Efficacy of arginine supplementation for the treatment of air leakage

Introduction

Postoperative persistent air leakage is a common complication after lung resections, even in video-assisted thoracic surgery.^1–6 On the other hand, nutrition has been noted to be a major factor related to wound healing. Although nutrition can significantly affect the healing process of air leakage, few reports have provided insights into such aspects. There have been recent advances in nutriology, and the role of arginine in patients who have experienced surgical stress has been emphasized.^7–9 Arginine is an essential amino acid, especially for children, and plays an important role in cell division, the healing of wounds, removing ammonia from the body, immune function, and the release of growth hormone. ¹⁰ Some studies have revealed that enteral arginine supplementation helps healing of pressure ulcers and reduces the frequency of infections and wound complications after major surgery for head and neck cancer.^5,6,9 Perioperative arginine supplementation appears to accelerate wound healing after surgery. Therefore, we studied whether postoperative enteral arginine supplementation could contribute to the resolution of prolonged air leakage after lung resections.

Patients and methods

The study protocol was examined and approved by the department research review board. Before each operation, written consent was obtained from all patients, thereby giving us permission to include their information in our study, with an understanding that their privacy would be protected. The board concluded that this study did not violate patient privacy and approved the consent form. From April 2009 to March 2012, among patients having undergone lung resections at our institutions, 42 patients who had continuous air leakage noted in the chest tube drainage bottle during the expiratory phase on the day of surgery and the next day, were enrolled in this study (Table 1). The diameter of the drainage tube was 8 mm, and the aspiration pressure was set between 2 and 6 cm H₂O. In all patients, a surgical sealant employing an absorbable polyglycolic acid sheet (Neoveil; Gunze Ltd., Kyoto, Japan) and 3 mL of fibrin glue (Bolheal; Kaketsuken, Kumamoto, Japan) were applied for the prevention of prolonged air leakage.^11,12 The patients were divided into two groups: the first group was 21 patients who agreed postoperatively to consume 3 packs a day of Arginaid (Nestle HealthCare Nutrition, Inc., NJ, USA), which amounts to 125 mL per pack, including 2500 mg of arginine.^13,14 A second group, serving as a control group, included the remaining 20 patients who did not consume Arginaid. All patients received hospital diets 3 times a day from postoperative day (POD) 1, and in the arginine supplementation group, 1 pack of Arginaid was added to each meal after informed consent was obtained from the patient. Consequently, the cost of the hospital diet was increased by approximately US$ 9 a day in the arginine supplementation group. The durations of air leakage and chest tube drainage were investigated and compared between the two groups. In the arginine supplementation group, the postoperative day when administration of Arginaid was started, and the durations of air leakage and chest tube drainage from administration of Arginaid were also investigated. These lengths of time were retrospectively confirmed using the clinical records made by the attending nurses.

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Table 1.

Characteristics of patients undergoing lung resection with and without arginine supplementation.

Variables	Arginine	Control	p value
No. of patients	21	21
Sex (M/F)	15/6	19/2	0.24
Age (years)	69.4 ± 8.3	62.5 ± 15.1	0.075
Diagnosis
Lung cancer	16	15	0.72
Emphysematous bulla	3	4	1.00
Pneumothorax	2	1	1.00
Tuberculoma	0	1	1.00
Surgery
Lung lobectomy	15	12	0.52
Lung wedge resection	1	4	0.34
Bullectomy	5	5	1.00
VATS/open operation	11/10	9/12	0.53
Smoker	15	19	0.24
Mean pack-years  (median)	45.0 ± 39.6 (40)	46.9 ± 28.3 (50)	0.86
Chemical pleurodesis	0	3	0.23

Quantitative data are described as mean ± standard deviation, or median and range. The data were analyzed using StatMate III software (ATMS, Inc., Tokyo, Japan). The durations of air leakage and chest tube drainage were compared between the two groups by Student’s t test after the F test for equal variances. A p value< 0.05 was considered to be statistically significant.

