Inpatients presenting worldwide for noncardiac surgery have a baseline 30-day mortality of 1.5%,1 which depends on the surgical procedure (0.07% for breast surgery, 5.97% for vascular surgery)2 and the presence of comorbidities. Diabetic patients, however, have a higher postoperative in-hospital mortality of 3.5% than nondiabetic controls matched by surgical procedure.3 Long-term mortality, as well as the incidence of infectious and cardiac complications, are higher in diabetic patients who represent an increasing medical and socio-economic burden.3 In 2000, the worldwide prevalence of diabetes was estimated to be 2.8% and is predicted to increase to 4.4% by 2030.4 Thus, an increasing number of patients with this important risk factor for postoperative complications5 will present for surgery. Apart from existing screening programmes for diabetes, perioperative physicians have to develop direct strategies to minimise the risk of surgery in this vulnerable patient population.
The current financial pressures on healthcare systems forces clinicians to periodically re-evaluate the economic impact of their daily practice. A recent systematic review on the influence of blood glucose concentration on the outcome of patients scheduled for ambulatory surgery concluded that there was insufficient evidence to recommmend the level of blood glucose concentration above which delaying surgery was justifiable.6 As a consequence, the question arises as to whether preoperative glucose testing has any influence on postoperative outcomes in patients without a history of diabetes or in diabetic patients, who are scheduled for elective surgery. The guidelines produced by the National Institute for Health and Clinical Excellence (NICE) in 2003 do not recommend preoperative testing of blood glucose concentration and haemoglobin A1C (HbA1C).7 There is a strong need to update the available evidence regarding noncardiac preoperative testing to renew and strengthen current recommendations. We therefore conducted a systematic review of the literature on various preoperative tests from 2001 to 20118 to update the findings of the earlier NICE review.7 Using the same methodological approach, we performed a systemic review of clinical trials reporting the impact of preoperative testing of blood glucose concentration and HbA1C on outcome after elective noncardiac surgery in patients aged at least 18 years.
Objective and research questions
Our research questions focused on the effectiveness of preoperative glucose testing in elective noncardiac surgery. Specifically, does the finding of abnormal results during preoperative laboratory testing of blood glucose concentration and HbA1C lead to changes in clinical management, and/or is this testing associated with reduced perioperative and postoperative complications such as mortality or morbidity (including complications and adverse events) in unselected patients, and patients with diabetes, scheduled for elective, noncardiac surgery?
Materials and methods
The methodology of this systematic review is based on the Scottish Intercollegiate Guidelines Network (SIGN) handbook,9 the PRISMA statement for reporting systematic reviews10 and the manual of the Ludwig Boltzmann Institute for Health Technology Assessment (HTA), Vienna.11 We classified the level of evidence of each study included according to the SIGN handbook9 (Table 1). The Cochrane Collaboration handbook12 was used to assess the risk of bias of the analysed studies.
We conducted a systematic literature search on 3 February 2011 that was updated on 13 March 2013 searching Medline, Embase, DARE-NHSEED-HTA (INAHTA) and The Cochrane Library. The search terms used in Medline and Embase are summarised in Table 2. Population (A), study design and outcome (B) and search strings for specific tests (C) were combined with ‘AND’ (A and B and C). The search terms within the three main categories (A, B and C) were combined with ‘OR’. In addition, we searched health technology assessments using the following sites: NHS Institute for Health and Clinical Excellence; Canadian Agency for Drugs and Technologies in Health; and National Coordinating Centre for Health Technology Assessment. Finally, we conducted a hand search reviewing the references of the included studies. The full search strategy is available in Appendix I (http://links.lww.com/EJA/A51).
Table 3 illustrates the PICOS framework (Population, Intervention, Control, Outcome, Study design) selection criteria. Eligible articles had to meet all the inclusion criteria.
Two reviewers independently screened each title and abstract of a potentially eligible report using Reference Manager (Version 12.0; Thomson Reuters, New York, USA) with the help of a standardised internal manual. We required general agreement for inclusion or exclusion of each publication. The two researchers discussed the articles in the case of disagreement, with the opinion of a third researcher decisive in cases of disagreement. We created six extraction tables for blood glucose concentration and HbA1C in order to present the following parameters (Appendix II and III, http://links.lww.com/EJA/A51):
- Table A: Characteristics of included studies;
- Table B: Results of included studies (multivariate analysis only);
- Table C: Description of abnormal tests and outcomes;
- Table D: Accuracy of the tests;
- Table E: Excluded studies.
