Introduction
Methods
Literature search
Inclusion and exclusion criteria
Data extraction
Results
Trial identification
Biomarker | Study | Country | Medical specialty | ICU | Sample size | Assessment tool | Event rate (%) | Biomarker value | Main findings |
---|---|---|---|---|---|---|---|---|---|
Acetylcholine |
Larsen (2010)
| USA | S | 196a | DRS-R98 | 14.3 | L | Anticholinergic treatment (olanzapine) associated with significantly lower incidence of delirium | |
204 | DSM-III | 40.2 | |||||||
Adenylate kinase
| |||||||||
Albumin |
Zhang (2018)
| China | S | Yes | 700 | CAM-ICU | 15.9 | L | Preoperative severe hypoalbuminemia (≤ 30 g/L) was associated with increased risk of postoperative delirium |
Guo (2016) | China | S | 572 | CAM, DSM-IV | 21 | L | Older age, history of stroke, lower albumin, higher blood glucose, higher total bilirubin, higher CRP, longer surgery duration, and higher volume of red blood cell transfusions are independent risk factors for postoperative delirium | ||
Capri (2014) | Italy | S | 351 | CAM | 13.4 | ND | High preoperative IL-6 level is a risk factor for postoperative delirium | ||
Larsen (2010)
| USA | S | 196a | DRS-R98 | 14.3 | L | Anticholinergic treatment (olanzapine) associated with significantly lower incidence of delirium | ||
204 | DSM-III | 40.2 | |||||||
Lee (2010) | Korea | S | 81 | CAM | 13.6 | L | Albumin level before surgery significantly lower in patients developing postoperative delirium | ||
Amyloid β1-40 |
Sun (2016)
| China | S | 257 | CAM | 21.8 | H | Elevated levels of inflammatory cytokines, cortisol, and amyloid β1-40 after surgery under general anesthesia may be involved in the onset of postoperative delirium among elderly oral cancer patients | |
ASAT | Plaschke (2016) | Germany | M | 100 | NuDESC | 29 | L | Plasma ChEA (AChE and BChE) not associated with delirium | |
Guo (2016) | China | S | 572 | CAM, DSM-IV | 21 | ND | Older age, history of stroke, lower albumin, higher blood glucose, higher total bilirubin, higher CRP, longer surgery duration, and higher volume of red blood cell transfusions are independent risk factors for postoperative delirium | ||
BDNF |
Brum (2015)
| Brazil | M | 70 | CAM | NA | L | BDNF levels significantly lower in delirium in oncology inpatients | |
Cholecystokinin
| |||||||||
Cholinesterase |
Plaschke (2016)
| Germany | M | 100 | NuDESC | 29 | ND | Plasma ChEA (AChE and BChE) not associated with delirium | |
Cerejeira (2012)
| Portugal | S | 101 | CAM, DSM-IV | 36.6 | L | Delirium associated with dysfunctional interaction between cholinergic and immune systems | ||
Cortisol |
Sun (2016)
| China | S | 257 | CAM | 21.8 | H | Elevated levels of inflammatory cytokines, cortisol, and amyloid β1-40 after surgery under general anesthesia may be involved in the onset of postoperative delirium among elderly oral cancer patients | |
Creatine kinase
| |||||||||
Creatine kinase BB
| |||||||||
CREB
| |||||||||
CRP |
Slor (2019)
| The Netherlands | S | 121 | CAM, DRS-R98 | 33.1 | NDd | CRP level trajectory after hip surgery coincides with delirium from the second day after surgery | |
Miao (2018) | China | S | 112 | DSM-IV | 43.8 | H | Potential roles of neopterin in pathophysiology and prediction of delirium in elderly patients after open abdominal surgery | ||
Vasunilashorn (2018)
| USA | S | 560 | CAM | 24 | NA | The signature of postoperative delirium is dynamic, with some proteins important prior to surgery (risk markers: CRP and AZGP1) and others during delirium (disease markers: IL-2, IL-6, and CRP). CRP, AZGP1, and SERPINA3 were identified as top set of delirium-related proteins | ||
