
==== Front
Int J Surg
Int J Surg
JS9
International Journal of Surgery (London, England)
1743-9191
1743-9159
Lippincott Williams & Wilkins Hagerstown, MD

38814286
IJS-D-23-02639
10.1097/JS9.0000000000001655
00029
3
Original Research
Nomogram for predicting intolerable postoperative early enteral nutrition following definitive surgery for small intestinal fistula: a cohort study
Tian Weiliang MD acaltstian@163.com

Luo Lei MD c912075993@qq.com

Xu Xin RN brn_xuxin@163.com

Zhao Risheng MD b*dr_zhaorisheng@163.com

Tian Tao MD d526505068@qq.com

Li Wuhan MD e2068379564@qq.com

Zhao Yunzhao MD dr_zhaoyunzhao@163.com
b*
Yao Zheng MD b*dr_yaozheng@163.com

a Research Institute of General Surgery, Jinling Hospital, Nanjing Medical University
b Department of General Surgery, Jiangning Hospital, Nanjing, Jiangsu
c Department of General Surgery, The Affiliated Zhuzhou Hospital Central South University, Zhuzhou
d Department of General Surgery, Shanghai 9th Hospital, Shanghai
e Department of General Surgery, Anhui Provincial Hospital, Hefei, Anhui, People’s Republic of China
* Corresponding authors. Address: Department of General Surgery, Jiangning Hospital, Hushan Road NO.169, Nanjing, Jiangsu, People’s Republic of China. Tel.: +861 585 051 6854. E-mail: dr_yaozheng@163.com (Z. Yao); Tel.: +861 595 191 9988. E-mail: dr_zhaorisheng@163.com (R. Zhao); Tel.: +139 517 431 89. E-mail: dr_zhaoyunzhao@163.com (Y. Zhao).
9 2024
29 5 2024
110 9 55955604
20 11 2023
8 5 2024
Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/

Background:

This study was designed to develop and validate a nomogram for predicting intolerable early enteral nutrition (EEN) following definitive surgery (DS) for small intestinal fistula.

Methods:

A total of 377 patients, recruited from January 2016 to September 2023, was randomly allocated into development (n=251) and validation (n=126) groups in a 2:1 ratio. Risk factors were identified using the nomogram. Its performance was assessed based on calibration, discrimination, and clinical utility, with validation confirming its effectiveness.

Results:

Of the 377 patients, 87 (23.1%) were intolerant to EEN, including 59 (23.1%) in the development cohort and 28 (22.1%) in the validation cohort (P=0.84). Four factors were identified as predictive of intolerable EEN: severe abdominal adhesion, deciliter of blood loss during DS, human serum albumin (Alb) input >40 g during and within 48 h post-DS, and the visceral fat area (VFA)/total abdominal muscle area index (TAMAI) ratio. The model demonstrated excellent discrimination, with a C-index of 0.79 (95% CI: 0.74–0.87, including internal validation) and robust calibration. In the validation cohort, the nomogram showed strong discrimination (C-index=0.77; 95% CI: 0.64–0.87) and solid calibration. Decision curve analysis affirmed the nomogram’s clinical utility.

Conclusion:

This research introduces a nomogram that enables the individualized prediction of intolerable EEN following DS for small intestinal fistula, demonstrating a possible clinical utility.

Keywords:

enteral nutrition
intestinal fistula
nomogram
outcomes
surgery
OPEN-ACCESSTRUE
SDCT
==== Body
pmcIntroduction

Highlights

Intolerable postoperative early enteral nutrition (EEN) depends on intraoperative trauma and postoperative status of patients.

Significantly different prognosis was detected after definitive surgery (DS) for small intestinal fistula.

An universal applicable nomogram for postoperative intolerable (EEN) after DS was developed.

Postoperative early enteral nutrition (EEN) is crucial in facilitating enhanced recovery after surgery (ERAS)1,2. It markedly improves postoperative outcomes in abdominal surgery3–5. However, a significant proportion of patients undergoing abdominal surgery experience intolerable EEN, with prevalence rates ranging from 11 to 75% for those who are unable to tolerate early enteral feeding postoperatively4,6,7. The decision to initiate EEN postsurgery depends on the patient’s condition and the degree of intraoperative trauma6. Intolerable EEN is considered an adaptive and protective physiological response to severe injury4,8. Naresh et al.7 noted that operative trauma in gastrointestinal (GI) surgery affects EEN tolerance. Moreover, research by Ortiz-Reyes et al.9 in an international multicenter pragmatic clinical trial demonstrated that EEN tolerance was associated with the severity of the patient’s condition in the ICU. Significant heterogeneity exists in definitive surgery (DS) for small intestinal fistulas10–12. The incidence of intraoperative trauma is significantly influenced by the abdominal conditions following a fistula13. In patients with adequate drainage, the abdominal cavity remains largely free from severe bacterial contamination and considerable peritoneal damage. In contrast, intestinal fluid leakage can lead to extensive peritoneal damage. Under these conditions, ongoing abdominal inflammation and pathological repair processes can cause obscured anatomical structures, fragile and adherent tissues, and notable intraoperative injury13. Huang et al.10 examined 315 cases of DS and found substantial variability in abdominal adhesion, intraoperative bleeding, and surgery duration among patients within the same treatment group, contributing to variations in postoperative fluid balance, lactate levels, and complications. An aggressive enteral nutrition (EN) strategy is not suitable for patients with significant surgical trauma or compromised postoperative conditions, requiring a more customized nutrition approach. Therefore, distinguishing patients who can tolerate EEN from those who cannot and need specialized postoperative care is essential for promoting optimal postoperative recovery. This study aims to develop and validate a model to predict EEN tolerance through a nomogram.

Materials and methods

This retrospective cohort study was conducted at two leading regional enterocutaneous fistula (ECF) centers, renowned for managing a substantial caseload of patients with intractable ECFs annually. All procedures adhered to the ethical principles outlined in the Declaration of Helsinki. The study’s reporting conformed to the strengthening the reporting of cohort, cross-sectional, and case–control studies in surgery (STROCSS) criteria14 (Supplemental Digital Content 1, http://links.lww.com/JS9/C674). Patients were referred from external hospitals for ECF treatment at our facilities.

