Diabetes and hyperglyacemia
Diabetes
It is established for over a decade that patients with Diabetes undergoing isolated CABG surgery are faced with a higher incidence of operation-related morbidity, mortality and post-procedural angina recurrence [
6,
7]. Numerous studies show that patients with Diabetes have a significantly greater risk [up to 44%] of readmission following discharge after CABG [
6,
8‐
12]. This finding is also supported by most recent British national data [
13]. Despite this, no specific guidance exists in the UK or Europe, as to the optimal level, or method of achieving adequate glycaemic control in patients undergoing cardiac surgery. In the US, guidelines have been available for almost a decade [
12].
Hyperglycaemia
Distinct from Diabetes, isolated hyperglycaemia is a long established marker of adverse outcome and increased LOS in numerous diverse clinical settings, in both patients with, and without Diabetes. Effects appear to be “dose-dependent”, as longer duration and higher levels of hyperglycaemia are both associated with increased morbidity and mortality [
14]. This relationship is also apparent in patients undergoing CABG surgery [
15], following acute myocardial infarction [MI] [
16], severe trauma, ischaemic stroke, and in critically ill medical [
17‐
19] and peri-operative neurosurgical patients within the ITU environment. Treatment of hyperglycaemia shows clinical outcome benefit [
17,
18,
20], however the optimal range and duration of glycaemic control is unclear and remains controversial.
Pre-operative hyperglycaemia in surgical patients
At present no specific guidance exists in the UK or Europe, regarding the detection and management of pre-operative hyperglycaemia in patients undergoing cardiac surgery.
The prevalence of hyperglycaemia amongst hospitalised patients is reported as high as 38%. Newly discovered in-hospital hyperglycaemia is associated with a higher mortality rate [16%] compared with hyperglycaemia for patients with known Diabetes [
21,
22], increased short-term morbidity, and also short and long-term mortality following non-cardiac surgery [
23,
24].
A retrospective analysis of 60,000 patients undergoing elective non-cardiac surgery from the Cleveland Clinic showed that pre-operative hyperglycaemia [random BG ≥12 mmol/l at pre-operative assessment] in patients without an established diagnosis of Diabetes increased 1 year mortality [
23]. Diabetic status significantly altered this relationship and for a given level of pre-operative hyperglycaemia; the risk of 1 year mortality was lower in the Diabetes patient group compared with non-diabetes. A similar relationship was demonstrated between pre-admission hyperglycaemia and increased in-hospital mortality in the ITU setting [
25], with therapeutic glycaemic control showing benefit in only those without a diagnosis of Diabetes [
18]. These findings prompted the authors to suggest that A] pre-operative hyperglycaemia should be given greater consideration in patients without Diabetes than those already diagnosed with Diabetes, and B] the expected benefits of adequate glycaemic control may be determined by the pre-operative diagnosis of Diabetes [
23]. This suggestion may be regarded as counter-intuitive, but emphasises the need to “glucose screen” all patients undergoing cardiac surgery, something that is currently not routine practice in the UK.
In another large study, over 20% of ~ 34,000 non-cardiac surgical patients were hyperglycaemic on admission [fasting BG > 6.1 mmol/l] without having a prior pre-operative diagnosis of Diabetes. In over half of these patients, a subsequent provisional diagnosis of Diabetes was made [
26]. Hatzakorzian et al., in a much smaller study of non-cardiac surgical patients showed a prevalence of pre-operative hyperglycaemia of greater than 25% [
27]. A study of 7310 patients by Lauruschkat et al. [
28], showed that the prevalence of undiagnosed Diabetes in patients undergoing CABG to be 29.6%. This was associated with increased rate of adverse outcomes, including those of cardiac resuscitation, re-intubation and prolonged ventilation. Anderson et al., in a study of 1895 patients undergoing CABG showed that patients not known to have Diabetes, but with an elevated pre-operative fasting BG [≥ 5.6 mmol/l] had double their expected 1-year mortality, and this was equivalent to patients known to have Diabetes [
29]. Key studies relating to the effects of hyperglycaemia on outcomes are summarised in Table
1.
