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Medical Department M (Endocrinology and Diabetes), Aarhus University Hospital (T.K.H., J.S.C.), and Department of Medical Microbiology and Immunology, University of Aarhus (S.T.), DK-8000 Aarhus, Denmark; and Department of Intensive Care Medicine, University of Leuven (P.J.W., G.V.d.B.), B-3000 Leuven, Belgium
Address all correspondence and requests for reprints to: Prof. Greet Van den Berghe, Department of Intensive Care Medicine, University of Leuven, B-3000 Leuven, Belgium. E-mail: greta.vandenberghe{at}med.kuleuven.ac.be.
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Abstract |
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From a study of 1548 patients randomly assigned to either conventional treatment or intensive insulin therapy at an intensive care unit (ICU) we included all 451 patients who needed prolonged intensive care (>5 d). CRP and MBL concentrations were measured on admission, d 5, d 15, and the last day in the ICU.
In all patients, serum MBL concentrations increased with time in the ICU (P < 0.0001). This acute phase response was suppressed by intensive insulin therapy at all time points studied (P < 0.02). Selectively in patients receiving conventional therapy, MBL concentrations at baseline were almost 3 times higher in survivors than in nonsurvivors (P = 0.04). Baseline CRP concentrations were elevated, but decreased with time in ICU (P < 0.0001). The decrease in CRP was significantly more pronounced in the intensive insulin-treated patients compared with the conventionally treated patients (P 
0.02) at all time points. Multivariate logistic regression analysis, corrected for all other determinants of outcome, revealed that the antiinflammatory action on CRP, but not on MBL, largely explained the beneficial effects of intensive insulin therapy on morbidity and mortality.
In conclusion, intensive insulin therapy exerts a powerful antiinflammatory effect during critical illness which at least partially explains improvement in morbidity and mortality. Possible adverse effects of low baseline MBL are overcome by intensive insulin therapy.
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Introduction |
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Within the last few years, two large scale studies of different hormone therapies have yielded remarkable results. Intensive insulin therapy to maintain normoglycemia during intensive care resulted in significant reductions in morbidity and mortality (1), whereas high dose GH treatment almost doubled mortality compared with placebo (2). In both studies the effects on mortality were present among patients receiving prolonged (>5 d) intensive care and were predominantly related to sepsis, inflammation, and lethal, multiple organ failure, but the exact mechanisms behind the opposite actions of insulin and GH remain speculative.
Serum levels of acute phase proteins, which are synthesized in the liver, can serve as indicators of the presence and extent of inflammation and tissue necrosis. Some of these proteins also have intrinsic antimicrobial properties and have been linked to innate immunity and host defense. C-Reactive protein (CRP) is the most prominent member of the first group (4), whereas mannose-binding lectin (MBL; also known as mannan-binding lectin) belongs to the latter.
Measurements of CRP concentrations are widely used to help clinicians differentiate between inflammatory and noninflammatory conditions and to monitor the course of a large number of diseases (4). The exact pathophysiological role of CRP in the inflammatory process remains unclear, but may involve binding to ligands such as polysaccharides found on the surface of bacteria and necrotic tissue, and activation of leukocytes and the complement system (5).
MBL plays an important role in innate immunity by recognizing and initiating opsonization of microorganisms (6). As a C-type lectin, MBL can bind specifically to patterns of terminal nonreducing sugars, including N-acetylglucosamine, mannose, and fucose. MBL binds to such carbohydrate structures on the surface of microorganisms, upon which it initiates complement activation through association with serine proteases (MBL-associated serine protease-1, -2, and -3) (7, 8, 9). This complex activates the complement system at the levels of C4 and C2 in a series of interactions that has been termed the lectin pathway of complement activation. The average serum concentration of MBL in the adult population is between 1000–2000 µg/liter, with very large variations (6). The between-subject differences in serum concentrations are primarily caused by genetic factors, and point mutations within exon 1 as well as in the promoter region of the MBL gene occur with high incidence. As a consequence, approximately one third of the population has MBL concentrations below 500 µg/liter, and more than 10% have concentrations below 50 µg/liter (10). Normally within-subject variations in MBL levels are very small (11), but serum concentrations increase during acute phase responses (12) and can be specifically induced by GH administration (11). However, although the genetically determined between-subject variations in basal MBL levels cover several orders of magnitude, the within-subject changes caused by acute phase responses or induced by GH are far smaller. Deficiency of MBL is associated with an increased incidence of infections (13, 14, 15, 16), but due to the redundancy of the immune system the increased risk may only be apparent if other coexisting immunological abnormalities are present. In line with this, it was recently reported that low levels of MBL in patients receiving cancer chemotherapy are associated with an increased frequency of febrile neutropenic episodes and severe infections (17, 18). The impact of MBL concentrations on the course of disease in otherwise immunocompetent critically ill patients has not been studied.
