Basic Concepts On Parentheral Nutrition By Irfan 4b271v

Basic Concepts in Parenteral Nutrition

Objectives • Basic concepts in nutrition • Basic concepts in parenteral nutrition • Nutrients in parenteral nutrition - role of amino acids - role of glucose -role of fat emulsion   - differentiation of MCT/LCT vs LCT • Multichamber bags

Energy stores of an adult Store

Quantity

Use

Exhaustion

Net body protein

10% BW

Glucose precursor

wide, situationdependent

Liver glycogen

300 g

Glucose precursor

 24 h

  Fat

20% BW

Fatty acid  40 days & glucose precursor

Net body protein  glucose 100 g  56 g Death from protein depletion occurs after loosing 1/3 to 1/2 of net body protein

Caloric value of nutrients Calories produced by the combustion of 1 gram of various substrates: Substrate Energy (kcal/g) Amino acids 4 Glucose 4 Fat 9   (10% emulsion: 1.1 kcal/ml) (20% emulsion: 2 kcal/ml) Glycerol 4 Alcohol 7

Metabolism, I

Adenosine triphosphate (i) Oxidation of food by which energy (ATP) is produced and heat is released Unit of energy used in nutrition is kilocalorie (kcal) or kilojoules (kJ)  1 kcal = 4.18 kJ (ii) Biochemical reactions   involving: Anabolism : Build up of body tissues and repair of injured or damaged tissues Catabolism: Breakdown of body tissues into simple molecules for energy production and recycling

Metabolism, II Anabolic reactions In food In the body Proteins  Proteins (Protein synthesis) Carbohydrates  Glycogen (Glycogenesis) Carbohydrates  LCT (Liponeogenesis) LCT  LCT (Fat synthesis) Main hormone of anabolism: Insulin Catabolic reactions Body stores Breakdown products   Glycogen  Glucose (Glycogenolysis) Proteins  Amino acids (Proteolysis) Amino acids  Glucose (Gluconeogenesis) Triglycerides (LCT)  Fatty acids (Lipolysis) + Glycerol LCT = long chain triglyceride

Basic Scheme of Metabolism In anaerobic state, lactate

Glucose G6P LAC

acetylCoA

KB

ketone bodies e.g cetone, acetoacetate 6-hydroxybutyrate

PYR

Glycogen Glucose-6phosphate pyruva te

AA

NH3 Ac-CoA LCFA   + GLY CIT OA Citrat e cycle ATP

glycolys is

Protein

Urea ▲ cycle ▶ Urea

LCT glycer ol Citric acid cycle = Krebs cycle= Tricarboxylic acid

Metabolic changes during starvation and stress Metabolic process

Starvation

Stress

Energy expenditure





Energy source: AA: Gluc: Fat

~ 5: 5: 90

~ 20: 40: 40

Proteolysis





Gluconeogenesis





unimportant

unimportant

increased

increased

normal



Ketonaemia



variable

Insulinaemia





anabolism

Minimize loss of lean body mass

Glycogenolysis Lipolysis Glycaemia

Effect of feeding

 

Phases of the stress response after trauma

Metabolic rate

Increased

duration depends on disease and success of therapy

Turning point

Increment depends on degree of   stress

Normal Decreased

Ebb Flow (days (~ 12-24 to weeks) h)

~1 day

Fat gain (~ 3 months)

Starvation and stress on energy expenditure and protein losses REE Resting (% 18) 0 16 0 14 0 12 0 10 0 8 0 6 0 0

energy expenditure

indicator Nitrogen losses for protein (g) loss 4 0

Major burn

30

Peritonitis

 2

Fracture

0

Starvation

1 0 0 1 0

2 0

3 0

4 day 0 s

0

1 0

2 0

3 0

Long (1977) Am. J. Clin. Nutr. 30, 1301-1310

4 0

days

Daily nitrogen losses in adults Clinical situation

Nitrogen loss (g/day)

Protein loss (g/day)

Body Weight loss (g/day)

Normal

11

70

330

Minor surgery

11-14

75-90

360-420

Major surgery

14-17

90-110

420-510

Multiple injury

15-25

95-160

450-750

 

Head injuryto great 20-30 125-190 Subject patient-specific variations600-900 Sepsis

20-30

125-190

600-900

1 g N  6.25 g protein  30 g muscle Severe 30-40 190-250 900-1200 mass burns Goldstein & Elwyn (1989) Ann Rev Nutr 9, 445-473 (adapted)

Consequences of metabolic changes • • • •

Severe wasting of lean body mass Decrease in critical repair processes Impairment of immune function Impairment of vital organ function

Impact of pre-existing malnutrition n = 709 Well  nourished Malnourished Complications

16.8%

27.0%

Mortality

4.7%

12.4%

Hospital stay

10.1 ± 11.7 days

16.7 ± 24.5 days

Hospital costs

 309%

Correia & Waitzberg (2003) Clin Nutr 22, 235-239

Objective of nutrition therapy • Avoid malnutrition • Maintain body tissue and functioning plasma protein stores • Prevent macro- and micro-nutrient deficiencies Normal  muscle mass  visceral protein    organ function  immune response  wound healing  complications  infections Multiple organ failure (lung, GI, liver,

Possible indications for clinical nutrition

- malnutrition

- intractable diarrhoea

- anorexia

- pancreatitis

- cancer

- peritonitis

- oropharyngeal trauma - renal failure - oesophageal strictures - hepatic failure, liver transplantation - gastrointestinal stenosis

 

- bone marrow transplantation

- operations of the GI tract

- multiple trauma

- bowel fistulae

- head injuries, neurosurgery, strokes

- inflammatory bowel disease

- severe burns

- radiation enteritis

- sepsis

- short bowel

- AIDS

Nutritional assessment • • • •

Medical history, disease severity Dietary history, recent food intake Physical examination, physiological function Anthropometric measurements - body weight (kg), recent unintentional wt loss - height (cm)   - body mass index (BMI) - mid arm circumference (MAC) - tricep skinfold (TSF), • Laboratory data • Immunocompetence data

Energy requirements during metabolic stress and its determination • Energy needs should be determined (i) in relation to expenditure (i.e. requirements) (ii) ability of a patient to metabolize substrates (monitor tolerance) • Indirect calorimetry determines energy expenditure based on O2 intake, CO2 output and minute ventilation

  - has about 95% accuracy

- machine not always available - require skilled technicians • Harris-Benedict Equation estimates resting energy requirements based on weight, height, age for each sex - equations used based on healthy volunteers - inclusion of stress, activity and fever factors tends to overestimate requirements

Basal metabolic rate Harris-Benedict Equation BMR (men)= 66 + (13.7 x BW) + (5 x H) - (6.8 x A) BMR (women) = 655 + (9.6 x BW) + (1.7 x H) - (4.7 x A)

  BW = body weight in kg H = height in cm A = age in years

Actual energy expenditure AEE = BMR x AF x TF x IF AF (Activity Factor) In bed 1.1 In bed, but mobile 1.2 Mobile 1.3 TF (Thermal Factor) 38oC 1.1 39oC 1.2 40oC 1.3 41oC 1.4

IF (Injury Factor) Uncomplicated patient 1.0 Postoperative state 1.1 Fractures   1.2 Sepsis 1.3 Peritonitis 1.4 Multiple trauma 1.5 Multiple trauma 1.6 & sepsis Burns 30 - 50% 1.7

Energy guidelines Energy requirements are based on the following guidelines: postoperative 25-30 kcal/kg/day polytrauma 30-35 kcal/kg/day sepsis 25-40 kcal/kg/day burns kcal/kg/day   is30-45 “25 - 30 kcal/kg/day suitable for most critically-ill patients” - ASPEN Guidelines, 1993 - Mirtallo et al., 1998 (National Advisory Group of 20 – 30 kcal/kg/day – latest revision, Mirtallo ASPEN) et al (2004), JPEN 28/6, S39-S70 ASPEN Guidelines (1993) JPEN 17/4 Supple, 12SA-26SA Mirtallo et al. (1998) JPEN 22, 49-66

Concept of nutritional Nutritional should be given: - when there is loss of weight associated with impairment of physiological functions, or - when the patient’s nutritional status is expected to worsen

Nutritional can be given either enterally or   parenterally

Key question: Does the patient have a functional GI tract?

Enteral: If the gut can be used safely, use it preferentially Parenteral: When the GIT does not work When the GIT should be rested When enteral intake is insufficient

Clinical decision making for nutrition Nutrition Assessment Decision to initiate specialized nutrition

Yes

Functional GI Tract

Enteral Nutrition Long-term Short-term Gastrostomy Jejunostomy

Nasogastric Nasoduodenal Nasojejunal

 

No Parenteral Nutrition Short-Term Peripheral PN

JPEN 17 (Suppl 4):7SA, 1993

Long-Term or Fluid Restriction Central PN

Routes of istration of PN Central route • can accommodate concentrated, hyperosmolar solutions • useful when fluid volume is restricted • suitable when feeding patients with a large nutrient or electrolyte needs, e.g. patients with significant malnutrition   or severe metabolic stress • can be maintained for prolonged periods (weeks to years), even at home (HPN) • must be maintained under strict aseptic techniques to avoid septic complications

Routes of istration of PN Peripheral route • limited to solutions < 900 mOsm/L • suitable for short term PN (< 2 weeks) • difficult to maintain peripheral access for long periods • sites may need changing every 72 h, or when   phlebitis occurs • appropriate when parenteral nutrition is used as a supplement to oral or enteral nutrition

When to start parenteral nutrition Assuming that there are no incompatibilities to the nutrients, PN can commence

- when the patient is in a stable haemodynamic condition - when there is no acid-base imbalance - when there is no electrolyte imbalance - when there is  no overhydration problems If these problems exist, they must first be corrected before PN can commence

Contraindications for specific nutrients General: - intolerance (e.g. allergy, inherited diseases) - critically increased levels Amino acids: - advanced liver disease  adapted hepatic formulation - infants  adapted pediatric formulation Glucose: - no specific contraindications if handle   correctly Fat: - severe hypertriglyceridaemia adults > 450 mg/dL infants > 250 mg/dL - severe thrombocytopenia platelets < 40000/mm3

Types of parenteral nutrition systems Bottle system: spike and hang individual bottles of solutions (e.g. glucose, amino acids, fat emulsion), or mixtures in bottles or kits (Vitrimix ) Compounding system: Hospital or industrially (CAPS - centralized ixing pharmacy service) prepared solutions filled in an ethylene vinyl acetate   and sets) by either gravity bag (e.g. Nutrimix bags or by an automated equipment (e.g. Caretronic or BAXA machine) Convenience system: ready-to-use 2- chamber bags (Nutriflex , Aminomix , Clinimix ) or 3-chamber bags (NuTRIflex Lipid, Kabiven , Clinomel )

 

Parenteral nutrition - Infusion regimens Continuous: Simultaneous infusion of all nutrients in 24 h - usual procedure in critically-ill patients - good tolerance due to even blood nutrients and hormone profiles Almost continuous: Simultaneous infusion of all nutrients in 18-20 h - useful to allow lipid clearance - tolerance as for  24 h - glucose 5% infusion during the TPN-free period Cyclic: Simultaneous infusion of all nutrients in 8-12 h - useful in home TPN - good tolerance after a period of adaptation Sequential: Not recommended as it does not improve nitrogen balance

Infusion regimens Sequential

AA + lipids Glucose n= 21 AIO bag n= 21

Continuous

Bolus

8 AM

2 PM

 

8 PM

2 AM

8 AM

Sandstrom et al. (1995) JPEN 19, 333 - 340

AIO but 5 times n= 23

Nitrogen balance after continuous, bolus or sequential TPN Cumulative Nitrogen Balance 1

Gram N

-4 -9

- 14

 

- 19

- 24

Continuous Bolus Sequential

- 29 - 34 2

3

4

5

6

Sandström et al. (1995) JPEN 19, 333-340

7

Days

Amounts and concentrations

 

Calculation of a PN regimen 45 year old man, 60 kg, 172 cm, abdominal surgery, in bed, 38 oC fever, Nout = 16 g Example 1 Calculate energy and protein requirments by Harris-Benedict equations Example 2   N intake = 16 g, non-protein calories ~125 kcal/g N Example 3 To give 1.5 g/kg/day AA, 3.5 g/kg/day glucose, 1.0 g/kg/day fat Example 4 to give 1.5 g/kg/day AA, total calories = 35 kcal/kg/day

Calculation of a PN regimen

Example 1 Calculate energy and protein requirments by Harris-B

 

Calculation of a PN regimen

 

PN delivery

 

Parenteral Nutrition Nutrients with calories

Nutrients without calories

Glucose

Fat

Amino acids

Electrolytes

Parenteral   Nutrition

Water

Vitamins/Minerals

Dosage recommendations for PN

30-40 mL/kg, Mirtallo et al (2004) a) b) Dosage per kg and day ASPEN dosage guidelines

