The Caffeine, Postoperative Delirium, and Change in Outcomes After Surgery (CAPACHINOS-2) Study

The objective of this study is to test the effects of caffeine on neurocognitive and clinical recovery after major surgery. Specifically, this trial tests the primary hypothesis that caffeine will reduce the incidence of postoperative delirium.

Study Overview

• Status: Recruiting
• Conditions: Postoperative Delirium; Postoperative Cognitive Dysfunction; Mild Cognitive Impairment
• Intervention / Treatment: Drug: Dextrose Water; Drug: Caffeine citrate; Drug: Caffeine citrate

Detailed Description

Delirium is a syndrome characterized by failure of basic cognitive functions that affects approximately 20-50% of older surgical patients. Delirium during surgical recovery is associated with increased mortality, cognitive and functional decline, and prolonged hospitalization. In fact, 3-year survival rates for acutely hospitalized patients with delirium, and subsyndromal delirium, are both less than 50%. Older age is predictive of delirium after surgery, and with aging surgical populations, the incidence of postoperative delirium and related complications are likely to increase in the coming years.

Caffeine represents a novel, neurobiologically informed candidate intervention for reducing risk of early postoperative delirium. Caffeine promotes arousal via adenosine receptor antagonism and improves cognitive function concurrent with increased cortical cholinergic tone. Our preliminary data suggest that caffeine reduces risk of postanesthesia care unit (PACU) delirium in adult non-cardiac surgery patients by optimizing cortical dynamics for cognition. Caffeine also optimizes key neurocognitive processes that support information processing and may improve other, related aspects of clinical recovery, such as rebound headache in habitual caffeine users. The objective of this trial is to thus test the effects of caffeine on neurocognitive and clinical recovery after major surgery. Specifically, the primary hypothesis is that caffeine will reduce the incidence of postoperative delirium. The secondary objectives are to (1) test whether caffeine positively impacts the quality of postoperative recovery via validated patient-reported measures and (2) identify neural correlates of delirium and Mild Cognitive Impairment via advanced electroencephalographic (EEG) analysis.

• Study Type: Interventional
• Enrollment (Estimated): 250
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Phillip Vlisides, MD; Phone Number: (734) 936-4280; Email: pvliside@umich.edu
• Study Contact Backup: Name: Amy McKinney, MA; Phone Number: (734) 647-8129; Email: adrongo@umich.edu

Study Locations

• United States
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • Recruiting
      • Michigan Medicine
      • Contact: Phillip Vlisides, MD; Phone Number: 734-936-4280; Email: pvliside@med.umich.edu
      • Contact: Amy McKinney, MA; Phone Number: 734-647-8129; Email: adrongo@med.umich.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 70 years and older (Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Adult (>/= 70 years old) undergoing non-cardiac, non-intracranial neurologic, non-major vascular surgery requiring general anesthesia with a planned admission for at least 48 hours.
2. Stated willingness to comply with all study procedures and availability for the duration of the study.
3. Provision of signed and dated informed consent form.

Exclusion Criteria:

1. Emergency surgery
2. Outpatient surgery
3. Severe cognitive impairment precluding the capacity for informed consent
4. Seizure disorder history
5. Intolerance or allergy to caffeine (based on subjective reporting or objective documentation)
6. Weight >130 kg (as a 3 mg/kg dose would approach the upper limit of daily intake recommended by the FDA)
7. Enrollment in conflicting research study
8. Patients in acute liver failure
9. Acute kidney injury preoperatively
10. Diagnosis of pheochromocytoma
11. Severe audiovisual impairment
12. Non-English speaking

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Control; Prepared intravenous piggyback solution of 5 percent dextrose water at multiple postoperative time points over a 30-minute infusion period.	Drug: Dextrose Water; Dextrose 5% in water
Experimental: Low-dose Caffeine; Prepared intravenous low-dose caffeine citrate (1.5 mg/kg) at multiple postoperative time points over a 30-minute infusion period.	Drug: Caffeine citrate; Low-dose caffeine citrate (1.5 mg/kg); Drug: Caffeine citrate; High-dose Caffeine citrate (3 mg/kg)
Experimental: High-dose Caffeine; Prepared intravenous high-dose caffeine citrate (3 mg/kg) at multiple postoperative time points over a 30-minute infusion period.	Drug: Caffeine citrate; Low-dose caffeine citrate (1.5 mg/kg); Drug: Caffeine citrate; High-dose Caffeine citrate (3 mg/kg)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Delirium	Any positive delirium screen (yes/no) as determined by the long-form Confusion Assessment Method (CAM)	Day of surgery through afternoon of postoperative day three

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Delirium Severity	For all participants screened for delirium, the associated severity score will be recorded using the Confusion Assessment Method Long Form Severity Score (CAM-S) (n, 0-19, with higher number indicating more severe delirium)	Day of surgery through afternoon of postoperative day three
Delirium Duration	The cumulative number of days (n) with a positive delirium screen will be calculated for all participants	Day of surgery through afternoon of postoperative day three
Patient-Reported Quality of Recovery	Assessed via the 15-item Quality of Recovery Score (n, 0-150, with higher number indicating better quality of recovery from the patient perspective)	Preoperative baseline through postoperative day three afternoon
Sedation	Any positive screen based on the Richmond Agitation Sedation Scale (RASS; n, -5 to +4). Scores from -5 to -2 will count as a positive screen for sedation.	Preoperative baseline through postoperative day three afternoon
Agitation	Any positive screen based on the Richmond Agitation Sedation Scale (RASS; n, -5 to +4). Scores from +2 to +4 will count as a positive screen for agitation	Preoperative baseline through postoperative day three afternoon
Headache	Headache severity will be assessed via 10-centimeter visual analog scale (0-100 mm, with higher score indicating more severe headache)	Preoperative baseline through postoperative day three afternoon
Cumulative Opioid Consumption	Postoperative opioid consumption, oral morphine equivalents (mg)	Day of surgery through postoperative day three afternoon

