Energy and Protein Needs During Early Feeding Following Traumatic Brain Injury
Several Cochrane reviews have established a reasonable basis for early and adequate feeding following traumatic brain injury (TBI), although the number and size of the trials supporting this recommendation are limited (Perel et al., 2006; Yanagawa et al., 2002). Improvements in mortality and neurological outcome have been suggested, with a relative risk for mortality of 0.67 (0.41–1.07) for early feeding compared to not feeding and of 0.75 (0.50–1.11) for death and disability (Perel et al., 2006). In a meta-analysis of studies of nutritional support in critical illness, including studies in TBI requiring admission to an intensive care unit (ICU), and using an intent-to-treat analysis, total parenteral nutrition (TPN) was found superior to enteral nutrition in reducing mortality, although it significantly increased the risk of infection (Doig et al., 2008). However, this improvement in mortality was related to the early and adequate feeding, because of patients who were fed adequately plus early by either enteral nutrition or TPN both did better than those receiving late enteral feeding (Doig et al., 2008). Although there are other meta-analyses that did not demonstrate any difference in mortality between parenteral and enteral feeding in the critically ill (Gramlich et al., 2004; Koretz et al., 2007; Mazaki and Ebisawa, 2008; Peter et al., 2005), only Doig et al. (2008) evaluated exclusively patients in the ICU. Certainly patients with TBI are among the most critically ill in terms of degree of catabolic stress; eliminating those with less serious conditions, such as post-operative patients, when conducting meta-analyses would seem appropriate. Early feeding is generally defined as beginning within the first 24 hours after injury (Doig et al., 2009), but the definition of adequacy is still somewhat uncertain. An analysis of prospective data on the outcome of TBI related to feeding in 797 patients in 22 centers gathered by the Brain Trauma Foundation in 2008 found that mortality was significantly improved by each 10 kcal/kg increase in intake, with the curve becoming asymptotic at about 25 kcal/kg (Hartl et al., 2008). The majority of patients (62 percent) did not reach 25 kcal/kg/day within seven days. The likelihood of death for patients with TBI who were not fed within five days of injury was double that of patients who were fed, and those not fed within seven days had four times greater likelihood of death (Hartl et al., 2008). Interestingly, the benefits of early feeding were most prominent in those with elevated
intracranial pressure, suggesting that nutrition was most effective in those likely to have the greatest injury response, with attenuation of that response a potential mechanism (Hartl et al., 2008). These findings should be contrasted with the earlier general recommendations of the Brain Trauma Foundation regarding nutrition in TBI that suggested full feeding to metabolic expenditure, which might approach 50 kcal/kg by seven days postinjury (Bratton et al., 2007), with the goal of maintaining lean tissue.
Traditionally, total daily energy expenditure has been considered to be composed of basal energy expenditure, often estimated by the Harris-Benedict equations; activity energy expenditure, which is generally quite limited in hospitalized, critically ill patients; and a small component due to the thermal effect of feeding, representing about 10 percent of the total. The Harris-Benedict equations estimate energy expenditure based on height, weight, sex, and age. A rough estimate of basal energy expenditure for most patients who are not severely malnourished and who are in the same age group is approximately 22–24 kcal/kg/day. Basal energy expenditure increases with injury in proportion to the degree of systemic inflammatory response, ranging usually from 0–100 percent increases from basal expenditure (Duke et al., 1970), with a similar range in TBI (McEvoy et al., 2009). It is likely that all military personnel experiencing TBI will be of normal body composition without malnutrition or obesity. In normal subjects, total energy intake must meet energy expenditure, and provision of adequate protein (0.8 g/kg) and other essential micronutrients is needed to maintain the protein content of the body, the lean body mass. However, for the critically ill, permissive underfeeding (i.e., the modest restriction of nutrient intake, specifically in critically ill patients, over a short term) is recommended. A recent study concluded that, for critically ill patients, permissive underfeeding (60–70 percent of calculated requirement) may be associated with lower mortality rates than underfeeding (90–100 percent of calculated requirement) (Arabi et al., 2011). With severe injury such as TBI, energy intakes in the range of 25–30 kcal/kg/day are generally recommended (Cerra et al., 1997; McClave et al., 2009). Harris-Benedict values are similar at 22–24 kcal/kg, but their calculation includes the additional factors of height, sex, and age. Both values are likely to be underestimates of total energy expenditure, and less likely to promote hyperglycemia for the first two weeks of injury. It should be noted that this concept of permissive underfeeding is different from the concept of underfeeding. Underfeeding is defined as a cumulative total caloric deficit of greater than 10,000 kcal (Bartlett et al., 1982) or a caloric intake of less than nine kcal/kg/day in the first seven days postinjury (Krishnan et al., 2003); both of these situations are associated with higher mortality rates. Furthermore, with the grossly inadequate caloric intake in underfeeding, protein intakes are often even more severely limited. For instance, in the trial of intensive insulin therapy in medical patients, while the caloric intakes were in the range of 1,500 kcal/day, protein intakes were less than 15 g/day