Diabetes is a risk factor for postoperative complications. Previous meta-analyses have shown that elevated glycated hemoglobin (HbA1c) levels are associated with postoperative complications in various surgical populations. However, this is the first meta-analysis to investigate the association between preoperative HbA1c levels and postoperative complications in patients undergoing elective major abdominal surgery.
PRISMA guidelines were adhered to for this study. Six databases were searched up to April 1, 2020. Primary studies investigating the effect of HbA1c levels on postoperative complications after elective major abdominal surgery were included. Risk of bias and quality of evidence assessments were performed. Data were pooled using a random effects model. Meta-regression was performed to evaluate different HbA1c cut-off values.
Twelve observational studies (25,036 patients) were included. Most studies received a ‘good’ and ‘moderate quality’ score using the NOS and GRADE, respectively. Patients with a high HbA1c had a greater risk of anastomotic leaks (odds ratio [OR]: 2.80, 95% CI [1.63, 4.83], P < 0.001), wound infections (OR: 1.21, 95% CI [1.08, 1.36], P = 0.001), major complications defined as Clavien-Dindo [CD] 3–5 (OR: 2.16, 95% CI [1.54, 3.01], P < 0.001), and overall complications defined as CD 1–5 (OR: 2.12, 95% CI [1.48, 3.04], P < 0.001).
An HbA1c between 6% and 7% is associated with higher risks of anastomotic leaks, wound infections, major complications, and overall postoperative complications. Therefore, guidelines with an HbA1c threshold > 7% may be putting pre-optimized patients at risk. Future randomized controlled trials are needed to explore causation before policy changes are made.
Diabetes mellitus is known to be a predisposing risk factor for postoperative complications, such as infections, poor wound healing, anastomotic leaks, and cardiac complications. Compared with non-diabetic patients, both in-hospital and long-term mortality rates are considerably higher in patients with diabetes [
The American Diabetes Association endorses the use of glycated hemoglobin (HbA1c) levels to monitor glycemic control in patients with diabetes [
Major abdominal surgery, defined as a major operation involving the abdominal and/or retroperitoneal compartment, is associated with high postoperative morbidity due to the extensive nature of the surgery. Despite the clinical significance of this, no previous systematic review or meta-analysis has investigated the association between preoperative HbA1c levels and postoperative complications in this population. Furthermore, there is no consensus on the HbA1c threshold at which it would be advisable to postpone elective surgery. The Joint British Diabetes Societies for Inpatient Care and the Association of Anesthetists of Great Britain and Ireland recommend further optimization of glycemic control at an HbA1c threshold of 8.5% [
Thus, there is a gap in the literature regarding the association between preoperative HbA1c levels and postoperative complications after elective major abdominal surgery despite the increasing incidence of both diabetes and abdominal surgery. The UK National Diabetes Inpatient Audit found that 21% of all surgical patients have diabetes, and general surgery (36%) and colorectal surgery (22%) are the surgical specialties with the highest prevalence [
This is the first meta-analysis to evaluate all the available evidence regarding the association between preoperative HbA1c levels and postoperative complications in the unique population of patients undergoing elective major abdominal surgery. Furthermore, we investigated whether a threshold HbA1c level could be used to predict an increase in postoperative complications. The findings from this meta-analysis could have implications for policies in various countries, as different HbA1c cut-off thresholds are currently being used in clinical practice.
