Ignite Creation Date:
2024-07-17 @ 11:37 AM
Last Modification Date:
2024-10-26 @ 3:33 PM
Study NCT ID:
NCT06480708
Status:
NOT_YET_RECRUITING
Last Update Posted:
2024-06-28
First Post:
2024-06-15
Brief Title:
Evaluation of the Ketogenic Diet to Improve Post Operative Cognitive Decline in Cardiac Surgery
Sponsor:
University of Missouri-Columbia
Organization:
University of Missouri-Columbia
Study Overview
Official Title:
Evaluation of the Ketogenic Diet to Improve Post Operative Cognitive Decline in Cardiac Surgery
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-06
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Postoperative cognitive decline POCD is a significant neurological problem that commonly follows coronary artery bypass grafting surgery CABG in elderly patients This can result in longer hospital stays and generate worsening morbidity and mortality Furthermore POCD often persists in some patients for more than a year and puts them at higher risk for developing Alzheimers Disease or dementia The cause of POCD is a topic of ongoing work with recent hypotheses linked with cell dysfunction and death in the brain and neuroinflammation related to the surgical trauma and related systemic inflammation In this project the investigators will test whether the pre-operative use 14 days of a ketogenic diet KD compared to a control diet CD will lower the incidence duration and severity of POCD in cardiac patients The ketogenic diet has been associated with improved memory function as well as reduction of inflammation in conditions such as epilepsy Alzheimers Disease and Parkinsons Disease A subset of patients from each group will also undergo a 7 Tesla magnetic resonance imaging and spectroscopy scan where key brain metabolites of mitochondrial function and neuronal integrity will be measured in the prefrontal cortex and hippocampus In the KD group cerebral b-hydroxybutyrate BHB to evaluate cerebral ketosis will also be measured These will be measured prior to starting the KDCD and after a minimum of 10 days on the KDCD From both CD and KD groups levels of key cytokines linked with inflammation will be measured during the protocol Our outcome parameters for POCD will include measures that evaluate cognition delirium and length of hospitalization The following hypotheses will be investigated 1 lower incidence duration and severity of POCD in the KD group compared to the CD group and 2 better pre-operative values of neuronal integrity and in the KD group higher levels of brain ketone levels will be associated with patients who do not experience POCD or have less severe POCD This project tests the use of the multi-factorial effects of the KD for an important problem in Anesthesiology With state-of-the-art imaging technology and cytokine evaluation the investigators hypothesize this work can have substantial implications for prevention and management of postoperative cognitive decline
Detailed Description:
Although there have been significant improvements in the mortality seen in cardiac surgery post-operative cognitive decline POCD remains a major problem occurring in up to 50 of elderly patients The classification of this problem has been difficult given the distinct aspects of post-operative delirium and post-operative cognitive dementia however with their many overlapping potential pathologies there is increasing recognition that these represent a continuum of post-operative cerebral dysfunction Overall the mean duration of POCD is four days but the cognitive decline can persist for months or even years after surgery As reviewed by Greaves in coronary artery bypass graft CABG patients POCD decreases to 25 6-12 months following surgery however 40 of patients who developed acute POCD will also experience long-term POCD lasting 1-5 years With POCD being a debilitating and costly problem for older patients there is a need for more effective preventative and interventional measures as well as a better understanding of underlying risk factors contributing to POCD development
The pathophysiology of POCD is clearly complex and for a given patient can be difficult to specifically identify causes Overall the literature suggests at least two major contributing and potentially overlapping hypotheses First multiple studies have suggested that anesthetics cause a range of molecular changes eg affecting apoptosis neuronal growth as well as learning Pre-clinical studies have found that volatile anesthetics increase amyloid-β Aβ peptide production and accumulation causing morphological changes to mitochondria disruption of calcium homeostasis increased permeability and ultimately apoptosis through activation of several caspases and human studies have linked such abnormalities with clinical measures of delirium and dementia