Phosphoremia (mmol/l) Calcemia (mmol/l) Postnatal age (days) Postnatal age (days) Urinary Calcium (mg/kg/d) Phosphoremia (mmol/l)

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1 3,0 3,2 Calcemia (mmol/l) 2,8 2,6 2,4 2,2 2,0 1,8 Phosphoremia (mmol/l) 3,0 2,8 2,6 2,4 2,2 2,0 1,8 1,6 1,4 1,2 1, Postnatal age (days) 1, Postnatal age (days) 35 3,5 Urinary Calcium (mg/kg/d) Urinary Phosphorus (mg/kg/d) Phosphoremia (mmol/l) 3,0 2,5 2,0 1,5 1,0 r=-0,33, p<0,0001 0, Senterre T 2011, 2012, submitted Birth weight z-score (Usher)

2 Positive correlation between kaliemia and phosphoremia 7 Kaliemia (mmol/l) Phosphoremia (mmol/l) ,2 3,0 2,8 2,6 2,4 2,2 2,0 1,8 1,6 1,4 1,2 1, Postnatal age (days) Postnatal age (days) Phosphoremia (mmol/l) 3,5 3,0 2,5 2,0 1,5 1,0 r=0,34, p<0,0001 0,5 2,5 3,0 3,5 4,0 4,5 5,0 5,5 6,0 6,5 7,0 Kaliemia (mmol/l) Senterre T 2011, 2012, submitted

3 Biological tolerance Base excess Senterre T 2011, 2012, submitted

4 days of life (r=-0,02, p=0,76) 4-7 days of life (r=-0,08, p=0,15) 8-14 days of life (r=0,11, p<0,05) Excès de base (mmol/l) Base Excess (mmol/l) Âge postnatal (jours) Protein intake (g/kg*d) 8 First 2 weeks of life r=-0.46, p< Base excess (mmol/l) Chloremia (mmol/l) Chloremia (mmol/l) Laboratory Normalized for natremia Senterre T 2011, 2012, submitted Postnatal age (days)

5 Biological tolerance Glucose Senterre T 2011, 2012, submitted

6 Glycemia (mmol/l) Glycemia (mmol/l) r=-0,31, p<0,0001 Glycemia (mmol/l) Postnatal age (days) Glycemia (mmol/l) Gestational age (weeks) 2 r=0,34, p<0, r=0,33, p<0, Invasive resp. support (days) Senterre 10 12T 2011, , 16 18submitted Parenteral glucose intake (g/kg/j)

7 Biological tolerance Urea Senterre T 2011, 2012, submitted

8 22 40 Uremia (mmol/l) Uremia (mmol/l) days of life (r=-0,01, p=0,92) 4-7 days of life (r=-0,12, p=0,13) 8-14 days of life (r=0,08, p=0,31) Postnatal age (days) Protein intake (g/kg*d) Uremia (mmol/l) days of life (r=0,61, p<0,0001) 4-7 days of life (r=0,73, p<0,0001) 8-14 days of life (r=0,60, p<0,0001) Weight evolution (% of BW) Natremia (mmol/l) Uremia (mmol/l) Senterre 2 3T 2011, , 5 submitted Creatininemia (µmol/l) Postnatal age (days)

9 Biological tolerance Creatinine Senterre T 2011, 2012, submitted

10 Creatininemia (µmol/l) Creatinine (µmol/l) r=-0,44, p<0, Postnatal age (days) Postnatal age (days) r=-0,28, p<0,0001 Creatininemia (µmol/l) Creatininemia (µmol/l) Invasive respiratory support (days) r=0,37, p<0, Senterre 29 T , , 32 submitted Gestational age (weeks)

11 Biologic tolerance incidence Period (1530 days) Litterature Na >150 mmol/l 16% D1-3 (19 /27 days) 30-40% K >7 mmol/l 0% % BE <-5 mmol/l 79% 31% after D3 ~100% Glucose >1,8 g/l (10mmol/L) 59% D0-14 (255 days) 20-90% Creatinine >115 µmol/l 29% D0-7 (72 /89 days) 80% Kermovant E 2012 Severe metabolic acidosis (BE<-10 mmol/l) ~50% Worsening during first 10 days of life Hypernatremia >150 mmol/l ~50% Intraventricular hemorrhage grade 2 ~50% Senterre T 2011, 2012, submitted