Cizginer (2017)
| USA | S | 556 | CAM | 24 | ND | Vocabulary knowledge, cognitive activities, and education significantly modified association of CRP and postoperative delirium | ||
Vasunilashorn (2017)
| USA | S | 560 | CAM, Chart Review | 24 | H | High preoperative and postoperative day 2 CRP are independently associated with incidence of delirium | ||
Egberts (2017) | The Netherlands | M | 86 | DSM-IV | 15.1 | H | No significant difference of CRP level among delirious and non-delirious patients | ||
Plaschke (2016) | Germany | M | 100 | NuDESC | 29 | H | Plasma ChEA (AChE and BChE) is not associated with delirium | ||
Nguyen (2016)
| Belgium | M + S | Yes | 101 | CAM-ICU | 78 | ND | High prolactin levels possible risk factor for delirium in septic patients | |
Sun (2016)
| China | S | 257 | CAM | 21.8 | H | Elevated levels of inflammatory cytokines, cortisol, and amyloid β1-40 after surgery under general anesthesia may be involved in the onset of postoperative delirium among elderly oral cancer patients | ||
Ritchie (2014)
| UK | M | 710 | CAM | 12.3 | H | Association between elevated CRP and delirium | ||
Guo (2016) | China | S | 572 | CAM, DSM-IV | 21 | H | Older age, history of stroke, lower albumin, higher blood glucose, higher total bilirubin, higher CRP, longer surgery duration, and higher volume of red blood cell transfusions are independent risk factors for postoperative delirium | ||
Cerejeira (2012) | Portugal | S | 101 | CAM, DSM-IV | 36.6 | H | Delirium is associated with unbalanced inflammatory response | ||
Lee (2011)
| Korea | S | 65 | K-DRS-98 | 28 | H | CRP levels within 24 and 72 h after hospitalization are significantly higher in patients with delirium | ||
Beloosesky (2004)
| Israel | S | 32 | CAM | 31.3 | H | CRP kinetics over 30 days after hip surgery is significantly associated with delirium and cardiovascular complications | ||
Dopamine
| |||||||||
Histamine H1
| |||||||||
Heat Shock Protein 70
| |||||||||
IL-2 |
Capri (2014)
| Italy | S | 351 | CAM | 13.4 | ND | High preoperative IL-6 level is a risk factor for postoperative delirium | |
Vasunilashorn (2018)
| USA | S | 560 | CAM | 24 | NA | The signature of postoperative delirium is dynamic, with some proteins important prior to surgery (risk markers: CRP and AZGP1) and others at the time of delirium (disease markers: IL-2, IL-6, and CRP). CRP, AZGP1, and SERPINA3 were identified as top set of delirium-related proteins | ||
IL-6 | Gao (2018) | China | S | Yes | 64 | CAM-ICU | 15.6 | NA | TEAS can alleviate POD in older patients with silent lacunar infarction and may be related to reduced neuroinflammation by lowering BBB permeability |
Miao (2018) | China | S | 112 | DSM-IV | 43.8 | H | Potential roles of neopterin in pathophysiology and prediction of delirium in elderly patients after open abdominal surgery | ||
Vasunilashorn (2018)
| USA | S | 560 | CAM | 24 | NA | The signature of postoperative delirium is dynamic, with some proteins important prior to surgery (risk markers: CRP and AZGP1) and others at the time of delirium (disease markers: IL-2, IL-6, and CRP). CRP, AZGP1, and SERPINA3 were identified as top set of delirium-related proteins | ||
Kuswardhani (2017)
| Indonesia | M | 60 | MDAS | NA | NA | CACI score, IL-6 levels, and sepsis have a strong relationship with delirium severity | ||
Xin (2017)
| China | S | 60c | NuDESC | 11.7 | ND | TNF-α significantly associated with postoperative delirium | ||