Recommended dosages, adults

Nutrient

Water 35 - 45 ml Na+ 1 - 3 mmol K+ 1 - 1.5 mmol Mg2+ 0.05 - 0.1 mmol Ca2+ 0.05 - 0.1 mmol Cl1 - 3 mmol Cl-/Acetate 1 : 1 ratio   Phosphate 0.2 - 0.5 mmol Amino acids 1.0 – 2.0 g Glucose 3.0 – 5.0 g Lipids 0.5 – 2.0 g Total energy 25-40 kcal Vitamins see appendix Trace elements see appendix

20 - 40 ml/kg and day 1 - 2 mmol/kg and day + replacem 1 - 2 mmol/kg and day 4 - 10 mmol/day 5 - 7.5 mmol/day no entry As needed to maintain acid-base 20 - 40 mmol/day 0.8 – 2.0 g < 7.0 g < 2.5 g 25-30 kcal/kg and day see appendix see appendix

a) Diverse sourcesb) JPEN 22 (1998) 49-66

Parenteral nutrition - Electrolytes Electrolytes: Composition and function of extracellular and intracellular spaces, acid base balance, catalyst for enzymes, bone mineralisation - sodium (Na+) bicarbonate (HCO3-)   - potassium (K+) (not essential, can - magnesium (Mg2+) be replaced by - calcium (2+) acetate) - chloride (Cl-) - phosphates (H2PO4-)

Parenteral nutrition – Micronutrients: Vitamins and trace elements • Important roles in: - metabolic homeostasis - enzyme pathways: as co-factors or as metalloenzymes - antioxidant activities - tissue integrity • Requirements are usually small, but a deficiency   can have major consequences - overt clinical deficiency: well characterized - subclinical deficiency: not so well characterized Insufficient micronutrient intake impairs ability to utilize macronutrients and maintain body defense mechanisms

Micronutrients – Vitamins Vitamins: essential organic micronutrients Lipid soluble vitamins

Water soluble vitamins

A (retinol)

B1 (thiamine)

D (calciferol)

B2 (riboflavin)

E (tocopherol) K (phylloquinone)

 

C (ascorbic acid) Folic acid Biotin Pantothenoc acid

B6 (pyridoxine) B12 (cyanocobalamin) Niacin (nicotinic acid)

Dosage recommendations for PNVitamins a) Children Children > 11 years Vitamin 0 - 10 years and adults b) Retinol (I.U.) c) 230 3330 a) Per kg body weight Calciferol (I.U.) d) 40 200 and day. For a body Tocopherol (I. U.) e) 0.7 10 weight > 10 kg dose as Phylloquinone (mg) 0.02 f) for 10 kg Ascorbic acid (mg) 8 100 b) Per day Folic acid (µg) 14 400   c) 1 I. U. = 0.3 µg Niacin (mg) 1.7 40 retinol Riboflavin (mg) 0.14 3.6 d) 40 I. U. = 1 µg Thiamine (mg) 0.12 3.0 calciferol Pyridoxine (mg) 0.1 4.0 e) 1 I. U. = 1 mg D,LαCyanocobalamin (µg) 0.1 5.0 tocopheryl acetate Pantothenic acid (mg)0.5 15 or Biotin (µg) 2 60 0.67 mg D-α-

tocopherol

AMA/NAG, JPEN 3 (1979) 258-265

f) 2 - 4 mg once a

Micronutrients – Trace elements Trace elements: essential inorganic micronutrients Iron (Fe)

Chromium (Cr)

Zinc (Zn)

Molybdenum (Mo)

Copper (Cu)

Fluoride (F)

Manganese (Mn) Iodine (I) Selenium (Se)

 

Cobalt (Cr)

Dosage recommendations for PN – Trace elements Adults

1) 2)

mg/d

Preterm Term Children 3) a) Starting 2nd month infants 3) infants 3) µg/kg x d or after reaching µg/kg x dµg/kg x d (max. per d) 2000 g bw

Iron Zinc Copper

0.5 - 5.0 200 a) 2.5 - 4.0 400 0.5 - 1.5 20 Chromium 0.01 - 0.02 0.20 Manganese 0.15 - 0.8 1.0 Molybdenum0.01 - 0.03 0.25 0.02 - 0.05 2.0 Selenium Iodide Fluoride

0.07 - 0.3 0.5 - 1.0

1.0 e)

100 b) 250 c)/100 20

 

0.20 1.0 0.25 2.0 1.0 e)

d)

no data b) 20 (300) c) 0.20 (5.0) 0.20 (5.0)

Not in the 1st three months For age up to three months

d) If older than three months

1.0 (50) 0.25 (5.0)e) Insufficient data available. Oral 2.0 (30) 1.0 (1.0) e)

recommendations are deemed to be appropriate also for PN

1) K. N. Jeejeebhoy, New Aspects of Clinical Nutrition (1983) 1 – 24 2) T. G. Baumgartner, Clinical Guide to Parenteral Micronutrition (1984) 3) H. L. Greene et al., Am. J. Clin Nutr. 48 (1988) 1324-1342

Amino acids in parenteral nutrition

 

Amino acids (AA) Essential AA isoleucineBranche leucine d chain AA valine (BCAA) methionine - Aromatic phenylalanine AA threonine tryptophan lysine

Non-essential AA histidine *

glycine

arginine*

serine*

alanine

proline

asparagine

tyrosine*- Aromatic (ornithine) AA

aspartic acid cysteine*

  glutamic acid glutamine

(* ?)

*Conditionally essential: essential in certain situation e.g. restricted ability to synthesize or increased requirements that cannot be met by de novo synthesis

http://www.cryst.bbk.ac.uk/education/AminoAcid/overvi ew.html

Body proteins: Functions & consequences of depletion Every protein in the body has a function Loss of protein means loss of Protein function Consequences of function depletion Immune response to infection

Lowered resistance

  Tissue regeneration Impaired wound healing, wound closure

Colloidosmotic pressure Development of interstitial oedema Net body protein is about 10% of body weight Organ functions Organ atrophy and Weight loss associated with protein loss and impairment dysfunction of physiological function greatly increases morbidity and mortality

Daily nitrogen losses in adults Clinical situation

Nitrogen Protein loss loss (g/day) (g/day)

Body Weight loss (g/day)

Normal

11

70

330

Minor surgery

11-14

75-90

360-420

Major surgery

14-17  

90-110

420-510

Multiple injury

15-25

95-160

450-750

Head injury 20-30 125-190 Subject to great patient-specific variations 600-900 Sepsis 20-30 125-190 600-900 Nitrogen: Protein = 1 g: 6.25 g Severe 30-40 190-250 900-1200 burns Goldstein & Elwyn (1989) Ann Rev Nutr 9, 445-473

Effects of amino acids and nonprotein calories Setting :

N balance

(g/d) 0

- 39 patients with burns or fractures of more than 2 long bon

-2

- 45-50 kcal/kg and day (GLC : LIP = 1 : 1)

-4

- N/~ AA intake (g/kg and day): 0/0; 0.1/0.8; 0.2/1.5; 0.25/1.9; 0.3

-6 -8 -10 -12 -14

 

0 g AA

~ 0.8 g AA

~ 1.5 g AA

~ 1.9 g AA

p < 0.05 vs 0 g AA

Larsson et al (1990) Br J Surg 77, 413-416

~ 2.2 g AA

Recommendation for protein (nitrogen) Protein (nitrogen) requirement for adults: Maintenance: 0.8 - 1.0 (0.12 – 0.16) (g/kg/day): Catabolic patients: 1.2 - 2.0 (0.19-0.32) g/kg/day Complementary source of calorie Amino Acids

 

Proteins: Structure Function

Energy: Glucose Lipids (free fatty acids) Non-protein calories = 100 - 200 kcal/g N grams of nitrogen Mirtallo et al. (1998) JPEN 22/2, 49-66 Mirtallo et al. (2004), JPEN 28/6, S39-S70

Some other recommendations for protein (nitrogen) Source ASPEN Safe Practice for PN revision 2004

Recommendation Protein for chronic renal failure with renal replacement therapy 1.2 – 1.5 g/kg/day Protein for patients with acute renal failure and catabolic 1.5 – 1.8 g/kg/day

ASPEN guidelines 1993 (p34SA)

“consensus is that 3 g/kg/day is   appropriate for adequate growth and nitrogen utilization for low birth weight infants ”.

ESPEN guidelines 1997 (p51, Table)

Protein or amino acids recommendation is 1.0 to 1.2 g/kg/day in liver disease and transplantation, .

Ziegler & Smith (1993)

“Goal for protein intake in most diabetic patients should be ~ 1.5 g/kg/day

Types & claimed indications of amino acid formulation Formulation

Indication

Standard

Parenteral nutrition for adults

Infant

Parenteral nutrition for neonates

Hepatic

Treatment of hepatic encephalopathy; parenteral nutrition for patients with severe liver disease

Renal

Parenteral nutrition for renal failure patients

 

High-branched Parenteral nutrition in sepsis chain amino acids

Characteristics of standard amino acid solutions: • Amino acid concentrations of 5 - 15% • With or without electrolytes • With or without carbohydrates (e.g. sorbitol, glucose, glycerol) • Contains the 8 essential amino acids ~ 35 - 45% • Amounts of each of the 8 essential amino acids generally based on oral protein intake pattern (Rose, egg protein potato & egg protein) • Range of non-essential  amino acids mostly incomplete, with relatively high concentrations of a few cheap amino acids (alanine, glycine) as sources of non-specific nitrogen • Glutamine, tyrosine and cysteine usually missing because of poor solubility – one formulation contains glutamine dipeptide (Glamin) • Glutamine dipeptide and tyrosine dipeptide overcomes solubility problems but expensive and under patent protection

Characteristics of amino acid solutions for infants • • • • •

Amino acid concentrations of 5 - 10% Generally without electrolytes Generally no carbohydrates content Contains the 8 essential amino acids ~ 45 - 55% Amounts of each of the 8 essential amino acids often based on mother’s milk   • Contains taurine – considered essential amino acids in neonates

Special amino acid solutions for infants “Optimal protein nutrition in this population is dependent on both the quantity of protein as well as its quality (composition). Neonates potentially differ qualitatively from adults because of their limited capacity to synthesize certain amino acids” ASPEN Board of Directors Guidelines (2002)

 

“Standard parenteral amino acid formulations are low in or do not have these amino acids (e.g. taurine, cysteine).” ASPEN Board of Directors Guidelines (1993)

JPEN 17/4 (Supple), 33SA-36SA; JPEN 26/1

Characteristics of amino acid solutions for severe liver disease (hepa solutions)

• Amino acid concentrations of 5, 8 & 10% • No or minimal electrolyte content • No carbohydrates content • Contains essential and non-essential amino acids • Increased amounts of branched-chain (leucine, isoleucine, valine) and decreased amounts of   aromatic (phenylalanine, tyrosine) amino acids, and of methionine compared to standard amino acid solutions • Nonessential amino acids often incomplete

Special hepatic amino acid solutions Hepatic encephalopath y “Most patients with liver disease who does not have HE can tolerate a protein source consisting of standard amino acids. When, in spite of conventional therapy with lactulose/ and/or neomycin, the presence of HE makes it impossible to provide adequate protein to a patient with liver disease, an enteral or parenteral product containing a liverspecific amino acids mixture should be used”.   ASPEN Board of Directors Guidelines (1993)

JPEN 17/4 (Suppl),14SA-15SA

Special hepatic amino acid solutions “Patients in coma (encephalopathy III-IV) can safely be given TPN regimens providing 25-30 kcal/kg/day non-protein energy plus 1.0 g/kg/day using BCAA-enriched amino acid solutions. ” “Coma solutions containing only BCAAs ... are   ESPEN Guidelines for nutrition in liver disease and unbalanced solutions and not recommended as a transplantation (1997) nitrogen source for parenteral nutrition.”

