Populations	Interventions	Comparators	Outcomes
Individuals: Who are undergoing hemodialysis	Interventions of interest are: Intradialytic parenteral nutrition	Comparators of interest are: Standard of care (eg, oral nutritional supplementation)	Relevant outcomes include: Overall survival Change in disease status Morbid events Health status measures Quality of life Treatment-related mortality Treatment-related morbidity

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 under dialysis, 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 (ie, 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

For patients receiving chronic dialysis, the National Kidney Foundation currently recommends a daily protein 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, 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. Intradialytic parenteral nutrition solutions are similar to those used for total parenteral nutrition. 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 intradialytic parenteral nutrition 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

Total parenteral nutrition solutions are compounded by an individual pharmacy from individual ingredients (eg, 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 the FDA increased its regulatory oversight under the Drug Quality and Security Act of 2013.

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

Related Policies

• None

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


Medicare Coverage:
Intradialytic parenteral nutrition is covered when NCD 180.2 and LCD L33798 criteria are met. Per NCD 180.2, coverage of nutritional therapy as a Part B benefit is provided under the prosthetic device benefit provision which requires that the patient must have a permanently inoperative internal body organ or function thereof. Therefore, enteral and parenteral nutritional therapy are normally not covered under Part B in situations involving temporary impairments.

Per Local Coverage Article: Parenteral Nutrition - Policy Article (A52515), in order to cover intradialytic parenteral nutrition (IDPN), documentation must be clear and precise to verify that the beneficiary suffers from a permanently impaired gastrointestinal tract and that there is insufficient absorption of nutrients to maintain adequate strength and weight. Records should document that the beneficiary cannot be maintained on oral or enteral feedings and that due to severe pathology of the alimentary tract, the beneficiary must be intravenously infused with nutrients.

For additional information and eligibility, refer to NCD 180.2 and LCD L33798.

National Coverage Determination (NCD) for Enteral and Parenteral Nutritional Therapy (180.2). Available to be accessed at CMS National Coverage Determinations (NCDs) Alphabetical Index search page: https://www.cms.gov/medicare-coverage-database/indexes/ncd-alphabetical-index.aspx.

Noridian Healthcare Solutions, LLC, Local Coverage Determination (LCD): Parenteral Nutrition (L33798). Available to be accessed at Noridian Healthcare Services, LLC, (DME MAC), Local Coverage Determinations (LCDs) search page: https://www.cms.gov/medicare-coverage-database/indexes/lcd-list.aspx?Cntrctr=389&ContrVer=1&CntrctrSelected=389*1&s=38&DocType=All&bc=AggAAAAAAAAAAA%3d%3d&#ResultsAnchor.

Local Coverage Article: Parenteral Nutrition - Policy Article (A52515). Available to be accessed at Noridian Healthcare Services, LLC, (DME MAC), Local Coverage Determinations (LCDs) search page: https://www.cms.gov/medicare-coverage-database/indexes/lcd-list.aspx?Cntrctr=389&ContrVer=1&CntrctrSelected=389*1&s=38&DocType=1&bc=AAgAAAAAAAAA&#aFinal.


Medicaid Coverage:
For members enrolled in Medicaid and NJ FamilyCare plans, Horizon BCBSNJ applies the above medical policy.

FIDE-SNP Coverage:

For members enrolled in a Fully Integrated Dual Eligible Special Needs Plan (FIDE-SNP): (1) to the extent the service is covered under the Medicare portion of the member’s benefit package, the above Medicare Coverage statement applies; and (2) to the extent the service is not covered under the Medicare portion of the member’s benefit package, the above Medicaid Coverage statement applies.

[RATIONALE: This policy was created in 2010 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through February 28. 2020.

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 policy 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 policy 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 policy.

Patients

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

The following practices are currently being used to make decisions about intradialytic parenteral nutrition.

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.

