DM Full Guideline (2010) - VA/DoD Clinical Practice Guidelines Home

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RATIONALE
VA/DoD Clinical Practice Guideline
for the Management of Diabetes Mellitus
Numerous controlled studies (randomized trials and meta-analyses)have examined either glucose lowering or insulin
infusion in patients with critical illness and acute myocardial infarction. The questions addressed in these studies and
the findings produced vary greatly. Controlled trials are lacking in patients admitted to general medical/surgical
wards and with acute stroke, although high quality observational studies do exist for these populations. While there
is little direct evidence specifically evaluating a blood glucose of < 180 mg/dl versus higher levels, the totality of
evidence and the importance of avoiding abnormalities in fluid status from glucosuria, make this a prudent and safe
upper limit for blood glucose level.
DISCUSSION
Glycemic control
Randomized trials examining glycemic control and/or insulin therapy are limited to the study of hospitalized patients
with severe illness (ICU, acute myocardial infarction, acute stroke). There have been no controlled trials conducted
in other settings. However, numerous observational studies, some of which are well controlled, have demonstrated a
strong relationship between hyperglycemia and mortality or morbidity (Baker et al., 2006; Bruno et al., 2008;
Falciglia et al., 2009; Kosiborod et al., 2005; McAlisyter et al., 2005; Pomposelli et al., 1998; Umpierrez et al.,
2002).
Tight glycemic control
The term “tight” glycemic control is not uniformly defined in the literature, and this has led to confusion in
discussions of published evidence on this topic. Although some studies have described even targets of glucose <
180 mg/dl as “tight”, the most recognized concept of tight control was introduced by Van den Berghe et al. in a
randomized trial of surgical ICU (SICU) patients that examined the effects of continuous insulin infusion to achieve
a target glucose of 80-110 mg/dl (Van den Berghe et al., 2001). The investigators demonstrated that establishing
normoglycemia resulted in substantial reductions in hospital and ICU mortality, bloodstream infections, renal
insufficiency, and the need for mechanical ventilation and blood transfusions. Despite the enthusiasm for adopting
tight glycemic control following publication of this study, subsequent trials have been unable to reproduce these
results. The same investigators conducted a similar study in patients admitted to the medical ICU (MICU) (Van den
Berghe et al., 2006a). Because the greatest benefit in the SICU study was observed in patients who remained in
intensive care for over 5 days, the investigators powered the MICU study to demonstrate improved outcomes in
those staying over 3 days. In this group, a significant decrease in mortality was observed, with absolute reductions
comparable to their study of SICU patients. However, no significant mortality difference was demonstrated in the
intent-to-treat or short-stay groups, although improvements for other important outcomes such as decreased
incidence of renal insufficiency, accelerated weaning of mechanical ventilation, and shortened length of stay were
demonstrated in the intent–to-treat group. Given the lack of mortality benefit in the short-stay group and the inability
to predict how long a patient would require care, these results raised some debate about the overall benefits of tight
glycemic control and whether it should be initiated on admission. Van den Berghe et al. performed a subsequent
analysis in which they pooled data from their two previously published SICU and MICU studies, demonstrating that
tight glycemic control not only reduced mortality in the long-stay group but also in the entire (intent-to-treat) cohort
(Van den Berghe et al., 2006b). Mortality rates in the first 3 days of ICU care were similar.
The VISEP trial was a four-arm study examining both fluid resuscitation and tight glycemic control (80-110 mg/dl)
in ICU patients with severe sepsis (Brunkhorst et al., 2008). The trial was stopped early due to high rates of
hypoglycemia (17% vs. 4%). Although it did not demonstrate a mortality benefit from tight glycemic control, the
trial was underpowered with only 537 subjects included in the final analysis. The recently published NICE-SUGAR
trial has been able to shed some light on tight glycemic control as it included over 6000 patients at surgical and
medical ICUs throughout Australia, New Zealand and Canada (Finfer et al., 2009). The investigators found no
reduction in 90-day mortality (primary outcome) in the study group receiving tight control (mean glucose 115
mg/dl) versus the control group (mean glucose 144 mg/dl). It was also noted that although there was no significant
difference in hospital or 28-day mortality between the 2 groups, there were significantly more deaths at 90 days in
the intensively treated group, raising many questions about the possible causative factors of death at 90 days after 4
days of intensive glucose control.
There is little evidence from controlled trials that specifically addresses glycemic control in patients with acute
stroke. The largest published trial examining tight glycemic control after acute stroke is the UK Glucose in Stroke
Trial (GIST) that examined the effects of a 24-hour intervention with GIK infusion to keep blood glucose 72-126
Module G: Glycemic Control Page 69