Clin Nutrition 16, 43-55

Characteristics of HBC amino acids solutions for high stress (coma solutions) • Amino acid concentrations of 3 - 5% • No or minimal electrolyte content • No carbohydrates content • Contain only the 3 branched-chain amino acid (leucine, isoleucine, valine), and hence unsuitable for nutritional purposes  • One radical concept even advocates the use of valine only

Amino acid solutions for patients with high stress Coma solutions: - BCAA only

Coma solutions are unbalanced; not recommended for parenteral nutrition - ESPEN consensus guidelines

 

Plauth et al (1997) Clin Nutrition 16, 43-55

Characteristics of amino acid solutions for renal failure • • • •

Amino acid concentrations of 5 - 7% No or minimal electrolyte content No carbohydrates content Originally with only the 8 essential amino acids and histidine (considered to be essential in RF); sometimes also include arginine – no longer recommended   • Later with both the essential and non-essential amino acids in a ratio of 60: 40 weight percent

Special renal amino acid solutions “On the basis of current evidence, nutritional to ARF patients should be accomplished with an intake containing a balanced mixture of both essential and non-essential amino acids ”. ASPEN Board of Directors Guidelines (1993)

 

B.Braun’s Way Amino Acid Solutions

 

Aminoplasmal (B.Braun) A standard amino acids solution • Versatile range of concentrations (5%E, 10%, 10%E,12.5%E, 15%, 15%E)* in different volumes (250 , 500 mL) 5% E & 10% E Available in Pakistan • Allows great flexibility in choice to cater for different nitrogen requirements of patients • Available for central and peripheral route of istration • 3 year shelf life

 

• Store at room temperature • Contain no preservatives e.g. sulphite

*See Additional Information from Dr R. Franke for composition under Standard AA formulations

Aminoplasmal (B.Braun)

Available in

Pakistan

• Contains 20 crystalline amino acids* - breakdown and re-synthesis of additional amino acids, which require extra energy expenditure is avoided “Conversion of one non-essential amino acid into another requires   time, energy and leads to nitrogen losses”

*Get Additional Information from B.Braun Product Consultant

Aminoplasmal Hepa 10% (B.Braun) Applied for registration Product Characteristics Dosage form

solution for IV infusion

Strength

10%*

Osmolarity

875 mOsm/L

Pack size

500 mL

Container

Glass  bottle

Shelf life

3 years

Storage temperature

below 25oC

*Get Additional Information from B.Braun Product Consultant

Aminoplasmal Hepa 10% (B.Braun) Contains - contains 20 amino acids* - without carbohydrates - minimal amount of electrolytes - no sulphite as preservative (since sulphite may increase the risk of hepatotoxicity)

 

*Get Additional Information from B.Braun Product Consultant

Aminoplasmal Hepa 10% (B.Braun) Indications • Normalization of amino acids imbalance resulting from liver insufficiency • Prophylaxis and therapy of hepatic encephalopathy • Parenteral nutrition in liver diseases when hepatic encephalopathy is either imminent or already manifested

 

Aminoplasmal Hepa 10% (B.Braun) Contraindications: • Disturbed amino acid metabolism of other than hepatic origin • Renal failure with pathological nitrogen levels • Established cardiac failure • Overhydration   • Acidosis • Hypokalemia • Hyponatraemia

Aminoplasmal Hepa 10% (B.Braun) Recommendation on route of istration: central venous Dosage Normal dose:

0.7 to 1.0 g/kg/day

(eq. 7 to 10 mL/kg/day) Maximum dose:

 1.5 g/kg/day

(eq. 15mL/kg/day)

e.g. a bottle for a 60 kg weight patient is eq. To 0.8 g/kg/day ~ 8 mL/kg/day

Aminoplasmal Hepa 10% (B.Braun) Infusion rates: Maintenance for PN: up to 1 mL/kg/h e.g. a 12-h infusion of a bottle to a 60 kg weight patient is equivalent to 0.7 mL/kg/h

  Treatment of hepatic coma: e.g. for a 70 kg weight patient, infuse 1st and 2nd h ~ 150 mL/h or 0.2 g/kg/h 3rd and 4th h

~ 75 mL/h or 0.1 g/kg/h

from 5th h ~ 45 mL/h or 0.06 g/kg/h

Aminoplasmal Hepa 10% (B.Braun) Clinical studies have shown the following: - normalization of plasma amino acids profile - normalization of FQ with concomitant improvement in HE scores - reduction of plasma ammonia levels - improvement in nitrogen balance and other   parameters of protein metabolism - improvement in liver function

Plasma amino acids in cirrhotics

% of normal

400

GLU ASP MET

300

PHE TYR

200

TRY

  100

0

THR

GLY HIS

SER LYS TAU

LEU

VAL

ILEU

Essential

PRO ALA

ORN

Non-Essential

Rosen et al. (1977) Gastroenterology 72, 483-487

ARG

Plasma AA imbalances & HE score in cirrhotics 4 3 2

 

1

Fischer quotient (FQ): ratio of molar conc’ns of the BCAA and AAA: FQ = Val + Leu + Ile Phe + Tyr

0 0 Alert

1

2 3 HE score

4 Comatous

Fischer et al (1976) Surgery 80, 77-91

Leweling et al. (1982, 1985) • Prospective, non comparative study on the effects of a Hepa solution (10%) on HE n = 21 patients with liver cirrhosis & HE: - 35 - 40 kcal/kg/day glucose - 1 g/kg/day BCAA-enriched AA solution - no neomycin or lactulose

  • Prospective, non comparative study on the effects of a Hepa solution (10%) on parameters of protein synthesis n = 11 patients with liver cirrhosis req. TPN because of gastric bleedings: - 35 - 40 kcal/kg/day NPC as glucose & lipids - 1.25 g/kg/day BCAA-enriched AA solution - daily infusions over 7 - 16 days

Normalization of Fischer Quotient FQ 4 3 2

 

1

21 patients with HE (35 infusion periods)

0 0

p 0.01

8h

Leweling et al. (1982) Aminos & Ammoniakstoffw,

Ammonia levels in blood g/dL 250

125

10 patients with HE

 

0 P  0.01 0 8h Leweling et al. (1982) Aminos & Ammoniakstoffw,

Nitrogen balance (example of a patient) gN 6 4 2

 

0 -2 -4 1

2

3 4 5

6

7 8 Day

9 10 11 12 13 14

Leweling et al. (1982) Aminos & Ammoniakstoffw, 193-202

PN with a BCAA-enriched solution in patients with liver cirrhosis %

mg/dL 6

PT

RBP

100

80 3

 

60

40

0 Start

p < 0.05 End

Start

p < 0.05

Leweling et al. (1985) Klin Ernahr 15, 306-33226

En d

Visceral protein & serum biochemistry

 

Leweling et al. (1985) Klin Ernahrung 15, 316 - 322

Glucose in parenteral nutrition

 

Glucose (Dextrose) • Most important source of energy in diet and in PN • Primary substrate for the generation of energy (ATP) for cellular metabolism • Each gram of glucose yields  4 kcal of energy • Certain organ systems are dependent solely on glucose: - Cells of the brain and CNS   - Cells of the adrenal medulla, RBC, WBC • Minimum daily requirement for glucose (100 - 150 g/day) • During prolonged starvation, the brain can switch to using ketone bodies as energy • Proven efficacy in sparing body protein in both starved and stressed patients • Easy to monitor serum and urine levels

Effect of glucose on protein losses in healthy subjects Cumulative protein losses Glucose

(g) 0

200 g/d 100 200

100 g/d

 

300

50 g/d

400

0 (fasting) 0

1

2

3

4

5

6 day s

Gamble (1947), Harvey Lectures 42, 247-273

Glucose homeostasis I • Plasma glucose is maintained within a narrow range • Normal fasting level in peripheral venous blood is 4 6 mmol/L or 70 - 110 mg/dL

Mechanisms responsible for glucose homeostasis: liver & muscle Glycogenesis: glucose  glycogen Glycogenolysis: glycogen  glucose   Gluconeogenesis: proteins  amino acids  glucose Liponeogenesis: glucose  fat hepatic glycogen replenishes plasma glucose; muscle glycogen only for local use liver & kidneys

Glucose homeostasis II • Plasma glucose is influenced by several hormones: Insulin Glucagon Growth hormone Corticosteroids Catecholamines Proinflammatory cytokines • As blood glucose level rises to > 150 mg/dL, insulin is released and facilitates uptake of glucose transport into cells, glycogenesis and liponeogenesis

 

• When blood glucose level falls, glucagon is released and produce the opposite effect of insulin • Both hormones are degraded by the liver • Increased levels of counter-regulatory hormones and pro-inflammatory cytokines results in gluconeogenesis

Glucose intake, glucose oxidation and respiratory quotient (RQ) • Glucose oxidation increases with glucose intake of up to 6 g/kg/day (4 - 5 mg/kg/min) • Further increase in glucose intake does not cause increase oxidation, but results in conversion to fat (liponeogenesis) • Respiratory quotient (RQ) is carbon  dioxide produced oxygen consumed • Glucose oxidation results in RQ of 1.0 • Liponeogenesis results in RQ of 8.7

Effect of glucose intake on glucose oxidation and liponeogenesis in burn patients Direct glucose oxidation Respiratory quotient

% 5 0 4

1. 2 1.

0 3 0 2 0 1 0 0

oxidation

0

liponeo genesis 

~ 2.9 ~ 5.8 ~ 8.6 ~ Glucose intake 11.5

(g/kg/day)

oxidation

1 1. 0 0. 9 0.

liponeo genesis

8 0. 7 0

~ ~ ~ ~ 2.9 Glucose 5.8 8.6 11.5 intake

(g/kg/day)

Burke et al. (1979) Ann. Surg. 190, 274-285

Problems with glucose in PN Problems with glucose in PN are the consequence of a) too high dosage b) too high infusion rate c) poor monitoring of the patient Clinical problems Hyperglycaemia

 

renal overflow

exogenous

Metabolic-clinical problems Liponeogenesis fatty infiltration of the liver

insulin

dehydration risk of (risk of hypoglycaemia hyperosmolar coma)

increase in minute ventilation

Influence of infusion rate on incidence of hyperglycaemia Retrospective study in patients not normally predisposed to hyperglycaemia Glucose infusion mg/kg/min

n

hyperglycaemia cases (%)

4

19

0

4.1 – 5

46

5 (11%)

5

37

18 (49%)

 

Rosmarin et al. (1996) Nutr Clin Prac 11, 151-

  PRCT 1548 patients - Conventional gp: 200 mg/dL

blood glucose kept at 180 -

- Insulin therapy gp: blood glucose kept at 80 - 110 mg/dL Strict glycaemic control at <110 mg/dL with insulin infusion

 

Van den Berghe (2004) ESPEN lecture, Lisbon

 

Van den Berghe (2004) ESPEN lecture, Lisbon

 

Van den Berghe (2004) ESPEN lecture, Lisbon

Strategy for using glucose in PN • Optimize delivery but do not exceed oxidative rate - infuse glucose slowly, at 2 - 4 mg/kg/min  5 - (6) g/kg/day) maximum in critically ill patients: 3 - 4 g/kg/day • Ensure normoglycaemia - in critically ill patients control serum glucose more   aggressively recommended level 80 - 110 mg/dL (4.4 – 6.1 mM) - when discharged from ICU, blood glucose should be maintained at 180 – 200 mg/dL (10.0 – 11.1 mmol/L) • Minimize liponeogenesis - use mixed fuel system of glucose + fat

Glucose in pediatric patients Dosage: Premature 10 - 20 g/kg/day Neonates 10 - 20 g/kg/day Older children 1 - 7 yrs 9 -12 g/kg/day 8 - 12 yrs 7 - 9 g/kg/day 13 – 18 yrs 4 – 7 g/kg/day

 

• Start at 6 mg/kg/min to 8 mg/kg/min • Advance by 1 to 2 mg/kg/min to a maximum of 12-14 mg/kg/min/day (17g/kg/day – 20 g/kg/day)

Baugh et al (1998) ASPEN Nutrition Manual, Chap 24

PN regimen without lipid A 50 kg patient requires ~ 30 kcal/kg/day total energy Total energy required = 50 x 30 = 1500 kcal/day If only amino acids and glucose are given, and amino acids is given at 1 g/kg/day Total amino acids =  50 x 1 = 50 g (1 bottle 500 mL10% soln) Protein calories = 50 x 4 kcal/g = 200 kcal

Exceedscalories recommended Non-protein = 1500 - 200 = 1300 kcal = 6.5 g/kg/day amount of glucose Amount of glucose = 1300/4 = 325 g

Glucose solutions & their osmolarity Product

Osmolarity (mOsm/L)

Glucose 5%

278

Glucose 10%

556

Glucose 20%

1110

Glucose 30% Glucose 40% Glucose 50%

1660 2220 2770

Glucose 70%

 

3880

Osmolarity of serum ~ 300 mOsm/L. Solutions with osmolarity > 300 mOsm/L are defined as hyperosmotic. Hyperosmotic and acidic pH of concentrated glucose solutions warrant their istration via large veins. Peripheral vein tolerance to hyperosmotic solution is highly patient-dependent, but tolerance is generally poor as solution osmolarities approach 800 to 900 mOsm/L.

Glucose alone versus a mixed fuel system only Mixed fuel system of glucose and lipids are better adapted to stress than glucose alone • Provides essential fatty acids - Adolph et al (1995) Ann Rev Metab 39, 251-260 • Produces better nitrogen retention - Bresson et al (1991) Am J Clin Nutr 54, 370-378 - Nose et al (1987) Pediatr Res 21, 538-541 • Less CO2 production with a mixed fuel system - Askanazi et al (1979)  Anaesthesiology 51, 192• Lipids oxidization increased in the critically ill while glucose oxidation decreased - Stoner et al (1983) Br J Surg 70, 32-53 - Jeevanandam et al (1990) Crit Care Med 18, 125-135 • Serum glucose is better controlled with a mixed fuel system - Hempel et al (1981) Infusionstherapie 3, 124-132

Relationship between glucose oxidation and sepsis scores in patients on PN

 

Stoner et al (1983) Br J Surg 70, 32-53

Relationship between fat oxidation and sepsis scores in patients on PN

 

Stoner et al (1983) Br J Surg 70, 32-53

Effect of glucose system and mixed fuel system on ventilation V

.

