Nutritional Support

Number: 0061

(Replaces CPB 144)

 

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References


Policy

Scope of Policy

This Clinical Policy Bulletin addresses nutritional support.

  1. Notes

    1. For members with such a plan benefit, specific nutritional support is considered to be a medical item only when it is administered enterally (i.e., by feeding tube) or parenterally (i.e., by intravenous administration) where the member has either (a) a permanentFootnote1* visited non-function or disease of the structures that normally permit food to reach the small bowel; or (b) disease of the small bowel that impairs digestion and absorption of an oral diet, either of which requires enteral or parenteral feedings to provide sufficient nutrients to maintain weight and strength commensurate with the member's overall health status. 

      Not all benefit plans cover nutritional support even in the circumstances stated above. Please check benefit plan descriptions.

    2. Aetna does not cover nutritional support that is taken orally (i.e., by mouth), unless mandated by state law.  Oral nutrition is not considered a medical item.  See section on Special Medical Foods below.
    3. Regular food products are not considered medical items.  Regular food products include food thickeners, baby food, gluten-free food products, high protein powders and mixes, low carbohydrate diets, normal grocery items, nutritional supplement puddings, weight-loss foods and formula (products to aid weight loss), or other regular grocery products that can be mixed in blenders and used with an enteral system regardless of whether these regular food products are taken orally or parenterally.  
  2. Medical Necessity

    Determinants of the route of administration of nutritional support include the functional status of the gastrointestinal tract and the anticipated duration of therapy.

    1. Enteral Tube Feedings

      Enteral nutrition is the provision of nutritional requirements through a tube into the stomach or small intestine.

      The short-term methods of enteral tube feedings include nasogastric, nasoduodenal and, less frequently, nasojejunal tubes.  Long-term enteral feedings are best administered by a percutaneous gastrostomy or jejunostomy tube.

      Aetna considers enteral tube feedings medically necessary when the member has either (a) permanent Footnote1* non-function or disease of the structures that normally permit food to reach the small bowel; or (b) disease of the small bowel that impairs digestion and absorption of an oral diet, either of which requires tube feedings to provide sufficient nutrients to maintain weight and strength commensurate with the member's overall health status.

      The member's condition could be either an anatomic abnormality (e.g., obstruction due to head and neck cancer or reconstructive surgery, etc.) or a motility disorder (e.g., severe dysphagia following a stroke, neuromuscular or disease of the central nervous system that interferes with the ability to chew or swallow, etc.).  Enteral nutrition is not considered medically necessary for members with a functioning gastrointestinal tract whose need for enteral nutrition is due to reasons such as anorexia or nausea associated with mood disorder, end-stage disease, etc.

      The member must require tube feedings to maintain weight and strength commensurate with the member's overall health status.  Adequate nutrition must not be possible by dietary adjustment and/or oral supplements.  Enteral nutrition may be considered medically necessary for members with partial impairments (e.g., a member with dysphagia who can swallow small amounts of food or a member with Crohn's disease who requires prolonged infusion of enteral nutrients to overcome a problem with absorption).

      Note: Enteral nutrition products that are administered orally and related supplies are not covered.

      Footnote1*Note: The member must have a permanent impairment. Permanence does not require a determination that there is no possibility that the member's condition may improve sometime in the future.  If the judgment of the doctor, substantiated in the medical record, is that the impairment can reasonably be expected to exceed 3 months (90 days), the test of permanence is considered met.  This is consistent with Center for Medicare and Medicaid Services (CMS) guidelines.

      Formulas consisting of semi-synthetic intact proteins or protein isolates (e.g., Enrich, Ensure, Ensure HN, Ensure Powder, Isocal, Lonalac Powder, Meritene, Meritene Powder, Osmolite, Osmolite HN, Portagen Powder, Renu, Sustacal, Sustagen Powder, Travasorb) are considered medically necessary for enteral feeding of the majority of older members who meet criteria for enteral feeding.  Formulas consisting of natural intact proteins or protein isolates (e.g., Compleat B, Compleat B Modified, Vitaneed) are considered medically necessary for enteral feeding of members with an allergy or intolerance to semi-synthetic formulas.  Calorically dense formulas are also considered medically necessary for enteral feedings if they are indicated.  The medical necessity for special formulas for enteral feedings must be justified in each member.

      Infant Formula

      Note: Infant formulas  are only covered if administered via the tube-feeding route and the criteria for coverage of enteral feedings are met.  Infant formulas given orally are not covered.  In addition, breast milk additive to prevent necrotizing enterocolitis in premature infants is only covered if administered via the tube-feeding route and the criteria for coverage of enteral feedings are met.

      Equipment

      Appropriate nutrients, administration supplies, and equipment are considered medically necessary for persons who meet criteria for enteral feedings.  Tube feedings are usually given by gravity feedings or syringe.  Pumps are considered medically necessary durable medical equipment (DME) only where gravity feedings or syringe feedings have caused complications or are otherwise not indicated (e.g., gravity feeding is not satisfactory due to reflux and/or aspiration, severe diarrhea, dumping syndrome, administration rate less than 100 ml/hr, blood glucose fluctuations, circulatory overload, gastrostomy/jejunostomy tube used for feeding).  More than 3 nasogastric tubes or 1 gastrostomy/jejunostomy tube every 3 months is rarely considered medically necessary.

      Note: Some Aetna plans exclude coverage of DME and supplies.  Please check benefit plan descriptions.

    2. Relizorb

      Aetna considers in-line digestive enzyme cartridges (e.g. Relizorb, Alcresta Pharmaceuticals) which connect to enteral feeding tubes for hydrolysis (digestion) of fats in enteral formula, medically necessary for persons diagnosed with exocrine pancreatic insufficiency (such as due to complications of diabetes, cystic fibrosis, pancreatitis, pancreatectomy, celiac disease, Crohn’s disease, ulcerative colitis, or congenital malformations of the pancreas) who meet criteria for enteral nutrition. More than two in-line digestive enzyme cartridges per day are considered not medically necessary. 

    3. Parenteral Nutrition/Total Parenteral Nutrition (TPN)

      Parenteral nutrition involves the delivery of micronutrients and macronutrients through catheters in central or peripheral veins.  In most instances, the central venous route is utilized; for long-term total parenteral nutrition (TPN), a central catheter (e.g., Hickman, Broviac, PIC) is burrowed through a subcutaneous tunnel on the anterior chest.

      Generally, the parenteral approach is considered medically necessary only if adequate nutritional intake is not possible via the oral or tube-feeding route.

      1. Aetna considers parenteral nutrition medically necessary for members who meet any of the following criteria:

        1. Documentation of a failure of enteral (i.e., oral or tube feeding) nutrition, as defined by either of the following:

          1. A non-edematous or post-dialysis documented loss of greater than 10 % of body weight over a 3-month period; or
          2. Total protein less than 6 g/dL or serum albumin less than 3.4 g/dL;
        2. A condition in which it is necessary for the gastrointestinal tract to be totally non-functioning for a period of time;
        3. Evidence of structural or functional bowel disease that makes oral and tube feedings inappropriate;
        4. Hyperemesis gravidarum (only in cases of failed medical management or when used in a step-therapy program);
        5. Member is peri-operative (regardless of disease state) and unable to tolerate oral or tube feedings.
      2. Parenteral nutrition may be either “self-mixed” (i.e., the member or family caregiver is taught to prepare the nutrient solution aseptically) or “pre-mixed”. The doctor must justify the need for pre-mixed parenteral nutritional solutions.
      3. Parenteral nutrition is not considered medically necessary for members with a functioning gastrointestinal tract whose need for parenteral nutrition is only due to:

        1. A physical disorder impairing food intake such as the dyspnea of severe pulmonary or cardiac disease;
        2. A psychological disorder impairing food intake such as depression;
        3. A side effect of a medication;
        4. A swallowing disorder;
        5. A temporary defect in gastric emptying such as a metabolic or electrolyte disorder;
        6. Disorders inducing anorexia such as cancer;
        7. Renal failure and/or dialysis.Footnote1* Members receiving intra-dialytic parenteral nutrition must meet the criteria for total parenteral nutrition set forth above.
      4. Aetna considers intra-peritoneal nutrition experimental, investigational, or unproven; however, intra-peritoneal amino acid (IPAA) supplementation is considered medically necessary for members on peritoneal dialysis when all of the following criteria are met:

        1. Inability to administer or tolerate adequate oral protein nutrition, including food supplements, or enteral tube feeding; and
        2. The combination of some oral or enteral intake that, when combined with IPAA, will meet the individual's nutritional goals; and
        3. There is evidence of inadequate dietary protein intake and protein malnutrition.
      5. Equipment

        If the criteria for parenteral nutrition are met, medically necessary nutrients, administration supplies, and equipment are considered medically necessary.

    4. Special Medical Foods Taken Orally

      Note: Aetna covers special medical foods only when mandated by state law.

      Special medical foods are used for the treatment of inborn errors of metabolism (histidinemia, homocystinuria, maple syrup urine disease [MSUD], phenylketonuria [PKU], and tyrosinemia).  The special oral formulas are designed to restrict intake of one or more amino acids.  Some states now have mandates requiring coverage of these dietary formulas.

      Aetna does not cover banked breast milk, food supplements, specialized infant formulas, vitamins and/or minerals taken orally (i.e., by mouth).

      Food supplements, specialized infant formulas (e.g., Alimentum, Elecare, Neocate, and Nutramigen), lactose-free foods, vitamins and/or minerals may be used to replace intolerable foods, for lactose intolerance, to supplement a deficient diet, or to provide alternative nutrition in the presence of such conditions as allergies, gastrointestinal disorders, hypoglycemia, and obesity.  Food supplements, lactose-free foods, specialized infant formulas, vitamins and/or minerals taken orally are not covered, even if they are required to maintain weight or strength and regardless of whether these are prescribed by a physician.

      Most Aetna plans do not specifically include coverage of infant formulas when taken orally.  In the absence of a specific inclusion or state mandate, specialized infant formulas are not covered.

  3. Experimental, Investigational, or Unproven

    Aetna considers the following nutritional support (not an all-inclusive list) experimental, investigational, or unproven because of insufficient evidence in the peer-reviewed literature:

    1. Levocarnitine supplementation to total parenteral nutrition;
    2. Use of infusion of levocarnitine as a part of total parenteral nutrition therapy in persons without primary or secondary carnitine deficiency or end-stage renal disease on hemodialysis because the clinical value of this approach has not been established;
    3. Enteral nutrition / enteral feeding

      1. Enteral nutrition for induction and maintenance of remission in adults with Crohn's disease
      2. Enteral nutrition for the treatment of eating disorders (except in life-saving cases of severe cases of anorexia nervosa)
      3. Enteral lactoferrin supplementation for prevention of sepsis and necrotizing enterocolitis in preterm infants;
    4. Percutaneous ultrasound gastrostomy for gastrostomy tube insertion;
    5. Relizorb (digestive enzyme cartridge) for the treatment of malabsorption related to graft-versus-host disease.

Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code Code Description

CPT codes covered if selection criteria are met:

99507 Home visit for care and maintenance of catheter(s) (e.g., urinary, drainage, and enteral)
99601 Home infusion/specialty drug administration, per visit (up to 2 hours)
+ 99602     each additional hour (List separately in addition to code for primary procedure)

Other CPT codes related to the CPB:

36555 - 36571 Insertion of central venous catheter
43246 Upper gastrointestinal endoscopy including esophagus, stomach, and either the duodenum and/or jejunum as appropriate; with directed placement of percutaneous gastrostomy tube
43510 Gastrotomy; with esophageal dilation and insertion of permanent intraluminal tube (e.g., Celestin or Mousseaux-Barbin)
43653 Laparoscopy, surgical; gastrostomy, without construction of gastric tube (e.g., Stamm procedure) (separate procedure)
43752 Naso- or oro-gastric tube placement, requiring physician's skill and fluoroscopic guidance (includes fluoroscopy, image documentation and report)
43762 - 43763 Replacement of gastrostomy tube, percutaneous, includes removal, when performed, without imaging or endoscopic guidance
43761 Repositioning of the gastric feeding tube, through the duodenum for enteric nutrition
43810 - 43832 Gastroduodenostomy, gastrojejunostomy; without vagotomy, with vagotomy, any type, gastrostomy, open; without construction of gastric tube (e.g., Stamm procedure) (separate procedure), neonatal, for feeding, or with construction of gastric tube (e.g., Janeway procedure)
+ 44015 Tube or needle catheter jejunostomy for enteral alimentation, intraoperative, any method (List separately in addition to primary procedure)
44372 Small intestinal endoscopy, enteroscopy beyond second portion of duodenum, not including ileum; with placement of percutaneous jejunostomy tube
44373     with conversion of percutaneous gastrostomy tube to percutaneous jejunostomy tube
44500 Introduction of long gastrointestinal tube (e.g., Miller-Abbott) (separate procedure)
48140 Pancreatectomy, distal subtotal, with or without splenectomy; without pancreatojejunostomy
49440 Insertion of gastrostomy tube, percutaneous, under fluoroscopic guidance including contrast injection(s), image documentation and report
49441 Insertion of duodenostomy or jejunostomy tube, percutaneous, under fluoroscopic guidance including contrast injection(s), image documentation and report
49446 Conversion of gastrostomy tube to gastro-jejunostomy tube, percutaneous, under fluoroscopic guidance including contrast injection(s), image documentation and report
49450 Replacement of gastrostomy or cecostomy (or other colonic) tube, percutaneous, under fluoroscopic guidance including contrast injection(s), image documentation and report
49451 Replacement of duodenostomy or jejunostomy tube, percutaneous, under fluoroscopic guidance including contrast injection(s), image documentation and report
49452 Replacement of gastro-jejunostomy tube, percutaneous, under fluoroscopic guidance including contrast injection(s), image documentation and report
74340 Introduction of long gastrointestinal tube (eg, Miller-Abbott), including multiple fluoroscopies and images, radiological supervision and interpretation

HCPCS codes covered if selection criteria are met:

Enteral lactoferrin supplementation – no specific code:

B4034 - B4083, B4102 - B9999 Enteral and Parenteral Therapy (except food thickener)
B4087 Gastrostomy/jejunostomy tube, standard, any material, any type, each
B4088 Gastrostomy/jejunostomy tube, low-profile, any material, any type, each
B4102 Enteral formula, for adults, used to replace fluids and electrolytes (e.g., clear liquids), 500 ml= 1 unit
B4103 Enteral formula, for pediatrics, used to replace fluids and electrolytes (e.g., clear liquids), 500 ml = 1 unit
B4104 Additive for enteral formula (e.g., fiber)
B4105 In-line cartridge containing digestive enzyme(s) for enteral feeding, each
B4149 Enteral formula, manufactured blenderized natural foods with intact nutrients, includes proteins, fats, carbohydrates, vitamins and minerals, may include fiber, administered through an enteral feeding tube, 100 calories = 1 unit
S5497 Home infusion therapy, catheter care/ maintenance, not otherwise classified; includes administrative services, professional pharmacy services, care coordination, and all necessary supplies and equipment (drugs and nursing visits coded separately), per diem
S5498 Home infusion therapy, catheter care/ maintenance, simple (single lumen), includes administrative services, professional pharmacy services, care coordination, and all necessary supplies and equipment (drugs and nursing visits coded separately), per diem
S5501 Home infusion therapy, catheter care/ maintenance, complex (more than one lumen), includes administrative services, professional pharmacy services, care coordination, and all necessary supplies and equipment (drugs and nursing visits coded separately), per diem
S5502 Home infusion therapy, catheter care/ maintenance, implanted access device, includes administrative services, professional pharmacy services, care coordination, and all necessary supplies and equipment (drugs and nursing visits coded separately), per diem (use this code for interim maintenance of vascular access not currently in use)
S5517 Home infusion therapy, all supplies necessary for restoration of catheter patency or declotting
S5518 Home infusion therapy, all supplies necessary for catheter repair
S5520 Home infusion therapy, all supplies (including catheter) necessary for a peripherally inserted central venous catheter (PICC) line insertion
S5521 Home infusion therapy, all supplies (including catheter) necessary for a midline catheter insertion
S5522 Home infusion therapy, insertion of peripherally inserted central venous catheter (PICC), nursing services only (no supplies or catheter included)
S5523 Home infusion therapy, insertion of midline central catheter, nursing services only (no supplies or catheter included)
S9342 Home therapy; enteral nutrition via pump; administrative services, professional pharmacy services, care coordination, and all necessary supplies and equipment (enteral formula and nursing visits coded separately), per diem
S9343 Home therapy; enteral nutrition via bolus; administrative services, professional pharmacy services, care coordination, and all necessary supplies and equipment (enteral formula and nursing visits coded separately), per diem
S9364 Home infusion therapy, total parenteral nutrition (TPN); administrative services, professional pharmacy services, care coordination, and all necessary supplies and equipment including standard TPN formula (lipids, specialty amino acid formulas, drugs other than in standard formula and nursing visits coded separately), per diem
S9365 Home infusion therapy, total parenteral nutrition (TPN); 1 liter per day, administrative services, professional pharmacy services, care coordination, and all necessary supplies and equipment including standard TPN formula (lipids, specialty amino acid formulas, drugs other than in standard formula and nursing visits coded separately), per diem
S9366 Home infusion therapy, total parenteral nutrition (TPN); more than 1 liter but no more than 2 liters per day, administrative services, professional pharmacy services, care coordination, and all necessary supplies and equipment including standard TPN formula (lipids, specialty amino acid formulas, drugs other than in standard formula and nursing visits coded separately), per diem
S9367 Home infusion therapy, total parenteral nutrition (TPN); more than 2 liters but no more than 3 liters per day, administrative services, professional pharmacy services, care coordination, and all necessary supplies and equipment including standard TPN formula (lipids, specialty amino acid formulas, drugs other than in standard formula and nursing visits coded separately), per diem
S9368 Home infusion therapy, total parenteral nutrition (TPN); more than 3 liters per day, administrative services, professional pharmacy services, care coordination, and all necessary supplies and equipment including standard TPN formula (lipids, specialty amino acid formulas, drugs other than in standard formula and nursing visits coded separately), per diem

HCPCS codes not covered for indications listed in the CPB:

A9152 Single vitamin/mineral/trace element, oral, per dose, not otherwise specified
A9153 Multiple vitamins, with or without minerals and trace elements, oral, per dose, not otherwise specified
B4100 Food thickener, administered orally, per oz

Other HCPCS codes related to the CPB:

S9123 Nursing care, in the home; by registered nurse, per hour (use for general nursing care only, not to be used when CPT codes 99500-99600 can be used)
S9124 Nursing care, in the home; by licensed practical nurse, per hour
S9432 Medical foods for non-inborn errors of metabolism
S9433 Medical food nutritionally complete, administered orally, providing 100% of nutritional intake
S9434 Modified solid food supplements for inborn errors of metabolism
S9435 Medical foods for inborn errors of metabolism
S9810 Home therapy; professional pharmacy services for provision of infusion, specialty drug administration, and / or disease state management, not otherwise classified, per hour (do not use this code with any per diem code)

ICD-10 codes covered if selection criteria are met (not all inclusive):

C00.0 - C21.8 Malignant neoplasm of lip, oral cavity, pharynx, esophagus, stomach, small intestine, colon, rectosigmoid junction, rectum, anus and anal canal
C76.0 Malignant neoplasm of head, face and neck
E08.00 – E13.9 Diabetes mellitus
E40, E41, E42, E43 Kwashiorkor, nutritional marasmus, marasmic kwashiokor and unspecified severe protein-calorie malnutrition
E44.0 - E44.1 Protein-calorie malnutrition of moderate and mild degree
E45 Retarded development following protein-calorie malnutrition
E46 Unspecified protein-calorie malnutrition
E84.0 - E84.9 Cystic fibrosis
I69.091
I69.191
I69.291
I69.391
I69.891
I69.991
Sequelae of cerebrovascular disease [dysphagia]
K22.4 Dyskinesia of esophagus
K50.00 – K50.919 Crohn’s disease
K51.00 – K51.319 Ulcerative colitis
K85.00 – K85.92 Acute pancreatitis
K86.81 Exocrine pancreatic insufficiency
K90.0 – K90.9 Celiac disease
O21.0 Mild hyperemesis gravidarum
O21.1 Hyperemesis gravidarum with metabolic disturbance
O21.2 Late vomiting of pregnancy
O21.8 Other vomiting complicating pregnancy
O21.9 Vomiting of pregnancy, unspecified
Q45.3 Other congenital malformations of pancreas and pancreatic duct
R13.0 - R13.19 Aphagia and dysphagia
Z93.1 Gastrostomy status
Z93.4 Other artificial openings of gastrointestinal tract status

ICD-10 codes not covered for indications listed in the CPB:

A40.0 - A40.9 Streptococcal sepsis [prevention of sepsis]
A41.9 Sepsis, unspecified organism [prevention of sepsis]
F01.50 - F80.2
F80.4 - F84.0
F84.3 - F99
Mental and behavioral disorders
K50.00 - K50.919 Crohn's disease
K55.30 Necrotizing enterocolitis, unspecified [prevention of necrotizing enterocolitis]
K55.31 Stage 1 necrotizing enterocolitis [prevention of necrotizing enterocolitis]
K55.32 Stage 2 necrotizing enterocolitis [prevention of necrotizing enterocolitis]
K55.33 Stage 3 necrotizing enterocolitis [prevention of necrotizing enterocolitis]
N17.0 - N19 Acute kidney failure and chronic kidney disease
Z99.2 Dependence on renal dialysis

Carnitine/Levocarnitine:

CPT codes covered if selection criteria are met:

