Use and Misuse of Parenteral Nutrition in Patients with Inflammatory Bowel Disease

Abstract

Malnutrition is a very common and often underrecognized condition among patients with inflammatory bowel diseases (IBD). This is most commonly due to increased nutritional requirements and gastrointestinal losses, along with reduced oral intake. Screening for malnutrition is an essential component of managing both inpatients and outpatients with IBD. Although enteral nutrition is the preferred route of supplementation, parenteral nutrition (PN) remains an important strategy and should be considered in certain situations, such as cases with short-bowel syndrome, high-output intestinal fistula, prolonged ileus, or small-bowel obstruction. Appropriate use of PN is critical in order to prevent associated complications. This review addresses the common indications for use of PN, the composition of PN, and the possible complications encountered with PN use, as well as scenarios of inappropriate PN use among patients with IBD. A clinical management algorithm for utilizing PN among patients with IBD is proposed in this review.

Lay Summary

Malnutrition is common and underrecognized among patients with inflammatory bowel diseases (IBD). Screening for malnutrition is an essential component of IBD management. Although enteral nutrition is the preferred route of supplementation, parenteral nutrition (PN) should be considered in certain situations. Appropriate use of PN is critical to prevent associated complications.

inflammatory bowel disease, IBD, malnutrition, parenteral nutrition, TPN, EN

Introduction

Nutritional deficits are the most frequently underrecognized problem among patients with inflammatory bowel diseases (IBD), especially those with Crohn’s disease (CD). Malnutrition has a significant impact on the prognosis of patients with IBD and is associated with increased complication rates and hospitalizations, mortality, and poor quality of life.¹ Screening for malnutrition is recommended by the European Society for Clinical Nutrition and Metabolism (ESPEN) at the time of diagnosis and periodically in all patients with IBD.² In adults, the risk of malnutrition can be identified with self-administered, validated screening tools like the Malnutrition Universal Screening Tool.³ Historically, malnutrition has been diagnosed using either serum albumin and/or serum prealbumin, a practice which is commonly used in research when correlating the malnutrition risk to chronic diseases such as IBD.^4,5 Serum proteins, however, have not been used by malnutrition experts in the field for over a decade due to their lack of sensitivity to protein intake, as well as their lack of specificity to malnutrition.⁶ These acute-phase inflammatory proteins are incredibly sensitive to inflammation and to fluid balance, which are common in patients with IBD, thus limiting their use for malnutrition identification in this patient population.^4,5 The Academy of Nutrition and Dietetics (AND), the American Society of Parenteral and Enteral Nutrition (ASPEN), and ESPEN are 3 of the world’s largest organizations of nutrition experts, leading nutrition-related research and publishing expert consensus recommendations. In 2009, ASPEN and ESPEN convened together, forming an International Consensus Guideline committee to develop a standardized, etiology-based approach for identifying malnutrition.⁵ In 2012, the AND and ASPEN combined to publish a consensus statement updating the identification and diagnosis of malnutrition, most commonly referred to as the AND/ASPEN criteria.⁵ The AND/ASPEN criteria is an etiology-based tool focusing on the cause of the malnutrition and then classifying it by severity. Through the use of a detailed nutritional history, as well as a practical, nutrition-focused physical exam by a trained clinician (generally a Registered Dietitian) quantifying weight loss, energy intake, loss of lean mass, subcutaneous fat mass, and fluid accumulation, as well as diminished functional status, clinicians are able to identify and classify the degree of malnutrition in adults.⁵ These newer criteria form the most widely used approach by experts in the field for adult patients.⁷ Other notable criterion available for use in adult populations are the Global Leadership Initiative on Malnutrition (GLIM) and ESPEN criteria. While the ESPEN criterion considers a body mass index (BMI) < 18.5 kg/m² or unintentional weight loss combined with reduced BMI or reduced fat free mass index as a diagnostic criterion, the GLIM criteria is a consensus-based framework that diagnoses malnutrition by the presence of at least 1 phenotypic criterion (weight loss, a low BMI, and reduced muscle mass) and 1 etiologic criterion (reduced food consumption, impaired assimilation of nutrients, and inflammation).⁸

The common causes of malnutrition among patients with IBD are primarily related to decreased oral intake; increased requirements and increased gastrointestinal losses during inflammatory states; malabsorption; disease activity; and possibly short gut in patients who have had previous or multiple surgical resections, as well as the use of certain medications.⁹ The odds for having malnutrition were 5.57 higher among patients with IBD when compared to non-IBD patients based on the national inpatient sample.¹ The overall prevalence of malnutrition in outpatient clinics was 16%; 56.8% of those patients had CD and 43.2% had ulcerative colitis (UC).^10,11 Malnutrition significantly impairs the healing of enterocutaneous fistulae,¹ a common indication for needing advanced nutrition support therapies such as enteral nutrition (EN) and/or parenteral nutrition (PN). Enteral nutrition is defined as providing nutrition through the gastrointestinal tract via a tube, catheter, or stoma that delivers nutrients distal to the oral cavity.¹² When fistulae are proximal in the gastrointestinal tract and/or have excessive output (>500 ml per 24 hours), EN support is often insufficient to meet estimated needs for healing, or it may be contraindicated. Bowel rest through nil per os (NPO) and initiation of PN support is often performed due to the perceived benefits of expediting the healing of fistulae. Parenteral nutrition is the intravenous infusion of nutrients through either a large vein in total parenteral nutrition (TPN), usually the superior vena cava, or a smaller peripheral vein in peripheral parenteral nutrition (PPN). Compared with PN, EN is the preferred form of nutrition support for all disease states, due to lower infection-related complications and preservation of the gastrointestinal function, unless there is a contraindication to use the gastrointestinal tract.¹³ Despite EN being preferred over PN, about 25% of patients hospitalized with UC and CD receive PN, compared to 6% among non-IBD patients.¹ Based on ESPEN practical guidelines, specifically for patients with IBD, it was recommended to delay elective surgery for 7–14 days when severe malnutrition is identified,² and PN is often the chosen form of nutrition support to provide bowel rest in preparation for elective surgery. The aim of this review is to provide the reader with a comprehensive update on the role of PN and its appropriate use and areas of misuse among patients with IBD.

