Table 1.
Summary of studies: Pre-operative serum tests
| Author, Year, Country | Study design | n | Cut-off age | Type of surgery | Included patients with dementia or cognitive impairment | Multivariate regression analysis performed | Pre-operative tests | POD assessment, Days post-surgery assessment | POD- mean age, % female | No POD – mean age, % female | Conclusion | Pre-op Test Predictive of POD |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Biomarkers | ||||||||||||
| Capri, 2014, Italy [8] | PC | 74 (37 w/ POD, 37 w/o POD) | > 65 | Any elective and emergency surgery, excluding cardiac | No | Yes | Plasma cytokine concentrations (TNF-a, IL-1b, IL-2, IL-6, IL-8, and IL-10) | CAM and DRS, D1,2,3 and 6 | 79.2 yr., 45.9% | 76.4 yr., 54% | High serum IL-6 (> 9 pg/mL) independently predicts POD. OR 4.9, [1.6–14.63; P < 0.0005]. |
Yes |
| Westhoff, 2013, Netherlands [9] | PC | 61 | > 75 | Emergency hip fracture | Yes | MA logistic regression analysis not performed but no significant correlation was found between age, cognitive function and levels of CSF cytokines. | 42 CSF and serum cytokines and chemokines | CAM, DRS-R- 98, D1–5 | 82.9 yr., 69.9% | 84.6 yr., 68.4% | Pre-op CSF Fms-like tyrosine kinase-3, IL-1r antagonist and IL-6. Pre-op serum IL-6 was significantly higher in patients with POD. Median levels in POD vs .no POD: 48.13 vs 23.16, P = 0.021. | Yes |
| Dillon, 2017, Israel and UK [10] | PC | 566, Sub cohort from SAGE | > 70, Pooled cohort (combined match pairs) | Elective major non-cardiac | No | Conditional logistic regression and sensitivity analysis performed. | Serum CRP | CAM and validated chart review, POD = D1–2 | 77.6 yr., 56% | 77.2 yr., 56% | Elevated pre-op CRP associated with POD (pre-op median paired difference with controlled subjects of 1.97 mg/L, P = 0.02). | Yes |
| Neerland, 2016, Norway & UK [11] | PC | 151 Oslo 99, Edinburgh 52 | > 60 | Emergency hip fracture | Yes | No | Serum and CSF CRP, IL-6 and soluble IL-6 receptor | CAM O: D1–5, E: D1–4, 7, 10,14 |
85 yr., 70% | 83 yr., 80% | Significantly high CSF levels of CRP in POD vs. no-POD, median 0.05mcg/mL vs. 0.01mcg/mL | Yes |
| Vasunilashorn, 2017, USA [12] | PC | 560 (sub cohort from SAGE) POD = 25% of participants |
> 70 | Major non-cardiac surgery | No | No | Serum CRP | CAM, D1 until discharge | 77.7 + − 5.0 yr., 60% | 76.5 + − 5.2 yr., 58% | Subjects with pre-op CRP of ≥3 mg/L had a 1.5 greater risk of delirium than subjects with CRP; 4 more delirium days (P < 0.001) and 1.4 times greater risk of prolonged LOS. | Yes |
| Xiang, 2017, China [13] | PC | 160 POD = 39(24.4%) |
> 65 | Laparoscopic surgery for colon carcinoma | No | Yes | Serum CRP | CAM-ICU D1–3 and 7 | 72.2 + − 5.8 yr., 41% |
69.4 + − 7.1 yr., 39.7% |
Pre-op CRP level: independent predictor of POD. POD vs. no POD CRP levels; 3.8 vs. 2.4 mg/L (OR: 5.87; 95% CI 2.22–11.4, P = 0.018). | Yes |
| Bohner, 2003, Germany [38] | PC | 153 | N/S | Elective Vascular surgery | No | No. Only Univariate analysis performed. | Pre-op: CRP, White cell count, platelets, LFTs, Creatinine, Urea, coagulation, Intra-op: BP, BG, glucose | DSM IV criteria, DRS > 12, D1–7 |
63.7 + − 10.3 yr., | 68.3 + − 8.5 yr., | Pre-op CRP significantly higher in POD vs. no POD; 3.4 vs. 1.7 mg/dL, P = 0.03. AT III (98% vs. 106%, p = 0.02), lower Hb 13.7 vs. 14.3 g/dL, P = 0.02). | Yes |
| Lemstra, 2008, Netherlands [14] | PC | 68 | > 70 | Elective hip replacement | Yes | No. Patients were matched for age, severe illness and MMSE score < 24 using a statistical analysis. | Serum CRP, IL-6, IGF-1 | CAM and DSM-IV daily | 80 yr., 55.6% | 78.5 yr., 74% | No difference between POD vs. no POD levels: CRP = 5.3 vs. 3 mgL− 1, P = 0.523; IL-6 = 3.6 vs. 3.0 pgmL− 1, P = 0.121; IGF-1 = 14.4 vs. 12.9 nmolL − 1, P = 0.675. | No |
