Fast-track- recovery surgery with a whey-protein-infused carbohydrate-loading drink pre-operatively and early oral feeding post-operatively among surgical gynaecological cancer patients: study protocol of an open-labelled, randomised controlled trial

Fast-track-recovery surgery (FTR) (also known as Enhanced Recovery After Surgery (ERAS)) has been proposed and established since 1999 by Professor Dr. Henrik Kehlet [1]. FTR is developed based on the concept of multimodal post-operative recovery programmes after it was realised that the unimodal intervention was impractical to solve multimodal perioperative morbidity problems. FTR surgery, also known as ERAS programmes, are increasingly been practiced in colorectal surgery [2], gastrointestinal surgery) [3] and various other surgical fields [4‐6]. One of the crucial parts in the FTR programme is early perioperative feeding which is safe and beneficial in post-operative recovery [7]. Many studies have highlighted the general FTR programme which includes providing patients solely with carbohydrate (CHO)-loading pre-operatively and allowing early oral feeding with clear fluid and followed by solid food only after 500 mL clear fluid is tolerated post-operatively [7‐10]. However, the effectiveness of providing a whey-protein-infused CHO-loading drink as the pre-operative CHO-loading drink remains unclear. Practical consideration for FTR surgery development in GC surgical patients is growing [11]. “The FTR programme includes evidence-based items designed to reduce perioperative stress, maintain post-operative physical function and accelerate recovery after surgery” [12]. Using a multi-modal stress-minimising approach has been shown repeatedly to reduce rates of morbidity, improve recovery and shorten length of hospital stay (LOS) after major colorectal surgery [13]. An updated consensus review of perioperative care of colorectal cancer patients has highlighted that the multimodal metabolic stress-minimising approach was demonstrated repeatedly to shorten LOS stay, promote recovery and reduce the morbidity rate after major colorectal surgery [14]. Clinical care of patients undergoing GC surgery is different between hospitals and countries; thus, it is necessary to understand the effectiveness of FTR surgery perioperative feeding specifically in Malaysia.

The primary modalities of cancer treatment are surgery, chemotherapy and radiotherapy; these may be used alone or in combination [15]. For those cancers which are well-defined and operable, surgery is the first-line treatment for GC [16]. Surgery, like an injury, causes catabolism which involves skeletal-muscle-tissue breakdown to release amino acids for wound-healing. Optimal nutritional status perioperatively supports speedy wound-healing, improves immunity and ensures the better post-surgical outcome. Other than calories and CHO, protein is crucial for post-operative recovery, promotes anabolism, slows down muscle catabolism and decreases the inflammatory phase [17]. Milk proteins are divided into two classes: whey and casein. Whey protein is a high-quality protein that is more easily digested and stimulates muscle-protein synthesis more than does casein. Fast digestion and absorption of whey protein is due to the high proportion of branched-chain amino-acid content which directly stimulates the early cellular processes involved in protein synthesis called initiation translation [18]. However, this might not be beneficial to people with milk allergy as they might also be allergic to whey protein [19].

Conventional pre- and post-operative feeding strategies, whereby prolonged fasting or rest for both the patient and their gastrointestinal tract, will delay patient recovery since the organic response to surgical trauma is enhanced by a prolonged period of fasting. Inadequate oral intake due to delayed oral feeding caused depletion of nutrient storage in a patient’s body. This is because of utilisation of energy which is converted from a protein source of body (muscle) which promotes catabolism. Thus, patients experience weight loss and muscle-mass loss post-operatively [20].

In order to overcome the complications of conventional surgical approaches, Kehlet and Wilmore [7] developed a multimodal perioperative protocol, named Enhanced Recovery after Surgery or the fast-track-recovery (FTR) surgery programme. One of keys to FTR programmes is a metabolic strategy to reduce perioperative stress and improve surgical outcomes. Nutritional intervention post-operatively is crucial. Studies of the FTR programme in gynaecological surgery has shown that FTR significantly reduce LOS and consequently leads to positive economic benefits without increasing readmission and complication rates [8, 9, 21]. Studies of the FTR protocol in gynaecological surgery have shown that FTR with pre-operative CHO-loading and post-operative early oral feeding significantly reduces LOS and consequently has positive economic benefits without increasing readmission and complication rates. The FTR protocol focus primarily on reducing perioperative stress, achieving satisfactory pain control, resumption of normal gastrointestinal function and early mobilisation [17, 20, 22].

