Results After 7 Days of Preoperative Nutritional Supplementation
Patient Enteral Nutritional Supplementation Compliance and Tolerance
All patients completed the preoperative nutritional treatment with a consumption of 400 mL per day. There were no differences between groups in the volume of preoperative drinks consumed. Preoperatively, the nutritional supplement drinks did not reduce the patients’ percentage of normal diet intake.
Nutritional Laboratory Parameters
The results at baseline and after 7 days of preoperative feeding are shown in Table 3. At the time of recruitment, there were no significant differences between the 2 groups in serum protein, albumin, prealbumin, transferring, and zinc; this was also true after the nutritional treatment. However, levels of serum proteins, albumin, and zinc after the nutritional intervention were significantly higher in both groups compared with the initial determination. No significant changes in the levels of transferrin were observed after 7 days of preoperative feeding in either group (Table 3).
The results at baseline and after 7 days of preoperative feeding are shown in Table 3. At recruitment, there were no significant differences between the 2 groups in hemoglobin levels, leukocytes, lymphocytes, procalcitonin, or C-reactive protein; this was also true after the nutritional treatment. However, the levels of hemoglobin (ERAS includes intravenous iron supplementation in cases of preoperative anemia) and lymphocytes after the nutritional intervention were significantly higher in both groups. No significant changes in the levels of leukocytes, procalcitonin, or C-reactive protein were observed after 7 days of preoperative feeding in either group (Table 3).
Surgery, Postoperative Treatment, and Postoperative Nutritional Supplementation
Of the patients, 74.6% (182) underwent laparoscopic surgery; 25.4% (62) underwent open surgery. Some 8.8% of the laparoscopically intervened patients required conversion to laparotomy (16). Sigmoidectomy and right hemicolectomy made up the majority of procedures performed (54.1%). The mean duration of surgery was 161.72 minutes (60–380). The median length of time spent in the recovery room was 208 minutes (60–540). There were no significant differences between the 2 groups in terms of the operative time or estimated intraoperative blood loss (121,210 mL ± 12,706 vs. 109,467 mL ± 11,804, P = 0,321). Table 2 shows the surgical techniques used and the surgical procedures followed.
Main Features of the Protocol and Their Compliance Rates
Table 4 shows the compliance rates for the main features outlined in the ERAS protocol by groups. We did not find significant differences between the groups. The overall compliance to the protocol was approximately 80% but varied widely in its various components without differences between the groups.
Patient Enteral Nutritional Supplementation Compliance and Tolerance
After surgery, supplement intake averaged 205 ± 12.61 mL on the operative day. There were no differences between groups in the volume of postoperative drinks consumed (211 ± 12.68 mL for HHS and 198 ± 12.56 mL for IEF; P = 0.389).
Postoperative nutritional supplement tolerance was determined to be good in 154 patients (79 patients for IEF and 75 patients for HHS) and poor in 67 patients (34 for IEF and 33 for HHS). No supplement was ingested by 23 patients (9 and 14 patients for IEF and HHS, respectively). There were no significant differences between groups (P = 0.940).
Among the patients with poor tolerance, 9 in each group had nausea (27.3% in HHS and 26.5% in IEF), 31 (36.4 and 55.9%, respectively) had heaviness, 11 had heartburn (24.2 and 8.8%, respectively), and 7 had vomiting (12.1% and 8.8%, respectively). There were no statistically significant differences (P = 0.263).
Some 62.3% (76) for HHS and 65.6% (80) for IEF complied with the postoperative nutritional protocol (P = 0.594). Postoperatively, the nutritional supplements did not reduce the percentage of normal diet consumed by the patients.
Postoperative Hospital Stay and Readmission Rate
The median length of the postoperative hospital stay was 5 days (3–52 days, 5 days for HHS (3–52) and 5 days for IEF (3–20)) with no difference between groups (P = 1.000). Of the patients, 3.27% (8 patients, 4 in each group) were readmitted following discharge for medical or surgical reasons without statistically significant between-group differences. Two patients presented with febrile syndrome, 3 with diarrhea, 1 with an abdominal wall abscess, 1 with a late anastomotic leak, and 1 with vomiting.
Table 5 summarizes the complications encountered. Approximately 71% of the patients had an uneventful postoperative course without complications. As shown in the table, globally, the patients who received immunonutrition presented with fewer complications (23% vs. 35.20%, P = 0.035).
