A prominent component of the hypermetabolic stress response is hyperglycemia. 1 Stress-induced hyperglycemia results from both an increase in hepatic gluconeogenesis and a resistance to the action of insulin in skeletal muscle (i.e., a decrease in peripheral glucose uptake). 2 Theoretically, the purpose of these metabolic alterations is to increase glucose availability as an energy source for glucose-dependent tissues, thus supporting the inflammatory response and wound healing. However, recent investigations have demonstrated that elevations in plasma glucose concentration impair immune function by altering cytokine production from macrophages, diminishing lymphocyte proliferation, and depressing intracellular bactericidal activity of leukocytes. 3–6 Furthermore, glucose concentrations above 220 mg/dL have been shown to glycosylate immunoglobulins, causing a significant reduction in opsonic activity. 7 These molecular and biochemical studies thus provide strong support of the long-held clinical belief that hyperglycemia predisposes a patient to infection and, once infected, impedes that patient’s ability to recover. There is also a well-documented impairment in wound healing in patients with diabetes mellitus. 8,9 Recent in vivo work has demonstrated that in experimentally induced diabetic animals with uncontrolled hyperglycemia, the tensile strength of a wound is significantly diminished. 10 These researchers have also shown that normalization of blood glucose in these diabetic animals ameliorated this impairment in tensile burst strength, thus providing substantial evidence for a hyperglycemic-induced detriment in wound healing. With the vast majority of severely burned patients dying from infectious complications and wound healing so critical for recovery, 11 victims of severe burn injury appear especially susceptible to the ravages of hyperglycemia and as a group most likely to demonstrate any clinical ramifications of a persistent elevation in plasma glucose. Thus, the purpose of this study was to determine whether the extent and severity of hyperglycemia correlates with any change in the frequency of infectious complications, the rate of wound healing, or any detriment in outcome in critically burned patients.
MATERIALS AND METHODS
Review of the medical records from January 1996 to July 1999 identified 58 patients admitted to the Shriners Burns Hospitals for Children in Galveston, Texas, with total body surface area burns greater than 60%. All patients were less than 18 years of age and were treated in a similar manner with early excision and skin grafting, exclusive use of enteral nutrition, and perioperative use of broad-spectrum antibiotics. No child was known to have diabetes or any abnormality in glucose before their burn injury. All plasma glucose values and microbiology data acquired during the entire hospitalization of these patients were obtained from a computerized laboratory database. Quantitative wound cultures were considered positive for infection if ≥ 105 organisms/g were identified. 12 Information on daily caloric and protein intake was obtained from review of dietary records from the nutrition service. Determination of skin graft take was obtained from review of the medical records. Specifically, physicians’ and/or nurses’ notations of graft take on removal of the operative wound dressings (usually on postoperative day 4 or 5) or comparison of operative records for body areas requiring reautografting were used to index graft take. The numbers of skin grafting procedures, and wound culture and blood culture findings were then indexed by the length of hospital stay in days. Information on which patients received subcutaneous insulin by a sliding scale regimen or were given insulin intravenously was obtained directly from pharmaceutical records. Identification of which patients received growth hormone was also obtained from review of pharmaceutical records.
Patients were divided into those deemed to have poor glucose control as defined as having over 40% of all plasma glucose values ≥ 7.8 mmol/L (140 mg/dL), and compared with patients deemed to have adequate control of their plasma glucose (i.e., ≤ 40% of all plasma glucose values were ≥ 7.8 mmol/L). The 7.8 mmol/L value is considered the threshold value for an abnormal plasma glucose concentration at our institution. Segregation of subjects at 40% was chosen arbitrarily with the intent to clearly identify that group of burn patients with frequent, pervasive hyperglycemia.
Student’s t test assuming unequal variance was used for statistical comparison between hyperglycemic versus normoglycemic patients for microbiology, dietary, and demographic data. Fisher’s exact test was used for statistical comparison of mortality and pharmacologic data. Values were considered significant for p ≤ 0.05.
As defined as over 40% of all plasma glucose ≥ 7.8 mmol/L (140 mL/dl), there were 33 severely burned patients with poorly controlled plasma glucose during their acute hospitalization. In contrast, 25 burned children were deemed to have adequate control of their plasma glucose (i.e., ≤ 40% of all glucose values were ≥ 7.8 mmol/L). These two groups were statistically similar in age, body size, and extent of burn (Table 1). Daily intake of protein and total calories was also similar between those patients with poorly and adequately controlled plasma glucose (Table 1). There was a trend toward a reduced length of hospital stay in those patients with poor glucose control (p = 0.072). When only comparing survivors, the length of stay was similar. There was a significant difference in the extent and severity of hyperglycemia between these two groups as defined as the percentage of glucose values ≥ 11.1 mmol/L (200 mg/dL) and 16.7 mmol/L (300 mg/dL) (Fig. 1). Patients with hyperglycemia did receive intravenous insulin and subcutaneous insulin by a sliding scale regimen with greater frequency than those patients deemed to have adequate glucose control (Table 2). The frequency of growth hormone administration was similar between patient groups.
