Peri‐operative glycemic control regimens for preventing surgical site infections in adults
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To summarize evidence for the impact of glycemic control in the peri‐operative period on the incidence of surgical site infections, hypoglycemia, level of glycemic control, all‐cause and infection‐related mortality, and hospital length of stay and to investigate for differences of effect between different levels of glycemic control.
Background
Surgical site infections (SSIs) can result in death, increased hospital length of stay, and increased resource utilization (Kirkland 1999). SSIs can range from simple wound infections involving the skin and subcutaneous tissues, to deep soft‐tissue infections, or infections of the space or organ manipulated during the surgical procedure. Depending on the location, depth, and severity of the infection, an SSI can cost up to tens of thousands of dollars per case (Fry 2002). Both pre‐existing patient diseases (such as diabetes) and modifiable risk factors (such as failure to use sterile precautions or to administer appropriate antibiotics prior to surgery) contribute to the development of these infections. One modifiable risk factor associated with SSIs is peri‐operative hyperglycemia or elevated blood glucose levels around the time of surgery (Estrada 2003; Pomposelli 1998; Trick 2000). While normal glucose levels in non‐diabetic non‐stressed patients range from 70‐110 mg/dL, glucose levels between 110 and 200 mg/dL have not traditionally been treated in the peri‐operative period. Currently, published guidelines from the Centers for Disease Control, that were based on observational data, (Zerr 1997) recommend peri‐operative treatment of hyperglycemia in patients with diabetes to achieve levels below 200 mg/dL (Mangram 1999). This recommendation, however, has been challenged by new evidence that more aggressive treatment of elevated glucose levels with insulin reduces infectious complications (Furnary 2004; Grey 2004; Van den Berghe 2001). The optimal glucose level is unknown, particularly since hypoglycemia (defined as glucose levels less than 40‐60 mg/dL) ‐ which can result in seizures, hypotension and death ‐ becomes of increasing concern with a lower glucose target (Bhatia 2006). A large amount of the available data evaluating the effect of different degrees of glycemic control on SSIs is limited to cardiac surgery patients, which raises questions about the generalisability of this information to other surgical patients (Furnary 2004; Van den Berghe 2001).
Hyperglycemia has been demonstrated to occur after surgical stress ‐ even after uncomplicated elective surgery ‐ and may increase the risk of infectious complications (Ljungqvist 2005). Hyperglycemia incites the release of pro‐inflammatory mediators and depresses the immune system, thus increasing susceptibility to bacterial infections(Cavaillon 2001; Delamaire 1997; Stephan 2002). In critically‐ill patients who require intensive care, treatment of hyperglycemia with intravenous insulin infusions results in fewer infections and improved outcome. The largest randomized trial (of more than 1500 patients) of strict glycemic control to maintain glucose levels less than 110 mg/dL as compared to less than 200 mg/dL in critically‐ill patients (the Leuven trial) demonstrated reduced bloodstream infections and improved mortality in patients receiving strict glycemic control (Van den Berghe 2001). Although the majority of patients were cardiac surgery patients, SSIs were not measured as an outcome. A smaller randomized trial in 61 critically‐ill surgical patients demonstrated that targeting blood glucose levels between 80‐120 mg/dL versus 180‐220 mg/dL resulted in fewer healthcare‐acquired infections, including SSIs. (Grey 2004).
Strict glycemic control has not been uniformly adopted in surgical patients, however, because both the reproducibility of the results of the Leuven trial and the generalisability to other patient groups have been challenged by subsequent randomized trials. A large multi‐center randomized trial by the German Competence Sepsis Network of two glycemic control regimens was stopped early due to the rate of hypoglycemia and lack of mortality benefit (Brunkhorst 2005), and an adequately‐powered follow up to the Leuven trial failed to demonstrate a mortality benefit in medical critically‐ill patients (Van den Berghe 2006). Furthermore, since not all surgical patients require intensive care post‐operatively, the question of generalisability of this trial is raised further.
In addition to randomized trials in critically‐ill patients, several studies ‐ largely published in the cardiothoracic surgery literature ‐ have reported an association between peri‐operative glucose levels and post‐operative infection rates(Estrada 2003; Furnary 2004; Trick 2000; Zerr 1997). A large proportion of these data were derived from retrospective and prospective cohort studies. Additionally, the timing of glucose control (pre‐, intra‐, or post‐operative) and the target levels vary between studies. Many of these studies utilize a threshold of 200 mg/dL to define hyperglycemia, which may still confer an increased risk for SSIs and mortality in critically‐ill cardiac‐surgery patients; the risks and benefits of a lower threshold remain to be clarified. In a large sequential cohort study, the Portland Diabetic Project demonstrated a benefit to continuous insulin infusion after cardiothoracic surgery in diabetic patients (Furnary 2004). Since 1991 they have continuously lowered the post‐operative glucose target from between 150 to 200 mg/dL (between 1991 and 1998), to between 125 to 175 mg/dL (in 1999), and then to between 100 and 150 mg/dL (in 2001). They have reported a corresponding reduction in deep sternal infections with strict glycemic control, with a significant decrease in infections with glucose levels below 175 mg/dL (Furnary 2004). Despite this, and as for other sequential cohort studies, confounding by other factors such as changes in surgical techniques over time, cannot be excluded. Moreover, despite the success of the Portland Diabetic Project, a pre‐ and post‐cohort study after implementation of a protocol to treat glucose levels greater than 110 mg/dL failed to demonstrate an improvement in the SSI rate in trauma patients (Collier 2005). Thus, the question of whether cardiac‐surgery patients differ from other surgical patients has been raised. One difference may be that hypothermic cardiopulmonary bypass results in significant hyperglycemia in patients with impaired glucose tolerance, and patients with diabetes who undergo heart bypass surgery require more insulin than those undergoing general surgical procedures (Kennedy 1994). Therefore, the benefits of using a lower glycemic target may be more profound amongst cardiothoracic surgery patients, particularly those with diabetes, than in general surgical patients.
