Saluda Medical Evoke® SCS System

{0} # **SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED)** # **I. GENERAL INFORMATION** Device Generic Name: Stimulator, Spinal-Cord, Totally Implanted for Pain Relief Device Trade Name: Saluda Medical Evoke® SCS System Device Product Codes: LGW, QRB Applicant's Name and Address: Saluda Medical Pty Ltd. 5 Eden Park Drive Macquarie Park, NSW 2113 Australia Date(s) of Panel Recommendation: None Premarket Approval Application (PMA) Number: P190002/S019 Date of FDA Notice of Approval: March 20, 2024 The original PMA (P190002) for the Evoke Spinal Cord Stimulation (SCS) System ("Evoke System") was approved on February 28, 2022, and is indicated as an aid in the management of chronic, intractable pain of the trunk and/or limbs, including unilateral or bilateral pain associated with any of the following: failed back surgery syndrome, intractable low back and leg pain. The SSED to support this indication is available on the CDRH website and is incorporated by reference here. The current supplement was submitted to expand the indications for the Evoke System to include painful diabetic peripheral neuropathy (DPN) of the lower extremities for open-loop stimulation for frequencies 1200 Hz and below. # **II. INDICATIONS FOR USE** The Saluda Medical Evoke SCS System is indicated as an aid in the management of chronic, intractable pain of the trunk and/or limbs, including unilateral or bilateral pain associated with the following: - Failed back surgery syndrome - Intractable low back and leg pain - Diabetic peripheral neuropathy of the lower extremities # **III. CONTRAINDICATIONS** The Evoke SCS System should not be used in patients who: - Do not receive effective pain relief during trial stimulation - Are unable to operate the Evoke SCS System - Are unsuitable surgical candidates PMA P190002/S019: FDA Summary of Safety and Effectiveness Data Page 1 of 72 {1} # IV. WARNINGS AND PRECAUTIONS The warnings and precautions can be found in the Saluda Medical Evoke System labeling. Safety information was updated using the most recent American Diabetes Association's Standard of Medical Care in Diabetes to address the increased risk and potential complications for diabetic peripheral neuropathy patients. Additional warnings were added to provide guidance for managing patients presenting with risk factors or sub-optimal glycemic control. Please note the following regarding the diabetic peripheral neuropathy indication: - The physiologic closed-loop controlled (PCLC) stimulation mode has not been evaluated for effectiveness in the diabetic peripheral neuropathy (DPN) population. - Frequencies greater than 1200 Hz have not been evaluated for effectiveness in the diabetic peripheral neuropathy (DPN) population. # V. DEVICE DESCRIPTION # A. System Description The Saluda Medical Evoke System is a rechargeable, upgradeable, multi-programmable, implantable, physiological closed-loop controlled neurostimulation system that delivers electrical stimulation to the spinal cord. The system consists of the following main components: - **Closed-Loop Stimulator (CLS)** - The CLS is a rechargeable, 25-channel physiologic closed-loop controlled implantable pulse generator (IPG or stimulator) which generates an electrical stimulus and measures and records the nerve fibers' response to stimulus (i.e., ECAPs). It has a lithium-ion rechargeable battery and connects to two 12-contact leads. Although named "Closed Loop Stimulator", this stimulator delivers both open-loop and closed-loop stimulation modes. - **External Closed-Loop Stimulator (eCLS)** – The eCLS provides stimulation by emulating the CLS during the intraoperative test and during the stimulation trial. The eCLS stimulation parameters are the same as the CLS. - **Lead and Lead Extension** – The lead delivers electrical stimulation to the targeted nerve through electrodes on the end of the lead. ECAPs are measured using non-stimulating electrodes on the lead. The lead extension connects the lead to the stimulator (CLS or eCLS) if additional length is required. - **Clinical Interface (CI)** – The programming system used by the clinician to program output stimulation parameters and measure and record ECAP signals. It is an off-the-shelf tablet computer installed with proprietary Saluda Medical software to allow programming of the CLS, eCLS, as well as data collection and analysis. - **Evoke Patient Controller (EPC)** – The EPC allows patients to adjust stimulation within clinician-prescribed program limits stored on the stimulator (CLS or eCLS). Adjustments include starting and stopping stimulation, increasing and decreasing stimulation intensity, and toggling between stimulation programs. - **Charger** – A battery-operated unit used to inductively charge the implanted stimulator (CLS) transcutaneously. The Charger battery is non-removable and rechargeable. PMA P190002/S019: FDA Summary of Safety and Effectiveness Data Page 2 of 72 {2} For additional details, refer to the Evoke SCS System manuals found at https://www.saludamedical.com/manuals. ### B. Principles of Operation Spinal cord stimulation (SCS) consists of applying an electrical stimulus to the spinal cord via electrodes implanted in the epidural space, which causes the activated fibers (e.g., Aβ-fibers) to generate action potentials. Aβ-fibers are the low-threshold sensory fibers in the dorsal column that contribute to inhibition of pain signals in the dorsal horn (1). The action potentials summed together form the electrically evoked compound action potential (ECAP). Therefore, ECAPs are a direct measure of spinal cord fiber activation that generates pain inhibition for an individual. The Evoke System is designed to operate in either of two modes: open-loop (fixed-output) stimulation mode or physiologic closed-loop controlled (PCLC) stimulation mode using ECAPs. The open-loop stimulation mode is equivalent to other commercially available SCS systems but has an additional feature to measure ECAPs. The Evoke System has the ability to measure ECAPs following every stimulation pulse from two electrodes not involved in stimulation. The recorded ECAP signal is sampled by the stimulator and processed to allow measurement of the ECAP amplitude. ECAP measurement may be performed in either stimulation mode. Additionally, the Evoke System uses ECAPs as a feedback mechanism in PCLC stimulation mode. The feedback mechanism minimizes the difference between the measured ECAP amplitude and the ECAP amplitude target (set by the clinician and adjusted by the patient using the pocket console) by automatically adjusting the stimulation current for every stimulus. In doing so, it maintains spinal cord activation near the target level (Figure 1).  Figure 1. Evoke System Physiologic Closed-Loop Controlled Stimulation using ECAPs ### VI. ALTERNATIVE PRACTICES AND PROCEDURES There are several alternatives for the treatment of diabetic peripheral neuropathy (DPN) of the PMA P190002/S019: FDA Summary of Safety and Effectiveness Data Page 3 of 72 {3} lower extremities. Generally, two different approaches are used to treat these patients: glycemic control and symptomatic pain treatment. Treatment of the underlying diabetes, if possible, is typically the primary approach to pain management through improved control of blood-sugar levels. In addition, pharmacologic treatments may be delivered to address pain symptoms. These include tricyclic anti-depressants, anti-convulsants α-2-δ modulators: gabapentin, pregabalin or valproate), and selective serotonin/norepinephrine re-uptake inhibitors (SSRI/SNRI). It is recommended that comorbidities be evaluated before selecting a first-line therapy. If a patient is refractory to one of the first-line therapies, a second or combination of other first-line drugs should be prescribed. Second-line therapies include opioid analgesics for acute rescue therapy. The recognition of dependence syndromes associated with the use of opioids complicates the treatment of symptoms refractory to first-line treatments. Non-pharmacologic treatments include physical therapy, cognitive therapy, and transcutaneous nerve stimulation (TENS). These therapies would be provided in conjunction or following first-line medical treatment, but before more invasive therapies are considered, and only under the direction of a pain management specialist. Each alternative has its own advantages and disadvantages. A patient should fully discuss these alternatives with his/her physician to select the method that best meets expectations and lifestyle. ## VII. MARKETING HISTORY The Evoke System is currently approved for commercial distribution in Australia, the European Union, the United Kingdom, and the United States. The device has not been withdrawn from marketing for any reason related to its safety or effectiveness. ## VIII. