Long term outcomes of no gut syndrome in children – A multicentre study

Abstract

Background

Children with extreme short bowel syndrome, including those who have undergone resection of the entire jejunum and ileum—termed "No Gut Syndrome" (NGS) in the adult literature—are now surviving due to advancements in parenteral nutrition (PN) and medical care. This study aims to describe the population characteristics and long-term outcomes of children with NGS.

Material and methods

A questionnaire was distributed to the paediatric intestinal failure (IF) centres in the UK to identify patients with NGS discharged home on PN. Inclusion criteria: infants/children < 18 years with duodenum plus up to 5 cm jejunum and colon (total/partial). Follow-up data was collected two years after the initial recruitment. A multicentre Health Research Authority approval was obtained.

Results

19/20 (95 %) IF centres managing 379 HPN patients responded − 27/379 (7 %) had ultrashort-bowel syndrome (U-SBS) and an additional 14/379 (4 %) NGS. Aetiology of NGS was - midgut volvulus (64 %), bowel ischaemia (22 %), necrotising enterocolitis (7 %), jejuno-ileal atresia (7 %).

Nine patients had a colonic remnant in continuity. Thirteen/14 patients (93 %) remained stable on PN with one weaned off following small bowel transplant. Nine/13 (69 %) patients received > 80 % of EAR as PN and 4/13 (31 %), 30–80 %. Eight/13 (61 %) tolerated some form of enteral nutrition. There were no deaths during the follow-up period. Educational outcomes were positive showing that 11/14 (79 %) are attending school, 2/14 (14 %) nurseries with 1 awaiting enrollment (7 %).

Conclusion

Advances in PN and health care have improved the long-term survival of patients with NGS. In addition, these children are attending school and participating in daily activities without significant limitation.

Introduction

Short Bowel Syndrome (SBS) defined as a reduction in small intestinal length is the commonest cause of intestinal failure (IF) in children [1]. The severity of SBS has traditionally been defined based on the length of the remaining small intestine (SI), measured from a key anatomical landmark known as the ligament of Treitz. This ligament marks the transition from the duodenum to the jejunum and measuring the remaining SI length distally, provides a standard method to assess the severity of SBS. The shorter the SI, the more severe the SBS and greater the challenges in managing nutrition and overall health [2], [3].

A subgroup of SBS with < 10 cm SI or < 10 % of the expected length for age is defined as ultrashort bowel syndrome (U-SBS) [4]. In 2015 a new term, “No gut syndrome” (NGS) i.e. near total enterectomy was defined by the adult literature as the removal of the entire jejunum and ileum secondary to mesenteric vascular events, trauma or abdominal tumours [5]. We are not aware of previous publications on NGS in paediatrics as historically, the loss of such a major portion of the SI was considered to have poor outcome and incompatible with life [6].

There has been considerable improvement in survival of children with IF over the last 10–15 years illustrating that long term PN represents a safe option with the number of children on HPN increasing over the years [7], [8] but the rarity of NGS combined with the wide range of diagnoses associated with IF and limited national and international data makes defining epidemiology, treatment and outcomes accurately a challenging task [6].

The primary aim of this study was to describe the population characteristics and long-term outcome in children with NGS. The secondary objective was to describe the prevalence of children on HPN and define the proportion of U-SBS and NGS patients discharged on HPN in the United Kingdom (UK).

Material and methods

Definition

The adult definition of NGS (the removal of the entire jejunum and ileum) was discussed in the Paediatric British Nutrition and Intestinal Failure Working Group (NIFWG) with representatives from gastroenterology, hepatology, general paediatrics and surgery. We proposed that the definition for NGS in infants/children is a SI length of up to 5 cm jejunum from the ligament of Treitz and colon (total/partial). The decision to include patients with ≤ 5 cm jejunum was based upon the difference in aetiology of gut loss in the paediatric group and the difficulties encountered at the time of resection to accurately measure the gut length in these children (the position of the ligament of Treitz may vary or may be unclear, especially in preterm babies in whom a nasojejunal tube may cause considerable stretching and distortion of the peritoneal attachments, and in those with midgut malrotation in whom the duodenal attachments are abnormal; the other considerations were the elasticity of the gut and the variability between measurements including judging viability differently) [9].

Data collection and management

An electronic questionnaire was developed by members of the NIFWG (Additional material 1) and sent in March 2021 to paediatric gastroenterologists from nationally approved IF and rehabilitation centres with established MDTs, to identify patients 0–18 years discharged on HPN with NGS. Data regarding the total number of patients on HPN and the number of patients with U-SBS was included.