99507 Home visit for care and maintenance of catheter(s) (e.g., urinary, drainage, and enteral)
99601 Home infusion/specialty drug administration, per visit (up to 2 hours)
99602      each additional hour (List separately in addition to code for primary procedure)

HCPCS codes covered if selection criteria are met:

J1955 Injection, levocarnitine, per 1 gm

Other HCPCS codes related to the CPB:

S9364 Home infusion therapy, total parenteral nutrition (TPN); administrative services, professional pharmacy services, care coordination, and all necessary supplies and equipment including standard TPN formula (lipids, specialty amino acid formulas, drugs other than in standard formula and nursing visits coded separately), per diem
S9365      1 liter per day, administrative services, professional pharmacy services, care coordination, and all necessary supplies and equipment including standard TPN formula (lipids, specialty amino acid formulas, drugs other than in standard formula and nursing visits coded separately), per diem
S9366      more than 1 liter but no more than 2 liters per day, administrative services, professional pharmacy services, care coordination, and all necessary supplies and equipment including standard TPN formula (lipids, specialty amino acid formulas, drugs other than in standard formula and nursing visits coded separately), per diem
S9367      more than 2 liters but no more than 3 liters per day, administrative services, professional pharmacy services, care coordination, and all necessary supplies and equipment including standard TPN formula (lipids, specialty amino acid formulas, drugs other than in standard formula and nursing visits coded separately), per diem
S9368      more than 3 liters per day, administrative services, professional pharmacy services, care coordination, and all necessary supplies and equipment including standard TPN formula (lipids, specialty amino acid formulas, drugs other than in standard formula and nursing visits coded separately), per diem

ICD-10 codes covered if selection criteria are met (not all inclusive):

E71.40 Disorder of carnitine metabolism, unspecified
E71.41 Primary carnitine deficiency
E71.42 Carnitine deficiency due to inborn errors of metabolism
E71.43 Iatrogenic carnitine deficiency
E71.440 Ruvalcaba-Myhre-Smith syndrome
E71.448 Other secondary carnitine deficiency
N18.6 End stage renal disease
Z99.2 Dependence on renal dialysis

ICD-10 codes not covered for indications listed in the CPB:

D89.810 - D89.813 Graft-versus-host disease [Malabsorption]

Enteral lactoferrin supplementation:

HCPCS codes covered if selection criteria are met:

Enteral lactoferrin supplementation - no specific code:

ICD-10 codes not covered for indications listed in the CPB:

A40.0 - A40.9 Streptococcal sepsis [prevention of sepsis]
A41.9 Sepsis, unspecified organism [prevention of sepsis]
K55.30 Necrotizing enterocolitis, unspecified [prevention of necrotizing enterocolitis]
K55.31 Stage 1 necrotizing enterocolitis [prevention of necrotizing enterocolitis]
K55.32 Stage 2 necrotizing enterocolitis [prevention of necrotizing enterocolitis]
K55.33 Stage 3 necrotizing enterocolitis [prevention of necrotizing enterocolitis]

Background

Parenteral nutrition involves the delivery of micronutrients and macronutrients through catheters in central or peripheral veins.  In most instances, the central venous route is utilized, and for long-term total parenteral nutrition a central catheter (e.g., Hickman, Broviac, PIC) is burrowed through a subcutaneous tunnel on the anterior chest.

Enteral nutrition can be administered via a small catheter placed through the nose into the stomach or by a surgically placed catheter into the stomach or intestines.  Enteral nutrition therapy may supplement protein and calories in a variety of situations where oral nutrition is not adequate, with the intention of providing part or all of the daily requirements.  Specialized diets for specific diseases or pathophysiologic situations may be administered via enteral nutrition.  These specialized diets may involve restricting a particular element of the diet (e.g., fat, lactose), adding a particular nutrient that may be required in larger amounts than are available from a regular diet (e.g., calcium, potassium), or altering the consistency of the diet (e.g., high-fiber, full-liquid).

The need for specialized foods is very common, and for most conditions, the specialized food is needed for the person's entire lifetime.  For example, in Europe and the United States, the prevalence of lactose intolerance is 7 to 20 % in Caucasians, and is as high as 80 to 95 % among Native Americans, 65 to 75 % among Africans and African Americans, and 50 % in Hispanics (Scrimshaw et al, 1988).  The prevalence exceeds 90 % in some populations in eastern Asia.

Another example of a common medical condition requiring a specialized diet is celiac disease (also called gluten-sensitive enteropathy and non-tropical sprue), with a prevalence of almost 1 % of the population (Fasano et al, 2003).  There are many other examples where specialized diets are prescribed, which could extend to specialized diets for hypertension, diabetes, or cardiovascular disease.

Aetna's policy on parenteral and enteral nutrition is similar to Medicare policy.  Medicare provides reimbursement under the part-B prosthetic-device benefit for parenteral and enteral nutrition.  Consistent with its policy of covering supplies necessary for use of prosthetics, Medicare will generally cover medically necessary supplies, equipment, and nutrients associated with parenteral and enteral nutrition if the coverage requirements for enteral or parenteral nutritional therapy are met under the prosthetic device benefit provision.

Sullivan et al (2010) evaluated the health benefits of an exclusively human milk-based diet compared with a diet of both human milk and bovine milk-based products in extremely premature infants.  Infants fed their own mothers' milk were randomized to 1 of 3 study groups.  Groups HM100 and HM40 received pasteurized donor human milk-based human milk fortifier (HMF) when the enteral intake was 100 and 40 ml/kg/day, respectively, and both groups received pasteurized donor human milk if no mother's milk was available.  Group BOV received bovine milk-based HMF when the enteral intake was 100 ml/kg/day and preterm formula if no mother's milk was available.  Outcomes included duration of parenteral nutrition, morbidity, and growth.  The 3 groups (total n = 207 infants) had similar baseline demographic variables, duration of parenteral nutrition, rates of late-onset sepsis, and growth.  The groups receiving an exclusively human milk diet had significantly lower rates of necrotizing enterocolitis (NEC; p = 0.02) and NEC requiring surgical intervention (p = 0.007).  The authors concluded that for extremely premature infants, an exclusively human milk-based diet is associated with significantly lower rates of NEC and surgical NEC when compared with a mother's milk-based diet that also includes bovine milk-based products.

Ganapathy et al (2012) evaluated the cost-effectiveness of a 100 % human milk-based diet composed of mother's milk fortified with a donor human milk-based HMF versus mother's milk fortified with bovine milk-based HMF to initiate enteral nutrition among extremely premature infants in the neonatal intensive care unit (NICU).  A net expected costs calculator was developed to compare the total NICU costs among extremely premature infants who were fed either a bovine milk-based HMF-fortified diet or a 100 % human milk-based diet, based on the previously observed risks of overall NEC and surgical NEC in a randomized controlled study that compared outcomes of these 2 feeding strategies among 207 very low birth-weight infants.  The average NICU costs for an extremely premature infant without NEC and the incremental costs due to medical and surgical NEC were derived from a separate analysis of hospital discharges in the state of California in 2007.  The sensitivity of cost-effectiveness results to the risks and costs of NEC and to prices of milk supplements was studied.  The adjusted incremental costs of medical NEC and surgical NEC over and above the average costs incurred for extremely premature infants without NEC, in 2011 US$, were $74,004 (95 % confidence interval [CI]: $47,051 to $100,957) and $198,040 (95 % CI: $159,261 to $236,819) per infant, respectively.  Extremely premature infants fed with 100 % human-milk based products had lower expected NICU length of stay and total expected costs of hospitalization, resulting in net direct savings of 3.9 NICU days and $8,167.17 (95 % CI: $4,405 to $11,930) per extremely premature infant (p < 0.0001).  Costs savings from the donor HMF strategy were sensitive to price and quantity of donor HMF, percentage reduction in risk of overall NEC and surgical NEC achieved, and incremental costs of surgical NEC.  The authors concluded that compared with feeding extremely premature infants with mother's milk fortified with bovine milk-based supplements, a 100 % human milk-based diet that includes mother's milk fortified with donor human milk-based HMF may result in potential net savings on medical care resources by preventing NEC.

Relizorb

Fat malabsorption is most common in individuals who cannot produce or secrete adequate amounts of digestive enzymes because of compromised pancreatic function. According to current United European Gastroenterology guidelines (Lohr, et al., 2018), "enteral nutrition is indicated with PERT [pancreatic enzyme replacement therapy] administered alongside where necessary (GRADE 2C, strong agreement)" in persons with pancreatic insufficiency who are unable to achieve adequate intake with oral nutrition.

There is little evidence to support how PERT is best administered and optimized in people with CF receiving enteral nutrition (van der Haak & Kench, 2017). In the absence of sufficient evidence, a number of techniques have been described including oral administration, PERT suspended in juice, PERT dissolved in bicarbonate and administered via an enteral feeding tube, and administration of crushed microspheres via an enteral feeding tube.

According to the manufacturer, Relizorb is considered a first of it's kind enzyme cartridge.  It is designed to mimic the action of pancreatic lipase for use in adults receiving enteral tube feedings (Medscape, 2015). Relizorb is an enzyme packed cartridge indicated for use in adults to hydrolyze fats in enteral formula. The cartridge fits in line with enteral feeding systems, and is connected between the infusion pump and the feeding tube. The active ingredient is the digestive enzyme lipase, attached to polymetric carriers together called iLipase. As the formula passes through Relizorb, it makes contact with the iLipase, and fats in the formula are modified to more absorbable forms prior to ingestion. It was cleared for marketing by the Food and Drug Administration (FDA) for this indication.  However, efficacy data are limited and Relizorb has not been compared to other methods of administration of PERT. Therefore, there is an insufficient evidence base to support its use at this time.

Schwarzenberg and associates (2016) stated that nutrition is integral to the care of individuals with cystic fibrosis (CF).  Better nutritional status is associated with improved pulmonary function.  In some individuals with CF, enteral tube feeding can be useful in achieving optimal nutritional status.  Current nutrition guidelines do not include detailed recommendations for enteral tube feeding.  The Cystic Fibrosis Foundation convened an expert panel to develop enteral tube feeding recommendations based on a systematic review of the evidence and expert opinion.  These guidelines addressed when to consider enteral tube feeding, assessment of confounding causes of poor nutrition in CF, preparation of the patient for placement of the enteral feeding tube, management of the tube after placement and education about enteral feeding.  These recommendations are intended to guide the CF care team, individuals with CF, and their families through the enteral tube feeding process.  The guideline stated that an inline cartridge enzyme (lipase) delivery system for enteral feeds was approved by the FDA for adults during the development of these guidelines; evaluation of its benefits and limits should be considered before use.