in the first three days (Van den Berghe et al., 2006). For reasonable retention of lean tissue with injury, both energy sufficient to meet at least basal energy expenditure and a greater amount of protein (up to 1.5 g/kg/day) are required (Bistrian and Babineau, 1998); even then, total sparing of lean tissue is often impossible in the acute phase of injury, due to the impact of the systemic inflammatory response on the protein catabolic rate (Jensen et al., 2010; Ling et al., 1997). The maximal amount of protein that can be utilized for protein synthesis (i.e., about 1.5 g/kg/day when accompanied by these modest energy intakes) was determined by isotope studies in severely burned individuals (Wolfe et al., 1983) and sophisticated measures of body composition change using in vivo neutron activation analysis (Ishibashi et al., 1998). A second and very important aspect of the relationship between nutrient intake and body composition during injury, including TBI, is that increasing energy intake adversely affects glucose homeostasis. When glucose intakes as TPN exceed 30 kcal/kg (or about 5 mg/kg/min,
representing 500 g of glucose per day for a 70 kg individual), the majority of hospitalized patients will have blood glucose levels greater than 200 mg/dL (Rosmarin et al., 1996). Because most patients suffering TBI, particularly military service members, are well nourished at the outset, serious protein-calorie malnutrition does not occur in the first seven days. However, because early plus adequate feeding in the critically ill can still improve outcome, the concept of permissive underfeeding (see above) has been developed (Burke et al., 2010; McCowen et al., 2000). A retrospective analysis of energy intakes and morbidity and mortality in the critically ill suggests that the middle tertile of intakes, 9–18 kcal/kg/day, provides the optimal outcome, with greater or lesser intakes associated with poorer outcomes (Krishnan et al., 2003). This strongly suggests that the mechanism for outcome improvement resulting from feeding early in the first week may be related to something other than optimal retention of lean body mass, such as providing sufficient glucose energy to meet the needs of key tissues including the brain, kidney, heart, and immune system, while maintaining protein synthetic rates for new protein synthesis, including for the immune system and tissue repair. Furthermore, permissive underfeeding may be beneficial by reducing the intensity of the systemic inflammatory response from a given level of injury (Burke et al., 2010). There is some support for this possibility in TBI, where patients receiving enhanced enteral nutrition showed lower levels of C-reactive protein than those receiving standard enteral nutrition during the first week after injury (Taylor et al., 1999). The greater likelihood of glucose homeostasis achieved with lower energy intakes may additionally reduce the known adverse impacts of hyperglycemia on morbidity and mortality outcomes in the critically ill (Fahy et al., 2009; McCowen et al., 2001; Pasquel et al., 2010). Most critically ill patients receive their invasive nutritional support by enteral nutrition rather than through TPN for a variety of reasons, including concerns about the relative safety and ease of administration of the two modes of feeding. However, enteral intakes are often limited by intestinal tolerance and temporary discontinuation for other procedures. Thus, although intakes of 25–30 kcal/kg/day are generally recommended in the critically ill (Cerra et al., 1997; McClave et al., 2009) to meet total energy expenditure and maintain lean tissue, intakes are usually substantially less than this, and generally less than 50 percent of goal (Krishnan et al., 2003), including in TBI (Hartl et al., 2008) during its initial phase. A small randomized trial of enhanced enteral feeding versus standard enteral feeding in TBI showed a significant reduction in infections and complications, with a suggestion of improved neurologic outcome (Taylor et al., 1999). Providing energy intake of at least 50 percent of energy needs up to 25–30 kcal/kg/day is likely appropriate for both the brain injury and for any associated critical injury. A corollary of this concept of permissive underfeeding is the interrelationship of energy and protein intake. When energy intakes are limited, supplying greater amounts of protein, up to 1.5 g/kg/day, will improve the preservation of lean body mass and improve protein synthetic rates (Hoffer et al., 1984; Ishibashi et al., 1998). Thus, it is beneficial to increase protein intakes when energy intake is less than energy expenditure. Because those enteral formulas generally employed have fixed compositions, either protein supplementation of present formulas or the development of new formula compositions incorporating these principles will need to be developed to test this hypothesis. Alternatively, enhanced enteral feeding techniques (Taylor et al., 1999) may need to be widely adopted. Beyond the initial two-week period, when the intensity of the systemic inflammatory response to TBI has generally remitted to some degree, attempting to provide sufficient energy to meet total energy expenditure in order to optimize protein metabolism is a reasonable goal. Estimating total energy expenditure by various formulas—including adding stress factors to the Harris-Benedict estimates—is inadequately sensitive, perhaps in part because nonseptic patients in medical ICU have less pronounced hypercatabolism than burn or trauma patients (Dickerson,
2011). Under these conditions, and particularly for patients with ventilatory support or that remain critically ill, measuring energy expenditure by indirect calorimetry is the gold standard. In patients who are recuperating well, careful assessment of energy and protein intake to meet estimated needs while monitoring weight changes at weekly intervals should suffice.
