Fish oil‐based lipid emulsion’s role in transitioning pediatric patients from plant‐based to combination plant and fish oil‐based lipid
emulsion
Kayley L iuzzo, PharmDPGY‐1 Pharmacy Pract ice ResidentChi ldren’s of Alabamakayley. l iuzzo@chi ldrensal .orgJune 17, 2018
This study was approved by University of Alabama at Birmingham (UAB) Investigational Review Board (IRB).
DISCLOSURE STATEMENT
I, nor any individuals involved with this project, have any financial relationships with any commercial supporters or providers
OBJECTIVES• Recognize indications for total parenteral nutrition (TPN) in the
pediatric patient population
• Review the pathophysiology of parenteral nutrition‐associated liver disease (PNALD)
• Describe the components of three lipid emulsions used at Children’s of Alabama (COA)
• Evaluate the safety, efficacy and cost of the above lipid emulsions in COA Intestinal Rehabilitation Clinic and inpatient gastroenterology patients
BACKGROUND• Short bowel syndrome (SBS) occurs due to loss of an extensive length
of small intestine resulting in inadequate absorption of enteral nutrients
• Causes include necrotizing enterocolitis (NEC), intestinal atresia, gastroschisis, malrotation with volvulus, meconium ileus, and Hirschsprung’s disease
• SBS is the most frequent mechanism of intestinal failure (IF)
• Patients often become TPN dependent and at risk for PNALD and central line‐associated blood stream infections (CLABSIs)
Spencer AU, Neaga A, West B, Safran J, Brown P, Btaiche I, Kuzma‐O'Reilly B, Teitelbaum DH. Pediatric short bowel syndrome: redefining predictors of success. Ann Surg. 2005 Sep;242(3):403‐9; discussion 409‐12.
PNALD• Defined as a spectrum of liver disease ranging from abnormal liver
enzymes to steatosis, fibrosis, and eventual cirrhosis
• Multifactorial causes including prolonged bowel rest leading to bacterial overgrowth, choline/taurine deficiency, and increased dextrose in TPN
• Treatment includes avoiding TPN if possible, or incorporating fish oil‐based lipid emulsion
• Patients with intestinal and liver failure may require intestine‐liver transplant
Mitra A, Ahn J. Liver Disease in Patients on Total Parenteral Nutrition. Clin Liver Dis. 2017 Nov;21(4):687‐695.Pironi L. Definitions of intestinal failure and the short bowel syndrome. Best Pract Res Clin Gastroenterol. 2016 Apr;30(2):173‐85.
LIPID EMULSIONS AT COAIntralipid® 20% Omegaven® SMOFlipid®
Compo
nents
20% soybean oil (omega‐6 fatty acids)1.2% egg phospholipids2.25% glycerinWater for injection
10% highly refined fish oil (omega‐3 fatty acids)• 1.25‐2.82% eicosapentaenoic acid
(EPA)• 1.44‐2.82% docosahexaenoic acid
(DHA)• 0.015‐0.0296% dl‐α‐tocopherol1.2% egg yolk phospholipid 2.5% glycerol
6% soybean oil (omega‐6 fatty acids)6% medium chain triglycerides (MCT)5% olive oil3% fish oil (omega‐3 fatty acids)1.2% egg phospholipids2.5% glycerin0.0163‐0.0225% all‐rac‐α‐tocopherol0.3% sodium oleateWater for injectionSodium hydroxide for pH adjustment
COA
Availability Unrestricted formulary product For compassionate use only through
Institutional Review Board approved study• Shipped from Germany (not FDA‐
approved in US)
Restricted formulary product
Intralipid® [package insert]. Uppsala, Sweden. Fresenius Kabi, 2016.;Omegaven® [package insert]. Bad Homburg, Germany, Fresenius Kabi, 2018.SMOFlipid® [package insert]. Uppsala, Sweden, Fresenius Kabi, 2016.
DOSINGIntralipid® 20% Omegaven® SMOFlipid®
Neo
nates
Premature:Initial dose: 1‐2 g/kg/day Maximum dose: 3‐5 g/kg/dayTerm:Initial dose: 1‐2 g/kg/dayMaximum dose: 3 g/kg/day
Per COA protocol:Dose on day 1: 0.5 g/kg/dayDose on day 2 and for remainder of therapy: 1 g/kg/day
Initial dose: 1 g/kg/dayMaximum dose: 3.6 g/kg/day
Infants a
nd
Child
ren
Infants:Initial dose: 1‐2 g/kg/dayMaximum dose: 3 g/kg/dayChildren 1‐10 years:Initial dose: 1‐2 g/kg/dayMaximum dose: 2‐3 g/kg/day
Usual reported dose: 2 g/kg/dayReported range: 1.5‐3.5 g/kg/day
Adolescents Children >11 years:
Initial dose: 1 g/kg/dayMaximum dose: 2.5 g/kg/day*Not to exceed 500 mL 20% fat emulsion on 1st day of therapy
Initial dose: 1 g/kg/dayMaximum dose: 2 g/kg/day
Lexicomp Online®, Pediatric & Neonatal Lexi‐Drugs®, Hudson, Ohio: Lexi‐Comp, Inc.; March 12, 2018.