A second major hypothesis is based in inflammatory changes because of the surgery or anesthetic Available literature has shown that volatile anesthetics can affect immune cell function and cardiac surgery itself which includes cardio-pulmonary bypass and organ reperfusion injury is a major activator of systemic inflammation and oxidative stress resulting in several proinflammatory cascades and ultimately increased neuroinflammation From there neuroinflammation has been linked to neurodegenerative diseases such as Alzheimers Disease Parkinsons Disease and HIV-dementia as well as cognitive dysfunction Consistent with both hypotheses patients with pre-surgical cerebral dysfunction have been found to be more vulnerable to POCD Preoperative neuroimaging studies have shown that whole-brain gray matter atrophy impaired white matter integrity decreased functional connectivity in the orbitofrontal cortex and cortical dysfunction are important predictors for POCD presumably because the challenges coronary artery bypass grafting CABG pose include lengthy anesthesia including volatile anesthetics that inactivates the brain are more detrimental in an already compromised brain
With the evident complexity of POCD it is hypothesized that a therapeutic approach that can act in multiple ways to modulate these pathophysiological effects may be constructive With its myriad effects on cell signaling changes in amyloid-beta or tau deposition anti-oxidant effects and effects on immunological function it is proposed that the ketogenic diet KD may be reasonable avenue for this Indeed the KD has now been studied in several small clinical trials for mild cognitive impairment Taylor 2018 used a 11 gram ratio of lipidnon-lipid foods calorically 70 fats 20 protein 10 carbohydrates to report on N10 participants who were able to complete the dietary plan over a course of 3 months All but one patient exhibited an improvement in the Alzheimers Disease Assessment Scale-Cognitive Subscale ADAS-cog scores with the mean ADAS-cog score starting at 255 which decreased to 214 p002 The KD has long been used for epilepsy and as reported by Poorshiri 2023 with a more aggressive diet calorically 90 calorie intake were fats N34 participants completed the diet for three months with 21 of the 34 62 of the participants responding positively with 50 seizure reduction
The KD has been considered in heart failure as well Von Bibra 2014 compared a mild low carbohydrate LC diet 25 carbohydrates 30 protein and 45 fat with low fat diets in patients with cardiac failure and type 2 diabetes for a period of three weeks The participants on the LC diet n16 had significant improvement in both their diastolic cardiac function and fasting glucose Thus the KD has been studied both in the laboratory and clinic finding improvements in both spheres With the limited timeframe available for our study a 14-day implementation of the KD vs control diet CD comparison will be implemented It might be argued that 14 days is insufficiently long to achieve the needed effect However the conversion of the brain from glucose to ketone oxidation can be performed efficiently As discussed for clinical management ketosis can be achieved by 2 to 4 days after starting the KD As well the original work from Freeman and Vining showed that a 3-day intervention in pediatric epilepsy could effectively reduce seizures by 50 With the direct provision of food per the study problems associated with meal preparation will be eliminated which the investigators believe will expedite the performance of the study A diet plan that calorically provides 702010 fatproteinCHO matching the profile of Taylor 2018 will be targeted
While this study can be entirely performed on a clinical basis the investigators believe that a better understanding of the success or not of the KD to reduce the occurrence of POCD may be had with metabolic imaging with MR spectroscopy In vivo human brain magnetic resonance spectroscopic MRS imaging have been used for more than 30 years to evaluate in vivo brain metabolism and function allowing measurements of N-acetyl aspartate NAA glutamate GLU creatine Cr and others NAA is strongly correlated with neuronal mitochondrial function with early work from Bates and Heales finding that NAA synthesis localized to neuronal mitochondria and correlated with adenosine-triphosphate ATP synthesis rates The MRS measurements can be quantified to tissue water or as a ratio taken to total Creatine tCr creatine phosphocreatine eg NAAtCr with tCr present in both neurons and glia this ratio provides a convenient index of neuronal mitochondrial function that is corrected for cerebral spinal fluid content which contains negligible quantities of these metabolites when compared to the tissue concentrations
