Association of a novel glycemic control index, time in range, with infectious complications after pancreatectomy

Introduction

Postoperative complications after pancreatectomy remain high despite recent improvements in surgical and perioperative management (1). In particular, postoperative blood glucose levels are strongly associated with surgical site infection (SSI) (2-4). Strict glycemic control is essential for the prevention of SSI, and there is a consensus that a target of ≤150 mg/dL is recommended for general surgery (5-7). In addition, it has recently become clear that glycemic variability is associated with postoperative adverse events, including SSI, 30-day readmission rates, and in-hospital mortality (8-10). Therefore, stable glycemic control is crucial. However, the conventional method, which involves blood glucose measurement using capillary point-of-care (POC) testing and adjustment of insulin concentration according to the measured values, is limited to point-by-point adjustments, and continuous real-time evaluation and intervention in glycemic variability is challenging.

The usefulness of continuous glucose monitoring (CGM) for stabilizing glycemic variability has become widely recognized (11,12). CGM enables real-time evaluation of glycemic variability by measuring interstitial glucose, thus providing a more complete glycemic profile than standard capillary POC testing (13,14). Time in range (TIR) is an index to evaluate glycemic variability; it indicates the percentage of time within the target blood glucose level per total measurement time (15). Recently, the usefulness of TIR, calculated from a seven-point glucose test instead of CGM, has been reported; it can be immediately used in routine clinical practice in combination with conventional methods (16).

If an association exists between TIR calculated from blood glucose measured via capillary POC testing and postoperative infectious complications, glycemic management based on TIR as an indicator may help prevent postoperative infectious complications. However, the association between TIR and postoperative infectious complications remains unclear. Therefore, the importance of real-time evaluation of glycemic variability with TIR during the postoperative period remains unclear.

This study aimed to clarify the association between TIR and infectious complications after pancreatectomy and evaluate the usefulness of TIR, a new glycemic control index, in postoperative glycemic control. We present this article in accordance with the STROBE reporting checklist (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-24-392/rc).

Methods

Patients

This retrospective cohort study was based on a database of patients who underwent pancreatectomies at Nara Medical University Hospital and Wakayama Medical University Hospital. A flowchart of this study is shown in Figure S1. A total of 1,101 patients who underwent pancreatectomy between January 2017 and December 2022 were included. The exclusion criteria were preoperative intra-abdominal infection (n=8) and insufficient data (n=10). A total of 1,083 patients were analyzed, including a discovery cohort (n=543) enrolled at Nara Medical University and a validation cohort (n=540) enrolled at Wakayama Medical University, Japan (Figure 1). This study was approved by the Local Ethics Committee on Clinical Investigation of Nara Medical University (No. 3668) and registered in the UMIN Clinical Trials Registry (UMIN000053087). Informed consent was obtained in the form of an opt-out option. Data on the following clinical characteristics were retrospectively obtained from the patients’ medical records. The study was conducted in accordance with the Declaration of Helsinki (and its subsequent amendments).

Figure 1 Population flow chart. TIR, time in range.

Definition and cutoff value of TIR

Postoperative glycemic control was performed using the conventional method with a cutoff of ≤150 mg/dL, as recommended by the American College of Surgeons/Surgical Infection Society Surgical Site Infection Guidelines 2016 Update (5). The general target blood glucose range of TIR is 70–180 mg/dL (15); however, the target blood glucose range in this study was set to 70–150 mg/dL to optimize postoperative glycemic control. TIR was calculated using a four-point glucose test during the first postoperative week using the following formula: number of times within the target range/total number of tests × 100%. Blood glucose was measured by a nurse four times a day, 1 hour before each meal and before bedtime. The cutoff value of TIR was set to the value at which Youden’s index was maximized by drawing a receiver operating characteristic curve for the onset of organ/space SSI (Table S1).

