Use of an Oral Nutritional Supplement Containing Calcium Beta-Hydroxy-Beta-Methylbutyrate (CaHMB), L-arginine, and L-glutamine May Have Helped Avoid Surgery That Could Have Led to Short Bowel Syndrome: A Case Report

Abstract

We present a case in which conservative therapy with oral nutritional supplements (ONS) containing calcium beta-hydroxy-beta-methylbutyrate (CaHMB), L-arginine (Arg), and L-glutamine (Glu) was performed for postoperative small intestine-incision site fistula due to suture failure following surgery for intestinal obstruction after a cesarean section and avoided surgery that carried a high risk of short bowel syndrome in short small intestine patient due to multiple surgeries for Crohn's disease. We report the case of a 39-year-old woman patient. She was diagnosed with Crohn's disease at 14 years old and has undergone multiple surgeries in the past. Jejunostomy was created in the remaining 150 cm of her small intestine. Cesarean section was performed due to preterm labor, but subsequently, the patient developed adhesive small bowel obstruction that was resistant to conservative treatment, and an open abdominal operation was performed. During the surgery, two extensive small intestine injuries were identified, but due to concerns about short bowel syndrome resulting from resection, suture reinforcement was performed. However, an intestine-wound fistula developed due to suture failure in the same area. Since the patient wished for conservative treatment, intestinal fluid was continuously aspirated while using a combination drink containing CaHMB, Arg, and Glu (Abound™, Abbott Japan LLC, Tokyo, Japan). After taking Abound™, there was a marked increase in granulation tissue and narrowing of the fistula. Intestinal fluid discharge stopped 13 days after taking Abound™, and the patient began eating on the 16th day. The patient was discharged on the 22nd day, and the wound healed on the 36th day.

Introduction

Proper nutritional management is one of the key factors in wound healing. As part of nutritional management for wound healing, it is recommended to appropriately administer nutrients, such as amino acids, the three major nutrients, vitamins, minerals, and fluids [1,2]. Recently, reports have emerged on the wound-healing-promoting effects of oral nutritional supplements (ONS) containing calcium beta-hydroxy-beta-methylbutyrate (CaHMB), L-arginine (Arg), and L-glutamine (Glu) as a treatment for pressure ulcers and postoperative wounds [3,4]. These nutrients play a key role in the wound-healing process by promoting the synthesis of proteins and collagen.

We present a case in which conservative therapy with ONS containing CaHMB/Arg/Glu was performed for a woman who developed a postoperative small intestine-incision site fistula due to suture failure following surgery for intestinal obstruction after a cesarean section. This patient had a residual small intestine of 150 cm due to multiple surgeries for Crohn's disease. We report this case because it is possible that this ONS containing CaHMB/Arg/Glu contributed to wound healing and helped avoid the reoperation, which could have increased the risk of short bowel syndrome.

Case presentation

The patient was a 39-year-old woman with Crohn's disease, which began at 14 years old. She had performed multiple surgeries involving subtotal colectomy and massive small bowel resection in the past, and the result was that she had an end jejunostomy constructed at a site with 150 cm of remaining jejunum. Ten years had passed since the last surgery; her condition had remained stable with regular infliximab treatments during that time.

She was admitted to the Department of Obstetrics and Gynecology at Toyama Prefectural Central Hospital due to threatened premature labor during her first pregnancy and gave birth by cesarean section at 35 weeks of pregnancy. However, small bowel obstruction was observed two days after the cesarean section, and despite conservative treatment using long intestinal tubes, no improvement was observed. The patient was referred to the Department of Surgery at the same hospital, where an open ileus surgery was performed 16 days after the cesarean section.

Surgical findings revealed adhesions with multiple loops at the cranial edge of the uterus, which were released by sharp incision, but one extensive seromuscular layer injury and one full layer injury nearby were also found. It was thought that it would be safer to perform intestinal resection and anastomosis reconstruction, but due to multiple surgeries for Crohn's disease, the remaining small intestine was 150 cm, and there was a high possibility that performing intestinal resection would lead to short bowel syndrome. Therefore, the damaged area of ​​the seromuscular layer was reinforced with sutures, and the damaged area of ​​all layers was sutured closed using a linear stapler.

