Blood glucose control following severe traumatic brain injury- unclear transition from beneficial to detrimental effects
John F. Stover, Surgical Intensive Care Medicine, University Hospital Zuerich, Switzerland
8 September 2008
In contemporary critical care it is essential to avoid induction of additional damage. This is of utmost imortance in patients with acute brain injuries. In this context, control of arterial blood glucose should be integrated in daily clinical routine. For this, however, the optimal range has not yet been defined. In addition, we are still lacking insight into time- dependent changes possibly requiring temporally adapted blood glucose levels. During the early phase disturbances in endogenous hormonal regulation, adaptation to artificial nutrition, hemodynamic instability, and activation of the systemic inflammatory response predispose patients to unpredictable changes in arterial blood glucose. Consequently, the early phase is overshadowed by an increased risk of hyperglycemic as well as insulin- induced hypoglycemic episodes. Not even sophisticated protocols could prevent insulin- induced hypoglycemia [1- 7]. Over time, as the patients become more stable, they are less prone to e.g., insulin- induced hypoglycemia. This could explain why the beneficial effects reported by van den Berghe are not observed during the first 3 [1, 2] to 5 days [3]. In our retrospective analysis beneficial effects in terms of reduced rate in infections and elevated intracranial pressure exceeding 20 mmHg were only observed after the first week [8]. During the first week there was even a significant increase in infection rate and norepinephrine requirement in patients in whom arterial blood glucose was maintained between 3.5- 6.5 compared to 5- 8 mmol/ l [8]. To date, it remains unclear whether low arterial blood glucose must be maintained within tight limits during the first 3- 7 days in these patients with the increased risk of hypoglycemia to induce subsequent beneficial effects. Thus, detailed investigations are important to determine if low arterial blood glucose maintained within tight limits after the 3rd or 7th day allowing higher limits during the first 3- 7 days will result in significant improval and reduced complications and mortality.
As pointed out by Paul M. Vespa [9] in his commentary to our retrospective analysis [8] the lowest possible blood glucose level void of detrimental effects must be determined for each individual patient. This is essential to define a detailed protocol for a prospective study to avoid adverse effects as e.g., induced cerebral metabolic distress [9], hypoglycaemia and rebound hyperglycemia. Increased rate of hypoglycemic episodes had resulted in premature termination of other trials [5] aimed at reproducing previously published positive effects of maintaining blood glucose between 4.4 and 6.1 mmol/ l [1- 3]. In an attempt to determine potentially optimal range in blood glucose levels we retrospectively investigated the concentration- dependent influence of arterial blood glucose on cerebral metabolic effects determined by microdialysis and changes in arterial- jugular venous differences (unpublished data). These new results strongly suggest that arterial blood glucose levels between 7 and 9 mmol/ l are superior to arterial blood glucose levels < 5 mmol/ l in terms of increased cerebral glucose uptake and improved cerebral metabolic stability.
Despite its simple principle of action more detailed investigations are required to characterize time-, duration-, and concentration- dependent effects of maintaining arterial blood glucose levels within certain limits in patients prone to glucose- induced brain damage.
References
1. van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, Vlasselaers D, Ferdinande P, Lauwers P, Bouillon R. Intensive insulin therapy in the critically ill patients. N Engl J Med 2001, 345: 1359-1367.
2. Van den Berghe G, Wilmer A, Hermans G, Meersseman W, Wouters PJ, Milants I, Van Wijngaerden E, Bobbaers H, Bouillon R. Intensive insulin therapy in the medical ICU. N Engl J Med 2006, 354: 449-461.
3. Van den Berghe G, Schoonheydt K, Becx P, Bruyninckx F, Wouters PJ. Insulin therapy protects the central and peripheral nervous system of intensive care patients. Neurology 2005, 64: 1348-1353.
4. Bilotta F, Caramia R, Cernak I, Paoloni FP, Doronzio A, Cuzzone V, Santoro A, Rosa G. Intensive Insulin Therapy After Severe Traumatic Brain Injury: A Randomized Clinical Trial. Neurocrit Care 2008, Epub before press
5. Brunkhorst FM, Engel C, Bloos F, Meier-Hellmann A, Ragaller M, Weiler N, Moerer O, Gruendling M, Oppert M, Grond S, Olthoff D, Jaschinski U, John S, Rossaint R, Welte T, Schaefer M, Kern P, Kuhnt E, Kiehntopf M, Hartog C, Natanson C, Loeffler M, Reinhart K; German Competence Network Sepsis (SepNet). Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med. 2008, 358: 125- 139.
6. McMullin J, Brozek J, McDonald E, Clarke F, Jaeschke R, Heels-Ansdell D, Leppert R, Foss A, Cook D. Lowering of glucose in critical care: a randomized pilot trial. J Crit Care 2007, 22: 112-118
7. Clayton SB, Mazur JE, Condren S, Hermayer KL, Strange C. Evaluation of an intensive insulin protocol for septic patients in a medical intensive care unit. Crit Care Med. 2006, 34: 2974-2978.
8. Meier R, Béchir M, Ludwig S, Sommerfeld J, Keel M, Steiger P, Stocker R, Stover JF. Differential temporal profile of lowered blood glucose levels (3.5 to 6.5 mmol/l versus 5 to 8 mmol/l) in patients with severe traumatic brain injury. Crit Care. 2008, 12: R98.
9. Vespa P, Boonyaputthikul R, McArthur DL, Miller C, Etchepare M, Bergsneider M, Glenn T, Martin N, Hovda D. Intensive insulin therapy reduces microdialysis glucose values without altering glucose utilization or improving the lactate/pyruvate ratio after traumatic brain injury. Crit Care Med 2006, 34: 850-856.