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Anesthetic Emergence	Time (minutes) from surgical closure to extubation	Duration of time from surgical dressing completion to anesthetic emergence (min); generally expected to be between 10 and 60 minutes
Pulmonary Complications	Composite outcome (yes/no) of any of the following: airway adjunct use, unplanned continuous positive airway pressure device, unplanned humidified high-flow oxygen, need for bag-mask ventilation, or reintubation	From extubation until end of postanesthesia care unit stay
Hospital Length of Stay	Total number of days (n) spent in the hospital, up to 30 days	Morning of surgery until day of hospital discharge, up to 30 days
Discharge Disposition	Proportion of patients in each group (%) discharged somewhere other than home (e.g., Long-Term Care Facility), up to 30 days	Day of hospital discharge, up to 30 days
30-Day Cognitive Function	Cognitive function score based on the Montreal Cognitive Assessment (n, 0-30, with higher scores reflecting higher cognitive function)	30 days after hospital discharge
30-Day Physical Function	Physical function score based on the Patient Reported Outcomes Measurement Information System (PROMIS) Physical Function 10a score (n, 10-50, with higher score indicating better physical function)	30 days after hospital discharge

Collaborators and Investigators

• Sponsor: University of Michigan
• Collaborators: National Institute on Aging (NIA)
• Investigators: Principal Investigator: Phillip Vlisides, MD, Assistant Professor of Anesthesiology

Publications and helpful links

General Publications

• Vlisides PE, Li D, McKinney A, Brooks J, Leis AM, Mentz G, Tsodikov A, Zierau M, Ragheb J, Clauw DJ, Avidan MS, Vanini G, Mashour GA. The Effects of Intraoperative Caffeine on Postoperative Opioid Consumption and Related Outcomes After Laparoscopic Surgery: A Randomized Controlled Trial. Anesth Analg. 2021 Jul 1;133(1):233-242. doi: 10.1213/ANE.0000000000005532.
• Kim H, McKinney A, Brooks J, Mashour GA, Lee U, Vlisides PE. Delirium, Caffeine, and Perioperative Cortical Dynamics. Front Hum Neurosci. 2021 Dec 20;15:744054. doi: 10.3389/fnhum.2021.744054. eCollection 2021.

Study record dates

Study Major Dates

• Study Start (Actual): February 20, 2023
• Primary Completion (Estimated): April 30, 2026
• Study Completion (Estimated): May 31, 2026

Study Registration Dates

• First Submitted: October 6, 2022
• First Submitted That Met QC Criteria: October 6, 2022
• First Posted (Actual): October 10, 2022

Study Record Updates

• Last Update Posted (Actual): March 13, 2024
• Last Update Submitted That Met QC Criteria: March 11, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Alzheimer's Disease; Mild Cognitive Impairment; Neurocognitive Disorders; Postoperative Delirium
• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Nervous System Diseases; Postoperative Complications; Neurologic Manifestations; Confusion; Neurobehavioral Manifestations; Neurocognitive Disorders; Cognition Disorders; Delirium; Cognitive Dysfunction; Postoperative Cognitive Complications; Emergence Delirium; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Purinergic Antagonists; Purinergic Agents; Anticoagulants; Phosphodiesterase Inhibitors; Purinergic P1 Receptor Antagonists; Chelating Agents; Sequestering Agents; Central Nervous System Stimulants; Calcium Chelating Agents; Caffeine; Citric Acid; Sodium Citrate; Caffeine citrate
• Other Study ID Numbers: HUM00218290; R01AG075005 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Clinical and electroencephalographic data will be preserved and made available for sharing. Data will be saved in various formats, such as comma-separated values (CSV), open document format (ODF), and European Data Format (EDF) for waveform data. Software programs designed to accommodate electroencephalographic waveform data (e.g., MATLAB) will be required for data access and analysis. Specific software and coding recommendations can be made available upon data sharing request.

Any data not permitted to be shared, as specified in written informed consent documents, will be withheld. Likewise, no data will be shared that may compromise the safety or privacy of participants, and no data will be shared that would violate local, state, or federal laws or policies (including the Health Insurance Portability and Accountability Act). All data will be de-identified.

• IPD Sharing Time Frame: Scientific data will be made available after primary trial manuscripts (for both clinical and electroencephalographic data) are accepted for publication. Data will be made available for as long as possible in compliance with National Institutes of Health and University of Michigan policies.
• IPD Sharing Access Criteria: Data will be shared upon execution of Data Use Agreements in compliance with University of Michigan policies and procedures. Interested researchers will need to contact the study PI (Dr. Vlisides) for obtaining data via Data Use Agreement. All data will be shared upon reasonable request after primary trial manuscripts are published.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

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