Perioperative Nutritional Support With Beta-hydroxy-beta-methylbutyrate, Arginine, and Glutamine in Surgery for Abdominal Malignancies

Although beta-hydroxy-beta-methylbutyrate (HMB), arginine (Arg), and glutamine (Gln) may contribute to wound healing, no prospective studies have investigated the efficacy of a compound consisting of HMB, Arg, and Gln (HMB/Arg/Gln) for reducing wound complications following open abdominal surgery. Objective. This study evaluates the usefulness of perioperative nutrition using HMB/Arg/Gln in patients who were scheduled to undergo open surgery for abdominal malignancies in a randomized controlled trial. Materials and Methods. Patients scheduled for open surgery for abdominal malignancies were randomized to receive HMB/Arg/Gln (1.2 g HMB, 7 g L-Arg, and 7 g L-Gln) or placebo (isocaloric juice). The supplements were provided once daily for 3 days preoperatively and once daily for 7 days postoperatively. The primary endpoint was the incidence of wound complications. Secondary endpoints included the incidence of other complications, postoperative duration of hospital stay, total-body skeletal muscle mass, handgrip strength, and skin water content. Results. Sixty-one patients were randomly assigned to either the HMB/Arg/Gln (n = 31) or the placebo (n = 30) group. One patient in the HMB/Arg/Gln group was ineligible because laparoscopic surgery was performed; thus, 60 patients were analyzed. The incidence of wound complications (20%) was the same in both groups (P = 1.000). There were no significant differences in the incidence of other complications, body composition, handgrip strength, or skin water content between the 2 groups. Serum growth hormone (GH) levels were significantly higher for patients whose total intake was > 80% of planned volume in the HMB/Arg/Gln group. Conclusions. The incidence of wound complications would not be reduced by perioperative HMB/Arg/Gln administration in patients who underwent open surgery. The efficacy of HMB/Arg/Gln for increasing serum GH levels needs to be validated in another large-scale randomized controlled trial.

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Nutrition Affects Chronic Wound Outcomes

Nutrition in Wound Care Management: A Comprehensive Overview

Wound complications are common following open surgery,¹ with reported incidences of wound infection of 6.3% to 18.2% after open gastrectomy,^2-4 5.8% to 18.8% after open distal pancreatectomy,^5-7 and 13.3% to 18.0% after open hepatectomy.^8,9 One of the main causes of wound complications is delayed wound healing. The healing process relies on collagen synthesis, and nutrients such as arginine (Arg) and glutamine (Gln), which promote collagen synthesis, play an important role and decrease the rate of wound complications.^10,11 The maintenance of lean body mass (LBM) is another essential factor that influences wound healing. When there is insufficient protein levels to heal a wound, LBM supplies the amino acids for protein synthesis. Therefore, the loss of LBM is directly related to delayed wound healing. Beta-hydroxy-beta-methylbutyrate (HMB), a leucine (Leu) metabolite, has been shown to increase LBM by stimulating muscle protein synthesis.^12–15

A compound consisting of HMB, Arg, and Gln (HMB/Arg/Gln) was shown to promote collagen synthesis, contribute to wound healing, and maintain LBM.^14,15 When sterile polytetrafluoroethylene tubes were implanted for 14 days in the subcutaneous tissue of healthy elderly adults with or without HMB/Arg/Gln supplementation, the amount of collagen synthesized in the tubes was significantly higher in the HMB/Arg/Gln group.¹⁶ Tatti and Barber¹⁷ reported that diabetic foot ulcers healed significantly more quickly when HMB/Arg/Gln was administered. A meta-analysis¹² found LBM was significantly increased in healthy adults following the administration of HMB. However, no prospective studies have investigated the efficacy of HMB/Arg/Gln in reducing wound complications or maintaining LBM following open abdominal surgery. Thus, this study evaluates the usefulness of perioperative nutrition using HMB/Arg/Gln in patients who were scheduled to undergo open surgery for abdominal malignancies in a randomized controlled trial (RCT).

