Clinical Practice & Epidemiology in Mental Health


ISSN: 1745-0179 ― Volume 13, 2017

Hypertension and Risk of Post-Operative Cognitive Dysfunction (POCD): A Systematic Review and Meta-Analysis



I. Feinkohl1, *, G. Winterer2, T. Pischon1, 2, 3
1 Molecular Epidemiology Research Group, Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
2 Charité – Universitaetsmedizin Berlin, Berlin, Germany
3 MDC/BIH Biobank, Max-Delbrueck-Center for Molecular Medicine in the Helmholtz Association (MDC), and Berlin Institute of Health (BIH), Berlin, Germany

Abstract

Background:

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.

Objective:

To evaluate the role of hypertension in POCD risk in a systematic review and meta-analysis.

Method:

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).

Results:

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; p=0.82), though among 8 studies with >75% males, we found hypertension associations with a 27% increased risk of POCD (RR 1.27, 95% CI 1.07, 1.49; p=0.005).

Conclusion:

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.

Keywords: Cognitive epidemiology, Blood pressure, Hypertension, Post-operative cognitive dysfunction, POCD, Meta-Analysis.


Article Information


Identifiers and Pagination:

Year: 2017
Volume: 13
First Page: 27
Last Page: 42
Publisher Id: CPEMH-13-27
DOI: 10.2174/1745017901713010027

Article History:

Received Date: 10/10/2016
Revision Received Date: 27/01/2017
Acceptance Date: 31/01/2017
Electronic publication date: 18/05/2017
Collection year: 2017

© 2017 Feinkohl et al.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: https://creativecommons.org/licenses/by/4.0/legalcode. This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


* Address correspondence to this author at the Max-Delbrueck-Center for Molecular Medicine (MDC), Robert-Roessle-Str. 10, D-13092 Berlin, Germany; Tel: 0049 30 9406-4595; E-mail: insa.feinkohl@mdc-berlin.de




INTRODUCTION

Post-operative cognitive dysfunction (POCD) occurs frequently after major surgery [1Evered LA, Silbert B, Scott DA. The impact of peri-operative period on cognition in older individuals. J Pharm Practice Res 2015; 45: 93-9.
[http://dx.doi.org/10.1002/jppr.1069]
]. It is broadly defined as an impairment of a patient’s cognitive functioning relative to their pre-surgery cognitive status [2Rundshagen I. Postoperative cognitive dysfunction. Dtsch Arztebl Int 2014; 111(8): 119-25.
[PMID: 24622758]
]. POCD is considered transient [2Rundshagen I. Postoperative cognitive dysfunction. Dtsch Arztebl Int 2014; 111(8): 119-25.
[PMID: 24622758]
] but may remain detectable for months and years after surgery [3Androsova G, Krause R, Winterer G, Schneider R. Biomarkers of postoperative delirium and cognitive dysfunction. Front Aging Neurosci 2015; 7: 112.
[http://dx.doi.org/10.3389/fnagi.2015.00112] [PMID: 26106326]
]. In patients with persistent POCD, it is known to negatively impact on everyday life tasks [4Ahlgren E, Lundqvist A, Nordlund A, Aren C, Rutberg H. Neurocognitive impairment and driving performance after coronary artery bypass surgery. Eur J Cardiothorac Surg 2003; 23(3): 334-40.
[http://dx.doi.org/10.1016/s1010-7940(02)00807-2] [PMID: 12614803]
], quality of life [5Funder KS, Steinmetz J, Rasmussen LS. Cognitive dysfunction after cardiovascular surgery. Minerva Anestesiol 2009; 75(5): 329-32.
[PMID: 19412153]
], subjective memory performance [6Plaschke K, Hauth S, Jansen C, et al. The influence of preoperative serum anticholinergic activity and other risk factors for the development of postoperative cognitive dysfunction after cardiac surgery. J Thorac Cardiovasc Surg 2013; 145(3): 805-11.
[http://dx.doi.org/10.1016/j.jtcvs.2012.07.043] [PMID: 22935445]
], emotional symptoms [7Gallo LC, Malek MJ, Gilbertson AD, Moore JL. Perceived cognitive function and emotional distress following coronary artery bypass surgery. J Behav Med 2005; 28(5): 433-42.
[http://dx.doi.org/10.1007/s10865-005-9010-y] [PMID: 16179981]
], and may predict more severe health consequences such as dementia and premature mortality [2Rundshagen I. Postoperative cognitive dysfunction. Dtsch Arztebl Int 2014; 111(8): 119-25.
[PMID: 24622758]
, 8Monk TG, Weldon BC, Garvan CW, et al. Predictors of cognitive dysfunction after major noncardiac surgery. Anesthesiology 2008; 108(1): 18-30.
[http://dx.doi.org/10.1097/01.anes.0000296071.19434.1e] [PMID: 18156878]
, 9Heyer EJ, Mergeche JL, Wang S, Gaudet JG, Connolly ES. Impact of cognitive dysfunction on survival in patients with and without statin use following carotid endarterectomy. Neurosurgery 2015; 77(6): 880-7.
[http://dx.doi.org/10.1227/NEU.0000000000000904] [PMID: 26308635]
]. Both the prevalence of hypertension and the likelihood of major surgery increase with advanced age [10Sarki AM, Nduka CU, Stranges S, Kandala NB, Uthman OA. Prevalence of hypertension in low- and middle-income countries: A systematic review and meta-analysis. Medicine 2015; 94(50): e1959.-13Preston SD, Southall AR, Nel M, Das SK. Geriatric surgery is about disease, not age. J R Soc Med 2008; 101(8): 409-15.
[http://dx.doi.org/10.1258/jrsm.2008.080035] [PMID: 18687864]
]. Indeed, hypertension is extremely common across the Western world, with approximately 30% of adults affected in the US [14Gillespie CD, Hurvitz KA. Prevalence of hypertension and controlled hypertension - United States, 2007-2010. MMWR supplements 2013; 62(3): 144-8.], and it is a well-established risk factor for cognitive impairment in older ages [15Van den Berg E, Kloppenborg RP, Kessels RPC, Kappelle LJ, Biessels GJ. Type 2 diabetes mellitus, hypertension, dyslipidemia and obesity: A systematic comparison of their impact on cognition. Biochimicia et Biophysica Acta 2009; 1792: 470-81.]. Yet, it is entirely unclear, whether or not patients with hypertension are also at increased risk of POCD. A role of hypertension as a risk factor for POCD is plausible on the basis that it increases the risk of post-operative delirium (POD) [16Zaal IJ, Devlin JW, Peelen LM, Slooter AJ. A systematic review of risk factors for delirium in the ICU. Crit Care Med 2015; 43(1): 40-7.
[http://dx.doi.org/10.1097/CCM.0000000000000625] [PMID: 25251759]
], which itself is strongly linked to POCD. Further, as part of the metabolic syndrome, hypertension often occurs in people with diabetes or obesity [17Alberti KG, Eckel RH, Grundy SM, et al. Harmonizing the metabolic syndrome: A joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 2009; 120(16): 1640-5.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.109.192644] [PMID: 19805654]
], which both have recently been identified as potential risk factors for POCD [18Feinkohl I, Winterer G, Pischon T. Obesity and post-operative cognitive dysfunction: a systematic review and meta-analysis. Diabetes Metab Res Rev 2016; 32(6): 643-51.
[http://dx.doi.org/10.1002/dmrr.2786] [PMID: 26890984]
, 19Feinkohl I, Winterer G, Pischon T. Diabetes, glycemia and risk of post-operative cognitive dysfunction: A meta-analysis. Diabetes Metab Res Rev 2017. [Epub ahead of print].
[http://dx.doi.org/10.1002/dmrr.2884] [PMID: 28063267]
], and it is common in surgical patients [6Plaschke K, Hauth S, Jansen C, et al. The influence of preoperative serum anticholinergic activity and other risk factors for the development of postoperative cognitive dysfunction after cardiac surgery. J Thorac Cardiovasc Surg 2013; 145(3): 805-11.
[http://dx.doi.org/10.1016/j.jtcvs.2012.07.043] [PMID: 22935445]
, 20Escobar L, Escobar R, Cordero-Ampuero J. Previous medical problems in 326 consecutive hip fracture patients. Hip Int 2006; 16(1): 57-61.
[PMID: 19219779]
]. Hypertension is potentially modifiable by using relatively cost-effective measures, including modification of diet and lifestyle or drug-treatment [21He J, Bazzano LA. Effects of lifestyle modification on treatment and prevention of hypertension. Curr Opin Nephrol Hypertens 2000; 9(3): 267-71.
[http://dx.doi.org/10.1097/00041552-200005000-00010] [PMID: 10847328]
]. Therefore, any association of hypertension with risk of POCD would have far-reaching implications for risk assessment in surgical patients and – potentially – for prevention of POCD. The objective of our study was therefore to conduct a systematic review and meta-analysis on epidemiological studies of hypertension, blood pressure and anti-hypertensive treatment prior to surgery and risk of POCD.