In a multi-center, randomized, double-blind, cross-over, open-label clinical trial, Freedman and colleagues (2017) evaluated the safety, tolerability, and fat absorption of a new in-line digestive cartridge (Relizorb) that hydrolyzes fat in enteral formula provided to patients with CF.  Plasma omega-3 fatty acid (FA) concentrations were measured and used as markers of fat absorption.  Gastro-intestinal symptoms were recorded to evaluate safety and tolerability.  Information regarding the effect of enteral nutrition (EN) on appetite and breakfast consumption was also collected.  Before study entry, participants had received EN for a mean of 6.6 years at a mean volume of approximately 800 ml, yet had a mean body mass index (BMI) of only 17.5 kg/m and omega-3 FA plasma concentrations were only 60 % of levels found in normal healthy subjects.  Compared with placebo, cartridge use resulted in a statistically significant 2.8-fold increase in plasma omega-3 FA concentrations.  There were no adverse experiences associated with cartridge use, and a decrease in the frequency and severity of most symptoms of malabsorption was observed with cartridge use.  Participants reported increased preservation of appetite and breakfast consumption with cartridge use compared with their pre-study regimen.  The authors concluded that the use of this in-line digestive cartridge was safe and well-tolerated, and resulted in significantly increased levels of plasma omega-3 FA used with enteral formula, suggesting an overall increased fat absorption. 

The authors of this manufacturer-sponsored study stated that the main drawback of this study was the small sample size (n = 34).  Despite the relatively small sample size, the study, however, included approximately 1 % of the population of patients with CF who receive EN.  In addition, the age range of the study population is representative of the population of patients with CF in the United States.  The authors stated that these study results should be generalizable to the larger population of patients with CF and exocrine pancreatic insufficiency who receive supplemental EN.  One author noted that (i) a recently approved in-line medical cartridge with immobilized lipase (Relizorb) hydrolyzes fats in enteral formulas just prior to delivery into the patient with an enteral feeding tube; and (ii) to eliminate the challenges of PERT administration, the Cystic Fibrosis Foundation indicates Relizorb may be used to deliver enteral formula in this population.

Freedman (2017) stated that patients with EPI have suboptimal secretion of pancreatic digestive enzymes and experience a range of clinical symptoms related to the malabsorption of fat.  In patients with EPI unable to meet their nutritional requirements, EN support is used to augment nutritional status.  In addition to protein and carbohydrate, EN formulas contain fats as a calorie source, as well as vitamins and minerals to help prevent nutritional deficiencies related to malabsorption.  Semi-elemental EN formulas are advantageous as they contain hydrolyzed protein, shorter chain carbohydrates, and may contain medium chain triglycerides as a fat source.  However, severely pancreatic insufficient patients may be unable to absorb complex long-chain triglycerides provided by EN formulas due to insufficient pancreatic lipase; replacement pancreatic enzyme products are recommended for these patients.  The author stated that currently, none of the FDA-approved PERT products are indicated for use in patients receiving EN and administration of enzymes by mixing into EN formula is not supported by guidelines as this route is associated with risks.  Relizorb (immobilized lipase) is a novel in-line digestive cartridge that has been designed to address the unmet need for PERT in patients receiving EN.  Relizorb efficacy and compatibility with a range of commercially available polymeric and semi-elemental formulas with varying nutrient, caloric content, and triglyceride chain lengths have been demonstrated.  In most formulas, Relizorb efficiently hydrolyzed greater than 90 % of fats within the formula into absorbable FAs and monoglycerides.

Freedman and colleagues (2018) noted that PI and malabsorption of fats lead to reduced caloric intake, inability to maintain weight, and increased GI symptoms; thus, EN is used in patients with CF and poor nutritional status. In an industry-sponsored study, these researchers evaluated safety, tolerability and improvement of FA status in red blood cell (RBC) membranes, a marker of long-term FA absorption, with an in-line digestive cartridge (Relizorb) that hydrolyzes fat in enteral formula.  Patients with CF receiving EN participated in a multi-center, 90-day open-label study during which Relizorb was used with overnight EN.  The primary end-point was change over time in RBC uptake of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA); GI symptoms were collected to evaluate safety and tolerability.  Several clinical and anthropometric parameters were also assessed throughout the study.  A total of 36 subjects completed the study with a mean age of 13.6 years, BMI of 17.7 and 6.2 years mean use of over-night EN.  Fat absorption significantly improved as shown by increased RBC levels of DHA+EPA, improved ω-6/ω-3 ratio, and increased plasma levels of DHA+EPA; Relizorb use was not associated with any unanticipated adverse events (AEs).  The authors concluded that this study established the safety and tolerability of Relizorb and showed its potential to normalize fat absorption, improve symptoms commonly associated with fat mal-absorption and enhance nutritional status in patients with CF receiving EN feedings.  They stated that this was the 1st prospective study to show EN can improve FA abnormalities in CF.  Since improvement in omega-3 levels has been shown to help pulmonary and inflammatory status as well as anthropometric parameters in CF, Relizorb may have important long-term therapeutic benefits in patients with CF.  Moreover, these investigators stated that it is not possible to draw definitive conclusions from the current and previous Relizorb studies regarding the influence of Relizorb use on changes in patient anthropometric measurements.

The authors stated that this study had several drawbacks.  It was a relatively small study (n = 36).  In addition, the study was strictly open-label and was not intended to compare outcomes between participants who did and did not use Relizorb.  Furthermore, other than enteral nutrition, dietary intake was not recorded during the study, limiting the ability to determine if oral caloric intake was adequate to lead to weight gain.  Additionally, the study may not have been long enough to observe an increase in body weight or BMI for patients in a relatively fat-starved condition.  Furthermore, because the current study did not measure body tissue composition, it is unknown whether subjects improved their tissue composition without changing body weight or size.  It may turn out that nutritional health may be more accurately measured using biomarkers other than the traditional body weight and BMI.  Body tissue composition, including fat mass, fat-free mass, and lean body mass may be more important to overall health than body size or mass.  It is likely that body tissue composition is an indirect measure of important cellular and molecular processes that may be directly measured using molecules such as long-chain polyunsaturated FAs (LCPUFAs), which are essential building blocks of cell membranes and play important roles in cell and tissue function throughout the body.

Sathe et al (2021) noted that pancreatic insufficiency occurs in most patients with CF contributing to malnutrition.  In the U.S., 3,600 patients with CF require enteral feeding (EF).  Oral pancreatic enzymes are commonly used with EF, despite not being designed or approved for this use.  An immobilized lipase cartridge (ILC) for extracorporeal digestion of EF was developed.  The sponsor provided it to patients via a structured program, which these researchers evaluated to assess the effectiveness of the ILC on nutritional status.  The program provided the ILC to patients prescribed the device while reimbursement efforts were ongoing.  Baseline anthropometric data were obtained and subsequent measurements of height, weight, and BMI were collected at 6 and 12 months.  Inclusion criteria were met by 100 patients (age = 0 to 45 years).  Over 12 months of use in patients greater than 2 years of age (n = 93), there were significant improvements observed in height and weight; z-scores with improvement trend was observed in BMI.  The frequency of achieving the 50th percentile increased steadily for weight and BMI from baseline to 12 months but not for height.  The authors concluded that this evaluation of a program to aid patient in gaining access to ILC showed that better growth was possible over standard of care (SOC).  The association of ILC use with significant improvements in anthropometric parameters over a 12-month period in patients with CF showed the effectiveness of ILC as rational enzyme therapy during EF.

Mielus et al (2022) stated that with increasing life expectancy of patients with CF, GI manifestations of the disease have been increasingly brought into focus.  These investigators carried out a systematic review of the PubMed database and ongoing phase-III clinical trials that aimed to summarize recent (published after June 1, 2016) studies reporting the effects of nutritional interventions on anthropometric measures (weight, height, and BMI) in patients with CF.  Two ongoing trials and 40 published studies (18 interventional and 22 observational) were identified.  Key findings supported the benefits of comprehensive, individualized nutritional plans, high-fat, high-calorie diet including high-quality carbohydrates, and enteric tube feeding (albeit the latter was derived from observational studies only).  In contrast, the supplementation of probiotics, lipids, docosahexaenoic, glutathione, or antioxidant-enriched multi-vitamin appeared to have little effect on anthropometric measures.  This review cited a study (Sathe et al, 2021) on the use of Relizorb (immobilized lipase cartridge) for extracorporeal digestion of enteral feedings.

In a retrospective study, Baghae Pour et al (2022) examined the impact of the Relizorb immobilized lipase cartridge with overnight EN on BMI or weight-for-length percentile, stool quality, and GI symptoms in children with CF and pancreatic insufficiency.  Frequency of diarrhea, steatorrhea, and malodorous stools significantly decreased at final visit compared with baseline (p = 0.008, p = 0.004, p = 0.031, respectively) . Improved BMI or weight-for-length percentile was observed in 10 out of 16 participants; however, the change was not significant.  The authors concluded that the use of Relizorb decreased frequency of most GI symptoms in pediatric patients with CF on EN.

Formula versus Donor Breast Milk for Feeding Preterm or Low Birth Weight Infants

Quigley and colleagues (2018) noted that when sufficient maternal breast milk is not available, alternative forms of EN for preterm or low birth weight (LBW) infants are donor breast milk or artificial formula.  Donor breast milk may retain some of the non-nutritive benefits of maternal breast milk for preterm or LBW infants.  However, feeding with artificial formula may ensure more consistent delivery of greater amounts of nutrients.  Uncertainty exists about the balance of risks and benefits of feeding formula versus donor breast milk for preterm or LBW infants.  In a Cochrane review, these investigators determined the effect of feeding with formula compared with donor breast milk on growth and development in preterm or LBW infants.  They used the Cochrane Neonatal search strategy, including electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 6), Ovid Medline, Embase, and the Cumulative Index to Nursing and Allied Health Literature (until June 8, 2017), as well as conference proceedings and previous reviews.  Randomized or quasi-randomized controlled trials (RCTs) comparing feeding with formula versus donor breast milk in preterm or LBW infants were selected for analysis.  Two review authors assessed trial eligibility and risk of bias and extracted data independently.  They analyzed treatment effects as described in the individual trials and reported risk ratios (RRs) and risk differences (RDs) for dichotomous data, and mean differences (MDs) for continuous data, with respective 95 % CIs.  These researchers used a fixed-effect model in meta-analyses and explored potential causes of heterogeneity in subgroup analyses.  They assessed the quality of evidence for the main comparison at the outcome level using "Grading of Recommendations Assessment, Development and Evaluation" (GRADE) methods.  A total of 11 trials, in which 1,809 infants participated in total, fulfilled the inclusion criteria; 4 trials compared standard term formula versus donor breast milk; and 7 compared nutrient-enriched preterm formula versus donor breast milk.  Only the 4 most recent trials used nutrient-fortified donor breast milk.  The trials contain various weaknesses in methodological quality, specifically concerns about allocation concealment in 4 trials and lack of blinding in most of the trials.  Formula-fed infants had higher in-hospital rates of weight gain (MD 2.51, 95 % CI: 1.93 to 3.08 g/kg/day), linear growth (MD 1.21, 95 % CI: 0.77 to 1.65 mm/week) and head growth (MD 0.85, 95 % CI: 0.47 to 1.23 mm/week).  These researchers did not find evidence of an effect on long-term growth or neurodevelopment.  Formula feeding increased the risk of necrotizing enterocolitis (typical RR 1.87, 95 % CI: 1.23 to 2.85; RD 0.03, 95 % CI: 0.01 to 0.06).  The GRADE quality of evidence was moderate for rates of weight gain, linear growth, and head growth (down-graded for high levels of heterogeneity) and was moderate for neurodevelopmental disability, all-cause mortality, and necrotizing enterocolitis (down-graded for imprecision).  The authors concluded that in preterm and LBW infants, feeding with formula compared with donor breast milk, either as a supplement to maternal expressed breast milk or as a sole diet, resulted in higher rates of weight gain, linear growth, and head growth and a higher risk of developing necrotizing enterocolitis.  The trial data did not show an effect on all-cause mortality, or on long-term growth or neurodevelopment.