Inclusion and exclusion criteria

For inclusion and exclusion criteria, the study focused on patients without inflammatory bowel disease who underwent EEN postoperatively following DS for small intestinal fistulas from January 2016 to September 2023. DS was contemplated only after attaining infection control and verifying the patients’ adequate physical and nutritional health. Eligibility for the study required that patients undergoing DS meet several criteria: first, discontinuation of antibiotics with no signs of infection for at least one month; second, a BMI of ≥18.0 kg/m2 and maintained normal physical strength (evidenced by walking over 5000 m daily, as monitored by smartphone apps); third, hemoglobin levels of ≥100 g/l; fourth, albumin (Alb) levels of ≥30 g/l; and finally, an interval of more than three months since the fistula’s occurrence. Exclusion criteria encompassed patients younger than 18 years or those with incomplete medical records. Participants were then randomized in a 2:1 ratio into development and validation cohorts.

Preoperative management

Preoperative management involved a comprehensive approach encompassing sepsis control, nutritional status enhancement, wound care, fistula anatomy assessment, surgery timing, and the surgical strategy15. Throughout the preoperative phase, EN [Nutrison Fiber, (1.5 kcal/ml), Nutricia] was administered via nasointestinal (NI) tubes, targeting an energy intake of 30 Kcal/kg/day. Parenteral nutrition (PN) was provided as needed. Patients with high-output fistulas (output >500 ml/day) were strictly prohibited from oral intake, while those with low or moderate output fistulas could consume oral fluids in limited quantities. Additionally, chyme reinfusion (CR) tubes were used for intestinal continuity in high-output cases. The NI tube also facilitated preoperative nutrition and was retained for perioperative GI decompression and nutrition. A nasogastric (NG) tube was inserted on the day of DS for potential postoperative gastric decompression.

DS

During DS, a meticulous dissection of the digestive tract was performed. Each small intestinal fistula underwent a laterolateral end-to-end anastomosis with a linear stapler. In cases of enteroatmospheric fistula, hernia repair was executed during DS using component separation technique combined with onlay mesh repair, and a biological patch was also applied. A negative pressure drainage system was placed under all incisions before surgery completion.

Postoperative care and EEN

Postoperatively, mechanical ventilation was ceased within 24 h. The objective was to maintain a mean arterial pressure (MAP) of at least 65 mmHg, with blood gas analysis every 8 h to guide intravenous fluid and vasoactive drug adjustments. Omeprazole was administered to prevent gastric stress hemorrhage, while drugs affecting GI motility were avoided. No medications affecting the digestive system, such as somatostatin analogs, smectite powder, loperamide, metoclopramide, mosapride, or neostigmine, were administered. Sufentanil was used intravenously for pain relief at a rate of 2 µg/h during the first 48 h postoperatively, with parecoxib provided for those experiencing insufficient pain alleviation. Second-generation cephalosporins were prescribed post-DS and discontinued once WBC counts and procalcitonin levels normalized. Patients were encouraged to ambulate once vital signs stabilized and vasoactive medications were ceased. Following the recommendations of the 19th edition of Sabiston Textbook of Surgery 13, Red blood cell and human serum Alb infusions were used to maintain hemoglobin ≥100 g/l and/or Alb ≥30 g/l within 48 h post-DS.

In this study, EEN was commenced postoperatively for all patients. Immediate post-DS intestinal and gastric decompressions were facilitated through NI and NG tubes. PN was provided for the first 24 h, with an energy intake of 30 Kcal/kg/day. EEN [Peptison Liquid, (1.0 kcal/ml), Nutricia] began on the second postoperative day in the supine position, starting at 20 ml/h through NI tubes, while continuing gastric decompression. In the absence of GI symptoms, this rate was this rate was maintained until bowel movement ensued. If GI symptoms, such as diarrhea exceeding three occurrences per day, abdominal distension with more than a 10% increase in abdominal circumference, or tympanic sounds upon examination, were observed, EEN was deemed intolerable, prompting the initiation of intestinal decompression through NI tubes. Notably, retching was not considered a sign of EEN intolerance due to the potential throat stimulation by NG and NI tubes. Following bowel movement, the EEN rate was gradually increased by 10 ml/hour/day. PN was discontinued once EEN met over 50% of the caloric needs. The NG tube was removed when output was below 100 ml/day16.

Definition of intolerable EEN and recovery of intestinal function

Intolerable EEN is characterized by the onset of GI symptoms post-EEN. It is crucial to note that ‘large’ gastric residual volumes (exceeding than 500 ml/day) post-EEN do not indicate intolerable EEN, as the use of an NG tube for GI decompression facilitates safe EEN administration via an NI tube in the absence of GI symptoms. Postoperative bowel movements signify the recovery of intestinal function, and EN can be incrementally increased provided there is no adverse effects such as diarrhea, bloating, or vomiting16.

Data collection and statistical analysis

Enhanced computed tomography (CT) scans and GI X-ray scans were performed a week before DS to evaluate adjacent structures and determine the fistula’s location. Preoperative laboratory tests were conducted at least every 4 days during the treatment period. Variables analyzed included demographic information, preoperative laboratory findings, fistula location and output, and body composition metrics [e.g. visceral fat area (VFA)/total abdominal muscle area index (TAMAI) ratio, VFA/ subcutaneous fat area (SFA)] using Image J (NIH, Bethesda) based on preoperative enhanced CT scans. Etiology, the time from the development of the fistula to admission, the time from the development of the fistula to DS, and any comorbidities were examined. Intraoperative parameters, including the degree of adhesion, the duration of DS, and volume of bleeding, were assessed during DS. Notably, the degree of adhesion was categorized into five grades (Supplementary Table 1, Supplemental Digital Content 2, http://links.lww.com/JS9/C675) according to Hobson et al.17, with grades IV and V abdominal adhesions considered severe18. Evaluations also included red blood cell and human serum Alb levels during and up to 48 h post-DS (assuming 5 g of Alb per 100 ml of plasma for transfusions19), C-reactive protein (CRP), WBC count, and vasoactive drug administration on the EEN day. Fluid balance from DS completion to EEN start was also analyzed. We presumed that patients’ Alb levels met the minimum DS criterion (above 30 g/l) and that every 10 g of Alb could increase plasma Alb concentration by ~2 g/l, based on a total blood volume of 5 l. Per Common Terminology Criteria for Adverse Events 5.020, Alb levels below 20 g/l could lead to severe complications. Thus, for patients with an Alb of 20 g/l, a minimum of ~40 g of Alb was required to reach the 30 g/l standard for postoperative maintenance within 48 h, serving as the postoperative Alb input threshold. According to the 19th edition of the Sabiston Textbook of Surgery 13, shock symptoms may emerge with over 15% blood loss, ~800 ml based on a 5 l blood volume per patient, equating to 4 units of red cell suspension, hence setting our threshold for intraoperative and perioperative blood transfusions at 4 units.