MATERIALS AND METHODS

Systematic Search Strategy

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 (e.g., adjusted analyses of POCD for hypertension), full texts were accessed. Reference lists of any review articles identified in the search and of included studies were screened for further original articles that also entered the full text review stage. The search adhered to MOOSE [22Stroup DF, Berlin JA, Morton SC, et al. Meta-analysis of observational studies in epidemiology: A proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA 2000; 283(15): 2008-12.
[http://dx.doi.org/10.1001/jama.283.15.2008] [PMID: 10789670]
] and PRISMA [23Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. PLoS Med 2009; 6(7): e1000097.
[http://dx.doi.org/10.1371/journal.pmed.1000097] [PMID: 19621072]
] guidelines, and was registered on the PROSPERO database (Registration No. CRD42016038236).

Study Selection

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 [24Davies HT, Crombie IK, Tavakoli M. When can odds ratios mislead? BMJ 1998; 316(7136): 989-91.
[http://dx.doi.org/10.1136/bmj.316.7136.989] [PMID: 9550961]
]) or in a form that allowed calculation of RR.

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 [25Shoair OA, Grasso Ii MP, Lahaye LA, Daniel R, Biddle CJ, Slattum PW. Incidence and risk factors for postoperative cognitive dysfunction in older adults undergoing major noncardiac surgery: A prospective study. J Anaesthesiol Clin Pharmacol 2015; 31(1): 30-6.
[http://dx.doi.org/10.4103/0970-9185.150530] [PMID: 25788770]
]. If an article lacking essential unreported information was suspected of duplicate reporting of another article that provided sufficient detail, the latter was selected for inclusion.

Data Extraction

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 [26Kelly MP, Garron DC, Javid H. Carotid artery disease, carotid endarterectomy, and behavior. Arch Neurol 1980; 37(12): 743-8.
[http://dx.doi.org/10.1001/archneur.1980.00500610023002] [PMID: 7447761]
]. For another that assessed three levels of cognitive change, “severe deterioration” was considered as POCD and contrasted with “no deterioration” and “mild deterioration” [27Di Carlo A, Perna AM, Pantoni L, et al. Clinically relevant cognitive impairment after cardiac surgery: A 6-month follow-up study. J Neurol Sci 2001; 188(1-2): 85-93.
[http://dx.doi.org/10.1016/S0022-510X(01)00554-8] [PMID: 11489290]
]. Another study compared various levels of cognitive impairment and we equated “major decline” with POCD [28Bitsch MS, Foss NB, Kristensen BB, Kehlet H. Acute cognitive dysfunction after hip fracture: Frequency and risk factors in an optimized, multimodal, rehabilitation program. Acta Anaesthesiol Scand 2006; 50(4): 428-36.
[http://dx.doi.org/10.1111/j.1399-6576.2005.00899.x] [PMID: 16548854]
]. Finally, one study assessed improvement in cognitive function after 1 year in a sample of patients who all were classified to suffer from POCD at 6-week follow-up [6Plaschke K, Hauth S, Jansen C, et al. The influence of preoperative serum anticholinergic activity and other risk factors for the development of postoperative cognitive dysfunction after cardiac surgery. J Thorac Cardiovasc Surg 2013; 145(3): 805-11.
[http://dx.doi.org/10.1016/j.jtcvs.2012.07.043] [PMID: 22935445]
]. “No improvement” was taken to represent POCD for that study. We included one study in which baseline cognitive assessment was performed after rather than prior to surgery in a small proportion (18%) of patients [28Bitsch MS, Foss NB, Kristensen BB, Kehlet H. Acute cognitive dysfunction after hip fracture: Frequency and risk factors in an optimized, multimodal, rehabilitation program. Acta Anaesthesiol Scand 2006; 50(4): 428-36.
[http://dx.doi.org/10.1111/j.1399-6576.2005.00899.x] [PMID: 16548854]
].