We here investigated whether low baseline MBL levels affect outcome in critically ill patients. Furthermore, as both MBL and CRP have pronounced and distinctive interactions with the complement system and leukocyte activity, and excessive inflammation may contribute to organ failure and death, we studied the effect of intensive insulin therapy on these inflammatory markers and documented their impact on outcome.
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Subjects and Methods |
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Study design
From the total study population of 1548 patients, we included all patients who received intensive care for more than 5 d, which was the group in which the mortality benefit of intensive insulin therapy occurred (1). Upon ICU admission, all patients were randomly assigned to receive either intensive or conventional insulin therapy. Insulin (Actrapid HM, Novo Nordisk, Copenhagen, Denmark) was administered as an insulin infusion (50 IU Actrapid HM in 50 ml 0.9% sodium chloride) using an infusion pump (Perfusor-FM, B. Braun, Melsungen, Germany). In the intensive treatment group the insulin infusion was started if blood glucose levels exceeded 6.1 mmol/liter and was adjusted to keep blood glucose between 4.4–6.1 mmol/liter, whereas in the conventional treatment group the insulin infusion was started at blood glucose levels above 12 mmol/liter and was adjusted to keep blood glucose between 10–11 mmol/liter (Fig. 1
).
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4,000 cells/µl) or leukocytosis (
12,000 cells/µl) was present and the number of days during which an episode of hypothermia (36 C) or hyperthermia (38 C) occurred were also analyzed. The incidence of acute renal failure requiring renal replacement therapy was recorded. Weekly electromyography screenings were performed for the diagnosis of critical illness polyneuropathy. The occurrence at any time during ICU stay of a positive electromyography for critical illness polyneuropathy, as defined by an electrophysiologist who was blinded for treatment allocation, was analyzed. The cause of death for all patients who died was established clinically by the attending physician and was confirmed on postmortem examination by a pathologist who was unaware of treatment assignment. MBL and CRP measurements
Blood samples were drawn within 24 h after admission to the ICU (baseline), and subsequently on d 5 and 15 and/or the last day of intensive care (i.e. the day of discharge or death) for determination of serum MBL and CRP. Samples at all time points were available in 203 of 209 patients who stayed in the ICU for more than 15 d, whereas complete sets of samples from baseline, d 5, and last day were available in 439 patients.
Serum MBL concentrations were measured in all available samples by an investigator who was blinded for treatment allocation using an in-house, time-resolved immunofluorometric assay (20). In brief, microtiter wells were coated with mannan, followed by incubation with diluted samples. After washing, europium-labeled monoclonal anti-MBL antibody (131-1, Immunolex, Copenhagen, Denmark) labeled with europium using reagents from Wallac, Inc. (Turku, Finland) was added, and after incubation and washing the amount of bound labeled antibody was assessed by time-resolved fluorometry (Delphia, Wallac, Inc.). Serum CRP concentrations were measured by immunoturbidimetric assay (Roche-Itachi-Modular-P, Roche, Basel, Switzerland). Normal CRP levels in healthy volunteers are below 5 mg/liter.
Statistical analysis
Differences between intervention groups were evaluated by Mann-Whitney U and 
2 tests. Changes in MBL and CRP concentrations over time during the ICU stay were analyzed by Friedman’s test for several related samples. Spearman correlation with two-tailed probability values was used to estimate the strength of association between variables. The impact of randomization schedule and baseline MBL and CRP levels on outcome variables (mortality, acute renal failure, bacteremia, prolonged need for antibiotic treatment, and polyneuropathy) was assessed by multivariate logistic regression analysis. In addition, multivariate logistic regression analysis was used to assess whether the changes in MBL and CRP over time explained clinical outcome variables. Data are given as medians with interquartile ranges unless specified otherwise, and statistical significance was assumed for P < 0.05. All statistical calculations were performed with StatView 5.0.1 for Macintosh (SAS Institute, Inc., Cary, NC).
