Postoperative enteral stimulation by gut feeding improves outcomes in severe acute pancreatitis

APPLIED NUTRITIONAL INVESTIGATION

Postoperative Enteral Stimulation by Gut Feeding Improves Outcomes in Severe Acute Pancreatitis Edmunds Austrums, MD, Guntars Pupelis, MD, and Kaspars Snippe, MD From the Department of Surgery, Stradina University, Clinical Hospital “Gailezers,” Riga, Latvia OBJECTIVE: We assessed the clinical effectiveness of postoperative enteral stimulation by gut feeding in patients with severe acute pancreatitis (SAP). METHODS: Medical records of 63 patients who were operated on within the past 4 y due to deterioration of SAP were included in this retrospective study. Patients were stratified in gut feeding (GF; n ⫽ 33) and standard therapy (ST; n ⫽ 30) groups according to the postoperative therapy provided. The GF group received postoperative standard therapy and enteral stimulation by gut feeding, and the ST group received standard therapy only. The Acute Physiology and Chronic Health Evaluation II score, incidence of the systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome (MODS), daily calories supply, complication rate, and outcomes were analyzed. RESULTS: Patient characteristics did not differ between groups when considering age and severity of the disease. All patients underwent similar surgical interventions. SIRS and MODS were observed initially with the same frequency in both groups. Regression of MODS and a lower postoperative complication rate was observed more often in the GF group. Development of early pulmonary complications was observed in 12.1% to 13.3% in both groups, irrespective of the time of surgery. Subsequently, pulmonary complications developed in 15.2% of GF patients compared with 43.3% of ST patients (P ⬍0.05). Acute renal insufficiency developed similarly in 33.3% of the GF patients and in 26.7% of the ST patients within 3 d after admission. Acute renal insufficiency developed later on only in the ST group (26.7%, P ⬍0.05). Wound- and catheter-related septic complications were considerably more frequent in the ST group (30.0%) than in the GF group (9.1%, P ⬍0.05). Intensive care and hospital stays did not differ. Postoperative gut feeding was associated with 6.1% mortality in the GF compared with 26.7% in the ST (P ⬍0.05). CONCLUSIONS: Enteral stimulation by gut feeding is an effective supplement in the postoperative therapy of patients with SAP. Nutrition 2003;19:487– 491. ©Elsevier Inc. 2003 KEY WORDS: enteral stimulation, gut feeding, severe acute pancreatitis, multiple organ dysfunction syndrome

INTRODUCTION Postoperative feeding is a controversial issue in patients with severe acute pancreatitis (SAP). Enteral nutrition (EN) has been reported to have certain limitations in the treatment of SAP in providing all of the necessary calories and nutrients.1 Impairment of gastrointestinal tract motility is common, even after uncomplicated abdominal surgery. Moreover, absence of nutrients in the gastrointestinal tract can lead to gut mucosal atrophy and further impairment of gut function.2 Several investigators have studied the advantages of small-volume EN and enteral stimulation in different experimental models3,4 and in pediatric patients.5,6 We found no data in the literature about the effect of small-volume enteral feeding in patients with SAP. The question remains as to whether the goal of supplying calories and nutrients is superior to the possibility of improving the recovery of gut function by providing enteral stimulation with small amounts of the enteral formula in the early phase of SAP. The role of the gut feeding (GF) is not properly defined, particularly in the subgroup of patients who undergo surgery due to progression of systemic inflammatory

Correspondence to: Edmunds Austrums, MD, Clinical Hospital “Gailezers,” 2, Hipokrata Street, Riga LV-1038, Latvia. E-mail: [email protected] Nutrition 19:487– 491, 2003 ©Elsevier Inc., 2003. Printed in the United States. All rights reserved.

response syndrome (SIRS) and organ dysfunction. Treatment of this subgroup of patients is associated with a high complication rate and unpredictable outcome.7 Enteral stimulation by GF consisting of small amounts of enteral formula has been clinically routine in the treatment of SAP in our hospital for the past 4 y. Specifically, GF has been used as a postoperative treatment modality and has positive clinical effect. Our retrospective study assessed the clinical effectiveness of postoperative enteral stimulation by GF in patients with SAP.

