Symposium 3

“Fl id d N t iti S t f th“Fluid and Nutrition Support of the Pre-term Infant in the First Week

of Life”

The choice of lipid in the preterm infantti d tpractice and controversy

Susan HillDepartment GastroenterologyDepartment Gastroenterology

Great Ormond Street Hospital for Children LondonChildren, London

• Introduction• HistoryHistory• Intralipid• Essential fatty acids• Lipid metabolism• Lipid metabolism• Special needs of the neonate• Newer lipid emulsions

PN available 40 yearsPN available 40 years

• 1628 William Harvey• 1656 Sir Christopher Wrenp

– Infusions via a bladder & sharpened quill in dogs• E’s + glucose• E s + glucose• 1930’s Robert Eltman: amino acids as a

protein hydrolysateprotein hydrolysate

BUT i v lipid needed forBUT i-v lipid needed for

• High energy content• Prevent lipogenesis from glucosePrevent lipogenesis from glucose• Co2 produced exacerbating resp failure

• PN was not considered viable until intralipid was invented

P N1960’s fat developed

P bl• Problems– Toxicity of low mol wt TGs– Cotton seed oil: only toxic >4 weeks

• SolutionSoya bean oil– Soya bean oil

– Wretlind & Schuberth 1963

• Wretlind A. Fat emulsions. In Lee HA(ed) Parenteral nutrition in acute metabolic illness. Academic Press, London.1974pp77-92.

IntralipidIntralipidLong-chain triglyceride (LCT)

soya bean emulsion +

egg-derived phospholipid

• LCT=16-20 C atoms• hydrolysed by LPLhydrolysed by LPL • cleared by Apo lipoprotein E and LDL

treceptors

• Carnitine –dependent transport into cells

Lipid emulsion size matterssize matters

• Particles need to be small enough g– to fit through capillary

<400 nm (0 4μm)– <400 nm (0.4μm)

• Destabilised by>Ca Mg; < fat volume; >acid:base aa’s– >Ca, Mg; < fat volume; >acid:base aa s

• Stabilised by– > glucose> glucose

How is lipid held in solution by egg lecithin?

• Fat emulsion formed by a prolonged process of homogenisationp g

Ch l i lik t t• Chylomicron-like structure– Fat particles separated by negatively-charged p p y g y g

‘tails’ of phospholipid (egg lecithin)

• i.e. charge repulsion maintains the emulsion

Carnitinedependent transport into cells

• fatty acids are activated in cytosol & transported into y y p

mitochondria

t i t it h d i f id ti t• must move into mitochondria for oxidation to occur• uses carnitine as a carrier via carnitine shuttle

Energy concentrationlipid vs glucoselipid vs glucose

(commercial lipid emulsions)V l A l ALipid

conc w/v

Volume (ml)

Approx energy (kcal)

Glucose conc w/v

volume Approx energy (kcal)

10% 500 5505% 1000 200

10% 500 55010% 1000 400

20% 500 100015% 1000 600

30% 330 1000 20% 1000 800

Lipid intakewhat to give

• 25-40% of non-protein calories in total PN feedingg

I f li id id ti t 4 /d• Infancy: max lipid oxidation at 4g/dayas long asas o g as

• ≤ 18g glucose/kg/day( d id i i f CHO d(or exceed oxidative capacity for CHO and net

lipogenesis occurs)

How to giveHow to give

• Continuous infusion– Maximum 20 hours

• LimitLimit – 2-3 days/ week if long-term

• Carnitine?Consider in infants on PN >4 weeks– ESPGHAN

Preterm infantPreterm infant

• Unpredictable fat utilisation and clearance

• Low plasma carnitine

• deficiency of taurine or cysteine• deficiency of taurine or cysteine

Complicationsliver disease

• Prematurity • liver diseasey• Low birth weight• Sepsis

– steatosis– Cirrhosis– cholestasisp

• Duration of PN use• Short gut syndrome

– Gall stones

g y• Multiple surgical

procedures• Absence of enteral feeds

Lipid monitoringPl t i l id (TG) l lPlasma triglyceride (TG) level

Serum bilirubin levelLi f ti t tLiver function tests

St li id f 4 h t tStop lipid for 4 hours pre-test

Essential fatty acidsEssential fatty acids

Essential fatty acidswhat are they?