The significance of each variable in the development cohort was evaluated through univariate logistic regression analysis to identify the independent risk factors for intolerable EEN. Variables with P<0.2 in the univariate analysis were included in the multivariate analysis. Notably, some patients developed postoperative abdominal infections from anastomotic leakage after DS, potentially affecting the initiation of postoperative EN. However, the exclusion of anastomotic leakage from the analysis was necessitated by the delayed identification of such complications following the cessation of EEN in intolerant patients and the diagnostic challenges regarding the precise timing of EEN initiation or intolerability. Consequently, inflammatory markers were considered at the onset of EEN. A nomogram was constructed from the results of the multivariate logistic regression analysis to provide a visual representation of the independent risk factors. The nomogram’s predictive accuracy was assessed using the concordance index (C-index) and calibration with 1000 bootstrap samples to reduce overfitting bias. Decision curve analysis was presented to evaluate the nomogram’s clinical utility in both the development and validation datasets. The Mann–Whitney U test and Fisher’s exact test were applied to continuous and categorical variables, respectively. Statistical analyses were executed using SPSS (version 26.0 for Windows; IBM, Analytics) and The R Project for Statistical Computing (version 4.3.1).

Results

Clinical characteristics

A total of 395 patients were initially considered for this study, all diagnosed with postoperative anastomotic fistula of the small intestine. Exclusions were made for patients under 18 years old (n=7) and those with incomplete medical records (n=11), resulting in 377 participants for analysis (149 from center A and 228 from center B). The median age was 54 years [interquartile range (IQR): 38–65], and the median BMI was 20.5 kg/m2 (IQR: 19.1–22.9). The time from fistula occurrence to DS averaged 4 months (IQR: 3–5). Fistulas resulted from small intestine anastomosis, with causes including small intestinal rupture (n=240, with 58 due to trauma, 149 identified postoperatively following abdominal surgery, and 33 found during treatment for obstruction from previous abdominal surgery), obstruction from prior surgery (n=113), mesenteric thrombosis (n=22), and perforation of unknown origin (n=2). The cohorts were divided into 251 patients for development and 126 for validation, with no significant demographic differences between them as shown in Table 1. Distribution within the cohorts was 97 patients from center A and 154 from center B in the development group, and 52 patients from center A and 74 from center B in the validation group.

Table 1 Characteristics of the patients.

Characteristics	Total	Development cohort	Validation cohort	P		
Center				0.63		
 A	149 (39.5)	97 (38.6)	52 (41.3)			
 B	228 (60.5)	154 (61.4)	74 (58.7)			
Male, No. (%)	217 (57.6)	143 (56.7)	74 (58.7)	0.79		
Age, years; (median, IQR)	54 (38–65)	53 (37-65)	55 (40-66)	0.51		
BMI, kg/m2, (median, IQR)	20.5 (19.1–22.9)	20.5 (19.1–23.0)	20.6 (19.1–22.9)	0.91		
Interval from fistula occurred to admission, days, (median, IQR)	14 (9–21)	15 (9–21)	14 (8–21)	0.82		
Interval from fistula occurred to definitive surgery, months, (median, IQR)	4.0 (3.0–5.0)	4.0 (3.0–5.0)	4.0 (3.0–5.0)	0.58		
Distance from Treitz to the fistula, No. (%)				0.40		
 <100 cm	56 (14.9)	40 (15.9)	16 (12.7)			
 ≥100 cm	321 (85.1)	211 (84.1)	110 (87.3)			
Length of small intestine, No. (%)				0.87		
 <300 cm	76 (20.2)	50 (19.9)	26 (20.6)			
 ≥300 cm	301 (79.8)	201 (80.1)	100 (79.4)			
Parenteral nutrition required, No. (%)	36 (9.5)	26 (10.4)	10 (7.9)	0.45		
High-output, No. (%)	125 (33.2)	89 (35.5)	36 (28.6)	0.18		
Etiology, No. (%)				0.58		
 Rupture	240 (63.7)	163 (64.9)	77 (61.1)			
 Obstruction	113 (30.0)	71 (28.3)	42 (33.3)			
 Others	24 (6.3)	17 (6.8)	7 (5.6)			
Entero-atmospheric fistula, No. (%)	101 (26.8)	67 (26.7)	34 (26.9)	0.95		
Hemoglobin before definitive surgery, g/l; (median, IQR)	124 (117–132)	126 (118–133)	123 (116–131)	0.17		
Albumin before definitive surgery, g/l; (median, IQR)	36.4 (35.6–38.1)	36.7 (35.2–37.6)	36.2 (36.1–38.4)	0.79		
C-reactive protein before definitive surgery, mg/l; (median, IQR)	8.2 (5.6–12.8)	8.2 (5.4–12.4)	8.3 (6.1–13.1)	0.46		
White blood cell before definitive surgery, 109/l; (median, IQR)	6.7 (5.9–7.4)	6.9 (6.3–7.5)	6.2 (5.8–7.2)	0.12		
 Severe adhesion, No. (%)	142 (37.7)	94 (37.5)	48 (38.1)	0.90		
 Duration of definitive surgery, hours; (median, IQR)	3.2 (2.4–4.2)	3.4 (2.2–4.1)	3.0 (2.1–4.5)	0.33		
 Deciliter of bleeding during definitive surgery, dl; (median, IQR)	4 (3–6)	4 (3–6)	4 (3–6)	0.86		
Sarcopenia,No. (%)	310 (82.2)	205 (81.7)	105 (83.3)	0.69		
Visceral fat area / subcutaneous fat area (median, IQR)	0.94 (0.65–1.24)	0.97 (0.66–1.26)	0.91 (0.65–1.27)	0.79		
Visceral fat area / total abdominal muscle area index (median, IQR)	2.56 (1.98–3.21)	2.59 (1.95–3.22)	2.45(1.99–3.15)	0.39		
Preoperative nutritional risk screening (NRS 2002) 2002>3, No. (%)	254 (67.2)	175 (69.7)	79 (62.2)	0.14		
Preoperative American Society of Anesthesiologists physical status classes (median, IQR)	2 (2–2)	2 (2–2)	2 (2–2)	0.87		
Hypertension, No. (%)	8 (2.1)	6 (2.4)	2 (1.6)	0.61		
Elevated fasting blood glucose, No. (%)	29 (7.7)	19 (7.6)	10 (7.9)	0.90		
The amount of red blood cell suspension input >4U during definitive surgery and within 48 h after definitive surgery, No. (%)	58 (15.4)	37 (14.7)	19 (15.1)	0.93	0.33	
The amount of human serum Albumin input >40 g during definitive surgery and within 48 h after definitive surgery, No. (%)	78 (20.7)	55 (21.9)	23 (20.1)	0.41	0.17	
Volume of postoperative drainage from nasointestinal tube until implement early enternal nutrition, ml, (median, IQR)	290 (220–330)	290 (220–330)	280 (220–340)	0.89		
Volume of postoperative drainage from nasogastric tube until implement early enternal nutrition,ml, (median, IQR)	250 (200–310)	260 (200–320)	250 (210–310)	0.74		
C-reactive protein on the day of implementation of early enternal nutrition, mg/l; (median, IQR)	70 (51–104)	71 (53–102)	68 (51–106)	0.68		
White blood cell on the day of implementation of early enternal nutrition, 109/l; (median, IQR)	13.6 (12.6–15.9)	13.6 (12.8–15.4)	13.7 (12.1–16.3)	0.69		
Procalcitonin >0.5 μg/l on the day of implementation of early enternal nutrition, No. (%)	279 (74.0)	189 (75.3)	90 (71.4)	0.42		
Using vasoactive drugs on the day of implementation of early enternal nutrition, No. (%)	34 (9.0)	21 (8.4)	13 (10.3)	0.53		
Postoperative fluid positive balance until implementation of early enternal nutrition, No. (%)	36 (9.5)	22 (8.8)	14 (11.1)	0.47		