We assessed the patients’ physical status using the classification proposed by the American Society of Anesthesiologists (ASA).13 The invasiveness of the surgical procedures was graded according to the classification for cardiac risk stratification produced by the American College of Cardiologists/American Heart Association.14 Data are presented as odds ratio (OR) and 95% confidence interval (95% CI). Two researchers classified the quality of the studies enrolled using the SIGN grading system (Table 1). We assessed the risk of bias by checking the single items of the table presented in Appendix IV, http://links.lww.com/EJA/A51, which summarises the various types of bias defined by the Cochrane Collaboration. Studies were assessed according to their quality, design and heterogeneity. When at least two trials presented homogeneous data on participants, interventions and outcome parameters, the results of the studies were pooled; otherwise, we reported a narrative summary.
The literature search retrieved 1343 records. After removal of 19 duplicate studies, we screened 1324 abstracts for eligibility. Eighty-three articles were selected for full-text analysis. Twenty-two studies15–36 met all the inclusion criteria and were included in the review (Fig. 1). Four studies analysed both preoperative blood glucose and HbA1C testing.22,25,26,36 The results regarding outcomes for blood glucose concentration and HbA1C are presented in the following order: changes in clinical management; mortality; and postoperative morbidity. Appendix IV, http://links.lww.com/EJA/A51 summarises the risk of bias of the single trials, which was high in the majority of categories, mainly due to the lack of randomised controlled trials (RCTs).
Preoperative blood glucose concentration
We included 17 clinical trials evaluating the effectiveness of preoperative blood glucose testing 17,18,20–23,25,26,28–36. Fifteen studies were obtained by database search and two by hand search.26,35 Two studies were retrospective case–control studies,31,32 with the remaining 15 cohort studies. Five cohort studies had a prospective design,18,20,22,25,36 whereas 10 were retrospective.17,21,23,26,28–30,33–35 Sixty trials were excluded (Appendix II, Table E, http://links.lww.com/EJA/A51; multiple reasons for exclusion).
Appendix II, http://links.lww.com/EJA/A51, presents the general characteristics, the results based on multivariate analysis, the definitions of abnormal values for blood glucose, accuracy, clinical outcome definitions in the single trials and level of evidence of all the included studies.
Changes in clinical management
None of the included studies reported changes in clinical management as a result of biochemical testing (Appendix II, Table B, http://links.lww.com/EJA/A51).
Two studies enrolling patients undergoing vascular surgery28 and noncardiac, nonvascular surgery31 found an association between elevated blood glucose levels and 30-day mortality. McGirt et al.28 reported an OR of 3.29 (1.07 to 10.09) among patients undergoing carotid endarterectomy. In patients scheduled for noncardiac, nonvascular surgery, serum glucose levels 6.1 to 11.1 mmol l−1 [OR 1.7 (1.4 to 2.1)] and serum glucose levels more than 11.1 mmol l−1 [OR 2.1 (1.3 to 3.5)] were independent risk factors for 30-day mortality.31 Among patients scheduled for vascular surgery,22 elevated blood glucose levels were associated with increased long-term mortality [OR 2.0 (1.1 to 3.8) for patients with impaired glucose regulation; OR 2.7 (1.2 to 5.6) for patients with diabetes]. Two other trials on unspecified surgical patients34 and patients undergoing pancreaticoduodenectomy35 did not observe a significant difference in mortality between patients presenting with elevated or normal preoperative blood glucose concentrations (Appendix II, Table B, http://links.lww.com/EJA/A51).
