Intensive glycemic control may be associated with increased mortality in adult ICU patients

Intensive glycemic control may be associated with increased mortality in adult ICU patients: results of the NICE-SUGAR.

Hyperglycemia is common in hospitalized patients in the ICU with a critical condition. Development of hyperglycemia in critical conditions associated with increased mortality and morbidity in various patient populations. The results of studies of intensive glycemic control in these patients were mixed. Conclusions of systematic reviews and meta-analysis were also contradictory. Despite this, many professional associations found it possible to recommend an intensive glucose control for routine use in ICU patients. The main impediments to widespread practice of intensive glycemic control, are the conflicting results of some studies, an associated increased risk of hypoglycemia and with the difficulty of achieving target levels of glycemia in some patients. The Study Group NICE-SUGAR (Normoglycaemia in Intensive Care Evaluation and Survival Using Glucose Algorithm Regulation) conducted an international multicenter study to examine the effect of intensive glucose control on mortality after 90 days in ICU patients.

Methods and progress in the study.

The study was performed in a randomized controlled design with parallel groups. The study included patients from 42 ICUs of hospitals, Australia, New Zealand, North America, including 38 specialized academic hospitals and four conventional hospitals. The study included patients who were expected to spend in the ICU more than three consecutive days. Included patients were randomly divided into two groups studied: a group of intensive glycemic controls (target blood glucose levels beyond 4.5 - 6.0 mmol / l) and a group of traditional controls (target value gyukozy blood - less than 10.0 mmol / l).

intensive glycemic control and cardiovascular disease an update
To control blood-glucose levels used insulin infusion in saline. Under the traditional glycemic control, insulin administered to patients if glucose levels exceed 10 mg / dL, with a decrease in blood glucose to 10.0 mmol / insulin infusion rate decreased, and at lower glucose levels below 8.0 mmol / l, insulin infusion stop. In the intensive glucose, control used the same tactics, but the thresholds of glycemia were respectively 6 and 4.5 mg / dL. Glycemic control was performed routinely staff the center-study participant. All other aspects of patient management, including nutritional support, were left to the discretion of the attending physicians.

Local study coordinator recorded the basic data have included patients, including some demographic characteristics, the value of the APACHE II scale and diagnostic criteria for severe sepsis. Admission to the ICU directly from the operating room or from the Chamber of awakening (recovery room) was classified as post-operative admission. The patient was classified as trauma patients if he went to the ICU within 48 hours of hospitalization due to injury. It was also given a history of diagnosis of diabetes and the use of systemic corticosteroids within 72 hours or more before randomization.

The primary outcome measured our patient was included in all-cause mortality within 90 days after randomization. Other outcome measures were evaluated: time to death or until the completion of the protocol, the mortality depending on the causes, duration of stay in ICU, duration of renal replacement therapy and the duration of mechanical ventilation, place of death (ICU, general ward, other), developments of new organ failure, the identification of positive bacterial cultures of blood, the need for transfusions of red blood cells and volume of transfusion.

The primary analysis of mortality at 90 days was performed using uncorrected chi-square test. It was also carried out a secondary analysis based on logistic regression for various selected subpopulations. Other binary endpoints were compared using chi-square test or Fisher's exact test. Quantitative variables were compared using unpaired t-test, Welch's test or the Wilcoxon test. Subgroup analyses of primary outcome measures were carried out based on an uncorrected test of interaction in the logistic model.

Just a study for the period from December 2004 to November 2008 included 6,104 patients who were random chiroway into two groups: 3054 patients in the intensive glycemic control and 3050 patients in the conventional glycemic control for the analysis of data was available 6,030 patients, among whom 5,275 (87.5%) were hospital patients in Australia and New Zealand.

Key baseline characteristics were similar in the groups studied. The average patient age (+ / - SD) was 60.4 + / - 17.2 years in the intensive glycemic control and 59.9 + / - 17.1 years in the group of traditional controls, mean baseline APACHE II on a scale of 21, 1 + / - 7.9 and 21.1 + / - 8.3 points; percentage of postoperative income amounted to 36, 9% and 37, 2% in the intensive and conventional glucose control group, respectively.