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 [29Suksompong S, Prakanratrana U, Chumpathong S, Sriyoschati S, Pornvilawan S. Neuropsychological alterations after coronary artery bypass graft surgery. J Med Assoc Thai 2002; 85(Suppl 3): S910-6.
[PMID: 12452229]
, 30Kadoi Y, Goto F. Factors associated with postoperative cognitive dysfunction in patients undergoing cardiac surgery. Surg Today 2006; 36(12): 1053-7.
[http://dx.doi.org/10.1007/s00595-006-3316-4] [PMID: 17123132]
].

Data Synthesis

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 [31Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997; 315(7109): 629-34.
[http://dx.doi.org/10.1136/bmj.315.7109.629] [PMID: 9310563]
]. Multiple fixed-effects meta-regression analyses explored differences between subgroups of studies. Specifically, studies were compared according to follow-up period (≤1 month versus >1 month), sample size (≤100 versus >100), mean sample age (≤65 years versus >65 years), surgery type (cardiac; non-cardiac; mixed surgery type) and sex (≤75% males versus >75% males). All cut-points for subgroup analyses were selected a priori to obtain around equally sized groups of studies without any pre-specified hypotheses. For example, for “sex”, the cut-point was selected on the basis that studies of POCD are often skewed toward inclusion of a greater proportion of males, because many studies focus on cardiac surgery which is more common in males than females [32Bo S, Gentile L, Cavallo-Perin P, Vineis P, Ghia V. Sex and BMI-related differences in risk factors for coronary artery disease in patients with type 2 diabetes mellitus. Acta Diabetol 1999; 36(3): 147-53.
[http://dx.doi.org/10.1007/s005920050158] [PMID: 10664319]
]. We therefore expected a cut-point at 75% males to result in two around equally sized groups of studies. Meta-regression was performed using SAS Enterprise Guide (version 4.3).

Quality Assessment

Both cohort and trial studies were scored by one investigator (IF) on the 22-item STROBE checklist of cohort studies [33STROBE checklist for cohort studies, Version 4. Bern: University of Bern 2007.], as all analyses on hypertension and POCD were observational in essence. No exclusion was applied based on STROBE scores.

RESULTS

Study Characteristics

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. 1).

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 [34Kadoi Y, Saito S, Fujita N, Goto F. Risk factors for cognitive dysfunction after coronary artery bypass graft surgery in patients with type 2 diabetes. J Thorac Cardiovasc Surg 2005; 129(3): 576-83.
[http://dx.doi.org/10.1016/j.jtcvs.2004.07.012] [PMID: 15746741]
-36Heyer EJ, Mergeche JL, Anastasian ZH, Kim M, Mallon KA, Connolly ES. Arterial blood pressure management during carotid endarterectomy and early cognitive dysfunction. Neurosurgery 2014; 74(3): 245-51.
[http://dx.doi.org/10.1227/NEU.0000000000000256] [PMID: 24335822]
] due to suspected duplicate reporting of other articles with more complete reporting [9Heyer EJ, Mergeche JL, Wang S, Gaudet JG, Connolly ES. Impact of cognitive dysfunction on survival in patients with and without statin use following carotid endarterectomy. Neurosurgery 2015; 77(6): 880-7.
[http://dx.doi.org/10.1227/NEU.0000000000000904] [PMID: 26308635]
, 30Kadoi Y, Goto F. Factors associated with postoperative cognitive dysfunction in patients undergoing cardiac surgery. Surg Today 2006; 36(12): 1053-7.
[http://dx.doi.org/10.1007/s00595-006-3316-4] [PMID: 17123132]
, 37Kadoi Y, Kawauchi C, Kuroda M, et al. Association between cerebrovascular carbon dioxide reactivity and postoperative short-term and long-term cognitive dysfunction in patients with diabetes mellitus. J Anesth 2011; 25(5): 641-7.
[http://dx.doi.org/10.1007/s00540-011-1182-8] [PMID: 21681532]
]. Twelve articles that addressed the research question were excluded due to failing to formally meet inclusion criteria but were considered qualitatively in sensitivity analyses. One article on cognitive symptoms following shunt surgery in hydrocephalus was excluded despite formally meeting inclusion criteria due to the neurosurgical nature of the surgery [38Kazui H, Mori E, Ohkawa S, et al. Predictors of the disappearance of triad symptoms in patients with idiopathic normal pressure hydrocephalus after shunt surgery. J Neurol Sci 2013; 328(1-2): 64-9.
[http://dx.doi.org/10.1016/j.jns.2013.02.020] [PMID: 23510566]
]. Screening of reference lists and an independent search identified 22 further relevant studies of which 21 met inclusion criteria. Overall, 24 articles were included [6Plaschke K, Hauth S, Jansen C, et al. The influence of preoperative serum anticholinergic activity and other risk factors for the development of postoperative cognitive dysfunction after cardiac surgery. J Thorac Cardiovasc Surg 2013; 145(3): 805-11.
[http://dx.doi.org/10.1016/j.jtcvs.2012.07.043] [PMID: 22935445]
, 9Heyer EJ, Mergeche JL, Wang S, Gaudet JG, Connolly ES. Impact of cognitive dysfunction on survival in patients with and without statin use following carotid endarterectomy. Neurosurgery 2015; 77(6): 880-7.
[http://dx.doi.org/10.1227/NEU.0000000000000904] [PMID: 26308635]
, 25Shoair OA, Grasso Ii MP, Lahaye LA, Daniel R, Biddle CJ, Slattum PW. Incidence and risk factors for postoperative cognitive dysfunction in older adults undergoing major noncardiac surgery: A prospective study. J Anaesthesiol Clin Pharmacol 2015; 31(1): 30-6.
[http://dx.doi.org/10.4103/0970-9185.150530] [PMID: 25788770]
-30Kadoi Y, Goto F. Factors associated with postoperative cognitive dysfunction in patients undergoing cardiac surgery. Surg Today 2006; 36(12): 1053-7.
[http://dx.doi.org/10.1007/s00595-006-3316-4] [PMID: 17123132]
, 37Kadoi Y, Kawauchi C, Kuroda M, et al. Association between cerebrovascular carbon dioxide reactivity and postoperative short-term and long-term cognitive dysfunction in patients with diabetes mellitus. J Anesth 2011; 25(5): 641-7.
[http://dx.doi.org/10.1007/s00540-011-1182-8] [PMID: 21681532]
, 39Smith MH, Wagenknecht LE, Legault C, et al. Age and other risk factors for neuropsychologic decline in patients undergoing coronary artery bypass graft surgery. J Cardiothorac Vasc Anesth 2000; 14(4): 428-32.
[http://dx.doi.org/10.1053/jcan.2000.7941] [PMID: 10972610]
-53Zhu S-H, Ji M-H, Gao D-P, Li W-Y, Yang J-J. Association between perioperative blood transfusion and early postoperative cognitive dysfunction in aged patients following total hip replacement surgery. Ups J Med Sci 2014; 119(3): 262-7.
[http://dx.doi.org/10.3109/03009734.2013.873502] [PMID: 24345210]
].

