Specialized Nutrition Support: Enteral & Parenteral Nutrition
Pharmaceutical Point of View on Parenteral Nutrition
Transcript of Pharmaceutical Point of View on Parenteral Nutrition
Hindawi Publishing CorporationThe Scientific World JournalVolume 2013 Article ID 415310 9 pageshttpdxdoiorg1011552013415310
Review ArticlePharmaceutical Point of View on Parenteral Nutrition
M Stawny1 R Olijarczyk1 E Jaroszkiewicz2 and A JeliNska1
1 Department of Pharmaceutical Chemistry Poznan University of Medical Sciences 6 Grunwaldzka 60-780 Poznan Poland2 School of Pharmacy De Montfort University The Gateway Leicester LE19 BH UK
Correspondence should be addressed to M Stawny stawnymaciejspsk2pl
Received 28 August 2013 Accepted 6 October 2013
Academic Editors T E Adrian and T Florio
Copyright copy 2013 M Stawny et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited
Parenteral nutritionmdasha form of administering nutrients electrolytes trace elements vitamins and watermdashis a widely used modeof therapy applied in many diseases in patients of different ages both at home and in hospital The success of nutritional therapydepends chiefly on proper determination of the patientrsquos energetic and electrolytic needs as well as preparation and administrationof a safe nutritional mixture As a parenterally administered drug it is expected to be microbiologically and physicochemicallystable with all of the components compatible with each other It is very difficult to obtain a stable nutritional mixture due to thefact that it is a complex two-phase drug Also the risk of incompatibility between mixture components and packaging should betaken into consideration and possibly eliminated Since parenteral nutrition is a part of therapy simultaneous use of drugs maycause pharmacokinetic and pharmacodynamic interactions as well as those with the pharmaceutical phase The aim of this paperis to discuss such aspects of parenteral nutrition as mixture stability methodology and methods for determining the stability ofnutritional mixtures and drugs added to them
1 Introduction
Parenteral nutrition entered clinical practice in the late 1960sandwas one of themost important developments inmedicineafter antisepsis anesthesia and antibiotics Currently par-enteral nutrition is a generally accepted and accessible way oftreatment when gastrointestinal system is either inefficienttotally nonfunctional or inaccessible [1]
Parenteral nutrition is a way of delivering in the formof intravenous infusion the nourishments necessary forthe maintenance of life such as amino acidsmdasha source ofproteins glucose and lipidsmdasha supply of energy and waterelectrolytes microelements and vitamins [2]
Parenteral nutrition is used primarily in therapies ofgastrointestinal patients after stomach resection with shortbowel syndrome intestinal fistula bowel obstruction andabsorption disorders (Crohnrsquos disease acute pancreatitis)and as perioperative treatment in malnourished or depletedpatients with extensive burns and those in shock and duringchemo- and radiotherapy [3]
There are three conditions that have to be met in orderto provide successful parenteral nutrition The amounts
of nutrients required for life maintenance must cover themetabolic and energetic needs of the patient The proportionbetween the content of nitrogen and the energy supplied bynutrients other than proteins (1 g of N should be equivalentto 130ndash200 kcal) and the ratio between the carbohydratesand lipids (50ndash75 kcal from carbohydrates per 25ndash50 kcalfrom lipids) have to be correct to ensure appropriate use ofthe components in the biochemical processes of the bodyAlso parenteral nutrition is expected to be individualized byaddressing not only the patientrsquos energetic and electrolyticneeds but also his or her general health status coexistingillnesses and emotional state [2]
From the pharmaceutical point of view nutritional mix-ture is a complex double-phase and sterile drug Suchdefinition of the nutritional mixture helps to avoid incom-patibilities between the ingredients and to maintain itsphysicochemical and microbiological stability Consideringthe profile of a parenterally nourished patient it mustbe remembered that parenteral nutrition may not be theonly medical intervention applied in a given case It iscommon that parenteral nutrition plays only a support partin the treatment of an underlying disease that involves
2 The Scientific World Journal
pharmacotherapy often polypragmasy which may causesevere interactions not only between the drugs being used butalso between parenteral mixture ingredients [4]
2 Mixture Stability in Parenteral Nutrition
Parenteral nutrition is a multicomponent medication Withabout fifty components coexisting in one container and thepossibility of interactions between them the container andexcipients it is probably themost complex therapy inmodernmedicine [4 5] Tables 1 and 2 show the contents of aminoacids and lipids in emulsion preparationsmdashthemost complexcomponents of parenteral nutrition
Themost important interactions in the aqueous phase areas follows
(1) Precipitation of Calcium Hydrogen Phosphate Thesediment is depositedwhen the product of concentra-tion of Ca2+ and HPO
4
2minus ions is above 72mmol2L2Many other factors such as pH and the content ofthe mixture the way it was prepared and storageconditions may affect the solubility of CaHPO
4
Currently the risk of precipitation of CaHPO4can be
eliminated by the use of organic calcium salts suchas gluconates and glycerophosphate which do notdissociate in aqueous solutions [6]
(2) Inactivation of Vitamins as They Are Highly Suscep-tible to Degradation Parenteral nutrition generallycontains vitamins at the minimal concentrations nec-essary for the body function Sometimes the clinicalstate of the patient requires additional supplementa-tion with high doses of some vitamins vitamin B
1
in severe malnutrition or vitamin C in patients withincreased cell catabolism Inactivation of vitaminsmay follow many mechanisms photolysis of vitaminA and B
1 oxidation of vitamin C reduction of
vitamin B1 or adsorption of vitamin A onto the
surface of the container [6]
Changes occurring in the lipid phase are equally dan-gerous Parenteral nutrition is a two-phase medication con-sisting of ow emulsion formed as a result of mixingthe aqueous (amino acids carbohydrates electrolytes andmicroelements) and the lipid phases
Lipid emulsions used in parenteral nutrition consist ofspherical particles of lipids of micellar structure and sizecomparable to chylomicrons External part of micelles ishydrophilic with a negative charge while on the insidelipophilic chains of fatty acids are present The negativecharge localized on the external part of the micelles preventstheir aggregation which can be the first sign of the degra-dation of lipid emulsions The biggest danger to the stabilityof micelles is the presence of di- or trivalent cations whichcan neutralize the negative charge on micelles leading to theformation of larger particles Therefore a crucial parametercharacterizing parenteral nutrition is the critical aggregationnumber (CAN)mdasha maximal concentration of cations abovewhich the aggregation of lipid particles can occur [5 7]
The literature presents two solutions to ensure the stabil-ity of parenteral nutrition One of them is based on the stabil-ity of components and chosen drugs in parenteral nutritionwithout the lipid emulsions Parenteral nutrition mixturesso-called 2 in 1 containing carbohydrates amino acidselectrolytes and trace elements are used most frequently inparenteral nutrition for neonatals and pediatric patients Inthese cases lipid emulsions with vitamins are administeredfrom a separate container and mixed with aqueous phase atthe vein access The reason for this is a high concentrationof cations above the CAN which could lead to the degrada-tion of lipid emulsions in the parenteral nutrition mixtures[5]
The other solution relies on the stability of the completeparenteral nutrition mixture which is much difficult toinvestigate due to the biphasic character of the mixture
3 Methods of Parenteral Nutrition Analysis
When approaching the problem of parenteral nutrition sta-bility one has to consider the complexity of the mixtureand analytical problems connected with the assessment ofits stability Despite the wide range of analytical techniquesavailable there are no methods for quick determination ofthe stability of parenteral nutrition It is therefore extremelyimportant to design an experiment and choose a techniquewhich will allow to determine all critical factors that mightinfluence its stability
The majority of studies were carried out on parenteralnutrition stored between 24 hours and several weeks intemperature ranges of 2ndash8∘C and 36ndash38∘C and with variousdegrees of exposure to light [8 9]
The influence of packaging on the stability of parenteralnutrition mixture was also studied [10 11] It was foundthat storage time and temperature as well as exposure tolight had the greatest effect on the stability of parenteralnutrition mixtures The following was observed increaseddecomposition of vit A in the presence of sunlight decreaseddecomposition of vitamins at low temperatures changesin colour during storage at room temperature decreaseddecomposition of vitamins in multilayered packaging phaseseparation of lipid emulsion during storage while theircontent appeared to have a lesser effect on their stability Thetype of amino acid and lipid emulsion the concentration ofelectrolytes and the addition of antioxidant vitamins werealso observed to affect the stability of parenteral nutritionmixtures [9ndash23]
At present international regulations do not indicatethe most suitable methodology for studying the stability ofparenteral nutrition mixtures or provide standards for theirphysicochemical safety
The stability of parenteral nutrition mixtures is generallyinvestigated in three areas
(1) stability of lipid emulsion and the effect of othercomponents on its degradation
(2) parameters characterizing the properties of parenteralnutrition mixtures
(3) stability of the components
The Scientific World Journal 3
Table1Com
positionof
somea
minoacid
solutio
ns
Aminop
lasm
al10
Aminop
lasm
alHEP
AAminom
el10
Aminosteril
10
Aminosteril
N-H
epa
Aminoven
infant
10
Nephrotect
Prim
ene
10
Vamin
14Va
minolact
[g10
00mL]
Isoleucine
89
88
585
467
104
80
58
67
42
31
Leucine
50
136
624
706
1309
130
128
100
59
70Lysin
eacetate
106
1002
971
169
Methion
ine
44
12468
41
11312
224
42
13Ph
enylalanine
47
1654
482
088
375
35
42
59
27
Threon
ine
42
46
50
421
44
44
82
37
42
36
Tryptoph
an16
1520
182
07
201
30
20
1414
Valin
e62
106
50
592
1008
987
7655
36
Arginine
115
88
966
1064
1072
7582
84
84
41
Histidine
30
47
33
288
28
476
9838
51
21
Glycine
120
63
755
1595
582
415
531
40
59
21
Alanine
105
83
155
150
464
9362
80
1263
Proline
55
7175
150
573
971
30
30
51
56
Asparticacid
56
25
191
60
25
41
Asparagine
055
Acetylcyste
ine
08
067
07
054
Glutamicacid
7257
50
1042
71Serin
e23
37
43
224
767
7640
34
38
Acetyltyrosin
e086
20
Tyrosin
e04
42
06
045
017
05
Lysin
e856
746
851
1168
56
Taurine
04
06
03
Cyste
ine
052
246
042
10N-glycyl-L
-tyrosin
e316
Ornith
ine
166
242
249
Cystine
042
10
4 The Scientific World Journal
Table 2 Composition of some lipid emulsion preparations
ClinOleic20
Intralipid10
Intralipid20
Intralipid30
LipofundinMCTLCT
10
LipofundinMCTLCT
20
LipofundinN 10
LipofundinN 20 SMOFlipid
[g1000mL]Olive oil 160 50Soybean oil 40 100 200 300 50 100 100 200 60Medium-chain triglycerides 50 100 60Lecithin from egg yolk 8 12 8 12Glycerol 25 25 25 25Fish oil 30
Organoleptic in particular visual assessment can givevital information on the stability of parenteral nutritionSince lipid emulsion is a very sensitive component thedegradation of emulsion frequently manifests itself by theseparation of phases Color change during storage may alsobe an indication of degradation whereas the measurement ofpH osmolarity and electrical conductance offer informationwith regard to initial changes in parenteral nutrition mixture[7]
As the lack of any changes is not synonymous with thestability of parenteral nutrition mixtures further investiga-tions are necessary The emulsion should be examined forany changes in particle size signs of lipid peroxidation andfactors that may cause or affect it In the aqueous phasethe concentrations of glucose amino acids and electrolytesneed to be monitored and if any loss occurs identificationof degradation products and their biological properties isnecessary
Lipid emulsions used in parenteral nutrition are owemulsions having a narrow pH range and low osmolaritywhich allows them to be given via peripheral intravenousaccess The stability of lipid emulsion is a resultant ofattractive forces mainly of van der Waals character andrepulsive forces (electrostatic and spherical) which act onlipid emulsion particles Electrostatic forces being dependenton the pH concentration of electrolytes and the pres-ence of surfactants have the largest effect as they preventemulsion particles from forming aggregates [21] One ofthe best parameters to characterize the stability of lipidemulsion particles is potential zeta an electric potentialformed just outside the Stern layer This potential deter-mines the strength of electrostatic interaction between theparticles [21] Zeta potential can be established with thehelp of the Doppler effect during electrophoresis (LaserDoppler Electrophoresis (LDE)) or via an electrophoreticlight scattering experiment (Electrophoretic Light Scattering(ELS))
The stability of lipid emulsions can be studied by measur-ing particle sizes using optical microscopy laser diffractionor dynamic light scattering These methods were used suc-cessfully in the determination of size and shape of emulsionparticles and their stability [12ndash15 22]
Atomic absorption spectroscopy (AAS) and inductivelycoupled plasma atomic emission spectroscopy (ICP-AES)are the most suitable techniques to determine metal ionconcentrations in parenteral nutrition [24] So far only oneinvestigation using ICP-AES and ICP-MS in the study ofmetal ions (Na and K ions) in parenteral nutrition wasreported [25] Antes et al [26] applied ICP-MS to detect thelevel of metals in raw materials used to produce parenteralnutrition such as solutions of amino acids glucose andelectrolytes The authors identified and assayed a numberof heavy metals present in the analyzed matrices such ascadmium mercury copper and manganese and found theirconcentrations exceeding the limit levels (Table 3)
Other methods reported more frequently for the analysisof metal ions were flame photometry capillary electrophore-sis and ion-selective electrodes but the results obtained maycarry large errors because of the complexity of the matrices[27ndash29]
The most common methods for glucose assays areenzymatic assays using glucose oxidase or hexokinase Inthe first method glucose is oxidized to gluconic acid andhydrogen peroxide is formed Hydrogen peroxide in thepresence of peroxidase reacts with the sodium salt of 221015840-azino-di-(3-ethyl-benzthiazoline-6-sulphonic acid) to give acolored product absorbing in the range 670ndash680 nm [30]The second relies on phosphorylation of glucose in thepresence of hexokinase and ATP and formation of glucose-6-phosphate and ADP Glucose-6-phosphate is oxidized to6-phosphogluconate and NAD is reduced to NADH For-mation of NADH is associated with increased absorbance at340 nm [31] Both assays can be done directly without anyinitial extractions using commercial tests The hexokinasemethod was used successfully by Bouchoud et al [11] If anassay indicates a lowered concentration of glucose in theparenteral nutrition than expected a reaction between someamino acid (lysine histidine or cysteine) and glucose canbe suspected The reaction between these substrates knownas Maillard reaction leads to the formation of unstableN-substituted glycosylamine which then degrades formingsmaller molecules containing an active subgroup O=CndashCndashN According to Fry and Stegink [32] the Mallard reactionis affected not only by the type of amino acid but also the pH
The Scientific World Journal 5
Table 3 Content of heavy metals in raw materials used in production of parenteral nutrition [26]
Element Certified value Amino acids Glucose Lipids[120583gkg]
As 2667 plusmn 041 262 plusmn 13 272 plusmn 12 269 plusmn 12
Cd 2279 plusmn 096 228 plusmn 12 231 plusmn 11 229 plusmn 08
Pb 2789 plusmn 014 270 plusmn 14 277 plusmn 13 278 plusmn 12
Hglowast 1590 plusmn 0018 157 plusmn 007 156 plusmn 006 161 plusmn 008
Cr 386 plusmn 16 375 plusmn 19 382 plusmn 16 379 plusmn 13
Cu 852 plusmn 12 875 plusmn 39 862 plusmn 42 843 plusmn 41
Mn 1215 plusmn 11 120 plusmn 51 120 plusmn 60 123 plusmn 58
Mo 4675 plusmn 026 468 plusmn 22 460 plusmn 22 474 plusmn 23
Ni 2740 plusmn 080 270 plusmn 13 267 plusmn 13 273 plusmn 11
V 1299 plusmn 037 129 plusmn 06 132 plusmn 06 129 plusmn 05
lowastResults are in [mgkg]
of the mixture temperature and the presence of electrolytes(Table 4)
HPLC methods can be used to determine concentrationof amino acids in parenteral nutrition mixture which donot contain any lipid emulsions In all-in-one mixturesseparation of aqueous and lipid phases is necessary Solidphase extraction (SPE) is predominant because analyte loss islow in contrast to classical extraction and it is effective andsimple to perform [33]
4 Drug Stability in Parenteral Nutrition
HPLC methods were used successfully in assays of vitaminsin parenteral nutrition mixtures especially in parenteralnutrition free from lipid emulsion Vazquez et al [34]designed a method that assayed 13 vitamins in one experi-ment using HPLC-UV-MS-MS The need for complex tan-dem spectrometry resulted from the low selectivity of the UVdetector and lack of a suitable chromophore in some of thevitamins assayed for example in pantothenic acid Ribeiro etal [23] assayed vitamins B
1and B
6using an HPLC method
with diode array detection vitamin B2utilizing fluorometry
and vitamin C by means of iodometric titration HPLCmethods were also used to assay cocarboxylase [35] vitaminA and E [19] and dehydroascorbic acid [36] Baumgartneret al [37] Iqbal et al [33] and Wade et al [38] designed amethod for chromatographic separation and assay of vitaminB1and ranitidine in two-in-one mixtures [37] cefepime
[33] and ceftazidime [38] This type of research althoughextremely important and carrying high clinical potential israrely undertaken because of the complexity of analyticalmethods
Parenteral nutrition is frequently only one of manytherapies used and patients are likely to be given other drugsaswellThese drugs which as a result of primary or coexistingdisease cannot be delivered via gastrointestinal system mustbe given intravenously either as an injection or infusionThatresults in the patient being given additional liquids either
as an isotonic salt solution or solution of glucose leading toeither hypernatraemia or hyperglycaemia Adding drugs toparenteral nutrition may eliminate this problem and reducethe cost of pharmacotherapy but one has to ensure thefollowing
(1) adequate drug stability by considering the effect ofparenteral nutrition on drug stability and the impactof the drug on parenteral nutrition stability and
(2) desired pharmacokinetic parameters during the longtime infusion in order to maintain the proper drugconcentration in the blood [4 39]
At the moment parenterally fed patients receive most ofindispensable drugs administered in the same way throughvascular access with a Y-connector The procedure mini-malizes but does not entirely eliminate the contact betweenthe drug and the components of the nutrition mixture Insome cases (Table 5) even a short-term contact between thedrug and the nutrition mixture can cause precipitation colorchange or phase separation That is the reason why beforeadministering the drug alongside the nutritional mixtureusing the Y-connector it must be assured that no interactionin the pharmaceutical phase will occur [39] Table 6 sum-marizes drugs compatible with the NuTRIflex Lipid Specialmixture [40] Some schemes for administering antibioticssimultaneously with parenteral nutrition are presented below[39ndash42]
(i) ampicillin infusion of not more than 20 minutes
(ii) ceftazidime infusion of not more than 30 minutes
(iii) ciprofloxacin infusion of not more than 30 minutes
(iv) imipenemcilastatin fast infusion (10ndash15min) stopsupply of parenteral nutrition rinse vascular accessbefore and after infusion
(v) vancomycin stop supply of parenteral nutrition rinsevascular access before and after infusion
6 The Scientific World Journal
Table 4 Percent of amino acid forming Maillard reaction products [32]
Amino acid Time [day]Storage temperature
4∘C 4∘C + electrolytes 25∘C 25∘C + electrolytes 60∘C 60∘C + electrolytes[]
Valine1 000 000 003 006 168 1657 000 000 029 098 mdash mdash30 000 000 040 127 mdash mdash
Isoleucine1 000 000 003 006 108 137 000 000 068 086 mdash mdash30 000 000 230 479 mdash mdash
Leucine1 008 012 006 030 101 1217 032 041 018 019 mdash mdash30 070 107 100 173 mdash mdash