In summary, permissive underfeeding (initially 50 percent of energy needs, progressing up to 25–30 kcal/kg/day in the first 2 weeks) is probably an appropriate feeding regimen to be initiated within the first 24 hours. A protein intake higher than that recommended (approximately 1.5 g/kg/day) for the general population also will be appropriate for TBI patients in order to improve synthesis of protein and preserve lean body mass. The optimal nutritional goals beyond two weeks postinjury are not yet determined, but an attempt to meet total energy needs along with continued provision of 1.5 g of protein kg/day seems appropriate.
There is extensive literature documenting the substantial association of hyperglycemia with poorer outcomes in the critically ill (Fahy et al., 2009; McCowen et al., 2001). Whether this reflects the severity of the illness or an actual impact of hyperglycemia on pathophysiological processes is not certain and there is evidence for both factors to happen (Aljada et al., 2006; Ling et al., 2007; McCowen et al., 2001). Hyperglycemia has also been shown to have an adverse impact in TBI (Salim et al., 2009); however, because neurons are an obligate consumer of glucose, the risks presented by hypoglycemia in injured brain tissue are substantially greater than for other tissues (Oddo et al., 2008). A retrospective analysis of outcome in 380 TBI patients found increased mortality with a blood glucose < 60 mg/dL and > 160 mg/dL, unrelated to the severity of injury (Liu-DeRyke et al., 2009). Similarly, using cerebral microdialysis glucose levels, a brain energy crisis associated with much higher mortality rates was seen with tight glucose control of 80–120 mg/dL versus intermediate levels of 121–180 mg/dL (Oddo et al., 2008). Intensive insulin therapy to treat hyperglycemia has certainly been shown to reduce the intensity of the systemic inflammatory response and improve outcome (Hansen et al., 2003; Van den Berghe et al., 2001). In 2001, Van den Berghe and colleagues examined the effect of intensive insulin therapy to maintain a goal glucose level of 80–110 mg/dL in surgical patients in the ICU and showed a dramatic reduction in morbidity and mortality. This landmark article changed critical care practice significantly over the ensuing decade. The majority of patients in this study received TPN, and all received 200 g parenteral glucose per day at initiation. The most common diagnosis was cardiac surgery, which is known to particularly benefit from glucose administration. Hyperglycemia that develops with TPN correlates with morbidity and mortality (Lin et al., 2007). A subsequent study in medical ICU patients by the same group did not show improved mortality, but morbidity was improved with intensive insulin therapy (Van den Berghe et al., 2006). In this later study, patients received only enteral nutrition, had much lower energy and protein intakes, and hypoglycemia was substantially more common in the intensive insulin therapy group than in the first study (Van den Berghe et al., 2001, 2006). Subsequent large, randomized, clinical trials conducted in multiple centers were unable to confirm similar benefits using these glucose goals. The Glucontrol Study (Preiser et al., 2009), a large multi-center randomized clinical trial of intensive insulin therapy of tight (80–110 mg/dL) versus intermediate control, was discontinued prematurely beause of the high level of protocol violation (Preiser et al., 2009). Even so, there was significantly more hypoglycemia, without difference in mortality, in the tight control group in this un-
derpowered study. The Nice/Sugar Study compared tight glucose control of 81–108 mg/dL to an intermediate level of below 180 mg/dL, and also found a significantly higher risk of hypoglycemia and increased mortality in the intensive insulin therapy group (Finfer et al., 2009). There were methodological differences between the original Van den Berghe study (2001) and succeeding versions, including different target ranges for blood glucose, different accuracies of glucometers, and varying levels of expertise of the participating institutional staff (Van den Berghe et al., 2009). All randomized trials following the initial Van den Berghe study also principally used enteral nutrition rather than TPN. Subsequent trials had tighter glucose control in the control group than in the original Van den Berghe study, where the control group received insulin only when blood glucose exceeded 200 mg/dL. Recent trials have thus been comparing very tight control accompanied by a high risk of hypoglycemia, to less severe control (to about the 150 mg/dL level) having much less risk of hypoglycemia but still substantially better glucose control than in previous years. Enteral nutrition may be an important factor in the development of hypoglycemia, as intestinal absorption is frequently impaired in the critically ill, and tube feeding is often interrupted for various