Clinical benefits of tight glycaemic control 2

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6

Clinical beneﬁts of tight glycaemic control: effect on

the kidney

Jan Gunst, MD, Miet Schetz, MD, PhD

*

Department and Laboratory of Intensive Care Medicine, University of Leuven, Herestraat 49, B-3000 Leuven, Belgium

Keywords: acute kidney injury critical illness hyperglycaemia glucose control insulin

Acute kidney injury is a frequent and life-threatening complication of critical illness. Prevention of this condition is crucial. Two randomized single center trials in critically ill patients have shown a decrease in acute kidney injury by tight glycaemic control, an effect that appears most pronounced in surgical patients. Subse-quent randomized trials did not confirm this renoprotective effect. This apparent contradiction is likely explained by methodological differences between studies, including different patient pop-ulations, insufficient patient numbers, comparison with a different control group, use of inaccurate blood glucose analyzers, and differences in the degree of reaching the target blood glucose level. The optimal glycaemic target for renoprotection in critical illness remains to be defined. Possible mechanisms underlying the renoprotective effect of tight glycaemic control are prevention of glucose overload and toxicity and the associated mitochondrial damage, an anti-inflammatory or anti-apoptotic effect, prevention of endothelial dysfunction, and an improvement of the lipid profile. Ó 2009 Elsevier Ltd. All rights reserved.

Introduction

Acute kidney injury (AKI) is a common complication of critical illness and its presence is an inde-pendent risk factor for mortality.1–3Because of the variability in how AKI is deﬁned and the differences in subpopulations studied, the reported incidence in intensive care patients varies between 1% and 25%. In order to streamline the research in the ﬁeld of AKI the ADQI (Acute Dialysis Quality Initiative) group proposed the RIFLE (Risk-Injury- Failure- Loss of kidney function-End stage renal disease)

*Corresponding author. Tel.: þ32 16 344021; Fax: þ32 16 344015.

E-mail addresses:jan.gunst@med.kuleuven.be(J. Gunst),marie.schetz@med.kuleuven.be(M. Schetz).

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Anaesthesiology

j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / b e a n

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criteria for classiﬁcation of AKI.1At present, this multilevel scoring system, based on changes in serum creatinine and/or in urine output, has been validated in multiple clinical studies. Compared to patients without AKI, there is a stepwise increase in the risk of death, going from RIFLE-Risk to RIFLE-Injury to RIFLE-Failure.4 As treatment of AKI is largely supportive, prevention is crucial. At present, no phar-macological intervention has demonstrated a protective effect on kidney function in critically ill patients and maintaining adequate hydration and haemodynamics and avoiding nephrotoxic substances remain the mainstay in prevention of AKI.5,6

About one third of patients with diabetes mellitus develop kidney disease and diabetes is the leading cause of end-stage renal disease in developed countries. The mechanism of diabetic nephropathy is incompletely elucidated. As well hemodynamic, metabolic and genetic factors are thought to be involved.7–11The role of strict glycaemic control in the management of diabetes has recently been questioned after three large randomized trials found no effect on macrovascular disease in patients with risk factors.12–14One of these trials was even prematurely stopped because of an increased mortality.12However, previous randomized trials have clearly shown a protective effect of strict glycaemic control on the development and progression of diabetic microangiopathy including nephropathy15–19and also one of the recent studies focusing on macrovascular complications, estab-lished a reduction in the incidence of nephropathy with more strict glucose control.13

Patients in the ICU commonly develop hyperglycaemia, the so-called stress-induced hyper-glycaemia, which is directly associated with adverse outcomes,20–22including kidney dysfunction. Indeed, several observational studies found an association between pre- or intraoperative hyper-glycaemia and postoperative AKI after cardiac surgery,23,24 between hyperglycaemia at cardiac catheterization and contrast nephropathy,25between hyperglycaemia during total parenteral nutrition and the development of AKI26,27_{and between hyperglycaemia and glomerular ﬁltration rate (GFR) in}

brain dead organ donors.28The induction of diabetes or acute hyperglycaemia in animals also increases the susceptibility to renal ischemia-reperfusion injury.29–31

In the past, stress-induced hyperglycaemia was interpreted as a beneficial metabolic adaptation and was not treated unless excessive (>200 mg/dl [11.1 mmol/l]).20This dogma was challenged by two single center randomized trials (the Leuven studies) showing a beneficial effect of tight glycaemic control (TGC) with intensive insulin therapy (IIT) on morbidity and/or mortality of critically ill patients.32,33After these positive studies, many centers worldwide adopted IIT as part of their usual care, and this treatment was implemented in several guidelines.34–37Subsequent trials, assessing the external validity of the results obtained in Leuven, showed conflicting results,38–43resulting in a lively debate.44–48