Table 1
Impact of newly discovered hyperglycaemia on the outcome of patients admitted to hospital
Umpierrez et al.22
n = 2030
medical patients | To determine the prevalence of in-hospital hyperglycemia and determine the survival of patients with hyperglycemia with and without a history of Diabetes | Newly discovered hyperglycemia was associated with a higher in-hospital mortality rate compared with those patients with a prior history of Diabetes and patients with normoglycemia. Patients with hyperglycaemia had longer length of hospital stay, a higher admission rate to an intensive care unit and were less likely to be discharged home. |
Abdelmalak et al.23
n = 61,536
surgical, non-cardiac surgery patients | To study the hypothesis that pre-operative BG levels and the Diabetes diagnosis status of the patients are related to surgical outcomes | One year mortality was significantly related to pre-operative BG. Hyperglycaemic patients with diagnosed Diabetes displayed a significantly lower 1 yr. mortality than hyperglycaemic patients without Diabetes |
Noordzij et al.24
n = 108,593
surgical, non-cardiac surgery patients | To determine the relationship between pre-operative BG levels and peri-operative mortality in non-cardiac and non-vascular surgery | Pre-operative hyperglycemia was found to be associated with increased cardiovascular mortality in patients undergoing non-cardiac and non-vascular surgery |
Whitcomb et al.25n = 2713 ITU patients | To assess the association between hyperglycemia and in-hospital mortality in different ITU departments | Higher mortality was seen in hyperglycemic patients without history of Diabetes in the cardiothoracic and neurosurgical units |
Anderson et al.29n = 1895 cardiac surgery patients | To determine whether pre-operative fasting BG is associated with an increased mortality after CABG. | Patients not known to have Diabetes but with an elevated pre-operative fasting BG had a 30 day and a 1-year mortality twice that of patients with normal values, and equivalent to patients known to have Diabetes |
Pre-operative HbA1c
In a prospective study of 3555 CABG patients, an HbA
1c ≥ 8.6% [70 mmol/l] was shown to be an independent risk factor for early adverse outcomes and mortality [
10]. The same group when conducting a study of 3201 patients demonstrated an HbA
1c ≥ 7.0% [53 mmol/l] to be associated with decreased 5 year survival following CABG, compared to patients having a value < 7.0% [53 mmol/l]
. More importantly, patients with well controlled Diabetes [HbA
1c < 7.0%], could achieve comparable outcomes to those patients without a diagnosis of Diabetes [
30]. Alserius et al., also demonstrated significantly reduced 3-year survival, and elevated rates of early superficial wound infection to be associated with HbA
1c ≥ 6.0% [42 mmol/l] following CABG [
31]. However, two studies [
32,
33] have failed to show a relationship between HbA
1c and LOS, significant early adverse outcomes, or long-term survival following CABG.
Arguably, the predictive value of pre-operative HbA
1c in cardiac surgical patients without Diabetes is less well studied. Hudson et al., in a retrospective observational study of 1474 elective patients showed an HbA
1c of ≥ 6% [42 mmol/l] in almost a third of patients [31%]. This was associated with elevated intra-operative BG values, a known predictor of adverse outcomes [
34], and in isolation, was shown to be an independent predictor of 30-day mortality [
35]. Other studies of patients not known to have Diabetes and undergoing percutaneous coronary, vascular or cardiac [
4] surgical interventions, also demonstrated a strong association between the pre-procedural elevated HbA
1c [30–58%], and risk of early adverse events. These findings suggest that pre-operative HbA
1c assessment will be useful as a screening tool in all patients undergoing cardiac surgery, both those with and without Diabetes.
Peri and post-operative hyperglycaemia
Intra-operative hyperglycaemia during cardiopulmonary bypass is an independent risk factor for mortality and morbidity in patients with and without Diabetes [
34,
36]. Insulin resistance rather than impaired secretion is considered responsible for this [
36]. However, it remains unclear whether hyperglycaemia per se, as opposed to increased insulin resistance, drives adverse outcomes. Furnary et al., proposed that improvement in underlying impaired myocardial glycometabolism was one of the predominant mechanisms underlying the favourable effects of insulin therapy, rather than pure achievement of euglycaemia [
8,
9] and this has been subsequently supported by other studies [
37,
38]. Overall, peri-operative control of hyperglycaemia via continuous insulin infusion was associated with decreased incidence of deep sternal wound infection, shortened hospital LOS, reduced rates of recurrent ischaemia, improved long-term survival and significantly decreased morbidity [
8,
11], in a large number of cardiac surgical patients [> 8000]. As such, it is now a globally accepted standard practice of care, although the precise stringency of control i.e. tight vs. moderate, timing and duration of intravenous therapy remain matters of debate [
7,
12].
