Pre-op Dietary Fat Intake and Baseline Inflammation in Older Adults Undergoing Major Non-cardiac Surgery: Examining Diet-related Risk Factors for Perioperative Neurocognitive Disorders in Obese and Normal BMI Patients
Conditions: Fat Consumption, Inflammatory Markers
Sponsor: Ohio State University

 
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Title: Preoperative dietary fat consumption and baseline inflammatory markers in older patients 
presenting for major non-cardiac surgery: A pilot study of dietary-related risk factors for perioperative 
neurocognitive disorders in obese and normal body mass index (BMI) patients  
  
BACKGROUND   
  
Postoperative cognitive impairment (POCI) places a significant burden on patients, caregivers, and 
healthcare resources. Brief or persistent disruption in cognitive recovery is the most common 
postoperative complication in older surgical patients, with approximately 1 of every 2 patients potentially 
experiencing POCI in the highest risk populations [1].  Postoperative declines in cognitive function are 
associated with alarming morbidity and mortality rates, including an increased susceptibility to developing 
Alzheimer’s disease [2-5]. Furthermore, a diagnosis of delayed or impaired postoperative cognitive 
recovery is associated with more than $17,000 additional Medicare charges in the year following surgery 
[6] and with more than 19 million surgeries a year in patients >65 [7], this is a major public health concern. 
A multitude of factors contribute to risk of POCI, but the increased incidence and sequalae in older 
patients is thought to be due to convergent pro-inflammatory responses occurring with aging and 
perioperative exposure to stress, significant tissue trauma and physiological derangements, and 
medications with pro-inflammatory characteristics like opiates [8-10].   
  
Diet is not currently emphasized as a significant or modifiable risk factor for postoperative cognitive 
impairment in older surgical patients. However, it is well known that consumption of diets high in 
saturated fats leads to increases in proinflammatory cytokines in the circulation and the brain [11-13]. 
Furthermore, overconsumption of saturated fats is a growing trend across all age groups including older 
adults, as they account for 55% of their daily calories [14-17]. A proinflammatory milieu has been 
repeatedly demonstrated through mechanistic and biomarker studies of perioperative cognitive 
dysfunction in older patients [18-20], but clinical studies on the direct role of diet or obesity status with 
an aging and cognitive recovery focus are missing from the perioperative literature, yet absolutely 
warranted based upon our preclinical work [21]. We have recently demonstrated that high-fat diet 
consumed prior to surgery caused exaggerated neuroinflammation and long-lasting memory impairment 
after surgery in older rats [21]. Furthermore, these effects were prevented by reducing the 
neuroinflammatory response either pharmacologically or by supplementing their diet with the omega 3 
fatty acid, docosahexaenoic acid (DHA). Thus, we believe the balance of pro-inflammatory and anti-
inflammatory effects of diet and nutritional status to be an additional convergent contributor with 
significant effects on postoperative cognitive recovery.  
  
STUDY QUESTION:  
This pilot study will 1) determine the feasibility of the Diet History Questionnaire-III (DHQ-III) for 
perioperative use and baseline observations of dietary fat consumption levels in geriatric patients; 2) 
measure levels of perioperative inflammatory markers in blood and cerebral fluid (CSF) in patients with 
normal body mass index (BMI), obese BMI, and patients with self-reported fat over-consumption 3) 
measure sample incidence of perioperative neurocognitive disorders in older patients with fat 
overconsumption including preexisting cognitive impairment, postoperative delirium, and persistent 
postoperative cognitive impairment, and 4) collect patient-reported considerations for future study of 
behavioral/dietary interventions in geriatric surgical candidates.  

 
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We hypothesize that a correlation will exist between BMI or fat over-consumption and proinflammatory 
blood and CSF markers in older patients presenting for elective surgery.  Likewise, fat over-consumption 
will increase risk of perioperative neurocognitive disorders.  
   