While early oral feeding is the preferred mode of nutrition, the avoidance of any nutritional support therapy bears the risk of underfeeding during the post-operative course after major surgery. To simplify pre-operative fasting, beverages containing CHOs have been used and recommended in the FTR protocol. Carbohydrate-loading with solely a CHO drink was widely used and proven positive and with beneficial outcomes [17, 20, 22]. Whey protein contains essential amino acids, especially branch-chain amino acids, which have a high degree of digestibility and rapid absorption in the small bowel, which is rapidly used by skeletal muscle during stress and greatly stimulates protein synthesis [23]. Perrone et al. [5] concluded that whey protein infused with CHO drinks as the CHO-loading drink prior to operation improves post-operative muscle strength, reduces fatigue, anxiety and discomfort as well as lowers the endocrine-metabolic response to trauma. The study aims to determine the effectiveness of FTR surgery with a whey-protein-infused CHO-loading drink and early oral feeding among surgical GC patients.

This study is an open-labelled, randomised controlled trial (RCT) conducted at the National Cancer Institute, Putrajaya, Malaysia. Since this is an open-labelled RCT study, blinding will not occur. The study is conducted in the Surgical Gynaecological Department which involves a multidisciplinary clinic and a female surgical ward. The RCT will conform to the Consolidated Standards of Reporting Trials (CONSORT) Statement for reporting RCTs with two arms, comparing an intervention group to a control group [24]. After consenting to participate, participants will be randomly allocating into the intervention group or the control group. Randomisation will be done using computer-generated random numbers.

The FTR surgery programme in Malaysia has mostly been conducted in gastroenterology (upper gastrointestinal and lower gastrointestinal) surgery and even in hepato-biliary surgery [29]. All of the post-operative outcomes in FTR studies are very convincing whereby they show shortened LOS, faster resumption of food tolerance and lower readmission rates. Although the impact of FTR on nutritional status, anti-inflammatory effects and functional status among surgical gastric cancer patients has been published by Makuuchi et al. [30], the impact of FTR among surgical GC patients remain unknown. The effectiveness of FTR in surgical GC patients also remains unexplored, especially in Malaysia.

Most of the available FTR surgery studies [7‐10] have investigated the effectiveness of a solely CHO-containing solution as the CHO-loading formula. An available study by Perrone et al. [11] showed a positive impact of whey-protein CHO-loading among cholecystectomy patients. However, the formula containing whey protein infused with a CHO drink has not been widely implemented as the CHO-loading drink among surgical GC patients. To our best knowledge, this is the first study that used a formula containing whey-protein infused with a CHO drink as the CHO-loading drink among surgical GC patients in Malaysia.

The value of pre-operative overnight fasting has come under doubt recently as, in fact, the incidence of surgery-related aspiration is very low and clinically important consequences of aspiration are even rarer [31]. Moreover, the appropriateness of overnight fasting has been raised because using it CHO reserves will become depleted and cause changes in the metabolism and metabolic responses [32]. Both nutritional compromise going into surgery and a prolonged pre-operative overnight fasting state worsen glycogen and muscle-mass depletion [33].

After a major operation, conventional post-operative care usually includes restrict oral intake to prevent post-operative ileus and, thus, to protect surgical anastomoses [34]. The other reason for nil-by-mouth post operation is to allow anastomoses time to heal before being stressed by the food transiting the gut [35]. In fact, 1–2 L of fluid is secreted by the stomach and pancreas and then absorbed by the small intestine daily [36, 37]. Hence, patients actually tolerated a high volume of fluid [38]. Moreover, within 24 h, starvation changes the body’s metabolism by increasing insulin resistance and depleting muscle function [39]. Early oral feeding post-operatively has been demonstrated to hasten the return of bowel function, improve oral tolerance and shorter LOS [21, 40]. Based on these study findings, nil-by-mouth post-operatively does not seem to be reasonable or beneficial.

Thus, we hypothesise that the FTR programme with a whey-protein-infused CHO drink as the CHO-loading drink pre-operatively, and early oral feeding post-operatively, can result in more positive post-operative outcomes including shortened LOS, catabolic minimisation in order to preserve muscle mass or functional status, and anabolic promotion among surgical GC patients. In the Malaysia healthcare system, this may lead to an immense advantage that may be achieved by the accomplished execution of an FTR surgery programme at an institutional level.

This study protocol version 3, dated 27 September 2017, received ethical approval by the MREC, Ministry of Health, Malaysia on 27 September 2017. The protocol was retrospectively registered at ClinicalTrials.​gov on 12 September 2018. Data recruitment started on 3 October 2017 and completed on 27 September 2019. This study protocol was submitted for publication on 21 May 2019 while the recruitment was ongoing and before the last patient’s last visit.