European Journal of Clinical Nutrition (2013) 67, 230–238
`& 2013 Macmillan Publishers Limited All rights reserved 0954-3007/13
`
`www.nature.com/ejcn
`
`REVIEW
`Aluminium in parenteral nutrition: a systematic review
`
`A Herna´ ndez-Sa´nchez, P Tejada-Gonza´lez and M Arteta-Jime´ nez
`
`Aluminium (Al) toxicity problem in parenteral nutrition solutions (PNS) is decades old and is still unresolved. The aim of this review
`is to gather updated information about this matter, regarding legislation, manifestations, diagnostics and treatment, patient
`population at risk and the actions to be taken to limit its accumulation. A structured search using MeSH vocabulary and Title/
`Abstract searches was conducted in PubMed (http://www.pubmed.gov) up to November 2012. Al is ubiquitous, facilitating its
`potential for exposure. Nevertheless, humans have several mechanisms to prevent significant absorption and to aid its elimination;
`therefore, the vast majority of the population is not at risk for Al toxicity. However, when protective gastrointestinal mechanisms are
`bypassed (for example, parenteral fluids), renal function is impaired (for example, adult patients with renal compromise and
`neonates) or exposure is high (for example, long-term PNS), Al is prone to accumulate in the body, including manifestations such as
`impaired neurological development, Alzheimer’s disease, metabolic bone disease, dyslipemia and even genotoxic activity. A high Al
`content in PNS is largely the result of three parenteral nutrient additives: calcium gluconate, inorganic phosphates and cysteine
`hydrochloride. Despite the legislative efforts, some factors make difficult to comply with the rule and, therefore, to limit the
`Al toxicity. Unfortunately, manufacturers have not universally changed their processes to obtain a lower Al content of parenteral
`drug products (PDP). In addition, the imprecise information provided by PDP labels and the high lot-to-lot variation make the
`prediction of Al content rather inaccurate.
`
`European Journal of Clinical Nutrition (2013) 67, 230–238; doi:10.1038/ejcn.2012.219; published online 13 February 2013
`
`Keywords: aluminium; parenteral nutrition; bone disease; metabolic; Food and Drug Administration; toxicity
`
`INTRODUCTION
`Aluminium (Al) toxicity in parenteral nutrition solutions (PNS) has
`been a problem for decades and is still unresolved. Europe lacks a
`global legislation about the upper limit for Al contamination. In
`the United States, in an effort to limit patients’ exposure to Al and
`to prevent cases of Al toxicity, the American Society for Clinical
`Nutrition (ASCN) and the American Society for Parenteral and
`Enteral Nutrition (ASPEN) Working Group on standards for Al
`content in PNS established in 1991 a series of thresholds (upper
`safe limit, unsafe limit, and toxic limit) for Al intake for patients on
`long-term PNS.
`The United States Food and Drug Administration (FDA)
`endocrinologic and metabolic drugs advisory panel, in 2004, and
`after several deferrals, issued a rule governing Al content in large
`volume parenterals (LVPs) and small volume parenterals (SVPs)
`used to prepare PNS.
`Because this regulation applies to industry only, ASPEN issued a
`statement in 2010 on Al in PNS that provides some guidance to
`clinicians.
`Despite the legislative efforts, some factors have made difficult
`to comply with the rules and, therefore, to limit the Al toxicity.
`In this article, we describe how much has been done to limit the Al
`content in PNS, and highlight its importance and the actions that
`should be taken to limit it.
`
`MATERIALS AND METHODS
`A structured search using MeSH vocabulary and Title/Abstract searches
`was conducted in PubMed (http://www.pubmed.gov) up to November
`2012. The language of the publications was restricted to English. The terms
`
`aluminium
`(((aluminium(Title/Abstract)) or
`follows:
`as
`used were
`(Title/Abstract)) and parenteral nutrition (Title/Abstract), rendering 107
`publications. Six were excluded according to language criteria, resulting in
`101 articles. References from these articles chosen were browsed, yielding
`an additional 30 papers for potential consideration.
`
`FINDINGS
`Al characteristics
`Al is the lightest, least dense and third most abundant mineral
`within the earth’s crust (8% by weight) after oxygen and silicon.1–8
`It has no known functions in the human body, although a
`significant role in biomolecular compaction has been proposed.5,9
`Its wide distribution clearly facilitates the potential for human
`exposure, which occurs through air, food and water, but it is also
`present in medical, cosmetic and environmental products.6,9 Of
`these, PNS stand out as a substantial source of this toxic metal, as
`many parenteral drug products (PDP) used to compound them
`contain Al as a contaminant or as a component of the raw
`materials.9,10
`It is estimated that humans ingest between 3 and 20 mg of Al
`per day.1,9 Food and beverages provide 2.5–13 mg of Al daily,
`whereas drinking water may account for 0.2–0.4 mg per day.
