name, title, affiliation phil ayers, pharmd, bcnsp, …...name, title, affiliation phil ayers,...

Name, Title, Affiliation Phil Ayers, PharmD, BCNSP, FASHP Chief, Clinical Pharmacy Services, Mississippi Baptist Medical Center Associate Clinical Professor, University of Mississippi School of Pharmacy Presentation Title Lipid Injectable Emulsions (ILE) Do’s and Don’ts Disclosures Speakers Bureau: Fresenius Kabi, Janssen Presentation Overview/Summary • In 2017, the ASPEN Parenteral Nutrition Safety Committee conducted a ILE Survey with Gap

Analysis. The survey revealed a number of institutions do not filter their ILE’s and infusion times vary from published recommendations.

Learning Objectives • Learning objectives for the presentation. At the conclusion of the presentation, the learner will be able to:

1. Summarize the 2017 ASPEN ILE survey and gap analysis. Key Takeaways/Fast Facts • The results of this survey conducted in late 2016 found a wide variation in practice, particularly

across patient age groups. Conclusion: These findings demonstrate the need for ongoing dissemination and education on standardized safe practices for ILE use.

Learning Assessment Questions

1. Question 2: 2-in-1 PN will have intravenous lipid emulsion (ILE) piggybacked along with the PN. What is the appropriate hang time for ILE when piggybacked with a 2-in-1 PN?

A. 8 hours B. 12 hours C. 18 hours D. 24 hours

Learning Assessment Answers:

1. Answer = B; Rationale: Current recommendations state that ILE within a TNA should have a maximum hang time of 24 hours. Recommendations also state than ILE piggybacked into a 2-in-1 PN solution should have a maximum hang time of 12 hours. Tubing should also be changed every 12 hours when ILE is piggybacked with 2-in-1 PN. These recommendations also state that if ILE is to be infused separately over > 12 hours, the dose should be divided into two parts with a new container and tubing every 12 hours.

References: 1. Christensen ML, Ayers P, Boullata. at.el. Lipid injectable emulsion survey with gap analysis.

NCP. 2017;32(5):694-702.

2017 ASPEN ILE Survey With Gap Analysis

ASPEN 2019 Nutrition Science & Practice Conference

Phil Ayers, PharmD, BCNSP, FASHPChief, Clinical Pharmacy ServicesMississippi Baptist Medical Center

Clinical Associate ProfessorUniversity of Mississippi School of Pharmacy

Jackson, MS

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• Fresenius Kabi Speakers Bureau

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Learning Objectives

Upon completion of this session, the learner will be able to….

1. Summarize the 2017 ASPEN Lipid Survey and Gap Analysis.

Lipid Injectable Emulsion Survey With Gap Analysis

ASPEN EDUCATION PROGRAM OUTLINE TEMPLATE Kathleen M Gura, PharmD, BCNSP, Manager Pharmacy Clinical Research Program, Boston Children’s Hospital, Boston MA The Use of Alternative ILEs in the Pediatric Population Disclosures Pharmaceutical advisory board

B Braun Baxter

Consultant B Braun Fresenius Kabi Pfizer Pediatric Center of Excellence Xellia Pharmaceuticals Northsea Therapeutics Alcresta Otsuka Pharmaceutical Factory

Patents/royalties for use of Omegaven Presentation Overview/Summary

For more than 50 years, soybean oil lipid emulsions were the mainstay of therapy in the pediatric patient. In 2016 a mixed oil emulsion was approved for use in adults and 2018 a pure fish oil emulsion became available for pediatric patients with PN associated liver disease. This session will discuss the approved and unapproved uses of these ILEs in pediatric patients and discuss potential the pros and cons of each product.

Learning Objectives At the conclusion of the presentation, the learner will be able to:

1. Understand when lipid restriction protocols can be safely used 2. Discuss the concerns of using a mixed oil IVLE in a pediatric patient 3. List which patients should not receive fish oil monotherapy

Key Takeaways/Fast Facts

1. Pure soybean oil emulsions may be an appropriate alternative to the newer lipid emulsions in certain patients with limited venous access and multiple intravenous medications.

2. Monitoring essential fatty acid status is important in patients receiving an alternative IVLE. 3. Lipid restriction protocols should not be used with alternative IVLEs.


Question 1: (True/false) Pure fish oil lipid emulsions contain only omega-3 fatty acids.

A. True B. False

Question 2: According to the Holman Index, biochemical essential fatty acid deficiency occurs then the triene;tetrane ratio is:

A. > 0.05 B. < 0.05 C. >0.2

ASPEN EDUCATION PROGRAM OUTLINE TEMPLATE

D. >0.4

Question 3: (true/false) Pure fish oil emulsions are FDA approved for use in preventing PN associated cholestasis in children.

A. True B. False

Question 4: (true/false) Under the right circumstances, soy/MCT/olive/fish oil lipid emulsions can cause EFAD.

A. True B. False

Question 5: (true/false) Fish oil monotherapy has been shown to be ineffective as a treatment of acetaminophen toxicity.

A. True B. False


1. Answer: B (false). Fish oil contains both omega-3 and omega-6 fatty acids and when dosed appropriately, can provide sufficient essential fatty acids to prevent deficiency.

2. Answer: C. According to the Holman Index, biochemical evidence of EFAD occurs when the triene:tetraene ratio is greater than 0.2. Physical signs occur when the ratio is greater than 0.4. Other laboratory ranges have been used to describe what is observed in healthy individuals eating a typical Western diet.

3. Answer: B (false). Pure fish oil emulsions are only FDA approved as a source of essential fatty acids and calories in children with PN associated cholestasis. It is not approved for preventing PNAC.

4. Answer: A (true). In patients who are totally PN dependent, lower doses of these mixed oil emulsions have been associated with EFAD. Monitoring of EFA status is necessary to ensuring adequate doses are being provided.

5. Answer: A (true) In animal models, fish oil monotherapy has been shown not to be effective in treating the hepatic damage seen with acetaminophen toxicity.

References 1.de Meijer VE, Le HD, Meisel JA, Gura KM, Puder M. Parenteral fish oil as monotherapy prevents essential fatty acid deficiency in parenteral nutrition–dependent patients. J Pediatr Gastroenterol Nutr. 2010;50:212-218. 2.Puder M, Valim C, Meisel JA, et al. Parenteral fish oil improves outcomes in patients with parenteral nutrition–associated liver injury. Ann Surg. 2009;250:395-402. Lee SI, Valim C, Johnston P, et al. Impact of fish oil–based lipid emulsion on serum triglyceride, bilirubin, and albumin levels in children with parenteral nutrition–associated liver disease. Pediatr Res. 2009;66(6):698-703.

ASPEN EDUCATION PROGRAM OUTLINE TEMPLATE 3.Diamond IR, Sterescu A, Pencharz PB, Kim JH, Wales PW. Changing the paradigm: omegaven for the treatment of liver failure in pediatric short bowel syndrome. J Pediatr Gastroenterol Nutr. 2009;48:209-215. 4.de Meijer VE, Gura KM, Meisel JA, Le HD, Puder M. Parenteral fish oil monotherapy in the management of patients with parenteral nutrition– associated liver disease. Arch Surg. 2010;145:547-551. 5.Vanek VW, Seidner DL, Allen P, Bistrian B, Collier S, Gura K, Miles JM, Valentine CJ, Kochevar M; Novel Nutrient Task Force, Intravenous Fat Emulsions Workgroup; American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) Board of Directors .A.S.P.E.N. position paper: Clinical role for alternative intravenous fat emulsions. Nutr Clin Pract. 2012 Apr;27(2):150-92. 6.Nehra D, Fallon EM, Carlson SJ, Potemkin AK, Hevelone ND, Mitchell PD, Gura KM Puder M. Provision of a Soy-Based Intravenous Lipid Emulsion at 1 g/kg/d Does Not Prevent Cholestasis in Neonates. JPEN J Parenter Enteral Nutr. 2012 Jul 5.