PN Indications

Despite recommendations from ASPEN to avoid the use of PN solely based on a medical diagnosis or disease state, in practice PN is often used for patients with IBD.¹⁴ An in-depth assessment of a patient’s ability to eat, nutritional status, and clinical goals, as well as absorptive capacity, should be at the forefront of the decision process when identifying the appropriateness of PN support. Parenteral nutrition for both CD and UC should only be considered as an intervention if EN is not possible due to intractable vomiting and/or diarrhea, an inability to attain or maintain access for EN support, and contraindications due to malabsorption, intestinal obstruction or ileus, intestinal ischemia, or shock.² Parenteral nutrition is specifically indicated in IBD patients when adequate nutrition (unable to meet 60% of goal) is not feasible through oral or enteral means for at least 7 to 10 days, which is often the case with a chronic intestinal obstruction, short bowel, high-output intestinal fistula (>500 ml/24 hours), and high-output ostomy (>2000 ml/24 hours).² Parenteral nutrition may additionally be indicated in patients with severe IBD who are malnourished, after 7 days in those unable to maintain ≥60% of their needs via oral or enteral nutrition, and in the preoperative patient where there is an anticipated need of 7 or more days of NPO prior to surgery.⁶ Overall, among patients with IBD, PN should rarely be used and should be reserved only for those patients who are unable to adequately be fed orally or enterally.²

The duration of PN depends on the type of surgery and the patient’s underlying condition. For instance, when a patient with IBD develops a postoperative high-output anastomotic leak and the planned reoperation is performed 3–6 months later, PN may be needed and the decision of whether to choose TPN or PPN depends on the length of time PN support is required, as well as the patient’s estimated nutrient needs. The PPN composition is limited by osmolarity restrictions, and thus may be insufficient to meet estimated nutrient needs. Prolonged PN additionally requires excellent venous access to tolerate the high osmolarity of the solution, and its use is only indicated for a 7- to 14-day infusion, limiting its availability for longer-term needs. Due to these constraints, its use is not appropriate in the home setting.

Complications of PN use

Parenteral nutrition is a complex prescription therapy with many potential safety concerns that warrant strict guidelines while selecting patients appropriate for this form of nutrition support. Complications associated with PN can be categorized as hepatobiliary- and gastrointestinal-related complications and others, including metabolic, mechanical, and infectious-related complications.

PN-Related Hepatobiliary Complications

Even without any underlying liver disease, hepatobiliary complications are more frequent in adults receiving long-term home TPN, with an incidence estimated to range from 15% to 85%.^15,16 The spectrum of injury ranges from biochemical to histological manifestations or a combination of both. Patients may develop transitory elevation of aminotransferases or cholestasis (both intrahepatic or centrilobular), cholangitis, hepatic steatosis and steatohepatitis, portal fibrosis, reactive bile duct proliferation, nonspecific portal and periportal inflammation, and even end-stage liver disease.¹⁷ Hepatobiliary complications can occur as early as 2 weeks after initiation of PN; however, they most commonly occur in those receiving long-term TPN and are less severe in patients with some oral intake.¹⁸ Elevation of aminotransferases usually subsides after stopping PN but can remain elevated for up to 4 weeks.

The incidence of cholestasis induced by PN is more commonly seen in children than in adults, and cholestasis is the most frequent PN-related hepatic dysfunction in children. Severe cholestasis induced by PN is characterized by bile duct regeneration, portal inflammation, and fibrosis.¹⁹ Its progression could be very rapid and, in some patients, liver cirrhosis may develop after 2 to 26 months of PN use.²⁰ Parenteral nutrition–associated cholestasis is defined as a serum-conjugated bilirubin ≥ 2 mg/dl with associated increases in γ-glutamyl transpeptidase, alkaline phosphatase, and serum transaminases in the absence of extrahepatic causes of cholestasis or drug-induced hepatotoxicity.²¹ A lack of cholecystokinin release due to a decrease or no oral intake leads to bile stasis and a decrease in enterohepatic circulation, together with increased deconjugation of bile acids.¹⁷ Other contributing factors may include the amounts of lipids and glucose infused, amino acid (AA) deficiency, and hypoalbuminemia. To avoid hepatobiliary-related complications associated with PN, clinicians, with the help of a Registered Dietitian, should administer adequate amounts of calories (ie, avoiding overfeeding), provide a balance of dextrose and lipids, and consider decreasing lipids to <1 g/kg/d,⁶ while working towards a cycled TPN schedule and maximizing the use of EN whenever possible (even if only at a diminished rate).¹⁷