`Drugs such as antacids can contribute up to 500 mg.6 However,
`despite this intake, it will not accumulate in the body. Humans
`have several mechanisms to prevent significant absorption of Al
`and to aid its elimination; therefore, the vast majority of the
`population is not at risk for Al toxicity from oral or enteral intake.9
`In healthy people, both the lungs and the skin are very effective at
`reducing Al absorption, as is the gastrointestinal tract, which
`
`Pharmacy department, Hospital Universitario de Getafe, Getafe, Madrid, Spain. Correspondence: Dr A Herna´ndez-Sa´nchez, Pharmacy department, Hospital Universitario de
`Getafe, Carretera A-42, 12,500, 28905 Madrid, Spain.
`E-mail: alfredo.hernandez@salud.madrid.org
`Received 9 March 2012; revised 9 December 2012; accepted 26 December 2012; published online 13 February 2013
`
`Nexus Ex. 1006
`1 of 9
`
`

`

`typically allows o1% of ingested Al into the blood stream.1,9,11,12
`Ninety nine per cent of absorbed Al is lost in the urine and a minor
`portion being cleared in the bile. Thus, the renal excretion is the
`primarily via of elimination.1,2,12,13
`However, when protective gastrointestinal mechanisms are
`bypassed (for example, parenteral fluids),
`renal
`function is
`impaired (for example, adult patients with renal compromise
`and neonates) or exposure is high (for example, long-term PNS),
`Al is prone to accumulate in the body, notably in bone, liver and
`central nervous system, and also in the spleen, kidneys and other
`tissues.1,14 PNS are then one of the parenteral fluids that pose
`greatest risk for Al accumulation owing to their Al content
`and their administration directly into the circulation bypassing the
`gastrointestinal tract.12
`
`Al in PDP
`Al is present in all the PDP used to elaborate PNS. Furthermore,
`product manipulation, containers and administration sets add Al
`to the mixture.10,15 Al contamination of PNS has been recognised
`since the 1980s, although it was higher than it is at present.9
`Previous studies from the 1980s estimated daily intakes of Al from
`80 to 100 mg/kg/day, which is almost 50-fold more than the
`present mean intake. This change is a function of
`reduced
`contamination of PNS through its additives.16
`A high Al content in PNS is largely the result of three PDP:
`calcium gluconate (CaGluc; up to 81%),
`inorganic phosphates
`(especially potassium) and cysteine hydrochloride.4,8,10,12,17–20
`Historically, replacement of casein hydrolysate with crystalline
`amino acids, which are very low in Al, substantially reduced the Al
`load 50–100 times in adult patients receiving PNS. This protein
`source is no longer available, and thus may no longer be
`considered a source of Al toxicity.1,14,16,21 Currently, there are
`other changes that may lead to Al reduction:
`Calcium and phosphorus are prescribed in small amounts but
`are relevant, as both are important sources of Al and have the
`potential for developing calcium phosphate precipitates. CaGluc is
`commonly used in PNS and has replaced calcium chloride (CaCl),
`because the risk of precipitation with phosphate is lower.17,22
`However, PNS made with CaCl contain significantly less Al
`compared with those made with CaGluc.17,23 Another strategy
`to reduce the risk of calcium phosphate precipitation is to use an
`organic source of phosphorus, more compatible with CaCl than
`the inorganic phosphates.2,3,10 However, although widely used in
`Europe, they are unavailable in many countries including the
`United States and Canada. Furthermore, although inorganic
`phosphates
`are considered as high Al-content products,
`potassium phosphate (KPho) usually renders more Al to PNS
`than sodium phosphate. Therefore, using a sodium or a mixed
`sodium–KPho solution rather than the potassium salt would
`significantly reduce Al exposure through PNS.3,24 Another issue is
`the under-mineralisation of bone in low-birth-weight
`infants
`receiving PNS partly because of
`the delivery of
`insufficient
`amounts of calcium and phosphorus,
`limited by the low
`solubility of calcium phosphate. A possible alternative is calcium
`glycerophosphate, which has confirmed as effective regarding
`mineral retention as equimolar intakes of calcium and phosphorus
`from CaGluc
`and KPho
`respectively. Also,
`and higher
`concentrations of these minerals can be kept in solution when
`they are provided as calcium glycerophosphate.25–27
`The amount of Al leached from glass containers with rubber
`closures is also a significant contributor of Al.10 For instance,
`repackaging CaGluc from glass containers to polyethylene vials
`reduces the mean Al concentration from 5000 to 195 mg/l (a 96%
`decrease).3,10,12 PDP should be stored in containers that do not
`interact physically or chemically with the preparations. This high
`chemical resistance is, however, obtained by the addition of
`mainly boric and Al oxides to glass, consequently turning glass
`
`231
`
`Aluminium in parenteral nutrition
`A Herna´ndez-Sa´nchez et al
`
`into a source of Al.28 Low pH favours exchange of metal ions from
`glass, whereas high-pH solutions promote the dissolution of the
`glass surface itself.29 Solutions such as CaGluc, sodium phosphate
`and sodium acetate form complex anions that dissolve Al from the
`glass containers during autoclaving.2,12,24 (Table 1). Table 2 shows
`the content of Al measured in different PNP as published in
`several
`recent studies. Table 3 lists some relevant products
`currently marketed for PNS preparations in Europe.