With regard to infectious complications, the percentage of wound cultures with > 105 organisms/g concentration for gram-positive organisms, gram-negative organisms, and yeast were similar between poorly and adequately controlled glucose groups (Fig. 2). Furthermore, the percentage of wound biopsies without infection (i.e. <105 organisms/g) was similar between groups. Even when indexed by the length of hospital stay, these patient groups were similar in the number of infected wounds. The percentage of blood cultures positive for gram-positive and gram-negative organisms was also similar regardless of glucose control (Fig. 2). However, there was a statistically greater frequency of fungemia in those patients deemed hyperglycemic. When indexed by length of hospital stay, patients with hyperglycemia had a significantly greater incidence of bacteremia and fungemia compared with patients with adequate glucose control (Fig. 3).
When indexed by length of hospital stay, hyperglycemic patients underwent statistically more skin grafting procedures than did their normoglycemic counterparts (Table 3). Furthermore, the percentage of graft take for each procedure was significantly less in the hyperglycemic patients. Mortality was significantly greater in those patients with poor glucose control (Table 3).
Hyperglycemia is a common problem after severe injury. 1 For example, in this survey, well over 50% of these severely burned children had persistently elevated plasma glucose during a significant percentage of their hospitalization. This is especially noteworthy considering that these otherwise normal size children, unlike their frequently overweight adult counterparts, typically have exceedingly well-controlled glucose values. 13 The persistence of this injury-induced hyperglycemia is even more striking considering the frequent use of insulin regimens in these patients. Since the intent to control plasma glucose with insulin was far more frequent in those patients with hyperglycemia, the abnormally elevated glucose does not appear related to any overt neglect from the physicians. Furthermore, since caloric intake between poorly and adequately controlled glucose patient groups was similar, this pervasive hyperglycemia is not merely a mismatch in caloric, nutrient administration. Thus, these findings suggest that the elevated plasma glucose in these burn victims is related to a selective intolerance of nutritional support intertwined with the hypermetabolic response to injury.
This study demonstrates that regardless of cause or effect, persistent hyperglycemia after severe injury is associated with a detrimental outcome clinically. A contributing factor to this adverse outcome may be a hyperglycemia-induced detriment in antimicrobial defense. Numerous studies have demonstrated deficits in immunity induced by elevations in plasma glucose. 4,5,14 For example, Black et al. have shown a depression in opsonic activity mediated by nonenzymatic glycosylation of circulating immunoglobulins that form after even brief intervals of hyperglycemia. 7 Furthermore, several molecular and biochemical studies have reported impairment in macrophage and lymphocyte function related to hyperglycemia. 3,4 Such laboratory findings support the contention of an impaired immunity associated with elevated plasma glucose that results clinically in a greater number and increased severity of infections similar to that seen in patients with diabetes mellitus. 15,16 This study demonstrates that despite the comparable incidence of wound infections, as defined as a set concentration of organisms within wound tissue, those patients with persistently elevated plasma glucose had a greater incidence of identifying those organisms within blood. Although bacteremia and/or fungemia may have in some way perpetuated the hyperglycemia, an alternative interpretation of this finding would suggest that hyperglycemia, with an associated impairment in immunity, led to a subsequent inability to contain or promptly clear those invading organisms. Thus, a hyperglycemia-induced detriment in immune function results in an incompetence of the wound barrier that, ergo, manifests as an increased incidence of bacteremia and fungemia. Therefore, as in diabetics with their noted increased incidence of infections, severely injured patients exhibiting hyperglycemia also appear to have a detriment in immunity, with an associated increased susceptibility to infection and a decreased ability to clear that infection once present.
Another apparent detrimental consequence of hyperglycemia is a delay in wound healing. Prior reports have evidenced retarded wound healing in patients with diabetes mellitus. 17 Furthermore, Verhofstad and Hendriks demonstrated that control of blood glucose before and then after bowel anastomosis in otherwise hyperglycemic diabetic rats normalized wound tensile strength. 10 The study by Verhofstad and Hendriks provides strong evidence of a hyperglycemia-induced detriment to wound healing. This study demonstrated that operative debridement and skin grafting was performed more frequently and the percentage of graft take was significantly less in those patients with hyperglycemia. Although it is plausible that a greater percentage of open wounds perpetuated the hypermetabolic response and hyperglycemia, it is also very probable that the more frequent requirement for debridement and poor graft take was a consequence of impaired wound healing in those patients with poor glucose control.
