Diabetic status and the relation of the three domains of glycemic control tomortality in critically ill patients: an international multicenter cohort study

Table 1 provides an overview of the nine different patientcohorts (Amsterdam (AM), Austin (AU), BayCare (BC), Birmingham (BI), Geelong (GE),Okayama (OK), Stamford (ST), Tufts (TU), and Vienna (VI)), the organizationalstructure of the ICUs, and the glycemic-control practices of the differentcenters.

The primary end point for this analysis was all-cause hospital mortality, defined asdeath before hospital discharge.

Patients were classified as having preexisting diabetes by documentation in theirmedical records. Disease severity was assessed by using APACHE II scores [37]. Descriptive statistics were calculated for all variables of interest.Continuous variables were summarized by using means and standard deviations, whereascategoric variables were summarized by using counts and percentages.

The primary outcome, mortality, was assessed in relation to the glycemic-controlmetric and control variables by using a logistic regression model adjusting forcorrelation among observations taken at the same center (that is, a generalizedestimating equation (GEE) model. Three models were run, one for each glycemicmeasure: hyperglycemia, hypoglycemia, and glycemic variability. The models included avariable denoting diabetic status, the glycemic measure, and the key interaction termof diabetic status and glycemic measure. Each model controlled for mean BG, age,APACHE II score, mechanical ventilation, ICU length of stay (LOS), as well asadjusting for center effects. The models on hyperglycemia and glycemic variabilityalso controlled for hypoglycemia (minimum BG <70 mg/dl). Each model was stratifiedby diagnostic category: medical or surgical. Patients admitted with trauma diagnoseswere included in the surgical cohort.

Before analysis, the set of variables was assessed for the presence ofmulticollinearity. A tolerance statistic less than or equal to 0.4 was considered toindicate the presence of multicollinearity, and in such cases, only one member of acorrelated set would be retained for the multivariable model.

Analyses were run by using SAS Version 9.2 (SAS Institute, Cary, NC, USA) and MedCalcV12.4.0.0 (Ostend, Belgium).

The institutional review boards of the different centers approved the investigation.The requirement for informed consent was waived because of the retrospective natureof the study and because the data were deidentified.

Patients with diabetes had higher mean BG, higher CV, and higher rates ofhypoglycemia than did patients without diabetes. The nine centers demonstratedconsiderable variation in the frequency of BG monitoring as well as in the intensityof glycemic control, as reflected by mean BG.

Figure 4A and 4B illustrates thecumulative impact of derangements in the three domains of glycemic control. Amongpatients without diabetes who had mean BG between 80 and 110, 110 and 140, and 140and 180 mg/dl, increasing CV and the occurrence of hypoglycemia were associated withincreased mortality, and their effect was cumulative. Among patients without diabeteswith mean BG > 180 mg/dl, no incremental impact was found of additionalderangements of glycemic control. Among patients with diabetes, hypoglycemia wasconsistently associated with increased mortality, but mean BG and CV did not have aconsistent, cumulative impact on mortality.

Figure 5A through F displays the resultsof multivariable analysis, assessing the independent association of bands within eachdomain with mortality.

Hyperglycemia is associated with increased mortality in the critically ill [2, 3, 14, 29‐31]. Increments of mean BG levels above 80 mg/dl are clearly associated withincreasing mortality among patients without diabetes. In contrast, a blunted relationexists between increasing mean BG levels above 80 mg/dl and mortality among patientswith diabetes [3, 29‐31]. It is likely that changes in glycemic-control practice over time havealtered the observed relation between mean BG and mortality. The currentinvestigation reflects contemporary practice; all patients were admitted to ICUspracticing at least "moderate" glycemic control; the range of mean BG values of thepatients without diabetes in the different centers (119 to 137 mg/dl) contrastssharply with the mean morning BG of the patients in the control arm of the firstLeuven trial of IIT (153 mg/dl) [4].

Hypoglycemia was the second of the three domains to be associated with increased riskof mortality in critically ill patients. Although most of the literature hasdescribed an independent association of severe hypoglycemia (minimum BG <40 mg/dl)with mortality [12‐15, 22], recent observational studies [16, 17] and prospective trial data [11] have identified mild hypoglycemia (minimum BG <70 mg/dl) as beingindependently associated with increased risk of mortality. Our findings confirm theseobservations for patients with and without diabetes.

Glycemic variability was the third of the three domains to be independentlyassociated with mortality in the critically ill [18‐25]. One observational study suggested that glycemic variability wasindependently associated with mortality only among critically ill patients withoutdiabetes [24]; our study confirms these findings.

Finally, the independent impact of diabetic status, without reference to glycemiccontrol, on the mortality of critically ill patients has been the subject of recentobservational studies that concluded that patients with diabetes did not experiencehigher mortality, and diabetes may, in fact, be protective [30‐36]. We demonstrated here that diabetes is independently associated withdecreased risk of mortality.