`
`Patient population at risk
`As the kidneys are the major route of Al elimination, the patients
`at greatest risk of accumulation receiving PNS are those with renal
`compromise and infants with immature renal function, although
`other patients who receive these Al-contaminated parenterals are
`also at risk for Al loading.10,12,14 (Table 4).
`
` During pregnancy, the foetus is susceptible to Al contamination,
`as it is transferred transplacentally. Al does not appear to
`transfer into breast milk in any appreciable. In animal models,
`less than 2% of a daily dose reached breast milk.1,13
` In premature infants,
`toxicity appears
`to be negatively
`correlated with gestational age.
`In addition to possessing
`immature renal function, they are more prone to Al toxicity
`because of their increased calcium and phosphorus require-
`ments,
`thus exposing them to more contaminants from
`parenterals that contain these minerals.1,16 Even intakes of
`o2 mg/kg/day, the level suggested by the ASCN/ASPEN as
`being safe, may be toxic in this population.1 Healthy neonates
`may be able to handle more Al; however, there are no such
`studies available upon which we could safely estimate
`acceptable upper levels of Al from parenteral or injectable
`sources in healthy children.11
` In adults, age represents a risk factor for kidney function
`impairment, as during normal aging humans lose up to 50% of
`their glomeruli between 40 and 85 years of age.11 Elderly
`patients may also be at a similar risk of Al-related toxicity.
`However, a study reveals that most patients with acute kidney
`injury who require PNS do not receive excessive exposure to Al.
`This was due, in part, to the fact that patients with better renal
`function received more calcium and smaller doses of
`phosphorus. Patients with the worst renal function were more
`apt to have hyperphosphatemia and would therefore receive
`PNS without phosphorus.8
` In geriatric patients, Al absorption becomes more efficient with
`advancing age; toxicity may not be as dependent on renal
`function owing to a weakened gastrointestinal protective
`barrier.1
` Other populations at risk for Al toxicity are burn patients who
`have received large amounts of albumin to maintain oncotic
`pressure, and plasmapheresis patients who have been given
`large amounts of albumin.1
`
`Al toxicity manifestations
`Reports of Al toxicity from PNS have been cited in the medical
`literature for several decades.2,12 Unfortunately, the published
`literature is primarily limited to studies published in the 1980s and
`1990s, and the majority of the literature supporting the need to
`minimise Al exposure in the PNS-dependent patient is more than
`30 years old.13 Recent publications refer back to these classic
`papers, and the actual prevalence of Al toxicity in the parenteral
`nutrition-dependent patients still remains to be unknown and
`difficult to calculate, as published evidence consists mainly of case
`reports or small studies.1
`levels include
`increased tissue Al
`Signs and symptoms of
`possibly neurodegenerative disorders such as dialysis encephalo-
`pathy, progressive dementia, impaired neurological development,
`
`& 2013 Macmillan Publishers Limited
`
`European Journal of Clinical Nutrition (2013) 230 – 238
`
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`

`232
`
`Aluminium in parenteral nutrition
`A Herna´ndez-Sa´nchez et al
`
`Critical
`
`High
`
`Critical
`
`Moderate
`
`intravenousfeeding.
`adjustedlossofonepointperdayof
`developmentindex(P¼0.03)withan
`associatedwithareductioninthemental
`impairment,increasingAlexposurewas
`ForpatientsonSwithnoneuromotor
`
`thanintakesunderthatthresholdP¼0.02
`lowerhipBMCby7.6%(95%CI:0.12-13,8)
`Patientsonintakesover55mg/kg/dayhad
`anysite.
`significantpredictorofadjustedBMCat
`continuousvariablefailedtobea
`ThetotalAlexposurefromPNSasa
`
`(n¼)
`PNS(4-5mg/kg/day)
`AD:Al-depleted
`day)(n¼26)
`[45mg/kg/
`S:standard-AlPNS
`PNS)
`of180ml/kg/dayof
`(meanAlexposure
`infants
`182premature
`
`(n¼33)
`PNS(3mg/kg/day)
`AD:Al-depleted
`day)(n¼26)
`[21.3mg/kg/
`S:standard-AlPNS
`(meanAlexposure)
`59patients
`
`Verystrongassociation
`
`Direct
`
`recommendations
`froms.d.PNSandtheFDA
`abovethemeanAlexposure
`significantthresholdiswell
`55mg/kg/dayofAlasa
`Themedianexposureof
`
`Critical
`
`High
`
`werethemostheavilycontaminated
`andpotassiumphosphate,bythisorder,
`Calciumgluconate,sodiumphosphate
`
`components
`16differentPN
`123samplesfrom
`
`Samplesmeasured
`manufacturersandsamples.