Hepatic steatosis ranges from 0% to 40% and liver cirrhosis ranges from 0% to 25% in patients receiving home TPN for 6 to 12 months, based on a European survey.²² Its incidence has decreased significantly, which has been correlated with modifications and improvements in the compounding of PN solutions, such as a decrease in lipids, the use of lower-phytosterol lipid products, and the decrease in dextrose provisions.^17,22 Despite these advances, hepatic steatosis remains the most common hepatobiliary complication associated with long-term TPN use. While the precise etiology of hepatic steatosis is still unclear, it might be related to oxidative stress, inflammatory causes, and other factors, including genetic and environmental influences.^23,24

End-stage liver disease is considered a rare complication of long-term PN, occurring in as many as 15% of patients based on a retrospective study and leading to high rates of morbidity and mortality.²⁵ End-stage liver disease was associated with a combination of chronic inflammation and short bowel syndrome in patients who had received prolonged home PN.²⁵ Biliary sludge, gallstones, and acalculous cholecystitis develop due to gallbladder dysfunction and subsequent gallbladder dilation and decreased gallbladder emptying, resulting in supersaturated bile. This is specifically seen in patients with ileal CD or after ileal resection, which causes disruption of the enterohepatic circulation and impacts the composition of bile.^26,27 The presentation and monitoring of these complications are mentioned in Table 1.

Table 1.

PN-related monitoring of hepatobiliary complications.^a

Complication	Presentation	Prevention and management
Elevation of aminotransferase	Mostly asymptomatic	Can occur within 2 weeks of initiation of PN, and levels can return to baseline even when PN is continued. Cycle infusion (PN infusion less than 24 hours, generally 12 hours). Reduce lipids to 50 to 100 g per week. Maximize oral or enteral intake.
Cholestasis	Direct or conjugated bilirubin ≥ 2 mg/dl, with elevation of alkaline phosphatase and gamma glutamyl transpeptidase	Decrease the rate of administration of IV lipids to < 1 gram per kilogram per day. Provide a balance of carbohydrate and lipids. Ursodeoxycholic acid can be tried if persistent cholestasis is present. If total bilirubin > 3 mg/dl, discontinue trace element products, and supplement zinc and selenium separately. Chromium may be supplemented if toxicity is not suspected. Maximize oral or enteral intake.
Hepatic steatosis	Mild to moderate elevation of aminotransferases, and slight elevation of alkaline phosphatase and total bilirubin	Prevent excess calorie administration. Appropriate balance of dextrose to fat. Cycle infusion (PN infusion less than 24 hours, generally 12 hours). Maximize oral or enteral intake.
Hepatic fibrosis or ESLD	Persistent elevation of aminotransferase	Maximize oral or enteral intake and prevent or treat bacterial overgrowth. Referral to hepatology to monitor progression of fibrosis by ultrasound or magnetic resonance imaging with elastography every year. Consider transplant evaluation for ESLD.
Gallstones or gallbladder sludge	Mostly asymptomatic	Maximize oral or enteral intake; cholecystectomy if symptomatic.

Abbreviations: ESLD, end-stage liver disease; IV, intravenous; PN, parenteral nutrition.

PN-Related Intestinal Complications

Parenteral nutrition has been associated with changes in the gut mucosal morphology,^28,29 blood flow, and intestinal functions like cell proliferation and apoptosis, enzymatic functions of the brush border,³⁰ immune defenses, permeability, barrier integrity,³¹ gallbladder motility,³² and the bacterial ecology.^17,33 In humans, PN has been associated with a decrease in enzymatic transport of AA, as well as glucose and vitamin A absorption.¹⁷ There are significant decreases in mucosal thickness and in the number of villous cells with PN use.²⁸ In humans, the effects of PN alone on intestinal mucosal immunity, intestine-derived inflammatory responses, and intestinal permeability have not been widely demonstrated.¹⁷ Intestinal failure is among the most feared complications of PN, and has been correlated with a lack of enteral stimulation, leading to a subsequent reduction of gastrointestinal function. The incidence of PN-related intestinal complications, with or without sufficient oral intake, is not well known given the lack of studies.