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Results |
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The 451 patients who required intensive care for more than 5 d (long-stay patients) were included for this analysis. These patients needed intensive care for a median of 20 d [interquartile range (IQR), 9–24], and their mean age at ICU admission was 61 ± 15 yr. The 208 patients who had been randomized to intensive insulin therapy received insulin throughout the ICU stay at a median dose of 70 IU/d (IQR, 47–93), whereas 124 of the 243 patients in the conventional treatment group received insulin for 41% (IQR, 14–92%) of the ICU stay at a median dose of 32 IU/d (IQR, 14–58) on the days insulin was given. There were no significant differences in age, sex, body mass index, reason for intensive care, or severity of illness scores between the 2 treatment groups on admission.
As previously reported (1), 71 of these long-stay patients died during intensive care. The cause of death was multiple organ failure with or without a proven septic focus in 83% of the cases, acute cardiovascular collapse in 13%, and severe brain damage in 4% of the cases. In the intensive insulin therapy group, the mortality during intensive care was significantly lower than in the conventional treatment group (10.6% vs. 20.2%; P = 0.005) (1). The incidence of acute renal failure requiring replacement therapy was reduced from 24% to 15% (P = 0.01) by intensive insulin therapy, and the incidence of critical illness polyneuropathy decreased form 45% to 22% (P < 0.0001).
Bacteremia occurred in 15% of intensive insulin-treated, long-stay patients compared with 25% of the conventionally treated patients (P = 0.01). Of all positive blood cultures, 34% were polymicrobial, with coagulase-negative staphylococci, enterococcus species, and nonfermenting, Gram-negative bacilli being the most frequently isolated pathogens. There were no significant differences in causative pathogens between the 2 study groups. A total of 445 patients received treatment with antibiotics for a median duration of 10 d (IQR, 6–18). Intensive insulin therapy significantly reduced the duration of antibiotic treatment from a median of 12 d (IQR, 6–21) to 9 d (IQR, 6–16; P = 0.002). Intensive insulin therapy also reduced the number of days during which leukopenia or leukocytosis was present from a median of 6 d (IQR, 2–13) to 4 d (IQR, 1–10; P = 0.02) and the number of days with hypo- or hyperthermia from a median of 10 d (IQR, 5–16) to 7 d (IQR, 4–11; P = 0.0004) independent of its preventive effect on bloodstream infections.
Serum MBL concentrations
Upon ICU admission, the average serum MBL concentration was 1019 µg/liter (median, 726 µg/liter; IQR, 245-1520), which is comparable with the level documented in healthy Danish and British subjects (6, 11). Admission MBL concentrations were identical in both insulin therapy groups [724 µg/liter (IQR, 255-1520) in the intensive insulin-treated group and 820 µg/liter (IQR, 241-1518) in the conventionally treated group; P = 0.96]. Also, the number of patients with a baseline MBL level below 500 µg/liter and the number with baseline MBL below 50 µg/liter was equal in both study groups (41% and 9.8%, respectively, in the intensive insulin group and 40% and 8.9%, respectively, in the conventionally treated group; P = 0.9 and P = 0.8, respectively).
Overall, baseline MBL levels tended to be lower in nonsurvivors (median, 550 µg/liter; IQR, 190-1390) than in survivors (median, 738 µg/liter; IQR, 260-1675; P = 0.13). In a subanalysis of the 243 conventionally treated patients, nonsurvivors revealed significantly lower baseline MBL concentrations compared with survivors [387 µg/liter (IQR, 190-1289) vs. 897 µg/liter (IQR, 246-1686), respectively; P = 0.04; Table 1]. The association between low levels of MBL and increased risk of death was even stronger on d 5 (P = 0.012) and on the last day in the ICU (P = 0.002). Likewise, the fraction of conventionally treated patients with MBL concentrations below 500 µg/liter was 54% among nonsurvivors compared with 36% among survivors (P = 0.02).
