| | Effect of Intensive Insulin Therapy and Pentastarch Resuscitation on Acute Kidney Injury in Severe Sepsis published online 03 June 2008. Commentary on Brunkhorst FM, Engel C, Bloos F, et al: Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med 358:125-139, 2008. Critically ill patients frequently develop acute kidney injury (AKI), particularly in the setting of advanced age and comorbidities superimposed on sepsis and acute circulatory or respiratory failure.1 Hyperglycemia is also common during critical illness,2 and tight glycemic control has been reported to decrease mortality in some critically ill patients, with secondary outcomes showing a lower incidence of AKI.3, 4, 5, 6 Patients with sepsis require fluid resuscitation to avoid decreased perfusion and organ dysfunction, including AKI. There is continued debate about the use of crystalloids versus colloids for volume replacement in patients with sepsis.7, 8 Colloid solutions may be useful in situations of major volume depletion and increased capillary permeability for improving tissue perfusion. Colloid solutions include hydroxyethyl starches (HESs), gelatin, dextran, and the natural colloid albumin. The selection of colloids depends on safety profiles, cost, and availability, with HES preparations widely used in Europe. Several HES preparations are available, with different combinations of molecular weight (MW) and molar substitution.9 Reported adverse effects of HESs include coagulopathy, anaphylactoid reactions, and renal impairment, which was recently summarized in the American Journal of Kidney Diseases.10 In the January 10, 2008, issue of the New England Journal of Medicine, Brunkhorst et al reported the effects of intensive insulin therapy and resuscitation with pentastarch, a second-generation low-MW HES (HES 200/0.5), on mortality and organ failure in patients with severe sepsis, called the Efficacy of Volume Substitution and Insulin Therapy in Severe Sepsis (VISEP) Study. What Did This Important Study Show?  From April 2003 to June 2005, a total of 537 patients with severe sepsis or septic shock at 18 multidisciplinary intensive care units (ICUs) in Germany were enrolled in a 2 × 2 factorial design trial, with patients randomly assigned to receive either intensive insulin therapy (IIT; n = 247) or conventional insulin therapy (CIT; n = 290) and either 10% pentastarch (HES 200/0.5; n = 262) or modified Ringer's lactate (RL; n = 275). Exclusion criteria included treatment with more than 1,000 mL of HES within 24 hours before study inclusion, preexisting renal failure requiring dialysis, or a serum creatinine level of 3.6 mg/dL or greater (to convert to μmol/L, multiply by 88.4). IIT aimed for a blood glucose level of 80 to 110 mg/dL (to convert to mmol/L, multiply by 0.05551), and CIT aimed for a blood glucose level of 180 to 200 mg/dL. For volume, the HES group could be administered up to 20 mL/kg/d of HES, then preferentially RL or other noncolloid fluids. The primary end points included 28-day mortality and morbidity defined by using the Sequential Organ Failure Assessment (SOFA) score. Secondary end points included 90-day mortality and rate of AKI, defined as doubling of serum creatinine level or need for renal replacement therapy (RRT). Baseline characteristics were similar in the 2 groups for insulin therapy, whereas for fluid resuscitation, renal dysfunction was greater in the RL group compared with the HES group (P = 0.02). For insulin therapy, there were no significant differences in 28- or 90-day mortality, mean SOFA scores, and AKI rates between IIT and CIT. Hypoglycemia, defined as blood glucose level of 40 mg/dL or less, occurred more frequently in the IIT compared with the CIT group (12% versus 2%; P < 0.0001) and led to early termination of the IIT arm. For fluid resuscitation, there were no statistically significant differences in 28- or 90-day mortality between the HES and RL groups, although there was a trend toward increased mortality in the HES group at 90 days (P = 0.09). There was also a greater rate of AKI in the HES group compared with the RL group (35% versus 23%; P = 0.002), as well as increased requirement for RRT (31% versus 19%; P = 0.001). The study was suspended after this finding. The rate of death at 90 days was significantly greater in patients who received volumes of HES exceeding 20 mL/kg/d (58% versus 31%; P < 0.001), which would have constituted protocol violation. No interactions between the 2 interventions were found with respect to mortality. However, there was a trend toward an interaction for AKI rates (P = 0.06), such that patients who received both IIT and HES had the greatest risk of AKI. How Does This Study Compare With Prior Studies? Insulin Therapy Possible mechanisms of insulin action in patients with critical illness include anti-inflammatory effects, anabolic and antiapoptotic effects, and prevention of endothelial dysfunction and hypercoagulability.11, 12 IIT has been a topic of renewed interest since the study by Van den Berghe et al3 in 2001, which reported decreased mortality in critically ill surgical patients when tight glycemic control (glucose level, 80 to 110 mg/dL) was implemented. A subsequent trial by the same investigators in critically ill medical patients was less impressive, showing mortality benefits only