PN-Related Metabolic Complications

Common metabolic complications associated with PN are hyperglycemia, fluid and electrolyte derangements, and refeeding syndrome.⁶ Hyperglycemia is the most common complication of PN support and is multifactorial in nature. While its occurrence is not an exclusive complication of PN support in patients with IBD, its etiology warrants awareness and a prompt response due to the frequency with which PN is used amongst the IBD patient population. A study examining the relationship between postoperative glycemic control and surgical site infections in colorectal surgical patients with diabetes mellitus found that poorly controlled glycemia was independently associated with postoperative complications and infection.³⁴ Excessive carbohydrate administration in PN is associated with hyperglycemia, along with hepatic steatosis and increased carbon dioxide production. Erroneous or excessive insulin provisions inside and outside the PN are common causes of hypoglycemia. Fluid and electrolyte derangements can commonly occur in patients with IBD secondary to fluid losses and malabsorption; however, they can additionally be a result of refeeding syndrome in those presenting with malnutrition.⁶ Refeeding syndrome is a dangerous sequalae of metabolic and electrolyte derangements, occurring within the first 5 days of reintroducing calories after a period of reduced or absent nutrient intake. A few of the more common comparative standards that indicate a risk of refeeding syndrome are no intake or negligible intake for 5 or more days, >5% total body weight loss in 1 month, and nutrition-focused physical findings of lean mass loss or fat mass loss.³⁵ If a refeeding risk is identified, it is recommended to check serum potassium, phosphorus, and magnesium prior to starting nutrition support of any kind, including dextrose-containing intravenous (IV) fluids. Refeeding labs should be repeated every 12 hours or more frequently, as needed, for 4 to 5 days. A shift of ≥10% in serum electrolytes can indicate refeeding and should be aggressively repleted. Close monitoring of vital signs and cardiorespiratory functions are recommended at initiation and every 4 hours thereafter for at least 72 hours. Nutrition support should be withheld until electrolytes are repleted. We suggest a dose of 100 mg of thiamin per day, in addition to 1 mg of folic acid prior to caloric reintroduction, and continued supplementation daily for 7 days.³⁵ Slow titration to the caloric goal is prudent, generally starting at 10–20 kcal/kg/d and slowly advancing by 33% of estimated energy needs every 1 to 2 days.³⁵ Fluid and electrolyte needs vary depending on the patient’s renal, fluid, and electrolyte statuses, coupled with their underlying disease process, the presence of malnutrition, and any losses that may occur. Metabolic bone disease is an additional complication of PN that is extremely important among the IBD population. Although its prevalence is unknown, it has been reported in up to 41% of long-term home TPN patients and in up to 67% of patients with intestinal failure who require TPN for 6 months or longer.^36,37 Essential fatty acid deficiency (EFAD) may occur in patients receiving lipid-free PN support within 1 to 3 weeks of starting this formulation.³⁸ Linoleic and α-linolenic acids are essential fatty acids that cannot be synthesized by the body, and thus must be provided exogenously. It is recommended that 1% to 2% of the daily energy intake be derived from linoleic acid and 0.5% of energy from linolenic acid.³⁸ This translates to roughly 1000 calories from a standard, soy-based lipid emulsion provided over 1 to 2 doses weekly. It is important to note that higher amounts of lipid products are required to prevent EFAD when using alternative oil–based lipid products, as these contain lower quantities of linoleic and linolenic acids.³⁸ In those unable to tolerate intravenous lipid emulsions, a trial of a topical skin application of safflower oil may be considered.³⁹ Proper formulation of PN support, including adequate amounts of lipid products, is necessary to prevent EFAD. Table 2 provides more detailed information regarding common metabolic complications associated with PN support, as well as recommendations for management.

Table 2.

Common metabolic complications associated with PN.^a

Complication	Etiology	Prevention and management
Hypo- and hyperglycemia	Hormone-mediated stress response to infection, surgical interventions, inflammation, and/or fasting. Excessive or insufficient dextrose loads. Excessive or insufficient insulin use.	Inclusion of adequate dextrose to target serum BG level of 140–180 while hospitalized. Keep insulin in PN components under 20 units/g/dextrose. Advancement of PN or EN should never be done until serum blood glucose is safely controlled.
Fluids or electrolytes	Intestinal losses from fistulae, high stool or ostomy output, emesis or nasogastric output, poor oral intake. Common losses in IBD: sodium, potassium, phosphorus, magnesium.	Repletion of lost fluids and electrolytes per clinical judgement, tight monitoring of intake or output, and matching composition of fluids lost to fluids replaced.
Refeeding syndrome	Potentially fatal shifts in fluids, electrolytes, and vitamins in malnourished patients from the hormonal and metabolic responses to being fed after a period of insufficient nutrient intake. Risks in patients with IBD are highest in those receiving inadequate nutrition for 5–7 days preceding nutrition support initiation and/or showing signs and symptoms of malnutrition, such as unintentional weight loss or lean mass or body fat loss.	Withholding of nutrition until electrolytes are repleted or stable, followed by slow introduction of EN or PN support (keeping energy intake < 15 kcal/kg/d for first 24–48 hours). Aggressive monitoring and repletion of potassium, phosphorus, magnesium, and sodium. Provision of 100 mg thiamin and 1 mg folic acid should be given prior to initiation of nutrition support and continued daily for 5–7 days.
Essential fatty acid deficiency	Prolonged inadequate intake of dietary fat. Highest risk is in long-term TPN patients receiving inadequate or no parenteral lipids (ILE or SMOF).	Provision of at least 50 g of intralipids twice weekly or, alternatively, 100 g once weekly if infusion limits allow. This translates to 250 ml of a 20% ILE over 10 to 12 hours twice weekly or 500 ml once weekly. SMOF or Clinolipid infused as 50 g, 3 times weekly
Immunosuppression	Activation of the arachidonic pathway and interference of phagocytosis and chemotaxis, by the 18 carbon omega-6 fatty acid preparation of ILE (ie, linoleic acid). Results in increased risk of infection.	Use of alternative oil–based ILEs, such as SMOF lipids, due to their demonstrating fewer proinflammatory and immunosuppressive properties. Withholding of soy-based ILEs in critically ill patients for the first week of PN infusion.
Elevated TG	Overinfusion of dextrose and/or rapid administration of ILE. Underlying disease process, such as liver disease or pancreatic dysfunction.	Target euglycemia. Reducing the dose of substrates and/or lengthening infusion times. Keep ILE or SMOF < 0.11 g/kg/hr. If serum TG > 400, consider reduction of infusion and discontinuation with TG > 1000.
Azotemia	Excessive amino acid provision, dehydration, and/or inadequate provision of nonprotein calories, resulting in increased demand of disposing the byproducts of the protein metabolism.	Adequate nonprotein calorie provision, reduction in amino acids (if clinically appropriate), and provision of adequate hydration for renal clearance.
Adverse reactions to lipid emulsions	Incidence of complications are low; however, the potential for allergic reactions to the egg, soy-based properties of ILE, and seafood components of SMOF are present.	Withholding lipids in the presence of known allergies unless the benefits outweigh the risks. Follow package insert recommendations on trialing dose.
Vitamin deficiencies or toxicity	GI and fluid losses, blood loss, or drug or nutrient interactions. Most common: B12, folate deficiencies in CD and ileal resections, along with the use of methotrexate and sulfasalazine. Iron in IBD is secondary to blood loss. Fat-soluble vitamins surrounding malabsorption and poor oral intake. Toxicities are more common in fat-soluble vitamins, particularly in those with renal function impairment.	Adult patients on PN should receive a standard, daily dose of parenteral multivitamins. 50–100 mg of thiamine and 1 mg of folic acid, in addition to PN multivitamin products, are recommended in those with pre-existing malnutrition and/or those at risk for malnutrition. IM B12 and or IV folate may be necessary as separate provisions. Parenteral iron is incompatible with PN formulations, and thus must be infused separately.
Mineral deficiencies or toxicity	GI fluid losses, poor intake. In CD: zinc deficiency is most common surrounding GI losses, while copper deficiency is more prevalent in those receiving excessive zinc supplementation. Toxicity: trace element products may exceed actual requirements, with contamination of PN components during manufacturing. Manganese, copper, and chromium are most common in long-term PN patients, nor is aluminum.	Adult patients should receive standard trace element products. Reduction of copper and manganese in patients with hepatobiliary disease, secondary to impaired excretion. Provision of chromium and/or manganese-free PN formulations are often necessary in long-term PN patients to minimize the risk of toxicity.
Metabolic bone disease	Corticosteroid use, inflammatory cytokines, and malabsorption.	CD and UC: 1500 mg elemental calcium 800–1000 IU vitamin D

