In-hospital glucose control and peri-operative care

In-hospital and perioperative hyperglycaemia is associated with increased morbidity and mortality, both for patients with- and without diabetes mellitus (DM). The present article will focus on the peri-operative considerations in patients with diabetes mellitus.

For the pathofysiology and treatment of in-hospital and ICU hyperglycaemia in patients without diabetes mellitus see our page on stress hyperglycaemia

In 2025 the worldwide prevalence of DM will increase to 300 million people[1]. People with DM are more likely to be admitted to the hospital, which translates into a prevalence of DM in hospitalised patients up to 40%[2]. Even more, the annual risk of being operated on is 2 to 6 fold increased in patients with diabetes as compared to patients without DM[3], making the peri-operative management of diabetes mellitus a relevant issue.

Hyperglycaemia and postoperative complications

Pre-operative hyperglycaemia

Patients with DM are prone to hyperglycaemia during and after surgery, which is associated with in-hospital morbidity and mortality[4][5]. The glycaemic control in the first 24 hours after surgery in DM patients is poor, and serum glucose > 8.3 mmol/l is associated with an increased risk of postoperative infections[6]. Furthermore, preoperative hyperglycaemia is predictive for one year mortality after surgery[7]. For several types of surgery, elevated HbA1c is associated with adverse outcomes and reduced long term survival[8][9][10][11], suggesting that preoperative regulation of DM is associated with postoperative complications.

Peroperative hyperglycaemia

In a large meta-analysis of 100.217 patients subjected to coronary artery bypass graft (CABG) surgery, a significantly increased risk of mortality up to 10 years after surgery was found in patients with DM, compared to patients without DM[5]. A retrospective study on tight glycaemic control (TGC) (6.9-9.7 mmol/l) versus conventional treatment (<11.1 mmol/l) during cardiac surgery showed a decreased rate of infection and improved survival. In a randomized study in 141 CABG patients with DM, tight glycaemic control (6.9-11.1 mmol/l) reduced the length of stay in the hospital, improved survival and decreased the rate of wound infections compared to conventional treatment (<13.9 mmol/l)[12]. However, two randomized trials in cardiac and non-cardiac surgery patients, including 20 and 29% patients with DM respectively, showed no differences in outcome between TGC (4.4-6.0 mmol/l) and conservative treatment (<11.1 mmol/l), despite a difference of 2.4 respectively 1.8 mmol/l in mean glucose at the end of surgery[13][14]. However postoperatively, all patients after cardiac surgery received TCG in the ICU, which might have masked the effect of the treatment applied during surgery.

Postoperative hyperglycaemia

The only postoperative study outside the ICU comparing TGC (4.4-6.1 mmol/l) with conventional treatment (10-11.1 mmol/l) showed a reduction in short term morbidity, but not in mortality outcome[15]. Lowering mean glucose in the first 24 hours after surgery from 9.7 mmol/l to 8.7 mmol/l significantly reduced postoperative complications and ICU admissions in the general surgery population[16]. Notably, in this trial patients were discharged to the ward with a mean glucose of 13.4 mmol/l. Thus, improving peri-operative glucose control probably facilitates postoperative management.

Target range

Strict glycaemic control is accompanied by an increased risk of hypoglycaemia and mortality compared to conventional treatment[17][18]. Especially in patients with diabetes, the benefit of strict glucose control seems to be limited [19]. A possible safer range of mean glucose between 7.0 and 9.0 mmol/l has been suggested, as mortality increases below and above this range[20]. For patients with DM this range might be different. The American Diabetes Association (ADA) suggests keeping peri-operative glucose < 10 mmol/l. According to the RABBIT trial, which showed a reduction in postoperative complication if glucose was brought down to 8.7 mmol/l, one could argue to keep glucose below 9 mmol/l[16][21].

