Relationship between perioperative glycemic control and postoperative infections

Abstract

Perioperative hyperglycemia in critically ill surgery patients increases the risk of postoperative infection (POI), which is a common, and often costly, surgical complication. Hyperglycemia is associated with abnormalities in leukocyte function, including granulocyte adherence, impaired phagocytosis, delayed chemotaxis, and depressed bactericidal capacity. These leukocyte deficiencies are the cause of infection and improve with tight glycemic control, which leads to fewer POIs in critically ill surgical patients. Tight glycemic control, such as intensive insulin therapy, has a risk of hypoglycemia. In addition, the optimal targeted blood glucose range to reduce POI remains unknown. Since 2006, we have investigated tight perioperative blood glucose control using a closed-loop artificial endocrine pancreas system, to reduce POI and to avoid hypoglycemia. In this Topic Highlight, we review the relationship between perioperative glycemic control and POI, including the use of the artificial pancreas.

Key Words: Glycemic control, Surgical site infection, Artificial pancreas, Insulin therapy, Glucose toxicity

INTRODUCTION

Recent evidence suggests that perioperative hyperglycemia is the main risk factor for the development of postoperative infection (POI)[1,2]. Intensive glucose control[3-7] leads to fewer POIs in critically ill surgical patients[1]. However, tight glycemic control[8-12] such as intensive insulin therapy (IIT)[3-7] has a risk of hypoglycemia. In addition, the optimal target range for blood glucose to reduce POI remains unknown[1,2,13-15]. We recently demonstrated that tight perioperative glycemic control can be achieved by using an artificial endocrine pancreas[16,17] for surgical patients, and that it was a safe and effective treatment for decreasing the incidence of POI, without increasing the risk of hypoglycemia[18-22].

In this Topic Highlight, we review the relationship between perioperative glycemic control and POI, including the use of an artificial pancreas.

RELATIONSHIP BETWEEN PERIOPERATIVE HYPERGLYCEMIA AND POI

Perioperative hyperglycemia in critically ill surgery patients increases the risk of POI, which is a common, and often costly, surgical complication[1,2,18-22]. It is well known that diabetic patients are at higher risk of postoperative complications, including POI, than non-diabetic surgery patients. Indeed, hyperglycemia correlates positively with POI in diabetic surgical patients[23] and with a poor prognosis following stroke or head injury[24,25]. POI is exacerbated by perioperative hyperglycemia in critically ill surgery patients[1].

Strict glycemic control decreases the risk of infection and improves other outcomes for trauma, cardiac, and critically ill non-diabetic surgery patients. Ramos et al[1] associated postoperative hyperglycemia with an increased risk of 30 d postoperative infectious complications and a longer hospital stay, independent of diabetic status. On the basis of these findings, they recommended evaluation of the possible benefits of postoperative glycemic control in general surgical patients[1].

Hyperglycemia is also associated with a sustained decrease in polymorphonuclear leukocyte function[26]. Abnormalities in leukocyte function[27] have been identified that are caused by the hyperglycemic state. These include abnormalities in granulocyte adherence[28], impaired phagocytosis[29], delayed chemotaxis[30], and depressed bactericidal capacity[29,31]. The degree of hyperglycemia that has been shown to impair phagocytic function is as low as 200 mg/dL[32]. These leukocyte deficiencies appear to improve with tight glycemic control[33]. Together with the demonstrated role of perioperative hyperglycemia in POI, it is clear that tight glycemic control should improve the clinical outcome for all surgical patients.

Insulin displays a potent and acute anti-inflammatory effect by inhibiting the tissue factor, plasminogen activator inhibitor-1[34], and the intranuclear nuclear factor κB (NF κB)[35]. Insulin plays a vital role, not only in blood glucose control, but also as an anti-inflammatory and anti-oxidant agent. Insulin suppresses the proinflammatory effects of NF κB, activator protein 1, early growth response 1, and high mobility group box 1[34-36], as well as inhibiting nicotinamide hypoxanthine dinucleotide oxidase action to reduce reactive oxygen species production[34,35].

IIT has been reported to reduce infection rates after neurosurgery; therefore, this approach might be an appropriate blood glucose control method to prevent POI[37]. However, clinical evidence is still needed to confirm the efficacy of IIT for strict blood glucose control in preventing POI. Although improved control of blood glucose fluxes have high potential to improve survival and decrease morbidity in surgical patients, the association between perioperative blood glucose range and the incidence of POI remains unclear in the majority of surgical patients due to lack of evidence. Further studies, including prospective randomized controlled trials, are necessary to clarify this issue.

THE OPTIMAL TARGET RANGE FOR BLOOD GLUCOSE TO PREVENT POI IN SURGICAL PATIENTS

Good long-term glycemic control is strongly associated with significantly fewer POIs in diverse surgical populations[38]. Zerr et al[39] reported that elevated blood glucose levels of more than 200 mg/dL in diabetic patients are associated with a higher incidence of deep sternal wound infection. Use of perioperative glycemic control in the range of 150-200 mg/dL significantly reduced POI in diabetic patients undergoing open heart surgery[40].