This chapter aims to give an overview of the studies evaluating the effect of glycaemic control on kidney function in critical illness, as well as a discussion of potential underlying mechanisms. Clinical studies

The first study that investigated the effects of IIT in critical illness was performed in Leuven in a predominantly surgical intensive care unit (ICU) and randomized 1548 patients to TGC (target 80–110 mg/dl [4.4–6.1 mmol/l]) or conventional glucose management. In the conventional group, insulin was only initiated when blood sugar levels exceeded 215 mg/dl (11.9 mmol/l), and insulin infusion was stopped when glycaemia dropped under 180 mg/dl (10 mmol/l). Mean morning blood glucose was 153 mg/dl (8.5 mmol/l) in the conventionally treated group and 103 mg/dl (5.7 mmol/l) in the group with TGC. Mortality was decreased by 42% (from 8 to 4.6%; P < 0.04) by TGC and also morbidity was significantly reduced, including a decreased incidence of renal impairment. More specifically, both the number of patients with peak plasma creatinine of >2.5 mg/dl [220

m

mol/l] or doubling of the admission serum creatinine, and the need for renal replacement therapy (RRT) were signiﬁcantly lowered (respectively from 12.3% to 9.0%, P ¼ 0.04 and from 8.2% to 4.8%, P ¼ 0.007).32

Subsequently, the same investigators conducted a similar randomized trial in their medical ICU. Glycaemic target in both groups was the same as in the previous trial. Mean morning blood glucose decreased from 153 mg/dl (8.5 mmol/l) in the conventionally treated group to 111 mg/dl (6.2 mmol/l) in the group with IIT. In the intention-to-treat group of 1200 patients, mortality was unaffected, but

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there was signiﬁcantly less morbidity, with a reduced incidence of new onset kidney injury (deﬁned as either a doubling of the admission serum creatinine or a peak serum creatinine of >2.5 mg/dl [220

m

mol/l]) (decrease from 8.9% to 5.9%, P ¼ 0.04). The need for RRT was not signiﬁcantly affected.33

A more detailed analysis of the renoprotective effect of TGC was performed by secondary analysis of the two Leuven studies using a RIFLE classification system with admission creatinine as baseline. In this analysis patients with pre-admission end-stage renal disease were excluded. The outcome parameters were RIFLE-Risk (peak/admission creatinine between 1.5 and 1.99), RIFLE-Injury (peak/ admission creatinine ratio between 2 and 2.99), RIFLE-Failure (peak/admission creatinine ratio 3), oliguria (daily urine output of <400 ml at any ICU day), need for RRT or AKI (any of the adverse renal outcomes). The incidence of all these adverse renal outcomes was significantly higher in the medical than in the surgical patients. In the pooled database IIT significantly reduced the incidence of both RIFLE-Injury (6.1 / 3.0%; P ¼ 0.03) and RIFLE-Failure (3.1 / 1.5%; P ¼ 0.005). The renoprotection was more pronounced in the surgical subgroup, where there was also a significant decrease in oliguria (5.6 / 2.6%; P ¼ 0.004), of the need for RRT (7.4 / 4.0%; P ¼ 0.008) and of the combined endpoint of AKI (13.7% / 10.0%: p ¼ 0.03). In the medical patients only the combined incidence of RIFLE-Injury and RIFLE-Failure was significantly reduced (9.2% / 6.0%; p ¼ 0.04). Compared with the surgical patients, the medical patients were more severely ill on admission with, in particular, a significantly higher admission serum creatinine. The use of this (already increased) admission creatinine to define the RIFLE criteria explains why the need for RRT (17%) was much higher than the incidence of RIFLE-Failure (3%). Amongst the medical patients that required RRT, 42% did so within the first 2 days after ICU admission. After exclusion of 16 surgical and 85 medical patients requiring early RRT, the effect of TGC on the need for RRT became statistically significant (8.8% / 6.7%; p ¼ 0.05).49_{This underscores}

the fact that TGC with IIT is a protective strategy that cannot prevent kidney damage that is already present on admission. Independent of randomization, the incidence of RIFLE-Injury or Failure was lowest (4%) in patients with a mean blood glucose <110 mg/dl (6.1 mmol/l), compared to 6.3% in patients with mean blood glucose levels of 110–150 mg/dl (6.1–8.3 mmol/l) and 8% in those with mean blood glucose above 150 mg/dl (>8.3 mmol/l) (p ¼ 0.0009). This underlies the importance of strict glycaemic control in achieving renoprotection.49,50

Two observational studies investigated the effect of implementing TGC on the incidence of AKI. Krinsley et al. studied 1600 consecutive patients in a mixed medical/surgical ICU. In this cohort, the incidence of kidney injury (deﬁned as serum creatinine >2.5 mg/dl [220

m

mol/l] or a doubling of the admission creatinine) decreased by 75% after implementation of TGC.51Lecomte et al. studied 1050 patients undergoing on-pump cardiac surgery. The number of patients reaching the RIFLE criteria was signiﬁcantly reduced from 60.4% to 46% (p ¼ 0.001) after institution of the TGC protocol, a difference that was mainly attributed to a reduction of RIFLE-Injury and RIFLE-Failure.52 Obviously, these implementation studies have limitations by the non-randomized design and the use of historical controls.

