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Glp 1 e seus análogos em terapia intesnsiva

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    Glp 1 e seus análogos em terapia intesnsiva Glp 1 e seus análogos em terapia intesnsiva Document Transcript

    • review article Diabetes, Obesity and Metabolism 13: 118–129, 2011. © 2010 Blackwell Publishing Ltdarticlereview The potential role of glucagon-like peptide-1 or its analogues in enhancing glycaemic control in critically ill adult patients J. Combes, S. Borot, F. Mougel & A. Penfornis ´ Department of Endocrinology-Metabolism and Diabetology-Nutrition, Jean Minjoz Hospital, University of Franche-Comte, Boulevard Fleming, Besancon, France ¸ Intravenous insulin therapy is the gold standard therapy for glycaemic control in hyperglycaemic critically ill adult patients. However, hypoglycaemia remains a major concern in critically ill patients, even in some populations who are not receiving infused insulin. Furthermore, the influence of factors such as glycaemic variability and nutritional support may conceal any benefit of strict glycaemic control on morbidity and mortality in these patients. The recently revised guidelines of the American Diabetic Association/American College of Clinical Endocrinologists no longer advocate very tight glycaemic control or normalization of glucose levels in all critically ill patients. In the light of various concerns over the optimal glucose level and means to achieve such control, the use of glucagon-like peptide-1 or its analogues administered intravenously may represent an interesting therapeutic option. Keywords: acute hyperglycaemia, exenatide, GLP-1 analogues, glycaemic control, insulin intensive management, intravenous insulin therapy, type 2 diabetes mellitus Date submitted 3 January 2010; date of first decision 9 February 2010; date of final acceptance 26 September 2010 Introduction instability of the patients, and the myriad examinations and treatments that they require. Furthermore, the occurrence of The prevalence of diabetes among hospitalized adults is poorly severe hypoglycaemia, the main complication of IIT, is also documented. In the USA, it is estimated to be between problematic [7,16,17]. 5 and 30–35% [1]. According to various reports, 19–27% In addition, there is some controversy as to whether there of patients hospitalized for acute conditions [e.g. severe is any direct benefit of insulin therapy on morbidity and infection, surgery or intensive care unit (ICU) admission with mortality, independently of its effect on glycaemia. We cannot significant stress response] have documented type 2 diabetes exclude from this debate the deleterious impact on mortality mellitus (T2DM), whereas previously undiagnosed diabetes secondary to severe hypoglycaemia or excessive glycaemic or stress hyperglycaemia is diagnosed at hospital admission variability, which could overshadow the survival benefit of in an additional 12–18% [2–4]. This may be a significant the insulin therapy [5,13,18–21]. Finally, other factors, such underestimation of the true incidence of T2DM or prediabetes as mode of nutritional support or the variability between in the heterogeneous critically ill population. Several studies glucose measurement methods also compound the difficulty of have shown the benefits of tight glycaemic control (TGC), obtaining TGC [22,23]. These factors constitute obstacles to the i.e. maintaining glycaemia at normal levels between 80 and efficacious application of IIT and have probably contributed 110 mg/dl (4.4–6 mmol/l), in certain situations of temporary to the conflicting evidence about the benefits of TGC on acute glycaemic imbalance in patients with T2DM or stress morbidity and mortality rates reported in several studies. The hyperglycaemia [5–14]. issue of the risk/benefit ratio of TGC and methods to obtain Continuous intravenous insulin therapy (IIT) represents it remain at the heart of the current controversy over ideal a reasonable approach to achieve target blood glucose (BG) glucose management in the ICU. levels. However, several obstacles hamper the effective use Glucagon-like peptide-1 (GLP-1) is one of a family of of this therapy, particularly in ICUs, where IIT imposes intestinal factors named incretins, which stimulate insulin many constraints, as well as an extra workload, as it is time production in response to nutrient intake. Through its consuming [15]. Complex glucose management algorithms are multiple glucose-regulating effects, GLP-1 plays an essential difficult to apply consistently in these settings, because of the role in maintaining glucose homeostasis. GLP-1 administered intravenously rapidly lowers glycaemia without the risk of Correspondence to: Alfred Penfornis, Department of Endocrinology-Metabolism and hypoglycaemia [24]. The use of GLP-1 or its analogues could ´ Diabetology-Nutrition, Jean Minjoz Hospital, EA 3920, University of Franche-Comte, Boulevard Fleming, Besancon 25000, France. ¸ become a useful alternative or adjunct to IIT in the future in E-mail: alfred.penfornis@univ-fcomte.fr acute hyperglycaemic ICU patients.
    • DIABETES, OBESITY AND METABOLISM review articleIntravenous Insulin Therapy Similarly, Goldberg et al. [7,33] estimate that the application of IIT protocols creates an extra workload of around 5 min/hSeveral studies have shown that continuous IIT is the optimal for nurses (hourly monitoring of BG, modification of insulinroute of administration in certain cases of transitory glycaemic dose, and data entry in the patient’s file) and this can beimbalance in patients with T2DM or stress hyperglycaemia. incompatible with the already high workload in certain ICUs.Its effect on glycaemic control is more rapid, more stable Finally, patient testing and procedures, changes in feedingand more reliable, and hypoglycaemia is less intensive and protocols, evolution of the initial disease and the possibleless frequent than after repeated subcutaneous injections of presence of co-morbidities combine to render problematic theinsulin [5]. However, IIT does pose some practical problems permanent and efficacious implementation of IIT protocols toin terms of feasibility and hypoglycaemia. BG measurement in reach TGC. Similarly, Wilson et al. [34] noted a wide variabilitythis setting requires reliable methods and nutritional support in practice in this area and concluded that one standardcan complicate the task of reaching target BG levels [22,23]. It protocol might not be suitable for all patients. Accordingremains debated whether there is currently sufficient benefit to Goldberg et al. [7], Kanji et al. [30] and Barth et al.