Insulin Resistance & Complications after Major Surgery – Can they be Ameliorated?

The development of insulin resistance and hyperglycaemia following surgery is a well-documented phenomenon which is associated with increased morbidity and mortality.1–3 Insulin sensitivity is reduced by approximately 50% following elective surgery and persists for at least five days postoperatively in the case of upper abdominal surgery. There is a dose-response relationship between the magnitude of surgery and the degree of insulin resistance postoperatively. In the case of colorectal surgery where the magnitude is variable, the change is closely correlated with the duration of surgery. Blood loss is the other independent predictor of the degree of insulin resistance. Therefore, this metabolic variable is governed by the degree of surgical trauma itself rather than any predisposing or associated factors.

It appears that in the postoperative context endogenous glucose production (EGP) in the liver is unaffected by the suppressive effect of insulin per se. Therefore, the changes in insulin sensitivity following surgery are secondary to alterations in peripheral glucose uptake alone. We may reasonably assume that as skeletal muscle is the largest organ involved it is the main metabolic site.

The precise mechanism behind this loss of insulin sensitivity is unknown but it has been demonstrated that providing carbohydrates pre-operatively can attenuate this effect.4–6 Pre-operative carbohydrate drinks were also found to reduce pre-operative anxiety and hunger.7 There is also evidence that pre-operative carbohydrate drinks may decrease post-operative muscle mass loss and function and attenuates protein catabolism. 6,8–11

In addition, receiving a carbohydrate drink two hours before the start of anaesthesia does not significantly affect the gastric residual volume compared to patients fasted overnight.2,4,7,12

This practice, in conjunction with several other interventions, has now become routine with the introduction of Enhanced Recovery Protocols (ERP). These have been shown to reduce length of stay and complication rates for major surgery.13-16 A recent ERAS cohort study showed that patients that were treated with preoperative carbohydrates, experienced a 44% reduction in the risk of postoperative symptoms.17

In the search for a treatment for the rare group of inherited, metabolic disorders known as Glycogen Storage Diseases (GSD), a hydrothermally processed maize starch (HPMS) was developed with the aim of providing overnight blood glucose stability with a lower glycaemic index (GI).18 Two small trials led to the development of a high-amylopectin-containing cornstarch. This compound demonstrated a longer duration of action and a lower initial increase in blood glucose with lower peak concentration compared to standard uncooked cornstarch. 18,19

Hydrothermally processed maize starches, or so-called Superstarch, have recently been used as an alternative to standard, maltodextrin (MAL) based drinks within sports nutrition. They are used to provide stable blood glucose concentrations over time and avoid a spike in insulin concentration, factors which are thought to be advantageous in endurance exercise. This was investigated in a comparison of SuperStarch to a standard MAL formulation in a randomized, controlled crossover trial in nine elite cyclists.19 These participants’ ingested 1mg/kg of either MAL or HPMS, rested for 30 minutes, exercised for 150 min at 70% peak VO2 and then at 100% peak VO2 until they fatigued. Following exercise another 1mg/kg of HPMS or MAL was taken and the participants then rested for 90 min. The researchers found that during exercise and recovery HPMS provided more stable blood glucose levels, blunted insulin release and increased levels of fatty acids and glycerol, suggesting increased lipolysis. There was also a reduced initial spike in blood glucose and insulin following ingestion of HPMS compared to MAL. Thus despite consuming a product manufactured from carbohydrate it seems to behave like a fat in the body and effectively maintains fat metabolism. This would translate into preservation of insulin sensitivity, the favourable inverse of insulin resistance.

A major concern regarding the administration of drinks to patients within 2 hours of induction of general anaesthesia is the risk of pulmonary aspiration secondary to regurgitation of gastric contents. Gastric emptying is influenced by carbohydrate load and by osmolality, with increasing osmolality associated with prolongation of gastric emptying.2,12,21-24 Therefore, it stands that increasing the complexity of the carbohydrate source would increase speed of gastric emptying whilst providing the same calorific content. Indeed this is the case, with maltodextrin based carbohydrate drinks currently given pre-operatively as part of ERP having little effect on gastric residual volume at the start of anaesthesia, and actually result in less residual volume than a starved state. 4,7,12

Preload®, the pre-operative carbohydrate drink used in ERP across the NHS and in our institution, has an osmolality of 135mOsm/kg when mixed in the standard dilution (one 50g sachet is diluted with 400ml water). Generation UCAN is a powder-based sports energy drink mix, which makes use of SuperStarch, which has an osmolality of 89mOsm/kg when 60g, is diluted into 500ml water. This indicates that Generation UCAN will be emptied from the stomach more rapidly than Preload®.

The rationale for this proof of concept study is that HPMS drinks given pre-operatively may result in a greater reduction in insulin resistance post-operatively than the standard maltodextrin containing carbohydrate drinks due to a longer duration of action, a greater reduction in peak glucose concentration, a greater reduction in post-operative blood insulin levels and a greater lipid oxidation. This in turn may lead to a greater reduction in muscle loss and morbidity, specifically infectious complications, and in turn time to fitness for hospital discharge.

The initial proof of concept study will primarily measure chnages in insulin resitance using the HOMA technique 25,26 which mathematically derives insulin sesnsitivity from paired blood glucose and insulin results. These will be obtained from each patient in a fasted state pre-operatively and then on each of the first 3 mornings post-operatively. Other relevant outcomes e.g. changes in daily hand grip strength, safety regarding gastric emptying (we will employ ultrasound measurement of gastric volumes prior to anaesthesia 27-29) and hospital length of stay will be compared.

If a physiological proof of concept is demonstrated then a subsequent study will be powered to show a clincally significant diffference in hsopital length of stay.

We look forward to delivering this study and gaining a further understanding of this intersting area of pathophysiology.

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