Abbreviations: BG, blood glucose; CD, Crohn’s disease; EN, enteral nutrition; GI, gastrointestinal; IBD, inflammatory bowel diseases; ILE, intralipid emulsion; IM, intramuscular; IV, intravenous; PN, parenteral nutrition; TG, triglycerides; TPN, total parenteral nutrition; UC, ulcerative colitis.

PN-Related Mechanical and Vascular Complications

Mechanical damage to the tissues directly from the catheter used for administration of PN may occur. Caution to avoid pneumothorax and chylothorax should be considered during catheter placement.⁹ Other complications that may be encountered include deep venous thrombosis, mostly in the upper extremities; embolization; thrombosis of the subclavicular vein due to the catheter; superior vena cava syndrome; pulmonary embolism; and postthrombotic syndrome.^9,40,41 In cases of thrombosis, prompt use of anticoagulation and, if needed, replacement of central venous access to prevent progression of the thrombosis is recommended.⁴² Peripherally inserted central venous catheters (PICCs) are the most commonly used access device for TPN, although central vein catheters (CVCs), especially through the subclavian, are also frequently used. Studies have shown that CVCs are associated with lower risks of infection in long-term PN, but PICCs are more cost effective, safer to insert, and more accessible, making PICCs the most placed catheters for PN. Peripherally inserted central venous catheters lines can remain inserted for approximately 3 months. Risk of displacement of PICCs is always a concern.⁴³ Nonthrombotic occlusions are the leading cause of intraluminal occlusions associated with central access devices, generally as a result of drug-heparin interactions, PN formulations with inappropriate ratios of calcium to phosphate, and lipid residue.⁶ Lipids that lead to catheter occlusion by waxy deposits can be cleared by a 70% ethanol solution.⁴⁴

PN-Related Infectious Complications

Total PN is considered an independent risk factor for developing central line–associated bloodstream infections among hospitalized patients (odds ratio, 2.65).⁴⁵ This risk is increased with duration of use and other concomitant infections, like pneumonia.⁴⁵ A large, multicenter, randomized study showed that infections occur through contamination of the catheter hub, seeding the proteinaceous biofilm that accumulates on the internal surface of the catheter; although use of fibrinolytic agents like urokinase to remove this biofilm decreased rates of sepsis, infections still occur.⁴⁶ In 1 study, there were no differences in postoperative complications in patients with UC when line infections were excluded.⁴⁷ Replacement of the catheter may be necessary for severe sepsis, superficial thrombophlebitis, repeated positive blood cultures, and infections due to Staphylococcus aureus, Pseudomonas aeruginosa, fungi, or mycobacteria, Gram-negative bacilli, enterococci, and fungi.⁴⁸ A recent, retrospective cohort study comparing malnourished patients with CD who were receiving preoperative PN to those receiving no PN found that patients who received preoperative PN for ≥60 days had a significantly lower incidence of developing noninfectious complications within 30 days of surgery.⁴⁹ The study additionally did not observe any increases in infectious complications associated with PN support, and found that patients with CD receiving PN had comparable overall postoperative complications to controls, despite being identified as having more severe disease and malnutrition.⁴⁹ It is important to note that these results were novel, since they were able to observe benefits in postoperative outcomes, despite efforts to control for malnutrition and disease severity.