[31],to IIT with the goal of normalization of glucose levels in the successful implementation of a protocol aiming at TGC withsetting of hyperglycaemia in the ICU. The factors that influence IIT requires a considerable investment of time in training,these results warrant further exploration. practice and evaluation, and in motivating the entire medical staff of the unit [33].FeasibilityMeijering et al. [25] performed a literature review of manage- Benefit of TGC with IIT in Different ICU Populationsment of patients with stress hyperglycaemia or T2DM using IITin certain acute situations. The severity of the initial glycaemic The effect of TGC in the ICU has been investigated inimbalance, the duration of the IIT, protocols for modification various clinical settings, such as patients with myocardialof the insulin dosage, target glycaemic levels and the frequency infarction, stroke, septicaemia, trauma, neurosurgical andof BG monitoring, all varied considerably between studies, cardiac surgical patients, and the heterogeneous medical andrendering pooled analysis of the results difficult to interpret. surgical population. Results have been conflicting and, to date,However, one common point was that many of these studies it has not been possible to establish with certainty that TGC isbrought to light considerable difficulties in attaining target BG beneficial in any particular disease setting.levels, although the frequency of capillary BG monitoring, with The meta-analysis by Wiener et al. included 29 randomizeda view to dose adaptation, ranged from once every 4 h to once studies totalling 8432 patients hospitalized in intensive careper hour. In two studies in patients with T2DM during the and showed that TGC with IIT is not associated with a signif-acute phase of myocardial infarction, the average glycaemic icant mortality benefit. Conversely, Griesdale et al. [20], in alevel obtained was reported to be 187 mg/dl (10.3 mmol/l) meta-analysis of 26 studies, concluded that patients in surgicalafter 12 h [26] and 150 mg/dl (8.2 mmol/l) after 48 h [27] of ICU yield a benefit from TGC [relative risk (RR) 0.63 (95% CIIIT, whereas the target range was between 70 and 140 mg/dl 0.44–0.91)] among the 14 trials that reported hypoglycaemia.(4–8 mmol/l). This meta-analysis did not include all the studies reviewed In another study of patients with T2DM hospitalized in Wiener’s analysis, but did include the Normoglycemia infor acute medical conditions, average BG obtained after Intensive Care Evaluation-Survival Using Glucose Algorithm24 h was 183 mg/dl (10.1 mmol/l), [target 110–130 mg/dl Regulation (NICE-SUGAR) data. In a previous meta-analysis(6–7 mmol/l)], despite hourly BG monitoring [28]. including 38 randomized studies and published prior to those Finally, in a further study in patients with diabetes during of Griesdale and Wiener, Pittas et al. [35] also observed a reduc-the acute phase of stroke, 24% of patients had glycaemic levels tion in mortality in the surgical ICU with TGC [RR 0.58 (95%above target values [<130 mg/dl (<7 mmol/l)] during the first CI 0.22–0.62)]. Taken together, these data show conflicting evi-24 h, despite BG monitoring every 2 h [29]. dence and remain difficult to interpret, in view of the numerous In their respective studies in this field, Kanji et al. [30], biases and the wide variations in methodology between studies.Goldberg et al. [7] and Barth et al. [31] showed that it is possibleto adequately control glycaemia and maintain BG within target Impact of the Existence of Documented Diabetesranges using standardized IIT protocols. However, all these on Morbidity–Mortality Outcomes and on the Benefitsauthors underline the difficulty for the nursing staff to apply of TGC in the ICUsuch protocols, particularly in the intensive care setting. They When interpreting the results of the studies mentioned above,propose four main reasons to explain these difficulties: it should be noted that there is a potential bias, in that there may1 Hyperglycaemia is considered to be less important than the have been a number of patients with undiscovered diabetes at gravity of the initial disease. admission, who were considered as having stress hypergly-2 Staff are not always aware of the necessity of maintaining caemia. In a meta-analysis of 15 studies in the setting of myocar- appropriate BG levels. dial infarction in the cardiac ICU, Capes et al. [36] showed that3 They are not always experienced in applying IIT protocols, the relative risk of in-hospital death in patients without known although this is changing with the increasing use of these diabetes and with elevated glucose levels was 3.9-fold higher protocols in the ICU setting [32,33]. than that of patients without diabetes and with lower glucose4 Fear of hypoglycaemia leads staff to tolerate high BG levels. concentrations. Among patients with known diabetes, for thoseVolume 13 No. 2 February 2011 doi:10.1111/j.1463-1326.2010.01311.x 119
    • review article DIABETES, OBESITY AND METABOLISMwho had BG concentrations above 180 mg/dl (10 mmol/l), the included (532 before and 578 after implementation of TGC withrisk of in-hospital death was moderately increased (RR 1.7) IIT). A significant reduction in mortality was observed amongcompared to patients with diabetes and normal glycaemia. The patients without diabetes between the historical era and the eraretrospective Cooperative Cardiovascular Project study [37] of TGC (18.7 vs. 13.5%), whereas there was a non-significantincluded 141 680 patients admitted to the ICU for myocardial reduction among patients with diabetes (22.6 vs. 19.2%).infarction, of whom 30.4% had known diabetes. This study Conversely, in a case-control study of 7285 patients undergo-showed that elevated BG levels were significantly associated ing IIT in medical and surgical ICUs, Rady et al. [42] observedwith mortality at 30 days in patients without known diabetes a twofold higher mortality in patients without diabetes vs.vs. those with diabetes. The risk of death began to increase when controls. It is noteworthy that, in these last three studies,glycaemia exceeded 110 mg/dl (6.1 mmol/l) in patients without hyperglycaemic patients without diabetes included those withknown diabetes, whereas the threshold was higher for patients undiagnosed diabetes or a prediabetic condition. Thus, thiswith diabetes. Similarly, Krinsley [38] and Whitcomb et al. [39] may reflect part of what Umpierrez et al. [3] observed in generalalso retrospectively noted a relationship between hypergly- hospital patients who were hyperglycaemic, but undertreatedcaemia at admission and survival in patients with diabetes in and/or not known to have T2DM on admission, but who hadboth medical and surgical ICUs. In Krinsley’s study, the lowest it nonetheless.hospital mortality (9.6%) was observed among patients with More recently, subgroup analysis in the NICE-SUGARmean glucose values between 80 and 99 mg/dl, and increased study [43] did not reveal any significant difference in theprogressively as glucose values increased, reaching 42.5% treatment effect between patients with and without diabetes.among patients with mean glucose values exceeding 300 mg/dl. Although results are disparate, it appears that patientsIn the study by Whitcomb et al., the association between hyper- without diabetes yield greater benefit from intensive glucoseglycaemia on ICU admission and in-hospital mortality was not control with IIT in medical and surgical ICUs than patientsuniform in the study population; hyperglycaemia was an inde- with diabetes, whereas in the setting of cardiac ICU, patientspendent risk factor only in patients without the history of with diabetes seem to obtain the greatest benefit.diabetes in the cardiac, cardiothoracic and neurosurgical ICUs. The HI-5 study [40] compared the benefit of IIT inmyocardial infarction in 116 patients with known diabetes Impact of Glycaemic Variability on Glycaemic Controland 128 patients with admission glycaemia above 140 mg/dl in the ICU(7.8 mmol/l) but without documented diabetes. IIT was not The benefit of TGC in the ICU setting with intensive IITassociated with a reduction in mortality. However, among has been assessed in some reports by the variation in thepatients with diabetes, there was a significant reduction in mean BG levels [44]. Glucose variability may confer an adversethe risk of re-infarction after >72 h (0 vs. 7.7%, p = 0.04), risk of mortality, independent of absolute glucose level andand a lower occurrence of the composite endpoint combining indeed is a stronger risk factor for mortality than averagedeath and any major cardiac event at 3 months (21.9 vs. 40.4%, glucose levels [44,45]. In a study of 5728 patients over 3 yearsp = 0.03). in a medical-surgical ICU, Hermanides et al. [46] studied In a study performed in surgical ICU patients, Van den glycaemic variability using the absolute variation in meanBerghe et al. [14] found that IIT aiming at TGC reduced mortal- hourly BG, as well as the standard deviation of mean BG,ity in critically ill patients, regardless of the existence of known which is the usual parameter used to analyse glycaemicdiabetes or hyperglycaemia. However, the effect was more pro- variability. IIT was initiated with a target BG range ofnounced in hyperglycaemic patients without known diabetes. 