MATERIALS AND METHODS Sixty-three patients with SAP who had undergone surgery in the Surgical Department of the Clinical Hospital “Gailezers” between September 1997 and October 2001 were included in this retrospective study. The diagnosis of SAP was based on the Atlanta classification.8 Only patients who had surgery due to the deterioration of SAP were included. According to their postoperative treatment, patients were stratified to two groups. The GF group consisted of 33 patients who received standard therapy (ST) and enteral stimulation by GF with at least 300 mL/d of enteral formula for more than 5 d. The ST group consisted of 30 patients who received ST without GF and survived for more than 5 d after surgery. The principles of ST in both groups were similar and included intravenous fluids, colloids, and a solution of dextrose, antibiotics, and 0899-9007/03/$30.00 doi:10.1016/S0899-9007(02)01095-X

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organ support according to intensive care standards. Due to the very limited medical budget, our patients did not receive routine parenteral nutrition before or after surgery. Indications for surgical treatment were obscure diagnose, deterioration of the clinical course of SAP, or signs of infection.9 –11 Computed tomography with intravenous contrast enhancement for the radiologic diagnose of necrotizing pancreatitis12 has been available in our hospital since 2000. In the study period, use of computed tomography and fine-needle aspiration was limited, so the diagnosis of necrotizing pancreatitis and the presence of infection were generally confirmed during the first surgical intervention. Maximal values of C-reactive protein supported the diagnosis. The first surgery was performed with the semiopen technique, and all patients recuperated in the intensive care unit after surgery. Feeding access distally from the duodenojejunal junction was ensured in all GF patients. The nasojejunal tube was introduced under fluoroscopic control before surgery in six patients, and five of them received GF before surgery. In 26 cases, the nasojejunal tube was introduced intraoperatively, and one intraoperative jejunostomy was performed. The GF protocol was started during the first 12 h postoperatively in the intensive care unit with halfstrength whole-protein formula (0.5 kcal/mL; PreNutrison, Nutricia, The Netherlands) and continued with full-strength wholeprotein formula (1 kcal/mL; Nutrison Standard, Nutricia) at the rate of 20 to 25 mL/h, providing by pump in 24 cases. With experience growing, we changed the mode of the initial feeding to bolus administration of the enteral formula at the rate of 20 mL/hour.13 We did not try to reach the recommended EN goal feeding of 25 kcal · kg⫺1 · d⫺1.14,15 The feeding rate was advanced slowly in cases of normal tolerance of the GF, to stimulate the gut until the bowel function was restored. Further, the volume and speed of GF were adjusted according to the individual’s tolerance toward the feeding formula and evidence of bowel transit. Oral feeding with a liquid diet was started similarly in all patients, depending on the patient’s postoperative recovery status and individual tolerance. In the GF group, the nasojejunal tube was evacuated when the patient had undergone 2 to 3 d of the initial oral feeding. Due to the inclusion criteria, we did not analyze the data from seven patients who died within 5 d after surgery. Six of those patients did not receive GF at all. All survivors were treated in the hospital until full regression of the acute inflammatory reaction that was proved clinically (no pain, tolerance of oral diet, and readiness to transfer to the outpatient department) and by laboratory data (normalization of serum amylase). The Second Acute Physiology and Chronic Health Evaluation scores were evaluated for all patients on admission. The clinical course of SIRS and development of multiple organ dysfunction syndrome (MODS) were analyzed. SIRS and MODS were defined according to the criteria of the 1991 Consensus Conference of the American College of Chest Physicians and the Society of Critical Care Medicine.16 A MODS was diagnosed if dysfunction of more than one organ was detected and required intervention to maintain homeostasis.17 Duration of GF and ST and the daily caloric intake were calculated retrospectively in all subjects. Development of pulmonary complications such as pleural effusion, atelectasis, and pneumonia also was assessed within 3 d after admission and later in the treatment period, irrespective of the timing of surgery. Development of acute renal failure was assessed similarly. Data on postoperative complications, intensive care stay, total hospital stay, and outcome were analyzed. Numeric values were expressed as means (standard deviations). Statistical comparison was made with a non-parametric method using the Mann-Whitney U test and the chi-square test. P ⬍0.05 was considered statistically significant. Data analysis was performed with SPSS 8.0 (SPSS Inc., Cary, NC, USA).