Enteral Nutrition for Induction / Maintenance of Remission in Crohn's Disease

Narula and associates (2018) noted that corticosteroids are often preferred over EN as induction therapy for Crohn's disease (CD).  Prior meta-analyses suggested that corticosteroids are superior to EN for induction of remission in CD.  Treatment failures in EN trials are often due to poor compliance, with drop-outs frequently due to poor acceptance of a naso-gastric (NG) tube and unpalatable formulations.  This systematic review was an update of a previously published Cochrane review.  These investigators evaluated the safety and effectiveness of exclusive EN as primary therapy to induce remission in CD and examined the importance of formula composition on effectiveness.  They searched Medline, Embase and CENTRAL from inception to July 5, 2017.  They also searched references of retrieved articles and conference abstracts; RCTs involving patients with active CD were considered for inclusion.  Studies comparing one type of EN to another type of EN or conventional corticosteroids were selected for review.  Data were extracted independently by at least 2 authors.  The primary outcome was clinical remission; secondary outcomes included adverse events (AEs), serious adverse events (SAEs) and withdrawal due to AEs.  For dichotomous outcomes, these researchers calculated the RR and 95 % CI.  A random-effects model was used to pool data.  They performed intention-to-treat (ITT) and per-protocol analyses for the primary outcome.  Heterogeneity was explored using the Chi-2 and I2 statistics.  The studies were separated into 2 comparisons: one EN formulation compared to another EN formulation; and EN compared to corticosteroids.  Subgroup analyses were based on formula composition and age.  Sensitivity analyses included abstract publications and poor quality studies.  These investigators used the Cochrane risk of bias tool to assess study quality.  They used the GRADE criteria to assess the overall quality of the evidence supporting the primary outcome and selected secondary outcomes.  A total of 27 studies (1,011 participants) were included; 3 studies were rated as low risk of bias; 7 studies were rated as high risk of bias, and 17 were rated as unclear risk of bias due to insufficient information; 17 trials compared different formulations of EN, 13 studies compared 1 or more elemental formulas to a non-elemental formula, 3 studies compared EN diets of similar protein composition but different fat composition, and 1 study compared non-elemental diets differing in glutamine enrichment.  Meta-analysis of 11 trials (378 subjects) demonstrated no difference in remission rates; 64 % (134/210) of patients in the elemental group achieved remission compared to 62 % (105/168) of patients in the non-elemental group (RR 1.02, 95 % CI: 0.88 to 1.18; GRADE very low quality).  A per-protocol analysis (346 participants) produced similar results (RR 1.04, 95 % CI: 0.91 to 1.18).  Subgroup analyses performed to evaluate the different types of elemental and non-elemental diets (elemental, semi-elemental and polymeric) showed no differences in remission rates.  An analysis of 7 trials including 209 patients treated with EN formulas of differing fat content (low fat: less than 20 g/1,000 kCal versus high fat: greater than 20 g/1,000 kCal) demonstrated no difference in remission rates (RR 1.03; 95 % CI: 0.85 to 1.26).  Very low fat content (less than 3 g/1,000 kCal) and very low long chain triglycerides demonstrated higher remission rates than higher content EN formulas.  There was no difference between elemental and non-elemental diets in AEs rates (RR 1.00, 95 % CI: 0.63 to 1.60; GRADE very low quality), or withdrawals due to AEs (RR 1.29, 95 % CI: 0.80 to 2.09; GRADE very low quality).  Common AEs included nausea, vomiting, diarrhea and bloating.  A total of 10 trials compared EN to steroid therapy.  Meta-analysis of 8 trials (223 participants) demonstrated no difference in remission rates between EN and steroids; 50 % (111/223) of patients in the EN group achieved remission compared to 72 % (133/186) of patients in the steroid group (RR 0.77, 95 % CI: 0.58 to 1.03; GRADE very low quality).  Subgroup analysis by age showed a difference in remission rates for adults but not for children.  In adults, 45 % (87/194) of EN patients achieved remission compared to 73 % (116/158) of steroid patients (RR 0.65, 95 % CI: 0.52 to 0.82; GRADE very low quality).  In children, 83 % (24/29) of EN patients achieved remission compared to 61 % (17/28) of steroid patients (RR 1.35, 95 % CI: 0.92 to 1.97; GRADE very low quality).  A per-protocol analysis produced similar results (RR 0.93, 95 % CI: 0.75 to 1.14).  The per-protocol subgroup analysis showed a difference in remission rates for both adults (RR 0.82, 95 % CI: 0.70 to 0.95) and children (RR 1.43, 95 % CI: 1.03 to 1.97).  There was no difference in AEs rates (RR 1.39, 95 % CI: 0.62 to 3.11; GRADE very low quality).  However, patients on EN were more likely to withdraw due to AEs than those on steroid therapy (RR 2.95, 95 % CI: 1.02 to 8.48; GRADE very low quality).  Common AEs reported in the EN group included heartburn, flatulence, diarrhea and vomiting, and for steroid therapy acne, moon facies, hyperglycemia, muscle weakness and hypoglycemia.  The most common reason for withdrawal was inability to tolerate the EN diet.

The authors concluded that very low quality evidence suggested that corticosteroid therapy may be more effective than EN for induction of clinical remission in adults with active CD.  Very low quality evidence also suggested that EN may be more effective than steroids for induction of remission in children with active CD.  Protein composition did not appear to influence the effectiveness of EN for the treatment of active CD.  EN should be considered in pediatric CD patients or in adult patients who can comply with NG tube feeding or perceive the formulations to be palatable, or when steroid side effects are not tolerated or better avoided.  These researchers stated that further research is needed to confirm the superiority of corticosteroids over EN in adults; and further research is needed to confirm the benefit of EN in children.  Furthermore, they stated that more effort from industry should be taken to develop palatable polymeric formulations that can be delivered without use of a NG tube as this may lead to increased patient adherence with this therapy.

Akobeng and colleagues (2018) stated that prevention of relapse is a major issue in the management of quiescent CD.  Current therapies (e.g., methotrexate, biologics, 6-mercaptopurine and azathioprine) may be effective for maintaining remission in CD, but these drugs may cause significant AEs.  Interventions that are safe and effective for maintenance of remission in CD are desirable.  These investigators evaluated the safety and efficacy of EN for the maintenance of remission in CD and examined the impact of formula composition on effectiveness.  They searched Medline, Embase, CENTRAL, the Cochrane IBD Group Specialized Register and clinicaltrials.gov from inception to July 27, 2018.  They also searched references of retrieved studies and reviews; RCTs including participants of any age with quiescent CD were considered for inclusion.  Studies that compared EN with no intervention, placebo or any other intervention were selected for review.  Two authors independently screened studies for inclusion, extracted data and assessed methodological quality using the Cochrane risk of bias tool.  The primary outcome was clinical or endoscopic relapse as defined by the primary studies.  Secondary outcomes included anthropometric measures (i.e., height and weight), quality of life (QOL), AEs, serious AEs (SAEs) and withdrawal due to AEs.  These researchers calculated the RR and 95 % CI for dichotomous outcomes.  For continuous outcomes, they calculated the MD and 95 % CI.  A random-effects model was used for the statistical analysis.  These researchers used the GRADE criteria to assess the overall certainty of the evidence supporting the primary outcome and selected secondary outcomes.  A total of 4 RCTs (262 adult participants) met the inclusion criteria; 1 study (n = 33) compared an elemental diet to a non-elemental (polymeric) diet; 1 study (n = 51) compared a half elemental diet to a regular free diet.  Another study (n = 95) compared an elemental diet to 6-mercaptopurine (6-MP) or a no treatment control group; 1 study (n = 83) compared a polymeric diet to mesalamine; 2 studies were rated as high risk of bias due to lack of blinding or incomplete outcome data.  The other 2 studies were judged to have an unclear risk of bias.  The studies were not pooled due to differences in control interventions and the way outcomes were assessed.  The effect of an elemental diet compared to a polymeric diet on remission rates or withdrawal due to AEs was uncertain; 58 % (11/19) of participants in the elemental diet group relapsed at 12 months compared to 57 % (8/14) of participants in the polymeric diet group (RR 1.01, 95 % CI: 0.56 to 1.84; very low certainty evidence); 32 % (6/19) of participants in the elemental diet group were intolerant to the enteral nutritional formula because of taste or smell and were withdrawn from the study in the first 2 weeks compared to zero participants (0/14) in the polymeric diet group (RR 9.75, 95 % CI: 0.59 to 159.93; low certainty evidence).  Anthropometric measures, QOL, AEs and SAEs were not reported as outcomes.  The effect of an elemental diet (half of total daily calorie requirements) compared to a normal free diet on relapse rates was uncertain; 35 % (9/26) of participants in the elemental diet group relapsed at 12 months compared to 64 % (16/25) of participants in the free diet group (RR 0.54, 95 % CI: 0.30 to 0.99; very low certainty evidence).  No AEs were reported.  This study reported no differences in weight change between the 2 diet groups.  Height and QOL were not reported as outcomes.  The effect of an elemental diet compared to 6-MP on relapse rates or AEs was uncertain; 38 % (12/32) of participants in the elemental diet group relapsed at 12 months compared to 23 % (7/30) of participants in the 6-MP group (RR 1.61; 95 % CI: 0.73 to 3.53; very low certainty evidence); 3 % (1/32) of participants in the elemental diet group had an AE compared to 13 % (4/30) of participants in the 6-MP group (RR 0.23, 95 % CI: 0.03 to 1.98; low certainty evidence); AEs in the elemental diet group included surgery due to worsening CD; AEs in the 6-MP group included liver injury (n = 2), hair loss (n = 1) and surgery due to an abscess (n = 1).  No SAEs or withdrawals due to AEs were reported.  Weight, height and QOL were not reported as outcomes.  The effect of a polymeric diet compared to mesalamine on relapse rates and weight was uncertain; 42 % (18/43) of participants in the polymeric diet group relapsed at 6 months compared to 55 % (22/40) of participants in the mesalamine group (RR 0.76; 95 % CI: 0.49 to 1.19; low certainty evidence).  The MD in weight gain over the study period was 1.9 kg higher in the polymeric diet group compared to mesalamine (95 % CI: -4.62 to 8.42; low certainty evidence); 2 participants in the polymeric diet group experienced nausea and 4 had diarrhea.  It was unclear if any participants in the mesalamine group had an AE.  Height, QOL, SAEs and withdrawal due to AEs were not reported as outcomes.