• Linoleic acid (LA)• -> arachidonic

• α-linolenic acid (ALA)• ->eicosapentaenoic (EPA) • ->docosahexaenoic

acids(DHA)Omega-6 Omega-3

• Neonate 0.25g/kg

0.5g/kg/d intralipidMINIMUMMINIMUM

Why are EFA’s essential?Why are EFA s essential?

• synthesis of prostaglandins• help regulate aspects of metabolismhelp regulate aspects of metabolism

– blood viscosity, i fl t– inflammatory processes

– blood cholesterol – fat levels– water balancewater balance

Essential fatty acids (EFA)Essential fatty acids (EFA)

• physiologic processes– skin

• neurologic complications– Numbness

– cell membranes – synthesizing important

– weakness– inability to walk

biologically active compounds

t l di d

– leg pain– blurred vision

• prostaglandins and • leukotrienes.

– development of normal– development of normal vision (animal studies)

What is EFA deficiency?What is EFA deficiency?

D i• Depression • Cardiovascular Disease • Type 2 Diabetes • Fatigue• Fatigue • Dry, itchy skin • Brittle hair and nails • Inability to concentrateInability to concentrate • Joint pain

Essential fatty acidsEssential fatty acids

• Stored in cell membranes

• Ratio omega 6:omega 3

• 2:1 up to 4:1 recommended• 2:1 up to 4:1 recommended

• average ratio population 10:1even 15:1even 15:1

Essential fatty acidsRatio ω6 :ω3 15:1 2:1 4:1Ratio ω6 :ω3 15:1 2:1 – 4:1

omega 6 omega 3g g

• pro-inflammatory • Anti-inflammatory

• grains, vegetable oils,

y

• cold water oily fishpoultry, eggs • cold water oily fish• green leafy

t blvegetables • walnuts

• 22/09/06 Latest News

• CAVEMAN HEALTH PLAN LAUNCHED BY GLASGOW DOCTOR

• unhealthy Brits …..look at diet ……try and eat more like cavemen

• Essential Health Clinic… measures levels of the vital essential fatty acids Omega 3 & Omega 6 in bloodstream.

• It is thought that in the days of cave men

– ratio of polyunsaturated Omega 3:Omega 6 EFAs in the blood stream was roughly equal.

balanced each other out to contribute equally to– balanced each other out to contribute equally to• immune response, blood clotting, oxygen transport, kidney function, healthy joints and skin…..

• High fat in modern diets

Ratio ω6 :ω3I fl f di l d f WBC• Influences type of mediator released from WBCs

via• altering available precursor for fatty acids

• Leukotriene (LT)B4: LTB5i fl t ti i fl tproinflammatory: anti-inflammatory

• LTB4 supports immune system in hyperinflammatory state

• Hospital stay reduced in adult surgical patients

Schulski et al Clin Nutr 1999

Lipid preparationsLipid preparations

How many lipid preparations?How many lipid preparations?

• Soya– Intralipid

• Fish oil– omegaven

• Olive oil • Mixed– Clinoleic – (Olive oil + soybean oil

Mixed– SMOF

• Soya( y10%)

• Structured lipids

y• coconut• Olive oilp

(MCT/LCT) • Fish oil

What are they?What are they?

• Soya/LCT – efa arachidonic acid

• Omegaven– Efa

• Olive oil/MUFA • Coconut oil/MCT– Oleic acid

• <peroxidation– not carnitine dependent

Intralipid/soya bean oildisadvantages

> 6 li l i id i fl t ff t• > ω6 linoleic acid :pro-inflammatory effect(polyunsaturated fatty acid)(p y y )

it i E• < vitamin E– > peroxidationp– < antioxidant capacity

-> immune suppression-> immune suppression

• phytosterols

SMOF

• S oyabean oil

• M edium chain triglycerides

• O live oil• O live oil

• F ish oil

SMOF 2g/kg

• Improved liver function• > rapid elimination from bloodstream> rapid elimination from bloodstream• < triglyceride half life

– Probably due to• > mct content• Optimal LCT content

ESPEN 2006 Goulet

SMOF trialSMOF 20% vs intralipid 20%

53 t b bi (26 SMOF 27 i t li id)• 53 premature babies (26 SMOF:27 intralipid)<34 weeks gestation (mean 30 weeks)

Birth weight 500 2000gBirth weight 500-2000gweight at start: SMOF 1.36kg intralipid 1.3kg

