Metabolic syndrome and surgical complications: a systematic review and meta-analysis of 13 million individuals

Background: Metabolic syndrome (MetS) is characterised by the presence of at least three of the five following components: insulin resistance, obesity, chronic hypertension, elevated serum triglycerides, and decreased high-density lipoprotein cholesterol concentrations. It is estimated to affect 1 in 3 people around the globe and is reported to affect 46% of surgical patients. For people with MetS who undergo surgery, an emerging body of literature points to significantly poorer postoperative outcomes compared with nonaffected populations. The aim of this study is to review the current evidence on the risks of surgical complications in patients with MetS compared to those without MetS. Methods: Systematic review and meta-analysis using PRISMA and AMSTAR reporting guidelines. Results: The meta-analysis included 63 studies involving 1 919 347 patients with MetS and 11 248 114 patients without MetS. Compared to individuals without the condition, individuals with MetS were at an increased risk of mortality (OR 1.75 95% CI: 1.36–2.24; P<0.01); all surgical site infection types as well as dehiscence (OR 1.64 95% CI: 1.52–1.77; P<0.01); cardiovascular complications (OR 1.56 95% CI: 1.41–1.73; P<0.01) including myocardial infarction, stroke, cardiac arrest, cardiac arrythmias and deep vein thrombosis; increased length of hospital stay (MD 0.65 95% CI: 0.39–0.9; P<0.01); and hospital readmission (OR 1.55 95% CI: 1.41–1.71; P<0.01). Conclusion: MetS is associated with a significantly increased risk of surgical complications including mortality, surgical site infection, cardiovascular complications, increased length of stay, and hospital readmission. Despite these risks and the high prevalence of MetS in surgical populations there is a lack of evidence on interventions for reducing surgical complications in patients with MetS. The authors suggest prioritising interventions across the surgical continuum that include (1) preoperative screening for MetS; (2) surgical prehabilitation; (3) intraoperative monitoring and management; and (4) postoperative rehabilitation and follow-up.


Background
Metabolic syndrome (MetS) is a health condition characterised by a cluster of physiological and biochemical conditions that heighten the risk of adverse health outcomes [1][2][3] .Although some variations exist in specific diagnostic criteria, consensus statements by the WHO, a Joint Interim Statement (JIS) by prominent health organisations, and the National Cholesterol Education Programme Adult Treatment Panel III (NCEP III) identify MetS as an accumulation of at least three of the following five components: insulin resistance, obesity, chronic hypertension, elevated serum triglycerides, and decreased high-density lipoprotein cholesterol concentrations [2,3] .
It is important to understand the impact of MetS on surgical outcomes.Although some studies have shown no association

HIGHLIGHTS
• This meta-analysis involving 13 million individuals from various countries provided evidence that metabolic syndrome (MetS) was associated with a moderately increased risk of surgical complications.• MetS was associated with an increased risk of adverse events including death, cardiovascular complications, surgical site infections, and hospital readmission.• Our findings suggest that there is a need to implement screening processes for MetS prior to surgery, alert the surgical team to risks associated with MetS.
between MetS and an increased risk of surgical complications [4,5] , there is a growing body of evidence suggesting those with the condition are at a greater risk of a range of serious adverse events during and after surgery [6][7][8][9][10][11][12] .Consequently, the costs of treating surgical patients with MetS are increased [5,13] .Evidence further suggests the accumulation of MetS components in individuals potentiates the risk of surgical complications compared to individual risk factors such as obesity [6] .For example, one study reported that patients with MetS have a higher rate of complications in bariatric surgery; in effect, this shows that patients undergoing bariatric surgery with MetS have a higher risk than those who have obesity alone [7] .Despite the quantum of literature investigating the effect of MetS on surgical outcomes, no systematic review and meta-analysis of the evidence has been performed to date.Moreover, to our knowledge, there are no reported interventions or guidelines in the literature on ameliorating the risks associated with MetS.There is a need for quality appraisal and synthesis of the accumulated evidence to identify whether MetS predisposes patients to a greater risk during surgery than those without MetS.The aim of this review is to therefore synthesise the evidence on the risks of surgical complications in patients with MetS compared to those without MetS.

