Continuous Glucose Monitoring in the Perioperative Period

Introduction

Substantial research has confirmed a critical link between perioperative glucose levels and perioperative complications including death.^1-3 Hyperglycemia has been found to be the main culprit and affects 20-40% of postoperative patients and up to 80% of patients having cardiac surgery, though hypoglycemia is equally dangerous.^1,2 Regardless of a preexisting diagnosis of diabetes mellitus (DM), higher glucose is an independent predictor of mortality for patients having cardiac surgery.⁴ In fact, a new diagnosis of hyperglycemia has been associated with three times higher mortality in ICU patients as compared to those with euglycemia or previously diagnosed diabetes.² Further, an independent association has been identified between mortality and glycemic variability, regardless of mean glucose.^5-7 Importantly, it has been shown that improved glucose control improves clinical outcomes and mortality in cardiac surgical patients.⁸

As a result, tight blood sugar control via intensive insulin therapy (IIT) has previously been investigated. A landmark trial in 2001 by van den Berghe and colleagues showed a reduction in morbidity and mortality in SICU patients by nearly half with use of IIT. This ushered an era of intensive insulin therapy and tight glycemic control (target blood sugar <110mg/dl) in critical care units worldwide.⁵ However, subsequent multicenter trials were aborted due to high rates of hypoglycemia and the inability to reach intended glycemic targets.^9,10 Most notably, the NICE-SUGAR trial showed an unexpected increase in mortality with tight glucose control, essentially eliminating acceptance of and investigation into this practice.¹¹ Currently, most organizations’ guidelines support a goal blood glucose of 140-180 mg/dL.^12-14 

Notably, despite being the standard of care in most ICUs, fingerstick capillary point of care (POC) glucose monitors have poor accuracy in critically ill patients compared to arterial or venous samples.¹⁵ Further, the current standard of intermittent glucose monitoring, regardless of the source, leaves significant opportunities for undetected perturbations.¹⁶ Given these issues, efforts have been made to improve glucose monitoring, particularly in critically ill patients. Some investigators have proposed that glucose should be continuously monitored as the “fifth vital sign.”^1,17

Wearable Monitoring Devices

Wearable medical devices are frequently encountered in ambulatory and medical settings and range from non-invasive portable blood pressure and pulse oximetry meters to adhesive ambulatory telemetry monitors and even subcutaneous medication infusion pumps. In the inpatient hospital setting, particularly the non-ICU ward, non-invasive continuous monitoring via wearable devices has shown tremendous promise in minimizing the gaps in vital sign acquisition seen with traditional intermittent monitoring protocols. More importantly, “wearables” have the potential to substantially reduce patient harm through earlier recognition and intervention of frequently missed hypotension, tachycardia, and opioid-induced respiratory depression.^18-19 As such, it is no surprise that diabetes technology has evolved to include patient-applied wearable devices; in many ways, this field has set a precedent for reliable, valid, minimally invasive monitoring and management devices.²⁰ 

Continuous Glucose Monitoring Technology

After over a century of more crude methods to assess glucose in the urine, glucose-oxidase reaction-based technology completely transformed glucose monitoring technologies in the 1960s with the advent of the first blood glucose test strip.^20,21 Despite this, self-monitoring technology for patients using fingerstick glucose measurement became reliable and widely applied in the late 1970s, and understandably remains a challenge for patient adherence.^20,22 Continuous glucose monitoring (CGM) technology emerged predominantly as an intravenous technology, primarily facilitated by microdialysis systems.²⁰ Unfortunately, this system is cumbersome, not portable, and depends on continuous blood extraction via an intravascular cannula, and thus was only applicable to the surgical or critically ill patient.²³ Subsequently, the first wearable sensors only lasted 72 hours, with fingerstick calibration needed every 6 to 12 hours, and glucose data collected and reviewed retrospectively by a physician, thus not viewable to the patient nor reliable for real-time treatment decisions.²²

With serial improvements from these early devices, CGM technology became relevant for the outpatient setting for patients, initially for those with type 1 DM. Since the Food and Drug Administration’s (FDA) approval of the first implantable CGM device in 1999, the technology has facilitated closer monitoring for patients and their physicians and improved medication compliance and patient satisfaction.^22,24 More importantly, they have reduced patient HbA1c levels and time out of range in type 1 and now type 2 DM populations, leading to better outcomes.^22,25-27 In fact, real-time CGM devices are now the standard of care for patients using insulin infusion pumps or multiple daily injections of insulin as a Grade A recommendation within the Standards of Care for Diabetes Technology by the American Diabetes Association.²⁴ More recently, integration with smartphone applications and subcutaneous insulin pumps has dramatically changed the landscape of blood sugar management, facilitating instantaneous and remote monitoring as well as closed-loop automatic insulin delivery systems meant to mimic an “artificial pancreas.”^22,28