Nutrition Volume 19, Number 6, 2003 TABLE I. PATIENTS’ DEMOGRAPHICS, ETIOLOGY, APACHE II SCORE, AND MODS ON ADMISSION

Age (y) Mean (SD) Range Male/Female Etiology (%) Alcohol Gallstone disease Other APACHE II score (mean [SD]) MODS on admission (%)

GF group (n ⫽ 33)

ST group (n ⫽ 30)

42.4 (13.2) 15–74 27/6

48.0 (14.1) 27–82 24/6

NS

55 24 21 9.15 (5.8)

57 23 20 9.0 (5.1)

NS NS NS NS

30

27

NS

P

APACHE, Acute Physiology and Chronic Health Evalutation; GF, gut feeding; MODS, multiple organ dysfunction syndrome; NS, not significant; SD, standard deviation; ST, standard therapy

RESULTS Patients’ demographics, etiology, and disease severity on admission were similar in both groups (Table I). Duration of symptoms before admission did not differ between GF and ST patients. Forty-nine patients were admitted within 3 d from the onset of disease (26 in the GF group and 23 in the ST group). Fourteen patients (seven from each group) were admitted 3 d after the onset of disease. The first surgical intervention was performed within the first week after admission in GF 27 patients and 25 ST patients. Six GF patients and five ST patients were operated on after the 7-d treatment due to progression of organ failure. All but six patients underwent laparotomy in the early phase of the disease, before the phase of sequestration. During laparotomy, acute necrotizing pancreatitis was detected in 29 (88%) GF patients and 25 (83%) ST patients. Frequency of acute enzymatic peritonitis, signs of peripancreatic infection detected in the first operation, and the number of re-interventions did not differ between groups (Table II). The maximal values of C-reactive protein were 295.7 (140.0) mg/L in the GF group and 227.4 (97.0) mg/dL in the ST group, with no statistical difference. Patients in the GF group received a mean of 21.4 (14.7) d of ST compared with 18.8 (18.0) d in the ST group. ST provided means of 491.1 (220.0) kcal/d in GF patients and 455.1 (151.6) kcal/d in ST patients. All 33 patients in the GF group tolerated GF, and no one dropped out from the study group. There was no aspiration of the enteral formula and no bowel necrosis associated with GF. GF was held for 1 to 5 d in four patients, mainly because of increased intra-abdominal pressure or repeated surgery. GF patients received an additional 712.6 (310.9) kcal/d by GF, which was provided for a mean of 16.0 (10.3) d. Therefore, the total nutritional daily intake after surgery was higher in the GF group (1203.8 ⫾ 391.8 kcal) than in the ST group (455.1 ⫾ 151.6 kcal; P ⬍0.0001). Oral feeding with the liquid diet was started at means of 10.5 (8.5) d and 9.1 (8.6) d after the initial operation in the GF and ST groups, respectively. The first audible bowel sounds after surgery appeared similarly in both groups: after 26.1 (13.2) h in GF patients and after 28.0 (17.1) h in ST patients. Passage of the first stool (⬎150 mL) was sooner in GF patients (after 61.1 ⫾ 26.9 h) than in ST patients

Nutrition Volume 19, Number 6, 2003

Postoperative Gut Feeding in Severe Acute Pancreatitis

TABLE II.

TABLE III.

FINDINGS FROM THE FIRST SURGICAL INTERVENTION AND NUMBER OF RE-INTERVENTIONS

INCIDENCE OF COMPLICATIONS

Necrotizing pancreatitis (%) Odematous pancreatitis (%) Traumatic pancreatitis (%) Enzymatic peritonitis (%) Peripancreatic infection (%) Re-interventions (n)

GF group (n ⫽ 33)

ST group (n ⫽ 30)