`Greatvarietyof
`
`Direct
`
`Critical
`
`High
`
`Critical
`
`Low
`
`Critical
`
`Moderate
`
`Critical
`
`High
`
`Critical
`
`High
`
`1.1±0.3vs0.8±0.3mmolP/kg/day
`1.2±0.2vs1.0±0.2mmolCa/kg/day
`FromCaGlucandKPhotoCaGP
`(mean±s.d.)
`CaandPretention
`
`(Po0.01)
`13.3±0.4vs2.4±0.1mmolP/kg/day
`(Po0.01)
`14.5±0.2vs2.2±0.3mmolCa/kg/day
`FromCaGPtoCaGlucandKPho
`CaandPretention(mean±s.e.m.)
`
`componentes
`werethemostAl-contaminated
`hydrochlorideandCalciumgluconate
`Sodiumphosphate,cysteine
`
`D:27;68;87.
`C:35;75;106.
`B:458;1661;3026.
`A:230;725;1056.
`days:
`Measuresmg/Algaa/l)at15.30and60
`byAl.
`glutamicacid(D)becamecontaminated
`Cysteine(A),cystine(B),aspartic(C)and
`
`higherAlconcentration.
`andsodiumphosphatecontainedthe
`Calciumgluconate,potassiumphosphate
`concentration.(Po0.05)
`significantlylowerthanthelabelled
`MeasuredAlconcentrationswere
`
`(n¼9)
`CaGlucþKPho
`CaGP(n¼6)
`16
`
`(n¼5)
`CaGluc&KPho
`CaGP(n¼5)
`10
`
`16products
`
`differentintervals.
`andAlmeasuredat
`glasstypeIIflask
`solutionsstoredin
`19aminoacid
`
`andP
`EquimolarintakesofCa
`
`Direct
`
`None
`
`None
`
`Strongassociation
`
`Direct
`
`PNScomponents
`Threelotsof16
`
`tested.
`theUnitedStateswere
`manufacturersavailablein
`Allproductsfromall
`
`Direct
`
`Importance
`
`Quality
`
`Effect
`
`Samplesize
`
`Othermodifyingfactors
`
`Summaryoffindings
`
`inconsistency
`Noimportant
`
`limitations
`Noserious
`
`Clinicaltrial
`
`prematurely
`ofinfantsborn
`neurologicdevelopment
`intravenousAlonthe
`perinatalexposureto
`Toinvestigatetheeffectof
`
`1997(31)
`Bishop
`
`Direct
`
`inconsistency
`Noimportant
`
`limitations
`Noserious
`
`Clinicaltrial
`
`termbonehealth
`adverselyaffectslong-
`neonatalAlexposurealso
`Totestthehypothesisthat
`
`200924
`Fewtrell
`Aluminiumtoxicitymanifestations
`
`inconsistency
`Noimportant
`
`limitations
`Noserious
`
`study
`Observational
`
`SourcesofAlinPNS
`
`1986(20)
`Koo
`
`inconsistency
`Noimportant
`
`limitations
`Noserious
`
`Clinicaltrial
`
`retention
`CaGlucþKPhoonmineral
`EfficacyofCaGPvs
`
`1991(26)
`Hanning
`
`piglets
`Studyin
`
`inconsistency
`Noimportant
`
`limitationsc
`Serious
`
`Clinicaltrial
`
`Direct
`
`inconsistency
`Noimportant
`
`Limitationsa,,b
`
`study
`Observational
`
`retention
`inPNSforCaandP
`CaGPvsCaGlucandKPho
`
`componentsofPNS
`contaminated
`Todeterminethemost
`
`1991(25)
`Draper
`
`2005(19)
`Driscoll
`
`inconsistency
`Noimportant
`
`limitations
`Noserious
`
`study
`Observational
`
`byAl
`contaminationofproducts
`ofglasspackingonthe
`Todeterminetheinfluence
`
`2001(28)
`Bohrer
`
`inconsistency
`Noimportant
`
`limitations
`Noserious
`
`study
`Observational
`
`Directness
`
`Consistency
`
`Quality
`
`Design
`
`compoundingPNS
`tobeusedwhen
`Al-contaminatedproducts
`Determinetheleast
`
`2011(45)
`Poole
`Aluminiuminparenteraldrugproducts
`
`Qualityassessment
`
`Purpose
`
`date
`Study/
`
`Table1.Gradingqualityofevidence
`
`European Journal of Clinical Nutrition (2013) 230 – 238
`
`& 2013 Macmillan Publishers Limited
`
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`

`

`Aluminium in parenteral nutrition
`A Herna´ndez-Sa´nchez et al
`
`233
`
`concentrations.dTheAlintakefromPNSwasnotmeasuredthroughtheactualPNSbutitscomponents.
