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Post-operative cognitive dysfunction (POCD) occurs frequently after major surgery. Hypertension is well-established as a risk factor for age-related cognitive impairment, but it is unclear whether or not it also increases the risk of POCD.
To evaluate the role of hypertension in POCD risk in a systematic review and meta-analysis.
PubMed, Ovid SP and the Cochrane Database of Systematic Reviews were searched for longitudinal studies of adults undergoing surgery with reporting of hypertension, blood pressure and/or anti-hypertensive treatment associations with POCD as relative risks or odds ratios. Fixed-effects meta-analyses were performed using Review Manager (version 5.3).
Twenty-four studies on 4317 patients (mean age 63 years) were included. None of the studies had set out to assess hypertension as a risk factor for POCD. Hypertension was used as a categorical predictor throughout and only 2 studies adjusted for potential confounders. Across all 24 studies, hypertension was not significantly associated with POCD risk (RR 1.01; 95% CI 0.93, 1.09;
Our findings do not support the hypothesis that hypertension is a risk factor for POCD. However, since none of the studies included in our analysis were hypothesis-driven and most did not adjust for potential confounders, further systematic investigations are needed to evaluate the role of hypertension in the epidemiology of POCD.
Post-operative cognitive dysfunction (POCD) occurs frequently after major surgery [
The PubMed, Ovid SP and Cochrane Database of Systematic Reviews were searched from their respective inception to 25th April 2016. Titles and abstracts were searched for the following terms: (((blood pressure OR systolic OR diastolic OR antihypertens* OR hypertens*))) AND ((post-operative cognit* OR postoperative cognit* OR POCD) OR ((surgery OR operation) AND (cognit OR intelligence OR MMSE OR Mini Mental OR dementia OR Alzheim* OR mild cognitive impairment OR MCI))). All titles and abstracts of articles that remained following removal of duplicates were screened against inclusion criteria by one investigator (IF). If they were deemed to potentially match inclusion criteria or if they appeared to have data on both hypertension and POCD (
We included studies that fulfilled all of the following criteria: i) prospective study of any design ii) sample of human adults (≥18 years old) undergoing surgery iii) full text in English language iv) ascertainment of blood pressure, hypertension and/or antihypertensive treatment prior to surgery v) reporting of these exposure variables with risk of POCD as relative risks (RR) or odds ratios (both taken as RR for the purpose of the present analysis, as odds ratios and RR are close to identical in assessments of rare outcomes [
Any type of surgery, any definition of POCD and any length of follow-up qualified for inclusion. Use of the term ‘POCD’ was not required. Studies on post-operative delirium, on hypotension or on blood pressure during surgery or in the post-operative period were not considered. Corresponding authors were contacted for any essential unreported information unless previous contact had been unsuccessful. That way, unpublished data were obtained for one article [
For each article, RR statistics on the respective longest follow-up period were extracted. Preference was given to fully adjusted multivariate models unless no adjustment was made. Data were tabulated for separate meta-analysis of each predictor as appropriate.
For one study which compared patients who had “improved” versus “not improved” on cognitive tests, “not improved” was used to represent POCD for the purpose of the present analysis [
For two studies, the originally reported upper limits of the 95% confidence intervals of their estimates were implausible, and for the purpose of the present analysis were calculated on the basis of the respective lower limit [
Extracted statistical data were entered into Review Manager (version 5.3; the Cochrane Collaboration) to calculate summary estimates in inverse variance fixed-effects models. Statistical heterogeneity was indexed by I2 and publication bias was evaluated through visual inspection of funnel plots and Egger’s regression analysis [
Both cohort and trial studies were scored by one investigator (IF) on the 22-item STROBE checklist of cohort studies [
The search yielded N=200 articles in PubMed, N=115 articles in Ovid SP and N=2 articles in the Cochrane Database. Following removal of duplicates, N=299 articles remained for screening (Fig.