OMEGA‐6 FATTY ACID PATHWAY
Linoleic acidLinoleic acid Gamma‐linolenic acidGamma‐
linolenic acid
Dihomo‐gamma‐linolenic
acid
Dihomo‐gamma‐linolenic
acid
PGE‐1(anti‐inflammatory)
Arachidonic acidArachidonic acid
PGE‐2(pro‐inflammatory)
LTB‐4(pro‐inflammatory)
Pullicino E, Revisiting Parenteral Nutrition‐Associated Liver Disease (PNALD). MMSG;1(1): Available from: http://mmsjournals.org/index.php/MDHG/article/view/7
OMEGA‐3 FATTY ACID PATHWAY
α‐Linoleic acidα‐Linoleic acid Steridonic acidSteridonic acid Eicosatetraenoicacid
Eicosatetraenoicacid
Eicosapentaenoicacid (EPA)
Eicosapentaenoicacid (EPA)
Docosahexaenoicacid (DHA)
Docosahexaenoicacid (DHA)
PGE‐3(anti‐inflammatory)
LTB‐5(anti‐inflammatory)
Pullicino E, Revisiting Parenteral Nutrition‐Associated Liver Disease (PNALD). MMSG;1(1): Available from: http://mmsjournals.org/index.php/MDHG/article/view/7
STUDY OBJECTIVE• To determine the role of Omegaven® by assessing the safety,
efficacy, and cost in patients transitioned from Intralipid® 20% to Omegaven® to SMOFlipid® compared to patients transitioned from Intralipid® 20% to SMOFlipid®
STUDY METHODS AND DESIGN
• Retrospective chart review from August 2013 through January 2018
• 2 patient groups evaluated (N=19)
• Omegaven® group (n=12):
• Control group (n=7):
Intralipid® 20%Intralipid® 20% Omegaven®Omegaven® SMOFlipid®SMOFlipid®
Intralipid® 20%Intralipid® 20% SMOFlipid®SMOFlipid®
STUDY METHODS AND DESIGN
Inclusion Criteria Exclusion Criteria
Age 0‐18 years No Intralipid® 20% exposure
Long‐term TPN Deceased
Followed in COA Intestinal Rehabilitation Clinic or by gastroenterology inpatient service if still admitted (e.gneonatal intensive care unit (NICU) patients)
STUDY METHODS AND DESIGN• Laboratory parameters assessed at the start of each lipid emulsion
• Incidence of CLABSIs and cost collected for duration of each lipid emulsion
Safety Efficacy Cost
• Direct bilirubin (DBili)• Aspartate transaminase (AST)• Alanine transaminase (ALT)• Triglycerides (TG)• Serum creatinine (SCr)• Number of CLABSIs
Height and weight Z‐scores• CDC calculator 0‐24 months
• Correcting for prematurity until 2 years of age
• WHO calculator for age 2‐18 years
Intralipid® 20% and SMOFlipid® covered by patients’ insurances
Inpatient and outpatient Omegaven® = direct cost to COA through compassionate use study
STUDY METHODS AND DESIGN• Statistical analysis: t‐test for equality of means
• Three analyses performed:
• Intralipid® 20% initiation• SMOFlipid® initiation• SMOFlipid® data collection stop date
INTRALIPID® 20% INITIATION
Variable P‐value Omegaven® Group Mean
Control Group Mean
Age in days 0.387 5* 34*
Weight Z‐score 0.010 0.44 ‐1.47
Height Z‐score 0.002 0.11 ‐2.01
DBili (mg/dL) 0.143 1.08 2.98
ALT (U/L) 0.786 76.14 87.57
AST (U/L) 0.807 86.57 95.57
SCr (mg/dL) 0.056 0.69 0.43
*denotes median
SMOFLIPID® INITIATION
Variable P‐value Omegaven® Group Mean
Control Group Mean
Age in days 0.000 1046* 79*
Weight Z‐score 0.120 ‐1.01 ‐2.10
Height Z‐score 0.007 ‐0.78 ‐2.87
DBili (mg/dL) 0.013 1.12 5.04
ALT (U/L) 0.069 125.08 58
AST (U/L) 0.944 111 108.57
TG (mg/dL) 0.226 61.9 55
SCr (mg/dL) 0.912 0.28 0.27
*denotes median
END OF SMOFLIPID®
Variable P‐value Omegaven® Group Mean
Control Group Mean
Age in days 0.000 1227* 174*
Weight Z‐score 0.003 ‐0.64 ‐2.50
Height Z‐score 0.000 ‐0.96 ‐3.86
DBili (mg/dL) 0.270 1.1 2.91
ALT (U/L) 0.900 87.5 92.29
AST (U/L) 0.671 87.08 106.57
TG (mg/dL) 0.832 49.45 39
SCr (mg/dL) 0.665 0.27 0.26
*denotes median
CLABSI FINDINGS
Total Numberof CLABSIs (n)
Total Number of Patients with CLABSIs
Total Number of Days on Each
Lipid
CLABSI Rate (n per 1000
catheter days)
Intralipid® 20% 5 3 1481 3.37
Omegaven® 65 10 8555 7.59
SMOFlipid® 13 5 1906 6.82
Total Numberof CLABSIs (n)
Total Numberof Patients with CLABSIs
Total Number of Days on Each
Lipid
CLABSI Rate (n per 1000
catheter days)
Intralipid® 20% 0 0 203 0
SMOFlipid® 6 5 791 7.58
Omegaven® Group (n=12)
Control Group (n=7)
COST FINDINGS
Mean Cost per Day
Mean Cost per Patient
Total Cost
Intralipid® 20% $10.39 $1,282.54 $15,390.48
