Short bowel syndrome (SBS) is a malabsorptive condition resulting from reduced functional small intestinal length. SBS is closely related to intestinal failure (IF), defined as the reduction of functional intestinal mass below that which can sustain life, resulting in parenteral nutrition (PN) support for 60 days or greater within a consecutive 74-day period. IF frequently results from intestinal resection necessitated by such diseases as necrotizing enterocolitis in children and Crohn’s disease in adults. Clinical manifestations of IF may include diarrhea, growth failure, bacterial overgrowth, and vitamin deficiencies. Nutritional rehabilitation is the cornerstone of IF management. Surgical interventions are aimed at preserving intestinal length and restoring continuity. Medical management involves individualized enteral and parenteral nutrition therapy, GLP-2 agonists (e.g., teduglutide) that promote mucosal growth, and drugs for symptom management such as antidiarrheals. Experimental therapies such as the use of devices to induce intestinal growth through distraction enterogenesis are under development for the treatment of IF. An interdisciplinary approach involving surgeons, gastroenterologists, dietitians, nurses, and social workers is crucial in the management of these complex patients. Ultimately, a combination of nutritional, medical, and surgical management may be necessary to improve clinical outcomes in patients with IF.
Intestinal failure (IF) is a condition in which the body is unable to adequately absorb nutrients and fluids through the gut. IF encapsulates several conditions in which there is a reduction of functional gut mass below that which can support life, such that supplemental intravenous nutrition is required to sustain normal growth and function. Before the late 1960s, a diagnosis of intestinal failure was considered incompatible with life. The development of intravenous nutrition was essential to improving IF care. Dr. Stanley Dudrick, a then-surgical resident under the mentorship of Dr. Jonathan Rhoads at the University of Pennsylvania, developed parenteral nutrition (PN) after observing malnutrition-related illness and death in patients who were unable to eat. Between 1964 and 1966, Dr. Dudrick conducted a series of experiments in which he grew Beagle puppies to regular adult animals solely through intravenous feeding. Dr. Dudrick, alongside such collaborators as Dr. Harry Vars, pioneered the use of PN during a time in which feeding entirely through the intravenous route was thought to be impractical, or even impossible. In 1967, an infant with intestinal atresia was the first patient placed on PN at the Children’s Hospital of Philadelphia. Since that time, advancements in PN and the establishment of multidisciplinary intestinal rehabilitation centers have changed IF from a nearly-fatal diagnosis to a manageable chronic condition.
The term intestinal failure is often used interchangeably with short bowel syndrome (SBS), a condition in which malabsorption occurs due to reduced intestinal length. However, IF also includes conditions related to inflammation (e.g., Crohn’s disease), intestinal dysmotility (e.g., Hirschsprung’s disease), primary epithelial abnormalities (e.g., microvillus inclusion disease), immune dysfunction (e.g., autoimmune enteropathy), and iatrogenic causes (e.g., radiation enteritis). Globally, SBS remains the most common cause of IF in both children and adults.
In infants, SBS is often the result of congenital intestinal atresias or massive bowel resection necessitated by such conditions as necrotizing enterocolitis (NEC), malrotation with volvulus, and medically refractory inflammatory bowel disease (IBD). The resultant SBS often leads to IF and the need for life-long PN. In the adult population, SBS-related IF has a multitude of causes including thromboembolic phenomena (e.g., superior mesenteric artery embolism with resultant bowel necrosis), traumatic injury, tumors, and IBD. Given the many conditions that fall under intestinal failure, a working definition of IF was developed by the American Society of Parenteral and Enteral Nutrition (ASPEN) in 2021. This consensus paper defined pediatric IF as patients dependent on supplemental PN for 60 days or greater within a 74-day interval. The present review summarizes the clinical manifestations and complications associated with intestinal failure, and discusses mainstay medical treatment and surgical options.
Patients with IF may suffer from complications affecting multiple organ systems. The hallmark of intestinal failure is the inadequate bowel function to absorb fluids and nutrients, and the major manifestations of this disease include diarrhea, dehydration, and malnutrition. There is a profound and predictable pattern of deficiencies based on the anatomy that is remaining. For example, resection of the ileum portends iron deficiency anemia and bile salt malabsorption, while loss of the jejunum may result in acidosis, electrolyte losses, and protein malabsorption. Diarrhea is often profuse in the setting of massive bowel loss, especially early in the course after bowel resection, necessitating intravenous fluid supplementation and titration of enteral feeds to limit this output. Naturally micronutrient and mineral deficiencies, such as vitamin D, calcium, magnesium, and phosphorus, culminate in the development of multiple comorbid conditions including metabolic bone disease and growth failure. Multiple studies have demonstrated that children with pediatric intestinal failure do not achieve their target genetic height.
