Effects of preoperative oral enzyme-hydrolyzed rice flour solution on gastric emptying and insulin resistance in patients undergoing laparoscopic cholecystectomy: a prospective randomized controlled trial

Surgical trauma and anesthesia factors can inevitably induce postoperative insulin resistance (IR) [1]. Traditional strategy of preoperative starvation aiming to prevent regurgitation and aspiration of stomach contents exacerbated the level of postoperative IR [2]. IR was a state of glycolipid metabolism disorder which increased endogenous glucose production, lessened glycogen synthesis and gluconeogenesis in hepatocytes, inhibited lipolysis metabolism, and finally lead to excessive consumption of triglyceride (TG) and protein storage [3]. Research showed that IR contributed to postoperative infection and other complications, prolonged hospital stays [4].

Preoperative oral carbohydrates (POC) treatment at least 2–3 h before surgery, as one of the important parts of enhanced recovery after surgery (ERAS), has been proved to bring perioperative benefits and promote recovery for patients [5]. Nowadays, there are multiple kinds of carbohydrates which develop inconveniences for homogeneous management and propaganda of POC among different departments. And some kinds are expensive to increase patient hospital expenses. Enzyme-hydrolyzed rice flour (EHR) is a cheap production containing various micromolecular saccharides which is converted from macromolecular starch through enzymolysis technology. EHR is easily soluble in water, and the solution is a clear liquid which meets the carbohydrate standard in ERAS guidelines [6]. Laparoscopic cholecystectomy (LC) is an effective treatment for gallbladder stones and cholecystitis. Although LC is a minimally invasive surgery with less trauma, it is also accompanied with stress response and postoperative IR [7]. POC has been proved to reduce IR in most types of surgery [8, 9], however the effect of POC on LC remains controversial [10, 11].

Previous research showed that antrum ultrasonography can accurately measure the quality and quantity of gastric contents [12]. In our preliminary study for 30 healthy volunteers, the outcomes showed that the gastric content measured by antrum ultrasonography returned to the fasting level 2 h after oral EHR solution. Therefore, we conducted a randomized prospective study to evaluate the gastric emptying by bedside antrum ultrasonography and the influence on IR of oral EHR solution 2-3 h before LC operation.

In total, 110 patients who underwent LC between January 2021 and March 2021 were enrolled in this study. Ultimately, there were 50 patients who completed the study in each group. The study scheme is shown in Fig. 1 .

Univariable analysis shows that demographics including gender ratio, age, BMI and ASA classification were similar between the two groups (P > 0.05). In general, there were no significant differences in time between intake and induction, operative duration and the intraoperative blood loss (P > 0.05, Table 1).

Preoperative oral carbohydrate (POC) has been recognized as an important element of guidelines for ERAS, and received increasing attention from anesthesiologists [18, 19]. POC has been demonstrated to provided lots of benefits for patient, such as reducing traumatic inflammatory response [20], relieving postoperative insulin resistance (IR) and organ dysfunction, improving subjective comfort [21] and accelerating postoperative rehabilitation. However, the categories of carbohydrate drinks are abundant [22] which bring an extensive choice for preoperative carbohydrate loading, also cause problems for homogeneous management and preoperative publicizing and education across different departments of identical hospital. Moreover, the high price of most carbohydrate products increases hospital expenses. Therefore, it is important to provide clinical application with optimal carbohydrate drinks with characteristics of effortless gastric emptying, agreeable palatability, good patient compliance to implement, being economical, promoting postoperative physical status. Enzyme-hydrolyzed rice flour (EHR) solution is convenient for unified administration, propaganda education, large-scale promotion and clinical application. In the study, we evaluate the gastric emptying of oral EHR solution, and its effect on IR.

The published data [23] showed that in non-diabetes population the plasma insulin level reached the peak (> 10 times of fasting value) at about 1 h after intake of a mixed-meal containing 50 g of carbohydrates, and kept at 2–4 times of fasting value at 2-3 h after intake. Previous study recommended patients to ingest 300-400 ml solution containing 50 g of carbohydrates 2–3 h before surgery [19]. Thus, we dissolved 2.5 packages of EHR (50 g, containing 46.5 g carbohydrates) in 300 ml warm water for patients in group E. Scholars [13] compared the differences between preoperative oral single-dose carbohydrate and double-dose carbohydrates. The outcomes showed that POC at the night before surgery did not consolidate the influence of POC at 2-3 h before surgery on insulin resistance, subjective comfort, inflammation and immunity, instead disturb the patients’ sleep quality conversely. Accordingly, we chose the regime of single-dose EHR solution loading 2–3 h before surgery in the study.

Bedside antrum ultrasonography is an accurate, quick and effective technology to evaluate the properties and volume of gastric contents [24]. Meanwhile, the technology is easy to grasp. The success rate of anesthesiologists in evaluating the properties of gastric contents by ultrasound can reach 95% after proper training (about 33 repeated examination) [25]. The researchers in the study have grasped this ultrasonic scanning technique after being trained.