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

Study	Dates	Studies	Participants	N (Range)	Design	Duration
Anderson et al (2018)2,	2009-2017	5 RCTs, 4 prospective cohort, 2 retrospective cohort	Mean age 65 years (37 to 80) Mean 50% male At least 6 months on dialysis prior to inclusion in study Mean serum albumin 3.77 g/dL (range 3.02 to 3.8 g/dL) BMI range 19.2 to 23.4 kg/m2	602 (12 to 196), excluding one large retrospective cohort study (N=24,196)	RCTs and observational studies	12 weeks to 2 years

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

Study	IDPN vs Oral Supplements: Mortality	IDPN vs Oral Supplements: Hospitalization	IDPN vs Oral Supplements: Quality of life	IDPN vs Oral Supplements: Nutritional Indicators	IDPN vs Dietary Counseling: Mortality	IDPN vs Dietary Counseling: Hospitalization	IDPN vs Dietary Counseling: Quality of life	IDPN vs Dietary Counseling: Nutritional Indicators	IDPN vs Usual Care: Mortality	IDPN vs Usual Care: Quality of life	IDPN vs Usual Care: Nutritional indicators
Anderson et al (2018)2,
Evidence	1 RCT3,	1 RCT3,	1 RCT3,	2 RCTs,3,4, 1 cohort study5,	1 RCT6,	1 RCT6,	1 RCT6,	1 RCT6,	3 cohort studies5,7,	1 RCT8,	2 RCTs,3,8, 3 cohort studies5,7,9,
Total N (range)	186 (NA)	186 (NA)	186 (NA)	238 (20 to 186)	107 (NA)	107 (NA)	107 (NA)	107 (NA)	24,305 (28 to 24,196)	40 (NA)	347 (12 to 186)
Effect	43% vs 39%; P = NS	# days hospitalized/days follow-up: 0.008 vs 0.06 (P = NS)	No difference in Karnofsky score (data NR)	Mean change: SA (g/dl): 0.18 (P =.048) vs 0.28 (P =.17) Mean change: BMI: -0.10 (P = 0.87) vs -0.10 (P =.69) MAC: -1 (P =.09) vs 0.47 (P =.35) TSF: -0.43 (P = 0.5) vs 0.42 (P =.66)	26.4% (14/53) vs 12.9% (7/54) (P-value NR)	59.0% vs 43.2%, P =.1509	(SF-12) score change from baseline at 16 wks. -2.74 vs 0.34, P =.1175	Positive response to IDPN (≥ 30mg/L increase in PA) 48.7% vs 31.8% at week 16 (P =.1164) Patients achieving > 15% increase from baseline at week 4, PA (mg/L): 41% vs 20.5%, P =.0415 Improved SGA score by one grade: 20.5% vs 13.6%, P =.4037	Survival: RR = 1.34, P <.01 (Cox) Time to death (mo) for nonsurvivors: 16.9 vs 7.5, P <.01 OR death: (SA ≥ 4.0 g/dL & CRE > 8.0 mg/dL) = 2.6 (95% CI 1.34 - 5.04) SA ≤ 3.3 =0.72 (P <.01) SA ≤ 3.0 g/dL = 0.57 (95% CI 0.44 - 0.77) Mortality: 0% vs 27.8%, (P <.02)	No improvement in functional capacity (data NR)	No difference in change in SA or PA (data NR) No difference in change in BMI (data NR) Mean change: SA (g/dL) 0.93 (P =.001) vs -0.14 (P = 0.316) Mean change: BMI 2.8 (P =.001) vs 0.03 (P =.981) Mean change: MIS -8.75 (P =.001) vs 0.25 (P =.716)
Summary	No improvement	No improvement	No improvement	Variable effect with no improvement except serum albumin in a single study	No improvement	No improvement	No improvement	Variable effects on serum prealbumin No improvement in serum albumin or subjective global assessment	Variable effect on mortality; effect differs by baseline serum albumin level	No improvement	Variable effect, with improvement in at least one nutritional indicator

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.

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. 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 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 the effects of the technology on health outcomes.

SUPPLEMENTAL INFORMATION
Practice Guidelines and Position Statements
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 policy is listed in Table 3.

Table 3. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
Ongoing
NCT04094038	The Effect of Intradialytic Parenteral Nutrition on Nutritional Status and Quality of Life in Hemodialysis Patients	166	Sep 2023

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Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

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Index:
Intradialytic Parenteral Nutrition
Parenteral Nutrition, Intradialytic

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.ncbi.nlm.nih.gov/books/NBK518608/. Accessed May 2020.

3. 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 May 2020.

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