Ignite Creation Date:
2024-05-06 @ 8:04 PM
Last Modification Date:
2024-10-26 @ 3:19 PM
Study NCT ID:
NCT06236854
Status:
RECRUITING
Last Update Posted:
2024-02-01
First Post:
2023-10-10
Brief Title:
Neuroimaging Risk of Postoperative Delirium
Sponsor:
Technical University of Munich
Organization:
Technical University of Munich
Study Overview
Official Title:
Investigating the Link Between Preoperative Glymphatic Transport and Postoperative Delirium
Status:
RECRUITING
Status Verified Date:
2023-10
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 delirium POD is a frequent disorder of consciousness arousal and attention in elderly patients following surgery The glymphatic system is a newly discovered waste cleaning system of the brain Glymphatic transport of CSF has been shown to be impaired by perioperative factors Reduced glymphatic transport has been related to a vicious cycle of neuroinflammatory marker build-up leading to increased glymphatic transport impairment leading eventually to neuronal damage and hence cognitive impairment Therefore glymphatic transport impairment has been suggested to be an important mechanism underlying POD But not everyone who undergoes surgery presents POD so what makes certain patients susceptible to POD It has been suggested that glymphatic transport may already be impaired at preoperative baseline which with the added burden of perioperative strain on the system tilts the patient into POD The primary aim of the current study is to measure glymphatic transport in patients preoperatively and assess whether patients who present POD POD patients show impairments in preoperative glymphatic transport relative to patients who do not present POD noPOD patients Two aspects of glymphatic transport will be assessed using two noninvasive MR techniques - fast-acquisition BOLD-fMRI and DTI-MR POD will be assessed using the 3D-CAM questionnaire and patients will also be assessed preoperatively for symptoms of depression statetrait anxiety and cognitive status using standardised self-report measures
Detailed Description:
Delirium is a fluctuating disturbance of consciousness with accompanying impairments in attention cognition perception emotional regulation psychomotor abilities as well as sleep-wake cycle regulation Delirium frequently occurs following surgery with general anaesthesia and presents a common postoperative complication in elderly patients 65 years Postoperative delirium POD refers to the occurrence of delirium from as early as the timepoint immediately following surgery ie at emergence from general anaesthesia and up to 30 days following surgery The reported occurrence of POD is highly variable ranging from 10 to 70 depending on the age of patients diagnostic criteria and the type of surgery Those especially vulnerable are the oldest patients with the most medically complex cases undergoing cardiac vascular or hip fracture surgery POD is associated with functional decline a linear association between mortality and number of delirious days has been reported POD has also been shown to increase risk of dementia up to 10-fold alongside a 2-fold increase in risk of institutionalisation and death POD increases the length of general hospital stay and is associated with more than doubling one-year medical costs Hence there is a drive to elucidate the mechanisms of POD and identify risk factors that can facilitate adequate patient care management to reduce POD occurrence both from a health and a costs perspective
Several risk factors for POD have been identified which can be categorised into two groups based on when they occur relative to surgery Preoperative baseline risk factors for POD include older age pre-existing cognitive impairment sensory and functional impairment use of psychotropic drugs history of major depressive disorder MDD institutional residence and greater comorbidity especially with regards to cardiovascular disease Peri-intraoperative precipitating risk factors include perioperative pain environmental unfamiliarity type of surgery disrupted sleep anaesthetic dosage use of a bladder catheter and the type of medications used An individuals risk of POD has been modelled as a sum of these baseline and precipitating risk factors where a heightened burden of baseline preoperative factors necessitates fewer periintraoperative precipitating factors to induce POD This interaction between baseline and precipitating factors follows the hypothesis of neural functional reserve which suggests that an individuals ability to tolerate situations that encompass stress to the brain or brain injury is dependent upon their baseline functional reserve - representing a patients resilience Baseline preoperative risk factors of POD can be seen as factors that reduce a patients reserve or resilience and peri-intraoperative precipitating risk factors can be seen as prime examples of situations encompassing stress on the brain A low functional reserve has been shown to be an independent risk factor for POD Therefore investigations of the underlying baseline preoperative neurological impairments that have the effect of reducing a patients resilience to peri-intraoperative stressors - and increase their risk of POD - are highly warranted The investigators will assess whether two potential baseline preoperative neural impairments contribute to a patients risk of POD
The glymphatic system is a recently discovered waste clearance system of the brain utilising the perivascular channels to sweep cerebrospinal fluid CSF through and away from the brains parenchyma taking waste products and extracellular metabolites with it essentially cleaning the brain Aquaporin-4 water channels located at astrocytic end-feed form an essential component of this system facilitating CSF movement from perivascular spaces into the interstitial space There are a small number of non-invasive measures available to assess aspects of glymphatic system function in humans The first measure was proposed by whereby fast fMRI acquisition TR400ms - with the boundary edge of the volume ie slice 0 placed at the level of the fourth ventricle - allows for the detection of fluid inflow arriving at the edge of the imaging volume with high signal intensity The acquired CSF signal with slow oscillations at around 005Hz were found to be of significantly higher amplitude during sleep vs wake driven by slow neural oscillations in the delta range 1-4Hz and was anticorrelated with fluctuations in the global grey matter BOLD signal A decrease in this anticorrelation was reported in patients with Parkinsons disease and was significantly related to lower cognitive performance on the Montreal Cognitive Assessment tool A relationship between reduced global BOLD-CSF flow coupling and severity of small vessel disease has been reported related to increased dilation of the perivascular space Hence the global BOLD-CSF coupling could provide an indication as to impaired glymphatic transport