Atrial fibrillation in patients with diabetes
The relationship between Diabetes status and post-operative AF requires clearer definition. Most studies do not show any clear association [
6], however, some studies show a decreased AF incidence in patients with elevated pre-operative HbA
1c [
10,
33,
39]. These studies reflect outcomes from a non-UK population, involving pre-dominantly off pump CABG surgery. The potential protective mechanisms of an elevated HbA
1c on post-operative AF are unclear. Kinoshita et al. [
39], propose that one plausible explanation is that patients with elevated HbA
1c require more insulin for adequate glycaemic control, a therapy which is shown to reduce post-operative AF [
8,
40]. In support, Lazar et al. have also demonstrated tighter glycaemic control via intravenous insulin to lower incidence of post-operative AF [
11].
CABG vs non-CABG cardiac surgery
The majority of evidence reviewed in this paper relates to CABG surgery as opposed to non-CABG surgery. Studies including non-CABG cardiac surgery did not clearly delineate outcomes relating to type of surgery, with the majority of patients having undergone CABG. Therefore it is difficult to draw firm conclusions regarding the relationship between deranged glycaemic control, outcomes and precise type of surgery. It is intuitive to think that the effects of deranged glycaemic control on outcomes, would be most prominent following CABG surgery as opposed to non-CABG surgery, due to the well-recognised and established effects on lipid metabolism, endothelial cell function, coronary artery disease, as well as arterial vascular properties / function although, this remains to be proven. Future studies should focus on defining whether deranged glycaemic control has differing effects on outcomes depending on type of surgery.
Optimal glycaemic care and barriers to standardisation
A critical factor hindering the establishment of clearly defined glycaemic control guidelines is the lack of consensus on what optimal treatment actually is [
7,
14]. Brief consensus was reached following 2001, when the Leuven Surgical Trial demonstrated reduced 1-year mortality among critically ill patients when BG levels were tightly controlled between 4.4–6.1 mmol/l as compared to 10.0–11.1 mmol/l [
17]. This study instigated an era of tight glycaemic control for all critically ill patients including cardiac surgical patients. The aim of tight control was reinforced by further studies showing beneficial effects of intensive insulin therapy in surgical, medical [
18,
20] and cardiac surgical patients [
8,
38]. The Portland Diabetic Project provided strong evidence of the adverse effects of hyperglycaemia in patients with Diabetes undergoing cardiac surgery, using an 8.3 mmol/l cut off target value [
8,
38].
The concept of tight glycaemic control in critically ill patients was called into question with the publication of the NICE-SUGAR Study [
37]. This study of 6104 patients failed to reproduce the findings of the Leuven Surgical Trial, and in fact demonstrated increased 90-day, all-cause mortality after surgery in the tight control group [
37]. In support of these findings more recent studies in CABG patients have either failed to demonstrate beneficial effects with tight control [
41‐
44], or shown superior beneficial effects with moderate control [7.0–9.9 mmol/l] [
45].
The recent randomised controlled GLUCO-CABG trial of 302 patients showed no difference in outcomes between intensive or conventional moderate glucose control in CABG patients with Diabetes [
46]. However, in patients without Diabetes intensive glucose control was associated with lower complication rate. This reinforces the idea from the Portland Diabetic Project and Cleveland Clinic group of the importance of Diabetic status [pre/peri-operative hyperglycaemia in patients with and without Diabetes] [
38]. Possibly a lower BG target is needed for patients without Diabetes, whereas a higher target is permissible for those with Diabetes.
The recently published American multicentre study of 4316 cardiac surgical patients by Greco et al., [
47] showed that, increasing hyperglycaemia above 180 mg/dl [10 mmol/l] in patients without Diabetes was associated with worsening outcomes. However, this relationship did not hold for patients with non-insulin treated Diabetes. Adding further complexity, this study demonstrated that in insulin treated group allowing BGs above 180 mg/dl [10 mmol/l] was beneficial, with worsening outcomes when “better” control was achieved.