`theintoxication.cCaGPwasinaconcentrationthatprovided3.6and7.1asmuchcalciumandphosphorus,respectively,tothePNSthanCaGPandKphos,asitssolubilityitsbettersolubilityallowhigher
`ourconfidenceintheestimateofeffectandislikelytochangetheestimate.aOnlyonemanufaturertested.bCalculationofAlconcentrationthroughthequantityexpressedonthelabeltendstooverestimate
`Moderate¼Furtherresearchislikelytohaveanimportantimpactonourconfidenceintheestimateofeffectandmaychangetheestimate.Low¼Furtherresearchisverylikelytohaveanimportantimpacton
`Administration;KPho,potassiumphosphate;PNS,parenteralnutritionsolution;sCr:serumcreatinine.Quality:High¼Furtherresearchisveryunlikelytochangeourconfidenceintheestimateofeffect.
`Abbreviations:AD,Alzheimer’sdisease;Al,aluminium;BMC,bonemineralcontent;CaGP,calciumglycerophosphate;CaGluc,calciumgluconate;CI,confidenceintervals;DFO,deferoxamine;FDA,FoodandDrug
`
`of40–80kg
`5typicaladultPNS
`
`None
`
`Direct
`
`inconsistency
`Noimportant
`
`Limitationsa,,b
`
`study
`Observational
`
`PNS
`CalculatingAlcontentin
`
`2005(19)
`Driscoll
`
`Critical
`
`Moderate
`
`exposure(o5mg/kg/day)
`29/36hadsafecalculatedaluminium
`
`36PNS
`
`None
`
`admission)
`thatof
`Z1.5times
`injury(sCr
`acuterenal
`adultswith
`Direct:
`
`inconsistency
`Noimportant
`
`Limitationsb
`
`study
`Observational
`
`Critical
`
`Moderate
`
`possibleonpatientsweighing450kg.
`MeetingtheFDArecommendationsonly
`23.14mg/kg/day.
`CalculatedaverageAlexposureis
`
`13384PNS
`
`lowestcontentavailable
`Productsusedwiththe
`
`Direct
`
`inconsistency
`Noimportant
`
`Limitationsb
`
`study
`Observational
`
`Critical
`
`High
`
`Critical
`
`Moderate
`
`Measured:3–5timestheFDAlimit
`Calculated5–10timestheFDAlimit
`Alcontent
`wastwiceasmuchastheactualmeasured
`ThecalculatedAlcontamination
`
`40neonatalPNS
`
`Verystrongassociation
`
`Direct
`
`inconsistency
`Noimportant
`
`limitations
`Noserious
`
`study
`Observational
`
`C:31.5vs73.3
`B:22.9vs54.9
`A:6vs6.3
`(mg/dl)
`MeasuredvscalculatedAlconcentration
`
`CaGlucþKPhos(C)
`CaGlucþNaPhos(B)
`CaClþNaPhos(A)
`each)
`12PNSsamples(4
`
`andC
`StrongassociationinB
`
`Direct
`
`inconsistency
`Noimportant
`
`Limitationsa
`
`study
`Observational
`
`Importance
`
`Quality
`
`Effect
`
`Samplesize
`
`Othermodifyingfactors
`
`Directness
`
`Consistency
`
`Quality
`
`Design
`
`Summaryoffindings
`
`Qualityassessment
`
`adults
`PNSinacutekidneyinjury
`forAltoxicitycausedby
`Todeterminethepotential
`
`fromPNS
`dailyAlloaddelivered
`Todeterminepatient’s
`
`FDArecommendations
`Alexposureexceedsthe
`ascertainwethertheactual
`contaminationinPNSand
`measuredAl
`Tocomparecalculatedvs
`
`2008(8)
`Brown
`
`2008(2)
`Poole
`
`2010(12)
`Poole
`
`vsCaGluc&KPho
`containingCaClþNaPhos
`concentrationsinPNS
`CalculatedvsmeasuredAl
`
`2012(17)
`Migaki
`Estimatingaluminiumloading
`
`Purpose
`
`date
`Study/
`
`(Continued)
`
`Table1.
`
`Critical
`
`High
`
`Critical
`
`Moderate
`
`Critical
`
`Moderate
`
`2.16±0.81mg/kg/day
`MeanAldailyintake
`
`80kg:mg/kg/day.
`70kg:8.4mg/kg/day
`60kg:9.8mg/kg/day
`50kg:11.6mg/kg/day
`40kg:14.3mg/kg/d
`
`57%(P¼0.75)
`Lowdose:62%vsstandarddose
`(sAlriseo50mg/lafterDFOtest)
`Successfultreatmentresponse
`
`(n¼21)
`5mg/kg/week
`Standarddose:
`(n¼21)
`2.5mg/kg/week
`Low-dosegroup:
`42
`
`None
`
`Direct
`
`inconsistency
`Noimportant
`
`limitations
`Noserious
`
`Clinicaltrial
`
`10children
`
`None
`
`Direct
`
`inconsistency
`Noimportant
`
`limitations
`Noserious
`
`study
`Observational
`
`Al20mg/lparticipants.