P

88 3 9 70 9 20

83 10 7 73 10 17

NS NS NS NS NS NS

GF, gut feeding; NS, not significant; ST, standard therapy

(70.2 ⫾ 34.3 h), but the difference did not reach statistical significance. SIRS developed in all 63 patients. On admission, MODS was observed in 30% of GF patients and 27% of ST patients. Progression of MODS during the first 2 d after surgery was observed in 45.4% and 46.7% of GF and ST patients, respectively. The clinical course of SAP was complicated by organ dysfunction in 87.9% of GF patients and 93.2% of ST patients. Further in the postoperative course, improvement of organ function was more evident in the GF group and resulted in a lower complication rate and a better outcome. Development of pulmonary complications was observed in 56% of ST patients compared with 27.3% of GF patients. There was no difference between groups in the occurrence of pulmonary complications evaluated within the 3-d period after admission. Incidence of pulmonary complications in the subsequent treatment period was considerably higher in the ST group (43.3%) than in the GF group (15.2%; P ⬍0.05). Acute renal insufficiency developed similarly in 33.3% of the GF group and 26.7% of the ST groups within 3 d after admission. Acute renal insufficiency developed later on only in the ST group (26.7%, P ⬍0.05; Table III). Secondary drain infection was observed in 54.5% of the GF group and 53% of the ST group. In contrast, wound- and catheter-related septic complications were considerably less in GF patients (9.1%) than in ST patients (30.0%, P ⬍0.05; Table III). Development of other postoperative complications was lower in the GF group but did not reach statistical significance (Table III). Intensive care unit and hospital stays did not differ between groups. Stays in the intensive care unit were 18.6 (15.6) d in the GF group and 18.0 (20.7) d in the ST group. Hospital stays were 44.3 (26.7) d in the GF group and 46.7 (31.2) d in the ST group. Patients were discharged with clinically resolved pancreatitis confirmed by normalization of laboratory values and radiologic findings. Normalization of serum amylase after the initial operation in survivors was observed during means of 4.9 (4.0) d in the GF group and 5.4 (4.3) d in the ST group. Postoperative enteral stimulation by GF was associated with 6.1% mortality in the GF group compared with 26.7% in the ST group (P ⬍0.05; Table IV).

MORTALITY ANALYSIS There were two cases of unfavorable outcome in the GF group. One patient was operated emergently due to blunt abdominal trauma with a partly ruptured pancreatic gland (injury class III) and total enzymatic peritonitis. Later the patient experienced two re-explorations of the abdominal cavity because of unresolved peritonitis, intestinal fistula, and obstruction of the left colon. The patient died from MODS progression and profuse gastrointestinal

Early pulmonary complications (%)* Late pulmonary complications (%)† Early renal insufficiency (%)* Late acute renal insufficiency (%)† Wound and catheter related septic complications (%) Gastrointestinal fistulas (%) Pancreatic fistulas (%) Gastrointestinal bleeding (%) Peripancreatic bleeding (%) Postoperative ileus (%)

489

GF group (n ⫽ 33)

ST group (n ⫽ 30)

P

12.1

13.3

NS

15.2

43.3

⬍0.05

33.3 0 9.1

26.7 26.7 30.0

NS ⬍0.05 ⬍0.05

6 3 9 3 3

13 13 10 10 10

NS NS NS NS NS

* Early complications: observed within 3 d of treatment after admission. † Late complications: observed after 3 d of treatment after admission. GF, gut feeding; NS, not significant; ST, standard therapy

bleeding 45 d after admission. The other patient had surgery 18 d after admission due to MODS progression and abdominal compartment syndrome. During the subsequent 20-d postoperative period, the clinical course was complicated by gastrointestinal bleeding, and the patient underwent re-exploration but died from progressive MODS. Overall, eight patients died in the ST group. One died 14 d after surgery from pulmonary embolism, despite successful regression of MODS and abdominal compartment syndrome. Other deaths were due to MODS progression on days 6, 15, 30, 41, 63, 78, and 103 after surgery. Three cases of unfavorable outcome were associated with bleeding from peripancreatic blood vessel erosion.