Subsequent randomized controlled trials, trying to confirm the benefit of TGC in other centers, have shown conflicting results.39–42Their general outcome will be discussed in other chapters of this issue. The effect on kidney function has only been reported in three studies. The VISEP (Volume substitution and Insulin therapy in Severe Sepsis) was a multicenter four-arm study designed to investigate both two choices of resuscitation fluid and the efficacy and safety of IIT in 537 patients with severe sepsis. The insulin arm was stopped prematurely, because the risk of hypoglycaemia was considered too high. Renal morbidity was defined as acute renal failure (at least doubling of baseline creatinine) or need for RRT. In these severely ill patients, neither of these outcome parameters was significantly affected by the intervention.39Two single center randomized trials, conducted in a mixed ICU and including respec-tively 532 and 504 patients, also could not establish an effect of TGC on the incidence of AKI or the need for RRT.40,41

The NICE-SUGAR (Normoglycaemia in Intensive Care Evaluation and Survival Using Glucose Algorithm Regulation) trial was a trial designed to assess the effectiveness of tight glycaemic control ‘‘in the real world’’. This multicenter trial was conducted in a mixed (medical-surgical) ICU pop-ulation, and compared TGC with a target of 81–108 mg/dl (4.5–6 mmol/l) with a more liberal glucose control (target glycaemia 180 mg/dl [10 mmol/l]). 6104 patients were included. Mean morning

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blood glucose levels decreased from 145 mg/dl (8.1 mmol/l) in the liberal glucose control group to 118 mg/dl (6.6 mmol/l) in TGC group. Unlike the Leuven studies, NICE-SUGAR investigators found an increased mortality risk in the intensively treated group (90 day mortality 27.5% vs. 24.9% in the control group; P ¼ 0.02). Excess mortality was attributed to cardiovascular causes, but it remains unclear what triggered this. Renal outcome was not different, with both incidence and duration of RRT being similar in both groups. No information was given concerning milder forms of renal injury.43

A meta-analysis, conducted before the NICE-SUGAR results were available, studied the effect of TGC on need for renal replacement therapy. Nine trials were included (including 2 small surgical studies, 3 abstracts and 1 unpublished manuscript). No difference was found between the two groups.53

How to explain these apparent conﬂicting results between the Leuven and the other trials? First, it should be emphasized that the effect of TGC on kidney function was a secondary endpoint in all randomized trials, and none of the studies was adequately powered to show or exclude such an effect. The Leuven studies have proven the concept that TGC can affect mortality and morbidity, including kidney injury, of critically ill patients compared with a conventional approach where hyperglycaemia was only corrected above 200 mg/dL. The conﬂicting results in the other randomized trials can be explained by differences in the design and particularly in the execution of the TGC. Design differences are mainly related to the type of patients included (surgical versus medical, severe sepsis versus general critical illness) and to the level of glycaemic control in the control group, that e.g. in NICE SUGAR was much lower than in the Leuven studies. Differences in the execution of TGC relate to difference in (the reliability of) the devices used to measure blood glucose level,54differences in blood sampling (arterial versus capillary), differences in achieving the target blood glucose level, the degree of overlap between the intervention and the control group and differences in the experience of the nursing staff.48Recent evidence suggests that glucose variability might even be more important than the mean blood glucose level.55–57

Animal data

Because of the difficulty to dissociate the effect of insulin from that of glucose control in the clinical setting, blood glucose and insulin levels were manipulated independently in a burn-injured paren-terally fed rabbit model of critical illness. After suppression of endogenous insulin production by alloxan, rabbits were randomly allocated to four study groups: normal insulin-normoglycaemia, high insulin-normoglycaemia, normal insulin-hyperglycaemia or high insulin-hyperglycaemia. This model confirmed the survival benefit and the renoprotective effect of TGC and demonstrated the deleterious effect of high blood glucose levels on the kidney, irrespective of the insulin level.58

Renoprotection by glycaemic control with insulin during critical illness: how does it work? A first question is whether the renal protection results from prevention of hyperglycaemia or from a direct effect of insulin. A pooled analysis of the Leuven studies showed that both glucose and insulin levels were higher in patients developing AKI, pointing to a predominant role of glucose normalization in determining outcome.49,50The association between insulin levels and outcome likely reflects a more pronounced insulin resistance in sicker patients, rather than a deleterious effect of hyperinsulinaemia per se. The importance of the normalization of glycaemia was confirmed in the previously mentioned animal model of critical illness, where normoglycaemia decreased kidney injury whereas hyper-insulinaemia did not protect the kidney.58

IIT could have an indirect renoprotective effect by diminishing the incidence of sepsis and, consequently, septic AKI. Although in the surgical Leuven study bacteraemia was decreased by TGC,32 this was not conﬁrmed in the medical study, with many patients being septic already on admission.33 A direct effect on the kidney seems therefore more plausible.