| Shen, 2016, China [15] | PC | 140 | > 65 | Elective open GI tumour resection | No | Yes | Serum IGF-1 | CAM, DRS-R98. D2,3 | 73.8 yr., 52.8% | 68.8 yr., 58.7% | Significantly low serum IGF-1 (POD vs. no-POD, 50.4 vs. 67 ng/mL), OR 2.52 (1.19–5.43). | Yes. Cut-off level 52.94 ng/ml, sensitivity of 80.8%, specificity of 80.6%. |
| Yen, 2016, USA [37] | PC | 98 | > 65 | Elective knee replacement | No | Yes | Serum IGF-1 | DSM-IV, DRS-R98 | 72.5 yr., 59% | 73.7 yr., 50% | No association. Median levels in POD vs. no POD = 62.6 vs. 65.9 ng/mL, P = 0.141. | No |
| Cerejeira, 2011, Portugal [16] | PC | 101 | > 60 | Elective total hip replacement | No | No | Plasma AChE and BuChE activity | CAM, D1,2,3 | 73.7 yr., 60% | 72.7 yr., 46% | AChE and BuChE 24 and 32% lower in patients with vs. without POD, respectively. Pre-operative differences between the two groups were controlled. | Yes |
| Cerejeira, 2012, Portugal [17] | PC | 101 | > 60 | Elective total hip replacement | No | No | Plasma AChE and BuChE and inflammatory mediator levels (CRP, IL-1b, and TNF-a) | CAM, D1,2,3 | 73.6 yr., 60% | 72.7 yr., 45.3% | Low baseline plasma cholinesterase activity associated with POD and positively correlates with high CRP, IL-6 and Pro-inflammatory/ Anti-inflammatory ratio. | Yes |
| Chen, 2014, China [18] | PC | 186 | > 65 | Emergency hip fracture | No | Yes | Plasma leptin | CAM, D1,2,3,7 and 1 month | 80.1 yr., 72% | 74.7 yr., 77% | Plasma leptin level is significantly lower in POD vs. no-POD, 4 vs. 7.5 ngmL− 1, P < 0.001). Hypoleptinaemia is an independent predictor of POD [OR 0.385, CI 0.28–0.517]. | Yes. Sensitivity 72.2%, Specificity 91.7% |
| Cunningham, 2017, UK [19] | PC | 315 | > 65 | Elective hip or knee replacement | No | Yes | Serum ApoE4 allele carriage and neuropsychological tests | CAM, D1,2,3 | 76.9 yr., 65% | 74 yr., 27.1% | ApoE4 genotype is not associated with POD. | No |
| Leung, 2007, USA [20] | PC | 190 | > 65 | Elective major non-cardiac | No | Yes | Serum apolipoprotein (APOE) genotype | CAM, D1–2 | 74.2 yr., NR | 72.3 yr., NR | Presence of at least one copy of APOE e4 allele is associated with increased risk of POD that persists 2 days post-op. (OR 3.64, 95% CI 1.51–8.77). |
Yes |
| Vasunilashorn, 2015, USA [21] | PC | 557 | > 70 | Any Elective major non-cardiac | No | Sensitivity analyses performed to test if dementia has any influence on association between ApoE and POD. | Serum Apolipoprotein E: e2, e4 carrier vs non-carrier and three category ApoE genotypes (e3e3, e3e4, e4e4, e2e2, e3e2) | CAM and validated chart review daily | ApoE genotype has no association with incidence, severity or duration of POD, RR for E4 = 1.0, CI 0.7–1. | No | ||
| Torbergsen, 2015, Norway & Scotland [22] | PC | 115 | NR | Emergency hip fracture | No | Yes | Serum vitamin levels (Vitamin A, B1, B6, vitamin B12, Folic acid, vitamin C, D, K) | CAM, D1–5 | 84.8 yr., 71% | 80.6 yr., 79% | Vitamin D deficiency (< 50 nmol/L) was independent predictor of POD. (Mean Vitamin D in POD vs. no-POD, 41 vs. 52 nmolL−1, P = 0.05). | Yes |
| Scholtens, 2017, Netherlands [23] | PC | 144 | > 65 | Emergency hip fracture | No | No | Morning plasma melatonin | CAM | 85.5 yr., 75% | 82.5 yr., 69% | Morning melatonin not associated with POD (p = 0.35) | No |
| Scholtens, 2016, Netherlands [7] | PC | 60 | > 65 | Emergency hip fracture | Yes | No but confounders (age and cognitive impairment) analysed and did not show any difference in CSF melatonin levels. | CSF melatonin | Delirium Observation Screening Scale, and DSM-IV, NS | 86.4 yr., 83.3% | 83.4 yr., 66% | Pre-operative CSF melatonin did not differ between POD and no-POD groups. No MA performed | No |
| Wyrobek, 2017, USA [24] | PC | 77 | > 70 | Major Spine surgery Median age = 75 years, 47% were female |
No | Yes | Intra-op serum brain derived neurotrophic factor (BDNF) | CAM, D1–4 CAM-ICU Validated chart review |
NR | NR | Subjects with POD vs no. without POD had a greater percentage of BDNF decline from baseline, median 75% (IQR 51–82) vs. 50% (IQR 14–79, P = 0.03). | Yes |