This meta-analysis has been reported in line with the PRISMA guidelines [
The following electronic databases were searched using the search strategy described in
The study selection was performed by two independent reviewers (JKLW and YK). Discrepancies were resolved by a third reviewer (HRA). The eligibility criteria were as follows: randomized controlled trials (RCTs) and observational studies investigating the association between HbA1c levels and postoperative complications by reporting outcomes in at least two HbA1c groups in adult patients undergoing major abdominal surgery. Studies on patients undergoing bariatric, total pancreatectomy, pediatric, emergency, and transplant surgery were excluded [
Data extraction was performed by two independent reviewers (JKLW and YK) and stored in proformas. The extracted data included study characteristics (author, year, country, study design, type of surgery), patient demographics (age, sex, sample size), intervention and comparator data (HbA1c cut-off value), and outcome data (postoperative complications including major, overall, gastrointestinal, infectious, cardiopulmonary, and renal complications), which were guided by the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) [
The risk of bias for the non-randomized observational studies was assessed using the Newcastle-Ottawa Quality Assessment Scale (NOS) [
The primary and secondary aims of this meta-analysis were to investigate the associations between preoperative HbA1c levels and major and overall postoperative complications, respectively, where major complications were defined as those fulfilling the Clavien-Dindo (CD) classification grades 3–5, and overall complications were defined as those fulfilling the CD grades 1–5 [
The postoperative complications extracted from the primary studies were initially graded according to the CD classification, and then grouped according to either the primary outcome (major postoperative complications) or secondary outcome (overall postoperative complications) analyses. Examples of postoperative complications that were included as major postoperative complications (primary outcome) include reoperation [
Statistical analyses were performed using Stata (2019. Stata Statistical Software: Release 16. StataCorp LLC. StataCorp.). Funnel plots, Begg’s rank correlation tests, and Egger’s regression asymmetry tests were used to assess publication bias [
No ethics approval or consent to participate was required, as only secondary data were used.
The search yielded 2,539 records. One additional record was identified through a manual search of the bibliographies. Fifteen and twelve records met the criteria for qualitative and quantitative analyses, respectively (
The study characteristics are summarized in
The most studied outcomes were infections [
According to the risk of bias assessment, all studies scored at least a 7/9 on the NOS, which equates to a “good quality” score after conversion to the AHRQ standards. Only one was graded as “poor quality.” Most studies lost points in the selection and outcome parameters (
Nine studies were included in this analysis [
Among the 12 studies reporting overall complications [
For the primary analysis, with Wang et al. ’s postoperative infection data included [
Six studies were included in this analysis [
Only two studies investigated the impact of HbA1c levels on postoperative ileus [
This analysis included six studies [
Three studies were included in this analysis [
Four studies were included in this analysis [
Only two studies reported outcomes on postoperative sepsis [
Only two studies reported cardiopulmonary complications [
Only one study reported acute kidney injury (AKI) events postoperatively. Oh et al. [
For the range of HbA1c cut-off values between 5.7% and 7.0%, there were no statistically significant effects on the development of major postoperative complications, overall postoperative complications, anastomotic leaks, overall infections, or wound infections (all P > 0.05). Bubble plots of the meta-regressions are presented in
Results from our meta-analysis showed that elevated HbA1c (> 6–7%) was associated with a higher risk of anastomotic leaks, wound infections, major postoperative complications (CD grades 3–5) and overall postoperative complications (CD grades 1–5), but not with overall infections and pneumonia.
The most important finding from this meta-analysis was that elevated HbA1c levels are associated with a higher risk of anastomotic leaks. This is an important observation as anastomotic leaks are one of the most serious complications associated with gastrointestinal surgery, resulting in a mortality rate as high as 16.4% and long hospital and intensive care unit admissions [
Our meta-analysis also found that lower HbA1c levels are not only associated with a lower risk of major postoperative complications (CD grade 3–5), but also with a lower risk of overall postoperative complications (CD grade 1–5). This has significant implications as it suggests that postponing elective surgery until an optimal HbA1c level is achieved may reduce the risk of both major and overall postoperative complications that negatively affect patients’ quality of life after surgery. These findings may also facilitate counseling during preoperative assessments to motivate patients to make lifestyle modifications and improve medication adherence.
