay without evidence of decreased functional status at hospital discharge. Rates of death in the ICU and in the hospital and rates of survival at 90 days were similar in the two groups. Patients in the late-initiation group, as compared with the early-initiation group, had fewer ICU infections (22.8% vs. 26.2%, P=0.008) and a lower incidence of cholestasis (P<0.001). The late-initiation group had a relative reduction of 9.7% in the proportion of patients requiring more than 2 days of mechanical ventilation (P=0.006), a median reduction of 3 days in the duration of renal-replacement therapy (P=0.008), and a mean reduction in health care costs of €1,110 (about $1,600) (P=0.04). We thus concluded that late initiation of parenteral nutrition was associated with faster recovery and fewer complications, as compared with early initiation.
Our Clinical trials
NCT00512122. Impact of Early Parenteral Nutrition Completing Enteral Nutrition in Adult Critically Ill Patients (EPaNIC). Completed - Long term follow-up Ongoing.
NCT00214916. Tight Glycemic Control With Intensive Insulin Treatment in PICU. Completed - Long term follow-up Ongoing.
NCT00115479. KULeuven Intensive Insulin Therapy Study in Medical Intensive Care Patients. Completed.
KULeuven Intensive Insulin Therapy Study in Surgical Intensive Care Patients.Completed.
Key publications
- G. Van den Berghe et al. Clinical review 95: Acute and prolonged critical illness as different neuroendocrine paradigms. The Journal of clinical endocrinology and metabolism. (1998) 83:1827-34.
- G. Van den Berghe et al. Neuroendocrinology of prolonged critical illness: effects of exogenous thyrotropin-releasing hormone and its combination with growth hormone secretagogues. The Journal of clinical endocrinology and metabolism. (1998) 83: 309-19,
- F. Weekers et al. A novel in vivo rabbit model of hypercatabolic critical illness reveals a biphasic neuroendocrine stress response. Endocrinology. (2002) 143: 764-74,
- G. Van den Berghe et al. Intensive insulin therapy in the critically ill patients. The New England journal of medicine. (2001) 345: 1359-67,
- G. Van den Berghe et al. Intensive insulin therapy in the medical ICU., The New England journal of medicine. (2006) 354: 449-61,
- G. Van den Berghe et al. Outcome benefit of intensive insulin therapy in the critically ill: Insulin dose versus glycemic control. Critical care medicine. (2003) 31: 359-66,
- G. Van den Berghe et al. Intensive insulin therapy in mixed medical/surgical intensive care units: benefit versus harm. Diabetes. (2006) 55: 3151-9,
- C Ingels et al. Strict blood glucose control with insulin during intensive care after cardiac surgery: impact on 4-years survival, dependency on medical care, and quality-of-life. European heart journal. (2006) 27: 2716-24
- G. Van den Berghe et al. Insulin therapy protects the central and peripheral nervous system of intensive care patients. Neurology. 2005-04: vol:64 issue:8 pages:1348-53,
- G. Hermans et al. Impact of intensive insulin therapy on neuromuscular complications and ventilator dependency in the medical intensive care unit. American journal of respiratory and critical care medicine. (2007) 175: 480-9.
- M. Schetz et al. Tight Blood Glucose Control Is Renoprotective in Critically Ill Patients. Journal of the American Society of Nephrology, (2008) 19: 571-8.
- D. Mesotten et al. Regulation of insulin-like growth factor binding protein-1 during protracted critical illness. The Journal of clinical endocrinology and metabolism. (2002) 87: 5516-23,
- T. Hansen et al. Intensive insulin therapy exerts antiinflammatory effects in critically ill patients and counteracts the adverse effect of low mannose-binding lectin levels. The Journal of clinical endocrinology and metabolism. (2003) 88: 1082-8.
- D. Mesotten et al. Contribution of circulating lipids to the improved outcome of critical illness by glycemic control with intensive insulin therapy. The Journal of clinical endocrinology and metabolism. (2004) 89: 219-26.
- I. Vanhorebeek et al. Protection of hepatocyte mitochondrial ultrastructure and function by strict blood glucose control with insulin in critically ill patients. Lancet. (2005) 365: 53-59,
- L. Langouche et al. Intensive insulin therapy protects the endothelium of critically ill patients. The Journal of clinical investigation. (2005) 115: 2277-86,
- B. Ellger et al. Survival benefits of intensive insulin therapy in critical illness: impact of maintaining normoglycemia versus glycemia-independent actions of insulin. Diabetes. (2006) 55: 1096-105,
- Intensive insulin therapy for patients in paediatric intensive care: a prospective, randomised controlled study. 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. Lancet. 2009 Feb 14;373(9663):547-56.
- Casaer MP, Mesotten D, Hermans G, Wouters PJ, Schetz M, Meyfroidt G, Van Cromphaut S, Ingels C, Meersseman P, Muller J, Vlasselaers D, Debaveye Y, Desmet L, Dubois J, Van Assche A, Vanderheyden S, Wilmer A, Van den Berghe G. Early versus late parenteral nutrition in critically ill adults. N Engl J Med. 2011 Aug 11;365(6):506-17. Epub 2011 Jun 29.
Key Presentations