On the third postoperative day (POD3), a wound infection was noted (Figure 1A); thereafter, no major problems were noted, and the patient began eating on POD6. However, intestinal obstruction was noted on POD10, and the patient was fasted; intestinal fluid leakage was noted from the infected wound on POD11 (Figure 1B). After detailed examination, the patient was diagnosed with a tubular fistula-type small intestine-wound fistula due to suture failure of reinforcement at the damaged small intestine (Figure 1C). No leakage of intestinal fluid into the free space within the peritoneal cavity was observed (Figure 2).

Figure 1. Findings of surgical site infection and small intestine-wound fistula.

(A) On surgical wound findings at the time of wound infection onset (POD3), the abdominal wall sutures were exposed. (B) On physical examination of small intestine-wound fistula at onset (POD11), the abdominal wall sutures (arrow) were detached in the upper half of the wound, suggesting wound infection extending into the abdominal cavity. (C) In the radiographic findings of small intestine-wound fistula, there was a distance between the lower edge of the infected wound (arrow) and the intestinal fistula opening (arrow heads), suggesting a tubular-type fistula. No contrast-enhanced findings extending into the abdominal cavity were observed.

POD: postoperative day.

Figure 2. Abdominal computed tomography findings. (A) Axial plane; (B) sagittal plane.

The leakage of intestinal fluid was confined to the surgical incision site (circle). On this examination, the size of the infected wound area was approximately 3.2 x 2.7 x 2.0 cm (length, width, depth).

Surgical treatment was considered an option for this patient. However, given the patient's stable general condition, the fistula was tubular type with the potential for spontaneous closure, and the desire to avoid short bowel syndrome associated with surgical intervention, it was decided to proceed with conservative management.

A peripherally inserted central venous catheter (PICC) was placed on POD12 via the basilic vein of the left upper arm, and total parenteral nutrition was initiated. Since her height/weight were 160 cm/47 kg, her basal energy expenditure (BEE) calculated using the Harris-Benedict formula was approximately 1,220 kcal. Nutritional management was carried out in accordance with this BEE.

Intestinal fluid was continuously suctioned, and the patient was given total parenteral nutrition and one packet of Abound™ (Abbott Japan LLC, Tokyo, Japan), an ONS containing CaHMB 2 g/Arg 7 g/Glu 7 g per packet, was administered orally daily on POD14 (Figure 3A). One packet of Abound™ in 300 cc of water was drunk slowly over the course of a day. PICC infection was identified on the fourth day after oral administration of Abound™ (OAD)/POD18, and nutritional management was via peripheral infusion alone. But after oral administration of the ONS, significant proliferation of granulation tissue and narrowing of the fistula were observed (Figure 3B); intestinal fluid discharge ceased on OAD13/POD27 (Figures 3C, 4), and the patient began eating on OAD16/POD30. 

Figure 3. Post-Abound™ oral administration wound findings. (A) OAD0/POD14, (B) OAD6/POD20, and (C) OAD13/POD27.

It can be seen that the granulation tissue is rapidly developing. The suction tube is no longer needed at OAD14/POD28.

OAD: oral administration day of Abound™; POD: postoperative day.

Figure 4. Radiographic findings on OAD13/POD27.

The infected wound has shrunk, and the tubular fistula has narrowed to the width of the drain (arrow: caudal margin of the infected wound, arrowhead: intestine).

OAD: oral administration day of Abound™; POD: postoperative day.

No further problems were observed, and the patient was discharged from the hospital on the OAD22/POD36. She continued taking Abound™ orally after being discharged from the hospital; the wound healed completely on the OAD36/POD50 (Figure 5). Currently, the patient is able to eat a normal diet, has no evidence of short bowel syndrome, and is able to breastfeed.

Figure 6 shows the amount of nutrition administered until discharge, and Figure 7 shows changes in nutritional status from before surgery through wound closure.

Figure 5. Post-Abound™ oral administration wound findings. (A) OAD19/POD33; (B) OAD27/POD41.

Before discharge, granulation tissue had risen to form a simple ulcerative wound. After discharge, further elevation of granulation tissue was observed, and it became escharified on OAD36/POD50.