12 Perspectives - Can Liège results be generalized and/or improved? Liège results = single center experience with home made, wellbalanced, standard PN solution What about an industrially manufactured multichamber bag PN solution for preterm infants like in adults? Potential additional safety issues: Reduction of risk of microbial contamination Reduction of errors associated with prescription, transcription and/or preparation of the TPN Guaranties concerning quality, stability and shelf-life of the factory Large variety of additions guaranteed by the manufacturer

13 NUMETA Product Description ClinOleic Primene + Electrolytes Glucose 1 st triple-chamber PN bag created specifically for preterm infants Contents Lipid emulsion: ClinOleic Protein/amino acid solution: Primene Glucose Electrolytes and minerals Ability to administer with or without lipids Peel Seals Infusion Port Additions Port

14 NUMETA is an optimized standardized PN solution formulated according to guidelines Tsang 2005 ESPEN- ESPGHAN 2005 Optimal intake Optimal solution Senterre Optimal solution NUMETA Based on 165 ml/kg Based on 130 ml/kg Fluids (ml/kg/d) Energy (Kcal/kg/d) Protein (g/kg/d) Glucose (g/kg/d) Fat (g/kg/d) Sodium (mmol/kg/d) Potassium (mmol/kg/d) Chloride (mmol/kg/d) Calcium (mmol/kg/d) Phosphorus (mmol/kg/d) Magnesium (mmol/kg/d)

15 NUMETA is Designed to Provide Adequate Nutrition With Flexible Dosing First day of life Stable growing period NUMETA volume (ml/kg/d) Amino acids (g/kg/d) Glucose (g/kg/d) Lipids (g/kg/d) Energy (kcal/kg/d) Sodium (mmol/kg/d) Potassium (mmol/kg/d) Magnesium (mmol/kg/d) Calcium (mmol/kg/d) Phosphate (mmol/kg/d)

16 NUMETA is Flexible Can be prescribed with or without lipids With Lipids Without Lipids Stability and compatibility data support additions of Amino acids Glucose Lipid Multivitamins* Trace minerals* Electrolytes Sterile water for injection Medications *Note that vitamins and trace minerals cannot be added to MCBs during manufacturing, and daily supplementation of vitamins and trace elements is recommended

17 Is it possible to use industrially prepared standardized PN in VLBW infants? The aim of our study was to evaluate, the first industrially prepared multiple-chamber PN bag specially designed for preterm infants with a composition based on most recent nutritional guideline recommendations

18 Could industrially prepared multichamber bags also be useful in the NICU? Multicenter study in 5 NICUS 3 in France, 2 in Belgium ClinOleic Primene + Electrolytes Glucose Primary objective: To evaluate the safety of NUMETA Ability to provide daily nutritional requirements in the recommended values Clinical use of optional activation of he lipid compartment Flexibility for individual adaptation Secondary objective: To provide information on biological parameters, adverse events, and weight gain Peel Seals Infusion Port Additions Port Rigo J. 2012

19 NUMETA Clinical Trial Patient Demographics Day of Inclusion Days 1-3 (n=34) Days 4-7 (n=35) >7 Days (n=28) Birth weight (g) 1571 ± ± ± 347 Gestational age (days) 219 ± ± ± 15 Postnatal age (days) 2.2 ± ± ± 6.5 PN duration (days) 8.4 ± ± ± 1.3 In terms of age and weight, the study population is representative of the NICU population Rigo J. 2012

20 Practical handling and ease of use Prescription-to-Infusion Time Comparator Ward-compounded bags Ready-to-use compounded bags Favors Standard Practice Favors Ped3CB Tailored premixes Visual Analog Scale* Ease of Bag Manipulation Comparator Ward-compounded bags Ready-to-use compounded bags Favors Standard Practice Favors Ped3CB Tailored premixes Visual Analog Scale* *Visual analog scale rating: scale of 0-10, with numbers <5 indicating low performance for Ped3CB and numbers >5 indicating high performance for Ped3CB compared with standard practice Rigo J. 2012

21 Weight gain and protein and energy intakes according to postnatal age at inclusion. Age inclusion 0-3 d n= d n=35 >7 d n=28 Parenteral intakes Protein (g/kg*d) Energy (kcal/kg*d) 2.50 ± ± ± ± ± ± 19 Enteral intakes Protein (g/kg*d) Energy (kcal/kg*d) 0.85 ± ± ± ± ± ± 19 Total intakes Protein (g/kg*d) Energy (kcal/kg*d) 3.36 ± ± ± ± ± ± 12 Weight gain (g/kg*d) 10.0 ± ± ± 9.4 Rigo J. 2012

