Perioperative Hypoglycemia in Diabetic Patients Undergoing Vitrectomy: a Masked CGM Prospective Observational Study

1. Background and Rationale Patients with diabetes mellitus undergoing surgery are exposed to multiple factors that can destabilize glycemic control, including preoperative fasting, the neuroendocrine stress response to surgery and anesthesia, and the perioperative use of insulin or oral hypoglycemic agents. Among the resulting glycemic disturbances, hypoglycemia is of particular clinical concern because it can be associated with neurological injury and cardiovascular complications, and because its symptoms are frequently masked under general anesthesia and sedation. An unrecognized intraoperative or early postoperative hypoglycemic episode may therefore go undetected and untreated.

In routine clinical practice, intraoperative glucose monitoring commonly relies on intermittent point-of-care testing (POCT), such as fingerstick capillary glucose measurement, or on blood gas analysis. These intermittent methods provide only discrete snapshots of glucose status and may fail to capture transient hypoglycemic episodes occurring between measurements. As a result, the true burden of perioperative hypoglycemia in surgical patients with diabetes is likely underestimated.

Continuous glucose monitoring (CGM) measures interstitial fluid glucose concentrations and provides a continuous record of glycemic trends. CGM has emerged as a tool that may allow more precise assessment of glycemic variability and detection of hypoglycemia in the perioperative setting, and recent studies have reported its usefulness for this purpose. Current guidelines recommend periodic intraoperative glucose measurement (approximately every one to two hours) in patients with diabetes, particularly those receiving insulin. In practice, however, glucose monitoring is frequently omitted during relatively short and hemodynamically stable ophthalmic procedures such as pars plana vitrectomy (TPPV).

HbA1c reflects chronic glycemic control but has limited ability to predict acute hypoglycemic events. Vitrectomy is notable for being performed in a high proportion of patients with diabetes, yet perioperative glycemic monitoring during such surgery remains limited. Consequently, hypoglycemia occurring intraoperatively or in the recovery room may not be adequately detected. There is a need to characterize the incidence and pattern of perioperative hypoglycemia in this population using a continuous monitoring approach. 2. Study Objectives The primary objective of this study is to estimate the incidence of perioperative hypoglycemia, defined as a CGM glucose value below 70 mg/dL (Level 1), in patients with diabetes undergoing vitrectomy, using masked CGM.

Secondary objectives are to evaluate:

The incidence of clinically significant hypoglycemia, defined as a CGM glucose value below 54 mg/dL (Level 2); Indices of glycemic variability during the perioperative period, including Time Below Range (TBR), maximum and minimum glucose values, and glucose excursion (maximum minus minimum glucose); Clinical risk factors associated with perioperative hypoglycemia, such as age, diabetes characteristics, HbA1c, insulin use, fasting duration, and operative time; The exploratory association between perioperative hypoglycemia and postoperative ophthalmic outcomes; and The exploratory, opportunistic concordance between standard-of-care POCT glucose values and time-matched CGM values.

This study is intended to characterize the limitations of current perioperative glucose monitoring strategies and to provide foundational data for the design of future risk-based monitoring strategies and CGM-based interventional research. 3. Study Hypotheses

The study is based on the following hypotheses:

Perioperative hypoglycemia occurs in patients with diabetes undergoing vitrectomy.

The occurrence of perioperative hypoglycemia is associated with clinical risk factors including age, diabetes characteristics, HbA1c, insulin use, fasting duration, and operative time.

CGM can continuously record glycemic variability during the perioperative period, and the concordance between CGM values and opportunistically obtained standard-of-care POCT values can be assessed in an exploratory manner. 4. Study Design and Setting This is a single-center, prospective, observational cohort study. It is non-interventional with respect to clinical management: a masked CGM device is applied solely for observational data collection and does not influence clinical decision-making. No randomization or treatment allocation is performed. Glycemic management is conducted entirely according to the existing standard of care. 5. Study Device The study uses the FreeStyle Libre 2® continuous glucose monitor (Abbott Diabetes Care). This device is an approved continuous glucose monitoring system in Korea. In this study it is applied in a masked, observational manner rather than for therapeutic glucose management. The sensor records interstitial glucose at frequent intervals, and data are retrieved after the monitoring period for analysis. 6. Eligibility Criteria

Inclusion criteria:

Adults aged 19 years or older; Diagnosed diabetes mellitus; Scheduled to undergo vitrectomy; Able to provide written informed consent.

Exclusion criteria:

CGM sensor placement not feasible; Known allergy to the sensor; Inability to obtain valid CGM data; Inability to provide voluntary informed consent. 7. Enrollment and Informed Consent Recruitment and consent are performed by the principal investigator and study staff. During a preoperative outpatient visit, the study is explained in full, and participants are given adequate time to decide on participation before written informed consent is obtained. Participation intent is reconfirmed before study procedures begin. Each participant is assigned a screening number and a subject number, and identification is performed using the screening number, subject number, and initials. Participants are enrolled sequentially according to the time of consent, with no randomization. Each participant receives a copy of the information sheet and consent form, and is informed that consent may be withdrawn at any time without penalty. 8. CGM Application and the Perioperative Monitoring Period Before surgery, a CGM sensor is placed on the participant's upper arm. After sensor insertion, an approximately one-hour warm-up period elapses during which valid glucose data are not generated; this warm-up interval is excluded from analysis.