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH Below is a list of the potential adverse effects (e.g., complications) associated with the use of the Evoke System. Every surgery involves potential risks, including death. In addition to these surgical risks, the risks associated with the implantation and use of a spinal cord stimulation system include: - Undesirable changes in stimulation sensation and/or location. - Uncomfortable changes in stimulation (over and/or under stimulation). - Temporary or persistent post-surgical pain at hardware implantation sites. - CLS migration or suboptimal placement, which may result in pain or difficulty in charging. - Seroma or hematoma at surgery sites. - Epidural hemorrhage, spinal cord injury, possible paralysis or other neurological complications. - Lead migration or suboptimal placement, which may result in undesirable stimulation changes. - Breakage of the lead, or malfunction or failure of other system components, which may result in undesirable changes or loss of stimulation. - Allergic response or tissue reaction to the implanted or external materials. PMA P190002/S019: FDA Summary of Safety and Effectiveness Data Page 4 of 72 {4} - • Infection that may require hospitalization with intravenous antibiotic therapy. - • Infection may result in epidural abscess that can lead to neurological harm. - • Cerebrospinal fluid (CSF) leakage with possible fistula formation. - • Gastrointestinal and/or genitourinary disruption or compromise. - • Inadequate pain relief following system implantation over time. - • Erosion of the implanted components through the skin. - • Weakness, clumsiness, numbness, abnormal sensations, or pain. - • Skin irritation. The patient may require surgery (including revision, explant, and replacement) as a result of any of the above. For the specific adverse events that occurred in the supporting data, see Table 2 “Summary of Safety Results in Selected Studies” and section X.D.1 below. ## IX. SUMMARY OF NONCLINICAL STUDIES Nonclinical bench and animal studies previously submitted in the Original PMA application (P190002) and supplements continue to support the safety of the commercially available Evoke System. No additional nonclinical studies were required to evaluate the safety of Evoke SCS therapy for the treatment of diabetic peripheral neuropathy (DPN) of the lower extremities. ## X. SUMMARY OF PRIMARY CLINICAL STUDIES The Evoke System is indicated as an aid in the management of chronic, intractable pain of the trunk and/or limbs, including unilateral or bilateral pain. The safety and effectiveness of the Evoke System has been previously established for the approved indications (see Section I). The clinical evidence supporting the safe and effective use of the Evoke System in the diabetic neuropathy population is based on a systematic review of published clinical scientific literature of commercially available SCS systems. Primary evidence comes from two randomized controlled trials in patients with diabetic peripheral neuropathy (DPN). Additional supplemental clinical evidence for safety was identified through the analysis of Evoke System clinical study safety data, investigating adverse event data related to the use of the Evoke System in patients with diabetes. ### A. Study Design The safety and effectiveness of the Evoke System to treat DPN was based primarily on a systematic review of published scientific literature reporting on the use of commercially available spinal cord stimulation (SCS) systems for the treatment of chronic intractable pain in a diabetic population. A systematic review of published literature was conducted by searching the Embase and PubMed databases for terms relating to SCS and diabetes. As a supplemental body of evidence to support safety, Saluda Medical also analyzed clinical study safety data from diabetic patients implanted with the Evoke System. Finally, a systematic search of the published literature was conducted to identify recent guidelines on perioperative care of diabetic patients to inform the labeling. PMA P190002/S019: FDA Summary of Safety and Effectiveness Data Page 5 of 72 {5} ## **Safety** The safety objective is to identify risks relevant to SCS to which diabetic patients are predisposed and to characterize the safety profile of SCS to treat DPN. The safety profile of the Evoke System to treat DPN was characterized through analysis of published scientific literature and clinical study safety data from patients implanted with the Evoke System. The analysis characterized the overall safety profile by common adverse events, as well as specifically examining the risks to which the diabetic population are pre-disposed such as inherent surgical complications that may occur more frequently or have greater impact in these patients. Publications reflecting the experience of patients treated with SCS for DPN and patients treated with SCS for any condition where a diagnosis of diabetes was considered were included. Publications reporting on studies where adverse events were reported in a comprehensive manner were pooled with the clinical study safety data of the Evoke System to create an overall safety profile. ## **Effectiveness** The effectiveness objective is to characterize the clinical benefits related to pain relief for SCS used to treat DPN when compared to the standard-of-care. The effectiveness of the Evoke System to treat DPN was demonstrated through analysis of clinical study results identified from the systematic review of published scientific literature. Effectiveness was demonstrated by the probability of treatment success. The probability of treatment success (i.e., Responder Rate or proportion of successfully treated subjects) was defined by a specified percent reduction in pain rating or Patient Global Impression of Change (PGIC) rating and the magnitude of pain relief as measured through reduction in pain scores from a Numeric Rating Scale (NRS) or Visual Analog Scale (VAS). Additionally, all publications reporting on the non-comparative studies (i.e., prospective single-arm studies) were included and summarized. ### **B. Evoke System Clinical Study Safety Data** Two Investigational Device Exemption (IDE) studies have been conducted evaluating the Evoke System to treat patients with chronic trunk and/or limb pain. The Evoke Study (NCT02924129), which is complete with 134 enrolled subjects, was a multicenter, double-blind, randomized controlled trial (RCT) with 36-month follow-up. The ECAP study (NCT04319887), which is ongoing with 300 enrolled subjects, is a prospective, multicenter, single-arm study with 24-month follow-up. The safety data for subjects enrolled in these studies who had diabetes were evaluated. ## **Data Selection** Subjects enrolled in the Evoke and ECAP studies were categorized into two cohorts: 1) Diabetes: patients with diabetes, and 2) non-Diabetes: patients without diabetes. The incidence of related adverse events up to 36 months following implantation were compared between the two cohorts to determine whether patients with diabetes who were implanted with SCS exhibited an increased risk of related adverse events when compared to the general population PMA P190002/S019: FDA Summary of Safety and Effectiveness Data Page 6 of 72 {6} of SCS patients. For both cohorts, the incidence of subsequent surgical interventions (i.e., device revision, replacement, or explant) following implantation were also evaluated. ### C. Literature Search Strategy The databases searched include Embase and PubMed. The databases were searched to ensure comprehensive coverage of globally published clinical evidence for medical device products and therapies. Two separate systematic searches and reviews were conducted. For both searches, the publications identified from databases were assessed for inclusion in the review through two steps. First, two reviewers independently screened initial search results for the selection criteria. Next, full-text copies of the selected publications were assessed independently by the same two reviewers for inclusion as final selections. Differences in selection between the two reviewers were discussed to confirm selection or rejection. A third party was not necessary to resolve disputed selections. 1. 1. Safety and effectiveness of SCS to treat DPN 1. a. Search terms (including expanded terms): Diabetes AND spinal cord stimulation or dorsal column stimulation 2. b. Search dates: 1984-2023 3. c. Selection criteria: 1. i. Safety: Publication must include data on a distinctly identifiable diabetic population and report comprehensive detail on adverse events or an analysis of the impact of a diabetic state on a safety-related outcome. 2. ii. Effectiveness: Publication must include data from studies on SCS to treat DPN with quantifiable information regarding pain reduction, probability of treatment success, or quality of life improvements. Any available meta-analyses were included if the report synthesized new data based on prospective studies. 2. 2. Clinical practice guidelines on perioperative care of diabetic patients 1. a. Search terms (including expanded terms): Diabetes AND Clinical practice guideline or consensus statement AND peri-, post-, pre- operative or surgical 2. b. Search dates: 2017-2023 3. c. Selection criteria: The guideline must provide specific recommendations for steps to be taken to avoid complications of surgery in a diabetic population. The publication must include a comprehensive list of specific steps, which are generalizable to SCS procedures. ### Results of search and screening #### *Clinical practice guidelines for perioperative care of diabetic patients* Initial screening was performed on 233 titles and abstracts resulting in the selection of 57 publications for full-text review. After full-text review, 30 publications were selected for inclusion. Guidelines are summarized in Table 1. PMA P190002/S019: FDA Summary of Safety and Effectiveness Data Page 7 of 72 {7} Table 1. Selected Guidelines | Author and Title | Summary | Recommendations | Noted Complications | | --- | --- | --- | --- | | American Diabetes Association Professional Practice Committee. 