`haemodialysisandserum
`doseofDFOin
`Efficacyofstandardvslow
`
`2010(34)
`Kan
`Deferoxaminetherapy
`
`onlong-termPNS
`contaminationofchildren
`TodeterminetheAl
`
`2003(16)
`Advenier
`
`& 2013 Macmillan Publishers Limited
`
`European Journal of Clinical Nutrition (2013) 230 – 238
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`234
`
`Aluminium in parenteral nutrition
`A Herna´ndez-Sa´nchez et al
`
`Table 2. Aluminium measured in different parenteral nutrition products according to recent published studies
`
`Aluminium mg/l
`
`Sterile water
`Amino acids solutions
`Dextrose
`
`Lipid emulsions
`Sodium glicerophosphate
`Calcium gluconate
`Potassium phosphate
`Sodium phosphate
`Potassium acetate
`Sodium acetate
`Calcium chloride
`Potassium chloride
`Sodium chloride
`Zinc chloride
`Magnesium sulphate
`Selenium
`Trace elements
`Paediatric trace elements
`Multi-trace elements
`Vitamins preparations
`Cysteina
`Chromium
`Copper
`
`Migaki et al
`JPEN 2012 (ref.16)
`
`Poole et al.
`JPPT 2011 (ref.45)
`
`Fewtrell et al.
`PNS 2011 (ref.15)
`
`Poole et al.
`JPGN 2010 (ref.12)
`
`Oliveira et al.
`JPEN 2010 (ref.46)
`
`Brown et al.
`2008 (ref.8)
`
`25a
`25d
`25a
`
`9400b
`37000a
`180a
`
`200a
`1000a
`100a
`
`300c
`2500b
`
`o5b, 5c, 6.6a, o5d, o5e
`7d
`20d, 14a
`
`—
`
`11g
`
`2487b, 2812c
`
`30g
`
`2g
`
`776j
`56j
`
`10j
`
`165b, 109c, 122a
`
`6250b, 30e
`
`6g, o2g, 24n
`
`o5e
`o5d
`7a
`
`15g
`
`3234c
`8280c
`622b
`42a
`83a
`o5a
`o5a
`41a
`14a
`87b
`
`414b
`
`14e
`
`3.8f
`90.1g, 124e
`19.2h, 17.3e, 13.5e, 4.6g,
`17.2g, 23f, 20.5i
`19.7g, 112.6g
`263.7g
`9205k, 19400k
`
`o1e
`3.1e, 5.9e
`12.5e
`
`1.3g
`
`278b
`223b
`
`62l
`2.9f, 1.6l, 62.5i
`
`63.1l, 87.3f
`
`1049m, 2065m, 1663m
`549o, 112.1p, 1509p
`
`57a
`
`15b
`
`25a
`10a
`
`Abbreviation: JPEN, Journal of Parenteral and Enteral Nutrition; JPGN, Journal of Pediatric Gastroenterology and Nutrition; JPPT, The Journal of Pediatric
`Pharmacology and Therapeutics; PNS, Proceedings of the Nutrition Society. Manufacturer: aHospira. bAmerican Regent. cAPP pharmaceuticals. dB. Braun
`Medical. eBaxter. fHalex Istar. gFresenius Kabi. hAster. iIsofarma. jNot specified kHypofarma. lEquipex. mDarrow. nIn-house preparation. oCrista´ lia. pFarmalab.
`
`Table 3. Relevant products currently marketed for parenteral nutrition
`solutions preparations in Europe
`
`Table 4. Patient population at risk of Al accumulation
`
`Brand name
`
`Amino acid solutions
`Aminofusin
`Aminopaed
`Aminoplasmal
`Aminosteril
`Aminoven
`Glamin
`Nephrotect
`Primene
`Tauramin
`Throphamine
`Travasol
`Synthamin
`Vamin
`Vaminolact
`
`Lipid emulsions
`ClinOleic
`Intralipid
`Ivelip
`Lipofundin
`Lipoplus
`Lipovenos
`Omegaven
`Smoflipid
`Soyacal
`Structolipid
`
`Vitamins preparations
`Cernevit
`Soluvit
`Vitalipid
`
`Trace elements
`Addamel
`Decan
`Peditrace
`
`Manufacturer
`
`Baxter
`Fresenius Kabi
`B. Braun
`Fresenius Kabi
`Fresenius Kabi
`Fresenius Kabi
`Fresenius Kabi
`Fresenius Kabi
`Grifols
`b. Braun
`Baxter
`Baxter
`Fresenius Kabi
`Fresenius Kabi
`
`Baxter
`Fresenius Kabi
`Baxter
`B. Braun
`B. Braun
`Fresenius Kabi
`Fresenius Kabi
`Fresenius Kabi
`Grifols
`Fresenius Kabi
`
`Baxter
`Fresenius Kabi
`Fresenius Kabi
`
`Fresenius Kabi
`Baxter
`Fresenius Kabi
`
`Patient population
`at risk
`
`Causes
`
`Renal compromise
`Foetus
`
`Premature infants
`
`Elderly patients
`
`Burn patients
`
`Kidneys are the major route of Al elimination
`During pregnancy Al is transferred
`transplacentally
`Al toxicity negatively correlated with
`gestational age: immature renal function,
`increased calcium and phosphorus
`requirements
`Weakened GI protective barrier
`Normal renal function deterioration
`Al-contaminated albumin to maintain oncotic
`pressure
`
`Abbreviations: Al, aluminium, GI, gastrointestinal.