CO2 (mL/min/m2)

300

RQ=1

A 

200



B

 

100

A

RQ=0.7 Gluc (kcal) 2400 1300 Lipids(kcal) 0 . VE (l/min) 10.8

0 0

100 200 . VO. (mL/min/m2) 2

300

Askanazi et al. (1979) Anesthesiology 51, 192

B

1100 6.35

Serum glucose profile during PN Carbohydrate only

Carbohydrate + fat

 

5th day

9th day

5th day

Hempel et al (1981) Infusionstherapie 3, 124132

9th day

Lipids in parenteral nutrition

 

Lipids • Naturally occurring organic compounds from plant and animals that are water insoluble • Some types of lipids to know - triglycerides (or triacylglycerols) – ester of glycerol + 3 fatty acids - phospholipids – ester of glycerol + 2 fatty acid + X,   with X = phosphate group tog with N-ds (e.g. choline, ethanolamine), hydrophilic has a polar head and 2 non-polar tails

– water loving

- cholesterol (most common steroid and precursor of all other steroids in animals) - others e.g. glycolipids related to brain and other hydrophobic nervous tissues - water repeling

Roles of lipids • Serve several functions in the body: - main source of stored energy (in adipose tissues, LCT) 9 kcal/g - metabolic fuel - essential component of cell membranes - insulate against injury and heat loss - pad critical organs  - act as precursors of important regulatory compounds such as prostaglandins and eicosanoids - serve as carriers of various lipid soluble substances e.g. fat soluble vitamins (A, D, E, K) in plasma

Characteristics of lipid emulsions for PN • Oil-in-water emulsions with 10%, 20% or 30% triglycerides • Different types of triglycerides • Different ratios of 3, 6, 9 • Egg yolk phospholipid as emulsifier • Glycerol to adjust for osmolality (~ 300 mOsm/kg) • pH ~ 8, unbuffered   • Mean lipid droplet size ~ 0.3 µm • High caloric density (10% ~ 1 kcal/mL, 20% ~ 2 kcal/mL) • Content of essential fatty acids mostly in the soya oil

Representation of an oil-in-water lipid emulsion Water

-

-

-

- -

-

Triglyceride

Phospholipid

-

- -

(+ glycerol)

-

-

-

-

  -

-

- -

-

-

Triglycerides - esters of glycerol and 3 fatty acids, also called triacylglycerols - classified depending on chain lengths of free fatty acids attached to glycerol backbone e.g. SCT, SCFA SCFA Short chain triglyceride MCT, LCT (SCT) SCFA MCFA   MCFA Medium chain triglyceride (MCT) MCFA Long chain triglycerideLCFA (LCT)

LCFA LCFA

Classification of triglycerides Structured triglyceride (SL) MCFA

MCFA

Defined

  Random

LCFA

MCFA/LCFA

MCFA/LCFA

MCFA/LCFA + MCT + LCT

Free fatty acids hydrocarbon chains carboxyl gp

• Free fatty acids (FFA) - empirical formula R-COOH • Has linear chain of even number of carbon atoms, that can be - saturated (no double bonds) - monounsaturated (1 C  C) or - polyunsaturated ( 2 C  C)   • FFA are named - SCFA with R = 2 and 4 - MCFA with R = 6, 8, 10 and 12 - LCFA with R = (14), 16, 18, 20, 22 and 24 • Essential FFA are - linoleic acid (omega 6, 6; 18: 2n6) - -linolenic acid (omega 3, 3; 18:3n3)

Names of the saturated fatty acids • C2 : • C4 : • C6 : • C8 : • C10: • C12:

Acetic acid (ethanoic acid) Butyric acid (butanoic acid) Caproic acid (hexanoic acid) Caprylic acid   (octanoic acid) Capric acid (decanoic acid) Lauric acid (dodecanoic acid)

• C14:

Myristic acid (tetradecanoic acid) • C16: Palmitic acid (hexadecanoic acid) • C18: Stearic acid (octadecanoic acid) • C20 : Araquidic acid (eicosanoic acid) • C22 : Behenic acid (docosanoic acid) • C24: Lignocerotic acid (Tetracosanoic acid)

Names of some of the unsaturated fatty acids Name

Abbreviation

C16:1, 7 Palmitoleic acid Oleic acid C18:1, 9 Linoleic acid C18:2, 6 γ-Linolenic acid C18:3, 6 Dihomo-ω-linolenic Cacid 20:3, 6   , 6 Arachidonic acid C20:4 α-Linolenic acid C18:3, 3 Eicosapentaenoic acid C20:5, 3 Docosahexaenoic acid C22:6, 3

Structure COOH COOH COOH COOH COOH COOH COOH COOH COOH

no of carbon atoms from  and the closest double bond  = methyl terminus, total no of double bonds non carboxyl carbon

otal no. of carbon atoms

Other components of lipid emulsions: • Phospholipids (egg yolk lecithin) - have both a hydrophobic (water repelling) and hydrophilic (water attracting) part, which enable interaction at both water and fatsoluble interfaces, making them ideal emulsifying agents • Glycerol - to adjust the osmolarity of the emulsion to that of blood • Sodium Oleate - to maintain stability of fat emulsions, especially when stored at room temperature   to - its stabilising effect is due  its acting as a co-emulsifier and  its causing a pH shift to higher values and neutralization of free fatty acids formed by hydrolysis of lipids during storage  Alpha tocopherol (only in BBraun lipid emulsion) - to protect against in vitro peoxidation and maintains vitamin E status

Storage temperature of lipid emulsions

 

Note well

Types of lipid emulsions e.g. Intralipid® LipofundinStructolipidNonNonLipofundin existen ® existen ® ®N MCT/LCT t t Clinoleic®, SLr SLd L M/L M Omegaven SLr SLd L L M/L L

L

L

M

 

M/L

M/L

SLr

SLd

SLr

SLd

LPL/HL LCFA + Glycerol MCFA + LCFA + Glycerol

Types of lipid emulsions • 100% LCT emulsions: Intralipid , Ivelip , Lipovenos , Lipofundin N • Mixed LCT emulsions: Liposyn II (Abbott) – safflower oil: soya oil of 1:1), Clinoleic  (Baxter- olive oil: soya oil of 4:1) • Special LCT emulsion: Omegaven  (only fish oil) • Physical mixed MCT/LCT: Lipofundin  MCT/LCT (BBraun   - MCT oil: soya oil of 1:1 (by weight)), Lipovenos  MCT Fresenius Kabi – same as Lipofundin  MCT/LCT) • Structured lipids: Structolipid (Fresenius Kabi randomized SL of MCT: LCT of 36:64 (by weight))

Evolution in parenteral lipid emulsions

  LCT: long chain triglyceride; MCT: medium chain triglyceride; PUFA: polyunsaturated fatty acids; FA: fatty acid; FO: fish oil

Driscoll et al. (2001) Chapter 3, Rombeau & Rolandelli 3rd Ed.

Use of lipids I Indication - as a source of essential fatty acids - as a source of energy Contraindication - in patients with disturbances in normal fat metabolism e.g. pathological hyperlipaemia, lipoid   nephrosis or acute pancreatitis accompanied by lipaemia, or that which is aggravated by hyperlipaemia - in conditions of shock and/or acid base imbalance, these conditions should be corrected before parenteral nutrition should be considered

Use of lipids II Adverse reactions Immediate reactions: nausea, vomiting, fever, sweating, chills, sleepiness, chest and back pains, dyspnoea, cyanosis, allergic reactions, hyperlipaemia, coagulability Delayed reactions:   enlarged liver, jaundice, enlargement of spleen, thrombocytopenia, leucopenia, transient disturbances in liver function test, overloading syndrome “AVOID COLD INFUSION OF FAT EMULSION”

Use of lipids III Precautions • Infusion rate should not exceed 0.11 g/kg/h as too rapid an infusion of fat emulsion can cause fat overloading; in critically ill patients, infusion should be as slow as possible (over 24 h) • When Lipofundin MCT/LCT is given too rapidly, hyperketonaemia (with metabolic acidosis) may result, especially if glucose is not given simultaneously • Monitoring of plasma  triglyceride is essential • Monitoring of haemogram, blood coagulation, liver function and platelet counts are important esp. if fat emulsion is given for extended period • Ensure patient is not intolerant to any component of the lipid emulsion e.g. egg yolk phospholipid) or is getting lipids from another source (in ICU when propofol is used for sedation) Stop if platelet counts < 40000/cm3

Practical aspects of fat infusion I Recommended daily dose

adult: 1.0 - 2.0 g/kg infant: 1.0 - 3.0 g/kg

Infusion rate

<0.11 g/kg/day; preferably over 24 h in critically ill patients

Amount of fat

15 to 40% of total calories. In selected hypermetabolic patients, with resistance to glucose utilization or impaired ventilatory capacity, the proportion of lipid calories could   be increased up to 50 or 55% of total calorie intake

Type of lipid emulsions 20% better than 10%; MCT/LCT better than LCT emulsion

Practical aspects of fat infusion II Mode of delivery

As a separate bottle or as part of an all-in-one ixture

Use of in-line filter Additions to lipid emulsions

Use a 1.2 m, and not a 0.22 mfilter Other than fat soluble vitamins, it is not recommended to add drugs or additives to the lipid emulsion, unless its compatibility and stability in the fat emulsion has been verified   Once opened, the bottle must be used within 24 h

Hang time of lipid emulsion Special monitoring

Check for hypertriglyceridaemia

Hypertriglyceridaemia with infusion of lipid emulsions • Severe hypertriglyceridaemia is defined as: > 450 mg/dl in adults > 250 mg/dL for infants  

• Hypertriglyceridaemia develops mostly because of: - high dosage - fast infusion rate  

 

• Some clinical conditions are known to be accompanied by hypertriglyceridaemia or reduced capacity to clear lipids, e.g. - acute pancreatitis - acute and chronic renal failure - diabetes mellitus - sepsis

Differences between MCT and LCT

Energy MCT LCT - saturated - monounsaturated - polyunsaturated linoleic (6) -linolenic (3)

+++

Structure Function 0

0

++   ++

++ ++

(+) (+)

+ +

+++ +++

+++ +++

Driscoll et al. (2001) Chapter 3, Rombeau & Rolandelli 3rd Ed.

Characteristics of MCT vs LCT

 

Metabolism of lipid emulsion FA

FA

Lipid emulsion

FA

Triglyceride

Glycerol glucose precursor

Phospholipid s Hydrolysis

re  esterification of triglycerides CO2 + Free fatty acid Oxidation H 2O Ketone bodies

-oxidation

reesterification of triglycerides

Hydrolysis of LCT in blood

LCFA LCFA

LCFA

Lipoprotein lipase Apolipoprotein C-II   Albumin LCFA

LCFA

LCFA

Transport bound to albumin

Hydrolysis of MCT in blood

MCFA MCFA

MCFA

Lipoprotein lipase No   need for apolipoprotein C-II No need for albumin MCFA

MCFA

MCFA

Transport not bound to albumin

Hydrolysis of MCT & LCT by lipoprotein lipase and hepatic lipase in vitro

Free fatty acid release Lipoprotein lipase (nmol/l ) 400

 

200 0

Hepatic lipase (nmol/l ) 800 400 0

0

20

40 (min) LCT

0

20

40 (min)

MCT

Deckelbaum et al., Biochemistry 29 (1990) 1136-1142

Intracellular metabolism of medium (MCFA) and long-chain fatty acids (LCFA) LCFA

LCFA-CoA

Cytos LCFAol

Carnitine LCFA

MCFACoA LCT

MCT

  AcCoA

MCFA KB

Mitochondri on

ATP

MCF A

Oxidation rates of MCT/LCT & LCT in severely injured patients p < 0.0002

Oxidation rates (%)

40 30 20

 

10 0

MCT/LCT (13C8)

LCT (13C18)

Adolph et al (1988) Clin Nutrition 7 (Supple), 78

Clinically relevant issues when using lipid emulsions in PN • Clearance of lipids • Protein sparing • Impact on liver function • Disturbances of immune functions • Impact on pulmonary gas exchange and haemodynamic parameters   • Peroxidative damage • Stability of “all-in-one” mixtures

Clearance of lipids: MCT/LCT vs LCT Clearance of MCT/LCT is faster than LCT • Wicklmayr et al (1988) Diabetic type II patients JPEN 12, 68-71 • Jiang et al (1993)

Surgical patients Annals Surgery 217, 175-184

 

