Abstract: Stress-induced hyperglycemia occurs frequently in Intensive Care Units (ICU). Intensive Insulin Therapy (IIT) may reduce mortality and morbidity in critically ill patients. The present study investigates the effect of normoglycemia on morbidity and mortality of medical and trauma critically ill patients at Mansoura Emergency Hospital, Egypt. A prospective study comparing 2 consecutive time periods before and after IIT protocol implementation: period I (conventional glycemic control) with target blood glucose level 120-180 mg dL-1 and period II (IIT group) with target blood glucose level 80 to 130 mg dL-1. One hundred patients were subjected to no protocol and other one hundred patients were subjected to IIT. Study endpoints were the incidences of sepsis, hospital deaths, durations of mechanical ventilation and hospital length of stay in the ICU or hospital. The number of the patients receiving IIT was significantly higher than conventional glycemic control (97 vs. 69%). Patients on IIT protocol received significantly larger mean insulin dose 45±15 vs. 16±10 unit day-1 with conventional control. The crude hospital mortality rates were 14% during conventional glycemic group vs. 10% during IIT group. Tight glycemic control with an average blood glucose value <150 mg dL-1 was associated with a decreased incidence of sepsis and mortality. Highest mortality was seen in patients older than 65 years of age with poor glycemic control. Severe hypoglycemia was recorded in 6% of IIT patients, as compared with 2% undergoing conventional control. Finally, normoglycemia with IIT is associated with decrease mortality and incidence of sepsis with no significant effect on the length of hospital stay or days on mechanical ventilation.
INTRODUCTION
Hyperglycemia is common in hospitalized patients particularly in critically ill patients who may not have the diagnosis of diabetes (Inzucchi, 2006). Severe hyperglycemia is associated with increased morbidity and mortality (Capes et al., 2000). Acute hyperglycemia has many deleterious effects on basic physiologic function. Hyperglycemia inhibits leukocytes functions increasing patient’s risk for developing an infection and has a more difficult time combating an existing infection (Pickkers et al., 2004). Hyperglycemia can also induce the release of pro-inflammatory mediators such as interleukin-6 (IL-6) and tumor necrosis factor α (TNF-α). These proinflammatory mediators worsen the disease states suchas sepsis, heart failure and acute thrombosis and contribute to the progression of atherosclerosis. Finally, ischemic events can be worsened by acute hyperglycemia since hyperglycemia increases platelet activation, fibrinogen and C-reactive protein (Pickkers et al., 2004).
The ADA (2007) issued guidelines regarding the optimal blood glucose ranges for hospitalized patients in 2007. The ADA recommended maintaining the random blood glucose level as close to 110 mg dL-1 as possible in critically ill patients. In hospitalized, non-critically ill patients, the recommended fasting blood glucose range had been 90-130 mg dL-1. Recently, the ADA and the American Association of Clinical Endocrinologists released updated guidelines recommending a target range of 140-180 mg dL-1 for the critically ill, with some patients benefitting from a range of 110-180 mg dL-1 (Moghissi et al., 2009).
Two observational (Reed et al., 2007; Van den Berghe et al., 2001) and two randomized (Van den Berghe et al., 2001, 2006) trials of surgical and medical critically ill patients have observed a higher incidence of favorable outcomes in critically ill patients treated with Intensive Insulin Therapy (IIT) to achieve a blood glucose level of 80 to 110 mg dL-1. However, other recently published studies suggest that there may be no benefit or even harm conferred by this approach in patients during cardiac surgery or recovering from cardiac arrest (Gandhi et al., 2007; Oksanen et al., 2007). In addition, two recent randomized trials of IIT in critically ill patients were stopped early due to lack of benefit and hypoglycemia associated with IIT (Angus and Abraham, 2005). Although, there is still debate whether the evidence is adequate to support a clear recommendation, the Institute for Healthcare Improvement (homepage) is recommending a care bundle for severe sepsis which includes intensive glycemic control. As a result of these recommendations tight glycemic control has increasingly become the standard of care for critically ill patients at many institutions.
