deeper into delirium
TRANSCRIPT
Deeper into deliriumPrince of Wales Hospital Sydney,
Australia
Disclosures
Acknowledgements
via ED, unwell, not himself. “Usually independent”
• O/E AMTS 6/10, GCS 14/15, RR 25, T 375 CXR – R basal consolidation, WCC 10.5, Creatinine 135, U/A – leucocytes, nitrites
• PDx – Comm. acq. pneumonia ± UTI
• Rx – IV fluids and Abs (Ceftriaxone)
Admitted under Resp Med
• First night on the ward: agitated, calling out for wife. S/B JMO, Rx Haloperidol 2.5mg “Day team to R/V”
• First day on the ward: “pleasantly confused”, “resting in bed”. Ward Drs: “Continue current Rx but add Roxithromycin, await culture results”
Second night • Play time!
• Calling out, climbing over bed rails, nursed in chair opposite nurses station, told to call if he wants to go to toilet
• Gets up to toilet alone and falls
• c/o pain in groin, unable to weight bear
• X-ray: #NOF
• Orthopaedics consulted
Second day
• 17:00 S/B Orthopaedics, booked for OT, Blood cultures – E. coli -> Anaesthetist: OT delayed
• ID consult: Infection covered, OK for OT
Third day
• 17:00 OT
punches nurse. Code Black. IV haloperidol + midazolam
AKI, small Troponin leak
• MMSE 12/30
• No. 1 Adverse Event for older people in hospital
• risk: falls, nursing home placement and death
• Despite 2,500 year history – no effective drugs
• No understanding of pathophysiology
Brain dysfunction
– Correct renal failure
– Replace hormone deficiencies
• Metabolic problem?
• Neurotransmitter imbalance?
• Stress response?
The concept of delirium • Since the late 19th century thought
to be due to transient alteration of cerebral metabolism
unspecified
• No difference in CSF ACh levels during delirium
• Resolution of delirium despite no change in Serum Anticholinergic Activity
• No benefit in delirium from AChEIs
Aberrant stress response, blood
Cereira J. J Geriatr Psychiatry Neurol 2013 Van Munster B. Brain Cognition 2010; 74:
P=0.04 on multivariate analysis
Cortisol in CSF Pearson A. BMC Research Notes 2010; 3:33.
P=0.029
But, what is the role of stress?
• In the context of delirium, is activation of stress response surprising?
• Association or causation?
• If delirium were due to a transient abnormality of metabolism, neurotransmitters, inflammation, one would expect complete recovery…
But.. (Sequelae of delirium)
• Follow up of delirium demonstrates • Increased mortality – up to 33% in hospital
– 2.11x higher mortality in the next 12 mths
• Increased LOS - 2x • 800% higher odds of dementia • More functional impairment • 3x more placement in nursing home • Worse outcomes if pre-existing dementia • Even after adjusting for severity of
medical illness and pre-existing dementia
Mortality after delirium McCusker J. Arch Int Med 2002; 162: 457.
How does this compare?
previous
dementia)
11.0%
On a population basis McCallum J. The continuum of care for older people. Aust Hlth
Rev 1995; 18: 40-54.
• Hospitalisation is unambiguously the major driver of loss of self care capacities and institutional placement in the elderly
• Although 80% of Aged Care Assessments are done in the community 2/3 of people who enter NH do so from hospital
Acceleration of cognitive decline in dementia by delirium
Gross AL. Arch Int Med 2012 172: 1324.
Delirium ↑ cognitive dysfunction in the popn. Davis DHJ. Brain 2012; 135: 2809-16.
Adjusted analysis Quinlan N. JAGS 2011; 59: S301
Odds of dementia after delirium Davis DHJ. Brain 2012;
So…
• That’s why delirium is a medical emergency in hospital
• In nursing home it may not be due to a confluence of late stage dementia and delirium
Delirium v. dementia
• So, if delirium causes cognitive and functional impairment…
• What causes dementia? Well, we know amyloid plaques and neurofibrillary tangles cause dementia…
Mod-severe diffuse plaques in neocortex
Community neuropath study. Lancet 2001; 357: 169-75
Mod-severe tangles in hippocampus Community neuropath study Lancet 2001; 357: 169
Dementia and brain cell numbers Andrade-Moraes CH. Brain 2013; 136: 3738-52.