72–126 mg/dl (4–6.9 mmol/l). This study showed that elevatedThe mortality rates were 8.4 vs. 4.7% in the conventional treat- glycaemic variability was associated with a significant increasement vs. intensive IIT groups, respectively, in patients without in mortality, while low glycaemic variability exerted a protectivediabetes, compared to 5.8 vs. 4% in patients with diabetes. In effect, even when mean BG remained high.a further study in 2006, Van den Berghe et al. [13] pooled the In a cohort of >66 000 ICU patients, Bagshaw et al. [47]data from their two prospective randomized studies in medical observed glycaemic variability [defined as the occurrence ofand surgical ICUs [target glycaemia range of 80–110 mg/dl hypoglycaemia <80 mg/dl (4.5 mmol/l) or hyperglycaemia(4.4–6.1 mmol/l) in the IIT group]. Among the 2748 patients >220 mg/dl (12 mmol/l) within 24 h of admission] in 2.9%included, there were 200 patients with diabetes in the conven- of patients. This early glycaemic variability was associated withtional therapy group and 207 in the intensive therapy group. a significant increase in the risk of ICU or hospital death.Contrary to the findings observed in patients without diabetes, Patients with glycaemic variability are generally older withintensive IIT showed no benefit on mortality in the subgroup of more co-morbidities, particularly heart failure and renalpatients with diabetes. Furthermore, risk of death mirrored that dysfunction. They also usually present with the most severeof patients without diabetes for all strata of BG control, with forms of disease and undergo the most aggressive therapy. Thesea non-significant increase in risk among patients with diabetes predisposing factors raise the question of whether glycaemicwhen average BG was below 110 mg/day (6.1 mmol/day). variability is a marker of disease severity or rather a risk factor In a single-centre retrospective cohort study, Krinsley [41] for morbidity and mortality.compared the outcome in patients admitted to surgical and Similarly, Egi et al. [45] retrospectively analysed 168 337 BGmedical ICUs before and during the era of TGC with IIT. measures in 7049 ICU patients and concluded that glycaemicPatients with diabetes represented 1110 of the 5365 patients variability (s.d. of mean BG) was independently associated with120 Combes et al. Volume 13 No. 2 February 2011
    • DIABETES, OBESITY AND METABOLISM review articlelonger ICU stay and higher ICU and hospital mortality. This could be explained by a lower risk of hyperglycaemia. Thus,relation was not observed among the subgroup of 728 patients early enteral nutrition is all the more recommended when IITwith known diabetes. is initiated in the ICU to treat hyperglycaemia, in order to In a prospective study of glycaemic variability in 191 patients allow better insulin dose adjustment. Van den Berghe et al.admitted to the ICUs for sepsis or septic shock, patients under- also underlined that caloric uptake is the main determiningwent intensive IIT to maintain BG between 80 and 140 mg/dl factor in deciding to adjust insulin doses, and in 62% of cases,(4.4–7.7 mmol/l) [48]. Results showed that a standard devia- hypoglycaemia results from non-adjustment of the dose oftion of BG levels >20 mg/dl (1.1 mmol/l) was associated with insulin when nutritional support is interrupted.significantly higher mortality than among patients with a stan- Vriesendorp et al. [59] also purport that non-adjustmentdard deviation <20 mg/dl (24 vs. 2.5%, p = 0.0195). Similar of insulin doses, when nutritional support (be it parenteral,results were observed by Ali et al. [49] in a retrospective study enteral or mixed) is reduced or temporarily interrupted, is oneof patients with sepsis. It would thus appear that glycaemic vari- of the main factors predisposing patients to hypoglycaemia (inability has a negative impact on outcome. Strategies to limit gly- 11% of hypoglycaemia cases).caemic variability should be an integral part of management of In a retrospective analysis of data from a subset of 211hyperglycaemia in the ICU setting in the future. However, it is of patients included in the ‘Glucontrol’ trial and 393 patients fromnote that, in the study by Van den Berghe et al. [13], in patients the Specialized Relative Insulin Nutrition Titration (SPRINT)hospitalized in mixed medical/surgical ICUs, the IIT did not initiative, Suhaimi et al. [60] showed that glycaemic variabilityconfer any major impact on improving glucose variability. is greater when insulin protocols do not take into account carbohydrate administration. Thus, it would appear that nutri-Impact of Nutritional Support on BG Control in the ICU tional support, particularly when it is modified or interrupted, may create a favourable environment for the occurrence ofThe effects of enteral or parenteral nutritional support on BG hypoglycaemia and greater glycaemic variability, through inad-control in ICU patients have been widely studied, but the results equate adjustment of IIT. This in turn can have a negativehave been discordant. Briefly, it would appear that both forms impact on glycaemic control in the ICU.of nutritional support are equivalent, and the most appropriate In the two studies by Van den Berghe carried out in themethod should be chosen taking into account the advantages medical [13] and surgical [14] ICU settings, patients initiallyand disadvantages in a given clinical situation. It has been shown received a high dose of glucose by the parenteral route (averagethat parenteral nutrition is used in 12–71% of patients, while 160 g/24 h) in the first few days, contrary to subsequententeral nutrition is used in 33–92% of ICU patients requiring studies, whose results were more equivocal. For example,nutritional support [50–55]. Several factors may explain this in the NICE-SUGAR study, average glucose administeredwide variability in the use of enteral and parenteral nutrition, intravenously was approximately 22 g/24 h.such as local practices, cost issues, nutritional status of the In a systematic review of trials that studied the impact ofpatient, the type and severity of the underlying pathology and TGC, Marik and Preiser [61] showed a significant relationshiptype of surgery. between the treatment effect of TGC on 28-day mortality and In a meta-analysis of 13 studies, Gramlich et al. [56] showed the proportion of calories provided parenterally. Conversely,that there was no difference in mortality between enteral and lack of early parenteral nutrition in such situations