Definitions of postoperative complications

The severity of postoperative complications was graded according to the Clavien-Dindo Classification (17). Postoperative pancreatic fistula was diagnosed according to the classification redefined by the International Study Group on Pancreatic Fistula in 2016 (1). Pancreatic fistula classified as Grade B are generally considered to be associated with infection. However, cases that require drainage for more than three weeks are classified as Grade B, even if there are no signs of infection based on negative drain cultures and the characteristics of the drain. The presence of SSI was determined according to the Centers for Disease Control and Prevention Guideline for the Prevention of Surgical Site Infection 2017 (18). For cases with a hospital stay of less than 30 days, if there were no visits or readmissions due to the onset of infectious complications by the time of outpatient follow-up after 30 days postoperatively, the absence of infectious complications was determined. Organ/space SSI was diagnosed based on positive culture results. However, in the few cases where culture specimens were unavailable, antibiotic therapy was administered after inclusion of suspicion of infection as an infectious complication.

Treatment strategy for infectious complications

The basic policy for antibiotic treatment for infections is consistent across the two participating institutions. Specifically, first-generation cephalosporins are administered immediately before and during surgery as a prophylactic measure against SSI. Prophylactic administration is limited to the day of surgery, with no further prophylactic doses given afterward. In cases where infectious complications are suspected, empirical treatment is initiated based on the infection focus and severity. The antibiotics used and the duration of treatment for common infectious complications was shown in Table S2. Additionally, bile cultures are routinely obtained during surgery, and this information is used to select antibiotics in cases of biliary-related infections, such as cholangitis. Culture tests for identifying causative organisms are conducted whenever possible, and definitive treatment is initiated once culture results are available. Antibiotic selection and treatment duration are determined in consultation with infectious disease specialists as needed.

Statistical analysis

Continuous variables were expressed as means and standard deviations, and the groups were compared using Welch’s t-test. Categorical variables were presented as numbers and percentages, and the groups were compared using Fisher’s exact test. A multivariate analysis was performed using a logistic regression model. The results were expressed as odds ratio (OR) and 95% confidence intervals (CI). We set a significance threshold of P<0.05. One-by-one propensity score matching (PSM) was performed to adjust for variations in patient characteristics. The propensity scores for each patient were calculated using logistic regression analysis involving the following variables: age, sex, body mass index (BMI), presence of diabetes mellitus (DM), preoperative hemoglobin A1c (HbA1c) levels, pancreatic ductal adenocarcinoma (PDAC), and operative procedures. Missing values were imputed using the mean. Ten cases with missing HbA1c values were imputed with the mean HbA1c. For blood glucose levels, missing values were also imputed with the mean. However, cases with fewer than 14 measurements within the first postoperative week were excluded due to insufficient data (n=10). All statistical analyses were performed using EZR software (https://cran.r-project.org/) (19).

Results

Patient characteristics

The characteristics of patients in the discovery cohort are presented in Table 1. Of the 543 patients, 210 (39%) had TIR ≥75% (well-controlled group), and 333 (61%) had TIR <75% (poorly controlled group). Regarding clinical parameters, the poorly controlled group before matching had significantly older age (P=0.009), lower rate of preoperative biliary drainage (P=0.001), and higher rate of DM (P<0.001), HbA1c ≥6.5% (P<0.001), and PDAC (P<0.001) than did the well-controlled group. Regarding operative parameters, the poorly controlled group before matching had significantly higher rates of distal pancreatectomy (DP) (P=0.001) and total pancreatectomy (TP) (P=0.004) than did the well-controlled group. After matching, the clinical and operative parameters of 143 patients in each group were balanced.

Postoperative outcomes

Postoperative outcomes in the discovery cohort are shown in Table 2. The infectious complications rate was significantly higher in the poorly controlled group than in the well-controlled group for all (31% vs. 43%, P=0.009) and matched patients (31% vs. 50%, P=0.003). Regarding infection type, organ/space SSI was significantly higher in the poorly controlled group in all (19% vs. 27%, P=0.02) and matched patients (20% vs. 35%, P=0.008); however, there were no significant differences in any other infection types between the two groups. In addition, the incidence of organ/space SSI tended to decrease with a better TIR (Figure 2).