In pathology the NAAtCr ratio has been related to many aspects of clinical and scientific interest For example the team previously performed hippocampal MR spectroscopic studies in epilepsy patients who underwent intracranial monitoring and micro dialysis sampling for seizure evaluation A significant negative relationship between NAAtCr to the micro dialysis extracellular measurements of the major inhibitory neurotransmitter gamma-aminobutyric acid GABA was found in patients with medial temporal lobe epilepsy MTLE while it was positive with neocortical non-MTLE patients The selectivity of these relationships was consistent with the view that in healthier brain the extracellular GABA increases appropriately with better mitochondrial function while in diseased tissue region of seizure onset GABA appears to fail to suppress the abnormal seizure activity ie GABA increases as mitochondrial function falls
MRS has also been used to measure the major cerebral ketone β-hydroxybutyrate BHB Under non-ketotic conditions the concentration of brain BHB is zero however with fasting or with use of the KD brain BHB rises to near millimolar levels the other major ketone is acetoacetate ACAC however as the redox couple to BHB the ratio of ACACBHB has been reported at 13 in fasted subjects and thus at much lower concentration In cerebral ketosis there is adaptation of BHB transport across the blood brain barrier giving a linear relationship between plasma and cerebral BHB The adaptation may be individual-dependent and thus measurements of brain BHB can provide an objective measure of the extent of cerebral ketosis In patients the measurement of BHB has been largely performed at 3 Tesla however because of its low and variable concentration it is a measurement that requires high signal-to-noise SNR With increasing therapeutic use of ketosis and the KD for neurological disorders a robust measurement of cerebral BHB can be very informative which should benefit from the higher SNR at 7T
The pathophysiology of POCD is clearly complex and for a given patient can be difficult to specifically identify causes Overall the literature suggests at least two major contributing and potentially overlapping hypotheses First multiple studies have suggested that anesthetics cause a range of molecular changes eg affecting apoptosis neuronal growth as well as learning Pre-clinical studies have found that volatile anesthetics increase amyloid-β Aβ peptide production and accumulation causing morphological changes to mitochondria disruption of calcium homeostasis increased permeability and ultimately apoptosis through activation of several caspases and human studies have linked such abnormalities with clinical measures of delirium and dementia A second major hypothesis is based in inflammatory changes because of the surgery or anesthetic Available literature has shown that volatile anesthetics can affect immune cell function and cardiac surgery itself which includes cardio-pulmonary bypass and organ reperfusion injury is a major activator of systemic inflammation and oxidative stress resulting in several proinflammatory cascades and ultimately increased neuroinflammation From there neuroinflammation has been linked to neurodegenerative diseases such as Alzheimers Disease Parkinsons Disease and HIV-dementia as well as cognitive dysfunction Consistent with both hypotheses patients with pre-surgical cerebral dysfunction have been found to be more vulnerable to POCD Preoperative neuroimaging studies have shown that whole-brain gray matter atrophy impaired white matter integrity decreased functional connectivity in the orbitofrontal cortex and cortical dysfunction are important predictors for POCD presumably because the challenges coronary artery bypass grafting CABG pose include lengthy anesthesia including volatile anesthetics that inactivates the brain are more detrimental in an already compromised brain
With the evident complexity of POCD it is hypothesized that a therapeutic approach that can act in multiple ways to modulate these pathophysiological effects may be constructive With its myriad effects on cell signaling changes in amyloid-beta or tau deposition anti-oxidant effects and effects on immunological function it is proposed that the ketogenic diet KD may be reasonable avenue for this Indeed the KD has now been studied in several small clinical trials for mild cognitive impairment Taylor 2018 used a 11 gram ratio of lipidnon-lipid foods calorically 70 fats 20 protein 10 carbohydrates to report on N10 participants who were able to complete the dietary plan over a course of 3 months All but one patient exhibited an improvement in the Alzheimers Disease Assessment Scale-Cognitive Subscale ADAS-cog scores with the mean ADAS-cog score starting at 255 which decreased to 214 p002 The KD has long been used for epilepsy and as reported by Poorshiri 2023 with a more aggressive diet calorically 90 calorie intake were fats N34 participants completed the diet for three months with 21 of the 34 62 of the participants responding positively with 50 seizure reduction
