NDT Advance Access originally published online on June 29, 2007
Nephrology Dialysis Transplantation 2007 22(10):2849-2855; doi:10.1093/ndt/gfm401
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Insulin therapy and acute kidney injury in critically ill patients—a systematic review
1Division of Nephrology, Department of Medicine, Caritas St Elizabeth's Medical Center, 2Division of Pulmonary and Critical Care Medicine, Caritas St Elizabeth's Medical Center and 3Institute for Clinical Research and Health Policy Studies, Tufts-New England Medical Center, Boston, MA, USA
Correspondence and offprint requests to: Bertrand L. Jaber, Caritas St Elizabeth's Medical Center, 736 Cambridge Street, Boston, MA 02135, USA. Email: bertrand.jaber{at}caritaschristi.org
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Abstract |
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Background. Intensive insulin therapy has been found to reduce mortality in some critically ill patients. We performed a systematic review and meta-analysis to ascertain the effect of intensive insulin therapy on the incidence of acute kidney injury (AKI) in adult critically ill patients.
Methods. We searched MEDLINE, SCOPUS and the Cochrane Central Register of Controlled Trials for studies that compared ‘conventional’ vs ‘intensive’ insulin therapy in critically ill patients. Studies were combined with random effects model meta-analyses.
Results. Five studies, three of which were randomized controlled trials, reported AKI as a secondary outcome. Two of the studies were non-concurrent prospective cohort studies. All were single-centre studies conducted in intensive care unit settings. By meta-analysis across all studies, intensive insulin therapy reduced the incidence of AKI by 38% [risk ratio (RR) 0.62; 95% confidence interval (CI) 0.47, 0.83; P = 0.001]. The findings of the randomized and cohort studies were similar and the studies were not statistically heterogeneous. Three studies reported the effect of insulin therapy on dialysis requirement. Overall, intensive insulin therapy reduced the incidence of dialysis requirement by 35%, however, this was not statistically significant (RR 0.65; 95% CI 0.40, 1.05; P = 0.08). The overall rate of hypoglycaemia in the conventional insulin therapy group was 1.3% (range 0.3–3.4%). Intensive insulin therapy was associated with a >4-fold increase in the risk of hypoglycaemia (RR 4.5; 95% CI 2.4, 8.5; P < 0.00001)
Conclusion. There is evidence that intensive insulin therapy initiated in critically ill adult patients is associated with a reduction in the incidence of AKI in medical and surgical settings. A large trial primarily designed to examine the effect of insulin on the prevention of AKI is needed to confirm this finding.
Keywords: acute kidney injury; acute renal failure; critical illness; hyperglycaemia; insulin; intensive care unit; meta-analysis
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Introduction |
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Acute kidney injury (AKI), assessed using absolute and relative increases in serum creatinine concentration, is associated with high morbidity and mortality [1], high in-hospital and post-hospitalization resource utilization [2] and high costs [3]. Moreover, outcomes are related directly to the severity of AKI [3].
Critically ill patients frequently develop AKI, particularly in the setting of advanced age and numerous comorbid conditions, superimposed on sepsis and acute circulatory or respiratory failure. Strategies aimed at preventing AKI in critically ill patients have primarily focused on aggressive early fluid resuscitation, particularly in sepsis [4]. Although the additional potential role of medications such as activated protein C, hydrocortisone and insulin therapy have not been fully elucidated [5], the latter intervention warrants further inquiry.
Hyperglycaemia is common during critical illness, irrespective of pre-existing diabetes mellitus, and is associated with adverse clinical outcomes [6]. In this setting, hyperglycaemia is often the result of numerous factors including insulin resistance, a surge in counter-regulatory hormones and inflammatory cytokines and the systemic administration of corticosteroids and sympathomimetics. Intensive insulin therapy aimed at maintaining normoglycaemia in the intensive care unit has been shown to reduce morbidity and mortality in some critically ill patients [7,8]. With respect to glycaemic control and renal protection, high glucose concentrations can evoke necrosis and apoptosis in cultured renal tubular epithelial cells [9] and mesangial cells [10], which is induced in part by an increase in oxidative stress. In addition, the administration of insulin to hyperglycaemic septic animals is associated with a decrease in the incidence of AKI [11]. In light of these in vitro and animal studies, the objective of this systematic review and meta-analysis was to ascertain the effect of intensive insulin therapy on the incidence of AKI in hospitalized hyperglycaemic critically ill patients.