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The Use of Alternative ILEs in the Pediatric Population

Kathleen M. Gura Pharm.D., BCNSP, FASHP, FPPAG FASPENCenter for Advanced Intestinal Rehabilitation (CAIR)

Boston Children’s HospitalAssistant Professor of Pediatrics, Harvard Medical School

[email protected]

Disclosures• Pharmaceutical advisory board

– B Braun– Baxter

• Consultant– B Braun– Fresenius Kabi– Pfizer Pediatric Center of Excellence– Xellia Pharmaceuticals– Northsea Therapeutics– Alcresta– Otsuka Pharmaceutical Factory

• Patents/royalties for use of Omegaven

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Disclosures

A licensing agreement exists between Boston Children’s Hospital & Fresenius Kabi for the use

of Omegaven in PNALD.

I will be discussing off labeled indications and products that are currently not FDA approved.

Learning Objectives

At the end of this session, participants will be able to:

• Understand when lipid restriction protocols can be safely used

• Discuss the concerns of using a mixed oil IVLE in a pediatric patient

• List which patients should not receive fish oil monotherapy

Deciding When to Use Which Lipid Emulsion When…..

Soybean Oils

Recommendation: Based on 2 level 2 studies, in critically ill patients who are not malnourished, are tolerating some EN, or when parenteral nutrition is indicated for short term use (< 10 days), withholding lipids high in soybean oil should be considered.

– insufficient data to make a recommendation about withholding lipids high in soybean oil in critically ill patients who are malnourished or those requiring PN for long term (> 10 days)

www.criticalcarenutrition.com 10.2 Strategies to Optimize Parenteral Nutrition and Minimize Risks: Use of lipids March 2013

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Intestinal Failure (IF) • Definition:

– PN dependence > 3 mo. • Over 60% of infants with IF develop

cholestasis (direct Bilirubin > 2 mg/dL)– Before 2004:mortality was 37.5% due

to liver failure and or sepsis (Boston Children’s Hospital)

– 78% mortality if bilirubin >3 mg/dL for 3 months

– Approach 90% mortality if cholestasis and remain on PN for > 1 year

– 1.4% of all deaths of children 4 years of age and under

Prevention of IFALD

Impact of Soybean Lipid Dose

Lipid Restriction 1g/kg/dayRollins et al J Pediatr Surg. 2013 Jun;48(6):1348-56

• Pilot study n=28• Prospective RCT• Infants > 26 weeks GA on >50%

total calories from PN• Compared 1g/kg/d to 3g/kg/d • Results:

– Ave PN duration 5.4 weeks– Tot increase in dbili from baseline

less in low dose group (p=0.04)– Weight z-score increased more in

3g/kg/d group– No EFAD

• CONCLUSION:– Markers of cholestasis rose at a

slower rate using 1g/kg/d IFE

Prophylactic Lipid Restriction 1g/kg/day

Sanchez et al J Pediatr Surg. 2013 Mar;48(3):573-8

• Surgical neonates (n=82) receiving 1g/kg/d retrospectively compared to control cohort (2g/kg/d) (n=132)

• Results: PNLAD less in 1g/kg/d group (22% vs. 43% p=0.003)

• Omegaven rescue used in 4 infants in standard dose vs. 2 infants in low dose group

Severe Lipid RestrictionCurrent Opinion in Organ Transplantation 2010,

15:330–333

• Protocol:– 1 g/kg/d twice weekly

– If EFAD develops: 1g/kg/day 3x/week

• If the EFAD persists: 2g/kg/day 3x/week

• Preliminary results indicate IFE restriction resulted in a statistical significant reduction in total bilirubin without impacting growth or causing EFAD

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• Multicenter study RCT

• 136 neonates <48 hrs of age randomized to low (1 g/kg/d, n=67) or high dose (~3g/kg/d n=69) SO

• Results– no difference in PNALD (69% vs 63%; 95% confidence interval, -

0.1 to 0.22; P = 0.45)

– weight, length, and head circumference at 28 DOL, discharge, and over time were not different (P > 0.2 for all)

• Conclusion: Compared with the control dose, low-dose SO was not associated with a reduction in PNALD or growth

BCH Experience:Intralipid Dose and Cholestasis

• Retrospective chart review: All patients who received PN/IL in the NICU at BCH between January 2007 – June 2011

• Inclusion Criteria– Age <2months at PN/IL initiation– On IL for at least 3 weeks at CHB– No PN/IL prior to transfer to CHB– Gastrointestinal surgical condition as indication for PN/IL

• Exclusion Criteria– Multisystem organ failure– Inconsistent IL dosing

1g/kg/day IL group

2-3 g/kg/day IL group

Nehra et al JPEN 2013 Jul;37(4):498-505

Patient characteristics while on parenteral nutrition

What About Switching the ILE Type?

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Safety and efficacy of Fish Oil Based Lipid Emulsion in the Prevention of PNALD

a double-blind randomized controlled clinical trial to compare Soybean oil to Fish oil at 1g/kg/day

• Primary outcome:– Incidence PNLAD

• Secondary outcomes:

– Safety

- Growth

- Infection risk

- EFA status

- Neurodevelopment

• Inclusion Criteria:– <3mo at enrollment

– Baseline d bili <1

– Expected PN > 21 days

• Exclusion criteria:– Shock

– Severe hemolytic disorder

– Baseline triglyceride >400 mg/dL

– Prior exposure to intravenous fat emulsion

Primary Outcome:Incidence of cholestasis

Median Weekly Direct BilirubinOM group

Week

Dir

ect

bili

rub

in

(mg

/dL

)

0 1 2 3 4 5 6 7 8 9 100

2

4

6

8

10

Median Weekly Direct BilirubinIL group

Week

Dir

ect

bili

rub

in

(mg

/dL

)

0 1 2 3 4 5 6 7 8 9 100

2

4

6

8

10

Soybean Oil Fish Oil

No difference in weekly median bilirubin values between groups

Nehra, et al.JPEN J Parenter Enteral Nutr June 14, 2013

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Secondary Outcomes:Growth

-2.5

-2

-1.5

-1

-0.5

0

0 1 2 3 4 5 6

Week

Me

dia

n W

eig

ht-

for-

ag

e Z

-sc

ore

Fish Oil

Soybean Oil

P=0.72

Secondary Outcomes:Infection rate

Soybean Oil(n=10)

Fish Oil (n=9)

Total # positive blood cultures

5 7

Total # positive stool cultures

2 2

Total # positive sputum cultures

1 0

Secondary Outcomes:Neurodevelopment

Soybean Oil Fish Oil P-value24 month Bayley

Cognitive

Language

Motor

95

106

99

93

111

101

0.76

0.56

0.76

24 month PARCA-R*

Cognition

Linguistic skills

Composite Score

26

33

59

29

77

98

1.00

0.30

0.30

*PARCA-R: Parent Reports of Child’s Abilities

Conclusions from the pilot study . . .

No adverse effects:

‐Growth‐Infection rate‐Fatty acid profiles‐Neurodevelopment

No difference in the incidence of cholestasis

Treatment of IFALD

Fish Oil Monotherapy

• Dose: 1g -1.5 g/kg/day

• All soy containing IFE discontinued

• Efficacy:– Boston (historical controls)

– LA (historical controls)

– Texas (historical controls)

– Hong Kong (prospective RCT)

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Direct Bilirubin

0 4 8 12 16 20 24 28 32 36

05

1015

05

Weeks from Baseline

Dir

ect

Bili

rubi

n (m

g/dL

) P < 0.0001

Soybean oil

Fish oil

•Parameter # 1: direct bilirubin; 80-125% of the value of the potential pair was tolerated

•Parameter # 2: Age at baseline; ± 28-day range was accepted for the potential pair

•Parameter # 3: Gestational age; 90-110% of the value of the potential pair was accepted

31 patients were included in the analysis and matched according to the above mentioned criteria

Boston ExperiencePair-Matching Analysis

Methodology

Results of Pair Matching

Hong Kong RCTNeonatology 2014;105:290-296

• 1.5 g/kg/day for both IFE

• 16 infants (FO n=9, SO n=7)

• no significant difference in reversal of IFALD at 4 months between groups– Rates of increase of Dbili &

ALT in SO group > FO group

• 13.5 vs.0.6 µmol/l/wk and 9.1 vs. 1.1 IU/l/wk (p = 0.03)

– ↑ EN associated with significant improvement of IFALD in FO group compared to SO

• Rate of increase of direct bilirubin in the SO group significantly higher than in the FO group (p = 0.03)

• ALT significantly worsened, increasing by 9.1 IU/l per week in the SO group (p < 0.01) but not in the FO group (1.1 IU/l per week, p = 0.71)

• Rate of increase of ALT in the SO group significantly greater than in the FO group (p = 0.02).