Omegaven® $78.72 $56,132.29 $673,479.48
SMOFlipid® $17.74 $2,818.89 $33,826.68
Mean Cost per Day
Mean Cost per Patient
Total Cost
Intralipid® 20% $10.29 $298.41 $2,088.87
SMOFlipid® $16.44 $1857.44 $13,002.08
Omegaven® Group (n=12)
Control Group (n=7)
LIMITATIONS• Small sample size
• Missing laboratory parameters for some patients
• Omegaven® group patients older than control group patients
• Difficult to evaluate long term effects of SMOFlipid®
CONCLUSIONS• Omegaven® associated with large number of CLABSIs, but similar
rate as SMOFlipid®
• At initiation of SMOFlipid® the Omegaven® group had a statistically significant difference in DBili compared to control group
• No statistically significant differences in laboratory parameters at SMOFlipid® stop date
FUTURE DIRECTIONS• Reserve Omegaven® for patients requiring rescue therapy to
provide cost savings to hospital
• Assess long term effects of SMOFlipid® by continuing to collect laboratory findings and CLABSI rates periodically
• Compare inpatient versus outpatient therapy
• Potentially remove Intralipid® 20% from COA formulary to reduce dispensing error mix‐ups with SMOFlipid®
ACKNOWLEDGEMENTS• David Galloway, MD
• Division of Pediatric Gastroenterology, Hepatology and Nutrition• Assistant Professor, Department of Pediatrics• University of Alabama at Birmingham
• Adrienne Travis, PharmD
• Investigational Study Pharmacist• Children’s of Alabama
• Tracy Jackson, PharmD
• Gastroenterology/Liver Transplant Clinical Pharmacist• Children’s of Alabama
ASSESSMENT QUESTIONWhich of the following make combination plant and fish oil‐based lipid emulsion (SMOFlipid®) suitable for pediatric patients requiring long term TPN?
A) It is covered by many insurances including Alabama Medicaid
B) There is a decreased rate of CLABSIs with this product
C) It has anti‐inflammatory properties due to the omega‐3 fatty acid component
D) A and C
E) All of the above
Fish oil‐based lipid emulsion’s role in transitioning pediatric patients from plant‐based to combination plant and fish oil‐based lipid
emulsion
Kayley L iuzzo, PharmDPGY‐1 Pharmacy Pract ice ResidentChi ldren’s of Alabamakayley. l iuzzo@chi ldrensal .orgJune 17, 2018
Disclosure Statement: I, nor any individuals involved with this project, have any financial relationships with any commercial supporters or providers
This study was approved by University of Alabama at Birmingham (UAB) Investigational Review Board (IRB).
OMEGAVEN® CRITERIAInclusion Criteria Exclusion Criteria
Newborn to 21 years of age Pregnancy
PN‐dependent (physically unable to maintain adequate nutrition enterally)
Other causes of liver disease such as Hepatitis C, Cystic Fibrosis, biliary atresia, ECMO‐induced
cholestasis
Has been receiving PN for >30 days Parent, guardian, and/or child unwilling to provide consent or assent
Lipid dose has been restricted to 1 g/kg/day for >30 days
Allergy to fish or egg protein
Trace elements (copper, manganese, chromium, zinc) reduced by half for >30 days
Chronic anticoagulant therapy
Expectation of PN for >30 more days Severe hemorrhagic disorder
Direct bilirubin >2.0 mg/dL on >2 consecutive draws and >1 week apart, after being on PN with
restricted lipids and trace elements for >30 days
Hospitalized at time of enrollment and/or initial dose of Omegaven®
SMOFLIPID® CRITERIA
• Warning: SMOFlipid® interacts with warfarin, decreasing effects of anticoagulation. Dosing and clinical effects should be monitored accordingly in these patients.
Indications Contraindications
Anticipated long‐term need for PN (>2weeks)
Presence of renal disease (SCr >upper limit of normal for age)
Signs of cholestasis after using soy lipids >2 weeks
Hypersensitivity to fish, egg, soybean or peanut protein
Transition from Omegaven® following period of normalization of TPN‐induced
cholestasis (Dbili <2 mg/dL)
Severe hypertriglyceridemia (TG>500 mg/mL)
Unable to use Omegaven® (e.g. clot, prothrombotic state, availability issues)
Elevated serum aluminum (>6 ng/mL)
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