With infectious complications having a major influence on survival and wound healing of such importance in recovery, any detriment in either aspect is likely to have a significant impact on outcome in victims of severe burn injury. This study clearly demonstrates a markedly worse survival in those burn patients with persistent hyperglycemia, presumably because of apparent deficiencies in immune function and wound healing. However, since hyperglycemia may be simply a marker reflecting an underlying physiologic derangement, which then predisposes to the observed higher mortality, a direct cause-and-effect relationship between poor glucose control and increased mortality cannot be ascertained from this study. Although this cause-and-effect relationship has been debated for some time, an expanding knowledge at the molecular level has frequently implicated excess glucose as toxic, thus suggesting the importance of normalizing plasma glucose concentrations. 18,19 Such intensive treatment is now being advocated for patients with insulin-dependent diabetes mellitus, where improved glucose control has been shown to slow the progression of diabetic retinopathy, nephropathy, and neuropathy. 20 As evidenced in this recent long-term diabetic study, episodes of hypoglycemia did occur more frequently in those patients undergoing the aggressive insulin regimen. Inducing hypoglycemia and its potential for adverse events is surely a major concern with implementing aggressive insulin therapy in severely injured patients. However, such a concern may be minimized by the frequent monitoring available in an intensive care setting. Regardless, the findings of this study highlight that hyperglycemia is an important risk factor that can adversely affect survival in severely burned patients. Although it is unknown whether more aggressive regimens to normalize glucose values may be warranted in critically injured patients, the association between persistent hyperglycemia and subsequent mortality in severely burned patients is evident, and a more intense focus on minimizing hyperglycemia in critically ill patients deserves strong consideration.
1. Tredget EE, Yu YM. The metabolic effects of thermal injury. World J Surg. 1992; 16: 68–79.
2. Jahoor F, Herndon DN, Wolfe RR. Role of insulin and glucagon in the response of glucose and alanine kinetics in burn-injured patients. J Clin Invest. 1986; 78: 807–814.
3. Losser MR, Bernard C, Beaudeux JL, Pison C, Payen D. Glucose modulates hemodynamic, metabolic, and inflammatory responses to lipopolysaccharide in rabbits. J Appl Physiol. 1997; 83: 1566–1574.
4. Reinhold D, Ansorge S, Schleicher ED. Elevated glucose levels stimulate transforming growth factor-beta 1 (TGF-beta 1), suppress interleukin IL-2, IL-6 and IL-10 production and DNA synthesis in peripheral blood mononuclear cells. Horm Metab Res. 1996; 28: 267–270.
5. Gregory R, McElveen J, Tattersall RB, Todd I. The effects of 3-hydroxybutyrate and glucose on human T cell responses to Candida albicans. FEMS Immunol Med Microbiol. 1993; 7: 315–320.
6. Moises RS, Heidenreich KA. Glucose regulates the expression of Gi-proteins in cultured BC3H-1 myocytes. Biochem Biophys Res Commun. 1992; 182: 1193–1200.
7. Black CT, Hennessey PJ, Andrassy RJ. Short-term hyperglycemia depresses immunity through nonenzymatic glycosylation of circulating immunoglobulin. J Trauma. 1990; 30: 830–832.
8. Moulin V, Lawny F, Barritault D, Caruelle JP. Platelet releasate treatment improves skin healing in diabetic rats through endogenous growth factor secretion. Cell Mol Biol (Noisy-le-grand). 1998; 44: 961–971.
9. Brown DL, Kao WW, Greenhalgh DG. Apoptosis down-regulates inflammation under the advancing epithelial wound edge: delayed patterns in diabetes and improvement with topical growth factors. Surgery. 1997; 121: 372–380.
10. Verhofstad MH, Hendriks T. Complete prevention of impaired anastomotic healing in diabetic rats requires preoperative blood glucose control. Br J Surg. 1996; 83: 1717–1721.
11. Wolf SE, Rose JK, Desai MH, Mileski JP, Barrow RE, Herndon DN. Mortality determinants in massive pediatric burns: an analysis of 103 children with > or = 80% TBSA burns (> or = 70% full-thickness). Ann Surg. 1997; 225: 554–565.
12. Heggers JP. Natural host defense mechanisms. Clin Plast Surg. 1979; 6: 505–513.
13. Desai D, March R, Watters JM. Hyperglycemia after trauma increases with age. J Trauma. 1989; 29: 719–723.
14. Baxter JK, Barbineau TJ, Apovian CM, et al. Perioperative glucose control predicts increased nosocomial infection in diabetics. Crit Care Med. 1990; 18: S207.
15. Zerr KJ, Furnary AP, Grunkemeier GL, Bookin S, Kanhere V, Starr A. Glucose control lowers the risk of wound infection in diabetics after open heart operations. Ann Thorac Surg. 1997; 63: 356–361.
16. Rayfield EJ, Ault MJ, Keusch GT, Brothers MJ, Nechemias C, Smith H. Infection and diabetes: the case for glucose control. Am J Med. 1982; 72: 439–450.
17. McMurry JF Jr. Wound healing with diabetes mellitus. Better glucose control for better wound healing in diabetes. Surg Clin North Am. 1984; 64: 769–778.
18. Porte D Jr. Diabetes complications: why is glucose potentially toxic? Science. 1996; 272: 699–700.
19. Skyler JS. Diabetic complications: the importance of glucose control. Endocrinol Metab Clin North Am. 1996; 25: 243–254.
20. The Diabetes Control, and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993; 329: 977–986.