To secure the most up to date information, the questionnaire was resubmitted and included all children with NGS discharged on HPN by 15/03/2022. We excluded patients > 18years, discharged on HPN after 15/03/2022 and with NGS secondary to a failed bowel transplant (separate group in terms of outcome).

Follow up data was collected for the included patients < 18 years, 2 years after initial recruitment, in March 2024 (Additional material 2).

A multicentre Health Research Authority approval was requested and obtained via the integrated research application system (IRAS) for a study to investigate the outcome and impact of NGS in paediatric patients. Data access approval for the chief investigator was acquired.

Clinical details were gathered from the patients’ medical records. Once collected, data was completely anonymized by the local team and was strictly confidential in accordance with all appropriate legislation. The anonymized data collected was collated and analysed by the chief investigator.

Data obtained

• 1)demographics: age, sex
• 2)patient history: perinatal history, gestational age, medical/relevant family history
• 3)SBS aetiology
• 4)surgeries: first major intestinal resection and initial anatomy (SI length, if colon was present/continuity, % colon remaining [10]), further abdominal surgeries, intestinal stomas/drains, reconnection surgery
• 5)nutrition: information about PN (PN dependency was divided into 3 groups - >80 % EAR (estimated average requirements), 30–80 % EAR or < 30 % EAR from PN [11], nights PN/week, hours PN/night, fat free nights/week), replacement intravenous (iv) fluids and enteral nutrition (EN)
• 6)complications: IF associated liver disease (IFALD), number of catheter-related bloodstream infections (CRBSI) in the last year, hospital admissions and outpatients’ attendance/year, other complications
• 7)clinician’s perceptions regarding parents’ perspective before PN was initiated, discussions about palliative care and challenges faced by health professionals
• 8)intestinal transplant: discussions with parents/transplant team and the indication and outcome if a patient had an intestinal transplant
• 9)psychological support for patient/family (referrals made by the primary intestinal rehabilitation teams) and palliative care involvement
• 10)current social interactions e.g. school, holidays, sports

Although there is not an accepted international biochemical definition of IFALD, using evidence from the current literature [8], [12], [13], [14], [15] and discussions with intestinal transplantation experts, we classified IFALD as follows:

• •Mild IFALD: liver function tests > 1.5 × upper limit normal and/or hyperbilirubinemia > 20 μmol/L and > 20 % total bilirubin persisting for > 2 weeks unrelated to infection where other causes of abnormal liver function or hyperbilirubinemia have been excluded (e.g. viral infections, surgical interventions)
• •Advanced cholestasis: conjugated bilirubin levels ≥ 75 μmol/L on at least 2 consecutive measurements separated by ≥ 2 weeks in the absence of active sepsis
• •Severe IFALD with portal hypertensive complications: conjugated bilirubin levels ≥ 75 μmol/L on at least 2 consecutive measurements separated by ≥ 2 weeks in the absence of active sepsis plus one or more of: thrombocytopenia defined as platelets < 150 × 10⁹/L; coagulopathy defined as INR > 1.5; hypoalbuminemia defined as albumin < 30 g/L; splenomegaly and ascites detected on ultrasound and history of at least one episode of variceal bleeding.

Data analysis

Analysis was performed in IBM SPSS Statistics for Windows Version 26. Kolmogorov–Smirnov test was performed to assess normality of data. Socio-demographic and medical information was summarized using descriptive statistics - means and standard deviations (SD) or alternatively medians and interquartile ranges (IQR), when data did not follow a normal distribution. Statistical significance for categorical/dichotomous variables was performed with the Pearson Chi-squared test. Mann–Whitney U-test was used to compare continuous variables. Statistical significance was defined as a P value < 0.05.

Results

Twenty centres out of 23 for which contact details were available, managing children on HPN in the UK participated, and 19/20 (95 %) responded to the initial survey. The response rate from the total number of centres was 82.6 %. The respondent centres managed a total of 379 HPN patients, among whom 27 (7 %) had U-SBS and 16 (4 %) NGS. Four centres reported cases where active treatment with long-term PN was not offered to similar patients. One patient was excluded for not meeting the age criteria of < 18years - a boy who developed NGS after superior mesenteric artery damage during the removal of a benign cystic teratoma age five. He transitioned to adult services on oral diet and PN 5 nights/week. During the 2024 follow-up, another patient was excluded since aged > 18 years. This patient had NGS after bowel infarction secondary to chemotherapy aged two years. Although transitioned to adult gastroenterology care on PN 7 nights/week, sadly passed away shortly after due to renal complications.