60 | 38.3 | ||||||||
Sun (2016)
| China | S | 257 | CAM | 21.8 | H | Elevated levels of inflammatory cytokines, cortisol, and amyloid β1-40 after surgery under general anesthesia may be involved in the onset of postoperative delirium among elderly oral cancer patients | ||
Capri (2014)
| Italy | S | 351 | CAM | 13.4 | H | High preoperative IL-6 level is a risk factor for postoperative delirium | ||
Jia (2014)
| China | S | 117b | DRS-R98 | 3.4 | H | The lower incidence of delirium is at least partly attributable to the reduced systemic inflammatory response mediated by IL-6 | ||
116 | 12.9 | ||||||||
Cerejeira (2012) | Portugal | S | 101 | CAM, DSM-IV | 36.6 | H | Delirium is associated with unbalanced inflammatory response | ||
van Munster (2011)
| The Netherlands | M + S | 870 | CAM | 35.7 | NA | Functional genetic variations in the IL-6, IL-6R, and IL-8 genes are not associated with delirium | ||
van Munster (2008)
| The Netherlands | S | 98 | CAM, DOS, DRS-R98 | NA | H | Patients with hyperactive or mixed subtype of delirium had significantly higher IL-6 levels than patients with hypoactive delirium. IL-6 and IL-8 may contribute to pathogenesis of postoperative delirium | ||
IL-8 |
Xin (2017)
| China | S | 60c | NuDESC | 11.7 | ND | TNF-α significantly associated with postoperative delirium | |
60 | 38.3 | ||||||||
Capri (2014)
| Italy | S | 351 | CAM | 13.4 | ND | High preoperative IL-6 level is a risk factor for postoperative delirium | ||
Cerejeira (2012) | Portugal | S | 101 | CAM, DSM-IV | 36.6 | H | Delirium is associated with unbalanced inflammatory response | ||
van Munster (2011)
| The Netherlands | M + S | 870 | CAM | 35.7 | NA | Functional genetic variations in the IL-6, IL-6R, and IL-8 genes are not associated with delirium | ||
van Munster (2008)
| The Netherlands | S | 98 | CAM, DOS, DRS-R98 | NA | H | IL-6 and IL-8 may contribute to pathogenesis of postoperative delirium | ||
IL-18 | |||||||||
Lactate dehydrogenase
| |||||||||
Leptin |
Chen (2014)
| China | S | 186 | CAM | 37.6 | L | Preoperative plasma leptin level may be a useful, complementary tool to predict delirium in general and prolonged delirium in elderly patients after hip surgery | |
Sanchez (2013)
| Colombia | M + S | 115 | CAM, DSM-IV | 23.5 | L | Leptin levels could be a useful clinical biomarker to establish risk in elderly patients | ||
Neopterin |
Egberts (2019)
| The Netherlands | S | Yes | 211 | CAM-ICU, DSM-IV | 38.4 | H | Acutely ill medical patients with delirium had higher levels of neopterin and higher phenylalanine/tyrosine ratios after elective cardiac surgery |
Miao (2018)
| China | S | 112 | DSM-IV | 43.8 | H | Potential roles of neopterin in pathophysiology and prediction of delirium in elderly patients after open abdominal surgery | ||
NSE
| |||||||||
PI3K
| |||||||||
Procalcitonin |
Sun (2016)
| China | S | 257 | CAM | 21.8 | H | Elevated levels of inflammatory cytokines, cortisol, and amyloid β1-40 after surgery under general anesthesia may be involved in the onset of postoperative delirium among elderly oral cancer patients | |
Protein C
| |||||||||
S-100β | Gao (2018) | China | S | Yes | 64 | CAM-ICU | 15.6 | NA | TEAS can alleviate POD in older patients with silent lacunar infarction and may be related to reduced neuroinflammation by lowering BBB permeability |
Xin (2017)
| China | S | 60c | NuDESC | 11.7 | ND | TNF-α is significantly associated with postoperative delirium | ||
60 | 38.3 | ||||||||
SDNF
| |||||||||