Proline1 000 000 001 001 031 0487 000 000 015 019 mdash mdash30 000 001 040 053 mdash mdash
Phenylalanine1 000 000 002 006 746 7867 000 000 057 084 mdash mdash30 000 001 064 256 mdash mdash
Lysine1 000 000 033 092 109 1127 000 030 176 361 mdash mdash30 000 050 260 105 mdash mdash
Arginine1 009 010 100 148 961 1527 061 106 180 289 mdash mdash30 096 561 396 961 mdash mdash
Alanine1 011 079 043 074 461 4547 016 101 075 103 mdash mdash30 081 091 145 141 mdash mdash
Glycine1 050 161 082 138 475 7977 052 154 212 333 mdash mdash30 174 255 359 671 mdash mdash
Methionine1 019 042 181 460 109 1357 110 200 390 890 mdash mdash30 281 382 841 147 mdash mdash
Histidine1 010 043 016 150 164 3117 022 044 042 338 mdash mdash30 030 082 150 130 mdash mdash
Serine1 090 110 151 260 851 1397 125 150 452 487 mdash mdash30 320 540 961 122 mdash mdash
Threonine1 053 143 111 211 967 1557 097 156 401 488 mdash mdash30 252 604 882 987 mdash mdash
Tryptophan1 229 433 402 544 660 1217 342 521 111 111 mdash mdash30 814 136 158 211 mdash mdash
A simultaneous supply of drugs and parenteral nutritionmay cause not only interactions in the pharmaceutical phasebut also pharmacokinetic and pharmacodynamic interac-tions resulting in a drug protein binding degree change
a cytochrome P450 activity modification or an alteration inthe distribution volume of drugs through a modified flow ofthe extracelluar fluid Such incompatibilities are difficult topredict and have not been adequately researched [39]
The Scientific World Journal 7
Table 5 Examples of drugs incompatible with parenteral nutrition [39]
Drugs incompatible with parenteral nutritionAciclovir Ganciclovir Na Methyldopate HClAmphotericin B Haloperidol Midazolam HClCiclosporine Heparin Minocycline HClDopamine HCl Hydrochloric acid Nalbuphine HClDoxorubicin Hydromorphone Ondansetron HClDoxycycline hyclate Iron dextran Pentobarbital NaDroperidol Levorphanol tartrate Phenobarbital NaFluorouracil Lorazepam Phenytoin Na
Table 6 Drugs compatible with NuTRIflex Lipid Special after 1 hour contact mixed in 1 1 (vv) proportions [40]
Drug Dose Drug DoseCalcium chloride 013mmolmL Ca Midazolam 25mgmLCefepime 100mgmL Morphine sulfate 5mgmLCyclosporine 25mgmL Noradrenaline 1mgmLFentanyl 005mgmL Octreotide 25 120583gmLFurosemide 10mgmL Ondansetron 2mgmLTropisetron 1mgmL Paracetamol 10mgmLMagnesium sulfate 04mmolmL Mg PiperacillinTazobactam 80mgmL (piperacillin)Meropenem 50mgmL Potassium phosphate 012mmolL PO4
Metoclopramide 5mgmL Tacrolimus 01mgmLMetronidazole 5mgmL Vancomycin 10mgmLComposition of NuTRIflex Lipid Special (BBraun Medical) per 1000mL amino acids 574 g Lipids 40 g glucose 144 g sodium 54mmol potassium 38mmolcalcium 42mmol magnesium 42mmol phosphate 16mmol chloride 48mmol Acetate 48mmol zinc 003mmol
5 Conclusion
Parenteral nutrition should involve administration of a fullybalanced nutritional mixture covering patientsrsquo energeticand water-electrolyte needs resulting in an improved healthstatus life maintenance or quality life enhancement
The success of parenteral nutrition therapy dependson preparation and administration of a safe nutritionalmixturemdasha physicochemically and microbiologically stabledrug The preparation of such mixture should be precededby analysing its composition and any interactions whichmight occur during preparation storage and infusion Itis equally important to develop and validate a method fordetermining mixture stability Stability analysis ought to beperformedbefore adding drugs to the nutritionalmixture andits administration via intravenous access
Therefore the role of the pharmacist should ensurethe therapeutic safety of parenteral nutrition in all itsaspects including parenteral nutrition mixture prepara-tion choice of an appropriate administration route anddrug form for the ongoing medication implementationof alternative treatment methods monitoring therapeuticand toxic effects and instructing the medical and nursingstaff about possible interactions of drugs with parenteralnutrition
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
References
[1] S J Dudrick ldquoHistory of parenteral nutritionrdquo Journal of theAmerican College of Nutrition vol 28 no 3 pp 243ndash251 2009
[2] N JM CanoM Aparicio G Brunori et al ldquoESPEN guidelineson parenteral nutrition adult renal failurerdquo Clinical Nutritionvol 28 no 4 pp 401ndash414 2009
[3] P Singer M M Berger G Van den Berghe et al ldquoESPENguidelines on parenteral nutrition intensive carerdquo ClinicalNutrition vol 28 no 4 pp 387ndash400 2009
[4] D CardonaMNadal J Estelrich andMAMangues ldquoReviewof drug stability in parenteral nutrition admixturesrdquo e-SPENJournal vol 8 no 4 pp 135ndash140 2013
[5] S Muhlebach ldquoBasics in clinical nutrition drugs and nutri-tional admixturesrdquo e-SPEN Journal vol 4 no 3 pp e134ndashe1362009
[6] M C Allwood and M C J Kearney ldquoCompatibility and stabil-ity of additives in parenteral nutrition admixturesrdquo Nutritionvol 14 no 9 pp 697ndash706 1998
8 The Scientific World Journal
[7] K Hippalgaonkar S Majumdar and V Kansara ldquoInjectablelipid emulsions-advancements opportunities and challengesrdquoAAPS PharmSciTech vol 11 no 4 pp 1526ndash1540 2010
[8] C Freitas and R H Muller ldquoEffect of light and temperature onzeta potential and physical stability in solid lipid nanoparticle(SLN) dispersionsrdquo International Journal of Pharmaceuticsvol 168 no 2 pp 221ndash229 1998
[9] M Skouroliakou C Matthaiou A Chiou et al ldquoPhysicochem-ical stability of parenteral nutrition supplied as all-in-one forneonatesrdquo Journal of Parenteral and Enteral Nutrition vol 32no 2 pp 201ndash209 2008
[10] T Gonyon P W Carter O Dahlem A Denet H Owen and JTrouilly ldquoContainer effects on the physicochemical propertiesof parenteral lipid emulsionsrdquo Nutrition vol 24 no 11-12 pp1182ndash1188 2008
[11] L Bouchoud F Sadeghipour M Klingmuller C Fonzo-Christe and P Bonnabry ldquoLong-term physico-chemical sta-bility of standard parenteral nutritions for neonatesrdquo ClinicalNutrition vol 29 no 6 pp 808ndash812 2010
[12] I G Telessy J Balogh J Turmezei J Dredan and R ZelkoldquoStability assessment of ow parenteral nutrition emulsionsin the presence of high glucose and calcium concentrationsrdquoJournal of Pharmaceutical and Biomedical Analysis vol 56 no2 pp 159ndash164 2011
[13] D F Driscoll K Giampietro D P Wichelhaus et al ldquoPhysico-chemical stability assessments of lipid emulsions of varying oilcompositionrdquo Clinical Nutrition vol 20 no 2 pp 151ndash157 2001
[14] I G Telessy J Balogh F Csempesz V Szente J Dredan and RZelko ldquoComparison of the physicochemical properties ofMCT-containing fat emulsions in total nutrient admixturesrdquo Colloidsand Surfaces B vol 72 no 1 pp 75ndash79 2009
[15] D F Driscoll J Nehne H Peterss K Klutsch B R Bistrianand W Niemann ldquoPhysicochemical stability of intravenouslipid emulsions as all-in-one admixtures intended for the veryyoungrdquo Clinical Nutrition vol 22 no 5 pp 489ndash495 2003
[16] A Sforzini G Bersani A Stancari G Grossi A Bonoliand G C Ceschel ldquoAnalysis of all-in-one parenteral nutritionadmixtures by liquid chromatography and laser diffractionstudy of stabilityrdquo Journal of Pharmaceutical and BiomedicalAnalysis vol 24 no 5-6 pp 1099ndash1109 2001
[17] M C J Kearney M C Allwood T Neale and G HardyldquoThe stability of thiamine in total parenteral nutrition mixturesstored in EVA and multi-layered bagsrdquo Clinical Nutrition vol14 no 5 pp 295ndash301 1995
[18] M D Lee J-E Yoon S-I Kim and I-C Kim ldquoStability oftotal nutrient admixtures in reference to ambient temperaturesrdquoNutrition vol 19 no 10 pp 886ndash890 2003
[19] M C Allwood and H J Martin ldquoThe photodegradation ofvitamins A and E in parenteral nutrition mixtures duringinfusionrdquo Clinical Nutrition vol 19 no 5 pp 339ndash342 2000
[20] M C Allwood ldquoLight protection during parenteral nutritioninfusion is it really necessaryrdquoNutrition vol 16 no 3 pp 234ndash235 2000
[21] C Washington ldquoStability of lipid emulsions for drug deliveryrdquoAdvanced Drug Delivery Reviews vol 20 no 2-3 pp 131ndash1451996
[22] D O Ribeiro B W Lobo N M Volpato V F Da VeigaL M Cabral and V P De Sousa ldquoInfluence of the cal-cium concentration in the presence of organic phosphorus onthe physicochemical compatibility and stability of all-in-oneadmixtures for neonatal userdquoNutrition Journal vol 8 no 1 pp51ndash60 2009
[23] D O Ribeiro D C Pinto LM T R Lima NM Volpato LMCabral andV P De Sousa ldquoChemical stability study of vitaminsthiamine riboflavin pyridoxine and ascorbic acid in parenteralnutrition for neonatal userdquoNutrition Journal vol 10 no 1 p 472011
[24] S Gorog Ed Identification and Determination of Impurities inDrugs Elsevier Amsterdam The Netherlands 2000
[25] N Marie C Verdier B Le Bot and G Burgot ldquoAnalysis ofsodium and potassium in total parenteral nutrition bags byICP-MS and ICP-AES critical influence of the ingredientsrdquoAmerican Journal of Analytical Chemistry vol 2 no 5 pp 573ndash581 2001
[26] F G Antes M F Mesko J S Barin C M Moreira E MM Flores and V L Dressler ldquoDevelopment of multi-elementalmethod for quality control of parenteral component solutionsusing ICP-MSrdquo Microchemical Journal vol 98 no 1 pp 144ndash149 2011
[27] EMM Flores V L Dressle S Nussbaumer et al ldquoDetermina-tion of potassium sodium calciumandmagnesium in total par-enteral nutrition formulations by capillary electrophoresis withcontactless conductivity detectionrdquo Journal of Pharmaceuticaland Biomedical Analysis vol 53 no 2 pp 130ndash136 2010
[28] M Koberda M Konkowski P Youngberg W R Jones and AWeston ldquoCapillary electrophoretic determination of alkali andalkaline-earth cations in various multiple electrolyte solutionsfor parenteral userdquo Journal of Chromatography vol 602 no 1-2pp 235ndash240 1992
[29] Q Yang M Jimidar T P Hamoir J Smeyers-Verbeke andD L Massart ldquoDetermination of alkali and alkaline earthmetals in real samples by capillary ion analysisrdquo Journal ofChromatography A vol 673 no 2 pp 275ndash285 1994
[30] N Gochman and J M Schmitz ldquoApplication of a new peroxideindicator reaction to the specific automated determination ofglucose with glucose oxidaserdquo Clinical Chemistry vol 18 no 9pp 943ndash950 1972
[31] D Compagnone and G G Guilbault ldquoGlucose oxidasehexoki-nase electrode for the determination of ATPrdquoAnalytica ChimicaActa vol 340 no 1ndash3 pp 109ndash113 1997
[32] L K Fry and L D Stegink ldquoFormation of Maillard reactionproducts in parenteral alimentation solutionsrdquo Journal of Nutri-tion vol 112 no 8 pp 1631ndash1637 1982
[33] M S Iqbal M B Bahari Y Darwis et al ldquoA RP-HPLC-UV method with solid phase extraction for determination ofcefepime in Total Nutrient Admixtures application to stabilitystudiesrdquo Current Pharmaceutical Analysis vol 8 no 1 pp 68ndash74 2012
[34] R Vazquez R Rotival S Calvez et al ldquoStability indicatingassay method on vitamins application to their stability studyin parenteral nutrition admixturesrdquo Chromatographia vol 69no 7-8 pp 629ndash635 2009
[35] M C Allwood and H Martin ldquoStability of cocarboxylase inparenteral nutritionmixtures stored inmultilayer bagsrdquoClinicalNutrition vol 17 no 5 pp 231ndash234 1998
[36] EGibbonsMCAllwood TNeal andGHardy ldquoDegradationof dehydroascorbic acid in parenteral nutrition mixturesrdquoJournal of Pharmaceutical and Biomedical Analysis vol 25 no3-4 pp 605ndash611 2001
[37] T G Baumgartner G N Henderson J Fox and U GondildquoStability of ranitidine and thiamine in parenteral nutritionsolutionsrdquo Nutrition vol 13 no 6 pp 547ndash553 1997
[38] C S Wade V Lampasona R E Mullins and R B ParksldquoStability of ceftazidime and amino acids in parenteral nutrient
The Scientific World Journal 9
solutionsrdquo American Journal of Hospital Pharmacy vol 48 no7 pp 1515ndash1519 1991
[39] J M Mirtallo ldquoDrug-nutrient interactions in patients receivingparenteral mutritionrdquo in Handbook of Drug-Nutrient Interac-tions J I Boullata and V T Armenti Eds Humana Press NewYork NY USA 2nd edition 2010
[40] L Bouchoud C Fonzo-Christe M Klingmuller and PBonnabry ldquoCompatibility of intravenous medications withparenteral nutrition in vitro evaluationrdquo Journal of Parenteraland Enteral Nutrition vol 37 no 3 pp 416ndash424 2013
[41] P Sabin J Monterde D Cardona L Lorente and C PastorldquoIncompatibilities between drugs and parenteral nutritionPreliminary studyrdquoThe Farm Clinic vol 2 pp 12ndash20 1985
[42] E Muntada J Masso-Muniesa A Del Pozo et al ldquoCompati-bility of drugs with total nutrient admixtures (TNA) containingdifferent lipid emulsionsrdquoClinicalNutrition vol 22 supplement1 p S102 2003
Submit your manuscripts athttpwwwhindawicom
PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom
Volume 2014
ToxinsJournal of
VaccinesJournal of
Hindawi Publishing Corporation httpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
AntibioticsInternational Journal of
ToxicologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Drug DeliveryJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Advances in Pharmacological Sciences
Tropical MedicineJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Medicinal ChemistryInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
AddictionJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Autoimmune Diseases
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Anesthesiology Research and Practice
ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Pharmaceutics
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
2 The Scientific World Journal
pharmacotherapy often polypragmasy which may causesevere interactions not only between the drugs being used butalso between parenteral mixture ingredients [4]
2 Mixture Stability in Parenteral Nutrition
Parenteral nutrition is a multicomponent medication Withabout fifty components coexisting in one container and thepossibility of interactions between them the container andexcipients it is probably themost complex therapy inmodernmedicine [4 5] Tables 1 and 2 show the contents of aminoacids and lipids in emulsion preparationsmdashthemost complexcomponents of parenteral nutrition
Themost important interactions in the aqueous phase areas follows
(1) Precipitation of Calcium Hydrogen Phosphate Thesediment is depositedwhen the product of concentra-tion of Ca2+ and HPO
4
2minus ions is above 72mmol2L2Many other factors such as pH and the content ofthe mixture the way it was prepared and storageconditions may affect the solubility of CaHPO
4
Currently the risk of precipitation of CaHPO4can be
eliminated by the use of organic calcium salts suchas gluconates and glycerophosphate which do notdissociate in aqueous solutions [6]
(2) Inactivation of Vitamins as They Are Highly Suscep-tible to Degradation Parenteral nutrition generallycontains vitamins at the minimal concentrations nec-essary for the body function Sometimes the clinicalstate of the patient requires additional supplementa-tion with high doses of some vitamins vitamin B
1
in severe malnutrition or vitamin C in patients withincreased cell catabolism Inactivation of vitaminsmay follow many mechanisms photolysis of vitaminA and B
1 oxidation of vitamin C reduction of
vitamin B1 or adsorption of vitamin A onto the
surface of the container [6]
Changes occurring in the lipid phase are equally dan-gerous Parenteral nutrition is a two-phase medication con-sisting of ow emulsion formed as a result of mixingthe aqueous (amino acids carbohydrates electrolytes andmicroelements) and the lipid phases
Lipid emulsions used in parenteral nutrition consist ofspherical particles of lipids of micellar structure and sizecomparable to chylomicrons External part of micelles ishydrophilic with a negative charge while on the insidelipophilic chains of fatty acids are present The negativecharge localized on the external part of the micelles preventstheir aggregation which can be the first sign of the degra-dation of lipid emulsions The biggest danger to the stabilityof micelles is the presence of di- or trivalent cations whichcan neutralize the negative charge on micelles leading to theformation of larger particles Therefore a crucial parametercharacterizing parenteral nutrition is the critical aggregationnumber (CAN)mdasha maximal concentration of cations abovewhich the aggregation of lipid particles can occur [5 7]
The literature presents two solutions to ensure the stabil-ity of parenteral nutrition One of them is based on the stabil-ity of components and chosen drugs in parenteral nutritionwithout the lipid emulsions Parenteral nutrition mixturesso-called 2 in 1 containing carbohydrates amino acidselectrolytes and trace elements are used most frequently inparenteral nutrition for neonatals and pediatric patients Inthese cases lipid emulsions with vitamins are administeredfrom a separate container and mixed with aqueous phase atthe vein access The reason for this is a high concentrationof cations above the CAN which could lead to the degrada-tion of lipid emulsions in the parenteral nutrition mixtures[5]
The other solution relies on the stability of the completeparenteral nutrition mixture which is much difficult toinvestigate due to the biphasic character of the mixture
3 Methods of Parenteral Nutrition Analysis
When approaching the problem of parenteral nutrition sta-bility one has to consider the complexity of the mixtureand analytical problems connected with the assessment ofits stability Despite the wide range of analytical techniquesavailable there are no methods for quick determination ofthe stability of parenteral nutrition It is therefore extremelyimportant to design an experiment and choose a techniquewhich will allow to determine all critical factors that mightinfluence its stability
The majority of studies were carried out on parenteralnutrition stored between 24 hours and several weeks intemperature ranges of 2ndash8∘C and 36ndash38∘C and with variousdegrees of exposure to light [8 9]
The influence of packaging on the stability of parenteralnutrition mixture was also studied [10 11] It was foundthat storage time and temperature as well as exposure tolight had the greatest effect on the stability of parenteralnutrition mixtures The following was observed increaseddecomposition of vit A in the presence of sunlight decreaseddecomposition of vitamins at low temperatures changesin colour during storage at room temperature decreaseddecomposition of vitamins in multilayered packaging phaseseparation of lipid emulsion during storage while theircontent appeared to have a lesser effect on their stability Thetype of amino acid and lipid emulsion the concentration ofelectrolytes and the addition of antioxidant vitamins werealso observed to affect the stability of parenteral nutritionmixtures [9ndash23]
At present international regulations do not indicatethe most suitable methodology for studying the stability ofparenteral nutrition mixtures or provide standards for theirphysicochemical safety
The stability of parenteral nutrition mixtures is generallyinvestigated in three areas
(1) stability of lipid emulsion and the effect of othercomponents on its degradation
(2) parameters characterizing the properties of parenteralnutrition mixtures
(3) stability of the components
The Scientific World Journal 3
Table1Com
positionof
somea
minoacid
solutio
ns
Aminop
lasm
al10
Aminop
lasm
alHEP
AAminom
el10
Aminosteril
10
Aminosteril
N-H
epa
Aminoven
infant
10
Nephrotect
Prim
ene
10
Vamin
14Va
minolact
[g10
00mL]
Isoleucine
89
88
585
467
104
80
58
67
42
31
Leucine
50
136
624
706
1309
130
128
100
59
70Lysin
eacetate
106
1002
971
169
Methion
ine
44
12468
41
11312
224
42
13Ph
enylalanine
47
1654
482
088
375
35
42
59
27
Threon
ine
42
46
50
421
44
44
82
37
42
36
Tryptoph
an16
1520
182
07
201
30
20
1414
Valin
e62
106
50
592
1008
987
7655
36
Arginine
115
88
966
1064
1072
7582
84
84
41
Histidine
30
47
33
288
28
476
9838
51
21
Glycine
120
63
755
1595
582
415
531
40
59
21
Alanine
105
83
155
150
464
9362
80
1263
Proline
55
7175
150
573
971
30
30
51
56
Asparticacid
56
25
191
60
25
41
Asparagine
055
Acetylcyste
ine
08
067
07
054
Glutamicacid
7257
50
1042
71Serin
e23
37
43
224
767
7640
34
38
Acetyltyrosin
e086
20
Tyrosin
e04
42
06
045
017
05
Lysin
e856
746
851
1168
56
Taurine
04
06
03
Cyste
ine
052
246
042
10N-glycyl-L
-tyrosin
e316
Ornith
ine
166
242
249
Cystine
042
10
4 The Scientific World Journal
Table 2 Composition of some lipid emulsion preparations
ClinOleic20
Intralipid10
Intralipid20
Intralipid30
LipofundinMCTLCT
10
LipofundinMCTLCT
20
LipofundinN 10
LipofundinN 20 SMOFlipid
[g1000mL]Olive oil 160 50Soybean oil 40 100 200 300 50 100 100 200 60Medium-chain triglycerides 50 100 60Lecithin from egg yolk 8 12 8 12Glycerol 25 25 25 25Fish oil 30
Organoleptic in particular visual assessment can givevital information on the stability of parenteral nutritionSince lipid emulsion is a very sensitive component thedegradation of emulsion frequently manifests itself by theseparation of phases Color change during storage may alsobe an indication of degradation whereas the measurement ofpH osmolarity and electrical conductance offer informationwith regard to initial changes in parenteral nutrition mixture[7]