Fig. (1)
Flow chart of systematic search.


Table 1
Summary of included studies.


Publication dates spanned 1980 to 2015 and studies originated in Europe, North America, Asia and Australia (Table 1). Analysis samples included a total of 4317 patients. Sample characteristics and study designs were heterogeneous. Mean age (where reported) ranged from 42 to 75 years (mean 63 ± 7 years). Samples included between 29% and 81% males (where reported) though 19 of 24 studies included more males than females. Patients were followed up for between 1 day and 5 years after surgery (median 36 days, interquartile range 7 to 90 days). Procedures included cardiac (N=16), non-cardiac (N=7) and mixed (N=1) types of surgery.

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 [41Wilson DA, Mocco J, DAmbrosio AL, et al. Post-carotid endarterectomy neurocognitive decline is associated with cerebral blood flow asymmetry on post-operative magnetic resonance perfusion brain scans. Neurol Res 2008; 30(3): 302-6.
[http://dx.doi.org/10.1179/016164107X230540] [PMID: 17803842]
], and in another as use of anti-hypertensive medication though it is unclear whether or not blood pressure readings were additionally considered [49Baba T, Goto T, Maekawa K, Ito A, Yoshitake A, Koshiji T. Early neuropsychological dysfunction in elderly high-risk patients after on-pump and off-pump coronary bypass surgery. J Anesth 2007; 21(4): 452-8.
[http://dx.doi.org/10.1007/s00540-007-0538-6] [PMID: 18008111]
]. One study determined hypertension from self-report which was verified using medical records [25Shoair OA, Grasso Ii MP, Lahaye LA, Daniel R, Biddle CJ, Slattum PW. Incidence and risk factors for postoperative cognitive dysfunction in older adults undergoing major noncardiac surgery: A prospective study. J Anaesthesiol Clin Pharmacol 2015; 31(1): 30-6.
[http://dx.doi.org/10.4103/0970-9185.150530] [PMID: 25788770]
]. Among all 24 articles, only 2 explicitly referred to arterial hypertension [6Plaschke K, Hauth S, Jansen C, et al. The influence of preoperative serum anticholinergic activity and other risk factors for the development of postoperative cognitive dysfunction after cardiac surgery. J Thorac Cardiovasc Surg 2013; 145(3): 805-11.
[http://dx.doi.org/10.1016/j.jtcvs.2012.07.043] [PMID: 22935445]
, 47Norkienė I, Samalavičius R, Misiūrienė I, Paulauskienė K, Budrys V, Ivaškevičius J. Incidence and risk factors for early postoperative cognitive decline after coronary artery bypass grafting. Medicina (Kaunas) 2010; 46(7): 460-4.
[PMID: 20966618]
] but we assume that all evaluated arterial rather than other forms of hypertension. Where reported, hypertension was present in between 14% of patients in a study of relatively young Asian patients (mean age 42 years [50Xu T, Bo L, Wang J, et al. Risk factors for early postoperative cognitive dysfunction after non-coronary bypass surgery in Chinese population. J Cardiothorac Surg 2013; 8: 204.
[http://dx.doi.org/10.1186/1749-8090-8-204] [PMID: 24175992]
]) and 99% of patients in an older German sample (mean age 69 years [6Plaschke K, Hauth S, Jansen C, et al. The influence of preoperative serum anticholinergic activity and other risk factors for the development of postoperative cognitive dysfunction after cardiac surgery. J Thorac Cardiovasc Surg 2013; 145(3): 805-11.
[http://dx.doi.org/10.1016/j.jtcvs.2012.07.043] [PMID: 22935445]
]). The Mini Mental State Examination (or national equivalent) was administered in 5 studies [28Bitsch MS, Foss NB, Kristensen BB, Kehlet H. Acute cognitive dysfunction after hip fracture: Frequency and risk factors in an optimized, multimodal, rehabilitation program. Acta Anaesthesiol Scand 2006; 50(4): 428-36.
[http://dx.doi.org/10.1111/j.1399-6576.2005.00899.x] [PMID: 16548854]
, 29Suksompong S, Prakanratrana U, Chumpathong S, Sriyoschati S, Pornvilawan S. Neuropsychological alterations after coronary artery bypass graft surgery. J Med Assoc Thai 2002; 85(Suppl 3): S910-6.
[PMID: 12452229]
, 50Xu T, Bo L, Wang J, et al. Risk factors for early postoperative cognitive dysfunction after non-coronary bypass surgery in Chinese population. J Cardiothorac Surg 2013; 8: 204.
[http://dx.doi.org/10.1186/1749-8090-8-204] [PMID: 24175992]
, 52Joudi M, Fathi M, Harati H, et al. Evaluating the incidence of cognitive disorder following off-pump coronary artery bypasses surgery and its predisposing factors. Anesth Pain Med 2014; 4(4): e18545.
[http://dx.doi.org/10.5812/aapm.18545] [PMID: 25337473]
, 53Zhu S-H, Ji M-H, Gao D-P, Li W-Y, Yang J-J. Association between perioperative blood transfusion and early postoperative cognitive dysfunction in aged patients following total hip replacement surgery. Ups J Med Sci 2014; 119(3): 262-7.
[http://dx.doi.org/10.3109/03009734.2013.873502] [PMID: 24345210]
]; all other studies used more detailed neuropsychological tests. Definition of POCD varied. In 6 studies, it was based on cognitive change relative to a non-surgical control group. POCD occurred in between 9% [27Di Carlo A, Perna AM, Pantoni L, et al. Clinically relevant cognitive impairment after cardiac surgery: A 6-month follow-up study. J Neurol Sci 2001; 188(1-2): 85-93.
[http://dx.doi.org/10.1016/S0022-510X(01)00554-8] [PMID: 11489290]
] and 75% [52Joudi M, Fathi M, Harati H, et al. Evaluating the incidence of cognitive disorder following off-pump coronary artery bypasses surgery and its predisposing factors. Anesth Pain Med 2014; 4(4): e18545.
[http://dx.doi.org/10.5812/aapm.18545] [PMID: 25337473]
] of patients. Statistical analyses of hypertension associations with POCD risk were adjusted for sociodemographic and clinical covariates in only 2 of the 24 studies [27Di Carlo A, Perna AM, Pantoni L, et al. Clinically relevant cognitive impairment after cardiac surgery: A 6-month follow-up study. J Neurol Sci 2001; 188(1-2): 85-93.
[http://dx.doi.org/10.1016/S0022-510X(01)00554-8] [PMID: 11489290]
, 37Kadoi Y, Kawauchi C, Kuroda M, et al. Association between cerebrovascular carbon dioxide reactivity and postoperative short-term and long-term cognitive dysfunction in patients with diabetes mellitus. J Anesth 2011; 25(5): 641-7.
[http://dx.doi.org/10.1007/s00540-011-1182-8] [PMID: 21681532]
]; all of the remaining analyses reported unadjusted RR statistics or descriptive data that allowed calculation of univariate RR.