The clearest strength of this study is its size. The 44,964 patients include patientsadmitted with a large array of medical, surgical, and trauma diagnoses, treated witha variety of glycemic-control protocols, substantially enhancing the generalizabilityof the investigation. Moreover, this is a modern cohort of patients treated in an eracharacterized by attention to glycemic control. Each of the nine centers maintained arobust database characterized by prospective data collection, creating an additionalimportant strength of this investigation: the breadth of demographic, clinicaloutcome, and glycemic data available for analysis. The absence of information aboutinsulin therapy is an important limitation. It is likely that important differencesexist between insulin-treated and insulin-naive patients regarding the relation ofthe three domains of glycemic control to mortality.

Another potential limitation is that the identification of diabetic status was madeon clinical grounds, based on all information available at the time of ICU admission.It is likely that some patients designated as without diabetes may actually have haddiabetes; HgbA1c levels were not obtained routinely, and, of course,glucose-tolerance testing could not be performed. Furthermore, we are unable todetermine whether the diabetes patients were categorized as type I or type II.Although most were likely type II, important differences may exist between the twogroups in their response to derangements in the domains of glycemic control.Additionally, we cannot provide details of nutritional therapy and cannot thereforeanalyze the interactions among glycemic control, nutritional therapy, and insulintreatment of hyperglycemia. Moreover, many of the glycemia data from several of thecenters included in this study were derived from capillary blood measured onpoint-of-care devices, a method associated with increased analytic inaccuracy [38‐41]. Nevertheless, any degree of measurement imprecision would only serve todampen the observed relations between glycemia and diabetic status.

Finally, we acknowledge that the observational nature of this investigation mandatesthat its conclusions must be considered to be hypothesis generating, rather thanproof of causality. Nevertheless, it would be unethical to randomize patients toinduced hyperglycemia, hypoglycemia, or increased glycemic variability.

Considerable evidence suggests that diabetes may alter the relation between glycemiaand mortality in critically ill patients [28]. Diabetes patients may develop a tolerance to hyperglycemia, and amoderate degree of hyperglycemia that might exert toxicity in a patient withoutdiabetes may be well tolerated in a patient with diabetes. This may explain thestrong relation seen between increasing mean BG levels and mortality in patientswithout diabetes, detailed in several large observational studies, but not amongthose with diabetes [3, 29‐31, 36, 42]. In a recent study [43], diabetes patients with poor preadmission glycemic control, reflected byhigh HgbA1c levels, had higher mortality when mean BG was tightly controlled duringICU stay compared with patients with high premorbid HgbA1c levels who had a highermean BG during ICU stay. These intriguing data parallel the results of largeinterventional studies in outpatient populations with type II diabetes [44, 45]. An extensive body of literature has explored the physiological basis ofthe deleterious impact of hypoglycemia [46‐51] demonstrated in interventional [4, 6, 11, 25] and observational [12‐17] studies; none of these has focused explicitly on the different impact thathypoglycemia may exert on patients with diabetes compared with those withoutdiabetes. Similarly, although various physiological mechanisms underlying the harmfuleffect of increased glycemic variability detailed in interventional [4, 6, 25] and observational [18‐24] studies have been proposed [52‐56], the reasons that glycemic variability has no or a muted independentassociation with risk of mortality in patients with diabetes compared with thestriking relation seen in patients without diabetes requires furtherclarification.

The central findings of the current investigation have important implications for thecare of critically ill patients. Hyperglycemia does not have the same associationwith mortality among critically ill patients without diabetes compared with thosewith diabetes. The euglycemic range was independently associated with the lowest riskof mortality among patients without diabetes but with higher mortality among patientswith diabetes. Additionally, important differences were noted when comparing medicaland surgical populations. These findings call into question the "one size fits all"strategy for glycemic control of critically ill patients. It may be most appropriateto establish lower glycemic target ranges for medical patients without diabetes thanfor patients with diabetes or for surgical patients without diabetes.

In addition, our observations call into question the appropriateness of recentlypublished glycemic-control guidelines that recommend a glycemic target range of 140to 180 mg/dl [57] or 140 to 200 mg/dl [58] for all critically ill patients. Furthermore, premorbid glycemic controlin diabetes may have an important impact on the consequences of glycemic control inthe ICU [43]. The optimal glycemic-control protocol may result not only fromstratifying patients by diabetic status, but also by additionally stratifyingpatients with diabetes based on the degree of preadmission glycemic control. Incontrast, the deleterious association of hypoglycemia with mortality, even atthreshold levels of <70 mg/dl, was observed in patients with diabetes and in thosewithout diabetes. Because hypoglycemia can never be the subject of a randomizedtrial, the data from this investigation, when combined with the findings fromprevious interventional [4, 6, 10, 11, 25] and observational [12‐17] studies, provide the strongest evidence basis for the goal of avoidinghypoglycemia in all critically ill patients.

Finally, increased glycemic variability, defined as CV > 20%, was identifiedin the current study as having a strong independent association with increased riskof mortality in patients without diabetes. These data provide strong impetus for thecreation of insulin-dosing strategies and the development of new technologies [59] for accurate continuous or near-continuous BG monitoring, with the goal ofreducing glycemic variability in critically ill patients. Further investigationshould stratify patient outcomes by specific admitting diagnosis; importantdifferences may be found within the broad medical and surgical categories that thecurrent investigation was underpowered to assess.

The design of future trials of IIT should include consideration of all three domainsof glycemic control as well as recognition of the differences in their associationwith mortality based on premorbid diabetes status.