As the lack of any changes is not synonymous with thestability of parenteral nutrition mixtures further investiga-tions are necessary The emulsion should be examined forany changes in particle size signs of lipid peroxidation andfactors that may cause or affect it In the aqueous phasethe concentrations of glucose amino acids and electrolytesneed to be monitored and if any loss occurs identificationof degradation products and their biological properties isnecessary
Lipid emulsions used in parenteral nutrition are owemulsions having a narrow pH range and low osmolaritywhich allows them to be given via peripheral intravenousaccess The stability of lipid emulsion is a resultant ofattractive forces mainly of van der Waals character andrepulsive forces (electrostatic and spherical) which act onlipid emulsion particles Electrostatic forces being dependenton the pH concentration of electrolytes and the pres-ence of surfactants have the largest effect as they preventemulsion particles from forming aggregates [21] One ofthe best parameters to characterize the stability of lipidemulsion particles is potential zeta an electric potentialformed just outside the Stern layer This potential deter-mines the strength of electrostatic interaction between theparticles [21] Zeta potential can be established with thehelp of the Doppler effect during electrophoresis (LaserDoppler Electrophoresis (LDE)) or via an electrophoreticlight scattering experiment (Electrophoretic Light Scattering(ELS))
The stability of lipid emulsions can be studied by measur-ing particle sizes using optical microscopy laser diffractionor dynamic light scattering These methods were used suc-cessfully in the determination of size and shape of emulsionparticles and their stability [12ndash15 22]
Atomic absorption spectroscopy (AAS) and inductivelycoupled plasma atomic emission spectroscopy (ICP-AES)are the most suitable techniques to determine metal ionconcentrations in parenteral nutrition [24] So far only oneinvestigation using ICP-AES and ICP-MS in the study ofmetal ions (Na and K ions) in parenteral nutrition wasreported [25] Antes et al [26] applied ICP-MS to detect thelevel of metals in raw materials used to produce parenteralnutrition such as solutions of amino acids glucose andelectrolytes The authors identified and assayed a numberof heavy metals present in the analyzed matrices such ascadmium mercury copper and manganese and found theirconcentrations exceeding the limit levels (Table 3)
Other methods reported more frequently for the analysisof metal ions were flame photometry capillary electrophore-sis and ion-selective electrodes but the results obtained maycarry large errors because of the complexity of the matrices[27ndash29]
The most common methods for glucose assays areenzymatic assays using glucose oxidase or hexokinase Inthe first method glucose is oxidized to gluconic acid andhydrogen peroxide is formed Hydrogen peroxide in thepresence of peroxidase reacts with the sodium salt of 221015840-azino-di-(3-ethyl-benzthiazoline-6-sulphonic acid) to give acolored product absorbing in the range 670ndash680 nm [30]The second relies on phosphorylation of glucose in thepresence of hexokinase and ATP and formation of glucose-6-phosphate and ADP Glucose-6-phosphate is oxidized to6-phosphogluconate and NAD is reduced to NADH For-mation of NADH is associated with increased absorbance at340 nm [31] Both assays can be done directly without anyinitial extractions using commercial tests The hexokinasemethod was used successfully by Bouchoud et al [11] If anassay indicates a lowered concentration of glucose in theparenteral nutrition than expected a reaction between someamino acid (lysine histidine or cysteine) and glucose canbe suspected The reaction between these substrates knownas Maillard reaction leads to the formation of unstableN-substituted glycosylamine which then degrades formingsmaller molecules containing an active subgroup O=CndashCndashN According to Fry and Stegink [32] the Mallard reactionis affected not only by the type of amino acid but also the pH
The Scientific World Journal 5
Table 3 Content of heavy metals in raw materials used in production of parenteral nutrition [26]
Element Certified value Amino acids Glucose Lipids[120583gkg]
As 2667 plusmn 041 262 plusmn 13 272 plusmn 12 269 plusmn 12
Cd 2279 plusmn 096 228 plusmn 12 231 plusmn 11 229 plusmn 08
Pb 2789 plusmn 014 270 plusmn 14 277 plusmn 13 278 plusmn 12
Hglowast 1590 plusmn 0018 157 plusmn 007 156 plusmn 006 161 plusmn 008
Cr 386 plusmn 16 375 plusmn 19 382 plusmn 16 379 plusmn 13
Cu 852 plusmn 12 875 plusmn 39 862 plusmn 42 843 plusmn 41
Mn 1215 plusmn 11 120 plusmn 51 120 plusmn 60 123 plusmn 58
Mo 4675 plusmn 026 468 plusmn 22 460 plusmn 22 474 plusmn 23
Ni 2740 plusmn 080 270 plusmn 13 267 plusmn 13 273 plusmn 11
V 1299 plusmn 037 129 plusmn 06 132 plusmn 06 129 plusmn 05
lowastResults are in [mgkg]
of the mixture temperature and the presence of electrolytes(Table 4)
HPLC methods can be used to determine concentrationof amino acids in parenteral nutrition mixture which donot contain any lipid emulsions In all-in-one mixturesseparation of aqueous and lipid phases is necessary Solidphase extraction (SPE) is predominant because analyte loss islow in contrast to classical extraction and it is effective andsimple to perform [33]
4 Drug Stability in Parenteral Nutrition
HPLC methods were used successfully in assays of vitaminsin parenteral nutrition mixtures especially in parenteralnutrition free from lipid emulsion Vazquez et al [34]designed a method that assayed 13 vitamins in one experi-ment using HPLC-UV-MS-MS The need for complex tan-dem spectrometry resulted from the low selectivity of the UVdetector and lack of a suitable chromophore in some of thevitamins assayed for example in pantothenic acid Ribeiro etal [23] assayed vitamins B
1and B
6using an HPLC method
with diode array detection vitamin B2utilizing fluorometry
and vitamin C by means of iodometric titration HPLCmethods were also used to assay cocarboxylase [35] vitaminA and E [19] and dehydroascorbic acid [36] Baumgartneret al [37] Iqbal et al [33] and Wade et al [38] designed amethod for chromatographic separation and assay of vitaminB1and ranitidine in two-in-one mixtures [37] cefepime
[33] and ceftazidime [38] This type of research althoughextremely important and carrying high clinical potential israrely undertaken because of the complexity of analyticalmethods
Parenteral nutrition is frequently only one of manytherapies used and patients are likely to be given other drugsaswellThese drugs which as a result of primary or coexistingdisease cannot be delivered via gastrointestinal system mustbe given intravenously either as an injection or infusionThatresults in the patient being given additional liquids either
as an isotonic salt solution or solution of glucose leading toeither hypernatraemia or hyperglycaemia Adding drugs toparenteral nutrition may eliminate this problem and reducethe cost of pharmacotherapy but one has to ensure thefollowing
(1) adequate drug stability by considering the effect ofparenteral nutrition on drug stability and the impactof the drug on parenteral nutrition stability and
(2) desired pharmacokinetic parameters during the longtime infusion in order to maintain the proper drugconcentration in the blood [4 39]
At the moment parenterally fed patients receive most ofindispensable drugs administered in the same way throughvascular access with a Y-connector The procedure mini-malizes but does not entirely eliminate the contact betweenthe drug and the components of the nutrition mixture Insome cases (Table 5) even a short-term contact between thedrug and the nutrition mixture can cause precipitation colorchange or phase separation That is the reason why beforeadministering the drug alongside the nutritional mixtureusing the Y-connector it must be assured that no interactionin the pharmaceutical phase will occur [39] Table 6 sum-marizes drugs compatible with the NuTRIflex Lipid Specialmixture [40] Some schemes for administering antibioticssimultaneously with parenteral nutrition are presented below[39ndash42]
(i) ampicillin infusion of not more than 20 minutes
(ii) ceftazidime infusion of not more than 30 minutes
(iii) ciprofloxacin infusion of not more than 30 minutes
(iv) imipenemcilastatin fast infusion (10ndash15min) stopsupply of parenteral nutrition rinse vascular accessbefore and after infusion
(v) vancomycin stop supply of parenteral nutrition rinsevascular access before and after infusion
6 The Scientific World Journal
Table 4 Percent of amino acid forming Maillard reaction products [32]
Amino acid Time [day]Storage temperature
4∘C 4∘C + electrolytes 25∘C 25∘C + electrolytes 60∘C 60∘C + electrolytes[]
Valine1 000 000 003 006 168 1657 000 000 029 098 mdash mdash30 000 000 040 127 mdash mdash
Isoleucine1 000 000 003 006 108 137 000 000 068 086 mdash mdash30 000 000 230 479 mdash mdash
Leucine1 008 012 006 030 101 1217 032 041 018 019 mdash mdash30 070 107 100 173 mdash mdash
Proline1 000 000 001 001 031 0487 000 000 015 019 mdash mdash30 000 001 040 053 mdash mdash
Phenylalanine1 000 000 002 006 746 7867 000 000 057 084 mdash mdash30 000 001 064 256 mdash mdash
Lysine1 000 000 033 092 109 1127 000 030 176 361 mdash mdash30 000 050 260 105 mdash mdash
Arginine1 009 010 100 148 961 1527 061 106 180 289 mdash mdash30 096 561 396 961 mdash mdash
Alanine1 011 079 043 074 461 4547 016 101 075 103 mdash mdash30 081 091 145 141 mdash mdash
Glycine1 050 161 082 138 475 7977 052 154 212 333 mdash mdash30 174 255 359 671 mdash mdash
Methionine1 019 042 181 460 109 1357 110 200 390 890 mdash mdash30 281 382 841 147 mdash mdash
Histidine1 010 043 016 150 164 3117 022 044 042 338 mdash mdash30 030 082 150 130 mdash mdash
Serine1 090 110 151 260 851 1397 125 150 452 487 mdash mdash30 320 540 961 122 mdash mdash
Threonine1 053 143 111 211 967 1557 097 156 401 488 mdash mdash30 252 604 882 987 mdash mdash
Tryptophan1 229 433 402 544 660 1217 342 521 111 111 mdash mdash30 814 136 158 211 mdash mdash
A simultaneous supply of drugs and parenteral nutritionmay cause not only interactions in the pharmaceutical phasebut also pharmacokinetic and pharmacodynamic interac-tions resulting in a drug protein binding degree change
a cytochrome P450 activity modification or an alteration inthe distribution volume of drugs through a modified flow ofthe extracelluar fluid Such incompatibilities are difficult topredict and have not been adequately researched [39]
The Scientific World Journal 7
Table 5 Examples of drugs incompatible with parenteral nutrition [39]
Drugs incompatible with parenteral nutritionAciclovir Ganciclovir Na Methyldopate HClAmphotericin B Haloperidol Midazolam HClCiclosporine Heparin Minocycline HClDopamine HCl Hydrochloric acid Nalbuphine HClDoxorubicin Hydromorphone Ondansetron HClDoxycycline hyclate Iron dextran Pentobarbital NaDroperidol Levorphanol tartrate Phenobarbital NaFluorouracil Lorazepam Phenytoin Na
Table 6 Drugs compatible with NuTRIflex Lipid Special after 1 hour contact mixed in 1 1 (vv) proportions [40]
Drug Dose Drug DoseCalcium chloride 013mmolmL Ca Midazolam 25mgmLCefepime 100mgmL Morphine sulfate 5mgmLCyclosporine 25mgmL Noradrenaline 1mgmLFentanyl 005mgmL Octreotide 25 120583gmLFurosemide 10mgmL Ondansetron 2mgmLTropisetron 1mgmL Paracetamol 10mgmLMagnesium sulfate 04mmolmL Mg PiperacillinTazobactam 80mgmL (piperacillin)Meropenem 50mgmL Potassium phosphate 012mmolL PO4
Metoclopramide 5mgmL Tacrolimus 01mgmLMetronidazole 5mgmL Vancomycin 10mgmLComposition of NuTRIflex Lipid Special (BBraun Medical) per 1000mL amino acids 574 g Lipids 40 g glucose 144 g sodium 54mmol potassium 38mmolcalcium 42mmol magnesium 42mmol phosphate 16mmol chloride 48mmol Acetate 48mmol zinc 003mmol
5 Conclusion
Parenteral nutrition should involve administration of a fullybalanced nutritional mixture covering patientsrsquo energeticand water-electrolyte needs resulting in an improved healthstatus life maintenance or quality life enhancement
The success of parenteral nutrition therapy dependson preparation and administration of a safe nutritionalmixturemdasha physicochemically and microbiologically stabledrug The preparation of such mixture should be precededby analysing its composition and any interactions whichmight occur during preparation storage and infusion Itis equally important to develop and validate a method fordetermining mixture stability Stability analysis ought to beperformedbefore adding drugs to the nutritionalmixture andits administration via intravenous access
Therefore the role of the pharmacist should ensurethe therapeutic safety of parenteral nutrition in all itsaspects including parenteral nutrition mixture prepara-tion choice of an appropriate administration route anddrug form for the ongoing medication implementationof alternative treatment methods monitoring therapeuticand toxic effects and instructing the medical and nursingstaff about possible interactions of drugs with parenteralnutrition
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
References
[1] S J Dudrick ldquoHistory of parenteral nutritionrdquo Journal of theAmerican College of Nutrition vol 28 no 3 pp 243ndash251 2009
[2] N JM CanoM Aparicio G Brunori et al ldquoESPEN guidelineson parenteral nutrition adult renal failurerdquo Clinical Nutritionvol 28 no 4 pp 401ndash414 2009
[3] P Singer M M Berger G Van den Berghe et al ldquoESPENguidelines on parenteral nutrition intensive carerdquo ClinicalNutrition vol 28 no 4 pp 387ndash400 2009
[4] D CardonaMNadal J Estelrich andMAMangues ldquoReviewof drug stability in parenteral nutrition admixturesrdquo e-SPENJournal vol 8 no 4 pp 135ndash140 2013
[5] S Muhlebach ldquoBasics in clinical nutrition drugs and nutri-tional admixturesrdquo e-SPEN Journal vol 4 no 3 pp e134ndashe1362009
[6] M C Allwood and M C J Kearney ldquoCompatibility and stabil-ity of additives in parenteral nutrition admixturesrdquo Nutritionvol 14 no 9 pp 697ndash706 1998
8 The Scientific World Journal
[7] K Hippalgaonkar S Majumdar and V Kansara ldquoInjectablelipid emulsions-advancements opportunities and challengesrdquoAAPS PharmSciTech vol 11 no 4 pp 1526ndash1540 2010
[8] C Freitas and R H Muller ldquoEffect of light and temperature onzeta potential and physical stability in solid lipid nanoparticle(SLN) dispersionsrdquo International Journal of Pharmaceuticsvol 168 no 2 pp 221ndash229 1998
[9] M Skouroliakou C Matthaiou A Chiou et al ldquoPhysicochem-ical stability of parenteral nutrition supplied as all-in-one forneonatesrdquo Journal of Parenteral and Enteral Nutrition vol 32no 2 pp 201ndash209 2008
[10] T Gonyon P W Carter O Dahlem A Denet H Owen and JTrouilly ldquoContainer effects on the physicochemical propertiesof parenteral lipid emulsionsrdquo Nutrition vol 24 no 11-12 pp1182ndash1188 2008
[11] L Bouchoud F Sadeghipour M Klingmuller C Fonzo-Christe and P Bonnabry ldquoLong-term physico-chemical sta-bility of standard parenteral nutritions for neonatesrdquo ClinicalNutrition vol 29 no 6 pp 808ndash812 2010
[12] I G Telessy J Balogh J Turmezei J Dredan and R ZelkoldquoStability assessment of ow parenteral nutrition emulsionsin the presence of high glucose and calcium concentrationsrdquoJournal of Pharmaceutical and Biomedical Analysis vol 56 no2 pp 159ndash164 2011
[13] D F Driscoll K Giampietro D P Wichelhaus et al ldquoPhysico-chemical stability assessments of lipid emulsions of varying oilcompositionrdquo Clinical Nutrition vol 20 no 2 pp 151ndash157 2001
[14] I G Telessy J Balogh F Csempesz V Szente J Dredan and RZelko ldquoComparison of the physicochemical properties ofMCT-containing fat emulsions in total nutrient admixturesrdquo Colloidsand Surfaces B vol 72 no 1 pp 75ndash79 2009
[15] D F Driscoll J Nehne H Peterss K Klutsch B R Bistrianand W Niemann ldquoPhysicochemical stability of intravenouslipid emulsions as all-in-one admixtures intended for the veryyoungrdquo Clinical Nutrition vol 22 no 5 pp 489ndash495 2003
[16] A Sforzini G Bersani A Stancari G Grossi A Bonoliand G C Ceschel ldquoAnalysis of all-in-one parenteral nutritionadmixtures by liquid chromatography and laser diffractionstudy of stabilityrdquo Journal of Pharmaceutical and BiomedicalAnalysis vol 24 no 5-6 pp 1099ndash1109 2001
[17] M C J Kearney M C Allwood T Neale and G HardyldquoThe stability of thiamine in total parenteral nutrition mixturesstored in EVA and multi-layered bagsrdquo Clinical Nutrition vol14 no 5 pp 295ndash301 1995
[18] M D Lee J-E Yoon S-I Kim and I-C Kim ldquoStability oftotal nutrient admixtures in reference to ambient temperaturesrdquoNutrition vol 19 no 10 pp 886ndash890 2003
[19] M C Allwood and H J Martin ldquoThe photodegradation ofvitamins A and E in parenteral nutrition mixtures duringinfusionrdquo Clinical Nutrition vol 19 no 5 pp 339ndash342 2000
[20] M C Allwood ldquoLight protection during parenteral nutritioninfusion is it really necessaryrdquoNutrition vol 16 no 3 pp 234ndash235 2000
[21] C Washington ldquoStability of lipid emulsions for drug deliveryrdquoAdvanced Drug Delivery Reviews vol 20 no 2-3 pp 131ndash1451996
[22] D O Ribeiro B W Lobo N M Volpato V F Da VeigaL M Cabral and V P De Sousa ldquoInfluence of the cal-cium concentration in the presence of organic phosphorus onthe physicochemical compatibility and stability of all-in-oneadmixtures for neonatal userdquoNutrition Journal vol 8 no 1 pp51ndash60 2009
[23] D O Ribeiro D C Pinto LM T R Lima NM Volpato LMCabral andV P De Sousa ldquoChemical stability study of vitaminsthiamine riboflavin pyridoxine and ascorbic acid in parenteralnutrition for neonatal userdquoNutrition Journal vol 10 no 1 p 472011
[24] S Gorog Ed Identification and Determination of Impurities inDrugs Elsevier Amsterdam The Netherlands 2000
[25] N Marie C Verdier B Le Bot and G Burgot ldquoAnalysis ofsodium and potassium in total parenteral nutrition bags byICP-MS and ICP-AES critical influence of the ingredientsrdquoAmerican Journal of Analytical Chemistry vol 2 no 5 pp 573ndash581 2001
[26] F G Antes M F Mesko J S Barin C M Moreira E MM Flores and V L Dressler ldquoDevelopment of multi-elementalmethod for quality control of parenteral component solutionsusing ICP-MSrdquo Microchemical Journal vol 98 no 1 pp 144ndash149 2011
[27] EMM Flores V L Dressle S Nussbaumer et al ldquoDetermina-tion of potassium sodium calciumandmagnesium in total par-enteral nutrition formulations by capillary electrophoresis withcontactless conductivity detectionrdquo Journal of Pharmaceuticaland Biomedical Analysis vol 53 no 2 pp 130ndash136 2010
[28] M Koberda M Konkowski P Youngberg W R Jones and AWeston ldquoCapillary electrophoretic determination of alkali andalkaline-earth cations in various multiple electrolyte solutionsfor parenteral userdquo Journal of Chromatography vol 602 no 1-2pp 235ndash240 1992
[29] Q Yang M Jimidar T P Hamoir J Smeyers-Verbeke andD L Massart ldquoDetermination of alkali and alkaline earthmetals in real samples by capillary ion analysisrdquo Journal ofChromatography A vol 673 no 2 pp 275ndash285 1994
[30] N Gochman and J M Schmitz ldquoApplication of a new peroxideindicator reaction to the specific automated determination ofglucose with glucose oxidaserdquo Clinical Chemistry vol 18 no 9pp 943ndash950 1972
[31] D Compagnone and G G Guilbault ldquoGlucose oxidasehexoki-nase electrode for the determination of ATPrdquoAnalytica ChimicaActa vol 340 no 1ndash3 pp 109ndash113 1997
[32] L K Fry and L D Stegink ldquoFormation of Maillard reactionproducts in parenteral alimentation solutionsrdquo Journal of Nutri-tion vol 112 no 8 pp 1631ndash1637 1982
[33] M S Iqbal M B Bahari Y Darwis et al ldquoA RP-HPLC-UV method with solid phase extraction for determination ofcefepime in Total Nutrient Admixtures application to stabilitystudiesrdquo Current Pharmaceutical Analysis vol 8 no 1 pp 68ndash74 2012
[34] R Vazquez R Rotival S Calvez et al ldquoStability indicatingassay method on vitamins application to their stability studyin parenteral nutrition admixturesrdquo Chromatographia vol 69no 7-8 pp 629ndash635 2009
[35] M C Allwood and H Martin ldquoStability of cocarboxylase inparenteral nutritionmixtures stored inmultilayer bagsrdquoClinicalNutrition vol 17 no 5 pp 231ndash234 1998
[36] EGibbonsMCAllwood TNeal andGHardy ldquoDegradationof dehydroascorbic acid in parenteral nutrition mixturesrdquoJournal of Pharmaceutical and Biomedical Analysis vol 25 no3-4 pp 605ndash611 2001
[37] T G Baumgartner G N Henderson J Fox and U GondildquoStability of ranitidine and thiamine in parenteral nutritionsolutionsrdquo Nutrition vol 13 no 6 pp 547ndash553 1997
[38] C S Wade V Lampasona R E Mullins and R B ParksldquoStability of ceftazidime and amino acids in parenteral nutrient
The Scientific World Journal 9
solutionsrdquo American Journal of Hospital Pharmacy vol 48 no7 pp 1515ndash1519 1991
[39] J M Mirtallo ldquoDrug-nutrient interactions in patients receivingparenteral mutritionrdquo in Handbook of Drug-Nutrient Interac-tions J I Boullata and V T Armenti Eds Humana Press NewYork NY USA 2nd edition 2010