Intolerance of EEN

No postoperative deaths were reported. Intolerance to EEN was observed in 23.1% (87/377) of patients, including 23.5% (59/251) in the development cohort and 22.2% (28/126) in the validation cohort (P=0.84). The duration of EEN for those intolerant was consistent across both groups (1 day, IQR: 1–2 days; P=0.69). Symptoms of intolerance manifested as abdominal distension (n=78), vomiting (n=7), and diarrhea (n=1). The median time to intestinal function recovery was longer in patients who tolerated EEN (5 days, IQR: 4–6 days vs. 9 days, IQR: 8–12 days; P<0.001). The decompression volume in the NI tube reached 360 (IQR: 240–440) ml, 470 (IQR: 370–520) ml, and 220 (IQR: 140–290) ml on the first, third, and seventh day after intolerance to EEN was observed, respectively.

Furthermore, removal of NG tubes was postponed in patients intolerant to EEN (3 days, IQR: 2–4 days vs. 8 days, IQR: 8–11 days; P<0.001). For these individuals, the NG tube decompression volumes were 30 (IQR: 10–40) ml, 240 (IQR: 200–300) ml, 410 (IQR: 320–580) ml, and 280 (IQR: 150–320) ml on the day of DS, and the first, third, and seventh day post-DS, respectively.

Development and validation of an intolerance nomogram

In the development cohort, multivariate logistic regression identified four factors associated with intolerable EEN: severe abdominal adhesion [odds ratio (OR) 3.62, 95% CI: 1.02–8.97; P=0.04], deciliter of blood loss during DS (OR 1.22, 95% CI: 1.01–1.48; P=0.04), human serum albumin (Alb) administration >40 g during and within 48 h post-DS (OR 2.90, 95% CI: 1.08–7.84; P=0.04), and VFA/TAMAI ratio (OR 1.51; 95% CI: 1.09–2.09; P=0.01; Table 2). These risk factors were employed to develop a nomogram for predicting the likelihood of intolerable EEN (Fig. 1). The model underwent internal validation using bootstrap methods, showcasing high precision with a concordance index (C-index) of 0.79 (95% CI: 0.74–0.87) and a bootstrap-corrected C-index of 0.79. The Hosmer–Lemeshow test indicated no significant discrepancies from an ideal fit in the development cohort (P=0.59), affirming the model’s predictive accuracy. Calibration plots corroborated the nomogram’s effectiveness in forecasting intolerable EEN, exhibiting a strong alignment between anticipated risks and actual events (Fig. 2A). In the validation cohort, the nomogram sustained a C-index of 0.77 (95% CI: 0.64–0.87) and showed reliable calibration in risk estimation (Fig. 2B), with the Hosmer–Lemeshow test revealing no significant variance (P=0.31).

Table 2 Risk factors for intolerable early enternal nutrition.