The authors concluded that the findings of this review were uncertain and no firm conclusions regarding the safety and efficacy of EN in quiescent CD could be drawn.  They stated that more research is needed to determine the safety and efficacy of using EN as maintenance therapy in CD.  Currently, there are 4 ongoing studies (estimated enrolment of 280 participants).  This review will be updated when the results of these studies are available.

Guidelines on clinical nutrition in inflammatory bowel disease from the European Society for Parentaral and Enteral Nutrition (Forbes, et al., 2017) state that "there is no 'IBD diet' that can be generally recommended to promote remission in IBD patients with active disease." The guidelines noted that, due to strong concerns over corticosteroid use and aiming for optimal growth in children, enteral nutrition is often first-line therapy for pediatric patients with active Crohn's disease. The guidelines noted that, although enteral nutrition as primary therapy in adults with Crohn's disease has also repeatedly been considered to be effective "the data are not robust." The guidelines note that "meta-analyses do not support the use of EN as primary treatment for acute exacerbations of CD in adults. Patchy clinical conviction and the data, which appear better than might be expected with placebo, ensure continuing controversy over its role in adults."

Early Enteral Nutrition for Individuals Who Have Severe Head Injury

Yi and colleagues (2019) noted that the role of early enteral nutrition (EEN) supplemented with probiotics (less than 48 hours) in improving clinical outcomes of patients with severe head injury (SHI) remains controversial.  In a meta-analysis, these investigators examined the efficacy of EEN supplemented with probiotics on clinical outcomes in these patients.  Systematic searches were performed in PubMed, Cochrane Central Register of Controlled Trials, China National Knowledge Infrastructure, Wanfang database, and Chinese Biomedical Literature to identify potential studies; 2 investigators checked citations, extracted data, appraised risk of bias, and then STATA 12.0 was used to perform statistical analysis.  A total of 18 trials were eventually included in the present study.  Meta-analysis indicated that EEN supplemented with probiotics was associated with decreased risk of infection (RR, 0.53; 95 % CI: 0.44 to 0.65), decreased risk of mortality (RR, 0.56; 95 % CI: 0.38 to 0.82), decreased risk of GI complications (RR, 0.19; 95 % CI: 0.13 to 0.25), and shortened stays in ICU (MD, -4.55; 96 % CI: -5.91 to -3.19).  The authors concluded that EEN supplemented with probiotics may be a promising alternative for patients with SHI because it decreased the risk of infection, mortality, and GI complications, as well as shortened the stays in ICU.  These researches stated that further large-scale and well-designed studies are needed to establish this conclusion.

Enteral Nutrition in the Treatment of Eating Disorders

Hale and Logomarsino (2019) stated that EN is frequently used in the treatment of anorexia nervosa (AN), and less commonly, bulimia nervosa (BN); yet, no standardized guidelines for treatment exist at this time.  These investigators examined the efficacy of EN in the treatment of eating disorders and made recommendations for clinical practice and future research.  They carried out a literature search of 7 databases.  The search strategy combined key terms anorexia nervosa, bulimia, and eating disorders with terms associated with EN.  There were no restrictions on publication date or language.  Studies that assessed the effect of EN on weight restoration, refeeding syndrome, and binge/purge behaviors in the treatment of AN and BN were included.  Of 73 full-text articles reviewed, 22 met inclusion criteria; 19 studies reported that significant short-term weight gain was achieved when EN was used for re-feeding malnourished AN patients; however, results varied for the 6 studies reporting on long-term weight gain, maintenance, and recovery.  In studies with a comparator, no significant differences were found between the EN and oral re-feeding cohorts regarding GI disturbance, re-feeding syndrome, or electrolyte abnormalities; 5 studies examined the effect of EN on binge/purge behaviors, suggesting that temporary exclusive EN decreased the frequency and severity of binge/purge episodes.  The authors concluded that although EN is an essential life-saving treatment in severe cases of AN, it does not guarantee long-term success or recovery.  The results of this systematic review highlighted the need for prospective controlled trials with adequate sample sizes to make comparisons between specific feeding methods, formulations, and defined short- and long-term outcomes.  These researchers stated that evidence-based standards for clinical practice are needed with specific guidelines for best results for AN and BN treatment.  Level of Evidence = I.

Early Enteral Nutrition Following Gastrointestinal Surgery

In a Cochrane review, Herbert and colleagues (2019) examined if early commencement of post-operative enteral nutrition (within 24 hours), oral intake and any kind of tube feeding (gastric, duodenal or jejunal), compared with traditional management (delayed nutritional supply) is associated with a shorter length of hospital stay (LOS), fewer complications, mortality and AEs in patients undergoing lower gastro-intestinal (GI) surgery (distal to the ligament of Treitz).  These investigators searched the Cochrane Central Register of Controlled Trials (CENTRAL, the Cochrane Library 2017, issue 10), Ovid Medline (1950 to November 15, 2017), Ovid Embase (1974 to November 15, 2017).  They also searched for ongoing trials in ClinicalTrials.gov and World Health Organization International Clinical Trials Registry Platform (November 15, 2017), and hand-searched reference lists of identified studies and previous systematic reviews.  These researchers included RCTs comparing early commencement of enteral nutrition (within 24 hours) with no feeding in adult patients undergoing lower GI surgery.  Two review authors independently assessed study quality using the Cochrane 'Risk of bias' tool tailored to this review and extracted data.  Data analyses were conducted according to the Cochrane recommendations.  They rated the quality of evidence according to GRADE.  Primary outcomes were LOS and post-operative complications (wound infections, intra-abdominal abscesses, anastomotic dehiscence, pneumonia).  Secondary outcomes were: mortality, AEs (nausea, vomiting), and QOL; LOS was estimated using MD (presented as mean +/- SD).  For other outcomes, these researchers estimated the common RR and calculated the associated 95 % CIs.  For analysis, these investigators used an inverse-variance random-effects model for the primary outcome (LOS) and Mantel-Haenszel random-effects models for the secondary outcomes.  They also performed Trial Sequential Analyses (TSA).  These researchers identified 17 RCTs with 1,437 patients undergoing lower GI surgery.  Most studies were at high or unclear risk of bias in 2 or more domains; 6 studies were judged as having low risk of selection bias for random sequence generation and insufficient details were provided for judgement on allocation concealment in all 17 studies.  With regards to performance and deception bias; 14 studies reported no attempt to blind subjects and blinding of personnel was not discussed either.  Only 1 study was judged as low risk of bias for blinding of outcome assessor.  With regards to incomplete outcome data, 3 studies were judged to be at high risk because they had more than 10 % difference in missing data between groups.  For selective reporting, 9 studies were judged as unclear as protocols were not provided and 8 studies had issues with either missing data or incomplete reporting of results.  LOS was reported in 16 studies (1,346 subjects).  The mean LOS ranged from 4 to 16 days in the early feeding groups and from 6.6 to 23.5 days in the control groups.  Mean difference in LOS was 1.95 (95 % CI: -2.99 to -0.91, p < 0.001) days shorter in the early feeding group.  However, there was substantial heterogeneity between included studies (I2 = 81 %, Chi2 = 78.98, p < 0.00001), thus the overall quality of evidence for LOS was low.  These results were confirmed by the TSA showing that the cumulative Z-curve crossed the trial sequential monitoring boundary for benefit.  These investigators found no differences in the incidence of post-operative complications: wound infection (12 studies, 1,181 subjects, RR 0.99, 95 % CI: 0.64 to 1.52, very low-quality evidence), intra-abdominal abscesses (6 studies, 554 subjects, RR 1.00, 95 % CI: 0.26 to 3.80, low-quality evidence), anastomotic leakage/dehiscence (13 studies, 1,232 subjects, RR 0.78, 95 % CI: 0.38 to 1.61, low-quality evidence; number needed to treat for an additional beneficial outcome (NNTB) = 100), and pneumonia (10 studies, 954 subjects, RR 0.88, 95 % CI: 0.32 to 2.42, low-quality evidence; NNTB = 333).  Mortality was reported in 12 studies (1,179 subjects), and showed no between-group differences (RR = 0.56, 95 % CI: 0.21 to 1.52, p = 0.26, I2 = 0 %, Chi2 = 3.08, p = 0.96, low-quality evidence).  The most commonly reported cause of death was anastomotic leakage, sepsis and acute myocardial infarction (MI); 7 studies (613 subjects) reported vomiting (RR 1.23, 95 % CI: 0.96 to 1.58, p = 0.10, I2 = 0 %, Chi2 = 4.98, p = 0.55, low-quality evidence; number needed to treat for an additional harmful outcome (NNTH) = 19), and 2 studies (118 subjects) reported nausea (RR 0.95, 0.71 to 1.26, low-quality evidence); 4 studies reported combined nausea and vomiting (RR 0.94, 95 % CI: 0.51 to 1.74, very low-quality evidence); 1 study reported QOL assessment; the scores did not differ between groups at 30 days after discharge on either QOL scale EORTC QLQ-C30 or EORTC QlQ-OV28 (very low-quality evidence).  The authors concluded that the findings of this review suggested that early enteral feeding may lead to a reduced post-operative LOS, however cautious interpretation must be taken due to substantial heterogeneity and low-quality evidence.  For all other outcomes (post-operative complications, mortality, AEs, and QOL) the findings were inconclusive, and further studies are needed to enhance the understanding of early feeding for these.  In this updated review, only a few additional studies have been included, and these were small and of poor quality.  To improve the evidence, future trials should address quality issues and focus on clearly defining and measuring post-operative complications to allow for better comparison between studies.  However due to the introduction of fast track protocols that already include an early feeding component, future trials may be challenging.  A more feasible trial may be to examine the effect of differing post-operative energy intake regimens on relevant outcomes.