NULL HYPOTHESIS:   
Diet-related information from patients is not easily assessed with the DHQ-III, and no preliminary 
relationships exist between BMI or fat over-consumption and proinflammatory blood and CSF markers.  
Likewise, no preliminary relationship exists between fat over-consumption and risk of perioperative 
neurocognitive disorders.    
  
OBJECTIVES  
  
Primary objective:  
• 
To determine ability to assess important nutritional factors in older surgical patients including 
dietary levels of fat consumption, waist circumference, BMI, and frailty status prior to surgery for 
correlation with inflammatory markers in blood and CSF, before and after elective surgery.  
  
Secondary Objectives:  
• 
To estimate incidence of perioperative neurocognitive disorders in the pilot cohort of older 
surgical patients with obesity or fat-overconsumption.  
• 
To evaluate patient perspectives on the importance of nutrition for recovery after surgery, 
experiences with dietary changes to improve health prior to any surgery, and willingness to take 
a supplement (DHA) prior to a future surgery.  
  
  
EXPERIMENTAL METHODS  
  
Study design:  
A single center, prospective pilot study for the examination of dietary levels of fat consumption with 
correlation of inflammatory markers prior to surgery and incidence of perioperative neurocognitive 
disorders in older surgical patients.   
  
Study Population:  
Obese or normal weight patients over the age of 60 scheduled to undergo a major abdominal or pelvic 
surgery, or total hip or knee joint arthroplasty at OSUWMC and complete the study.    
  
Sample size:  
A total of 60 patients from the Ohio State University Wexner Medical Center (OSUWMC) will be included. 
In total, 30 subjects with BMI > 30 will be collected for the Obese Group and another 30 subjects for the 
normal BMI (25-30) group. In total, 15 subjects scheduled to undergo major abdominal or pelvic surgery 

 
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and 15 subjects scheduled to undergo total hip or knee joint arthroplasty will be recruited to each BMI 
group (Normal vs. >30 BMI). Assuming approximately 15% of consented patients either fail screening or 
do not complete the study after consent, we expect to consent 70 patients.  
  
Table 1. Study population distribution.   
N= 60  
Obese            
(BMI >30)  
Normal Group 
(BMI 25-30)  
THA-TKA  
15  
15  
Major 
abdominal or 
pelvic surgery   
15  
15  
  
Experimental Methods:  
  
This 60-patient pilot trial will be completed and analyzed over a 12-month period. Because the nutritional 
status and dietary habits could potentially be very different in patients, we are targeting these separate 
patient cohorts.   
  
Detailed patient-reported diet information about the month preceding surgery using the “Diet History 
Questionnaire” (Appendix C) will be collected prior to surgery.   
  
Blood draw collection – Up to 32 mL of blood will be collected. A  maximum of 16 mL prior to surgery, and  
16 mL the morning after surgery.  
 
CSF sample collection - It is routine care at OSUWMC for patients undergoing TKA and knee arthroscopy 
or, major abdominal or pelvic surgery to receive preoperative neuraxial anesthesia for pain management. 
In placing the standard local anesthesia spinal block or intrathecal morphine injection, the subarachnoid 
space is accessed via a spinal needle [22]. Free flow of CSF from the needle is used to confirm that the 
subarachnoid space has been accessed [22]. In normal situations, this CSF is wasted. Therefore, the 
selected patient population is an ideal population to study CSF. Up to 1 mL of free flow CSF will be 
collected, then, the anesthetic/analgesic agent will be injected.  CSF will be evaluated for inflammatory 
markers.  
  
Evaluation of Perioperative Neurocognitive Disorders - A baseline preoperative telephone-Montreal 
Cognitive Assessment (T-MoCA, Appendix B) will be completed prior to surgery to classify participants as 
‘impaired’ or ‘not impaired’.  We will complete a confusion assessment method assessment (CAM-3D, 
Appendix A) twice daily starting on the day of surgery (postoperative) until discharge day. In addition 
authorized research personnel will review electronic medical records after surgery to document any 
clinical delirium diagnostic and classify participants as ‘delirium positive’ or ‘delirium negative’. At 3 
months after surgery, the TMoCA will be repeated and compared to preoperative score for an estimate 
of persistent neurocognitive disorder.  
  