The pathophysiology of AKI is complex and not fully understood. Research points to a complex interplay between ischaemia-reperfusion and inﬂammation affecting both endothelial and tubular epithelial cells and leading to oxidant injury, mitochondrial dysfunction, and cell death by

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apoptosis/necrosis.59–64Most of these pathways are also involved in the development of diabetic complications and are affected by hyperglycaemia and insulin.

Prevention of oxidative and nitrosative stress

Oxidative stress is considered a key factor in the pathogenesis of both diabetes complications (including diabetic nephropathy)65–67_{and AKI.}60_{Cells that do not rely on insulin for glucose uptake}

and are exposed to elevated blood glucose levels, normally decrease the transport of glucose across the plasma membrane into the cytosol by downregulating facilitative glucose transporters. In critical illness however, glucose transporters have shown to be upregulated.68Hence, critically ill patients may be more vulnerable to acute hyperglycaemia.69In these patients hyperglycaemia will induce cellular glucose overload with concomitant increased formation of reactive oxygen species (ROS) that may be produced both in the mitochondria and the cytosol.66,70,71These ROS cause oxidation of macromole-cules including proteins, lipids, carbohydrates and DNA and result in cellular damage. Superoxide reacts with NO to form peroxynitrite, another reactive species. In critically ill patients, ischaemia-reperfusion- or sepsis-induced oxidative stress and upregulation of inducible NO synthase (iNOS) may further amplify the generation of reactive species. A recent animal study indeed found more severe kidney damage and more evidence of oxidative stress if renal ischaemia-reperfusion was preceded by the induction of hyperglycaemia.29In a subpopulation of the surgical Leuven study including patients with prolonged ICU stay, elevated NO levels appeared to be an independent predictor of AKI and were decreased by TGC.49,72

Mitochondrial dysfunction

The mitochondria seem particularly vulnerable to glucose toxicity. Indeed, in the surgical Leuven study ultrastructural abnormalities of mitochondria in human liver biopsies taken immediately postmortem could be prevented by strict glycaemic control, which also improved the activity of respiratory chain complex I and IV.73Similar results were seen in the renal cortex, in hepatocytes and cardiomyocytes of critically ill rabbits.74,75In this rabbit experiment, as already stated before, hyper-glycaemia induced an increase of serum creatinine. This increased serum creatinine correlated with cortical glucose levels, whereas mitochondrial respiratory chain activities showed an inverse corre-lation with serum creatinine and with cortical glucose, pointing to a role of cellular glucose overload in the induction of mitochondrial dysfunction and kidney injury.74

Anti-inﬂammatory effects

Inflammation is an important contributor to the development of AKI.60,61Hyperglycaemia has been shown to have pro-inflammatory effects whereas insulin has anti-inflammatory effects.76 In the surgical Leuven study, TGC with IIT lowered C-reactive protein (CRP) levels, independently of the prevention of infections.32However, no effect was observed on a series of cytokines.72The effect on CRP was confirmed in a rabbit model of critical illness.77In the medical Leuven study, the effect on CRP was only present in the long-stay patients.33

Prevention of endothelial dysfunction

The role of the endothelium in the pathogenesis of both diabetes complications78and AKI79is increasingly recognized. In a subgroup of the surgical Leuven study with prolonged ICU stay, TGC with IIT has shown to improve endothelial function, reﬂected by reduced circulating ICAM-1 and E-selectin levels.72In this subgroup patients with AKI had higher levels of ICAM-1 and E-selectin which may point to an important contribution of endothelial activation/damage to AKI. However, higher levels of adhesion molecules in AKI may also have resulted from decreased clearance.49In a rabbit model of critical illness, endothelial function, measured by endothelium-dependent relaxation of isolated aortic rings, was better preserved in the presence of normoglycaemia vs. hyperglycaemia, irrespective of insulin levels.58

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Antiapoptotic effects

Evidence suggests that apoptosis is a major mechanism of cell death in ischaemic AKI.59,62The role of apoptosis in septic AKI is less clear.64In vitro experiments in human proximal tubular epithelial cells show an induction of apoptosis by exposure to high glucose concentrations.80–82In contrast, insulin can exert antiapoptotic effects through the PI3-kinase-Akt pathway.83A renal ischaemia-reperfusion model in diabetic rats demonstrates renoprotection and inhibition of apoptosis with insulin pretreatment.84