Results

There were no significant differences between the two groups in terms of the number of smokers, pack-years, and other variables. In the arginine supplementation group, the administration of Arginaid was started on POD 2.5 (median, POD 2), however, those days were widely scattered from POD 1 to 6. The mean durations of air leakage and chest tube drainage were significantly shorter in the arginine supplementation group compared to the control group (4.4 ± 2.4 vs. 6.7 ± 3.1 days and 6.5 ± 2.7 vs. 8.3 ± 3.0 days, respectively; Table 2). In the arginine supplementation group, the time until there were changes in air leakage and chest tube drainage after the administration of arginine supplementation were 2.5 ± 1.7 and 4.8 ± 2.0 days (median, 2 and 4.5 days), respectively. Chemical pleurodesis employing 50–100 mL of autologous blood or 100 mg of minocycline dissolved in 100 mL of normal saline was performed postoperatively in 3 patients in the control group. Hyperphosphatemia, as a postoperative complication associated with the administration of Arginaid, was noted in 1 patient who was on hemodialysis. However, it was temporary and not critical, and was rapidly resolved by hemodialysis. In this patient, Arginaid was administered for 3 days although the air leak had been successfully stopped the day after the administration was started. No other complication associated with Arginaid was found.

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Table 2.

Duration of air leakage and chest tube drainage in patients with and without arginine supplementation.

Variable	Arginine	Control	p value
Air leakage (days)
Mean	4.4 ± 2.4	6.7 ± 3.1	0.010
Median [range]	4 [1–9]	6 [3–15]
Drainage (days)
Mean	6.5 ± 2.7	8.3 ± 3.0	0.042
Median [range]	6 [2–12]	8 [4–16]
Air leakage after arginine (days)
Mean	2.6 ± 1.5
Median [range]	2 [1–6]
Drainage after arginine (days)
Mean	4.7 ± 1.9
Median [range]	5 [2–9]

Discussion

Prolonged air leakage is a common complication after lung surgery, even after video-assisted thoracoscopic surgery, and the reported incidence ranges from 15% to 18%. ¹⁵ At present, various procedures using fibrin glue, sheets of synthetic material, and strips of reinforcing material to buttress the staples are added intraoperatively to prevent air leakage.^15,16 Despite employing such techniques, moderate air leaks that may become prolonged are still frequently found the day after surgery. In such cases, we often take a “wait and see” approach, because the leak seals spontaneously within 2 or 3 days of surgery in most cases. ¹⁷ However, some of these cases require pleurodesis.^18,19 It often takes days to make such clinical decisions as there are currently no markers that can predict whether an air leak may become prolonged or not, but the decision to start postoperative nutrition therapy can be made quickly, and it is easy to implement even under such conditions.

Based on the evidence that arginine improves wound healing,^5,6,10 it is reasonable to hypothesize that arginine can facilitate the healing process of persistent air leakage. Our results actually demonstrate that postoperative enteral arginine supplementation can significantly reduce the duration of air leakage after lung resections, although this study was based on limited number of cases and performed retrospectively. We should not underestimate the basic fact that postoperative nutrition plays an important role in the wound healing process.

With respect to the use of enteral arginine supplementation for the treatment of persistent air leaks after lung surgery, we do not believe that it represents an alternative to pleurodesis, but rather a parallel treatment that might improve patient outcome. Fortunately, almost all patients are able to consume food orally the day after lung surgery, so this nutritional supplementation can be easily started if there are concerns about prolonged air leakage. We believe that even if the air leakage is persistent despite nutritional treatment, the conditions for wound healing will still be improved until pleurodesis is performed, allowing for a faster post-pleurodesis recovery. Thus the treatments will not interfere with each other but are likely to work in cooperation, providing a two-fold method for treating air leaks. However, particular attention should be paid to hyperphosphatemia, which is usually subclinical in the short-term in patients with renal dysfunction, because Arginaid includes 630 mg of phosphate per pack. ¹⁴ Incidentally, food allergy also should be considered. We concluded that enteral arginine supplementation may contribute to stopping air leaks and may promote the early removal of a chest tube after lung surgery. After lung resections, this nutritional treatment can be considered earlier if there is a concern about the air leak becoming prolonged.