Findings of Included Studies and Meta-Analysis: Hypertension

All included studies were on hypertension and so were entered into a single meta-analysis (Fig. 2). Overall, there was no association between hypertension and risk of POCD (RR 1.01; 95% CI 0.93, 1.09; p=0.82). This risk estimate represents a largely unadjusted relationship of hypertension with POCD as only 2 studies applied statistical adjustment [27Di Carlo A, Perna AM, Pantoni L, et al. Clinically relevant cognitive impairment after cardiac surgery: A 6-month follow-up study. J Neurol Sci 2001; 188(1-2): 85-93.
[http://dx.doi.org/10.1016/S0022-510X(01)00554-8] [PMID: 11489290]
, 37Kadoi Y, Kawauchi C, Kuroda M, et al. Association between cerebrovascular carbon dioxide reactivity and postoperative short-term and long-term cognitive dysfunction in patients with diabetes mellitus. J Anesth 2011; 25(5): 641-7.
[http://dx.doi.org/10.1007/s00540-011-1182-8] [PMID: 21681532]
]. The finding was similar when the analysis was repeated using a random-effects model (RR 1.06; 95% CI 0.94, 1.19; p=0.34). Statistical heterogeneity between studies was low to moderate (chi2 (23)=35.68; p=0.04; I2=36%) with no evidence of publication bias (Fig. 3; Egger’s regression analysis, p=0.129).

Fig. (2)
Forest plot of meta-analysis on hypertension and POCD risk.


Fig. (3)
Funnel plot of meta-analysis on hypertension and POCD risk.


Subgroup Analyses and Meta-Regression: Hypertension

Results of subgroup analyses are summarized in Fig. (4). Associations of hypertension with risk of POCD were statistically non-significant in all subgroups of studies based on follow-up period (≤1 month, RR 0.94, 95% CI 0.85, 1.05; >1 month RR 1.09, 95% CI 0.97, 1.23; meta-regression p=0.099), sample size (≤100, RR 1.21, 95% CI 0.90, 1.63; >100, RR 0.99, 95% CI 0.92, 1.08; meta-regression p=0.216), mean sample age (≤65 years, RR 0.99, 95% CI 0.90, 1.09; >65 years, RR 1.09, 95% CI 0.90, 1.34; meta-regression p=0.387) and type of surgery (cardiac, RR 1.00, 95% CI 0.92, 1.09; non-cardiac RR 1.08, 95% CI 0.88, 1.32; mixed RR 0.70, 95% CI 0.34, 1.45; meta-regression p=0.303 to p=0.521). However, when analyses were restricted to 8 studies with >75% males, hypertension was overall associated with a 27% increased risk of POCD (RR 1.27, 95% CI 1.07, 1.49; p=0.005). Of these, a single study applied statistical adjustment for sociodemographic and clinical covariates [37Kadoi Y, Kawauchi C, Kuroda M, et al. Association between cerebrovascular carbon dioxide reactivity and postoperative short-term and long-term cognitive dysfunction in patients with diabetes mellitus. J Anesth 2011; 25(5): 641-7.
[http://dx.doi.org/10.1007/s00540-011-1182-8] [PMID: 21681532]
] so that the pooled estimate is largely unadjusted. Studies on ≤75% males revealed no association of hypertension with POCD (RR 1.03, 0.92, 1.15). The difference in risk estimates between these two groups of studies (≤75% males versus >75% males) approached statistical significance (meta-regression p=0.052; Fig. 4).

