Description:
Intradialytic parenteral nutrition is the infusion of an intravenous hyperalimentation formula, such as amino acids, glucose, and lipids, during dialysis, to treat protein calorie malnutrition in an effort to decrease the morbidity and mortality experienced in patients with renal failure.

For individuals who are undergoing hemodialysis who receive intradialytic parenteral nutrition, the evidence includes multiple randomized controlled trials, observational studies, and systematic reviews of these studies. The relevant outcomes are overall survival, change in disease status, morbid events, health status measures, quality of life, treatment-related mortality and morbidity.Published systematic reviews, which includedrandomized controlled trials but could not pool data, haveconcluded that the current evidence does not demonstrate benefits in patient outcomes with the use of intradialytic parenteral nutrition for those who would not otherwise qualify for total parenteral nutrition. The evidence is insufficient to determine the effects of the technology on health outcomes. 

Background
PROTEIN CALORIE MALNUTRITION
Protein calorie malnutrition occurs in an estimated 25% to 40% of patients undergoing dialysis. The cause of malnutrition in patients on dialysis is often multifactorial and may include underdialysis, chronic inflammation, protein loss in the dialysate solution (particularly in peritoneal dialysis), untreated metabolic acidosis, and decreased oral intake.

Diagnosis
The clinical evaluation of malnutrition is multifactorial but typically includes measurement of serum albumin. Serum albumin levels correlate with nutritional status but are imperfect measures of nutrition because they can be affected by other disease states. Protein calorie malnutrition is associated with increased morbidity and mortality. For example, the risk of death is increased more than 10-fold in those whose serum albumin levels are less than 2.5 g/dL, and those with a serum albumin near the normal range (i.e., 3.5-3.9 g/dL) have a mortality rate twice as high as those with an albumin level greater than 4.0 g/dL.

Treatment
In patients receiving chronic dialysis, the National Kidney Foundation currently recommends a daily protein intake of 1.2 g/kg or more in patients undergoing hemodialysis and 1.3 g/kg or more in patients undergoing peritoneal dialysis.¹ When malnutrition is present, a stepwise approach to treatment is generally used, beginning with dietary counseling and diet modifications, followed by oral nutrition supplements, and then by enteral nutrition supplements or parenteral nutrition supplements if needed. 

Intradialytic parenteral nutrition (IDPN), which refers to the infusion of hyperalimentation fluids at the time of hemodialysis or peritoneal dialysis, has been investigated as a technique to treat protein calorie malnutrition in an effort to decrease associated morbidity and mortality. IDPN solutions are similar to those used for total parenteral nutrition (TPN). A typical solution contains 10% amino acids, 40% to 50% glucose, 10% to 20% lipids, or a mixture of carbohydrate or lipids, depending on patient needs. In hemodialysis, the IDPN infusion is administered through the venous port of the dialysis tubing, typically, 30 minutes after dialysis has begun, and continued throughout the dialysis session.

Regulatory Status
TPN solutions are compounded by an individual pharmacy from individual ingredients (e.g., dextrose, amino acids, trace elements) into a finished medication based on a prescription and are not required to have approval from the U.S. Food and Drug Administration (FDA) through a new drug application process. Compounding pharmacies have historically been subject to regulation by state pharmacy boards, although FDA has increased its regulatory oversight with the Drug Quality and Security Act of 2013. 

Peritoneal dialysis solutions are regulated as drugs by FDA. One amino acid-based peritoneal dialysate, Nutrineal™ PD4, 1.1% Amino Acid Peritoneal Dialysis Solution (Baxter Corp.) is available commercially outside of the United States, but has not been FDA approved. 