This review will consider the evidence for the impact of glycemic control (target blood glucose below the conventional target of 200 mg/dL) in the peri‐operative period for prevention of surgical site infections. This review will evaluate whether the evidence supports the use of strict glycemic control to normalize glucose levels to 110 mg/dL in both cardiac and general surgical patients without increasing harm due to hypoglycaemia. Furthermore, differences in outcome with other glycemic targets between 110 and 200 mg/dL will be evaluated.
Objectives
To summarize evidence for the impact of glycemic control in the peri‐operative period on the incidence of surgical site infections, hypoglycemia, level of glycemic control, all‐cause and infection‐related mortality, and hospital length of stay and to investigate for differences of effect between different levels of glycemic control.
Methods
Criteria for considering studies for this review
Types of studies
Prospective randomized controlled trials (RCTs) or quasi‐randomized studies (QRCTs), in which patients were assigned to different glucose control regimens pre‐, intra‐, or post‐operatively will be included.
Types of participants
People aged 18 years of age or above who are undergoing a surgical procedure, (i.e. an operation in which a skin incision is made).
Types of interventions
One glycemic control regimen compared with another glycemic control regimen pre‐, intra‐, and/or post‐operatively. Since conventional therapy is to treat glucose levels above 200 mg/dL, comparison will be made between conventional treatment (of glucose values above 200 mg/dL) and lower targets (between 110 and 200 mg/dL) or between two regimens evaluating glycemic targets both below 200 mg/dL. Only glycemic control regimens using medications to lower glucose levels (oral, subcutaneous, and/or intravenous) will be included. A subgroup analysis will be performed of studies using intravenous insulin as the lower targets for glycemic control are not achievable in hyperglycemic patients with oral medications or subcutaneous insulin alone, and insulin infusions have a higher theoretical risk of hypoglycemia. Pre‐operative glycemic control will be limited to within one week before surgery as the effects of long‐term glucose control on outcome is a separate question.
Types of outcome measures
Primary outcomes
The primary outcome will be the incidence of surgical site infections as defined by the study authors.
Secondary outcomes
When reported, the following secondary outcomes will also be recorded:
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incidence and severity of hypoglycemia (defined as less than 60 mg/dL);
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level of glycemic control (percentage of measurements within the target range);
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all‐cause and infection‐related mortality;
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length of hospital stay.
Search methods for identification of studies
Electronic searches
We will search the following electronic databases to identify trials for inclusion in this review:
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The Cochrane Wounds Group Specialised Register;
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The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, latest issue);
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MEDLINE (1966 to date);
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EMBASE (1980 to date);
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Current Contents (1993 to date).
The provisional search strategy for CENTRAL will be:
#1MeSH descriptor Blood Glucose explode all trees
#2MeSH descriptor Hypoglycemic Agents explode all trees
#3MeSH descriptor Hyperglycemia explode all trees
#4MeSH descriptor Hypoglycemia explode all trees
#5MeSH descriptor Insulin explode all trees
#6blood glucose:ti,ab,kw
#7(hypoglycaemi* or hypoglycemi*) NEXT (agent* or drug*):ti,ab,kw
#8(glucose or glycaemic or glycemic) NEXT control*:ti,ab,kw
#9oral NEXT (hypoglycaemi* or hypoglycemi*):ti,ab,kw
#10glucose NEXT target:ti,ab,kw
#11insulin:ti,ab,kw
#12(#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11)
#13MeSH descriptor Surgical Wound Infection explode all trees
#14surg* NEAR/5 infection*:ti,ab,kw
#15surgical NEAR/5 wound*:ti,ab,kw
#16MeSH descriptor Infection Control, this term only
#17(#13 OR #14 OR #15 OR #16)
#18(#12 AND #17)
This strategy will be modified where necessary for MEDLINE, EMBASE and CINAHL. ClinicalTrials.gov will be searched for relevant ongoing studies.