Fig. (4)
Analyses of subgroups of studies according to A) follow-up, B) sample size, C) mean sample age, D) surgery type and E) proportion of males, and F) overall pooled effects.
*data missing for N=3 studies.
**data missing for N=1 study.


Qualitative Summary of Relevant Excluded Studies

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 [8Monk TG, Weldon BC, Garvan CW, et al. Predictors of cognitive dysfunction after major noncardiac surgery. Anesthesiology 2008; 108(1): 18-30.
[http://dx.doi.org/10.1097/01.anes.0000296071.19434.1e] [PMID: 18156878]
, 54Stroobant N, van Nooten G, De Bacquer D, Van Belleghem Y, Vingerhoets G. Neuropsychological functioning 35 years after coronary artery bypass grafting: does the pump make a difference? Eur J Cardiothorac Surg 2008; 34(2): 396-401.
[http://dx.doi.org/10.1016/j.ejcts.2008.05.001] [PMID: 18524617]
-57Kotekar N, Kuruvilla CS, Murthy V. Post-operative cognitive dysfunction in the elderly: A prospective clinical study. Indian J Anaesth 2014; 58(3): 263-8.
[http://dx.doi.org/10.4103/0019-5049.135034] [PMID: 25024467]
]. Here, hypertension associations with POCD were described in narrative form only [54Stroobant N, van Nooten G, De Bacquer D, Van Belleghem Y, Vingerhoets G. Neuropsychological functioning 35 years after coronary artery bypass grafting: does the pump make a difference? Eur J Cardiothorac Surg 2008; 34(2): 396-401.
[http://dx.doi.org/10.1016/j.ejcts.2008.05.001] [PMID: 18524617]
-57Kotekar N, Kuruvilla CS, Murthy V. Post-operative cognitive dysfunction in the elderly: A prospective clinical study. Indian J Anaesth 2014; 58(3): 263-8.
[http://dx.doi.org/10.4103/0019-5049.135034] [PMID: 25024467]
], or descriptive data were insufficient to calculate RR [8Monk TG, Weldon BC, Garvan CW, et al. Predictors of cognitive dysfunction after major noncardiac surgery. Anesthesiology 2008; 108(1): 18-30.
[http://dx.doi.org/10.1097/01.anes.0000296071.19434.1e] [PMID: 18156878]
]. Of these studies, all except one [56Khan AH, Khilji SA. Neurological outcome after coronary artery bypass surgery. J Ayub Med Coll Abbottabad 2005; 17(1): 18-21.
[PMID: 15929520]
] found no association of hypertension with POCD. Other studies that failed to meet inclusion criteria on the basis of study design revealed more mixed evidence. In one imaging study, hypertension was unrelated to changes in the P300 component reflective of cognitive processing across surgery [58Kilo J, Czerny M, Gorlitzer M, et al. Cardiopulmonary bypass affects cognitive brain function after coronary artery bypass grafting. Ann Thorac Surg 2001; 72(6): 1926-32.
[http://dx.doi.org/10.1016/S0003-4975(01)03199-X] [PMID: 11789773]
]. An analysis of hospital records showed interaction effects of hypertension with exposure to surgery in prediction of dementia diagnosis [59Chen CW, Lin CC, Chen KB, Kuo YC, Li CY, Chung CJ. Increased risk of dementia in people with previous exposure to general anesthesia: A nationwide population-based case-control study. Alzheimers Dement 2014; 10(2): 196-204.
[http://dx.doi.org/10.1016/j.jalz.2013.05.1766] [PMID: 23896612]
]; another reported no such evidence [60Yu WK, Chen YT, Wang SJ, Kuo SC, Shia BC, Liu CJ. Cataract surgery is associated with a reduced risk of dementia: A nationwide population-based cohort study. Eur J Neurol 2015; 22(10): 1370-7.
[http://dx.doi.org/10.1111/ene.12561]
]. Three studies on continuous cognitive change reported null or marginal findings [61Yocum GT, Gaudet JG, Teverbaugh LA, et al. Neurocognitive performance in hypertensive patients after spine surgery. Anesthesiology 2009; 110(2): 254-61.
[PMID: 19194152]
, 62Pereira-Filho AA, Pereira AG, Pereira-Filho NA, et al. Long-term behavioral and cognitive outcomes following clipping for incidental unruptured intracranial aneurysms. Neuropsychology 2014; 28(1): 75-83.
[http://dx.doi.org/10.1037/neu0000010] [PMID: 24245927]
] or detrimental effects [63Tully PJ, Baker RA, Knight JL, Turnbull DA, Winefield HR. Neuropsychological function 5 years after cardiac surgery and the effect of psychological distress. Arch Clin Neuropsychol 2009; 24(8): 741-51.
[http://dx.doi.org/10.1093/arclin/acp082] [PMID: 19875394]
] of hypertension. Finally, one study that did not differentiate between POCD and POD reported a lower risk of these outcomes in patients with hypertension [64Wolman RL, Nussmeier NA, Aggarwal A, et al. Cerebral injury after cardiac surgery: identification of a group at extraordinary risk. Multicenter Study of Perioperative Ischemia Research Group (McSPI) and the Ischemia Research Education Foundation (IREF) Investigators. Stroke 1999; 30(3): 514-22.
[http://dx.doi.org/10.1161/01.STR.30.3.514] [PMID: 10066845]
].