Thioredoxin |
Wu (2017)
| China | S | 192 | CAM | 36.5 | H | Thioredoxin in postoperative serum may be a potential biomarker to predict postoperative delirium and POCD in elderly patients | |
TNF-α | Gao (2018) | China | S | Yes | 64 | CAM-ICU | 15.6 | NA | TEAS can alleviate POD in older patients with silent lacunar infarction and may be related to reduced neuroinflammation by lowering BBB permeability |
Xin (2017)
| China | S | 60c | NuDESC | 11.7 | H | TNF-α is significantly associated with postoperative delirium | ||
60 | 38.3 | ||||||||
Brum (2015) | Brazil | M | 70 | CAM | NA | ND | No cross-sectional relationship of BDNF and TNF-α blood levels with delirium in oncology inpatients has been demonstrated | ||
Capri (2014)
| Italy | S | 351 | CAM | 13.4 | ND | High preoperative IL-6 level is a risk factor for postoperative delirium | ||
Cerejeira (2012) | Portugal | S | 101 | CAM, DSM-IV | 36.6 | ND | Delirium is associated with unbalanced inflammatory response (see CRP, IL-6, and IL-8) | ||
8-iso-prostaglandin F2α |
Zheng (2016)
| China | S | 182 | CAM | 37.4 | H | Postoperative plasma 8-iso-prostaglandin F2α levels may have the potential to predict postoperative delirium and POCD in elderly patients | |
Additional reported biomarkers resulting from literature search
| |||||||||
AZGP1 |
Vasunilashorn (2018)
| USA | S | 560 | CAM | 24 | L | The signature of postoperative delirium is dynamic, with some proteins important prior to surgery (risk markers: CRP and AZGP1) and others at the time of delirium (disease markers: IL-2, IL-6, and CRP). CRP, AZGP1, and SERPINA3 were identified as top set of delirium-related proteins | |
BUN | Miao (2018) | China | S | 112 | DSM-IV | 43.8 | ND | Potential roles of neopterin in pathophysiology and prediction of delirium in elderly patients after open abdominal surgery | |
Kuswardhani (2017)
| Indonesia | M | 60 | MDAS | NA | NA | BUN only has a weak role in delirium severity in elderly patients with infection | ||
Creatinine | Miao (2018) | China | S | 112 | DSM-IV | 43.8 | ND | Potential roles of neopterin in pathophysiology and prediction of delirium in elderly patients after open abdominal surgery | |
Bakker (2012) | The Netherlands | S | Yes | 201 | CAM-ICU | 31.3 | H | Creatinine level is one of the three independent risk factors for delirium after cardiac surgery | |
ILGF-1 | Miao (2018) | China | S | 112 | DSM-IV | 43.8 | L | Potential roles of neopterin in pathophysiology and prediction of delirium in elderly patients after open abdominal surgery | |
IL-1β |
Xin (2017)
| China | S | 60c | NuDESC | 11.7 | ND | TNF-α significantly associated with postoperative delirium | |
60 | NuDESC | 38.3 | ND | ||||||
Capri (2014)
| Italy | S | 351 | CAM | 13.4 | ND | High preoperative IL-6 level is a risk factor for postoperative delirium | ||
Cerejeira (2012) | Portugal | S | 101 | CAM, DSM-IV | 36.6 | ND | Delirium is associated with unbalanced inflammatory response (see CRP, IL-6, and IL-8) | ||
IL-12 |
van Munster (2008)
| The Netherlands | S | 98 | CAM, DOS, DRS-R98 | NA | ND | IL-6 and IL-8 may contribute to the pathogenesis of postoperative delirium | |
ILGF-1 |
Chu (2016)
| China | S | 103 | CAM, DSM-IV | 22.3 | ND | No association found between preoperative ILGF-1 levels and postoperative delirium | |
MMP-9 | Gao (2018) | China | S | Yes | 64 | CAM-ICU | 15.6 | NA | TEAS can alleviate POD in older patients with silent lacunar infarction and may be related to reduced neuroinflammation by lowering BBB permeability |
NLR |