Improvement of lipid proﬁle

Critical illness is associated with disturbances in lipid metabolism. Besides achieving normogly-caemia, IIT has shown to improve the lipid proﬁle of critically ill patients.85A post hoc analysis of the Leuven studies suggests that an improved lipid proﬁle might contribute to the renoprotective effect.49 This is supported by an animal model of renal ischaemia-reperfusion, administering HDL before ischaemia. Reduced endothelial activation and protection against oxidative stress might play a role.86 Summary

In summary, the Leuven studies have shown that glycaemic control can protect the kidney of critically ill patients on condition that the intervention is started early in the course of the disease process (as is mostly the case in surgical patients), that the intervention reaches the preset targets and that a reliable method is used to measure blood glucose and to administer insulin. Subsequent randomized trials could not confirm the renal benefit, which is probably related to differences in the design and the execution of the studies. Future trials, taking into account the above mentioned requirements, should establish the optimal glycaemic target and the patient population benefiting most from TGC. These trials should also establish the optimal indicator to evaluate the quality of blood glucose control.

Practice points

Hyperglycaemia in critically ill patients is associated with AKI.

Prevention of excessive hyperglycaemia in critical illness appears renoprotective, although study results are conﬂicting.

The evidence for a renoprotective effect of tight glycaemic control is strongest for patients admitted after elective major surgery.

Differences between trials may be explained by methodological differences, including the inclusion of different types of patients, a different glucose target in the control group, the use of inaccurate glucose analyzers and inadequate sampling sites and the degree of success in reaching the glycaemic target.

Research agenda

Further research is needed to identify the optimal glycaemic target in speciﬁc patient pop-ulations, and to improve practical tools for implementation in clinical practice.

Mechanisms involved in renoprotection by glycaemic control/insulin administration should be further clariﬁed.

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Acknowledgements

This work was supported by Research Foundation-Flanders (FWO), Belgium (G.0585.09) and the Research Council of the Katholieke Universiteit Leuven (GOA2007/14). FWO Research Assistant Fellowship to J.G.

Conﬂict of interest

We declare to have no conﬂict of interest. References

1. Bellomo R, Ronco C, Kellum JA, et al, the ADQI workgroup. Acute renal failure – deﬁnition, outcome measures, animal models, ﬂuid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Critical Care 2004; 8: R204–R212.

2. Lameire N, Van Biesen W & Vanholder R. Acute renal failure. Lancet 2005; 365: 417–430.

3. Coca SG, Yusuf B, Shlipak MG et al. Long-term risk of mortality and other adverse outcomes after acute kidney injury: a systematic review and meta-analysis. American Journal of Kidney Diseases 2009; 53: 961–973.

4. Ricci Z, Cruz D & Ronco C. The RIFLE criteria and mortality in acute kidney injury: a systematic review. Kidney International 2008; 73: 538–546.

5. Lameire N, Van Biesen W & Vanholder R. Acute kidney injury. Lancet 2008; 372: 1863–1865. 6. Venkataraman R & Kellum JA. Prevention of acute renal failure. Chest 2007; 131: 300–308.

7. Wolf G. New insights into the pathophysiology of diabetic nephropathy: from haemodynamics to molecular pathology. European Journal of Clinical Investigation 2004; 34: 785–796.

8. Caramori ML & Mauer M. Diabetes and nephropathy. Current Opinion in Nephrology and Hypertension 2003; 12: 273–282. 9. Schrijvers BF, De Vriese AS & Flyvbjerg A. From hyperglycemia to diabetic kidney disease: the role of metabolic,

hemo-dynamic, intracellular factors and growth factors/cytokines. Endocrine Reviews 2004; 25: 971–1010.

10. Singh DK, Winocour P & Farrington K. Mechanisms of disease: the hypoxic tubular hypothesis of diabetic nephropathy. Nature Clinical Practice. Nephrology 2008; 4: 216–226.

11. Wang S, Mitu GM & Hirschberg R. Osmotic polyuria: an overlooked mechanism in diabetic nephropathy. Nephrology, Dialysis, Transplantation 2008; 23: 2167–2172.

12. Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein HC, Miller ME et al. Effects of intensive glucose lowering in type 2 diabetes. The New England Journal of Medicine 2008; 358: 2545–2559.

13. ADVANCE Collaborative Group, Patel A, MacMahon S et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. The New England Journal of Medicine 2008; 358: 2560–2572.

14. Duckworth W, Abraira C, Moritz T, et al, VDAT Investigators. Glucose control and vascular complications in veterans with type 2 diabetes. The New England Journal of Medicine 2009; 360: 129–139.

15. 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. The New England Journal of Medicine 1993; 329: 977–986.

16. The Diabetes Control and Complications (DCCT) Research Group. Effect of intensive therapy on the development and progression of diabetic nephropathy in the Diabetes Control and Complications Trial. Kidney International 1995; 47: 1703–1720.