OAD: oral administration day of Abound™; POD: postoperative day.

Figure 6. Postoperative nutritional progress and events.

PPN 1: Glucose 150 g, Amino acid 60 g, Vitamin B1, B6, B12; PPN 2: Glucose 150 g, Amino acid 60 g, Vitamin B1, B6, B12, Intravenous lipid emulsion 20%/250cc

TPN: Glucose 262.5 g, Amino acid 65 g, Vitamin A, B1, B2, B6, B12, C, D, E, K, niacin, folic acid, biotin, trace elements (Fe, Mn, Zn, Cu, I).

Ev.1: Intestinal fluid leakage was noted from the infected wound; Ev.2: Central venous catheter infection was detected; Ev.3: Intestinal fluid discharge ceased. It appears that the volume of discharge from the wound has been decreasing since OAD5.

PPN: peripheral parenteral nutrition, TPN: total parenteral nutrition, PN: parenteral nutrition, EN: enteral nutrition, POD: postoperative day, OAD: oral administration day of Abound™, D/C: discharge from the hospital, Ope: operation.

Figure 7. Nutritional status from before surgery through wound closure.

Ev.1: Intestinal fluid leakage was noted from the infected wound; Ev.2: Central venous catheter infection was detected; Ev.3: Intestinal fluid discharge ceased; Ev.4: The wound healed completely.

POD: postoperative day, OAD: oral administration day of Abound™, D/C: discharge from the hospital, Ope: operation, Alb: serum albumin level, CRP: serum C-reactive protein level.

Discussion

Crohn's disease is a chronic inflammatory disease of the gastrointestinal tract characterized by discontinuous distribution of full-thickness granulomatous inflammation and fistula formation. Treatment for Crohn's disease primarily involves drug therapy, but surgical intervention may be performed to improve quality of life when strictures or fistulas develop. However, repeated intestinal resection may lead to short bowel syndrome, defined by clinical symptoms associated with a remaining small bowel of less than 200 cm in continuity from the ligament of Treitz [5]. Therefore, it is considered important to avoid surgical bowel resection whenever possible in Crohn's disease.

In this case, previous surgical records indicated that the length of the remaining small intestine was 150 cm. Although the remaining intestinal length already met the criteria for short bowel syndrome, no clinical symptoms were present, and the patient was able to carry out daily activities. However, since there was a very high risk of developing short bowel syndrome if the intestine were resected during this operation, the treatment plan was established to avoid intestinal resection, including management of complications. Consequently, we had no choice but to opt for spontaneous resolution. Amidst this situation, the wound healing promotion effects of Abound™, an ONS containing CaHMB/Arg/Glu, have been reported [1,2], and we decided to use this ONS in this case as well.

Normal wound healing consists of the hemostasis, inflammation, proliferation, and remodeling phases. Many studies have documented the need for supplementation with amino acids such as Glu, CaHMB, and Arg to promote wound healing [6,7].

Glu has been reported to serve as an energy source for cells involved in wound healing, such as macrophages, lymphocytes, and fibroblasts, thereby promoting wound healing [8]. Furthermore, it has been demonstrated that it is the primary energy substrate for intestinal mucosal cells [9], that oral administration suppresses intestinal mucosal atrophy [10], and that it maintains lymphocyte counts and the intestinal cytokine environment, thereby suppressing the decline in intestinal immune function [11].

Arg is a nonessential amino acid produced endogenously in the kidneys from intestinal citrulline. It serves as a substrate for nitric oxide (NO), which is present within macrophage cells and is thought to promote the activation of immune responses. Numerous reports have documented the wound-healing-promoting effects of arginine [12,13]. Although hydroxyproline is considered an amino acid unique to collagen, it has been reported that arginine plays a significant role in the production of hydroxyproline [14].

CaHMB is a metabolite of leucine, a branched-chain amino acid. It has been reported to promote protein synthesis via the mammalian target of rapamycin pathway, which is involved in cell division and growth, and to suppress body protein degradation by inhibiting the ubiquitin-proteasome system [15]. Additionally, it has been shown to enhance muscle mass when combined with exercise [16].