 
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DHQ-III will be administered before surgery. In addition, a patient-centered survey will be administered 
prior to discharge, we will ask patients about their interest in diet-related factors to support successful 
recovery after surgery and willingness to consider diet-changes and/or daily use of DHA supplementation 
for a future surgery, so we can refer them to the appropriate specialist.   
   
Table 2. Scheduled of Procedures   
 
Study Procedure  
Screening    
Day -7       
– Day 1 
Pre-Op 
Surgery 
Day  
Post-Op 
Surgery 
Day  
PO Day 1  
Day 2 
through 
Discharge  
Day 90       
+/- 7 days 
Phone call 
Follow-up    
Informed Consent & HIPAA  
X  
X  
 
 
  
  
Inclusion & Exclusion Criteria   
X  
X  
 
 
  
  
Demographics  
X  
X  
 
 
  
  
Medical History   
X  
X  
 
 
  
  
CSF sample collection   
  
X  
 
 
  
  
Blood Draw sample collection   
  
X  
 
X  
 
  
t-MoCA   
 
X  
 
 
  
X  
3DCAM Assessment   
  
 
X (PM)  
X 
(AM+PM)  
X 
(AM+PM)  
  
DHQ-III 
 
X  
 
 
 
 
Discharge survey  
  
 
 
 
X (prior to 
discharge)  
  
Adverse Events  
 
 
X  
X  
X  
X  
 
Statistical Method:   
Data will be summarized using appropriate descriptive statistics, including means, standard deviations, 
medians, ranges, and proportions. Continuous data will explore using parametric or non-parametric ttests 
as appropriate.  Categorical data will be presented as frequencies or proportions and explored using a chi-
square or Fisher's Exact test. Logistic regression will be employed for patient characteristics, inflammatory 
markers, diet data, and outcomes to evaluate potential relationships with obesity groups. These analyses 
will be used to calculate descriptive effect size estimates; however, formal comparisons will be limited 
due to pilot sample size and study design.  All statistical analyses will be performed using SAS/STAT 
software version 9.4 (SAS Institute Inc., Cary, NC).  
  
Eligibility Criteria:   
 
Inclusion Criteria:  
1. ≥ 60 years of age or older  
2. Capable and willing to consent   
3. English speaking  
4. Anticipated ASA physical status I-III  
5. Scheduled to undergo major abdominal or pelvic surgery, or total hip or knee joint arthroplasty 
under general anesthesia with planned spinal anesthetic/analgesic.    

 
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Exclusion Criteria:  
1. Illiterate  
2. ASA physical status V, VI  
3. Active Axis I or II psychiatric disorders including bipolar disorder, schizophrenia, dementia, alcohol, 
or drug abuse.   
4. Preoperative benzodiazepine administration (i.e. Midazolam, Diazepam)  
5. Past medical history of any inflammatory autoimmune disease processes (rheumatic arthritis (RA), 
systemic lupus erythematosus (SLE), autoinflamatory syndrome, etc.)  
 Knowledge Translation / Future Directions:   
This pilot study will provide 3 critical pieces of information for future clinical trial design: 1) baseline 
observations of dietary fat consumption levels, overall nutritional status, and measurement of 
inflammatory markers in older surgical patients, 2) sample incidence of postoperative delirium and 
persistent neurocognitive disorder in older patients with fat overconsumption prior to surgery, 3) patient 
reported considerations for future study of behavioral/dietary interventions in older surgical candidates. 
It will inform study power and enrollment goals for a future large-scale randomized-controlled trial for 
further characterization and preoperative nutritional interventions.   
  
