Intranasal Insulin Improves Postoperative Neurocognitive Disorders in Elderly Patients

Intranasal Insulin Improves Postoperative Neurocognitive Disorders in Elderly Patients: a Multicenter, Randomized, Double-blind, Placebo-controlled Study

Postoperative neurocognitive disorders (PND) are common postoperative complication of central nervous system, leading to increased risk of the working ability loss after surgery, longer hospital stay, increased medical costs and increased surgical mortality. It is classified as perioperative neurocognitive disorders in mental disorders.Aging is an important demographic characteristic in China, and the elderly is also a population susceptible to PND. There is a lack of targeted prevention and control measures for PND. Central insulin resistance is an important mechanism of cognitive impairment in elderly patients, and exogenous supply of central insulin may be an important measure to improve PND. Compared with conventional subcutaneous and intravenous supply, intranasal insulin administration not only has little effect on blood glucose and insulin levels, but also enters the center through the blood-brain barrier easily and efficiently. Long-term use of intranasal insulin can improve the cognitive function of chronic diseases, but there is a lack of clinical studies on improving PND by intranasal insulin. This study will verify the effectiveness of intranasal insulin in the PND improvement of elderly patients.

Study Overview

• Status: Recruiting
• Conditions: Postoperative Neurocognitive Disorders
• Intervention / Treatment: Drug: Intranasal insulin; Drug: Intranasal saline

Detailed Description

This study is intended to carry out a large sample, multicenter, double-blind, randomized, placebo, and controlled clinical study. Elderly non diabetes patients undergoing elective extrathoracic, breast, orthopedic, urinary, abdominal, and gynecological operations under general anesthesia are included. They are randomly divided into intranasal insulin group or saline group. Before anesthesia induction, they are given the first nasal spray, once per hour, 20 IU insulin or equal volume saline each time until the end of the operation. Follow up 1 day before operation, 1-7 days after operation, 30 days and 12 months respectively, and evaluate cognition with relevant scales. To verify that compared with the same volume of saline, intranasal insulin can reduce the incidence of postoperative delirium, the incidence of PND 1 year after surgery, and the related cognitive quantitative indicators of ApoE- ɛ4 Gene susceptibility, intraoperative EEG parameters, NfL, IL-6, IL-10, CRP and other biochemical indicators were used to explore the mechanism of intranasal insulin to improve PND.

• Study Type: Interventional
• Enrollment (Anticipated): 438
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Qiang Wang, MD,PHD; Phone Number: 0086-18049286968; Email: dr.wangqiang@139.com

Study Locations

• China
  • Shannxi
    • Xi'an, Shannxi, China, 029710061
      • Recruiting
      • First Affiliated Hospital of Xian Jiaotong University
      • Contact: Qiang Wang, MD,PHD; Phone Number: 0086-18049286968; Email: dr.wangqiang@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 65 years and older (Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients under general anesthesia through oral intubation;
• Patients undergoing elective extrathoracic, breast, orthopaedic, urological, abdominal and gynecological operations;
• Age ≥ 65 years;
• Cardiac function grade I~II (NYHA standard), ASA grade I~III;
• Volunteer for anticipating study and sign an informed consent form;

Exclusion Criteria:

• Diabetes patients;
• Previous history of craniocerebral and spinal cord trauma, surgery, stroke, and inability to place electrodes on the head;
• History of nasal cavity stuffiness, epistaxis, rhinitis, and nasopharynx surgery; The operation position is prone and it is difficult to implement intranasal administration;
• Those who cannot cooperate with the assessment of the scale or have delirium before operation;
• Preoperative fasting blood glucose<4 mmol/L;
• Those who have participated in other clinical trials.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Health Services Research
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intranasal insulin group; Before anesthesia induction, give the first insulin nasal spray, once per hour, 20 IU each time, until the end of the operation	Drug: Intranasal insulin; Put insulin injection into nasal special drug delivery device.Before anesthesia induction, give the first insulin nasal spray, once per hour, 20 IU each time, until the end of the operation; Other Names: Insulin injection，H10890001,Jiangsu Wanbang Biochemical Medicine Group Co., Ltd
Placebo Comparator: Saline group; Before anesthesia induction, give the equal volumes'saline nasal spray, once per hour, 20 IU each time, until the end of the operation	Drug: Intranasal saline; Put 0.9% sodium chloride into nasal special drug delivery device.Before anesthesia induction, give the first equal volume saline nasal spray, once per hour, 20 IU each time, until the end of the operation; Other Names: 0.9% sodium chloride，H20013250,Shanghai Baite Medical Supplies Co., Ltd

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of postoperative delirium	Whether or not postoperative delirium happens	0-7 days after surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of delayed neurocognitive recovery within 30 days after surgery	Whether or not delayed neurocognitive recovery happens	0-30 days after surgery
Incidence of neurocognitive disorders within 1 year after surgery	Whether or not neurocognitive disorders happens	30 day-1 year after surgery
The PND Incidence	Whether or not postoperative neurocognitive disorders happensevents after surgery	0 day-1 year after surgery
Intraoperative electroencephalogram parameters	The intraoperative parameters recorded by electroencephalogram, including BIS occurrence time, the duration with PSI less than 25, spectrum analysis, power spectrum analysis.	Surgery day
the level of Neurocognitive biomarkers	Neurocognitive biomarkers includes amyloid-beta protein and tau protein.	0 day-1 year after surgery
ApoE-ε4 susceptibility	Whether or not carry ApoE-ε4	1 day before surgery