Anteroposterior (AP) and craniocaudal (CC) antral diameters in the right lateral decubitus (RLD) are measured to obtain the cross-sectional area of the antrum (CSA). Then the gastric volume can be calculated based on the formula of Perlas (2013) model [15] which is expressed as GV (ml) = 27.0 + 14.6 × CSA (cm²)-1.28 × age. The suitable range of the formula are 18–85 years, 45–110 kg and more than 145 cm heigh. Besides general population, further studies showed that the formula can be applied in obesity and pregnancy accurately [26, 27]. In the study, there is no difference between the ΔGV from the formula and the actual drinking volume 300 ml which further verify the applicability of the formula in estimating gastric emptying in the study.

The results of GV exhibited no significant differences between two groups at the three time points: before oral administration (V₀), immediately after oral administration (V₁) and before anesthesia induction(V₂), and no differences between GV₂ and GV₀ in the two groups. The outcomes suggest that the gastric emptying rates of 300 ml water and EHR solution are similar, and both of them returned to the fasting value after 2–3 h. Meanwhile, there was no reflux or aspiration occurred during anesthesia induction, which indicated that 300 ml EHR solution loading 2–3 h before surgery cannot increase the risk of reflux aspiration.

Postoperative IR is a depressed state of glucose uptake and utilization by peripheral target organs and tissues, which result in abnormal metabolism of glucose, lipid and protein, and is associated with hyperglycemia reactions, infection and prolonged hospital stay [28]. The hyperinsulinemic euglycemic clamp (HEC) technique is the gold-standard to evaluate insulin sensitivity. However, the technique is hard to be widely applied in clinic because it is expensive, technically demanding and time-consuming. The homeostatic model assessment (Homa), which has been validated as a noteworthy correlation with HEC technique [29, 30], includes the indicators of Homa-IR, Homa-β, Homa-IS. It has been proposed that POC can reduce postoperative IR [31], we also observed the reduction of Homa-IR, and the increase of Homa-β, Homa-IS following preoperative oral EHR solution at the first day after operation.

There are various mechanisms behind the alleviation of postoperative IR induced by POC. Shi et al. [32] found that POC reduced postoperative IR via stimulating AMPK, which suppressed the phosphorylation of mTOR and insulin receptor substrate-1 (IRS-1) after colorectal resection. Also, study [33] indicated that POC attenuated the development of postoperative IR which was associated with the alternation pyruvate dehydrogenase kinase (PDK4) in muscle. The experiment in rats showed [34] that POC improves postoperative insulin sensitivity in skeletal muscles through the PI3K/AKT/mTOR pathway.

The main components of EHR are maltodextrin, oligosaccharide malt and polyglucose. Maltodextrin [35] is a kind of polysaccharide that is easily absorbable and relieves stress of digestive system for patients; oligosaccharide is characterized by low sweetness, low caloric, hypoosmolality, occurs continuous hydrolysis reaction in intestines which could increases blood glucose slightly and prolong the duration of energy supply; although polyglucose barely provide energy, as soluble cellulose, it increases the intestinal chyme volume and patients’ satiety, slows the absorption of carbohydrate, what is more, the short chain fatty acids produced from polyglucose by intestinal flora enhances intestinal mucosal barrier, reduce the absorption of endotoxin and play an important anti-inflammatory role which maybe one of the factors to relieve IR and promote intestinal peristalsis [36, 37]. As a result, in the study oral EHR solution decreased VAS scores of fatigue, hunger and anxiety, reduced the incidence of nausea, enhanced handgrip strength and shorten exhaust time. These are in accordance with the previous conclusions [38, 39] that POC improved the postoperative subjective well-being, reduced nausea and ameliorated gastrointestinal motility in surgical patients.

Skeletal muscle is one of the main target tissues of insulin. Insulin resistance disrupts both the amount and the timing of glucose into skeletal muscle [40]. Previous study [41] showed that POC inhibited the activity reduction of glycogen synthase in muscle biopsy, and maintain quadriceps femoris muscle strength while compared with placebo group. Gysel et al. [42] demonstrated that descending handgrip force were already present in healthy men with lower insulin sensitivity. Consequently, POC alleviated postoperative IR which would improve the uptake and storage of carbohydrate in skeletal muscle, and would be beneficial to ameliorate muscle function. Therefore, the decreased postoperative IR might be the reason for better handgrip strength in group E at Pos 1d in this study.

There are still limitations in the study. Firstly, a group that fasted before surgery, as a control to show the impact of preoperative fasting, was not set. Secondly, effects between glucose solution and enzyme-hydrolyzed rice flour solution were not compared. In addition, the similar research on other types of surgery needs to be further carried out.

In conclusion, oral 300 ml of enzyme-hydrolyzed rice flour solution 2-3 h before surgery in patients undergoing laparoscopic cholecystectomy did not increase the occurrence of reflux and aspiration during anesthesia induction with a normal gastric emptying, ameliorated postoperative insulin resistance, improved the subjective comfort, and promoted postoperative gastrointestinal function recovery.