How long should you remain on fish oil monotherapy?

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Long-Term Outcomes in Children With Intestinal Failure-Associated Liver Disease Treated With 6

Months of Intravenous Fish Oil Followed by Resumption of Intravenous Soybean Oil

(JPEN J Parenter Enteral Nutr. 2018 Nov 8)

• Children treated who resumed SO after FO; prospectively followed for 4.5 years or until death, transplant, or PN stop

• 1°outcome cumulative incidence rate IFALD return

• 48 subjects

– 71% IFALD resolution after 6 mo.

– 27 resumed SO

• IFALD 26%

• Transplant 6% 31

Omegaven isn’t a wonder drug…..

Predictors of Intravenous Fish Oil (Omegaven®) Failure in the

Treatment of Parenteral Nutrition-Associated Liver Disease

Am J Clin Nutr. 2016 Sep;104(3):663-70.

Study Design

Retrospective review of prospectively collected data for patients started on FO (Omegaven®) therapy at BCH from January 2004 to December 2014.

• Inclusion criteria: – All patients with PNALD who received at least 1 dose of FO

therapy from January 1, 2004 to December 31, 2014

• Exclusion criteria:– Patients who started FO at outside institution

– Patients who are still cholestatic (only included patients who have either failed or reversed)

• 85.7% cholestasis reversed (156/182)

• 14.3% failed FO therapy (26/182)– 8 transplants (6 multivisceral, 2 liver)

– 18 deaths

• 16.9% of pts transferred from OSH with PNALD vs. 9.4% of pts who developed PNALD at BCH failed FO therapy.– 20/118 [16.9%] vs. 6/64 [9.4%], P=0.16

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Results

Am J Clin Nutr. 2016 Sep;104(3):663-70.

Results

• Patients who failed therapy had more advanced biochemical liver disease at time of FO initiation:– Lower GGT, platelets; Higher DB, INR, PELD

• Patients who failed therapy had higher rates (than

patients whose cholestasis resolved) of:– History of GI bleeding

– Mechanical ventilation &/or sepsis at time of FO initiation

– Neurologic, genetic/chromosomal, or endocrine comorbidity at FO initiation

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Am J Clin Nutr. 2016 Sep;104(3):663-70.

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Independent Predictors of Treatment Failure

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PELD = 4.8[ln(TB)] + 18.57[ln(INR)] – 6.87[ln(albumin)] + 4.36 (if age <1 yr) + 6.67 (if growth failure)

Reversed(n=128)

Treatment failure(n=20)

P OR (95% CI)

Baseline PELD score ≥ 15

30 (23%) 13 (65%) 0.005 4.7 (1.6, 13.9)

History of GI bleed 22 (17%) 9 (45%) 0.006 4.6 (1.5, 13.8)

Patient age ≥16 weeks at FO initiation

47 (37%) 14 (70%) 0.004 5.5 (1.7, 17.5)

Ventilator at FO initiation

16 (13%) 7 (35%) 0.002 6.8 (2.1, 22.5)

Am J Clin Nutr. 2016 Sep;104(3):663-70.

Lessons learned…• Patients who failed therapy were older and

had more advanced biochemical and clinical liver disease at FO initiation.– However, many patients with similar labs and

acuity responded to FO therapy.

• Early initiation of FO therapy once biochemical cholestasis is detected in PN-dependent patients is recommended. – 85 pts since 2011: 3 deaths, 1 LTx

• Reversibility of PNALD cannot be reliably determined.

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Patients who shouldn’t be treated with Omegaven….

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Acetaminophen Toxicity

Animals fed a fish oil-based diet were more susceptible, rather than resistant, to APAP-induced hepatotoxicity

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JPEN J Parenter Enteral Nutr. 2013 Mar;37 (2):268-73.

Other Approaches

• SMOFlipid

• 50/50 blend FO + SO

• Reduced dose SO

SMOFlipid• Birmingham Children’s

• Case series infants/ children with PNALD while on SO & switched to SMOFlipid (n=8)

• 1 patient died, 1 listed for transplant

• Remaining 6: “sudden, often dramatic and sustained fall in bilirubin 1-3 months after switching to SMOFlipid”

Source:Protheroe/Murphy

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Concerns with SMOFlipid

• Not FDA approved in children

• Dosing important

• Low doses– Cause EFAD

• Higher doses– no hepatoprotective

benefits

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Authors Study Design Cohort Lipid dose Length of time

Outcomes

Goulet et al (2010)

Single-center, prospective, randomized, double-blind study comparing SMOFlipid to SOLE

28 children (5 month - 11 years) on home PN at least 4 weeks with short bowel syndrome, chronicintestinal pseudo-obstruction, or congenital disease of GI mucosa

2 g/kg/day 29 d • Total bilirubin• ω-3 fatty acids• Lipid peroxidation• Plasma α-tocopherol

*Safe and well tolerated, decreased liver

enzymes/bilirubin

Tomsits et al(2010)

Prospective, randomized, double-blind trial comparing SMOFlipid to SOLE

60 premature neonates (age 3-7 days, gestational age ≤ 34 weeks, birth weights 1000-2500 g) on PN for minimum 7 -14 days.

0.5 g/kg/day day 1Increased by

0.5 g/kg/day up to 2 g/kg/day

7-14 d • Triglyceride levels• GGT levels• ω-6 to ω-3 ratio• Plasma α-tocopherol• Liver enzymes

*Safe and well tolerated, decreased GGT, consistent with

maintained liver fxn

Rayyan et al(2012)

Prospective, double blind, randomized trial comparing SMOFlipid to SOLE

53 neonates (<34 week gestation, birth weight 500-2000g) on PN x 7 days minimum

1 g/kg/day days 1-32 g/kg/day day 43 g/kg/day day 53.5 g/kg/day day 6-14

7-14 d • Total and direct bilirubin• Triglyceride levels• ω-6 to ω-3 ratio

*Safe and well tolerated, increase EPA & DHA, decreased GGT & DB

Diamond et al(2017)

Pilot, multicenter, prospective, randomized, blinded trial comparing SMOFlipid to SOLE

24 infants (<24 months) with short bowel syndrome or intestinal failure with hyperbilirubinemia on PN

1-3 g/kg/day 8 wks • Serum conjugated bilirubinSMOFlipid reduces the risk

of progressive IFALD in children with intestinal

failure

Repa et al(2017)

Prospective, single-center, double-blind randomized control trial comparing SMOFlipid to SOLE

230 ELBW infants (birth weight <1000g) on PN

3 g/kg/day 15-35 d • Serum conjugated bilirubin• Triglyceride levels • Liver enzymes

*Incidence of IFALD not decreased, no effect on ROP, no difference in hypertriglyceridemia

Authors Study Design Cohort Lipid dose Length of time

Outcomes

Goulet et al (2010)

Single-center, prospective, randomized, double-blind study comparing SMOFlipid to SOLE

28 children (5 month - 11 years) on home PN at least 4 weeks with short bowel syndrome, chronicintestinal pseudo-obstruction, or congenital disease of GI mucosa

2 g/kg/day 29 d • Total bilirubin• ω-3 fatty acids• Lipid peroxidation• Plasma α-tocopherol

*Safe and well tolerated, decreased liver

enzymes/bilirubin

Tomsits et al(2010)

Prospective, randomized, double-blind trial comparing SMOFlipid to SOLE

60 premature neonates (age 3-7 days, gestational age ≤ 34 weeks, birth weights 1000-2500 g) on PN for minimum 7 -14 days.