Neonates and pediatrics • Menci et al (2004) Neonates Clin Nutr 23/4, 906

Elimination from blood: MCT/LCT vs LCT % 100

Diabetic type IIb patients after overnight fast

MCT/LCT (half-life 39.8 min) LCT (half-life 64.2 min)

 

n=7

50 0

0

20

40

60

80min

Wicklmayr et al (1988) JPEN 12, 68-71

Metabolic tolerance in neonates Neonates (1750 g – 3930 g, aged 8-21 days, n = 22)

 

Menci et al (2004) Clin Nutrition 23/4,

Clinically relevant issues when using lipid emulsions in PN • Clearance of lipids • Protein sparing • Impact on liver function • Disturbances of immune functions • Impact on pulmonay gas exchange and haemodynamic parameters   • Peroxidative damage • Stability of “all-in-one” mixtures

Protein sparing: MCT/LCT vs LCT Protein sparing: MCT/LCT is superior to LCT Adults • Dennison et al. (1988) Malnourished after GI surgery • Ball (1993) ICU (mixed surgical/trauma) • Czarnetzki et al.(1988) Acute pancreatitis • Jiang et al. (1993) GI surgery • Garnacho-Montero et  al (2002) Septic patients Neonates & Paediatrics • Bresson et al. (1986) Infants • Lima et al., 1989 preterm neonates • Lai & Chen, 2000 pediatrics after surgery • Gentili et al., 2001 preterm & term neonates (mixed surgical/medical)

Protein sparing: MCT/LCT vs LCT Adult • Dennison et al. (1988) JPEN 12, 15-19 • Lohlein et al (1989) Beitr. Inf. Klin Ern. 20, 156-164 • Ball (1993) Intensive Care Med 19, 89-95 • Czarnetzki et al.(1988) Proc 10th Cong ESPEN Aug 1988, pp 83-99 • Jiang et al (1993) Annals   Surg 217, 175-184 • Garnacho-Montero et al (2002), Nutrition 18, 134-138 Pediatric • Bresson et al. (1986) Clin Nutr 5 (Suppl), 54 • Lima (1989) • Lai & Chen (2000) Nutrition 16, 401-406 • Gentili et al (2000) RINPE 18, 134-142 [MCT/LCT only]

Garnacho-Montero et al (2002): MCT/LCT vs LCT • Prospective, randomized controlled trial in septic patients with peritonitis (26 /group) • Regimen: 30 kcal/kg day (glucose: fat ratio = 60:40) 1.4  0.2 g AA/kg/day lipids as 10% MCT/LCT or 10% LCT   • TPN for 10 days postoperative

Nutrition 18, 134-138

Protein metabolism: MCT/LCT vs LCT Nitrogen balance g/24 h

Retinol binding protein mg/dL

p < 0.01

p < 0.001

2

16

n = 26/gp 1.5

12

 

8

1

4

0.5

0

0

MCT/LCT

LCT

MCT/LCT

LCT

Garnacho-Montero et al (2002) Nutrition 18, 134-138

Lai & Chen (2000): MCT/LCT vs LCT • Prospective randomized double blind study • Paediatric surgical patients (2 - 6 years old), n = 20/group • Regimen: total energy: ~71 kcal/kg/day over 24 h amino acid: 2 g/kg/day   12 g/kg/day glucose: lipids: 1.5 g/kg/day over 12 h as MCT/LCT or LCT • TPN started 2 days postop, for 14 days

Nutrition 16, 401-406

Protein metabolism: MCT/LCT vs LCT N balance in surgical paediatric patients *#

mg/kg/day

80 60

*#

* #

19/group

*#

*#

MCT/LCT LCT

*

 

40 20 0

1 2 3 4 * vs day1 p < 0.05

5

14 day 6 7 # vs LCT p < 0.05

Lai & Chen (2000) Nutrition 16, 401-406

Clinically relevant issues when using lipid emulsions in PN • Clearance of lipids • Protein sparing • Impact on liver function • Disturbances of immune functions • Impact on pulmonay gas exchange and haemodynamic parameters   • Peroxidative damage • Stability of “all-in-one” mixtures

Liver function: MCT/LCT vs LCT Liver function: MCT/LCT superior to LCT Adults • Balderman et al.(1989) • Dennison et al.(1988) surgery patients   • Carpentier et al.(1988) bowel syndrome

Stroke patients Malnourished GI Patients with short

Neonates & Paediatrics • Lai & Chen, 2000 pediatrics • Gentili et al., 2001 preterm & term neonates

Liver function: MCT/LCT vs LCT Adult • Dennison et al (1988) JPEN 12, 15-19 • Carpentier et al (1989) Clin Nutr 8 (Supple), 31 • Baldermann et al (1991) JPEN 15, 601-603 Paediatric   • Goulet et al (1992) Nutrition 8, 333-337 [HPN] • Lai & Chen (2000) Nutrition 16, 401-406 • Gentili et al (2000) RINPE 18, 134-142 [MCT/LCT only]

Liver function tests: MCT/LCT vs LCT 3 patients with SB on HPN. 50% of NPC as U/LMCT/LCT p < 0.01 week 1 vs weeks 250 4-9 MCT/LCT LCT 200 -GT 150

 

SGPT

100 50

SGOT

0 1

2

3

4

5

6

7

8

9 10 11 12 weeks

Carpentier et al. (1989) Clin Nutrition 8, (Supple) 31

Liver function test: MCT/LCT Conversion vs LCT product from haem of RBCs

mg/d L serum bilirubin 3 *

Setting: TPN after abdominal surgery (n = 15) each lipid was infused over 5 days

*

* 2

*

 

1

MCT/LCT LCT *p < 0.05 MCT/LCT vs LCT

0 1

2

3

4

5 days

Dennison et al. (1988) JPEN 12, 15-19

Gentili et al. (2000) MCT/LCT in neonates • Prospective non-comparative study • Critically-ill neonates - 26 term and 26 preterm, mixed medical and surgical cases (include 13 LBW, 7 VLBW and 2 ELBW infants) • Regimen: 80-90 kcal/kg/day 7-18 g/kg/day glucose 2 g/kg/day Lipofundin MCT/LCT20%   3 g/kg/day amino acids fluid intake ~ 90 - 140 mL/kg/day • TPN duration: 21.3  11.2 days (range 10-49)

Gentili et al. (2000) RINPE (2000) 18, 134-142

Liver function tests: MCT/LCT Plasma transaminase IU 100

AST

80

n= 52

ALT

60

 

40 20 0

BFN

D1

D3

D7

D14 D28 D49

AfPN

Gentili et al. (2000) RINPE 18, 134-142 (adapted)

Clinically relevant issues when using lipid emulsions in PN • Clearance of lipids • Protein sparing • Impact on liver function • Disturbances of immune functions • Impact on pulmonay gas exchange and haemodynamic parameters   • Peroxidative damage • Stability of “all-in-one” mixtures

Immune function: MCT/LCT vs LCT Immune function: MCT/LCT superior to LCT Adults • Gogos et al (1990) Malnourished, cancer patients • Marsili et al (1992) COPD patients • Waitzberg et al (1997) Malnourished cancer patients • Kuse et al (2002)   Liver transplant patients • Sedman et al (1991) Malnourished cancer patients Neonates & Paediatrics • Jouanneau et al (1996) premature neonates • Lai & Chen, 2000 pediatrics

Immune function: MCT/LCT vs LCT Adult • Gogos et al (1990) Am J Clin Nutr 51, 119-122 • Sedman et al (1991) Br J Surg 78, 1396-1399 • Marsili et al (1992) Clin Nutr 11 (Supple), 45 • Waitzberg et al (1997) 13, 128-132 • Kuse et al (2002) Transpl Int 15, 272-277   • Grau et al (2003) Nutr Hosp18, 259-266 Neonates & Paediatrics • Jouanneau et al (1996) Arch Pediatr 4, 912 • Lai & Chen (2000) Nutrition 16, 401-406

Immune function (Thelper / Tsuppressor cell ratio): MCT/LCT vs LCT B: TPN in COPD patients A: TPN in int. med. patients 2.15 2.11 2.10 1.931.89 1.90 2.0 1.70 1.65

1.0

0

 

E = 1316

0 10 0 E 0 E 0 10 days ns p < 0.05 ns p < 0.05 A: Gogos et al. (1990) Am J Clin Nutrition 51, days 119-122 B: Marsili et al. (1992) Clin Nutrition 11(suppl), 45

Phagocyte function: MCT/LCT vs LCT 100 Setting: preoperative TPN of malnourished GI cancer patients n = 10

% killed bacteria

90 80 70

 

60

Fig shows differences of values before and after lipid infusion

50 40 30 MCT/LCT

LCT

Waitzberg et al. (1997) Nutrition 13, 128-132

Intra-abdominal abscesses after major GI surgery

% patients

*

MCT/LCT (n = 26) LCT (n = 31)

*  

All pts

Noncancer

Canc er

Grau et al (2003) Nutr Hosp 18, 259-266

Clinically relevant issues when using lipid emulsions in PN • Clearance of lipids • Protein sparing • Impact on liver function • Disturbances of immune functions • Impact on pulmonay gas exchange and haemodynamic parameters   • Peroxidative damage • Stability of “all-in-one” mixtures

Haemodynamics and gas exchange: MCT/LCT vs LCT Haemodynamics and pulmonary gas exchange: MCT/LCT superior to LCT Adults • Fiaccadori et al (1997) Heart valve replacement • Smyrniotis et al (2001) Acute pancreatitis/ARDS • Faucher et al (2003) Patients with ARDS

 

• Radermacher et al (1992) Septic patients [MCT/LCT only) Neonates & Paediatric lacking comparative studies

Lung function: MCT/LCT vs LCT Adult • Radermacher et al (1992) Intensive Care Med 18, 231-234 [non-comparaive study] • Fiaccadori et al (1997) RINPE 15, 6-14 • Smyrniotis et al (2001) Clin Nutr 20, 139-143 • Faucher et al (2003) Chest 124, 285-291

 

Neonates & Paediatric • Lacking comparative studies [adverse findings with LCT]

Haemodynamic parameters: MCT/LCT vs LCT

Systemic vascular resistance

Cardiac index

 

Setting: Heart valve replacement patients (13/group) 20% MCT/LCT or LCT, infused at 1 mL/kg/h for 2 h (0.2 g/kg/h), via CVC, 24 h after operation

Fiaccadori et al (1997) RINPE 15, 6-14

Pulmonary gas exchange: MCT/LCT vs LCT Systemic O2 consumption

O2 delivery

 

Setting: Heart valve replacement patients (13/group) 20% MCT/LCT or LCT, infused at 1 mL/kg/h for 2 h (0.2 g/kg/h), via CVC, 24 h after operation

Fiaccadori et al (1997) RINPE 15, 6-14

Effects on haemodynamics and gas exchange Patients

Lipid MPAP emulsion No change  (p<0.05)

Cardiac surgery1

MCT/LCT LCT

Sepsis, ARDS2

No MCT/LCT   change LCT  (p<0.05) No change

QVA/QT -

PaO2/FiO2 -

No change

No change

 (p<0.05)

 (p<0.05)

No change

No change

Pancreati MCT/LCT tis LCT  RINPE 15,   3 (1) Fiaccadori et al (1997) 6-14, (2) Smirniotis et al. ARDS (p<0.05) (3) (p<0.05) (p<0.05) (1998) Int Care Med 24, 1029-1033, Smyrniotis et al. (2001) Clin Nutrition 20, 139-143 (4) Faucher et al.  (2003) Chest 124, 285-291

Clinically relevant issues when using lipid emulsions in TPN • Clearance of lipids • Protein sparing • Impact on liver function • Disturbances of immune functions • Impact on pulmonay gas exchange and haemodynamic parameters   • Peroxidative damage • Stability of “all-in-one” mixtures

Lipid emulsion & Peroxidation • Lipid emulsions made up of LCT contain high amounts of LC-PUFA but relatively little amounts -tocopherol • LC-PUFA are particularly vulnerable to free radical attack, with an increased production of peroxidative catabolites • Lipid hydroperoxides decompose to form highly toxic products such as aldehydes, which can cause severe damage to cell membranes - inactivating receptors - inactivating membrane-bound enzymes   - affecting the fluidity of the cell membranes • Complications arising from peroxidation: - increased haemolysis - pulmonary complications - impairment of immune response - tissue damage (e.g.retinopathy in premature infants, pulmonary dysplasia

Peroxidation: MCT/LCT vs LCT Peroxidation: MCT/LCT is less susceptible than LCT • Zimmermann et al (1993) J Pharm Clin 12, 300301 • Siderova et al (1995) Clin Nutr 14, 47-48 • Arborati et al (1998) JPEN 22, S5   Clin Nutr 16 Supple 2, 31 • De Leeuw et al (1998) • Manuel-y-Keenoy et al (2002) Eur J Clin Nutr 56, 121-128

Peroxidation (TBARS production): MCT/LCT vs LCT

mol per L emulsion

2000 

  

x

1000

 0

x

LCT

x

  