	Univariate analysis	Multivariate Analysis	
Characteristics	OR (95% CI)	P	OR (95% CI)	P	
Center		0.95			
 A	Ref				
 B	0.98 (0.54–1.79)				
Male	1.04 (0.57–1.87)	0.91			
Age	1.01 (0.99–1.03)	0.26			
BMI	0.96 (0.85–1.09)	0.52			
Interval from fistula occurred to admission	0.97 (0.91–1.12)	0.39			
Interval from fistula occurred to definitive surgery	0.89 (0.67–1.33)	0.33			
Distance from Treitz to the fistula	
 <100 cm	Ref				
 ≥100 cm	0.91 (0.41–1.99)	0.81			
Length of small intestine	
 <300 cm	Ref				
 ≥300 cm	1.69 (0.81–1.77)	0.17	1.47 (0.71–2.08)	0.23	
Parenteral nutrition required	1.48 (0.58–2.41)	0.66			
High-output	1.34 (0.74–2.44)	0.34			
Etiology	
 Rupture	Ref				
 Obstruction	1.34 (0.71–2.55)	0.38			
 Others	1.53 (0.51–4.62)	0.46			
Entero-atmospheric fistula	4.81 (2.56–9.01)	<0.001	1.63 (0.57–4.65)	0.35	
Hemoglobin before definitive surgery	0.99 (0.97–1.03)	0.92			
Albumin before definitive surgery	1.04 (0.90–1.19)	0.60			
C-reactive protein before definitive surgery	1.02 (0.98–1.07)	0.30			
White blood cell before definitive surgery	1.04 (0.82–1.33)	0.70			
 Severe abdominal adhesion	4.39 (2.37–8.15)	<0.001	3.62 (1.02–8.97)	0.04	
 Duration of definitive surgery	1.48 (1.21–1.80)	<0.001	1.16 (0.82–1.65)	0.39	
 Deciliter of bleeding during definitive surgery	1.32 (1.18–1.48)	<0.001	1.22 (1.01–1.48)	0.04	
Sarcopenia	1.38 (0.77–2.48)	0.28			
Visceral fat area / subcutaneous fat area	2.37 (0.78–6.36)	0.29			
Visceral fat area / total abdominal muscle area index	1.47 (1.12–1.94)	0.006	1.51 (1.09–2.09)	0.01	
Preoperative nutritional risk screening (NRS 2002) >3	1.22 (0.64–2.34)	0.55			
Preoperative American Society of Anesthesiologists physical status classes	1.07 (0.79–1.69)	0.42			
Hypertension	1.31 (0.25–6.95)	0.75			
Elevated fasting blood glucose	2.02 (0.76–5.39)	0.16	1.98 (0.72–4.89)	0.22	
The amount of red blood cell suspension input >4 U during definitive surgery and within 48 h after definitive surgery	1.97 (0.88–3.78)	0.10	1.87 (0.78–3.49)	0.37	
The amount of human serum Albumin input >40 g during definitive surgery and within 48 h after definitive surgery	8.71 (4.45–17.06)	<0.001	2.90 (1.08–7.84)	0.04	
Volume of postoperative drainage from nasointestinal tube until implement early enternal nutrition	1.03 (0.97–1.08)	0.17	1.02 (0.85–1.08)	0.29	
Volume of postoperative drainage from nasogastric tube until implement early enternal nutrition	1.01 (0.95–1.06)	0.78			
C-reactive protein on the day of implementation of early enternal nutrition	1.01 (1.00–1.02)	<0.001	1.01 (0.98–1.05)	0.19	
White blood cell on the day of implementation of early enternal nutrition	1.17 (1.09–1.25)	<0.001	1.07 (0.96–1.18)	0.25	
Procalcitonin >0.5 μg/l on the day of implementation of early enternal nutrition	1.38 (0.68–2.81)	0.38			
Using vasoactive drugs on the day of implementation of early enternal nutrition	4.17 (1.67–10.39)	0.02	2.36 (0.46–11.9)	0.29	
Postoperative fluid positive balance until implementation of early enternal nutrition	4.65 (1.89–11.41)	0.001	2.08 (0.39–8.56)	0.44	

Figure 1 Nomogram model predicating the intolerable early enternal nutrition. The nomogram was developed in the development cohort, with the severe abdominal ahesion, VFA/TAMAI, The amount of human serum Alb input >40 g during and within 48 h post-DS, Deciliter of bleeding during DS. Alb, Albumin; DS, definitive surgery; VFA/TAMAI, Visceral fat area / Total abdominal muscle area index.

Figure 2 (A) Calibration curve of the nomogram model in the development cohort. (B) Calibration curve of the nomogram in the validation cohort.

Risk of intolerable EEN based on the nomogram scores

The optimal cutoff for the nomogram scores was established at 160. The sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, and negative likelihood ratio for distinguishing between the presence and absence of intolerable EEN were 74.8%, 72.4%, 57.6%, 91.3%, 2.8, and 0.35 in the development cohort, and 68.9%, 77.3%, 55.2%, 91.1%, 3.1, and 0.40 in the validation cohort, respectively.

Clinical use

The decision curve analysis depicted in Figures 3A and B for the development and validation cohorts, respectively, indicated that the nomogram is beneficial for predicting intolerable EEN when patients or physicians have a threshold probability >10%, offering greater utility than using the nomogram indiscriminately or not using it at all.

Figure 3 (A) Decision curve analysis for the nomogram model in the development cohort. (B) Decision curve analysis for the nomogram model in the validation cohort.

Discussion

This research introduced and confirmed a perioperative, signature-based nomogram for the individualized forecasting of intolerance to EEN after DS in patients with small intestinal fistula. The nomogram integrates four principal predictors: severe abdominal adhesion, the VFA/TAMAI ratio, the requirement for human serum Alb input exceeding 40 g during and within 48 h post-DS, and the amount of blood loss during DS, efficiently pinpointing patients at an elevated risk for intolerable EEN.

Given the rarity of DS for small intestinal fistula, postoperative EEN in patients undergoing DS has not garnered widespread attention. While DS for a small intestinal fistula may appear straightforward, its complexity can escalate due to abdominal adhesions10,12,13,21. Tian et al.18 reported a study involving 479 patients undergoing DS, noting an overall recurrence rate of 9.3%, which is consistent with Ren et al.12, who observed a 7.3% recurrence rate in 356 patients undergoing DS for ECF, with most surgeries lasting under 3 h and blood loss below 300 ml. However, in patients with severe adhesions, Tian et al.18 found a median blood loss of 1000 ml and longer surgery times, resulting in a higher recurrence rate of 20.2% and a median time to defecation of 8 days. In contrast, a subgroup of 296 patients without severe adhesions had a lower recurrence rate of only 3.4%. Additionally, abdominal infections occurring in the early stages of fistula formation can lead to adhesions due to peritoneal damage from abdominal contamination. The resolution of these adhesions relies on peritoneal fibrinolytic activity, which becomes impaired by persistent abdominal inflammation due to inadequate drainage22. Consequently, patients with severe adhesions during DS face increased surgical challenges and trauma, leading to prolonged chronic inflammation18, which may intensify postoperative acute inflammation and delay recovery5,18.