Braungart and Siminas (2020) noted that prolonged post-operative fasting has been the traditional model of care following pediatric GI surgery.  In contrast, early feeding has become well established in the adult population, where meta-analyses have shown early introduction of enteral feeding to be beneficial to hospital stay and patient outcomes.  In a systematic review, these researchers examined the safety and effectiveness of early enteral feeding versus traditional enteral feeding after GI anastomosis in children in the pediatric literature.  They carried out a comprehensive literature search of the English literature (PubMed, Ovid, Embase data-bases) from inception to present according to the PRISMA guidelines.  Included studies were evaluated according to the MINORS criteria.  Outcomes for time to 1st feed and full feeds, and discharge, and risk of major complications were synthesized.  A total of 10 studies comprising 451 patients were included in the analysis.  All studies aimed at examining the safety of early feeding in pediatric GI surgery, with or without a fast-track program.  Only 4 studies compared the study group to a control group in which patients were fed in a traditional way (traditional feeding).  Most studies defined early feeding as feeds commenced less than or equal to 24 hours post-operatively (range of 2 to 72 hours).  Mean time to 1st feed was significantly lower in the early feeding group, but not significantly lower for the mean time to full feeds and mean hospital stay.  Bowel obstruction and anastomotic breakdown were classed as major complications.  There was no significant difference in their occurrence in both groups.  The authors concluded that although the studies identified were few and heterogeneous, they showed that there was no clear advantage of keeping children "nil by mouth" and no clear disadvantage of providing early enteral nutrition following elective GI surgery.  Moreover, these researchers stated that larger RCTs are needed to examine the true impact on post-operative complications, healthcare-associated costs, and to examine patient-reported outcome measures.

Enteral Lactoferrin Supplementation for Prevention of Sepsis and Necrotizing Enterocolitis in Preterm Infants

Pammi and Suresh (2020) stated that lactoferrin could enhance host defenses and may be effective for prevention of sepsis and necrotizing enterocolitis (NEC) in preterm neonates.  In a Cochrane review, these researchers examined the safety and effectiveness of lactoferrin supplementation to enteral feeds for prevention of sepsis and NEC in preterm neonates.  In addition, they evaluated the effects of lactoferrin supplementation to enteral feeds on the duration of positive-pressure ventilation, development of chronic lung disease (CLD) or peri-ventricular leukomalacia (PVL), length of hospital stay to discharge among survivors, and adverse neurological outcomes at 2 years of age or later.  These investigators used the standard search strategy of Cochrane Neonatal to update their search.  They searched the Cochrane Central Register of Controlled Trials (CENTRAL 2019, Issue 9), Medline via PubMed (1966 to January 20, 2020), PREMEDLINE (1996 to January 20, 2020), Embase (1980 to January 20, 2020), and CINAHL (1982 to January 20, 2020).  These researchers also searched clinical trials data-bases, conference proceedings, and the reference lists of retrieved articles for RCTs and quasi-randomized trials.  They included RCTs evaluating enteral lactoferrin supplementation at any dose or duration to prevent sepsis or NEC in preterm neonates; and used the standard methods of Cochrane Neonatal and the GRADE approach to examine the certainty of evidence.  Meta-analysis of data from 12 RCTs showed that lactoferrin supplementation to enteral feeds decreased late-onset sepsis (typical RR 0.82, 95 % CI: 0.74 to 0.91; typical RD -0.04, 95 % CI: -0.06, -0.02; NNTB 25, 95 % CI: 17 to 50; 12 studies, 5,425 participants, low-certainty evidence) and decreased LOS (MD -2.38, 95 % CI: -4.67, -0.09; 3 studies, 1,079 participants, low-certainty evidence).  Sensitivity analysis including only good methodological certainty studies suggested a decrease in late-onset sepsis with enteral lactoferrin supplementation (typical RR 0.87, 95 % CI: 0.78 to 0.97; typical RD -0.03, 95 % CI: -0.05 to -0.0; 9 studies, 4,702 participants, low-certainty evidence).  There were no differences in NEC stage II or III (typical RR 1.10, 95 % CI: 0.86 to 1.41; typical RD -0.00, 95 % CI: -0.02 to 0.01; 7 studies, 4,874 participants; low-certainty evidence) or “all-cause mortality” (typical RR 0.90, 95 % CI: 0.69 to 1.17; typical RD -0.00, 95 % CI: -0.01 to 0.01; 11 studies, 5,510 participants; moderate-certainty evidence).  One study reported no differences in neurodevelopmental testing by Mullen's or Bayley III at 24 months of age after enteral lactoferrin supplementation (1 study, 292 participants, low-certainty evidence).  Lactoferrin supplementation to enteral feeds with probiotics decreased late-onset sepsis (RR 0.25, 95 % CI: 0.14 to 0.46; RD -0.13, 95 % CI: -0.18 to -0.08; NNTB 8, 95 % CI: 6 to 13; 3 studies, 564 participants; low-certainty evidence) and NEC stage II or III (RR 0.04, 95 % CI: 0.00 to 0.62; RD -0.05, 95 % CI: -0.08 to -0.03; NNTB 20, 95 % CI: 12.5 to 33.3; 1 study, 496 participants; very low-certainty evidence), but not “all-cause mortality” (very low-certainty evidence).  Lactoferrin supplementation to enteral feeds with or without probiotics had no effect on CLD, duration of mechanical ventilation or threshold retinopathy of prematurity (low-certainty evidence).  Investigators reported no adverse effects in the included studies.  The authors found low-certainty evidence from studies of good methodological quality that lactoferrin supplementation of enteral feeds decreased late-onset sepsis but not NEC of greater than or equal to stage II or “all-cause mortality” or neurodevelopmental outcomes at 24 months of age in preterm infants without adverse effects.  Low-to-very low certainty evidence suggested that lactoferrin supplementation of enteral feeds in combination with probiotics decreased late-onset sepsis and NEC of greater than or equal to stage II in preterm infants without adverse effects, however, there were few included studies of poor methodological quality.  These researchers stated that the presence of publication bias and small studies of poor methodology that may inflate the effect size made recommendations for clinical practice difficult.

In a RCT, Pehlevan and colleagues (2020) examined the effect of Lactobacillus and Bifidobacterium together with oligosaccharides and lactoferrin on the development of NEC or sepsis in very low birth weight neonates.  Neonates with a gestational age of less than or equal to 32 weeks and birth weight of less than or equal to 1,500 g were enrolled.  The study group received a combination of synbiotics and lactoferrin, whereas the control group received 1 ml of distilled water as placebo starting with the 1st feed until discharge.  The outcome measures were the incidence of NEC stage of greater than or equal to 2 or late-onset culture-proven sepsis and NEC stage of greater than or equal to 2 or death.  Mean birth weight and gestational age of the study (n = 104) and the control (n = 104) groups were 1,197 ± 235 g versus 1,151 ± 269 g and 29 ± 1.9 versus 28 ± 2.2 weeks, respectively (p > 0.05).  Neither the incidence of NEC stage greater than or equal to 2 or death, nor the incidence of NEC stage greater than or equal to 2 or late-onset culture-proven sepsis differed between the study and control groups (5.8 % versus 5.9 %, p = 1; 26 % versus 21.2 %, p = 0.51). The only significant difference was the incidence of all stages of NEC (1.9 % versus 10.6 %, p = 0.019).  The authors concluded that the combination of synbiotics and lactoferrin did not reduce NEC severity, sepsis, or mortality.

Home Enteral Nutrition After Esophagectomy for Esophageal Cancer

Liu and colleagues (2020) stated that not only has the placement rate of enteral feeding tubes during operations for esophageal cancer increased, but also has number of patients who choose to continue enteral feeding at home instead of removing the feeding tube at discharge.  In a systematic review, these researchers examined the impacts of home enteral nutrition (HEN) after esophagectomy in esophageal cancer patients.  This systematic review was carried out in accordance with PRISMA and Cochrane guidelines.  English and Chinese data-bases, including PubMed, Embase, Web of Science, the Cochrane Library, Scopus, CBM, CNKI, and Wan Fang were searched from inception to December 7, 2019; RCTs evaluating the short-term outcomes of HEN following esophagectomy in cancer patients were included.  The risk of bias of the included studies was appraised according to the Cochrane risk of bias tool.  The summary of relative risk (RR) / weighted mean difference (WMD) estimates and corresponding 95 % CI were calculated using fixed- and random-effects models.  A total of 9 RCTs involving 757 patients were included in the meta-analysis.  Compared with oral diet, HEN was associated with significantly increased body weight (WMD 3 kg, 95 % CI: 2.36 to 3.63, p < 0.001), BMI (WMD 0.97 kg/m, 95 % CI: 0.74 to 1.21, p < 0.001), albumin (WMD 3.43 g/L, 95 % CI: 2.35 to 4.52, p < 0.001), hemoglobin (WMD 7.23 g/L, 95 % CI: 5.87 to 8.59, p < 0.001), and total protein (WMD 5.13 g/L, 95 % CI: 3.7 to 6.56, p < 0.001).  No significant differences were observed in pre-albumin and GI adverse reactions.  Physical (WMD 8.82, 95 % CI: 6.69 to 10.95, p < 0.001) and role function (WMD 12.23, 95 % CI: 2.72 to 21.74, p = 0.01) were also significantly better in the HEN group.  The nausea/vomiting (WMD -5.43, 95 % CI: -8.29 to -2.57, p = 0.002) and fatigue symptoms (WMD -11.76, 95 % CI: -16.21 to -7.32, p < 0.001) were significantly reduced.  Appetite loss (WMD -8.48, 95 % CI: -14.27 to -4.88, p = 0.001), diarrhea (WMD -3.9, 95 % CI: -7.37 to -0.43, p = 0.03), and sleep disturbance (WMD -7.64, 95 % CI: -12.79 to -2.5, p = 0.004) in the HEN group were also significantly less than the control group.  The authors concluded that HEN improved nutrition status, physical and role function, and reduced nausea/vomiting, fatigue, appetite loss, diarrhea, and sleep disturbance compared with an oral diet in esophageal cancer patients post-surgery; and HEN did not increase adverse reactions.

The authors stated that a major drawback of this study was that HEN after an esophagectomy for cancer is mainly used in China; thus, the current evidence is mainly based on studies performed in Chinese populations, so it is unclear how applicable these findings are to other regions.  These researchers stated that multi-center studies with better methodological quality are needed to examine the effects of long-term HEN and provide more data and evidence to reinforce these findings.

Percutaneous Ultrasound Gastrostomy for Gastrostomy Tube Insertion

Cool and colleagues (2020) noted that percutaneous ultrasound gastrostomy (PUG) technique was developed to allow for gastrostomy tube insertion to be performed solely under ultrasound (US) guidance without need for fluoroscopy or endoscopy.  These researchers discussed the new device, proposed PUG technique, and the 1st-in-human experience.  A total of 5 patients had PUG tube insertion carried out as part of a Health Canada approved investigational study.  All procedures were successful with no complications within 30 days post-procedure.  Mean total procedure time was 50 ± 13 mins; 2 of 5 procedures needed temporary fluoroscopy use to localize the orogastric balloon position within the stomach to achieve magnetic gastropexy. 