Method
We conducted a systematic literature search according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations (see Fig. 1) and in compliance with Assessing the Methodological Quality of Systematic Reviews (AMSTAR) guidelines [8,9] .A review protocol was registered a priori with PROSPERO (BLINDED) and also researchregistry.com(reviewregistry1703).The review protocol is published elsewhere (BLINDED).

Search strategy
We used the database search approach recommended by Bramer and colleagues [10] searching: CINAHL, Embase, Google Scholar (Top 200), PsycINFO, PubMed, and Web of Science.Database searches were supplemented by backward and forward citation tracking of included articles using Scopus.A date limitation of greater than or equal to 1998 was applied to the search strategy to reflect the first formal definition of MetS [2] .The full search strategy is provided (see Table 1).

Eligibility criteria
We included published peer-reviewed studies that reported on the effect of MetS on the occurrence of surgical complications in adult patients undergoing invasive surgery.Studies were included if they were prospective or retrospective observational studies that reported on 30-day complications in adult surgical patients diagnosed with MetS.As the criteria to establish a diagnosis of MetS may vary, we accepted the definition of MetS as defined by the study authors.Studies were excluded if they reported on surgical complications greater than 30 days or minor surgical procedures (e.g.lesion removal) (see Table 2. Inclusion and Exclusion Criteria).

Study selection
Following the initial search for studies, citations were exported into EndNote software [11] .
After the removal of duplicates, the title and abstracts of studies were screened by two independent reviewers (P.N. and N.R.) against inclusion and exclusion criteria to identify studies for potential inclusion.The full-text of each selected article was screened by two independent reviewers (P.N. and N.R.) to determine eligibility against the inclusion and exclusion criteria.Disagreement consensus was achieved through discussion between reviewers (P.N. and N.R.).

Data management
One review author (P.N.) extracted data from the included studies using a preconstructed data extraction form.Authors were contacted in instances of missing or ambiguous data.Studies were excluded where the author did not respond, or data extraction was not possible.Extracted data was entered into Review Manager (RevMan) Version 5.4.1 [12] , which another review author (N.R.) independently checked for accuracy.

Data extraction
Outcomes of interest were the risk of complications within 30 days of surgery, length of stay (LOS), and hospital readmission.We accepted the definition for each surgical complication provided by the authors of each included study and extracted data on 30-day surgical complications.Outcomes included were mortality, surgical site infection (SSI) (any SSI, superficial SSI, deep SSI, organ space SSI, and dehiscence), cardiovascular complications (arrhythmia, myocardial infarction (MI), cardiac arrest, stroke, deep vein thrombosis (DVT), LOS, and hospital readmission.For categorical data, the number of events in the control, and exposure cohorts were extracted.For continuous data, the mean difference (MD) and SD values were extracted.

Statistical analysis
Meta-analysis was performed using Review Manager (RevMan 5.4.1) [12].The effect estimate with a 95% CI were extracted from each included study.We extracted the effect size reflecting the greatest degree of adjustment for possible confounding factors when multiple effect sizes with different degrees of covariate adjustment were reported in a study.For continuous variables, to estimate the summary effect size we used a random-effects model and the inverse-variance method to obtain MDs and SDs with 95% CIs.For dichotomous variables, the Mantel-Haenszel formula was used to produce a single summary measure of association to obtain odds ratios (ORs) along with its CIs.We used a random-effects model for pooled analysis regardless of heterogeneity since this model estimates the effect with consideration to the variance between studies, rather than ignoring heterogeneity by employing a fixed effect model [14] .Heterogeneity of studies was estimated using the Higgins I 2 statistic [15] and described as .limit 3 to (full-text and human and english) 5. limit 4 to yr = "1998 -Current" 6. limit 5 to (full-text and human and english language) 7. limit 6 to ((embase or "preprints (unpublished, non-peer-reviewed)") and journal) *For the purposes of this study, invasive surgery was considered any surgical procedure involving a skin incision and surgical dissection below the level of the dermis (excludes skin excisions, biopsy etc.) and/or instrumentation of a natural orifice in conjunction with an excisional procedure (urology, gynaecology, etc.).
low (25%), moderate (25-55%), and high ( > 75%) [16] .The P-value for statistical significance was set at ≤ 0.05.We removed one study at a time to observe the effect on the results.We then calculated an overall estimate of effect size using a random-effects meta-analysis based on the adjusted OR of all included studies.