17. U.K. Prospective Diabetes Study Group. Intensive blood glucose control with sulfonylureas or insulin compared with conventional treatment and risk for complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352: 837–853.

18. Writing Team for the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Sustained effect of intensive treatment of type 1 diabetes mellitus on development and progression of diabetic nephropathy: the Epidemiology of Diabetes Interventions and Complications (EDIC) study. JAMA : The Journal of the American Medical Association 2003; 290: 2159–2167.

19. Fioretto P, Bruseghin M, Berto I et al. Renal protection in diabetes: role of glycaemic control. Journal of the American Society of Nephrology 2006; 17: S86–S89.

20. Mizock BA. Alterations in fuel metabolism in critical illness: hyperglycaemia. Best Practice & Research. Clinical Endocri-nology & Metabolism 2001; 15: 533–551.

21. Bagshaw SM, Egi M, George C, Bellomo R & the ANZICS Database Management Committee. Early blood glucose control and mortality in critically ill patients in Australia. Critical Care Medcine 2009; 37: 463–470.

22. Kosiborod M, Rathore SS, Inzucchi SE et al. Admission glucose and mortality in elderly patients hospitalized with acute myocardial infarction: implications for patients with and without recognized diabetes. Circulation 2005; 111: 3078–3086. 23. Gandhi GY, Nuttall GA, Abel MD et al. Intraoperative hyperglycemia and perioperative outcomes in cardiac surgery

patients. Mayo Clinic Proceedings. Mayo Clinic 2005; 80: 862–866.

24. Mangano CM, Diamondstone LS, Ramsay JG et al. Renal dysfunction after myocardial revascularization: risk factors, adverse outcomes, and hospital resource utilization. The Multicenter Study of Perioperative Ischemia Research Group. Annals of Internal Medicine 1998; 128: 194–203.

25. Turcot DB, Kiernan FJ, McKay RG et al. Acute hyperglycemia: implications for contrast-induced nephropathy during cardiac catheterization. Diabetes Care 2004; 27: 620–621.

26. Cheung NW, Napier B, Zaccaria C et al. Hyperglycemia is associated with adverse outcomes in patients receiving total parenteral nutrition. Diabetes Care 2005; 28: 2367–2371.

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27. Lin LY, Lin HC, Lee PC et al. Hyperglycemia correlates with outcomes in patients receiving total parenteral nutrition. The American Journal of the Medical Sciences 2007; 333: 261–265.

28. Blasi-Ibanez A, Hirose R, Feiner J et al. Predictors associated with terminal renal function in deceased organ donors in the intensive care unit. Anesthesiology 2009; 110: 333–341.

29. Hirose R, Xu F, Dang K et al. Transient hyperglycemia affects the extent of ischemia-reperfusion-induced renal injury in rats. Anesthesiology 2008; 108: 402–414.

30. Moursi M, Rising CL, Zelenock GB et al. Dextrose administration exacerbates acute renal ischemic damage in anesthetized dogs. Archives of Surgery 1987; 122: 790–804.

31. Podrazik RM, Natale JE, Zelenock GB et al. Hyperglycemia exacerbates and insulin fails to protect in acute renal ischemia in the rat. The Journal of Surgical Research 1989; 46: 572–578.

*32. Van den Berghe G, Wouters P, Weekers F et al. Intensive insulin therapy in critically ill patients. The New England Journal of Medicine 2001; 345: 1359–1367.

*33. Van den Berghe G, Wilmer A, Hermans G et al. Intensive insulin therapy in the medical ICU. The New England Journal of Medicine 2006; 354: 449–461.

34. American Diabetes Association. Standards of medical care in diabetes - 2008. Diabetes Care 2008; 31(Suppl. 1): S12–S54. 35. AACE Diabetes Mellitus Clinical Practice Guidelines Task Force. American association of clinical endocrinologists medical

guidelines for clinical practice for the management of diabetes mellitus. Endocrine Practice 2007; 13(Suppl. 1): 1–68. 36. Dellinger RP, Levy MM, Carlet JM et al. Surviving sepsis campaign: international guidelines for management of severe

sepsis and septic shock: 2008. Critical Care Medcine 2008; 36: 296–327.

37. Ryde´n L, Standl E, Bartnik M, et alTask Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology (ESC) & European Association for the Study of Diabetes (EASD). Guidelines on diabetes, pre-diabetes, and cardiovascular diseases; executive summary. European Heart Journal 2007; 28: 88–136.

38. Devos P, Preiser J & Melot C. Impact of tight glucose control by intensive insulin therapy on ICU mortality and the rate of hypoglycaemia: ﬁnal results of the glucontrol study (European Society of Intensive Care Medicine 20th Annual Congress abstract 0735). Intensive Care Medicine 2007; 33(Suppl. 2): S189.