Misuse of PN

There is limited evidence surrounding the misuse of PN specific to patients with IBD. Most studies evaluating this have, however, defined inappropriate use of PN based on variance from ASPEN clinical guidelines. The misuse of PN in studies has been variable, with single-center studies reporting misuse rates ranging between 5% and 45%.^50,51 Clinical audits with the intent to utilize results as part of quality improvement plans are recommended to evaluate and address concerns surrounding the use and misuse of PN support.¹⁴ It is not uncommon in practice for perioperative PN support infusions to be requested for infusion lengths well under 7 days of infusion. Duration of PN use, however, should be at the forefront of discerning whether or not PN is indicated in those patients with IBD. Most expert consensus for PN infusion is that the benefits are often not observed until at least 7 days of infusion, particularly in cases where TPN is used. In a 1987 report of 14 randomized controlled trials (RCTs) reviewing the benefits of PN versus no advanced nutrition support for patients undergoing elective surgery, positive outcomes were found in only 1 of the 14 trials included.⁵² Upon further review, it was noted that in 7 of the 14 RCTs, PN was provided for 7 days or less. A more detailed meta-analysis of 33 RCTs involving >2500 surgical patients showed a 10% reduction in the risk of postoperative complications and an absolute risk reduction from 40% to 30% in patients receiving perioperative PN compared with those receiving no advanced nutrition support therapies.⁵³ Although there was some overlap between the 2 reports, Klein et al.⁵³ were able to give more data, reviewing 8 studies not included in prior analyses. Upon review, the Klein et al.⁵³ report showed that in 13 out of the 14 studies that showed positive outcomes, PN was given for at least 7 days, with only 1 report providing PN for only 5–7 days. A more interesting finding from the meta-analysis by Klein et al.⁵³ was that the benefit of PN was lost if it was first initiated in the immediate postoperative period. This was the first study to formally recommend that if adequate nutrition through either oral or EN support is not feasible, surgery should be delayed for 7 to 10 days to allow for preoperative PN support optimization, specifically in patients with a gastrointestinal (GI) cancer.⁵³ Experts in the field adopted this recommendation and have incorporated this practice into enhanced recovery after surgery protocols. For patients requiring urgent surgery, it has been suggested that PN initiation be delayed for 5–7 days postoperatively due to increases in complications of up to 10% observed in those receiving PN immediately following surgery.⁵⁴ Of note, these studies were conducted in gastric cancer patients, and not patients with IBD. Braunschweig et al.³³ showed similar findings in a meta-analysis of 7 studies, comparing early PN in postcardiac surgical patients with no advanced nutrition support therapy. It was observed that those who received no advanced nutrition support showed better outcomes, with reductions in infectious complications by 23% and in overall complications by 13% (relative risk, 0.087; P < .10).³³ These findings have been further reinforced in a newer, 2011 the early parenteral nutrition completing enteral nutrition in adult critically ill patients (EPaNIC) study trial, showing improved outcomes in intensive care unit (ICU) patients when PN was delayed, with infectious complications decreasing from 40.2% in those receiving early PN on ICU day 3 to 29.9% in those receiving late PN on ICU day 8 (P = .01).⁵⁵ Reanalyses of the EPaNIC trial have demonstrated significant adverse effects with the use of PN outside of intestinal failure, and it has been suggested that the use of PN be tightly scrutinized in those patients undergoing elective surgeries.⁵⁵ It is recommended that clinicians closely follow ASPEN clinical guidelines as part of a decision tree to identify those patients in which PN support would be indicated. It is highly recommended and common for hospitals to have algorithms included in their PN support policies to assist with the decision-making on whether or not PN support is appropriate for use. Please see Figure 1 for an example algorithm for determining the appropriateness of PN support in patients with IBD that aligns with ASPEN clinical guidelines.

Figure 1.

Example decision tree to determine whether PN is indicated. ^A prolonged ileus is an ileus lasting longer than 7 to 10 days. *A GI fistula is a case in which EN support is unable to be placed proximal to the fistula or in which the volume of the fistula is >500 ml per day. Abbreviation: ASPEN, American Society of Parenteral and Enteral Nutrition; EN, enteral nutrition; GI, gastrointestinal; NPO, nil per os; PN, parenteral nutrition; PPN, prolonged parenteral nutrition; TPN, total parenteral nutrition; SBS, short bowel syndrome.

Contraindications of PN Use

The most notable contraindication for PN use is when the GI tract is functional and can be used. The desire for bowel rest, while notable in practice, is not based on science and often results in unnecessary risks associated with PN infusion. In a systematic review of RCTs evaluating the efficacy of PN support in patients with various disease states, including CD, there were insufficient data identified demonstrating that bowel rest was necessary to induce remission of CD.⁵⁶ Other reasonable contraindications for PN use are documented allergic reactions to the components of PN, like allergies to eggs and fish, since the lipids within PN contain traces of egg and other, newer formulations include fish or other preservatives as additives that may cause allergic reactions. In practice, this is considered a more relative contraindication that is dependent on the severity of the allergy. Trials of lipids at small doses have been successfully completed to rule out the need to unnecessarily avoid intravenous lipid emulsions. Severe electrolyte derangements must be corrected, and the patient must be hemodynamically stable before initiation of PN.