A second recent approach was developed using diffusion tensor imaging DTI of diffusion-weighted images to evaluate the motion of water molecules along deep medullary veins and their accompanying perivascular spaces running perpendicular to the ventricular walls on a transverse slice at the level of the lateral ventricle bodies At this location the distribution of different fibre types allows for the discernment of water diffusivity along the perivascular space independently from that within corticofugal corona radiata projection fibres running in the craniocaudal direction ie z-axis and superior longitudinal fascicle association fibres running in the anterior-posterior direction ie y-axis This approach called the DTI-ALPS method ie diffusion tensor imaging along the perivascular space can non-invasively measure glymphatic transport ie CSF flow through the perivascular space at this specific location as the perivascular space runs perpendicular to both the projection and association fibres Regions of interest are first manually labelled from a T1-weighted scan to measure diffusivities within these fibres along three directions x y and z Perivascular diffusion can be evaluated independently from diffusion along projection and association areas by identifying the ratio of the mean x-axis diffusivity in both areas to the mean diffusivity of these areas at the axes perpendicular to the x-axis and fibre tracts ie the y-axis for projection fibres and z-axis for association fibres
Perioperative factors such as the type of GA in combination with various other perioperative factors may alter postoperative brain function by affecting the glymphatic system Dysfunction of this system that removes harmful metabolites from the brain can lead to neurological disorders and neuroinflammation Reduced glymphatic system transport leads to an increased accumulation of amyloid-beta and tau inducing neuroinflammation leading to a chain of processes that end in neuronal damage Postoperative increases in amyloid-beta and tau have been reported and shown to be a risk factor for POD As outlined above different anaesthetics have differential effects on the glymphatic system and anaesthetic type has been shown to be a risk factor for POD in patients Volatile anaesthetics such as isoflurane or sevoflurane have a higher chance of causing POD whereas intravenous anaesthetics such as dexmedetomidine and propofol seemingly rather have a protective effect against POD
Elderly patients but not young people are highly susceptible to POD triggering the question of why this group is selectively susceptible As outlined previously preoperative risk factors for POD include preclinical Alzheimers disease cerebral microemboli vascular dementia hyperglycaemia and other neurovascular diseases or neurodegeneration all of which show glymphatic transport impairment Ageing is associated with degenerative changes such as depolarised or downregulated aquaporin-4 sleep deprivation and reduced cerebrovascular pulsatility all of which have the potential to impair glymphatic system transport In line with the functional reserve hypothesis it has been suggested that susceptible patients at risk of POD have pre-existing glymphatic system impairment that progresses slowly without significant cognitive impairment and that the perioperative risk factors exacerbate the pre-existing glymphatic damage beyond the compensatory limit resulting in significant cognitive changes This theory suggests that baseline preoperative measures of glymphatic system transport can be informative on the risk of POD Our primary aim is to investigate whether baseline preoperative measures of glymphatic system transport can be useful in identifying patients at risk of POD utilising the two non-invasive MR-based measures outlined previously
The overall aim of the current study is to investigate potential underlying pathobiological mechanisms that contribute to POD to further understand the mechanisms of this frequent disorder in the elderly and enhance perioperative care and patient management Whether an impairment in glymphatic system transport at preoperative baseline can be informative on risk of POD will be assessed All target values will be assessed at preoperative baseline Assessment of whether a patient is classified as a POD patient or a noPOD patient is based on a diagnosis of delirium on any of the five days following surgery including the day of surgery
Several risk factors for POD have been identified which can be categorised into two groups based on when they occur relative to surgery Preoperative baseline risk factors for POD include older age pre-existing cognitive impairment sensory and functional impairment use of psychotropic drugs history of major depressive disorder MDD institutional residence and greater comorbidity especially with regards to cardiovascular disease Peri-intraoperative precipitating risk factors include perioperative pain environmental unfamiliarity type of surgery disrupted sleep anaesthetic dosage use of a bladder catheter and the type of medications used An individuals risk of POD has been modelled as a sum of these baseline and precipitating risk factors where a heightened burden of baseline preoperative factors necessitates fewer periintraoperative precipitating factors to induce POD This interaction between baseline and precipitating factors follows the hypothesis of neural functional reserve which suggests that an individuals ability to tolerate situations that encompass stress to the brain or brain injury is dependent upon their baseline functional reserve - representing a patients resilience Baseline preoperative risk factors of POD can be seen as factors that reduce a patients reserve or resilience and peri-intraoperative precipitating risk factors can be seen as prime examples of situations encompassing stress on the brain A low functional reserve has been shown to be an independent risk factor for POD Therefore investigations of the underlying baseline preoperative neurological impairments that have the effect of reducing a patients resilience to peri-intraoperative stressors - and increase their risk of POD - are highly warranted The investigators will assess whether two potential baseline preoperative neural impairments contribute to a patients risk of POD