Implication
• Loss of cognitive and self-care functions indicates neuronal loss
• But CT scan and MRI scans generally demonstrate no evidence of infarcts
• Need to postulate some mechanism of diffuse neuronal loss
Inflammatory hypothesis of delirium
IL-1β + IL-6
• Phagocytosis, microglial proliferation
• Weaken blood brain barrier
Cunningham C. Biol Psych 2009; 65: 304.
Spatial learning in a Y-maze Cunningham C. Biol Psych 2009; 65: 304.
Acute effects on motor tasks of LPS
Cunningham C. Biol Psych 2009; 65: 304.
.
Stained for IL-1β
Multiplex CSF analysis (pg/μL) Delirium
(N=22) Dementia
Mean (SD) Mean (SD) *P value
Il1B 7.6 (1.7) 7.5 (0) 1.00 IL10 0.68 (0.35) 0.45 (0.12) .002 IFNalpha 13.5 (4.6) 12.5 (0) .347 IL6 30.6 (1)07.2) 3.6 (5.0) .027 IL12 4.2 (4.3) 5.9 (6.7) .312 RANTES 129.5 (66.0) 130.6 (169.4) .045 Eotaxin 2.5 (0) 2.5 (0) 1.000 IL13 5.8 (8.9) 3.5 (0.9) .171 IL15 11.9 (1.9) 12.3 (0.7) .736 IL17 10 (0) 10 (0) No diff IL2R 20 (0) 20 (0) No diff MIP1alpha 8.1 (3.3) 7.3 (0.4) .419 GMCSF 2.5 (0) 2.5 (0) 1.000 MIP1beta 10.2 (7.1) 7.6 (6.9) .048 MCP1 975.8 (700.1) 742.2 (313.4) .313 IL5 2.5 (0) 2.5 (0) 1.000 IFNgamma 1 (0) 1 (0) No diff TNFalpha 2.6 (0.4) 2.5 (0) .347 IL1RA 15.2 (24.2) 10.0 (0) .347 IL2 9.8 (3.1) 8.8 (3.1) .311 IL7 12.5 (0) 12.5 (0) 1.000 MIG 27.3 (72.2) 17.8 (24.0) .936 IL4 2.5 (0) 2.5 (0) 1.000 IL8 864.0 (2165.2) 186.9 (95.1) .004 IP10 229.3 (222.9) 237.6 (170.4) .810 TNFR I 2243.1 (1329.9) 1422.7 (601.5) .014 TNFR II 2657.6 (1888.9) 2001.6 (1080.1) .351 DR5 28.7 (45.2) 10.6 (13.4) .074
CSF Cytokines –Interleukin 10
p = 0.002 after bootstrapping
Inflammation Neuro
If there is a final common pathway
• We need to look in human subjects
• Need to exclude the noise of individual conditions by including multiple aetiologies
• Compared two groups with delirium – General Acute Geriatric Medicine
(Sydney)
28
15
10
209
inconsistent changes between delirium patients
no significant changes
262 total proteins quantified by iTRAQ
Proteomics: Pathway analysis (STRING v9.05) of proteins whose iTRAQ ratio is correlated with Mini Mental State Exam score. Proteins dysregulated in the Cerebrospinal Fluid of subjects with mild or moderate delirium relative to the mild AD control with no delirium.
Protein functional categories altered in delirium in iTRAQ study
Functional Category Overall change in protein expression level
Possible Physiological Relevance In Delirium?
Acute phase proteins upregulated Response to increased inflammation
Apolipoproteins downregulated Response to compromise of vascular system or debris clearance from neuronal damage
Immunoglobulins upregulated Increased inflammation
Signaling proteins upregulated
Vascular Function downregulated Compromised vascular system function
WHAT ABOUT METABOLISM?
p=0.005 P<0.001
CSF Protein CSF Glucose
Caplan GA. J Gerontol Med Sci 2010; 65A: 1130-6.