clinical procedures while insulin continues to be administered. Additionally, TPN at full feeding levels may provide from 300–400 g of glucose per day, which elicits much higher insulin levels than enteral nutrition with the same amount of nutrient intake (Wene et al., 1975). Insulin resistance that occurs with hyperinsulinemia may therefore be partially protective against the development of insulin-induced hypoglycemia. In the critically ill, 400–500 g of glucose per day, provided into arterial circulation by TPN, should meet cerebral metabolic needs despite maximal suppression of gluconeogenesis by insulin levels of 100–200 μU/mL elicited by TPN (Bistrian, 2011). Although hypoglycemia might sometimes arise through insulin-mediated glucose uptake in insulin-responsive tissues when assessed by venous access, this would reflect the presence of an arterial-venous glucose difference that can arise in those that are fully fed. Even though hypoglycemia might sometimes be detected in venous blood or even by capillary determinations, neuroglycopenia should be unlikely when TPN provides more than 300 g of glucose in 24 hours. This interpretation is supported by the recent reevaluation of the impact of enteral and parenteral nutrition by Van den Berghe and colleagues, combining data from both their medical and surgical studies (Bistrian, 2010; Meyfroidt and Van den Berghe, 2010). They found that glucose variability was significantly greater in enterally fed patients, and hypoglycemia 2.2 times more common than in patients receiving TPN (Meyfroidt and Van den Berghe, 2010).
The important issues concerning glucose homeostasis to be determined in TBI are whether intensive insulin therapy should be employed, and if so, what the goal level for glucose should be? It is likely that if enteral nutrition is to remain the principal mode of support, and levels of nutritional support are increased by such means as nursing algorithms, acceptance of higher residuals, and maintaining flow rates and new formulas, then mild hyperglycemia greater than 160 mg/dL will probably become more common. This situation may thus benefit from intense insulin therapy with an intermediate goal for blood glucose. Several trials of intensive insulin therapy in TBI have been conducted. One small study that sought very tight control of 80–110 mg/dL showed no short- or long-term improvement with intensive insulin therapy, with much greater incidence of hypoglycemia (82.1 percent versus 17.5 percent) (Coester et al., 2010). A second study with similar blood glucose goals also found significantly more hypoglycemia events (a median of 7 versus 15) than with less-stringent glucose control, and no change in Glasgow Outcome Score (Bilotta et al., 2008). Finally, a study in TBI patients in a Neonatal Intensive Care Unit (NICU) found improved Glasgow Outcome Scores at six months in the intensively treated group, with shorter NICU
stays and significantly reduced infections (Yang et al., 2009). Goals for levels of nutritional support and for blood glucose homeostasis therefore still remain to be firmly established.
CONCLUSIONS AND RECOMMENDATIONS
Several reviews and guidelines have established regimens for early feeding after severe trauma, including severe TBI. The use of generic critical illness guidelines for ICU patients with polytrauma is prevalent; however, development of specific sections that identify unique concerns relative to TBI may be warranted. Although further research in TBI populations is required, the committee concluded that the existing evidence on TBI raises questions about the appropriateness of the following three areas of current generic clinical practice guidelines: (1) the targets for early and adequate feeding, (2) the target range of serum glucose for tight glucose control, and (3) the type of feeding regimen for intense insulin therapy.
Current generic guidelines for critically ill patients indicate feeding to meet energy needs by day 7; however, it may be more appropriate to focus on the energy consumption within 72 hours and not 7 days. There is sufficient evidence to indicate the importance of feeding trauma patients shortly after injury. For example, in a retrospective multi-center study of TBI patients, lower mortality rates were found when patients were fed during the first five to seven days after a TBI. Such a study, however, does not provide evidence to develop best feeding practices, because feeding regimens were not uniform across centers. Although patients with severe TBI will remain in intensive care for variable amounts of time, it would be appropriate to develop best feeding practices for both the period initially following TBI, when the systemic inflammatory response is likely to be at its height, and in the later period (commencing at about two weeks), when concern about lean tissue maintenance and repletion assumes greater importance and tolerance to feeding is likely to be improved.