wouldparenteral nutrition in critically ill patients. However, they did even appear to be associated with an increase in the numberobserved a significant reduction in infectious complications of deaths. Marik and Preiser hypothesize that the differencein patients receiving enteral nutrition. The higher infectious between the positive results of Van den Berghe’s two studiesrisk observed with parenteral nutrition could be secondary to and the conflicting results observed thereafter could be at leastthe higher incidence of hyperglycaemia with this method, as partially explained by the use of early parenteral nutrition highcompared with enteral feeding [56,57]. in glucose. The influence of nutritional support on BG control has Increased glucose turnover and insulin resistance may allowbeen less extensively studied among patients receiving IIT in the body to provide sufficient supplies of the glucose thatthe ICU. Van den Berghe et al. [58] showed, in a prospective, is vital to certain organs. However, the initiation of IITrandomized study among 1548 ICU patients, that the benefit of without administration of additional glucose, by suppressingstrict BG control was similar regardless of whether nutritional the body’s adaptive response, could have a deleterious effect onsupport was enteral, parenteral or mixed. Dan et al. [57] prognosis [62]. Future studies are needed to identify the impactobserved similar findings in a retrospective study of a mixed of nutritional support on the effect of strict glycaemic controlmedical–surgical ICU. in the ICU and to elucidate whether there is a benefit from Van den Berghe et al. [58] observed that with similar levels of early parenteral high-glucose nutritional support associatednutritional support, the insulin doses required to normalize BG with intensive IIT.[target 80–100 mg/dl (4.4–6 mmol/l)] were 26% higher whennutritional support was by the parenteral route, as comparedto the enteral route, because of the incretin effects. According Hypoglycaemiato Van den Berghe, parenteral nutrition incurs a higher risk of In intervention studies among patients with diabetes inhyperglycaemia through insufficient or delayed adaptation of various acute situations where IIT aiming at TGC is used,insulin doses. These same authors also indicate that the benefit hypoglycaemia is not always reported [9,25,26]. When it isof early initiation of enteral nutrition observed in certain studies recorded, the incidence varies widely from one study to another,Volume 13 No. 2 February 2011 doi:10.1111/j.1463-1326.2010.01311.x 121
    • review article DIABETES, OBESITY AND METABOLISMranging from 0 to 17.7% [40,63–71]. Analysis and comparison In a retrospective study, Krinsley and Grover [73] alsoof these figures are difficult, as the duration of therapy, identified diabetes and sepsis as predisposing factors for hypo-glycaemia targets and insulin protocols differ significantly glycaemia, but further observed that mechanical ventilation,between studies. renal insufficiency and severity of illness were also risk factors The diabetes and insulin–glucose infusion in acute myocar- for hypoglycaemia.dial infarction (DIGAMI) 1 and DIGAMI 2 studies, which Heightened awareness of the predisposing factors forincluded a large number of T2DM patients during the acute hypoglycaemia, combined with more frequent BG controlsphase of myocardial infarction, used robust methodology to in the population at risk, could help to reduce the incidence ofillustrate that even with staff who are well trained in the applica- hypoglycaemia.tion of IIT protocols, and despite average BG results often above However, in a retrospective multicentre cohort studytarget levels with frequent monitoring, hypoglycaemia remains including 7820 patients hospitalized with acute myocardialfrequent [11,66]. In DIGAMI 1 [66], 46 of the 306 patients with infarction and who were hyperglycaemic on admission, whileT2DM (15%) in the group treated by IIT in the first 24 h were hypoglycaemia was associated with increased mortality, thisreported to have hypoglycaemia, although BG monitoring was risk was confined to patients who developed hypoglycaemiaperformed every 1 or 2 h, target levels were between 130 and spontaneously [74]. In contrast, iatrogenic hypoglycaemia after180 mg/dl (7–10 mmol/l) and average BG in the first 24 h was insulin therapy was not associated with higher mortality risk.174 ± 60 mg/dl (9.6 ± 3.3 mmol/l). In DIGAMI 2 [11], in thetwo groups of T2DM patients (n = 474 and 473, respectively) Benefit of TGC by IIT on Morbidity and Mortality intreated by IIT during the first 24 h, with the same target BG Intensive Carelevels and the same monitoring frequency as above, the rate The meta-analysis by Wiener et al. [19], published in 2008,of hypoglycaemia was 12.7 and 9.6%, respectively. Average BG included 29 randomized studies totalling 8432 patientsduring the first 24 h was 165 mg/dl (9.1 mmol/l). In the two hospitalized in intensive care and showed that TGC by IITstudies by Van den Berghe et al. in the surgical [14] and med- is not associated with a significant reduction in mortality, but isical [13] ICU setting, hypoglycaemia was reported to occur in associated with a significantly increased risk of hypoglycaemia.5.1 and 18.7%, respectively. Two multicentre studies, namely The recently published randomized NICE-SUGAR study [43]the Efficacy of Volume Substitution and Insulin Therapy in included over 6000 patients in intensive care and showed aSevere Sepsis (VISEP) [18] and Glucontrol [72] studies, were significant increase in cardiovascular and all-cause mortalityprematurely stopped. In both these studies, the target glycaemia at 90 days in the group with intensive BG control [targetlevels were the same as those used in the two Van den Berghe 81–108 mg/dl (4.4–5.9 mmol/l)] compared to the controlstudies, that is, 80–110 mg/dl (4.4–6.1 mmol/l) [13,14]. The group [target 180 mg/dl or less (10 mmol/l)]. This findingVISEP study included 537 patients, of whom 163 had dia- was also observed in the subgroups of patients hospitalized inbetes [18]. The trial was stopped because of the increased rate of medical and surgical ICUs. The results of the NICE-SUGARsevere hypoglycaemia in the group receiving intensive insulin study are at odds with those observed in previous studies intreatment (12.1 vs. 2.1% in the conventional therapy group, critical care [14], surgery [13] and the paediatric setting [75].p < 0.01) and there was no significant difference between This discrepancy in the results could be explained by differencesgroups in terms of morbidity and mortality at 28 and 90 days. in parameters such as inclusion criteria, the methods used toThe Glucontrol study [72] was prematurely stopped after the measure BG, staffing ratios, patient populations, incidenceinclusion of 1101 patients because of a high rate of unintended of diabetes and, in particular, the intervention itself, that is,protocol violations (based on the evaluation of available BG the method used to obtain strict BG control. In addition,measures). Although ICU mortality was similar in the two the results of the single-centre randomized controlled trial ofgroups (15.3% in the intermediate BG control group vs. 17.2% intensive IIT by Van den Berghe et al. in 2001 have given rise toin the intensive IIT group), higher rates of severe hypoglycaemia some debate. This unblinded study concluded that ‘intensivewere observed in the intensive therapy arm. insulin therapy to maintain