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In all patients regardless of treatment group, MBL concentrations increased significantly with time in intensive care (P < 0.0001; Fig. 2). This rise was independent of the baseline MBL concentration and was mostly attributable to the survivors, with the highest relative increases in serum MBL concentrations observed in the conventionally treated survivors. Intensive insulin therapy blunted the rise in serum MBL levels significantly at all time points (Fig. 3). However, the beneficial effect of insulin on mortality and morbidity was not significantly related to the suppressive effect on serum MBL concentrations, as indicated by multivariate logistic regression analysis (Table 2). The suppressive effect of insulin on MBL levels was present even among survivors without bloodstream infections (n = 155 in the intensive treatment group and n = 145 in the conventional treatment group; P < 0.05 at all time points; data not shown). Regardless of treatment group, patients who developed bacteremia revealed a lower relative increase in MBL levels on d 15 compared with those who did not develop bacteremia (P 0.02).
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Serum CRP concentrations upon ICU admission were equally elevated in both study groups [median 132 µg/liter; interquartile range, 64–217) in the intensive insulin group and median 135 µg/liter (interquartile range, 70–214) in the conventionally treated group; P = 0.8] and were equal in survivors and nonsurvivors. It was the insulin therapy group, and not the baseline CRP level, that significantly determined the risk of bacteremia, polyneuropathy, acute renal failure, and mortality, as indicated by multivariate logistic regression analysis. Both a high baseline CRP level and being randomized to the conventional insulin therapy group significantly and independently increased the risk of prolonged (>10 d) antibiotic treatment and of prolonged inflammation, as indicated by multivariate logistic regression analysis.
The acute phase CRP response started to level off after d 5 in both groups (Fig. 4). Intensive insulin therapy significantly suppressed serum CRP concentrations at all time points (Fig. 4), an effect that was also present in those patients who did not develop bacteremia. The suppressive effect of intensive insulin therapy on CRP after d 5 at least partially explained its beneficial effect on acute renal failure and mortality, but not polyneuropathy (Table 2
), as indicated by multivariate logistic regression analysis, which is in contrast to the effect of insulin on serum MBL concentrations. Indeed, after correction for other risk factors and compared with a CRP level of less than 50 mg/liter, the relative risk of death increased 41-fold (95% confidence interval, 11–160) for a CRP concentration exceeding 200 mg/liter on the last day of intensive care (P < 0.0001; Fig. 5). On d 15 and on the last day, nonsurvivors in both study groups had equally high CRP levels, which were significantly higher than the CRP levels in conventionally and intensively insulin-treated survivors, with the suppressive effect of insulin on CRP levels also present among survivors only (Table 1).
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= 0.43; P < 0.0001) and hypo-/hyperthermia ( = 0.46; P < 0.0001). There were no significant correlations between the relative changes in MBL and CRP from baseline at any time point. |
Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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More than two thirds of patients admitted to intensive care units develop signs of the systemic inflammatory response syndrome (22), caused by either infection or tissue damage, and a substantial number of these patients progress to shock and multiple organ failure. Stress hyperglycemia is a prominent feature in critically ill patients. Maintaining normoglycemia with insulin significantly prevented multiple organ failure and bloodstream infections, and shortened the duration of antibiotic treatment, the number of days with leukopenia/leukocytosis, and the duration of hypo-/hyperthermia; together these resulted in less lethality. Whether these beneficial effects are attributable to the prevention of hyperglycemia, the increased availability of insulin, or a combination of both remains speculative. Multivariate logistic regression analysis revealed that the antiinflammatory effect of intensive insulin therapy, as indicated by the lowering of circulating CRP, to a large extent explained the prevention of acute renal failure and mortality. Although, theoretically, suppression of the acute phase CRP response with insulin could be a secondary phenomenon to its effect on severe infections and mortality, it was present even among uninfected survivors, which points to a direct antiinflammatory effect. In rat hepatoma cells, insulin has been shown to inhibit cytokine-induced transcription of acute phase proteins (23). However, in the current study, the direct hepatic effects of insulin cannot with certainty be distinguished from its effects on glycemic control, as both occurred concomitantly. In patients with type II diabetes, treatment with insulin, but not improved glycemic control per se, has been shown to reduce circulating CRP (24), which is in favor of a direct effect of insulin on the hepatic acute phase response. Insulin is indeed emerging as a molecule with strong antiinflammatory properties, suppressing the generation of a range of early proinflammatory substances, including TNF
, macrophage migration inhibitory factor, superoxide anions, and intranuclear nuclear factor-
B (25, 26). A recent study, however, showed that short-term hyperinsulinemia per se can also induce proinflammatory responses in euglycemic healthy volunteers (27). In addition, hyperglycemia has been shown to exert direct proinflammatory effects in nondiabetic rats (28).