0.5 g/kg/day day 1Increased by

0.5 g/kg/day up to 2 g/kg/day

7-14 d • Triglyceride levels• GGT levels• ω-6 to ω-3 ratio• Plasma α-tocopherol• Liver enzymes

*Safe and well tolerated, decreased GGT, consistent with

maintained liver fxn

Rayyan et al(2012)

Prospective, double blind, randomized trial comparing SMOFlipid to SOLE

53 neonates (<34 week gestation, birth weight 500-2000g) on PN x 7 days minimum

1 g/kg/day days 1-32 g/kg/day day 43 g/kg/day day 53.5 g/kg/day day 6-14

7-14 d • Total and direct bilirubin• Triglyceride levels• ω-6 to ω-3 ratio

*Safe and well tolerated, increase EPA & DHA, decreased GGT & DB

Diamond et al(2017)

Pilot, multicenter, prospective, randomized, blinded trial comparing SMOFlipid to SOLE

24 infants (<24 months) with short bowel syndrome or intestinal failure with hyperbilirubinemia on PN

1-3 g/kg/day 8 wks • Serum conjugated bilirubinSMOFlipid reduces the risk

of progressive IFALD in children with intestinal

failure

Repa et al(2017)

Prospective, single-center, double-blind randomized control trial comparing SMOFlipid to SOLE

230 ELBW infants (birth weight <1000g) on PN

3 g/kg/day 15-35 d • Serum conjugated bilirubin• Triglyceride levels • Liver enzymes

*Incidence of IFALD not decreased, no effect on ROP, no difference in hypertriglyceridemia

SMOFlipid failed to reverse IFALD

• Korea

• Case reports (n=2)– Received 2-3 g/kg/d

SMOFlipid

– IFALD developed

• IFALD reversed upon discontinuing SMOFlipid and switching to Omegaven monotherapy

46

Essential Fatty Acid Status in Surgical Infants Receiving Parenteral Nutrition With a Composite

Lipid Emulsion: A Case Series(JPEN J Parenter Enteral Nutr. 2018 May 30)

• 4 infants receiving SMOFlipid® as their IV lipid source

– essential fatty-acid status, triglycerides, and dosing strategy reviewed

• Conclusions– May render infants at risk for EFAD.

• Should be dosed appropriately to prevent EFAD

– Hypertriglyceridemia and cholestasis are known adverse effects and require monitoring

47

Essential Fatty Acid Status in Surgical Infants Receiving Parenteral Nutrition With a Composite Lipid Emulsion: A Case Series

Essential Fatty Acid Status in Surgical Infants Receiving Parenteral Nutrition With a Composite Lipid Emulsion: A Case Series, First published: 30 May 2018, DOI: (10.1002/jpen.1311)

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Triglyceride and Direct Bilirubin Levels

Essential Fatty Acid Status in Surgical Infants Receiving Parenteral Nutrition With a Composite Lipid Emulsion: A Case Series, First published: 30 May 2018, DOI: (10.1002/jpen.1311)

50/50 FO + SOJ Pediatr Gastroenterol Nutr. 2009 Feb;48(2):209-15

• Canada

• 12 patients with PNALD

• 1g/kg/d SO + 1g/kg/d FO

• 5 cases, hepatic dysfunction while on the blended regimen progressed until Intralipid® stopped and Omegaven® was given alone

• Complete resolution of PNALD occurred in 9 patients (75%)

Control: 3 g/kg/d, Intervention: 1 g/kg twice weekly, n = 31 each group

Results:

42% resolution (fat reduction)

10% resolution control group

Cober et al, J Pediatr 2012;160:421-7

SOY LIPID RESTRICTIONJ Pediatr. 2012 Mar;160(3):421-7.

Putting it all together….

52

Pros and Cons Soybean Oil ILE

• Pros– 50+ years of experience

– 1g/kg/day does not cause EFAD

– Lots of compatibility information

• Cons– High risk of IFALD

– Rich in phytosterols, omega-6 fatty acids

– Low in alpha-tocopherol

53

Pros and ConsFish Oil ILE

• Pros– Improves hepatic function in IFALD

– Rich in omega-3 fatty acids, alpha-tocopherol

– Low in phytosterol content

• Cons– Need at least 1g/kg/day to prevent EFAD

– 10% emulsion

– Little compatibility information

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Pros and ConsSoy-MCT-Olive-Fish ILE

Pros

-20% emulsion

-can use to reduce GIR

-contains MCT – more stable TNAs

Cons

-3g/kg/d = 1g/kg/day soybean ILE

-not approved for use in pediatric patients

-limited compatibility data

-dose low: EFAD, dose high: IFALD

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Gura’s Thoughts

• New start – Intralipid or SMOFlipid at age appropriate

doses (i.e., 3g/kg/day if neonate)

• Limited vascular access/lots of IV meds– Intralipid 1g/kg/day

• Need to reduce GIR, no IFALD present– SMOFlipid

• IFALD – Omegaven

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4 Lipid Emulsions Oil Red-O

CHOW PN + IL

PN + SMOF PN + OM

PN +ClinOleic ®

Meisel JA et al Journal of Pediatric Surgery 2011; 46:666-673

There is no ideal ILEMonitoring is essential!

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Never assume….

59 60

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References• Waitzberg DL, Torrinhas RS, Jacintho TM. New parenteral lipid emulsions for

clinical use. JPEN J Parenter Enteral Nutr. 2006;30:351-367.

• Le HD, Meisel JA, de Meijer VE, Gura KM, Puder M. The essentiality of arachidonic acid and docosahexaenoic acid. Prostaglandins Leukot Essent Fatty Acids. 2009;81:165-170.

• Serhan CN. Controlling the resolution of acute inflammation: a new genus of dual anti-inflammatory and proresolving mediators. J Periodontol. 2008;79(8)(suppl):1520-1526.

• Serhan CN, Chiang N, Van Dyke TE. Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators. Nat Rev Immunol. 2008;8:349-361.

• Serhan CN, Yacoubian S, Yang R. Anti-inflammatory and pro-resolving lipid mediators. Annu Rev Pathol. 2008;3:279-312.

• Driscoll DF. Lipid injectable emulsions: 2006. Nutr Clin Pract. 2006;21: 381-386.

• Bach AC, Frey A, Lutz O. Clinical and experimental effects of medium chain-triglyceride-based fat emulsions—a review. Clin Nutr. 1989;8: 223-235.

• Bockus HL, Sarett HP, Hashim SA, Anderson CM, Isselbacher KJ, Jeffries

• GH. Panel discussion of practical problems in usage of medium chain triglycerides. In: Senior JR ed. Medium Chain Triglycerides. Philadelphia:University of Pennsylvania Press, 1968:193.

References• Pianese P, Salvia G, Campanozzi A, et al. Sterol profiling in red blood cell

membranes and plasma of newborns receiving total parenteral nutrition. J Pediatr Gastroenterol Nutr. 2008;47:645-651.

• Ling WH, Jones PJ. Dietary phytosterols: a review of metabolism, benefits and side effects. Life Sci. 1995;57:195-206.

• Ostlund RE Jr, McGill JB, Zeng CM, et al. Gastrointestinal absorption and plasma kinetics of soy Delta(5)-phytosterols and phytostanols in humans. Am J Physiol Endocrinol Metab. 2002;282:E911-E916.

• Ball MJ. Parenteral nutrition in the critically ill: use of a medium chain triglyceride emulsion. Intensive Care Med. 1993;19:89-95.

• Jiang ZM, Zhang SY, Wang XR, Yang NF, Zhu Y, Wilmore D. A comparison of medium-chain and long-chain triglycerides in surgical patients. Ann Surg. 1993;217:175-184.