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Methods |
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Data sources
We conducted a comprehensive literature search for studies of intensive insulin therapy for critically ill patients in MEDLINE (from 1966 to February 2007), SCOPUS (from 1960 to February 2007) and the Cochrane Central Register of Controlled Trials. Search terms included ‘hyperglycaemia’, ‘insulin’, ‘mortality’, ‘glucose-insulin-potassium’, ‘critical illness’, ‘intensive care unit’, ‘glucose control’, ‘glycaemic control’, ‘tight glycaemic control’, ‘blood sugar control’, ‘renal impairment’, ‘acute renal failure’ or ‘acute kidney injury’. We also performed manual searches of bibliographies in retrieved articles, relevant review articles and study references; and we reviewed abstracts from proceedings of annual meetings of the ‘American Society of Nephrology’ (from 2000 to 2006) and the ‘European Society of Intensive Care Medicine’ (from 2004 to 2006). English and non-English language studies were included in the search.
Study selection and data extraction
Study eligibility criteria included studies that reported AKI as either a primary or secondary outcome in adult critically ill patients who received either ‘conventional’ or ‘intensive’ insulin therapy. Upon finding that only a small number of randomized controlled trials (RCTs) were identified, we included non-concurrent prospective cohort studies that compared two periods of care, i.e. before and after implementation of an intensive insulin therapy protocol. We also included non-peer-reviewed scientific abstracts. Critically ill patients were defined in the individual studies as those admitted to the medical or surgical intensive care unit. We accepted the authors’ definitions of conventional and intensive insulin therapy adopted in the individual studies. Two reviewers (G.T. and M.C.R.) independently screened abstracts according to eligibility criteria. Retrieved full-text articles were screened using the same criteria.
Each accepted study was double data extracted. The following data were extracted as available: year of publication, study design and duration, sample size, hospital setting and timing of intensive insulin therapy, glucose threshold for intensive insulin therapy, APACHE II score, pre-existing diabetes mellitus, baseline serum creatinine, incidence of AKI, need for renal replacement therapy and incidence of hypoglycaemia as a result of insulin therapy. The quality of included studies was assessed based on randomization, allocation concealment and intention-to-treat analysis.
Statistical analysis
The primary measure of treatment effect was the risk ratio (RR) of AKI. Meta-analyses were performed using a random-effects model, which assigns a weight to each study based on both the within-study variance and the between-study heterogeneity. An overall weighted rate of AKI and hypoglycaemia was calculated in the conventional insulin therapy group. Heterogeneity in RR and risk difference among the studies was assessed using the chi-square test. Exploratory subgroup analyses were also performed. The number needed to treat (NNT) or harm (NNH)—namely severe hypoglycaemia requiring intervention, for a given therapy—were also calculated. For every study, an appreciation of the clinical risk/benefit ratio was then portrayed through the NNH/NNT ratio. A ratio of less than one indicates that the clinical risk outweighs the clinical benefit of the therapy.
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Results |
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Study characteristics
We identified 295 potentially relevant articles in our initial search, of which 48 were selected for further review based on abstracts (Figure 1). Only three RCTs comparing conventional insulin therapy (target glucose 180–200 mg/dl) to intensive insulin therapy (target glucose 80–100 mg/dl) reported AKI as secondary outcomes [12–14]. AKI was defined as a serum creatinine increase to
2.5 mg/dl [12–14] or a 2-fold increase in serum creatinine [12,13]. All three were single-centre trials conducted in an intensive care unit setting, with varying methodological quality. Two trials were of high quality with randomization and clear method of allocation generation, and analysis done with intention to treat [12,13]. Strict blinding was not possible in these two studies because of the need for safe insulin titration; however, investigators that were blinded to treatment assignment interpreted the study results. One randomized study was considered to be of intermediate quality, as it did not specify method of allocation generation, blinding or whether an intention-to-treat analysis was adopted [14]. Two non-concurrent prospective cohort studies, which included one full-text article and one abstract, were also added to the primary analysis, but targeted a less strict glycaemic control (Table 1) [15,16]. One of these studies used the aforementioned AKI definition [16], whereas the other adopted the RIFLE ‘Injury’ scoring system [17] to define AKI [15].
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The characteristics and results of the five individual studies included in the analysis are summarized in Tables 1 and 2. Upon entry to the intensive care unit, the mean APACHE II score of study subjects ranged from 9 to 23, and 12 to 17% had diabetes (among the four studies that reported the data). The incidence of AKI in the conventional insulin therapy group varied among the individual studies, ranging from 1.5% to 22%.
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Prevention of AKI
The primary analysis included the three RCTs, totalling 2864 analysable subjects (Figure 2) [12–14]. The overall weighted rate of AKI in the conventional insulin therapy group was 11.3% (range 8.9–22.4%). Combining data using the random-effects model, intensive insulin therapy reduced the incidence of AKI by 38% (RR 0.62, 95% confidence interval [CI] 0.41, 0.96; P = 0.03). The test for heterogeneity among these three trials was not significant (Q = 4.37, P > 0.10). Notably, the same investigators performed two of the three single-centre RCTs.