[40] L Bouchoud C Fonzo-Christe M Klingmuller and PBonnabry ldquoCompatibility of intravenous medications withparenteral nutrition in vitro evaluationrdquo Journal of Parenteraland Enteral Nutrition vol 37 no 3 pp 416ndash424 2013
[41] P Sabin J Monterde D Cardona L Lorente and C PastorldquoIncompatibilities between drugs and parenteral nutritionPreliminary studyrdquoThe Farm Clinic vol 2 pp 12ndash20 1985
[42] E Muntada J Masso-Muniesa A Del Pozo et al ldquoCompati-bility of drugs with total nutrient admixtures (TNA) containingdifferent lipid emulsionsrdquoClinicalNutrition vol 22 supplement1 p S102 2003
Submit your manuscripts athttpwwwhindawicom
PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom
Volume 2014
ToxinsJournal of
VaccinesJournal of
Hindawi Publishing Corporation httpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
AntibioticsInternational Journal of
ToxicologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Drug DeliveryJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Advances in Pharmacological Sciences
Tropical MedicineJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Medicinal ChemistryInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
AddictionJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Autoimmune Diseases
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Anesthesiology Research and Practice
ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Pharmaceutics
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
The Scientific World Journal 3
Table1Com
positionof
somea
minoacid
solutio
ns
Aminop
lasm
al10
Aminop
lasm
alHEP
AAminom
el10
Aminosteril
10
Aminosteril
N-H
epa
Aminoven
infant
10
Nephrotect
Prim
ene
10
Vamin
14Va
minolact
[g10
00mL]
Isoleucine
89
88
585
467
104
80
58
67
42
31
Leucine
50
136
624
706
1309
130
128
100
59
70Lysin
eacetate
106
1002
971
169
Methion
ine
44
12468
41
11312
224
42
13Ph
enylalanine
47
1654
482
088
375
35
42
59
27
Threon
ine
42
46
50
421
44
44
82
37
42
36
Tryptoph
an16
1520
182
07
201
30
20
1414
Valin
e62
106
50
592
1008
987
7655
36
Arginine
115
88
966
1064
1072
7582
84
84
41
Histidine
30
47
33
288
28
476
9838
51
21
Glycine
120
63
755
1595
582
415
531
40
59
21
Alanine
105
83
155
150
464
9362
80
1263
Proline
55
7175
150
573
971
30
30
51
56
Asparticacid
56
25
191
60
25
41
Asparagine
055
Acetylcyste
ine
08
067
07
054
Glutamicacid
7257
50
1042
71Serin
e23
37
43
224
767
7640
34
38
Acetyltyrosin
e086
20
Tyrosin
e04
42
06
045
017
05
Lysin
e856
746
851
1168
56
Taurine
04
06
03
Cyste
ine
052
246
042
10N-glycyl-L
-tyrosin
e316
Ornith
ine
166
242
249
Cystine
042
10
4 The Scientific World Journal
Table 2 Composition of some lipid emulsion preparations
ClinOleic20
Intralipid10
Intralipid20
Intralipid30
LipofundinMCTLCT
10
LipofundinMCTLCT
20
LipofundinN 10
LipofundinN 20 SMOFlipid
[g1000mL]Olive oil 160 50Soybean oil 40 100 200 300 50 100 100 200 60Medium-chain triglycerides 50 100 60Lecithin from egg yolk 8 12 8 12Glycerol 25 25 25 25Fish oil 30
Organoleptic in particular visual assessment can givevital information on the stability of parenteral nutritionSince lipid emulsion is a very sensitive component thedegradation of emulsion frequently manifests itself by theseparation of phases Color change during storage may alsobe an indication of degradation whereas the measurement ofpH osmolarity and electrical conductance offer informationwith regard to initial changes in parenteral nutrition mixture[7]
As the lack of any changes is not synonymous with thestability of parenteral nutrition mixtures further investiga-tions are necessary The emulsion should be examined forany changes in particle size signs of lipid peroxidation andfactors that may cause or affect it In the aqueous phasethe concentrations of glucose amino acids and electrolytesneed to be monitored and if any loss occurs identificationof degradation products and their biological properties isnecessary
Lipid emulsions used in parenteral nutrition are owemulsions having a narrow pH range and low osmolaritywhich allows them to be given via peripheral intravenousaccess The stability of lipid emulsion is a resultant ofattractive forces mainly of van der Waals character andrepulsive forces (electrostatic and spherical) which act onlipid emulsion particles Electrostatic forces being dependenton the pH concentration of electrolytes and the pres-ence of surfactants have the largest effect as they preventemulsion particles from forming aggregates [21] One ofthe best parameters to characterize the stability of lipidemulsion particles is potential zeta an electric potentialformed just outside the Stern layer This potential deter-mines the strength of electrostatic interaction between theparticles [21] Zeta potential can be established with thehelp of the Doppler effect during electrophoresis (LaserDoppler Electrophoresis (LDE)) or via an electrophoreticlight scattering experiment (Electrophoretic Light Scattering(ELS))
The stability of lipid emulsions can be studied by measur-ing particle sizes using optical microscopy laser diffractionor dynamic light scattering These methods were used suc-cessfully in the determination of size and shape of emulsionparticles and their stability [12ndash15 22]
Atomic absorption spectroscopy (AAS) and inductivelycoupled plasma atomic emission spectroscopy (ICP-AES)are the most suitable techniques to determine metal ionconcentrations in parenteral nutrition [24] So far only oneinvestigation using ICP-AES and ICP-MS in the study ofmetal ions (Na and K ions) in parenteral nutrition wasreported [25] Antes et al [26] applied ICP-MS to detect thelevel of metals in raw materials used to produce parenteralnutrition such as solutions of amino acids glucose andelectrolytes The authors identified and assayed a numberof heavy metals present in the analyzed matrices such ascadmium mercury copper and manganese and found theirconcentrations exceeding the limit levels (Table 3)
Other methods reported more frequently for the analysisof metal ions were flame photometry capillary electrophore-sis and ion-selective electrodes but the results obtained maycarry large errors because of the complexity of the matrices[27ndash29]
The most common methods for glucose assays areenzymatic assays using glucose oxidase or hexokinase Inthe first method glucose is oxidized to gluconic acid andhydrogen peroxide is formed Hydrogen peroxide in thepresence of peroxidase reacts with the sodium salt of 221015840-azino-di-(3-ethyl-benzthiazoline-6-sulphonic acid) to give acolored product absorbing in the range 670ndash680 nm [30]The second relies on phosphorylation of glucose in thepresence of hexokinase and ATP and formation of glucose-6-phosphate and ADP Glucose-6-phosphate is oxidized to6-phosphogluconate and NAD is reduced to NADH For-mation of NADH is associated with increased absorbance at340 nm [31] Both assays can be done directly without anyinitial extractions using commercial tests The hexokinasemethod was used successfully by Bouchoud et al [11] If anassay indicates a lowered concentration of glucose in theparenteral nutrition than expected a reaction between someamino acid (lysine histidine or cysteine) and glucose canbe suspected The reaction between these substrates knownas Maillard reaction leads to the formation of unstableN-substituted glycosylamine which then degrades formingsmaller molecules containing an active subgroup O=CndashCndashN According to Fry and Stegink [32] the Mallard reactionis affected not only by the type of amino acid but also the pH
The Scientific World Journal 5
Table 3 Content of heavy metals in raw materials used in production of parenteral nutrition [26]
Element Certified value Amino acids Glucose Lipids[120583gkg]
As 2667 plusmn 041 262 plusmn 13 272 plusmn 12 269 plusmn 12
Cd 2279 plusmn 096 228 plusmn 12 231 plusmn 11 229 plusmn 08
Pb 2789 plusmn 014 270 plusmn 14 277 plusmn 13 278 plusmn 12
Hglowast 1590 plusmn 0018 157 plusmn 007 156 plusmn 006 161 plusmn 008
Cr 386 plusmn 16 375 plusmn 19 382 plusmn 16 379 plusmn 13
Cu 852 plusmn 12 875 plusmn 39 862 plusmn 42 843 plusmn 41
Mn 1215 plusmn 11 120 plusmn 51 120 plusmn 60 123 plusmn 58
Mo 4675 plusmn 026 468 plusmn 22 460 plusmn 22 474 plusmn 23
Ni 2740 plusmn 080 270 plusmn 13 267 plusmn 13 273 plusmn 11
V 1299 plusmn 037 129 plusmn 06 132 plusmn 06 129 plusmn 05
lowastResults are in [mgkg]
of the mixture temperature and the presence of electrolytes(Table 4)
HPLC methods can be used to determine concentrationof amino acids in parenteral nutrition mixture which donot contain any lipid emulsions In all-in-one mixturesseparation of aqueous and lipid phases is necessary Solidphase extraction (SPE) is predominant because analyte loss islow in contrast to classical extraction and it is effective andsimple to perform [33]
4 Drug Stability in Parenteral Nutrition
HPLC methods were used successfully in assays of vitaminsin parenteral nutrition mixtures especially in parenteralnutrition free from lipid emulsion Vazquez et al [34]designed a method that assayed 13 vitamins in one experi-ment using HPLC-UV-MS-MS The need for complex tan-dem spectrometry resulted from the low selectivity of the UVdetector and lack of a suitable chromophore in some of thevitamins assayed for example in pantothenic acid Ribeiro etal [23] assayed vitamins B
1and B
6using an HPLC method
with diode array detection vitamin B2utilizing fluorometry
and vitamin C by means of iodometric titration HPLCmethods were also used to assay cocarboxylase [35] vitaminA and E [19] and dehydroascorbic acid [36] Baumgartneret al [37] Iqbal et al [33] and Wade et al [38] designed amethod for chromatographic separation and assay of vitaminB1and ranitidine in two-in-one mixtures [37] cefepime
[33] and ceftazidime [38] This type of research althoughextremely important and carrying high clinical potential israrely undertaken because of the complexity of analyticalmethods
Parenteral nutrition is frequently only one of manytherapies used and patients are likely to be given other drugsaswellThese drugs which as a result of primary or coexistingdisease cannot be delivered via gastrointestinal system mustbe given intravenously either as an injection or infusionThatresults in the patient being given additional liquids either
as an isotonic salt solution or solution of glucose leading toeither hypernatraemia or hyperglycaemia Adding drugs toparenteral nutrition may eliminate this problem and reducethe cost of pharmacotherapy but one has to ensure thefollowing
(1) adequate drug stability by considering the effect ofparenteral nutrition on drug stability and the impactof the drug on parenteral nutrition stability and
(2) desired pharmacokinetic parameters during the longtime infusion in order to maintain the proper drugconcentration in the blood [4 39]
At the moment parenterally fed patients receive most ofindispensable drugs administered in the same way throughvascular access with a Y-connector The procedure mini-malizes but does not entirely eliminate the contact betweenthe drug and the components of the nutrition mixture Insome cases (Table 5) even a short-term contact between thedrug and the nutrition mixture can cause precipitation colorchange or phase separation That is the reason why beforeadministering the drug alongside the nutritional mixtureusing the Y-connector it must be assured that no interactionin the pharmaceutical phase will occur [39] Table 6 sum-marizes drugs compatible with the NuTRIflex Lipid Specialmixture [40] Some schemes for administering antibioticssimultaneously with parenteral nutrition are presented below[39ndash42]
(i) ampicillin infusion of not more than 20 minutes
(ii) ceftazidime infusion of not more than 30 minutes
(iii) ciprofloxacin infusion of not more than 30 minutes
(iv) imipenemcilastatin fast infusion (10ndash15min) stopsupply of parenteral nutrition rinse vascular accessbefore and after infusion
(v) vancomycin stop supply of parenteral nutrition rinsevascular access before and after infusion
6 The Scientific World Journal
Table 4 Percent of amino acid forming Maillard reaction products [32]
Amino acid Time [day]Storage temperature
4∘C 4∘C + electrolytes 25∘C 25∘C + electrolytes 60∘C 60∘C + electrolytes[]
Valine1 000 000 003 006 168 1657 000 000 029 098 mdash mdash30 000 000 040 127 mdash mdash
Isoleucine1 000 000 003 006 108 137 000 000 068 086 mdash mdash30 000 000 230 479 mdash mdash
Leucine1 008 012 006 030 101 1217 032 041 018 019 mdash mdash30 070 107 100 173 mdash mdash
Proline1 000 000 001 001 031 0487 000 000 015 019 mdash mdash30 000 001 040 053 mdash mdash
Phenylalanine1 000 000 002 006 746 7867 000 000 057 084 mdash mdash30 000 001 064 256 mdash mdash
Lysine1 000 000 033 092 109 1127 000 030 176 361 mdash mdash30 000 050 260 105 mdash mdash
Arginine1 009 010 100 148 961 1527 061 106 180 289 mdash mdash30 096 561 396 961 mdash mdash
Alanine1 011 079 043 074 461 4547 016 101 075 103 mdash mdash30 081 091 145 141 mdash mdash
Glycine1 050 161 082 138 475 7977 052 154 212 333 mdash mdash30 174 255 359 671 mdash mdash
Methionine1 019 042 181 460 109 1357 110 200 390 890 mdash mdash30 281 382 841 147 mdash mdash
Histidine1 010 043 016 150 164 3117 022 044 042 338 mdash mdash30 030 082 150 130 mdash mdash
Serine1 090 110 151 260 851 1397 125 150 452 487 mdash mdash30 320 540 961 122 mdash mdash
Threonine1 053 143 111 211 967 1557 097 156 401 488 mdash mdash30 252 604 882 987 mdash mdash
Tryptophan1 229 433 402 544 660 1217 342 521 111 111 mdash mdash30 814 136 158 211 mdash mdash
A simultaneous supply of drugs and parenteral nutritionmay cause not only interactions in the pharmaceutical phasebut also pharmacokinetic and pharmacodynamic interac-tions resulting in a drug protein binding degree change
a cytochrome P450 activity modification or an alteration inthe distribution volume of drugs through a modified flow ofthe extracelluar fluid Such incompatibilities are difficult topredict and have not been adequately researched [39]
The Scientific World Journal 7
Table 5 Examples of drugs incompatible with parenteral nutrition [39]
Drugs incompatible with parenteral nutritionAciclovir Ganciclovir Na Methyldopate HClAmphotericin B Haloperidol Midazolam HClCiclosporine Heparin Minocycline HClDopamine HCl Hydrochloric acid Nalbuphine HClDoxorubicin Hydromorphone Ondansetron HClDoxycycline hyclate Iron dextran Pentobarbital NaDroperidol Levorphanol tartrate Phenobarbital NaFluorouracil Lorazepam Phenytoin Na
Table 6 Drugs compatible with NuTRIflex Lipid Special after 1 hour contact mixed in 1 1 (vv) proportions [40]
Drug Dose Drug DoseCalcium chloride 013mmolmL Ca Midazolam 25mgmLCefepime 100mgmL Morphine sulfate 5mgmLCyclosporine 25mgmL Noradrenaline 1mgmLFentanyl 005mgmL Octreotide 25 120583gmLFurosemide 10mgmL Ondansetron 2mgmLTropisetron 1mgmL Paracetamol 10mgmLMagnesium sulfate 04mmolmL Mg PiperacillinTazobactam 80mgmL (piperacillin)Meropenem 50mgmL Potassium phosphate 012mmolL PO4
Metoclopramide 5mgmL Tacrolimus 01mgmLMetronidazole 5mgmL Vancomycin 10mgmLComposition of NuTRIflex Lipid Special (BBraun Medical) per 1000mL amino acids 574 g Lipids 40 g glucose 144 g sodium 54mmol potassium 38mmolcalcium 42mmol magnesium 42mmol phosphate 16mmol chloride 48mmol Acetate 48mmol zinc 003mmol
5 Conclusion
Parenteral nutrition should involve administration of a fullybalanced nutritional mixture covering patientsrsquo energeticand water-electrolyte needs resulting in an improved healthstatus life maintenance or quality life enhancement
The success of parenteral nutrition therapy dependson preparation and administration of a safe nutritionalmixturemdasha physicochemically and microbiologically stabledrug The preparation of such mixture should be precededby analysing its composition and any interactions whichmight occur during preparation storage and infusion Itis equally important to develop and validate a method fordetermining mixture stability Stability analysis ought to beperformedbefore adding drugs to the nutritionalmixture andits administration via intravenous access
Therefore the role of the pharmacist should ensurethe therapeutic safety of parenteral nutrition in all itsaspects including parenteral nutrition mixture prepara-tion choice of an appropriate administration route anddrug form for the ongoing medication implementationof alternative treatment methods monitoring therapeuticand toxic effects and instructing the medical and nursingstaff about possible interactions of drugs with parenteralnutrition
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
References
[1] S J Dudrick ldquoHistory of parenteral nutritionrdquo Journal of theAmerican College of Nutrition vol 28 no 3 pp 243ndash251 2009
[2] N JM CanoM Aparicio G Brunori et al ldquoESPEN guidelineson parenteral nutrition adult renal failurerdquo Clinical Nutritionvol 28 no 4 pp 401ndash414 2009
[3] P Singer M M Berger G Van den Berghe et al ldquoESPENguidelines on parenteral nutrition intensive carerdquo ClinicalNutrition vol 28 no 4 pp 387ndash400 2009
[4] D CardonaMNadal J Estelrich andMAMangues ldquoReviewof drug stability in parenteral nutrition admixturesrdquo e-SPENJournal vol 8 no 4 pp 135ndash140 2013
[5] S Muhlebach ldquoBasics in clinical nutrition drugs and nutri-tional admixturesrdquo e-SPEN Journal vol 4 no 3 pp e134ndashe1362009
[6] M C Allwood and M C J Kearney ldquoCompatibility and stabil-ity of additives in parenteral nutrition admixturesrdquo Nutritionvol 14 no 9 pp 697ndash706 1998
8 The Scientific World Journal
[7] K Hippalgaonkar S Majumdar and V Kansara ldquoInjectablelipid emulsions-advancements opportunities and challengesrdquoAAPS PharmSciTech vol 11 no 4 pp 1526ndash1540 2010
[8] C Freitas and R H Muller ldquoEffect of light and temperature onzeta potential and physical stability in solid lipid nanoparticle(SLN) dispersionsrdquo International Journal of Pharmaceuticsvol 168 no 2 pp 221ndash229 1998
[9] M Skouroliakou C Matthaiou A Chiou et al ldquoPhysicochem-ical stability of parenteral nutrition supplied as all-in-one forneonatesrdquo Journal of Parenteral and Enteral Nutrition vol 32no 2 pp 201ndash209 2008
[10] T Gonyon P W Carter O Dahlem A Denet H Owen and JTrouilly ldquoContainer effects on the physicochemical propertiesof parenteral lipid emulsionsrdquo Nutrition vol 24 no 11-12 pp1182ndash1188 2008
[11] L Bouchoud F Sadeghipour M Klingmuller C Fonzo-Christe and P Bonnabry ldquoLong-term physico-chemical sta-bility of standard parenteral nutritions for neonatesrdquo ClinicalNutrition vol 29 no 6 pp 808ndash812 2010
[12] I G Telessy J Balogh J Turmezei J Dredan and R ZelkoldquoStability assessment of ow parenteral nutrition emulsionsin the presence of high glucose and calcium concentrationsrdquoJournal of Pharmaceutical and Biomedical Analysis vol 56 no2 pp 159ndash164 2011
[13] D F Driscoll K Giampietro D P Wichelhaus et al ldquoPhysico-chemical stability assessments of lipid emulsions of varying oilcompositionrdquo Clinical Nutrition vol 20 no 2 pp 151ndash157 2001
[14] I G Telessy J Balogh F Csempesz V Szente J Dredan and RZelko ldquoComparison of the physicochemical properties ofMCT-containing fat emulsions in total nutrient admixturesrdquo Colloidsand Surfaces B vol 72 no 1 pp 75ndash79 2009
[15] D F Driscoll J Nehne H Peterss K Klutsch B R Bistrianand W Niemann ldquoPhysicochemical stability of intravenouslipid emulsions as all-in-one admixtures intended for the veryyoungrdquo Clinical Nutrition vol 22 no 5 pp 489ndash495 2003
[16] A Sforzini G Bersani A Stancari G Grossi A Bonoliand G C Ceschel ldquoAnalysis of all-in-one parenteral nutritionadmixtures by liquid chromatography and laser diffractionstudy of stabilityrdquo Journal of Pharmaceutical and BiomedicalAnalysis vol 24 no 5-6 pp 1099ndash1109 2001
[17] M C J Kearney M C Allwood T Neale and G HardyldquoThe stability of thiamine in total parenteral nutrition mixturesstored in EVA and multi-layered bagsrdquo Clinical Nutrition vol14 no 5 pp 295ndash301 1995
[18] M D Lee J-E Yoon S-I Kim and I-C Kim ldquoStability oftotal nutrient admixtures in reference to ambient temperaturesrdquoNutrition vol 19 no 10 pp 886ndash890 2003
[19] M C Allwood and H J Martin ldquoThe photodegradation ofvitamins A and E in parenteral nutrition mixtures duringinfusionrdquo Clinical Nutrition vol 19 no 5 pp 339ndash342 2000
[20] M C Allwood ldquoLight protection during parenteral nutritioninfusion is it really necessaryrdquoNutrition vol 16 no 3 pp 234ndash235 2000
[21] C Washington ldquoStability of lipid emulsions for drug deliveryrdquoAdvanced Drug Delivery Reviews vol 20 no 2-3 pp 131ndash1451996
[22] D O Ribeiro B W Lobo N M Volpato V F Da VeigaL M Cabral and V P De Sousa ldquoInfluence of the cal-cium concentration in the presence of organic phosphorus onthe physicochemical compatibility and stability of all-in-oneadmixtures for neonatal userdquoNutrition Journal vol 8 no 1 pp51ndash60 2009
[23] D O Ribeiro D C Pinto LM T R Lima NM Volpato LMCabral andV P De Sousa ldquoChemical stability study of vitaminsthiamine riboflavin pyridoxine and ascorbic acid in parenteralnutrition for neonatal userdquoNutrition Journal vol 10 no 1 p 472011