A number of publications have reported a possible association between low levels of MBL and increased risk of infections, particularly in patients who are immunocompromised, such as children with immature antibody repertoire (15, 16), patients with acquired immunodeficiency syndrome (29), or patients with malignancies receiving chemotherapy or stem cell transplantation (17, 18, 30). Only 1 report of unusual and severe infections in 5 adults with no other known immune deficiency suggested that MBL deficiency may confer a life-long risk of infection (31). The current subanalysis of the 243 conventionally treated patients revealed that MBL levels on admission were almost 3 times higher in survivors as in nonsurvivors, in favor of a vulnerability associated with low MBL levels in critically ill patients who are presumably immunocompetent. Intensive insulin therapy, however, not only reduced the risk of severe infections and lethality, but also overruled the increased vulnerability associated with low MBL levels, which may point to a common pathway. Indeed, although a selection bias cannot be totally ruled out, our observations suggest that the conventionally treated, critically ill patients, because of hyperglycemia and/or lack of insulin effect, may be less immunocompetent than the intensive insulin-treated group, and in that situation a low MBL level does seem to predispose to adverse outcome. The association between low levels of MBL and outcome of conventionally treated ICU patients was not restricted to severe MBL deficiency, but was evident even when using a concentration of less than 500 µg/liter as a cut-off level for functional MBL deficiency, as previously suggested by Peterslund et al. (18).
MBL is known to activate complement after binding to a broad range of pathogens (32), and it seems plausible that MBL may protect against sepsis and multiple organ failure through early neutralization of invading microorganisms. However, the exact antimicrobial mechanism of MBL probably depends on the nature of the infecting organism and may involve enhanced phagocytosis through deposition of complement factors on the surface of the microorganism or direct destruction through the membrane attack complex (C5b-9) (6). As intensive insulin therapy overcomes the adverse effects of a low baseline MBL level, immune enhancement through similar mechanisms may be operative.
The high prevalence of point mutations in the MBL gene has been interpreted as evidence of some biological advantage associated with low circulating MBL (6). Recent studies have shown that MBL mediates complement activation after endothelial hypoxia, thereby potentially aggravating the resulting postischemic injury (33). Likewise, it has been suggested that CRP directly participates in local inflammatory processes in infarcted tissues during sepsis (34). Consequently, suppression of the acute phase response of CRP and MBL may partially mediate the advantageous effects of intensive insulin therapy in critically ill patients with ischemic injury and of glucose-insulin-potassium infusion in patients after acute myocardial infarction (35, 36).
In conclusion, we found that intensive insulin therapy suppresses the hepatic acute phase response, as indicated by circulating CRP levels, and that this antiinflammatory property at least partially explains the beneficial effects on organ failure and mortality in surgical critically ill patients. Low levels of MBL may predict a poor outcome in protracted critical illness, but the unfavorable effects of low baseline MBL can be neutralized by intensive insulin therapy.
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Acknowledgments |
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Footnotes |
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S.T. is a cofounder of NatImmune A/S, a biotech company producing recombinant MBL. The current research did not receive support from NatImmune.
J.S.C. is a recipient of an unrestrictive research grant from Novo Nordisk, Denmark.
G.V.d.B. is a holder of an unrestrictive research chair from Novo Nordisk, Denmark.
Abbreviations: CRP, C-reactive protein; ICU, intensive care unit; IQR, interquartile range; MBL, mannose-binding lectin.
Received September 23, 2002.
Accepted December 3, 2002.