Quality assessment
Two independent reviewers (P.N. and N.R.) performed quality assessment.Each included study was critically appraised using the Newcastle-Ottawa Scale (NOS) for observational studies.
The NOS is a widely used and endorsed scale to assess the quality of observational studies [17,18] .The NOS is validated for assessing three quality parameters, namely, selection, comparability, and outcome divided across eight specific items.Studies were independently screened and scored (0-9) by two reviewers (P.N. and N.R.).Each study was assessed against criteria and scored according to good (7-9), fair (4-6), and poor quality (< 4).Discrepancy in assessment scores were resolved through discussion and consensus (see Table 3).

Mortality
Mortality within 30 days of surgery was reported in 44 studies considered for meta-analysis.Across these studies, a total of 333 488 patients with MetS underwent surgery versus 1 449 817 surgical patients without MetS.We found fifteen of 44 studies reported an increased risk of mortality across a range of surgical types including bariatric [39,43,57] , cardiac [19,42] , ear, nose, and throat (ENT) [35] , emergency [31] , endocrine [59,84] , gastrointestinal [40] , hepatobiliary [23,33,34] , neurosurgery [49] , and orthopaedic [47] .Twenty-five studies considered for meta-analysis found no association with 30-day mortality between MetS and non-MetS patients across a wide range of surgical types.Three studies focusing on orthopaedic and vascular surgical patients reported those with MetS were at less risk of 30-day mortality [4,5,67] .One study focused on gynaecological surgery reported no deaths in either group between the MetS and non-MetS groups [22] .On pooling of effect estimates, surgical patients with MetS were at 1.75 times the risk of death within 30 days after surgery compared to patients without MetS (OR 1.75 95% CI: 1.36-2.24;P < 0.0001) (see Fig. 2).

Cardiovascular events
MI MI within 30 days of surgery was reported in 32 studies included for meta-analysis.Across these studies, a total of 301 376 patients with MetS underwent surgery versus 116 6298 without MetS.We found 7 of 32 studies reported an increased risk of MI across a range of surgeries including bariatric [43,57] , colorectal [60] , hepatobiliary [23] , orthopaedics [5] , and vascular [4,62] .Twenty-five studies reported no association between 30-day operative MI and patients with or without MetS.Meta-analysis of studies revealed surgical patients with MetS were at 1.63 times the risk of MI within 30 days after surgery compared to patients without MetS (OR 1.63 95% CI: 1.30-2.03;P = 0.001) (see Fig. 3 for all Cardiovascular Events).

Stroke
Stroke was reported in 31 studies included for meta-analysis.Across these studies, a total of 278 809 patients with MetS underwent surgery versus 1 010 989 surgical patients without MetS.We identified that 9 out of 31 studies reported an increased risk of stroke across a range of surgeries including bariatric [57] , cardiac [41,76] , emergency general surgery [31] , endocrine [59] , orthopaedic [5] and vascular [53,62] .Twenty-one studies reported no association with 30-day stroke between MetS and non-MetS patients across a range of surgeries.No strokes occurred in a single study [85] .The link between MetS and stroke within 30 days of surgery was identified following a meta-analysis.Individuals with MetS were at 1.64 times the risk of stroke within 30 days after surgery compared to patients without MetS (OR 1.64 95% CI: 1.39-1.93];P = 0.00001).