Wearable CGM technology includes a subcutaneous sensor, a transmitter, and a receiver or monitor.²² Whereas the first wearable CGM device required tethering between the sensor/transmitter and receiver with tubing, modern devices typically use Bluetooth technology to facilitate wireless communication between the transmitter and CGM device.²² Over time, improvements were made to allow patient glucose visualization prospectively, then instantaneously and, later still, continuous glucose data with shorter warm-up periods, fewer or no calibrations, longer wear times (up to 14 days for non-implantable devices) and increasing types of alarms to alert users to acute or projected episodes of hypo- or hyperglycemia.^21,22 While modern versions of the original intravascular CGMs are more accurate than the subcutaneous counterparts, their invasive nature and lack of portability are significant limitations to their clinical applications.¹⁶

While scattered work examined the utility of wearable CGMs in the inpatient setting, the Coronavirus Disease 2019 due to the SARS-CoV-2 infection pandemic facilitated a tremendous opportunity for broader CGM application. To minimize patient-provider contact and thus demands on personal protective equipment at the peak of the pandemic, the FDA exercised enforcement discretion under a plan for medical devices that allowed the temporary use of CGM in hospitalized patients.²⁹ Subsequently, studies examined CGM utility in both the inpatient wards and intensive care unit settings.^30-32 Limiting their applications, however, the predominance of these studies were small and observational, with many retrospective reviews. 

Continuous Glucose Monitoring Devices in Hospitalized Patients

Studies of non-ICU patients have revealed that CGMs reduce the incidence of hypoglycemia and hyperglycemia.^17,33 Unfortunately, several randomized controlled trials of CGMs in critically ill patients found inconsistent reductions in the incidence of hypoglycemia.^34-36 However, these studies had small and highly variable patient populations and insulin management strategies, which likely significantly impacted study outcomes.³⁷ Further, while presumably improved glycemic control and prevention of hypoglycemia via CGMs should improve patient outcomes, studies have not consistently demonstrated this.^23,37 Nonetheless, a recent meta-analysis of insulin administration guided by CGM recently demonstrated reductions in hypoglycemia (RR 0.35), glucose variability, infection (RR 0.21), and mortality (RR 0.54) across 19 studies of critically ill adults.³⁷ Notably, the maximum number of patients in a single trial examined in this meta-analysis was 174, with a median of only 24 patients.³⁷ On top of reduced patient discomfort by reducing or eliminating hourly POC testing for patients on insulin infusions, CGMs have also been shown to reduce nursing staff workload.^34,37-39

Sensor accuracy in critically ill and surgical patients remains a question and primary barrier to the broader application of CGM in the hospital setting. Subcutaneous readings from the interstitial fluid lag behind blood levels due to glucose transport by as much as 20 minutes, which may be dangerously late in patients experiencing wide glucose swings.⁴⁰ Tissue malperfusion due to hypotension, hypothermia, hypoxia, acidosis, and electrolyte disturbances, which frequently exist in critical care and major surgery, may impede or inhibit appropriate sensor capture.^24,41 Further, signal loss, presumably due to electromagnetic interference during surgery, has been reported.^23,42,43 Historically, alongside the local vasoconstrictive effect of vasopressors, interference from multiple medications, including acetaminophen, heparin, ascorbic acid, and others, decreases the reliability of CGM sensors.^23,24 However, several small series have shown no impact of vasopressors^43-45 and modern sensors are designed to minimize or eliminate medication effects.⁴⁶ As such, multiple studies using more contemporary CGMs demonstrate acceptable device accuracy in ICU and surgical patients regardless of these possible interferences.^23,30,43,47

Continuous Glucose Monitoring in the Intraoperative Period

Studies explicitly examining intraoperative CGM applications represent a small fraction of the literature. A recent scoping review by Lim and colleagues identified only 22 studies, of which five focused exclusively on neonates or children.⁴⁸ Of these, only two were randomized controlled trials. The largest adult study population was only 76 patients, with a median of only 22 patients.⁴⁸ Notably, only one study met accuracy metrics for CGMs, including guidelines from the International Organization for Standardization, Clinical and Laboratory Standards Institute, and the FDA, largely limiting these devices to only experimental applications in this setting.⁴⁸

Conclusions

Continuous glucose monitoring has profound potential to improve the care and outcomes of patients with dysglycemia in the perioperative period. Unfortunately, to this point, research has demonstrated inconsistent conclusions regarding its safety and application, mostly limited by small studies with marked variability in glucose and insulin management protocols. As such, tremendous opportunity exists for more robust randomized-controlled trials to assess CGM technology in the perioperative period effectively.

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