Figure 2 Total number of patients and incidence of organ/space SSI per time in range. The line graph showing the incidence rate of organ/space SSI in the discovery cohort (A,B) and validation cohort (C,D). TIR, time in range; SSI, surgical site infection.

Association between organ/space SSI and TIR in the validation cohort

We demonstrated the association between TIR <75% and organ/space SSI in the discovery cohort, as described above. Afterward, we tested the usefulness of TIR in another independent cohort to prove the versatility of this indicator. In the validation cohort, PSM was performed using the same factors as in the discovery cohort and adjusted for patient characteristics (Table S3). After matching, the incidence of organ/space SSI was significantly higher in the poorly controlled group, and as in the discovery cohort, there were no significant differences in other infectious complications. In addition, we conducted multivariate analysis of the risk factors for organ/space SSI in the discovery and validation cohorts. Male sex, BMI ≥25 kg/m², PDAC, and TIR <75% (discovery cohort: OR: 2.13, 95% CI: 1.30–3.50, P=0.003; validation cohort: OR: 1.95, 95% CI: 1.10–3.47, P=0.02) were independent risk factors for organ/space SSI (Table 3). These factors were perfectly matched in the discovery and validation cohorts.

Risk factors for TIR <75% after pancreatectomy

We analyzed the risk factors for TIR <75% to identify the population requiring intensive glycemic control. Multivariate analysis of the risk of TIR <75% in the discovery and validation cohorts is presented in Table 4. Factors associated with an independent risk of TIR <75% were the presence of DM, HbA1c ≥6.5%, and DP or TP. Similar to the risk of organ/space SSIs, these factors were matched perfectly in the discovery and validation cohorts.

Discussion

We showed that a TIR <75% was a risk factor for organ/space SSI after pancreatectomy in two independent cohorts. This is the first study to show an association between TIR and organ/space SSI after pancreatectomy, including a cutoff value. TIR is convenient and immediately applicable in daily practice. Furthermore, this study suggests that TIR is a risk factor for organ/space SSI even in two groups with balanced patient backgrounds established through PSM. This finding may provide valuable information for planning future prospective studies. However, regarding infection type, TIR was not associated with other infectious complications. Previous studies on SSI reported different risk factors depending on the type of SSI (20-22). Hyperglycemia was reported to be a risk factor only for organ/space SSI and not for superficial SSI after elective colorectal operation (21). Although these findings support our results, the factors involved remain unclear and require further investigation.

Postoperative hyperglycemia is the most important risk factor for SSI, and higher blood glucose levels are associated with higher risk (23). In this study as well, postoperative hyperglycemia was identified as a strong risk factor for organ/space SSI (Tables S4,S5). The mechanisms by which hyperglycemia contributes to infection include impaired chemotaxis, phagocytosis, and production of reactive oxygen species, which in turn affect the immune system (24). Insulin has anabolic, anti-inflammatory, anticoagulant, and anti-apoptotic effects (25,26). Moreover, it has recently become clear that besides absolute blood glucose levels, glycemic variability is a risk factor for SSI. As a mechanism by which blood glucose variability may be a risk factor for infectious complications, spike-like hyperglycemia induces more inflammatory cytokines, such as interleukin (IL)-6 and tumor necrosis factor-alpha, than does sustained hyperglycemic (27). Furthermore, IL-6 levels were lower in the group in which stable glycemic control was achieved using an artificial pancreas (28).