The most common complications were surgical (19.25%; 47 patients) followed by infectious complications (17.25%; 42). The most common surgical complications were paralytic ileus (10.65%; 26) and anastomosis leakage (6.55%; 16) (Table 6). Finally, the most common infectious complications were surgical site infection (superficial and deep incisional site infection (11%; 27) and organ/space infection (1.6%; 3)), urinary tract infection (0.8%; 2), and respiratory infection (2%; 5). Nineteen patients (8.8%) required repeat surgery. Causes included anastomotic leakage (16), hemoperitoneum (2), and internal hernia (1). No patients died during the hospital stay or following discharge.
Table 5 shows the differences between the groups. There were fewer complications in IEF than HHS, primarily due to a significant decrease in infectious complications (23.8% vs. 10.7%, P = 0.0007). Among the infectious complications, surgical site infection was significantly different between groups (17.2% vs. 5.7%, P = 0.0005). After excluding patients with anastomotic dehiscence, surgical site infection remains higher in HHS (12.7% vs. 4.4%, P = 0.039). Other infectious complications were lower for IEF but without statistically significant differences. When the analysis according to the approach path is performed, we observe that, apart from this, a decrease in infectious complications occurs (P = 0.044 for laparoscopic surgery and P = 0.049 for conventional surgery).
Complications according to the Clavien-Dindo13 classification are shown in Table 7. To further analyze complications, we divided them into minor (Clavien-Dindo I–II) and major (Clavien-Dindo III–IV) and observed a minor complication incidence of 19.3% (for IEF and HHS, 25.4% vs. 13.1%, respectively, with statistically significant differences (P = 0.048)) and major complication incidence of 9.8% (9.8% vs. 9.8%).
Nutritional Laboratory Parameters
For both groups, the postoperative serum protein, albumin, prealbumin, transferring, and zinc levels were substantially decreased compared with the preoperative levels. The postoperative serum levels show a similar drop between groups (Table 3).
In both groups, postoperative serum hemoglobin levels were substantially decreased compared with preoperative levels (P = 0.000). Likewise, we observed an increase in white blood cell count, C-reactive protein, and procalcitonin and decreased lymphocyte count compared with their preoperative values. All of these postoperative changes were similar between the 2 groups, with the exception of lymphocyte levels in the plasma. This decrease was greater in the HHS patients, that is, IEF patients had higher levels of lymphocytes on the third postoperative day (P = 0.023). Postoperative levels are shown in Table 3.
This trial showed that the combination of ERAS care and immunonutrient supplements reduces postoperative complications. Patients receiving immunonutrients preoperatively and postoperatively had fewer complications (primarily infectious) than those who received standard supplements. Notably, this study is the first to demonstrate the advantages of using immunonutrients in an ERAS protocol. Guidelines22 currently recommend the use of immunonutrients within these protocols; however, these recommendations have been based on scant scientific evidence. This study provides stronger evidence for this recommendation.
The first issue to be addressed when analyzing the results of our study is the use of nutritional supplements in well-nourished patients. The role of these supplements in malnourished patients is obvious; however, the role of nutritional supplements in well-nourished patients who are undergoing colorectal surgery is currently debated. Traditionally, supplementation would not be recommended for these patients; however, its use in maintaining or even improving the nutritional status of patients before surgery has spread. As our results show, supplements led to significant improvements in nutritional values (in both the IEF and HHS groups) despite being consumed for only 7 days preoperatively. Levels of serum proteins, albumin, and zinc after nutritional intervention increased even though we only include normo-nourished patients. It is therefore possible to improve the nutritional status of these patients with short-term preoperative supplementation, regardless of whether the products contain immunonutrients. Our results are consistent with a recent meta-analysis23 published by Hegazi et al, which recommended the use of preoperative nutritional supplements to prepare surgical patients regardless of their nutritional status.
However, surgery is a stressor on the patient and induces changes in the activity of both innate and adaptive immunity.24 Immune system responses after surgery can be inappropriate in some cases (e.g., systemic inflammatory response syndrome). To modulate this response, patients have recently received nutritional formulas containing certain immunonutrients, primarily arginine, glutamine, omega-3 fatty acids, and nucleotides. However, scientific evidence regarding the effectiveness of this supplementation is limited. Our results improve our knowledge of the benefits of using these substances in surgical patients.