DISCUSSION EN for treatment of SAP is considered cautiously by a large number of surgeons and intensive care specialists. There are two different approaches in the nutrition support of acute pancreatitis. Some recommend pancreatic rest with total parenteral nutrition,18,19 whereas others use EN in the complex therapy of SAP.20 –22 Our experience with EN in the treatment of patients with SAP dates back to 1997. Postoperative EN as a modality of enteral stimulation by GF was used until 2000, when we started using early EN as part of a conservative treatment protocol. This is the main reason why our study includes only postoperative patients. There are few reports on the clinical effectiveness of postoperative EN in the treatment of SAP.23 To date, four controlled studies have been published that compare parenteral and enteral nutrition in the management of acute pancreatitis20,24 –26; however, the feasibility of the early postoperative GF is beyond the scope of those articles. Although the rationale of using EN is doubtful in the early phase of SAP, our results demonstrated a possible positive physiologic effect of GF on the recovery of bowel function and supports our previous results.27 Direct signs of postoperative recovery of bowel function, such as appearance of the first audible bowel sounds and passage of the first stool, did not differ in this study. Despite the clinical course of MODS, postoperative recovery in patients who received enteral stimulation by GF had better overall treatment results.

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Nutrition Volume 19, Number 6, 2003 TABLE IV.

ICU STAY, HOSPITAL STAY, AND MORTALITY

Days in ICU (mean [SD]) Days in hospital (mean [SD]) Mortality (%)

GF group (n ⫽ 33)

ST group (n ⫽ 30)

P

18.6 (15.6)

17.4 (20.5)

NS

44.3 (26.7)

46.7 (31.2)

NS

6.1

26.7

⬍0.05

GF, gut feeding; ICU, intensive care unit; NS, not significant; ST, standard therapy

Clinically based evidence has shown that EN decreases septic complications in acute pancreatitis and can attenuate the acutephase response.20 The importance of early recovery of gut function in patients with SAP has been delineated in several publications. However, the real efficacy of postoperative EN has not be determined because of difficulties providing the calculated amount of the enteral formula.1 Windsor et al. found good results of enteral feeding after comparing EN with total parenteral nutrition in patients with mild and severe acute pancreatitis.20 Nevertheless, five of those 16 patients developed nausea and fullness. This complication can be observed more often in cases in which large amounts of feeding formula are provided enterally, especially in patients with impaired bowel function. Despite the fact that the real amount of the enterally provided feeding was significantly less than the calculated goal feeding, this treatment resulted in a lower complication rate. Similarly, 65% to 72% of the calculated goal feeding was provided in other studies and showed a positive effect of EN.24,25 In 1998 Okada et al. described normalization of immune function after small-volume enteral feeding in infants.5 Our experience supports their findings in that small volumes of enterally provided feeding formula can improve recovery of bowel function and may have a positive immunomodulatory effect.28 Based on those observations, we did not try to provide the theoretically required calorie supply (the so-called goal feeding) but did provide small-volume GF only to feed the gut and provide enteral stimulation. The treatment modality used in this study is not a standard nutrition support. Our strategy was based on the simple assumption that recovery of bowel function is more important in the early postoperative period than delivery of the optimal amount of nutrients and calories via EN. Progressive improvement of the bowel function allowed augmentation of the daily enterally provided volume of the feeding formula and significantly complemented nutrition support by GF. Our study investigated the question of whether GF with a minimum of 300 mL/d of enteral formula for 5 d was sufficient to improve postoperative recovery in patients with SAP. The answer was affirmative. Patients who received at least 300 mL/d of the enteral formula demonstrated better outcomes and fewer complications. The effect of the small-volume GF could be explained by the fact that improvement of the gut-barrier function reduces sequestration of the fluid in the third space. The findings that low-dose enteral feedings could stimulate the intestinal mucosa, thereby preventing atrophy and potential bacterial translocation,29,30 might be positively related with our results. Despite the considerably large initial number of cases with renal dysfunction and pulmonary complications, development of acute renal failure and pulmonary complications after the third day of treatment was observed in significantly fewer cases in the GF group than in the ST group.