[24] S Gorog Ed Identification and Determination of Impurities inDrugs Elsevier Amsterdam The Netherlands 2000
[25] N Marie C Verdier B Le Bot and G Burgot ldquoAnalysis ofsodium and potassium in total parenteral nutrition bags byICP-MS and ICP-AES critical influence of the ingredientsrdquoAmerican Journal of Analytical Chemistry vol 2 no 5 pp 573ndash581 2001
[26] F G Antes M F Mesko J S Barin C M Moreira E MM Flores and V L Dressler ldquoDevelopment of multi-elementalmethod for quality control of parenteral component solutionsusing ICP-MSrdquo Microchemical Journal vol 98 no 1 pp 144ndash149 2011
[27] EMM Flores V L Dressle S Nussbaumer et al ldquoDetermina-tion of potassium sodium calciumandmagnesium in total par-enteral nutrition formulations by capillary electrophoresis withcontactless conductivity detectionrdquo Journal of Pharmaceuticaland Biomedical Analysis vol 53 no 2 pp 130ndash136 2010
[28] M Koberda M Konkowski P Youngberg W R Jones and AWeston ldquoCapillary electrophoretic determination of alkali andalkaline-earth cations in various multiple electrolyte solutionsfor parenteral userdquo Journal of Chromatography vol 602 no 1-2pp 235ndash240 1992
[29] Q Yang M Jimidar T P Hamoir J Smeyers-Verbeke andD L Massart ldquoDetermination of alkali and alkaline earthmetals in real samples by capillary ion analysisrdquo Journal ofChromatography A vol 673 no 2 pp 275ndash285 1994
[30] N Gochman and J M Schmitz ldquoApplication of a new peroxideindicator reaction to the specific automated determination ofglucose with glucose oxidaserdquo Clinical Chemistry vol 18 no 9pp 943ndash950 1972
[31] D Compagnone and G G Guilbault ldquoGlucose oxidasehexoki-nase electrode for the determination of ATPrdquoAnalytica ChimicaActa vol 340 no 1ndash3 pp 109ndash113 1997
[32] L K Fry and L D Stegink ldquoFormation of Maillard reactionproducts in parenteral alimentation solutionsrdquo Journal of Nutri-tion vol 112 no 8 pp 1631ndash1637 1982
[33] M S Iqbal M B Bahari Y Darwis et al ldquoA RP-HPLC-UV method with solid phase extraction for determination ofcefepime in Total Nutrient Admixtures application to stabilitystudiesrdquo Current Pharmaceutical Analysis vol 8 no 1 pp 68ndash74 2012
[34] R Vazquez R Rotival S Calvez et al ldquoStability indicatingassay method on vitamins application to their stability studyin parenteral nutrition admixturesrdquo Chromatographia vol 69no 7-8 pp 629ndash635 2009
[35] M C Allwood and H Martin ldquoStability of cocarboxylase inparenteral nutritionmixtures stored inmultilayer bagsrdquoClinicalNutrition vol 17 no 5 pp 231ndash234 1998
[36] EGibbonsMCAllwood TNeal andGHardy ldquoDegradationof dehydroascorbic acid in parenteral nutrition mixturesrdquoJournal of Pharmaceutical and Biomedical Analysis vol 25 no3-4 pp 605ndash611 2001
[37] T G Baumgartner G N Henderson J Fox and U GondildquoStability of ranitidine and thiamine in parenteral nutritionsolutionsrdquo Nutrition vol 13 no 6 pp 547ndash553 1997
[38] C S Wade V Lampasona R E Mullins and R B ParksldquoStability of ceftazidime and amino acids in parenteral nutrient
The Scientific World Journal 9
solutionsrdquo American Journal of Hospital Pharmacy vol 48 no7 pp 1515ndash1519 1991
[39] J M Mirtallo ldquoDrug-nutrient interactions in patients receivingparenteral mutritionrdquo in Handbook of Drug-Nutrient Interac-tions J I Boullata and V T Armenti Eds Humana Press NewYork NY USA 2nd edition 2010
[40] L Bouchoud C Fonzo-Christe M Klingmuller and PBonnabry ldquoCompatibility of intravenous medications withparenteral nutrition in vitro evaluationrdquo Journal of Parenteraland Enteral Nutrition vol 37 no 3 pp 416ndash424 2013
[41] P Sabin J Monterde D Cardona L Lorente and C PastorldquoIncompatibilities between drugs and parenteral nutritionPreliminary studyrdquoThe Farm Clinic vol 2 pp 12ndash20 1985
[42] E Muntada J Masso-Muniesa A Del Pozo et al ldquoCompati-bility of drugs with total nutrient admixtures (TNA) containingdifferent lipid emulsionsrdquoClinicalNutrition vol 22 supplement1 p S102 2003
Submit your manuscripts athttpwwwhindawicom
PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom
Volume 2014
ToxinsJournal of
VaccinesJournal of
Hindawi Publishing Corporation httpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
AntibioticsInternational Journal of
ToxicologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Drug DeliveryJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Advances in Pharmacological Sciences
Tropical MedicineJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Medicinal ChemistryInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
AddictionJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Autoimmune Diseases
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Anesthesiology Research and Practice
ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Pharmaceutics
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
4 The Scientific World Journal
Table 2 Composition of some lipid emulsion preparations
ClinOleic20
Intralipid10
Intralipid20
Intralipid30
LipofundinMCTLCT
10
LipofundinMCTLCT
20
LipofundinN 10
LipofundinN 20 SMOFlipid
[g1000mL]Olive oil 160 50Soybean oil 40 100 200 300 50 100 100 200 60Medium-chain triglycerides 50 100 60Lecithin from egg yolk 8 12 8 12Glycerol 25 25 25 25Fish oil 30
Organoleptic in particular visual assessment can givevital information on the stability of parenteral nutritionSince lipid emulsion is a very sensitive component thedegradation of emulsion frequently manifests itself by theseparation of phases Color change during storage may alsobe an indication of degradation whereas the measurement ofpH osmolarity and electrical conductance offer informationwith regard to initial changes in parenteral nutrition mixture[7]
As the lack of any changes is not synonymous with thestability of parenteral nutrition mixtures further investiga-tions are necessary The emulsion should be examined forany changes in particle size signs of lipid peroxidation andfactors that may cause or affect it In the aqueous phasethe concentrations of glucose amino acids and electrolytesneed to be monitored and if any loss occurs identificationof degradation products and their biological properties isnecessary
Lipid emulsions used in parenteral nutrition are owemulsions having a narrow pH range and low osmolaritywhich allows them to be given via peripheral intravenousaccess The stability of lipid emulsion is a resultant ofattractive forces mainly of van der Waals character andrepulsive forces (electrostatic and spherical) which act onlipid emulsion particles Electrostatic forces being dependenton the pH concentration of electrolytes and the pres-ence of surfactants have the largest effect as they preventemulsion particles from forming aggregates [21] One ofthe best parameters to characterize the stability of lipidemulsion particles is potential zeta an electric potentialformed just outside the Stern layer This potential deter-mines the strength of electrostatic interaction between theparticles [21] Zeta potential can be established with thehelp of the Doppler effect during electrophoresis (LaserDoppler Electrophoresis (LDE)) or via an electrophoreticlight scattering experiment (Electrophoretic Light Scattering(ELS))
The stability of lipid emulsions can be studied by measur-ing particle sizes using optical microscopy laser diffractionor dynamic light scattering These methods were used suc-cessfully in the determination of size and shape of emulsionparticles and their stability [12ndash15 22]
Atomic absorption spectroscopy (AAS) and inductivelycoupled plasma atomic emission spectroscopy (ICP-AES)are the most suitable techniques to determine metal ionconcentrations in parenteral nutrition [24] So far only oneinvestigation using ICP-AES and ICP-MS in the study ofmetal ions (Na and K ions) in parenteral nutrition wasreported [25] Antes et al [26] applied ICP-MS to detect thelevel of metals in raw materials used to produce parenteralnutrition such as solutions of amino acids glucose andelectrolytes The authors identified and assayed a numberof heavy metals present in the analyzed matrices such ascadmium mercury copper and manganese and found theirconcentrations exceeding the limit levels (Table 3)
Other methods reported more frequently for the analysisof metal ions were flame photometry capillary electrophore-sis and ion-selective electrodes but the results obtained maycarry large errors because of the complexity of the matrices[27ndash29]
The most common methods for glucose assays areenzymatic assays using glucose oxidase or hexokinase Inthe first method glucose is oxidized to gluconic acid andhydrogen peroxide is formed Hydrogen peroxide in thepresence of peroxidase reacts with the sodium salt of 221015840-azino-di-(3-ethyl-benzthiazoline-6-sulphonic acid) to give acolored product absorbing in the range 670ndash680 nm [30]The second relies on phosphorylation of glucose in thepresence of hexokinase and ATP and formation of glucose-6-phosphate and ADP Glucose-6-phosphate is oxidized to6-phosphogluconate and NAD is reduced to NADH For-mation of NADH is associated with increased absorbance at340 nm [31] Both assays can be done directly without anyinitial extractions using commercial tests The hexokinasemethod was used successfully by Bouchoud et al [11] If anassay indicates a lowered concentration of glucose in theparenteral nutrition than expected a reaction between someamino acid (lysine histidine or cysteine) and glucose canbe suspected The reaction between these substrates knownas Maillard reaction leads to the formation of unstableN-substituted glycosylamine which then degrades formingsmaller molecules containing an active subgroup O=CndashCndashN According to Fry and Stegink [32] the Mallard reactionis affected not only by the type of amino acid but also the pH
The Scientific World Journal 5
Table 3 Content of heavy metals in raw materials used in production of parenteral nutrition [26]
Element Certified value Amino acids Glucose Lipids[120583gkg]
As 2667 plusmn 041 262 plusmn 13 272 plusmn 12 269 plusmn 12
Cd 2279 plusmn 096 228 plusmn 12 231 plusmn 11 229 plusmn 08
Pb 2789 plusmn 014 270 plusmn 14 277 plusmn 13 278 plusmn 12
Hglowast 1590 plusmn 0018 157 plusmn 007 156 plusmn 006 161 plusmn 008
Cr 386 plusmn 16 375 plusmn 19 382 plusmn 16 379 plusmn 13
Cu 852 plusmn 12 875 plusmn 39 862 plusmn 42 843 plusmn 41
Mn 1215 plusmn 11 120 plusmn 51 120 plusmn 60 123 plusmn 58
Mo 4675 plusmn 026 468 plusmn 22 460 plusmn 22 474 plusmn 23
Ni 2740 plusmn 080 270 plusmn 13 267 plusmn 13 273 plusmn 11
V 1299 plusmn 037 129 plusmn 06 132 plusmn 06 129 plusmn 05
lowastResults are in [mgkg]
of the mixture temperature and the presence of electrolytes(Table 4)
HPLC methods can be used to determine concentrationof amino acids in parenteral nutrition mixture which donot contain any lipid emulsions In all-in-one mixturesseparation of aqueous and lipid phases is necessary Solidphase extraction (SPE) is predominant because analyte loss islow in contrast to classical extraction and it is effective andsimple to perform [33]
4 Drug Stability in Parenteral Nutrition
HPLC methods were used successfully in assays of vitaminsin parenteral nutrition mixtures especially in parenteralnutrition free from lipid emulsion Vazquez et al [34]designed a method that assayed 13 vitamins in one experi-ment using HPLC-UV-MS-MS The need for complex tan-dem spectrometry resulted from the low selectivity of the UVdetector and lack of a suitable chromophore in some of thevitamins assayed for example in pantothenic acid Ribeiro etal [23] assayed vitamins B
1and B
6using an HPLC method
with diode array detection vitamin B2utilizing fluorometry
and vitamin C by means of iodometric titration HPLCmethods were also used to assay cocarboxylase [35] vitaminA and E [19] and dehydroascorbic acid [36] Baumgartneret al [37] Iqbal et al [33] and Wade et al [38] designed amethod for chromatographic separation and assay of vitaminB1and ranitidine in two-in-one mixtures [37] cefepime
[33] and ceftazidime [38] This type of research althoughextremely important and carrying high clinical potential israrely undertaken because of the complexity of analyticalmethods
Parenteral nutrition is frequently only one of manytherapies used and patients are likely to be given other drugsaswellThese drugs which as a result of primary or coexistingdisease cannot be delivered via gastrointestinal system mustbe given intravenously either as an injection or infusionThatresults in the patient being given additional liquids either
as an isotonic salt solution or solution of glucose leading toeither hypernatraemia or hyperglycaemia Adding drugs toparenteral nutrition may eliminate this problem and reducethe cost of pharmacotherapy but one has to ensure thefollowing
(1) adequate drug stability by considering the effect ofparenteral nutrition on drug stability and the impactof the drug on parenteral nutrition stability and
(2) desired pharmacokinetic parameters during the longtime infusion in order to maintain the proper drugconcentration in the blood [4 39]
At the moment parenterally fed patients receive most ofindispensable drugs administered in the same way throughvascular access with a Y-connector The procedure mini-malizes but does not entirely eliminate the contact betweenthe drug and the components of the nutrition mixture Insome cases (Table 5) even a short-term contact between thedrug and the nutrition mixture can cause precipitation colorchange or phase separation That is the reason why beforeadministering the drug alongside the nutritional mixtureusing the Y-connector it must be assured that no interactionin the pharmaceutical phase will occur [39] Table 6 sum-marizes drugs compatible with the NuTRIflex Lipid Specialmixture [40] Some schemes for administering antibioticssimultaneously with parenteral nutrition are presented below[39ndash42]
(i) ampicillin infusion of not more than 20 minutes
(ii) ceftazidime infusion of not more than 30 minutes
(iii) ciprofloxacin infusion of not more than 30 minutes
(iv) imipenemcilastatin fast infusion (10ndash15min) stopsupply of parenteral nutrition rinse vascular accessbefore and after infusion
(v) vancomycin stop supply of parenteral nutrition rinsevascular access before and after infusion
6 The Scientific World Journal
Table 4 Percent of amino acid forming Maillard reaction products [32]
Amino acid Time [day]Storage temperature
4∘C 4∘C + electrolytes 25∘C 25∘C + electrolytes 60∘C 60∘C + electrolytes[]
Valine1 000 000 003 006 168 1657 000 000 029 098 mdash mdash30 000 000 040 127 mdash mdash
Isoleucine1 000 000 003 006 108 137 000 000 068 086 mdash mdash30 000 000 230 479 mdash mdash
Leucine1 008 012 006 030 101 1217 032 041 018 019 mdash mdash30 070 107 100 173 mdash mdash
Proline1 000 000 001 001 031 0487 000 000 015 019 mdash mdash30 000 001 040 053 mdash mdash
Phenylalanine1 000 000 002 006 746 7867 000 000 057 084 mdash mdash30 000 001 064 256 mdash mdash
Lysine1 000 000 033 092 109 1127 000 030 176 361 mdash mdash30 000 050 260 105 mdash mdash
Arginine1 009 010 100 148 961 1527 061 106 180 289 mdash mdash30 096 561 396 961 mdash mdash
Alanine1 011 079 043 074 461 4547 016 101 075 103 mdash mdash30 081 091 145 141 mdash mdash
Glycine1 050 161 082 138 475 7977 052 154 212 333 mdash mdash30 174 255 359 671 mdash mdash
Methionine1 019 042 181 460 109 1357 110 200 390 890 mdash mdash30 281 382 841 147 mdash mdash
Histidine1 010 043 016 150 164 3117 022 044 042 338 mdash mdash30 030 082 150 130 mdash mdash
Serine1 090 110 151 260 851 1397 125 150 452 487 mdash mdash30 320 540 961 122 mdash mdash
Threonine1 053 143 111 211 967 1557 097 156 401 488 mdash mdash30 252 604 882 987 mdash mdash
Tryptophan1 229 433 402 544 660 1217 342 521 111 111 mdash mdash30 814 136 158 211 mdash mdash
A simultaneous supply of drugs and parenteral nutritionmay cause not only interactions in the pharmaceutical phasebut also pharmacokinetic and pharmacodynamic interac-tions resulting in a drug protein binding degree change
a cytochrome P450 activity modification or an alteration inthe distribution volume of drugs through a modified flow ofthe extracelluar fluid Such incompatibilities are difficult topredict and have not been adequately researched [39]
The Scientific World Journal 7
Table 5 Examples of drugs incompatible with parenteral nutrition [39]
Drugs incompatible with parenteral nutritionAciclovir Ganciclovir Na Methyldopate HClAmphotericin B Haloperidol Midazolam HClCiclosporine Heparin Minocycline HClDopamine HCl Hydrochloric acid Nalbuphine HClDoxorubicin Hydromorphone Ondansetron HClDoxycycline hyclate Iron dextran Pentobarbital NaDroperidol Levorphanol tartrate Phenobarbital NaFluorouracil Lorazepam Phenytoin Na
Table 6 Drugs compatible with NuTRIflex Lipid Special after 1 hour contact mixed in 1 1 (vv) proportions [40]
Drug Dose Drug DoseCalcium chloride 013mmolmL Ca Midazolam 25mgmLCefepime 100mgmL Morphine sulfate 5mgmLCyclosporine 25mgmL Noradrenaline 1mgmLFentanyl 005mgmL Octreotide 25 120583gmLFurosemide 10mgmL Ondansetron 2mgmLTropisetron 1mgmL Paracetamol 10mgmLMagnesium sulfate 04mmolmL Mg PiperacillinTazobactam 80mgmL (piperacillin)Meropenem 50mgmL Potassium phosphate 012mmolL PO4
Metoclopramide 5mgmL Tacrolimus 01mgmLMetronidazole 5mgmL Vancomycin 10mgmLComposition of NuTRIflex Lipid Special (BBraun Medical) per 1000mL amino acids 574 g Lipids 40 g glucose 144 g sodium 54mmol potassium 38mmolcalcium 42mmol magnesium 42mmol phosphate 16mmol chloride 48mmol Acetate 48mmol zinc 003mmol
5 Conclusion
Parenteral nutrition should involve administration of a fullybalanced nutritional mixture covering patientsrsquo energeticand water-electrolyte needs resulting in an improved healthstatus life maintenance or quality life enhancement
The success of parenteral nutrition therapy dependson preparation and administration of a safe nutritionalmixturemdasha physicochemically and microbiologically stabledrug The preparation of such mixture should be precededby analysing its composition and any interactions whichmight occur during preparation storage and infusion Itis equally important to develop and validate a method fordetermining mixture stability Stability analysis ought to beperformedbefore adding drugs to the nutritionalmixture andits administration via intravenous access
Therefore the role of the pharmacist should ensurethe therapeutic safety of parenteral nutrition in all itsaspects including parenteral nutrition mixture prepara-tion choice of an appropriate administration route anddrug form for the ongoing medication implementationof alternative treatment methods monitoring therapeuticand toxic effects and instructing the medical and nursingstaff about possible interactions of drugs with parenteralnutrition
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
References
[1] S J Dudrick ldquoHistory of parenteral nutritionrdquo Journal of theAmerican College of Nutrition vol 28 no 3 pp 243ndash251 2009
[2] N JM CanoM Aparicio G Brunori et al ldquoESPEN guidelineson parenteral nutrition adult renal failurerdquo Clinical Nutritionvol 28 no 4 pp 401ndash414 2009
[3] P Singer M M Berger G Van den Berghe et al ldquoESPENguidelines on parenteral nutrition intensive carerdquo ClinicalNutrition vol 28 no 4 pp 387ndash400 2009
[4] D CardonaMNadal J Estelrich andMAMangues ldquoReviewof drug stability in parenteral nutrition admixturesrdquo e-SPENJournal vol 8 no 4 pp 135ndash140 2013
[5] S Muhlebach ldquoBasics in clinical nutrition drugs and nutri-tional admixturesrdquo e-SPEN Journal vol 4 no 3 pp e134ndashe1362009
[6] M C Allwood and M C J Kearney ldquoCompatibility and stabil-ity of additives in parenteral nutrition admixturesrdquo Nutritionvol 14 no 9 pp 697ndash706 1998
8 The Scientific World Journal
[7] K Hippalgaonkar S Majumdar and V Kansara ldquoInjectablelipid emulsions-advancements opportunities and challengesrdquoAAPS PharmSciTech vol 11 no 4 pp 1526ndash1540 2010
[8] C Freitas and R H Muller ldquoEffect of light and temperature onzeta potential and physical stability in solid lipid nanoparticle(SLN) dispersionsrdquo International Journal of Pharmaceuticsvol 168 no 2 pp 221ndash229 1998
[9] M Skouroliakou C Matthaiou A Chiou et al ldquoPhysicochem-ical stability of parenteral nutrition supplied as all-in-one forneonatesrdquo Journal of Parenteral and Enteral Nutrition vol 32no 2 pp 201ndash209 2008
[10] T Gonyon P W Carter O Dahlem A Denet H Owen and JTrouilly ldquoContainer effects on the physicochemical propertiesof parenteral lipid emulsionsrdquo Nutrition vol 24 no 11-12 pp1182ndash1188 2008
[11] L Bouchoud F Sadeghipour M Klingmuller C Fonzo-Christe and P Bonnabry ldquoLong-term physico-chemical sta-bility of standard parenteral nutritions for neonatesrdquo ClinicalNutrition vol 29 no 6 pp 808ndash812 2010
[12] I G Telessy J Balogh J Turmezei J Dredan and R ZelkoldquoStability assessment of ow parenteral nutrition emulsionsin the presence of high glucose and calcium concentrationsrdquoJournal of Pharmaceutical and Biomedical Analysis vol 56 no2 pp 159ndash164 2011