BG at or below 110 mg/dl reduces In the NICE-SUGAR study, a significantly higher rate morbidity and mortality among critically ill patients in theof hypoglycaemia was also observed in the group receiving surgical ICU’. Among the several limitations of this studyintensive IIT as compared to the conventional therapy group that have been raised [76], it is of note that the study was(6.8 vs. 0.5%, p < 0.001) [43]. strongly biased towards postoperative cardiothoracic surgical The incidence of hypoglycaemia is reportedly similarly in patients, and mainly showed benefits for patients in the ICU formedical and surgical ICU patients [59] and hypoglycaemia >5 days. Furthermore, all patients initially received a high doseremains an independent risk factor for mortality in ICU of glucose by the parenteral route, followed by initiation ofpatients. Certain predisposing factors for hypoglycaemia in either total parenteral nutrition, enteral feeding or combinedthe ICU have been identified. Vriesendorp et al. [59] analysed feeding, which is a highly unusual practice. A recent meta-data from a cohort of 2272 patients admitted to the ICU, analysis [20] including 26 randomized studies, with a total ofand identified the following predisposing factors: reduction of 13 567 patients in intensive care, including the NICE-SUGARnutrition without a corresponding adjustment of insulin ther- data, showed, as in Wiener’s meta-analysis, that intensive IITapy, documented diabetes, sepsis, use of inotropic medication increases the risk of hypoglycaemia sixfold, without any benefitor octreotide and venovenous haemofiltration with bicarbonate on mortality, except in the subgroup of patients admitted tosubstitution fluid. surgical intensive care.122 Combes et al. Volume 13 No. 2 February 2011
    • DIABETES, OBESITY AND METABOLISM review article In light of the NICE-SUGAR data, the American DiabetesAssociation (ADA) and American Association of ClinicalEndocrinologists (AACE) [77] recently revised their guidelineson inpatient glycaemic control. Although the previousADA guidelines advocated initiation of insulin infusion forICU patients in the aim of maintaining BG <140 mg/dl(7.7 mmol/l), and if possible <110 mg/dl (6 mmol/l) forpatients in surgical intensive care, the revised guidelinesnow recommend that for critically ill patients, BG shouldbe maintained between 140 and 180 mg/dl (7.7–9.9 mmol/l),aiming preferably to approach the lower end of this range.Lower BG levels may be appropriate in selected patients. In therecent revision of the ‘Surviving Sepsis’ guidelines, initiationof glycaemic control is recommended, targeting BG levels<150 mg/dl after initial stabilization for the management ofpatients with severe sepsis or septic shock [78]. However,target BG <110 mg/dl (<6 mmol/l) is not recommended inany circumstances. We cannot exclude the hypothesis that a certain proportion Figure 1. Glucagon-like peptide-1 (GLP-1) secretion and metabolism.of deaths may be caused by unidentified severe hypoglycaemia Bioactive GLP-1(7-36) amide and GIP (1–42) are released from the(such as in patients with consciousness disorders, often small intestine after meal ingestion and enhance glucose-stimulatedunder sedation and whose mechanisms of hormonal counter- insulin secretion (incretin action). Dipeptidyl peptidase-4 (DPP-4) rapidly converts GLP-1 to its inactive metabolite GLP-1(9-36) in vivo. Inhibitionregulation are altered). Such an excess could mask the benefit of DPP-4 activity prevents GLP-1 degradation, thereby enhancing incretinof TGC on mortality [13,18–21,59]. action. GIP (glucose-dependent insulinotropic polypeptide) is another In addition, the practical obstacles associated with the use incretin. Adapted with permission from Ref. [107].of IIT outlined above underline how difficult it is to obtainappropriate and stable BG control. Indeed, in the NICE-SUGAR study, even with a complex and computerized IITprotocol, investigators reported that, on average, patient BGlevels were within the target range only 40% of the time [43]. Therefore, it would seem that, at present, the benefit ofTGC for patients in intensive care may be concealed by thelack of reliable tools for IIT that can effectively maintaintarget BG levels without danger of excess hypoglycaemia. TheCGAO-REA study (impact of computerized glucose control incritically ill patients), which is currently ongoing, may providenew information in this setting.Incretin–GLP-1Physiological DataGLP-1 is a gut hormone produced by the proglucagon gene in Figure 2. Chemical structure of native human glucagon-like peptide-1. Adapted with permission from Ref. [108].the L-cells located predominantly in the distal small intestine.It is secreted in response to nutrient intake (figure 1). Themain circulating form in humans is the GLP-1(7-36) amide • GLP-1 dose dependently inhibits glucagon secretion, but(figure 2). The half-life of GLP-1 is extremely short (1–2 min)because it is rapidly inactivated by the ubiquitous, non- without preventing hormonal counter-regulation at BG levelsspecific enzyme dipeptidyl peptidase-4 (DPP-4), leading to below 65 mg/dl (3.5 mmol/l). • It slows gastric emptying, reduces intestinal peristalsis andthe formation of its inactive metabolite (figure 1) [79,80]. reduces secretory activity in the upper digestive tract throughGLP-1 Possesses Several Important Pharmacodynamic Properties. mechanisms initiated by the vagal nerve and the autonomicIt stimulates insulin secretion in a dose-dependent manner, nervous system [82].but this effect disappears when BG levels are below 80 mg/dl • Finally, GLP-1 promotes satiety, which can lead to reduced(4.4 mmol/l) as the insulinotropic activity of GLP-1 is strictly food intake and weight loss [83]. This effect could beglucose-dependent [79]. On top of the insulinotropic effects, mediated by vagal afferent activity or could result from aGLP-1 stimulates insulin production and exerts a trophic effect direct action of circulating GLP-1 on areas of the centralon β cells (differentiation of progenitor cells, reduction of nervous system with receptors that are not protected by theapoptosis and proliferation of β cells) (figure 3) [81]. blood–brain barrier.Volume 13 No. 2 February 2011 doi:10.1111/j.1463-1326.2010.01311.x 123
    • review article DIABETES, OBESITY AND METABOLISMFigure 3. Glucagon-like peptide-1 (GLP-1) action in peripheral tissues. The majority of the effects of GLP-1 are mediated by direct interaction withGLP-1 receptors on specific tissues. However, the actions of GLP-1 in liver, fat and muscle most probably occur through indirect mechanisms. Adaptedwith permission from Ref. [107].GLP-1 in the Treatment of T2DM Intravenous (IV) Administration of GLP-1GLP-1 possesses two essential characteristics that enhance Efficacy. Several studies have shown that continuous IVits potential as a treatment for T2DM. First, the majority infusion of GLP-1 makes it possible to normalize fastingof its effects are exerted very rapidly in the presence and postprandial (PP) glycaemia in patients with T2DMof hyperglycaemia and cease as soon as BG returns to suffering from moderate to severe glycaemic imbalance (apartnormal levels. Second, in patients with T2DM, secretion of from episodes of acute decompensation) [85,86]. SimilarGLP-1 may be diminished, but sensitivity to GLP-1 remains efficacy is observed regardless of whether patients wereunchanged. These particular characteristics combine to make initially treated with sulphonylurea [86,87], metformin [88]GLP-1 a focus of research for the treatment of T2DM in or pioglitazone [89]. Normalization of fasting BG in T2DMsituations of acute hyperglycaemia. However, in the case patients can be obtained within approximately 4 h after theof ICU patients, hyperglycaemia is often stress-induced and start of GLP-1 infusion. When fasting glycaemia is abovepatients are not known to have T2DM. Also, with counter- 270 mg/dl (15 mmol/l), normalization may take longer [90].regulatory hormones potentially altered during critical illnessand altered gluconeogenesis or glycogenolysis (e.g. in those Dosage and Side Effects. In most studies, the most efficaciouswith decompensated liver or relative starvation), the global and best tolerated dose of GLP-1 when administered by infusionpotential of GLP-1 remains to be elucidated through further is from 1 to 1.2 pmol/kg/min. This does not increase the risk ofresearch. hypoglycaemia [85,86,91–95]. There exists a dose-dependent relationship between the dose of GLP-1 administered and deceleration of gastric emptying which may cause digestive sideSubcutaneous Injection of GLP-1 effects after food intake. Higher doses improve BG levels consid-Subcutaneous injection of high doses of GLP-1 (1.5 nmol/kg) erably, but also significantly increase the rate of side effects [87].makes it possible to rapidly normalize BG levels in patients However, Meier et al. [91] showed in a recent study that nor-with T2DM. However, the effect is of short duration, because malization of fasting and PP glycaemia (test meal of 250 kcal)of the rapid inactivation of GLP-1, and therefore regular in patients with T2DM was not dose-dependent at doses lowersubcutaneous injections every 2 h are required to maintain than 1.2 pmol/kg/min. GLP-1 administered at doses of 0.4, 0.8BG levels within the normal range [84]. or 1.2 pmol/kg/min by overnight infusion, or started 1 h before124 Combes et al. Volume 13 No. 2 February 2011
    • DIABETES, OBESITY AND METABOLISM review articlea meal, normalized BG levels in the same manner both in the observed from week 1 and persisted till 6 weeks, with a reduc-fasting state and 4 h after the meal. However, unlike the lower tion of 1.3% (12 mmol/mol) in HbA1c. At this dose, BG levelsdoses of GLP-1, gastric emptying was almost completely inhib- were thus not normalized, but tolerance was good [98].ited 4 h after meal intake at the 1.2 pmol/kg/min dose. These Over a period of 3 months, subcutaneous administration ofadverse effects of GLP-1 activity on intestinal motility and diges- GLP-1 in elderly patients (75 ± 2 years) with T2DM at a dosetive secretions may compound the reduction in gastric empty- of 2.4 pmol/kg/min was shown to be as efficacious as treatmenting frequently observed in ICU patients. This renders the use of by oral antidiabetic agents (metformin and/or sulphonylureaGLP-1 difficult in medical–surgical patients with gastrointesti- treatment) to maintain HbA1c at 7% (53 mmol/mol), withnal or pancreatic diseases as well as in patients with diabetic gas- good tolerance and without the risk of hypoglycaemiatroparesis. Whether GLP-1-based therapies might increase the observed with secretagogues [97]. However, it is unlikelyrisk of aspiration and alter gastrointestinal tract caloric intake, that subcutaneous administration, whether continuous orbecause of the changes they can induce in gastric emptying and not, would be a viable option for ICU patients, because offood absorption, should be closely monitored in these critical the absorption difficulties linked to the frequent presence ofsituations. However, Deane et al. [96] have shown, in critically vasoconstriction or peripheral oedema, and the potential forill mechanically ventilated patients, without known diabetes, haematoma or infection in or around the sites of recurrentthat exogenous GLP-1 slows gastric emptying only when the lat- subcutaneous infusions or injections in frail patients.ter is normal, but not when it is already spontaneously delayed. Controlled Intervention StudiesContinuous or Discontinuous Infusion. Infusion of 1 pmol/kg/ Although it has been shown that continuous IV infusion ofmin of GLP-1 for 4 h in patients with T2DM in the fasting state, GLP-1 at doses of 1–1.2 pmol/kg/min makes it possible towith average initial BG of 210 ± 16 mg/dl (11.7 ± 0.9 mmol/l), rapidly normalize fasting and PP BG levels with good tolerancenormalizes glycaemia at the end of infusion [87 ± 7 mg/dl in diabetic patients with severe, transitory glycaemic imbalance(4.8 ± 0.4 mmol/l)] and for up to 4 h afterwards if patients (apart from episodes of acute decompensation), there is aremain fasting [92,93]. If food is given after the interruption paucity of controlled intervention studies in this setting. Inof GLP-1 infusion, then BG rises within 1 h to levels similar to particular, data are lacking about the use of GLP-1 in the highlythose observed after the infusion of placebo [95]. However, if complex, dynamic and often unstable ICU patient who mayfood is ingested while maintaining an infusion of GLP-1, BG have little hepatic or pancreatic reserve.remains normal [91,94]. In a randomized study of eight patients with T2DM, In patients with poorly controlled T2DM and normal food Schmoelzer et al. [99] observed that GLP-1 infusion at a doseintake of 3 meals/day, only a continuous infusion of GLP-1 of 1.2 pmol/kg/min over 8 h normalized BG to the same extentmade it possible to maintain normal BG levels over a 24-h as IIT, with a more rapid effect, without dose adaptation andperiod. Interruption of the infusion for 6 h during the night without hypoglycaemia.resulted in elevated fasting BG levels, similar to those observed In a study among eight patients with T2DM who hadunder 24-h placebo infusion. The beneficial effect on BG levels undergone major surgery, Meier et al. [24] observed that withcan persist for up to 1 week if continuous IV infusion of GLP-1 infusion of GLP-1 over 8 h at a dose of 1.2 pmol/kg/minis maintained [87]. between the second and eighth postoperative day, a normoglycaemic fasting BG range was reached within 150 min, with good tolerance and without hypoglycaemia. In aContinuous Subcutaneous Infusion of GLP-1 randomized study of GLP-1 IV infusion vs. placebo in 20The therapeutic use of GLP-1 for the long term is hampered patients during the postoperative phase, Sokos et al. showedby the necessity of IV administration. In this context, studies that in the 12 h preceding and the 48 h following coronaryhave been carried out to test continuous subcutaneous pump artery bypass graft surgery, GLP-1 at a dose of 1.5 pmol/kg/mininfusion over periods ranging from 48 h [90] to 3 months [97]. achieved better glycaemic control, with less frequent use of IIT,Administration by the subcutaneous route achieves circulating and 45% less insulin was required to obtain the same glycaemicGLP-1 concentrations that are more or less equivalent to those control compared to when IV insulin was used. Furthermore,obtained by the IV route by radio-immunological dosing, but GLP-1 achieved comparable haemodynamic recovery, withfor reasons that remain to be identified, the therapeutic efficacy less use of inotropic and anti-arrhythmic medication [100].and the side effects are less. Thus, doses of 2.4–4.8 pmol/kg/min These beneficial effects are in line with the GLP-1-inducedare necessary by subcutaneous administration, compared to improvements in left ventricular ejection fraction in micedoses of 0.4–1.2 pmol/kg/min by the IV route to obtain a subjected to ischaemia–reperfusion [101].significant therapeutic effect [90,97,98]. In another randomized study of GLP-1 IV infusion vs. IIT In a parallel group study of 20 patients with poorly among 20 patients with T2DM over the 12 h following coronarycontrolled T2DM [HbA1c 9.2 ± 1.8% (77 ± 17 mmol/mol)], artery bypass graft surgery, GLP-1 at a dose of 3.6 pmol/kg/minZander et al. showed that GLP-1 administered by subcutaneous obtained normalized glycaemia levels as efficaciously as IIT,infusion at a dose of 4.8 pmol/kg/min for 6 weeks lowered fast- with good tolerance and no reported hypoglycaemia [102].ing BG from 261 to 183 mg/dl (14.4–10.1 mmol/l), and average A further study showed that infusion of GLP-1 over 4 hplasma BG as assessed by an 8-h profile of BG concentrations makes it possible to normalize BG levels in severely ill patientswas reduced by 100 mg/dl (5.5 mmol/l). These effects were hyperglycaemic during total parenteral nutrition [103].Volume 13 No. 2 February 2011 doi:10.1111/j.1463-1326.2010.01311.x 125