`
`Alzheimer’s disease (AD) and Parkinson’s disease, as well as
`metabolic bone disease including impaired bone growth, bone
`pain, proximal muscle weakness, multiple nonhealing fractures,
`premature osteoporosis, osteopenia and osteomalacia. Microcytic
`anaemia and cholestasis have been described as well.1,2,4,6,11,12,30
`(Table 1).
`
`Impaired neurological development
`A key study by Bishop et al.31 that contributed to the FDA rule
`governing Al contamination compared neurological development
`in premature infants who received a standard PNS formula
`(median: 45 mg/kg/day of Al) or an Al-depleted formula (median:
`4–5 mg/kg/day of Al) for a period of 5–16 days. The authors
`estimated that
`for
`infants receiving the standard PNS,
`the
`expected reduction in the Bayley Mental Development Index
`score would be 1 point per day of intravenous feeding.12
`
`Alzheimer disease
`Al has a direct and active access to the brain, where it accumulates
`in a region-specific manner that highly implicates its involvement
`
`European Journal of Clinical Nutrition (2013) 230 – 238
`
`& 2013 Macmillan Publishers Limited
`
`Nexus Ex. 1006
`5 of 9
`
`

`

`Table 5.
`
`Thresholds for aluminium delivered by parenterales and plasma levels
`
`Safe dose/level
`
`Unsafe dose/level
`
`Toxic dose/level
`
`Large volume parenterals
`
`Small volume parenterals
`
`Aluminium in parenteral nutrition
`A Herna´ndez-Sa´nchez et al
`
`235
`
`ASCN/ASPEN
`FDA
`K/DOQI
`
`E15–30 mg/kg/day
`45 mg/kg/day
`50–300 mg/la
`
`E60 mg/kg/day
`—
`4300 mg/la
`
`E2 mg/kg/day
`p5 mg/kg/day
`o50 mg/la
`Abbreviations: ASCN, American Society for Clinical Nutrition; ASPEN, American Society for Parenteral and Enteral Nutrition; FDA, Food and Drug
`Administration; K/DOQI, Kidney Disease Outcomes Quality Initiative. aAfter deferoxamine test.
`
`—
`p25 mg/l
`—
`
`—
`Not established
`—
`
`in AD. Experimental data clearly show that all neurophysiological
`parameters required for AD are efficiently targeted for impair-
`ment by Al.11
`
`Metabolic bone disease
`complication
`a well-known
`is
`Metabolic
`bone
`disease
`of prolonged PNS use due to Al toxicity.1,10,24 Although their
`exact incidence has not yet been established with certainty,
`percentages range from 30%–40% to 100% in various case
`reports.21
`In the
`The clinical picture of bone involvement is variable.
`majority of cases, patients are asymptomatic, whereas in others
`they may manifest bone pain or fractures for minimal traumas,
`which are typically vertebral fractures. The finding of a reduced
`bone mineral density is common, although not dissimilar to that
`observed in the control groups, and is likely sustained mostly
`by the metabolic consequences of the underlying disease.21 In
`infants, the development of metabolic bone disease can occur
`more quickly.1 Neonates who are exposed to parenteral Al may
`have reduced lumbar spine and hip bone mass during adole-
`scence, which are potential risk factors for later osteoporosis and
`hip fracture.24
`The candidate mechanisms for Al toxicity include suppression of
`parathyroid hormone secretion14,21 and Al accumulation primarily
`in bone , which reduces bone formation thereby contributing to
`adynamic bone disease.3,14,24 Finally, Al-like lead is thought to
`have either a primary or secondary suppressive effect on the renal
`enzyme 25-hydroxyvitamin D-1a hydroxylase. This enzyme
`converts
`circulating
`25-hydroxyvitamin D into
`1,
`25-
`dihydroxyvitamin D at the level of the renal tubule. The latter
`metabolite is the corticosteroid hormone form of the vitamin and
`exerts maximum biological activity.14,21
`
`Hepatotoxicity
`Very little is known about the hepatotoxic effects of Al in either
`animals or humans. The mechanism of Al toxicity is far from clear
`understanding, but it is suggested that Al generates reactive oxygen
`species (ROS) that cause lipid peroxidation and oxidative damage to
`proteins and DNA.