Patients

At a single site in Osaka, Japan, a randomized, double-blind, placebo-controlled trial was conducted, with the following eligibility criteria: patients were ≥ 20 years of age, had adequate organ function, and had planned open surgery for abdominal malignancies. Exclusion criteria included patients needing emergency surgery, a history of laparotomy with repeated incision, continuous corticosteroid use, uncontorolled or insulin-treated diabetes, or active infection. The investigators managed the recruitment and enrollment of patients. Consecutive patients were randomly assigned (1:1) to either the HMB/Arg/Gln group or the placebo group using a computer-generated permuted-block sequence with a block size of 4. The random allocation sequence was generated by the investigator and stratified by the type of disease. Patients and investigators were blinded to group assignment. All patients provided written informed consent prior to randomization. This study was approved by the Institutional Review Board of Osaka University Hospital (Osaka, Japan) and registered with UMIN-CTR, UMIN 000012553.

Procedures

In the HMB/Arg/Gln group, a compound consisting of 1.2 g of HMB, 7 g of L-Arg, and 7 g of L-Gln (Abound; Abbott Japan, Tokyo, Japan) was administered after being dissolved in 250 mL of tap water. Patients in the placebo group received an equivalent amount of isocaloric juice (Bireley’s; Asahi Soft Drinks, Tokyo, Japan) with a similar taste as the HMB/Arg/Gln compound. In addition to a regular hospital diet, the 250-mL supplements were provided once daily for 3 days preoperatively and once daily for 7 days postoperatively. Patients could intake water or other drinks freely unless there was a fluid restriction. All patients received appropriate systemic antibiotics approximately 30 minutes preoperatively as part of standard surgical site infection (SSI) prophylaxis.

During surgery, body temperatures of patients were appropriately maintained by anesthesiologists. Patients usually were administered intravenous (IV) fluids according to the normal clinical pathway for each disease. The dose of IV fluids was adjusted and occasionally changed according to the body weight of each patient.

Patients who underwent gastrectomy received 1 L of IV solution containing 4.2 g of L-Leu and 3.15 g of L-Arg (BFLUID; Otsuka Pharmaceutical Factory, Tokushima, Japan) and 1 L of glucose-electrolyte solution (SOLDEM 3A; Terumo Corp, Tokyo, Japan) for 6 days postoperatively, as well as a 1-time administration of 1 g of cefazolin sodium on the first postop night.

Patients who underwent hepatectomy received 1 L of L-Arg and 1 L of glucose-electrolyte solution for 5 days postoperatively, as well as 1 g of flomoxef sodium and 600 mg of clindamycin hydrochloride twice daily for 2 days postoperatively.

Patients who underwent pancreatectomy received 2 L of glucose-electrolyte solution for 6 days postoperatively, as well as 1 g of flomoxef sodium and 600 mg of clindamycin hydrochloride twice daily for 2 days postoperatively.

Evaluations

The primary endpoint was the incidence of wound complications, defined as seroma, superficial incisional SSI, and wound dehiscence. Superficial incisional SSI was defined as infections occurring within 30 days following surgery that implicate only the skin or subcutaneous tissue of the incision, according to a US Centers for Disease Control and Prevention guideline.¹⁸

The secondary endpoints were the incidence of postoperative complications, excluding wound complications, that occurred during hospitalization; duration of hospital stay after surgery; total-body skeletal muscle mass (TSM); handgrip strength; and skin water content. The severity of postoperative complications (excluding wound complications) was evaluated according to the Clavien-Dindo classification system.^19,20

The data of body weight (BW), TSM, LBM, handgrip strength, skin water content, and serum growth hormone (GH) level were collected before and after the administration of HMB/Arg/Gln or placebo. Both TSM and LBM were measured using bioelectrical impedance analysis (Karada Scan HBF-214; Omron, Kyoto, Japan). Handgrip strength was tested using a hand dynamometer (DIGITAL HANDGRIP METER MCZ-5041; Macros, Tokyo, Japan). Skin water content was measured on the inner side of the arm with a skin moisture analyzer (Moisture Checker MY-808S; Scalar, Tokyo, Japan). Serum GH level was measured using electrochemiluminescence immunoassay (Elecsys hGH; Roche-Diagnostics, Rotkreuz, Switzerland).