It should be noted that a significant association between preoperative HbA1c levels and the risk of overall infections and pneumonia was not found in our pooled results. These findings were not consistent with a well-cited study by Dronge et al. [
Regarding the rationales for excluding certain populations, patients undergoing pancreatic and bariatric surgery were excluded from this meta-analysis because the postoperative glucose metabolism in these patients is different from that in patients undergoing other types of abdominal surgeries [
The main strength of this study is that this is the first meta-analysis investigating the association between preoperative HbA1c levels and postoperative complications exclusively in the elective major abdominal surgery population, as the majority of previous meta-analyses have been conducted on cardiac, bariatric, and orthopedic populations [
This meta-analysis has some limitations. Some studies that met the inclusion criteria of abdominal surgery had to be excluded since they also included non-abdominal surgeries, and we were unable to attain the data on abdominal surgeries separately. To overcome this limitation, we applied the Duval and Tweedie nonparametric trim and fill method to adjust the meta-analysis by incorporating theoretical missing trials. Some studies categorized patients according to their diabetes diagnosis status instead of their HbA1c status, and not everyone who had a diabetes diagnosis had an elevated HbA1c level. To adjust for this, we only included patients with HbA1c levels available and categorized them according to their HbA1c status. Another limitation was the inclusion of studies that used different HbA1c cut-off points. For this reason, we have provided a conservative conclusion that an HbA1c level > 6–7% is associated with higher risk of postoperative complications. Additionally, it was not possible to perform subgroup analyses, although these are crucial, accounting for the fact that some of the included patients had comorbidities such as cancer and patient-level data for these factors were unavailable. While this is a possible limitation, for diabetes optimization, HbA1c levels also allow for an attempt to optimize the preoperative phase similar to how we optimize pre-operative patients at high risk of malnutrition (for example, patients with gastrointestinal cancers).
The main implication of this study is to guide future RCTs. Our findings suggest that an elevated HbA1c level of 6–7% may be associated with a higher risk of postoperative complications. Currently, only the US guidelines recommend a target HbA1c of 7% [
In conclusion, the findings from our meta-analysis show that elevated HbA1c levels are associated with a higher risk of developing anastomotic leaks, wound infections, and major and overall postoperative complications, but not overall infections and pneumonia. This implies that patients fare better postoperatively if a target HbA1c level ≤ 7% is set before undergoing elective major abdominal surgery. Our findings can help to guide future RCTs to determine if current guidelines on the recommended cut-off values for HbA1c levels should be reviewed, as the HbA1c thresholds currently used in clinical practice are all above 7%. Further studies using ROC analyses to investigate the exact HbA1c cut-off value associated with an increase in postoperative complications should also be performed.
This work was supported by the funding department of the Department of Anesthesiology, Singapore General Hospital, Singapore. H.R.A. is a recipient of the SingHealth Duke-NUS Nurturing Clinician Scientists Scheme Award (project number 12/FY2017/P1/15-A29) and the National Medical Research Council (NMRC), Singapore, Clinician Investigator Salary Support scheme 2018–2020. The funding sources played no role in the design of this study or the analysis and interpretation of the results.
No potential conflict of interest relevant to this article was reported.
Joanna K. L. Wong (Conceptualization; Data curation; Formal analysis; Investigation; Methodology; Writing – original draft)
Yuhe Ke (Data curation; Formal analysis; Investigation; Methodology; Writing – original draft)
Yi Jing Ong (Data curation; Formal analysis; Investigation; Methodology; Writing – original draft)
HuiHua Li (Formal analysis; Investigation; Methodology; Writing – original draft)
Ting Hway Wong (Investigation; Methodology; Writing – review & editing)
Hairil Rizal Abdullah (Conceptualization; Methodology; Project administration; Supervision; Writing – original draft; Writing – review & editing)
Search strategy.
Thresholds for converting the Newcastle-Ottawa scales to AHRQ standards.
Newcastle-Ottawa Scale for Risk of Bias Assessment of Studies
Funnel plot of major postoperative complications.
Funnel plot of overall complications (CD1 and above, using Wang et al’s data on postoperative infections).
(A) Funnel plot and (B) forest plot of overall complications (CD1 and above, using Wang et al’s data on anastomotic leak) (P < 0.001).
Funnel plot of all anastomotic leaks.
Funnel plot of all infectious complications.
Funnel plot of all wound infections.
(A) Funnel plot and (B) forest plot of all pneumonia (P = 0.026).
Bubble plots displaying meta-regression for (A) Major postoperative complications (CD3-5), (B) Overall postoperative complications (CD1-5), (C) Anastomotic leaks, (D) Overall infections, and (E) Wound infections.
PRISMA flowchart.
Forest plot of the effect of HbA1c level on major postoperative complications (P < 0.001).
Forest plot of the effect of HbA1c level on overall complications (P < 0.001).
Forest plot of the effect of HbA1c level on anastomotic leak (P < 0.001).