CSF Lactate Caplan GA. J Gerontol: Med Sci 2010; 65A: 1130.
Correlation Coefficient = 0.48; p = 0.043 Correlation Coefficient = 0.15; p = 0.52
Prognostic value of CSF Lactate in delirium
Caplan GA. J Gerontol: Med Sci 2010; 65A: 1130.
0
0.5
1
1.5
2
2.5
• Spillover from blood
• Demonstrated in Alzheimer’s dementia
• Most commonly by SPECT
Cerebral Blood Flow Velocity Caplan JAMDA 2014; 15: 355-60.
p < 0.05 v AD p < 0.01 v Delirium p < 0.001 v AI
DSD vs the rest on mean Flow Velocity
Sensitivity = 0.875 Specificity = 0.788 AUC = 0.884 p = 0.001
Delirium Post-delirium
PI 1.8 1.7 (p=.055)
Delirium severity + CBF Caplan JAMDA 2014; 15: 355-60.
R = -0.39; p = 0.009
T P value
CAM 7.832 <0.001
IQCODE 3.564 0.01
APACHE 0.171 0.013
• Confirms association of postop delirium and reduced cerebral blood flow
18F-FDG PET in Delirium
Number of Patients with Hypometabolism, n (%)
Any cortical region 13 (100%)
Global cortical Marked, diffuse: 7 (54%)
Frontal lobe Bilateral frontal: 6 (46%)
Parietal lobe Bilateral parietal: 5 (38%)
Temporal lobe Bilateral temporal: 3 (23%)
Occipital lobe Bilateral occipital: 1 (8%)
Subcortical regions Bilateral basal ganglia: 1 (8%)
Bilateral thalami: 1 (8%)
Representative Case 1
Normal Brain
(n=6)
Temporoparietal
cortex
Thalamus Bilateral increase (1)
Lower Metabolism Observed in More Severe Delirium
Notes: Spearman’s rho (ρ) used to assess correlations PCC: posterior cingulate cortex
Correlation with
Cerebral hypometabolism
Neuronal dysfunction
• But as Geriatricians we have an obligation to investigate
• Current work gives us possible alternative therapeutic targets
Disclosures
Acknowledgements
via ED, unwell, not himself. “Usually independent”
• O/E AMTS 6/10, GCS 14/15, RR 25, T 375 CXR – R basal consolidation, WCC 10.5, Creatinine 135, U/A – leucocytes, nitrites
• PDx – Comm. acq. pneumonia ± UTI
• Rx – IV fluids and Abs (Ceftriaxone)
Admitted under Resp Med
• First night on the ward: agitated, calling out for wife. S/B JMO, Rx Haloperidol 2.5mg “Day team to R/V”
• First day on the ward: “pleasantly confused”, “resting in bed”. Ward Drs: “Continue current Rx but add Roxithromycin, await culture results”
Second night • Play time!
• Calling out, climbing over bed rails, nursed in chair opposite nurses station, told to call if he wants to go to toilet
• Gets up to toilet alone and falls
• c/o pain in groin, unable to weight bear
• X-ray: #NOF
• Orthopaedics consulted
Second day
• 17:00 S/B Orthopaedics, booked for OT, Blood cultures – E. coli -> Anaesthetist: OT delayed
• ID consult: Infection covered, OK for OT
Third day
• 17:00 OT
punches nurse. Code Black. IV haloperidol + midazolam
AKI, small Troponin leak
• MMSE 12/30
• No. 1 Adverse Event for older people in hospital
• risk: falls, nursing home placement and death
• Despite 2,500 year history – no effective drugs
• No understanding of pathophysiology
Brain dysfunction
– Correct renal failure
– Replace hormone deficiencies
• Metabolic problem?
• Neurotransmitter imbalance?
• Stress response?
The concept of delirium • Since the late 19th century thought
to be due to transient alteration of cerebral metabolism
unspecified
• No difference in CSF ACh levels during delirium
• Resolution of delirium despite no change in Serum Anticholinergic Activity
• No benefit in delirium from AChEIs
Aberrant stress response, blood
Cereira J. J Geriatr Psychiatry Neurol 2013 Van Munster B. Brain Cognition 2010; 74:
P=0.04 on multivariate analysis
Cortisol in CSF Pearson A. BMC Research Notes 2010; 3:33.