16. Diabetes Care 2022 (2) Diabetes care in the hospital: Standards of Medical Care in Diabetes—2022. | Article from the American Diabetes Association provides guidelines for the care of diabetic patients in the hospital. Article includes a specific section on the care of perioperative patients. | - The target range for blood glucose in the perioperative period should be 80–180 mg/dL (4.4–10.0 mmol/L). - A preoperative risk assessment should be performed for patients with diabetes who are at high risk for ischemic heart disease and those with autonomic neuropathy or renal failure. - Metformin should be withheld on the day of surgery. - SGLT2 inhibitors must be discontinued 3–4 days before surgery. - Withhold any other oral glucose lowering agents the morning of surgery or procedure and give half of NPH dose or 75–80% doses of long-acting analog or pump basal insulin. - Monitor blood glucose at least every 2–4 hours while the patient is taking nothing by mouth and dose with short- or rapid- acting insulin as needed. | - "perioperative complications", no specifics provided | | Arthur et al. Braz J Cardiovasc Surg. 2018 (3) Perioperative Management of the Diabetic Patient Referred to Cardiac Surgery | Presents recommendations for perioperative management of hyperglycemia in patients (with or without diabetes) undergoing cardiovascular surgery. | - All diabetic patients should receive continuous insulin infusion during surgery and for at least 24 hours postoperatively to maintain blood glucose levels < 180 mg/dL. - Intravenous insulin therapy is preferred due to rapid titration. - Continuous insulin infusion should be used instead of subcutaneous injections or intermittent intravenous insulin bolus. - Diabetic patients receiving continuous insulin should maintain it until after dinner the night before surgery. - All hypoglycemic agents and non-insulin oral diabetes medications should be maintained up to 24 hours before surgery. - Level of glycated HbA1c should be assessed prior to surgery. Adequate glycemic control is associated with HbA1c < 7%. - Before surgery, blood glucose level should be below 180 mg/dL. - Patients with or without diabetes and persistently elevated blood glucose levels (> 180 mg/dL) should receive intravenous insulin infusions to maintain blood glucose levels ≤ 180 mg/dL during their stay in ICU. | - Neurological events - Neurobehavioral deficits, and neurological-related deaths - All-cause mortality, myocardial infarction, acute heart failure - Recurring angina, wound infection | PMA P190002/S019: FDA Summary of Safety and Effectiveness Data Page 8 of 72 {8} | Author and Title | Summary | Recommendations | Noted Complications | | --- | --- | --- | --- | | | | • Patients requiring ≥ 3 days in ICU due to ventilator dependence or the need for inotropes, continuous venovenous hemodialysis or hemofiltration, and antiarrhythmic intra-aortic balloon or left ventricular assist device should receive continuous infusion of intravenous insulin to maintain a blood glucose level < 150 mg/dL, regardless of whether or not they are diabetics. • Oral antidiabetics should be restarted in patients with adequate blood glucose levels, with few exceptions. | | | Berhe et al. Intl. J. Surg. 2017 (4) Guideline on perioperative glycemic control for patients with diabetic mellitus: Resource limited areas. | Review and guideline of diabetic patients undergoing surgery, differentiated by minor or major surgery, aimed at resource limited health systems | • Urinalysis and electrolyte test results should be available at pre-operative screening. • Prioritize operation for first of the day. • Fast before surgery, unless procedure later in day, then light meal with half dose of fast acting insulin. • When fasting, check glucose every 2 hours, and 1 hour prior to surgery. • Target range for blood glucose: o 108-180 mg/dL and 72-216 mg/dL is acceptable o Postpone elective surgery if over 300 mg/dL or HbA1c > 69 mmol/L, and consult specialist for management | • Post-operative infection • Surgery stress causing diabetic ketoacidosis • Hyperglycemia • Hyperosmolar state • Increased morbidity and mortality • Hypoglycemia leading to somnolence, confusion, seizures, irreversible neurological injuries • Impaired wound healing • Increased occurrence in cardiac arrhythmias | | Bhattacharya et al. World J Diabetes. 202 (5) Expert opinion on the preoperative medical optimization of adults with diabetes undergoing metabolic surgery | Provides recommendations on perioperative medical management for individuals with diabetes mellitus who are undergoing metabolic surgery. | • Initial preoperative assessment should include a comprehensive medical, psychosocial and drug history, along with physical examination. • Tests for FPG (fasting plasma glucose), postprandial glucose and HbA1c should be included in laboratory workup. • A glycemic target of HbA1c <7% before surgery is a reasonable goal. • Medical nutrition therapy, physical exercise, and pharmacotherapy should be optimally integrated to attain that goal. Pharmacological agents known to induce weight loss, such as sodium-glucose co- | • Postoperative hyperglycemia • Wound Infection • Acute renal failure | PMA P190002/S019: FDA Summary of Safety and Effectiveness Data Page 9 of 72 {9} | Author and Title | Summary | Recommendations | Noted Complications | | --- | --- | --- | --- | | | | transporter-2 inhibitors and glucagon-like peptide-1 receptor agonists, should be considered as part of the treatment armamentarium whenever feasible. Drugs known to cause weight gain, such as sulfonylureas and thiazolidinediones, should be avoided as long-term therapeutic strategy if possible. The perioperative risks of deranged glycemic control vs benefits of early metabolic surgery have to be assessed on a case-to-case basis if glycemic control cannot be attained preoperatively despite optimal medical treatment. If a strategy of restricting calories with meal replacement therapy is employed in the preoperative weeks, the anti-diabetic medications would need to be reduced to prevent hypoglycemia. • After admission, most non-insulin based therapies should be stopped, and the patient should be transitioned to insulin as per institutional practice. Severe degrees of hyperglycemia will require intravenous insulin infusion. Target glucose of 100 to 180 mg/dL (5.5-10 mmol/L) is acceptable in the perioperative period. | | | Chan et al. Anaesth. Intensive Care Med. 2020 (6) Preoperative cardiac optimization | Guideline for peri-operative cardiac optimization, considering diabetes among other comorbidities | • Peri-operative target for blood glucose of 6-10 mmol/L. • Glycemic control should be checked at the time of surgery. • Diabetic patients should be identified early in pre-operative pathway. • Tests for comorbidities should be conducted including electroconvulsive therapy (ECT), urea and electrolytes for all patients. • Surgery should be scheduled early in the day to avoid disruption of glycemic control. | Autonomic neuropathy can cause perioperative hemodynamic instability | | Cheisson et al. Anaesthesia, critical care & pain medicine. 2018 (7) Perioperative management of adult diabetic patients – Intraoperative Period | Practice guideline focusing on the intra-operative management of diabetic patients from the French Society of Anaesthesia and Intensive Care and | • Avoid prolonged fasting by scheduling procedures early in the day. • Have a blood glucose goal of 5-10 mmol/L, avoiding hypoglycemia. • If insulin is required, use fast acting analog subcutaneously with electronic syringe with IV glucose. | • Infections • Delayed wound healing • Increased morbidity and mortality | PMA P190002/S019: FDA Summary of Safety and Effectiveness Data Page 10 of 72 {10} | Author and Title | Summary | Recommendations | Noted Complications | | --- | --- | --- | --- | | | the French society for the Study of Diabetes | - Replace insulin pump with immediate IV management during procedure. - Monitor glucose every 1-2 hours and potassium every 4 hours if under insulin control, and consider 3.8 mmol/L hypoglycemia requiring intervention. - All solutes may be used, including Ringer's lactate, in the peri-operative period. - Peri-operative control is dictated by 3 factors: diabetes type, pre-operative control, and type of surgery. - Manage risk of nausea and vomiting to facilitate resumption of food intake after surgery. - Manage post-operative pain closely to avoid hyperglycemia. | | | Cheisson et al. Anaesthesia Critical Care & Pain Medicine. 2018 (8) Perioperative management of adult diabetic patients. Postoperative period. | Practice guideline focusing on the post-operative management of diabetic patients from the French Society of Anaesthesia and Intensive Care and the French Society for the Study of Diabetes | - Maintain subcutaneous insulin via electronic syringe until glucose stabilizes (<10 mmol/L) and discontinue when normal feeding resumes. - Manage discontinuation with appropriate slow and fast acting insulins. - Resume treatments based on diabetes type, management regimen and post-operative glucose levels. | Hyperglycemia (ketoacidosis) and Hypoglycemia | | Cornelius et al. Anesth Prog. 2017 (9) Patients With Type 2 Diabetes: Anesthetic Management in the Ambulatory Setting: Part 2: Pharmacology and Guidelines for Perioperative Management | An analysis of diabetic medication pharmacology and guidelines for blood glucose management in an ambulatory surgery setting. | - Antidiabetic drugs should not be taken on the day of surgery, but should not be discontinued the day prior to surgery. - Metformin may be discontinued 24-48 hours prior to surgery in patients with renal insufficiency. - Post-surgical medication regimens only should be restarted after normal food intake resumes. - Short-acting or rapid-acting insulin therapy should be withheld on the morning of surgery. - Long and intermediate acting insulin should be taken at 75-100% and 75% respectively the evening prior to the surgery day. | - Postoperative nausea and vomiting - Compromised wound healing - Postoperative glycemic stability | PMA P190002/S019: FDA Summary of Safety and Effectiveness Data Page 11 of 72 {11} | Author and Title | Summary | Recommendations | Noted Complications | | --- | --- | --- | --- | | | | Mixed/intermediate insulin doses should be taken in the morning at 50% of usual dose. • In the anesthetized diabetic patient, 70 mg/dL (3.9 mmol/L) of blood glucose is the trigger level for treatment for hypoglycemia. • Hypoglycemia is managed in conscious patients through diet + gel/glucose tablets. Unconscious patients can receive intravenous administration of dextrose. • Hyperglycemia is typically managed by subcutaneous or intravenous insulin administration. • Blood glucose level less than 180 mg/dL (10.0 mmol/L) is optimal for the ambulatory office setting. • Diabetic patients should be treated as the first patient early in the morning | | | Dortch et al. Aesthetic Surgery Journal. 