    • review article DIABETES, OBESITY AND METABOLISM Finally, Deane et al. [104] assessed the effect of exogenous the apparently inferior efficacy as compared to insulin and theGLP-1 on the glycaemic response to enteral nutrition need for insulin–GLP-1 combination therapy in some patients.in patients with critical illness-induced hyperglycaemia. In Intervention studies with exenatide are currently ongoingthis randomized double-blind placebo-controlled crossover [see http://clinicaltrials.gov: IV exenatide (Byetta®) for thestudy, seven mechanically ventilated critically ill patients, treatment of perioperative hyperglycaemia, NCT00882050; IVnot previously known to have diabetes, received two IV exenatide in coronary ICU patients, NCT00736229], which mayinfusions of GLP-1 (1.2 pmol/kg/min) and placebo over answer some of these outstanding questions and subsequently270 min, while a mixed nutrient liquid was infused via help evaluate the potential benefit of GLP-1 therapy ona postpyloric feeding catheter. Acute, exogenous GLP-1 morbidity and mortality.infusion markedly attenuated the glycaemic response to enteralnutrition in all these critically ill patients, with reduced overall Acknowledgementglycaemic response during enteral nutrient stimulation andreduced peak BG [GLP-1 (10.1 ± 0.7 mmol/l) vs. placebo We would like to thank Fiona Ecarnot for translation and(12.7 ± 1.0 mmol/l); p < 0.01]. The same authors, in a similar editorial assistance.study design, showed that exogenous GLP-1 lowers PPglycaemia in 25 critically ill patients after intragastric feeding. Conflict of InterestThis may occur, at least in part, by reducing the rate of J. C. and A. P. took the decision to write this review and werecarbohydrate absorption [96]. responsible for writing the manuscript. All authors contributed to the research and analysis of literature and drafting andGLP-1 Analogues revising the manuscript. Prof. Penfornis reports receiving an investigator-initiated research grant and honoraria for speakingAs the therapeutic use of GLP-1 is considerably limited by its engagements from Eli Lilly. No other potential conflicts ofvery short half-life, GLP-1 receptor agonists (GLP-1 analogues), interest relevant to this review were reported.which are active for longer, have been developed. Exendin-4 or exenatide (Byetta®, Amylin PharmaceuticalsInc., San Diego, CA, USA) is the first GLP-1 mimetic to be Referencesapproved for the treatment of T2DM. The approved dose for 1. Cowie CC, Rust KF, Ford ES et al. Full accounting of diabetes and pre-exenatide is 5–10 μg, twice daily, by subcutaneous injection. diabetes in the U.S. population in 1988–1994 and 2005–2006. Diabetes Care 2009; 32: 287–294.A subcutaneous injection of 5–10 μg of exenatide exerts itsbiological effects for a duration of 5–7 h [105]. 2. Pili-Floury S, Mitifiot F, Penfornis A et al. Glycaemic dysregulation in nondiabetic patients after major lower limb prosthetic surgery. Diabetes A recent study in 13 patients with diabetes with BG within Metab 2009; 35: 43–48.normal range {[HbA1c at 6.1% (43 mmol/mol)], plasma BG 3. Umpierrez GE, Isaacs SD, Bazargan N, You X, Thaler LM, Kitabchi AE.between 70 and 101 mg/dl (4.4 and 5.6 mmol/l)} and receiving Hyperglycemia: an independent marker of in-hospital mortality inglucose infusion showed that IV infusion of exenatide at a patients with undiagnosed diabetes. J Clin Endocrinol Metab 2002; 87:dose of 25 ng/min augmented first- and second-phase insulin 978–982.secretion and brought BG down from 300 mg/dl (16.5 mmol/l) 4. Wexler DJ, Nathan DM, Grant RW, Regan S, Van Leuvan AL, Cagliero E.to initial values in less than 3 h with excellent tolerance [106]. Prevalence of elevated hemoglobin A1c among patients admitted to the Results of ongoing longer-term studies with exenatide by IV hospital without a diagnosis of diabetes. J Clin Endocrinol Metab 2008;infusion in T2DM patients with acute glycaemia imbalance are 93: 4238–4244.keenly awaited. 5. Clement S, Braithwaite SS, Magee MF et al. Management of diabetes and hyperglycemia in hospitals. Diabetes Care 2004; 27: 553–591. 6. Furnary AP, Gao G, Grunkemeier GL et al. Continuous insulin infusionConclusion reduces mortality in patients with diabetes undergoing coronary arteryGLP-1 administered by IV infusion makes it possible to rapidly bypass grafting. J Thorac Cardiovasc Surg 2003; 125: 1007–1021.normalize and stabilize BG in hyperglycaemic patients with 7. Goldberg PA, Siegel MD, Sherwin RS et al. Implementation of a safediabetes. GLP-1 therapy, at a dose of 1–1.2 pmol/kg/min, is and effective insulin infusion protocol in a medical intensive care unit.well tolerated, without the risk of hypoglycaemia, and reduces Diabetes Care 2004; 27: 461–467.the frequency of capillary BG testing. GLP-1 therapy shows 8. Hermans G, Wilmer A, Meersseman W et al. Impact of intensive insulingreat promise as a new therapeutic alternative to intensive IIT therapy on neuromuscular complications and ventilator dependency in the medical intensive care unit. Am J Respir Crit Care Med 2007; 175:in situations of glycaemic imbalance in patients with T2DM. 480–489.Administration of GLP-1 receptor agonists by the IV route 9. Lazar HL, Chipkin SR, Fitzgerald CA, Bao Y, Cabral H, Apstein CS. Tightcan compensate for the current difficulties in access to GLP-1 glycemic control in diabetic coronary artery bypass graft patientstherapy. Treatment with GLP-1 or its analogues needs to improves perioperative outcomes and decreases recurrent ischemicbe explored further through larger-scale studies to confirm events. Circulation 2004; 109: 1497–1502.encouraging results from preliminary studies. Remaining 10. Malmberg K. Prospective randomised study of intensive insulin treatmentareas of concern that require clarification include tolerance on long term survival after acute myocardial infarction in patients with(particularly gastrointestinal tolerance in ICU patients being diabetes mellitus. DIGAMI (Diabetes Mellitus, Insulin Glucose Infusion intube fed or in postoperative patients at high risk for ileus), Acute Myocardial Infarction) Study Group. BMJ 1997; 314: 1512–1515.126 Combes et al. Volume 13 No. 2 February 2011
