Despite biological plausibility and some evidence from observational cohort studies for an association between reduced surgical site infections and strict glycaemic control (usually defined as treatment of glucose levels greater than 200 mg/dL), only five randomised controlled trials were identified that addressed the question of peri-operative glycaemic control and SSIs. These trials were all very different although all all patients had an initial postoperative stay in the intensive care unit. There was significant heterogeneity in the patient populations studied, in particular with regard to diabetes status,type of surgery and mortality risk. The glycaemic control regimens also differed significantly in terms of timing (intra-operative versus intra- and post-operative), duration of the study protocol post-operatively (12 hours to end of ICU stay), route of administration (continuous insulin infusion versus intravenous insulin infusion and push versus subcutaneous insulin), and target glucose ranges (maximum and minimum glucose levels, width of acceptable target range, and degree of overlap between study arms). Due to the heterogeneity, a meta-analysis was not deemed appropriate.
All five RCTs reported infection as an outcome measure however not all trials reported the rates of SSIs or only reported a subgroup of SSIs (such as deep sternal wound infections after cardiac surgery). Of the trials reporting SSIs, three had a baseline rate in the conventional glycaemic control group of less than or equal to 5%. None of these trials were individually powered to identify a difference with such a low baseline rate, likely accounting for the use of composite outcomes. The trials were too heterogeneous to combine. The other two trials that reported a difference in infection rates had much higher baseline infection rates and/or used a composite outcome. Grey 2004
had a baseline SSI rate of 30%, which likely reflects the severity of illness of the patients (as evidenced by the fact that 44% of patients in the standard group and 50% of patients in the strict glucose control group required vasopressors). Lazar 2004
also had a higher baseline rate of infection in the conventional therapy group, but did not specify how many of the infections were either pneumonia or SSI. Additionally, the higher baseline infection rate in the control arm may be due to a higher than conventionally acceptable mean glucose concentration in that group (above 200 mg/dL). Both studies had (at least) moderate risk of bias.
In addition to the differences in the glycaemic control regimens used, post-operative nutrition protocols were either not described in detail or not described at all. Both baseline nutritional status and post-operative nutrition may have been potential confounders. Malnutrition as well as obesity are risk factors for infectious complications. No serum markers or anthropomorphic measurements of baseline nutritional status were reported. However, three studies (Grey 2004
; Li 2006
; Gandhi 2007
) reported baseline Body Mass Indices (BMIs) for the randomised patients. The mean BMIs in all three studies were in the overweight range (25 to 30 kg/m2
). Additionally, post-operative nutrition can also affect outcome in that enteral nutrition is associated with fewer infectious complications and a shorter length of stay than parenteral nutrition (Mazaki 2008
). Two of the studies reported following standardized nutrition guidelines post-operatively, but did not describe the details (Grey 2004
; Bilotta 2007
). The other three studies were all in cardiac surgery patients; the composition of the post-operative diets were not described in detail, or whether differences existed based on diabetes status.
This review is unable to confirm the findings from observational cohort studies, most notably the Diabetic Portland Project. Furnary 2004
which demonstrated a reduction in sternal wound infections, mortality, and hospital length of stay with progressive lowering of the target glucose range among diabetic cardiac surgery patients over time. One potential reason for the lack of effect of strict glycaemic control in the RCTs of cardiac surgery patients may be that the glycaemic control in the conventional group may have been lower than that in the historical cohorts in the observational studies. In the Gandhi 2007
trial, which was the largest of the 5 trials reviewed and at low risk of bias, the mean 24 hour postoperative glucose level was less than 110 mg/dL in both groups. In the Furnary 2004
study, maintenance of post-operative glucose levels in the 100 to 150 mg/dL range for 3 days improved outcome. Thus, both groups in the Gandhi trial were within the target range proposed by the Portland Project and demonstrated low sternal infection and mortality rates. Because of data from observational cohort studies, use of higher glycaemic targets in the conventional treatment arm (above 200 mg/dL), such as in the Lazar 2004
trial, may no longer be accepted.
Although not a primary outcome measure listed in the review protocol, theoretically, the same rationale for reduction in SSIs with strict glycaemic control should apply to other nosocomial infections. Because of differences in the infections recorded, data from the trials cannot be combined. Bilotta 2007
reported a composite infection outcome that included urinary tract infections, pneumonia and SSI, as a primary outcome measure and identified a large difference in infection rates between treatment arms. The generalisability of this trial may be limited however given that only patients undergoing emergent cerebral aneurysm clipping were enrolled and all patients received steroids. Thus, given the biologic plausibility and the difficulty of powering future trials on SSI rate alone, future trials should consider evaluating nosocomial infections as a primary outcome measure.
Hypoglycaemia rates and adequacy of glucose control are difficult to compare between studies for several reasons. The strict and conventional glycaemic control regimens not only differed in target ranges between the groups (except for Li 2006
which used the same target range for both groups) but also in the frequency of glucose measurements. The strict control groups received more blood glucose measurements than the conventional control groups, potentially resulting in a measurement bias, particularly when reported as percentage of hyper- or hypoglycaemic levels of the total. Additionally, studies differed in the reporting of hyper- and hypoglycaemia, using either the percentage of patients who experienced at least one episode of hyper/hypoglycaemia versus the percentage of glucose measurements greater or less than the cut-off value. Of the three studies that measured hypoglycaemia, all reported a higher rate of hypoglycaemia in the strict glycaemic control group, with Grey 2004
reporting 32% of patients having at least one episode of hypoglycaemia. None of the studies reported adverse outcomes secondary to hypoglycaemia.
In the Leuven trial of strict versus conventional insulin therapy in surgical ICU patients, Van den Berghe 2001
identified a mortality reduction of 32% with intensive insulin therapy (or strict glycaemic control). The major reduction was in deaths due to a septic focus and multi-organ failure amongst patients receiving intensive insulin therapy for five or more days. None of the 5 RCTs included in this review included infection-related mortality as an outcome measure. Short-term all-cause mortality was not significantly different between treatment arms in any of the studies, although baseline risk factors were different due to very heterogeneous populations between studies. Whilst the all-cause mortality rate was twice as high in the conventional glycaemic control arm compared with the strict control arm in the Grey 2004
trial, this difference was not statistically significant, possibly due to lack of power. In the Lazar 2004
trial, there was no difference in 30-day mortality, but there was an increase in 2-year mortality in the no-GIK group due to cardiovascular complications. The death rate in the study by Gandhi 2007
was too low to detect a difference (only four deaths overall). Future trials must consider the potential harms as well as benefits of strict glycaemic control.
The length of stay was shorter associated with strict glycaemic control in only one study (Lazar 2004
) there being no difference in the remaining studies, although they are likely underpowered. Bilotta 2007
, Gandhi 2007
, Lazar 2004
, and Li 2006
) did not show a difference in mortality and, although not statistically significant, Grey 2004
reported more deaths in the conventional glycaemic control group.