2016 (10) Perioperative Glycemic Control in Plastic Surgery: Review and Discussion of an Institutional Protocol | Practice guideline for care of diabetic patients undergoing plastic surgery with specific procedure examples as well as a generalized protocol from the Mayo Clinic | • Outpatient guidelines: ○ Pre-operative screening to include HbA1c. ○ If HbA1c >8%, refer to primary care physician for optimization. ○ Monitor blood glucose in post-anesthesia unit. ○ Goal of <180 mg/dL following surgery. ○ Patients should be instructed to resume customary monitoring and resume fast acting insulin if discontinued prior to surgery. | • Wound infection • Wound healing • Impaired immunologic defense mechanisms • Increased mortality | | Galtier et al. DIAMS study group. J Visc Surg. 2020 (11) Bariatric surgery and the perioperative management of type 2 diabetes: Practical guidelines | Provides results of survey amongst physicians for guidelines of perioperative management for diabetes patients in the specific context of bariatric/metabolic surgery | • Pre-operatively, screening for retinopathy and cardiac ultrasound should be performed. • HbA1c <8% is required in the pre-operative period for most experts screened. • 26.4% and 36.3% of experts determined that metformin should be stopped earlier than other hypoglycemic compounds for 48 and 24 hours before surgery, respectively. • Oral hypoglycemic compounds should be stopped the morning of surgery, and GLP-1 agonists should be stopped 24 hours before the day of surgery (45%) or the day of (25%). | • Microvascular complications | PMA P190002/S019: FDA Summary of Safety and Effectiveness Data Page 12 of 72 {12} | Author and Title | Summary | Recommendations | Noted Complications | | --- | --- | --- | --- | | Galway et al. World J Diabetes. 2021 (12) Perioperative challenges in management of diabetic patients undergoing non-cardiac surgery. | Provides management guidelines for pre-operative assessment and management for non-cardiac surgery diabetes patients in the pre-operative, intraoperative, and post-operative phases | • Fast-acting insulin and long-acting insulin are stopped in the morning of the surgery for, respectively, 60% and 45% of the experts. • Post-operatively, insulin pump treatment should not be stopped, basal insulin should be halved, and prandial insulin should be stopped except for severe hyperglycemia patients. • Sulfonylureas should be stopped in immediate post-operative period. • In the preoperative phase, target HbA1c should be less than 8%. It is also recommended that the patient's blood glucose not exceed 300 mL/dL, that they do not have a hyperosmolar hyperglycemic state, and do not have diabetic ketoacidosis. • Preoperatively, antidiabetic medication should be adjusted or withheld accordingly to prevent accidental hyperglycemic/hypoglycemic episodes (should withhold metformin, glucagon-like peptide-1 agonists, sulfonylureas, and thiazolidinediones on day of surgery, and SGLT2 should be withheld at least 3 days before surgery) • Long-acting insulin should be reduced by 50% on the morning of surgery. Intermediate acting insulin should be maintained the day before surgery, but a 25% or 50% reduction in doses is recommended the night before and the day of surgery. Short acting insulin should generally be avoided on the day of surgery and only be administered according to actual blood glucose levels. • Intraoperatively, insulin should be administered when glucose levels are above 180 mg/dL, and intravenous glucose when the levels are below 70 mg/dL. The general range is from 110 - 180 mg/dL, with an upper limit of 216 mg/dL for patients with poor control. | • Postoperative complications: diabetic ketoacidosis, and hyperglycemic hyperosmolar nonketotic state • Acute renal failure, acute myocardial infarction • Longer ICU and hospital stay | | Grant et al. Clinical Medicine, Journal of the Royal College of Physicians of London. (13) | Practice guideline focusing on the perioperative management of | Referrals for surgery on all patients with diabetes should be evaluated for: • HbA1c within 3 months of referral should be evaluated. • Control of comorbidities and all medications. | • Surgical related infection • Raise plasma glucose levels • Increase insulin resistance | PMA P190002/S019: FDA Summary of Safety and Effectiveness Data Page 13 of 72 {13} | Author and Title | Summary | Recommendations | Noted Complications | | --- | --- | --- | --- | | New guidance on the perioperative management of diabetes. | diabetic patients from the UK's Center of Perioperative Care (CPOC) | Before Surgery - Assess and Optimize • Diabetes • Comorbidities - Ensure shared decision making. • Weight Management • Exercise • Smoking Cessation • If HbA1c >69 mmol/mol (8.5%) refer for optimization before undertaking surgery, where clinically safe and possible. Develop individualized plan for: • Pre- and post-surgery medication changes. • Day surgery or inpatient surgery. • Timing of surgery - scheduling of surgery should aim to minimize the period of fasting for patients with diabetes. • Communicate plan with patient, primary care, surgical, anesthetic and diabetes teams to ensure pre-operative optimization. On Admission: • Ensure medicines reconciliation maintain capillary blood glucose at 6-12mmol/L document CBG, renal profile, lactate ketones in emergency patients ensure patients with T1D are never denied insulin. Medication Adjustment: • Long-acting or premixed insulin can usually be continued the day before and day of surgery but with a dose reduction (usually between 50%-80% depending on the type of insulin used). A rare but potentially serious and life-threatening association between SGLT-2i and euglycemic DKA has been recognized, the risk of which is increased when there is a restriction to food or fluid intake (such as fasting for surgical procedures). SGLT-2i should, | • Diabetic ketoacidosis (DKA) • Hyperosmolar hyperglycemic state (HHS) • Hyper- or hypoglycemia | PMA P190002/S019: FDA Summary of Safety and Effectiveness Data Page 14 of 72 {14} | Author and Title | Summary | Recommendations | Noted Complications | | --- | --- | --- | --- | | | | therefore, be withheld in any patient who has been hospitalized for major surgery or acute serious illness. • Ketones levels should be monitored daily, even if asymptomatic with normal blood glucose levels, and the drugs should only be restarted once the clinical condition has stabilized and normal oral intake is established. During Surgery • Glucose should be maintained between 6-12mmol/L. • Capillary blood glucose (CBG) should be checked at induction and at least hourly if on insulin or insulin secretagogues, otherwise a minimum of 2 hourly. • Immediate access to glucose meter, ketone meter and hypoglycemia management. Return to Ward • Blood glucose should continue to remain in the target range of 6–12 mmol/L. • Aim for early eating and drinking should enable patients to promptly restore their usual diabetes regimen. • Appropriate use of anti-emetics and analgesia, avoidance of intravenous fluids if able to meet needs orally or enterally, and promotion of mobilization. Discharge • Communicate with patients all medication changes, plan for future diabetes care, importance of self-management. | | | Harrop et al. Neurosurgery. 2021 (14) Congress of Neurological Surgeons Systematic | This evidence-based guidelines provides a Grade B recommendation regarding HbA1c levels in diabetic | • Diabetic individuals undergoing spine surgery should have a preoperative hemoglobin A1C (HbA1c) test before surgery and be counseled regarding the increased risk of reoperation or infection if the level is >7.5 mg/dL. | • Infection | PMA P190002/S019: FDA Summary of Safety and Effectiveness Data Page 15 of 72 {15} | Author and Title | Summary | Recommendations | Noted Complications | | --- | --- | --- | --- | | Review and Evidence-Based Guidelines for Perioperative Spine: Preoperative Surgical Risk Assessment | patients undergoing spine surgery. | | | | Jinjing et al. Diabetes Metab Res Rev. 2021 (15) Chinese clinical practice guidelines for perioperative blood glucose management | Article provides guidelines that are intended to improve perioperative blood glucose management. | • Perform comprehensive assessment of patient's preoperative blood glucose levels and diabetes associated complications that can affect surgical prognosis. • Medical staff should communicate at least once during management of perioperative blood glucose. • Endocrinologist consultation for patients with preoperative acute complications or severe chronic complications of diabetes. • Endocrinologist consultation is recommended for perioperative patients with significant and frequent hypoglycemia, high glucose fluctuations and glucose levels that do not fall within the standard range. • For patients with Fasting plasma glucose (FPG) between 6.1 and 7 mmol/L and high risk of diabetes, oral glucose tolerance test (OGTT) is suggested for measuring the fasting glucose levels and venous blood glucose levels 2 hours after oral administration of glucose. • For patients with high preoperative blood glucose levels but without confirmed diabetes, initial management according to the principles for patients with diabetes is suggested. • Persons with diabetes should have priority for surgery and preferred time for surgery is early in the morning. If surgery cannot be performed in the morning, monitor blood glucose levels continuously in the ward to detect and treat hypoglycemia and metabolic disorders due to fasting. • If random blood