    • DIABETES, OBESITY AND METABOLISM review article 11. Malmberg K, Ryden L, Wedel H et al. Intense metabolic control by means safety of blood glucose control in critically ill adults. Intensive Care Med of insulin in patients with diabetes mellitus and acute myocardial 2004; 30: 804–810. infarction (DIGAMI 2): effects on mortality and morbidity. Eur Heart J 31. Barth MM, Oyen LJ, Warfield KT et al. Comparison of a nurse initiated 2005; 26: 650–661. insulin infusion protocol for intensive insulin therapy between adult 12. Scalea TM, Bochicchio GV, Bochicchio KM, Johnson SB, Joshi M, Pyle A. surgical trauma, medical and coronary care intensive care patients. BMC Tight glycemic control in critically injured trauma patients. Ann Surg Emerg Med 2007; 7: 14. 2007; 246: 605–610; discussion 10–12. 32. Furnary AP, Wu Y. Clinical effects of hyperglycemia in the cardiac surgery 13. Van den Berghe G, Wilmer A, Milants I et al. Intensive insulin therapy population: the Portland Diabetic Project. Endocr Pract 2006; 12(Suppl. in mixed medical/surgical intensive care units: benefit versus harm. 3): 22–26. Diabetes 2006; 55: 3151–3159. 33. Studer C, Sankou W, Penfornis A et al. Efficacy and safety of an insulin 14. Van den Berghe G, Wouters P, Weekers F et al. Intensive insulin therapy infusion protocol during and after cardiac surgery. Diabetes Metab 2010; in the critically ill patients. N Engl J Med 2001; 345: 1359–1367. 36: 71–78. 15. Aragon D. Evaluation of nursing work effort and perceptions about blood 34. Wilson M, Weinreb J, Hoo GW. Intensive insulin therapy in critical care: a glucose testing in tight glycemic control. Am J Crit Care 2006; 15: review of 12 protocols. Diabetes Care 2007; 30: 1005–1011. 370–377. 35. Pittas AG, Siegel RD, Lau J. Insulin therapy for critically ill hospitalized 16. Bode BW, Braithwaite SS, Steed RD, Davidson PC. Intravenous insulin patients: a meta-analysis of randomized controlled trials. Arch Intern infusion therapy: indications, methods, and transition to subcutaneous Med 2004; 164: 2005–2011. insulin therapy. Endocr Pract 2004; 10(Suppl. 2): 71–80. 36. Capes SE, Hunt D, Malmberg K, Gerstein HC. Stress hyperglycaemia and 17. Egi M, Bellomo R, Stachowski E et al. Hypoglycemia and outcome in increased risk of death after myocardial infarction in patients with and critically ill patients. Mayo Clin Proc 2010; 85: 217–224. without diabetes: a systematic overview. Lancet 2000; 355: 773–778. 18. Brunkhorst FM, Engel C, Bloos F et al. Intensive insulin therapy and 37. Kosiborod M, Rathore SS, Inzucchi SE et al. Admission glucose and pentastarch resuscitation in severe sepsis. N Engl J Med 2008; 358: mortality in elderly patients hospitalized with acute myocardial infarction: 125–139. implications for patients with and without recognized diabetes. 19. Wiener RS, Wiener DC, Larson RJ. Benefits and risks of tight glucose Circulation 2005; 111: 3078–3086. control in critically ill adults: a meta-analysis. JAMA 2008; 300: 933–944. 38. Krinsley JS. Association between hyperglycemia and increased hospital 20. Griesdale DE, de Souza RJ, van Dam RM et al. Intensive insulin therapy mortality in a heterogeneous population of critically ill patients. Mayo and mortality among critically ill patients: a meta-analysis including Clin Proc 2003; 78: 1471–1478. NICE-SUGAR study data. CMAJ 2009; 180: 821–827. 39. Whitcomb BW, Pradhan EK, Pittas AG, Roghmann MC, Perencevich EN. 21. Gandhi GY, Murad MH, Flynn DN et al. Effect of perioperative insulin Impact of admission hyperglycemia on hospital mortality in various infusion on surgical morbidity and mortality: systematic review and intensive care unit populations. Crit Care Med 2005; 33: 2772–2777. meta-analysis of randomized trials. Mayo Clin Proc 2008; 83: 418–430. 40. Cheung NW, Wong VW, McLean M. The hyperglycemia: Intensive Insulin 22. Martindale RG, McClave SA, Vanek VW et al. Guidelines for the provision Infusion in Infarction (HI-5) study: a randomized controlled trial of insulin and assessment of nutrition support therapy in the adult critically ill infusion therapy for myocardial infarction. Diabetes Care 2006; 29: patient: Society of Critical Care Medicine and American Society for 765–770. Parenteral and Enteral Nutrition: executive summary. Crit Care Med 2009; 37: 1757–1761. 41. Krinsley JS. Glycemic control, diabetic status, and mortality in a heterogeneous population of critically ill patients before and during 23. Rice MJ, Pitkin AD, Coursin DB. Review article: glucose measurement in the era of intensive glycemic management: six and one-half years the operating room: more complicated than it seems. Anesth Analg experience at a university-affiliated community hospital. Semin Thorac 2010; 110: 1056–1065. Cardiovasc Surg 2006; 18: 317–325. 24. Meier JJ, Weyhe D, Michaely M et al. Intravenous glucagon-like peptide 42. Rady MY, Johnson DJ, Patel BM, Larson JS, Helmers RA. Influence of 1 normalizes blood glucose after major surgery in patients with type 2 individual characteristics on outcome of glycemic control in intensive diabetes. Crit Care Med 2004; 32: 848–851. care unit patients with or without diabetes mellitus. Mayo Clin Proc 25. Meijering S, Corstjens AM, Tulleken JE, Meertens JH, Zijlstra JG, Ligtenberg 2005; 80: 1558–1567. JJ. Towards a feasible algorithm for tight glycaemic control in critically ill patients: a systematic review of the literature. Crit Care 2006; 10: R19. 43. Finfer S, Chittock DR, Su SY et al. Intensive versus conventional glucose control in critically ill patients. N Engl J Med 2009; 360: 1283–1297. 26. Davies RR, Newton RW, McNeill GP, Fisher BM, Kesson CM, Pearson D. Metabolic control in diabetic subjects following myocardial infarction: 44. Krinsley JS. Glycemic variability: a strong independent predictor of difficulties in improving blood glucose levels by intravenous insulin mortality in critically ill patients. Crit Care Med 2008; 36: 3008–3013. infusion. Scott Med J 1991; 36: 74–76. 45. Egi M, Bellomo R, Stachowski E, French CJ, Hart GK. Variability of blood 27. Hendra TJ, Yudkin JS. An algorithm for tight glycaemic control in diabetic glucose concentration and short-term mortality in critically ill patients. infarct survivors. Diabetes Res Clin Pract 1992; 16: 213–220. Anesthesiology 2006; 105: 244–252. 28. Bonnier M, Lonnroth P, Gudbjornsdottir S, Attvall S, Jansson PA. Valida- 46. Hermanides J, Vriesendorp TM, Bosman RJ, Zandstra DF, Hoekstra JB, tion of a glucose-insulin-potassium infusion algorithm in hospitalized Devries JH. Glucose variability is associated with intensive care unit diabetic patients. J Intern Med 2003; 253: 189–193. mortality. Crit Care Med 2010; 38: 838–842. 29. 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    • review article DIABETES, OBESITY AND METABOLISM 49. Ali NA, O’Brien JM Jr, Dungan K et al. Glucose variability and mortality in 69. Pezzarossa A, Taddei F, Cimicchi MC et al. Perioperative management patients with sepsis. Crit Care Med 2008; 36: 2316–2321. of diabetic subjects. Subcutaneous versus intravenous insulin admin- 50. De Jonghe B, Appere-De-Vechi C, Fournier M et al. A prospective survey istration during glucose-potassium infusion. Diabetes Care 1988; 11: of nutritional support practices in intensive care unit patients: What is 52–58. prescribed? What is delivered? Crit Care Med 2001; 29: 8–12. 70. Stefanidis A, Melidonis A, Tournis S et al. Intensive insulin treatment 51. Heyland DK, Schroter-Noppe D, Drover JW et al. Nutrition support in the reduces transient ischaemic episodes during acute coronary events in critical care setting: current practice in Canadian ICUs—opportunities for diabetic patients. Acta Cardiol 2002; 57: 357–364. improvement? 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