Prescribed protocol of glycemic control has been fully implemented in 5997 patients: 2998 patients at the intensive monitoring and 2,999 patients of the traditional glycemic control average duration of treatment of patients investigated by the protocol of glycemic control was 4.2 days (interquartile range: 1,9 - 8,7 days) in the intensive control and 4.3 days (interquartile range: 2,0 - 9,0 days) traditional control group (p = 0, 69). The study protocol was stopped prematurely in 304 out of 3,054 patients (10%) in the intensive glycemic control and in 225 of 3,050 patients (7.4%) in the conventional control. The reasons for early termination of participation in the study were: a request by the patient or his representatives (26 patients [0.9%] of intensive control and 22 patients [0.7%] of conventional glucose control), or request the attending physician for early termination of participation in study (115 patients [3.8%] and 48 [1.6%], respectively), with the development of serious adverse events (13 patients [0.4%] and 1 patient [<0.1%], respectively), Thetransfer of patients to palliative therapy (116 patients [3.8%] and115patients [3.8%], respectively) andother reasons (34patients [1.1%] and39 patients [1.3%], respectively) . Patients of intensive glycemic control in general, received meaningfully more insulin (2,931 of 3, 014 patients [97.2%] compared to 2080 of 3014 patients [69.0%], respectively, p <0,001). They received more than the average number of doses of insulin than those of tradition the traditional(50.2 + / - 38.1 IU per day compared with.9. + /- 29.0 respectively, p <0,001).The average glucose level over time participation in the study was significantly lower in the comprehensive control group than in the conventional glycemic control (6.4 +/ - 1.0 mmol /l compared with 8.0 + / - 1.3 mmol /l, respectively, p <0,001). During the first 14 days after randomization, the average caloric nonproteins food is not statistically different between groups and amounted to 891 + / - 490 kcal in the intensive control and 972 + / - 500 kcal in a group of traditional controls (p = 0, 14), including 624 + / - 496 kcal (70.0%) and 623 + / - 496 kcal (71.4%), respectively, in the form of enteral nutrition, 173 + / - 359 kcal (19.4%) and 162 + / - 345 kcal (18,6%) in the form of parenteral nutrition and 93.4 + / - 88.8 kcal (10.5%) and 87.2 + / -93.5 kcal (10, 0) in the form of intravenous solutions of glucose. After the randomization bólshee number of patients at the intensive monitoring in comparison with patients of control group receiving conventional corticosteroids (1042 of 3010 [34.6%], compared with 955 of 3,009 [31.7%], p = 0.02). The most common indications for corticosteroids in both groups were treated septic shock. The absolute numbers of patients in septic shock were not statistically different between groups (p = 0.42). On the 90 th days after randomization, 829 patients died from 3010 (27.5%) in the intensive control and 751 of 3012 patients (24.9%) in the conventional control. The absolute difference in mortality between the groups was 2.6% (95% CI, 0,4 - 4, 8), and the odd's ratio for mortality in the intensive control was 1.14 (95% CI 1.02 - 1.28, p = 0, 04). Mortality difference persisted and after balancing the groups on the main pre-defined underlying risk factors (odd's ratio after equilibration, 1.14, 95% CI 1,01 - 1, 29; p = 0, 04). In general, the distributions of patients on the possible causes of death were similar between the groups (p = 0, 12), but in the intensive control, bolshee noted the number of deaths associated with cardiovascular events (absolute difference - 5, 8%; p = 0, 02) . In both groups, death of patients in most cases had occurred in the ICU (546 of 829 patients [65.9%] and 498 out of 751 patients [66.3%], respectively). In both groups of patients who died more than 90% of cases, potentially life-sustaining treatment is not used or was stopped. During the study, periods were noted statistically significant differences between groups in median stay in ICU or in the hospital. By the 90 th day of 3016, seven patients (0.2%) out of intensive glycemic control, and 6 of 3014 patients (0.2%) in the traditional controls were still in the ICU (p = 0, 78), and 174 patients ( 5, 8% and 166 patients (5.5%) were still in hospital (p = 0.66). Number of patients who developed new organ dysfunction after inclusions in the study were similar between groups (p = 0, 11). Furthermore, not mentioned differences between the groups on the number of days of mechanical ventilation, renal replacement therapy, the detection rate of positive bacterial cultures of blood and frequency of transfusions of red blood cells. Subpopulation's analysis revealed no statistically significant differences in mortality rates for the 90 th day between subgroups of operated and un-operated patients (p = 0, 10), patients with severe sepsis and without (p = 0.93), patients with diabetes and without (p = 0, 60), as well as between subgroups of patients with an APACHE II on admission and more than 25 (p = 0, 84). In the subpopulation, analysis was a trend towards lower levels of mortality in the intensive control in the subgroup of trauma patients (41/421 patients in the intensive control vs. 57/465 patients in the conventional glucose control, odds ratio 0.77 [95% CI 0, 50 - 1, 18], p = 0.07) and in the subgroup of patients treated with corticosteroids (134/392 vs. 140/378 patients, respectively, odds ratio 0.88 [95% CI 0.66 - 1.19], p = 0.06). Severe hypoglycemia (defined as blood glucose below 2.2 mmol / L) was detected in 206 out of 3,016 patients (6.8%) in the intensive management, compared with 15 out of 3,014 patients (0.5%) in the traditional control hyperglycemia (odds ratio 14.7, 95% CI 9.0 - 25.9, p <0,001). Notreported on the identification of any long-term effects of severe hypoglycemia. Conclusions. In the large international randomized trial of intensive glycemic control (4,5 - 6,0 mmol / l) compared with conventional glycemic control (<10.0 mmol / L) was associated with increased mortality in adult ICU patients. Differences persisted after adjustment for major risk factors for adverse out comes. Severe hypoglycemia (less than 2.2 mmol / L) also significantly more common in the intensive control group compared with the conventional glycemic control.

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