Four studies20,21,34,35 analysed the impact of preoperative blood glucose levels on the cumulative incidence of postoperative complications. Blood glucose ranging from 5.5 to 6.9 mmol l−1 and glucose levels more than 6.9 mmol l−1 were associated with an increased incidence of complications [OR 2.2 (1.05 to 4.27) and 3.05 (1.52 to 6.13), respectively] after unspecified surgery.34 Abnormal preoperative blood glucose levels were not associated with an increased incidence of postoperative complications in patients undergoing noncardiac surgery20 or pancreaticoduodenectomy21,35. Elevated serum glucose levels were, however, related to an increased incidence of cardiac complications in patients scheduled for vascular surgery. Impaired glucose tolerance was associated with a higher incidence of myocardial ischaemia [OR 2.2 (1.3 to 3.9)], troponin-T release [OR 3.8 (2.1 to 7.0)], 30-day major cardiac events [OR 4.3 (1.4 to 13.5)] and 30-day composite of cardiac events [OR 2.4 (1.4 to 4.1)]. Diabetic patients showed similar increases in the incidence of myocardial ischaemia [OR 2.6 (1.4 to 4.9)], troponin-T release [OR 3.9 (2.0 to 7.7)], 30-day major cardiac events [OR 4.8 (1.4 to 16.6)] and 30-day composite of cardiac events [OR 3.9 (2.1 to 7.3)], in addition to a greater incidence of long-term cardiac events [OR 3.1 (1.5 to 6.4)].22 This association was also demonstrated in trials on patients scheduled for carotid endarterectomy [myocardial infarction OR 4.29 (1.28 to 14.39) with blood glucose >11.1 mmol l−1]28 or miscellaneous noncardiac procedures [perioperative cardiovascular events OR 2.1 (0.99 to 4.49) for impaired fasting glucose and OR 6.4 (3.57 to 11.48) for diabetes].18 In patients undergoing carotid endarterectomy, elevated serum glucose levels were a risk factor for perioperative stroke or transient ischaemic attack [OR 2.78 (1.37 to 5.67)].28
There was no association between blood glucose and the incidence of postoperative infections in patients undergoing noncardiac surgery26, general and vascular surgery17,33 and those undergoing foot and ankle surgery.36 Elevated blood glucose concentrations were, however, an independent risk factor for infectious complications in orthopaedic surgery [1-year prosthetic joint infection: blood glucose 6.1 to 6.9 mmol l−1: NS; blood glucose >6.9 mmol l−1: OR 4.41 (1.31 to 14.83)].25 Similar results have been shown in patients having spinal surgery32 [OR 5.3 (2.5 to 11.2) for patients with preoperative glucose levels more than 6.9 mmol l–1 and OR 3.3 (1.4 to 7.5) for an elevated serum glucose level (preoperative random or fasting serum glucose level of >6.9 mmol l−1or postoperative random serum glucose level of >11.1 mmol l−1)].
Two studies reported on the accuracy and positive predictive values of preoperative blood glucose testing for pulmonary embolism, in-hospital mortality and prosthetic joint infection.25,29 One study provided data on accuracy and positive predictive value for postoperative pulmonary embolism. The accuracy using a lower cut-off of blood glucose of at least 6.1 mmol l−1 was 73.0% with a positive predictive value of 2.0%. With an upper cut-off of blood glucose of at least 11.1 mmol l−1, the accuracy was 96.8% with a positive predictive value of 5.1%.29 The same study provided data on accuracy and positive predictive value for in-hospital mortality. The accuracy using a blood glucose cut-off of at least 11.1 mmol l−1 was 98.1% with a positive predictive value of 0.7%.29 One further study provided data on accuracy and positive predictive value for postoperative prosthetic joint infection rate within 1 year. The accuracy using an abnormal blood glucose definition of at least 7.0 mmol l−1 was 78.9% with a positive predictive value of 2.5%24 (Appendix II, table D, http://links.lww.com/EJA/A51).
Preoperative concentration of HbA1C
We included nine clinical trials evaluating the effectiveness of preoperative HbA1C testing.15,16,19,22,24–27,36 Seven studies were obtained by database search compared with two studies retrieved by hand search.26,27 All the studies were cohort trials, five with a prospective design,22,24,25,27,36 while the remaining four were retrospective studies.15,16,19,26 Twenty-one studies were excluded (Appendix III, Table E, http://links.lww.com/EJA/A51; multiple reasons for exclusion possible). Appendix III, http://links.lww.com/EJA/A51 presents the general characteristics of the nine included trials on preoperative HbA1C testing, results based on multivariate analysis, definitions of abnormal values for HbA1C, data on accuracy (when applicable), clinical outcome definitions and the level of evidence of the trials enrolled. Appendix III, http://links.lww.com/EJA/A51, Table B further provides data from multivariate analysis on mortality and postoperative morbidity in clinical trials for HbA1c testing.
Changes in clinical management
None of the included studies reported changes in clinical management as a result of biochemical testing (Appendix III, Table B, http://links.lww.com/EJA/A51)
Preoperative HbA1C levels were not associated with increased 30-day mortality in a cohort of 38 989 patients undergoing major or cardiac surgery15 or colorectal surgery.24 In contrast to these results, Feringa et al.22 found an association between the level of HbA1C in preoperative testing and long-term mortality within 2.5 years [OR 3.6 (1.2 to 11.1)]. Six studies did not provide data on the association between the level of HbA1C in preoperative testing and mortality.16,19,25–27,36
Preoperative HbA1C concentrations were not associated with an increased number of complications in patients undergoing cardiac and major noncardiac surgery.15 In patients scheduled for colorectal surgery,24 HbA1C concentrations more than 6% (42 mmol mol−1) were associated with an increased incidence of postoperative complications [OR 2.9 (1.1 to 7.9)]). HbA1C concentrations ≤6% (42 mmol mol−1) predicted an earlier start of oral feeding (adjusted P = 0.013 after multiple linear regression, OR not available) and lower levels of C-reactive protein during the first 3 days after surgery (adjusted P = 0.008 after multiple linear regression, OR not available).