Patient demographics

The final number of patients analysed was 14 with 8 (57 %) males. The median age at resection was 2.2 months [IQR 0.5–13.8]. The age at discharge on HPN was 9 months [IQR 7–18]. The age at the end of the study was 9.8 years [IQR 5.7–12.2]. All patients had been on HPN for at least 2 years.

The gestational age was 35.3 weeks [IQR 34.1–40]. Three patients were diagnosed antenatally (dilated bowel), two with atresia and one with antenatal volvulus. Two patients had diagnosed chromosomal abnormalities – a 22q11 deletion with large VSD corrected and an unbalanced translocation between chromosome 5p and 7p (Cri du Chat syndrome but smaller 5 p deletion than classic Cri du Chat) with multiple VSDs and PDA repaired. Four patients had learning difficulties including those with a chromosomal disorder. There was no maternal or family history of interest.

Aetiology NGS and bowel anatomy

The aetiology of NGS was midgut volvulus in 9/14 cases (64 %) – 1 antenatal volvulus, 3 neonatal volvulus and 5 later in life; 3 (21 %) had bowel ischaemia; 1 extensive necrotising enterocolitis (NEC) secondary to congenital cardiac malformation and 1 jejuno-ileal atresia. The median resection time from birth was 2.1 months [IQR 0.5 – 10] with one child experiencing volvulus at 4 years of age.

The median length of small bowel remaining was 0 cm [IQR 0–1.75] – 5/14 (36 %) patients had ≤ 5 cm of jejunum and 9/14 (64 %) only duodenum. 13/14 (93 %) patients had a colonic remnant (4/13 – 100 % colon, 2/13 – estimated 70 %, 3/13 - estimated 60 %, 1/13 – estimated 40 % and 3/13 – estimated 15 %), the median % colon being 75 % [IQR 30–100]. The colon was in continuity in 9 cases (64 %) – 4/9 with 100 % colon, 1/9 with estimated 70 % colon, 2/9 with estimated 60 % colon, 1/9 with estimated 40 % colon and 1/9 with estimated 15 % colon. The mean duration between resection and reconnection was 1.1 years (SD 1.2). From 5 patients that did not have colon in continuity, 3 had duodenostomies (2 with a mucus fistula), one had a jejunostomy and one had a gastro-jejunal tube in the duodenal stump (jejunal extension to drain gastric secretions).

Three (14 %) underwent lengthening procedures – all had serial transverse enteroplasty (STEP procedures) and one also had tapering of the duodenum. Other surgeries included adhesiolysis and dilatation of a duodeno-colic stricture. 8/14 patients have a gastrostomy.

Outcomes

- Nutrition: The median time to discharge on HPN following resection was 23.6 weeks [IQR 14.2–31.8]. Thirteen patients remained on PN at last follow up with one weaned off PN after small bowel transplant. PN was delivered over 12 h [IQR 12–13], 10 patients were on PN 7 nights/week, 1 each on 6, 4 and 3 nights. Nine (70 %) patients received > 80 % EAR as PN and 4/13 (31 %) 30–80 %. None had less than 30 % of EAR offered by PN. There was no significant difference seen in PN dependency (> 80 % EAR/30–80 %EAR) in relation to length of SI, colon in continuity, length of colon, presence of colon and age at resection (Table 1). Four/thirteen were receiving additional iv fluids. Eight (62 %) were tolerating some form of EN with 4 on oral diet, 3 on blended diet (PEG) with some oral intake and 1 on commercially available formula (PEG).

Table 1.

PN dependency outcomes.

Variable		EAR 30–80 % (N)	EAR > 80 % (N)	pvalue
SI length				0.51
	0 cm	2	6
	> 0 cm	2	3
Colon continuity				0.65
	Yes	3	6
	No	1	3
Length colon				0.51
	< 50 %	2	3
	≥ 50 %	2	6
Colon present				0.69
	Yes	4	8
	No	0	1
Age resection (months)				0.36
		4	9
	Median [IQR]	6.8 [0.6–40.4]	1.4 [0.4–4.1]

One patient was started on GLP-2 analogue (teduglutide). This was a term infant with neonatal volvulus, 5 cm jejunum and full colon in continuity from 6 months age, weaned from PN at 4 years of age and remained off PN for 2.4 years. At the time of data collection, he was back on PN 3 nights/week.

• -Bowel transplant: The possibility of small bowel transplant was discussed initially in 11 (79 %) cases and three (14 %) were referred to a transplant centre for assessment. One/14 patients had an isolated bowel transplant secondary to irreversible IF (family and transplant team decision) at 3.5 years of age. He was on PN 7 nights/week for 1.4 years at the time of the transplant. The stoma was closed 7 months post-transplant and he is currently off PN on full oral fluid and nutrition intake.
• -Lifestyle activities: Eleven patients were of school age - eight were in mainstream school with three attending special needs schools. Nine were attending full time and two only 3–4 days. Two were attending nursery with one awaiting to be enrolled.