[13] D F Driscoll K Giampietro D P Wichelhaus et al ldquoPhysico-chemical stability assessments of lipid emulsions of varying oilcompositionrdquo Clinical Nutrition vol 20 no 2 pp 151ndash157 2001
[14] I G Telessy J Balogh F Csempesz V Szente J Dredan and RZelko ldquoComparison of the physicochemical properties ofMCT-containing fat emulsions in total nutrient admixturesrdquo Colloidsand Surfaces B vol 72 no 1 pp 75ndash79 2009
[15] D F Driscoll J Nehne H Peterss K Klutsch B R Bistrianand W Niemann ldquoPhysicochemical stability of intravenouslipid emulsions as all-in-one admixtures intended for the veryyoungrdquo Clinical Nutrition vol 22 no 5 pp 489ndash495 2003
[16] A Sforzini G Bersani A Stancari G Grossi A Bonoliand G C Ceschel ldquoAnalysis of all-in-one parenteral nutritionadmixtures by liquid chromatography and laser diffractionstudy of stabilityrdquo Journal of Pharmaceutical and BiomedicalAnalysis vol 24 no 5-6 pp 1099ndash1109 2001
[17] M C J Kearney M C Allwood T Neale and G HardyldquoThe stability of thiamine in total parenteral nutrition mixturesstored in EVA and multi-layered bagsrdquo Clinical Nutrition vol14 no 5 pp 295ndash301 1995
[18] M D Lee J-E Yoon S-I Kim and I-C Kim ldquoStability oftotal nutrient admixtures in reference to ambient temperaturesrdquoNutrition vol 19 no 10 pp 886ndash890 2003
[19] M C Allwood and H J Martin ldquoThe photodegradation ofvitamins A and E in parenteral nutrition mixtures duringinfusionrdquo Clinical Nutrition vol 19 no 5 pp 339ndash342 2000
[20] M C Allwood ldquoLight protection during parenteral nutritioninfusion is it really necessaryrdquoNutrition vol 16 no 3 pp 234ndash235 2000
[21] C Washington ldquoStability of lipid emulsions for drug deliveryrdquoAdvanced Drug Delivery Reviews vol 20 no 2-3 pp 131ndash1451996
[22] D O Ribeiro B W Lobo N M Volpato V F Da VeigaL M Cabral and V P De Sousa ldquoInfluence of the cal-cium concentration in the presence of organic phosphorus onthe physicochemical compatibility and stability of all-in-oneadmixtures for neonatal userdquoNutrition Journal vol 8 no 1 pp51ndash60 2009
[23] D O Ribeiro D C Pinto LM T R Lima NM Volpato LMCabral andV P De Sousa ldquoChemical stability study of vitaminsthiamine riboflavin pyridoxine and ascorbic acid in parenteralnutrition for neonatal userdquoNutrition Journal vol 10 no 1 p 472011
[24] S Gorog Ed Identification and Determination of Impurities inDrugs Elsevier Amsterdam The Netherlands 2000
[25] N Marie C Verdier B Le Bot and G Burgot ldquoAnalysis ofsodium and potassium in total parenteral nutrition bags byICP-MS and ICP-AES critical influence of the ingredientsrdquoAmerican Journal of Analytical Chemistry vol 2 no 5 pp 573ndash581 2001
[26] F G Antes M F Mesko J S Barin C M Moreira E MM Flores and V L Dressler ldquoDevelopment of multi-elementalmethod for quality control of parenteral component solutionsusing ICP-MSrdquo Microchemical Journal vol 98 no 1 pp 144ndash149 2011
[27] EMM Flores V L Dressle S Nussbaumer et al ldquoDetermina-tion of potassium sodium calciumandmagnesium in total par-enteral nutrition formulations by capillary electrophoresis withcontactless conductivity detectionrdquo Journal of Pharmaceuticaland Biomedical Analysis vol 53 no 2 pp 130ndash136 2010
[28] M Koberda M Konkowski P Youngberg W R Jones and AWeston ldquoCapillary electrophoretic determination of alkali andalkaline-earth cations in various multiple electrolyte solutionsfor parenteral userdquo Journal of Chromatography vol 602 no 1-2pp 235ndash240 1992
[29] Q Yang M Jimidar T P Hamoir J Smeyers-Verbeke andD L Massart ldquoDetermination of alkali and alkaline earthmetals in real samples by capillary ion analysisrdquo Journal ofChromatography A vol 673 no 2 pp 275ndash285 1994
[30] N Gochman and J M Schmitz ldquoApplication of a new peroxideindicator reaction to the specific automated determination ofglucose with glucose oxidaserdquo Clinical Chemistry vol 18 no 9pp 943ndash950 1972
[31] D Compagnone and G G Guilbault ldquoGlucose oxidasehexoki-nase electrode for the determination of ATPrdquoAnalytica ChimicaActa vol 340 no 1ndash3 pp 109ndash113 1997
[32] L K Fry and L D Stegink ldquoFormation of Maillard reactionproducts in parenteral alimentation solutionsrdquo Journal of Nutri-tion vol 112 no 8 pp 1631ndash1637 1982
[33] M S Iqbal M B Bahari Y Darwis et al ldquoA RP-HPLC-UV method with solid phase extraction for determination ofcefepime in Total Nutrient Admixtures application to stabilitystudiesrdquo Current Pharmaceutical Analysis vol 8 no 1 pp 68ndash74 2012
[34] R Vazquez R Rotival S Calvez et al ldquoStability indicatingassay method on vitamins application to their stability studyin parenteral nutrition admixturesrdquo Chromatographia vol 69no 7-8 pp 629ndash635 2009
[35] M C Allwood and H Martin ldquoStability of cocarboxylase inparenteral nutritionmixtures stored inmultilayer bagsrdquoClinicalNutrition vol 17 no 5 pp 231ndash234 1998
[36] EGibbonsMCAllwood TNeal andGHardy ldquoDegradationof dehydroascorbic acid in parenteral nutrition mixturesrdquoJournal of Pharmaceutical and Biomedical Analysis vol 25 no3-4 pp 605ndash611 2001
[37] T G Baumgartner G N Henderson J Fox and U GondildquoStability of ranitidine and thiamine in parenteral nutritionsolutionsrdquo Nutrition vol 13 no 6 pp 547ndash553 1997
[38] C S Wade V Lampasona R E Mullins and R B ParksldquoStability of ceftazidime and amino acids in parenteral nutrient
The Scientific World Journal 9
solutionsrdquo American Journal of Hospital Pharmacy vol 48 no7 pp 1515ndash1519 1991
[39] J M Mirtallo ldquoDrug-nutrient interactions in patients receivingparenteral mutritionrdquo in Handbook of Drug-Nutrient Interac-tions J I Boullata and V T Armenti Eds Humana Press NewYork NY USA 2nd edition 2010
[40] L Bouchoud C Fonzo-Christe M Klingmuller and PBonnabry ldquoCompatibility of intravenous medications withparenteral nutrition in vitro evaluationrdquo Journal of Parenteraland Enteral Nutrition vol 37 no 3 pp 416ndash424 2013
[41] P Sabin J Monterde D Cardona L Lorente and C PastorldquoIncompatibilities between drugs and parenteral nutritionPreliminary studyrdquoThe Farm Clinic vol 2 pp 12ndash20 1985
[42] E Muntada J Masso-Muniesa A Del Pozo et al ldquoCompati-bility of drugs with total nutrient admixtures (TNA) containingdifferent lipid emulsionsrdquoClinicalNutrition vol 22 supplement1 p S102 2003
Submit your manuscripts athttpwwwhindawicom
PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom
Volume 2014
ToxinsJournal of
VaccinesJournal of
Hindawi Publishing Corporation httpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
AntibioticsInternational Journal of
ToxicologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Drug DeliveryJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Advances in Pharmacological Sciences
Tropical MedicineJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Medicinal ChemistryInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
AddictionJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Autoimmune Diseases
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Anesthesiology Research and Practice
ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Pharmaceutics
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
The Scientific World Journal 5
Table 3 Content of heavy metals in raw materials used in production of parenteral nutrition [26]
Element Certified value Amino acids Glucose Lipids[120583gkg]
As 2667 plusmn 041 262 plusmn 13 272 plusmn 12 269 plusmn 12
Cd 2279 plusmn 096 228 plusmn 12 231 plusmn 11 229 plusmn 08
Pb 2789 plusmn 014 270 plusmn 14 277 plusmn 13 278 plusmn 12
Hglowast 1590 plusmn 0018 157 plusmn 007 156 plusmn 006 161 plusmn 008
Cr 386 plusmn 16 375 plusmn 19 382 plusmn 16 379 plusmn 13
Cu 852 plusmn 12 875 plusmn 39 862 plusmn 42 843 plusmn 41
Mn 1215 plusmn 11 120 plusmn 51 120 plusmn 60 123 plusmn 58
Mo 4675 plusmn 026 468 plusmn 22 460 plusmn 22 474 plusmn 23
Ni 2740 plusmn 080 270 plusmn 13 267 plusmn 13 273 plusmn 11
V 1299 plusmn 037 129 plusmn 06 132 plusmn 06 129 plusmn 05
lowastResults are in [mgkg]
of the mixture temperature and the presence of electrolytes(Table 4)
HPLC methods can be used to determine concentrationof amino acids in parenteral nutrition mixture which donot contain any lipid emulsions In all-in-one mixturesseparation of aqueous and lipid phases is necessary Solidphase extraction (SPE) is predominant because analyte loss islow in contrast to classical extraction and it is effective andsimple to perform [33]
4 Drug Stability in Parenteral Nutrition
HPLC methods were used successfully in assays of vitaminsin parenteral nutrition mixtures especially in parenteralnutrition free from lipid emulsion Vazquez et al [34]designed a method that assayed 13 vitamins in one experi-ment using HPLC-UV-MS-MS The need for complex tan-dem spectrometry resulted from the low selectivity of the UVdetector and lack of a suitable chromophore in some of thevitamins assayed for example in pantothenic acid Ribeiro etal [23] assayed vitamins B
1and B
6using an HPLC method
with diode array detection vitamin B2utilizing fluorometry
and vitamin C by means of iodometric titration HPLCmethods were also used to assay cocarboxylase [35] vitaminA and E [19] and dehydroascorbic acid [36] Baumgartneret al [37] Iqbal et al [33] and Wade et al [38] designed amethod for chromatographic separation and assay of vitaminB1and ranitidine in two-in-one mixtures [37] cefepime
[33] and ceftazidime [38] This type of research althoughextremely important and carrying high clinical potential israrely undertaken because of the complexity of analyticalmethods
Parenteral nutrition is frequently only one of manytherapies used and patients are likely to be given other drugsaswellThese drugs which as a result of primary or coexistingdisease cannot be delivered via gastrointestinal system mustbe given intravenously either as an injection or infusionThatresults in the patient being given additional liquids either
as an isotonic salt solution or solution of glucose leading toeither hypernatraemia or hyperglycaemia Adding drugs toparenteral nutrition may eliminate this problem and reducethe cost of pharmacotherapy but one has to ensure thefollowing
(1) adequate drug stability by considering the effect ofparenteral nutrition on drug stability and the impactof the drug on parenteral nutrition stability and
(2) desired pharmacokinetic parameters during the longtime infusion in order to maintain the proper drugconcentration in the blood [4 39]
At the moment parenterally fed patients receive most ofindispensable drugs administered in the same way throughvascular access with a Y-connector The procedure mini-malizes but does not entirely eliminate the contact betweenthe drug and the components of the nutrition mixture Insome cases (Table 5) even a short-term contact between thedrug and the nutrition mixture can cause precipitation colorchange or phase separation That is the reason why beforeadministering the drug alongside the nutritional mixtureusing the Y-connector it must be assured that no interactionin the pharmaceutical phase will occur [39] Table 6 sum-marizes drugs compatible with the NuTRIflex Lipid Specialmixture [40] Some schemes for administering antibioticssimultaneously with parenteral nutrition are presented below[39ndash42]
(i) ampicillin infusion of not more than 20 minutes
(ii) ceftazidime infusion of not more than 30 minutes
(iii) ciprofloxacin infusion of not more than 30 minutes
(iv) imipenemcilastatin fast infusion (10ndash15min) stopsupply of parenteral nutrition rinse vascular accessbefore and after infusion
(v) vancomycin stop supply of parenteral nutrition rinsevascular access before and after infusion
6 The Scientific World Journal
Table 4 Percent of amino acid forming Maillard reaction products [32]
Amino acid Time [day]Storage temperature
4∘C 4∘C + electrolytes 25∘C 25∘C + electrolytes 60∘C 60∘C + electrolytes[]
Valine1 000 000 003 006 168 1657 000 000 029 098 mdash mdash30 000 000 040 127 mdash mdash
Isoleucine1 000 000 003 006 108 137 000 000 068 086 mdash mdash30 000 000 230 479 mdash mdash
Leucine1 008 012 006 030 101 1217 032 041 018 019 mdash mdash30 070 107 100 173 mdash mdash
Proline1 000 000 001 001 031 0487 000 000 015 019 mdash mdash30 000 001 040 053 mdash mdash
Phenylalanine1 000 000 002 006 746 7867 000 000 057 084 mdash mdash30 000 001 064 256 mdash mdash
Lysine1 000 000 033 092 109 1127 000 030 176 361 mdash mdash30 000 050 260 105 mdash mdash
Arginine1 009 010 100 148 961 1527 061 106 180 289 mdash mdash30 096 561 396 961 mdash mdash
Alanine1 011 079 043 074 461 4547 016 101 075 103 mdash mdash30 081 091 145 141 mdash mdash
Glycine1 050 161 082 138 475 7977 052 154 212 333 mdash mdash30 174 255 359 671 mdash mdash
Methionine1 019 042 181 460 109 1357 110 200 390 890 mdash mdash30 281 382 841 147 mdash mdash
Histidine1 010 043 016 150 164 3117 022 044 042 338 mdash mdash30 030 082 150 130 mdash mdash
Serine1 090 110 151 260 851 1397 125 150 452 487 mdash mdash30 320 540 961 122 mdash mdash
Threonine1 053 143 111 211 967 1557 097 156 401 488 mdash mdash30 252 604 882 987 mdash mdash
Tryptophan1 229 433 402 544 660 1217 342 521 111 111 mdash mdash30 814 136 158 211 mdash mdash
A simultaneous supply of drugs and parenteral nutritionmay cause not only interactions in the pharmaceutical phasebut also pharmacokinetic and pharmacodynamic interac-tions resulting in a drug protein binding degree change
a cytochrome P450 activity modification or an alteration inthe distribution volume of drugs through a modified flow ofthe extracelluar fluid Such incompatibilities are difficult topredict and have not been adequately researched [39]
The Scientific World Journal 7
Table 5 Examples of drugs incompatible with parenteral nutrition [39]
Drugs incompatible with parenteral nutritionAciclovir Ganciclovir Na Methyldopate HClAmphotericin B Haloperidol Midazolam HClCiclosporine Heparin Minocycline HClDopamine HCl Hydrochloric acid Nalbuphine HClDoxorubicin Hydromorphone Ondansetron HClDoxycycline hyclate Iron dextran Pentobarbital NaDroperidol Levorphanol tartrate Phenobarbital NaFluorouracil Lorazepam Phenytoin Na
Table 6 Drugs compatible with NuTRIflex Lipid Special after 1 hour contact mixed in 1 1 (vv) proportions [40]
Drug Dose Drug DoseCalcium chloride 013mmolmL Ca Midazolam 25mgmLCefepime 100mgmL Morphine sulfate 5mgmLCyclosporine 25mgmL Noradrenaline 1mgmLFentanyl 005mgmL Octreotide 25 120583gmLFurosemide 10mgmL Ondansetron 2mgmLTropisetron 1mgmL Paracetamol 10mgmLMagnesium sulfate 04mmolmL Mg PiperacillinTazobactam 80mgmL (piperacillin)Meropenem 50mgmL Potassium phosphate 012mmolL PO4
Metoclopramide 5mgmL Tacrolimus 01mgmLMetronidazole 5mgmL Vancomycin 10mgmLComposition of NuTRIflex Lipid Special (BBraun Medical) per 1000mL amino acids 574 g Lipids 40 g glucose 144 g sodium 54mmol potassium 38mmolcalcium 42mmol magnesium 42mmol phosphate 16mmol chloride 48mmol Acetate 48mmol zinc 003mmol
5 Conclusion
Parenteral nutrition should involve administration of a fullybalanced nutritional mixture covering patientsrsquo energeticand water-electrolyte needs resulting in an improved healthstatus life maintenance or quality life enhancement
The success of parenteral nutrition therapy dependson preparation and administration of a safe nutritionalmixturemdasha physicochemically and microbiologically stabledrug The preparation of such mixture should be precededby analysing its composition and any interactions whichmight occur during preparation storage and infusion Itis equally important to develop and validate a method fordetermining mixture stability Stability analysis ought to beperformedbefore adding drugs to the nutritionalmixture andits administration via intravenous access
Therefore the role of the pharmacist should ensurethe therapeutic safety of parenteral nutrition in all itsaspects including parenteral nutrition mixture prepara-tion choice of an appropriate administration route anddrug form for the ongoing medication implementationof alternative treatment methods monitoring therapeuticand toxic effects and instructing the medical and nursingstaff about possible interactions of drugs with parenteralnutrition
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
References
[1] S J Dudrick ldquoHistory of parenteral nutritionrdquo Journal of theAmerican College of Nutrition vol 28 no 3 pp 243ndash251 2009
[2] N JM CanoM Aparicio G Brunori et al ldquoESPEN guidelineson parenteral nutrition adult renal failurerdquo Clinical Nutritionvol 28 no 4 pp 401ndash414 2009
[3] P Singer M M Berger G Van den Berghe et al ldquoESPENguidelines on parenteral nutrition intensive carerdquo ClinicalNutrition vol 28 no 4 pp 387ndash400 2009
[4] D CardonaMNadal J Estelrich andMAMangues ldquoReviewof drug stability in parenteral nutrition admixturesrdquo e-SPENJournal vol 8 no 4 pp 135ndash140 2013
[5] S Muhlebach ldquoBasics in clinical nutrition drugs and nutri-tional admixturesrdquo e-SPEN Journal vol 4 no 3 pp e134ndashe1362009
[6] M C Allwood and M C J Kearney ldquoCompatibility and stabil-ity of additives in parenteral nutrition admixturesrdquo Nutritionvol 14 no 9 pp 697ndash706 1998
8 The Scientific World Journal
[7] K Hippalgaonkar S Majumdar and V Kansara ldquoInjectablelipid emulsions-advancements opportunities and challengesrdquoAAPS PharmSciTech vol 11 no 4 pp 1526ndash1540 2010
[8] C Freitas and R H Muller ldquoEffect of light and temperature onzeta potential and physical stability in solid lipid nanoparticle(SLN) dispersionsrdquo International Journal of Pharmaceuticsvol 168 no 2 pp 221ndash229 1998
[9] M Skouroliakou C Matthaiou A Chiou et al ldquoPhysicochem-ical stability of parenteral nutrition supplied as all-in-one forneonatesrdquo Journal of Parenteral and Enteral Nutrition vol 32no 2 pp 201ndash209 2008
[10] T Gonyon P W Carter O Dahlem A Denet H Owen and JTrouilly ldquoContainer effects on the physicochemical propertiesof parenteral lipid emulsionsrdquo Nutrition vol 24 no 11-12 pp1182ndash1188 2008
[11] L Bouchoud F Sadeghipour M Klingmuller C Fonzo-Christe and P Bonnabry ldquoLong-term physico-chemical sta-bility of standard parenteral nutritions for neonatesrdquo ClinicalNutrition vol 29 no 6 pp 808ndash812 2010
[12] I G Telessy J Balogh J Turmezei J Dredan and R ZelkoldquoStability assessment of ow parenteral nutrition emulsionsin the presence of high glucose and calcium concentrationsrdquoJournal of Pharmaceutical and Biomedical Analysis vol 56 no2 pp 159ndash164 2011
[13] D F Driscoll K Giampietro D P Wichelhaus et al ldquoPhysico-chemical stability assessments of lipid emulsions of varying oilcompositionrdquo Clinical Nutrition vol 20 no 2 pp 151ndash157 2001
[14] I G Telessy J Balogh F Csempesz V Szente J Dredan and RZelko ldquoComparison of the physicochemical properties ofMCT-containing fat emulsions in total nutrient admixturesrdquo Colloidsand Surfaces B vol 72 no 1 pp 75ndash79 2009
[15] D F Driscoll J Nehne H Peterss K Klutsch B R Bistrianand W Niemann ldquoPhysicochemical stability of intravenouslipid emulsions as all-in-one admixtures intended for the veryyoungrdquo Clinical Nutrition vol 22 no 5 pp 489ndash495 2003
[16] A Sforzini G Bersani A Stancari G Grossi A Bonoliand G C Ceschel ldquoAnalysis of all-in-one parenteral nutritionadmixtures by liquid chromatography and laser diffractionstudy of stabilityrdquo Journal of Pharmaceutical and BiomedicalAnalysis vol 24 no 5-6 pp 1099ndash1109 2001
[17] M C J Kearney M C Allwood T Neale and G HardyldquoThe stability of thiamine in total parenteral nutrition mixturesstored in EVA and multi-layered bagsrdquo Clinical Nutrition vol14 no 5 pp 295ndash301 1995
[18] M D Lee J-E Yoon S-I Kim and I-C Kim ldquoStability oftotal nutrient admixtures in reference to ambient temperaturesrdquoNutrition vol 19 no 10 pp 886ndash890 2003
[19] M C Allwood and H J Martin ldquoThe photodegradation ofvitamins A and E in parenteral nutrition mixtures duringinfusionrdquo Clinical Nutrition vol 19 no 5 pp 339ndash342 2000
[20] M C Allwood ldquoLight protection during parenteral nutritioninfusion is it really necessaryrdquoNutrition vol 16 no 3 pp 234ndash235 2000
[21] C Washington ldquoStability of lipid emulsions for drug deliveryrdquoAdvanced Drug Delivery Reviews vol 20 no 2-3 pp 131ndash1451996
[22] D O Ribeiro B W Lobo N M Volpato V F Da VeigaL M Cabral and V P De Sousa ldquoInfluence of the cal-cium concentration in the presence of organic phosphorus onthe physicochemical compatibility and stability of all-in-oneadmixtures for neonatal userdquoNutrition Journal vol 8 no 1 pp51ndash60 2009
[23] D O Ribeiro D C Pinto LM T R Lima NM Volpato LMCabral andV P De Sousa ldquoChemical stability study of vitaminsthiamine riboflavin pyridoxine and ascorbic acid in parenteralnutrition for neonatal userdquoNutrition Journal vol 10 no 1 p 472011
[24] S Gorog Ed Identification and Determination of Impurities inDrugs Elsevier Amsterdam The Netherlands 2000
[25] N Marie C Verdier B Le Bot and G Burgot ldquoAnalysis ofsodium and potassium in total parenteral nutrition bags byICP-MS and ICP-AES critical influence of the ingredientsrdquoAmerican Journal of Analytical Chemistry vol 2 no 5 pp 573ndash581 2001