Adverse Event Reporting:  
An Adverse Event (AE) is defined as any untoward medical occurrence in a patient or clinical investigation 
subject. An AE can be any unfavorable and unintended sign, symptom, abnormal laboratory finding or a 
temporally disease associated with the subject’s participation in the research, whether or not considered 
related to the subject’s participation in the research. Planned hospital admissions and/or surgical 
operations for an illness or disease that existed before the subject was enrolled in a clinical study are not 
to be considered as AEs.  
  
All adverse events will be evaluated according to their relevance and significance to the study. They will 
be graded according to severity, expectedness, relation to the study treatment, and whether the event 
did or did not require additional treatment.  
 All unanticipated problems that meet the following criteria will be reported to the IRB:  
• 
Unexpected (in terms of nature, severity, or frequency) given (a) the research procedures that are 
described in the protocol-related documents, such as the IRB-approved research protocol and 
informed consent document, or the Investigation Brochure, and (b) the characteristics of the 
subject population being studied.  
• 
Related or possibly related to participation in the research (possibly related means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by 
procedures involved in the research); and  
• 
Suggests that the research places subjects or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or recognized.  
  

 
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A Severe Adverse Event (SAE) is any untoward medical occurrence that:  
• 
Results in death.  
• 
Is life-threatening.  
• 
Results in persistent or significant disability/incapacity.  
• 
Requires in-subject hospitalization or prolongs hospitalization.  
• 
Is a congenital anomaly/birth defect.  
• 
Is another medically-significant event that, based upon appropriate medical judgment, may 
jeopardize the subject and may require medical or surgical intervention to prevent one of the 
outcomes listed above.  
  
Withdrawal Criteria from the study: According with the Declaration of Helsinki, participants have the right 
to withdraw from the study at any time for any reason.  The principal investigator also has the right to 
remove a subject from the study.  Reasons for which a subject may be removed from the study include:  
• 
An adverse event  
• 
The request of the subject, his/her legal representative or caregiver, investigator, whether for 
administrative or other reasons  
• 
Non - compliance with medication, protocol violation or unreliable, behavior  
• 
Any clinically significant abnormal laboratory values, or other clinically significant abnormalities 
identified by the principal investigator according to his clinical judgment, will be followed by 
appropriate tests and/or procedures until these values have returned to normal or to clinically 
acceptable levels or can be attributed to other causes other than study drug.  
  
The principal Investigator may withdraw an enrolled and treated subject from the study for any of the 
following reasons:  
• 
Occurrence of a serious or intolerable adverse event.  
• 
Emergence of a clinically significant change in a laboratory parameter(s).  
• 
The subject requests to be discontinued from the study.  
• 
A protocol violation sufficiently serious as to require subject withdrawal. General or specific 
changes in the subject's condition that render further treatment unreasonable or unsafe within 
the standards of clinical practice in the judgment of the Principal Investigator or treating physician. 
Any subject may leave the study at any time. If the subject decides to stop participating in the 
study, there will be no penalty. The subjects will not lose any benefits to which they are otherwise 
entitled.   
  
REFERENCES   
   
1. 
Tasbihgou, S.R. and A.R. Absalom, Postoperative neurocognitive disorders. Korean journal of 
anesthesiology, 2021. 74(1): p. 15.  