| Zhang, 2017, China [25] | PC | 700 111 (15.9%) |
> 65 | Elective non -cardiac surgery who were admitted to ICU | No | Yes | Pre-op serum albumin levels | CAM-ICU D1–7 | 76.2 + −7.8 yr., 47.7% | 74.0 + − 6.6 yr., 38% |
Pre-op severe hypoalbuminemia (< 30.0 g/L) was associated with increased risk of POD (OR 2.727, 95% CI 1.28–5.797, P = 0.009) . | Yes |
| Hall, 2016, Norway and Scotland [26] | PC | 139 (Oslo- 85, Edinburgh- 54) |
Oslo- > 60, Edin > 61 |
Emergency hip fracture | Yes | Yes | Serum and CSF neopterin. | CAM, D1–5 | 85 yr., 70% | 82 yr., 77% | Higher pre-op CSF neopterin in POD vs. no-POD. (Median 29.6 vs 24.7 nmolL− 1, P = 0.003). | Yes |
| Hov, 2016, Norway [27] | PC | 120 | NR | Emergency hip fracture | Yes | No | Serum and CSF albumin. q-albumin (ratio of CSF albumin to serum albumin) | CAM, D1–5 | 85 yr., 70% | 83 yr., 83% | CSF barrier dysfunction (q-albumin> 10.2). Significant difference in POD vs. no POD group, n = 11 (16% vs 0%, P = 0.022). | Yes |
| Watne, 2014, Norway [28] | PC | 151 Oslo = 99 Edin = 52 |
Oslo- NR, Edin > 60, 84. | Emergency hip fracture | No | Yes | Serum and CSF anticholinergic activity | CAM D1–5 | Oslo: 75% Edin: 60% |
Oslo 72%, Edin: 75% | Serum or CSF anticholinergic activity is not an important mechanism in POD. | No |
| Watne, 2016, Norway [29] | PC | 77 | > 70 | Emergency hip fracture | No | Yes | Serum and CSF monoamine precursors | CAM D1–5 | 86 yr., 70% | 84 yr., 61% | Higher CSF monoamine precursors (tryptophan, tyrosine, phenylalanine, methionine, 5-HIAA) in delirium patients suggests high monoaminergic activity in CNS during delirium. | Yes |
| Hov 2017, Norway [30] | PC | Hip fracture = 98 Elective surgery = 50 |
> 70 | Hip fracture and elective surgery (gynae, urology or orthopaedic | No | No | Serum and CSF S100B and phosphorylated tau (P-tau) concentration | CAM D1–5 | Prevalent delirium- 85 yr., 75%, Incident delirium- 88 yr., 56% | 84 yr., 78% | Significant difference in CSF S100B in patients with vs. without incident delirium (1.38 vs. 1.08 μgrams/L, P = 0.013). | Yes |
| Hall, 2013, Scotland [31] | PC | 45 | > 60 | Emergency hip fracture | Yes | No | Serum and CSF S100B | CAM and DRS-R98, D1–4,7,10–14 | 81.3 yr., 63% | 78.9 yr., 73% | No significant difference in log10 CSF S100B in POD vs no-POD during the 2-week period (mean: −0.239 vs −0.308 respectively; student’s t-test t = 1.25, df = 43, P = 0.218). | No |
| Westhoff, 2015, Netherlands [32] | PC | 53 | > 75, mean age 83.1, 67.9% | Emergency hip fracture | Yes | Yes | CSF proteins (low complement factor C3, fibulin-1, 1-beta-1,3 N-acetylglucosaminyl-transferase in POD, high neural cell adhesion molecule-2, fibrinogen, zinc-α-2-glycoproteinandhaptoglobin level in POD) | CAM, D1–5 | NR | NR | Discrepencies of results between proteomic ccohort and validation cohort. | No |
| Witlox, 2011, Netherlands [33] | PC | 76 | > 75 | Emergency hip fracture | Yes | Yes | CSF levels of senile plaques B amyloid and neurofibrillary tangles (Ptau) | CAM, D1–5 | 84.7 yr., 67% | 82.4 yr., 67% | CSF markers for plaque and tangle formation are not strongly associated with POD. | No |
PC Prospective cohort, n number, POD Post-operative delirium, TNF tumour necrosis factor, IL interleukin, CAM confusion assessment method, DRS delirium rating scale, D1 day 1, AChE acetylcholinesterase, BChE butylcholinesterase, CRP c-reactive protein, MMSE mini mental state examination, SAGE Successful Ageing after Elective Surgery, NR not recorded, AT III angiotensin III, Hb hemoglobin, 5-HIAA 5-hydroxyindoleacetic acid, GI gastrointestinal, CSF cerebral spinal fluid, CAM-S Confusion Assessment Method- Short Form, DSM-IV Diagnostic and Statistical Manual 4th, IGF Insulin Like Growth Factor, PACU post-anaesthesia care unit, GA general anaesthesia, ICU intensive care unit, GABA gamma amino butyric acid, Fms Fat Mobilising substance, OR odds ratio, CBF cerebral blood flow, MA multivariate analysis