`In addition, Al caused hepatic haemorrhage,
`cellular degeneration and necrosis of hepatocytes.30
`Animal models definitely indicate an effect of Al on bile
`metabolism, although there has never been any proven rela-
`tionship between hepatic Al content in humans and degree of
`cholestasis.14
`
`Dyslipemia
`Al toxicity, along with oxidative stress (H2O2), has been associated
`levels of L-carnitine, diminished b-oxidation and
`with lower
`increased lipid accumulation in human astrocytes and hepato-
`cytes compared with the controls. L-carnitine is an amino acid
`derivative indispensable for the metabolism of lipids. Its synthesis
`is a multistep enzymatic process that necessitates the participa-
`tion of lysine, methionine and a-ketoglutarate (KG). Exposure of
`the Al- and H2O2-treated cells to a-KG led to the recovery
`of L-carnitine production with the concomitant reduction in ROS
`
`levels. It appears that the channelling of KG to combat oxidative
`stress results in decreased L-carnitine synthesis, an event that
`contributes to the dyslipidemia observed during Al and H2O2
`insults in these mammalian cells. Hence, KG may help alleviate
`pathological conditions induced by oxidative stress.32
`
`Genotoxic activity
`There are only a few studies in the literature about the genotoxic
`activities of Al. However,
`it has been found that Al
`induces
`chromosomal aberrations and DNA damage.6
`
`DIAGNOSTICS AND TREATMENT
`The widely used analytical technique for the direct detection of
`the Al in biological fluids is the graphite furnace atomic absorption
`spectrometry,7 although blood levels continue to be a poor
`predictor of the presence or absence of Al toxicity. Similarly, urine
`concentrations have also been used, but the relationship of these
`levels to disease severity has not been clearly established.1 On the
`other hand, although an increased Al intake does not necessarily
`lead to an increased serum Al concentration, as this may be offset
`by an increase in urinary Al excretion, its high value should alert of
`a risk of toxicity.3,16 The deferoxamine (DFO) infusion test has
`been used to determine the total Al load. DFO is a chelating agent
`that removes Al from tissue stores and allows for more accurate
`serum levels (see below).1 However, the lack of standardised
`testing makes the diagnosis of Al toxicity difficult. A thorough
`medical history and evaluation of clinical signs and symptoms in
`conjunction with laboratory tests and imaging studies are
`necessary in order to make an accurate diagnosis.13
`Treatment options in the management of Al toxicity continue to
`be limited. Some agents have been proposed, although DFO is the
`most widely used substance. However, reduction or elimination
`of Al-rich components continues to be the most effective means
`of management.1,13
`
`Taurine
`The toxic effects of Al may be mitigated by taurine through the
`improvement of the cellular antioxidant defence system, stabilisa-
`tion of cell membrane, and prevention of lipid peroxidation. It also
`seems to have direct beneficial effects on liver parenchymal cells.
`The chemical similarity of taurine to acetylcysteine, an agent used
`to treat heavy metal-induced toxicity, and the fact that cysteine is
`a precursor of taurine,
`is an encouraging factor to use taurine
`against metal-induced hepatotoxicity.30
`
`a-ketoglutarate
`Exposure of the Al- and H2O2-treated cells to KG led to the
`recovery of L-carnitine production, with the concomitant reduc-
`tion in ROS levels, reducing lipid accumulation.32
`
`Iron
`The potential for complications of Al exposure is closely related to
`the patient’s iron status. The iron transport protein transferrin
`serves as the primary Al-binding ligand, accounting for as much as
`
`& 2013 Macmillan Publishers Limited
`
`European Journal of Clinical Nutrition (2013) 230 – 238
`
`Nexus Ex. 1006
`6 of 9
`
`

`

`Aluminium in parenteral nutrition
`A Herna´ndez-Sa´nchez et al
`
`236
`
`90% of all binding. Moreover, when iron is bound to transferrin,
`the overall affinity of transferrin for Al is reduced.13
`
`Deferoxamine
`DFO chelation therapy has been used to treat PNS-associated Al
`toxicity. In 2003, the Kidney Disease Outcomes Quality Initiative
`recommended a DFO test if there are elevated serum Al levels
`(60–200 mg/l) or clinical signs and symptoms of Al toxicity. If Al
`levels are 4200 mg/l, DFO test should be delayed until intensive
`dialysis reduces Al below that threshold to avoid DFO-induced
`neurotoxicity. The test is considered positive if the increment of
`serum Al is 450 mg/l over the serum Al level previous to DFO test,
`and a different management is proposed according to that level
`(algorithm 1).33 The recommended dose of DFO is 5 mg/kg, both
`treatment (weekly) and test, although an article