The glymphatic system is a recently discovered waste clearance system of the brain utilising the perivascular channels to sweep cerebrospinal fluid CSF through and away from the brains parenchyma taking waste products and extracellular metabolites with it essentially cleaning the brain Aquaporin-4 water channels located at astrocytic end-feed form an essential component of this system facilitating CSF movement from perivascular spaces into the interstitial space There are a small number of non-invasive measures available to assess aspects of glymphatic system function in humans The first measure was proposed by whereby fast fMRI acquisition TR400ms - with the boundary edge of the volume ie slice 0 placed at the level of the fourth ventricle - allows for the detection of fluid inflow arriving at the edge of the imaging volume with high signal intensity The acquired CSF signal with slow oscillations at around 005Hz were found to be of significantly higher amplitude during sleep vs wake driven by slow neural oscillations in the delta range 1-4Hz and was anticorrelated with fluctuations in the global grey matter BOLD signal A decrease in this anticorrelation was reported in patients with Parkinsons disease and was significantly related to lower cognitive performance on the Montreal Cognitive Assessment tool A relationship between reduced global BOLD-CSF flow coupling and severity of small vessel disease has been reported related to increased dilation of the perivascular space Hence the global BOLD-CSF coupling could provide an indication as to impaired glymphatic transport
A second recent approach was developed using diffusion tensor imaging DTI of diffusion-weighted images to evaluate the motion of water molecules along deep medullary veins and their accompanying perivascular spaces running perpendicular to the ventricular walls on a transverse slice at the level of the lateral ventricle bodies At this location the distribution of different fibre types allows for the discernment of water diffusivity along the perivascular space independently from that within corticofugal corona radiata projection fibres running in the craniocaudal direction ie z-axis and superior longitudinal fascicle association fibres running in the anterior-posterior direction ie y-axis This approach called the DTI-ALPS method ie diffusion tensor imaging along the perivascular space can non-invasively measure glymphatic transport ie CSF flow through the perivascular space at this specific location as the perivascular space runs perpendicular to both the projection and association fibres Regions of interest are first manually labelled from a T1-weighted scan to measure diffusivities within these fibres along three directions x y and z Perivascular diffusion can be evaluated independently from diffusion along projection and association areas by identifying the ratio of the mean x-axis diffusivity in both areas to the mean diffusivity of these areas at the axes perpendicular to the x-axis and fibre tracts ie the y-axis for projection fibres and z-axis for association fibres
Perioperative factors such as the type of GA in combination with various other perioperative factors may alter postoperative brain function by affecting the glymphatic system Dysfunction of this system that removes harmful metabolites from the brain can lead to neurological disorders and neuroinflammation Reduced glymphatic system transport leads to an increased accumulation of amyloid-beta and tau inducing neuroinflammation leading to a chain of processes that end in neuronal damage Postoperative increases in amyloid-beta and tau have been reported and shown to be a risk factor for POD As outlined above different anaesthetics have differential effects on the glymphatic system and anaesthetic type has been shown to be a risk factor for POD in patients Volatile anaesthetics such as isoflurane or sevoflurane have a higher chance of causing POD whereas intravenous anaesthetics such as dexmedetomidine and propofol seemingly rather have a protective effect against POD
Elderly patients but not young people are highly susceptible to POD triggering the question of why this group is selectively susceptible As outlined previously preoperative risk factors for POD include preclinical Alzheimers disease cerebral microemboli vascular dementia hyperglycaemia and other neurovascular diseases or neurodegeneration all of which show glymphatic transport impairment Ageing is associated with degenerative changes such as depolarised or downregulated aquaporin-4 sleep deprivation and reduced cerebrovascular pulsatility all of which have the potential to impair glymphatic system transport In line with the functional reserve hypothesis it has been suggested that susceptible patients at risk of POD have pre-existing glymphatic system impairment that progresses slowly without significant cognitive impairment and that the perioperative risk factors exacerbate the pre-existing glymphatic damage beyond the compensatory limit resulting in significant cognitive changes This theory suggests that baseline preoperative measures of glymphatic system transport can be informative on the risk of POD Our primary aim is to investigate whether baseline preoperative measures of glymphatic system transport can be useful in identifying patients at risk of POD utilising the two non-invasive MR-based measures outlined previously
The overall aim of the current study is to investigate potential underlying pathobiological mechanisms that contribute to POD to further understand the mechanisms of this frequent disorder in the elderly and enhance perioperative care and patient management Whether an impairment in glymphatic system transport at preoperative baseline can be informative on risk of POD will be assessed All target values will be assessed at preoperative baseline Assessment of whether a patient is classified as a POD patient or a noPOD patient is based on a diagnosis of delirium on any of the five days following surgery including the day of surgery
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