Cardiac arrhythmias
Cardiac arrhythmias within 30 days of surgery were reported in nine studies included for meta-analysis with a total sample of 2117 patients with MetS versus 2828 surgical patients without MetS.In the studies considered for meta-analysis, 2 out of 9 studies reported an increased risk of cardiac arrhythmias during cardiac surgery [50,64] , while the remaining seven studies identified no association with 30-day cardiac arrhythmias between MetS and non-MetS patients across a range of surgeries.Pooling of effect estimates revealed surgical patients with MetS were at 1.41 times the risk of cardiac arrhythmias within 30 days after surgery compared to patients without MetS (OR 1.41 95% CI: 1.04-1.91;P = 0.03).

Cardiac arrest
Cardiac arrest within 30 days of surgery was reported in 15 of the included studies.Across these studies, a total of 48 830 patients with MetS underwent surgery versus 411 573 patients without MetS.Ten of 15 studies reported an increased risk of cardiac arrest across bariatric [43] , colorectal [60] , endocrine [59] gastroenterology [40] , hepatobiliary [33,34,66] , orthopaedic [47] , and vascular surgeries [4,53] .The remaining five studies included for meta-analysis found no association with cardiac arrest within 30 days of surgery.Pooling of effect estimates revealed surgical patients with MetS were at 1.89 times the risk of cardiac arrest compared to patients without MetS, (OR 1.89 95% CI: 1.5-2.39;P < 0.00001).

Grouped cardiovascular complications
A total of 40 of 63 studies reported a grouped outcome of cardiovascular complications that were not categorised by specific type within 30 days of surgery comprising 700 123 patients with MetS versus 2 963 949 surgical patients without MetS.Surgical patients with MetS were at 1.56 times the risk of any cardiovascular complication within 30 days after surgery compared to patients without MetS (OR 1.56 95% CI: 1.41-1.73;P = 0.00001).

Deep SSI
Deep SSIs within 30 days of surgery were reported in 18 studies.Across these studies, a total of 87 918 patients with MetS underwent surgery versus 458 382 surgical patients without MetS.In eight included studies, an increase in deep SSI was observed across a range of surgeries including bariatric [43] , cardiac [76] , colorectal [60] emergency general surgery [31] , orthopaedic [47,67,72] , and vascular [4] .The remaining 10 studies included for meta-analysis reported no association with 30-day deep SSI.Pooling of effect estimates revealed surgical patients with MetS were at 1.69 times the risk of 30-day deep SSI compared to patients without MetS, (OR 1.69 95% CI: 1.40-2.04;P = 0.00001).

Organ space SSI
The incidence of organ space SSIs within 30 days of surgery was reported in 12 studies.Across these studies, a total of 26 943 patients with MetS underwent surgery versus 340 171 surgical patients without MetS and were monitored for organ space SSIs.
In 2 of 12 studies, an increase was reported in organ space SSIs across endocrine [84] and orthopaedic [67] , specialities while 10 studies found no association.Pooling of effect estimates revealed surgical patients with MetS were at 1.3 times the risk of organ space SSIs within 30 days of surgery compared to patients without MetS, (OR 1.3 95% CI: 1.05-1.61;P = 0.02).

Dehiscence
Wound dehiscence within 30 days of surgery was reported in 18 studies.Across these studies, a total of 72 056 patients with MetS underwent surgery versus 420 428 surgical patients without MetS.In five studies, an increase in wound dehiscence was observed across a range of surgeries including colorectal [60] , emergency general surgery [31] , plastics [77] , urologic [58] , and vascular [4] .Twelve studies included for meta-analysis found no association with 30-day wound dehiscence between MetS and non-MetS patients.In a single study [32] where wound dehiscence was an outcome, none were observed.Pooling of effect estimates revealed surgical patients with MetS were at 1.59 times the risk of 30-day wound dehiscence compared to patients without MetS, (OR 1.59 95% CI: 1.28-1.97;P = 0.0001).