Critical care guidance for TBI recommends increasing the amount of calories provided beyond actual energy expenditure. The committee concluded that, although increasing the amount of calories beyond expenditure might better improve lean tissue preservation, this feeding regimen increases the risk for hyperglycemia or gastrointestinal intolerance, depending on the feeding regimen employed (parenteral nutrition or enteral nutrition, respectively). The target, therefore, may not be meeting energy needs, but rather a specified level of permissive underfeeding (i.e., the modest restriction of nutrient intake).
Maintenance of glucose above 60 mg/dL and below 150–160 mg/dL probably improves TBI outcome. Intense insulin therapy makes this achievable, but if enteral feeding is used, there is also substantial risk of hypoglycemia due to normal feeding interruptions occurring in conjunction with constant levels of insulin, variations in the rate of food absorption from the gut, and delivery of food to the liver before the systemic circulation when maintaining a narrow range of glucose (80–110 mg/dL). Because of these risks, the goal for glucose in enteral feeding with intense insulin therapy should be higher, probably 150 or 160 mg/dL. The amounts of 300–400 g/day of parenteral glucose, usually provided with the direct infusion of glucose into the systemic circulation through TPN, exceed the maximal rate of hepatic glucose production in the critically ill in the postabsorptive state. Since insulin works to lower serum glucose primarily by inhibiting hepatic glucose production and all the glucose required is already provided with TPN, hypoglycemia is unlikely under these circumstances. However, there may occasionally be much lower venous glucose levels, reflecting insulin’s effect to increase uptake of glucose in insulin-sensitive tissue. This effect is not systemic, and therefore would not be an issue unless one is concerned only with venous glucose levels. Current generic guidelines have not established whether tight control of serum glucose at 80–110 mg/dL or a slightly higher range (e.g., less than 150 mg/dL) is more appropriate
for critical illness, particularly TBI where the potential for hypoglycemia is more damaging. Thus, there may be rationale for considering a slightly higher range (e.g., less than 150 mg/dL) while factoring for variation of the range depending on the feeding regimen (i.e., enteral or parenteral). This higher level may be more consistent with clinical practice guidelines for immediate post-stroke treatment as a model of brain injury.
RECOMMENDATION 6-1. The committee recommends that evidence-based guidelines include the provision of early (within 24 hours after injury) nutrition (more than 50 percent of total energy expenditure and 1–1.5 g/kg protein) for the first two weeks after injury. This intervention is critical to limit the intensity of the inflammatory response to TBI, and to improve outcome.
RECOMMENDATION 6-2. DoD should conduct human trials to determine appropriate levels of blood glucose following TBI to minimize morbidity and mortality. These should be clinical trials of early feeding using intensive insulin therapy to maintain blood glucose concentrations at less than 150–160 mg/dL versus current usual care of severe TBI in ICU settings for the first two weeks.
RECOMMENDATION 6-3. DoD should conduct clinical trials of the benefits of insulin therapy for care of acute TBI in inpatient settings with TPN alone (or plus enteral feeding) versus enteral feeding alone. The goals for blood glucose in the TPN group should be lower (e.g., less than 120 mg/dL) than in the enteral group (e.g., less than 150–160 mg/dL). Variables to measure include clinical outcomes and incidence of hypoglycemia.
RECOMMENDATION 6-4. DoD should conduct studies to determine the optimal goals for nutrition (e.g., when to begin meeting total energy expenditure for optimal lean tissue maintenance or repletion) after the first two weeks following severe injury.
Aljada, A., J. Friedman, H. Ghanim, P. Mohanty, D. Hofmeyer, A. Chaudhuri, and P. Dandona. 2006. Glucose ingestion induces an increase in intranuclear nuclear factor kappaB, a fall in cellular inhibitor kappaB, and an increase in tumor necrosis factor alpha messenger RNA by mononuclear cells in healthy human subjects. Metabolism: Clinical and Experimental 55(9):1177–1185.
Arabi, Y. M., H. M. Tamim, G. S. Dhar, A. Al-Dawood, M. Al-Sultan, M. H. Sakkijha, S. H. Kahoul, and R. Brits. 2011. Permissive underfeeding and intensive insulin therapy in critically ill patients: A randomized controlled trial. American Journal of Clinical Nutrition 93(3):569–577.