glucose is ≥12.0 mmol/L or HbA1c is ≥9%, surgery delay is suggested, for elective surgeries. For patients in emergency surgery showing ketoacidosis or for patients in hyperosmolar coma, recommend that metabolic disorder, pH and osmotic pressure first be corrected. | • Surgical site infection • Edema • Prerenal renal insufficiency | PMA P190002/S019: FDA Summary of Safety and Effectiveness Data Page 16 of 72 {16} | Author and Title | Summary | Recommendations | Noted Complications | | --- | --- | --- | --- | | | | - Anesthesiologist should choose appropriate aesthetic and narcotic drugs according to type of surgery and patients' blood glucose level. During surgery, anesthesiologists should control depth of anesthesia, reduce stress response, rationally use hormones and glucose-containing solutions, actively monitor blood glucose levels and promptly resolve issues that arise. - Target perioperative blood glucose level is 6.0-10.0 mmol/L for longer and medium-length surgeries to prevent hypoglycemia, the target blood glucose level can be increased up to 12.0 mmol/L. Monitor every 1-2 hours intraoperatively and every 2-4 hours postoperatively. - For cardiac surgery patients, target is 8.3-11.1 mmol/L and for postoperative blood glucose control is less than 12.0 mmol/L. Monitor every 0.5-1 hours intraoperatively and postoperatively every 2-4 hours. - For neurosurgical patients, target glucose is 5.0-10.0 mmol/L for interoperative control and less than 12.0 mmol/L postoperatively. Monitor every 1-2 hours intraoperatively and postoperatively every 2-4 hours. - For patients undergoing "fine surgery" (minimally invasive or microsurgical), the target preoperative blood glucose level is 5.0-7.2 mmol/L. for patients with a long disease course and who have difficulty for glucose control may be increased up to <8.3mmol/L. target for intraoperative blood glucose control is 6.7-11.1 mmol/L and postoperatively <12.0 mmol/L, monitor intraoperatively every 1-2 hours and postoperatively every 4-6 hours. - For patients in postoperative intensive care or under mechanical ventilation and patients without cardiovascular disease or liver and kidney dysfunction, target glucose level is 7.8-10.0 mmol/L. For patients with cardiovascular and cerebrovascular disease or liver and kidney dysfunction, the target for blood glucose control is 8.0-12.0 mmol/L; however, the upper limit of the target blood glucose level can be extended up to 13.9 mmol/L. The blood glucose levels are monitored every 1-4 hours (2C). | | PMA P190002/S019: FDA Summary of Safety and Effectiveness Data Page 17 of 72 {17} | Author and Title | Summary | Recommendations | Noted Complications | | --- | --- | --- | --- | | | | - Strengthen staff awareness of the importance of the prevention of hypoglycemia. - Patients should be managed to prevent hypoglycemia and keep blood glucose levels between 5.6 and 10.0 mmol/L. Glucose can be provided intravenously or orally depending on the patient's conditions. - For surgeries less than 1 hour it is not necessary to perform insulin therapy for diabetic patients if blood glucose levels are adequately controlled by previously administered oral antidiabetic agents. During fasting period, sulfonylurea drugs and non-sulfonylurea insulin secretagogues should be stopped. SGLT2 inhibitors should be avoided in case of surgical procedures. - Patients under intraoperative insulin therapy should continue to receive insulin therapy during postoperative fasting period until they start eating, following which oral anti-diabetic agents can be resumed. - Diabetic patients with normal renal function do not need to stop taking metformin before surgery. If an intraoperative iodine contrast agent is necessary, metformin should not be taken 24 hours before surgery. For patients with abnormal renal function, metformin should not be taken 48 hours before surgery, and not restarted until renal function is normal. - All staff administering insulin should be properly trained. - Use of insulin perioperatively is allowed and adjusted for the specific patient and level of blood glucose control achieved. - Diabetic patients receiving continuous enteral nutrition or intravenous nutritional support may use variable rate intravenous insulin infusions or continuous subcutaneous insulin infusions for blood glucose management. - Peripheral blood glucose levels should immediately be examined after surgery. - Patients receiving glucocorticoids postoperatively should undergo blood glucose monitoring every hour within 4 hours of administration. For diabetic patients receiving NSAIDs | | PMA P190002/S019: FDA Summary of Safety and Effectiveness Data Page 18 of 72 {18} | Author and Title | Summary | Recommendations | Noted Complications | | --- | --- | --- | --- | | | | (particularly in combination with biguanides and glitazones), there is a possible risk of oedema and prerenal renal insufficiency caused by insufficient renal perfusion during hypovolemia. In such cases, physicians should closely monitor blood glucose and renal function monitoring. • Establish a team of nurses specializing in diabetes who are fully involved in management of perioperative blood glucose levels. • Hospitals should provide adequate support and education for patients and be integrated into physician training. | | | Kheniser et al. J Diabetes Complications. 2018 (16) Diabetes management before, during, and after bariatric and metabolic surgery | Provides guidelines for pharmacological regimens during the preoperative to postoperative period for diabetic patients undergoing metabolic/bariatric surgery. | • A target HbA1c of < 6.5-7.0% is recommended prior to surgery, and 7.0-8.0% for patients with long-term diabetes or are poorly controlled. • Maintaining blood glucose levels between 140-180 mg/dL is recommended. • Adherence to a subcutaneous rapid acting or continuous insulin infusion is recommended when blood glucose levels are <180 mg/dL but > 140 mg/dL (subcutaneous) and above >180 mg/dL (continuous). • If a patient has been using longer-acting insulins, half of basal dose can be administered in the morning of surgery. • Premixed human insulin is not recommended, and another basal regimen at half the premixed dose during the morning of surgery as a replacement is recommended. • A patient's insulin dosage should be below 0.6 units/kg to reduce risk of hypoglycemic events. • If blood glucose levels on admission are between 140-200 mg/dL, basal bolus regimen at 0.4/kg/day is given (evenly split between basal and bolus). For levels of 201-400 mg/dL, 0.5 units/kg/day are given. If fasting glucose is still >140 mg/dL, basal dose is increased by 20%. Basal insulin is decreased by 20% if hypoglycemic threshold is passed (<70 mg/dL). • Post-operative anti-diabetic regime should be adjusted depending on needs of the patient. | • Hypoglycemic and hyperglycemic episodes • Diabetic ketoacidosis (abdominal pain, nausea, vomiting) | PMA P190002/S019: FDA Summary of Safety and Effectiveness Data Page 19 of 72 {19} | Author and Title | Summary | Recommendations | Noted Complications | | --- | --- | --- | --- | | Kuzulugil et al. Curr Opin Anaesthesiol. 2019 (17) Recent advances in diabetes treatments and their perioperative implications | General perioperative management guideline for diabetes patients with an emphasis on glycemic control measures (avoiding hyperglycemia and hypoglycemia via therapeutic agents). There is also a short section on preoperative glycemic control. | • Optimal blood glucose target for hospitalized patients is approx. 106-180 mg/ml (6-10 mmol/L). • There is significant variability across clinical practices when it comes to anti-hyperglycemic medications. • Metformin can be withheld on the day of surgery. • Sulfonylureas should be ceased before surgery (~24 hour-period). • SGLT2 inhibitors should be ceased before surgery, and administered again postoperatively when patient is feeling well/eating normally. • DPP4 inhibitors, and GLP-1 agonists can be withheld or continued perioperatively without major clinical outcome variance between the approaches. • GLP-1 agonists possibly should be encouraged to be withheld due to some nausea effects. • Improved hospital care delivery standards/clinical processes will help glycemic control. | • Increase in hospital stay • Diabetic ketoacidosis (SGLT2) • Nausea + Vomiting (GLP-1) | | Leung et al. Health Serv Insights. 2017 (18) Perioperative Management of Patients with Diabetes | Perioperative guideline on assessment and management of diabetic patients and in regards to surgery, anesthesia, hyperglycemic, medication regiment, transition to ward and discharge. | • Identification of non-diabetic patients who could possibly develop hyperglycemia due to surgery induced stress. Evaluation of HbA1c should be conducted to distinguish patients with elevated levels to identify unrecognized diabetes or prediabetes condition from "de novo" stress hyperglycemia. • Perioperative Glycemic Targets - Reference to ADA recommendation of targeting a perioperative glucose target of 80 to 180 mg/dL. • Preoperative Assessment - assessment of glycemic control and any diabetes associated complications. • Comprehensive cardiac evaluation includes resting electrocardiography for intermediate and high-risk surgeries and if cardiac disease is suspected, stress or coronary artery angiography as indicated. • Baseline laboratory data may include measurement of serum creatinine level to assess for chronic kidney disease, HbA1c if not previously available within the past 3 months, and blood glucose | • Hyperglycemia • Postoperative infection • Poor wound healing • Increased mortality • Metabolic derangements • Diabetic ketoacidosis (DKA) | PMA P190002/S019: FDA Summary of Safety and Effectiveness Data Page 20 of 72 {20} | Author and Title | Summary | Recommendations | Noted Complications | | --- | --- | --- | --- | | | | level, recommended