Critical illness-induced dysglycaemia: diabetes and beyond

Type 2 diabetes has reached epidemic proportions in many parts of the world. The disease is projected to continue to increase and double within the foreseeable future. Dysglycaemia develops in the form of hyperglycaemia, hypoglycaemia and marked glucose variability in critically ill adults whether they are known to have premorbid diabetes or not. Patients with such glucose dysregulation have increased morbidity and mortality. Whether this is secondary to cause and effect from dysglycaemia or is just related to critical illness remains under intense investigation. Identification of intensive care unit (ICU) patients with unrecognised diabetes remains a challenge. Further, there are few data regarding the development of type 2 diabetes in survivors after hospital discharge. This commentary introduces the concept of critical illness-induced dysglycaemia as an umbrella term that includes the spectrum of abnormal glucose homeostasis in the ICU. We outline the need for further studies in the area of glucose regulation and for follow-up of the natural history of abnormal glucose control during ICU admission and beyond.

undiagnosed [2]. Th ese patients cannot be treated, and are vulnerable to short-term and long-term complications [3][4][5]. Th e true prevalence of diabetes in hospitalised patients is not known, due to the heterogeneous patient population and limitations in diagnostic tests [6]. Th e prevalence in intensive care unit (ICU) patients is perhaps 25% or higher, depending on unit specialty and patient demographics [6].
Adults with diabetes have at least double the annual mortality compared with adults without diabetes [7]. Paradoxically, several studies of hospitalised patients have demonstrated that hyperglycaemic individuals without known diabetes have signifi cantly greater morbidity and mortality than either patients with known diabetes or those with normal glucose tolerance [8][9][10][11]. Hyperglycaemic patients without diabetes include those with undiagnosed diabetes, prediabetes (impaired fasting glucose and impaired glucose tolerance) or stressinduced hyperglycaemia (SIH) -defi ned as patients with elevated blood glucose that reverts to normal after illness subsides and counterregulatory hormone and infl ammatory mediator surge abates [6]. Large, retrospective studies in critically ill adults have shown that hyperglycaemic patients with diabetes have lower ICU and hospital mortality and shorter length of ICU stay than critically ill hyperglycaemic patients without diabetes [8][9][10]. Th is increased mortality in hyperglycaemic patients without diabetes occurs despite this population having lower absolute glucose levels than those with diabetes. Similar fi ndings were reported in hospitalised general care patients [11].
How can this paradox be explained? First, patients without diabetes may have unexpected hyperglycaemia that is frequently left untreated. Umpierrez and colleagues showed that insulin therapy was provided to 77% of patients with known diabetes, compared with 35% of hyperglycaemic patients without diabetes [11]. Second, the critically ill nondiabetic hyperglycaemic population comprises patients with undiagnosed diabetes and patients with SIH [6,12]. Whether hyperglycaemia and adverse outcomes in the nondiabetic cohort are due to SIH, or are simply a marker of severity of illness, remains unknown. Prospective studies with clearly defi ned Abstract Type 2 diabetes has reached epidemic proportions in many parts of the world. The disease is projected to continue to increase and double within the foreseeable future. Dysglycaemia develops in the form of hyperglycaemia, hypoglycaemia and marked glucose variability in critically ill adults whether they are known to have premorbid diabetes or not. Patients with such glucose dysregulation have increased morbidity and mortality. Whether this is secondary to cause and eff ect from dysglycaemia or is just related to critical illness remains under intense investigation. Identifi cation of intensive care unit (ICU) patients with unrecognised diabetes remains a challenge. Further, there are few data regarding the development of type 2 diabetes in survivors after hospital discharge. This commentary introduces the concept of critical illness-induced dysglycaemia as an umbrella term that includes the spectrum of abnormal glucose homeostasis in the ICU. We outline the need for further studies in the area of glucose regulation and for follow-up of the natural history of abnormal glucose control during ICU admission and beyond.
nondiabetic cohorts are needed to diff erentiate between undiagnosed diabetes and SIH.
Accurately diagnosing hyperglycaemic ICU patients with new diabetes while they are still hospitalised, however, remains diffi cult. Fasting plasma glucose values and oral glucose tolerance tests can only be used in ICU survivors after discharge, as these tests are inaccu rate during critical illness [6,12]. Recently endorsed by the Inter national Expert Committee [13] and the American Diabetes Association as a diagnostic criterion for diabetes mellitus [14], haemoglobin A 1c may prove useful in categorising inpatients [15]. But haemoglobin A 1c must be used carefully, as it may be inaccurate in conditions that shorten or prolong the survival of erythrocytes and in patients receiving blood transfusions [13]. Likewise, its value may vary by racial or ethnic group [16]. Ambulatory follow-up at 6 to 8 weeks post recovery aff ords the best opportunity to look back and diagnose type 2 diabetes [12].