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An expanded analysis was performed where the two cohort studies were included, totalling 5165 analysable subjects (Figure 2). The overall weighted rate of AKI in the conventional insulin therapy group was 9.2% (range 1.5–22.4%). Combining data using the random-effects model, intensive insulin therapy reduced the incidence of AKI by 38% (RR 0.62; 95% CI 0.47, 0.83; P = 0.001). The test for heterogeneity among the studies was not significant (Q = 6.72, P > 0.10).
Three studies examined the effect of insulin therapy on the need for renal replacement therapy in 3016 subjects [12,13,16]; in one study however, dialysis requirement was reported only in patients who stayed in the intensive care unit for more than 3 days [13]. The overall weighted rate of renal replacement therapy in the conventional insulin therapy group was 11.1% (range 4.3–22.7%). By meta-analysis, intensive insulin therapy reduced the incidence of dialysis requirement by 35% (RR 0.65; 95% CI 0.40, 1.05; P = 0.08), which was not statistically significant. The studies were significantly heterogeneous in effect (Q = 6.73, P < 0.05).
Insulin-related severe hypoglycaemia
Four studies reported the incidence of severe hypoglycaemia related to insulin therapy, totalling 4464 analysable subjects (Table 2) [12–15]. In three studies, severe hypoglycaemia was defined as a glucose level of <40 mg/dl [12,13,15], but in one study the cut-off blood glucose value was not defined and no associated symptoms were reported [14]. Notably, these definitions of severe hypoglycaemia differ from a commonly used system that grades need for assistance (grade 3) and loss of consciousness with or without convulsions (grade 4) [18].
In the first study, two patients receiving intensive insulin therapy had hypoglycaemic episodes with sweating and agitation, consistent with grade 3 severe hypoglycaemia, but no instances of haemodynamic deterioration or convulsions (grade 4) [12]. The second study reported no associated adverse events seen with severe hypoglycaemia, but the rate of reported hypoglycaemia in the intensive insulin therapy group was lower as the target blood glucose level was higher (140 mg/dl) [15]. In the third study, two patients in the conventional group, and three patients in the intensive group died within 24 h of developing the hypoglycaemic event [13]. In this particular study, independent risk factors for hypoglycaemia included intensive insulin therapy, stay in the intensive care unit for more than 3 days, liver failure and renal failure requiring dialysis.
The overall weighted rate of hypoglycaemia in the conventional insulin therapy group was 1.3% (range 0.3–3.4%). In the primary meta-analysis restricted to the three RCTs [12–14], intensive insulin therapy was associated with 
6-fold increase in the relative risk of hypoglycaemia (RR 5.8; 95% CI 3.9, 8.7; P < 0.00001). When the two cohort studies were added to the analysis [15,16], intensive insulin therapy was associated with an >4-fold increase in the relative risk of hypoglycaemia (RR 4.5; 95% CI 2.4, 8.5; P < 0.00001). The effects across studies were not significantly heterogeneous (Q = 5.19, P > 0.10).
For the two studies reporting a higher incidence of severe hypoglycaemia in the intensive insulin therapy group [12,13,15], whereas the estimated NNH with intensive insulin therapy to result in one case of hypoglycaemia was 23 and 6, respectively, the estimated NNT with intensive insulin therapy to prevent one case of AKI was 31 and 33. In these instances where harm was defined as a blood glucose level of <40 mg/dl, the clinical risk/benefit ratio was 0.7 and 0.2, respectively, indicating that the clinical risk might outweigh the clinical benefit of the therapy.
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Discussion |
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The present meta-analysis demonstrates that intensive insulin therapy initiated in hyperglycaemic critically ill patients is associated with a reduction in the incidence of AKI in medical and surgical settings. Although multiple studies have documented the effect of strict glycaemic control and intensive insulin therapy on mortality in critically ill patients, only a few have reported renal outcomes. The adverse consequences of hyperglycaemia during stress, and the metabolic and non-metabolic effects of insulin in critical illness have been well described [19]. The observed benefits of intensive insulin therapy on mortality, bacteraemia and inflammation have been attributed primarily to maintenance of normoglycaemia rather than absolute levels of exogenous insulin [20,21]; however, one study has indicated that the insulin dose per se might be an independent determinant in the prevention of AKI [21]. Possible mechanisms of insulin action include anti-inflammatory effects through suppression of cytokine production, anabolic and anti-apoptotic effects and prevention of endothelial dysfunction and hypercoagulability [22]. Hyperglycaemia-induced white cell dysfunction might further contribute to inflammatory responses in the kidney [5], and insulin therapy administered to hyperglycaemic septic animals attenuates organ injury including AKI [11].