• Socha P, Koletzko B, Demmelmair H, et al. Short-term effects of parenteral nutrition of cholestatic infants with lipid emulsions based on medium chain and long-chain triacylglycerols. Nutrition. 2007;23:121-126.

• Lehner F, Demmelmair H, Röschinger W, et al. Metabolic effects of intravenous LCT or MCT/LCT lipid emulsions in preterm infants. J Lipid Res. 2006;47:404-411.

References• de Meijer VE, Le HD, Meisel JA, Gura KM, Puder M. Parenteral fish oil as

monotherapy prevents essential fatty acid deficiency in parenteral nutrition–dependent patients. J Pediatr Gastroenterol Nutr. 2010;50:212-218.

• Puder M, Valim C, Meisel JA, et al. Parenteral fish oil improves outcomes in patients with parenteral nutrition–associated liver injury. Ann Surg. 2009;250:395-402.

• Lee SI, Valim C, Johnston P, et al. Impact of fish oil–based lipid emulsion on serum triglyceride, bilirubin, and albumin levels in children with parenteral nutrition–associated liver disease. Pediatr Res. 2009;66(6):698-703.

• Diamond IR, Sterescu A, Pencharz PB, Kim JH, Wales PW. Changing the paradigm: omegaven for the treatment of liver failure in pediatric short bowel syndrome. J Pediatr Gastroenterol Nutr. 2009;48:209-215.

• de Meijer VE, Gura KM, Meisel JA, Le HD, Puder M. Parenteral fish oil monotherapy in the management of patients with parenteral nutrition– associated liver disease. Arch Surg. 2010;145:547-551.

• Vanek VW, Seidner DL, Allen P, Bistrian B, Collier S, Gura K, Miles JM, Valentine CJ, Kochevar M; Novel Nutrient Task Force, Intravenous Fat Emulsions Workgroup; American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) Board of Directors .A.S.P.E.N. position paper: Clinical role for alternative intravenous fat emulsions. NutrClin Pract. 2012 Apr;27(2):150-92.

• Nehra D, Fallon EM, Carlson SJ, Potemkin AK, Hevelone ND, Mitchell PD, Gura KM

Puder M. Provision of a Soy-Based Intravenous Lipid Emulsion at 1 g/kg/d Does Not

Prevent Cholestasis in Neonates. JPEN J Parenter Enteral Nutr. 2012 Jul 5.

ASPEN EDUCATION PROGRAM OUTLINE TEMPLATE Name, Title, Affiliation Todd W Mattox, PharmD, BCNSP; Medicine/Surgery Clinical Pharmacist Moffitt Cancer Center; Tampa, Florida Presentation Title ILE: Does and Don’ts- The Utility of Alternative ILEs in the Adult Population Disclosures I have a commercial relationship with Fresenius Kabi as a consultant. I will not include any practice recommendations and will address only evidence-based science in my presentation Presentation Overview/Summary • Data and recommendations for use of mixed oil intravenous lipid emulsion (IVLE) in adults are not

clear. A large portion of the currently available data is based on investigations of formulations that were previously only available in Europe. In addition, the heterogeneity between published investigations further complicates evaluation of clinical use. Multiple meta-analyses have been conducted to evaluate the clinical utility of mixed oil IVLE and have reported conflicting results. Mixed oil IVLE has been reported to have a positive impact on a variety of important clinical outcomes. This case report will focus on the use of mixed oil IVLE in a critically ill patient with impaired triglyceride clearance.

Learning Objectives At the conclusion of the presentation, the learner will be able to: 1. Summarize current evidenced based considerations for use of alternative IVLE in adult patients

who require PN support 2. Explain the role of a 4-oil IVLE formulation in a critically ill adult patient with hypertriglyceridemia

Key Takeaways/Fast Facts • Data and recommendations for use of mixed oil intravenous lipid emulsion (IVLE) in adults are not

clear • Data from previous investigations of alternative IVLE in patients requiring PN support have

demonstrated a positive effect on triglyceride clearance


1. Four-oil intravenous lipid emulsions have been investigated for potential clinical advantages including

a. Stabilization of 3-in-1 PN solutions b. Prevention of micronutrient deficiencies associated with injectable soybean emulsions c. Improved triglyceride clearance d. Enhance carnitine metabolism in pediatric patients


2. Factors contributing to conflicting recommendations for routine clinical use of alternative IVLE in adults include

a. Lack of comparative studies between specific IVLE formulations b. Inconsistent sources & doses of omega-3 fatty acids utilized in investigations c. Lack of heterogeneity between published investigations d. All of the above


1. Answer = C; SMOF lipid has demonstrated improved triglyceride clearance which is thought to be related to the medium chain triglyceride component

2. Answer = D; Clinical use of alternative IVLE in adults is not clear for a variety of reasons but primarily due to lack of heterogeneity between published investigations, lack of comparative studies between specific IVLE formulations and inconsistent sources and doses of omega-3 fatty acids utilized in investigations.

References

1. Kreymann KG, Heyland DK, de Heer G, Elke G. Intravenous fish oil in critically ill and surgical patients-historical remarks and critical appraisal. Clin Nutr 2018; 37:1075-1081

2. Bae HJ, Young G, Seong JM, Gwak HS. Outcomes with perioperative fat emulsions containing omega-3 fatty acid: A meta-analysis of randomized controlled trials Am J Health-Syst Pharm. 2017;74:904-918.

3. Mateu-de Antonio J, Florit-Sureda M. New strategy to reduce hypertriglyceridemia during parenteral nutrition while maintaining energy intake. JPEN J Parenter Enteral Nutr 2016;40:705-712.

4. Zaloga GP. Phytosterols, lipid administration, and liver disease during parenteral nutrition. JPEN J Parenter Enteral Nutr. 2015;39(suppl 1):39S-60S

5. Antébi H, Mansoor O, Ferrier C, et al. Liver function and plasma antioxidant status in intensive care unit patients requiring total parenteral nutrition: comparison of 2 fat emulsions. JPEN J Parenter Enteral Nutr. 2004;28:142-148.

The Utility of Alternative ILEs in the Adult Population

ILE: Does and Don’ts


Todd W Mattox, PharmD, BCNSPMedicine/Surgery Clinical Pharmacist

Moffitt Cancer CenterTampa, Florida

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Disclosures

• I have a commercial relationship with Fresenius Kabi as a consultant. I will not include any practice recommendations and will address only evidence-based science in my presentation.

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Learning Objectives


1. Summarize current evidenced based considerations for use ofalternative IVLE in adult patients who require PN support

2. Explain the role of a 4-oil IVLE formulation in a critically ill adult patientwith hypertriglyceridemia

Clinical Use of Mixed IVLE in Adults

• IVLE provide a source of concentrated calories and essential fatty acids (FA)

• The oil source of IVLE influences cellular FA content which impacts a variety of metabolic processes such as essential FA status, cytokine production, triglyceride clearance and liver function in pts receiving PN

• The clinical relevance of oil-dependent metabolic changes associated with IVLE use in adult pts receiving PN is not clear

• Lack of comparative studies between specific formulations


• Heterogeneity between published investigations• Patient populations; Small sample sizes• Types of controls• Sources & doses of omega-3 FA• Biochemical and clinical end points

• Conflicting recommendations from a variety of sources• International Professional Nutrition Societies acknowledge a role for

lower ω-6: ω-3 IVLE• ASPEN, ESPEN, Canadian Critical Care Nutrition


• Areas Investigated for Clinical Advantages

▪ Mortality & ventilation days in critically-ill▪ Infectious complications▪ ICU length of stay▪ Effect on Markers of Inflammation▪ PN associated liver disease▪ Serum triglyceride clearance


• Areas Investigated for Clinical Advantages

▪ Mortality & ventilation days in critically-ill▪ Infectious complications▪ ICU length of stay▪ Effect on Markers of Inflammation▪ PN associated liver disease▪ Serum triglyceride clearance

MCC Criteria for Use: SMOF Lipid

▪ Critically ill patients requiring PN

▪ Patients who require PN support after HSCT

▪ Patients receiving SO-IVLE who develop hypertriglyceridemia

▪ Patients receiving SO IVLE who develop severe liver dysfunction

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Patient Case Study: Adult Critical Care➢ 52 yo woman with recurrent metastatic mucinous adenocarcinoma of

sigmoid colon cancer with peritoneal involvement admitted for cytoreductivesurgery, hyperthermic intraperitoneal chemotherapy (HIPEC), bilateral ureteral stent placement and hernia repair.