for patients even without prior history of diabetes to avoid undiagnosed diabetes. • Patients treated with oral medications and/or noninsulin injectable - The morning of surgery, most organizations advise discontinuing oral and noninsulin injectable medications. ○ SGLT-2 inhibitors may increase the risk of volume depletion and DKA and should be withheld the day of surgery. ○ Metformin should be avoided as it may increase the risk of renal insufficiency and lactic acidosis. ○ Thiazolidinediones should be avoided due to potential fluid retention, peripheral edema and congestive heart failure. • Patients treated with insulin - Basal/bolus insulin regimens should be considered to be the most physiologic, as they best mimic normal pancreatic secretory function. • Patients with type 1 diabetes or insulin-treated type 2 diabetes should be instructed to continue their usual meal plan and insulin regimen until the night before surgery. • Perioperative Glucose Monitoring and Insulin Strategies - Blood sugar should be checked before surgery and every 1 to 2 hrs. intraoperatively. Most diabetic patients can be managed with subcutaneous insulin perioperatively. Critically ill patients, insulin-treated patients undergoing longer and complicated surgeries or T1D patients should be managed with an intravenous insulin infusion with frequent glucose monitoring (at least hourly) with adjustments to maintain glucose targets. • Transition to Ward and Discharge - Patients should be transitioned to subcutaneous basal/bolus insulin regimen prior to intake of solid food. Insulin Infusion to subcutaneous insulin transitions should overlap at least 1 to 2 hours after first dose of subcutaneous insulin to prevent gap in insulin coverage. For patients previously not treated insulin, a subcutaneous regimen totaling 0.2 to 0.5 units/kg of body weight depending on the patient's insulin sensitivity should be given. | | PMA P190002/S019: FDA Summary of Safety and Effectiveness Data Page 21 of 72 {21} | Author and Title | Summary | Recommendations | Noted Complications | | --- | --- | --- | --- | | Livshetz & Nett, Tech. Orthop. 2019 (19) Perioperative Management of Diabetes for Total Joint Arthroplasty: A Consensus Article | Review covering questions of screening, HbA1c level cut-offs, and guidelines for practice in total joint arthroplasty | • Given lack of consensus for HbA1c limits of 7%, <8% seems prudent to mitigate risks. • All patients should be screened for HbA1c levels and orthopedic surgery should be postponed if spot glucose checks result in >200 mg/dL on the day of surgery. • ADA guidelines should be followed for peri-operative glucose control (pre-prandial 80-130 mg/dL and < 180 mg/dL post-prandial). | • Wound complications • Thrombosis • Surgical site infection | | Mechanick et al. Endocr Pract. 2019 (20) Clinical Practice Guidelines For The Perioperative Nutrition, Metabolic, And Nonsurgical Support Of Patients Undergoing Bariatric Procedures - 2019 Update: Cosponsored By American Association Of Clinical Endocrinologists/American College Of Endocrinology, The Obesity Society, American Society For Metabolic & Bariatric Surgery, Obesity Medicine Association, And American Society Of Anesthesiologists - Executive Summary | Updated clinical practice guidelines for the perioperative nutrition, metabolic, and nonsurgical support of patients undergoing bariatric procedures. | • Preoperative glycemic control, A1C value of 6.5% to 7.0% or less and peri-procedural blood glucose levels of 80 to 180 mg/dL. • Intra-/perioperative IV insulin is recommended for glycemic control. In type 2 diabetics, postoperatively, the use of all insulin secretagogues (sulfonylureas and meglitinides), sodium-glucose cotransporter-2 inhibitors and thiazolidinediones should be discontinued and insulin doses adjusted to minimize risk of hypoglycemia. Except for metformin and incretin-based therapies, antidiabetic medications should be withheld if there is no evidence of hyperglycemia. Metformin and or incretin-based therapies may be continued postoperatively in patients with type 2 diabetes until prolonged clinical resolution of type 2 diabetes is demonstrated by normalized glycemic targets. Subcutaneous insulin therapy, using a rapid-acting insulin analogue (insulin lispro, aspart, or glulisine) before meals and a basal long-acting insulin analogue (insulin glargine, detemir, or degludec) should be used to achieve glycemic targets (140 to 180 mg/dL) in hospitalized patients not in intensive care (Grade D). In the intensive care unit (ICU), IV regular insulin as part of a standard intensive insulin therapy protocol should be used to control hyperglycemia to a 140 to 180 mg/dL blood glucose target (Grade D). Endocrinology consultation should be considered for patients with type-1 diabetes (T1D), or with T2D and uncontrolled hyperglycemia (Grade D). | | | Mumdzic & Munir, Surgery. 2020 (21) | Peri-operative guidance on peri-operative diabetes | • Pre-operative evaluation should include history, kidney function, blood count and coagulation profile, updated HbA1c. | • Increased postoperative morbidity and mortality | PMA P190002/S019: FDA Summary of Safety and Effectiveness Data Page 22 of 72 {22} | Author and Title | Summary | Recommendations | Noted Complications | | --- | --- | --- | --- | | Perioperative management of diabetes and corticosteroid supplementation | management and supplemental corticosteroid treatment | • Refer for expert optimization of glucose control if HbA1c > 8.5% for elective surgeries. • Intra-operative levels of 6-10 mmol/L should be the goal (6-12 mmol/L is acceptable). • Diet-managed Type 2 diabetics may not require therapy and are not at risk for hypoglycemia, though if they become hyperglycemic they can be managed with fast acting insulin. • Management of glucose should be made with consideration of surgery complexity as to how many missed meals will be experienced. | | | Robinson et al. Anaesth. Intensive Care Med. 2020 (22) Perioperative management of diabetes | Review of perioperative diabetes management with background information, management steps and recommendations on special populations/situations | • Referrals for surgery should include HbA1c in the last 3 months, BMI, eGFR, and accurate medication list. • Thorough pre-operative assessment for cardiovascular disease, diabetic nephropathy, autonomic neuropathy, peripheral neuropathy, diabetic retinopathy, obesity, autoimmune disease, and HIV. • Postpone elective surgery if HbA1c > 69 mmol/mol (8.5%) to confirm optimization and consult with multidisciplinary team to proceed. • Minimize fasting time by early scheduling (first of day or within first 1/3rd of schedule). • Perioperative glucose management plan should be made based on pre-operative levels to adjust medications including insulin. • Intra-operative levels of 6-10 mmol/L should be the goal (6-12 mmol/L is acceptable). • Patients should be provided with information on managing their diabetes upon discharge. | • Post-operative infection (surgical site or systemic) • Cardiovascular events • Acute kidney injury • Stroke | | Roth et al. Interdisciplinary Diabetes and Nutrition in Operative Intensive Care Medicine Competence Group. Dtsch Arztebl Int. 2021 (23) | Provides blood sugar management guidelines for diabetic patients in intensive care units. | • A target range between 7.8 and 10 mmol/L (140-180 mg/dL) is the goal for diabetic patients in the intensive care unit, as it optimizes clinical outcomes while avoiding hypoglycemia. • Insulin therapy should not be initiated until a level of 10 mmol/L (180 mg/dL). | • Wound/systemic infections • Immune dysfunction (impaired leukocyte function and phagocytosis) | PMA P190002/S019: FDA Summary of Safety and Effectiveness Data Page 23 of 72 {23} | Author and Title | Summary | Recommendations | Noted Complications | | --- | --- | --- | --- | | Blood Sugar Targets in Surgical Intensive Care—Management and Special Considerations in Patients With Diabetes | | • The range between 4.4 to 6.1 mmol/L (79-110 mg/dL) is not recommended for diabetes patients due to risk of hypoglycemia. • Hyperglycemia and hypoglycemia should be avoided. | • Oxidative tissue stress, mitochondrial aberration, endothelial dysfunction • Hemodynamic effects (osmotic diuresis/dehydration, volume depletion, hypoperfusion, electrolyte/acid-base balance disorders | | Simha & Shah, JAMA. 2019 (24) Perioperative Glucose Control in Patients With Diabetes Undergoing Elective Surgery. | Description of management of blood glucose in perioperative period with guidance on insulin management | • HbA1c should be checked in all patients. • Postpone elective surgery if HbA1c > 8% and would require intensifying of diabetes management strategies. • Postpone elective surgery in severe hyperglycemia (>250 mg/dL). • Reduce insulin prior to surgery (50-75%), with half-dose on day of surgery if glucose is elevated. • Schedule procedure in the AM to reduce duration of fasting. • Intra-operative management to <180 mg/dL without causing hypoglycemia. • Re-check blood glucose post-operatively, with a goal of preprandial 100-140 mg/dL and random 100-180 mg/dL. | • Wound infection • Pneumonia • Sepsis • Cardiovascular events | | Song et al. Endocrine. 2019 (25) Critical appraisal and systematic review of guidelines for perioperative diabetes management. | An analysis and comparison of various perioperative management guidelines, an assessment of quality through the AGREE II guideline evaluation tool. | • Blood glucose level target range is 5-12 mmol/L. • HbA1c, hyperglycemia, and hypoglycemia should be managed. • Blood glucose should be monitored generally once per 1-2 hours for perioperative patients. • Oral anti-diabetic drugs (metformin, sulphonylureas, etc.) should be generally discontinued on day of surgery, but strategy and guidelines for this vary significantly. • Insulin therapy should be managed depending on the needs of the patient. | | | Stryker. The Journal of Arthroplasty. 