in those with a minimum ICU stay of 3 days.4 Both these single-center randomized controlled trials (RCTs; known as the Leuven studies) also reported decreased AKI rates in the IIT group. Our recent meta-analysis of published RCTs examining IIT and AKI rates included 2,864 patients and showed a statistically significant 38% risk reduction in AKI with IIT (relative risk [RR], 0.62; 95% confidence interval, 0.41 to 0.96).13 All trials reported AKI as a secondary end point, and variable AKI definitions were used. When the VISEP Study results are added to our original analysis, now with 3,397 patients, we observe a 36% risk reduction in AKI with IIT. However, this pooled estimate is no longer statistically significant (RR, 0.74; 95% confidence interval, 0.47 to 1.17; Fig 1A). The VISEP Study showed no beneficial effects of IIT on mortality or AKI rates. The investigators suggested that IIT was probably beneficial in the surgical ICU study of Van den Berghe et al3 because it decreased the effect of the high parenteral glucose load used in these patients. However, a post hoc analysis of the Leuven studies suggested that the benefit of IIT was independent of the parenteral glucose load.14 The VISEP Study population was mixed, and subgroup analysis of their surgical versus medical patients would be needed for better comparison with the Leuven studies. The demonstration of 3% to 4% reduction in mortality with IIT would require 5,000 to 6,000 subjects,15 and the VISEP Study clearly was short of that sample size. In this context, the Normoglycemia in Intensive Care Evaluation and Survival Using Glucose Algorithm Regulation (NICE-SUGAR) Study, an ongoing international trial of IIT with a targeted enrollment of 6,100 subjects, will hopefully provide more definitive answers.16, 17 Severe hypoglycemia is a serious adverse reaction that is likely to occur more frequently when strict glycemic control is implemented. Severe prolonged hypoglycemia can result in convulsions, coma, and irreversible brain damage. Identifiable risk factors for hypoglycemia include IIT, ICU stay longer than 3 days, liver failure, and renal failure requiring dialysis. Similar to the VISEP Study, another multicenter trial examining the effect of 2 glucose treatment regimens (the GLUCONTROL Study) in a mixed ICU population was stopped after enrolling 1,101 patients because of greater rates of hypoglycemia with IIT.18 Our revised meta-analysis of randomized studies including the VISEP Study also shows a greater than 5-fold increased RR of hypoglycemia (RR, 5.2; 95% confidence interval, 3.7 to 7.3; Fig 1B). The VISEP Study did not describe the clinical consequences of hypoglycemia, which are of practical importance. In clinical practice, implementation of tight glycemic control is challenging and raises the question of whether benefits can be observed with less strict regimens. In an observational study, lower mortality and AKI rates were observed with less strict IIT (target glucose levels < 140 mg/dL) compared with CIT (targeted glucose > 200 mg/dL), and no significant difference in hypoglycemia was observed between the 2 strategies.5 Less strict glycemic control (glucose level < 150 mg/dL) has also been suggested, at least during the first 3 days of ICU stay.19 However, exploratory analyses pooling the data sets from the Leuven studies showed a greater survival benefit with blood glucose levels less than 110 mg/dL compared with levels of 110 to 150 mg/dL.14 The VISEP Study failed to show significant differences in survival rates when blood glucose levels were stratified. Are the reported effects on mortality and organ function caused by glycemic control or actions of insulin independent of glycemia? The beneficial effects on mortality, bacteremia, and inflammation have been attributed primarily to maintenance of normoglycemia.20, 21 However, one study indicated that the insulin dose per se may be an independent determinant of AKI prevention.20 However, in an experimental sepsis model in which glucose and insulin levels were manipulated independently, normoglycemia was more important for prevention of AKI.22 Because hypoglycemia is an independent predictor of death, the potential beneficial effects of insulin in the VISEP Study might have been masked by the development of hypoglycemia. This emphasizes the need for larger clinical trials that examine AKI as a primary outcome and to identify optimal target blood glucose levels in critically ill patients. Fluid Resuscitation Colloids augment oncotic pressure and help minimize edema formation, and the kidney is the major route of clearance for artificial colloids.23 The in vivo MW of HES is a function of its in vitro MW reported by the manufacturer, the degree of hydroxyethyl substitution, and the C2/C6 ratio, which refers to the hydroxyethylation carbon positions 2 and 6 of the glucose molecule.9 A high degree of substitution and high C2/C6 ratio results in a larger in vivo MW and consequently slower degradation and elimination of HES. Critically ill patients have low renal perfusion pressure, and an increase in oncotic pressure caused by artificial colloids can further decrease glomerular filtration rate. Based on this pathogenesis, high in vivo MW HES solutions are assumed to be more nephrotoxic.23 Most published studies on the use of HES