Preoperative HbA1C concentrations were not associated with an increased incidence of perioperative myocardial infarction in one trial involving vascular surgery patients.27 This is in contrast to another vascular surgery study that observed an increased incidence of myocardial ischaemia [OR 2.8 (1.3 to 6.0)], troponin-T release [OR 2.1 (1.1 to 6.5)] and major cardiac events after 30-day [OR 5.3 (1.7 to 16.6)] and 2.5-year follow-up [OR 5.6 (2.1 to 14.6)].22 In this study, elevated HbA1C concentrations were also associated with an increased 30-day composite of cardiac events [OR 3.0 (CI 1.4 to 6.5)].22
Five studies analysed the impact of HbA1C concentration on infectious complications. One trial on noncardiac surgery involving 647 patients calculated an OR of 2.13 (1.23 to 3.70) for infectious complications if preoperative HbA1C concentrations were more than 7% (53 mmol mol−1).19 A larger study of 55 408 patients undergoing noncardiac surgery could, however, not confirm these results.26 Glycated haemoglobin predicted the incidence of postoperative prosthetic joint infections in patients undergoing knee replacement surgery [OR 1.60 (1.09 to 2.37) per 1% unit increase in HbA1C],25 but did not predict infectious complications in patients scheduled for foot and ankle surgery.36 HbA1C concentrations were not associated with infectious complications after colorectal surgery.24
One study provided data on the accuracy and the positive predictive value for postoperative prosthetic joint infection rate within 1 year. The accuracy using an abnormal HbA1c definition of at least 6.5% (48 mmol mol−1) was 55.1% with a positive predictive value of 2.84%.25
The general level of evidence for the impact of routine preoperative testing of blood glucose or HbA1C on the perioperative management of surgical patients and on postoperative outcome is low. Randomised control trials comparing patients with preoperative tests for blood glucose or HbA1C with an adequate control group (i.e. patients without the respective test) are lacking. All the studies in this review evaluated patients with known diabetes in conjunction with otherwise healthy patients. Therefore, the ORs denoting an increased risk for patients with diabetes only convey the information that diabetes is a risk factor for increased perioperative and postoperative morbidity and mortality, but do not imply that preoperative testing predicts or alters postoperative outcome. To show the latter, patients with and without diabetes would need to be evaluated separately.
Several of the cohort studies analysed in this systematic review refer indirectly to clinical situations in which preoperative testing for blood glucose or HbA1C might be indicated. Definitions for abnormal values of blood glucose and HbA1C vary between the studies, further complicating the interpretation of the results.
Patients scheduled for vascular, orthopaedic and spinal surgery should be considered separately. Various studies observed an association between preoperative blood glucose concentration and the risk of infectious complications among patients undergoing spinal surgery, knee or hip replacement25,32 and orthopaedic trauma patients.37 We excluded the latter study because the authors enrolled patients undergoing urgent and emergent surgery. Elevated preoperative blood glucose concentrations in patients undergoing vascular surgery were correlated to a higher incidence of cardiac and vascular complications (cardiac events, myocardial ischaemia, release of markers for myocardial damage,22 myocardial infarction28 and cerebrovascular ischaemic events28). Furthermore, preoperative hyperglycaemia was also associated with an increased 30-day mortality in patients scheduled for general surgery31 and an increased long-term mortality in vascular surgery patients.22 Finally, elevated preoperative blood glucose levels correlated with abnormal postoperative values and worsening of postoperative outcomes.38
We did not find an association between elevated levels of HbA1C and negative postoperative outcomes in an unselected general surgical population. There is some evidence, however, that diabetic patients and patients scheduled for vascular22 or joint replacement25 surgery may represent a subgroup with elevated risk. In these patients, we observed an association between elevated preoperative values for HbA1C and the incidence of cardiac22 or infectious complications.25 In patients scheduled for colorectal surgery, elevated levels of HbA1C were associated with a prolonged recovery, higher postoperative blood glucose levels and infectious complications. Even slightly elevated values of HbA1C [6.1 to 7% (43 to 53 mmol mol-1)] were associated with an increased cardiac morbidity after vascular surgery in patients with primarily undiagnosed prediabetes.39 We did not include this trial in our analysis, as the authors enrolled patients scheduled for elective as well as for emergent surgery. There is ambiguous evidence for the impact of testing for HbA1c on postoperative mortality. Elevated concentrations of HbA1C were not associated with increased postoperative 30-day mortality in patients scheduled for cardiac and major surgery15 but predicted an increased long-term mortality in vascular surgery patients.22,27