 MCT/LC T



10 20 30 45 min TBARS = Thiobarbituric acid reactant substances Zimmerman et al. (1993) J Pharm Clin 12, 300-301

Fatty acid composition of LCT and MCT/LCT emulsions FA (g/100g total) 8:0 10:0 12:0 14:0 16:0 16:1n-7 18:0 18:1n-9 18:2n-6 18:3n-3 20:0 20:4n-6 22:6n-3

LCT 20% 0.01 10.07

 

4.25

1.74

MCT/LCT 20% 31.4 17.5 0.29 0.01 5.10 0.09 0.05 2.24 23.80 12.08 53.91 27.46 5.78 2.90 0.75 0.36 0.19 0. 0.0

Dahlan et al (1992) Clin Nutr 11, 262-268

Lipids,

B.Braun,s Way

 

Lipofundin N and MCT/LCT

 

*See Additional Information from Dr R. Franke under Product Compositions: Lipids

-tocopherol (g/mL)

Plasma Vitamin E in HPN patients supplemented with 200 mg tocopherol/day 30

n=8 

20

10















3

4

5

6 months













-1

0

0



1

  

2

Siderova et al. (1995) Clin Nutrition 14, 47-48

Clinically relevant issues when using lipid emulsions in TPN • Clearance of lipids • Protein sparing • Impact on liver function • Disturbances of immune functions • Impact on pulmonay gas exchange and haemodynamic parameters   • Peroxidative damage • Stability of “all-in-one” mixtures

Oil-in-water emulsion Lipid emulsion particles kept apart by net negative charges described as Zeta potentials

    

  



  

      

    

  



  

     

Oil-in-water emulsion    

 

 Normal size ~ 0.3 M  

   



high cation concentrations

  pH changes

  

   Oversize fat globules > 5 M  



  

   

Advantage of MCT/LCT: Stability MCT/LCT is more stable than LCT in AIO emulsions • Müller & Heinemann (1994) Int J Pharm 107, 121132 • Driscoll et al (2000) JPEN 24, 15-22 • Driscoll et al (2001) Clin Nutr 20, 151-157 • Driscoll et al (2003) Clin Nutr 22, 489-496

Protocol of Driscoll et al. (2000) •Particle size distribution of lipid emulsion •TNA ixtures with: total calories: 25 kcal/kg/day total volume: 25 mL/kg/day AA: 1.5 g/kg/day glucose 2.8 g/kg/day   fat: ~ 20% of total calories as LCT or MCT/LCT 20% plus electrolyte, micronutrients

JPEN 24, 15-22

Particle size distribution of lipid emulsion TNA ixtures at different sampling time Samples

Time of sampling

T1 T2 T3 T4 T5

immediately after preparation of TNA after 4 days storage at 4oC after 6 h at 25oC   h at 25oC after 24 after 30 h at 25oC

Particle size was quantified using a single particleoptical sensing device that uses laser light extinction. Mean particle size of the lipid droplets was determined by dynamic light scatter using a submicron particle sizer Driscoll et al. (2000) JPEN 24, 15-22

Mean particle sizes (MPS) between TNA formulations 400

* p<0.05 p<0.005

MCT/LCT LC T

**

MPS (mm)

380 360

**

*  

340 320 300 T1

T2

T3

Driscoll et al (2000) JPEN 24, 15-22

T4

T5

Lipid droplet counts (%fat) of TNA formulations 0.7

MCT/LCT LC T

* p<0.01

PFAT > 1.75 m

0.6

*

0.5 0.4 0.3

*

 

*

0.2 0.1

0.0 T1

T2

T3

Driscoll et al (2000) JPEN 24, 15-22

T4

T5

Lipid droplet counts (%fat) of TNA formulations MCT/LCT LC T

0.35 0.30

* * p<0.01

0.25 PFAT > 5 m

0.20

 

0.15 0.10 0.05

0.00

T1

T2

T3

Driscoll et al (2000) JPEN 24,

T4

T5

Advantages of MCT/LCT vs LCT Compared to LCT, MCT/LCT emulsion • Gives more rapid clearance of lipids • Gives better nitrogen balance • Diminishes TPN-related incidences of liver dysfunction • Maintains immune function   • Has no adverse influence on haemodynamic status • Has no adverse influence of pulmonary function • Is less susceptible to peroxidative damage • Is more stability in “all-in-one” mixtures

Other issues: ketogenesis  

Ketonaemia in different situations Ketonaemia (mmol/l )1 2 1 0 8

11.5

6.25

6

 

4 2 0

A : 12 h fast or LCT infusion (1,2) B : 18 h fast or MCT/LCT infusion (1,2) C : 3 d fast (1) D : 7 d fast (1) E : ketoacidosis in type I diabetics (3)

0.3 0.6 A

B

3. 0 C

D

E

1) Sapir et al.(1975) Metabolism 24, 23-33 46

2) Dawes et al.(1986) World J. Surg. 10, 38-

Acid-base balance with MCT/LCT Setting : Infusion of 50 g lipids (MCT/LCT) into type I diabetics after an overnight fast and without istration of insulin (mmol/l) 7.45

26

pH

7.40

24

7.35

22

7.30

20 Infusion

0 1 2 3 4

(mm Hg) 48

HCO3-

44

 

40 36

Infusion

24 h

pCO2

0 1 2 3 4

Infusion

24 h

0 1 2 3 4

24 h

Sailer (1988), Beitr. Infusionsther. klin. Ernähr. 20, 88-98

Ketogenesis: Lipid alone and in the presence of glucose

MCT/LCT only

  MCT/LCT + gluc

Kolb & Sailer (1984) JPEN 8, 285-289

Ketogenesis in paediatric patients

 

Lima et al (1988) Acta Scand Paediatr 77,

Ketones as fuel Organ

Fuel

Skeletal, Cardiac muscle

Fatty acids glucose

Ketones

Nervous system, Blood cells

Glucose

Ketones

Liver

Fatty acids (medium > long) Glucose

 

Intestinal mucosa

Glutamine Aspartic acids

Ketones

Colonic mucosa

Fatty acids Glutamine

Ketones

Lymphocytes

Fatty acids Glucose

Ketones Glutamine

Lipofundin MCT/LCT: Summary • wide clinical experience with Lipofundin MCT/LCT • Extensive clinical data cf Structolipid or Clinoleic; papers quoted for Lipovenos MCT mainly those using Lipofundin MCT/LCT • Lipofundin MCT/LCT has been on market for since 1984 in Europe • Use in HPN patients  > 6 months • Safe and efficacious in preterm and term neonates • Safe and efficacious in patients with sepsis, diabetes, renal failure, liver failure, pancreatitis, and also in pregnancy • Stability in compounding mixtures and convenience systems established

Multichamber PN bags

 

Challenges facing nutrition • Patients differ • After illness or trauma, their metabolic conditions and requirements differ • The challenges are: - to provide nutrition adapted to their individual requirement   - with appropriate amount of nutrients - in a timely manner - by the most suitable route

Types of parenteral nutrition systems Bottle system: spike and hang individual bottles of solutions (e.g. glucose, amino acids, fat emulsion), or mixtures in bottles or kits (Vitrimix ) Compounding system: Hospital or industrially (CAPS - centralized ixing pharmacy service) prepared solutions filled in an ethylene vinyl acetate   and sets) by either gravity bag (e.g. Nutrimix bags or by an automated equipment (e.g. Caretronic or BAXA machine) Convenience system: ready-to-use 2- chamber bags (Nutriflex , Aminomix , Clinimix ) or 3-chamber bags (NuTRIflex Lipid, Kabiven , Clinomel )

Parenteral nutrition system: Single bottle system Glucos e

AA

Lipids

 

Glucos AA e

Lipids

Parenteral nutrition system: Kit system - Vitrimix® 250 Intralipid® 20% ml lipi ds Transfer set

Vamin ® Glucos e

  Do not cover basal need s

Under partial vacuu m 750 ml Osmolarity not suitable for PPN

Comments on Vitrimix® • Still quite popular in many countries, though it has considerable disadvantages as compared to more modern and convenient concepts • Among the disadvantages are: - need to combine two separate bottles every 12 h - electrolyte contents do not even cover basal daily requirements - need for further additions of electrolytes or for their   separate istration - osmolality of 1130 mOsm/kg does not allow istration of Vitrimix® through peripheral veins, without a high risk of producing thrombophlebitis

Parenteral nutrition system: Compounding Can be without or with lipids in the bag All-in-one (AIO) or Total Nutrient ixture (TNA) infers inclusion of lipids

 

Meguid (1989) Nutrition 5, 343344

Error rates of manual vs partially automated AIO (%) 40

37

30 22 20

 

10

AIO - manual preparation

0

AIO - partially automated preparation

Flynn et al. (1997), Am. J. Health-Syst. Pharm. 54, 904-912

Advantages of multichamber bags • Storage at room temperature • Storage at the ward is possible • Fast mixing of chamber content • Uniform preparation • Higher level of safety resulting from lower rate of errors   resulting from reduced • Higher level of safety danger of contamination • Simplified logistical organisation • Savings of costs and time

Convenience vs. Compounding

 

Metabolic benefits of AIO istration • Better nitrogen balance and fat utilization when given in a continuous infusion over 24 h • Less effect on immune function (e.g. from disturbance of fat clearance by RES) • Less electrolyte fluctuations Cumulative Nitrogen Balance 1

Gram N

-4

 

-9

- 14 - 19

- 24

Continuous Bolus Sequential

- 29 - 34 2

3

4

5

6

7

Days

 

 

 

Two-chamber bags: Nutriflex® (B.Braun) Peri

Basal

Plus

Special

Amino acids (g/L)

40

32

48

70

Glucose (g/L)

80

125

150

240

Total energy (kcal/L)

480

630

790

1240

Non-protein calories (kcal/L)

320

500

600

960

Osmolarity (mOsm/L)

900

1150

1400

2100

Pack Size (L)

1, 2

1, 2

1, 1.5, 2

1, 1.5

Shelf life (yr)

2

2

2

1.5

<25

<25

<25

<25

Storage temp (oC)

 

Shelf lives after allowed additions of electrolytes, vitamins, and trace elements Shelf life after mixing + additions (lipids, Original shelf life electrolytes, vitamins, trace elements) Nutriflex® peri 24 months at < 25°C 6 days at 2-8°C + 48 h at room temp.

a) b)

Nutriflex® basal24 months at < 25°C 6 days at 2-8°C + 48 h at room temp.

b)

Nutriflex® plus 24 months at < 25°C 6 days at 2-8°C + 48 h at room temp.

c)

Nutriflex® special 18 months at < 25°C 6 days at 2-8°C + 48 h at room temp.

c)

 

a) With Lipofundin® MCT/LCT 10% and no further electrolyte additions only 48 h at room temperatu b) Only with Lipofundin® MCT/LCT 10% and 20%. With Lipofundin® N 20% and Intralipid® 20% onl temperature. c) Only with Lipofundin® MCT/LCT 10% and 20%. With Lipofundin® N 10%/20% and Intralipid® 20% limitation to 48 hours at room temperature.

Allowed additions of vitamins and trace elements to Nutriflex® regimens with lipids Tracutil® or Vitalipid® Soluvit®Cernevit® Unit (ml) Additrace® N Adult Nutriflex® peri 2000 + 500a) Nutriflex® basal2000 + 500a) Nutriflex® plus 2000 + 500b) Nutriflex® special 1500 + 500b)

 

2

2

2

2

2

2

2

2

2

2

2

2

1

1

1

1

a) Lipofundin® MCT/LCT 10% and 20%, Lipofundin® N 20%, Intralipid® 20%. b) Lipofundin® MCT/LCT 10% and 20%, Lipofundin® N 10% and 20%, Intralipid® 2

Allowed electrolyte additions to Nutriflex® regimens with lipids Maximal final content (mmol) Unit (ml)

Na+ + K+Mg2+

Ca2+ Phosphate (i + o)

Nutriflex® peri 2000 + 500a)

200c)

15

15

11.4 + 4.8d)/7.3e)

Nutriflex® basal 2000 + 500a)

400

20

20

25.6 + 4.8d)/7.3e)

Nutriflex® plus 2000 + 500b)

400

20

20

40

Nutriflex® special 1500 + 500b)

300

15

16

22.1 + 4.8d)/7.3e)

 

+ 4.8d)/7.3e)

a) Lipofundin® MCT/LCT 10% and 20%, Lipofundin® N 20%, Intralipid® 10% and 20%. b) Lipofundin® MCT/LCT 10% and 20%, Lipofundin® N 10% and 20%, Intralipid® 20%. c) Limitation in order to maintain possibility of peripheral istration, not due to instability. d) Organic phosphate from 10% lipid emulsions. e) Organic phosphate from 20% lipid emulsions.