At this stage, 259 articles were excluded most commonly due to focusing on unrelated research topics including delirium, intra- or post-operative blood pressure or animal studies, or due to reporting of cognitive function as an exclusion criterion. Thus, full texts of 40 articles were accessed. Six articles qualified for inclusion of which 3 were excluded [
Author, year, location | Total N enrolled in study | N completed follow-up | Male | Type of surgery, anesthesia | Mean age ± SD or median (IQ) | Follow-up | Cognitive measurement | Definition/ incidence of POCD | Hypertension exposure | Adjustment variables | Original reporting of exposure association with POCD as descriptive data and/or RR (95% CI) | STROBE score |
---|---|---|---|---|---|---|---|---|---|---|---|---|
Kelly |
41 | 35 | 66% | Carotid end-arterectomy |
62 ± 8 | 4 to 8 weeks | 12 neuro-psychological tests |
“Not improved” used as POCD and compared with “improved” in present analysis. |
Hypertension not defined. |
None | 8/16 (50.0%) “improved” had hypertension. |
13/22 |
Smith |
381 | 319 | 81%b | CABG |
40% >65 yearsb | 1 month | 9 neuro-psychological tests | POCD defined as decline of ≥20% on ≥2 of tests. |
Hypertension not defined. |
None | RR 1.0 (0.58, 1.72) | 19/22 |
Di Carlo |
123 | 110 | 71% | CABG or intra-cardiac surgery |
64 ± 9 | 6 months | 4 neuro-psychological tests; MMSE. |
“Severe deterioration” used as POCD and compared with “unchanged” in present analysis. |
Hypertension not defined. |
Education, partial pressure of carbon dioxide (only significant predictors retained in final model along with hypertension) | RR 5.33 (1.03, 27.64) | 19/22 |
Suksompong |
110 | 110 | 76% | CABG |
62 ± 8 | 3 to 5 days | Thai Mental State Exam | POCD defined as decline of ≥1 SD on cognitive test. |
Hypertension not defined. |
None | RR 3.75 (1.10, 11.53) | 14/22 |
Swaminathan |
625 | 282 | 71% | CABG | 61 ± 10 | 6 weeks | 4 factors of cognitive domains derived from 7 neuro-psychological tests | POCD defined as decline of ≥1SD on any of the 4 cognitive domains. |
Hypertension not defined. |
None | 68/112 (60.7%)c with POCD have hypertension. |
19/22 |
Kadoi & Goto (2006) |
95 | 88 | 80% | CABG |
62 ± 11 | 6 months | 5 neuro-psychological tests; MMSE | Definition of POCD unclear. |
Hypertension not defined. |
None | RR 1.5 (0.9, 1.8) | 11/22 |
Bitsch |
100 | 96 | 29% | Hip fracture |
POCD group: 86 (77 – 85) |
7 days | MMSE |
“Major decline” used as POCD in present analysis. |
Hypertension not defined. |
None | 7/17 (41.2%) with “major decline” have hypertension. |
20/22 |
Baba |
218 | 218 | 70% | CABG |
71 ± 6 | 7 days | 4 neuro-psychological tests | POCD defined as decline of ≥20% on ≥ 3 tests. |
Hypertension defined as “history of hypertension with anti-hypertensive medication”. |
None. | 30/39 (76.9%) with POCD have hypertension. |
16/22 |
Koch |
24 | 22 | 41%b | Knee/hip replace-ment surgery |
74 ± 6b | 3 months | 11 neuro-psychological tests | POCD defined as decline of ≥20% on ≥2 tests. |
Hypertension not defined. |
None | 8/10 (80.0%) with POCD have hypertension. |
14/22 |
Mathew |
677 | 513 | 71% | CABG |
61 ± 10 | 6 weeks | 4 factors of cognitive domains derived from 5 neuropsychological tests | POCD defined as ≥1 SD change on ≥1 of the 4 factor scores. |
Hypertension not defined. |
None | 113/183 (61.8%) with POCD have hypertension. |
19/22 |
Hong |
103 | 100 | 38% | Valvular heart surgery |
53 ± 11 | 7 days | MMSE, TMT-A, Grooved Pegboard |
POCD defined as impairment on ≥1 of 3 tests. |
Hypertension not defined. |
None | 1/23 (4.3%) with POCD have hypertension. |
17/22 |
Wilson |
22d | 21d | 76% | Carotid end-arterectomy |
69 ± 8 | 1 day | 5 neuro-psychological tests. |
POCD defined as total deficit score ≥2 SD mean change in total deficit score of control group. |
Hypertension defined |
None | 21/33 (63.6%) with POCD have hypertensiond. |