In that same meta-analysis, no significant differences were observed between preoperative immunonutrition and standard nutrition in their effects on postoperative clinical outcomes for any type of surgery,23 while our results indicate otherwise. Inmunonutrition supplementation reduces global complications and infectious complications and may even, as some studies indicate, reduce anastomotic leaks.25–27 Perioperative administration was associated with a statistically significant reduction in anastomotic dehiscence, whereas a reduction in noninfective complications was demonstrated with postoperative administration in another meta-analysis.28 Our results are consistent with these meta-analyses; however, despite observing a lower incidence of anastomotic leaks, these results were not statistically significant. Notably, infectious complications were clearly reduced when the diet was supplemented with immunonutrients. However, due to the improvements in nutritional analytical values in both groups and because the best results in terms of morbidity and mortality were obtained in the immunonutrition group, we recommend that immunonutrient supplementation be provided both preoperatively and postoperatively.
Our study is one of few that focus only on patients undergoing treatment for colorectal cancer. Most existing studies include a variety of gastrointestinal surgeries. Additionally, the published results are contradictory in some cases.
For example, Braga et al29 demonstrated that perioperative administration of enteral supplements enriched with arginine, RNA, and omega-3 fatty acids decreases the rate of postoperative infections. The same group, which is based at the University of San Rafael in Milan, performed another interesting study comparing 4 groups: 1 group received arginine supplements and omega-3 fatty acids for 5 days preoperatively; another group, pre- and postoperative immunonutrient supplements; a third group, standard isoenergetic and isonitrogenous supplements; and a fourth group, no supplements. In this study, immunonutrition supplementation improved immune response and increased intestinal microperfusion and oxygenation. There are additional benefits to the postoperative extension of immunonutrition.30 Horie et al31 stated that preoperative immunonutrition can reduce the rate of surgical site infection.
However, not all published results find benefits of immunonutrients in terms of postoperative infection. Helminen et al32 observed no benefit for routinely prescribed immunonutrition. Sorensen et al33 (elective surgery for colorectal cancer) and Finco et al34 (laparoscopic colorectal surgery) reached the same conclusion.
Another important aspect of our study is the less marked reduction in lymphocyte values experienced by the immunonutrition group postoperatively. As the only value with statistically significant differences in both groups, we can assume that the existing difference in postoperative complications between the groups may result from these values. In fact, it has recently been reported that a shift toward Th2 dominance in the Th1/Th2 cytokines during the early postoperative period is directly associated with infectious complications.35 Matsuda et al36 described a correction in the balance of Th1/Th2 cytokines in patients with colorectal cancer who were undergoing surgery and received an oral diet supplemented with arginine, omega-3 fatty acids, and ribonucleic acid. They concluded that this balance correction may be an important determinant of the clinical benefits of immunonutrients and of how immunonutrition reduces postsurgical infections.
The degree of compliance with the items included in the ERAS program is an important factor in the reduction of postoperative complications and the achievement of early recovery of our patients. In our study, compliance was higher than 80%. If we compare these results with those recently published by The ERAS Compliance Group37 (overall compliance of 76.6% for colon cancer and 75.0% for rectal cancer), the compliance rates are very similar and much higher than those published when we started these programs.10 It is therefore shown that compliance increases as the teams gain experience in these protocols.
Although ERAS reduces the risk of complications compared with the traditional treatment scheme38 and each of the steps outlined in ERAS is based on scientific evidence, it is necessary to continue working on methods to reduce complications. Immunonutrition represents one of these potential points of entry.
Our study has some limitations. First, the number of cases was insufficient to make robust conclusions and the sample size has been calculated to obtain a statistically significant difference for infectious complications. We suggest a study with more participants to check if noninfectious complications also decreased when inmunonutientes enriched supplements are used. Second, not all patients could ingest all postoperative supplements, although there were no differences in intake between the 2 groups. Likewise, although similar in composition (except immunonutrients), there is a global difference of approximately 100 kcal per day between the 2 nutritional supplements, we do not believe that influence, as well as this dietary supplement was consumed in addition to normal food intake. Third, not being double-blind study could contribute to some form of bias. On the other hand, our study was performed at 6 reference centers in Spain with multidisciplinary teams who were fully dedicated to colorectal surgery and had previous experience in the implementation of ERAS programs. Therefore, it may be difficult to reproduce our results in nonexperienced groups. Finally, despite using 2 comparable groups, we included various surgical procedures and 2 modalities (laparoscopic and conventional).
Based on the data from the present multicenter, randomized study, the implementation of ERAS protocols including immunonutrient-enriched supplements reduces complications in patients undergoing colorectal resection. However, further studies are needed to understand how immunonutrients improve the prognosis of patients with colorectal cancer and the potential mechanisms involved in immunonutrient-enriched supplements reduces the complications of patients undergoing colorectal resection.
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Copyright © 2016 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.
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