Owing to these limitations, few studies have attempted to defi ne the true prevalence of diabetes in ICU patients with unexpected inpatient hyperglycaemia. Recently, Mullhi and colleagues showed in ICU survivors (n = 30) with new hyperglycaemia that 46.7% (n = 14) had undiagnosed diabetes and 30% had a prediabetes state (n = 9 impaired fasting glycaemia or glucose tolerance) during their ICU stay [17]. Similarly, the natural history of ICU patients with inpatient hyperglycaemia but without diabetes merits further study. Gornik and colleagues recently reported that 15.2% of septic ICU patients with documented SIH and normal, post-discharge glucose tolerance developed diabetes within 5 years of hospital discharge, versus 4.2% of normoglycaemic ICU patients [18]. Th e authors hypo the sised that stress may uncover latent metabolic disturbance. Gornik and colleagues presented very similar fi ndings in Critical Care about the development of type 2 diabetes in 17.1% of patients with SIH among nearly 600 heterogeneous critically ill patients followed for 5 years after ICU discharge [19]. Th ese longitudinal data reveal the importance of continued surveillance of this high-risk population.
Inpatients may also experience other types of glucose dysregulation. Large, randomised controlled trials from the past decade, which investigated the impact of preventing pronounced hyperglycaemia during critical illness with insulin infusion, report increased mortality associated with hypoglycaemia [20][21][22][23]. Egi and colleagues showed that increased mortality in mildly hypoglycaemic patients (blood glucose <80 mg/dl) may be independent of insulin use [21]. Th eir fi ndings suggest that altered glucose metabolism, as well as exogenous overtreatment with insulin, may play a meaningful role in critical illness and mortality. In a retrospective cohort analysis of 7,820 patients with acute myocardial infarction, Kosiborod and colleagues reported that patients who developed spontaneous hypoglycaemia had an increased mortality while those who developed it secondary to insulin therapy did not [24]. Several studies have also demonstrated increased mortality with either hypo glycaemia or hyperglycaemia [20,21]. Glucose variability may confer an adverse risk of mortality, independent of absolute glucose level [23] -although recently the Leuven group retrospectively analysed their two large prospective glucose control trials, and determined that the reduced mortality observed with intensive insulin therapy in the trials was not attributable to an eff ect on blood glucose variability [25]. Th e accompanying editorial by Krinsley, however, raised additional factors such as frequency of hypoglycaemia and method of glucose measurement that may have infl uenced these fi ndings [26]. Limitations in existing glucose monitoring technology further complicate the above issues. Th is diffi culty cannot be ignored when applying protocols to control and regulate blood glucose [27].
We suggest a broader view of glucose dysregulation in the critically ill patient based on numerous factors (Table 1). We apply the term critical illness-induced dysglycaemia to patients with hyperglycaemia, hypo glycaemia or glucose variability. Patients without diabetes, but with other features of critical illness-induced dysglycaemia, appear to be at risk to develop overt type 2 diabetes. Th ese patients should undergo longi tudinal evaluation and intervention for the develop ment of subsequent type 2 diabetes.
Th e decade ending in 2009 witnessed an explosion in publications about ICU glycaemic control, beginning Table 1

. Factors impacting critical illness-induced dysglycaemia
Continued growth of abnormal glucose homeostasis in adults Heterogeneous intensive care unit patient population Uncertainty as to whether hyperglycaemia may cause adverse outcomes, or may simply be the eff ect of counterregulatory hormone surge indicating severity of illness Need for further clarifi cation of the incidence of co-existing factors in the development of and role of hypoglycaemia (<80 mg/dl) on intensive care unit outcome Ongoing debate over the ideal method and frequency of glucose measurement, the optimal glucose level to maintain in adult intensive care unit populations, and the modulation of glucose variability with the landmark Leuven trial in 2001 [28]. Formal recom mendations in 2004 endorsed tight glycaemic control [29]. Th e decade ended with the 2009 publication of the NICE-SUGAR study [22], and less stringent critical care glucose control guidelines [30]. Th e concept of critical illness-induced dysglycaemia encompasses all of these factors. We issue a call to recognise the heterogeneous inpatient hypoglycaemic or hyperglycaemic popu lation, in order to study hyperglycaemic subpopulations, to determine diagnostic alternatives for diagnosis of unrecognised inpatients with diabetes, and to develop better monitoring and application of safe, closed-loop systems.