The importance of glycemic variability has been recognized, and many indices have been developed to evaluate glycemic variability (29). We focused on TIR in this study for the following three reasons. First, the usefulness of TIR calculated from blood glucose measured via capillary POC testing has been reported; thus, postoperative blood glucose measurements could be used in the analysis (16). The second reason is the simplicity of TIR. Although the calculation method is simple, the greatest advantage of TIR is that the results are intuitive and easy to use in daily practice. For example, if the target value is set at 75%, as in this study, the target will be achieved if blood glucose is controlled such that the target is achieved in three out of four daily tests. Third, we anticipate the future use of CGM in postoperative glycemic management. TIR in CGM is a common indicator, as management guidelines have been published (15). In recent years, the use of CGM has become more widespread owing to the rapid technological progress of devices in the field of DM. It is easy to predict an increase in the number of surgeries performed in patients with DM using CGM, and postoperative glycemic control using CGM may become more common. The findings of this study may bridge the gap between conventional and new methods of glycemic control with CGM, ushering an era of postoperative glycemic control with CGM that may occur in the future.

This study revealed DM, HbA1c ≥6.5%, DP, and TP as risk factors for a TIR <75%. On the other hand, when examining organ/space SSI, preoperative glucose intolerance, such as a history of DM and HbA1c ≥6.5%, which are generally cited as SSI risk factors, were not independent risk factors. This may be related to the fact that a significant portion of organ/space SSI is attributed to pancreatic fistulas, where the texture of the pancreas plays a critical role. In other words, in cases of hard pancreas (typically found in patients with PDAC), the risk of pancreatic fistula-related SSI is low, and such cases often present with glucose intolerance. Conversely, in cases of soft pancreas (typically found in non-PDAC patients), where the risk of pancreatic fistula-related SSI is high, preoperative glucose intolerance is less common. This could mask the association of preoperative glucose intolerance with the risk of organ/space SSI. Indeed, in the cohort of this study, organ/space SSI occurrence was low in PDAC patients, while the prevalence of preoperative glucose intolerance was high, supporting this notion (Table S6). However, preoperative glucose intolerance is not unrelated to infection; it is suggested that it is a strong risk factor for TIR, thereby influencing organ/space SSI through TIR. These findings also imply that postoperative glycemic management is more critical than preoperative glycemic status.

Stable glycemic control with low glycemic variability in high-risk patients is crucial for preventing organ/space SSI. However, in clinical practice, glycemic control in patients with widely fluctuating postoperative blood glucose levels is challenging. Glycemic control in patients after TP is particularly difficult, and none of the patients in the two-center cohorts in this study achieved a TIR <75%. A bihormonal artificial pancreas (BIHAP) is used in refractory glycemic control cases to overcome this problem. The BIHAP can administer insulin and glucagon while monitoring blood glucose in real time, enabling stable blood glucose control with minimal risk of hypoglycemia (2,28,30). It reduces postoperative infectious complications (31). However, the large size of the device and the fact that the catheter remains connected to the patient’s body may hinder the patient’s ability to leave the bed after surgery. Recently, however, a portable BIHAP was developed (32). In addition, it can provide more stable blood glucose control than conventional diabetes treatment after TP in the outpatient setting (33) and is expected to be applied to glycemic control after pancreatectomy.

This study has several limitations. First, it was a retrospective cohort study. To minimize selection bias, we included all patients who underwent pancreatectomy at the two surgical centers according to standard selection criteria. Second, we calculated TIR using four-point glucose tests. It has been considered that the greater the number of measurements, the more accurately the TIR can be calculated, which is closely related to CGM. Cases with fewer than 14 measurements and less than half of the total number of scheduled measurements during the first postoperative week were excluded owing to insufficient data to ensure accuracy. Furthermore, the optimal evaluation period for TIR is not yet clear. In this study, we assessed TIR over the longest available period of one week, assuming that a longer evaluation period would allow for a more accurate assessment of glucose fluctuations, given that blood glucose measurements were taken four times daily. However, TIR at the third and fifth days after surgery was also an independent risk factor for organ/space SSI (data not shown). As research progresses, it may be possible to identify high-risk groups for infectious complications at an earlier time point. Finally, the results of PSM in this study indicated a reduction in the proportion of cases with preoperative glucose intolerance, suggesting that careful interpretation is needed regarding the impact of stabilizing postoperative glucose fluctuations on infectious complications in such cases. Despite these limitations, this study provides useful information on the relationship between TIR and organ/space SSI after pancreatectomy.