Preoperative tests for diabetes must be seen in the context of the general screening of a healthy population. If a surgical patient did not participate in these screening programs, preoperative testing for blood glucose seems desirable in vascular surgery,23 a cohort with a high incidence of diabetes. Dunkelgrun et al.40 performed an oral glucose tolerance test in patients without a history or signs of impaired glucose tolerance or diabetes, who were scheduled for vascular surgery. 36.3% of these patients had an impaired glucose tolerance or newly diagnosed diabetes, and preoperative glucose levels significantly predicted the risk of myocardial ischaemia within an observation period of up to two days after surgery. These patients also had an increased incidence of cardiovascular events and a higher mortality in the longer term.41 The authors concluded that an oral glucose tolerance test might be indicated as a routine preoperative test in these high-risk patients. We did not include these trials in our systematic review because the oral glucose tolerance test was not a primary study parameter, but these studies demonstrate the importance of a detailed evaluation of both the procedural and patient-related aspects prior to undertaking preoperative testing.
Preoperative Hb1AC more than 7% (53 mmol mol−1) was a predictor of postoperative hyperglycaemia in patients with diabetes undergoing elective noncardiac surgery.42 We excluded this study from our analysis, as we did not consider postoperative blood glucose a direct outcome parameter. This study, however, underlines the importance of postoperative glucose control in diabetic patients and might justify preoperative screening for Hb1AC in a well defined risk group. In the light of the evidence discussed above, we recommend risk stratification prior to preoperative testing for blood glucose or HbA1C in otherwise healthy patients. Although testing seems to be justified in particular risk groups such as patients scheduled for joint replacement, spinal or vascular surgery, unselective testing should be avoided. We did not identify sufficiently powered studies to give recommendations for diabetic patients in particular. The standards of state of the art diabetes care should, therefore, be observed in the preoperative assessment of patients with diabetes. Moreover, physicians should clearly distinguish between preoperative assessment and screening programmes for preventive medicine.
This review has some strengths and limitations. We restricted our comprehensive search to the evidence published from 2001 to 2013 because this time period guaranteed an overlap of more than one year with the NICE review and the preceding HTA report, which included studies published from 1966 to 2002. As both the NICE review and the HTA report involved analysis of a high quality, we decided to update the NICE review rather than repeating it. Furthermore, our results confirm the conclusions of the authors of the NICE report. Both our study and the NICE report are characterised by a lack of RCTs, a low number of high quality studies and a high heterogeneity amongst the included studies. Thus, neither the NICE researchers nor we could perform a meta-analysis, and therefore, a combined meta-analysis of all the trials included in the NICE review and our review would not have been reasonable. The design of a study is critical to judge the quality of evidence. We preferred to use the SIGN classification rather than the GRADE approach to assess the level of evidence, as only observational studies were included in this systematic review. The GRADE approach allows a very detailed distinction in quality of evidence primarily for RCTs. We found our approach to be more applicable and feasible to distinguish the quality of evidence for observational studies.
No data derived from high quality studies support the effectiveness of routine testing for preoperative blood glucose concentration and HbA1c in otherwise healthy adult patients undergoing elective, noncardiac surgery. Thus, both the NICE review and this systematic review do not recommend routine preoperative testing for blood glucose or HbA1C in otherwise healthy patients. Preoperative testing for blood glucose or HbA1c might be justified as a screening test among patients at elevated risk, such as those scheduled for vascular and major orthopaedic surgery. Further research, especially large scale multicentre RCTs, are necessary to explore the effectiveness of the preoperative testing of glucose in elective surgical patients, to support clinicians and policy makers in making informed decisions.
Acknowledgements relating to this article
Assistance with the systematic review: none.
Financial support and sponsorship: this study was supported by the Austrian Federal Ministry of Health and the Austrian Society of Anaesthesiology, Resuscitation and Intensive Care Medicine.
Conflicts of interest: none.
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