39. Brunkhorst FM, Engel C, Bloos F, et al, German Competence Network Sepsis (SepNet). Intensive insulin therapy and pentastarch resuscitation in severe sepsis. The New England Journal of Medicine 2008; 358: 125–139.

40. Arabi YM, Dabbagh OC, Tamim HM et al. Intensive versus conventional insulin therapy: a randomized controlled trial in medical and surgical critically ill patients. Critical Care Medcine 2008; 36: 3190–3197.

41. De La Rosa GdC, Donado JH, Restrepo AH et al. Strict glycaemic control in patients hospitalised in a mixed medical and surgical intensive care unit: a randomised clinical trial. Critical Care 2008; 12: R120.

42. Bilotta F, Caramia R, Paoloni FP et al. Safety and efﬁcacy of intensive insulin therapy in critical neurosurgical patients. Anesthesiology 2009; 110: 611–619.

*43. Finfer S, Chittock DR, Su SY, et al, NICE-SUGAR Study Investigators. Intensive versus conventional glucose control in critically ill patients. The New England Journal of Medicine 2009; 360: 1283–1297.

44. Inzucchi SE & Siegel MD. Glucose control in the ICU – how tight is too tight? The New England Journal of Medicine 2009; 360: 1346–1349.

45. Preiser JC. NICE-SUGAR: the end of a sweet dream? Critical Care 2009; 13: 143.

46. Comi RJ. Glucose control in the intensive care unit: a roller coaster ride or a swinging pendulum? Annals of Internal Medicine 2009; 150: 809–811.

47. Fahy BG, Sheely AM & Coursin DB. Glucose control in the intensive care unit. Critical Care Medcine 2009; 37: 1769–1776. 48. Van den Berghe G, Schetz M, Vlasselaers D, et al. Intensive insulin therapy in critically ill patients: NICE-SUGAR or Leuven

blood glucose target? The Journal of Clinical Endocrinology and Metabolism, in press (PMID: 19531590).

*49. Schetz M, Vanhorebeek I, Wouters PJ et al. Tight blood glucose control is renoprotective in critically ill patients. Journal of the American Society of Nephrology 2008; 19: 571–578.

*50. Van den Berghe G, Wilmer A, Milants I et al. Intensive insulin therapy in mixed medical/surgical intensive care units: beneﬁt versus harm. Diabetes 2006; 55: 3151–3159.

51. Krinsley JS. Effect of an intensive glucose management protocol on the mortality of critically ill adult patients. Mayo Clinic Proceedings. Mayo Clinic 2004; 79: 992–1000 [Erratum in: Mayo Clinic Proceedings. Mayo Clinic 2005; 80: 1101]. 52. Lecomte P, Van Vlem B, Coddens J et al. Tight perioperative glucose control is associated with a reduction in renal

impairment and renal failure in non-diabetic cardiac surgical patients. Critical Care 2008; 12: R154.

53. Wiener RS, Wiener DC & Larson RJ. Beneﬁts and risks of tight glucose control in critically ill adults: a meta-analysis. JAMA : The Journal of the American Medical Association 2008; 300: 933–944.

*54. Scott MG, Bruns DE, Boyd JC & Sacks DB. Tight glucose control in the intensive care unit: are glucose meters up to the task? Clinical Chemistry 2009; 55: 18–20.

55. Egi M, Bellomo R, Stachowski E et al. Variability of blood glucose concentration and short-term mortality in critically ill patients. Anesthesiology 2006; 105: 244–252.

56. Krinsley JS. Glycemic variability: a strong independent predictor of mortality in critically ill patients. Critical Care Medcine 2008; 36: 3008–3013.

57. Egi M, Bellomo R & Reade MC. Is reducing variability of blood glucose the real but hidden target of intensive insulin therapy? Critical Care 2009; 13: 302.

*58. Ellger B, Debaveye Y, Vanhorebeek I et al. Survival beneﬁts of intensive insulin therapy in critical illness. Diabetes 2006; 55: 1096–1105.

59. Devarajan P. Update on mechanisms of ischemic acute kidney injury. Journal of the American Society of Nephrology 2006; 17: 1503–1520.

60. Chatterjee PK. Novel pharmacological approaches to the treatment of renal ischemia-reperfusion injury: a comprehensive review. Naunyn-Schmiedeberg’s Archives of Pharmacology 2007; 376: 1–43.

61. Bonventre J. Ischemic acute renal failure: an inﬂammatory disease? Kidney International 2004; 66: 480–485.

62. Kaushal GP, Basnakian AG & Shah SV. Apoptotic pathways in ischemic acute renal failure. Kidney International 2004; 66: 500–506.