22 Estimation of weight gain o All patients' body weight in perspective Simulation of the weight gain curve Rigo J. 2012

23 Maximal parenteral intakes /kg*d Maximal PN intake Espghan/Espen Tsang et al n=97, Mean ±SD AA (g) 3.6 ± Glucose (g) 15.4 ± Lipid (g) 2.8 ± (up to 4) 3-4 Energy (kcal) 104 ± Na (mmol) 2.45 ± (up to 7) 3-5 (up to 7) K (mmol) 2.38 ± Cl (mmol) 3.57 ± Ca (mmol) 1.46 ± P (mmol) 1.45 ± Mg (mmol) 0.50 ± Rigo J. 2012

24 Intakes from the bag, from the supplements and combined. n NUMETA Additions NUMETA + additions Mean ± SD Mean ±SD Mean ±SD Protein (g/kg/d) ± ± ± 0.7 Glucose (g/kg/d) ± ± ± 2.9 Lipid (g/kg/d) ± ± ± 0.6 Energy (kcal/kg/d) ± ± 19 Na (mmol/kg/d) ± ± ± 2.30 K (mmol/kg/d) ± ± ± 0.50 Cl (mmol/kg/d) ± ± ± 2.31 Ca (mmol/kg/d) ± ± ± 0.29 P (mmol/kg/d) ± ± ± 0.30 Mg (mmol/kg/d) ± ± 0.10 Rigo J. 2012

25 Supplementations Amino acids 17/854 days (2%) 0.69 ± 0.28 g/kg*d Glucose 34/854 days (4%) 3.20 ± 2.05 g/kg*d Lipid 9/854 days (1%) 1.12 ± 0.43 g/kg*d Sodium 359 /854 days (42%) 4.31 ± 3.64 mmol/kg*d Potassium 37 /854 days (4%) 1.43 ± 1.04 mmol/kg*d Calcium 40 /854 days (4%) 0.64 ± 0.41 mmol/kg*d Phosphorus 21 /854 days (2%) 0.79 ± 0.42 mmol/kg*d Macronutrient supplementation 56/854 days (6,6%) in 20 infants (20.6%) However, supplementation directly in the chamber bag accounted for only 18 days of perfusion (2%) in 11 infants Electrolytes and minerals supplementation 387/854 days (45%) in 65 infants However, addition to the chamber bag accounted for 185 days of perfusion (21.7%) in 36 infants (37.1%) In all, additions in the CB bags represented 197 days of perfusion (23.1%) in 43 infants (44.3 %) Rigo J. 2012

26 Biological parameters at inclusion, after 5 days and at the end of the study initial Day 5 final Triglycerides (mmol/l) 1.16 ± 0, ± ± 0.58 Urea (mmol/l) 10.7 ± ± ± 6.3 Glucose (mmol/l) 5.5 ± ± ± 1.7 Sodium (mmol/l) 141 ± ± ± 3 Potassium (mmol/l) 4.5 ± ± ± 0.7 Calcium (mmol/l) 2.4 ± ± ± 0.1 Phosphates (mmol/l) 2.0 ± ± ± 0.5 Bicarbonates (mmol/l) 21.0 ± ± ± 3.0 Rigo J 2012

27 Conclusion 1. These studies suggest that standardized PN solution can be used NICU 2. NUMETA allows to provide nutritional intakes similar to the needs of preterm infants, in the range of most recent expert s recommendations 3. Minimal adjustments of NUMETA allows to meet individual variability of electrolytes and mineral needs 4. NUMETA is well accepted by physicians, nurses and pharmacists 5. These studies also suggest that cumulative nutritional deficit and postnatal growth restriction should disappeared from the NICU in most VLBW and ELBW infants Senterre T 2011, 2012, submitted, Rigo J 2012

28 Thank you for your attention You are welcome in Liège

29 Introduction

30 Incidence (%) Prematurity in Europe Preterm Very preterm ,3 4 7,1 5,9 5,9 5,4 7,5 5,9 6,3 5,7 5,8 7,2 5,4 6,2 2 0 Austria 1,4 0,9 Belgium Czech Rep. 1,1 Denmark 1,1 France 0,9 Germany 1,3 1 Italy Netherlands 2 1,1 1,1 0,9 0,8 0,8 1,4 Poland Portugal Spain Sweden UK USA 2010 European Foundation for the Care of Newborn Infants