16/22 |
Slater |
265 | 240 | 84% | CABG |
65 ± 10 | 3 months | 5 neuro-psychological tests; MMSE | POCD defined as ≥1 SD decline on ≥1 tests. |
Hypertension not defined. |
None | 116/143 (81.1%) with POCD have hypertension. |
20/22 |
Dieleman |
281 | 240 | 73% | CABG |
61 ± 9 | 5 years | 10 neuro-psychological tests. |
POCD defined as composite RCI ≤ -1.96 and/or RCI ≤--1.96 in ≥2 tests, or diagnosis of dementia or stroke during follow-up. |
Hypertension not defined. |
None | 23/82 (28.0%) with POCD have hypertension. |
17/22 |
Norkiene |
127 | 127 | 81% | CABG |
60 ± 7 | 7 to 9 days | 6 neuro-psychological tests; MMSE | POCD defined as ≥1 SD decline on ≥2 tests. |
Hypertension not defined. |
None | 61/68 (89.7%) with POCD have hypertension. |
15/22 |
Kadoi |
129 | 124 | 80% | CABG |
61 ± 5 | 7 days | 5 neuro-psychological tests; MMSE | POCD defined as decline of ≥1 SD on ≥2 of 6 tests. |
Hypertension not defined. |
Age, carbon dioxide reactivity, jugular venous oxygen saturation, diabetic retinopathy, insulin therapy | RR 1.4 (1.0, 1.8) | 13/22 |
Medi |
120 | 120 | 72% | Radio- |
56 ± 10 | 3 months | 8 neuro-psychological tests to calculate RCIa. RCI summed across tests and divided by SD of RCI sum of controls to obtain composite RCI. |
POCD defined as RCI <-1.96 on ≥2 tests and/or composite RCI <-1.96. |
Hypertension not defined. |
None | RR 0.5 (0.18, 1.6) | 15/22 |
Plaschke |
139 | 117 | 76% | CABG |
69 ± 8 | 3 months | 6 neuro-psychological tests with 12 outcome variables used to calculate RCIa. |
POCD defined as RCI ≥1.96 on ≥2 tests and/or composite RCI ≥1.96. |
Hypertension not defined. |
None | 30/30 (100.0%) with POCD had hypertension. |
19/22 |
Xu |
182 | 176 | 53% | Non-coronary bypass surgery (cardiac and non-cardiac surgery) |
42 ± 19 | 3 to 5 days | MMSE. |
POCD defined as RCI≥1. |
Hypertension not defined. |
None | 6/58 (10.3%) with POCD have hypertension. |
14/22 |
Fontes |
281 | 229 | 69% | CABG, valve or CABG + valve |
67 ± 10 | 1 year | 4 factors of cognitive domains derived from 5 neuro-psychological tests. |
“No cognitive recovery” used as POCD in present analysis. |
Hypertension not defined. |
None | 69/103 (67.0%) with “cognitive recovery” have hypertension. |
18/22 |
Joudi |
171 | 171 | Unreported. | Off-pump CABG |
64 ± 10 | 1 day | MMSE | Unclear definition of POCD. |
Hypertension not defined. |
None | 80/129 (61.9%) with POCD have hypertension. |
13/22 |
Zhu |
313 | 205 | 51% | Total hip replacement surgery |
75 ± 6 | 7 days | MMSE | POCD defined as ≥1 SD decline on MMSE. |
Hypertension not defined. |
None | 29/56 (51.8%) with POCD have hypertension. |
15/22 |
Heyer |
662 | 585 | 65% | Carotid end- |
34.4% ≥75 years old | 1 day | Unclear number of neuro-psychological tests of 4 cognitive domains. |
POCD defined as ≥2 SD worse performance on ≥2 cognitive domains and/or ≥1.5 SD worse performance on all 4 cognitive domains. |
Hypertension not defined. |
None | 84/145 (57.9%) with POCD have hypertension. |
17/22 |
Shoair |
69 | 69 | 33% | Noncardiac surgery. |
71 ± 5 | 3 months | 5 neuro-psychological tests |
POCD defined RCI <1.96 on ≥2 tests and/or composite RCI <1.96. |
Hypertension defined by combination of self-report and verification on basis of medical records. |
None | 5/11 (45.5%) with POCD have hypertension. |
19/22 |
Publication dates spanned 1980 to 2015 and studies originated in Europe, North America, Asia and Australia (Table
All articles were on hypertension rather than systolic or diastolic blood pressures as linear measures. In the majority of studies (n=21), we found no information on how hypertension was defined or assessed. In 1 study, it was defined as systolic blood pressure >140 mmHg or use of anti-hypertensive treatment [
All included studies were on hypertension and so were entered into a single meta-analysis (Fig.