Searching other resources
The reference lists for all eligible trials, key textbooks, and relevant systematic reviews will be handsearched for additional trials. Trial report authors will be contacted to identify any additional published or unpublished data. Handsearching of the following conference proceedings from the past 10 years' meetings will be carried out ‐ Surgical Infection Society, European Surgical Infection Society, American College of Surgeons, Society of Critical Care Medicine and Society of Cardiac Surgeons.
The search will not be limited by language or publication status. Non‐English language papers will be translated with the assistance of a native speaker and included if relevant.
Data collection and analysis
The standard method for conducting a systematic review, as described in the Cochrane Collaboration Handbook, version 4.2.5, will be used for this review.
Selection of studies
Independently two authors will screen the titles and abstracts of trials identified by the search and then assess the full versions of all relevant articles for inclusion in the review according to predetermined selection criteria. Any disagreement will be resolved by discussion and, if necessary, the third author.
Data extraction and management
Details of the studies will be abstracted by one author and then checked by another author. Authors of studies will be contacted when possible to provide missing information. The following information will be included on the data extraction form:
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Publication details.
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Study design (inclusion/exclusion criteria, method of allocation, sample size calculations).
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Patient population (age, diabetes, pre‐operative glucose level, type of surgical procedure(s), number of patients, pre‐operative risk stratification for SSI using the National Nosocomial Infection Surveillance System or NNIS score, use of standard preventive measures (sterile precautions, antibiotic administration)).
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Setting of treatment (including country).
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Duration of treatment and follow up.
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Details of intervention and control or comparison strategy (timing of treatment pre‐, intra‐, or post‐operatively) insulin or oral hypoglycemics, glucose target range).
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Outcome measures (SSIs, hospital length of stay, all‐cause and infection‐related mortality, hypoglycemia less than 60 mg/dL, level of glycemic control or percentage of glucose values in range).
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Adverse effects (for example hypoglycemia).
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Withdrawals (per group with numbers and reasons).
Assessment of risk of bias in included studies
The methodological quality of the studies will be assessed using the following quality checklist:
Adequacy of the randomisation process:
Trials will be awarded the following grades for adequacy of the randomization process:
A = adequate sequence generation reported using random number tables, computer random number generator, coin tossing, or shuffling.
B = did not specify one of the adequate reported methods in (A) but mentioned randomization method.
C = other method of allocation that may not be random.
Adequacy of allocation concealment
Trials will be awarded the following grades for allocation concealment:
A = adequate: a randomization method described that would not allow an investigator/participant to know or influence an intervention group before an eligible participant entered the study, such as central randomization; serially numbered, opaque, sealed envelopes.
B = unclear: trial states that it is randomized, but no information on the method used is reported or a method is reported that was not clearly adequate.
C = inadequate: inadequate method of randomization used, such as alternate medical record numbers or unsealed envelopes; or any information in the study that indicated that investigators or participants could influence the intervention group.
Blinding
The following points will be graded as yes for present, no for absent, and not reported if the relevant information is not stated in the trial report:
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Blinding of investigators.
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Blinding of participants.
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Blinding of outcome assessor.
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Blinding of data analysis.
Intention‐to‐treat analysis
A ‐ yes: either specifically reported by authors that ITT analysis was undertaken and this was confirmed on study assessment, or not stated but evident from study assessment that it was.
B ‐ unclear: either described as ITT analysis, but unable to confirm on study assessment, or not reported and unable to confirm by study assessment.
C ‐ no: lack of ITT analysis confirmed on study assessment (i.e. patients who were randomized were either not included in the analysis because they did not receive the study intervention, withdrew from the study or were not included because of protocol violation) regardless of whether an analysis is described as ITT.
Completeness of follow‐up
Percentage of participants for whom data was complete at defined study end‐point.
Measures of treatment effect
Dichotomous outcomes (SSIs and mortality) will be reported as risk ratios (RR) and risk differences (RD) with 95% confidence intervals (CIs). The data will be pooled for the meta‐analysis using the RR given that the incidence of SSIs may be low such that the RD may be very small, and given the variation in baseline risk for SSIs, RRs may be more consistent across studies. Continuous outcomes (e.g. length of stay) will be reported as weighted mean differences (WMD) with 95% CI. If appropriate, statistical heterogeneity will be assessed using the chi squared statistic (P value less than 0.1).
Assessment of heterogeneity
Heterogeneity between study results will also be assessed using the I² statistic. This examines the percentage of total variation across studies due to heterogeneity rather than to chance. Values of I² over 75% indicate a high level of heterogeneity.
Subgroup analysis and investigation of heterogeneity
If present, possible sources of heterogeneity will be explored using subgroup analyses. Possible sources include: use of insulin infusion versus subcutaneous insulin or oral medication; type of surgical procedure in particular, cardiothoracic versus general surgical procedures; diabetic versus non‐diabetic patients; and timing of glycemic control (pre‐, intra‐, or post‐operative). If the subgroup analyses do not reveal a source of heterogeneity, we will perform a meta‐regression evaluating the different glycemic targets between 110 and 200 mg/dL.
Sensitivity analysis
Sensitivity analyses will be performed if a single large trial appears to be driving the results of the meta‐analysis.