DISCUSSION

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 [14Gillespie CD, Hurvitz KA. Prevalence of hypertension and controlled hypertension - United States, 2007-2010. MMWR supplements 2013; 62(3): 144-8.], older [11McDonald M, Hertz RP, Unger AN, Lustik MB. Prevalence, awareness, and management of hypertension, dyslipidemia, and diabetes among United States adults aged 65 and older. J Gerontol A Biol Sci Med Sci 2009; 64(2): 256-63.
[http://dx.doi.org/10.1093/gerona/gln016] [PMID: 19181717]
], and in surgical populations [6Plaschke K, Hauth S, Jansen C, et al. The influence of preoperative serum anticholinergic activity and other risk factors for the development of postoperative cognitive dysfunction after cardiac surgery. J Thorac Cardiovasc Surg 2013; 145(3): 805-11.
[http://dx.doi.org/10.1016/j.jtcvs.2012.07.043] [PMID: 22935445]
, 20Escobar L, Escobar R, Cordero-Ampuero J. Previous medical problems in 326 consecutive hip fracture patients. Hip Int 2006; 16(1): 57-61.
[PMID: 19219779]
], and because it is modifiable. Anti-hypertensive treatment has been linked to a reduced risk of age-related cognitive impairment [65Tully PJ, Hanon O, Cosh S, Tzourio C. Diuretic antihypertensive drugs and incident dementia risk: A systematic review, meta-analysis and meta-regression of prospective studies. J Hypertens 2016; 34(6): 1027-35.
[http://dx.doi.org/10.1097/HJH.0000000000000868] [PMID: 26886565]
], though a Cochrane review of randomized controlled trials – which help shed light on the issue of causality – found that the overall evidence on anti-hypertensive treatment and risk of cognitive impairment was inconclusive [66McGuinness B, Todd S, Passmore P, Bullock R. Blood pressure lowering in patients without prior cerebrovascular disease for prevention of cognitive impairment and dementia. Cochrane Database Syst Rev 2009; (4): Cd004034.
[http://dx.doi.org/10.1002/14651858.CD004034.pub3] [PMID: 19821318]
].

A number of candidate contributors to reports of blood pressure links with cognitive risk [15Van den Berg E, Kloppenborg RP, Kessels RPC, Kappelle LJ, Biessels GJ. Type 2 diabetes mellitus, hypertension, dyslipidemia and obesity: A systematic comparison of their impact on cognition. Biochimicia et Biophysica Acta 2009; 1792: 470-81., 67Sharp SI, Aarsland D, Day S, Sønnesyn H, Ballard C. Hypertension is a potential risk factor for vascular dementia: Systematic review. Int J Geriatr Psychiatry 2011; 26(7): 661-9.
[http://dx.doi.org/10.1002/gps.2572] [PMID: 21495075]
] have been identified and complex interplays among a range, or all, are likely. Fifty percent of patients with hypertension are affected by insulin resistance which impairs cognitive function directly for instance through alterations in cerebral blood flow, as well as indirectly through associated inflammatory response [68Craft S. The role of metabolic disorders in Alzheimer disease and vascular dementia: Two roads converged. Arch Neurol 2009; 66(3): 300-5.
[http://dx.doi.org/10.1001/archneurol.2009.27] [PMID: 19273747]
]. Disease of the cerebral vasculature as the basis of the increased risk of cognitive impairment seen in people with hypertension [69Dubow J, Fink ME. Impact of hypertension on stroke. Curr Atheroscler Rep 2011; 13(4): 298-305.
[http://dx.doi.org/10.1007/s11883-011-0187-y] [PMID: 21626308]
] finds support in reports of a reduced risk of cerebral infarction following improved blood pressure control [70PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack. Lancet 2001; 358(9287): 1033-41.
[http://dx.doi.org/10.1016/S0140-6736(01)06178-5] [PMID: 11589932]
]. In line with a now well-established vascular component of Alzheimer’s disease [68Craft S. The role of metabolic disorders in Alzheimer disease and vascular dementia: Two roads converged. Arch Neurol 2009; 66(3): 300-5.
[http://dx.doi.org/10.1001/archneurol.2009.27] [PMID: 19273747]
, 71Benarroch EE. Neurovascular unit dysfunction: A vascular component of Alzheimer disease? Neurology 2007; 68(20): 1730-2.
[http://dx.doi.org/10.1212/01.wnl.0000264502.92649.ab] [PMID: 17502556]
], hypertension is further associated with deposition of the beta amyloid peptide [72Perrotta M, Lembo G, Carnevale D. Hypertension and dementia: Epidemiological and experimental evidence revealing a detrimental relationship. Int J Mol Sci 2016; 17(3): 347.
[http://dx.doi.org/10.3390/ijms17030347] [PMID: 27005613]
]. Recently, low beta amyloid in cerebrospinal fluid (indicative of pre-clinical early stages of Alzheimer’s disease neuropathology) has also been linked to the development of POCD [73Evered L, Silbert B, Scott DA, Ames D, Maruff P, Blennow K. Cerebrospinal fluid biomarker for Alzheiumer disease predicts postoperative cognitive dysfunction. Anesthesiology 2016; 124(2): 353-61.
[http://dx.doi.org/10.1097/ALN.0000000000000953] [PMID: 26580833]
]. On the basis of that type of evidence, the present null finding across all included studies is surprising, but may be due to a number of factors. Statistical power was limited by high prevalence of hypertension in some studies (e.g., 99% [6Plaschke K, Hauth S, Jansen C, et al. The influence of preoperative serum anticholinergic activity and other risk factors for the development of postoperative cognitive dysfunction after cardiac surgery. J Thorac Cardiovasc Surg 2013; 145(3): 805-11.
[http://dx.doi.org/10.1016/j.jtcvs.2012.07.043] [PMID: 22935445]
]). We further suspect ascertainment bias. Patients with poor health may not have undergone as detailed blood pressure assessment as healthier patients so that hypertension remained undetected. At the same time, these patients may have been prone to POCD. Definition of hypertension was rarely specified, and as is common in the research literature [41Wilson DA, Mocco J, DAmbrosio AL, et al. Post-carotid endarterectomy neurocognitive decline is associated with cerebral blood flow asymmetry on post-operative magnetic resonance perfusion brain scans. Neurol Res 2008; 30(3): 302-6.
[http://dx.doi.org/10.1179/016164107X230540] [PMID: 17803842]
, 49Baba T, Goto T, Maekawa K, Ito A, Yoshitake A, Koshiji T. Early neuropsychological dysfunction in elderly high-risk patients after on-pump and off-pump coronary bypass surgery. J Anesth 2007; 21(4): 452-8.
[http://dx.doi.org/10.1007/s00540-007-0538-6] [PMID: 18008111]
, 74Feinkohl I, Keller M, Robertson CM, et al. Cardiovascular risk factors and cognitive decline in older people with type 2 diabetes. Diabetologia 2015; 58(7): 1637-45.
[http://dx.doi.org/10.1007/s00125-015-3581-0] [PMID: 25847351]
] likely often included the criterion “use of anti-hypertensive treatment”. This is despite uncertainty on its relationship with risk of age-related cognitive impairment per se [65Tully PJ, Hanon O, Cosh S, Tzourio C. Diuretic antihypertensive drugs and incident dementia risk: A systematic review, meta-analysis and meta-regression of prospective studies. J Hypertens 2016; 34(6): 1027-35.
[http://dx.doi.org/10.1097/HJH.0000000000000868] [PMID: 26886565]
, 75McGuinness B, Craig D, Bullock R, Passmore P. Statins for the prevention of dementia (review). Cochrane Libr 2009; 2009(2): CD003160.] and a lack of knowledge of its relationship with POCD. Hypertension could also have been well-controlled for years in patients on anti-hypertensive treatment. Finally, normotensive patients may have suffered from white-coat [76Franklin SS, Thijs L, Hansen TW, OBrien E, Staessen JA. White-coat hypertension: New insights from recent studies. Hypertension 2013; 62(6): 982-7.
[http://dx.doi.org/10.1161/HYPERTENSIONAHA.113.01275] [PMID: 24041952]
] and anxiety-induced hypertension due to scheduled surgery [77Gonçalves KK, Silva JI, Gomes ET, Pinheiro LL, Figueiredo TR, Bezerra SM. Anxiety in the preoperative period of heart surgery. Rev Bras Enferm 2016; 69(2): 397-403.
[PMID: 27280578]
]. Overall, any actual underlying links of blood pressure with POCD risk may have been eliminated by such “dilution” of “hypertension” groups.