Inducing unnecessary and dangerous hypoglycaemic events with insulin, historically represented another issue driving reluctance to employ stringent BG control protocols. However, these events are now recognised as being rare and avoidable [
3,
46], provided BG is frequently monitored.
The lack of consensus amongst the studies we have analysed in this review may be due to the heterogeneity with regards to treatment of hyperglycaemia, glycaemic control protocols, glucose measurement protocols, the glucose metrics employed, their validity and relevance, as well as the individual population demographics. The best metric of glycaemic control remains a matter of debate, and many have been utilised. Average BG over 3 days [3-BG] is considered a good measure [
38,
48]. Studies show that metrics incorporating glucose values over longer time periods have greater prognostic relevance in comparison to isolated glucose measurements from just the first 24 or 48-h of an index event e.g. surgical operation or hospitalisation [
49]. Metrics of variability/complexity of the circadian glucose pattern are also proposed to be of greater importance than actual BG levels [
50].
Future targeted therapies
The multiple proposed detrimental downstream pathways of hyperglycaemia / insulin resistance, and positive effects of insulin therapy following cardiac surgery are largely unknown and require further detailed definition [
3]. They are not the focus of this review, but they are of importance with respect to the development of future targeted therapies. Altered free fatty acid metabolism, endothelial dysfunction, reduced nitric oxide bioavailability and accumulation of reactive oxygen species are implicated [
3]. So too is protein kinase C-dependent vasoconstriction, vascular inflammation and platelet aggregation; as well as advanced glycation products [AGE] driven pro-inflammatory cascades [
3]. In addition to the metabolic benefits, improved myocardial recovery following myocardial ischemia and direct improvement of contractile function are thought to occur with insulin therapy. Increasing evidence now suggests that reduction in BG variability, rather than absolute levels, to be a major determinant of the beneficial effects of insulin therapy [
50]. Other proposed beneficial mechanisms include; membrane stabilization, anti-arrhythmic effects, improved glucose utilization, improved cardiac output via vasodilation and lowering of total peripheral resistance, and improved immune function [
3].
Improving clinical outcomes
The detrimental effects of hyperglycaemia and Diabetes on cardiac surgery outcomes are well recognised. Despite that, clear treatment guidance is still lacking in UK and Europe and this has to be addressed. It is vital for all disciplines associated with the care of cardiac surgical patients, to engage in addressing the discrepancy in quality of outcomes observed in patients with poor glycaemic control. By looking into this discrepancy in outcomes, a decision needs to be made as to whether this discrepancy is A] acceptable, B] modifiable, and if so how, and C] is enough currently being done to minimise, or potentially abolish it. We feel that the current dogma stating that “patients with Diabetes have worse outcomes than patients without Diabetes following cardiac surgery” is potentially wrong, as these patients are currently not receiving best therapy, and this dogma must be challenged.
Proposal’s for quality service improvement
The extensive evidence reviewed in this article provides a sufficient mandate to commence a national / international initiative to standardise and improve the quality of glycaemic control in patients undergoing cardiac surgery in UK and Europe.
In the US, a national initiative to improve post-operative glycaemic control in cardiac patients has already commenced in the form of a
Surgical
Care
Improvement
Project
[SCIP] [
21,
48]. This initiative involves collection and analysis of specific performance measures relating to glycaemic control in all participating cardiac centres, with subsequent public reporting of outcomes and compliance. In addition the Society of Thoracic Surgeons [STS] have published detailed US practice guidelines relating to pre-, intra- and post-operative glycaemic management of patients with and without Diabetes undergoing cardiac surgery; Table
2 [
12]. The STS practice guidelines include: A] active control of BGs < 180 mg/dl[10 mmol/l] for all patients during the intra- and post-operative period B] all patients with Diabetes receive an insulin infusion in the operating room and for at least 24 h postoperatively C] pre-operative HbA
1c measurement in all patients with Diabetes and those at high risk of post-operative hyperglycaemia
, to optimise glycaemic management, and identify patients requiring more aggressive glycaemic control, D] pre-discharge in-patient education of all patients with Diabetes and E] appropriate follow up and communication with primary care physician.