Policy:

• Intradialytic parenteral nutrition may be considered MEDICALLY NECESSARY when it is offered as an alternative to a regularly scheduled regimen of total parenteral nutrition only in those patients who would be considered candidates for total parenteral nutrition (TPN), i.e., a severe pathology of the alimentary tract that does not allow absorption of sufficient nutrients to maintain weight and strength commensurate with the patient’s general condition.
• Intradialytic parenteral nutrition is considered NOT MEDICALLY NECESSARY in those patients who would be considered a candidate for TPN, but for whom the intradialytic parenteral nutrition is not offered as an alternative to TPN, but in addition to regularly scheduled infusions to TPN.
• Intradialytic parenteral nutrition is investigational and/or unproven and therefore considered NOT MEDICALLY NECESSARY in those patients who would not otherwise be considered candidates for TPN.

Policy Guidelines
Patients who are considered candidates for TPN are those who have a severe pathology of the alimentary tract that does not allow absorption of sufficient nutrients to maintain weight and strength commensurate with the patient’s general condition.

This policy is only addresses intravenous parenteral nutrition as an adjunct to hemodialysis (not peritoneal dialysis).

Benefit Application
BlueCard/National Account Issues
As discussed further in the Rationale section, Medicare coverage for intradialytic parenteral nutrition is considered contractually excluded for those who would not otherwise qualify for total parenteral nutrition (TPN). For those who do qualify, claims may be reviewed for medical necessity to determine whether the intradialytic parenteral nutrition is offered in lieu of scheduled infusions of TPN (considered medically necessary), or offered in addition to regularly scheduled infusions of TPN (potentially not medically necessary)

Rationale
This evidence review was created in December 2003 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through Feb. 14, 2022.

Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life, and ability to function-including benefits and harms. Every clinical condition has specific outcomes that are important to patients and managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of technology, two domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

For patients who qualify for total parenteral nutrition and are concomitantly receiving hemodialysis, it is reasonable to administer intradialytic parenteral nutrition solution, which is similar to a total parenteral nutrition solution. intradialytic parenteral nutrition is administered via the existing venous port of the dialysis tubing rather than through an alternative intravenous site. This evidence review focuses on studies evaluating whether intradialytic parenteral nutrition as an adjunct to hemodialysis improves outcomes for individuals who may be at risk for malnutrition but who would not otherwise receive parenteral nutrition.

Intradialytic Parenteral Nutrition
Clinical Context and Therapy Purpose
The purpose of intradialytic parenteral nutrition in patients who are undergoing hemodialysis is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does intradialytic parenteral nutrition improve the net health outcome in patients who are undergoing hemodialysis?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is patients who are undergoing hemodialysis.

The cause of malnutrition in patients on dialysis is often multifactorial and may include underdialysis, chronic inflammation, protein loss in the dialysate solution (particularly in peritoneal dialysis), untreated metabolic acidosis, and decreased oral intake.

Interventions
The therapy being considered is intradialytic parenteral nutrition. Intradialytic parenteral nutrition is the infusion of an intravenous hyperalimentation formula, such as amino acids, glucose, and lipids, during dialysis, to treat protein calorie malnutrition.

Comparators
Relevant comparators are standard of care. When malnutrition is present, a stepwise approach to treatment is generally used, beginning with dietary counseling and diet modifications, followed by oral nutrition supplements, and then by enteral nutrition supplements or parenteral nutrition supplements if needed.

Outcomes
The general outcomes of interest are overall survival, change in disease status, morbid events, health status measures, quality of life, treatment-related mortality, and treatment-related morbidity.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.
• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
• Studies with duplicative or overlapping populations were excluded.

Review of Evidence
Systematic Reviews
A systematic review conducted for the U.S. Department of Veterans Affairs Evidence Synthesis Program was published in 2018 (Table 1).² The review addressed the effectiveness and adverse effects of intradialytic parenteral nutrition for the treatment of malnutrition in hemodialysis patients (Table 1). The reviewers included five RCTs and six comparative observational studies (four prospective and two retrospective). The reviewers also identified three systematic reviews but because they did not include a formal quality assessment of individual studies or did not include any relevant primary studies, these were used only to identify additional primary studies. Outcomes included clinically relevant improvements in individual indicators of nutrition status, global nutrition status, mortality, morbidity, hospitalization, and quality of life. Included primary studies compared intradialytic parenteral nutrition to oral supplements, dietary counseling, or usual care. Usual care was not well-defined in the studies and could include dietary counseling or oral supplements based on patient condition and physician recommendation. The study sample sizes were small (range 12 to 196), with the exception of one large retrospective cohort study (n = 24196). The criteria for malnutrition varied across the studies, with most using serum albumin of < 3.5 g/dL or < 4.0 g/dL along with at least one other predictor of malnutrition (weight loss, BMI, nutritional score or assessment). No studies compared intradialytic parenteral nutrition to enteral nutrition.