Severe adhesions and substantial blood loss during DS underscore the complexity and associated trauma of the procedure. Severe adhesions can extend the duration of surgery and, along with significant trauma, result in tissue edema and exudation, hindering digestive function recovery18. In addition, significant blood loss during DS is indicative of surgical trauma. Patients undergoing extensive blood loss may necessitate postoperative fluid resuscitation, which could lead to secondary damage to the digestive tract due to the intestinal mucosa’s heightened sensitivity23. This sensitivity is influenced by blood pressure fluctuations, the administration of vasoactive drugs, and the occurrence of edema, all of which can contribute to the development of intolerable EEN10,18.

The VFA/TAMAI ratio was identified as a prognostic indicator for postoperative complications. Elevated VFA/TAMAI ratios, coupled with preoperative chronic inflammation, are attributed to adverse outcomes. Chronic inflammation disrupts immune balance and impairs the body’s healing capabilities24, leading to a higher incidence of complications. Tian et al.18 observed that patients with elevated VFA/TAMAI ratios demonstrated significant postoperative acute inflammation, leading to poorer outcomes. The presence of increased abdominal fat and the fragility of abdominal organs in regions with pronounced chronic inflammation can exacerbate surgical trauma, intensify postoperative inflammation, and elevate the incidence of intolerable EEN. Furthermore, the immune dysregulation observed in patients with chronic inflammation indicates that the level of inflammation might not directly align with inflammatory markers such as CRP and WBC counts24. The analysis in our study, comparing preoperative inflammatory markers between patients who tolerated EEN and those intolerant to it, corroborates this perspective.

Albumin serves as a critical marker for nutrition, inflammation, and prognostic outcomes25. During acute inflammatory responses, hypoalbuminemia may arise from albumin leakage due to bleeding and digestive tract exudation26,27, augmented by increased capillary permeability that allows albumin to move from the intravascular to the interstitial compartment28, and further exacerbated by dilution from intravenous fluid administration. A meta-analysis of 90 cohort studies involving acutely ill patients29 found that a 10 g/l reduction in serum albumin correlated with a 137% increase in mortality and an 89% increase in morbidity. In our research, the need to administer significant amounts of albumin to sustain plasma albumin levels above 30 g/l within 48 h post-DS reflects the extent of intraoperative trauma, postoperative acute inflammation, and overall patient condition, which naturally correlates with delayed GI recovery. Unlike specific inflammatory markers such as CRP and WBC measured on the day of EEN, supplementing albumin within 48 h post-DS to maintain serum albumin ≥30 g/l may better represent the duration of sustained inflammation during this period, thereby offering a more accurate prognosis. This reasoning supports the incorporation of albumin supplementation into the nomogram, while CRP and WBC were not included. Notably, in patients who were intolerant to ENN, the volume of gastric decompression reached its peak on the third day postoperatively, as opposed to the first and seventh days, suggesting a potential temporary impairment of early postoperative GI secretory function in cases of DS with substantial trauma. This observation highlights the challenge in distinguishing between mild and severe GI injuries based solely on volumes of GI decompression fluids.

Factors such as sex, age, condition, plasma Alb level, length of hospital stay, nutrient factors (dosage form, concentration, temperature, osmotic pressure, patient position, and feeding speed), mechanical ventilation and its duration, use of GI motility drugs, sedatives, vasoactive drugs, and antibiotics may affect postoperative tolerance to exclusive enteral nutrition (EEN).

While previous research30,31 has associated male sex and advanced age with increased rates of EEN failure, these variables did not significantly influence the outcomes in our study. This divergence could be due to our distinct postoperative EEN method, which involved the use of a NI tube rather than the NG tube or oral administration typically employed in other studies. In our protocol, gastric retention served as a marker for EEN tolerance. The higher incidence of EEN intolerance observed in males through NG tube or oral pathways in other investigations might be related to sex-specific physiological differences in the digestive system. Men tend to have more acidic gastric juice, larger gastric volumes, and lower glutathione activity than women32. However, by relieving the NG tube and delivering nutrients directly into the small intestine via the NI tube, our approach likely mitigated the influence of these physiological disparities on EEN tolerance. The significance of sex on intestinal motility is diminished in our context, considering that although the small intestine is longer in males, females exhibit slower colon motility. While age is intuitively considered a risk factor for EEN intolerance, this notion is not consistently corroborated. In our study, age was analyzed as a continuous variable, which did not yield significant results as opposed to binary categorization. Furthermore, the median age of 54 years in our patient cohort suggests that the relatively moderate age distribution might have lessened the impact of age on EEN tolerance.

In our clinical observations, there was significant individual variability in how surgical trauma affected postoperative tolerance to EEN. Identifying patients preoperatively who would face significant trauma from the DS procedure proved challenging. As a result, we adopted a cautious approach, treating every patient as if they were likely to undergo a challenging procedure with significant trauma. To optimize outcomes, DS was only conducted after ensuring effective infection control and confirming that patients had achieved optimal physical and nutritional status. By adhering to these stringent preoperative criteria, we aimed to minimize potential confounders, ensuring that variables such as preoperative health status, plasma Alb levels, and duration of hospital stay prior to DS remained consistent across the patient cohort undergoing DS.