[26] F G Antes M F Mesko J S Barin C M Moreira E MM Flores and V L Dressler ldquoDevelopment of multi-elementalmethod for quality control of parenteral component solutionsusing ICP-MSrdquo Microchemical Journal vol 98 no 1 pp 144ndash149 2011
[27] EMM Flores V L Dressle S Nussbaumer et al ldquoDetermina-tion of potassium sodium calciumandmagnesium in total par-enteral nutrition formulations by capillary electrophoresis withcontactless conductivity detectionrdquo Journal of Pharmaceuticaland Biomedical Analysis vol 53 no 2 pp 130ndash136 2010
[28] M Koberda M Konkowski P Youngberg W R Jones and AWeston ldquoCapillary electrophoretic determination of alkali andalkaline-earth cations in various multiple electrolyte solutionsfor parenteral userdquo Journal of Chromatography vol 602 no 1-2pp 235ndash240 1992
[29] Q Yang M Jimidar T P Hamoir J Smeyers-Verbeke andD L Massart ldquoDetermination of alkali and alkaline earthmetals in real samples by capillary ion analysisrdquo Journal ofChromatography A vol 673 no 2 pp 275ndash285 1994
[30] N Gochman and J M Schmitz ldquoApplication of a new peroxideindicator reaction to the specific automated determination ofglucose with glucose oxidaserdquo Clinical Chemistry vol 18 no 9pp 943ndash950 1972
[31] D Compagnone and G G Guilbault ldquoGlucose oxidasehexoki-nase electrode for the determination of ATPrdquoAnalytica ChimicaActa vol 340 no 1ndash3 pp 109ndash113 1997
[32] L K Fry and L D Stegink ldquoFormation of Maillard reactionproducts in parenteral alimentation solutionsrdquo Journal of Nutri-tion vol 112 no 8 pp 1631ndash1637 1982
[33] M S Iqbal M B Bahari Y Darwis et al ldquoA RP-HPLC-UV method with solid phase extraction for determination ofcefepime in Total Nutrient Admixtures application to stabilitystudiesrdquo Current Pharmaceutical Analysis vol 8 no 1 pp 68ndash74 2012
[34] R Vazquez R Rotival S Calvez et al ldquoStability indicatingassay method on vitamins application to their stability studyin parenteral nutrition admixturesrdquo Chromatographia vol 69no 7-8 pp 629ndash635 2009
[35] M C Allwood and H Martin ldquoStability of cocarboxylase inparenteral nutritionmixtures stored inmultilayer bagsrdquoClinicalNutrition vol 17 no 5 pp 231ndash234 1998
[36] EGibbonsMCAllwood TNeal andGHardy ldquoDegradationof dehydroascorbic acid in parenteral nutrition mixturesrdquoJournal of Pharmaceutical and Biomedical Analysis vol 25 no3-4 pp 605ndash611 2001
[37] T G Baumgartner G N Henderson J Fox and U GondildquoStability of ranitidine and thiamine in parenteral nutritionsolutionsrdquo Nutrition vol 13 no 6 pp 547ndash553 1997
[38] C S Wade V Lampasona R E Mullins and R B ParksldquoStability of ceftazidime and amino acids in parenteral nutrient
The Scientific World Journal 9
solutionsrdquo American Journal of Hospital Pharmacy vol 48 no7 pp 1515ndash1519 1991
[39] J M Mirtallo ldquoDrug-nutrient interactions in patients receivingparenteral mutritionrdquo in Handbook of Drug-Nutrient Interac-tions J I Boullata and V T Armenti Eds Humana Press NewYork NY USA 2nd edition 2010
[40] L Bouchoud C Fonzo-Christe M Klingmuller and PBonnabry ldquoCompatibility of intravenous medications withparenteral nutrition in vitro evaluationrdquo Journal of Parenteraland Enteral Nutrition vol 37 no 3 pp 416ndash424 2013
[41] P Sabin J Monterde D Cardona L Lorente and C PastorldquoIncompatibilities between drugs and parenteral nutritionPreliminary studyrdquoThe Farm Clinic vol 2 pp 12ndash20 1985
[42] E Muntada J Masso-Muniesa A Del Pozo et al ldquoCompati-bility of drugs with total nutrient admixtures (TNA) containingdifferent lipid emulsionsrdquoClinicalNutrition vol 22 supplement1 p S102 2003
Submit your manuscripts athttpwwwhindawicom
PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom
Volume 2014
ToxinsJournal of
VaccinesJournal of
Hindawi Publishing Corporation httpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
AntibioticsInternational Journal of
ToxicologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Drug DeliveryJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Advances in Pharmacological Sciences
Tropical MedicineJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Medicinal ChemistryInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
AddictionJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Autoimmune Diseases
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Anesthesiology Research and Practice
ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Pharmaceutics
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
6 The Scientific World Journal
Table 4 Percent of amino acid forming Maillard reaction products [32]
Amino acid Time [day]Storage temperature
4∘C 4∘C + electrolytes 25∘C 25∘C + electrolytes 60∘C 60∘C + electrolytes[]
Valine1 000 000 003 006 168 1657 000 000 029 098 mdash mdash30 000 000 040 127 mdash mdash
Isoleucine1 000 000 003 006 108 137 000 000 068 086 mdash mdash30 000 000 230 479 mdash mdash
Leucine1 008 012 006 030 101 1217 032 041 018 019 mdash mdash30 070 107 100 173 mdash mdash
Proline1 000 000 001 001 031 0487 000 000 015 019 mdash mdash30 000 001 040 053 mdash mdash
Phenylalanine1 000 000 002 006 746 7867 000 000 057 084 mdash mdash30 000 001 064 256 mdash mdash
Lysine1 000 000 033 092 109 1127 000 030 176 361 mdash mdash30 000 050 260 105 mdash mdash
Arginine1 009 010 100 148 961 1527 061 106 180 289 mdash mdash30 096 561 396 961 mdash mdash
Alanine1 011 079 043 074 461 4547 016 101 075 103 mdash mdash30 081 091 145 141 mdash mdash
Glycine1 050 161 082 138 475 7977 052 154 212 333 mdash mdash30 174 255 359 671 mdash mdash
Methionine1 019 042 181 460 109 1357 110 200 390 890 mdash mdash30 281 382 841 147 mdash mdash
Histidine1 010 043 016 150 164 3117 022 044 042 338 mdash mdash30 030 082 150 130 mdash mdash
Serine1 090 110 151 260 851 1397 125 150 452 487 mdash mdash30 320 540 961 122 mdash mdash
Threonine1 053 143 111 211 967 1557 097 156 401 488 mdash mdash30 252 604 882 987 mdash mdash
Tryptophan1 229 433 402 544 660 1217 342 521 111 111 mdash mdash30 814 136 158 211 mdash mdash
A simultaneous supply of drugs and parenteral nutritionmay cause not only interactions in the pharmaceutical phasebut also pharmacokinetic and pharmacodynamic interac-tions resulting in a drug protein binding degree change
a cytochrome P450 activity modification or an alteration inthe distribution volume of drugs through a modified flow ofthe extracelluar fluid Such incompatibilities are difficult topredict and have not been adequately researched [39]
The Scientific World Journal 7
Table 5 Examples of drugs incompatible with parenteral nutrition [39]
Drugs incompatible with parenteral nutritionAciclovir Ganciclovir Na Methyldopate HClAmphotericin B Haloperidol Midazolam HClCiclosporine Heparin Minocycline HClDopamine HCl Hydrochloric acid Nalbuphine HClDoxorubicin Hydromorphone Ondansetron HClDoxycycline hyclate Iron dextran Pentobarbital NaDroperidol Levorphanol tartrate Phenobarbital NaFluorouracil Lorazepam Phenytoin Na
Table 6 Drugs compatible with NuTRIflex Lipid Special after 1 hour contact mixed in 1 1 (vv) proportions [40]
Drug Dose Drug DoseCalcium chloride 013mmolmL Ca Midazolam 25mgmLCefepime 100mgmL Morphine sulfate 5mgmLCyclosporine 25mgmL Noradrenaline 1mgmLFentanyl 005mgmL Octreotide 25 120583gmLFurosemide 10mgmL Ondansetron 2mgmLTropisetron 1mgmL Paracetamol 10mgmLMagnesium sulfate 04mmolmL Mg PiperacillinTazobactam 80mgmL (piperacillin)Meropenem 50mgmL Potassium phosphate 012mmolL PO4
Metoclopramide 5mgmL Tacrolimus 01mgmLMetronidazole 5mgmL Vancomycin 10mgmLComposition of NuTRIflex Lipid Special (BBraun Medical) per 1000mL amino acids 574 g Lipids 40 g glucose 144 g sodium 54mmol potassium 38mmolcalcium 42mmol magnesium 42mmol phosphate 16mmol chloride 48mmol Acetate 48mmol zinc 003mmol
5 Conclusion
Parenteral nutrition should involve administration of a fullybalanced nutritional mixture covering patientsrsquo energeticand water-electrolyte needs resulting in an improved healthstatus life maintenance or quality life enhancement
The success of parenteral nutrition therapy dependson preparation and administration of a safe nutritionalmixturemdasha physicochemically and microbiologically stabledrug The preparation of such mixture should be precededby analysing its composition and any interactions whichmight occur during preparation storage and infusion Itis equally important to develop and validate a method fordetermining mixture stability Stability analysis ought to beperformedbefore adding drugs to the nutritionalmixture andits administration via intravenous access
Therefore the role of the pharmacist should ensurethe therapeutic safety of parenteral nutrition in all itsaspects including parenteral nutrition mixture prepara-tion choice of an appropriate administration route anddrug form for the ongoing medication implementationof alternative treatment methods monitoring therapeuticand toxic effects and instructing the medical and nursingstaff about possible interactions of drugs with parenteralnutrition
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
References
[1] S J Dudrick ldquoHistory of parenteral nutritionrdquo Journal of theAmerican College of Nutrition vol 28 no 3 pp 243ndash251 2009
[2] N JM CanoM Aparicio G Brunori et al ldquoESPEN guidelineson parenteral nutrition adult renal failurerdquo Clinical Nutritionvol 28 no 4 pp 401ndash414 2009
[3] P Singer M M Berger G Van den Berghe et al ldquoESPENguidelines on parenteral nutrition intensive carerdquo ClinicalNutrition vol 28 no 4 pp 387ndash400 2009
[4] D CardonaMNadal J Estelrich andMAMangues ldquoReviewof drug stability in parenteral nutrition admixturesrdquo e-SPENJournal vol 8 no 4 pp 135ndash140 2013
[5] S Muhlebach ldquoBasics in clinical nutrition drugs and nutri-tional admixturesrdquo e-SPEN Journal vol 4 no 3 pp e134ndashe1362009
[6] M C Allwood and M C J Kearney ldquoCompatibility and stabil-ity of additives in parenteral nutrition admixturesrdquo Nutritionvol 14 no 9 pp 697ndash706 1998
8 The Scientific World Journal
[7] K Hippalgaonkar S Majumdar and V Kansara ldquoInjectablelipid emulsions-advancements opportunities and challengesrdquoAAPS PharmSciTech vol 11 no 4 pp 1526ndash1540 2010
[8] C Freitas and R H Muller ldquoEffect of light and temperature onzeta potential and physical stability in solid lipid nanoparticle(SLN) dispersionsrdquo International Journal of Pharmaceuticsvol 168 no 2 pp 221ndash229 1998
[9] M Skouroliakou C Matthaiou A Chiou et al ldquoPhysicochem-ical stability of parenteral nutrition supplied as all-in-one forneonatesrdquo Journal of Parenteral and Enteral Nutrition vol 32no 2 pp 201ndash209 2008
[10] T Gonyon P W Carter O Dahlem A Denet H Owen and JTrouilly ldquoContainer effects on the physicochemical propertiesof parenteral lipid emulsionsrdquo Nutrition vol 24 no 11-12 pp1182ndash1188 2008
[11] L Bouchoud F Sadeghipour M Klingmuller C Fonzo-Christe and P Bonnabry ldquoLong-term physico-chemical sta-bility of standard parenteral nutritions for neonatesrdquo ClinicalNutrition vol 29 no 6 pp 808ndash812 2010
[12] I G Telessy J Balogh J Turmezei J Dredan and R ZelkoldquoStability assessment of ow parenteral nutrition emulsionsin the presence of high glucose and calcium concentrationsrdquoJournal of Pharmaceutical and Biomedical Analysis vol 56 no2 pp 159ndash164 2011
[13] D F Driscoll K Giampietro D P Wichelhaus et al ldquoPhysico-chemical stability assessments of lipid emulsions of varying oilcompositionrdquo Clinical Nutrition vol 20 no 2 pp 151ndash157 2001
[14] I G Telessy J Balogh F Csempesz V Szente J Dredan and RZelko ldquoComparison of the physicochemical properties ofMCT-containing fat emulsions in total nutrient admixturesrdquo Colloidsand Surfaces B vol 72 no 1 pp 75ndash79 2009
[15] D F Driscoll J Nehne H Peterss K Klutsch B R Bistrianand W Niemann ldquoPhysicochemical stability of intravenouslipid emulsions as all-in-one admixtures intended for the veryyoungrdquo Clinical Nutrition vol 22 no 5 pp 489ndash495 2003
[16] A Sforzini G Bersani A Stancari G Grossi A Bonoliand G C Ceschel ldquoAnalysis of all-in-one parenteral nutritionadmixtures by liquid chromatography and laser diffractionstudy of stabilityrdquo Journal of Pharmaceutical and BiomedicalAnalysis vol 24 no 5-6 pp 1099ndash1109 2001
[17] M C J Kearney M C Allwood T Neale and G HardyldquoThe stability of thiamine in total parenteral nutrition mixturesstored in EVA and multi-layered bagsrdquo Clinical Nutrition vol14 no 5 pp 295ndash301 1995
[18] M D Lee J-E Yoon S-I Kim and I-C Kim ldquoStability oftotal nutrient admixtures in reference to ambient temperaturesrdquoNutrition vol 19 no 10 pp 886ndash890 2003
[19] M C Allwood and H J Martin ldquoThe photodegradation ofvitamins A and E in parenteral nutrition mixtures duringinfusionrdquo Clinical Nutrition vol 19 no 5 pp 339ndash342 2000
[20] M C Allwood ldquoLight protection during parenteral nutritioninfusion is it really necessaryrdquoNutrition vol 16 no 3 pp 234ndash235 2000
[21] C Washington ldquoStability of lipid emulsions for drug deliveryrdquoAdvanced Drug Delivery Reviews vol 20 no 2-3 pp 131ndash1451996
[22] D O Ribeiro B W Lobo N M Volpato V F Da VeigaL M Cabral and V P De Sousa ldquoInfluence of the cal-cium concentration in the presence of organic phosphorus onthe physicochemical compatibility and stability of all-in-oneadmixtures for neonatal userdquoNutrition Journal vol 8 no 1 pp51ndash60 2009
[23] D O Ribeiro D C Pinto LM T R Lima NM Volpato LMCabral andV P De Sousa ldquoChemical stability study of vitaminsthiamine riboflavin pyridoxine and ascorbic acid in parenteralnutrition for neonatal userdquoNutrition Journal vol 10 no 1 p 472011
[24] S Gorog Ed Identification and Determination of Impurities inDrugs Elsevier Amsterdam The Netherlands 2000
[25] N Marie C Verdier B Le Bot and G Burgot ldquoAnalysis ofsodium and potassium in total parenteral nutrition bags byICP-MS and ICP-AES critical influence of the ingredientsrdquoAmerican Journal of Analytical Chemistry vol 2 no 5 pp 573ndash581 2001
[26] F G Antes M F Mesko J S Barin C M Moreira E MM Flores and V L Dressler ldquoDevelopment of multi-elementalmethod for quality control of parenteral component solutionsusing ICP-MSrdquo Microchemical Journal vol 98 no 1 pp 144ndash149 2011
[27] EMM Flores V L Dressle S Nussbaumer et al ldquoDetermina-tion of potassium sodium calciumandmagnesium in total par-enteral nutrition formulations by capillary electrophoresis withcontactless conductivity detectionrdquo Journal of Pharmaceuticaland Biomedical Analysis vol 53 no 2 pp 130ndash136 2010
[28] M Koberda M Konkowski P Youngberg W R Jones and AWeston ldquoCapillary electrophoretic determination of alkali andalkaline-earth cations in various multiple electrolyte solutionsfor parenteral userdquo Journal of Chromatography vol 602 no 1-2pp 235ndash240 1992
[29] Q Yang M Jimidar T P Hamoir J Smeyers-Verbeke andD L Massart ldquoDetermination of alkali and alkaline earthmetals in real samples by capillary ion analysisrdquo Journal ofChromatography A vol 673 no 2 pp 275ndash285 1994
[30] N Gochman and J M Schmitz ldquoApplication of a new peroxideindicator reaction to the specific automated determination ofglucose with glucose oxidaserdquo Clinical Chemistry vol 18 no 9pp 943ndash950 1972
[31] D Compagnone and G G Guilbault ldquoGlucose oxidasehexoki-nase electrode for the determination of ATPrdquoAnalytica ChimicaActa vol 340 no 1ndash3 pp 109ndash113 1997
[32] L K Fry and L D Stegink ldquoFormation of Maillard reactionproducts in parenteral alimentation solutionsrdquo Journal of Nutri-tion vol 112 no 8 pp 1631ndash1637 1982
[33] M S Iqbal M B Bahari Y Darwis et al ldquoA RP-HPLC-UV method with solid phase extraction for determination ofcefepime in Total Nutrient Admixtures application to stabilitystudiesrdquo Current Pharmaceutical Analysis vol 8 no 1 pp 68ndash74 2012
[34] R Vazquez R Rotival S Calvez et al ldquoStability indicatingassay method on vitamins application to their stability studyin parenteral nutrition admixturesrdquo Chromatographia vol 69no 7-8 pp 629ndash635 2009
[35] M C Allwood and H Martin ldquoStability of cocarboxylase inparenteral nutritionmixtures stored inmultilayer bagsrdquoClinicalNutrition vol 17 no 5 pp 231ndash234 1998
[36] EGibbonsMCAllwood TNeal andGHardy ldquoDegradationof dehydroascorbic acid in parenteral nutrition mixturesrdquoJournal of Pharmaceutical and Biomedical Analysis vol 25 no3-4 pp 605ndash611 2001
[37] T G Baumgartner G N Henderson J Fox and U GondildquoStability of ranitidine and thiamine in parenteral nutritionsolutionsrdquo Nutrition vol 13 no 6 pp 547ndash553 1997
[38] C S Wade V Lampasona R E Mullins and R B ParksldquoStability of ceftazidime and amino acids in parenteral nutrient
The Scientific World Journal 9
solutionsrdquo American Journal of Hospital Pharmacy vol 48 no7 pp 1515ndash1519 1991
[39] J M Mirtallo ldquoDrug-nutrient interactions in patients receivingparenteral mutritionrdquo in Handbook of Drug-Nutrient Interac-tions J I Boullata and V T Armenti Eds Humana Press NewYork NY USA 2nd edition 2010
[40] L Bouchoud C Fonzo-Christe M Klingmuller and PBonnabry ldquoCompatibility of intravenous medications withparenteral nutrition in vitro evaluationrdquo Journal of Parenteraland Enteral Nutrition vol 37 no 3 pp 416ndash424 2013
[41] P Sabin J Monterde D Cardona L Lorente and C PastorldquoIncompatibilities between drugs and parenteral nutritionPreliminary studyrdquoThe Farm Clinic vol 2 pp 12ndash20 1985
[42] E Muntada J Masso-Muniesa A Del Pozo et al ldquoCompati-bility of drugs with total nutrient admixtures (TNA) containingdifferent lipid emulsionsrdquoClinicalNutrition vol 22 supplement1 p S102 2003
Submit your manuscripts athttpwwwhindawicom
PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom
Volume 2014
ToxinsJournal of
VaccinesJournal of
Hindawi Publishing Corporation httpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
AntibioticsInternational Journal of
ToxicologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Drug DeliveryJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Advances in Pharmacological Sciences
Tropical MedicineJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Medicinal ChemistryInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
AddictionJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Autoimmune Diseases
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Anesthesiology Research and Practice
ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Pharmaceutics
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
The Scientific World Journal 7
Table 5 Examples of drugs incompatible with parenteral nutrition [39]
Drugs incompatible with parenteral nutritionAciclovir Ganciclovir Na Methyldopate HClAmphotericin B Haloperidol Midazolam HClCiclosporine Heparin Minocycline HClDopamine HCl Hydrochloric acid Nalbuphine HClDoxorubicin Hydromorphone Ondansetron HClDoxycycline hyclate Iron dextran Pentobarbital NaDroperidol Levorphanol tartrate Phenobarbital NaFluorouracil Lorazepam Phenytoin Na
Table 6 Drugs compatible with NuTRIflex Lipid Special after 1 hour contact mixed in 1 1 (vv) proportions [40]
Drug Dose Drug DoseCalcium chloride 013mmolmL Ca Midazolam 25mgmLCefepime 100mgmL Morphine sulfate 5mgmLCyclosporine 25mgmL Noradrenaline 1mgmLFentanyl 005mgmL Octreotide 25 120583gmLFurosemide 10mgmL Ondansetron 2mgmLTropisetron 1mgmL Paracetamol 10mgmLMagnesium sulfate 04mmolmL Mg PiperacillinTazobactam 80mgmL (piperacillin)Meropenem 50mgmL Potassium phosphate 012mmolL PO4
Metoclopramide 5mgmL Tacrolimus 01mgmLMetronidazole 5mgmL Vancomycin 10mgmLComposition of NuTRIflex Lipid Special (BBraun Medical) per 1000mL amino acids 574 g Lipids 40 g glucose 144 g sodium 54mmol potassium 38mmolcalcium 42mmol magnesium 42mmol phosphate 16mmol chloride 48mmol Acetate 48mmol zinc 003mmol
5 Conclusion
Parenteral nutrition should involve administration of a fullybalanced nutritional mixture covering patientsrsquo energeticand water-electrolyte needs resulting in an improved healthstatus life maintenance or quality life enhancement
The success of parenteral nutrition therapy dependson preparation and administration of a safe nutritionalmixturemdasha physicochemically and microbiologically stabledrug The preparation of such mixture should be precededby analysing its composition and any interactions whichmight occur during preparation storage and infusion Itis equally important to develop and validate a method fordetermining mixture stability Stability analysis ought to beperformedbefore adding drugs to the nutritionalmixture andits administration via intravenous access
Therefore the role of the pharmacist should ensurethe therapeutic safety of parenteral nutrition in all itsaspects including parenteral nutrition mixture prepara-tion choice of an appropriate administration route anddrug form for the ongoing medication implementationof alternative treatment methods monitoring therapeuticand toxic effects and instructing the medical and nursingstaff about possible interactions of drugs with parenteralnutrition