Collaborators and Investigators

• Sponsor: First Affiliated Hospital Xi'an Jiaotong University
• Collaborators: LanZhou University; Tongji Hospital; The First Affiliated Hospital of Zhengzhou University; Tang-Du Hospital; Sichuan Provincial People's Hospital; Second Hospital of Shanxi Medical University; 521 Hospital of NORINCO Group
• Investigators: Study Chair: Qiang Wang, MD,PHD, First Affiliated Hospital of Xian JiaotongUniversity

Publications and helpful links

General Publications

• Evered L, Silbert B, Knopman DS, Scott DA, DeKosky ST, Rasmussen LS, Oh ES, Crosby G, Berger M, Eckenhoff RG; Nomenclature Consensus Working Group. Recommendations for the nomenclature of cognitive change associated with anaesthesia and surgery-2018. Br J Anaesth. 2018 Nov;121(5):1005-1012. doi: 10.1016/j.bja.2017.11.087. Epub 2018 Jun 15.
• Liu Y, Xiao W, Meng LZ, Wang TL. Geriatric Anesthesia-related Morbidity and Mortality in China: Current Status and Trend. Chin Med J (Engl). 2017 Nov 20;130(22):2738-2749. doi: 10.4103/0366-6999.218006.
• Evered L, Scott DA, Silbert B, Maruff P. Postoperative cognitive dysfunction is independent of type of surgery and anesthetic. Anesth Analg. 2011 May;112(5):1179-85. doi: 10.1213/ANE.0b013e318215217e. Epub 2011 Apr 7.
• Jayaraj RL, Azimullah S, Beiram R. Diabetes as a risk factor for Alzheimer's disease in the Middle East and its shared pathological mediators. Saudi J Biol Sci. 2020 Feb;27(2):736-750. doi: 10.1016/j.sjbs.2019.12.028. Epub 2019 Dec 26.
• Li X, Run X, Wei Z, Zeng K, Liang Z, Huang F, Ke D, Wang Q, Wang JZ, Liu R, Zhang B, Wang X. Intranasal Insulin Prevents Anesthesia-induced Cognitive Impairments in Aged Mice. Curr Alzheimer Res. 2019;16(1):8-18. doi: 10.2174/1567205015666181031145045.
• Chen Y, Dai CL, Wu Z, Iqbal K, Liu F, Zhang B, Gong CX. Intranasal Insulin Prevents Anesthesia-Induced Cognitive Impairment and Chronic Neurobehavioral Changes. Front Aging Neurosci. 2017 May 10;9:136. doi: 10.3389/fnagi.2017.00136. eCollection 2017.
• Zhang Y, Dai CL, Chen Y, Iqbal K, Liu F, Gong CX. Intranasal Insulin Prevents Anesthesia-Induced Spatial Learning and Memory Deficit in Mice. Sci Rep. 2016 Feb 16;6:21186. doi: 10.1038/srep21186.
• Claxton A, Baker LD, Hanson A, Trittschuh EH, Cholerton B, Morgan A, Callaghan M, Arbuckle M, Behl C, Craft S. Long-acting intranasal insulin detemir improves cognition for adults with mild cognitive impairment or early-stage Alzheimer's disease dementia. J Alzheimers Dis. 2015;44(3):897-906. doi: 10.3233/JAD-141791. Erratum In: J Alzheimers Dis. 2015;45(4):1269-70.
• Benedict C, Hallschmid M, Schultes B, Born J, Kern W. Intranasal insulin to improve memory function in humans. Neuroendocrinology. 2007;86(2):136-42. doi: 10.1159/000106378. Epub 2007 Jul 20.
• Chapman CD, Schioth HB, Grillo CA, Benedict C. Intranasal insulin in Alzheimer's disease: Food for thought. Neuropharmacology. 2018 Jul 1;136(Pt B):196-201. doi: 10.1016/j.neuropharm.2017.11.037. Epub 2017 Nov 24.
• Benedict C, Hallschmid M, Hatke A, Schultes B, Fehm HL, Born J, Kern W. Intranasal insulin improves memory in humans. Psychoneuroendocrinology. 2004 Nov;29(10):1326-34. doi: 10.1016/j.psyneuen.2004.04.003.
• Novak V, Milberg W, Hao Y, Munshi M, Novak P, Galica A, Manor B, Roberson P, Craft S, Abduljalil A. Enhancement of vasoreactivity and cognition by intranasal insulin in type 2 diabetes. Diabetes Care. 2014;37(3):751-9. doi: 10.2337/dc13-1672. Epub 2013 Oct 7.
• Brunner YF, Kofoet A, Benedict C, Freiherr J. Central insulin administration improves odor-cued reactivation of spatial memory in young men. J Clin Endocrinol Metab. 2015 Jan;100(1):212-9. doi: 10.1210/jc.2014-3018. Erratum In: J Clin Endocrinol Metab. 2016 Oct;101(10 ):3863.

Study record dates

Study Major Dates

• Study Start (Actual): November 7, 2022
• Primary Completion (Anticipated): July 31, 2023
• Study Completion (Anticipated): August 31, 2023

Study Registration Dates

• First Submitted: November 6, 2022
• First Submitted That Met QC Criteria: November 6, 2022
• First Posted (Actual): November 14, 2022

Study Record Updates

• Last Update Posted (Actual): November 14, 2022
• Last Update Submitted That Met QC Criteria: November 6, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Keywords: postoperative neurocognitive disorders; Intranasal insulin
• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Disease; Neurocognitive Disorders; Hypoglycemic Agents; Physiological Effects of Drugs; Insulin; Insulin, Globin Zinc
• Other Study ID Numbers: XJTU1AF2022LSK-265

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: The research plan will not be made public until the research results are published
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No