Forest plot of the effect of HbA1c level on overall infections (P = 0.031).
Forest plot of the effect of HbA1c level on wound infections (P = 0.001).
Clavien-Dindo Classification Definitions
Grades | Definition [ |
---|---|
I | Any deviation from normal postoperative course without need for pharmacological treatment or surgical, endoscopic, or radiological interventions |
Allowed therapeutic regimens: antiemetics, antipyretics, analgesics, diuretics, electrolytes, and physiotherapy | |
This grade also includes wound infections opened at the bedside | |
II | Requiring pharmacological treatment with drugs other than those included in the grade I complications |
Also includes blood transfusions and total parenteral nutrition | |
III | Requiring surgical, endoscopic, or radiological interventions |
a: Not under general anesthesia | |
b: Under general anesthesia | |
IV | Life-threatening complication (including central nervous system complications) |
a: Single organ dysfunction (including dialysis) | |
b: Multi-organ dysfunction | |
V | Death |
Including brain hemorrhage, ischemic stroke, or subarachnoid bleeding but excluding transient ischemic attacks.
Study Characteristics
Study | Country | Study design | Type of surgery | Sample size, n | HbA1c cut-off (no. of patients, percentage) | Time window between HbA1c level result and surgery | Outcome measures |
---|---|---|---|---|---|---|---|
Lee et al. 2015 [ |
South Korea | Retrospective | Nephrectomy (radical and partial) for renal cell carcinoma | n = 3075 | ≥ 6.8% (n = 158, 50%) | Within 6 months of the surgery | · Progression-free survival |
< 6.8% (n = 158, 50%) | · Cancer specific survival | ||||||
· Overall survival | |||||||
Gustafsson et al. 2009 [ |
Sweden | Prospective | Elective colorectal resection (including cancer, inflammatory bowel disease, benign pathology) | n = 120 | > 6.0% (n = 31, 25.8%) | 1 day before surgery | · Postoperative glucose control |
≤ 6.0% (n = 89, 74.2%) | · Magnitude of inflammatory response | ||||||
· Postoperative recovery | |||||||
· 30-day overall morbidity | |||||||
Goh et al. 2017 [ |
Singapore | Retrospective | Colorectal surgery | n = 149 | ≥ 8% (n = 31, 23.8%) | Within 3 months of the surgery | · Postoperative complications (CD grade 2 and above) |
< 8% (n = 99, 76.2%) | |||||||
Goodenough et al. 2015 [ |
USA | Prospective | *Abdominal surgery | n = 1017 | ≥ 6.5% (n = 183, 41.8%) | Within 3 months of the surgery | · Primary: Major complication CD grade 3–5 within 30 days |
< 6.5% (n = 255, 52.8%) | · Secondary: Any complication, including CD grade 1–2 | ||||||
Kamarajah et al. 2018 [ |
UK | Prospective | Gastrointestinal and hepatobiliary surgery | n = 381 | ≥ 6.5% (n = 49, 27.1%) | Within 3 months of the surgery | · Primary: 30-day complications defined by CD |
< 6.5% (n = 132, 72.9%) | · Secondary: Major complications, 30-day readmission rates, postoperative care setting | ||||||
Huang et al. 2017 [ |
China | Retrospective | Surgical resection for gastrointestinal cancer | n = 209 | ≥ 7% (n = 67, 56.8%) | Not stated | · 30-day and 180-day mortality rates |
< 7% (n = 51, 43.2%) | · Postoperative complications | ||||||
· Length of hospital stay | |||||||
Jones et al. 2017 [ |
USA | Retrospective | Gastrointestinal surgery | n = 21541 | > 6.5% (n = 8822, 41.0%) | Within 3 months of the surgery | · Any post-operative complication |