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B and stimulates IB in mononuclear cells in obese subjects: evidence for an anti-inflammatory effect? J Clin Endocrinol Metab 7:3257–3265
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 W. Cao and Y. Duan Breath Analysis: Potential for Clinical Diagnosis and Exposure Assessment Clin. Chem., May 1, 2006; 52(5): 800 - 811. [Abstract] [Full Text] [PDF]
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 G. Van den Berghe, A. Wilmer, G. Hermans, W. Meersseman, P. J. Wouters, I. Milants, E. Van Wijngaerden, H. Bobbaers, and R. Bouillon Intensive Insulin Therapy in the Medical ICU N. Engl. J. Med., February 2, 2006; 354(5): 449 - 461. [Abstract] [Full Text] [PDF]
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R. W. Schrier Beneficial effects of intensive insulin therapy in critically ill patients Nephrol. Dial. Transplant., February 1, 2006; 21(2): 285 - 287. [Full Text] [PDF]
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 L. Langouche, I. Vanhorebeek, and G. Van den Berghe Glycaemic control in trauma patients, is there a role? Trauma, January 1, 2006; 8(1): 13 - 19. [Abstract] [PDF]
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A. L. D. Riis, T. K. Hansen, S. Thiel, C. H. Gravholt, S. Gjedde, L. C. Gormsen, J. O. L. Jorgensen, J. Weeke, and N. Moller Thyroid hormone increases mannan-binding lectin levels Eur. J. Endocrinol., November 1, 2005; 153(5): 643 - 649. [Abstract] [Full Text] [PDF]
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A. X. Freire, L. Bridges, G. E. Umpierrez, D. Kuhl, and A. E. Kitabchi Admission Hyperglycemia and Other Risk Factors as Predictors of Hospital Mortality in a Medical ICU Population Chest, November 1, 2005; 128(5): 3109 - 3116. [Abstract] [Full Text] [PDF]
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J.-P. Collet and G. Montalescot The acute reperfusion management of STEMI in patients with impaired glucose tolerance and type 2 diabetes Diabetes and Vascular Disease Research, October 1, 2005; 2(3): 136 - 143. [Abstract] [PDF]
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 L. H. Bouwman, P. Eerligh, O. T. Terpstra, M. R. Daha, P. de Knijff, B. E.P.B. Ballieux, G. J. Bruining, A. R. van der Slik, A. Roos, and B. O. Roep Elevated Levels of Mannose-Binding Lectin at Clinical Manifestation of Type 1 Diabetes in Juveniles Diabetes, October 1, 2005; 54(10): 3002 - 3006. [Abstract] [Full Text] [PDF]
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 M. Kosiborod, S. S. Rathore, S. E. Inzucchi, F. A. Masoudi, Y. Wang, E. P. Havranek, and H. M. Krumholz Admission Glucose and Mortality in Elderly Patients Hospitalized With Acute Myocardial Infarction: Implications for Patients With and Without Recognized Diabetes Circulation, June 14, 2005; 111(23): 3078 - 3086. [Abstract] [Full Text] [PDF]
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D. A. Schaumberg, R. J. Glynn, A. J. Jenkins, T. J. Lyons, N. Rifai, J. E. Manson, P. M. Ridker, and D. M. Nathan Effect of Intensive Glycemic Control on Levels of Markers of Inflammation in Type 1 Diabetes Mellitus in the Diabetes Control and Complications Trial Circulation, May 17, 2005; 111(19): 2446 - 2453. [Abstract] [Full Text] [PDF]
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G. Van den Berghe Insulin vs. strict blood glucose control to achieve a survival benefit after AMI? Eur. Heart J., April 1, 2005; 26(7): 639 - 641. [Full Text] [PDF]
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B. R. Bistrian and K. C. McCowen Nutr Clin Pract, December 1, 2004; 19(6): 650 - 651. [Full Text] [PDF]
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Y. Ma, B. Toth, A. B. Keeton, L. T. Holland, I. H. Chaudry, and J. L. Messina Mechanisms of Hemorrhage-Induced Hepatic Insulin Resistance: Role of Tumor Necrosis Factor-{alpha} Endocrinology, November 1, 2004; 145(11): 5168 - 5176. [Abstract] [Full Text] [PDF]
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F. B. Stentz, G. E. Umpierrez, R. Cuervo, and A. E. Kitabchi Proinflammatory Cytokines, Markers of Cardiovascular Risks, Oxidative Stress, and Lipid Peroxidation in Patients With Hyperglycemic Crises Diabetes, August 1, 2004; 53(8): 2079 - 2086. [Abstract] [Full Text] [PDF]