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
References
[1] S J Dudrick ldquoHistory of parenteral nutritionrdquo Journal of theAmerican College of Nutrition vol 28 no 3 pp 243ndash251 2009
[2] N JM CanoM Aparicio G Brunori et al ldquoESPEN guidelineson parenteral nutrition adult renal failurerdquo Clinical Nutritionvol 28 no 4 pp 401ndash414 2009
[3] P Singer M M Berger G Van den Berghe et al ldquoESPENguidelines on parenteral nutrition intensive carerdquo ClinicalNutrition vol 28 no 4 pp 387ndash400 2009
[4] D CardonaMNadal J Estelrich andMAMangues ldquoReviewof drug stability in parenteral nutrition admixturesrdquo e-SPENJournal vol 8 no 4 pp 135ndash140 2013
[5] S Muhlebach ldquoBasics in clinical nutrition drugs and nutri-tional admixturesrdquo e-SPEN Journal vol 4 no 3 pp e134ndashe1362009
[6] M C Allwood and M C J Kearney ldquoCompatibility and stabil-ity of additives in parenteral nutrition admixturesrdquo Nutritionvol 14 no 9 pp 697ndash706 1998
8 The Scientific World Journal
[7] K Hippalgaonkar S Majumdar and V Kansara ldquoInjectablelipid emulsions-advancements opportunities and challengesrdquoAAPS PharmSciTech vol 11 no 4 pp 1526ndash1540 2010
[8] C Freitas and R H Muller ldquoEffect of light and temperature onzeta potential and physical stability in solid lipid nanoparticle(SLN) dispersionsrdquo International Journal of Pharmaceuticsvol 168 no 2 pp 221ndash229 1998
[9] M Skouroliakou C Matthaiou A Chiou et al ldquoPhysicochem-ical stability of parenteral nutrition supplied as all-in-one forneonatesrdquo Journal of Parenteral and Enteral Nutrition vol 32no 2 pp 201ndash209 2008
[10] T Gonyon P W Carter O Dahlem A Denet H Owen and JTrouilly ldquoContainer effects on the physicochemical propertiesof parenteral lipid emulsionsrdquo Nutrition vol 24 no 11-12 pp1182ndash1188 2008
[11] L Bouchoud F Sadeghipour M Klingmuller C Fonzo-Christe and P Bonnabry ldquoLong-term physico-chemical sta-bility of standard parenteral nutritions for neonatesrdquo ClinicalNutrition vol 29 no 6 pp 808ndash812 2010
[12] I G Telessy J Balogh J Turmezei J Dredan and R ZelkoldquoStability assessment of ow parenteral nutrition emulsionsin the presence of high glucose and calcium concentrationsrdquoJournal of Pharmaceutical and Biomedical Analysis vol 56 no2 pp 159ndash164 2011
[13] D F Driscoll K Giampietro D P Wichelhaus et al ldquoPhysico-chemical stability assessments of lipid emulsions of varying oilcompositionrdquo Clinical Nutrition vol 20 no 2 pp 151ndash157 2001
[14] I G Telessy J Balogh F Csempesz V Szente J Dredan and RZelko ldquoComparison of the physicochemical properties ofMCT-containing fat emulsions in total nutrient admixturesrdquo Colloidsand Surfaces B vol 72 no 1 pp 75ndash79 2009
[15] D F Driscoll J Nehne H Peterss K Klutsch B R Bistrianand W Niemann ldquoPhysicochemical stability of intravenouslipid emulsions as all-in-one admixtures intended for the veryyoungrdquo Clinical Nutrition vol 22 no 5 pp 489ndash495 2003
[16] A Sforzini G Bersani A Stancari G Grossi A Bonoliand G C Ceschel ldquoAnalysis of all-in-one parenteral nutritionadmixtures by liquid chromatography and laser diffractionstudy of stabilityrdquo Journal of Pharmaceutical and BiomedicalAnalysis vol 24 no 5-6 pp 1099ndash1109 2001
[17] M C J Kearney M C Allwood T Neale and G HardyldquoThe stability of thiamine in total parenteral nutrition mixturesstored in EVA and multi-layered bagsrdquo Clinical Nutrition vol14 no 5 pp 295ndash301 1995
[18] M D Lee J-E Yoon S-I Kim and I-C Kim ldquoStability oftotal nutrient admixtures in reference to ambient temperaturesrdquoNutrition vol 19 no 10 pp 886ndash890 2003
[19] M C Allwood and H J Martin ldquoThe photodegradation ofvitamins A and E in parenteral nutrition mixtures duringinfusionrdquo Clinical Nutrition vol 19 no 5 pp 339ndash342 2000
[20] M C Allwood ldquoLight protection during parenteral nutritioninfusion is it really necessaryrdquoNutrition vol 16 no 3 pp 234ndash235 2000
[21] C Washington ldquoStability of lipid emulsions for drug deliveryrdquoAdvanced Drug Delivery Reviews vol 20 no 2-3 pp 131ndash1451996
[22] D O Ribeiro B W Lobo N M Volpato V F Da VeigaL M Cabral and V P De Sousa ldquoInfluence of the cal-cium concentration in the presence of organic phosphorus onthe physicochemical compatibility and stability of all-in-oneadmixtures for neonatal userdquoNutrition Journal vol 8 no 1 pp51ndash60 2009
[23] D O Ribeiro D C Pinto LM T R Lima NM Volpato LMCabral andV P De Sousa ldquoChemical stability study of vitaminsthiamine riboflavin pyridoxine and ascorbic acid in parenteralnutrition for neonatal userdquoNutrition Journal vol 10 no 1 p 472011
[24] S Gorog Ed Identification and Determination of Impurities inDrugs Elsevier Amsterdam The Netherlands 2000
[25] N Marie C Verdier B Le Bot and G Burgot ldquoAnalysis ofsodium and potassium in total parenteral nutrition bags byICP-MS and ICP-AES critical influence of the ingredientsrdquoAmerican Journal of Analytical Chemistry vol 2 no 5 pp 573ndash581 2001
[26] F G Antes M F Mesko J S Barin C M Moreira E MM Flores and V L Dressler ldquoDevelopment of multi-elementalmethod for quality control of parenteral component solutionsusing ICP-MSrdquo Microchemical Journal vol 98 no 1 pp 144ndash149 2011
[27] EMM Flores V L Dressle S Nussbaumer et al ldquoDetermina-tion of potassium sodium calciumandmagnesium in total par-enteral nutrition formulations by capillary electrophoresis withcontactless conductivity detectionrdquo Journal of Pharmaceuticaland Biomedical Analysis vol 53 no 2 pp 130ndash136 2010
[28] M Koberda M Konkowski P Youngberg W R Jones and AWeston ldquoCapillary electrophoretic determination of alkali andalkaline-earth cations in various multiple electrolyte solutionsfor parenteral userdquo Journal of Chromatography vol 602 no 1-2pp 235ndash240 1992
[29] Q Yang M Jimidar T P Hamoir J Smeyers-Verbeke andD L Massart ldquoDetermination of alkali and alkaline earthmetals in real samples by capillary ion analysisrdquo Journal ofChromatography A vol 673 no 2 pp 275ndash285 1994
[30] N Gochman and J M Schmitz ldquoApplication of a new peroxideindicator reaction to the specific automated determination ofglucose with glucose oxidaserdquo Clinical Chemistry vol 18 no 9pp 943ndash950 1972
[31] D Compagnone and G G Guilbault ldquoGlucose oxidasehexoki-nase electrode for the determination of ATPrdquoAnalytica ChimicaActa vol 340 no 1ndash3 pp 109ndash113 1997
[32] L K Fry and L D Stegink ldquoFormation of Maillard reactionproducts in parenteral alimentation solutionsrdquo Journal of Nutri-tion vol 112 no 8 pp 1631ndash1637 1982
[33] M S Iqbal M B Bahari Y Darwis et al ldquoA RP-HPLC-UV method with solid phase extraction for determination ofcefepime in Total Nutrient Admixtures application to stabilitystudiesrdquo Current Pharmaceutical Analysis vol 8 no 1 pp 68ndash74 2012
[34] R Vazquez R Rotival S Calvez et al ldquoStability indicatingassay method on vitamins application to their stability studyin parenteral nutrition admixturesrdquo Chromatographia vol 69no 7-8 pp 629ndash635 2009
[35] M C Allwood and H Martin ldquoStability of cocarboxylase inparenteral nutritionmixtures stored inmultilayer bagsrdquoClinicalNutrition vol 17 no 5 pp 231ndash234 1998
[36] EGibbonsMCAllwood TNeal andGHardy ldquoDegradationof dehydroascorbic acid in parenteral nutrition mixturesrdquoJournal of Pharmaceutical and Biomedical Analysis vol 25 no3-4 pp 605ndash611 2001
[37] T G Baumgartner G N Henderson J Fox and U GondildquoStability of ranitidine and thiamine in parenteral nutritionsolutionsrdquo Nutrition vol 13 no 6 pp 547ndash553 1997
[38] C S Wade V Lampasona R E Mullins and R B ParksldquoStability of ceftazidime and amino acids in parenteral nutrient
The Scientific World Journal 9
solutionsrdquo American Journal of Hospital Pharmacy vol 48 no7 pp 1515ndash1519 1991
[39] J M Mirtallo ldquoDrug-nutrient interactions in patients receivingparenteral mutritionrdquo in Handbook of Drug-Nutrient Interac-tions J I Boullata and V T Armenti Eds Humana Press NewYork NY USA 2nd edition 2010
[40] L Bouchoud C Fonzo-Christe M Klingmuller and PBonnabry ldquoCompatibility of intravenous medications withparenteral nutrition in vitro evaluationrdquo Journal of Parenteraland Enteral Nutrition vol 37 no 3 pp 416ndash424 2013
[41] P Sabin J Monterde D Cardona L Lorente and C PastorldquoIncompatibilities between drugs and parenteral nutritionPreliminary studyrdquoThe Farm Clinic vol 2 pp 12ndash20 1985
[42] E Muntada J Masso-Muniesa A Del Pozo et al ldquoCompati-bility of drugs with total nutrient admixtures (TNA) containingdifferent lipid emulsionsrdquoClinicalNutrition vol 22 supplement1 p S102 2003
Submit your manuscripts athttpwwwhindawicom
PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom
Volume 2014
ToxinsJournal of
VaccinesJournal of
Hindawi Publishing Corporation httpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
AntibioticsInternational Journal of
ToxicologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Drug DeliveryJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Advances in Pharmacological Sciences
Tropical MedicineJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Medicinal ChemistryInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
AddictionJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Autoimmune Diseases
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Anesthesiology Research and Practice
ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Pharmaceutics
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
8 The Scientific World Journal
[7] K Hippalgaonkar S Majumdar and V Kansara ldquoInjectablelipid emulsions-advancements opportunities and challengesrdquoAAPS PharmSciTech vol 11 no 4 pp 1526ndash1540 2010
[8] C Freitas and R H Muller ldquoEffect of light and temperature onzeta potential and physical stability in solid lipid nanoparticle(SLN) dispersionsrdquo International Journal of Pharmaceuticsvol 168 no 2 pp 221ndash229 1998
[9] M Skouroliakou C Matthaiou A Chiou et al ldquoPhysicochem-ical stability of parenteral nutrition supplied as all-in-one forneonatesrdquo Journal of Parenteral and Enteral Nutrition vol 32no 2 pp 201ndash209 2008
[10] T Gonyon P W Carter O Dahlem A Denet H Owen and JTrouilly ldquoContainer effects on the physicochemical propertiesof parenteral lipid emulsionsrdquo Nutrition vol 24 no 11-12 pp1182ndash1188 2008
[11] L Bouchoud F Sadeghipour M Klingmuller C Fonzo-Christe and P Bonnabry ldquoLong-term physico-chemical sta-bility of standard parenteral nutritions for neonatesrdquo ClinicalNutrition vol 29 no 6 pp 808ndash812 2010
[12] I G Telessy J Balogh J Turmezei J Dredan and R ZelkoldquoStability assessment of ow parenteral nutrition emulsionsin the presence of high glucose and calcium concentrationsrdquoJournal of Pharmaceutical and Biomedical Analysis vol 56 no2 pp 159ndash164 2011
[13] D F Driscoll K Giampietro D P Wichelhaus et al ldquoPhysico-chemical stability assessments of lipid emulsions of varying oilcompositionrdquo Clinical Nutrition vol 20 no 2 pp 151ndash157 2001
[14] I G Telessy J Balogh F Csempesz V Szente J Dredan and RZelko ldquoComparison of the physicochemical properties ofMCT-containing fat emulsions in total nutrient admixturesrdquo Colloidsand Surfaces B vol 72 no 1 pp 75ndash79 2009
[15] D F Driscoll J Nehne H Peterss K Klutsch B R Bistrianand W Niemann ldquoPhysicochemical stability of intravenouslipid emulsions as all-in-one admixtures intended for the veryyoungrdquo Clinical Nutrition vol 22 no 5 pp 489ndash495 2003
[16] A Sforzini G Bersani A Stancari G Grossi A Bonoliand G C Ceschel ldquoAnalysis of all-in-one parenteral nutritionadmixtures by liquid chromatography and laser diffractionstudy of stabilityrdquo Journal of Pharmaceutical and BiomedicalAnalysis vol 24 no 5-6 pp 1099ndash1109 2001
[17] M C J Kearney M C Allwood T Neale and G HardyldquoThe stability of thiamine in total parenteral nutrition mixturesstored in EVA and multi-layered bagsrdquo Clinical Nutrition vol14 no 5 pp 295ndash301 1995
[18] M D Lee J-E Yoon S-I Kim and I-C Kim ldquoStability oftotal nutrient admixtures in reference to ambient temperaturesrdquoNutrition vol 19 no 10 pp 886ndash890 2003
[19] M C Allwood and H J Martin ldquoThe photodegradation ofvitamins A and E in parenteral nutrition mixtures duringinfusionrdquo Clinical Nutrition vol 19 no 5 pp 339ndash342 2000
[20] M C Allwood ldquoLight protection during parenteral nutritioninfusion is it really necessaryrdquoNutrition vol 16 no 3 pp 234ndash235 2000
[21] C Washington ldquoStability of lipid emulsions for drug deliveryrdquoAdvanced Drug Delivery Reviews vol 20 no 2-3 pp 131ndash1451996
[22] D O Ribeiro B W Lobo N M Volpato V F Da VeigaL M Cabral and V P De Sousa ldquoInfluence of the cal-cium concentration in the presence of organic phosphorus onthe physicochemical compatibility and stability of all-in-oneadmixtures for neonatal userdquoNutrition Journal vol 8 no 1 pp51ndash60 2009
[23] D O Ribeiro D C Pinto LM T R Lima NM Volpato LMCabral andV P De Sousa ldquoChemical stability study of vitaminsthiamine riboflavin pyridoxine and ascorbic acid in parenteralnutrition for neonatal userdquoNutrition Journal vol 10 no 1 p 472011
[24] S Gorog Ed Identification and Determination of Impurities inDrugs Elsevier Amsterdam The Netherlands 2000
[25] N Marie C Verdier B Le Bot and G Burgot ldquoAnalysis ofsodium and potassium in total parenteral nutrition bags byICP-MS and ICP-AES critical influence of the ingredientsrdquoAmerican Journal of Analytical Chemistry vol 2 no 5 pp 573ndash581 2001
[26] F G Antes M F Mesko J S Barin C M Moreira E MM Flores and V L Dressler ldquoDevelopment of multi-elementalmethod for quality control of parenteral component solutionsusing ICP-MSrdquo Microchemical Journal vol 98 no 1 pp 144ndash149 2011
[27] EMM Flores V L Dressle S Nussbaumer et al ldquoDetermina-tion of potassium sodium calciumandmagnesium in total par-enteral nutrition formulations by capillary electrophoresis withcontactless conductivity detectionrdquo Journal of Pharmaceuticaland Biomedical Analysis vol 53 no 2 pp 130ndash136 2010
[28] M Koberda M Konkowski P Youngberg W R Jones and AWeston ldquoCapillary electrophoretic determination of alkali andalkaline-earth cations in various multiple electrolyte solutionsfor parenteral userdquo Journal of Chromatography vol 602 no 1-2pp 235ndash240 1992
[29] Q Yang M Jimidar T P Hamoir J Smeyers-Verbeke andD L Massart ldquoDetermination of alkali and alkaline earthmetals in real samples by capillary ion analysisrdquo Journal ofChromatography A vol 673 no 2 pp 275ndash285 1994
[30] N Gochman and J M Schmitz ldquoApplication of a new peroxideindicator reaction to the specific automated determination ofglucose with glucose oxidaserdquo Clinical Chemistry vol 18 no 9pp 943ndash950 1972
[31] D Compagnone and G G Guilbault ldquoGlucose oxidasehexoki-nase electrode for the determination of ATPrdquoAnalytica ChimicaActa vol 340 no 1ndash3 pp 109ndash113 1997
[32] L K Fry and L D Stegink ldquoFormation of Maillard reactionproducts in parenteral alimentation solutionsrdquo Journal of Nutri-tion vol 112 no 8 pp 1631ndash1637 1982
[33] M S Iqbal M B Bahari Y Darwis et al ldquoA RP-HPLC-UV method with solid phase extraction for determination ofcefepime in Total Nutrient Admixtures application to stabilitystudiesrdquo Current Pharmaceutical Analysis vol 8 no 1 pp 68ndash74 2012
[34] R Vazquez R Rotival S Calvez et al ldquoStability indicatingassay method on vitamins application to their stability studyin parenteral nutrition admixturesrdquo Chromatographia vol 69no 7-8 pp 629ndash635 2009
[35] M C Allwood and H Martin ldquoStability of cocarboxylase inparenteral nutritionmixtures stored inmultilayer bagsrdquoClinicalNutrition vol 17 no 5 pp 231ndash234 1998
[36] EGibbonsMCAllwood TNeal andGHardy ldquoDegradationof dehydroascorbic acid in parenteral nutrition mixturesrdquoJournal of Pharmaceutical and Biomedical Analysis vol 25 no3-4 pp 605ndash611 2001
[37] T G Baumgartner G N Henderson J Fox and U GondildquoStability of ranitidine and thiamine in parenteral nutritionsolutionsrdquo Nutrition vol 13 no 6 pp 547ndash553 1997
[38] C S Wade V Lampasona R E Mullins and R B ParksldquoStability of ceftazidime and amino acids in parenteral nutrient
The Scientific World Journal 9
solutionsrdquo American Journal of Hospital Pharmacy vol 48 no7 pp 1515ndash1519 1991
[39] J M Mirtallo ldquoDrug-nutrient interactions in patients receivingparenteral mutritionrdquo in Handbook of Drug-Nutrient Interac-tions J I Boullata and V T Armenti Eds Humana Press NewYork NY USA 2nd edition 2010
[40] L Bouchoud C Fonzo-Christe M Klingmuller and PBonnabry ldquoCompatibility of intravenous medications withparenteral nutrition in vitro evaluationrdquo Journal of Parenteraland Enteral Nutrition vol 37 no 3 pp 416ndash424 2013
[41] P Sabin J Monterde D Cardona L Lorente and C PastorldquoIncompatibilities between drugs and parenteral nutritionPreliminary studyrdquoThe Farm Clinic vol 2 pp 12ndash20 1985
[42] E Muntada J Masso-Muniesa A Del Pozo et al ldquoCompati-bility of drugs with total nutrient admixtures (TNA) containingdifferent lipid emulsionsrdquoClinicalNutrition vol 22 supplement1 p S102 2003
Submit your manuscripts athttpwwwhindawicom
PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom
Volume 2014
ToxinsJournal of
VaccinesJournal of
Hindawi Publishing Corporation httpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
AntibioticsInternational Journal of
ToxicologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Drug DeliveryJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Advances in Pharmacological Sciences
Tropical MedicineJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Medicinal ChemistryInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
AddictionJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Autoimmune Diseases
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Anesthesiology Research and Practice
ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Pharmaceutics
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
The Scientific World Journal 9
solutionsrdquo American Journal of Hospital Pharmacy vol 48 no7 pp 1515ndash1519 1991
[39] J M Mirtallo ldquoDrug-nutrient interactions in patients receivingparenteral mutritionrdquo in Handbook of Drug-Nutrient Interac-tions J I Boullata and V T Armenti Eds Humana Press NewYork NY USA 2nd edition 2010
[40] L Bouchoud C Fonzo-Christe M Klingmuller and PBonnabry ldquoCompatibility of intravenous medications withparenteral nutrition in vitro evaluationrdquo Journal of Parenteraland Enteral Nutrition vol 37 no 3 pp 416ndash424 2013
[41] P Sabin J Monterde D Cardona L Lorente and C PastorldquoIncompatibilities between drugs and parenteral nutritionPreliminary studyrdquoThe Farm Clinic vol 2 pp 12ndash20 1985
[42] E Muntada J Masso-Muniesa A Del Pozo et al ldquoCompati-bility of drugs with total nutrient admixtures (TNA) containingdifferent lipid emulsionsrdquoClinicalNutrition vol 22 supplement1 p S102 2003
Submit your manuscripts athttpwwwhindawicom
PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom
Volume 2014
ToxinsJournal of
VaccinesJournal of
Hindawi Publishing Corporation httpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
AntibioticsInternational Journal of
ToxicologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Drug DeliveryJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Advances in Pharmacological Sciences
Tropical MedicineJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Medicinal ChemistryInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
AddictionJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Autoimmune Diseases
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Anesthesiology Research and Practice
ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Pharmaceutics
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of
Submit your manuscripts athttpwwwhindawicom
PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom
Volume 2014
ToxinsJournal of
VaccinesJournal of
Hindawi Publishing Corporation httpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
AntibioticsInternational Journal of
ToxicologyJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
StrokeResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Drug DeliveryJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Advances in Pharmacological Sciences
Tropical MedicineJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Medicinal ChemistryInternational Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
AddictionJournal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
BioMed Research International
Emergency Medicine InternationalHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Autoimmune Diseases
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Anesthesiology Research and Practice
ScientificaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Journal of
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
Pharmaceutics
Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014
MEDIATORSINFLAMMATION
of