P=0.029
But, what is the role of stress?
• In the context of delirium, is activation of stress response surprising?
• Association or causation?
• If delirium were due to a transient abnormality of metabolism, neurotransmitters, inflammation, one would expect complete recovery…
But.. (Sequelae of delirium)
• Follow up of delirium demonstrates • Increased mortality – up to 33% in hospital
– 2.11x higher mortality in the next 12 mths
• Increased LOS - 2x • 800% higher odds of dementia • More functional impairment • 3x more placement in nursing home • Worse outcomes if pre-existing dementia • Even after adjusting for severity of
medical illness and pre-existing dementia
Mortality after delirium McCusker J. Arch Int Med 2002; 162: 457.
How does this compare?
previous
dementia)
11.0%
On a population basis McCallum J. The continuum of care for older people. Aust Hlth
Rev 1995; 18: 40-54.
• Hospitalisation is unambiguously the major driver of loss of self care capacities and institutional placement in the elderly
• Although 80% of Aged Care Assessments are done in the community 2/3 of people who enter NH do so from hospital
Acceleration of cognitive decline in dementia by delirium
Gross AL. Arch Int Med 2012 172: 1324.
Delirium ↑ cognitive dysfunction in the popn. Davis DHJ. Brain 2012; 135: 2809-16.
Adjusted analysis Quinlan N. JAGS 2011; 59: S301
Odds of dementia after delirium Davis DHJ. Brain 2012;
So…
• That’s why delirium is a medical emergency in hospital
• In nursing home it may not be due to a confluence of late stage dementia and delirium
Delirium v. dementia
• So, if delirium causes cognitive and functional impairment…
• What causes dementia? Well, we know amyloid plaques and neurofibrillary tangles cause dementia…
Mod-severe diffuse plaques in neocortex
Community neuropath study. Lancet 2001; 357: 169-75
Mod-severe tangles in hippocampus Community neuropath study Lancet 2001; 357: 169
Dementia and brain cell numbers Andrade-Moraes CH. Brain 2013; 136: 3738-52.
Implication
• Loss of cognitive and self-care functions indicates neuronal loss
• But CT scan and MRI scans generally demonstrate no evidence of infarcts
• Need to postulate some mechanism of diffuse neuronal loss
Inflammatory hypothesis of delirium
IL-1β + IL-6
• Phagocytosis, microglial proliferation
• Weaken blood brain barrier
Cunningham C. Biol Psych 2009; 65: 304.
Spatial learning in a Y-maze Cunningham C. Biol Psych 2009; 65: 304.
Acute effects on motor tasks of LPS
Cunningham C. Biol Psych 2009; 65: 304.
.
Stained for IL-1β
Multiplex CSF analysis (pg/μL) Delirium
(N=22) Dementia
Mean (SD) Mean (SD) *P value
Il1B 7.6 (1.7) 7.5 (0) 1.00 IL10 0.68 (0.35) 0.45 (0.12) .002 IFNalpha 13.5 (4.6) 12.5 (0) .347 IL6 30.6 (1)07.2) 3.6 (5.0) .027 IL12 4.2 (4.3) 5.9 (6.7) .312 RANTES 129.5 (66.0) 130.6 (169.4) .045 Eotaxin 2.5 (0) 2.5 (0) 1.000 IL13 5.8 (8.9) 3.5 (0.9) .171 IL15 11.9 (1.9) 12.3 (0.7) .736 IL17 10 (0) 10 (0) No diff IL2R 20 (0) 20 (0) No diff MIP1alpha 8.1 (3.3) 7.3 (0.4) .419 GMCSF 2.5 (0) 2.5 (0) 1.000 MIP1beta 10.2 (7.1) 7.6 (6.9) .048 MCP1 975.8 (700.1) 742.2 (313.4) .313 IL5 2.5 (0) 2.5 (0) 1.000 IFNgamma 1 (0) 1 (0) No diff TNFalpha 2.6 (0.4) 2.5 (0) .347 IL1RA 15.2 (24.2) 10.0 (0) .347 IL2 9.8 (3.1) 8.8 (3.1) .311 IL7 12.5 (0) 12.5 (0) 1.000 MIG 27.3 (72.2) 17.8 (24.0) .936 IL4 2.5 (0) 2.5 (0) 1.000 IL8 864.0 (2165.2) 186.9 (95.1) .004 IP10 229.3 (222.9) 237.6 (170.4) .810 TNFR I 2243.1 (1329.9) 1422.7 (601.5) .014 TNFR II 2657.6 (1888.9) 2001.6 (1080.1) .351 DR5 28.7 (45.2) 10.6 (13.4) .074