The dose of HMB/Arg/Gln or placebo and the severity of postoperative complications were assessed by nurses or doctors, all of whom were blinded to the assigned group.

Statistical analysis

The investigators planned a sample size of 60 patients, which would provide a power of 70% with a 1-sided significance level of 0.2 to detect superiority in the reduction of the frequency of wound complications. Although wound complications occurred in 12% of patients after open gastrointestinal surgery in a large-scale trial,²¹ the present study included many patients who planned hepatobiliary-pancreatic surgery, which has a higher risk of wound complications than gastrointestinal surgery. Thus, wound complications were anticipated in 5% of patients in the HMB/Arg/Gln group and 20% in the placebo group. No interim analysis was planned or carried out.

The χ² test for categorical variables and the Mann-Whitney U test for continuous variables were used. Logistic regression was used for subgroup analysis. A P value < .05 was considered statistically significant, except for the analysis of the primary endpoint. All statistical analyses were performed using SPSS Statistics software, version 23 (IBM Corp, Armonk, NY).

A total of 61 patients were enrolled from December 2013 to July 2015 (when the last patient exited), with 31 randomly assigned to the HMB/Arg/Gln group and 30 to the placebo. The trial profile is shown in Figure 1. One patient in the HMB/Arg/Gln group was ineligible because laparoscopic surgery was performed; thus, 60 eligible patients were analyzed for all endpoints.

The background characteristics of the eligible patients were well-balanced (Table 1). One patient in the HMB/Arg/Gln group, who had recurrence of hepatocellular carcinoma in the abdominal wall, underwent resection at the recurrence site. In 51 patients, antibiotics were only administered within 2 days after surgery, whereas the remaining 9 patients continued antibiotics due to postoperative complications.

Overall compliance rates with oral HMB/Arg/Gln and placebo were 95% and 90% of planned volume, respectively. There were no deaths or Clavien-Dindo grade IV complications in either group. Table 2 lists the incidence of postoperative complications and the durations of hospital stays after surgery for both groups. As the primary endpoint, the incidences of wound complications (20%) were the same in the 2 groups (2-sided P = 1.000; 1-sided P = .500). Among wound complications, seroma occurred in 6 patients and superficial incisional SSIs were in 2 patients in either group. The incidences of other complications were similar between the 2 groups: 4 patients (13%) in the HMB/Arg/Gln group and 6 patients (20%) in the placebo group. In an exploratory analysis, only data on the patients whose total intake dose was ≥ 80% of planned volume were used, but the incidence of wound complications was essentially unchanged (21% vs. 28%; P = .601).

The investigators performed a subgroup analysis to identify the interactions between background characteristics and the effect of HMB/Arg/Gln (Figure 2). No subgroup showed a significant decrease in the incidence of wound complications with HMB/Arg/Gln. The subgroups with an odds ratio of 0.50 for wound complications with HMB/Arg/Gln were body mass index (BMI) ≥ 23 kg/m², gastrectomy, and blood loss ≥ 330 mL, but even these subgroups did not demonstrate statistical significance (BMI ≥ 23 kg/m²; P = .482; blood loss ≥ 330 mL; P = .413).

Table 3 summarizes the results of other evaluations of the 2 groups. There were no significant differences in body composition, handgrip strength, or skin water content between the 2 groups. The median change of serum GH level was 0.227 ng/mL in the HMB/Arg/Gln group and -0.002 ng/mL in the placebo group, which did not show a significant difference (P = .057). An exploratory analysis examining only patients whose total intake dose ≥ 80% of planned volume showed the serum GH level significantly increased after administration of HMB/Arg/Gln as compared with the placebo (median change, +0.242 ng/mL vs. -0.012 ng/mL; P = .036).

