Although emerging literature has documented the strong association between hypoglycemia during acute and critical illness and an increased risk of mortality [
9,
11-
18], this is the first investigation that has focused explicitly on the association of hypoglycemia with ICU LOS, the predominant driver of resource utilization in this population. The salient finding of this investigation is that patients sustaining even a single episode of BG < 70 mg/dL during ICU stay incurred substantially greater LOS than did those without an episode of hypoglycemia: 1.8 (1.0-3.3) vs. 3.0 (1.5-6.7) days (
p < 0.0001). This observation was independent of survivor status or severity of illness, as reflected by admission APACHE II score. The relationship between ICU LOS and hypoglycemia was remarkably consistent in these three separate cohorts of patients. Finally, there was a dose response relationship between hypoglycemia and resource utilization: the number of discrete episodes of hypoglycemia was directly and positively correlated with ICU LOS.
The major interventional trials of IIT [
4-
8,
10] as well as large observational cohort studies [
12,
13,
16,
17] describing the association of hypoglycemia with mortality do not detail differences in ICU LOS comparing those who experienced hypoglycemia to those who did not. However, the findings of the current investigation corroborate the limited data available in the literature that do address this topic. Arabi et al. analyzed severe hypoglycemic events (BG < 40 mg/dL) that occurred in their randomized, controlled trial of IIT [
9]. ICU LOS (median, IQR) was considerably longer in patients with hypoglycemia than in those without: 5.8 (2.0-12.9) vs. 1.0 (0.8-1.9) (
p value not supplied). Additionally, Vriesendorp and colleagues performed an observational cohort study of patients sustaining severe hypoglycemia (BG < 45 mg/dL) [
15]. Index cases and controls were matched by the time of the hypoglycemic event. The median (range) time in days from the index moment to death or hospital discharge was longer in patients with hypoglycemia: 11 (0-204) vs. 8 (0-146;
p value not provided).
The multicenter, international nature of the investigation increases the generalizability of the findings; the heterogeneous 6,240 patient cohort were admitted with varying severities of illness and ICU LOS and treated in ICUs using different glycemic targets, measurement technologies, and glycemic management protocols. One limitation is the absence of data differentiating between spontaneous and therapy-induced hypoglycemia; it is unclear whether these may have the same association with increased ICU LOS. The use of bedside glucometers for measurement of capillary blood is an additional limitation of this investigation, because this measurement technology has been associated with analytic inaccuracies, especially in the hypoglycemic range [
30-
32]. Notably, the retrospective nature of this investigation is an acknowledged weakness. This was unavoidable, because it would be unethical to perform a randomized, controlled trial of induced hypoglycemia in a population of critically ill patients. However, while the design of the study precludes proof of causality, there are several lines of evidence that suggest strongly that hypoglycemia led to increased resource utilization, rather than was a consequence of more frequent BG measurements in patients who required longer ICU stays. Hypoglycemia occurred early in the course of ICU stay; 47% and 72% of the patients with hypoglycemia in the ST and NL cohorts, respectively, experienced an episode within the first 48 hours of ICU stay. Moreover, the relationship between hypoglycemia and increased LOS was independent of severity of illness; patients with hypoglycemia who had mild, moderate, or severe levels of illness, reflected by APACHE II score sustained significantly longer LOS than did those without hypoglycemia, and this relationship was seen for survivors as well as nonsurvivors.
There are some possible links between hypoglycemia and worsened outcome or complicated course of critical illness [
25,
33]. First, the physiological mechanisms triggered by hypoglycemia are commonly impaired during critical illness. These include the inhibition of insulin release, typically occurring when BG is < 80 mg/dl, an increased release of glucagon, epinephrine, and growth hormone when BG is < 65 mg/dl, and increase release of cortisol when BG is < 55 mg/dl [
34]. During critical illness, exogenous insulin is infused and the levels of glucagon, epinephrine, cortisol, and growth hormone are typically already elevated. Second, large swings in BG, as observed when hypoglycemia is aggressively treated with a large amount of intravenous glucose, are typically associated with cellular damage [
35]. Third, the detrimental effects of hypoglycemia are well documented in the brain. Indeed, glucose is the preferential energetic substrate in the brain. The absence of cerebral stores of glucose and the diffusive character of transport imply that the glucose concentration in neurons and glial cells is entirely determined by BG [
35].
The main driver of the cost of care of patients admitted to the ICU is length of stay [
21,
22,
36]. This investigation, demonstrating consistent evidence of increased ICU LOS among critically ill patients sustaining hypoglycemia compared with those without hypoglycemia, has important implications for the management of these patients. Although this study must be considered hypothesis-generating, the evidence from this study and other recent investigations strongly suggests that avoidance of hypoglycemia has a beneficial effect not only on survival, but on cost, an important goal in the context of estimates that ICU care consumes 20-30% of individual hospital's resources and 0.5-1.0% of US Gross National Product [
19,
20].
1 Marcus J Schultz,2,3 Peter E Spronk,2,4 Floris van Braam Houckgeest,5 Johannes P van der Sluijs,6 Christian Mélot,7 and Jean-Charles Preiser7,8
This article has been 