Glucose lowering drugs and peri-operative care

Currently, several glucose-lowering agents are used in the treatment of DM type 2. The ones most commonly used are metformin, sulfonylurea derivatives (SU’s), the newer incretins (GLP-1 agonists and DDP-4 inhibitors) and of course insulin. The mechanism of action of these drugs can be found in Management. Historically, metformin has been associated with lactate acidosis. In a Cochrane analysis in 2010, the risk of lactate acidosis for patients using metformin was estimated at 4.3 per 100,000 patient years versus 5.4 per 100,000 patient years in patients not using metformin[22]. Studying the 330 published case reports on metformin and lactate acidosis, an alternative cause of the acidosis, such as liver disease or sepsis, almost always was present[25]. Nowadays studies have emerged, showing that intentional metformin use during cardiac surgery does not increase lactate plasma levels and lowers peri-operative glucose levels[23]. Even more, metformin use before ICU admission is associated with decreased ICU mortality[24]. In conclusion, the evidence to withhold metformin on the day of surgery is weak and current guidelines state to continue metformin during surgery[25]. Sulfonylurea derivatives stimulate insulin release, thereby increasing the peri-operative risk of hypoglycaemia. The incidence of hypoglycaemia (<3.1 mmol/l) is 10% in outpatients using SU’s[26]. The incidence of hypoglycaemia significantly increases during fasting for the Ramadan, which is somewhat comparable to fasting before surgery[27]. Furthermore warning signs of hypoglycaemia, such as irritation, headaches, palpitations, confusion, aggressive behaviour and loss of consciousness, are masked when a patient is anesthetized. One should therefore withhold SU’s on the day of surgery until the patient resumes oral intake. Incretins enhance glucose dependent insulin release with a very low intrinsic risk of hypoglycaemia [28]. In combination with insulin or SU’s this risk does not seem to be increased[29]. However incretins are relatively new on the market and peri-operative data are scarce. Finally, the total daily insulin dosage is initially expected to decrease due to peri-operative fasting and immobility. In contrast, surgical stress due to major surgery and starvation induces a catabolic state and increases insulin resistance[26]. Little is known about the optimal dose of insulin before surgery. One study compared insulin glargine, two-thirds of the total daily insulin dose combined with a glucose 5% infusion on the morning of surgery, to a GIK infusion, showing lower glucose levels in the glargine group without reaching statistical significance[30]. Consensus exists about continuation of long acting insulin the evening before surgery[26][31]. It is debatable whether this should be the regular amount or whether the dosage should be reduced by 25 to 50%. Short-acting mealtime insulins should be discontinued on the day of surgery, because of their pronounced peak effect, suboptimal duration of action and thus a risk of hypoglycaemia[32]. Patients treated with an insulin pump are advised to reduce the basal rate of their pump to 50%. If duration of surgery is longer than 2 hours, the pump should be stopped and an intravenous glucose/insulin infusion should be started, because the lack of familiarity of most anaesthesia providers with these pumps[32].

Treatment algorithms during surgery

In contrast to the numerous published protocols and strategies on glucose regulation during surgery, there is a lack of comparative studies. Furthermore, adherence to these protocols is notoriously poor[31][33]. Few studies have compared different regimes (e.g. GIK infusions, iv. bolus of insulin or insulin sc.) for patients with DM type 2 during surgery, without a significant difference in glucose values during surgery[34]. For insulin naïve well controlled patients with DM type 2, Raucoules-Aimé et al. demonstrated that a ‘no insulin no glucose’ regimen is a simple strategy for controlling glucose as long as glucose is frequently measured and hyperglycaemia is treated with an iv. bolus of insulin[35]. Patients with DM type 1 need a continuous exogenous insulin source, usually with a glucose/insulin infusion, to prevent diabetic ketoacidosis.[32] The preferred route of administering insulin during surgery is the intravenous route, due to the more predictable pharmacokinetics of intravenous insulin. Subcutaneous administration of insulin becomes more unpredictable during the perioperative period as a result of the altered perfusion of subcutaneous tissue, especially in the severely ill patient [36].

A controversial topic remains whether patients with DM should receive dexamethasone during surgery as prophylaxis for post-operative nausea and vomiting (PONV). Several studies have shown a slight but significant increase in glucose values after dexamethasone administration, but change in glucose is similar or even smaller in patients with DM type 2 compared to patients without DM[37][37][38][39]. The increase in serum glucose due to dexamethasone is 1.6 mmol/l[40]. Risk factors for developing hyperglycaemia (8.3 mmol/l) after dexamethasone usage are an elevated BMI and a high baseline HbA1c[40]. Thus, keeping in mind that certain patients are more at risk for developing hyperglycaemia than others after dexamethasone injection, the benefit of reduced PONV and early resumption of oral intake should be weighted against the risk of iatrogenic hyperglycaemia.

After the patient is discharged to the ward, postoperative glucose care continues. Several studies have shown better glycaemic control in patients with DM when treated according to a pre-set protocol compared to management without a protocol[41]. A postoperative basal bolus regime improves glucose control and lowers postoperative morbidity compared to a sliding scale regime[16][42].

In conclusion

With the growing prevalence of diabetes outside the hospital, an increasing number of diabetes patients will be encountered in the operating room. Despite the clear association between peri-operative hyperglycaemia and postoperative complications, evidence with regard to the optimal glucose regulation protocol and target range is scarce. For now, peri-operative plasma glucose should be targeted below 10 mmol/l, perhaps with continuation of the patient’s own metformin and insulin if needed. Improving postoperative glucose control significantly lowers complications in diabetes patients after surgery and this process should be initiated as soon as the patient with diabetes enters the hospital.

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