Following completion of warm-up, CGM glucose data are collected at approximately 15-minute intervals from the end of warm-up until discharge from the post-anesthesia care unit (PACU). For the purposes of this study, the perioperative period for data collection is defined as the interval "from completion of CGM warm-up until PACU discharge." Within this interval, CGM glucose data, POCT glucose values, and surgical and anesthetic variables are collected. Data are obtained across the relevant care settings, including the operating room and the PACU. 9. Masking (Blinding) and Unblinding Procedures Single-blinding is applied. Blinding begins at the time of sensor placement and is maintained until PACU discharge and sensor removal (or until the end of the 14-day sensor wear period). During the primary data-collection interval (the perioperative period defined above), all clinical staff involved in care-anesthesiologists, the operating surgeon, and PACU nurses-have no access to CGM data. The CGM sensor is applied in a masked manner: no reader is distributed, the device is not linked to the participant's own smartphone, and alarms are disabled, so that real-time glucose values are not displayed. This is applied uniformly to all participants.

Routine unblinding is performed collectively after data collection for all participants has been completed. Study staff log in to a dedicated research LibreView® account and download each participant's sensor data. The downloaded raw data are de-identified (matched by research number) and converted into an analysis dataset. This procedure is performed under the confirmation of the principal investigator, and the unblinding date, operator, and downloaded subject numbers are recorded in an unblinding log. Unblinded data are not transmitted to the clinical care team.

Because this is a non-interventional observational study in which CGM does not affect clinical care and all glycemic management follows the standard of care (POCT), individual emergency unblinding is, in principle, not required. However, if a medical reason directly related to participant safety arises (for example, the need for post hoc review following a serious adverse event), the principal investigator may selectively unblind that participant's CGM data. In such cases, the reason, date, requestor, and approver of the emergency unblinding are recorded separately in the unblinding log and, where necessary, reported to the IRB. 10. Data Collected

During the study, the following data are collected:

Demographic variables; Underlying conditions, including diabetes type (Type 1 or Type 2), duration of diabetes, and insulin use; Surgical and anesthetic variables; CGM glucose data (masked, at approximately 15-minute intervals; clinicians do not view these data during the study period); POCT glucose values obtained according to standard care, including recovery-room (PACU) glucose measurements.

At each time point, continuous CGM glucose data and intermittent standard-of-care glucose measurements are collected together. 11. Outcome Measures

Primary outcome:

Incidence of perioperative hypoglycemia (CGM glucose \< 70 mg/dL, Level 1). Definition: CGM glucose below 70 mg/dL. Determination: occurrence of at least one such episode during the perioperative period.

Secondary outcomes: 1. Incidence of clinically significant hypoglycemia. Definition: CGM glucose below 54 mg/dL (Level 2). Determination: at least one episode during the perioperative period. 2. Opportunistic POCT-CGM concordance (exploratory). Standard-of-care POCT glucose values obtained at the discretion of clinical judgment are compared with CGM values at the same time point (within ±5 minutes) to assess concordance. Because the institution does not have a standardized intraoperative POCT protocol during TPPV, measurement timing is not fixed; this is therefore performed as an exploratory analysis rather than a formal outcome. 3. Glycemic variability indices: Time Below Range (TBR; \< 70 mg/dL and \< 54 mg/dL), maximum and minimum glucose values during the perioperative period, and glucose excursion (maximum minus minimum glucose). 4. Exploration of clinical risk factors for perioperative hypoglycemia: analysis of the association between hypoglycemia and factors such as age, diabetes characteristics, HbA1c, insulin use, fasting duration, and operative time. 5. Association between perioperative hypoglycemia and postoperative ophthalmic outcomes (exploratory): changes in best-corrected visual acuity (BCVA), and postoperative ophthalmic complication rates including recurrent vitreous hemorrhage, retinal redetachment, elevated intraocular pressure, and the need for additional surgery or procedures. Because the primary aim of the study is to estimate the incidence of perioperative hypoglycemia, ophthalmic outcomes are analyzed as exploratory endpoints. BCVA changes and ophthalmic complications are assessed from medical records of routine outpatient follow-up visits (for example, approximately one week and one to three months after surgery), without any additional study-specific visits.

Hypoglycemia is classified according to ADA/Danne et al. criteria (Level 1: \< 70 mg/dL; Level 2: \< 54 mg/dL). 12. Statistical Analysis Continuous variables are summarized as mean ± standard deviation or as median with interquartile range, as appropriate, and categorical variables are presented as frequencies and percent

• Incidence of clinically significant hypoglycemia (CGM glucose < 54 mg/dL, Level 2) [Срок оценки: From completion of CGM warm-up until PACU discharge (perioperative period)]
• Time Below Range (TBR) during the perioperative period [Срок оценки: From completion of CGM warm-up until PACU discharge (perioperative period)]
• Minimum perioperative glucose [Срок оценки: From completion of CGM warm-up until PACU discharge (perioperative period)]
• Maximum perioperative glucose [Срок оценки: From completion of CGM warm-up until PACU discharge (perioperative period)]
• Glucose excursion during the perioperative period [Срок оценки: From completion of CGM warm-up until PACU discharge (perioperative period)]
• Odds ratio for perioperative hypoglycemia by clinical risk factor (exploratory) [Срок оценки: From completion of CGM warm-up until PACU discharge (perioperative period)]
• Opportunistic POCT-CGM concordance (exploratory) [Срок оценки: From completion of CGM warm-up until PACU discharge (perioperative period)]
• Change in best-corrected visual acuity (BCVA) (exploratory) [Срок оценки: Up to 3 months after surgery (routine outpatient follow-up; e.g., 1 week and 1-3 months)]
• Incidence of postoperative ophthalmic complications (exploratory) [Срок оценки: Up to 3 months after surgery (routine outpatient follow-up; e.g., 1 week and 1-3 months)]