Egberts (2017)
| The Netherlands | M | 86 | DSM-IV | 15.1 | H | NLR levels are significantly increased in patients with delirium | |
Prolactin |
Nguyen (2016)
| Belgium | M + S | Yes | 101 | CAM-ICU | 78 | H | High prolactin levels are a possible risk factor for delirium in septic patients |
Phenylalanine–tyrosine ratio |
Egberts (2019)
| The Netherlands | S | Yes | 211 | CAM-ICU, DSM-IV | 38.4 | H | Acutely ill medical patients with delirium had higher levels of neopterin and higher phenylalanine–tyrosine ratios after elective cardiac surgery |
SERPINA3 |
Vasunilashorn (2018)
| USA | S | 560 | CAM | 24 | H | The signature of postoperative delirium is dynamic, with some proteins important prior to surgery (risk markers: CRP and AZGP1) and others at the time of delirium (disease markers: IL-2, IL-6, and CRP). CRP, AZGP1, and SERPINA3 were identified as top set of delirium-related proteins |
Study characteristics
Biomarkers
Function | Assigned biomarker | Established clinical use |
---|---|---|
Cytokine | IL-1β | Inflammatory marker |
IL-2 | ||
IL-6 | ||
IL-8 | ||
IL-12 | ||
IL-18 | ||
TNF-α | ||
Enzyme | Adenylate kinase | Marker of liver cell damage |
ASAT | Marker of cell damage | |
Cholinesterase | Marker of liver synthetic function | |
CK | Marker of muscle damage | |
CK-BB | Tumor marker | |
LDH | Marker of tissue breakdown | |
NSE | Tumor marker; brain damage marker | |
PI3K | ||
Growth factor | BDNF | Diagnosis of growth hormone deficiency; marker of pituitary function |
IGF-1 | ||
Hormone | Cholecystokinin | |
Cortisol | Marker of adrenal function | |
Leptin | ||
Prolactin | Marker of pituitary gland/hypothalamus function; fertility assessment; tumor marker | |
Metabolic product | Amyloid | |
Phenylalanine–tyrosine ratio | ||
Neuronotrophic factor | S-100β | Tumor marker; brain damage marker |
SDNF | ||
Neurotransmitter | Acetylcholine | |
Dopamine | ||
Histamine | ||
Transcription factor | CREB | |
Transport protein | Albumin | Nutritional marker, negative acute phase protein |
Other | AZGP1 | |
BUN | Marker of kidney function | |
Creatinine | Marker of kidney function | |
CRP | Inflammatory marker, positive acute phase protein | |
HSP70 | ||
Metalloproteinase-9 | Proinflammatory marker | |
Neopterin | Marker of infection | |
NLR | ||
Procalcitonin | Proinflammatory marker | |
Protein C | ||
Thioredoxin | ||
8-iso-prostaglandin F2α |
Function | Assigned biomarker | Biomarker of delirium | Clinically useful |
---|---|---|---|
Cytokine | IL-1β | – | – |
IL-2 | ? | – | |
IL-6 | + | – | |
IL-8 | ? | – | |
IL-12 | – | ||
IL-18 | NR | – | |
TNF-α | ? | – | |
Enzyme | Adenylate kinase | NR | – |
ASAT | ? | – | |
Cholinesterase | ? | – | |
CK | NR | – | |
CK-BB | NR | – | |
LDH | NR | – | |
NSE | NR | – | |
PI3K | NR | – | |
Growth factor | BDNF | + | – |
ILGF-1 | + | – | |
Hormone | Cholecystokinin | NR | – |
Cortisol | + | – | |
Leptin | + | – | |
Prolactin | + | – | |
Metabolic product | Amyloid | + | ? |
Phenylalanine–tyrosine ratio | + | ? | |
Neuronotrophic factor | S-100β | – | – |
SDNF | NR | – | |
Neurotransmitter | Acetylcholine | + | – |
Dopamine | NR | – | |
Histamine | NR | – | |
Transcription factor | CREB | NR | – |
Transport protein | Albumin | + | ? |
Other | AZGP1 | + | – |
BUN | ? | – | |
Creatinine | + | ? | |
CRP | + | + | |
HSP70 | NR | – | |
Metalloproteinase-9 | + | ? | |
Neopterin | + | ? | |
NLR | + | ? | |
Procalcitonin | + | ? | |
Protein C | NR | – | |
Thioredoxin | + | – | |
SERPINA3 | + | – | |
8-iso-prostaglandin F2α | + | – |