Abound™ contains key nutrients essential for promoting wound healing (per packet: CaHMB: 2 g, Glu: 7 g, Arg: 7 g, energy: 79 kcal, carbohydrates: 7.9 g, fat: 0 g). William et al. reported that when Abound was administered at a dose of two packets per day for 14 days, the amount of hydroxyproline at the wound site showed no change on day seven after the start of administration compared to the control group, but had increased significantly by day 14 ​​​​[17]. Therefore, oral administration of Abound™ may promote collagen synthesis at the wound site through the production of hydroxyproline. Since the proliferative phase of wound healing is the period when collagen synthesis peaks and granulation tissue forms, it is thought that taking Abound™ during this phase may be effective in promoting wound healing. It should be noted that while the aforementioned study reported the efficacy of taking two packets per day for two consecutive weeks, there is no consensus on the optimal dosage or duration of treatment. However, in terms of safety, no cases of renal or hepatic dysfunction have been reported even with the administration of two pouches per day for two weeks to elderly adults with wounds [17].

In this case, a patient who had undergone multiple surgeries for Crohn's disease and was documented as having a diagnosis corresponding to short bowel syndrome developed postoperative wound dehiscence with a small bowel wound fistula. To avoid short bowel syndrome resulting from surgery and because it was a tubular fistula type where closure was expected with appropriate management [18], conservative treatment was chosen. However, prolonged treatment was anticipated. Intestinal fluid accumulation at the wound site was relatively well managed via wall suction. Anticipating early fistula closure and improvement of the infected wound, oral administration of Abound™ at a dose of one packet per day was initiated. The reason for administering one packet of Abound™ per day was to avoid placing any strain on the abdominal cavity during suture failure. But, intestinal fluid discharge ceased on OAD13, enabling subsequent eating. The patient was discharged on OAD22, and wound healing was confirmed on OAD36. The aforementioned literature indicated that taking two packets a day for two weeks led to an increase in hydroxyproline at the wound site [17]. However, in this case, it is possible that even one packet a day was effective. Further investigation is required to determine whether administering one packet per day leads to an increase in the amount of hydroxyproline at the wound site.

The following limitations of this case study can be noted. We cannot make a clinical comparison since Abound™ was used immediately after this event occurred. Therefore, it is possible that the same results would have been obtained even without using the ONS. It is also unclear whether there is a direct causal relationship with the ONS, as the amount of hydroxyproline at the wound site has not been measured. But intestinal fluid discharge from the fistula had almost completely ceased one week after the start of Abound™, and the fistula closed in less than two weeks. Based on these results, we speculate that Abound™ likely played a significant role in achieving such early healing despite the relatively extensive wound dehiscence involving a small intestinal wound and the primary nutritional support was via peripheral intravenous infusion only. This resulted in avoiding short bowel syndrome, enabling normal food intake, and allowing for breastfeeding.

However, while Arg contained in Abound™ serves as a substrate for NO, NO possesses tissue-damaging effects. Consequently, negative aspects such as tissue damage in severe conditions are also considered, and reports indicate it may be hazardous in severe sepsis cases [19]. The pros and cons of administering arginine under invasive conditions have been debated for a long time, and no consensus has yet been reached. When using nutritional supplements containing arginine, it is necessary to bear this point in mind. On the other hand, it has been reported that an ONS containing CaHMB/Arg/Glu is not effective in healing chronic wounds [20]. When using Abound™ for wound healing, it is necessary to determine the appropriate timing.

Conclusions

We reported a case in which the use of Abound™, ONS containing CaHMB, Glu, and Arg, for a postoperative small intestine wound fistula in a long-term Crohn's disease patient with 150 cm of remaining small intestine may have avoided reoperation that could have led to short bowel syndrome. Reports of this ONS promoting wound healing are occasionally seen, but this was one case where we experienced it firsthand. We will continue to actively utilize this ONS whenever the opportunity arises and explores its potential for promoting wound healing. We are currently using this ONS to manage cases of postoperative anastomotic leakage in colorectal cancer patients who are eligible for conservative treatment. We have been able to use it without any particular problems. As far as we can tell, no studies on this topic have been published, so we intend to conduct further research and report our findings.