2016 (26) | Peri-operative guidance on checking and managing blood | • Peri-operative screening in all patients with >200 mg/dL, further screened for HbA1c. • Goal of <7% HbA1c, though may be higher with individual cases. | • Delayed wound healing • Deep infection | PMA P190002/S019: FDA Summary of Safety and Effectiveness Data Page 24 of 72 {24} | Author and Title | Summary | Recommendations | Noted Complications | | --- | --- | --- | --- | | Modifying Risk Factors: Strategies that Work Diabetes Mellitus | glucose in patients with and without diabetes diagnosis undergoing total joint arthroplasty. | - Unmanageable levels should be referred to dietician or patient's primary physician. - Short acting insulin or oral regimens withheld on morning of surgery, with long-acting agents or infusion pumps continued. - Post-operative insulin regimens can resume after resumption of regular diet. | - Thrombosis - Mortality | | Vervoort et al. J Card Surg. 2022 (27) Sweet victory: Optimizing glycemic control after coronary artery bypass grafting | Presents guidelines on peri and post-operative glycemic control for patients specifically undergoing coronary artery bypass grafting. | - Glycemic control is best achieved with continuous insulin infusions rather than intermittent subcutaneous insulin injections or intermittent intravenous insulin boluses. - Patients with and without diabetes with high serum glucose (>180 mg/dl) should receive intravenous insulin infusions to maintain serum glucose <180 mg/dl for ICU care duration. - Patients with diabetes should receive insulin infusion in OR and for at least 24 hours postoperatively to keep serum levels <180 mg/dl. - Patients who need 3 or more days in ICU due to ventilatory dependency or general heart complications should receive continuous insulin infusion to keep blood glucose <150 mg/dl. - Oral hypoglycemic medications should be restarted in patients who achieved target blood glucose levels if there are not contraindications. - If an intravenous insulin infusion is initiated in the preoperative period, it should be continued throughout the intraoperative and early postoperative period according to institutional protocols to maintain serum glucose ≤180 mg/dl. - A target blood glucose level ≤110 mg/dl should be achieved in the fasting and premeal states after transfer to the floor. - Before intravenous insulin infusions are discontinued, patients should be transitioned to a subcutaneous insulin schedule using institutional protocols. - Oral hypoglycemic medications should be restarted in patients who have achieved target blood glucose levels if there are no contraindications. Insulin dosages should be reduced accordingly. | - Sepsis | PMA P190002/S019: FDA Summary of Safety and Effectiveness Data Page 25 of 72 {25} | Author and Title | Summary | Recommendations | Noted Complications | | --- | --- | --- | --- | | | | • Before discharge, all patients with diabetes and those who have started a new glycemic control regimen should receive inpatient education regarding glucose monitoring, medication administration (including subcutaneous insulin injection if necessary), nutrition, and lifestyle modification. | | | Vongsumran et al. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy. 13 (pp 2593-2601), 2020 (28) Standardized glycemic management versus conventional glycemic management and postoperative outcomes in type 2 diabetes patients undergoing elective surgery. | A review of the efficacy of Conventional perioperative glycemic control protocol (CG) versus Standardized glycemic control protocol (SG). There was no significant difference in the percentage of hypoglycemic events between the CG and SG protocols | • Keeping blood glucose at less than 180 mg/dL but above 108 mg/dL can reduce mortality rates in critically ill surgical patients. Patients with blood glucose levels above 200 mg/dL perioperatively have an increased rate of infection. • Per FDA - SGLT-2i should be discontinued at least 3 days prior to scheduled surgery to reduce the risk of ketoacidosis. | • Mortality • Infection | | Wang et al. Clinical Neurology and Neurosurgery, 2021 (29) Perioperative optimization for patients undergoing elective spine surgery. | General perioperative guideline on management of patients in regard to medications, diabetes, hypertension, smoking, renal function, BMI, psychosocial aspects, and frailty. | • HbA1c goal of < 7% • Pre-prandial glucose 90-130 mg/dL • Post-prandial glucose < 180 mg/dL • First-start surgical case (early in the surgery day). • Insulin Glucose Tolerance Test (GTT), IV management perioperative) for >200 mg/dL. • Continue home insulin, discontinue atypical hyperglycemic agents. • Cancellation of procedure if in diabetic ketoacidosis or >400 mg/dL. | • Delayed wound healing • Infection • Thrombosis • Mortality | | Seisa et al. Journal of Clinical Endocrinology and Metabolism, 2022 (30) | This article supports the development of clinical practice guidelines for | • Continuous glucose monitoring. • Combine neutral protamine hagedorn (NPH) and basal-bolus insulin. • Emphasize inpatient diabetes education. | • Length of hospital stay • Hypoglycemia and hyperglycemia events • Hospital readmissions | PMA P190002/S019: FDA Summary of Safety and Effectiveness Data Page 26 of 72 {26} | Author and Title | Summary | Recommendations | Noted Complications | | --- | --- | --- | --- | | A Systematic Review Supporting the Endocrine Society Clinical Practice Guideline for the Management of Hyperglycemia in Adults Hospitalized for Noncritical Illness or Undergoing Elective Surgical Procedures. | management of hyperglycemia in adults hospitalized for noncritical illness undergoing elective surgical procedures. | - Achieve preoperative HbA1c level < 7% when possible. - Hospitalized patients with type 2 diabetes and mild hyperglycemia can be treated with glucagon-like peptide-1 agonists or dipeptidyl peptidase-4 inhibitors if indicated. - All findings were associated with a low or very low level of certainty. Additionally, several factors supported opposite recommendations depending on the outcome measured. This emphasizes the need for shared decision making and consideration of all available factors. | | | Williams et al. Journal of Patient Centered Research Reviews, 2023 (31) Impact of Perioperative Dexamethasone on Hospital Length of Stay and Glycemic Control in Patients With Type 2 Diabetes Undergoing Total Hip Arthroplasty. | Evaluation of length of hospital stay in patients with type II diabetes when prescribed dexamethasone perioperatively. | - Dexamethasone can be safely administered to patients with type II diabetes during surgical procedures to relieve subsequent pain and nausea. - Those taking insulin may benefit from having their postoperative care managed by diabetes specialists due to increased insulin resistance in the first 24 hours following surgery. | - Elevated blood glucose levels | PMA P190002/S019: FDA Summary of Safety and Effectiveness Data Page 27 of 72 {27} # *Safety and Effectiveness Literature Search* Initial screening was performed on 690 titles and abstracts resulting in the selection of 133 publications for full-text review. After full text review, articles were selected for inclusion based on safety, effectiveness, or as meta-analyses. The following number of publications were selected for each category: - Safety: 26 publications. Several studies resulted in multiple publications. Safety information was extracted from the publication with the longest follow-up from each study that included comprehensive adverse event information and is included in Table 2. - Effectiveness: 15 publications. Several studies resulted in multiple publications. Effectiveness data was extracted from all publications and included in total for each cohort. This information is reported in Table 3. - Meta-analyses: 8 publications reported meta-analyses of studies of SCS to treat DPN. The reports are summarized in Table 4. PMA P190002/S019: FDA Summary of Safety and Effectiveness Data Page 28 of 71 {28} **Table 2. Summary of Safety Results in Selected Studies** | Publication | Study Design | N | Follow-up period | Safety data | Relevance and Limitations | | --- | --- | --- | --- | --- | --- | | Tesfaye et al. 1996 (32), Daousi et al. 2005 | Prospective observational study for SCS use for the treatment of DPN. Included a double-blind test stimulation period. | 10 patients, 8 received permanent implants | 3.3-year mean, up to 7 years | 3 patients died from myocardial infarction at 2 months, 2 years and 4 years post-implant. Lead migration requiring revision occurred in 2 patients, 2 patients required antibiotics for superficial wound infection, 1 system removed after 4 months for system failure, 1 hematoma at implant site without clinical impact, 1 lead failure due to trauma required replacement. | Relevance: First study evaluating SCS for DPN specifically. Long term follow-up of safety/complications. Limitations: Small, single arm open label study. No comparator. | | TenVaarwerk et al. 1999 (33) | A retrospective, multicenter study of patients treated with spinal cord stimulation between 1987 and 1997 | 517 patients with angina pectoris and a permanent SCS implant, 14% identified as having Insulin Dependent Diabetes Mellitus | Median follow-up was 23 months (range of 0 to 128 months) | Insulin dependent diabetes was the only important risk factor between the groups (survivors vs non-survivors, p = 0.05). Diabetes (p = 0.01) was significantly correlated with mortality. | Relevance: Review of diabetes as a co-factor associated with mortality. Determination that there was a significant difference in mortality in the diabetic population. Limitations: Retrospective, follow-up times variable, no separate DPN population. No analysis of