As a child grows, the bowel increases in length in proportion to a child’s linear growth. It has been shown that remnant small bowel length is a predictor of stunted linear growth and dependence on parenteral nutrition. The younger a child is at the time of the initial intestinal injury, the greater the potential for compensatory growth. This increase in absorptive surface area, as well as the decrease in protein and calorie needs as a child ages, contribute to the achievement of enteral autonomy. A consequence of this bowel adaptation is the potential for stricture and dilation leading to dysmotility. This predisposes patients to small bowel bacterial overgrowth and chronic inflammation, which may manifest as anastomotic ulcers and gastrointestinal bleeding.
Routine surveillance and expectant management of potential complications is a critical component of treating patients with intestinal failure. Long term complications such as metabolic bone disease, liver disease, and nephrocalcinosis may not be detected without routine screening. This leaves children with IF vulnerable to sequelae of liver disease, kidney disease, and growth failure. Annual abdominal ultrasounds to assess hepatic parenchymal echotexture and vasculature, renal parenchyma, and spleen are recommended. Biennial dual-energy X-ray absorptiometry (DXA) and bone age evaluations, beginning at the age of 5, are recommended to assess bone mineral density. Routine laboratory work should include evaluation of micronutrients, iron stores, and hepatic function. Inflammatory markers, including C-reactive protein (CRP), may be helpful in patients with growth failure to rule out chronic inflammation as a cause.
Patients with intestinal failure may experience a myriad of complications that affect the liver, stomach, small intestines, colon, and bones. Malabsorption-related issues can manifest as diarrhea, vitamin deficiencies, low bone density, and overall poor growth. Patients are additionally susceptible to complications associated with indwelling foreign bodies such as central venous catheters (particularly bloodstream infections) and feeding tubes for enteral access (e.g., malposition of gastrostomy tube).
The primary goal of intestinal rehabilitation is achieving enteral autonomy. In the acute phase immediately following bowel resection, nutritional support is primarily parenteral. With the return of bowel function, enteral feeds may then be initiated at a trophic rate and titrated to stool output. It is recommended to initiate enteral feeds as early as possible after surgery, ideally within days, to promote intestinal adaptation. This process occurs through villus lengthening, increased crypt depth, mucosal hyperplasia, and bowel dilation. Glutamine is a source of fuel and a trigger for hypertrophy in enterocytes, and as such it has been hypothesized that the supplementation of glutamine in the diet improves enteral tolerance. However, this was not shown to either improve enteral tolerance or decrease PN dependence.
While ideal enteral feeding protocols have not been identified, some studies have demonstrated that the administration of elemental formulas can improve enteral tolerance, which is defined as the cessation of vomiting or diarrhea resulting in diaper dermatitis. As such, our intestinal rehabilitation center recommends the administration of elemental formula that is titrated to stool output and/or vomiting for patients with IF. In the inpatient setting where stool output can be more easily quantified, 2 mL/kg/h of stool is generally considered the safe upper limit. For outpatients, the number of stools per day is used as a guide for determining enteral tolerance, acknowledging that this can be a subjective metric; the goal is to limit overnight bowel movements and associated perianal irritation. Early in the course of an IF diagnosis, enteral feeds are administered continuously at a low rate that is subsequently increased pending patient tolerance. The timing of feeds, continuous versus bolus, is patient- and caregiver-dependent.
Long-term use of parenteral nutrition places patients at risk of developing numerous complications, most notably problems associated with central venous catheter (CVC) use. CVC-associated complications may include line fracture, occlusions, additional procedures for repair or replacement, and importantly bloodstream infections. Children with IF who present to the emergency department with fever have high rates of central-line associated bloodstream infections (CLABSI), estimated to be 47.5% at a tertiary pediatric referral center. According to this study, factors associated with CLABSI include low white blood cell and platelet counts at initial presentation, as well as higher temperature in the emergency department. Patients on home PN who present with fever should be admitted for antibiotic treatment until CLABSI can be ruled out. The duration of admission has traditionally been 48 h, though some studies have proposed 24 h as a safe and more cost-effective alternative.
Other CVC-related complications include occlusions and fractures, which may be influenced by the type of locking solution used. In a cohort of pediatric patients with IF, ethanol lock therapy was associated with a 1.65 times greater risk of mechanical CVC complications (i.e., repairs and replacements) compared to heparin locks. During a recent shortage of ethanol lock, a compassionate use trial involving a small cohort of pediatric patients with IF receiving 4% tetrasodium ethylenediaminetetraacetic acid (EDTA) demonstrated reduced rates of CVC-related complications, including hospital admission and mortality. This therapy is not yet approved in the US, despite its approval for pediatric use in Europe, Canada, and Australia. The selection of the type of CVC for home PN administration is often a collaborative decision between the patient and care team, and takes into account factors such as individual lifestyle and anatomy. A meta-analysis of patients on home PN demonstrated that use of peripherally-inserted central catheters (PICC) was associated with similar rates of CLABSI compared to tunneled catheters, and a lower relative risk (0.16, range 0.04–0.64) compared to ports. All patients