Six patients were documented in patient records to have participated in some form of sports including PE, skiing, horse riding, dancing, football and netball and six patients were not documented to do any sports either because they were too young or had special needs. There were no responses received for two patients.

Eleven/14 centres responded to the question about going on holidays and 8/11 patients were reported to have been on a holiday, four of whom went abroad regularly. Psychological/palliative care support: Seven cases (50 %) were offered palliative care support at the time of initiation of treatment, and one was supported by palliative care teams whilst awaiting a bowel transplant. Seven (50 %) received psychological support.

• -Health Care Professionals’ Perceived Challenges in Managing NGS Patients: one high stoma output, one poor weight gain and food aversion, one recurrent CRBSI initially, one hypoglycemia, three reported parents’ expectation and the difficulty of accepting not having a “normal child” and one difficult social circumstance.
• -Admissions and outpatient’s reviews: The median number of admissions in the last year was 2 [IQR 0–2.75], related to complications. The median outpatients’ reviews with the IF team in the last year was 6 [IQR 4–7.5], the number again depended on complications, for example one patient with severe liver disease was often seen.
• -Patient deaths: There were no patients deaths.

We excluded 4 patients with NGS secondary to failed bowel transplant. They all had NGS for a relatively short period of time after first bowel graft was removed and all have been re-transplanted.

Complications

• -IFALD: two patients (14 %) had severe IFALD and were on the waiting list for combined liver and intestinal transplant. 3 (21 %) had mild IFALD and 9 (64 %) had no liver disease.
• -CRBSI: Eleven/13 patients on PN (85 %) had no CRBSIs and 2 (15 %) had at least one CRBSI in the last year.
• -Renal complications were reported in three cases – one bilateral mild nephrocalcinosis and moderate kidney disease, one borderline elevated cystatin C and a third had nephrocalcinosis since birth and recently developed calcium oxalate stones.
• -Hypoglycemia was found in two cases. Both had NGS secondary to bowel ischemia and had sigmoid-rectum (15 % colon) which was not in continuity. One had mild IFALD and one severe IFALD, being on the waiting list for transplant. Both were on 7 nights PN/week, over 14 h with the hypoglycemic episodes happening during PN cycling. The first one was extensively investigated and no cause for the hypoglycemia was found although this improved subsequently. The second case was under investigation at the end of the study.
• -Other complications included three cases of small bowel bacterial overgrowth (SIBO) treated with antibiotics, three developed gallstones one requiring cholecystectomy, one recurrent pancreatitis, one duodenitis treated with steroids, two cases of gastric drainage tube blockage, one case of high intestinal fluid losses treated with Octreotide with minimal improvement, two poor weight gain, four food aversion, one case of anxiety and anger outbursts that required psychological support.

When we looked at the impact of EN on complications we found no significant difference in incidence of IFALD (p = 0.7), hypoglycemia (p = 0.6), transplant waiting list (p = 0.6) and added fluids (p = 0.1).

Discussion

Despite being classified as a single organ failure, NGS was historically deemed incompatible with life, and there are anecdotal accounts of active treatment not being pursued. Our study is the first to examine NGS in the paediatric population and the only one to assess outcomes for patients discharged on HPN, including their daily activities. Since 1949, the adult literature has reported isolated case studies on this condition [16], [17], [18], [19], [20], and a 2018 series presented findings on 13 adult patients [21], primarily focusing on surgical management and post-operative outcomes. In adapting the adult definition for children, we included patients with a minimal jejunal remnant from the ligament of Treitz (≤ 5 cm) to address the challenges of measuring bowel length in children.

Our cohort of 14 cases is the largest to date, capturing data from 19/23 UK HPN centres.

NGS is not uncommon, comprising 4 % of all children on HPN, along with an additional 7 % U-SBS, who have limited potential for bowel adaptation and PN discontinuation [22]. However, the experience in individual centres was limited with only two centres managing more than one case during the study period.

Our findings indicate that NGS patients that are offered active treatment seem to have favourable outcomes in terms of survival, however none has achieved enteral autonomy except for the transplanted one. Notably, many NGS patients seem integrated with their peers, attending schools/nurseries, participating in sports and going on holidays. Some have transitioned to adult care after years on PN.