diabetes related to SCS complications. | | Petrakis et al. 1999 (34) | Retrospective study of diabetic patients with peripheral arterial occlusive disease (PAOD) to evaluate pain relief and reduction of amputation rate with SCS | 64 diabetic PAOD patients | 58 months mean follow-up (20-128 months) | Of 14 patients with rest pain and no lesions (most similar to the DPN population being evaluated in this study), 1 patient required limb amputation, and one had a generator infection leading to removal of the device. Overall diabetic cohort had 8 battery replacement procedures following normal end of device life, 2 lead migrations requiring lead revision, 2 Infections requiring explant. | Relevance: Early study describing SCS in a diabetic population. PAOD is common in diabetic patients and frequently overlaps with DPN. Limitations: Open label, no comparator. | | de Vos et al. 2009 (35) | Prospective, open label, observational trial for diabetic patients with | 11 patients enrolled, 9 received permanent implant | 30 months | Surgical revision due to inadequate connection between the lead and the extension cable in 2 patients. After revision the pain relief reappeared in both patients. One patient had a mild infection that was treated easily with | Relevance: Few safety events which were resolvable. Limitations: Open label design. Single center, small trial without comparator. | PMA P190002/S019: FDA Summary of Safety and Effectiveness Data Page 29 of 72 {29} | Publication | Study Design | N | Follow-up period | Safety data | Relevance and Limitations | | --- | --- | --- | --- | --- | --- | | | chronic pain | | | antibiotics, without any influence on the SCS treatment. One death which was reported as unrelated to SCS. | | | Mekhail et al. 2011 (36) | Retrospective review of case series in patients with SCS for intractable pain (Failed Back Surgery Syndrome, Complex Regional Pain Syndrome (CRPS), Peripheral Vascular Disease (PVD), visceral pain, neuropathy over a 5-year period | 707 patients, 56 patients were diabetic | Variable, from 3 months to 7 years | Pain at the generator site (86), seroma without infection (1), lead migration (119), lead connection failure (50), and lead break (33). There were 32 (4.5%) patients that had infections. Of those with diabetes (56 patients total), 5 (9%) developed infections. | Relevance: Large evaluation of SCS experience over a 5-year period with a range of pain etiologies. This article reports safety issues primarily related to infection and device failures. Diabetic patients were noted to have a higher, though non-significant, rate of infection. Long-term follow-up included. Limitations: No specific effectiveness data provided. Retrospective nature of study can lead to bias. Small diabetic population. | | Pluijms et al. 2012 (37), Pluijms et al. 2015 (38), Slangen et al. 2013 (39), Slangen et al. 2014 (40), van Beek et al. 2015 (41), van Beek et al. 2018 (42) Zuidema et al 2022 (43) | Prospective, randomized, open-label multicenter RCT to assess the effectiveness of SCS in combination with best medical treatment (BMT) compared with BMT only in patients with PDPN in the lower limbs. Patients were pooled from all subjects reported in Pluijms 2012 | 49 patients enrolled 40 patients had a successful trial and received a permanent implant 19 continued use of the device at 8 or more years and consented to participate in the study | Up to 10 years | - 13 battery replacements due to depletion (5 had 2 replacements) - 10 pain in the battery pocket (1 revision without complete resolution) - 9 reported uncomfortable stimulation - 6 device removals due to loss of efficacy - 5 lead migrations with revisions - 4 lead failures which were replaced - 2 infections leading to explant - 1 participant had a dural puncture during attempted trial lead implantation. 3 days later the patient had a subdural hematoma causing midline shift and eventual death - During the 8-10 year follow-up, many patients needed either one (53%) or two (24%) replacements the original non-rechargeable IPG - There were no new AEs reported in the 8-10 | Relevance: Patients from a randomized, multi-center, 2 arm trial of SCS in patients with DPN compared to best medical treatment were combined with a cohort of patients in a single arm, open label study. Long term follow-up to 10 years. Many device explants happened in the first two to three years; however, after this period, device explants were less frequently observed. The ten-year survival probability was equal to 0.66 (95% CI: 0.53–0.83). Limitations: Open label. No control group for the 5- or 10-year follow-up period. Study enrollment over 4 years, potential for increased expertise in | PMA P190002/S019: FDA Summary of Safety and Effectiveness Data Page 30 of 72 {30} | Publication | Study Design | N | Follow-up period | Safety data | Relevance and Limitations | | --- | --- | --- | --- | --- | --- | | | and Slangen 2014 | | | year follow-up | surgeons or nurses who implant or change SCS settings. | | de Vos et al. Feb 2014 (44) | Open label study in patients with 6 months experience SCS tonic stimulation to determine efficacy of switching to burst. | 48 patients total, 12 with DPN | 2 weeks | 1 patient had worsening pain; side effects mentioned by patients were headaches (3), dizziness, and the sensation of “heavy legs” (2). | Relevance: First study assessing a switch to burst after having tonic stimulation. This is very different from patients who started with burst. Many missed the paresthesia as a feedback signal that the SCS system is functioning. Limitations: Only 2-week evaluation. No opportunity to change stimulation. Single center study with small number of DPN patients. Potential selection bias by reviewing patients with implants. Safety data not specific to DPN population. | | de Vos et al. Nov 2014 (45) | Open label, randomized trial with conventional medical practice (control) compared to SCS | 60 patients with DPN were enrolled and randomized to SCS (n = 40) or control (n = 20) treatment. 3 SCS patients did not have successful trial stimulation, and 1 additional patient was withdrawn after deciding to enter into another study. 36 completed 6-m f/u. | 6 months | AEs related to the implantation included: pain due to the IPG (2), lead migration (1), perceived incomplete overlap of the paresthesia with the painful area during trial stimulation leading to a second electrode lead placed (1); infection during trial stimulation (1); coagulopathy in 1 patient complicated the implantation procedure and prolonged hospitalization. Potentially unrelated complications included 2 infections resulting in unstable blood glucose levels, 1 femur fracture, and 1 cardiac arrest. In the control group, there were 2 infections, 1 carotid artery stenosis, 1 myocardial infarction, 1 atrial fibrillation episode, and 1 coronary bypass surgery. | Relevance: Randomized trial compared to BMT. Detailed adverse events information including relatedness. The authors indicate the need to carefully monitor blood glucose levels in the presence of infection. Limitations: Open label design with limited follow-up (6 months). Patients were aware that they would be offered trial SCS after 6 months. It cannot be ruled out that some of the data collected in this group was biased by this prospect. | PMA P190002/S019: FDA Summary of Safety and Effectiveness Data Page 31 of 72 {31} | Publication | Study Design | N | Follow-up period | Safety data | Relevance and Limitations | | --- | --- | --- | --- | --- | --- | | Bir et al. 2016 (46) | Retrospective study, not specific to DPN. However, there is an analysis of the effect of diabetes on revision free survival. | 141 cases where participants had an SCS system implanted | Mean follow-up was 31.49 months | Revision free survival (RFS) in non-diabetics was 43 months, in diabetics was 35 months. The effect of diabetes on RFS was not statistically significant. | Relevance: Comparison of revision free survival curves with diabetes as a co-factor. Diabetes was not associated with a significant difference. Limitations: Retrospective (limitations on data collection, follow-up times are variable), not specific to DPN. | | Denisova et al. 2016 (47) | Prospective, open label trial for patients with chronic spinal cord pain | Total of 136 patients with neuropathic pain syndrome underwent test stimulation, 75 received the permanent implant SCS. | 6-18 months | 2 SCS removals due to pain at generator implant site, 4 lead migrations required surgical revision/repositioning | Relevance: General SCS safety rates. Limitations: No data specific to the DPN population except for the statement that significant regression of pain was achieved in patients with diabetic neuropathy. | | Hoelzer et al. 2017 (48) | Multi-center, retrospective review in patients treated for FBSS, CRPS, Post-Herpetic Neuralgia, and other chronic pain conditions | 2737 patients who had SCS implantation between Jan 2007 and June 2014 16.5% had diabetes | 1 year | Primary placement infection rate: 2.19% Revision infection rate: 3.09% Total infection rate: 2.45% Rate of infection when no occlusive dressing was applied was 3.86% vs. 1.69% when an occlusive dressing was used. Rate of infection was 1.78% for patients who received post-operative antibiotics (78.3%). No post-operative antibiotics rate of infection was 4.09%. Analysis of surgical site infection association with diabetes. Infection rate for patients with diabetes: 1.99% without diabetes: 2.54% (p = 0.49) | Relevance: Large review that analyzed diabetes as a co-factor for prediction of surgical site infection. Diabetes did not demonstrate a statistically significant influence on the rate of infection. Applying a sterile occlusive dressing while in the operating room significantly decreased the rate of infection generally. Limitations: Retrospective design, reporting bias, and the inherent restra…