Nutriflex® Lipid

 

Handling NuTRIflex® Lipid

1. Always start by pressing the upper left chamber (glucose) to mix with the lower chamber (amino acids).

 

2. Add electrolytes and trace elements via the additive port (red cap).

Handling NuTRIflex® Lipid

3. Finally, press the upper right chamber containing MCT/LCT lipid emulsion to mix with the lower chamber. Add vitamins.

 

Mix thoroughly before inserting the giving set.

Handling NuTRIflex® Lipid

  5. To save space, fold the bag and hang it on the drip stand using the loop.

Handling NuTRIflex® Lipid

  Port system • Low risk for needle stick injury • Easy to grip and firm fitting • No leakage after removal

• Stable ports made of hard plastic • Self-sealing

Other products

 

Small overly pliable ports with increase risk of needlestick injuries

Features of bag materials and handling Feature

NuTRIflex Lipid 

Clinomel / Kabiven /St OliClinomel ructoKabiv  en

Co-extruded bag foil

Yes

Not known

Not known

Free of latex

Yes

Yes

Yes

Additions to the lipid-free mixture

Possible &   easy

Possible but difficult

Impossible

Shelf life at 20oC

24 months

24 months

24 months

Functionality of peel seals

Tight, easy to open

(Too) easy to open

Tight, easy to open

Easy, by hand

Easy, by hand

Easy, by hand

Opening of protective overwrap

NuTRIflex® Lipid - the material (V90) • PVC free • Three-layer film (co-extruded): Exterior: Polyamide Medial: Polypropylene extrusion binder Interior: Polypropylene • No adhesive between the film layers • Polypropylene is inert to solution components - in particular to lipids   • Can be heat sterilised in autoclaves • Fulfils ecological criteria • Harder than PVC. This together with the overwrap (V97d) provides optimal protection against the infiltration of atmospheric oxygen and easy opening of the peel seam • No aluminium foil packaging is necessary

Properties of the multilayer foil The lower the water and oxygen permeability the better NuTRIflex® Kabiven Oliclinome Lipid ® l® H 20 permeability (g/m2/d)

0.25

O2 permeability (mL/m2/d)

150

0.66

1.79

1570

1380

 

Dupertuis et al., 2005, JPEN 29/2, 125130Data from

NuTRIflex Lipid Prospective comparative study on istration time of TPN 2000

Time in sec

1600 1200 800

1524  312

 

1221  48 675  95

400 0

Single Bottle Hospital NuTRIflex System Compounding Lipid

Pichard et al. (2000), Clin Nutrition 19, 245-251

NuTRIflex Lipid Prospective comparative study on application costs of TPN

costs in %

200 150 100

150 % 120 %

100 %

 

50 0

Single Bottle Hospital NuTRIflex System Compounding Lipid

Pichard et al. (2000), Clin Nutrition 19, 245-251

NuTRIflex Lipid Regimens

 

Additional additives

 

Shelf lives of NuTRIflex® Lipid after additions of electrolytes, vitamins , and trace elements

NuTRIflex® Lipid peri NuTRIflex® Lipid plus NuTRIflex® Lipid plus without electrolytes NuTRIflex® Lipid special NuTRIflex® Lipid special without electrolytes

Original shelf life Shelf life after mixing + additions (electrolytes, vitamins, trace elements) 24 months at 4 days at 2-8°C + 48 h at room <25°C temp 24 months at 4 days at 2-8°C + 48 h at room <25°C temp   24 months at 4 days at 2-8°C + 48 h at room <25°C temp 24 months at <25°C 24 months at <25°C

4 days at 2-8°C + 48 h at room temp 4 days at 2-8°C + 48 h at room temp

Multichamber bags target Possible with ~ 80 % of adult patients who are stable Target areas of Nutriflex and NuTRIflex Lipid - intensive care wards - surgical wards - medical wards   - pharmacy - out patient markets - Home TPN Not possible – neonates and infants less than 2 years old

Advantages of the NuTRIflex® Lipid system • Chamber configuration assures safe mixing – the only multichamber bag system that allows ixture according to compounding guidelines • Special port system provides easy grip, prevents needle injuries and no leakage after removal • Range of products provides well balanced compositions of protein and energy for patients in   ICU and general wards • Electrolytes content covers basic requirements, reducing the need for further additions, although compatibility and stability data offer safe limits for additions • Only system that comes with Lipofundin® MCT/LCT (3-chamber bag)

Additional Information from B.Braun Product Consultant

Dosage recommendations for PN Recommended dosages, adults

Nutrient

a) Dosage per kg and day ASPEN dosage guidelines

Water 35 - 45 ml Na+ 1 - 3 mmol K+ 1 - 1.5 mmol Mg2+ 0.05 - 0.1 mmol Ca2+ 0.05 - 0.1 mmol Cl1 - 3 mmol Cl-/Acetate 1 : 1 ratio   Phosphate 0.2 - 0.5 mmol Amino acids 1.0 – 2.0 g Glucose 3.0 – 5.0 g Lipids 0.5 – 2.0 g Total energy 25-40 kcal Vitamins see appendix Trace elements see appendix

b)

20 - 40 ml/kg and day 1 - 2 mmol/kg and day + replacem 1 - 2 mmol/kg and day 4 - 10 mmol/day 5 - 7.5 mmol/day no entry As needed to maintain acid-base 20 - 40 mmol/day 0.8 – 2.0 g < 7.0 g < 2.5 g 25-30 kcal/kg and day see appendix see appendix

a) Diverse sourcesb) JPEN 22 (1998) 49-66

Dosage recommendations for PN Water and electrolytes, children For body weight: < 1500 g 1500 - 2000 g 2.5 - 10 kg > 10 - 20 kg > 20 kg

Daily water: 120 - 150 ml/kg 110 - 130 ml/kg 100 ml/kg 1000 ml for 10 kg + 50 ml/ kg for each kg > 10 1500 ml for 20 kg + 20 ml/ kg for each kg > 20

Electrolytes: Neonates Infants/childrenAdolescents   Na+ (mmol) 2 - 5 /kg x day 2 - 6 /kg x day Individualised K+ (mmol) 1 - 4 /kg x day 2 - 3 /kg x day Individualised Mg2+ (mmol) 0.15 - 0.25 /kg x day 0.15 - 0.25 /kg x day5 - 15/day Ca2+ (mmol) 1.5 - 2.0 /kg x day 0.5 - 1.25 /kg x day 5 - 10/day Cl- (mmol) 1 - 5 /kg x day 2 - 5 /kg x day Individualised Phosphate (mmol) 1 - 2 /kg x day 0.5 - 1 /kg x day 10 - 40/day

JPEN 22 (1998) 49-66

Dosage recommendations for PN Calorific nutrients, children

Calorific nutrient Dosage

a) b)

Protein

Neonates Infants Children Adolescents

2.5 - 3.0 g/kg x day 2.0 - 2.5 g/kg x day 1.5 - 2.0 g/kg x day 0.8 - 2.0 g/kg x day

NP calories

< 6 months 120   6 - 12 months 90 1 - 7 years 80 7 - 12 years 60 > 12 - 18 years 30

Lipids

< 4 g/kg x day for neonates

-

140 kcal/kg x day 120 kcal/kg x day 100 kcal/kg x day 75 kcal/kg x day 60 kcal/kg x day

< 3 g/kg and day for SGA neonates and preterm neonates less than 32 weeks GA

a) JPEN 22 (1998) 49-66

Dosage recommendations for PN Calorific nutrients, children

Calorific nutrient Dosage

a) b)

Total calories

Preterm neonate 85 - 150 Term neonate 100 - 120 Infants 80 - 100 Children 1 – 3 years 75 - 90 Children 4 - 6 years 65 - 75 Children 7-10 years 55 - 75 Children 10 40 - 60   - 18 years

kcal/kg x day kcal/kg x day kcal/kg x day kcal/kg x day kcal/kg x day kcal/kg x day kcal/kg x day

Protein

Infant/child (< 11 years) 2.0 – 3.0 Adolescent (> 11 years) 1.5 – 2.5

g/kg x day g/kg x day

Glucose

Infant/child (< 11 years) ~ 14.4 – 20.2g/kg x day Adolescent (> 11 years) max. ~ 8.6 g/kg x day

Lipids

Infant/child (< 11 years) 3.0 (max. 4.0) g/kg x day Adolescent (> 11 years) 2.5 – 3.0 g/kg x day

S. ACRA; Pediatric Annals 28 (1999) 113-120

Dosage recommendations for PN Vitamins a) Children Children > 11 years Vitamin 0 - 10 years and adults b) Retinol (I.U.) c) 230 3330 a) Per kg body weight Calciferol (I.U.) d) 40 200 and day. For a body Tocopherol (I. U.) e) 0.7 10 weight > 10 kg dose as Phylloquinone (mg) 0.02 f) for 10 kg Ascorbic acid (mg) 8 100 b) Per day Folic acid (µg) 14 400   c) 1 I. U. = 0.3 µg Niacin (mg) 1.7 40 retinol Riboflavin (mg) 0.14 3.6 d) 40 I. U. = 1 µg Thiamine (mg) 0.12 3.0 calciferol Pyridoxine (mg) 0.1 4.0 e) 1 I. U. = 1 mg D,LαCyanocobalamin (µg) 0.1 5.0 tocopheryl acetate Pantothenic acid (mg)0.5 15 or Biotin (µg) 2 60 0.67 mg D-α-

tocopherol

AMA/NAG, JPEN 3 (1979) 258-265

f) 2 - 4 mg once a

Dosage recommendations for PN Trace elements Adults

1) 2)

mg/d

Preterm Term Children 3) infants 3) infants 3) µg/kg x d µg/kg x dµg/kg x d (max. per d)

Iron Zinc Copper

0.5 - 5.0 200 a) 2.5 - 4.0 400 0.5 - 1.5 20 Chromium 0.01 - 0.02 0.20 Manganese 0.15 - 0.8 1.0 Molybdenum0.01 - 0.03 0.25 0.02 - 0.05 2.0 Selenium Iodide Fluoride

0.07 - 0.3 0.5 - 1.0

1.0 e)

100 b) 250 c)/100 20

 

0.20 1.0 0.25 2.0 1.0 e)

d)

no data 20 (300) 0.20 (5.0) 0.20 (5.0) 1.0 (50) 0.25 (5.0) 2.0 (30) 1.0 (1.0) e)

a) Starting 2nd month or after reaching 2000 g bw b) Not in the 1st three months c) For age up to three months

d) If older than three months

e) Insufficient data available. Oral recommendations are deemed to be appropriate also for PN

1) K. N. Jeejeebhoy, New Aspects of Clinical Nutrition (1983) 1 – 24 2) T. G. Baumgartner, Clinical Guide to Parenteral Micronutrition (1984) 3) H. L. Greene et al., Am. J. Clin Nutr. 48 (1988) 1324-1342

Product composition: Standard AA formulations B. Braun

Aminoplasmal®-

FreAmine® 5% E 10% 10% E12.5% E15% 15% E III 14 Number of amino acids 20 20 20 20 18 18 97 Amino acids (g/l) 50 100 100 125 150 150 15.3 Nitrogen (g/l) 8 16 16 20 24 24 0 Carbohydrate (g/l) 0 0 0 0 0 0 388 Total calories (kcal/l) 200 400 400 500 600 600 10 Sodium (mmol/l) 43   0 43 43 0 50 0 Potassium (mmol/l) 25 0 25 25 0 30 0 Magnesium (mmol/l) 2.6 0 2.6 2.6 0 2.6 0 Calcium (mmol/l) 0 0 0 0 0 0 20 Inorganic phosphate (mmol/l) 9 0 9 9 0 9 <3 Chloride (mmol/l) 29 57 57 72 0 36 0 Anionic acetate (mmol/l) 59 0 59 59 0 35 950 Osmolarity (mOsm/l)590 885 1035 1250 1290 1480

Product composition: Lipids Lipofundin® N and Lipofundin® MCT/LCT

N 10% Soya oil (g/l) Medium-chain triglycerides (g/l) Egg yolk phospholipids (g/l) Glycerol (g/l) α-Tocopherol (mg/l) Osmolarity (mOsm/kg) Calories (kcal/l)

 

100

200

50

100

0

0

50

100

8

12

8

12

25 25 25 25 90 + 20 180+ 4085 + 20170+ 40 350-380290-320 345 a) 380 a) 1072 2008 1022 1908

Phosphate equivalents (mmol/l) 9.7 a) mOsm/l.