Composition of PN

Parenteral nutrition formulations include energy substrates, such as carbohydrates, proteins (as AAs), and fat, as well as electrolytes, vitamins, and trace elements. Sterile water for injection is also added to provide the necessary volume to the PN formulation. Table S1 includes a list of the commercially available electrolytes for parenteral use, and Table S2 includes the trace minerals for parenteral use. Parenteral nutrition can be provided via dextrose-AA formulations, in which lipids are infused separately, or total-nutrient admixtures (dextrose; AA and lipids in 1 bag) and can be either compounded to individually meet a patient’s needs or purchased as a standardized, premixed formulation. The combination of these components, when compounded and based on the patient’s individual requirements, as estimated by a Registered Dietitian, is most likely to meet a patient’s individualized needs, and thus is the preferred way to provide PN support. Table 3 lists the major ingredients found in PN, and Table 4 lists the commercially available parenteral multivitamin products for adults.

Table 3.

Major PN composition.^a

Additive	Description or available concentrations	Notations or limitations	kcals/g
Carbohydrates	2.5%–70% dextrose or most commercially available energy substrates	Acidic, varying osmolarity dependent on concentration. High concentrations > 10% reserved for CPN due to the potential of thrombophlebitis in peripheral veins.	3.4 kcal/g
Proteins	3.5%–20% crystalline AA source. Available in standard, balanced AA stock solutions. Mixture of both essential and nonessential AAs.	Osmolarity limitations with PPN due to the potential for thrombophlebitis in peripheral veins. Disease-specific formulations are expensive and lack solid evidence for their use. There is no IBD-specific formulation.	4 kcal/g
Fats	ILE: There 4 commercially available ILE products in the United States. Two contain all long-chain triglycerides composed of 100% soybean oil and 1 contains a 50:50 blend of safflower oil and soybean oil. SMOF lipid is a newer product to the US market containing soybean oil, MCT oil, olive oil, and fish oil. It was developed out of concerns regarding the high content of proinflammatory omega-6 polyunsaturated fatty acids found in traditional ILE products. This newer ILE product capitalizes on the beneficial attributes of oils from nonsoybean oil sources while reducing the proinflammatory effects of the omega-6 fatty acids.	Stability challenges in total nutrient admixtures and infusion limitations in infusion schedules. ILE cannot be infused separately for longer than 12 hours due to the risks of bacterial growth and line infection. Relatively contraindicated in the presence of an allergy or hypersensitivity to egg, fish, soy, and/or peanut protein.	10 kcal/g
Sterile water	Sterile water, added for volume and hydration	Volume limitations in the setting of multiple IV infusions (critical care setting), renal dysfunction, or poor quality venous access.	NA

Abbreviations: AA, amino acid; CPN, central parenteral nutrition; ILE, injectable lipid emulsions; IV, intravenous; NA, not applicable; PN, parenteral nutrition; PPN, peripheral parenteral nutrition.

Table 4.

Commercially available parenteral multivitamin products for adults (IBD and non-IBD).^a

Vitamin	Dose available per 10 ml
Fat-soluble vitamins
Vitamin A (retinol)	1 mg (330 USP units)
Vitamin D (ergocalciferol or cholecalciferol)	5 mcg (200 USP units)
Vitamin E (dl-alpha tocopheryl acetate)	10 mg (10 USP units)
Vitamin K (phytonadione)	150 mcg
Water-soluble vitamins
Vitamin B1 (thiamin)	6 mg (available in additional 100-mg infusions)
Vitamin B2 (riboflavin 5-phosphate sodium)	3.6 mg
Vitamin B6 (pyridoxine HCl)	6 mg
Niacinamide	40 mg
Dexpanthenol (d- panthothenyl alcohol)	15 mg
Biotin	60 mcg
Folic acid	600 mcg (available in additional 1-mg infusions)
Vitamin B12 (cyanocobalamin)	5 mcg
Vitamin C (ascorbic acid)	200 mg

Abbreviations: IBD, inflammatory bowel diseases; USP, United States Pharmacopeia.

Carbohydrate

The most common commercially available energy substrate for carbohydrates is dextrose. It can be added in concentrations ranging from 2.5% to 70%. Dextrose solutions are considered acidic, with pH values ranging from 3.5 to 6.5, with varying osmolarities dependent on the concentration. Higher concentrations (>10%) are generally reserved for central venous infusion due to their potential to cause thrombophlebitis in peripheral veins. Dextrose solutions provide 3.4 kcal/g.

Protein

Crystalline AAs are the protein source used in PN formulations. They are available in standard, balanced, AA stock solutions with concentrations ranging from 3.5% to 20%. The products are mixtures of both essential and nonessential AAs. While there are commercially available formulations for specific disease states, these are generally reserved for patients meeting their intended indications and are notably more expensive than standard formulations. There is no disease-specific AA product for IBD. Amino acids provide 4 kcal/g.