5.7–6. 5% (n = 8118, 37.7%) | · Infectious complications (wound infection, pneumonia, urinary tract infection, sepsis) | ||||||
< 5.7% (n = 4601, 21.4%) | · Post-discharge outcomes (readmission within 14 d, readmission within 30 d) | ||||||
Villamiel et al. 2019 [ |
Philippines | Retrospective | Elective colorectal surgery | n = 157 | > 7% (n = 15, 34.1%) | Not stated | · Primary: Length of hospital stay |
≤ 7% (n = 29, 65.9%) | · Secondary: Discharge within 30 postoperative days, postoperative complications, reoperation, pneumonia, wound infection | ||||||
Okamura et al. 2017 [ |
Japan | Retrospective | Esophagectomy for esophageal cancer | n = 300 | ≥ 6.5% (n = 27, 9%) | Within 3 months of the surgery | · Anastomotic leak |
6.0–6.4% (n = 50, 16.7%) | |||||||
< 6.0% (n = 223, 74.3%) | |||||||
Oh et al. 2018 [ |
South Korea | Retrospective | Elective major laparoscopic abdominal surgery | n = 1885 | ≥ 6.0% (n = 628, 33.3%) | Within 1 month of the surgery | · Acute kidney injury (post-operative day 0–3, stage 1–3) |
< 6.0% (n = 1257, 66.7%) | |||||||
Chen et al. 2018 [ |
China | Retrospective | Colorectal surgery | n = 126 | > 6.3%, (n = 67, 53.2%) | Not stated | · Anastomotic leak |
≤ 6.3% (n = 59, 46.8%) | |||||||
Zhou et al. 2019 [ |
China | Retrospective | Colorectal and upper gastrointestinal surgery | n = 118 | 7–8% (n = 27, 22.9%) | Not stated | · Postoperative delirium |
6.5 ≤ 7% (n = 27, 22.9%) | |||||||
5.7 ≤ 6.5% (n = 34, 28.8%) | |||||||
< 5.7% (n = 30, 25.4%) | |||||||
Dai et al. 2017 [ |
China | Retrospective | Colorectal surgery | n = 201 | > 7% (n = 112, 55.7%) | Not stated | · Anastomotic leak |
≤ 7% (n = 89, 44.3%) | · Length of stay | ||||||
· Duration of surgery | |||||||
· Major intra-operative bleeding | |||||||
· Infections | |||||||
· Acute myocardial infarction | |||||||
Zhang et al. 2008 [ |
China | Retrospective | Cholecystectomy | n = 86 | > 7.0 | Not stated | · Anastomotic leak |
< 7.0 | · Infections | ||||||
Number of patients per group not reported | |||||||
Wang et al. 2010 [ |
China | Retrospective | Gastrointestinal tumor surgery | n = 82 | < 6.2 (n = 47, 79.7%) | Not stated | · Bloatedness |
≥ 6.2 (n = 35, 42.7%) | · Nausea and vomiting | ||||||
· Anastomotic leak | |||||||
· Time to flatus | |||||||
· Length of hospital stay |
Included four gynecological procedures that constituted only 0.7% of the total number of surgeries.
GRADE Evidence Profile
Quality assessment | No. of patients | Relative Effect (95% CI) | Quality | |||||||
---|---|---|---|---|---|---|---|---|---|---|
No. of studies | Design | Risk of bias | Inconsistency | Indirectness | Imprecision | Other considerations | Elevated HbA1c | Normal HbA1c | ||
9 | Observational studies | Moderate | - | - | - | - | 586 | 1024 | OR 2.16 (1.54, 3.01) | ⊕⊕⊕⊖ |
Moderate | ||||||||||
12 | Observational studies | Moderate | - | - | - | Large effect size | 10063 | 15030 | OR 2.12 (1.48, 3.04) | ⊕⊕⊕⊖ |
Moderate | ||||||||||
6 | Observational studies | Moderate | - | - | - | - | 339 | 608 | OR 2.80 (1.63, 4.83) | ⊕⊕⊖⊖ |
Low | ||||||||||
6 | Observational studies | Moderate | - | - | Serious | 9082 | 13024 | OR 1.69 (1.05, 2.71) | ⊕⊕⊖⊖ | |
Low | ||||||||||
3 | Observational studies | Moderate | - | - | Serious | 8920 | 12859 | OR 1.21 (1.08, 1.36) | ⊕⊕⊖⊖ | |
Low | ||||||||||
4 | Observational studies | Moderate | Serious | - | Serious | - | 8935 | 12888 | OR 0.77 (0.61, 0.97) | ⊕⊕⊖⊖ |
Low |
OR: odds ratio.