Additionally, we diligently worked to ameliorate the condition of patients experiencing significant trauma following the DS in the postoperative period, endeavoring to correct hypoproteinemia, anemia, and hypoperfusion. Our objective was to reduce the variance in postoperative conditions between patients who encountered substantial surgical trauma and those who underwent a less complicated DS procedure. Our postoperative management aimed to standardize patient conditions, effectively reducing potential confounders. Key aspects of postoperative care, such as nutritional factors (dosage form, concentration, temperature, osmotic pressure, patient position, and feeding rate), mechanical ventilation, and the use of antibiotics and sedatives, were uniformly applied across all patients, irrespective of their EEN status. Although the use of sufentanil could impact the recovery of intestinal function, its administration was consistent for all patients. Parecoxib was employed for additional analgesia, with a negligible effect on intestinal motility. The uniform absence of GI motility drugs further ensured minimal variability among the patient cohort. In our efforts, we incurred various costs to achieve comparably favorable conditions in postoperative patients. For example, blood cells and Alb transfusions were performed to maintain hemoglobin levels ≥100 g/l and Alb levels ≥30 g/l, respectively; vasoactive drugs were administered on the day of EEN, and the accumulated postoperative fluid positive balance was monitored until EEN implementation after DS. Our univariate factor analysis revealed statistical differences in these interventions between patients with and without intolerable EEN. Yet, only postoperative Alb transfusion emerged as a significant factor associated with intolerable EEN. Following an extensive DS, a higher need for Alb supplementation signals an acute reduction in Alb in postoperative patients, now recognized as a marker of acute inflammation prognosis25. Inflammation is characterized by changes in vascular permeability33, leading to significant Alb leakage into the tissue space33. Administered Alb cannot be entirely retained in the plasma, and red blood cells will not overflow due to vascular permeability changes. The Alb administered cannot be completely retained in plasma, unlike red blood cells, which are less affected by changes in vascular permeability. Therefore, the volume of Alb transfused post-DS is a more accurate reflection of inflammation than the volume of red blood cells transfused. While the administration of vasoactive drugs on the day of EEN and the positive fluid balance postoperatively also indicated responses to surgical trauma, the principal contributor to severe trauma is extensive dissection of abdominal tissue, which provokes both systemic and local inflammation, including intestinal exudation and edema. These inflammatory responses directly impede intestinal function recovery, potentially resulting in EEN intolerance.

The determinants of postoperative outcomes in DS for small intestinal fistula are multifaceted. However, our study offers a comprehensive analysis that includes preoperative, intraoperative, and postoperative variables. The four variables ultimately included in the nomogram spanned all three phases, yielding a C-index of 0.79 in the development cohort and 0.77 in the validation cohort. This demonstrates the model’s predictive value for identifying patients at risk of postoperative intolerance to EEN. The meticulous selection of patients based on specific characteristics indicates that our model has broad applicability for individuals with small intestinal fistula, suggesting its potential utility in clinical settings.

This study acknowledges several limitations. Firstly, potential biases inherent to its retrospective design and the modest sample size warrant caution, although the sample size is arguably adequate given the uncommon nature of small intestinal fistula cases with extensive abdominal adhesions. Secondly, unlike the conventional early postoperative fluid diet, our approach to EEN involved feeding through NI tubes. Thirdly, our criteria for defining EEN intolerance, which rely on the NI route for EEN and thus disregard gastric residual volumes as a marker of intolerance, deviate from conventional definitions. This deviation might limit the generalizability of our nomogram to settings where traditional postoperative nutritional strategies are employed. However, the postoperative nutritional support management in this study was more sophisticated, accurately reflecting the level of intestinal function recovery and the entire digestive tract’s tolerance to EEN. Fourthly, the inherent complexity and variability of small intestinal fistula treatment, especially during the perioperative period, present additional challenges. Nonetheless, the rigorous DS criteria and postoperative care protocols in our study aimed to reduce confounding preoperative variables, enhancing the reliability of our findings. Additionally, the study population was relatively young [median age of 54 years (IQR: 38–65)] and well-nourished [median BMI of 20.5 kg/m2 (IQR: 19.1–22.9)], which may not fully represent the typical real-world demographic, often characterized by older and mildly malnourished patients. Consequently, the findings of this study might vary in a broader population. Lastly, an ideal validation of these results would involve a large observational cohort. The definitive conclusions must be substantiated through external validation, specifically designed to accurately reflect the diverse patient demographics encountered in clinical settings.

In conclusion, EEN is recognized as a nutritional intervention that enhances GI function recovery and mitigates intestinal inflammatory response. Yet, in patients with compromised postoperative conditions and significant trauma, the likelihood of EEN intolerance is elevated. Implementing EEN to in these scenarios may intensify GI distress, thereby impeding postoperative healing. Our study, concentrating on a cohort characterized by relative youth and favorable nutritional status, developed a nomogram that integrates four perioperative risk factors to ascertain the likelihood of EEN intolerance following DS for small intestinal fistula. Given the high rates of postoperative EEN intolerance, the insights from this research will aid in identifying high-risk patients and formulating improved nutritional management strategies for them.

Ethical approval

This study was approved by the ethics committee of Jinling Hospital (2023DZKY048-07).

Consent

Written informed consent was obtained from the patient for publication and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.

Sources of funding

None

Author contribution

R.Z., Y.Z., W.L., and T.T.: provide research objects; X.X. and R.Z.: collected and analyzed the data; Z.Y., X.X., and W.T.: wrote the main manuscript text; X.X.: prepared figures and revised the manuscript; Z.Y.: designed the research; L.L., W.T., and X.X.: revised the manuscript; L.L.: provides statistical analysis consultation and interprets the data; X.X., L.L., and W.T.: were the first authors; Z.Y., Y.Z., and R.Z.: were the corresponding authors.

Conflicts of interest disclosure

The authors declare that they have no financial conflict of interest with regard to the content of this report.

Research registration unique identifying number (UIN)

Name of the registry: Researchregistry.

Unique identifying number or registration ID: Researchregistry9717.

Hyperlink to your specific registration (must be publicly accessible and will be checked): https://www.researchregistry.com/browse-theregistry#home/registrationdetails/655b64ab99ad4c0028f647d5/

Guarantor

Zheng Yao.

Data availability statement

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Supplementary Material

Acknowledgements

The authors would thank Bullet Edits Limited for the linguistic editing and proofreading for the manuscript.

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Supplemental Digital Content is available for this article. Direct URL citations are provided in the HTML and PDF versions of this article on the journal's website, www.lww.com/international-journal-of-surgery.