The objective of the present study was to investigate the effect of implementing a policy of tight glycemic control on the morbidity and mortality in a mixed population of medical and trauma critically ill patients at Mansoura Emergency Hospital, Egypt. In this study, we conducted prospective study comparing 2 consecutive time periods before and after IIT protocol implementation: period I (no protocol/conventional glycemic control) with target blood glucose level 120-180 mg dL-1 and period II (IIT group) with target blood glucose level 80 to 130 mg dL-1. The main study endpoints were the incidences of sepsis, hospital deaths, durations of mechanical ventilation and hospital length of stay in the ICU or hospital. Hypoglycemia was considered as serious adverse events.
MATERIALS AND METHODS
Study design: The present study was prospective study conducted in ICU at Mansoura Emergency Hospital during the period between July 1st, 2008 to January 30th, 2009. The study period was divided into 2 periods corresponding to changing glycemic control goals and insulin therapy protocols:
| • | Period I (conventional glycemic control): This period started from July 1st, 2008 to September 30th, 2008; during this period, there was no specific glycemic control protocol and hyperglycemia was treated by a mix of subcutaneous and intravenous insulin, with a general target blood glucose of 120 to 180 mg dL-1 |
| • | Period II (intensive insulin therapy IIT group): This period started from October 1st to January 30th, 2009. During this period tight glycemic control with intensive insulin therapy was placed with target blood glucose of 80 to 130 mg dL-1 |
Inclusion Criteria the Intensive Insulin Therapy (IIT) Protocol had 3 Entry Criteria
| • | An adult patient (age 18 years or older) with morbidity significant enough to warrant designation as a critically ill patient |
| • | Anticipated duration of ICU stay greater than 24 h with minimum 3-day length of stay |
| • | At least 2 blood glucose measurements greater than 150 mg dL-1 within the first 48 h of ICU admission |
The protocol was implemented after a period of training for staff in the units and was accompanied by ongoing supervision and assessment by a representative of the nursing and physician staff of the units.
To evaluate the effect of tight glycemic control, we divided subjects into those whose mean blood glucose measurement on day 3 of the IIT was <150 mg dL-1 (tight control) and >150 mg dL-1 (poor control). To evaluate the effect of IIT on age, subjects were divided into 2 groups: younger (age <65 years) and older (age >65 years).
Tight glycemi control algorithm consisted of a basal-bolus regimen. A Total Daily Dose (TDD) of insulin was determined based on patient-specific parameters. The TDD was then divided into a long-acting insulin (insulin NPH (0.4xTDD)) and a short-acting insulin (regular insulin (0.15xTDD)). A target range of 80-130 mg dL-1 was established in an effort to achieve tighter control of blood glucose without risking high rates of hypoglycemia. All blood glucose measurements were determined by point-of-care testing.
To assess the effect of successful glycemic control, an average blood glucose value <150 mg dL-1 on day 3 was used to define tight glycemic control and an average blood glucose value >150 mg dL-1 was used to define poor glycemic control as described previously (Furnary et al., 2004).
Assessments and data collection: Clinical and demographic information, such as diagnosis and outcome, for both groups (IIT and conventional protocol) were entered into a prospectively collected secure database.
At baseline, demographic and clinical characteristics, including the Acute Physiology and Chronic Health Evaluation II (APACHE II) score (Knaus et al., 1985) (which can range from 0 to 71, with higher scores indicating more severe illness) and the diagnostic criteria for severe sepsis (Bone et al., 1992) were collected. Patients were classified as having diabetes on the basis of their medical history and were classified as having trauma if the ICU admission occurred within 48 h after admission to the hospital for trauma. Previous treatment with corticosteroids was defined as treatment with systemic corticosteroids for 72 h or more immediately before admission to ICU.
From the time of study enrollment to the time of discharge from the ICU, we recorded all blood glucose measurements, insulin administration, blood cultures that were positive for pathogenic organisms, type and volume of all enteral and parenteral nutrition and additional intravenous glucose administered and corticosteroid administration. Also, we recorded the cardiovascular, respiratory, renal, hepatic and hematologic components of the Sequential Organ Failure Assessment (SOFA, for which scores can range from 0 to 4 for each organ system, with higher scores indicating more severe dysfunction) (Vincent et al., 1998). The use of mechanical ventilation and renal-replacement therapy were also recorded.
Outcome measures: The primary outcomes recorded were incidences of sepsis, hospital deaths (in the ICU or when transferred to the medical floor).