Uncategorised SSI
A total of 40 of the 63 studies reported SSIs; however, did not provide a classification according to standardised definitions.Across these studies, a total of 477 207 patients with MetS underwent surgery versus 2 295 152 surgical patients without MetS and were monitored for an SSI occurring within 30 days of surgery.Surgical patients with MetS were at 1.64 times the risk of an uncategorised SSI within 30 days after surgery compared to patients without MetS (OR 1.64 95% CI: 1.52-1.77;P = 0.00001).

Hospital readmission
Hospital readmission within 30-day of surgery was reported in 22 studies included for meta-analysis.Across these studies, a total of 109 910 patients with MetS underwent surgery versus 650 525 surgical patients without MetS.In the studies considered for meta-analysis, 14 out of 22 were statistically associated with an increase in hospital readmission across a range of surgeries including bariatric [39] , endocrine [32,59] , ENT [35] , emergency general surgery [31] , gastrointestinal [40] , orthopaedic [6,46,47,67,73,78] , and plastics [56,77] .The remaining eight studies included for meta-analysis found no association with hospital readmission between MetS and non-MetS patients.Pooling of effect estimates revealed surgical patients with MetS were at 1.55 times the risk of hospital readmission compared to patients without MetS, (OR 1.55 95% CI: 1.41-1.71;P = 0.00001) (see Fig. 5).

Hospital LOS
Hospital LOS was reported in 24 included studies.Across these studies, a total of 298 619 patients with MetS underwent surgery versus 3 888 671 surgical patients without MetS.In 13 of 24 studies, an increased length of hospital stay was reported across a range of surgeries including cardiac [42,64,76] , endocrine [59] , hepatobiliary [34] , orthopaedic [26,48,67,72,78,86] , plastics [77] , and urology [74] .Two studies focusing on orthopaedic and hepatobiliary surgical patients [27,55] reported those with MetS were at less risk of increased hospital LOS.A further nine studies found no association with the length of hospital stay between MetS and non-MetS patients across a range of surgeries.Pooling of effect estimates revealed surgical patients with MetS experienced an increased length of hospital stay (MD 0.65 95% CI: 0.39-0.9;P = 0.00001) (see Fig. 6).