Critical Care
Blood glucose control following severe traumatic brain injury- unclear transition from beneficial to detrimental effects
8 September 2008
In contemporary critical care it is essential to avoid induction of additional damage. This is of utmost imortance in patients with acute brain injuries. In this context, control of arterial blood glucose should be integrated in daily clinical routine. For this, however, the optimal range has not yet been defined. In addition, we are still lacking insight into time- dependent changes possibly requiring temporally adapted blood glucose levels. During the early phase disturbances in endogenous hormonal regulation, adaptation to artificial nutrition, hemodynamic instability, and activation of the systemic inflammatory response predispose patients to unpredictable changes in arterial blood glucose. Consequently, the early phase is overshadowed by an increased risk of hyperglycemic as well as insulin- induced hypoglycemic episodes. Not even sophisticated protocols could prevent insulin- induced hypoglycemia [1- 7]. Over time, as the patients become more stable, they are less prone to e.g., insulin- induced hypoglycemia. This could explain why the beneficial effects reported by van den Berghe are not observed during the first 3 [1, 2] to 5 days [3]. In our retrospective analysis beneficial effects in terms of reduced rate in infections and elevated intracranial pressure exceeding 20 mmHg were only observed after the first week [8]. During the first week there was even a significant increase in infection rate and norepinephrine requirement in patients in whom arterial blood glucose was maintained between 3.5- 6.5 compared to 5- 8 mmol/ l [8]. To date, it remains unclear whether low arterial blood glucose must be maintained within tight limits during the first 3- 7 days in these patients with the increased risk of hypoglycemia to induce subsequent beneficial effects. Thus, detailed investigations are important to determine if low arterial blood glucose maintained within tight limits after the 3rd or 7th day allowing higher limits during the first 3- 7 days will result in significant improval and reduced complications and mortality.
As pointed out by Paul M. Vespa [9] in his commentary to our retrospective analysis [8] the lowest possible blood glucose level void of detrimental effects must be determined for each individual patient. This is essential to define a detailed protocol for a prospective study to avoid adverse effects as e.g., induced cerebral metabolic distress [9], hypoglycaemia and rebound hyperglycemia. Increased rate of hypoglycemic episodes had resulted in premature termination of other trials [5] aimed at reproducing previously published positive effects of maintaining blood glucose between 4.4 and 6.1 mmol/ l [1- 3]. In an attempt to determine potentially optimal range in blood glucose levels we retrospectively investigated the concentration- dependent influence of arterial blood glucose on cerebral metabolic effects determined by microdialysis and changes in arterial- jugular venous differences (unpublished data). These new results strongly suggest that arterial blood glucose levels between 7 and 9 mmol/ l are superior to arterial blood glucose levels < 5 mmol/ l in terms of increased cerebral glucose uptake and improved cerebral metabolic stability.
Despite its simple principle of action more detailed investigations are required to characterize time-, duration-, and concentration- dependent effects of maintaining arterial blood glucose levels within certain limits in patients prone to glucose- induced brain damage.
References
1. van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, Vlasselaers D, Ferdinande P, Lauwers P, Bouillon R. Intensive insulin therapy in the critically ill patients. N Engl J Med 2001, 345: 1359-1367.
2. Van den Berghe G, Wilmer A, Hermans G, Meersseman W, Wouters PJ, Milants I, Van Wijngaerden E, Bobbaers H, Bouillon R. Intensive insulin therapy in the medical ICU. N Engl J Med 2006, 354: 449-461.
3. Van den Berghe G, Schoonheydt K, Becx P, Bruyninckx F, Wouters PJ. Insulin therapy protects the central and peripheral nervous system of intensive care patients. Neurology 2005, 64: 1348-1353.
4. Bilotta F, Caramia R, Cernak I, Paoloni FP, Doronzio A, Cuzzone V, Santoro A, Rosa G. Intensive Insulin Therapy After Severe Traumatic Brain Injury: A Randomized Clinical Trial. Neurocrit Care 2008, Epub before press
5. Brunkhorst FM, Engel C, Bloos F, Meier-Hellmann A, Ragaller M, Weiler N, Moerer O, Gruendling M, Oppert M, Grond S, Olthoff D, Jaschinski U, John S, Rossaint R, Welte T, Schaefer M, Kern P, Kuhnt E, Kiehntopf M, Hartog C, Natanson C, Loeffler M, Reinhart K; German Competence Network Sepsis (SepNet). Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med. 2008, 358: 125- 139.
6. McMullin J, Brozek J, McDonald E, Clarke F, Jaeschke R, Heels-Ansdell D, Leppert R, Foss A, Cook D. Lowering of glucose in critical care: a randomized pilot trial. J Crit Care 2007, 22: 112-118
7. Clayton SB, Mazur JE, Condren S, Hermayer KL, Strange C. Evaluation of an intensive insulin protocol for septic patients in a medical intensive care unit. Crit Care Med. 2006, 34: 2974-2978.
8. Meier R, Béchir M, Ludwig S, Sommerfeld J, Keel M, Steiger P, Stocker R, Stover JF. Differential temporal profile of lowered blood glucose levels (3.5 to 6.5 mmol/l versus 5 to 8 mmol/l) in patients with severe traumatic brain injury. Crit Care. 2008, 12: R98.
9. Vespa P, Boonyaputthikul R, McArthur DL, Miller C, Etchepare M, Bergsneider M, Glenn T, Martin N, Hovda D. Intensive insulin therapy reduces microdialysis glucose values without altering glucose utilization or improving the lactate/pyruvate ratio after traumatic brain injury. Crit Care Med 2006, 34: 850-856.
Competing interests
none