Strict glycemic control to prevent surgical site infections in gastroenterological surgery

Abstract Perioperative hyperglycemia is a risk factor for surgical site infections (SSI). Although the recommended target blood glucose level (BG) is 140–180 mg/dL for critically ill patients, recent studies conducted in patients undergoing surgery showed a significant benefit of intensive insulin therapy for the management of perioperative hyperglycemia. The aim of the present review is to evaluate the benefits of strict glycemic control for reducing SSI in gastroenterological surgery. We carried out a post‐hoc analysis of the previously published data from research on the risk factors for SSI. The highest BG within 24 hours after surgery was evaluated. A total of 1555 patients were enrolled in the study. In multivariate analysis, a dose–response relationship between the level of hyperglycemia and the odds of SSI was demonstrated when compared with the reference group (≤150 mg/dL) (odds ratio [OR] = 1.68, 95% confidence interval [CI] 1.14–2.49 for 150–200 mg/dL; and OR = 2.15, 95% CI 1.40–3.29 for >200 mg/dL). Unexpectedly, hyperglycemia was not a significant risk factor for SSI among diabetes patients. By contrast, non‐diabetes patients with a BG of >150 mg/dL were found to have increased odds of SSI. In conclusion, a target BG of ≤150 mg/dL is recommended in patients without diabetes who undergo gastroenterological surgery. Additional study is required to determine an optimal target BG in diabetes patients. Because of the risk of hypoglycemia, a conventional protocol is indicated for patients admitted to the general ward where frequent glucose measurement is not assured.

appropriate perioperative insulin therapy is required in patients with hyperglycemia. [3][4][5][6][7] Data regarding the impact of long-term glucose control on SSI have been conflicting in patients with diabetes mellitus (DM). In DM patients who underwent major non-cardiac surgery, a hemoglobin (Hb) A1c level of <7% was significantly associated with decreased infectious complications with an adjusted odds ratio (OR) of 2.13. 9 In contrast, Latham et al. 8 reported that DM and postoperative hyperglycemia were independently associated with the development of SSI. However, among DM patients, elevated Hb Alc values were not associated with a statistically significantly increased risk of infection. Acott et al. 10 also described that there was no correlation between risk of complication and Hb A1c level.
These reports suggest that short-term perioperative glucose control may be more impactful in decreasing SSI than long-term control of Hb A1c.
Earlier guidelines for prevention of SSI from the Centers for Disease Prevention and Control (CDC) 3

published in 1999
recommended perioperative treatment of hyperglycemia (≥200 mg/ dL) in patients with DM. The Surgical Care Improvement Project 5 (SCIP) developed a quality performance measure to maintain the 6 a.m. controlled blood glucose level (BG) at <200 mg/dL in cardiac surgery (<180 mg/dL in the updated version 11 ). This recommendation has been challenged by recent studies suggesting that an even lower target BG is required to prevent SSI. [12][13][14][15][16][17][18] The intensive insulin administration protocol (intensive protocol), however, leads to an increased risk of hypoglycemia, which, in turn, is associated with increased morbidity and mortality. 19,20 It seems that very strict glycemic control has modest benefits, with adverse effects often outweighing these advantages in critically ill patients. However, recent studies have indicated differing results for certain patient subgroups, such as surgical patients with acute operative hyperglycemia in the immediate postoperative period. [12][13][14][15][16] As patients with DM have a higher risk of cardiovascular disease, and the association with SSI was significantly higher for cardiac surgery compared with other surgeries in DM patients 21 22 which raised questions about the generalizability of the results to patients undergoing other surgical procedures. 12 Vigorous studies have been recently conducted to clarify the efficacy of tight (strict) glycemic control in patients undergoing gastroenterological surgery, and four of 15 randomized clinical trials (RCT) comparing intensive with conventional protocols were carried out in patients undergoing abdominal surgery (nine were conducted for cardiac surgery). 23 The definition of intensive protocol varies from 'moderately strict glycemic control' with an upper limit target of 150 mg/dL to 'very strict control' with a target of 110 mg/dL (  26,28,29 The NICE-SUGAR trial, 19 which included a relatively small number of patients with elective surgery (12.5%), was carried out in critically ill patients at high risk of death (Acute Physiology and Chronic Health Evaluation [APACHE] II score, 21.1; death at day 28, 21.5%), and 21.6% of the patients already had sepsis at the time of randomization.
A post-hoc analysis of the NICE-SUGAR study database 20 showed that very strict control leads to moderate and severe hypoglycemia, both of which are associated with an increased risk of death, whereas high incidence of hypoglycemia possibly leads to increased mortality in patients assigned to a group under very strict control.
Therefore, it would be prudent to ensure that strategies for managing the BG in critically ill patients focus not only on the control of hyperglycemia but also on avoidance of hypoglycemia. The clustered ranking plot reported by Yamada et al. 28 provided precise risk estimates and better information about the hierarchy of target BG ranges for achieving safe and effective glycemic control in critically ill patients, and a BG of 140-180 mg/dL achieved the best outcome in relation to all-cause mortality and hypoglycemia. Surviving Sepsis Campaign guidelines 30 for the management of severe sepsis and septic shock recommended a protocolized approach with a target upper BG of 180 mg/dL rather than 110 mg/dL.
Although the recommended target BG is 140-180 mg/dL for most ICU patients, 27 a recent meta-analysis 23 comparing the efficacy between an intensive and a conventional protocol in patients undergoing surgery showed a significant benefit for the intensive protocol in reducing SSI. Beneficial effects in reducing SSI were confirmed in studies with very strict and moderately strict control, and the effect was similar in both groups (P = 0.328). 6 Although a higher risk of hypoglycemic events was observed with the intensive protocol, the protocol including a very strict control group did not increase the risk of postoperative death and stroke compared with the conventional protocol in surgical patients, 23 and it was concluded that an intensive protocol can be carried out safely without the risk of serious adverse events in surgical patients (  Table 3.
Among surgical procedures, hepatobiliary-pancreatic surgery and esophagectomy were independent risk factors for postoperative hyperglycemia.
T A B L E 2 Clinical outcomes of intensive insulin therapy and recommendation for glycemic control in patients undergoing surgery and in those who are critically ill     (Table 7).
Recently, a computer-based insulin infusion protocol has been introduced in the ICU setting, for which improved glycemic control over the manual protocol was reported. 38 Saur et al. 39  appropriate insulin delivery and management protocol according to the best available evidence. Further RCT comparing moderately strict control and very strict control are needed to clarify the optimal intensive protocol that reveals a beneficial effect in reducing SSI without a significantly increased risk of hypoglycemia.

CONF LICTS OF INTEREST
Authors declare no conflicts of interest for this article.