Secondary outcome measures were durations of mechanical ventilation, renal-replacement therapy and duration of hospital stay in the ICU and hospital.
Tertiary outcomes were incidence of new organ failure and positive blood culture.
The primary outcome was also examined in 4 pairs of subgroups: patients with and those without diabetes, patients with and those without trauma, patients with and those without severe sepsis and patients treated and those not treated with corticosteroids.
Serious adverse events: A blood glucose level of 60 mg dL-1 or less was considered a serious adverse event. When, the blood glucose level was measured with a bedside point-of-care analyzer, we requested that the treating clinician obtain a blood sample for laboratory confirmation.
Statistical analysis: Differences between groups were evaluated using the Student t- test, the Chi-square test and the Fisher test. All statistical tests were 2-tailed. Data are presented as Mean±SE and p<0.05 were regarded as statistically significant.
RESULTS
Study population: patient demographic and characteristics: The study population consisted of adult patients admitted to the ICU at Mansoura Emergency hospital which included broader population of critically ill patients a mix of trauma, surgical, stroke and medical Intensive Care Unit (ICU) patients during the period from July 1st, 2008 to January 30th, 2009. During this 7 months interval, 200 patients admitted to the 10-bed, mixed-service medical ICU were included in this study. Of these 200 patients, 100 patients were placed on IIT protocol and remaining 100 patients received a conventional glycemic control. The demographic data of present study population are presented in the Table 1.
The distributions of demographic and baseline characteristics of the patient population were broadly similar across the two groups (Table 1). The majority of the patients in both group especially in IIT group were 65 years of age or older. The Mean±SD age was 65±13 years in the Intensive-Insulin Therapy (IIT) group and 62±15 years in the conventional-control group, respectively; the percentage of male patients, 73 and 69%; the mean APACHE II score, 25.1±7.91 and 25.1±8.31 and the percentage of trauma and surgical admissions was 25 and 22% in IIT group and conventional glycemic-control group respectively. Compared with patients admitted for IIT group, history of type I diabetes was less frequent in patients admitted in conventional glycemic group, whereas type II diabetes was more common in the latter periods (Table 1). Blood glucose at ICU admission was lower in conventional glycemic group compared with the IIT group. Requirement for mechanical ventilation at ICU admission was frequently high at admission in both groups (94% in IIT group vs. 92% in conventional group). Patient receiving corticosteroid prior and during to ICU admission were similar in both groups. The most common indication for corticosteroid administration in both groups was the treatment of septic shock, COPD/asthma exacerbation and chemotherapy regimen in cancer patient.
Insulin administration and treatment effects: Patients undergoing intensive glucose control were more likely than those undergoing conventional control to have received insulin 97 vs.69%, p<0.001 and they received a larger mean insulin dose 45±15 units day-1 vs. 16±10 with conventional control; p<0.001 (Table 2).
The average 6 a.m. blood glucose concentrations as measured in the central laboratory was 145 mg dL-1 in conventional glycemic control group vs. 118 mg dL-1 in IIT group (Table 2).
Outcomes: Overall, the crude hospital mortality rates were 14% during conventional glycemic group vs. 10% during IIT group (p>0.05) (Table 3). Overall, the distributions of proximate causes of death were similar in the two groups. However, deaths from cardiovascular causes were more common in the intensive insulin therapy group 40 vs. 28.6% in the conventional-control group (p = 0.07). In the intensive insulin therapy group and the conventional-control group, the majority of deaths occurred in the ICU 70 and 71.4%, respectively or in the hospital after discharge from the ICU 30 and 28.6%, respectively (Table 3). There was near significant difference in the rates of positive blood cultures between both groups (10 % in IIT group vs. 14 % in conventional glycemic control group).
| Table 1: | Patient demographic and clinical characteristics |
| Table 2: | Blood glucose management and levels according to treatment group |
| Table 3: | Outcomes and adverse events |
| Table 4: | Patient’s outcomes during hospital stay in relation to glycemic control and age |
There was no significant difference between the two groups in the median length of stay in the ICU or hospital. The number of patients in whom new single or multiple organ failures developed were similar with intensive and conventional glucose control (p = 0.11) (Table 3). There was no significant difference between the two groups in the numbers of days of mechanical ventilation and renal replacement therapy (Table 3).