solutions were small, nonrandomized, and had short observation periods. One study reported an 80% rate of osmotic nephrosis-like lesions on biopsy specimens from kidneys transplanted from deceased donors who were administered HES 200/0.62 compared with only 14% before HES implementation.24 A retrospective study in which HES 200/0.5 and HES 450/0.7 were used in a similar patient population showed no differences in delayed graft function at 14 days. However, greater serum creatinine levels were observed in the first 7 days of administering HES 450/0.7, which has a greater in vivo MW.25 Although these data suggest that low in vivo MW HES may be less nephrotoxic, administration of low-MW HES 70/0.5 and HES 130/0.4 has been associated with the appearance of urinary markers of kidney injury in patients undergoing major surgery.26, 27 The first major randomized trial in patients with sepsis was conducted by Schortgen et al28 comparing HES 200/0.60 to 0.66 with gelatin and showed a greater incidence of AKI (defined as a 2-fold increase in creatinine level or need for RRT) in the HES group, but no effect on survival. Criticisms of this study include a higher baseline creatinine level in the HES group, small sample size, and short follow-up duration of 34 days. Conversely, the VISEP Study is the first trial to show a trend toward greater mortality at 90 days, with survival curves for the 2 study groups beginning to diverge at approximately 30 days. Longer follow-up would likely show a clear difference in mortality. A systematic review of RCTs on the use of HES for fluid management in patients with sepsis totaling 1,062 patients, including 537 patients from the VISEP Study, showed an almost 2-fold increased risk of AKI with HES compared with crystalloids.29 Post hoc analyses of the VISEP Study showed the cumulative dose of HES to be a significant independent predictor for both mortality and RRT at 90 days. The median cumulative dose of HES in the VISEP Study was 70 mL/kg compared with 31 mL/kg in the study by Schortgen et al.28 The latter study did not report a relation between HES cumulative dose and AKI. Individual case reports in the literature have indicated that AKI can occur even after a single small-volume administration of HES in the absence of risk factors for renal dysfunction.30 The VISEP Study also showed that even patients who had received a lower dose of HES were more likely to develop AKI, including a higher RRT need at 90 days, compared with those receiving crystalloids. What Should Clinicians and Researchers Do? Potential criticisms of the VISEP Study include the choice of high-lactate–containing solutions for the crystalloid group and a high serum creatinine level exclusion criterion of 3.6 mg/dL, which exceeds the recommended specification for use of HES. Although there was no a priori reason to suspect interaction between IIT and resuscitation with HES, this was found with respect to AKI. When the IIT arm was stopped after the first safety analysis, these patients remained in the study for the fluid resuscitation strategy with CIT. In light of the finding of interaction, we can only speculate about whether this might have affected the study results. The definition of AKI in the VISEP Study combined serum creatinine level and RRT; these 2 endpoints should ideally be analyzed separately. Notwithstanding these comments, the study raises important issues about the practical implications of targeting strict glycemic control and is the first RCT to show increased mortality with the use of HES for fluid management in patients with sepsis. Although the findings of HES 200/0.5 used in this study cannot be extrapolated to other types of HES, it seems prudent to avoid HES for fluid resuscitation in patients with sepsis because adverse effects have been reported throughout the spectrum of HES solutions. On the issue of IIT and AKI, although preliminary data in the literature indicate benefit of IIT, our updated meta-analysis of AKI as a secondary end point does not show a benefit of IIT and a large multicenter RCT is required with assessment of AKI as a primary outcome, using the AKI Network criteria for a uniform definition.31 However, even with a benefit of IIT on mortality and AKI, the risk of severe inadvertent hypoglycemia cannot be minimized. The NICE-SUGAR study, which would be the largest randomized trial to date on mortality in critically ill patients, will likely shed more light on the benefit of survival with IIT, and we suggest that until then, less strict glycemic control protocols be followed. Acknowledgements Support: None. Financial Disclosure: None. References 1. 1Schrier RW, Wang W. Acute renal failure and sepsis. N Engl J Med. 2004;351:159–169.
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a Caritas St. Elizabeth's Medical Center, Boston, Massachusetts b Tufts Medical Center, Boston, Massachusetts c Caritas St. Elizabeth's Medical Center, Boston, Massachusetts  Address correspondence to Bertrand L. Jaber, MD, MS, Caritas St. Elizabeth's Medical Center, Medicine, Division of Nephrology, 736 Cambridge St, Boston, MA 02135.
PII: S0272-6386(08)00763-4 doi:10.1053/j.ajkd.2008.04.008 © 2008 National Kidney Foundation, Inc. Published by Elsevier Inc All rights reserved. | |
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