Published online 29 May 2024
==== Refs
References

1 Noba L Rodgers S Chandler C . Enhanced Recovery After Surgery (ERAS) reduces hospital costs and improve clinical outcomes in liver surgery: a systematic review and meta-analysis. J Gastrointest Surg 2020;24 :918–932.31900738
2 Cavallaro P Bordeianou L . Implementation of an ERAS pathway in colorectal surgery. Clin Colon Rectal Surg 2019;32 :102–108.30833858
3 Gianotti L Besselink MG Sandini M . Nutritional support and therapy in pancreatic surgery: a position paper of the International Study Group on Pancreatic Surgery (ISGPS). Surgery 2018;164 :1035–1048.30029989
4 Reintam Blaser A Deane AM Preiser JC . Enteral feeding intolerance: updates in definitions and pathophysiology. Nutr Clin Pract 2021;36 :40–49.33242218
5 Boelens PG Heesakkers FF Luyer MD . Reduction of postoperative ileus by early enteral nutrition in patients undergoing major rectal surgery: prospective, randomized, controlled trial. Ann Surg 2014;259 :649–655.24169163
6 Klappenbach RF Yazyi FJ Alonso Quintas F . Early oral feeding versus traditional postoperative care after abdominal emergency surgery: a randomized controlled trial. World J Surg 2013;37 :2293–2299.23807124
7 Naresh D Kefalianos J Watters D . Who tolerates early enteral feeding after colorectal surgery? ANZ J Surg 2020;90 :1335–1339.32418349
8 Burcharth J Falkenberg A Schack A . The effects of early enteral nutrition on mortality after major emergency abdominal surgery: a systematic review and meta-analysis with Trial Sequential Analysis. Clin Nutr 2021;40 :1604–1612.33744604
9 Ortiz-Reyes L Patel JJ Jiang X . Early versus delayed enteral nutrition in mechanically ventilated patients with circulatory shock: a nested cohort analysis of an international multicenter, pragmatic clinical trial [published correction appears in Crit Care. 2022 Jun 28;26(1):192]. Crit Care 2022;26 :173.35681220
10 Huang M Tian W Luo S . Duration of postoperative hyperlactatemia has predictive value in recurrent fistula after major definitive surgery for intestinal fistula. BMC Surg 2022;22 :14.35033052
11 Liao Y Tao S Yao Z . Chyme reinfusion improved outcomes after definitive surgery for small-intestinal enteroatmospheric fistula in patients with enteral nutrition. Nutr Clin Pract 2022;37 :634–644.35094427
12 Ren H Ren J Hu Q . Prediction of procalcitonin for postoperative intraabdominal infections after definitive operation of intestinal fistulae. J Surg Res 2016;206 :280–285.27884320
13 Varatorn R Suchato C . Sabiston Textbook of Surgery The Biological Basis of Modern Surgical Practice 19th Edition 2012. 2012DOI:10.31524/bkkmedj.2012.09.020.
14 Mathew G Agha R STROCSS Group . STROCSS 2021: strengthening the reporting of cohort, cross-sectional and case-control studies in surgery. Ann Med Surg (Lond) 2021;72 :103026.34820121
15 Visschers RG Olde Damink SW Winkens B . Treatment strategies in 135 consecutive patients with enterocutaneous fistulas. World J Surg 2008;32 :445–453.18175171
16 Xu X Cai L Tian W . Effects of different preoperative enteral nutrition feeding routes on the duration of gastrointestinal decompression after definitive surgery for small intestinal fistula. Langenbecks Arch Surg 2021;406 :2837–2848.34398262
17 Hobson KG DeWing M Ho HS . Expression of transforming growth factor beta1 in patients with and without previous abdominal surgery. Arch Surg 2003;138 :1249–1252.14609876
18 Tian W Zhao R Xu X . Chyme reinfusion reducing the postoperative complications after definitive surgery for small intestinal enteroatmospheric fistula: a cohort study. Front Nutr 2022;9 :708534.35265651
19 Mayr WR . Guide to the preparation, use and quality assurance of blood components, 13th edition. Vox Sanguinis 2010;93 :279 279.
20 U.S. Department of Health And Human Services, National Institutes of Health, National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE) Version 5 OL. 2017. https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_8.5x11.pdf
21 Ren H Ren J Wang G . The non-thyroidal illness syndrome is associated with postoperative surgical site infections in enterocutaneous fistulae. Int J Surg 2018;51 :213–217.29427748
22 Levi M van der Poll T . Inflammation and coagulation. Crit Care Med 2010;38 (2 Suppl ):S26–S34.20083910
23 Martens EC Neumann M Desai MS . Interactions of commensal and pathogenic microorganisms with the intestinal mucosal barrier. Nat Rev Microbiol 2018;16 :457–470.29904082
24 Schrager MA Metter EJ Simonsick E . Sarcopenic obesity and inflammation in the InCHIANTI study. J Appl Physiol (1985) 2007;102 :919–925.17095641
25 Evans DC Corkins MR Malone A . The use of visceral proteins as nutrition markers: an ASPEN Position Paper [published correction appears in Nutr Clin Pract. 2021 Aug;36(4):909]. Nutr Clin Pract 2021;36 :22–28.33125793
26 Dubois MJ Orellana-Jimenez C Melot C . Albumin administration improves organ function in critically ill hypoalbuminemic patients: a prospective, randomized, controlled, pilot study. Crit Care Med 2006;34 :2536–2540.16915107
27 Redelmeier DA . New thinking about postoperative hypoalbuminemia: a hypothesis of occult protein-losing enteropathy. Open Med 2009;3 :e215–e219.21688758
28 Caironi P Gattinoni L . The clinical use of albumin: the point of view of a specialist in intensive care. Blood Transfus 2009;7 :259–267.20011637
29 Vincent JL Dubois MJ Navickis RJ . Hypoalbuminemia in acute illness: is there a rationale for intervention? A meta-analysis of cohort studies and controlled trials. Ann Surg 2003;237 :319–334.12616115
30 Jang A Jeong O . Tolerability of early oral nutrition and factors predicting early oral nutrition failure after gastrectomy. Clin Nutr 2020;39 :3331–3336.32146072
31 Di Fronzo LA Cymerman J O’Connell TX . Factors affecting early postoperative feeding following elective open colon resection. Arch Surg 1999;134 :941–946.10487587
32 Freire AC Basit AW Choudhary R . Does sex matter? The influence of gender on gastrointestinal physiology and drug delivery. Int J Pharm 2011;415 :15–28.21640175
33 Opal SM van der Poll T . Endothelial barrier dysfunction in septic shock. J Intern Med 2015;277 :277–293.25418337