Van den Berghe et al[3] demonstrated that tight glycemic control (IIT) to maintain blood glucose levels in the target range of 80-110 mg/dL improved morbidity and mortality in the surgical intensive care unit (ICU). However, a recent large study by NICE-SUGAR Study Investigators[15] completely denied the effectiveness of IIT shown by Van den Berghe et al[3]. Contrary to Van den Berghe’s first trial[3], IIT increased mortality among adults in the ICU and a blood glucose target less than 180 mg/dL (most frequent blood glucose value of 142 mg/dL) resulted in lower mortality than did a target of 81-108 mg/dL (most frequent blood glucose value of 107 mg/dL)[15]. Recent meta-analysis[41] including NICE-SUGAR[15], concluded that IIT significantly increased the risk of hypoglycemia and conferred no overall mortality benefit among critically ill patients; however, this therapy might be beneficial to patients admitted to a surgical ICU. Some patients might benefit from IIT, although the characteristics of such patients remain to be clearly defined, as does the effect of different blood glucose algorithms, the method of measuring blood glucose, and the influence of nutritional strategies[41]. Unfortunately, however, the optimal targeted blood glucose range to prevent POI remains unclear, especially in the intraoperative targeted blood glucose zone. IIT is also a risk factor for hypoglycemia (≤ 40 mg/dL)[3,4,12-15], which is linked to serious neurological events. Hypoglycemia is the major potential harm of tight glucose control. Tight glycemic control without hypoglycemia will be required in the future.

TIGHT PERIOPERATIVE GLYCEMIC CONTROL USING A CLOSED-LOOP ARTIFICIAL ENDOCRINE PANCREAS SYSTEM

Since 2006, we have been developing a closed-loop artificial pancreas system[16-20] (STG-22, Nikkiso Co. Ltd., Tokyo) to achieve perioperative glycemic control and prevent POI in general surgery, without the risk of hypoglycemia associated with tight glycemic control.

Firstly, we confirmed that the STG-22[21,22] could reliably and accurately measure blood glucose concentration similarly to the ABL 800FLEX machine (Radiometer Medical Aps, Brtheta;nshtheta;j, Denmark) recommended by the National Committee for Clinical Laboratory[21,22]. This closed-loop glycemic control system maintained stable blood concentrations by the automatic infusion of regular insulin and/or glucose into the circulation[18].

Secondly, we performed two prospective randomized clinical trials and found that tight perioperative glycemic control using a closed-loop artificial pancreas system (STG-22, Nikkiso Co. Ltd., Tokyo) decreased surgical site infection (SSI) in patients who underwent pancreatectomy[19] or hepatectomy[20]. In our reports, perioperative blood glucose levels were continuously monitored using an artificial endocrine pancreas[16-20] and glucose levels were controlled using either the sliding scale method[42] (SS group: targeted blood glucose zone of 150-200 mg/dL) or the artificial pancreas (AP group: targeted blood glucose zone of 80-110 mg/dL). In our study of patients who had undergone a pancreatectomy, the AP group, maintained near-normal glycemia, whereas the blood glucose levels of the SS group plateaued at approximately 200 mg/dL between 4 and 6 h after pancreatectomy[19]. In addition, the incidence of SSI in the AP group (0%) was significantly lower than that of the SS group (about 30%). In our study of patients who had undergone a hepatectomy[20], the AP group again maintained near-normal glycemic control and a reduction in the incidence of SSI. As a consequence, the length of stay and cost of hospitalization was reduced. It is worth noting that there were no incidents of hypoglycemia using a closed-loop artificial pancreas system, despite maintaining blood glucose levels similar to those obtained with IIT. Our results support the conclusions of previous reports[1,38-40] that glycemic control could be a simple intervention to decrease the risk of infectious complications resulting from hyperglycemia after surgery.

Thirdly, to date, more than 200 general surgeries (hepatic resection, pancreatic resection, esophageal resection, and emergency operations) have been performed under tight perioperative glycemic control using an artificial pancreas (STG-22) with no incidence of hypoglycemia[20]. To avoid hypoglycemia in tight glycemic control and improve POI in surgery, the closed-loop artificial endocrine pancreas system is an effective and safe means. Furthermore, novel perioperative glycemic control using an artificial pancreas markedly improved the labor burden on nursing staff, and hence reduced concerns about hypoglycemia[43].

Finally, because an ideal comparative study of tight glycemic control should be carried out under conditions without risk of hypoglycemia, blood glucose control using a closed-loop artificial pancreas system might be beneficial for the detection of the optimal target range for blood glucose in surgical patients.

CONCLUSION

Perioperative hyperglycemia increases the risk of POI. Therefore, perioperative glycemic control in patients undergoing surgery is beneficial to reduce POI. As a closed-loop artificial pancreas system is able to perform tight glycemic control without increasing the risk of hypoglycemia, it might be a safe and useful blood glucose control system in critically ill surgical patients. At present, however, the perioperative optimal target range for blood glucose to reduce POI remains uncertain. Further studies are needed to address this issue.