CSF Cytokines –Interleukin 10
p = 0.002 after bootstrapping
Inflammation Neuro
If there is a final common pathway
• We need to look in human subjects
• Need to exclude the noise of individual conditions by including multiple aetiologies
• Compared two groups with delirium – General Acute Geriatric Medicine
(Sydney)
28
15
10
209
inconsistent changes between delirium patients
no significant changes
262 total proteins quantified by iTRAQ
Proteomics: Pathway analysis (STRING v9.05) of proteins whose iTRAQ ratio is correlated with Mini Mental State Exam score. Proteins dysregulated in the Cerebrospinal Fluid of subjects with mild or moderate delirium relative to the mild AD control with no delirium.
Protein functional categories altered in delirium in iTRAQ study
Functional Category Overall change in protein expression level
Possible Physiological Relevance In Delirium?
Acute phase proteins upregulated Response to increased inflammation
Apolipoproteins downregulated Response to compromise of vascular system or debris clearance from neuronal damage
Immunoglobulins upregulated Increased inflammation
Signaling proteins upregulated
Vascular Function downregulated Compromised vascular system function
WHAT ABOUT METABOLISM?
p=0.005 P<0.001
CSF Protein CSF Glucose
Caplan GA. J Gerontol Med Sci 2010; 65A: 1130-6.
CSF Lactate Caplan GA. J Gerontol: Med Sci 2010; 65A: 1130.
Correlation Coefficient = 0.48; p = 0.043 Correlation Coefficient = 0.15; p = 0.52
Prognostic value of CSF Lactate in delirium
Caplan GA. J Gerontol: Med Sci 2010; 65A: 1130.
0
0.5
1
1.5
2
2.5
• Spillover from blood
• Demonstrated in Alzheimer’s dementia
• Most commonly by SPECT
Cerebral Blood Flow Velocity Caplan JAMDA 2014; 15: 355-60.
p < 0.05 v AD p < 0.01 v Delirium p < 0.001 v AI
DSD vs the rest on mean Flow Velocity
Sensitivity = 0.875 Specificity = 0.788 AUC = 0.884 p = 0.001
Delirium Post-delirium
PI 1.8 1.7 (p=.055)
Delirium severity + CBF Caplan JAMDA 2014; 15: 355-60.
R = -0.39; p = 0.009
T P value
CAM 7.832 <0.001
IQCODE 3.564 0.01
APACHE 0.171 0.013
• Confirms association of postop delirium and reduced cerebral blood flow
18F-FDG PET in Delirium
Number of Patients with Hypometabolism, n (%)
Any cortical region 13 (100%)
Global cortical Marked, diffuse: 7 (54%)
Frontal lobe Bilateral frontal: 6 (46%)
Parietal lobe Bilateral parietal: 5 (38%)
Temporal lobe Bilateral temporal: 3 (23%)
Occipital lobe Bilateral occipital: 1 (8%)
Subcortical regions Bilateral basal ganglia: 1 (8%)
Bilateral thalami: 1 (8%)
Representative Case 1
Normal Brain
(n=6)
Temporoparietal
cortex
Thalamus Bilateral increase (1)
Lower Metabolism Observed in More Severe Delirium
Notes: Spearman’s rho (ρ) used to assess correlations PCC: posterior cingulate cortex
Correlation with
Cerebral hypometabolism
Neuronal dysfunction
• But as Geriatricians we have an obligation to investigate
• Current work gives us possible alternative therapeutic targets