Tight glycemic control with an average blood glucose value <150 mg dL-1 in patient receiving either IIT protocol or conventional protocol was associated with a decreased incidence of sepsis compared with poor glycemic control and a decreased mortality rate (Table 4). Mortality rate in the poor control group was approximately 10 fold greater than that of the tight control group. The greatest mortality rate was seen in patients >65 years of age with poor glycemic control (Table 4).
| Table 5: | Patient’s outcomes during hospital stay in relation to subgroup analysis |
Subgroup analyses suggested no significant difference in the treatment effect for the comparisons of operative and non operative patients (p = 0.10), patients with and those without diabetes (p = 0.60), patients with and those without severe sepsis (p = 0.93). Tests for interaction indicated a possible trend toward subgroup-specific treatment effects for patients with trauma as compared with those without trauma (p<0.05) and for patients receiving corticosteroids at baseline as compared with those not receiving corticosteroids (p<0.05) (Table 5).
Serious adverse events: Severe hypoglycemia (defined as a blood glucose level ≤60 mg dL-1) was recorded in 6% patients undergoing IIT, as compared with 2% undergoing conventional control (p<0.001). No long-term sequelae of severe hypoglycemia were reported in both groups (Table 3).
DISCUSSION
During the stress of critical illness, endogenous catecholamines, glucocorticoids, glucagon and Cytokine levels are all increased (Axelrod and Reisine, 1984; Finnerty et al., 2006). Despite normal insulin levels, the increase in stress hormones creates a state of insulin resistance by decreasing insulin receptor binding and activation, as well as the availability of glucose transporters (Mizock, 1995). Elevated glucagon and catecholamine levels stimulate hepatic glucose production. In addition, patients receive medications (e.g., catecholamines, corticosteroid) and nutritional support, which also increase blood glucose levels. All of these factors contribute to the development of a hyperglycemic state. Restoration of euglycemia has been shown repeatedly to reduce the incidence of hospital-acquired infection and sepsis and to increase survival in critically ill and injured patients (Furnary et al., 2004; Reed et al., 2007; Scalea et al., 2007; Van den Berghe et al., 2001).
The present study compared 2 consecutive time periods before and after IIT protocol implementation in our ICU: period I (no protocol/conventional glycemic control) with target blood glucose level 120-180 mg dL-1 and period II (IIT group) with target blood glucose level 80 to 130 mg dL-1. Present study showed that number of the patients receiving ITT was significantly higher than conventional glycemic control 97 vs. 69%. Furthermore patients on IIT protocol received a significantly larger mean insulin dose 45±15 vs. 16±10 unit day-1 with conventional control. The crude hospital mortality rates were 14% during conventional glycemic group vs. 10% during IIT group. The patients in present study with a mean blood glucose <150 mg dL-1 by day 3 were considered tightly controlled and these patients had lower hospital death rates and decreased incidence of sepsis compared with poor glycemic control. The greatest mortality rate was seen in patients older than 65 years of age with poor glycemic control. Placement of IIT protocol has no significant effect on the hospital length of stay in the ICU or hospital and days on mechanical ventilation. Furthermore, subgroup analyses suggested no significant difference in the treatment effect for the comparisons of operative and non operative patients, patients with and those without diabetes and patients with and those without severe sepsis. However, there was significant difference subgroup-specific treatment for patients with trauma when compared with those without trauma and for patients receiving corticosteroids at baseline when compared with those not receiving corticosteroids. Severe hypoglycemia was reported in 6% of patients undergoing IIT, as compared with 2% undergoing conventional control. No long-term sequelae of severe hypoglycemia were reported.
Present study was in agreement with previous four prior published studies that have observed at least some reduction in mortality associated with IIT in critically ill patients. Van den Berghe et al. (2001) reported the results of a large randomized trial of IIT in patients admitted to a surgical ICU, approximately 60% of whom had undergone cardiac surgery. IIT (blood glucose range of 80 to 110 mg dL-1) was associated with a reduction in mortality from 8.0 to 4.6% compared with conventionally treated patients (blood glucose range of 180 to 200 mg dL-1) in addition to reductions in multiple morbidities (Van den Berghe et al., 2001). In a subsequent study, Van den Berghe et al. (2006) randomly assigned patients admitted to a medical ICU to IIT or conventional blood glucose management. There was no clear mortality benefit for IIT in the intention to-treat population, whether for ICU (24.2% IIT group vs. 26.8% conventional treatment group) or hospital (37.3% IIT vs. 40% conventional treatment group) mortality.