Bartlett, R. H., R. E. Dechert, J. R. Mault, S. K. Ferguson, A. M. Kaiser, and E. E. Erlandson. 1982. Measurement of metabolism in multiple organ failure. Surgery 92(4):771–779.
Bilotta, F., R. Caramia, I. Cernak, F. P. Paoloni, A. Doronzio, V. Cuzzone, A. Santoro, and G. Rosa. 2008. Intensive insulin therapy after severe traumatic brain injury: A randomized clinical trial. Neurocritical Care 9(2):159–166.
Bistrian, B. R. 2010. Parenteral feeding and intensive insulin therapy. Critical Care Medicine 38(9):1922; author reply 1922–1923.
Bistrian, B. R. 2011. Is total parenteral nutrition protective against hypoglycemia during intense insulin therapy? A hypothesis. Critical Care Medicine (Published electronically February 10, 2011).
Bistrian, B. R., and T. Babineau. 1998. Optimal protein intake in critical illness? Critical Care Medicine 26(9):1476–1477.
Bratton, S. L., R. M. Chestnut, J. Ghajar, F. F. McConnell Hammond, O. A. Harris, R. Hartl, G. T. Manley, A. Nemecek, D. W. Newell, G. Rosenthal, J. Schouten, L. Shutter, S. D. Timmons, J. S. Ullman, W. Videtta, J. E. Wilberger, and D. W. Wright. 2007. Guidelines for the management of severe traumatic brain injury. XII. Nutrition. Journal of Neurotrauma 24(Suppl 1.):S77–S82.
Burke, P. A., L. S. Young, and B. R. Bistrian. 2010. Metabolic vs nutrition support: A hypothesis. Journal of Parenteral and Enteral Nutrition 34(5):546–548.
Cerra, F. B., M. R. Benitez, G. L. Blackburn, R. S. Irwin, K. Jeejeebhoy, D. P. Katz, S. K. Pingleton, J. Pomposelli, J. L. Rombeau, E. Shronts, R. R. Wolfe, and G. P. Zaloga. 1997. Applied nutrition in ICU patients. A consensus statement of the American College of Chest Physicians. Chest 111(3):769–778.
Coester, A., C. R. Neumann, and M. I. Schmidt. 2010. Intensive insulin therapy in severe traumatic brain injury: A randomized trial. Journal of Trauma 68(4):904–911.
Dickerson, R. N. 2011. Optimal caloric intake for critically ill patients: First, do no harm. Nutrition in Clinical Practice 26(1):48–54.
Doig, G. S., F. Simpson, S. Finfer, A. Delaney, A. R. Davies, I. Mitchell, and G. Dobb. 2008. Effect of evidence-based feeding guidelines on mortality of critically ill adults: A cluster randomized controlled trial. The Journal of the American Medical Association 300(23):2731–2741.
Doig, G. S., P. T. Heighes, F. Simpson, E. A. Sweetman, and A. R. Davies. 2009. Early enteral nutrition, provided within 24 h of injury or intensive care unit admission, significantly reduces mortality in critically ill patients: A meta-analysis of randomised controlled trials. Intensive Care Medicine 35(12):2018–2027.
Duke, J. H., Jr., S. B. Jorgensen, J. R. Broell, C. L. Long, and J. M. Kinney. 1970. Contribution of protein to caloric expenditure following injury. Surgery 68(1):168–174.
Fahy, B. G., A. M. Sheehy, and D. B. Coursin. 2009. Glucose control in the intensive care unit. Critical Care Medicine 37(5):1769–1776.
Finfer, S., D. R. Chittock, S. Y. Su, D. Blair, D. Foster, V. Dhingra, R. Bellomo, D. Cook, P. Dodek, W. R. Henderson, P. C. Hebert, S. Heritier, D. K. Heyland, C. McArthur, E. McDonald, I. Mitchell, J. A. Myburgh, R. Norton, J. Potter, B. G. Robinson, and J. J. Ronco. 2009. Intensive versus conventional glucose control in critically ill patients. The New England Journal of Medicine 360(13):1283–1297.
Gramlich, L., K. Kichian, J. Pinilla, N. J. Rodych, R. Dhaliwal, and D. K. Heyland. 2004. Does enteral nutrition compared to parenteral nutrition result in better outcomes in critically ill adult patients? A systematic review of the literature. Nutrition 20(10):843–848.