Lipid Injectable Emulsions

Fatty acid sources of PN formulations are commonly referred to as intralipid emulsions (ILEs). These are generally used to provide energy and promote euglycemia, as well as prevent EFAD. There are 4 types of commercially available ILE products in the United States. Two of these products contain all long-chain triglycerides composed of 100% soybean oil, and 1 contains a 50:50 blend of safflower oil and soybean oil. SMOF lipid and Clinolipid are newer products to the US market, with SMOF containing soybean oil, medium chain triglyceride (MCT) oil, olive oil, and fish oil, and Clinolipid containing soybean and olive oil. They were developed out of concerns regarding the high content of proinflammatory omega-6 polyunsaturated fatty acids found in traditional ILE products. These newer ILE products capitalize on the beneficial attributes of oils from nonsoybean oil sources, while reducing the proinflammatory effects of the omega-6 fatty acids. While they are preferred for nutrition support by clinicians in patients with IBD and in patients with gastrointestinal surgeries, due to the perceived benefits from the lower phytosterol content and anti-inflammatory omega-3 fatty acids, they are contraindicated in patients with known hypersensitivity to soybean, fish, egg, or peanut protein.^6,57 Lipid emulsions provide 10 kcal/g, and have safety limitations of infusing over 12 hours when administered separate from the PN formulation, as it is considered a vector for infection.

PN Composition for Patients with IBD

Although there is no single compositional recipe recommended for all patients with IBD, the composition of PN for these patients should ensure the provision of adequate energy and protein to support their metabolic needs, as well as to replenish losses of fluids and electrolytes. While resting energy expenditure is elevated during active inflammation of CD, the total energy expenditure is not significantly impacted.⁵⁸ Common ways to estimate energy needs for patients include indirect calorimetry, standardized equations such as the Mifflin St. Jeor, and/or short-hand equation to either maintain (20–25 kcal/kg) or gain weight (25–40 kcal/kg), if indicated.⁶ While indirect calorimetry is the gold standard for estimating energy needs, it is often costly and not realistic for most health-care settings. Protein requirements may be elevated in CD patients because of increased intestinal inflammation or fistulae, postoperative wound healing needs, and short bowel syndrome. Protein recommendations for patients with CD are generally 1 to 1.5 g/kg,⁶ although no RCTs have investigated the optimal protein intake in this population.⁵⁹ There is limited evidence to support a substantial increase in resting or total energy expenditure with UC in the absence of malnutrition; however, the protein needs are increased during active disease due to high protein turnover and increased losses equivalent to those of active CD.^2,6 Fluid needs are estimated using either 1 ml per kcal provided, weight-based equations such as 25 to 35 ml per kg, and/or the Holliday-Segar Formula: 1500 ml for the first 20 kg of body weight plus 20 ml per kg of remaining body weight.⁶ While there are no specific guidelines for electrolyte repletion in patients with IBD, clinicians can often predict needs based on a thorough history and evaluation of the overall care plan. Malnourished patients who are at risk for refeeding syndrome, for instance, have a high probability of needing aggressive repletion of phosphorus, potassium, and magnesium, so nutrition support clinicians, generally Registered Dietitians and/or Pharmacists with training in PN management, will closely watch and tightly replete these electrolytes. If these are too low for repletion in the PN formulation, additional repletion may be necessary at times. Repletion of GI losses in the patient with IBD should be prioritized, keeping in mind the amount of volume, as well as the electrolyte composition of the fluid lost. A good example is when a patient with IBD presents with a high-ileostomy output; the practitioner would anticipate the need to replace more sodium and chloride compared to in patients with a high-colostomy output. If the output is chronically high, such as with short bowel syndrome, patients often require additional IV hydration and electrolyte repletion outside of the compounding limits of PN support.⁶ If a patient requires long-term home PN support, please refer to Table 5 which provides detailed recommendations for monitoring the long-term home PN patient.

Table 5.

Home PN monitoring.^a

Lab or test	Frequency
Standard labs: BMP, MG, Phos, Hepatic function panel, plasma proteins, CBC	Acute care: daily until stable; every 12 hours if there is a high risk for refeeding syndrome. Home PN: 1–2 times weekly × 4 weeks until stable. Once per month thereafter.
Trace elements, vitamins, phospholipid fatty acid profile (Triene:Tetraene ratio)	Every 3 to 6 months, with more frequency if there is concern for deficiency or toxicity
Bone mineral density tests	Annually
Provider assessment
RD and MD or CNSC or APP assessing: oral or enteral intake; fluid balance; labs; weight changes; NFPA; appropriateness of PN prescription; and/or continued need of PN	1 month after discharge with home PN, then every 3–6 months per clinician discretion

Abbreviations: APP, Advanced-Practice Provider; BMP, basic metabolic panel; CBC, complete blood cell; CNSC, Certified Nutrition Support Clinician; MD, Medical Doctor; MG, magnesium; NFPA, Nutrition-Focused Physical Exam; Phos, phosphorus; PN, parenteral nutrition; RD, Registered Dietitian.

Conclusions

Malnutrition among patients with IBD is an underrecognized problem that greatly impacts the response to medical therapy, surgical outcomes, and overall quality of life. Enteral nutrition is the preferred route for nutrition optimization but, in certain situations, PN is favored, especially in patients with short bowel syndrome, high-output gastrointestinal fistula, or complete small bowel obstruction. Parenteral nutrition is indicated if EN is not possible due to other reasons, such as ileus, intestinal ischemia and shock, or intestinal failure with high-ostomy output. It is extremely important that prescribing providers are aware of the indications and misuse of PN when committing patients to this route of nutrition. It is crucial for the prescribing team to monitor for PN-related complications and make appropriate changes as soon as any complications arise.