The ideal target glucose level in critically ill patients remains largely unknown, due to concern for severe inadvertent hypoglycaemia [23]. Although several insulin infusion protocols in the intensive care unit setting have been proposed, further studies are needed on protocol standardization [24]. In an interim safety analysis of the VISEP (Efficacy of Volume Substitution and Insulin Therapy in Severe Sepsis) Study, a large multi-centre RCT examining the choice of fluid resuscitation and the efficacy and safety of intensive insulin therapy in patients with severe sepsis and septic shock, the insulin arm was stopped because of an increased rate of severe hypoglycaemia (<40 mg/dl), and no significant difference in mortality between patients treated with conventional and intensive insulin therapy [25]. Although no consensus definition exists for hypoglycaemia, a study of healthy volunteers demonstrates that physiological changes occur at a blood glucose level of 65 mg/dl, with increased levels of counter-regulatory hormones; adrenergic symptoms develop at a level of 55 mg/dl; and cognitive dysfunction is present at 45 mg/dl [26]. Van den Berghe et al. [12,13] targeted very strict glycaemic control with target blood glucose level ranging between 80 and 100 mg/dl, with severe hypoglycaemia defined as a blood glucose level of <40 mg/dl; it might be prudent to target less strict blood glucose levels to reduce the risk of treatment-related hypoglycaemia.
The NNH/NNT ratio is an important indicator of the clinical risk/benefit ratio from an intervention, and should be greater than one. Two of three studies documented a higher incidence of severe hypoglycaemia in the intensive insulin therapy group, as defined by a blood glucose level of <40 mg/dl. In this instance, the clinical risk/benefit ratio ranged between 0.2 and 0.7, arguing that the risk might outweigh the benefit of insulin therapy, when harm is defined as severe hypoglycaemia. Whereas these indicators might be simple to interpret, weaknesses include lack of unit standardization in terms of time horizon and outcomes, need for similar risk populations and lack of cut-off threshold for effectiveness. A comparison of the clinical consequences of ‘severe’ hypoglycaemia to that of AKI is unknown and purely speculative, rendering this risk/benefit ratio even more difficult to interpret. So much depends on the definition of severe hypoglycaemia, and which of these two conditions has a worse long-term prognosis. Nevertheless, this analysis suggests that future studies examining the impact of insulin therapy on clinical outcomes in critically ill patients need to track very thoroughly, potential short- and long-term harm resulting from hypoglycaemia associated with the therapy.
In a recently published single-centre RCT, maintaining normoglycaemia during cardiac surgery did not improve survival [27]. In this particular study, the intensive insulin treatment group had more strokes than the conventional treatment group, and the incidence of AKI was not different between the two groups [27]. These results are in agreement with a previous study where attempted control of hyperglycaemia during cardiopulmonary bypass also had no significant effect on the incidence of cognitive deficits, and failed to shorten the length of hospital stay [28]. Whereas short-lived intra-operative glycaemic control might not be clinically beneficial, the aggressive control of hyperglycaemia in the post-operative period is likely to be of greater importance in improving patient outcomes.
In the present meta-analysis, only a small number of published studies examining AKI as the outcome of interest could be identified, and in these instances, variable definitions of AKI were used in individual studies. In addition, AKI was a secondary endpoint in all the selected studies. To assess the likelihood that the present meta-analysis had a biased sample, when we reviewed a previously published meta-analysis examining the effect of insulin therapy on mortality in critically ill patients [7,8], only one of four studies were significant, arguing against publication bias. Although we combined studies of various designs for the pooled estimates, separate analyses restricted to the RCTs yielded similar results.
Two large ongoing multi-centre RCTs of glycaemic control comparing an intensive with conventional insulin regimen, are expected to enrol a combined 8000 subjects [29,30]. Whereas the primary outcomes of these trials are all-cause mortality, dialysis requirement is a secondary outcome.
In summary, the present meta-analysis suggests that intensive insulin therapy initiated in hyperglycaemic critically ill adult patients might have a secondary beneficial effect on the prevention of AKI in medical and surgical settings. These preliminary data call for a large multi-centre RCT to assess the effect of insulin on AKI as a primary outcome, using the RIFLE criteria [17] for a uniform clinical definition, with careful monitoring of short- and long-term consequences of treatment-associated hypoglycaemia. Further studies are also required to decipher the effect of insulin dose vs glycaemic control on the prevention of AKI, as well as optimal target blood glucose levels in the critically ill that minimize the risk of severe hypoglycaemia.
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B.L.J. was supported by a grant from the National Institutes of Health (DK065102). O.L. was supported by a grant from the American Heart Association (AHA #0535367N). The authors wish to acknowledge Dr Curtis Chui and Dr Daqing Guo for their assistance in translating the article by Wang et al. [14].
This work was presented in part at the 39th Annual Meeting of the American Society of Nephrology, San Diego, CA, USA, 16–19 November 2006.
The results presented in this article have not been published previously in whole or part, except in abstract format.
Conflict of interest statement. None declared.
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Accepted in revised form: 29. 5.07
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