Hansen, T. K., S. Thiel, P. J. Wouters, J. S. Christiansen, and G. Van den Berghe. 2003. Intensive insulin therapy exerts antiinflammatory effects in critically ill patients and counteracts the adverse effect of low mannose-binding lectin levels. Journal of Clinical Endocrinology and Metabolism 88(3):1082–1088.
Hartl, R., L. M. Gerber, Q. Ni, and J. Ghajar. 2008. Effect of early nutrition on deaths due to severe traumatic brain injury. Journal of Neurosurgery 109(1):50–56.
Hoffer, L. J., B. R. Bistrian, V. R. Young, G. L. Blackburn, and D. E. Matthews. 1984. Metabolic effects of very low calorie weight reduction diets. Journal of Clinical Investigation 73(3):750–758.
Ishibashi, N., L. D. Plank, K. Sando, and G. L. Hill. 1998. Optimal protein requirements during the first 2 weeks after the onset of critical illness. Critical Care Medicine 26(9):1529–1535.
Jensen, G. L., J. Mirtallo, C. Compher, R. Dhaliwal, A. Forbes, R. F. Grijalba, G. Hardy, J. Kondrup, D. Labadarios, I. Nyulasi, J. C. Castillo Pineda, and D. Waitzberg. 2010. Adult starvation and disease-related malnutrition: A proposal for etiology-based diagnosis in the clinical practice setting from the international consensus guideline committee. Journal of Parenteral and Enteral Nutrition 34(2):156–159.
Koretz, R. L., A. Avenell, T. O. Lipman, C. L. Braunschweig, and A. C. Milne. 2007. Does enteral nutrition affect clinical outcome? A systematic review of the randomized trials. American Journal of Gastroenterology 102(2):412–429; quiz 468.
Krishnan, J. A., P. B. Parce, A. Martinez, G. B. Diette, and R. G. Brower. 2003. Caloric intake in medical ICU patients: Consistency of care with guidelines and relationship to clinical outcomes. Chest 124(1):297–305.
Lin, L. Y., H. C. Lin, P. C. Lee, W. Y. Ma, and H. D. Lin. 2007. Hyperglycemia correlates with outcomes in patients receiving total parenteral nutrition. American Journal of the Medical Sciences 333(5):261–265.
Ling, P. R., J. H. Schwartz, and B. R. Bistrian. 1997. Mechanisms of host wasting induced by administration of cytokines in rats. American Journal of Physiology 272(3 Pt 1):E333–339.
Ling, P. R., R. J. Smith, and B. R. Bistrian. 2007. Acute effects of hyperglycemia and hyperinsulinemia on hepatic oxidative stress and the systemic inflammatory response in rats. Critical Care Medicine 35(2):555–560.
Liu-DeRyke, X., D. S. Collingridge, J. Orme, D. Roller, J. Zurasky, and D. H. Rhoney. 2009. Clinical impact of early hyperglycemia during acute phase of traumatic brain injury. Neurocritical Care 11(2):151–157.
Mazaki, T., and K. Ebisawa. 2008. Enteral versus parenteral nutrition after gastrointestinal surgery: A systematic review and meta-analysis of randomized controlled trials in the English literature. Journal of Gastrointestinal Surgery 12(4):739–755.
McClave, S. A., R. G. Martindale, V. W. Vanek, M. McCarthy, P. Roberts, B. Taylor, J. B. Ochoa, L. Napolitano, and G. Cresci. 2009. Guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (ASPEN). Journal of Parenteral and Enteral Nutrition 33(3):277–316.
McCowen, K. C., C. Friel, J. Sternberg, S. Chan, R. A. Forse, P. A. Burke, and B. R. Bistrian. 2000. Hypocaloric total parenteral nutrition: Effectiveness in prevention of hyperglycemia and infectious complications—a randomized clinical trial. Critical Care Medicine 28(11):3606–3611.
McCowen, K. C., A. Malhotra, and B. R. Bistrian. 2001. Stress-induced hyperglycemia. Critical Care Clinics 17(1):107–124.
McEvoy, C. T., G. W. Cran, S. R. Cooke, and I. S. Young. 2009. Resting energy expenditure in non-ventilated, non-sedated patients recovering from serious traumatic brain injury: Comparison of prediction equations with indirect calorimetry values. Clinical Nutrition 28(5):526–532.
Meyfroidt, G., and G. Van den Berghe. 2010. The authors reply. Critical Care Medicine September 38(9).
