Fish oil based lipid emulsion s role in transitioning pediatric patients from plant based to combination plant and fish oil based lipid emulsion Kayley Liuzzo, PharmD PGY 1 Pharmacy Practice Resident Children s of Alabama kayley.liuzzo@childrensal.org June 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.
Components COA Availability LIPID EMULSIONS AT COA Intralipid 20% Omegaven SMOFlipid 20% soybean oil (omega 6 fatty acids) 1.2% egg phospholipids 2.25% glycerin Water for injection Unrestricted formulary product 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 tocopherol 1.2% egg yolk phospholipid 2.5% glycerol For compassionate use only through Institutional Review Board approved study Shipped from Germany (not FDAapproved in US) 6% soybean oil (omega 6 fatty acids) 6% medium chain triglycerides (MCT) 5% olive oil 3% fish oil (omega 3 fatty acids) 1.2% egg phospholipids 2.5% glycerin 0.0163 0.0225% all rac α tocopherol 0.3% sodium oleate Water for injection Sodium hydroxide for ph adjustment 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.
DOSING Neonates Infants and Children Adolescents Intralipid 20% Omegaven SMOFlipid Premature: Initial dose: 1 2 g/kg/day Maximum dose: 3 5 g/kg/day Term: Initial dose: 1 2 g/kg/day Maximum dose: 3 g/kg/day Infants: Initial dose: 1 2 g/kg/day Maximum dose: 3 g/kg/day Children 1 10 years: Initial dose: 1 2 g/kg/day Maximum dose: 2 3 g/kg/day Children >11 years: Initial dose: 1 g/kg/day Maximum dose: 2.5 g/kg/day *Not to exceed 500 ml 20% fat emulsion on 1 st day of therapy Per COA protocol: Dose on day 1: 0.5 g/kg/day Dose on day 2 and for remainder of therapy: 1 g/kg/day Initial dose: 1 g/kg/day Maximum dose: 3.6 g/kg/day Usual reported dose: 2 g/kg/day Reported range: 1.5 3.5 g/kg/day Initial dose: 1 g/kg/day Maximum dose: 2 g/kg/day Lexicomp Online, Pediatric & Neonatal Lexi Drugs, Hudson, Ohio: Lexi Comp, Inc.; March 12, 2018.
OMEGA 6 FATTY ACID PATHWAY PGE 2 (pro inflammatory) Linoleic acid Gammalinolenic acid Dihomogamma linolenic acid Arachidonic acid LTB 4 (pro inflammatory) PGE 1 (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
OMEGA 3 FATTY ACID PATHWAY PGE 3 (anti inflammatory) α Linoleic acid Steridonic acid Eicosatetraenoic acid Eicosapentaenoic acid (EPA) LTB 5 (anti inflammatory) Docosahexaenoic acid (DHA) 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): Intralipid 20% Omegaven SMOFlipid Control group (n=7): Intralipid 20% SMOFlipid
STUDY METHODS AND DESIGN Inclusion Criteria Age 0 18 years Long term TPN Followed in COA Intestinal Rehabilitation Clinic or by gastroenterology inpatient service if still admitted (e.g neonatal intensive care unit (NICU) patients) Exclusion Criteria No Intralipid 20% exposure Deceased
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 Number of CLABSIs (n) Omegaven Group (n=12) 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 Number of CLABSIs (n) Control Group (n=7) Total Number of 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
COST FINDINGS Omegaven Group (n=12) 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 Control Group (n=7) 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
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 QUESTION Which 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 Liuzzo, PharmD PGY 1 Pharmacy Practice Resident Children s of Alabama kayley.liuzzo@childrensal.org June 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 CRITERIA Inclusion Criteria Newborn to 21 years of age PN dependent (physically unable to maintain adequate nutrition enterally) Has been receiving PN for >30 days Lipid dose has been restricted to 1 g/kg/day for >30 days Trace elements (copper, manganese, chromium, zinc) reduced by half for >30 days Expectation of PN for >30 more days 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 Exclusion Criteria Pregnancy Other causes of liver disease such as Hepatitis C, Cystic Fibrosis, biliary atresia, ECMO induced cholestasis Parent, guardian, and/or child unwilling to provide consent or assent Allergy to fish or egg protein Chronic anticoagulant therapy Severe hemorrhagic disorder
SMOFLIPID CRITERIA Indications Anticipated long term need for PN (>2 weeks) Signs of cholestasis after using soy lipids >2 weeks Transition from Omegaven following period of normalization of TPN induced cholestasis (Dbili <2 mg/dl) Unable to use Omegaven (e.g. clot, prothrombotic state, availability issues) Contraindications Presence of renal disease (SCr >upper limit of normal for age) Hypersensitivity to fish, egg, soybean or peanut protein Severe hypertriglyceridemia (TG>500 mg/ml) Elevated serum aluminum (>6 ng/ml) Warning: SMOFlipid interacts with warfarin, decreasing effects of anticoagulation. Dosing and clinical effects should be monitored accordingly in these patients.