Despite significant technical and medical challenges, 70 % of patients maintained continuity of the colon without the need for a stoma. While our study did not demonstrate a statistically significant benefit, the limited sample size may have impacted the robustness of the results. Regardless, it was observed that only 1/9 patients in continuity developed liver disease (mild) in comparison with all five patients with a stoma. Six/8 patients that received EN had the colon in continuity, so there was a tendency to tolerate more enteral feeds if reconnected.

The aetiology of NGS in children differs from that reported in adults, in whom massive resections are typically due to mesenteric ischemia from SMA/SMV thrombus or embolus, trauma, intra-abdominal fibroids [5], [21]. In our cohort, the most common cause of significant bowel loss was volvulus, despite not being the primary cause of SBS in children, which is NEC, gastroschisis, and intestinal atresia [23].

We also explored the time from resection to discharge on HPN to determine if stabilization takes longer compared to other conditions; however, we found no existing literature on this interval for other pathologies. Additionally, our study is the first to report the use of Teduglutide in a NGS patient outside of a clinical trial [24]. Since this medication was recently initiated in just one patient, further data is needed before making recommendations.

In contrast to the adult literature [21], only one bowel transplant was performed in our cohort, with two patients on the waiting list due to IFALD. Our data suggest that paediatric teams and families prefer to continue long-term PN for irreversible IF, reserving transplantation as a last resort [25].

Cruz et al. noted a significant issue in adult cases was managing high intestinal fluid losses (20), for which various interventions were attempted. In our paediatric population, only one patient experienced this problem, potentially because of a higher number of colonic reconnections (70 %) and the greater adaptability of the gastrointestinal tract in the growing child [26].

There clearly is a role for early psychology input as demonstrated by half of the patients needing ongoing support. However, there were several different reasons for psychological support - food aversion, manage increased levels of anxiety and associated depression [27], [28].

Although not unique to NGS, one of the challenges faced by health professionals was the grieving of parents for a “normal child”, off PN. Being able to eat has a social, moral and cultural meaning as described in many publications [29].

Our study had its limitations – given the rarity of the condition, the small number of patients and the heterogeneity of the group, the statistical analysis had a limited relevance. Another limitation is the design of the study with the data being obtained from questionnaires which can have a risk of bias. Unfortunately, a cohort study with cumulative incidence of the different outcomes was very difficult to obtained being a multicentre study with limited patient enrolment per site, sometimes with different surgical or MDT approaches. Additionally, the information about patient social interactions (school, holidays, sports, etc) was obtained from involved healthcare professionals, not from direct surveys from patients and families which it’s another recognised limitation. Moreover, the information about psychological support offered to families may be incomplete.

Despite these, for the first time in the literature we proposed a definition for NGS in paediatric patients and we described the largest cohort to date, including long-term outcomes after at least 2 years on HPN.

Conclusion

In conclusion, long-term survival and normal daily life activities (school/nursery attendance, sports, holidays) are achievable for paediatric patients with NGS. Surgeons, neonatologists, and paediatric gastroenterologists should discuss the option of HPN with families at the time of resection. Despite the technical and clinical challenges, duodeno-colonic reconnection is feasible and can improve outcomes.

CRediT authorship contribution statement

Sue Protheroe: Writing – review & editing, Resources. Sunita Rajani: Writing – review & editing, Resources. CERNAT ELENA: Writing – review & editing, Writing – original draft, Visualization, Validation, Supervision, Resources, Project administration, Methodology, Formal analysis, Data curation, Conceptualization. Catherine Richards: Writing – review & editing, Supervision, Methodology, Conceptualization. Susan Hill: Writing – review & editing, Validation, Supervision, Methodology. Camilla Salvestrini: Writing – review & editing, Resources. Rachel Wood: Writing – review & editing, Resources. Chris Smith: Writing – review & editing, Resources. Assad Butt: Writing – review & editing, Resources. Arun Urs: Writing – review & editing, Resources. Sally Buxton: Writing – review & editing, Resources. Akshay Batra: Writing – review & editing, Validation, Supervision, Resources, Methodology, Data curation, Conceptualization. Jeng Cheng: Writing – review & editing, Resources. Jenny Goldthorpe: Writing – review & editing, Resources. Jonathan Hind: Writing – review & editing, Validation, Supervision, Resources, Methodology. Jutta Koglmeier: Writing – review & editing, Resources. Nkem Onyeador: Writing – review & editing, Resources.

Ethical clearance

Ethics approval has been obtained with the REC reference number 22/HRA/0800 dated 28 September 2022.

Patient's/Guardian's consent

Not required.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Appendix A. Supplementary material

Supplementary material

Supplementary material