• Pts cytoreductive surgery included greater omenectomy, multiple peritonectomies for tumor removal, splenectomy and distal pancreatectomy, capsular lesion resections, small bowel resection and subsequent heated mitomycin intraperitoneal chemotherapy

➢POD 2 Transfer to ICU for further management of hypoxia requiringheated high flow nasal cannula oxygen

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Patient Case Study: Adult Critical Care

➢POD 8 Nutrition Intervention• Conservative approach with PN was chosen in view of suspected

pancreatic leak in setting of respiratory instability which was determined to be an unacceptable risk factor for bedside feeding tube placement

Anthropometrics

• Wt: 108 kg• Ht: 160 cm• IBW: 52.2 kg• BMI: 42 kg/m2

Goal PN Regimen

• AA: 130 gm/day• Dex: 300 gm/day

- Electrolytes, MVI, TE• IVLE: SO-IVLE 20% 250 mL/day

Est. Daily Requirements

• Calories: 1700 (approx; Mifflin St Jeor)

• Protein: 105-130 g

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➢POD 38 Development of intra-abdominal abscesses and peritonitis requiring return to the operating room for exploratory laparotomy, abdominal washout, and adhesiolysis at multiple sites.

• Post operatively, patient developed hypoxia and respiratory failurerequiring mechanical ventilation and hypotension requiring vasopressor support

• Dexmedetomidine was initiated for ICU sedation, which was later changed to propofol

Patient Case Study: Adult Critical Care

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Days of PN Therapy

Triglyceride Levelmg/dL

ILE Source Notes

1 292 SO-IVLE4 18411 16218 29725 21539 288 SO-IVLE Return to OR;

dexmedetomidine46 352 SO-IVLE + propofol Dexmedetomidine changed

to Propofol48 311 Propofol

Receiving approx. 70 gm/day SO-IVLE

SO-IVLE held

50 Propofol Dc’d; SMOFlipid 20% 250 mL added to PN regimen

53 230 SMOFlipid60 16267 243

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Days of PN Therapy

Triglyceride Levelmg/dL

ILE Source Notes

1 292 SO-IVLE4 18411 16218 29725 21539 288 SO-IVLE Return to OR;

dexmedetomidine46 352 SO-IVLE + propofol Dexmedetomidine changed

to Propofol48 311 Propofol

Receiving approx. 70 gm/day SO-IVLE

SO-IVLE held

50 Propofol Dc’d; SMOFlipid 20% 250 mL added to PN regimen

53 230 SMOFlipid60 16267 24373 Pt expired

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Summary

• Data from previous investigations of alternative IVLE in patients requiring PN support have demonstrated a positive effect on triglyceride clearance

• This case illustrates an association with use of an alternative IVLE containing Soybean oil, MCT oil, Olive oil and Fish oil with improvement in triglyceride concentrations in a complicated critically ill patient receiving PN

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References

1. Kreymann KG, Heyland DK, de Heer G, Elke G. Intravenous fish oil in critically ill and surgical patients-historical remarks and critical appraisal. Clin Nutr 2018; 37:1075-1081

2. Bae HJ, Young G, Seong JM, Gwak HS. Outcomes with perioperative fat emulsions containing omega-3 fatty acid: A meta-analysis of randomized controlled trials Am J Health-Syst Pharm.2017;74:904-918.

3. Mateu-de Antonio J, Florit-Sureda M. New strategy to reduce hypertriglyceridemia during parenteral nutrition while maintaining energy intake. JPEN J Parenter Enteral Nutr2016;40:705-712.

4. Zaloga GP. Phytosterols, lipid administration, and liver disease during parenteral nutrition.JPEN J Parenter Enteral Nutr. 2015;39(suppl 1):39S-60S

5. Antébi H, Mansoor O, Ferrier C, et al. Liver function and plasma antioxidant status in intensive care unit patients requiring total parenteral nutrition: comparison of 2 fat emulsions. JPEN JParenter Enteral Nutr. 2004;28:142-148.

Questions [email protected]

ASPEN EDUCATION PROGRAM OUTLINE TEMPLATE Name, Title, Affiliation Jay M Mirtallo, MS, RPh, BCNSP, FASHP, FASPEN, Clinical Practice Specialist, The American Society for Parenteral and Enteral Nutrition and Professor Emeritus, The Ohio State University, College of Pharmacy Presentation Title Overview and History of ILEs Available in the United States Disclosures I have a commercial relationship with Fresenius Kabi as a member of speaker’s bureau and consultant. I also consult with Coram Home Infusion, MedEdicus and Wolters Kluwer. I will provide practice recommendations that are based on formal structured review of the literature and will state inclusion and exclusion criteria. Presentation Overview/Summary Clinicians have had over 4 decades experience with Soy based ILE. Along this journey, there have been many issues with ILE use that needed to be addressed. ILE is a complex formula that has physico-chemical properties that present issues with stability and compatibility. Although an excellent source of essential fatty acids, Soy ILE is scrutinized for its usefulness as an energy source and its role in physiologic processes related to immunity, infection, coagulation and stress. The safety of Soy ILE is dependent on daily dose, infusion rate, duration of therapy and administration method. This led to the evolution of ILE products not commercially available in the United States until recently. In our quest to find ILE that have a lower content of omega-6 fatty acids, a reliable source of omega-3 fatty acids and an efficient energy source, we now have ‘alternative’ ILE available to consider. Its an exciting time for PN therapy due to the approval of the ‘alternative’ ILEs and the discussion of if, when and how these will be put into use. Learning Objectives At the conclusion of the presentation, the learner will be able to:

1. Discuss the variables to consider when selecting ILE products for use in practice 2. State the advantages of ILE over dextrose as a PN calorie source 3. Describe the characteristics of the various oils used in ILE products 4. Compare the compositional difference in ILE products available in the US

Key Takeaways/Fast Facts Variables to consider when selecting ILE products for use in practice

• Cost • Stability • Compatibility • Metabolism • Oxidized for energy • Free radical production • Triglyceride clearance • Administration: as TNA or separate infusion, multi-chamber product • Physiologic impact on immunity, infection, coagulation and stress response

Learning Assessment Questions 1. is an advantage of ILE use as a calorie source in PN

A. Reduced fluid volume due to caloric density B. Reduced glucose load C. Increased carbon dioxide production D. Decreased in-use contamination

2. The infusion rate of ILE associated with a lower rate of hypertriglyceridemia is

g/kg/d. A. < 1.5 B. 2.0 C. > 1.5


D. >2.5

3. A characteristic of oil is its reliable triglyceride clearance A. Soy B. Olive C. Medium Chain Triglycerides (MCT) D. Fish

4. An important compositional difference of the new ‘Alternative’ ILE products as compared with

Soy ILE is . A. The inclusion of fish oil B. The particle size of the emulsion C. Reduced omega-6 fatty acid content D. The inclusion of medium chain triglycerides

Learning Assessment Answers: 1. Answer = B: Although oral fat is more calorically dense than dextrose, because the

concentration of lipid in ILE (20%) is lower that dextrose (50-70%) before admixture in PN, it is not always more calorically dense. Fat oxidation has a lower amount of carbon dioxide produced than carbohydrate and ILE. ILE due to its lower osmolality and oil characteristic may support microbial growth better than dextrose based PN if inadvertently contaminated.