• treated 7-14 daysymean age at start SMOF 6 days, intralipid 6.3 days

• Single centre randomised double-blind controlled trial

Rayyan M FRANC Ped2007

SMOF trialSMOF 20% vs intralipid 20%

• Safety criteriaSafety criteria– Serum triglycerides– Haematology

• Efficacy criteria– Days to regain birth weightHaematology

– Biochemistry– Adverse events

y g g– Body weight– Body height– Adverse events

– TolerabilityVital signs

ody e g t– Mechanical ventilation

– Vital signs

SMOF trialSMOF 20% vs intralipid 20%

T t t• Treatment

• Lipid introduction– day 1-3: 1g/kg/day

• Mechanism of action

– day 4: 2g/kg’day– Plasma fatty acid profile

– day 5: 3g/kg/day– Red blood cells

phospholipids

– day 6-14: 3.5g/kg/day

Results SMOF trialSMOF 20% vs intralipid 20%

Serum triglycerides– SMOF 0.52-0.71 mmol/l Intralipid 0.53-0.68mmol/l

– HaematologyBi h i t– Biochemistry

Adverse events– Adverse eventsSMOF 5:intralipid 7 (possiby drug related)Death due to prematurity SMOF 1:intralipid2Death due to prematurity SMOF 1:intralipid2

– TolerabilityTolerability– Vital signs

SMOF trialSMOF 20% vs intralipid 20%SMOF 20% vs intralipid 20%

Conclusion• Safe and effective

• Reduces ω6: ω3

• May benefit brain and retina at time ofMay benefit brain and retina at time of rapid development

Omegaven fish oilOmegaven fish oil

C 1 34 k t ti l• Case 1, 34 week gestation male– Intra-uterine mid-gut volvulus + gastroschisis– 22cm dilated duodenum– STEP procedure -> 52cmp

PN– By 6 weeks: cholestasis steatosis bile duct proliferationBy 6 weeks: cholestasis, steatosis, bile duct proliferation,

mild fibrosis

– By 6 months: portal-portal bridging fibrosisBy 6 months: portal portal bridging fibrosis

Listed for small bowel transplantGura K et al PEDIATRICS 118; 2006Gura K et al PEDIATRICS 118; 2006

Omegaven fish oilOmegaven fish oil

C 1• Case 1– Omegaven 0.2g-1g/kg/day– 11 hour cycled PN– 2.5g/kg/day protein + 15% dextrose.g g y p

+Breast milk 15ml/hour over 24 hoursBreast milk 15ml/hour over 24 hours

Aged 15 months: thriving ; normal dvtAged 15 months: thriving ; normal dvtcholestasis resolved < 60 days

Omegaven fish oil Case 2

• 25 weeks 850g• 25 weeks, 850g

• Terminal ileum: perforation+ fibrous adhesions aged 6 weeksaged 6 weeks– Total PN

li h bi i l l• >liver enzymes, >prothrombin time, < platelets

• Omegaven 0.5g/kg/d. Total PN Aged 4 months: normal liver function

Gura K et al PEDIATRICS 118; 2006

OmegavenGura K unpublished

• 18 further patients

• 1g/kg/day omegaven

no adverse effectsno adverse effects

Bilirubin returned to normal 66 days vs 478 daysp< 0 01 BUT historical controlsp< 0.01 BUT historical controls

>ω-3 in phospholipids

Lipidsefa

• Can they be given as an enteral supplement?supplement?

Yes walnut oilYes walnut oil

(Salmon, flax seeds)

Conclusion:Conclusion:Lipid in PN p

S f ti l f tt id d it i E•Source of essential fatty acids and vitamin E• Concentrated energy sourcegy•IsotonicP t t h t d d ti f it i A•Protects photodegradation of vitamin A

•Prevents essential fatty acid deficiency•Essential for survival

What to give and whyWhat to give and why

L h i f ‘ ti l’• Long chain efas ‘essential’BUT

• Balance with shorter chain fats

• Vitamin E

• Sufficient fat to enable growthSufficient fat to enable growth that

D l t h• Does least harm

Where are we today?Where are we today?

Soya bean is a tried and tested ‘safe’ fat source

BUT li di d iliver disease and sepsis

improved ω 3: ω 6 with fish oilslikely to improve outcomelikely to improve outcome