(9)

63. Wan L, Bagshaw SM, Langenberg C et al. Pathophysiology of septic acute kidney injury: what do we really know? Critical Care Medcine 2008; 36(Suppl.): S198–S203.

64. Singer M. Mitochondrial function in sepsis: acute phase versus multiple organ failure. Critical Care Medcine 2007; 35(Suppl.): S441–S448.

65. Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature 2001; 414: 813–820.

66. Forbes M, Coughlan MT & Cooper ME. Oxidative stress as a major culprit in kidney disease in diabetes. Diabetes 2008; 57: 1446–1454.

67. Ha H, Hwang IA, park JH et al. Role of reactive oxygen species in the pathogenesis of diabetic nephropathy. Diabetes Research and Clinical Practice 2008; 82(Suppl. 1): S42–S45.

68. Langouche L, Vander Perre S, Wouters P & Van den Berghe G. Expression of glucose transporters in critical illness (abstract). Critical Care 2006; 10(Suppl. 1): P252.

*69. Van den Berghe G. How does blood glucose control with insulin save lives in intensive care? The Journal of Clinical Investigation 2004; 9: 1187–1195.

70. Choi SW, Benzie IFF, Ma SW et al. Acute hyperglycemia and oxidative stress: direct cause and effect? Free Radical Biology & Medicine 2008; 44: 1217–1231.

71. Monnier L, Mas E, Ginet C et al. Activation of oxidative stress by acute glucose ﬂuctuations compared with sustained chronic hyperglycemia in patients with type 2 diabetes. JAMA : The Journal of the American Medical Association 2006; 295: 1681–1687.

72. Langouche L, Vanhorebeek I, Vlasselaers D et al. Intensive insulin therapy protects the endothelium of critically ill patients. The Journal of Clinical Investigation 2005; 115: 2277–2286.

73. Vanhorebeek I, De Vos R, Mesotten D et al. Protection of hepatocyte mitochondrial ultrastructure and function by strict blood glucose control with insulin in critically ill patients. Lancet 2005; 365: 53–59.

74. Vanhorebeek I, Gunst J, Ellger B et al. Hyperglycemic damage to renal tissue in an animal model of prolonged critical illness. Kindey International 2009; 76: 512–520.

75. Vanhorebeek I, Ellger B, De Vos R et al. Tissue-speciﬁc glucose toxicity induces mitochondrial damage in a burn injury model of critical illness. Critical Care Medcine 2009; 37: 1355–1364.

76. Dandona P, Chaudhuri A, Ghanim H et al. Anti-inﬂammatory effects of insulin and the pro-inﬂammatory effects of glucose. Seminars in Thoracic and Cardiovascular Surgery 2006; 18: 293–301.

77. Weekers F, Giulietti AP, Michalaki M et al. Metabolic, endocrine, and immune effects of stress hyperglycemia in a rabbit model of prolonged critical illness. Endocrinology 2003; 144: 5329–5338.

78. Schalkwijk CG & Stehouwer CD. Vascular complications in diabetes mellitus: the role of endothelial dysfunction. Clinical Science (London, England : 1979) 2005; 109: 143–159.

79. Molitoris BA & Sutton TA. Endothelial injury and dysfunction: role in the extension phase of acute renal failure. Kidney International 2004; 66: 496–499.

80. Allen DA, Harwood S, Varagunam M et al. High glucose-induced oxidative stress causes apoptosis in proximal tubular epithelial cells and is mediated by multiple caspases. The FASEB Journal 2003; 17: 908–910.

81. Ortiz A, Ziyadeh FN & Neilson EG. Expression of apoptosis-regulatory genes in renal proximal tubular epithelial cells exposed to high ambient glucose and in diabetic kidneys. Journal of Investigative Medicine 1997; 45: 50–56.

82. Samikkannu T, Thomas JJ, Bhat J et al. Acute effect of high glucose on long term cell growth: a role for transient glucose increase in proximal tubule cell injury. American Journal of Physiology. Renal Physiology 2006; 291: F162–F175. 83. Meier M, Nitschke M, Hocke C et al. Insulin inhibits caspase-3 activity in human renal tubular epithelial cells via the

PI3-Kinase/Akt pathway. Cellular Physiology and Biochemistry 2008; 21: 279–286.

84. Melin J, Hellberg O, Larsson E et al. Protective effect of insulin on ischemic renal injury in diabetes mellitus. Kidney International 2002; 61: 383–392.

85. Mesotten D, Swinnen JV, Vanderhoydonc F et al. Contribution of circulating lipids to the improved outcome of critical illness by glycaemic control with intensive insulin therapy. The Journal of Clinical Endocrinology and Metabolism 2004; 89: 219–226.

86. Thiemermann C, Patel NSA, Kvale EO et al. High Density Lipoprotein (HDL) reduces renal ischemia/reperfusion injury. Journal of the American Society of Nephrology 2003; 14: 1833–1843.