Oddo, M., J. M. Schmidt, E. Carrera, N. Badjatia, E. S. Connolly, M. Presciutti, N. D. Ostapkovich, J. M. Levine, P. Le Roux, and S. A. Mayer. 2008. Impact of tight glycemic control on cerebral glucose metabolism after severe brain injury: A microdialysis study. Critical Care Medicine 36(12):3233–3238.
Pasquel, F. J., R. Spiegelman, M. McCauley, D. Smiley, D. Umpierrez, R. Johnson, M. Rhee, C. Gatcliffe, E. Lin, E. Umpierrez, L. Peng, and G. E. Umpierrez. 2010. Hyperglycemia during total parenteral nutrition: An important marker of poor outcome and mortality in hospitalized patients. Diabetes Care 33(4):739–741.
Perel, P., T. Yanagawa, F. Bunn, I. Roberts, R. Wentz, and A. Pierro. 2006. Nutritional support for head-injured patients. Cochrane Database of Systematic Reviews (4):CD001530.
Peter, J. V., J. L. Moran, and J. Phillips-Hughes. 2005. A metaanalysis of treatment outcomes of early enteral versus early parenteral nutrition in hospitalized patients. Critical Care Medicine 33(1):213–220; discussion 260–211.
Preiser, J. C., P. Devos, S. Ruiz-Santana, C. Melot, D. Annane, J. Groeneveld, G. Iapichino, X. Leverve, G. Nitenberg, P. Singer, J. Wernerman, M. Joannidis, A. Stecher, and R. Chiolero. 2009. A prospective randomised multi-centre controlled trial on tight glucose control by intensive insulin therapy in adult intensive care units: The Glucontrol study. Intensive Care Medicine 35(10):1738–1748.
Rosmarin, D. K., G. M. Wardlaw, and J. Mirtallo. 1996. Hyperglycemia associated with high, continuous infusion rates of total parenteral nutrition dextrose. Nutrition in Clinical Practice 11(4):151–156.
Salim, A., P. Hadjizacharia, J. Dubose, C. Brown, K. Inaba, L. S. Chan, and D. Margulies. 2009. Persistent hyperglycemia in severe traumatic brain injury: An independent predictor of outcome. American Surgeon 75(1):25–29.
Taylor, S. J., S. B. Fettes, C. Jewkes, and R. J. Nelson. 1999. Prospective, randomized, controlled trial to determine the effect of early enhanced enteral nutrition on clinical outcome in mechanically ventilated patients suffering head injury. Critical Care Medicine 27(11):2525–2531.
Van den Berghe, G., P. Wouters, F. Weekers, C. Verwaest, F. Bruyninckx, M. Schetz, D. Vlasselaers, P. Ferdinande, P. Lauwers, and R. Bouillon. 2001. Intensive insulin therapy in the critically ill patients. The New England Journal of Medicine 345(19):1359–1367.
Van den Berghe, G., A. Wilmer, G. Hermans, W. Meersseman, P. J. Wouters, I. Milants, E. Van Wijngaerden, H. Bobbaers, and R. Bouillon. 2006. Intensive insulin therapy in the medical ICU. The New England Journal of Medicine 354(5):449–461.
Van den Berghe, G., M. Schetz, D. Vlasselaers, G. Hermans, A. Wilmer, R. Bouillon, and D. Mesotten. 2009. Clinical review: Intensive insulin therapy in critically ill patients: Nice-sugar or leuven blood glucose target? Journal of Clinical Endocrinology and Metabolism 94(9):3163–3170.
Wene, J. D., W. E. Connor, and L. DenBesten. 1975. The development of essential fatty acid deficiency in healthy men fed fat-free diets intravenously and orally. Journal of Clinical Investigation 56(1):127–134.
Wolfe, R. R., R. D. Goodenough, J. F. Burke, and M. H. Wolfe. 1983. Response of protein and urea kinetics in burn patients to different levels of protein intake. Annals of Surgery 197(2):163–171.
Yanagawa, T., F. Bunn, I. Roberts, R. Wentz, and A. Pierro. 2002. Nutritional support for head-injured patients. Cochrane Database of Systematic Reviews (3):CD001530.
Yang, M., Q. Guo, X. Zhang, S. Sun, Y. Wang, L. Zhao, E. Hu, and C. Li. 2009. Intensive insulin therapy on infection rate, days in NICU, in-hospital mortality and neurological outcome in severe traumatic brain injury patients: A randomized controlled trial. International Journal of Nursing Studies 46(6):753–758.