None of these explanations could reasonably account for reports of associations of hypertension with age-related cognitive impairment [15Van den Berg E, Kloppenborg RP, Kessels RPC, Kappelle LJ, Biessels GJ. Type 2 diabetes mellitus, hypertension, dyslipidemia and obesity: A systematic comparison of their impact on cognition. Biochimicia et Biophysica Acta 2009; 1792: 470-81., 67Sharp SI, Aarsland D, Day S, Sønnesyn H, Ballard C. Hypertension is a potential risk factor for vascular dementia: Systematic review. Int J Geriatr Psychiatry 2011; 26(7): 661-9.
[http://dx.doi.org/10.1002/gps.2572] [PMID: 21495075]
, 78Duron E, Hanon O. Hypertension, cognitive decline and dementia. Arch Cardiovasc Dis 2008; 101(3): 181-9.
[http://dx.doi.org/10.1016/S1875-2136(08)71801-1] [PMID: 18477946]
] and POD [16Zaal IJ, Devlin JW, Peelen LM, Slooter AJ. A systematic review of risk factors for delirium in the ICU. Crit Care Med 2015; 43(1): 40-7.
[http://dx.doi.org/10.1097/CCM.0000000000000625] [PMID: 25251759]
], however. All studies of hypertension would be equally affected. We therefore have to consider the possibility that our finding is not due to bias but reflects some difference of (potentially sex-specific) hypertension links with POCD versus other forms of impairment. This would be consistent for instance with associations of hypertension with risk of stroke [69Dubow J, Fink ME. Impact of hypertension on stroke. Curr Atheroscler Rep 2011; 13(4): 298-305.
[http://dx.doi.org/10.1007/s11883-011-0187-y] [PMID: 21626308]
] but mixed results for post-operative stroke in particular [79Cook DJ, Huston J III, Trenerry MR, Brown RD Jr, Zehr KJ, Sundt TM III. Postcardiac surgical cognitive impairment in the aged using diffusion-weighted magnetic resonance imaging. Ann Thorac Surg 2007; 83(4): 1389-95.
[http://dx.doi.org/10.1016/j.athoracsur.2006.11.089] [PMID: 17383345]
, 80Hogue CW Jr, Murphy SF, Schechtman KB, Dávila-Román VG. Risk factors for early or delayed stroke after cardiac surgery. Circulation 1999; 100(6): 642-7.
[http://dx.doi.org/10.1161/01.CIR.100.6.642] [PMID: 10441102]
].

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 [81Hoeymans N, Smit HA, Verkleij H, Kromhout D. Cardiovascular risk factors in relation to educational level in 36 000 men and women in The Netherlands. Eur Heart J 1996; 17(4): 518-25.
[http://dx.doi.org/10.1093/oxfordjournals.eurheartj.a014903] [PMID: 8733083]
] and POCD [82Feinkohl I, Winterer G, Spies CD, Pischon T. Cognitive reserve and the risk of postoperative cognitive dysfunction - A systematic review and meta-analysis. Dtsch Arztebl Int 2017; 114(7)], as well as potential interaction effects of hypertension with intraoperative blood pressure control warrant evaluation. Finally, frailty, which is related to blood pressure control [83Odden MC, Beilby PR, Peralta CA. Blood pressure in older adults: the importance of frailty. Curr Hypertens Rep 2015; 17(7): 55.
[http://dx.doi.org/10.1007/s11906-015-0564-y] [PMID: 26068656]
], may be an important concept to recognize in cognitive epidemiology [84Kojima G, Taniguchi Y, Iliffe S, Walters K. Frailty as a predictor of Alzheimer disease, vascular dementia, and all dementia among community-dwelling older people: A systematic review and meta-analysis. J Am Med Dir Assoc 2016; 17(10): 881-8.
[http://dx.doi.org/10.1016/j.jamda.2016.05.013] [PMID: 27324809]
] including that of POCD.

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.

CONFLICT OF INTEREST

The authors confirm that this article content has no conflict of interest.

ACKNOWLEDGEMENTS

Declared none.

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