The smaller number of wound- and catheter-related septic complications was another beneficial effect of the GF, and it is in accordance with findings of other studies in which EN resulted in fewer infective complications.31,32 This finding could be related to improved local tissue immune response and increased resistance to bacterial contamination of the patients who received postoperative GF. Local inflammation of the pancreas in SAP is associated with SIRS, and reactive changes in practically all organ systems lead to MODS in the most severe cases.9,33 Progression of MODS is the main course of death in SAP.34 We observed improvements in organ dysfunction and better outcomes in patients who received GF despite the fact that most of these patients had surgery in the early phase of the disease and previous conservative therapy failed to improve the clinical course of SIRS and/or MODS. There is clinical evidence that enteral stimulation by GF, starting with 300 mL/d of enterally provided feeding formula, is a safe and effective treatment modality for improvement of bowel function postoperatively in SAP patients. There is substantial evidence that GF can attenuate MODS and improve outcomes in this category of patients. Further prospective studies are necessary for a better understanding of possible immunomodulatory mechanisms of GF in SAP.

ACKNOWLEDGMENTS The authors thank U. Berkis, MSc (Mathematics), for assistance with statistical analysis.

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Nutrition Volume 19, Number 6, 2003 16. American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 1992;20:864 17. Rangel-Frausto MS, Pittet D, Costigan M, et al. The natural history of the systemic inflammatory response syndrome (SIRS). A prospective study. JAMA. 1995;273:117 18. Sitzmann JV, Steinborn PA, Zinner MJ, Cameron JL. Total parenteral nutrition and alternate energy substrates in treatment of severe acute pancreatitis. Surg Gynecol Obstet 1989;168:311 19. British Society of Gastroenterology. United Kingdom guidelines for the management of acute pancreatitis. Gut 1998;42(suppl 2):S1 20. Windsor AC, Kanwar S, Li AG, et al. Compared with parenteral nutrition, enteral feeding attenuates the acute phase response and improves disease severity in acute pancreatitis. Gut 1998;42:431 21. Brian LE. Enteral nutrition support in acute pancreatitis. Ann Pharmacother 2000;34:514 22. Beger HG, Rau B, Isenmann R. Prevention of severe change in acute pancreatitis: prediction and prevention. J Hepatobiliary Pancreat Surg 2001;8:140 23. Kalacinski J, Kalacinska B, Kurczych K, Wojdylo A. The effect of nutritional support on the perioperative course in patients after extensive surgical procedures. Wiad Lek 1997;50(suppl 1, pt 2):447 24. Kalfarenzos F, Kehagias J, Mead N, Kokkinis K, Gogos CA. Enteral nutrition is superior to parenteral nutrition in severe acute pancreatitis: results of a randomised prospective trial. Br J Surg 1997;84:1665

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25. McClave SA, Greene LM, Snider HL, et al. Comparison of the safety of early enteral vs parenteral nutrition in mild acute pancreatitis. JPEN 1997;21:14 26. Hernandez-Aranda JC, Gallo-Chico B, Ramirez-Barba EJ. Nutritional support in severe acute pancreatitis. Controlled clinical trial. Nutr Hosp 1996;11:160 27. Pupelis G, Austrums E, Jansone A, Sprucs R, Wehbi H. Randomised trial of safety and efficacy of postoperative enteral feeding in patients with severe pancreatitis: preliminary report. Eur J Surg 2000;166:383 28. Eckerwall G, Andersoon R. Early enteral nutrition in severe acute pancreatitis: a way of providing nutrients, gut barrier protection, immunomodulation, or all of them? Scand J Gastroenterol 2001;36:449 29. Border JR, Hassett J, LaDuca J, et al. The gut origin septic states in blunt multiple trauma (ISS ⫽ 40) in the ICU. Ann Surg 1987;2064:427 30. Martin KE. The use of early enteral nutrition in abdominal trauma. J Trauma Nurs 1996;3:65 31. Kudsk KA, Croce MA, Fabian TC, et al. Enteral versus parenteral feeding. Effects on septic morbidity after blunt and penetrating abdominal trauma. Ann Surg 1992;215:503 32. Moore FA, Feliciano DV, Andrassy RJ, et al. Early enteral feeding, compared with parenteral, reduces postoperative septic complications. The results of a meta-analysis. Ann Surg 1992;216:172 33. Kingsnorth A. Role of cytokines and their inhibitors in acute pancreatitis. Gut 1997;40:1 34. Mann DV, Hershman MJ, Hittinger R, Glazer G. Multicentre audit of death from acute pancreatitis. Br J Surg 1994;81:890