2. Answer = A: in the study by Liop, ILE infusion rate was correlated with hypertriglyceridemia with the frequency being lower at a rate of <1.5 g/kg/d (24.9% compared with 54.5% at rates > 1.5 g/kg/d). A rate >2.5 g/kg/d should not be exceeded according to all ILE package inserts.

3. Answer = C: MCT is also efficiently oxidized, soy oil is useful for essential fatty acids, olive oil is not metabolized to active biproducts and fish oil provides a rich source of omega 3 fatty acids

4. Answer = C; Although fish oil and medium chain fatty acids are positive additions to ILE formulations, not all ILEs contain fish oil and/or MCT but the ‘alternatives all have a lower content of omega 6 fatty acids.

References 1. Huschak G, Nieden K, Hoell T, et al. Olive oil based nutrition in multiple trauma patients: a pilot

study. Intens Care Med 31:1202-1208. 2. Mirtallo JM, Powell CR, Campbell S, et al. Invited review: cost effective nutrition support. Nutr Clin

Pract 198;7;2:142-151. 3. Mirtallo J, Canada T, Johnson D, et al.; Task Force for the Revision of Safe Practices for Parenteral

Nutrition. Safe practices for parenteral nutrition. J Parenter Enteral Nutr 2004;28(suppl):S39-70. 4. Mirtallo JM, Dasta JF, Kleinschmidt KC, Varon J. State of the Art Review. Intravenous fat emulsion:

current applications, safety profile and clinical implications. Ann Pharmacother 2010;44:688-700. 5. Llop J, Sabin P, Garau M, et al.; the Hospital Pharmacy Artificial Nutrition Group of Catalonia. The

importance of clinical factors in parenteral nutrition–associated hypertriglyceridemia. Clin Nutr 2003;22:577-83.

6. Salvian AJ, Allardyce DB. Impaired bilirubin secretion during total parenteral nutrition. J Surg Res 1980;28:547-55

7. Pedersen CA, Schneider PJ, Schecklehoff DJ. ASHP national survey of pharmacy practice in hospital settings: dispensing and administration – 2011. Am J Health Syst Pharm 2012;69:768-785.

8. Storey MA, Weber RJ, Besco K, et al. Evaluation of parenteral nutrition errors in an era of drug shortages. Nutr Clin Pract 2015;31:211-217.

9. Mirtallo JM. Parenteral nutrition ordering processes. J Parenter Enter Nutr 2012;36:29S-31S. 10. Grimble R. Fatty acid profile of modern lipid emulsions: scientific consideration for creating the ideal

composition. Clin Nutr 2005 (1,suppl):9-15.

Overview and History of ILEs Available in the United States


Jay M. Mirtallo, MS, RPh, BCNSP, FASHP, FASPENProfessor Emeritus, The Ohio State University, College of Pharmacy

Clinical Specialist, American Society for Parenteral and Enteral Nutrition

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Disclosures

• I have a commercial relationship with Fresenius Kabi as a member of speaker’s bureau and consultant. I also consult with Coram Home

Infusion, MedEdicus and Wolters Kluwer. I will provide practice recommendations that are based on formal structured review of the literature and will state inclusion and exclusion criteria.

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Learning Objectives


• Discuss the variables to consider when selecting ILE products for usein practice

• State the advantages of ILE over dextrose as a PN calorie source

• Describe the characteristics of the various oils used in ILE products

• Compare the compositional difference in ILE products available in theUS

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Role of Lipid (ILE) in Parenteral Nutrition

Prevention of Essential Fatty Acid (EFA) deficiencyDose:

Linoleic acid 2.5% of caloriesLinolenic acid 0.5% of calories

Energy sourceReduce dextrose load/dose

Precursor to biochemical products of immunity, coagulation and stress response

20% Lipid Emulsion Composition: A Complex Pharmaceutical Formulation

Product Soy ILE

OilSoybean 20%

Egg yolk phosphatide 1.2%

Glycerin 2.25%

Osmolarity 260

pH 6-8.9

Fat particle size 0.5

Size 100, 250, 500, 1000

Lipid Advantage over Glucose as a Calorie Source

• Reduced Glucose from PN for Glucose Control

• Trauma pts (N=33)o ILE group

- Lower blood glucose (133 vs 156 mg/dl)- Lower carbon dioxide production- Decreased minute volume- Shorter duration of mechanical ventilation

Huschak et al. Intensive Care Med 31: 1202-1208, 2005

PN Pulmonary Complications: Hypercapnea

Dextrose dose > 5 mg/kg/min

or

Caloric dose > 150% of Needs

Lungs

Carbon dioxide production

Respiratory failure in Pts

with limited pulmonary reserve

Prolonged mechanical ventilation

• Less CO2 produced per molecule of fat than per molecule of dextrose

• Respiratory quotient (RQ) dextrose = 1

• RQ fat = 0.7

ILE: Limitations to Use

• Limitations to use as a Calorie SourceoCost

oStability

oContamination

oMetabolism more complicated than dextrose

ILE: Cost Effective Nutrition Support

• Lipid emulsions 15 x more expensive than dextrose

• Restricted use: savings of $75,000 per yro Diabetes or diabetes of stress

o Impaired pulmonary function

- CO2 retentiono TPN-induced liver disease

• Hold Lipid for 3 weeks for EFAD prevention

Mirtallo et al. Nutr Clin Pract 1987;12:142

ILE: Stability Concerns

• Emulsion destabilizationo Aggregation

o Creaming - reversible

o Coalescence - irreversible

o ‘Oiling ‘ out

- Excess particle size▪ > 6 microns

IV Lipid Emulsions: Stability Concerns• Adverse effects of Administration

oParticle size > 6

- Fat embolism- Acute reactions

▪ Hypotension

▪ Pulmonary hypertension

▪ Acidosis

- More rapid clearance by RES in liver, spleen andlungs

Mirtallo et al. JPEN 2004;28:S39-S70

ILE: In-Use Contamination

• Microbial growth characteristicso Lipid emulsion alone

- Intermittent infusion separate from PN- Characteristics supporting microbrial growth

▪ Iso-osmotic

▪ High pH

▪ Glycerol

o As TNA

Mirtallo et al. Ann Pharmacother 44:688, 2010

ILE: In-Use Contamination

• Malassezia furfuro Dependent on exogenous fatty acids

- Sebaceous glands and surrounding tissueso Propoful –

- hang time- aseptic technique- contaminated equipment in preparation


ILE: In-Use Contamination• Malassezia furfur

o Nutritional use

- Repackaging for neonatal PN useo CDC limit hang time

- 12 hours separate from PN- 24 hours in PN- Syringe: ? 6 hrs- TNA: 24 hours along with administration set


Soy ILE: Metabolic Fate of IV Lipid


ILE: Factors affecting Clearance

• Phospholipid contento Phospholipid:Tg ratio

- 4 X greater in 10% vs 20% emulsion• Particle size

o Increase size hastens clearance

• Infusion rate o Amount: >1.5 g/kg/d

o Continuous

- Fewer fluctuations in serum Tg- Improved fat oxidation- Immune function

Hypertriglyceridemia• Plasma clearance

o Phospholipid concentration: 10 vs 20%

- Phospholipid:triglyceride ratio• Infusion rate: exceed lipolytic capacity of endothelial lipases

o Influence of critical illness

o Accumulation of TG in RES

o Displacement of bilirubin from albumin by FFA

Hypertriglyceridemia• Side effects of lipids- rapid administration

o Rate not to exceed

- 0.11 g/kg/hr healthcare environment (continuous)- 0.15 g/kg/hr homecare (cyclic)

• Caution to prevento Pancreatitis in adults

o Hyperlipidemia and fat overload in neonates

Hypertriglyceridemia (6-30%)

• Infusion rate (g/kg/d)o < 1.5 62/249 24.9%

o > 1.5 6/11 54.5%

• Risk factor 62/215 28.8%o Renal failure

o Gluc > 180

o Prednisone

o Pancreatitis

o sepsis

• No Risk Factor 6/45 13.3%

• Important to monitor triglycerides at baseline and periodically thereafter

Liop et al. Clin Nutr 22:577, 2003

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Fat Overload Syndrome

Other symptoms

LethargyTachycardiaHeadacheNausea, vomiting, abdominal pain Hepatosplenomegaly Cough with hemoptysis