Discussion
This review of 13 167 461 participants across 63 included studies demonstrates that patients with MetS undergoing surgery are at an increased risk of adverse outcomes within 30 days postoperatively.While components of MetS (insulin resistance, obesity, chronic hypertension, elevated serum triglycerides, and decreased high-density lipoprotein) [87][88][89][90] are known to be independent risk factors for adverse surgical outcomes, our metaanalysis demonstrates an increased risk of adverse outcomes where these risk factors accumulate to meet the MetS diagnostic criteria.Our review indicates that where surgical patients are identified with MetS, they have a 75% increased risk of death; a 56% increased risk of cardiovascular complications; a twofold increased risk of any SSI; and a 55% increased risk of hospital readmission.Considering MetS is both highly prevalent and associated with an increased likelihood of adverse complications after surgery, our findings indicate the need to (1) identify MetS in surgical patients using evidence-based screening approaches, and (2) implement guidelines that treat relevant components of MetS at optimal time points around surgery .Adopting standardised diagnostic criteria for MetS could facilitate improved detection and the initiation of management strategies throughout the surgical continuum to improve patient outcomes.For instance, most routine preoperative assessments are likely to include assessments that record NCEP III diagnostic criteria of insulin resistance, obesity, chronic hypertension, elevated serum triglycerides, and decreased high-density lipoprotein.Hospital systems should incorporate alerts where a patient meets the diagnostic criteria for MetS as part of existing presurgical screening processes to allow better detection of this patient cohort and identification of the risks associated with a diagnosis of MetS prior to surgery.Identifying these risks is important as it is well established that there is an additive effect of risk factors on short-term and long-term surgical outcomes that can be demonstrated using surgical risk calculators such as the ACS-NSQIP and CeDAR [91] .Based on the results of our review, it is likely that the surgical risks imposed by MetS criteria are also additive in nature and should be incorporated into existing surgical risk calculators to provide a more comprehensive assessment of the risk profile of this patient cohort.Furthermore, it is important to impart awareness of the risk to patients with MetS as part of the consent process.This conversation needs to occur contemporaneously with efforts to minimise communication bias, discrimination, and weight stigmatisation [92] .Treating MetS effectively may necessitate delaying elective surgery or implementing an enhanced recovery after surgery protocol, which in turn, may increase patient frustration, anxiety and challenges with surgical optimisation.
Healthcare providers should therefore take steps to implement prehabilitative, intraoperative, and rehabilitative approaches to care to improve patient recovery, facilitate earlier discharge from the hospital, and potentially reduce healthcare costs by lowering or eliminating complications associated with MetS including hospital readmission.Surgical optimisation interventions have shown promise for some of the diagnostic criteria of MetS such as treating obesity [93] and hypertension [94] prior to surgery, thus, there is the potential to adapt elements of existing interventions and guidelines for MetS patients to eliminate or reduce operative risks.It is also vital that the surgical team is attentive to practices that reduce SSI including weight-based dosing of prophylactic antibiotics [95] , redosing of prophylactic antibiotics in longer operations [96] , glucose optimisation [97] , glove changes [98] , and the use of alcoholic skin preparation prior to skin closure [99] .Postoperative follow-up and rehabilitation of these patients should also emphasise initiatives that reduce the risk of potential postoperative complications, such as SSIs [100,101] , venous thromboembolism events [102,103] , and cardiovascular complications [104,105] .
One limitation of this review stems from the varying definitions of MetS used in the included studies, which can lead to population heterogeneity and complicate result comparisons.Additionally, the inclusion of retrospective observational studies, drawing data from medical records databases, introduces potential biases and limitations, including incomplete information, selection bias, and possible confounding factors.In summation, the review provides valuable insights and is the largest review of the surgical risks patients with MetS face.It also provides socio-ecological validity by drawing evidence globally from countries with similarly developed health systems and highlights a significant risk profile which, heretofore, has not been addressed with review level evidence.

Conclusion
Our review is the largest, most-comprehensive analysis of postoperative surgical complications in MetS.Our findings highlight that surgical patients with MetS are at a heightened risk of a range of adverse outcomes in the 30 days following surgery.Based on our findings, firstly, there is a need to implement evidence-based screening approaches to identify MetS in surgical patients to facilitate early detection and initiate management strategies prior to, during, and after surgery for improved outcomes.Secondly, the surgical team must be aware of the increased risks associated with MetS, be alerted to a diagnosis preoperatively, communicate risks to the patient during the consent process, and treat components of the condition to avoid the risks of adverse events.In conclusion, early detection, personalised management, and comprehensive perioperative care for MetS patients are essential to mitigate risks, enhance outcomes, and potentially reduce healthcare costs by minimising complications and readmissions.

Figure 5 .
Figure 5. Hospital length of stay.

Table 1
Search Strategy.
"metabolic syndrome" OR "deadly quartet" AND surgery OR surgical OR perioperative OR preoperative OR intraoperative OR postoperative Web of Science surgery (Title) or surgery (Abstract) or surgical (Title) or surgical (Abstract) or perioperative (Title) or perioperative (Abstract) or preoperative (Title) or preoperative (Abstract) or intraoperative (Title) or intraoperative (Abstract) or postoperative (Title) or postoperative (Abstract) AND metabolic syndrome (Title) or metabolic syndrome (Abstract) or deadly quartet (Title) or deadly quartet (Abstract) Embase 1. metabolic syndrome.ab.or metabolic syndrome.ti.or deadly quartet.ab.or deadly quartet.ti. 2. surgery.ab.or surgery.ti.or surgical.ab.or surgical.ti.or perioperative.ab.or perioperative.ti.or intraoperative.ab.or intraoperative.ti.or preoperative.ab.or preoperative.ti.or postoperative.ab.or postoperative.ti. 3. 1 and 2 4

Table 2
Inclusion and exclusion criteria.

Table 3
Table of included studies.