Conclusions

We showed that TIR <75% during the first week after pancreatectomy is a risk factor for organ/space SSI. This study provides an important finding for future post-pancreatectomy glycemic management.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-24-392/rc

Data Sharing Statement: Available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-24-392/dss

Peer Review File: Available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-24-392/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-24-392/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was approved by the Local Ethics Committee on Clinical Investigation of Nara Medical University (No. 3668) and registered in the UMIN Clinical Trials Registry (UMIN000053087). Informed consent was obtained in the form of an opt-out option. The study was conducted in accordance with the Declaration of Helsinki (and its subsequent amendments).

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Bassi C, Marchegiani G, Dervenis C, et al. The 2016 update of the International Study Group (ISGPS) definition and grading of postoperative pancreatic fistula: 11 Years After. Surgery 2017;161:584-91.
2. Hanazaki K, Kitagawa H, Yatabe T, et al. Perioperative intensive insulin therapy using an artificial endocrine pancreas with closed-loop glycemic control system: the effects of no hypoglycemia. Am J Surg 2014;207:935-41.
3. Yoneda A, Takesue Y, Takahashi Y, et al. Improvement in Hyperglycemia Prevents Surgical Site Infection Irrespective of Insulin Therapy in Non-diabetic Patients Undergoing Gastrointestinal Surgery. World J Surg 2020;44:1450-8.
4. Uchiyama K, Ueno M, Ozawa S, et al. Risk factors for postoperative infectious complications after hepatectomy. J Hepatobiliary Pancreat Sci 2011;18:67-73.
5. Ban KA, Minei JP, Laronga C, et al. American College of Surgeons and Surgical Infection Society: Surgical Site Infection Guidelines, 2016 Update. J Am Coll Surg 2017;224:59-74.
6. de Vries FE, Gans SL, Solomkin JS, et al. Meta-analysis of lower perioperative blood glucose target levels for reduction of surgical-site infection. Br J Surg 2017;104:e95-e105.
7. Global Guidelines for the Prevention of Surgical Site Infection. Geneva: World Health Organization; 2018.
8. Rodriguez-Merchan EC, Delgado-Martinez AD. Risk Factors for Periprosthetic Joint Infection after Primary Total Knee Arthroplasty. J Clin Med 2022;11:6128.
9. Hsieh CJ. High Glucose Variability Increases 30-Day Readmission Rates in Patients with Type 2 Diabetes Hospitalized in Department of Surgery. Sci Rep 2019;9:14240.
10. Jeon CY, Furuya EY, Berman MF, et al. The role of pre-operative and post-operative glucose control in surgical-site infections and mortality. PLoS One 2012;7:e45616.
11. Lind M, Polonsky W, Hirsch IB, et al. Continuous Glucose Monitoring vs Conventional Therapy for Glycemic Control in Adults With Type 1 Diabetes Treated With Multiple Daily Insulin Injections: The GOLD Randomized Clinical Trial. JAMA 2017;317:379-87.
12. Beck RW, Riddlesworth T, Ruedy K, et al. Effect of Continuous Glucose Monitoring on Glycemic Control in Adults With Type 1 Diabetes Using Insulin Injections: The DIAMOND Randomized Clinical Trial. JAMA 2017;317:371-8.
13. Gomez AM, Umpierrez GE. Continuous glucose monitoring in insulin-treated patients in non-ICU settings. J Diabetes Sci Technol 2014;8:930-6.
14. Spanakis EK, Urrutia A, Galindo RJ, et al. Continuous Glucose Monitoring-Guided Insulin Administration in Hospitalized Patients With Diabetes: A Randomized Clinical Trial. Diabetes Care 2022;45:2369-75.