The KD has been considered in heart failure as well Von Bibra 2014 compared a mild low carbohydrate LC diet 25 carbohydrates 30 protein and 45 fat with low fat diets in patients with cardiac failure and type 2 diabetes for a period of three weeks The participants on the LC diet n16 had significant improvement in both their diastolic cardiac function and fasting glucose Thus the KD has been studied both in the laboratory and clinic finding improvements in both spheres With the limited timeframe available for our study a 14-day implementation of the KD vs control diet CD comparison will be implemented It might be argued that 14 days is insufficiently long to achieve the needed effect However the conversion of the brain from glucose to ketone oxidation can be performed efficiently As discussed for clinical management ketosis can be achieved by 2 to 4 days after starting the KD As well the original work from Freeman and Vining showed that a 3-day intervention in pediatric epilepsy could effectively reduce seizures by 50 With the direct provision of food per the study problems associated with meal preparation will be eliminated which the investigators believe will expedite the performance of the study A diet plan that calorically provides 702010 fatproteinCHO matching the profile of Taylor 2018 will be targeted
While this study can be entirely performed on a clinical basis the investigators believe that a better understanding of the success or not of the KD to reduce the occurrence of POCD may be had with metabolic imaging with MR spectroscopy In vivo human brain magnetic resonance spectroscopic MRS imaging have been used for more than 30 years to evaluate in vivo brain metabolism and function allowing measurements of N-acetyl aspartate NAA glutamate GLU creatine Cr and others NAA is strongly correlated with neuronal mitochondrial function with early work from Bates and Heales finding that NAA synthesis localized to neuronal mitochondria and correlated with adenosine-triphosphate ATP synthesis rates The MRS measurements can be quantified to tissue water or as a ratio taken to total Creatine tCr creatine phosphocreatine eg NAAtCr with tCr present in both neurons and glia this ratio provides a convenient index of neuronal mitochondrial function that is corrected for cerebral spinal fluid content which contains negligible quantities of these metabolites when compared to the tissue concentrations
In pathology the NAAtCr ratio has been related to many aspects of clinical and scientific interest For example the team previously performed hippocampal MR spectroscopic studies in epilepsy patients who underwent intracranial monitoring and micro dialysis sampling for seizure evaluation A significant negative relationship between NAAtCr to the micro dialysis extracellular measurements of the major inhibitory neurotransmitter gamma-aminobutyric acid GABA was found in patients with medial temporal lobe epilepsy MTLE while it was positive with neocortical non-MTLE patients The selectivity of these relationships was consistent with the view that in healthier brain the extracellular GABA increases appropriately with better mitochondrial function while in diseased tissue region of seizure onset GABA appears to fail to suppress the abnormal seizure activity ie GABA increases as mitochondrial function falls
MRS has also been used to measure the major cerebral ketone β-hydroxybutyrate BHB Under non-ketotic conditions the concentration of brain BHB is zero however with fasting or with use of the KD brain BHB rises to near millimolar levels the other major ketone is acetoacetate ACAC however as the redox couple to BHB the ratio of ACACBHB has been reported at 13 in fasted subjects and thus at much lower concentration In cerebral ketosis there is adaptation of BHB transport across the blood brain barrier giving a linear relationship between plasma and cerebral BHB The adaptation may be individual-dependent and thus measurements of brain BHB can provide an objective measure of the extent of cerebral ketosis In patients the measurement of BHB has been largely performed at 3 Tesla however because of its low and variable concentration it is a measurement that requires high signal-to-noise SNR With increasing therapeutic use of ketosis and the KD for neurological disorders a robust measurement of cerebral BHB can be very informative which should benefit from the higher SNR at 7T
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None