However, IIT was associated with reduced in-hospital mortality in those patients who remained in the ICU for more than 3 days. In two studies that reported outcomes before and after implementation of an intensive glucose management protocol, mortality after implementation of the protocol was improved compared with prior to protocol implementation (Krinsley, 2004; Marfella et al., 2003). However, neither study adjusted for severity of illness or other factors that may have changed over time.
Furthermore, study conducted by Lacherade et al. (2007) concluded that the greater mortality rate may be directly related to failure to maintain glucose control over time and that tighter glucose control may decrease mortality. These studies corroborated the report of Scalea et al. (2007) in which a similar result was seen in a large trauma population.
These observational studies also leave open the possibility that hyperglycemia is a result of comorbidities and infectious processes rather than a direct contributor to mortality. In other words, did hyperglycemia occur as a consequence of infection/morbidity, or was hyperglycemia a risk factor for acquiring infection? A post hoc analysis of Van den Berghe et al. (2001) revealed a linear correlation between the degree of hyperglycemia and the risk of death; in a 2003 study (Van den Berghe et al., 2003). Van den Berghe et al. (2003) demonstrated that this correlation persisted after correction for insulin dose and severity of illness. Multivariate logistic regression analysis of these data confirmed the independent role of blood glucose control in achieving most of the clinical benefits of IIT and highlights the importance of lowering blood glucose levels.
Although, present study did not have sufficient enrollment to support a meaningful multivariate analysis, a similar argument regarding hyperglycemia as a consequence or as a risk factor of sepsis may be made by analysis of the temporal sequence of events.
The effect of age on the outcome of critically ill, present study demonstrated greatest mortality rate in patients older than 65 years of age with poor glycemic control.
Although, present study was not sufficiently powered to address the issue of age as a separate variable, we observed that the morbidity and mortality associated with poor glycemic control was dramatically greater in elderly critically ill patients. Patients older than 65 years of age with poor glycemic control have the greatest mortality rate. This result supports several reports showing greater ICU mortality in the elderly (Leong and Tai, 2002; Ruiz-Bailen et al., 2002; Tran et al., 1990).
There are some limitations to present study. First, only a small population of patients was analyzed in this study. Second, although the association of tight glycemic control by day 3 has been used by other researchers to predict outcomes (Furnary et al., 2004; Van den Berghe et al., 2001). The optimal interval for achievement of glycemic control and the duration of maintenance to achieve maximal survival benefit are both unknown. Third, despite our effort to control for confounding by assessing patient characteristics across the two study periods and adjusting for any baseline differences seen, the possibility of bias remains. Finally, although the 150 mg dL-1 glucose criterion was convenient for this study and has been used in previous studies, there is no universally accepted value to define optimal glycemic control. Levels of recommended glycemic control range from 110 to 150 mg dL-1 with various populations and studies (Finnerty et al., 2006; Furnary et al., 2004; Preiser and Devos, 2007; Van den Berghe et al., 2001). It remains to be determined which goal is associated with the maximal benefit of reduced sepsis and death, balanced against the risk of hypoglycemia. Nonetheless, our results strongly support the concept that medical, surgical and trauma patients benefit from aggressive management of glycemic levels. The major strength of the current study lies in the availability of extensive clinical data that allowed adjustment for severity of illness across time periods.
In conclusion, the present study demonstrated that tight glycemic control is associated with reduced mortality rate and incidence of sepsis in critically ill patients when placed on IIT. Patient survival in ICU is associated with tight glycemic control. This preliminary study reveals an association between improved management of blood glucose and beneficial outcomes in critically ill patients and indicates the need for a larger study to confirm these findings. In addition, present data suggest that hyperglycemia may be especially difficult to control in both elderly and these patients therefore may be at higher risk of sepsis and mortality. Further exploration of the benefit of tight glycemic control in the elderly in both the medical and surgical ICU is warranted and essential.
CONCLUSION
Tight glycemic control with IIT is associated with decrease hospital mortality and incidence of sepsis. Patients older than 65 years of age with poor glycemic control have the greatest mortality rate.