15. Battelino T, Danne T, Bergenstal RM, et al. Clinical Targets for Continuous Glucose Monitoring Data Interpretation: Recommendations From the International Consensus on Time in Range. Diabetes Care 2019;42:1593-603.
16. Beck RW, Bergenstal RM, Riddlesworth TD, et al. Validation of Time in Range as an Outcome Measure for Diabetes Clinical Trials. Diabetes Care 2019;42:400-5.
17. Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg 2004;240:205-13.
18. Berríos-Torres SI, Umscheid CA, Bratzler DW, et al. Centers for Disease Control and Prevention Guideline for the Prevention of Surgical Site Infection, 2017. JAMA Surg 2017;152:784-91.
19. Kanda Y. Investigation of the freely available easy-to-use software 'EZR' for medical statistics. Bone Marrow Transplant 2013;48:452-8.
20. Lawson EH, Hall BL, Ko CY. Risk factors for superficial vs deep/organ-space surgical site infections: implications for quality improvement initiatives. JAMA Surg 2013;148:849-58.
21. Serra-Aracil X, García-Domingo MI, Parés D, et al. Surgical site infection in elective operations for colorectal cancer after the application of preventive measures. Arch Surg 2011;146:606-12.
22. Blumetti J, Luu M, Sarosi G, et al. Surgical site infections after colorectal surgery: do risk factors vary depending on the type of infection considered? Surgery 2007;142:704-11.
23. Ata A, Lee J, Bestle SL, et al. Postoperative hyperglycemia and surgical site infection in general surgery patients. Arch Surg 2010;145:858-64.
24. Turina M, Miller FN, Tucker C, et al. Effects of hyperglycemia, hyperinsulinemia, and hyperosmolarity on neutrophil apoptosis. Surg Infect (Larchmt) 2006;7:111-21.
25. Dandona P, Aljada A, Mohanty P, et al. Insulin inhibits intranuclear nuclear factor kappaB and stimulates IkappaB in mononuclear cells in obese subjects: evidence for an anti-inflammatory effect? J Clin Endocrinol Metab 2001;86:3257-65.
26. Hansen TK, Thiel S, Wouters PJ, et al. Intensive insulin therapy exerts antiinflammatory effects in critically ill patients and counteracts the adverse effect of low mannose-binding lectin levels. J Clin Endocrinol Metab 2003;88:1082-8.
27. Esposito K, Nappo F, Marfella R, et al. Inflammatory cytokine concentrations are acutely increased by hyperglycemia in humans: role of oxidative stress. Circulation 2002;106:2067-72.
28. Akabori H, Tani M, Kitamura N, et al. Perioperative tight glycemic control using artificial pancreas decreases infectious complications via suppression of inflammatory cytokines in patients who underwent pancreaticoduodenectomy: A prospective, non-randomized clinical trial. Am J Surg 2020;220:365-71.
29. Service FJ. Glucose variability. Diabetes 2013;62:1398-404.
30. Yoshimoto T, Ikemoto T, Morine Y, et al. Impact of using a perioperative artificial endocrine pancreas in pancreatic resection. Ann Gastroenterol Surg 2020;4:591-6.
31. Okabayashi T, Nishimori I, Maeda H, et al. Effect of intensive insulin therapy using a closed-loop glycemic control system in hepatic resection patients: a prospective randomized clinical trial. Diabetes Care 2009;32:1425-7.
32. Blauw H, Onvlee AJ, Klaassen M, et al. Fully Closed Loop Glucose Control With a Bihormonal Artificial Pancreas in Adults With Type 1 Diabetes: An Outpatient, Randomized, Crossover Trial. Diabetes Care 2021;44:836-8.
33. van Veldhuisen CL, Latenstein AEJ, Blauw H, et al. Bihormonal Artificial Pancreas With Closed-Loop Glucose Control vs Current Diabetes Care After Total Pancreatectomy: A Randomized Clinical Trial. JAMA Surg 2022;157:950-7.