 
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2. 
Moskowitz, E.E., et al., Post-operative delirium is associated with increased 5-year mortality. The 
American Journal of Surgery, 2017. 214(6): p. 1036-1038.  
3. 
Evered, L., et al., Recommendations for the nomenclature of cognitive change associated with 
anaesthesia and surgery—2018. Anesthesiology, 2018. 129(5): p. 872-879.  
4. 
Bickel, H., et al., High risk of cognitive and functional decline after postoperative delirium: a 
threeyear prospective study. Dementia and geriatric cognitive disorders, 2008. 26(1): p. 26-31.  
5. 
Leighton, S.P., et al., Delirium and the risk of developing dementia: a cohort study of 12 949 
patients. Journal of Neurology, Neurosurgery & Psychiatry, 2022. 93(8): p. 822-827.  
6. 
Boone, M.D., et al., Economic burden of postoperative neurocognitive disorders among US 
Medicare patients. JAMA network open, 2020. 3(7): p. e208931-e208931.  
7. 
CfDCa, P., Number of all-listed procedures for discharges from short-stay hospitals, by procedure 
category and age: United States. 2010.  
8. 
Wang, P., et al., Neurovascular and immune mechanisms that regulate postoperative delirium 
superimposed on dementia. Alzheimer's & Dementia, 2020. 16(5): p. 734-749.  
9. 
Muscat, S.M., et al., Postoperative cognitive dysfunction is made persistent with morphine 
treatment in aged rats. Neurobiology of aging, 2021. 98: p. 214-224.  
10. 
Muscat, S.M., et al., Selective TLR4 antagonism prevents and reverses morphine-induced persistent 
postoperative cognitive dysfunction, dysregulation of synaptic elements, and impaired BDNF 
signaling in aged male rats. Journal of Neuroscience, 2023. 43(1): p. 155-172.  
11. 
Madison, A.A., et al., Afternoon distraction: a high-saturated-fat meal and endotoxemia impact 
postmeal attention in a randomized crossover trial. The American Journal of Clinical Nutrition, 
2020. 111(6): p. 1150-1158.  
12. 
Spencer, S.J., et al., High-fat diet and aging interact to produce neuroinflammation and impair 
hippocampal-and amygdalar-dependent memory. Neurobiology of aging, 2017. 58: p. 88-101.  
13. 
Butler, M.J., et al., Fatty food, fatty acids, and microglial priming in the adult and aged 
hippocampus and amygdala. Brain, behavior, and immunity, 2020. 89: p. 145-158.  
14. 
Fryar, C.D., M.D. Carroll, and C.L. Ogden, Prevalence of overweight, obesity, and extreme obesity 
among adults: United States, trends 1960–1962 through 2009–2010. Hyattsville, MD: National 
Center for Health Statistics, 2012.  
15. 
Fakhouri, T.H., Prevalence of obesity among older adults in the United States, 2007-2010. 2012: 
US Department of Health and Human Services, Centers for Disease Control and ….  
16. 
Ogden, C.L., et al., Prevalence of obesity among adults and youth: United States, 2011-2014. 2015.  
17. 
Shan, Z., et al., Trends in dietary carbohydrate, protein, and fat intake and diet quality among US 
adults, 1999-2016. Jama, 2019. 322(12): p. 1178-1187.  
18. 
Vasunilashorn, S.M., et al., Application of multiple omics to Understand Postoperative Delirium 
Pathophysiology in humans. Gerontology, 2023. 69(12): p. 1369-1384.  
19. 
McKay, T.B., et al., Exploring the Pathophysiology of Delirium: An Overview of Biomarker Studies, 
Animal Models, and Tissue-Engineered Models. Anesthesia & Analgesia, 2022: p. 10.1213.  
20. 
Liu, X., Y. Yu, and S. Zhu, Inflammatory markers in postoperative delirium (POD) and cognitive 
dysfunction (POCD): a meta-analysis of observational studies. PloS one, 2018. 13(4): p. e0195659.  
21. 
Muscat, S.M., et al., Post-operative cognitive dysfunction is exacerbated by high-fat diet via TLR4 
and prevented by dietary DHA supplementation. Brain, Behavior, and Immunity, 2024. 116: p. 
385401.  

 
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22. 
Afolayan, J.M., et al., Intrathecal tramadol versus intrathecal fentanyl for visceral pain control 
during bupivacaine subarachnoid block for open appendicectomy. Niger J Clin Pract, 2014. 17(3): 
p. 324-30.  
  
  
  
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix A. Confusion Assessment Method (3D-CAM)  

 
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Appendix B. Telephone-Montreal Cognitive Assessment (T-MoCA)  

 
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 Appendix C. Diet History Questionnaire (file attached)