In a prospective, industry-sponsored, single-arm, pilot study, Accorsi and associates (2021) reported the results of the 1st-in-human clinical trial examining the safety and efficacy of the PUG technique.  This study included 25 adult patients under investigational device exemption (IDE; mean age of 64 ± 15 years, 92 % men, 80 % inpatients, mean BMI of 24.5 ± 2.7 kg/m2).  A propensity score-matched retrospective cohort of 25 patients who received percutaneous radiologic gastrostomy (PRG) was generated as an institutional control (mean age of 66 ± 14 years, 92 % men, 80 % inpatients, mean BMI of 24.0 ± 2.7 kg/m2).  Primary outcomes included successful insertion and 30-day procedure-related AEs.  Secondary outcomes included procedural duration, sedation requirements, and hospital LOS.  All PUG procedures were successful, including 3/25 [12 %] carried out bedside within the intensive care unit (ICU).  There was no significant difference between PUG and PRG in rates of mild AEs (3/25 [12 %] for PUG and 7/25 [28 %] for PRG, p = 0.16) or moderate AEs (1/25 [4 %] for PUG and 0/25 for PRG, p = 0.31).  There were no severe AEs or 30-day procedure-related mortality in either group.  Procedural room time was longer for PUG (56.5 ± 14.1 mins) than PRG (39.3 ± 15.0 mins, p < 0.001).  PUG procedure time was significantly shorter after a procedural enhancement, the incorporation of a Gauss meter to facilitate successful magnetic gastropexy; LOS for outpatients did not significantly differ (2.4 ± 0.5 days for PUG and 2.6 ± 1.0 days for PRG, p = 0.70).  The authors concluded that the PUG appeared effective with a safety profile similar to PRG.  These researchers stated that bedside point-of-care (POC) gastrostomy tube insertion using the PUG technique shows promise.  The use of PUG as a portable method of gastrostomy insertion may prove complementary to these established methods and warrants further investigation to establish the optimal patient populations and role within the interventional radiology practice.

The authors stated that the relatively small sample size (n = 25) of this pilot study was a drawback, an issue which was compounded in cases where subgroup analyses were necessary (e.g., data relating to cases using a Gauss meter).  This drawback was especially relevant with respect to rare outcomes such as moderate AEs, found to be 4 % for PUG and 0 % for PRG in this trial.  Power calculations revealed that the sample size of 25 yielded an estimated margin of error of 7.7 % for these outcomes, showing that reliable detection of a difference in these rare outcomes requires a larger study.  Similar drawbacks apply to the detection of 30-day procedure-related mortality (reported at 1 % for both PRG and PEG).  In addition, PUG was carried out by 2 interventional radiologists (IRs) with substantial experience in diagnostic US interpretation and percutaneous US-guided needle procedures.  The safety and efficacy of the PUG procedure in the hands of non-IR operators should not be assumed.  This was a safety and efficacy study for a new device and procedural technique, and as such, was not designed as a RCT.  Although efforts were made to control potential confounders in the matching of retrospective controls, some unidentified selection bias may remain.  For example, the number of operators involved in the retrospective cohort was larger than those prospectively performing PUG insertion, so operator-dependent factors were not controlled for in the propensity match.  Lastly, PUG procedural room times were measured prospectively by an independent technologist as part of the study protocol, whereas PRG procedural room times were retrospectively obtained from EMR records.  As such, there may be bias related to inconsistencies or variabilities in the way PRG times were recorded.  Nevertheless, this remains the best available data for comparison to this retrospective cohort.

Infusion of Carnitine / Levocarnitine as a Part of Total Parenteral Nutrition Therapy

Pichard et al (1985) stated that carnitine-free TPN is claimed to result in a carnitine deficiency with subsequent impairment of fat oxidation.  These researchers examined the possible benefit of carnitine (L-carnitine) supplementation on post-operative fat and nitrogen utilization.  A total of 16 patients undergoing total esophagectomy were evenly randomized and received TPN without or with L-carnitine supplementation (74 mumol/kg/day) during 11 post-operative days.  On day 11, a 4-hour infusion of L-carnitine (125 mumol/kg) was carried out in both groups.  The effect of supplementation was examined by indirect calorimetry, nitrogen balance, and repeated measurements of plasma lipids and ketone bodies.  Irrespective of continuous or acute supplementation, respiratory quotient and fat oxidation were similarly maintained throughout the study in both groups whereas N balance appeared to be more favorable without carnitine.  The authors concluded that carnitine-supplemented TPN did not improve fat oxidation or promote nitrogen utilization in the post-operative phase.

Roulet et al (1989) examined the effects of continuous and acute L-carnitine supplementation of TPN on protein and fat oxidation in severe catabolism.  A critically ill and severely mal-nourished male patient received TPN (non-protein energy = 41 Kcal/kg/day, provided equally as fat and glucose) over 38 days, without L-carnitine for 23 days and with carnitine supplements (15 mg/kg/day) for the following 15 days.  Subsequently, he was given carnitine-free enteral nutrition for 60 more days.  A 4-hour infusion of 100-mg L-carnitine was given on day 11 of each TPN period.  Indirect calorimetry was performed after 11 days of either carnitine-free or supplemented TPN and at the initiation of enteral nutrition.  Additional measurements were performed 4 hours and 24 hours after the acute infusions of carnitine.  The rate of protein oxidation and the respiratory quotient were found to be higher, and the rate of fat oxidation to be lower, with carnitine-supplemented TPN, than with either carnitine-free TPN or enteral nutrition.  Th authors concluded that acute infusion of carnitine resulted in an increased rate of protein oxidation and a reduced rate of fat oxidation on both TPN-regimens; and these unfavorable effects on protein metabolism may be due to an impairment of fat oxidation by excess amounts of carnitine.

Sandstedt et al (1991) examined the effects of L-carnitine supplemented TPN on lipid, energy and nitrogen metabolism.  A total of 16 severely injured patients were studied during the first 8 days following trauma.  An L-carnitine solution (3 g = 18.6 mmol) was added to the fat emulsion and infused over 16 hours in a blind, randomized fashion to 50 % of the patients.  Plasma triglyceride, free fatty acid (FA) and 3-OH-butyrate concentrations increased during the fat infusion; and fell to pre-infusion concentrations within 24 hours.  There were no differences in plasma levels before, during or after infusion between the groups.  ATP and phosphocreatine in muscle tissue were not influenced by carnitine supplementation.  Glycogen, however, remained unchanged in the carnitine group and fell in the non-carnitine group.  A cumulative nitrogen balance measured from day 2 to day 8 was equally negative in both groups.  Plasma carnitine levels were significantly higher in the supplemented group from day 3.  The mean daily urinary carnitine excretion was increased 15-fold in the supplemented group.  Muscle carnitine, however, remained unchanged in both groups and did not differ between them.  The authors concluded that this study did not demonstrate any beneficial effects of parenterally administered L-carnitine on lipid, energy or nitrogen metabolism except for maintaining normal muscle glycogen levels in critically ill patients receiving TPN during the early phase after trauma.

In a review on “Pediatric parenteral nutrition-associated liver disease and cholestasis”, Orso et al (2016) stated that a carnitine deficiency has also been associated to the pathogenesis of hepatic steatosis.  The carnitine deficiency, which is involved in the transport of long chain triglycerides (LCT) across the mitochondrial membrane for oxidation, has been described in pre-term infants because of limited stocks and reduced synthesis; however, the opportunity of carnitine supplementation in PN remains controversial.

Guthrie and Burrin (2021) noted that provision of supplemental carnitine can increase the serum levels of carnitine.  Infants who have carnitine deficiency from genetic disorders have rapid recovery from supplemental carnitine.  The benefit of carnitine supplementation for infants on PN is still unclear.  There should be some caution with the use of parenteral carnitine.  In adult critically ill patients, parenteral carnitine has been shown to either reduce fat oxidation and increase protein oxidation or help maintain muscle glycogen stores, but not improve lipid or energy metabolism.  Currently, animal model studies are needed to examine if TPN supplementation of carnitine is tolerated and beneficial.

Furthermore, an UpToDate review on “Nutrition support in critically ill patients: Parenteral nutrition” (Seres, 2022) does not mention infusion of L-carnitine / levocarnitine as a management / therapeutic option.

Levocarnitine Supplementation to Total Parenteral Nutrition

Sgambat et al (2021) stated that carnitine plays a key role in energy production in the myocardium and is efficiently removed by continuous kidney replacement therapy (CKRT).  Effects of levocarnitine supplementation on myocardial function in children receiving CKRT have not been investigated.  In a single-center, pilot cohort study (n = 48 children), these investigators examined the effects of levocarnitine supplementation on myocardial strain in children receiving CKRT for acute kidney injury (AKI).  Children (n = 9) with AKI had total (TC) and free plasma carnitine (FC) measurements and echocardiogram for longitudinal and circumferential strain at baseline (before CKRT) and follow-up (on CKRT for greater than 1 week with intravenous (IV) levocarnitine supplementation, 20 mg/kg/day).  Intervention group was compared with 3 controls: CKRT controls (n = 10) received CKRT for more than 1 week (+AKI, no levocarnitine); ICU controls (n = 9) were parenteral nutrition-dependent for more than 1 week (no AKI, no levocarnitine); and healthy controls (n = 20).  In the Intervention group, TC and FC increased from 36.0 and 18 μmol/L to 93.5 and 74.5 μmol/L after supplementation.  TC and FC of un-supplemented CKRT controls declined from 27.2 and 18.6 μmol/L to 12.4 and 6.6 μmol/L, which was lower versus ICU controls (TC 32.0, FC 26.0 μmol/L), p < 0.05.  Longitudinal and circumferential strain of the Intervention group improved from - 18.5 % and - 18.3 % to - 21.1 % and - 27.6 % after levocarnitine supplementation; strain of CKRT controls (-14.4 %, -20 %) remained impaired and was lower versus Intervention and healthy control groups at follow-up, p < 0.05.  The authors concluded that levocarnitine supplementation was associated with repletion of plasma carnitine and improvement in myocardial strain.  Moreover, these researchers stated that while larger studies are needed to further examine clinical outcomes associated with carnitine supplementation, the findings of this trial suggested that IV carnitine supplementation may benefit pediatric patients undergoing a prolonged course of CKRT.

The authors stated that this single-center, pilot study was limited by small sample size (n = 48).  The small sample size may have limited the ability to detect significant differences in demographics and clinical characteristics, and these investigators were unable to conduct multi-variable analyses.  However, given that it was a pilot study, these findings provided a launching point for future investigations.  Although these researchers were unable to adjust for confounding variables statistically, the study design was strengthened by the comparison of the intervention group with 3 different control groups, which aided in teasing out whether changes in plasma carnitine status and myocardial strain may be related to carnitine supplementation, CKRT, or to critical illness alone.  Performance of speckle tracking echocardiography in healthy controls was important to provide age-matched reference data, since normal reference ranges for myocardial strain in children have not been established.  Collection of plasma carnitine levels of ICU control patients provided a reference for carnitine status in children who were critically ill without the exposure of CKRT.  It would have been interesting to also carry out echocardiograms in the ICU controls; however, this was not feasible due to budget constraints.  Despite inclusion of the 3 control groups, the authors acknowledged that they were likely unable to control for all possible factors that could influence myocardial strain in a critically ill pediatric population.  These researchers stated that larger RCTs are needed to more definitively prove a causal relationship between carnitine supplementation and improved myocardial function in children receiving CKRT.


References

The above policy is based on the following references:

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