Table 2
Summary of the US STS guidelines for glycaemic control during adult cardiac surgery (2008)
A] active control of BGs < 180 mg/dl[10 mmol/l] for all patients during the intra- and post-operative period |
B] all patients with Diabetes receive an insulin infusion in the operating room and for at least 24 h postoperatively |
C] pre-operative HbA1c measurement in all patients with Diabetes and those at high risk of post-operative hyperglycaemia, to optimise glycaemic management, and identify patients requiring more aggressive glycaemic control |
D] pre-discharge in-patient education of all patients with Diabetes and |
E] appropriate follow up and communication with primary care physician |
It is inevitable that practice and outcomes around the UK and Europe in relation to patients with Diabetes or pre-diabetes varies between individual treatment centres. However, the formation of national guidelines, standardisation of care, centralised reporting and open sharing of glycaemic performance data is critical to improving future standards of care. Formation of this structure along with a national glycaemic SCIP would also serve to incentivise service improvement. An example of such a novel potential European SCIP is shown in Table
3. In addition the novel care pathway utilised in our unit is shown in Table
4.
Table 3
Potential Steps for Facilitating Service Improvement in Diabetic / Pre-diabetic Patients Undergoing Cardiac Surgery
Step 1 |
Publication of detailed and specific guidelines regarding: Pre-operative screening of all patients undergoing elective cardiac surgery and therapeutic intervention for Diabetes / pre-diabetes |
Pre-operative target glycaemic criteria permitting elective surgery e.g. HbA1c < 7.5% |
Methods, triggers and duration of intra-operative and post-operative glycaemic control |
Post-operative / pre-discharge target criteria of glycaemic control on ITU and ward e.g. blood glucose ≤12 mM pre-discharge |
Early post-discharge follow up by family doctor / Diabetes specialist team to ensure ongoing good glycaemic control |
Step 2 |
Establishment of a dedicated cardiac diabetic specialist team in every cardiac surgical unit to facilitate: Pre-, peri-, post-operative and discharge glycaemic control and planning |
Patient and professional education at all levels and communication with primary and community care services |
Step 3 |
Establishment of specific national diabetic cardiac Surgical Care Improvement Project (SCIP) Europe-wide to include: Introduction of relevant and appropriate performance quality measures e.g.:- |
HbA1c measurement in 100% of elective patients undergoing cardiac surgery |
Pre-operative point of care fasting blood glucose of ≤8 mM in 95% of operated patients |
Pre-operative HbA1c value of < 7.5% in 95% of elective patients going for cardiac surgery |
Median post-operative LOS of diabetic patients ≤1.0 day greater than median postoperative LOS for non-diabetic patients |
Pre-discharge blood glucose range of 4–12 mM (day before discharge) in 95% of all patients going for cardiac surgery |
Post-discharge review by diabetic specialist nurse or family doctor within 1 week in 95% of patients |
Incidence of deep sternal wound infection for diabetic patient within the 95% CI of non-diabetic patient A peri-operative glycaemic control multi-disciplinary working group in every cardiac surgical unit, responsible for monitoring and reporting SCIP adherence and compliance. |
Table 4
Oxford Heart Centre Diabetes Care Pathway
• Routine pre-operative diabetic screening for all cardiac surgical elective patients (HbA1c). Via GP or part of Pre Assessment Clinic(PAC) |
• Routine diabetic screening for all cardiac surgical urgent in-patients (HbA1c) |
• Point of care diabetic specialist team review of all diabetic, OR selectively identified “High Glycaemic Risk” cardiac surgical patients |
• Automatic / mandatory ITU, ward, point of ITU discharge and pre-hospital discharge diabetic specialist team review of all diabetic, OR selectively identified “High Glycaemic Risk” cardiac surgical patients |
• Automatic / mandatory GP or specialist nurse post-discharge follow up arrangement on agreed day e.g. day 4 |
• Routine pre-operative blood glucose measurement on admission of all surgical patients |
• Establishment of a glycaemic control working group responsible for regular monitoring, auditing and presenting glycaemic control performance data |
• New standardised Intravenous Insulin protocol for all patients undergoing cardiac surgery and guidelines for management of hyper and hypo-glycaemia |