Table 1. Systematic Review Characteristics

RCT: randomized controlled trial; BMI: body mass index.

Compared to oral supplements and dietary counseling, intradialytic parenteral nutrition did not improve the patient health outcomes mortality, hospitalization, or quality of life (See Table 2). Observational studies found mixed results for intradialytic parenteral nutrition compared to usual care for mortality, with results differing based on baseline serum albumin levels. The effect of intradialytic parenteral nutrition on nutritional indicators also varied across comparisons and studies.

Table 2. Systematic Review Results

IDPN: intradialytic parenteral nutrition; RCT: randomized controlled trial; N: sample size; NA: not applicable; NS: nonsignificant; NR: not reported; SA: serum albumin; BMI: body mass index; OR: odds ratio; PA: serum prealbumin; SGA: subjective global assessment; RR: relative risk; CI: confidence interval; SF-12: 12-Item Short-Form Health Survey; TSF: tricep skin fold; MAC: mid-arm circumference.

The reviewers concluded that "IDPN does not appear to improve patient health or clinically important nutritional outcomes compared to the standard and recommended treatments of oral supplementation or dietary counseling." They further concluded, "Although IDPN has not been explicitly studied in hemodialysis patients who have failed adequate trials of or are unable to receive dietary counseling, oral, and/or enteral tube feeding due to malfunctioning GI tract or other issues, since evidence — albeit limited — has not raised concerns about IDPN safety, we agree with existing guidelines that it appears reasonable to consider use of IDPN in this population."²

Randomized Controlled Trials
Five RCTs on intradialytic parenteral nutrition were included in the systematic review conducted by Anderson et al. (2018)² and are discussed above.

Section Summary
Published systematic reviews, which included randomized controlled trials but could not pool data, have concluded that the current evidence does not demonstrate benefits in patient outcomes with the use of intradialytic parenteral nutrition for those who would not otherwise qualify for total parenteral nutrition.

Summary of Evidence
For individuals who are undergoing hemodialysis who receive intradialytic parenteral nutrition, the evidence includes multiple randomized controlled trials, observational studies, and systematic reviews of these studies. Relevant outcomes are overall survival, change in disease status, morbid events, health status measures, quality of life, treatment-related mortality and morbidity. Published systematic reviews, which included randomized controlled trials but could not pool data, have concluded that the current evidence does not demonstrate benefits in patient outcomes with the use of intradialytic parenteral nutrition for those who would not otherwise qualify for total parenteral nutrition. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements
Guidelines or position statements will be considered for inclusion in Supplemental Information if they were issued by, or jointly by, a U.S. professional society, an international society with U.S. representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

National Kidney Foundation
In 2001, the National Kidney Foundation clinical guidelines established target daily protein requirements in patients undergoing chronic dialysis.¹ In 2008, the National Kidney Foundation updated its pediatric nutrition guidelines to recommend a trial of intradialytic parenteral nutrition to augment inadequate nutritional intake for malnourished children (body mass index for height and age < 5th percentile) receiving maintenance hemodialysis who are unable to meet their nutritional requirements through oral and tube feeding.³