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 G. Van den Berghe Tight Blood Glucose Control With Insulin in "Real-Life" Intensive Care Mayo Clin. Proc., August 1, 2004; 79(8): 977 - 978. [PDF]
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J. S. Krinsley Effect of an Intensive Glucose Management Protocol on the Mortality of Critically Ill Adult Patients Mayo Clin. Proc., August 1, 2004; 79(8): 992 - 1000. [Abstract] [PDF]
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D. LeRoith Editorial: A Blast from the Past--Insulin Does It Again! J. Clin. Endocrinol. Metab., July 1, 2004; 89(7): 3103 - 3104. [Full Text] [PDF]
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 K. S Lewis, S. L Kane-Gill, M. B. Bobek, and J. F Dasta Intensive Insulin Therapy for Critically Ill Patients Ann. Pharmacother., July 1, 2004; 38(7): 1243 - 1251. [Abstract] [Full Text] [PDF]
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T. K. Hansen, L. Tarnow, S. Thiel, R. Steffensen, C. D. Stehouwer, C. G. Schalkwijk, H.-H. Parving, and A. Flyvbjerg Association Between Mannose-Binding Lectin and Vascular Complications in Type 1 Diabetes Diabetes, June 1, 2004; 53(6): 1570 - 1576. [Abstract] [Full Text] [PDF]
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E. S. Nylen and B. Muller Endocrine Changes in Critical Illness J Intensive Care Med, March 1, 2004; 19(2): 67 - 82. [Abstract] [PDF]
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 S. K. Andersen, J. Gjedsted, C. Christiansen, and E. Tonnesen The roles of insulin and hyperglycemia in sepsis pathogenesis J. Leukoc. Biol., March 1, 2004; 75(3): 413 - 421. [Abstract] [Full Text] [PDF]
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M. Zeller, Y. Cottin, M.-C. Brindisi, G. Dentan, Y. Laurent, L. Janin-Manificat, I. L'Huillier, J.-C. Beer, C. Touzery, H. Makki, et al. Impaired fasting glucose and cardiogenic shock in patients with acute myocardial infarction Eur. Heart J., February 2, 2004; 25(4): 308 - 312. [Abstract] [Full Text] [PDF]
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S. Clement, S. S. Braithwaite, M. F. Magee, A. Ahmann, E. P. Smith, R. G. Schafer, and I. B. Hirsch Management of Diabetes and Hyperglycemia in Hospitals Diabetes Care, February 1, 2004; 27(2): 553 - 591. [Full Text] [PDF]
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D. Mesotten, J. V. Swinnen, F. Vanderhoydonc, P. J. Wouters, and G. Van den Berghe Contribution of Circulating Lipids to the Improved Outcome of Critical Illness by Glycemic Control with Intensive Insulin Therapy J. Clin. Endocrinol. Metab., January 1, 2004; 89(1): 219 - 226. [Abstract] [Full Text] [PDF]
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Z. T. Bloomgarden Aspects of Blood Pressure, Lipid, and Glycemic Treatment Diabetes Care, January 1, 2004; 27(1): 264 - 269. [Full Text] [PDF]
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F. Weekers, A.-P. Giulietti, M. Michalaki, W. Coopmans, E. Van Herck, C. Mathieu, and G. Van den Berghe Metabolic, Endocrine, and Immune Effects of Stress Hyperglycemia in a Rabbit Model of Prolonged Critical Illness Endocrinology, December 1, 2003; 144(12): 5329 - 5338. [Abstract] [Full Text] [PDF]
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T. K. Hansen, S. Thiel, S. T. Knudsen, C. H. Gravholt, J. S. Christiansen, C. E. Mogensen, and P. L. Poulsen Elevated Levels of Mannan-Binding Lectin in Patients with Type 1 Diabetes J. Clin. Endocrinol. Metab., October 1, 2003; 88(10): 4857 - 4861. [Abstract] [Full Text] [PDF]
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 K. A. Janes, J. G. Albeck, L. X. Peng, P. K. Sorger, D. A. Lauffenburger, and M. B. Yaffe A High-throughput Quantitative Multiplex Kinase Assay for Monitoring Information Flow in Signaling Networks: Application to Sepsis-Apoptosis Mol. Cell. Proteomics, July 1, 2003; 2(7): 463 - 473. [Abstract] [Full Text] [PDF]
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) and the conventionally treated group (
) of prolonged critically ill patients. Data are the mean ± SEM. As intended, blood glucose levels were significantly different between the two groups (P < 0.0001) at all time points after randomization.
%) in patients receiving intensive insulin therapy (