Lipofundin® N MCT/LCT MCT/LCT 20% 10% 20%

14.5

9.7

14.5

Product composition: 2-chamber bags (B. Braun) Nutriflex®, 1000 ml

Nutriflex®/... without el. Total volume (ml) Amino acids (g) Nitrogen (g) Glucose (g) Glucose calories (kcal) Total calories (kcal) Sodium (mmol) Potassium (mmol) Magnesium (mmol) Calcium (mmol) Zinc (mmol) Chloride (mmol) Phosphate (mmol) Acetate (anionic) (mmol) Osmolarity (mOsm/l)

peri 1000 40 5.7 80 320 480 27   15 4.0 2.5 0 31.6 5.7 19.5 900

basal 1000 32 4.6 125 500 630 49.9 30 5.7 3.6 0 50 12.8 35 1140

plus 1000 48.1 6.8 150 600 790 37.2/0 25/0 5.7/0 3.6/0 0 35.5/0 20/0 22.9/0 1400/1250

special 1000 70 10.0 240 960 1240 40.5/0 25.7/0 5.0/0 4.1/0 0 49.5/0 14.7/0 22/0 2100/1940

Product composition: 2-chamber bags (B. Braun) Nutriflex®, 1500 ml and 2000 ml

Nutriflex®/...without el.

peri Total volume (ml) 2000 Amino acids (g) 80 Nitrogen (g) 11.4 Glucose (g) 160 Glucose calories (kcal) 640 960 Total calories (kcal) Sodium (mmol) 54 Potassium (mmol) 30 Magnesium (mmol) 8.0 Calcium (mmol) 5.0 Zinc (mmol) 0 Chloride (mmol) 63.2 Phosphate (mmol) 11.4 Acetate (anionic) (mmol) 39 Osmolarity (mOsm/l) 900

 

basal plus plus special 1500 2000 2000 1500 64 72.2 96.2 105 15.0 9.2 10.2 13.6 360 250 225 300 1440 1000 900 1200 1260 1185 1580 1860 99.8 55.8/0 74.4/0 60.8/0 60 37.5/0 38.6/0 50/0 11.4 8.55/0 7.5/0 11.4/0 7.2 5.4/0 7.2/0 6.15/0 0 0 0 0 100 53.3/0 71/0 74.3/0 25.6 30/0 40/0 22.1/0 70 34.4/0 45.8/0 33/0 1140 1400/1250 1400/1250 2100/19 40

Product composition: 3-chamber bags (B. Braun) NuTRIflex® Lipid peri

NuTRIflex® Lipid peri

1250 ml 1875 ml 2500 ml Total volume (ml) 2500 1250 1875 Amino acids (g) 60 80 40 Nitrogen (g) 5.7 8.6 11.4 Glucose (g) 80 120 160 50 Lipids (g) 75 100 Glucose calories (kcal) 320 480 640 Lipid calories (kcal) 475 715 950   Total calories (kcal) 955 1435 1910 Sodium (mmol) 50 75 100 Potassium (mmol) 30 45 60 Magnesium (mmol) 3.0 4.5 6.0 Calcium (mmol) 3.0 4.5 6.0 Zinc (mmol) 0.03 0.045 0.06 Chloride (mmol) 48 72 96 Phosphate (i +(mmol) o) 7.5 + 3.6 11.3 + 5.4 15 + 7.3 Acetate (anionic) (mmol) 40 60 80 Osmolality (mOsm/kg) 920 920 920 No electrolyte-free version available.

Lipids: Lipofundin® MCT/LCT 20%

Product composition: 3-chamber bags (B. Braun) NuTRIflex® Lipid plus

NuTRIflex® Lipid plus/...without el.

1250 ml 1875 ml Total volume (ml) 1250 1875 Amino acids (g) 48 72 Nitrogen (g) 6.8 10.2 Glucose (g) 150 225 Lipids (g) 50 75 Glucose calories (kcal) 600 900 Lipid calories (kcal) 475 715   Total calories (kcal) 1265 1900 Sodium (mmol) 50/0 75/0 Potassium (mmol) 35/0 52.5/0 Magnesium (mmol) 4.0/0 6.0/0 Calcium (mmol) 4.0/0 6.0/0 Zinc (mmol) 0.03/0 0.045/0 Chloride (mmol) 45/0 67.5/0 Phosphate (i +(mmol) o) 18.6/3.6 27.9/5.4 Acetate (anionic) (mmol) 45/0 67.5/0 Osmolality (mOsm/kg) 1540/1350 1540/1350

2500 ml 2500 96 13.6 300 100 1200 950 2530 100/0 70/0 8.0/0 8.0/0 0.06/0 90/0 Lipids: 37.3/7.3 Lipofundin® 90/0 1540/1350 MCT/LCT 20%

Value after the slash for the electrolyte-free version.

Product composition: 3-chamber bags (B. Braun) NuTRIflex® Lipid special

NuTRIflex® Lipid special/...without el.

1250 ml 1875 ml Total volume (ml) 1250 1875 Amino acids (g) 71.8 108 Nitrogen (g) 10.0 15.0 Glucose (g) 180 270 Lipids (g) 50 75 Glucose calories (kcal) 720 1080 Lipid calories (kcal) 475 715   Total calories (kcal) 1475 2215 Sodium (mmol) 67/0 100.5/0 Potassium (mmol) 70.5/0 47/0 Magnesium (mmol) 7.95/0 5.3/0 Calcium (mmol) 7.95/0 5.3/0 Zinc (mmol) 0.06/0 0.04/0 Chloride (mmol) 90/0 60/0 Phosphate (i +(mmol) o) 23.6/ 3.6 35.4/5.4 Acetate (anionic) (mmol) 60/0 90/0 Osmolality (mOsm/kg)2090/1840 2090/1840

2500 ml 2500 144 20.0 360 100 1440 950 2950 134/0 94/0 10.6/0 10.6/0 0.08/0 120/0 Lipids: 47.3/7.3 Lipofundin® 120/0 2090/1840 MCT/LCT 20%

Value after the slash for the electrolyte-free version.

List of abbreviations a = Age AA = Amino acids AAA = Aromatic amino acids Ac = Acetate Ac-CoA = Acetyl coenzyme A AEE = Actual energy expenditure AEEestim.. = Measured actual energy expenditure AIDS = Acquired immunodeficiency syndrome Ala = Alanine Ala-Gln = Alanyl-glutamine ALAT = Alanine amino transferase ALB-FA = Albumin-Fatty acids-Complex Apo-CII = Apolipoprotein CII approx. = Approximately ARF = Acute renal failure Arg = Arginine ASAT = Aspartate amino transferase Asp = Aspartic acid ATP = Adenosine triphosphate  = Alpha

 

BCAA = BMR = BSA = BUN = BUNE = hours BUNS = bw = C = Carbon °C = 2+ Ca/Ca = C. albicans C-C = CFU = CIT = Cl/Cl= cm = CMR = CNS = CO2 = COOH = 3+ Cr/Cr = Cu/Cu2+ = CVC =

Branched-chain amino acids Basal metabolic rate Body surface area Blood urea nitrogen Blood urea nitrogen after 24 Blood urea nitrogen at 0 hours Body weight Degrees Celsius Calcium = Candida albicans Carbon-Carbon bond Colony-forming unit Citrate Chloride Centimetres Chylomicron remnants Central nervous system Carbon dioxide Carboxylic group Chromium Copper Central venous catheter

List of abbreviations d = Day dl = Decilitre  = Delta (difference) + e. = with electrolytes EAA = Essential amino acids EAA + His= Essential amino acids plus histidine E. coli = Escherichia coli EEAA = Energy expenditure from amino acids e.-fr. = Electrolyte-free e.g. = For example (“exempli gratia”) EN = Enteral nutrition etc. = And so on (“et cetera”) EVA = Ethyl vinyl acetate F/F = Fluoride FA = Fatty acid 3+ Fe/Fe = Iron FQ = Fischer quotient Ftbw = Factor for total body water g = Gramme gN = Grammes of nitrogen GA = Gestational age GAP = Glyceryl aldehyde phosphate

 

GI = Gastrointestinal GLC = Glucose GLC : LIP = Glucose : Lipid calorie ratio g/d = Grammes per day g/kg = Grammes per kilogramme body weight g/kg bw = Grammes per kilogramme body weight g/kg bw x d = Grammes per kg body weight and day g/kg bw x h = Grammes per kg body weight and hour g/kg x d = Grammes per kg body weight and day g/l = Grammes per litre Gln = Glutamine Glu = Glutamic acid Gly = Glycine GLY = Glycerol Gly-Gln = Glycyl-glutamine GLY-P = Glyceryl phosphate Gly-Tyr = Glycyl tyrosine 2 g/m BSA = Grammes per square meter body surface area -GT = Gamma-glutamyl transpeptidase

List of abbreviations h = hour H = Hydrogen HBC = High branched-chain HCO3= Hydrogen carbonate (bicarbonate) HE = Hepatic encephalopathy H2PO4 = Dihydrogen phosphate (inorganic phosphate) H2SO4 = Sulphuric acid His = Histidine HL = Hepatic lipase H2 O = Water ht= height I = Iodine ICU = Intensive care unit i.e. = that is (“id est”) Ile = Isoleucine i. + o. = Inorganic and organic I. U. = International units i. v. = Intravenous JPEN = Journal of Parenteral and Enteral Nutrition

 

K/K+ = Potassium KB = Ketone bodies kcal = Kilocalories kcal/d = Kilocalories per day kcal/g = Kilocalories per gramme kcal/kg = Kilocalories per kg body weight kcal/kg bw = Kilocalories per kg body weight and day kcal/kg bw x d = Kilocalories per kg body weight and day kcal/l = Kilocalories per litre kcal/ml = Kilocalories per millilitre kcal% = Percent of total kilocalories kg = Kilogramme kJ = Kilojoules kJ/l = Kilojoules per litre

List of abbreviations l = Litre mg/d = Milligrammes per day LAC = Lactate mg/dl = Milligrammes per decilitre LAK = Lymphokine-activated killer mg/kg bw x d = Milligrammes per kg body LCFA = Long-chain fatty acids weight and day LCFA-CoA = Long-chain fatty acids coenzyme A Mg/Mg2+ = Magnesium LCFA-Carn... = Carnitine ester of LCFA MG = Monoglyceride LCT= Long-chain triglycerides min = Minutes Lctl. = Lactulose ml = Millilitres Leu = Leucine ml/kg = Millilitres per kg body weight LIP = Lipids ml/kg bw x min = Millitres per kg body log = logarithmic weight per minute LPL = Lipoprotein lipase mm3 = Cubic millimetres LPS = LIpopolysaccharide mmol = Millimoles Lys = Lysine mmol/l = Millimoles per litre m2 = Square metres 2+ Mn/Mn = Manganese max. = maximally Mo = Molybdenum MCFA = Medium-chain fatty acids = Milliosmoles MCFA-CoA= Medium-chain fatty acids coenzyme A mOsm mOsm/kg = Milliosmoles per kg solvent MCT = Medium-chain triglycerides Met= Methionine mOsm/l = Milliosmoles per litre of solution mg = Milligrammes MR = Metabolic rate

 

List of abbreviations µg = Microgrammes µg/kg x d = Microgrammes per kg body weight and day µm = Micrometres µmol = Micromoles µmol/l = Micromols per litre N = Nitrogen Na/Na+ = Sodium Nbal = Nitrogen balance NBT = Nitroblue tetrazolium NEAA = Nonessential amino acids Neom. = Neomycin NH3 = Ammonia Nin = Nitrogen intake NK = Natural killer cells N/kg bw = Nitrogen per kg body weight Nout = Nitrogen loss no. = Number NP = Nonprotein kilocalories NP-kcal/g N = Nonprotein kilocalories per gramme N n. s. = not significant

 

O/O2 = Oxygen OA = Oxaloacetate OP = Oligopeptides Orn = Ornithine orig. + add. = Originally contained plus additions p< = Probability of error lees than p> = Probability of error more than P = Phosphate P. aeruginosa = Pseudomonas aeruginosa pH = Potentia hydrogenii Phe = Phenylalanine Pi = Inorganic phosphate PICC = Peripherally inserted central catheter PL = Phospholipids PN = Parenteral nutrition p. o. day = Postoperative day Pro = Proline PT = Prothombin time PYR = Pyruvate

List of abbreviations RBC = Red blood cells RBP = Retinol-binding protein REE = Resting energy expenditure Ren. med.= Renal medulla RQ = Respiratory quotient S = Sulphur S. aureus = Staphylococcus aureus SCFA = Short-chain fatty acids SCT = Short-chain triglycerides Se = Selenium Ser = Serine SGA = Small for gestational age SIRS = Systemic inflammatory response syndrome SLd = Defined structured lipids SLr = Randomised structured lipids SPC = Summary of product characteristics suppl. = Supplement

 

Tau TBARS

= Taurine = Thiobarbituric acid reactive substances temp. = Temperature TF = Thermal factor TG = Triglycerides TH = T-helper cell TH/TS = T-helper to T-suppressor cell ratio Thr = Threonine TPN = Total parenteral nutrition tot. en. = Total energy Try = Tryptophan TS = T-suppressor cells Tyr = Tyrosine U = Units U/l = Units per litre UUN = Urinary urea nitrogen Val = Valine VCO2 = Volume of expired carbon dioxide VLDL = Very low density lipoproteins VO2 = Volume of consumed oxygen vs. = versus  = Omega Zn/Zn2+ = Zinc