American Society for Parenteral and Enteral Nutrition
In 2010, the American Society for Parenteral and Enteral Nutrition issued guidelines on nutritional support in adults in acute and chronic renal failure. The American Society for Parenteral and Enteral Nutrition assigned a level C recommendation (supported by at least one level II investigation) that intradialytic parenteral nutrition should not be used as a nutritional supplement in malnourished chronic kidney disease-V hemodialysis patients. The basis for the recommendation was a large randomized controlled trial that found mortality rates did not differ between malnourished patients receiving intradialytic parenteral nutrition and malnourished patients receiving oral supplements without intradialytic parenteral nutrition. An additional concern was that intradialytic parenteral nutrition "is limited by the need to complete the entire nutrient infusion during the hemodialysis" treatment, which may cause adverse events because of the rapid infusion of glucose and lipids. The American Society for Parenteral and Enteral Nutrition further recommended larger randomized controlled trials "in malnourished patients are needed to ensure that a clinical benefit of IDPN does not exist."¹⁰

U.S. Preventive Services Task Force Recommendations
Not applicable

Ongoing and Unpublished Clinical Trials
One currently unpublished trial that might influence this review is listed in Table 3.

Table 3. Summary of Key Trials

References

1. Kopple JD. The National Kidney Foundation K/DOQI clinical practice guidelines for dietary protein intake for chronic dialysis patients. Am J Kidney Dis. Oct 2001; 38(4 Suppl 1): S68-73. PMID 11576926
2. Anderson J, Peterson K, Bourne D, Boundy E. Evidence Brief: Use of Intradialytic Parenteral Nutrition (IDPN) to Treat Malnutrition in Hemodialysis Patients. VA ESP Project #09-199; 2018; https://www.hsrd.research.va.gov/publications/esp/idpn-supplemental.pdf. Accessed April 22, 2022.
3. KDOQI Work Group. KDOQI Clinical Practice Guideline for Nutrition in Children with CKD: 2008 update. Executive summary. Am J Kidney Dis. Mar 2009; 53(3 Suppl 2): S11-104. PMID 19231749
4. Liu Y, Xiao X, Qin DP, et al. Comparison of Intradialytic Parenteral Nutrition with Glucose or Amino Acid Mixtures in Maintenance Hemodialysis Patients. Nutrients. Jun 02 2016; 8(6). PMID 27271658
5. Oguz Y, Bulucu F, Vural A. Oral and parenteral essential amino acid therapy in malnourished hemodialysis patients. Nephron. Oct 2001; 89(2): 224-7. PMID 11549907
6. Capelli JP, Kushner H, Camiscioli TC, et al. Effect of intradialytic parenteral nutrition on mortality rates in end-stage renal disease care. Am J Kidney Dis. Jun 1994; 23(6): 808-16. PMID 8203363
7. Hiroshige K, Iwamoto M, Kabashima N, et al. Prolonged use of intradialysis parenteral nutrition in elderly malnourished chronic haemodialysis patients. Nephrol Dial Transplant. Aug 1998; 13(8): 2081-7. PMID 9719170
8. Thabet AF, Moeen SM, Labiqe MO, et al. Could intradialytic nutrition improve refractory anaemia in patients undergoing haemodialysis?. J Ren Care. Sep 2017; 43(3): 183-191. PMID 28636166
9. Joannidis M, Rauchenzauner M, Leiner B, et al. Effect of intradialytic parenteral nutrition in patients with malnutrition-inflammation complex syndrome on body weight, inflammation, serum lipids and adipocytokines: results from a pilot study. Eur J Clin Nutr. Jun 2008; 62(6): 789-95. PMID 17522619
10. Brown RO, Compher C, McClave S, et al. A.S.P.E.N. clinical guidelines: nutrition support in adult acute and chronic renal failure. JPEN J Parenter Enteral Nutr. Jul-Aug 2010; 34(4): 366-77. PMID 20631382
11. Kopple JD, Foulks CJ, Piraino B, et al. Proposed Health Care Financing Administration guidelines for reimbursement of enteral and parenteral nutrition. Am J Kidney Dis. Dec 1995; 26(6): 995-7. PMID 7503076
12. Department of Health and Human Services, Health Care Financing Administration. HCFA Rulings. Ruling No. 96-3. 1996; https://www.cms.gov/Regulations-and-Guidance/Guidance/Rulings/downloads//hcfar963.pdf. Accessed April 22, 2022.

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This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

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