Excessive accumulation of serum lipids

Acute onset:FeverJaundiceIrritabilitySpontaneous hemorrhageHyperlipidemia

Fat Overload Syndrome

• Childreno 10 month to 9 years

o Large daily doses

- 3.3-5.4 g/kg/dayo Long duration

- 28-114 days

• Extreme effects when administered beyond therecommended daily dose and infusion rates


ILE: Cholestatic Jaundice• Excessive dosage

o 3 g/kg/day

• Long-term useo Mean duration 45 days

• Significant increaseo Alkaline phosphatase

o Bilirubin

o Cholesterol

• Liver biopsyo Periportal, mixed inflammatory infiltrates

o Bile duct proliferation in portal triads

o Canalicular bile plugs

• Improvement with lower dose or PN discontinued

Salvian AJ, Allardyce DB. J Surg Res 28:547, 1980

Parenteral Nutrition Associated Liver Disease (PNALD)

• Prevalence increases with duration of PN therapy

• Role of fat emulsionso Fat source

oPhytosterol content

oDose

- > 1g/kg/day in long term PN patients

Lipid Peroxidation• Alterations in various organs as a result of tissue

peroxidative damageo ‘Free radicals’

-React with all cellular components:▪Proteins

▪Nucleic acids

▪ Lipids

o α-tocopherol inhibits lipid peroxidation

ILE: Systems Issues

• TNA vs separate intermittent infusion

• Look alike-sound alike

• Safetyo Infusion rate

oDuration

oMedication errors

Method of Compounding PN

Pedersen et al Am J Health-Syst Pharm 2012;69:768-85

24 hour nutrient infusion system – transition to automated compounding

Safety of System: Lipid Emulsions

• Medication errors occur with fat emulsionsoSeparate administration from PN

• Nodes involvedoOrder

- Lack of standard method of ordering IVFEo Administration

-Misinterpretation of the rate on the IVFE order- Improper programming of infusion pump

Storey et al. Nutr Clin Pract 2015;31:211

ILE: PN Ordering Practicesg/kg/dg/dg/L of PNVolume of % original concentration% final concentrationg/total volume of PNKcal/dayVolume of % concentration to be added to or infused separate from PNml/dml/L of PNG per total PN volumeNonprotein kcal

Mirtallo JM. J Parenter Enter Nutr 2012;36:29S-31S

ILE: Clinical Implications

Soy IVE are relatively safe when used according to manufacturer best practice recommendations

o Dose < 2.5 g/kg/d

o Infusion rate: < 0.11 g/kg/h

• Tg levels may be improved with use of 20% vs 10% product

• Use of Soy IV ILE require careful monitoring of triglycerides and otherorgan systems affected from long term use.

Evolution of ILE ProductsObjective

• ‘Dilution’ of ω-6 fatty acid contentoOils that are easily metabolizable and do not exacerbate

inflammatory stress

- MCT, Olive OiloAdd ω-3 fatty acids from fish oil

• Ultimately achieve a ratio of ω-6:ω-3 of 2:1-4:!

Grimble. Clin Nutr (Suppl) 2005;1:9-15

Oil Characteristics

• Soybeano Rich source of Essential fatty acids

o Omega 6 fatty acids – more proinflammatory

• Medium chain triglycerideso Efficient energy source

o Reliable triglyceride clearance

• Olive oil (Oleic acid)o Reduce polyunsaturated fatty acid load (peroxides)

o Neutral end product

• Fish oilo Omega 3 fatty acids – less proinflammatory

U.S. Lipid Product Composition

Brand Intralipid®Nutralipid®

Smoflipid® Clinolipid® Omegaven®

Oil Source Soybean 100% Soybean 30%Medium Chain

30%Olive Oil 25%Fish Oil 15%

Soybean 20%Olive Oil 80%

Fish Oil

Fat Composition (% Mean Value(Range)Linoleic acid 53 19.5 13.8-22% 1.5%Linolenic acid 7.5 2.5 0.5-4.2% 1.1%Oleic acid 24.5 (19-30) (23-35) 44.3-79.5% 4-11%Eicosapentanoicacid (EPA)

0 2.3 13-26%

Docosahexaenoic acid (DHA)

0 2.3 14-27%

Package Insert:Intralipid®, Nutralipid®, Smoflipid®, Clinolipid®, Omegaven®

Summary

• Variables to consider when selecting ILE products for use in practiceo Cost

o Stability

o Compatibility

o Metabolism

- Oxidized for energy- Free radical production- Triglyceride clearance

o Administration: as TNA or separate infusion, multi-chamber product

o Physiologic impact on immunity, infection, coagulation and stress response

Conclusion

• Safety and efficacy of Soy ILE has been shown to be dependent oninfusion rate, daily dose (g/kg) and duration.o Current guidelines for use in the US address the problems from Soy ILE that

limits dose and use in particular patient populations

• Issues concerning the efficacy as a calorie source, triglyceride clearance and physiologic effects on immunity, coagulation and stress response ledto an evolution in ILE products not commercially available in the US until recently

• Its an exciting time for PN therapy due the approval of ‘alternative’ ILEs

and the discussion of if, where and how these will be put into use


1. is an advantage of ILE use as a calorie source in PNa) Reduced fluid volume due to caloric densityb) Reduced glucose loadc) Increased carbon dioxide productiond) Decreased in-use contamination


2. The infusion rate of ILE associated with a lower rate of hypertriglyceridemia is g/kg/d.a) < 1.5b) 2.0c) > 1.5d) >2.5


3. A characteristic of oil is its reliable triglyceride clearancea) Soyb) Olivec) Medium Chain Triglycerides (MCT)d) Fish


4. An important compositional difference of the new ‘Alternative’ ILE

products as compared with Soy ILE is .a) The inclusion of fish oilb) The particle size of the emulsionc) Reduced omega-6 fatty acid contentd) The inclusion of medium chain triglycerides

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References

• Huschak G, Nieden K, Hoell T, et al. Olive oil based nutrition in multiple trauma patients: a pilot study. Intens Care Med 31:1202-1208.

• Mirtallo JM, Powell CR, Campbell S, et al. Invited review: cost effective nutrition support. Nutr Clin Pract 198;7;2:142-151.

• Mirtallo J, Canada T, Johnson D, et al.; Task Force for the Revision of Safe Practices for Parenteral Nutrition. Safe practices for parenteral nutrition.JPEN J Parenter Enteral Nutr 2004;28(suppl):S39-70.

• Mirtallo JM, Dasta JF, Kleinschmidt KC, Varon J. State of the Art Review.Intravenous fat emulsion: current applications, safety profile and clinical implications. Ann Pharmacother 2010;44:688-700.

• Llop J, Sabin P, Garau M, et al.; the Hospital Pharmacy Artificial Nutrition Group ofCatalonia. The importance of clinical factors in parenteral nutrition–associated hypertriglyceridemia. Clin Nutr 2003;22:577-83.

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References

• Salvian AJ, Allardyce DB. Impaired bilirubin secretion during total parenteral nutrition. J Surg Res 1980;28:547-55

• Pedersen CA, Schneider PJ, Schecklehoff DJ. ASHP national survey ofpharmacy practice in hospital settings: dispensing and administration –2011. Am J Health Syst Pharm 2012;69:768-785.

• Storey MA, Weber RJ, Besco K, et al. Evaluation of parenteral nutritionerrors in an era of drug shortages. Nutr Clin Pract 2015;31:211-217.

• Mirtallo JM. Parenteral nutrition ordering processes. J Parenter Enter Nutr 2012;36:29S-31S.

• Grimble R. Fatty acid profile of modern lipid emulsions: scientific consideration for creating the ideal composition. Clin Nutr 2005 (1,suppl):9-15.

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