Results of subgroup analyses are summarized in Fig. (
Several studies strictly failed to meet inclusion criteria but may supplement our analyses. Five studies were on hypertension and POCD but were excluded due to lack of statistical detail [
Here, we set out to combine the current epidemiological evidence on associations of pre-surgery hypertension, blood pressure and anti-hypertensive treatment with risk of post-operative cognitive dysfunction (POCD). All included articles were on hypertension and overall, we found little evidence of an association with POCD. However, all studies were of exploratory nature, and only 2 studies adjusted for potential confounders and, therefore, our meta-analysis does not rule out a (potentially causal) relationship. In subgroup analyses, we also found that among studies with proportion of males >75%, hypertension statistically significantly increased the risk of POCD by 27%. The finding warrants confirmation but may support hypertension as a contributing factor to POCD risk in a sub-set of patients.
There is a great deal of interest in hypertension as a cognitive risk factor due to high prevalence in the general [
A number of candidate contributors to reports of blood pressure links with cognitive risk [
None of these explanations could reasonably account for reports of associations of hypertension with age-related cognitive impairment [
We are unable to determine this on the basis of our results. From a clinical perspective, our findings indicate that hypertension at the time of presenting for surgery provides little information on the cognitive risk of a patient. However, the exploratory nature of the studies included here has to be considered. None set out to assess hypertension and risk of POCD. Only 2 of 24 included studies applied statistical adjustment, and these 2 built large statistical models without any pre-specified hypotheses. Thus, our finding should be seen as preliminary pending evaluation in further epidemiological studies targeted at the research question. With sex as a potential risk modifier, male and female samples would ideally be investigated separately. Blood pressure readings and use of anti-hypertensive medication (leading to normalization of blood pressure) should also be considered separately and studies should attempt to capture samples that include hypertensive and hypertension-free patients at equal proportion. The role of cognitive reserve, which predicts both late-life hypertension [
A number of limitations must be considered. POCD definition was heterogeneous across studies and definitions of hypertension were generally lacked. Thus, we are unable to tease out the influence of blood pressure versus anti-hypertensive treatment on POCD risk. Statistical analyses in the primary studies were rarely adjusted for potential confounders. For sex in particular, the present analysis indicated that hypertension associations with POCD may be limited to samples that include a large proportion of males. Therefore, an influence of confounding by factors such as sex on our pooled estimates is likely. We performed several statistical tests in stratified analyses, which introduced risk of type I error; thus, these subgroup results are to be interpreted cautiously.
We conclude that current research studies do not support the hypothesis that hypertension is a risk factor for POCD; however, these studies had not set out to investigate the risk associated with hypertension and rarely considered potential confounding factors in their analyses. Adequately designed studies are urgently needed to elucidate the definitive role of hypertension in the epidemiology of POCD.
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No Animals/Humans were used for studies that are base of this research.
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The authors confirm that this article content has no conflict of interest.
Declared none.