This is the first double-blind RCT to evaluate the usefulness of HMB/Arg/Gln in patients who were scheduled to undergo open surgery for abdominal malignancies. In previous studies,^14,17 HMB/Arg/Gln was reported to promote wound healing and maintain LBM. However, the present trial showed HMB/Arg/Gln did not reduce the incidence of wound complications in patients who underwent open surgery for abdominal malignancies. The investigators of this study also found no significant benefit of HMB/Arg/Gln, even in secondary endpoints. Thus, from this study’s results, the authors would not recommend the perioperative use of HMB/Arg/Gln for the purpose of promoting wound healing or maintaining LBM.

Tatti and Barber¹⁷ investigated the efficacy of HMB/Arg/Gln in wound healing in patients with diabetic foot ulcers. Patients did not receive HMB/Arg/Gln during treatment of primary ulcers but were administered the compound during treatment of recurrent ulcers. Recurrent ulcers were found to heal significantly sooner than primary ulcers (81 vs. 246 days; P < .001).¹⁷ Deutz et al¹⁴ investigated the efficacy of HMB on LBM in healthy elderly adults confined to 10 days of complete bed rest. They administered 1.5 g of HMB or placebo starting 5 days prior to bed rest until 8 weeks after bed rest. Although LBM significantly decreased after 10 days of bed rest in the placebo group, it was preserved in the HMB group.¹⁴ In these 2 studies,^14,17 HMB/Arg/Gln or HMB was administered for a longer period than in the study reported herein. The lower dosage of the compound in the present study might be a reason why the investigators observed no difference in the incidence of wound complications and LBM between the HMB/Arg/Gln and placebo groups.

This study demonstrated significantly higher serum GH levels of patients whose total intake dose was ≥ 80% of planned volume in the HMB/Arg/Gln group. Growth hormone is a peptide hormone produced mainly by the somatotroph cells in the pituitary gland.²² The relationship between Arg intake and increased serum GH levels has been shown in several studies.^23-25 The secretion of somatostatin, which inhibits GH release, is prevented by Arg; as a result, Arg increases serum GH levels.^23-25 Although the postoperative increase of serum GH levels also has been demonstrated in several studies,^26-28 serum GH levels decreased until the fifth day after surgery.^26,28-30 In the present study, the influence of surgical stress on serum GH levels was thought to have disappeared by 7 days postoperatively, at which time patients stopped receiving the supplements, thus serum GH levels might have been increased by HMB/Arg/Gln intake. A previous study³¹ reported the efficacy of perioperative administration of GH. Liu et al³¹ demonstrated that the peripheral CD4+/CD8+ lymphocyte ratio decreased significantly less in patients who received GH before and after abdominal surgery than those in the placebo group, which indicates that GH may attenuate the depression of cellular immunity following surgical stress.

A limitation of this study was its small sample size. This may have led to low statistical power for proving the benefit of perioperative HMB/Arg/Gln administration, but the investigators could not show even a slight tendency of HMB/Arg/Gln to reduce the incidence of wound complications or maintain body composition. Thus, even if they conducted a large-scale RCT, this completely negative result would not be reversed.

The small amount of HMB/Arg/Gln administered in this study also might have led to a negative result. However, patients who underwent abdominal surgery usually cannot take a liquid compound as much as healthy volunteers or patients with other diseases. On the other hand, this study indicated that HMB/Arg/Gln might increase serum GH levels; thus, further investigation with a larger sample size is needed to validate this effect.

The study results show the incidence of wound complications would not be reduced by perioperative nutritional support with a compound consisting of HMB/Arg/Gln in patients who underwent open surgery for abdominal malignancies. The efficacy of HMB/Arg/Gln for increasing serum GH levels needs to be validated in another large-scale RCT.

Affiliation: Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka, Japan

Correspondence: Yukinori Kurokawa, MD, PhD, Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2-E2, Yamadaoka, Suita, Osaka 565-0871, Japan; ykurokawa@gesurg.med.osaka-u.ac.jp

Disclosure: Yuichiro Doki received unrestricted research grant from Abbott Japan. The remaining authors disclose no financial or other conflicts of interest.